case of the week: cases presented with cortical dysplasia

CLINICAL PICTURE:

11 years old female patient presented with congenital left sided hemiaplasia and Lennox Gastaut syndrome. The patient's family gave a history of west syndrome during the first year of the patient's life. Fundus examination revealed chorioretinal lacunae. EEG examination revealed 1.5 C/S slow spike/slow wave discharge of Lennox Gastaut syndrome. The patient's scholastic achievement was very poor.

RADIOLOGICAL FINDINGS:

Figure 1. Precontrast MR T1 images showing a huge right sided intraventricular /parenchymal cyst associated with agenesis of the septum pellucidum. The corpus callosum is markedly hypoplastic and deficient. The cerebral cortex is lissencephalic. Notice the right sided hemimegalencephaly and the subependymal nodular heterotopia. Subcortical band heterotopia can also be appreciated.

Figure 2. Precontrast MR T1 images showing a huge right sided intraventricular /parenchymal cyst associated with agenesis of the septum pellucidum. The corpus callosum is markedly hypoplastic and deficient. The cerebral cortex is lissencephalic. Notice the right sided hemimegalencephaly and the subependymal nodular heterotopia.

CASE OF THE WEEK

PROFESSOR YASSER METWALLY

CLINICAL PICTURE

RADIOLOGICAL FINDINGS

2

www.yassermetwally.com

Figure 3. MR T2 images showing a huge right sided intraventricular /parenchymal cyst associated with agenesis of the septum pellucidum. The corpus callosum is markedly hypoplastic and deficient. The cerebral cortex is lissencephalic. Notice the right sided hemimegalencephaly and the subependymal nodular heterotopia. Subcortical band heterotopia can also be appreciated.

Figure 4. Precontrast MR T1 images showing A huge right sided intraventricular /parenchymal cyst. The cerebral cortex is lissencephalic. Notice the right sided hemimegalencephaly and the subependymal nodular heterotopia. Subcortical band heterotopia can also be appreciated.

3


Figure 5. Precontrast MR T1 images showing a huge right sided intraventricular /parenchymal cyst. The corpus callosum is markedly hypoplastic and deficient. The cerebral cortex is lissencephalic. Notice the subependymal nodular heterotopia and hypoplasia of the optic nerve. The cerebellum and brain stem are also hypoplastic.

Figure 6. Precontrast MR T1 images showing a huge right sided intraventricular /parenchymal cyst. The cerebral cortex is lissencephalic. Notice the right sided hemimegalencephaly and the subependymal nodular heterotopia.

Figure 7. Precontrast MR T1 images showing marked hypoplasia of the cerebellum and brain stem.

4


Criteria that are highly suggestive of Aicardi syndrome

Partial or complete callosal agenesis

Cortical dysplasia

Gross asymmetry of the hemispheres

Periventricular or subcortical heterotopias

Cysts of the choroid plexus or around the third ventricle is highly suggestive of AS

DIAGNOSIS: AICARDI SYNDROME ASSOCIATED WITH MULTIPLE CORTICAL DYSPLASIAS THAT INCLUDE HEMIMEGALENCEPHALY, LISSENCEPHALY, HETEROTOPIAS, AND SEPTO-OPTIC DYSPLASIA.

DISCUSSION:

The Aicardi syndrome (AS) is classically defined as a triad of abnormalities that includes agenesis of the corpus callosum, infantile spasms, and chorioretinal lacunae (1,2). Other eye defects and costovertebral and other malformations occur frequently. The syndrome has been observed exclusively in individuals with two X chromosomes, and only one familial case is known (3,4).

Progress in neuroimaging has revealed that the central nervous system malformation in AS is not limited to agenesis of the corpus callosum but consists of a complex of abnormalities characterized by severe neuronal migration defects with periventricular and subcortical heterotopias, cortical polymicrogyria, and a tendency toward the development of cystic formations in the choroid plexuses and in other parts of the brain (3-5). The migration anomalies may even be more important for the definition of AS than callosal agenesis, which is a non- specific finding. Similarly, the eye abnormalities are often complex, and defects of closure of the primitive cupula are commonly present (6-8).

The incidence of AS is unknown. More than 300 cases are known to this writer, and at least 170 cases have been published. In series of infantile spasms, AS may account for up to 4% of cases (9), but a selection bias is probable in series originating from tertiary referral centers.

CLASSICAL FINDINGS IN AICARDI SYNDROME

The classical picture of AS has been outlined in several articles (3,6, 1 0, I 1). The seizures are typically infantile spasms. These have been the only seizure type in 86 of 184 patients (47%) and have been associated with other seizures, especially partial motor attacks, in 65 of 184 patients (35%) (6). The partial seizures often begin before the infantile spasms, at times as early as the first few days of life (6,12). The age at first seizure was less than 3 months in 68% of 146 patients and less than I month in 23%. The age at the first spasm in 137 patients was less than I month in 18% and less than 3 months in 56%. Typical tonic spasms have been reported even during the neonatal period, and AS is one possible cause of the "early infantile epileptic encephalopathy" described by Ohtahara et al. (13). Partial seizures and infantile spasms often occur in association, a focal or lateralized tonic or clonic seizure being followed by a similarly lateralized cluster of spasms. The focal seizure is manifested on the EEG by a localized discharge of repetitive spikes lasting 10-30 s. The spasms follow immediately after the spikes and are associated with a series of slow complexes, often with a superimposed fast rhythm that is usually of higher amplitude on the side of the initial

Figure 8. Chorioretinal lacunae

DIAGNOSIS:

DISCUSSION

5


partial discharge. The complexes occur 6- 20 s apart, and no paroxysmal activity appears between them. The initial partial seizure and the spasms that follow appear to represent a single attack that usually occurs on awakening or on changing from slow wave to REM sleep (12,14). Such periodic spasms are also associated with other brain malformations (14).

Typical hypsarrhythmia is rare in AS (18% of 137 cases). The most common interictal EEG abnormality is an asymmetrical pseudo-periodic tracing with bursts of paroxysmal irregular slow and sharp waves of 3- to 6-s duration, separated by a relatively flat EEG for 5-20 s. Such bursts may occur independently over each hemisphere or may remain unilateral, with various abnormalities over the other hemisphere, the so-called "split-brain" EEG (6). The tracings more commonly evolve into multifocal paroxysmal abnormalities than into typical hypsarrhythmia. At a late stage, spike-and- wave complexes are unusual (6,9).

The choroidal lacunae are multiple rounded whitish or pinkish areas ranging in size from one-tenth to several disc diameters. They are in the same plane as the retina, so that vessels do not bend on crossing their border. Pigment deposits may be visible at their periphery and may increase with age (6,15). The largest lacunae tend to cluster around the disc, whereas small pinkish lesions tend to be more peripheral. They are usually bilateral, but unilateral lacunae can be seen even when the opposite eye is not microphthalmic. Typical lacunae are probably pathognomonic of AS. Colobomata are a very common finding and are of significance for the diagnosis, especially when lacunae are few or atypical. Unlike the lacunae, they are frequently unilateral. Colobomatous discs are surrounded by pigmented rings in many cases. Other eye abnormalities, including persistence of the primary vitreous, anterior synechiae, and microphthalmia, are not uncommon. In one patient, the appearance was that of retinal detachment suggestive of the Walker- Warburg syndrome. Interestingly, despite the very abnormal ophthalmoscopic aspect, useful vision is often preserved as far as can be assessed. The ERG has been found normal or only mildly altered in several patients. The visual evoked potentials are usually present but abnormal, probably as a result of the cortical abnormalities. The fundoscopic appearance results from thinning of the choroid and sclera in the areas corresponding to the lacunae where the pigment epithelium is depigmented or hypopigmented (7), with degeneration of the rods and cones (8). There is no evidence of inflammatory lesions, and the appearance is suggestive of an early developmental disorder.

Agenesis of the corpus callosum was complete in 137 of 152 patients for whom the information was available and was partial in 15 (10%). Partial agenesis is usually posterior (6), but cases of agenesis of both the genu and the splenium, with preservation of the body of the callosum, are known (16). The ventricular contour is not smooth as it is in most cases of callosal agenesis and the ventricles, including the third ventricle, have markedly irregular contours. In most cases there is also marked asymmetry between the two hemispheres, the larger one commonly but not consistently contralateral to a hemiplegia when present or to the side most involved by the spasms. Various abnormalities of the posterior fossa have also been reported (6).

The neurologic and mental impairment in AS is almost always very marked. The estimated survival rate in one study (17) was 75% at 6 years and 40% at 15 years. Epilepsy persists in most patients as infantile spasms, which is unusual with other causes. Approximately one-third of patients are unable to feed themselves and only one-quarter are able to walk. Only rare patients can use two-word sentences (3). One patient had relatively well-developed language at age 14 years (17). According to McGregor et al. (17), a worse prognosis was correlated with larger lacunar size. Hemiplegia is commonly present but it is seldom isolated, and some degree of contralateral involvement is the rule. Mild microcephaly is common but is never present at birth. Indeed, some infants have large heads that may result from hydrocephalus or from the development of large intracranial cysts. Although an occasional patient has been operated on for shunting of hydrocephalus due to aqueductal stenosis or for drainage of a cyst, this is seldom justified because the cysts do not usually continue to increase in postnatal life and ventricular dilatation usually remains static even when marked.

NEW FINDINGS IN AICARDI SYNDROME

Over the past few years the diagnosis of AS has been facilitated by modern imaging techniques. These have shown that agenesis of the corpus callosum is virtually never an isolated finding but is part of a complex of developmental abnormalities. Migration anomalies are probably present in all cases. They include periventricular and/or subcortical nodular heterotopias, which are responsible for the irregular contours of the lateral ventricles, and cortical dysplasia with thickening of the cortical plate and abnormal rectilinear or blurred interface between gray and white matter involving one or both hemispheres to a variable degree. These dysplastic areas probably correspond pathologically to polymicrogyria (3, 5,15,18,19). Periventricular heterotopias are easily detectable, but the diagnosis of subcortical heterotopias and cortical dysplasia requires high-quality MRI. Cysts are frequently revealed on MRI. They can involve the glomus of the choroid plexus on one or both sides and/or the region of the third ventricle and pineal gland, where they may be single or multiple and may be quite large (Fig. 1). The cysts give a slightly more intense signal than CSF and their walls may enhance with gadolinium contrast. Cysts around the third ventricle were probably responsible for the distorted appearance of this ventricle on MRI or CT scan, which could not result from heterotopias. Cysts of the cerebral hemispheres are uncommon. Cysts of the posterior fossa have been reported (3,6). Most of them correspond to partial agenesis of the cerebellar vermis, to a megacisterna magna, or to arachnoid cysts. True intraparenchymal cysts are uncommon. The combination of cysts of the choroid plexus in association with agenesis of the corpus callosum permits the antenatal diagnosis of AS (20). Solid tumors, especially papillomas of the choroid plexus, have been reported in several patients (3,6) and may be multiple (21). Peripheral embryonic tumors have also been described (22,23).

6


The combination of partial or complete callosal agenesis, cortical dysplasia, gross asymmetry of the hemispheres, periventricular or subcortical heterotopias, and cysts of the choroid plexus or around the third ventricle is highly suggestive of AS (3). Incomplete forms in which one or several components are lacking are not uncommon. Such forms are confirmed as AS by the presence of other typical manifestations, especially choroidal lacunae. There is probably no good reason to single out one component of the malformation complex so that cases without callosal agenesis but with heterotopias and/or cortical dysplasia can be diagnosed when other cardinal features are present. Two such cases (both with lacunae and one with vertebral abnormalities) are known to this author.

Criteria that are highly suggestive of Aicardi syndrome

Partial or complete callosal agenesis

Cortical dysplasia

Gross asymmetry of the hemispheres

Periventricular or subcortical heterotopias

Cysts of the choroid plexus or around the third ventricle is highly suggestive of AS

PATHOLOGY

Pathologic data on AS are scanty, and detailed microscopic examination of the brain is available for only two cases (5,18). Total or partial absence of the corpus callosum was found in all verified cases, usually with the presence of Probst bundles. Other structures may be lacking, such as the first cranial nerve and the mammary bodies. Other commissures, e.g., the fornix or the anterior commissure (6), may be absent, but this is inconstant.

Abnormalities of gyration were found in all studied cases (5-7,15,18). Their macroscopic aspect is variable, but microgyria is found microscopically and is of the unlayered type (18), taking the form of a thin, undulating cellular ribbon without any laminar organization. Fusion of the molecular layers of facing convolutions may result in the appearance of a pachygyric cortex (5). Heterotopias include subcortical neurons scattered in the white matter. Cysts have been reported in several cases (3,18,24) and were of ependymal origin.

Pathologic findings are consistent with an etiologic factor acting before the end of the migration period and the development of the corpus callosum, which is complete by 14 weeks of gestational age (25).

NOSOLOGIC LIMITS OF AS: THE PROBLEM OF INCOMPLETE FORMS

Figure 1. Huge cyst in a case of Aicardi syndrome. The cyst probably arises from the pineal area and develops into the left parietooccipital lobe, displacing and compressing the lateral ventricle. Note also agenesis of the corpus callosum and abnormal appearance of the posterior cortex on both sides, suggestive of migration disorder.

Figure 2. Image shows a cross-section of an eye in a patient with Aicardi syndrome. The arrow indicates chorioretinal lacunae.

7


Because there is no laboratory marker specific for AS, the classical triad remains the cornerstone of diagnosis. The existence of incomplete forms, however, seems likely, and cases without callosal agenesis have been already discussed. In addition to the two cases above, six cases of possible AS without callosal agenesis are known (6). All six had infantile spasms and choroidal lacunae, and four had irregular ventricular contours on CT. None of these patients underwent an MRI. Cases without infantile spasms have been reported (6) and may not be rare. Recognition of the spasms may be difficult because they are often quite asymmetrical and atypical and are frequently associated with partial seizures, which may be the predominant seizure type. Isolated partial seizures are not unusual at onset or late in the course, but they may be absent altogether.

The existence of AS cases without lacunae is particularly difficult to accept, because these are considered pathognomonic for the syndrome. There are, however, female patients with a suggestive brain malformation,, infantile spasms, and other abnormalities who might represent atypical forms. I know of three such patients who presented with infantile spasms and agenesis of the corpus callosum. Two of these had periventricular heterotopias on CT scan and an asymmetrical burst-suppression pattern on EEG. One girl had bilateral colobomata of the disk and another a small pigmented retinal area on one side. None of them had undergone MRI.

GENETIC AND CYTOGENETIC DATA

The original hypothesis that AS is an X-linked dominant disorder that is lethal at an early stage of gestation for affected hemizygous male conceptuses appears most compatible with the observed data (2,3,6). Only females are affected, with the exception of two phenotypical males with two X chromosomes (26). The male child with an XY karyotype reported by Curatolo et al. (27) is too atypical to be included (6,28, 29). This hypothesis is also consistent with the sporadic occurrence of the syndrome. Only one instance of familial recurrence in two sisters is reported (4) and this remains difficult to explain because no chromosomal abnormality was found in these patients. Another finding difficult to reconcile with the hypothesis is the occurrence of AS in only one of a pair of monozygotic twins, the co-twin being completely normal as a young adult (30). If this report is confirmed, it might be explained by extreme nonrandom inactivation of the abnormal X chromosome in the normal twin or, less probably, by a postzygotic mutation during early embryonic development.

The strong suspicion of an abnormality of an X chromosome in patients with AS has been reinforced by the finding of skewed X inactivation in the lymphocytes of some patients (31). Patients with nonrandom inactivation were found to be more severely affected than those with a random pattern, suggesting that selection against abnormal cells in the developing neural tissue led to aberrant brain development. However, a normal inactivation pattern has been found in other cases (30,32).

A possible locus for AS on the short arm of the X chromosome has been suggested by several case reports of eye abnormalities with callosal agenesis or other brain abnormalities (33-36) associated with translocations or other chromosomal abnormalities at Xp22.3. However, none of the reported patients had the typical triad of AS, even though microphthalmia (3), chorioretinal lesions reminiscent of the lacunae (Aughton et al., personal communication, 1991), other eye abnormalities (33,34), agenesis of the corpus callosum (36) or other brain defects (35), and costovertebral malformations (33) were present in variable associations. Four of these children also had focal dermal hypoplasia or Golz disease, a sex linked disorder with lethality for hemizygous males mapping at Xp22.3 (36). Such cases suggest that the Xp22.3 region is involved in the genesis of both Golz syndrome and AS. They could represent contiguous gene syndromes involving both loci. Intensive search for an AS gene in the Xp22.3 region is being pursued.

SUMMARY

AS is an uncommon malformation complex that affects mostly the eyes and the central nervous system. Brain malformation constitutes the core of the syndrome. Agenesis of the corpus callosum is the most easily detectable but probably not the most characteristic feature. Migration anomalies, including periventricular and subcortical nodular heterotopias and cortical dysplasia, and a tendency towards the formation of ependymal cysts in the glomus of the choroid plexuses and/or near of the third ventricle, are major components of the complex and may occur even in the presence of a complete corpus callosum. The resulting seizures, usually asymmetrical infantile spasms, and mental retardation constitute a severe disability with a much reduced life expectancy. The syndrome is probably due to a chromosomal accident involving one X chromosome. The Xp22.3 region is a prime candidate for location of one or several responsible genes, and demonstration of a DNA abnormality in this region will permit a better definition of the limits of the syndrome and perhaps help our understanding of some aspects of the development of the central nervous system.

AS is an uncommon malformation complex that affects mostly the eyes and the central nervous system. Brain malformation constitutes the core of the syndrome. Agenesis of the corpus callosum is the most easily detectable but probably not the most characteristic feature. Migration anomalies, including periventricular and subcortical nodular heterotopias and cortical dysplasia, and a tendency towards the formation of ependymal cysts in the glomus of the choroid plexuses and/or near of the third ventricle, are major components of the complex and may occur even in the presence of a complete corpus callosum. The

SUMMARY

8


resulting seizures, usually asymmetrical infantile spasms, and mental retardation constitute a severe disability with a much reduced life expectancy. The syndrome is probably due to a chromosomal accident involving one X chromosome. The Xp22.3 region is a prime candidate for location of one or several responsible genes, and demonstration of a DNA abnormality in this region will permit a better definition of the limits of the syndrome and perhaps help our understanding of some aspects of the development of the central nervous system.

The diagnosis of AS is based upon the classic triad of corpus callosal agenesis, chorioretinal lacunae and infantile spasm. But there is a range of costovertebral, ocular and cerebral abnormalities associated with this disorder.(2) The cerebral gray-matter heterotopias and other cortical malformations act as epileptogenic foci.(2) Their seizures typically start in early childhood and are usually intractable. Besides infantile spasm, other seizure types are also demonstrated. Dissociated burst-suppression or burst-suppression pattern appearing asymmetrically in either cerebral hemisphere is a characteristic EEG finding in AS.(8) The developmental delay in AS is generally profound, involving both motor and language skills. Chevrie and Aicardi in their analysis of 184 patients of AS observed that none had acquired meaningful speech.(9) But of late a larger spectrum of the disease has been recognized and it had been found that higher functioning AS individuals do exist.(2) Most of the AS cases die at an early age primarily due to aspiration pneumonitis. But some do live into their adolescent years and even in their twenties.(2) Good visual function in AS patients do occur if the fovea is uninvolved with chorioretinal lacunae.

Cerebral heterotopias, interhemispheric cysts, optic nerve coloboma, microphthalmia, thoracolumbar kyphoscoliosis are the known associated features in AS. Severe psychomotor impairment and absence of meaningful speech had also been noted. (3,4,5,6)

Addendum

A new version of this PDF file (with a new case) is uploaded in my web site every week (every Saturday and remains available till Friday.)

To download the current version follow the link "http://pdf.yassermetwally.com/case.pdf". You can also download the current version from my web site at "http://yassermetwally.com". To download the software version of the publication (crow.exe) follow the link:

http://neurology.yassermetwally.com/crow.zip The case is also presented as a short case in PDF format, to download the short case follow the link:

http://pdf.yassermetwally.com/short.pdf At the end of each year, all the publications are compiled on a single CD-ROM, please contact the author to know more

details. Screen resolution is better set at 1024*768 pixel screen area for optimum display. For an archive of the previously reported cases go to www.yassermetwally.net, then under pages in the right panel, scroll

down and click on the text entry "downloadable case records in PDF format" Also to view a list of the previously published case records follow the following link (http://wordpress.com/tag/case-record/)

or click on it if it appears as a link in your PDF reader

References

1. Aicardi J, Lefebvre J, Lerique-Koechlin A. A new syndrome: spasms in flexion, callosal agenesis, ocular abnormalities. Electroencephalogr Clin Neurophysiol 1965;19:609-10.

2. Aicardi J, Chevrie JJ, Rousselie F. Le syndrome agdndsie calleuse, spasmes en flexion, lacunes chorioretiniennes. Arch Franc Pgdiatr 1969;26: 1103-20.

3. Aicardi J, Chevrie JJ. The Aicardi syndrome. In: Lassonde M, Jeeves MA, eds. Callosal agenesis: the natural split brain. New York: Plenum Press, 1995.

4. Molina JA, Mateos F, Merino M, Epifanio JL, Gorrono M. Aicardi syndrome in two sisters. J Pediatr 1989;115:282-3.

5. Billette de Villemeur T, Robain 0, Chiron C. Unlayered polymicrogyria and agenesis of the corpus callosum: a relevant association? Acta Neuropathol (Berl) 1992;83:265-70.

6. Chevrie JJ, Aicardi J. The Aicardi syndrome;, In: Meldrum BS, ed. Recent advances in epilepsy, Vol. 3. Edinburgh: Churchill Livingstone, 1986: 189-210.

7. McMahon RG, Bell RA, Moore RW, Ludwin SK. Aicardi syndrome. A clinicopathological study. Arch Ophthalmol 1984;102:250-3.

8. Del Pero RA, Mets MB, Tripathy RC, Torezynski E. Anomalies of retinal architecture in Aicardi syndrome. Arch Ophthalmol 1986;104:1659-64.

REFERENCES

9


9. Aicardi J. Epilepsy in children, 2nd ed. New York: Raven Press, 1994:l-3.

10. Donnenfeld AE, Packer RJ, Zackai EH, Chee CM, Sellinger B, Emmanuel BS. Clinical, cytogenetic and pedigree findings in 18 cases of Aicardi syndrome. Am J Med Genet 1989;32:461-7.

11. Yamagata T, Momoi M, Miyamoto S, Kobayashi S, Kamoshita S. Multi-institutional survey of the Aicardi syndrome in Japan. Brain Dev 1990;12: 760-5.

12. Bour F, Chiron C, Dulac 0, Plouin P. Caractres electrocliniques des crises dans le syndrome d'Aicardi. Rev EEG Neurophysiol Clin 1986;16: 341-53.

13. Ohtahara S, Ohtsuka Y, Yamatogi Y, Oka E. The early infantile epileptic encephalopathy with suppression burst: developmental aspects. Brain Dev 1987;9:371-6.

14. Gobbi G, Bruno L, Pini A, Rossi PG, Tassinari CA. Periodic spasms: an unclassified type of epileptic seizure in childhood. Dev Med Child Neural 1987;29:766-75.

15. De Jong JGY, Delleman JW, Houben M, et al. Agenesis of the corpus callosum, infantile spasms, ocular anomalies (Aicardi's syndrome): clinical and pathological findings. Neurology 1976;26: 1152-8.

16. Aicardi J, Chevrie JJ, Baraton J. Agenesis of the corpus callosum. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology, Vol. 6. Brain malformations. Amsterdam: North-Holland, 1987:149-73.

17. McGregor DL, Menezes A, Buncic JR. Aicardi syndrome (AS): natural history and predictors of severity. Can J Neurol Sci 1993;20(suppl 2):S36.

18. Ferrer 1, Cusi MV, Liarte A, Campistol J. A Golgi study of the polymicrogyric cortex in Aicardi syndrome. Brain Dev 1986;8:518-25.

19. Baieari P, Marki A, Thelen M, Laub MC. MR imaging in Aicardi,s syndrome. Am J Neuroradiol 1988;9:805-6.

20. Roland EH, Flodmark 0, Hill A. Neurosonographic features of Aicardi syndrome. J Child Neurol 1989;4:307-10.

21. Hamano K, Matsubara T, Shibata S, et al. Aicardi syndrome accompanied by auditory disturbances and multiple brain tumors. Brain Dev 199 1; 13:438- 41.

22. Tanaka T, Takahura H, Takashima S, Kodama T, Hasegawa H. A rare case of Aicardi syndrome with severe brain malformation and hepatoblastoma. Brain Dev 1985;7:507-12.

23. Togawa T, Mimaki T, Ono J. Aicardi syndrome associated with embryonal carcinoma. Pediatr Neural 1989;5:45-7.

24. Brihaye L, Gillet P, Parmentier R, Peetrons A. Agenesie de la commissure calleuse associee A un kyste dpendymaire. Arch Suisses Neurol Psychi- atr 1956;77:415-31.

25. Barkovich A, Norman D. Anomalies of the corpus callosum: correlation with further anomalies of the brain. Am J Neuroradiol 1988;9:493-501.

26. Hopkins IJ, Humphrey 1, Keith CG, Susman M, Webb GC, Turner EK. The Aicardi syndrome in a 47XXY male. Aust Paediatr J 1979;15:278-80.

27. Curatolo P, Libutti G, Dalla Piccola B. Aicardi syndrome in a male infant. J Pediatr 1980;96: 286-7.

28. Aicardi J. The Aicardi syndrome in a male infant [Letter]. J Pediatr 1980;97:1040-41.

29. Hunter AGW. Aicardi syndrome in a male infant [Reply]. J Pediatr 1980;97:1041.

30. Costa T, Greer W, Duckworth M, Rysiecki M, Musarella M, Ray P. Monozygotic twins discordant for Aicardi syndrome [Abstract]. Am J Hum Genet 1990;47(suppl 5)202:14.

31. Neidich JA, Nussbaum RL, Packer RJ, Emanuel BS, Puck JM. Heterogeneity of clinical severity and molecular lesions in Aicardi syndrome. J Pediatr 1990; 1 16:911-7.

32. Wieacker P, Zimmer J, Ropeers HH. X-inactivation pattern in two syndromes with probable X-linked dominant, male lethal inheritance. Clin Genet 1985;28:238-42.

33. Ropers HH, Zuffardi 0, Biancai E, Tiepolo L. Agenesis of corpus callosum, ocular and skeletal anomalies (X-linked dominant Aicardi's syndrome) in a girl with balanced X/3 translocation. Hum Genet 1982;61:364-8.

34. Donnenfeld AE, Graham JM, Packer RJ, Aquino R, Berg SZ, Emanuel BS. Microphthalmia and chorioretinal lesions in a girl

10


with an Xp22.2 pter deletion and partial 3p trisomy: clinical observations relevant to Aicardi syndrome gene localization. Am J Med Genet 1990;37:182-6.

35. Al-Gazali LI, Muller RF, Caine A, et al. An XX male and two (X;Y) females with linear skin defects and congenital microphthalmia: a new syndrome at Xp22.3. J Med Genet 1988;25:638-9.

36. Friedman PA, Rao KW, Jeplin SW, Aylsworth AS. Provisional deletion mapping of the focal dermal hypoplasia (FDH) gene to Xp22.31 [Abstract]. Am J Hum Genet 1988;43:A50.

32- Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 9.4a October 2008

11


CLINICAL PICTURE:

A 7 years old female patient presented clinically with Lennox Gastaut syndrome.


Figure 1. Cortical dysplasia. Precontrast MRI T1 images showing lissencephaly, microgyria, pachygyria, hypointense cystic white matter changes specially affecting the right head of caudate nucleus and the globus pallidus on the right side. The lissencephalic changes are most marked in the bifrontal regions. Notice the subependymal nodular heterotopia specially involving the frontal horns bilaterally. There is also reduction of the brain volume and moderate degree of central atrophy.

CASE OF THE WEEK


CLINICAL PICTURE


12


Figure 2. Cortical dysplasia. MRI FLAIR images showing lissencephaly, microgyria, pachygyria, hyperintense cystic white matter changes specially affecting the right head of caudate nucleus and the globus pallidus on the right side. The lissencephalic changes are most marked in the bifrontal regions. Notice the subependymal nodular heterotopia specially involving the frontal horns bilaterally, nodules are also seen subependymally in the left body of the lateral ventricles (C). There is also reduction of the brain volume and moderate degree of central atrophy.

Figure 3. Cortical dysplasia. MRI T2 images showing lissencephaly, microgyria, pachygyria, hyperintense cystic white matter changes specially affecting the right head of caudate nucleus and the globus pallidus on the right side. The lissencephalic changes are most marked in the bifrontal regions. Notice the subependymal nodular heterotopia specially involving the frontal horns bilaterally. There is also reduction of the brain volume and moderate degree of central atrophy.

13


Figure 4. Cortical dysplasia. MRI FLAIR images showing lissencephaly, microgyria, pachygyria, hyperintense cystic white matter changes specially affecting the right head of caudate nucleus and the globus pallidus on the right side. The lissencephalic changes are most marked in the bifrontal regions. Notice the subependymal nodular heterotopia specially involving the frontal horns bilaterally, nodules are also seen subependymally in the left body of the lateral ventricles (C). There is also reduction of the brain volume and moderate degree of central atrophy. The hippocampi are atrophic and hyperintense bilaterally (possible mesial temporal sclerosis).

DIAGNOSIS: CORTICAL DYSPLASIA

DISCUSSION:

The brain is a seemingly nonsegmented organ that is, however, formed in a segmented fashion by the overlap of genes that define anatomic and probably functional components of the brain. Other genes and their encoded proteins regulate the processes of cell proliferation and migration; many of these genes have been identified based upon discoveries of human and mouse disease-causing genes.

Human brain developmental disorders represent clinical challenges for the diagnosing clinician as well as for the treating physician. Some disorders represent well-defined clinical and genetic entities for which there are specific tests; others have ill-defined genetic causes, while others can have both genetic and destructive causes. In most cases the recognition of a disorder of brain development portends certain developmental disabilities and often seizure disorders that can be very difficult to treat. In addition, it now bears upon the treating physician to recognize the genetic causes, and to properly advise patients and their families of the risks of recurrence or refer them to the proper specialist who can do so. The genetics of some of these disorders are not all well defined at present, and the recognition of some disorders is variable; what is known is presented herein.

The genetics and signaling utilized in brain development is briefly reviewed to provide the framework for the understanding of human brain developmental disorders. The well-defined genetic disorders of brain development are discussed, and a brief suggested algorithm for evaluation and for counseling of patients is provided.

BRAIN DEVELOPMENT

Overview

General mechanisms tend to recur in all phases of brain development, and these include induction, cell proliferation, cell fate determination (differentiation), cell process formation and targeting (synapse formation), and

DIAGNOSIS:

DISCUSSION

14


cell movement (migration). Induction is the process by which one group of cells or tissue determines the fate of another by the release of soluble factors or inducers. Cell fate or differentiation is dependent upon this process of induction, and probably can best be understood as the initiation of a genetic program by the recognition of an inducing molecule and/or expression of a transcriptional regulator. In general, it is rare that a cell in the nervous system is born and differentiates in the same location that it finally resides. Rather, cells migrate over long distances to reach their final locations. Similarly, cells in the nervous system must extend processes over long distances to reach their synaptic targets.

Neural tube formation

The human brain is formed from the neuroectoderm, a placode of cells that are induced to differentiate from the surrounding ectoderm by the presence of the notochord at about 18 days gestation. Candidate inducing factors include the retinoids, follistatin, and Noggin [1-4]. The neuroectoderm develops folds in the lateral aspects that begin to approximate in the region of the future medulla and fuse at 22 days gestation. This closure is known as neurulation, and results in the formation of a tube termed the neural tube [5]. The anterior neural tube closes by about 24 days gestation and serves as the foundation for further brain development; the posterior neural tube closes by about 26 days gestation and serves as the foundation for further spinal cord development. Defects in the closure of the neural tube lead to encephaloceles or myelomeningoceles.

Nervous system segmentation

At the rostral end of the newly closed neural tube flexures delineate the primary vesicles, which are designated as the hindbrain (rhombencephalon), mesencephalon, and forebrain (prosencephalon). The primary vesicles can be further subdivided into secondary vesicles that will form adult brain structures. The hindbrain can be divided into the metencephalon and myelencephalon, which will become the pons, cerebellum, and medulla oblongata of the adult. The mesencephalon will be the midbrain, and the prosencephalon divides into the telencephalon (two telencephalic vesicles) and diencephalon. The telencephalic vesicles will become the cerebral hemispheres; the diencephalon will become the thalamus and hypothalamus.

Regional specification of the developing telencephalon is an important step in brain development, and is likely under control of a number of genes that encode transcription -regulators. In the fruit fly, Drosophila, these genes are involved in segmentation of this animal and define structures such as hair-like spiracles. Not surprisingly, the role of these genes in human brain development differs, yet it appears that the general role of these proteins is that of regional specification of clones of cells destined to form specific brain structures. Homeobox and other transcription genes encode some of these transcriptional regulators and these "turn on" genes by binding to specific DNA sequences, and in so doing initiate genetic programs that lead to cell and tissue differentiation. EMX2, a transcriptional regulator, has a homolog in Drosophila that defines the hair spiracles and has been implicated in human brain malformations.

DISORDERS OF SEGMENTATION

Schizencephaly

Schizencephaly (cleft in brain) has been regarded by many as a migration abnormality; however, it is best understood as a disorder of segmentation because one of the genes that is abnormal in the more severe and familial forms is EMX2 [6,7]. Thus, this developmental disorder, at least in the more severe cases, appears to be the result of failure of regional specification of a clone of cells that are destined to be part of the cortex.

Clinically, these patients vary depending upon the size of the defect and upon whether bilateral disease is present [8]. The clefts extend from the pia to the ventricle and are lined with a polymicrogyric gray matter (see the discussion in Polymicrogyria) [9]. The pia and ependyma are usually in apposition, especially in severe cases. The defect is termed open-lipped if the cleft walls are separated by cerebrospinal fluid, and closed-lipped if the walls are in contact with one another. Bilateral schizencephaly is associated with mental retardation and spastic cerebral palsy; affected patients often are microcephalic. Seizures almost always accompany severe lesions, especially the open-lipped and bilateral schizencephalies. The exact frequency of seizures in patients with the less severe lesions is uncertain. Most patients in whom schizencephaly is diagnosed undergo neuroimaging because of seizures. Therefore, a bias in favor of a universal occurrence of seizures in this disorder is noted. Hence, patients with schizencephaly who do not have epilepsy might exist, but the malformation remains undetected because no imaging is performed.

15


Seizure type and onset may also vary in this disorder. Patients may experience focal or generalized seizures, and some will present with infantile spasms. The onset varies from infancy to the early adult years. Seizures may be easily controlled or may be recalcitrant to standard anticonvulsant therapy.

Figure 3a. MRI T1 (A,B) and CT scan (D) showing open-lip schizencephaly with pachygyria. Notice the associated encephalocele that is sometimes associated with cortical dysplasias

Figure 1. Closed-lip schizencephaly. Sagittal T1-weighted MRI shows gray matter (arrows) extending from cortex to a dimple in the surface of the left lateral ventricle. The lips of the schizencephaly are in apposition, making this a "closed-lip" schizencephaly.

Figure 2. Bilateral open-lip schizencephaly. A,B: Axial T2-weighted images show open-lip schizencephalies in both hemispheres. Both images show vessels in the gray matter-lined clefts and large vessels (arrows) run at the outer surface of the right hemispheric cleft. This does not represent a vascular malformation.

16


Improvements in neuroimaging have enhanced the recognition of schizencephalic lesions [9-13]. The lesions may occur in isolation or may be associated with other anomalies of brain development such as septo-optic dysplasia (see Disorders of prosencephalic cleavage) [14].

Disorders of segmentation likely represent a heterogeneous set of abnormalities of varying etiologies. One theory holds that an early (first-trimester) destructive event disturbs subsequent formation of the cortex. Another theory is that segmental failure occurs in the formation of a portion of the germinal matrix or in the migration of primitive neuroblasts. Certainly, the finding of mutations of the EMX2 gene in some patients with the open-lipped form of schizencephaly supports the latter hypothesis.

Prosencephalon cleavage

At about 42 days of gestation, the prosencephalon undergoes a division into two telencephalic vesicles that are destined to become the cerebral hemispheres. The anterior portion of this cleavage is induced by midline facial structures and the presence of the notochord. Abnormalities of this process are thought to result in holoprosencephaly, septo-optic dysplasia, and agenesis of the corpus callosum [I 5]. One of the important molecules responsible for the induction of this cleavage is Sonic hedgehog [16]. This protein is produced by the notochord, ventral forebrain, and the floor plate of the neural tube [17]. It interacts through at least one receptor, PTCH-A human homolog of patched, and alters the expression of transcription factors [18,19]. Furthermore, in an interesting link between these ventral inductive events and segmentation, Sonic hedgehog can alter the expression of the transcriptional regulating genes when applied to proliferating cells at critical times in development [21]. This ties the inductive proteins to the expression of transcriptional regulating genes and gives a hint as to the mechanisms involved in inductive processes.

Figure 3b. Open-lip schizencephaly with cortical dysplasia

17


Figure 4a. Agenesis of the corpus callosum

Other molecules of interest in this inductive process are the retinoids, which are lipids capable of crossing membranes and that have been shown to exist in posterior to anterior gradients across embryos [3,20]. Retinoic acid can alter the pattern of transcriptional factors in neuroepithelial cells [3] and can downregulate Sonic hedgehog, perhaps explaining some of the head defects seen in retinoid embryopathy [17,22].

Agenesis of the corpus callosum

Figure 4b. Agenesis of the corpus callosum

DISORDERS OF PROSENCEPHALIC CLEAVAGE

Holoprosencephaly

Holoprosencephaly is a heterogeneous disorder of prosencephalon cleavage that results from a failure of the

Etiology •Both genetic and sporadic Pathogenesis •Unknown,

Epidemiology

•Agenesis of the corpus callosum may be part of an extensive malformation complex or the callosum may be partially or completely absent or hypoplastic in an otherwise normal brain.

•The malformation is relatively rare.

General Gross Description

•The brain in agenesis of the corpus callosum shows batwing shaped ventricles as well as loss of the corpus callosum and there is no cingulate gyrus.

•The remainder of the abnormalities depend on what syndrome or other malformations are associated with the defect. In most cases there is a bundle of white matter processes on both cerebral hemispheres in the area where the corpus callosum should be, called the bundle of Probst. In some patients there is a lipoma or other tumor in the area where the corpus callosum should be.

General Microscopic Description

•None

Clinical Correlation

•Patients with agenesis of the corpus callosum may be normal or may have neurological abnormalities dependent on the other accompanying malformations.

18


prosencephalic vesicle to cleave normally. Three forms of this disorder have been described: alobar, semilobar, and lobar [23,24]. In the alobar form, the telencephalic vesicle completely fails to divide, producing a single horseshoe-shaped ventricle, sometimes with a dorsal cyst, fused thalami, and a malformed cortex. In the semilobar form, the interhemispheric fissure is present posteriorly, but the frontal and, sometimes, parietal lobes, continue across the midline [25]; in some cases just ventral fusion is noted. In the lobar form, only minor changes may be seen: the anterior falx and the septum pellucidum usually are absent, the frontal lobes and horns are hypoplastic, and the genu of the corpus callosum may be abnormal.

Figure 5. This is holoprosencephaly in which there is a single large ventricle with fusion of midline structures, including thalami. The affected fetuses and neonates typically have severe facial defects, such as cyclopia, as well. Underlying chromosomal abnormalities, such as trisomy 13, or maternal diabetes mellitus are possible causes, but some cases are sporadic.

Holoprosencephaly is associated with a spectrum of midline facial defects. These include cyclopia, a supraorbital proboscis, ethmocephali, in which the nose is replaced by a proboscis located above hypoteloric eyes; cebocephaly, in which hypotelorism and a nose with a single nostril are seen; and premaxillary agenesis, with hypotelorism, a flat nose, and a midline cleft lip [26].

19


Figure 6. (left three images) A,B semilobar holoprosencephaly from the same patient, C a patient with lobar holoprosencephaly. Arrowhead in A points to lack of ventral interhemispheric cleavage. Arrowhead in B points to fused thalami. The septum pellucidum is absent in B. In C notice the horseshoe or mushroom shaped single ventricle designated by * , arrowhead in C points to lack of interhemispheric fissure. (right image) MRI -Holoprosencephaly: This 6-day-old girl presented with laryngeal malacia and a diminished level of arousal. This proton density axial MR image shows an absence of the anterior horns of the lateral ventricles, fused thalami and absence of the corpus callosum anteriorly.

Only children who have the lobar and semilobar forms are known to survive for more than a few months. An infant affected with the severe form is microcephalic, hypotonic, and visually inattentive [25]. In infants with the less severe forms of holoprosencephaly, myoclonic seizures frequently develop and, if the infant survives, autonomic dysfunction, failure to thrive, psychomotor retardation, and atonic or spastic cerebral palsy often are present. Some infants with the lobar form may be only mildly affected and, for example, present as a relatively mild spastic diplegia. Pituitary defects may be associated with these malformations, and may result in neuroendocrine dysfunction [27]. One, therefore, has to wonder how much genetic overlap exists between this condition and septo-optic dysplasia to be described below.

Holoprosencephaly has been associated with maternal diabetes [28], retinoic acid exposure, cytomegalovirus, and rubella [29]. Chromosome abnormalities associated with this disorder include trisomies 13 and 18; duplications of 3p, 13q, and 18q; and deletions in 2p, 7q, 13q, and 18q [30]. Of particular concern to the clinician is the existence of an autosomal dominant form in which mutations in Sonic Hedgehog lead to variable expression of holoprosencephaly. In the mildest form of this genetic disorder, patients may have a single central incisor, a choroid fissure coloboma, or simply attention deficit disorder; a parent of a child with holoprosencephaly manifesting these features should be considered to be at high risk for recurrence of holoprosencephaly in their children (up to 50% risk) [31,32]. A number of other genes (HPE] (21 q22.3), HPE2 (2p2 1), HPE3 (7q36), HPE4 (18p), ZIC2, SIX3 (2p2l), and PATCHED) have been associated with holoprosencephaly, and although potentially inherited in an autosomal recessive fashion, most occurrence seems to be random [33,34].

Septo-optic dysplasia

Septo-optic dysplasia (de Morsier syndrome) is a disorder characterized by the absence of the septum pellucidum, optic nerve hypoplasia, and hypothalamic dysfunction. It may be associated with agenesis of the corpus callosum. This disorder should be considered in any patient who exhibits at least two of the above abnormalities and perhaps even solely hypothalamic dysfunction [35]. Septo-optic dysplasia also appears to involve prosencephalic cleavage and development of anterior telencephalic structures [36]. About 50% of patients with septo-optic dysplasia have schizencephaly [14].

20


Patients may present with visual disturbance, seizures, mental retardation, hemiparesis (especially if associated with schizencephaly), quadriparesis, or hypothalamic dysfunction. Endocrine abnormalities may include growth hormone, thyroid hormone, or antidiuretic hormone function or levels. The consideration of septo-optic dysplasia necessitates an evaluation of the hypothalamic-pituitary axis because as many as 60% of the children with this disorder might exhibit evidence of a disturbance of endocrine function [37]. This evaluation can include thyroid function studies and electrolytes; these patients are at high risk for growth retardation.

The recent identification of patients with this condition that harbor mutations in the transcriptional regulator gene HESX1, suggest that the mechanism of this disorder is likely genetic and a patterning or segmental abnormality [38]. Even though the genetic abnormality has been identified for a minority of patients, there exists the possibility that this may not represent an entirely genetic disorder because associations have been made with young maternal age, diabetes, the use of anticonvulsants, phencyclidine, cocaine, and alcohol [39],

DISORDERS OF CELL PROLIFERATION

Normal cell proliferation

Following telencephalic cleavage, a layer of proliferative pseudostratified neuroepithelium lines the ventricles of the telencephalic vesicles. These cells will give rise to the neurons and glia of the mature brain. The generation of the proper complement of cells is a highly ordered process that results in the generation of billions of neurons and glia. Neuroepithelial processes extend from the ventricular surface to the pial surface, and the nuclei of the primitive neuroepithelial cells move from the cortical surface in a premitotic phase to a mitotic phase near the ventricle. Cells divide at the most ventricular aspects of the developing telencephalon, and after division move back toward the pial surface. The pial processes of neuroepithelial cells near the ventricle often will detach from the cortical surface before a new cycle begins.

Neuroepithelial cells divide in so-called proliferative units such that each unit will undergo a specific number of divisions resulting in the appropriate number of cells for the future cortex. Abnormalities in the number of proliferative units or in the total number of divisions can lead to disorders of the brain manifested by abnormal brain size and, therefore, an unusually small or large head circumference. Two such disorders resulting in small head size -radial microbrain and microcephaly vera- are believed to result from abnormalities of this phase of neurodevelopment [40]. Disorders in which too many cells are generated in the proliferative phase result in megalencephaly (large brain) or, if proliferative events go awry on only one side of the developing cortex, hemimegalencephaly.

The genes and molecules involved in regulating the proliferative cycles in human brain formation are likely similar

Figure 7. Septo-optic dysplasia associated with schizencephaly. Arrows in A,B point to absent septum pellucidum, arrow in C, and black arrowhead in D point to open lip schizencephaly, white arrow head point to polymicrogyria in D

21


to those involved in other species. This cell cycle in the brain can be divided into a number of distinct phases: mitosis (M), first gap (GI), deoxyribonucleic acid synthesis (S), and second gap (G2) [41]. These phases appear to be regulated by key molecules to check the advancement of proliferation. Some cells enter a resting state (GO) that they maintain throughout life. Others temporarily enter this phase to await a specific signal to proliferate later. Probably the GI-S transition regulation determines the number of cell cycles and, therefore, the complement of cells that will make brain [40]. Cyclins are proteins that appear to be involved in cell cycle control. These proteins are activating subunits of cyclin-dependent kinases. Cyclins DI, D2, D3, C, and E seem to control the key transition of a cell to the GI S interface; this transition is regarded as important because it commits a cell to division [42-44]. Cyclin E seems to be the gatekeeper for this transition, and is essential for movement from the GI to the S phase [42,45].

The number of cells that finally make up the mature nervous system is less than that generated during proliferation. Cells appear not only to be programmed to proliferate during development but to contain programs that lead to cell death [46,47]. The term apoptosis (from the Greek, meaning "a falling off ") has been applied to this programmed loss of cells [48].

Non-neoplastic proliferative disorders

Microcephaly

Although primary microcephaly may be a normal variant, in the classic symptomatic form, clinical and radiologic examinations reveal a receding forehead, flat occiput, early closure of fontanelles, and hair anomalies such as multiple hair whirls and an anterior cowlick. Neuroimaging may show small frontal and occipital lobes, open opercula, and a small cerebellum [24]. The cortex may appear thickened and the white matter reduced. Histologic examination may show a reduction of cell layers in some areas and an increase in others [49].

Neurologic findings also vary. Only mild psychomotor retardation may be noted, sometimes associated with pyramidal signs, or more severe retardation, seizures, and an atonic cerebral palsy might be evidenced. Primary microcephaly is seen in many genetic syndromes and, in its isolated form, may be autosomal recessive, autosomal dominant, or X-linked [50-52]. Microcephaly vera is the term most often alyplied to this genetic form of microcephaly. Affected children present with a head circumference that is usually more than 4 standard deviations below the mean, hypotonia, and psychomotor retardation. They later show mental retardation, dyspraxias, motor incoordination and, sometimes, seizures. On histologic examination, neurons in layers 11 and III are depleted [53].

Destructive lesions of the forming brain, such as those caused by teratogens and by infectious agents, also may result in microcephaly. Teratogens of note are alcohol, cocaine, and hyperphenylalaninemia (maternal phenylketonuria) [54]. Intense radiation exposure (such as that from a nuclear explosion) in the first trimester, can cause microcephaly [55]. Microcephaly and intracranial calcifications are likely due to well-recognized in utero infections caused by cytomegalovirus, toxoplasmosis, or the human immunodeficiency virus.

Megalencephaly and hemimegalencephaly

The terms megalencephaly and hemimegalencephaly refer to disorders in which the brain volume is greater than normal (not owing to the abnormal storage of material); usually, the enlarged brain is accompanied by macrocephaly, or a large head. Although considered by some to be a migration disorder, the increase in brain size in these disorders appears to be attributable to errors in neuroepithelial proliferation, as the microscopic appearance of the brain is that of an increase in number of cells (both neurons and glia) and in cell size [56-59].

Typically, patients are noted to have large heads at birth, and may manifest an accelerated head growth in the first few months of life [60,61]. Children with megalencephaly or hemimegalencephaly may come to medical attention when presenting with seizures, a developmental disorder (mental retardation), hemihypertrophy, or a hemiparesis (opposite the affected hemisphere). Seizures vary both in onset and in type, and usually are the most problematic symptom. sometimes necessitating hemispherectomy or callosotomy [58].

Approximately 50% of patients with linear sebaceous nevus syndrome have hemimegalencephaly [62,63]. Many patients with hypomelanosis of Ito also have hemimegalencephaly [64]. The neuropathologic and clinical pictures of these associations appear to be identical to the isolated hemimegalencephalies.

Neoplastic proliferative disorders

22


Lesions of proliferation after an abnormal induction event during brain development may be malformative, hamartomatous, neoplastic, or a combination. Malformative disorders consisting of neoplasias on a background of disordered cortex or in association with focal cortical dysplasia include dysembryoplastic neuroepithelial tumor and ganglioglioma. [103,104]

Dysembryoplastic neuroepithelial tumours

Dysembryoplastic neuroepithelial tumors are supratentorial, predominantly temporal lobe tumors that are typically multinodular with a heterogeneous cell composition, including oligodendrocytes, neurons, astrocytes, and other cells. These lesions are typically fairly well-demarcated, wedge-shaped lesions extending from the cortex to the ventricle. Calcification, enhancement, and peritumoral edema are lacking on neuroimaging studies. These low-attenuation lesions may suggest an infarct on computed tomography (CT), although there is no volume loss over time, and scalloping of the inner table or calvarial bulging suggests slow growth. Lesions are low in signal on Tl-weighted images and high in signal on T2- weighted images and often have a multinodular or pseudocystic appearance. There is a spectrum of pathology in dysembryoplastic neuroepithelial tumors. On one end of the spectrum are multinodular lesions with intervening malformed cortex, in which there is some hesitation to use the designation tumor. On the other end are lesions, which are clearly neoplastic and have clinically demonstrated some growth potential. Because the term dysembryoplastic neuroepithelial tumor has only recently been introduced, such malformative and neoplastic lesions were previously labeled as hamartomas, gangliogliomas, or mixed gliomas. [100,101,102]

Gangliogliomas

Gangliogliomas are typically demonstrated within the temporal lobe. In one large series of 51 gangliogliomas, 84% were found in the temporal lobe, 10% were found in the frontal lobe, 2% were found in the occipital lobe, and 4% were found in the posterior fossa. These lesions are typically hypodense (60% to 70%) on CT, with focal calcifications seen in 35% to 40%, contrast enhancement in 45% to 50%, and cysts in nearly 60%. The reported incidence of calcifications demonstrated on imaging in pediatric gangliogliomas is higher, seen in 61% of one series of 42 children. Features on MR imaging are less specific, with solid components isointense on TI-weighted images, bright on proton density images, and slightly less bright on T2-weighted images. Although imaging features are not specific, an enhancing, cystic temporal lobe lesion with focal calcification should suggest the diagnosis of ganglioglioma. The pathologic features that suggest the diagnosis of ganglioglioma include a neoplastic glial and neoronal component and calcification. Because calcifications are often poorly demonstrated on MR imaging and because they increase specificity of imaging findings, documentation of calcium should be sought on CT after MR imaging demonstration of a temporal lobe tumor. [97,98,99]

DISORDERS OF NEURONAL DIFFERENTIATION

Normal differentiation

At the time of neuronal differentiation the neural tube consists of four consecutive layers: (1) the ventricular zone, the innermost layer, which gives rise to neurons and all of the glia of the central nervous system; (2) the subventricular zone, which is the adjacent, more superficial layer and is the staging area from which postmitotic neurons begin to differentiate and to migrate; (3) the intermediate zone, which is the contiguous, more superficial zone, and which is destined to become the cortical plate and the future cerebral cortex; and (4) the marginal zone, which is the outermost zone and is composed of the cytoplasmic extensions of ventricular neuroblasts, corticopetal fibers, and the terminal processes of radial glia (which, at this time, are completely spanning the neural tube).

Differentiation of neuroepithelial cells begins in the subventricular layer at approximately gestational day 26. The older, larger pyramidal cells are the first cells to be born and probably differentiate early to act as targets in the migration of the nervous system.

Tuberous sclerosis

Disorders such as tuberous sclerosis, in which both tumor development and areas of cortical dysplasia are seen, might be a differentiation disorder. The brain manifestations of this disorder include hamartomas of the subependymal layer, areas of cortical migration abnormalities (tubers, cortical dysgenesis), and the development of giant-cell astrocytomas in upwards of 5% of affected patients. Two genes for tuberous sclerosis have been identified: TSCI (encodes for Hamartin) has been localized to 9q34 [65], and TSC2 (encodes for Tuberin) has been localized to 16pl3.3 [65].

23


Figure 8. Postmortem specimens showing cortical tubers in (A) and subependymal tubers in (B)

DISORDERS OF MIGRATION

Normal migration

At the most rostral end of the neural tube in the 40- to 41 -day-old fetus, the first mature neurons, Cajal-Retzius cells, begin the complex trip to the cortical surface. Cajal-Retzius cells, subplate neurons, and corticopetal nerve fibers form a preplate [66]. The,neurons generated in the proliferative phase of neurodevelopment represent billions of cells poised to begin the trip to the cortical surface and to form the cortical plate. These neurons accomplish this task by attaching to and migrating along radial glial in a process known as radial migration or by somal translocation in a neuronal process [67]. The radial glia extend from the ventricle to the cortical surface. In the process of migration, the deepest layer of the cortical plate migrates and deposits before the other layers. Therefore, the first neurons to arrive at the future cortex are layer VI neurons. More superficial layers of cortex then are formed-the neurons of layer V migrate and pass the neurons of layer VI; the same process occurs for layers IV, 111, and 11. The cortex therefore is formed in an inside-out fashion [67-69].

A possible mode of movement in neuronal migration on glia would be the attachment of the neuroblast to a matrix secreted by either the glia or the neurons. The attachment of the neuron would be through integrin receptors, cytoskeletal-linking membrane-bound recognition sites for adhesion molecules. That attachment serves as a stronghold for the leading process and soma of the migrating neuron. Neuron movement on radial glia involves an extension of a leading process, neural outgrowth having an orderly arrangement of microtubules. Shortening of the leading process owing to depolymerization or shifts of microtubules may result in movement of the soma relative to the attachment points. This theory of movement of neurons also must include a phase of detachment from the matrix at certain sites, so that the neuron can navigate successfully along as much as 6 cm of developing cortex (the maximum estimated distance of radial migration of a neuron in the human). Finally, the movement of cells must stop at the appropriate location, the boundary between layer I and the forming cortical plate. Therefore, some stop signal must be given for the migrating neuron to detach from the radial glia and begin to differentiate into a cortical neuron. Perhaps that signal is REELIN, a protein that is disrupted in the mouse mutant Reeler and is expressed

Figure 9. Postmortem specimen showing cortical tubers, the affected gyri are abnormally broad and flat.

24


solely in the Caial Retizius cells at this phase of development [66,70-73].

Migration disorders

Advanced neuroimaging techniques, particularly magnetic resonance imaging, have allowed the recognition of major migration disorders and of the frequency of more subtle disorders of migration. Some of these disorders are associated with typical clinical features that might alert the clinician to the presence of such malformations even before imaging is obtained. In other disorders, the clinical features are so varied that a strong correlation between imaging and the clinical presentation points to a specific genetic syndrome.

Lissencephaly

Lissencephaly (smooth brain) refers to the external appearance of the cerebral cortex in those disorders in which a neuronal migration aberration leads to a relatively smooth cortical surface. One should not consider only agyria in making this diagnosis, rather, the full spectrum includes agyria and pachygyria. Gyri and sulci do not form in this disorder because the lack of cortical-cortical attractive forces owing to improper axon pathways. At least two types have been identified: classic lissencephaly, and cobblestone lissencephaly. The distinction is based upon the external appearance and upon the underlying histology, and can be made with neuroimaging.

Figure 10. Pachygyric (A), and agyric (B) lissencephalic brain

Classic lissencephaly

Classic lissencephaly may occur in isolation, owing to LIS1 or Doublecortin aberrations or in combination with somatic features and LIS1 deletions in the Miller-Dieker syndrome. The hallmarks on imaging are a lack of opercularization (covering of the sylvian fissure), large ventricles or colpocephaly (dilated posterior horns), and agyria or pachygyria. The corpus callosum is almost always present, and the posterior fossa is usually normal, although a form of lissencephaly does exist that includes cerebellar hypoplasia.

The LIS1 protein forms complexes with other cellular proteins that are crucial for cell division, migration, and intracellular transport. Complete loss of LIS1 is fatal. Deletion of one copy of the gene is causes lissencephaly. The LIS1 gene is found in 17q13.3 location.

Doublecortin (DCX), a gene on Xq22.3-q23 that codes for a microtubule associated protein, is responsible for migration of neurons. Mutation of this gene results in band heterotopia

25


Figure 11. Classical lissencephaly with patchy agyria/agyria, thick Cortex and band heterotopia

LIS1 genetic syndromes

The Miller-Dieker phenotype consists of distinct facial features that include bitemporal hallowing, upturned nares, and a peculiar burying of the upper lip by the lower lip at the corners of the mouth. The lissencephaly is usually more severe than isolated lissencephaly, and the prognosis is worse. Most affected patients die in the first few years of life.

By both molecular and cytogenetic techniques, deletions in the terminal portion of one arm of chromosome 17 can be found in approximately 90% of Miller-Dicker lissencephaly cases [74]. The deletions of the terminal part of chromosome 17 in these cases have included microdeletions [74], ring 17 chromosome [75], pericentric inversions [76], and a partial monosomy of 17pl3.3 [77]. The most appropriate genetic test is a fluorescent in situ hybridization (FISH) for LIS1; this test involves marking chromosome 17 at the centromere and LIS1 with fluorescent probes.

The greatest risk to future offspring exists when a parent harbors a balanced translocation involving this region of chromosome 17. In families that are affected in this manner, screening by amniocentesis can be performed in subsequent pregnancies. Therefore, it is recommended that both parents have screening for chromosome 17 rearrangements by FISH for LIS1. Should a translocation be present in a parent, then the LIS1 fluorescence will be on another chromosome.

26


Figure 12. A, Type I lissencephaly, agyria type. Axial T2-weighted image shows a brain with a "figure-8" configuration secondary to the immature Sylvian fissures. A band of neurons (arrows) that was arrested during migration lies between the thin cortex and the lateral ventricles. B, Type 1 lissencephaly, pachygyria type. Axial T2-weighted image is similar to that shown in (A), with the exception that a few broad gyri with shallow sulci are present. C, Type 1 lissencephaly, pachygyria type. Axial T2-weighted image shows broad, flat gyri with shallow sulci throughout the cerebrum.

Isolated lissencephaly

Classic lissencephaly without somatic or facial features represents a distinct genetic syndrome from Miller-Dieker, but it involves the same gene LIS1. Approximately 40% of patients with isolated lissencephaly have FISH detectable deletions of LIS1, and about 20% of additional patients harbor mutations of this gene [78-80]. The remaining patients may have mutations involving promoter regions of LIS1 or abnormalities of other genes such as Doublecortin or the involvement of other genes that have not been recognized.

The genetic risk of recurrence is highest when rearrangements of chromosome 17 exist in one parent. This is rare in isolated lissencephaly, but could occur. Therefore, it would be prudent to perform FISH for LIS1 in the parents of children with isolated lissencephaly who have FISH proven deletions for the LIS1 region.

The prognosis for this disorder is better than that for Miller-Dieker syndrome, but it is not consistent with long-term survival. These patients typically present in the first few months of life with hypotonia, lack of visual fixation, and often seizures. Patients with lissencephaly will uniformly have seizures and profound mental retardation. Often, seizures are very difficult to control and require multiple anticonvulsant drugs.

X-linked lissencephaly

The imaging of X-linked lissencephaly looks nearly identical to the images of lissencephaly involving LIS1. Patients have classic lissencephaly, and the neurologic presentation described above. However, the skeletal and other anomalies seen in the Miller-Dieker are not noted in this form of lissencephaly. When viewing the images from patients with lissencephaly owing to abnormalities of LIS1 and of Doublecortin it is apparent that differences in an anterior to posterior gradient of severity exists [81-83]. Doublecortin mutations result in anterior greater than posterior severity, whereas LIS1 mutations result in posterior greater than anterior severity [84].

In addition, X-linked lissencephaly occurs mostly in boys; girls who are heterozygous for Doublecortin mutations have band heterotopia [80,81,85]. Women with band heterotopia have been known to give birth to boys with lissencephaly. In female patients, the less severe phenotype probably is attributed to random lyonization of the X chromosome, such that in a variable number of cells, normal gene expression is seen and, in the remaining cells, the Doublecortin mutation-containing X chromosome is expressed. It is presumed that those cells expressing the abnormal X chromosome will be arrested in the migration to the surface of the brain and reside in a subcortical band.

27


Figure 13. Gross specimen showing lissencephaly with pachygyria and agyria

Figure 14. Lissencephaly with abnormally smooth agyric, pachygyric cortex

Figure 15. Lissencephaly with abnormally smooth agyric cortex

28


When viewing images from patients with this disorder, a thick band of tissue that is isointense with cerebral gray matter is seen within what should be the white matter of the hemispheres. The overlying gyral appearance may vary from normal cortex to a pachygyria. A brain biopsy performed in a patient demonstrated well-preserved lamination in cortical layers I-IV [86]. Layers V-VI were not clearly separated and merged with underlying white matter. Beneath the white matter was a coalescent cluster of large, well-differentiated neurons.

Lissencephaly with cerebellar hypoplasia

The association of lissencephaly with cerebellar hypoplasia represents a distinct malformation from both a genetic and clinical standpoint to those described above. The cerebellar hypoplasia is usually extreme, and the brainstem may be small. Patients may or may not have an associated microcephaly. This disorder is often inherited in an autosomal recessive fashion and may be due to mutations in REELIN in some families [87].

Figure 16. A, Band heterotopia with pachygyria. B, band heterotopia with mild periventricular nodular heterotopia

Figure 17. Lissencephalic brain with hydrocephalus and cerebellar hypoplasia

29


Cobblestone lissencephaly

Cobblestone lissencephalies are disorders in which a smooth configuration of cortex is noted, but the distinction from classic lissencephaly is made based upon the clinical association of eye abnormalities, muscle disease, and progressive hydrocephalus. The term "cobblestone" refers to the appearance of the cortical surface upon pathologic examination. In these disorders, cells pass their stopping point and erupt over the surface of the cortex into the subarachnoid spaces. This results in a cobblestone street appearance to the surface, and therefore, the name.

Figure 19. A, Type II lissencephaly, Cobblestone lissencephaly (Walker-Warburg syndrome). The cortex is lissencephalic and thickened, with an irregular gray matter-white matter junction that probably represents the bundles of disorganized cortex surrounded by fibroglial tissue. The patient has been shunted for hydrocephalus. The brain is hypomyelinated. B, Presumed microcephalia vera. The brain is completely smooth (lissencephaly) with a very thin cortex. No layer of arrested neurons is present in the white matter. C, Presumed radial microbrain. Axial T2- weighted image shows an immature gyral pattern and hypomyelination. Cortical thickness is normal. This patient was profoundly microcephalic (head circumference 19 cm).

Figure 18. MRI showing a mild form of lissencephaly (pachygyria), the brain have a few broad, flat gyri with thick cortex and separated by shallow sulci (pachygyria). The cerebellum and the brain stem are hypoplastic, the brain volume is also reduced especially the temporal lobes.

30


The Walker-Warburg, muscle-eye-brain, and HARD +/- syndromes are likely all varying degrees of the same entity. Abnormalities that may or may not be seen in these disorders include muscular dystrophy, ocular anterior chamber abnormalities, retinal dysplasias (evidenced by abnormal electroretinogram and visual evoked responses), hydrocephalus (usually of an obstructive type), and encephaloceles. The Walker-Warburg syndrome might be diagnosed even if the ocular examination and muscle biopsies are normal if on MRI, an abnormal white matter signal and a thickened falx suggest the diagnosis. Neuroimaging of the muscle-eye-brain disorders often reveals focal white matter abnormalities.

Fukuyama muscular dystrophy is distinguished from the Walker Warburg-like syndromes by the severity of the muscular dystrophy [88-91]. This disorder is seen more often in Japan than in the Western hemisphere, probably because it is the result of a founder mutation. Patients typically present with evidence of a neuronal migration defect, hypotonia, and depressed reflexes. Recent identification of Fukutin as the causative gene in this disorder should provide insight into the pathogenesis of the cobblestone lissencephalies [92]. This disorder is inherited as an autosomal recessive disorder.

The cobblestone lissencephalies often have an associated cerebellar and brainstem hypoplasia, and therefore may be difficult to distinguish from lissencephaly with cerebellar hypoplasia described above. The presence of eye abnormalities, elevated CPK, or other evidence for the presence of muscle disease and progressive hydrocephalus distinguish this disorder. These disorders may be inherited in an autosomal recessive manner.

Table 1. The lissencephalies syndromes

Figure 20. Cobblestone lissencephaly

TYPE DESCRIPTION GENE LIS1 genetic syndromes

The Miller-Dieker phenotype consists of distinct facial features that include bitemporal hallowing, upturned nares, and a peculiar burying of the upper lip by the lower lip at the corners of the mouth. The lissencephaly is usually more severe than isolated lissencephaly, and the prognosis is worse. Most affected patients die in the first

By both molecular and cytogenetic techniques, deletions in the terminal portion of one arm of chromosome 17 can be found in approximately 90% of Miller-Dicker lissencephaly cases [74]. The deletions of the terminal part of chromosome 17 in these cases have included microdeletions [74], ring 17 chromosome [75], pericentric inversions [76], and a partial

31


Polymicrogyria

Polymicrogyria (many small gyri) is a disorder often considered to be a neuronal migration disorder, but alternate theories exist regarding its pathogenesis, The microscopic appearance of the lesion is that of too many small abnormal gyri. The gyri may be shallow and separated by shallow sulci, which may be associated with an apparent increased cortical thickness on neuroimaging. The multiple small convolutions may not have intervening sulci, or the sulci may be bridged by fusion of overlying molecular layer, which may give a smooth appearance to the brain's surface. The interface of white matter with gray matter is not distinct and often this observation serves as the

few years of life. monosomy of 17pl3.3 [77]. The most appropriate genetic test is a fluorescent in situ hybridization (FISH) for LIS1; this test involves marking chromosome 17 at the centromere and LIS1 with fluorescent probes.

Isolated lissencephaly

Classic lissencephaly without somatic or facial features represents a distinct genetic syndrome from Miller-Dieker,

It involves the same gene LIS1. Approximately 40% of patients with isolated lissencephaly have FISH detectable deletions of LIS1, and about 20% of additional patients harbor mutations of this gene [78-80]. The remaining patients may have mutations involving promoter regions of LIS1 or abnormalities of other genes such as Doublecortin or the involvement of other genes that have not been recognized.

X-linked lissencephaly-subcortical band heterotopia (XLIS-SBH)

The imaging of X-linked lissencephaly looks nearly identical to the images of lissencephaly involving LIS1. Patients have classic lissencephaly, and the neurologic presentation described above. However, the skeletal and other anomalies seen in the Miller-Dieker are not noted in this form of lissencephaly.

In addition, X-linked lissencephaly occurs mostly in boys; girls who are heterozygous for Doublecortin mutations have band heterotopia [80,81,85]

LIS1 gene mutation results in lissencephaly

Doublecortin gene mutation results in band heterotopia (Doublecortin (DCX), a gene on Xq22.3-q23 that codes for a microtubule associated protein, is responsible for migration neurons. Mutation of this gene results in band heterotopia)


The association of lissencephaly with cerebellar hypoplasia represents a distinct malformation from both a genetic and clinical standpoint to those described above. The cerebellar hypoplasia is usually extreme, and the brainstem may be small. Patients may or may not have an associated microcephaly.

This disorder is often inherited in an autosomal recessive fashion and may be due to mutations in REELIN in some families [87].

Cobblestone lissencephalies

are disorders in which a smooth configuration of cortex is noted, but the distinction from classic lissencephaly is made based upon the clinical association of eye abnormalities, muscle disease, and progressive hydrocephalus. The term "cobblestone" refers to the appearance of the cortical surface upon pathologic examination. In these disorders, cells pass their stopping point and erupt over the surface of the cortex into the subarachnoid spaces. This results in a cobblestone street appearance to the surface, and therefore, the name.

?

32


confirmation of the presence of polymicrogyria.

Figure 21. Polymicrogyria

Figure 22. A, Polymicrogyria. B, pachygyria with polymicrogyria, notice the subependymal nodular heterotopia

Polymicrogyria has also been associated with genetic and chromosomal disorders. It is found in disorders of peroxisomal metabolism such as Zellweger syndrome and neonatal adrenal leukodystrophy . Familial bilateral frontal polymicrogyria and bilateral perisylvian polymicrogyria have been reported. Therefore, if no identifiable cause of the polymicrogyric malformation is found, the recurrence risk may be that of an autosomal recessive disorder. A bilateral parasagittal parieto-occipital polymicrogyria has also been described.

The clinical picture varies depending on the location, extent, and cause of the abnormality. Microcephaly with severe developmental delay and hypertonia may result when polymicrogyria is diffuse. When polymicrogyria is unilateral, focal deficits might be seen. Epilepsy often is present, characterized by partial complex seizures or partial seizures that secondarily generalize. The age at presentation and severity of seizures depends on the extent of the associated pathology.

33


Figure 23. A, pachygyria with polymicrogyria. B, pachygyria with polymicrogyria, notice the subependymal nodular heterotopia

Bilateral perisylvian dysplasia is a disorder of perisylvian polymicrogyria resulting in an uncovered sylvian fissure on neuroimaging and on sagittal imaging an extension of the sylvian fissure to the top of the convexity. Patients with bilateral perisylvian dysplasia have a pseudobulbar palsy, and often dysphagia can impair proper nutrition. The majority of patients have epilepsy with early onset; infantile spasms are common.

Figure 24. Polymicrogyria with pachygyria

34


Figure 25. Polymicrogyri. In B the patient also had meningomyelocele, obstructive hydrocephalic and Arnold -Chiari type II malformation

The cause of this syndrome remains unknown, although hints of a genetic mechanism exist. Detailed chromosomal analyses have revealed deletions of chromosomes 1, 2, 6, 21, and 22 [93], and an X-linked form has been also described [94,95]. Monozygotic twins and siblings with this disorder have been described, suggesting a possible autosomal recessive mechanism. Some speculate that this is a disorder of regional specification, given the bilateral, symmetric nature of the lesions.

Heterotopias

Heterotopias are collections of normal-appearing neurons in an abnormal location, presumably secondary to a disturbance in migration. The exact mechanism of the migration aberration has not been established, although various hypotheses have been proposed. These include damage to the radial glial fibers, premature transformation of radial glial cells into astrocytes, or a deficiency of specific molecules on the surface of neuroblasts or of the radial glial cells (or the receptors for those molecules) that results in disruption of the normal migration process [96]. Heterotopias often occur as isolated defects that may result in only epilepsy. However, when they are multiple, heterotopias might also be associated with a developmental disorder and cerebral palsy (usually spastic). In addition, if other migration defects such as gyral abnormalities are present, the clinical syndrome may be more profound. Usually, no cause is apparent. Occasionally, heterotopias may be found in a variety of syndromes, including neonatal adrenal leukodystrophy, glutaric aciduria type 2, GMI gangliosidosis, neurocutaneous syndromes, multiple congenital anomaly syndromes, chromosomal abnormalities, and fetal toxic exposures.

35


Figure 26. Subependymal nodular heterotopia

Heterotopias may be classified by their location: subpial, within the cerebral white matter, and in the subependymal region. When subependymal, one must consider the X-linked dominant disorder associated with Filamin mutations (Xq28). Leptomeningeal heterotopias often contain astrocytes mixed with ectopic neurons and may resemble a gliotic scar. They may be related to discontinuities in the external limiting membrane and often are associated with cobblestone lissencephaly. These subarachnoid heterotopias are responsible for the pebbled appearance of the surface of the brain. White matter heterotopias may be focal, subcortical, or diffuse. They may cause distortion of the ventricles and may be associated with diminished white matter in the surrounding area.

Figure 27. CT scan showing Subependymal nodular heterotopia with cerebellar hypoplasia

36


Figure 28. MRI showing Subependymal nodular heterotopia

SUMMARY

The progress made in the understanding of the genetics of human brain malformations has lead to insight into the formation of brain and into mechanisms of disease affecting brain. It bears upon neurologists and geneticists to recognize the patterns of diseases of brain formation, to properly diagnose such disorders, to assess the recurrence risk of these malformations, and to guide families with appropriate expectations for outcomes. This article may serve as a guide to neurologists in their approach to these disorders. Because this area is one of rapid progress, the clinician is advised to seek more current information that may be available through on-line databases and other sources.

Table 2. Definition of developmental disorders.

SUMMARY

Type Comment Schizencephaly

(Disorder of segmentation)


Megalencephaly

(Non-neoplastic disorder of neuronal proliferation)

The terms megalencephaly and hemimegalencephaly refer to disorders in which the brain volume is greater than normal (not owing to the abnormal storage of material); usually, the enlarged brain is accompanied by macrocephaly, or a large head.

Microcephaly


The term microcephaly refers to disorders in which the brain volume is smaller than normal

Dysembryoplastic neuroepithelial tumor and ganglioglioma


37


Addendum




http://pdf.yassermetwally.com/short.pdf At the end of each year, all the publications are compiled on a single CD-ROM, please contact the author to

know more details. Screen resolution is better set at 1024*768 pixel screen area for optimum display. For an archive of the previously reported cases go to www.yassermetwally.net, then under pages in the right

panel, scroll down and click on the text entry "downloadable case records in PDF format" Also to view a list of the previously published case records follow the following link

(http://wordpress.com/tag/case-record/) or click on it if it appears as a link in your PDF reader

References

[1] Brockes J. Reading the retinoid signals. Nature 1990;145(6278):766-8.

Lissencephaly

(Disorder of neuronal migration)

Lissencephaly (smooth brain) refers to the external appearance of the cerebral cortex in those disorders in which a neuronal migration aberration leads to a relatively smooth cortical surface. One should not consider only agyria in making this diagnosis, rather, the full spectrum includes agyria and pachygyria.

Agyria


Extreme end of lissencephaly (sever lissencephaly) spectrum in which gyri are completely absent and the brain surface is completely smooth.

Pachygyria


The other end of lissencephaly spectrum (mild lissencephaly), the brain have a few broad, flat gyri separated by shallow sulci (pachygyria). The cortex is thick in pachygyria.

Polymicrogyria

(disorder of neuronal migration)

Polymicrogyria (many small gyri) is a disorder often considered to be a neuronal migration disorder, but alternate theories exist regarding its pathogenesis, The microscopic appearance of the lesion is that of too many small abnormal gyri. The gyri may be shallow and separated by shallow sulci, which may be associated with an apparent increased cortical thickness on neuroimaging. The multiple small convolutions may not have intervening sulci, or the sulci may be bridged by fusion of overlying molecular layer, which may give a smooth appearance to the brain's surface.

Heterotopias


Heterotopias are collections of normal-appearing neurons in an abnormal location, presumably secondary to a disturbance in migration. Heterotopias may be classified by their location: subpial, within the cerebral white matter, and in the subependymal region.

Tuberous sclerosis

(Differentiation disorder)

Disorders such as tuberous sclerosis, in which both tumor development and areas of cortical dysplasia are seen, might be a differentiation disorder. The brain manifestations of this disorder include hamartomas of the subependymal layer, areas of cortical migration abnormalities (tubers, cortical dysgenesis), and the development of giant-cell astrocytomas in upwards of 5% of affected patients.

REFERENCES

38


[2] Lemire R, Loeser J, Leech R, et al. Normal and abnormal development of the human nervous system. New York: Harper & Row; 1975.

[3] Scotting PJ, Rex M. Transcription factors in early development of the central nervous system. Neuropathol Appl Neurobiol 1996;22:469 81.

[4] Thaller C, Eichele G. Isolation of 3,4-didehrdroretinic acid, a novel morphogenetic signal in the chick wing bud. Nature 1990;345(6278):815-22.

[5] Geelan JA, Langman J. Closure of the neural tube in the cephalic region of the mouse embryo. Anat Rec 1977;189:625-40.

[6] Brunelli S, Faiella A, Capra V, et al. Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly. Nat Genet 1996;12:94-6.

[7] Hillburger AC, Willis JK, Bouldin E, et al. Familial schizencephaly. Brain Dev 1993;15: 234-6.

[8] Barkovich AJ, Kjos BO. Schizencephaly: correlation of clinical findings with MR characteristics. Am J Neuroradiol 1992;13:85-94.

[9] Barth P. Disorders of neuronal migration. Can J Neurol Sci 1987;14:1-16.

[10] Barkovich A, Chuang S, Norman D. MR of neuronal migration anomalies. Am J Neuroradiol 1987;8:1009-17.

[11] Barkovich A, Kjos B. Schizencephaly: correlation of clinical findings with MR characteristics. Am J Neuroradiol 1992;13:85-94.

[12] Brodtkorb E, Nilsen G, Smevik 0, et al. Epilepsy and anomalies of neuronal migration: MRI and clinical aspects. Acta Neurol Scand 1992;86:24-32.

[13] Kuzniecky R. Magnetic resonance imaging in developmental disorders of the cerebral cortex. Epilepsia 1994;35(Suppl 6):S44-56.

[14] Aicardi J, Goutieres F. The syndrome of absence of the septum pellucidum with porencephalies and other developmental defects. Neuropediatrics 1981;12:319-29.

[15] Leech R, Shuman R. Midline telencephalic dysgenesis: report of three cases. J Child Neurol 1986;1:224-32.

[16] Smith J. Hedgehog, the floor plate, and the zone of polarizing activity. Cell 1994;76:193-6.

[17] Helms JA, Kim CH, Hu D, et al. Sonic hedgehog participates in craniofacial morphogenesis and is down-regulated by teratogenic doses of retinoic acid. Dev Biol 1997;187:25-35.

[18] Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 1996;272:1668-71.

[19] Stone DM, Hynes M, Armanini M, et al. The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 1996;384:129-34.

[20] Conlon RA. Retinoic acid and pattern formation in vertebrates. Trends Genet 1995; 1 1:314-9.

[21] Nakagawa Y, Kaneko T, Ogura T, et al. Roles of cell-autonomous mechanisms for differential expression of region-specific transcription factors in neuroepithelial cells. Development 1996; 122:2449-(A.

[22] Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med 1985; 313:837-41.

[23] Barkovich AJ. Imaging aspects of static encephalopathies. In Miller G, Ramer JC, editors Static encephalopathies of infancy and childhood. New York: Raven Press; 1992. p. 45-94

[24] Dobyns WB. Cerebral dysgenesis: causes and consequences. In Miller G, Ramer JC, editors. Static

39


encephalopathies of infancy and childhood. New York: Raven Press; 1992. p. 235-48.

[25] Nyberg DA, Mack LA, Bronstein A, et al. Holoprosencephaly: prenatal monographic diagnosis. Am J Radiol 1987;149:1051-8.

[26] Souza JP, Siebert JR, Beckwith JB. An anatomic comparison of cebocephaly and ethmocephaly. Teratology 1990;42:347-57.

[27] Romshe CA, Sotos JF. Hypothalamic-pituitary dysfunction in siblings of patients with holoprosencephaly. J Pediatr 1973;83:1088-90.

[28] Barr M, Hansen JW, Currey K, et al. Holoprosencephaly in infants of diabetic mothers J Pediatr 1983;102:565-8.

[29] Cohen MMJ, Lemire RJ. Syndromes with cephaloceles. Teratology 1983;25:161-72.

[30] Muenke M. Clinical, cytogenetic, and molecular approaches to the genetic heterogeneity of holoprosencephaly. Am J Med Genet 1989;34:237-45.

[31] Heussler HS, Suri M, Young ID, et al. Extreme variability of expression of a Sonic Hedgehog mutation: attention difficulties and holoprosencephaly. Arch Dis Child 2002;86:293-6.

[32] Roessler E, Belloni E, Gaudenz K, et al. Mutations in the human Sonic hedgehog gene cause holoprosencephaly. Nat Genet 1996;14:357-60.

[33] Ming JE, Kaupas ME, Roessler E, et al. Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly. Hum Genet 2002;110: 297-301.

[34] Wallis D, Muenke M. Mutations in holoprosencephaly. Hum Mutat 2000;16:99 108.

[35] Brickman JM, Clements M, Tyrell R, et al. Molecular effects of novel mutations in Hesxl/HESXI associated with human pituitary disorders. Development 2001;128:5189-99.

[36] Ouvier R, Billson F. Optic nerve hypoplasia: a review. J Child Neurol 1986;1:181-8.

[37] Costin G, Murphree AL. Hypothalamic-pituitary function in children with optic nerve hypoplasia. Am J Dis Child 1985;139:249-54.

[38] Dattani MT, Martinez-Barbera JP, Thomas PQ, et al. Mutations in the homeobox gene HESXI/Hesxl associated with septo-optic dysplasia in human and mouse. Nat Genet 1998; 19:125-33.

[39] Patel H, Tze WJ, Crichton JU, et al. Optic nerve hypoplasia with hypopituitarism: septo- optic dysplasia with hypopituitarism. Am J Dis Child 1975;129:175-80.

[40] Caviness VS, Takahashi T. Proliferative events in the cerebral ventricular zone. Brain Dev 1995;17:159-63.

[41] Ross ME. Cell division and the nervous system: regulating the cycle from neural differentiation to death. Trends Neurosci 1996;19:62 8.

[42] Matsushime H, Quelle DE, Shurtleff SA, et al. D-type cyclin-dependent kinase activity in mammalian cells. Mol Cell Biol 1994;14:2066-76.

[43] Meyerson M, Harlow M. Identification of GI kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol 1994;14:2077-86.

[44] Pardee AB. GI events and regulation of cell proliferation. Science 1989;246:603-8.

[45] Sherr CJ. GI phase progression: cycling on cue. Cell 1994;79:551 5.

[46] Clarke PG. Developmental cell death: morphological diversity and multiple mechanisms. Anat Embryol (Berl)

40


1990;181:195-213.

[47] Schwartz LM, Smith SW, Jones MEE, et al. Do all programmed cell deaths occur via apoptosis? Proc Natl Acad Sci USA 1993;90:980-4.

[48] Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972;26:239-57.

[49] Warkany J, Lemire RJ, Cohen MM. Mental retardation and congenital malformations of the central nervous system. Chicago: Year Book Medical; 1981. p. 13-40.

[50] Haslam R, Smith DW. Autosomal dominant microcephaly. J Pediatr 1979;95:701-5.

[51] Optiz JM, Holt MC. Microcephaly: general considerations and aids to nosology. Craniofac Genet Dev Biol 1990;10:175-204.

[52] Renier WO, Gabreels FJM, Jasper TWJ, et al. An x-linked syndrome with microcephaly, severe mental retardation, spasticity, epilepsy and deafness. J Ment Defic Res 1982;26: 27-40.

[53] Evrard P, De Saint-Georges P, Kadhim H, et al. Pathology of prenatal encephalopathies. In French JH, Harel S, Casaer P, editors. Child neurology and development disabilities. Baltimore: PH Books; 1989. p. 153-76.

[54] Lenke RR, Levy HL. Matemal phenylketonuria and hyperphenylaianinemia. N Engl J Med 1980;303:1202-8.

[55] Yamazaki JN, Schull WJ. Perinatal loss and neurological abnormalities among children of the atomic bomb. Nagasaki and Hiroshima revisited, 1949 to 1989. JAMA 1990;264: 605-9.

[56] Barkovich AJ, Chuang SH. Unilateral megalencephaly: correlation of MR imaging and pathologic characteristics. Am J Neuroradiol 1990; 1 1:523-3 1.

[57] DeRosa MJ, Secor DL, Barsom M, et al. Neuropathologic findings in surgically treated hemimegalencephaly: immunohistochemical, morphometric and ultrastructural study. Acta Neuropathol (Berl) 1992;84:250-60.

[58] Renowden S, Squier M. Unusual magnetic resonance and neuropathological findings in hemi-megalencephaly: report of a case following hemispherectomy. Dev Med Child Neurol 1994;36:357-69.

[59] Rintahaka P, Chugani H, Messa C, et al. Hemimegalencephaly: evaluation with positron emission tomography. Pediatr Neurol 1993;9:21-8.

[60] DeMyer W. Megalencephaly in children. Clinical syndromes, genetic patterns and differential diagnosis from other cases of megalencephaly. Neurology 1972;22:634-A3.

[61] DeMyer W. Megalencephaly: types, clinical syndromes and management. Pediatr Neurol 1986;2:321-8.

[62] Hager BC, Dyme IZ, Guertin SR, et al. Linear nevus sebaccous syndrome: megalencephaly and heterotopic gray matter. Pediatr Neurol 1991;7:45-9.

[63] Pavone L, Curatolo P, Rizzo R, et al. Epidermal nevus syndrome: a neurologic variant with hemimegalencephaly, gyral malformation, mental retardation, seizures, and facial hemihypertrophy. Neurology 1991;41:266-71.

[64] Jelinek JE, Bart RS, Schiff GM. Hypomelanosis of Ito ("incontinentia pigmenti achromians"): report of three cases and review of the literature. Arch Dermatol 1973;107: 596-601.

[65] Haines JL, Short MP, Kwiatkowski DJ, et al. Localization of one gene for tuberous sclerosis within 9q32-9q34, and further evidence for heterogeneity. Am J Hum Genet 1991; 49:764--72.

[66] Ogawa M, Miyata T, Nakajima K, et al. The reeler gene-associated antigen on Cajal- Retzius neurons is a crucial molecule for laminar organization of cortical neurons. Neurons 1995;14:899-912.

41


[67] Sidman R, Rakic P. Neuronal migration with special reference to developing human brain, a review. Brain Res 1973;62:1-35.

[68] Aicardi J. The place of neuronal migration abnormalities in child neurology. Can J Neurol Sci 1994;21:185-93.

[69] Angevine J, Sidman R. Autoradiographic study of cell migration during histogenesis of cerebral cortex of the mouse. Nature 1961;192:766-8.

[70] D'Arcangelo G, Miao GG, Chen S-C, et al. A protein related to extracellular matrix proteins deleted in the mouse reeler. Nature 1995;374:719 23.

[71] D'Arcangelo G, Miao GG, Curran T. Detection of the reelin breakpoint in reeler mice. Brain Res Mol Brain Res 1996;39:234-6.

[72] Hirotsune S, Takahara T, Sasaki N, et al. The reeler gene encodes a protein with an EGF- like motif expressed by pioneer neurons. Nat Genet 1995;10:77-83.

[73] Rommsdorff M, Gotthardt M, Hiesberger T, et al. Reeler/disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell 1999;97:689-701.

[74] Ledbetter SA, Kuwano A, Dobyns WB, et al. Microdeletions of chromosome 17pl3 as a cause of isolated lissencephaly. Am J Hum Genet 1992;50:182-9.

[75] Sharief N, Craze J, Summers D, et al. Miller-Dieker syndrome with ring chromosome 17. Arch Dis Child 1991;66:710-2.

[76] Greenberg F, Stratton R, Lockhart L, et al. Familial Miller-Dieker syndrome associated with pericentric inversion of chromosome 17. Am J Med Genet 1986;23:853-9.

[77] Dobyns WB, Stratton RF, Parke JT, et al. Miller-Dieker syndrome: lissencephaly and monosomy 17p. J Pediatr 1983;102:552-8.

[78] Chong SS, Pack SD, Roschke AV, et al. A revision of the lissencephaly and Miller-Dieker syndrome critical regions in chromosome 17pl3.3. Hum Mol Genet 1997;6:147 55.

[79] Lo Nigro C, Chong SS, Smith ACM, et al. Pbint mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. Hum Mol Genet 1997;6:157-64.

[80] Pilz DT, Matsumoto N, Minnerath S, et al. LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation. Hum Mol Genet 1998;7: 2029-37.

[81] Gleeson JG, Luo RF, Grant PE, et al. Genetic and neuroradiological heterogeneity of double cortex syndrome. Ann Neurol 2000;47:265-9.

[82] Leventer RJ, Pilz DT, Matsumoto N, et al. Lissencephaly and subcortical band heterotopia: molecular basis and diagnosis. Mol Med Today 2000;6:277-84.

[83] Matsumoto N, Leventer RJ, Kuc J, et al. Mutation analysis of the DCX gene and genotype/phenotype correlation in subcortical band heterotopia. Eur J Hum Genet 2000;9(t):5-12.

[84] Dobyns WB, Truwit CL, Ross ME, et al. Differences in the gyral pattern distinguish chromosome 17-linked and X-linked lissencephaly. Neurology 1999;53:270-7.

[85] Gleeson JG, Allen KM, Fox JW, et al. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 1998;92:63-72.

[86] Palmini A, Andermann F, Aicardi J, et al. Diffuse cortical dysplasia, or the "double cortex syndrome": the clinical and epileptic spectrum in 10 patients. Neurology 1991;41: 1656-62.

[87] Hong SE, Shugart YY, Huang DT, et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is

42


associated with human RELN mutations. Nat Genet 2000;26:93-6.

[88] Fukuyama Y, Ohsawa M, Suzuki H. Congenital progressive muscular dystrophy of the Fukuyama type-clinical, genetic and pathologic considerations. Brain Dev 1981;3:1-29.

[89] Takashirna S, Becker L, Chan F, et al. A Golgi study of the cerebral cortex in Fukuyama- type congenital muscular dystrophy, Walker-type "lissencephaly," and classical lissencephaly. Brain Dev 1987;9:621-6.

[90] Toda T, Miyake M, Kobayashi K, et al. Linkage-disequilibrium mapping narrows the Fukuyama-type congenital muscular dystrophy (FCMD) candidate region to less than 100 kb. Am J Hum Genet 1996;59:1313-20.

[91] Toda T, Yoshioka M, Nakahori Y, et al. Genetic identity of Fukuyama-type congenital muscular dystrophy and Walker-Warburg syndrome. Ann Neurol 1995;37:99-101.

[92] Kobayashi K, Nakahori Y, Miyake M, et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 1998;394:388-92.

[93] Worthington S, Turner A, Elber J, et al. 22q II deletion and polymicrogyria-cause or coincidence? [In Process Citation]. Clin Dysmorphol 2000;9:193-7.

[94] Leventer RJ, Lese CM, Cardoso C, et al. A study of 220 patients with polymicrogyria delineates distinct phenotypes and reveals genetic loci on chromosome I p, 2p, 6q, 21 q and 22q. Am J Hum Gen 2001;70(Suppi):Abstract.

[95] Villard L, Nguyen K, Winter RM, et al. X-linked bilateral perisylvian polymicrogyria maps to Xq28. In Am J Hum Gen 2001;70(Suppl):Abstract.

[96] Raymond AA, Fish D, Sisodiya S, et al. Abnormalities of gyration, heterotopias, tuberous sclerosis, focal cortical dysplasia, microdysgenesis, dysembryoplastic neuroepithelial tumour and dysgenesis of the archicortex in epilepsy: clinical, EEG and neuroimaging features in I 00 adult patients. Brain 1995; 1 18:629-60.

[97] Dome HL, O'Gorman AM, Melanson D: Computed tomography of intracranial gangliogliomas. AJNR Am j Neuroradiol 7:281-285, 1986

[98] Otsubo H, Hoffman Hj, Humphreys RP, et al: Detection and management of gangliogliomas in children. Surg Neurol 38:371-378,1992

[99] Zentner J, Wolf HK, Ostertun B, et al: Gangliogliomas: Clinical, radiological, and histopathological findings in 51 patients. I Neurol Neurosurg Psychiatry 57:1497- 1502,1994

[100] Daumas-Duport C, Scheithauer BW, Chodkiewicz JP: Dysembryoplastic neuroepithelial tumor: A surgically curable tumor of young patients with intractable partial seizures. Neurosurgery 23:545-556, 1988

[101] Jay V, Becker LE, Otsubo H, et al: Pathology of temporal lobectomy for refractory seizures in children: Re-

[102] Kuroiwa T, Bergey GK, Rothman MI, et al: Radiologic appearance of the dysembroplastic neuroepithelial tumor. Radiology 197:233-238,1995

[103] Barkovich Aj, Kuzniecky RI, Dobyns WB, et al: A classification scheme for malformations of cortical development. Neuropediatrics 27:59-63, 1996

[104] Becker LE: Central neuronal tumors in childhood: Relationship to dysplasia. J Neurooncol 24:13-19, 1995

[105] Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 10.4a October 2009

43


CLINICAL PICTURE:

10 years old male patient presented clinically with mental subnormality, Lennox-Gastaut syndrome.


Figure 1. Precontrast MRI T1 images showing lissencephaly with mild central atrophy, cerebellar vermial hypoplasia and vertically orientated folia instead of the normal horizontal folia pattern

Figure 2. Precontrast MRI T1 images and MRI T2 image (C) showing cerebellar hypoplasia, vermial hypoplasia,

CASE OF THE WEEK


CLINICAL PICTURE


44


possible subependymal nodular heterotopia and vertically orientated folia instead of the normal horizontal folia pattern.


The association of lissencephaly with cerebellar hypoplasia represents a distinct malformation from both a genetic and clinical standpoint to those described above. The cerebellar hypoplasia is usually extreme, and the brainstem may be small. Patients may or may not have an associated microcephaly. This disorder is often inherited in an autosomal recessive fashion and may be due to mutations in REELIN in some families (26).

DIAGNOSIS: CORTICAL/CEREBELLAR DYSPLASIA

DISCUSSION:

Figure 3. MRI showing a mild form of lissencephaly (pachygyria), the brain have a few broad, flat gyri with thick cortex and separated by shallow sulci (pachygyria). The cerebellum and the brain stem are hypoplastic, the brain volume is also reduced especially the temporal lobes. In particular there Hypoplasia of the cerebellar vermis and Vertically orientated folia instead of the normal horizontal folia pattern

DIAGNOSIS:

DISCUSSION

45


In newborns, minor cerebellar dysplasias are found histologically in the white matter and nodulus of the vermis. These midline cerebellar dysplasias are common features of human cerebellar development (2). Major cortical cerebellar dysplasias, however, represent a pathologic finding. They have been reported in congenital muscular dystrophies and related syndromes or in intrauterine infection (8–14). Only one case of isolated cerebellar cortical dysplasias has been described (8).

Cerebellar cortical dysplasia may be associated with widespread cerebral malformations and cases with isolated cerebellar abnormalities are rare. They are associated with a poor prognosis and severe neurocognitive defects, with global or motor developmental delay, hypotonia, oculomotor disease, and facial and skeletal deformities.

Figure 1. Dandy-Walker complex. Axial inversion-recovery (IR) T1-weighted image (11520/60/400/2 [TR/TE/TI/excitations]) shows bilateral, vertical, orientated folia of the cerebellar cortex associated with an enlarged fourth ventricle.

The most relevant MR appearance of cerebellar cortex in patients with cerebellar dysplasia included: defective, large, or vertical fissures; irregular gray/white matter junction; lack of normal arborization of the white matter; and heterotopia within cerebellar hemispheres, all findings leading to disorganized foliation. Vertical abnormal fissures in vermis are also present and in sagittal images its presence is shown as an abnormal foliation of vermian lobules. Other radiologic findings were cortical thickening, hemispheric hypertrophy, and cystlike cortical inclusions.

Box 1. Characteristic features of cerebellar cortical dysplasia

Defective development of the cerebellar vermis Vertically orientated folia instead of the normal horizontal folia pattern Defective, large, or vertical fissures Irregular gray/white matter junction Lack of normal arborization of the white matter Vertical abnormal fissures in vermis are also present

46


Figure 2. A, Coronal IR T1-weighted image (11520/60/400/2) shows rostral vermian dysgenesis (black arrowhead), bilateral abnormal arborization of the white matter (double black arrowhead), and linear heterotopia (white arrow). B, Axial T2-weighted image (5000/120/2 [TR/TE/excitations]) shows vermian dysgenesis (short arrow) associated with mega cisterna magna and prominent appearance of the superior cerebellar peduncles (long arrow).

The reported patient had no metabolic or congenital muscular dystrophy (CMD) disease. In particular, the radiologic aspect of CMD described by Barkovich (5) was not present in the reported patient, including white matter abnormalities associated with cortical supratentorial dysplasia and cystlike cortical abnormalities of cerebellar white matter. Cystlike cortical abnormalities have been also reported in Fukuyama disease. These abnormalities may represent subarachnoid spaces engulfed by the fusion of disorganized folia (12). In cases of isolated cortical cerebellar dysplasia, Demaerel et al (8) suggested that cystic inclusions represent sequelae of the migration of neurons, which form the external granular layer of cerebellar cortex at 11 to 13 weeks of gestation, or remnants of daughter cells, which migrate to form part of the outer molecular layer and inner granular layer at 16 weeks.

Figure 3. Axial T2-weighted images (5000/120/2) show cystlike inclusions (arrows), cortical dysplasia (arrowhead), and pons hypoplasia (black arrowhead) (A) associated with medial vermian fissure (long arrow), occipital polymicrogyria, white matter hyperintensity, and ventricular enlargement (B)

The understanding of cerebellar cortical dysplasia is facilitated by knowledge of cerebellar cortical development. Cerebellar cortical neurons have a dual origin. Up to about 10 weeks of gestation, the neural cells that will form the

47


deep nuclei and the Purkinje layer of cerebellar cortex migrate radially outward from the germinal matrix. In contrast, at approximately 10 to 11 weeks, the neurons that will form the granular layer migrate tangentially over the cerebellar surface (15). The early signs of foliation, which manifest prior to the formation of a fissure, are a local increase in premigratory granular cells and an indentation of the Purkinje cell layer.

Up to the 40th week, the cerebellar lamellae are made up of four layers: the external granular layer, the molecular layer, the Purkinje cell layer, and the internal granular layer. During the first 6 to 8 months of extrauterine life, the external granular layer subsides progressively as its cells migrate inward and the cerebellar lamellae assume their adult appearance with only three layers (16). The external granular layer, Purkinje cell layer, and the overlaying meningeal cells may be involved in the mechanism of foliation (17).

Immunohistochemical observations described in the developed mutant rat with cerebellar malformations have shown that the cerebellar lamination is disturbed by abnormal perivascular aggregations of the external granule cells (EGCs). The abnormal aggregation of EGCs is preceded by an aberrant migration and misorientation of Purkinje cells in the hemispheres and a disturbed arrangement of glial fibers, suggesting that Purkinje cell settlement may be a key in cerebellar development. Moreover, a close relationship between defective development of the cerebellar vermis and cerebellar dysplasia is present. These findings have also been described in human cerebellar cortical dysplasia (2, 18). The stage during which the perivascular aggregations of EGCs are found in the rat corresponds to human gestation at 24 to 27 weeks (19). According to these reports, mutation of a gene expressed in cerebellar development (17) or congenital infection, toxins, or radiation (15) are different causes affecting migration and proliferation in cerebellum, leading to vermian and cerebellar dysplasia and hypoplasia. These findings were present in 11 of our patients. Nevertheless, only one had chromosomal abnormalities and another patient had congenital infection.

Figure 4. A, Axial IR T1-weighted image (11520/60/400/2) shows right cerebellar hypertrophy with vertical folia in an 8-year-old boy with ataxia and psychomotor retardation. B, Coronal T2-weighted image (5000/120/2) shows associated malformations: minor parietal lobe (double arrow) and ventricle enlargement, nodular heterotopia (long arrow) and white matter hyperintensity (short arrows).

Figure 5. Ten-month-old boy with spastic tetraparesia, developmental delay, and difficulty in swallowing. Coronal T2-weighted image (5000/120/2) shows right cerebellar cortical disorganization without normal fissures associated with hyperplasia of the right cerebellar lobe and cortical thickening. Note white matter hyperintensities (black arrowheads) and cortical dysplasia (white arrows) in supratentorial images

48


Figure 6. MR imaging findings in a 4-year-old boy with microcephalia, motor delay, and facial deformities. A, Coronal IR T1-weighted image (11520/60/400/2) shows bilateral cerebellar defective foliation and irregularity of the gray/white matter junction (black arrowheads). Note subependymal heterotopia along the floor of the left temporal horn (white arrow). B, Coronal IR T1-weighted images (11520/60/400/2) shows heterotopia (white arrow) and associated cortical dysplasia of parahippocampal gyrus (asterisk).

Cerebellar dysplasia may be continuous as well as contiguous to a posterior fossa tumor. Jay (3) has previously described this association. There was disorganization of the cortex, with fusion of folia, disorganization and misorientation of Purkinje cells, and irregularly oriented and tangled radial glialike processes, suggesting a role for abnormality of radial glia in the pathogenesis of the lesion. The authors proposed a possible pathogenetic association between cortical dysplasia and development of the tumor. Cortical dysplasia was considered to be an aberrant neuronal migration or maturation, and its presence contiguous to the tumor suggested that the tumor arose as an abnormal genetic control in the migration and differentiation of neuronal precursors.

Figure 7. MR imaging findings in a 1 year-old boy with facial deformities, hypotonia, and developmental delay. A, Coronal IR T1-weighted image (11520/60/400/2) shows medial vermian fissure (arrow). B, Sagittal IR T1-weighted

49


image (same parameters) shows lack of normal fissures of the vermis associated with inferior vermis hypoplasia.

MR imaging findings showed that dysplasia is frequently associated with other malformations. Few cases of isolated unilateral cerebellar cortical dysplasias have been described. Demaerel et al (8) reported one case with bilateral cerebellar dysplasia. MR imaging characteristics were defective or vertically oriented foliation, frequently associated with vermian dysplasia.

Unusual malformations of cerebellum have been previously described in literature (eg, hamartoma associated with cerebral atrophy [20], macrocerebellum associated with delayed myelinisation [21], hemimegalenchephaly with cerebellar involvement [22], and cerebellar monstrous hypertrophy [23]). Another new cerebellar malformation was reported with a partial midline fusion of the cerebellar hemispheres (17), and Demarel et al (24) described vermian changes with associated cerebellar abnormalities. In these cases, vertical folia and abnormal fissures were associated with defective foliation. As previously described, when cortical dysplasia was associated with polymicrogyria and other associated malformations, cerebellar abnormalities may have represented not only a single entity, but a spectrum of more extensive morphologic changes (8).

Investigations are indicated to understand the association among cerebellar cortical dysplasias, minor facial anomalies, and hand-skeletal deformities with supratentorial malformations. Indeed, abnormalities of the expression of the homeobox genes could lead to the development of malformations of the cerebellum, basal forebrain and visual system, mandibular and maxillary arch patterning, and finger skeletal anomalies (25).

SUMMARY

In conclusion, cerebellar cortical dysplasias may result from different causes, both genetic and acquired. They have been reported in congenital muscular dystrophies and related syndromes or in intrauterine infection. The most common features seem to be the vertically orientated folia instead of the normal horizontal folia pattern, disorganized foliation, and defective or abnormal fissures. In most cases, cerebellar cortical dysplasia is associated with other cerebral malformations and immunohistological findings suggest that abnormal cell migration caused by

Figure 8. Lissencephalic brain with hydrocephalus and cerebellar hypoplasia

SUMMARY

50


a disorder in early gestation result in cerebellar dysplasia. A genetic effect responsible for the human vermis defect and cerebellar dysplasia has not been identified yet. Our study suggests that cerebellar cortical dysplasia is a common feature in cases with widespread cerebral malformations and this can be related to the technical advances providing high-quality tridimensional MR imaging of the cerebellum in a period of renewed and widespread interest in the cerebellar involvement in cognitive processing.

Addendum








References

1. Rorke LB, Fogelson MH, Riggs HE. Cerebellar heterotopia in infancy. Dev Med Child Neurol 1968;10:644-650

2. Yachnis AT, Rorke LB, Trojanowki JQ. Cerebellar dysplasias in humans: Development and possible relationship to glial and primitive neuroectodermal tumors of the cerebellar vermis. J Neuropathol Exp Neurol 1994;53:61-71

3. Jay V. Coexistence of cerebellar primitive neuroectodermal tumor and cerebellar dysplasia: case report. Pediatr Pathol Lab Med 1996;16:837-843

4. Friede RL. Developmental Neuropathology. 2nd ed. Berlin Heidelberg New York: Springer 1989;361-371

5. Barkovich AJ. Neuroimaging manifestations and classification of congenital muscular dystrophies. AJNR Am J Neuroradiol 1998;19:1389-1396

6. Ramaeker VT, Heimann G, Reul J, Thron A, Jaeken J. Genetic disorders and cerebellar structural abnormalities in childhood. Brain 1997;120:1739-1751

7. Sugita K, Ando M, Makino M, Takanashi J, Fujimoto N, Niimi H. Magnetic resonance imaging of the brain in congenital rubella virus and cytomegalovirus infections. Neuroradiology 1991;33:239-242

8. Demarel P, Lievel-Lagae PC, Baert AL. MR of cerebellar cortical dysplasia. AJNR Am J Neuroradiol 1998;19:984-986

9. Kimura S, Sasaki Y, Kobayashi T, et al. Fukuyama-type congenital muscular dystrophy and the Walker-Warburg syndrome. Brain Dev 1993;15:182-191

10. Aida N, Tamagawa K, Takada K, et al. Brain MR in Fukuyama congenital muscular dystrophy. AJNR Am J Neuroradiol 1996;17:605-613

REFERENCES

51


11. Takada K, Nakamura H. Cerebellar micropolygyria in fukuyama congenital muscular dystrophy in fetal and pediatric cases. Brain Dev 1990;12:774-778

12. Aida N, Yagishita A, Takada K, Katsumata Y. Cerebellar MR in Fukuyama congenital muscular dystrophy: polymicrogyria with cystic lesions. AJNR Am J Neurodiol 1994;15:1755-1759

13. Aida N, Tamagawa K, Takada K, et al. Brain MR in Fukuyama congenital muscular dystrophy. AJNR Am J Neuroradiol 1996;17:605-613

14. Leon GA. Observations on cerebral and cerebellar microgyria. Acta Neuropathol 1920;20:278-287

15. Barth PG, Pontocerebellar hypoplasias. An overview of a group of inherited neurodegenerative disorders with fetal onset. Brain Dev 1993;15:411-422

16. Larroche JC, Morphological criteria of central nervous system development in the human foetus. J Neuroradiology 1981;8:93-108

17. Takanashi J, Sugita K, Barkovich AJ, Takano H, Kohno Y. Partial midline fusion of cerebellar hemispheres with vertical folia: a new cerebellar malformation? AJNR Am J Neuroradiol 1999;20:1151-1153

18. Kuwamura M, Shirota A, Yamate J, Kotani T, Sakuma S. Analysis of aberrant neuronal migrations in the hereditary cerebellar vermis defect (CVD) rat using bromodeoxyuridine immunohistochemistry. Acta Neuropathol 1998;95:143-148

19. Kuwamura M, Ishida A, Yamate J, Kato K, Kotani T, Sakuma S. Chronological and immunohistochemical observations of cerebellar dysplasia and vermis defect in the hereditary cerebellar vermis defect (CVD) rat. Acta Neuropathol 1997;94:549-556

20. Hayashi K, Mizobuchi K, Taguchi K, Ohsumi S, Ikehara I, Kobayashi K. A case of cerebellar hamartoma suggesting abnormal cell migration. Acta Neuropathol 1986;69:283-287

21. Bodensteiner J, Bradley Schaefer B, Keller G, Thompson J, Bowen MK. Macrocerebellum: neuroimaging and clinical features of a newly recognized condition. J Child Neurol 1997;12:365-368

22. Nuri Sener R. MR demonstration of cerebral hemimegalencephaly associated with cerebellar involvement (total hemimegalencephaly). Comput Med Imaging Graph 1997;21:201-204

23. Leon GA, Grant JA, Darling CF. Monstruous Crablike hypertrophy of the cerebellar vermis and its relationship with Lhermitte-Duclos disease. J Neurosurg 1996;85:157-162

24. Demaerel P, Wilms G, Marchal G. Rostral vermian cortical dysplasia: MRI. Neuroradiology 1999;41:190-194

25. Hallonet M, Hollemann T, Pieler T, Gruss P. Vax1, a novel homeobox-containing gene, directs development of the basal forebrain and visual system. Genes Dev 1999;23:3106-3114

26. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 10.4a October 2009

52


CLINICAL PICTURE:

9 years old female patient presented clinically with Lennox-Gastaut syndrome.


Figure 1. Postcontrast CT scan showing Lissencephaly, pachygyria,and subependymal nodular heterotopia.

CASE OF THE WEEK


CLINICAL PICTURE


Figure 2. Postcontrast CT scan showing Lissencephaly, pachygyria,and subependymal nodular heterotopia. Also notice cerebellar hypoplasia and mild central atrophy.

DIAGNOSIS:

53


DIAGNOSIS: CORTICAL DYSPLASIA

DISCUSSION:

Abnormalities have long been recognized in the brains of children with developmental delay and seizures. The advent of newer imaging techniques, such as high-resolution (thin slice three-dimensional gradient recalled echo [GREI) magnetic resonance (MR) imaging and surface reconstructions of three-dimensional data sets, has led to a greater in vivo understanding of these malformations. There has been reclassification of the disorders of cortical malformations according to embryologic stages of brain cortex development at which these malformations are proposed to have occurred. These stages are cellular proliferation, cellular migration to the developing cortex, and cortical organizations.

MALFORMATIONS OF ABNORMAL CELL PROLIFERATION

Nonneoplastic

The earliest lesions resulting in cortical malformations are those with onset during the period of cellular proliferation in the germinal zones. During the seventh fetal week, germinal layers begin to form in the vesicle walls of telencephalic outpouchings (vesicles) at the foramina of Monro. Cortical malformations occurring during this stage of neuronal and glial proliferation may be generalized, multifocal, or focal. Generalized malformations of abnormal cell proliferation include microcephaly with diminished cortical thickness or with diminished sulcation. Commonly imaged focal or multifocal lesions include nonneoplastic disorders, such as hemimegalencephaly, focal cortical dysplasia (with balloon cells), and forme fruste tuberous sclerosis.

Hemimegalencephaly may be associated with neurocutaneous or hemiovergrowth syndromes, such as hypomelanosis of Ito, epidermal nevus syndrome, or neurofibromatosis type 1. Proposed causes for hemispheric overgrowth in hemimegalencephaly include abnormal cellular proliferation and heteroploidy, defective cellular metabolism, or possibly an insult to the developing brain in the mid to late second trimester. In the event of a later insult to the developing brain, brain plasticity allows for the development of new synapses in the damaged brain, permitting the persistence of supernumerary axons and the potential for white matter overgrowth. Neuropathologic and neuroimaging features in hemimegalencephaly are abnormal neurons, lack of gray-white matter demarcation, disarrayed cortical lamination, gray matter heterotopias, broad gyri, and signal changes reflecting hypomyelination and gliosis. It is postulated that foci of agyria, with macroscopic heterotopias, extensive white matter gliosis, and less hemispheric white matter overgrowth, likely result from an earlier, more severe insult with destruction of the radial glial fibers. The variable patterns of cortical and white matter involvement demonstrated with neuroimaging likely reflect the variability in severity and timing of the precipitating insult. [1,5,19,23]

Figure 1. Tl -weighted (TR 600/TE 15) and T2-weighted (I R 2800/ TE 90) axial images (A and B) demonstrate overgrowth of the right cerebral hemisphere in a patient with developmental delay, seizures, and

DISCUSSION

54


hemimegalencephaly. Note the abnormal white matter signal and the unilateral ventriculomegaly.

Focal cortical dysplasia is characterized by neocortical abnormalities. The pathologic spectrum of focal cortical dysplasia includes significant abnormalities of neuronal size, shape, orientation, and lamination; indistinctness of the gray-white junction; and variability in cortical thickness. Large bizarre neurons with abnormal Nissl patterns, giant neurons, binucleate neurons, a variable degree of cortical gliosis, and balloon cells with abundant pale eosinophilic cytoplasm are found. These balloon cells are similar to those seen in the cortical tubers and white matter lesions of tuberous sclerosis, and there is much overlap in the pathology of focal cortical dysplasia and tuberous sclerosis. Failure of myelin arborization, blurring of gray-white margins, variable sulcal depth and cortical thickness, and occasional hazy or dystrophic calcification may be appreciated on neuroimaging. Evidence of dual pathology, or focal cortical dysplasia in association with hippocampal sclerosis, should be sought. [8,14,17,21,26,28,32]

Imaging features in limited or forme fruste tuberous sclerosis include demonstration of a solitary smooth pyramidal-shaped gyri with a central depression and abnormal signal of the subcortical white matter. The cortical and subcortical lesions are uncommonly calcified, tend not to enhance, and are best demonstrated on MR. These children lack the calcified subependymal nodules of tuberous sclerosis as well as other organ system lesions. The cortical tubers are characterized by aberrant neurons, scattered balloon cells, and gliosis. The white matter lesions of tuberous sclerosis are characterized by decreased myelin and accumulations of balloon cells. Although there are similarities in the pathology of focal cortical dysplasia and the form fruste of tuberous sclerosis, the latter has, in general, more abundant balloon cells. [15,17, 18,22,24]

Neoplastic

Lesions of proliferation after an abnormal induction event during brain development may be malformative, hamartomatous, neoplastic, or a combination. Malformative disorders consisting of neoplasias on a background of

Figure 2. Tl -weighted (TR 600/TE 15) sagittal (A) and axial images (B), and T2-weighted (TR 3000/ TE 120) axial image (C) in a child with severe microcephaly showing a thin cortical ribbon. A Tl -weighted axial image (D) in a second child with a similar degree of microcephaly reveals fewer gyri and less well developed sulcation.

55


disordered cortex or in association with focal cortical dysplasia include dysembryoplastic neuroepithelial tumor and ganglioglioma. [5,7]

Dysembryoplastic neuroepithelial tumors

Dysembryoplastic neuroepithelial tumors are supratentorial, predominantly temporal lobe tumors that are typically multinodular with a heterogeneous cell composition, including oligodendrocytes, neurons, astrocytes, and other cells. These lesions are typically fairly well-demarcated, wedge-shaped lesions extending from the cortex to the ventricle. Calcification, enhancement, and peritumoral edema are lacking on neuroimaging studies. These low-attenuation lesions may suggest an infarct on computed tomography (CT), although there is no volume loss over time, and scalloping of the inner table or calvarial bulging suggests slow growth. Lesions are low in signal on Tl-weighted images and high in signal on T2- weighted images and often have a multinodular or pseudocystic appearance. There is a spectrum of pathology in dysembryoplastic neuroepithelial tumors. On one end of the spectrum are multinodular lesions with intervening malformed cortex, in which there is some hesitation to use the designation tumor. On the other end are lesions, which are clearly neoplastic and have clinically demonstrated some growth potential. Because the term dysembryoplastic neuroepithelial tumor has only recently been introduced, such malformative and neoplastic lesions were previously labeled as hamartomas, gangliogliomas, or mixed gliomas. [9,17,20]

Figure 3. A, Dysembryoplastic neuroepithelial tumour (frontobasal surgical specimen). Irregular thickening of the cerebral cortex with multiple cortical and subcortical nodules. This complex tumour consists of a mixture of glial cells and nerve cells and is often associated with dysplastic cortical foci. It can occur in any part of the brain and generally causes long-standing focal seizures. B, Dysembryoplastic neuroepithelial tumour (MT x40). Oligodendroglial-like cells arranged in groups or columns within a loose, microcystic matrix containing several solitary "floating" neurons and numerous congestive capillaries. Calcifications are possible.

56


Figure 4. Dysembryoplastic neuroepithelial tumor. Wedge-shaped, nonenhancing, very low signal intensity lesion on Tl -weighted (TR 600/TE 15) axial image (A) demonstrating very high signal intensity lesion on the T2-weighted (TR 2800/TE 90) (B) axial image. Note the scalloping of the inner table, the multiple septations, and the lack of vasogenic edema or mass effect on the adjacent brain and ventricle. Pathologic specimen (Figure 3A) demonstrates nodules on an abnormal background of cortical dysplasia, and a specimen of one of the nodules seen on high power (Fig.3B) demonstrates oligodendroglial-like cells, some of which are actually immature neurons.

Gangliogliomas

Gangliogliomas are typically demonstrated within the temporal lobe. In one large series of 51 gangliogliomas, 84% were found in the temporal lobe, 10% were found in the frontal lobe, 2% were found in the occipital lobe, and 4% were found in the posterior fossa. These lesions are typically hypodense (60% to 70%) on CT, with focal calcifications seen in 35% to 40%, contrast enhancement in 45% to 50%, and cysts in nearly 60%. The reported incidence of calcifications demonstrated on imaging in pediatric gangliogliomas is higher, seen in 61% of one series of 42 children. Features on MR imaging are less specific, with solid components isointense on T1-weighted images, bright on proton density images, and slightly less bright on T2-weighted images. Although imaging features are not specific, an enhancing, cystic temporal lobe lesion with focal calcification should suggest the diagnosis of ganglioglioma. The pathologic features that suggest the diagnosis of ganglioglioma include a neoplastic glial and neuronal component and calcification. Because calcifications are often poorly demonstrated on MR imaging and because they increase specificity of imaging findings, documentation of calcium should be sought on CT after MR imaging demonstration of a temporal lobe tumor. [11,27,33]

Figure 5. A large,calcified, enhancing ganglioglioma with heterogeneous signal is demonstrated within the occipital lobe of a macrocephalic child on CT (A), and Tl -weighted (TR 600/TE 15) axial images before precontrast (B) and after (C) contrast administration. Location of ganglioglioma in this child is atypical.

57


DISORDERS OF CELLULAR MIGRATION TO THE CORTEX

The onset of neuronal migration to the cortex occurs during the eighth fetal week. Initially, cells in the germinal zone elongate with the nucleus remaining in the portion of cell that is furthest from the ventricular surface. After mitosis, the newly formed cells are distant from the ventricular surface. Later in neuronal migration, as distance to travel increases, migration occurs along the radial glial fibers (RGF), which span the distance from the ventricular surface to pia. Disorders of neuronal migration occur when migration is halted. Abnormalities of neuronal migration may occur with damage to the RGF by placental ischemia, infection (cytomegalovirus), or maternal trauma or with altered chemotaxis of neurons along the fibers from toxin exposure or inborn errors of metabolism. Diffuse disorders of disruption of neuronal migration include band heterotopia, classic (type 1) lissencephaly, and cobblestone (type 2) lissencephaly. Marginal glioneuronal heterotopia and nodular cortical dysplasias, nests of ectopic glial elements and gray matter within the leptomeninges and at the crown of the gyri, are believed to be the result of overmigration, possibly through areas of superficial necrosis or disruption of the external glial limitans. These findings, recognizable only on pathologic specimens, are believed to give rise to the lacy or cobblestoned cortex in type 2 lissencephaly. More focal disorders of disrupted neuronal migration include subependymal or subcortical neuronal ectopia and heterotopias. Disorders of neuronal migration are characterized on imaging studies by gray matter localized along the pathways of migration to the cortex. These gray matter rests, nodules, or masses share the attenuation (CT) and signal characteristics (MR imaging) of normal gray matter on all imaging sequences. Small deposits of heterotopia may be identified with high-resolution gradient volume acquisitions, which augment tissue contrast between gray and white matter. [3,5]

Figure 6. Pachygyric (A), and agyric (B) lissencephalic brain

Figure 7. A, Type II lissencephaly, Cobblestone lissencephaly (Walker-Warburg syndrome). The cortex is lissencephalic and thickened, with an irregular gray matter-white matter junction that probably represents the bundles of disorganized cortex surrounded by fibroglial tissue. The patient has been shunted for hydrocephalus. The brain is hypomyelinated. B, Presumed microcephalia vera. The brain is completely smooth (lissencephaly) with a very thin cortex. No layer of arrested neurons is present in the white matter. C, Presumed radial microbrain. Axial T2- weighted image shows an immature gyral pattern and hypomyelination. Cortical thickness is normal. This patient was profoundly microcephalic (head circumference 19 cm).

58


Band heterotopia results from an early arrest of neuronal migration and gives the appearance of a continuous double cortex. The appearance has also been likened to a three-layer cake with the cortex and bilaterally symmetric, circumferential, subcortical layers of band heterotopia separated from each other by a thin white matter band. The cortex may be relatively normal or pachygyric. Shallow sulci are common. Band heterotopia has been reported to be an X-linked disorder with heterozygous females demonstrating band heterotopia and hemizygous males having classic lissencephaly. Seizures are common in band heterotopia, and mental retardation may be mild or moderate. Severity of symptoms correlates with the degree of disorganization of the overlying cortex, thickness of the continuous band of heterotopic gray matter, amount of T2 prolongation, and degree of ventriculomegaly The brain in lissencephaly type I may have a smooth surface (complete lissencephaly) or may have a nearly smooth surface with some gyral formation along the inferior frontal and temporal lobes. The thick cortex has a four-layered cortex composed of a molecular outer layer, an outer cellular layer, a cell sparse layer, and an inner cellular layer composed of arrested neurons. The arrest relates to a disruption of neuronal travel along the RGF, either from laminar necrosis or from disrupted chemotaxis. Imaging demonstrates broad, flat gyri with a thickened cortex and scanty white matter. Sylvian fissures are primitive, leading to an hourglass configuration of the brain. Type 2 or cobblestone lissencephaly is recognizable by its irregular surface, abnormal myelin, and the accompanying orbital and cerebellar anomalies. [2,10,29]

Figure 8. A, Band heterotopia with pachygyria. B, band heterotopia with mild periventricular nodular heterotopia

Figure 9. Subependymal nodular heterotopia

59


Periventricular nodular heterotopia may be solitary, isolated lesions or may diffusely line the walls of both lateral ventricles. These lesions mimic the appearance of the subependymal tubers in tuberous sclerosis, although they do not calcify. When diffuse and bilateral, periventricular nodular heterotopia may be associated with mild cerebellar hypoplasia. Patients with periventricular or subependymal heterotopias may present with late-onset seizures, acquire normal early milestones, have normal motor development, and be of average or above-average intelligence. This disorder has been linked to markers in distal Xq28. Subcortical gray matter heterotopias also may be focal or diffuse. The greater the heterotopic mass, the more dysplastic the overlying cortex. Those patients with thick heterotopias and overlying gyral anomalies are more likely to have associated psychomotor delay. Deep infolding of thickened cortex, or deep clefts lined by heterotopia, often frontal, may also occur and are frequently associated on imaging with primitive vertical venous structures. [3,4,10,12,13,16]

DISORDERS OF CORTICAL ORGANIZATION

The primitive sylvian fissure is the first sulcus to form, at approximately 14 to 20 weeks, whereas the rolandic fissure, the parieto-occipital, and the superior temporal gyri form later. By 32 to 33 weeks, large numbers of cortical sulci are visible, and by 38 to 40 weeks, there is a nearly normal adult sulcal pattern. After full-term birth, the sulci continue to deepen over the next weeks. The final group of disorders are those that are associated with disruption of the process of gyral formation and subsequent cellular organization of the cortex. These disorders include generalized polymicrogyria (PMG) or focal and multifocal disorders such as focal PMG, bilateral symmetric PMG, and schizencephaly with or without PMG. The imaging appearance of dysplasias of cortical organization includes abnormalities of the cortical gyral pattern without radiographically evident subjacent heterotopias. The imaging appearance of generalized or focal polymicrogyria can be quite variable. Typically, there is a thick cortex with many small gyri separated by shallow sulci. The gyri may, however, be so small that they are difficult to discern on imaging. The appearance then is of a flat thickened cortex, simulating pachygyria or agyria. Small areas of cortical thickening may be better defined with adjunctive three-dimensional MR reformatted images. Bilateral opercular or perisylvian syndrome is a bilateral symmetric PMG disorder consisting of primitive sylvian fissures, primitive draining veins, and symmetric involvement of the operculum with polymicrogyria or pachygyria. Patients may present with seizures, motor and speech disorders, mental retardation, and a congenital pseudobulbar syndrome. Schizencephaly, or gray matter lined clefts of the brain, occurs after disruption of the RGF units from the ventricle to the pial surface. Smaller clefts may have coapted walls or closed lips. Larger clefts, or those with open lips, may allow free communication of the ventricles with the pericerebral spaces. [4,5]

Also included in disorders of cortical organization are cortical dysplasia without balloon cells, with imaging

Figure 10. CT scan showing Subependymal nodular heterotopia with cerebellar hypoplasia

Figure 11. MRI showing Subependymal nodular heterotopia

60


features similar to the previously described focal cortical dysplasia with balloon cells, and microdysgenesis. Small foci of cortical dysplasia may require serial imaging over time, becoming apparent only when myelin maturation is complete. Other foci may be apparent only with high-resolution, high-contrast imaging, such as is possible with GRE sequences. Microdysgenesis is radiographically undetectable with pathologic features consisting of subtle neocortical abnormalities: neuronal ectopias within the white matter, abnormal neurons within the molecular layer, neuronal clustering; bare areas within cortical layers two to six, and Chaslin's subpial gliosis. [6,17,31]

Figure 13. Bilateral opercular dysplasia is present in a 14-year-old with a history of spastic diplegia and recent onset of seizures. Primitive Sylvian fissures lined by thickened cortex are seen on Tl -weighted (TR 600/TE 15) (A) and T2-weighted (TR 2800/TE 90) (B) axial images.

Figure 12. Lissencephaly Type 1. Tl -weighted (TR 600/ TE 15) (A) and T2-weighted (TR 3000/TE 120) (B) coronal images in a severely delayed patient with Miller-Dieker syndrome show a smooth cortical surface. Thickened cortex with rare gyri along the inferior temporal lobes is seen on Tl-weighted (C) and T2-weighted (D) coronal images in a patient with agyria-pachygyria complex and seizures.

61


Figure 14. Closed-lip schizencephaly is seen on the right, and a deep cleft on the left on T1 -weighted (TR 600/TE 15) (A) and T2-weighted (TR 2800/TE 90) (B) axial images in a 2-year-old with psychomotor delay and microcephaly. Open-lip schizencephaly is documented on Tl -weighted (C) and T2-weighted (D) coronal views in a 2-year-old presenting with spastic quadriparesis.

Figure 15. Open-lip schizencephaly with cortical dysplasia

62


Figure 16. Bilateral open lip schizencephaly

SUMMARY

Lissencephaly is the most severe of the disorders discussed in this case recport and the most easily diagnosed by magnetic resonance imaging (MRI). In all types of lissencephaly the surface of the brain is abnormally smooth, with shallow sulci and an abnormal gyral pattern. In some types of lissencephaly the gyri are also abnormally broad and flat. lissencephaly can be divided by MRI criteria into five categories.

Type I Lissencephaly

In type I lissencephaly, neuronal migration to the cortex has stopped before completion. Therefore, a band of neurons lies in the subcortical region, separated from an abnormally thin cortex by a layer of white matter. The cortex may be completely smooth (completely lissencephaly or agyria) or may have a few broad, flat gyri separated by shallow sulci (pachygyria), a pattern that may be present in parts of otherwise completely lissencephalic brains. Band heterotopias in which the cortex appears nearly normal have been arbitrarily included in a separate section in this chapter. However, the reader should recognize that these are most likely a mild form of type I lissencephaly. Depending on the severity of the lissencephaly, affected children may be microcephalic or normocephalic and may range from profoundly retarded to nearly normal. Similarly, the neurologic findings and the occurrence of associated anomalies vary with the severity of the migration defect.

On imaging studies, patients with type I lissencephaly have a smooth cortex that may be agyric, pachygyric, or both, with an underlying layer of arrested neurons. The white matter is typically diminished in volume and the Sylvian fissures are most commonly shallow and vertically oriented. The layer of white matter separating the cortex from the layer of arrested neurons has a variable appearance depending on the severity of the lissencephaly and the state of myelination, which are, in turn, dependent on the patient's age. Patients with severe lissencephaly have a thick layer of white matter separating the cortex from the layer of arrested neurons, whereas those with milder lissencephaly (mild pachygyria) have thinner layers of arrested neurons and thinner layers of white matter separating the cortex from the arrested neurons. The gross appearance of the brain resembles that of the fetus before 23 or 24 weeks of gestation, when sulci normally begin to form. The middle cerebral arteries typically lie close to the inner table of the skull because there are no sulci in which they can lie. The severely affected cerebrum has a figure-8 appearance on axial images as a result of the shallow vertical sylvian fissures. In severe agyria, sagittal images may show a hypoplastic corpus callosum, with a small splenium and absent rostrum. The brainstem

SUMMARY

63


often appears hypoplastic, probably because many of the corticospinal and corticobulbar tracts do not form. Areas of pachygyria also have a thickened cortex, but broad gyri and shallow sulci are present. As stated earlier, the layer of arrested neurons and the layer of white matter separating it from the cortex are thinner in pachygyric areas than in agyric sections. Pachygyria can be focal or diffuse. When focal, it can occur in any part of the brain but is most common, in my experience, in the parieto-occipital regions. When diffuse, it is often associated with regions of agyria and tends to be more severe in the parieto-occipital region of the brain and least severe in the frontal and temporal lobes.

Type II Lissencephaly

Type 11 lissencephaly occurs in the Walker-Warburg syndrome and in Fukuyama's congenital muscular dystrophy. It is characterized pathologically by lissencephaly, microphthalmia with retinal dysplasia, callosal hypogenesis, cerebellar cortical dysplasia, cerebellar vermian hypoplasia, hypomyelination, and hydrocephalus, which may result from obliteration of the subarachnoid spaces by thickened, fibrous meninges (3,11-14). Histologically, the cortex is characterized by a lack of lamination and disruption by penetrating vessels and fibroglial bundles that are continuous with the fibroglial tissue obliterating the subarachnoid spaces. The cortex is thicker than normal but not as thick as the combined cortex, layer of white matter, and layer of arrested neurons of type I lissencephaly.

MR imaging studies mirror the pathologic findings. The cortex is lissencephalic and thick, with an irregular gray-white matter junction that probably represents the bundles of disorganized cortex surrounded by fibroglial tissue. Ventricles are large, and the patient has often been shunted before CT or MRI scans are obtained. The corpus callosum is hypogenetic or absent and the cerebellar vermis is always hypogenetic-hypoplastic with agenesis of the inferior vermis. The white matter is almost completely unmyelinated. About half of patients have an occipital encephalocele or evidence of a repaired encephalocele.

Type III Lissencephaly (Microcephalia Vera)

The term "microcephalia vera" has been used to describe several genetic and sporadic developmental brain anomalies. Patients typically present with microcephaly and moderate developmental delay but no focal neurologic findings. Histopathologic examination of one brain of an affected 26-week gestational age fetus showed no migratory disorder. However, the germinal zone was completely depleted at an age when the normal germinal zone is of maximal volume.

Pathologic examination shows a thin cerebral, cortex, diminished cerebral white matter, shallow sulci, and markedly diminished callosal axons. The only MR study published of a presumed case of microcephalia vera shows a very small brain with complete lissencephaly and an extremely thin cortex. No layer of arrested neurons was identified.

Type IV Lissencephaly (Radial Microbrain)

The term "radial microbrain" has been used to describe patients born at term with markedly reduced brain size despite normal gyral patterns, normal cortical thickness, normal cortical lamination, and absence of destruction or gliosis (18). However, the number of neocortical neurons was only 30% of normal. All affected patients had profound microcephaly and non-CNS anomalies, such as nephropathy and acromicria. We have performed MRI on three infants that we believe fulfill the criteria for radial microbrain. All had profound microcephaly, delayed myelination, and a slightly immature gyral pattern. We presume that the myelination delay is due to lack of production of oligodendrocyte precursors by the depleted germinal zones.

Type V Lissencephaly (Diffuse Polymicrogyria)

Diffuse polymicrogyria is a type of smooth brain that involves the entire cerebrum. Patients with this severe condition typically are microcephalic and present with developmental delay or the onset of seizures in the first 6-8 months of postnatal life. In our experience, most patients with diffuse polymicrogyria have congenital cytomegalovirus infections. MR images show a slightly thickened cortex (typically 5-7 mm) with irregularly "bumpy" outer and inner surfaces. The ventricles are typically enlarged and the white matter hypomyelinated. Patients with diffuse polymicrogyria are differentiated from those with Walker-Warburg syndrome by the absence of callosal and ocular anomalies and by the "bumpy" outer cortical surface. The outer cortical surface in the Walker- Warburg syndrome is typically smooth on MRI studies.

Addendum

64









References

I. Barkovich Aj, Chuang SH: Unilateral megalencephaly: Correlation of MR imaging and pathologic characteristics. AJNR Am j Neuroradiol 11:525-531, 1990

2. Barkovich Aj, Guerrini R, Battaglia, et al: Band heterotopia: Correlation of outcome with magnetic resonance imaging parameters. Ann Neurol 36:609-617, 1994

3. Barkovich Aj, Knos BO: Gray matter heterotopias: MR characteristics and correlation with developmental and neurologic manifestations. Radiology 182:493- 499,f992

4. Barkovich Aj, Kjos BO: Nonlissencephalic cortical dysplasias: Correlation of imaging findings with clinical deficits. AJNR Am J Neuroradiol 13:95-103, 1992

5. Barkovich Aj, Kuzniecky RI, Dobyns WB, et al: A classification scheme for malformations of cortical development. Neuropediatrics 27:59-63, 1996

6. Bastos AC, Korah IP, Cendes F, et al: Curvilinear reconstruction of 3D magnetic resonance imaging in patients with partial epilepsy: A pilot study. Magn Reson Imaging 13:1107-1112, 1995

7. Becker LE: Central neuronal tumors in childhood: Relationship to dysplasia. J Neurooncol 24:13-19, 1995

8. Cochrane DD, Poskitt Kj, Norman MG: Surgical implications of cerebral dysgenesis. Can J Neurol Sci 18:181-195, 1991

9. Daumas-Duport C, Scheithauer BW, Chodkiewicz JP: Dysembryoplastic neuroepithelial tumor: A surgically curable tumor of young patients with intractable partial seizures. Neurosurgery 23:545-556, 1988

10. Dobyns WB, Truwit CL: Lissencephaly and other malformations of cortical development: 1995 update. Neuropediatrics 26:132-147, 1995

11. Dome HL, O'Gorman AM, Melanson D: Computed tomography of intracranial gangliogliomas. AJNR Am j Neuroradiol 7:281-285, 1986

12. Dubeau F, Tampieri D, Lee N, et al: Periventricular and subcortical nodular heterotopia: A study of 33 patients. Brain 118:1273-1287, 1995

13. Eksioglu YZ, Scheffer IE, Cardenas P, et al: Periventricular heterotopia: An X-linked dominant epilepsy locus causing aberrant cerebral cortical development. Neuron 16:77-87,1996

14. Farrell MA, DeRosa Mj, Curran JG, et al: Neuropathologic findings in cortical resections (including

REFERENCES

65


hemispherectomies) performed for the treatment of intractable childhood epilepsy. Acta Neuropathol 83:246-259,1992

15. Freide RL: Dysplasias of cerebral cortex. In Developmental Neuropathology, ed 2. Berlin, Springer-Verlag, 1989

16. Jardine PE, Clarke MA, Super M: Familial bilateral periventricular nodular heterotopia mimics tuberous sclerosis. Arch Dis Child 74:244-246, 1996

17. Jay V, Becker LE, Otsubo H, et al: Pathology of temporal lobectomy for refractory seizures in children: Review of 20 cases including some unique malformative lesions. J Neurosurg 79:53-61, 1993

18. Jay V, Edwards V, Rutka JT. Crystalline inclusions in a subependymal giant cell tumor in a patient with tuberous sclerosis. Ultrastruct Pathol 17:503-513, 1993

19. Yimura M, Yoshino K, Maeoka Y, et al: Hypomelanosis of Ito: MR findings. Pediatr Radiol 24:68-69,1994

20. Kuroiwa T, Bergey GK, Rothman MI, et al: Radiologic appearance of the dysembroplastic neuroepithelial tumor. Radiology 197:233-238,1995

21. Kuzniecky R, Garcia JH, Gaught E, et al: Cortical dysplasia in temporal lobe epilepsy: Magnetic resonance imaging correlations. Ann Neurol 29:293-298,1991

22. Martin N, Debussche C, De Broucker, et al: Gadolinium-DTPA enhanced MR imaging in tuberous sclerosis. Neuroradiology 31:492-497, 1990

23. Manz Hj, Phillips TM, Rowden G, et al: Unilateral megalencephaly, cerebral cortical dysplasia, neuronal hypertrophy, and heterotopia. Acta Neuropathol 45:97- 103, 1979

24. Menor F, Marti-Bonmati L, Mulas F, et al: Neuroimaging in tuberous sclerosis: A clinico-radiological evaluation in pediatric patients. Pediatr Radiol 22:485- 489, 1992

25. Miller DC, Lang FF, Epstein Fj: Central nervous system gangliogliomas: Part 1. Pathology. f Neurosurg 79: 859-866,1993

26. Moreland DB, Glasauer FE, Egnatchik JG, et al: Focal cortical dysplasia. J Neurosurg 68:487-490, 1988

27. Otsubo H, Hoffman Hj, Humphreys RP, et al: Detection and management of gangliogliomas in children. Surg Neurol 38:371-378,1992

28. Otsubo H, Hwang P, Jay V, et al: Focal cortical dysplasia in children with localization related epilepsy: EEG, MRI and SPECT findings. Pediatr Neurol 9:101-107, 1993

29. Paimini A, Andermann F, Aicardi J, et al: Diffuse cortical dysplasia, or the 'double cortex' syndrome: The clinical and epileptic spectrum in 10 patients. Neurology 41:1656-1662, 1991

30. Raymond AA, Fish DR, Stevens JM, et al: Subependymal heterotopia: A distinct neuronal migration disorder associated with epilepsy. J Neurol Neurosurg Psychiatry 57:1195-1202, 1994

31. Rolland Y, Adamsbaum C, Sellier N, et al: Opercular malformations: Clinical and MRI features in 11 children. Pediatr Radiol 25(suppl 1):S2-8,1995

32. Taylor DC, Falconer MA, Bruton Cj, et al: Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry 34:369-387, 1971

33. Zentner J, Wolf HK, Ostertun B, et al: Gangliogliomas: Clinical, radiological, and histopathological findings in 51 patients. I Neurol Neurosurg Psychiatry 57:1497- 1502,1994

34. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 11.1a. January 2010

66


CLINICAL PICTURE: CLINICAL PICTURE: A 6 years old male patient presented clinically with intractable complex partial seizure. The child is mentally subnormal.


Figure 1. Precontrast MRI T1 image (A) and postcontrast MRI T1 images (B,C) showing evidence of lissencephaly and pachygyria. Also observed an intracortical mass in the left posterior parieto-occipital; area. The mass is hypointense on precontrast scans with no observable postcontrast enhancement. The mass has a very minimal mas effect. No evidence of perilesional edema is observed.

CASE OF THE WEEK


CLINICAL PICTURE


Figure 2. MRI T2 images showing showing similar finding observed in figure 1. The mass is hyperintense on the MRI T2 images, purely intracortical with minimal mass effect. Also noted lissencephaly, pachygyria with probable subependymal heterotopia. No evidence of perilesional edema is observed.

67


Figure 3. MRI FLAIR images. The left parieto-occipital mass is hyperintense on FLAIR images, purely intracortical with mild mass effect. Also observed lissencephaly, polymicrogyria and subependymal nodular heterotopia. No evidence of perilesional edema is observed.

Stereotactic biopsy of the cortical mass revealed a Dysembryoplastic neuroepithelial tumor [DNET]. SEE figure 4.

Dysembryoplastic neuroepithelial tumor [DNET] is a relatively newly described benign tumor arising within the supratentorial cortex and almost always associated with partial complex seizures. These lesions may occasionally appear cystic and show one of the three characteristics which include: a) specific glioneuronal element, b) nodular component, or c) association with cortical dysplasia.

MR scan usually demonstrates a focal cortical lesion most commonly in the temporal lobe that is hypodense on T1 and hyperintense on T2 weighted studies. It is not uncommon for a small subset of these tumors to resemble benign cysts with slightly increased signal on proton density-weighted and FLAIR sequences. Post-contrast enhancement and calcification may also occur occasionally.

Imaging Findings for Dysembryoplastic neuroepithelial tumor

Imaging characteristics of dysembryoplastic neuroepithelial tumor is similar to those of other low-grade glial tumors and may not be possible to distinguish this tumor from diffuse astrocytoma, ganglioglioma, oligodendroglioma, or other low-grade neoplasms.

At CT, the tumor manifests as a hypoattenuating mass.

Calcification may be seen.

Figure 4. Photomicrograph (original magnification, x160; hematoxylineosin stain) of a dysembryoplastic neuroepithelial tumor with cystic degeneration shows a trabecular pattern (long arrows) of glial elements, including astrocytes and oligodendrocytes. Oligodendroglial cells (arrowhead) contain small dark nuclei, whereas the astrocytic cells (short arrow) are somewhat larger with pink cytoplasm.

68


Remodeling of the adjacent inner table of the skull may also be seen.

At MR imaging, dysembryoplastic neuroepithelial tumors most commonly manifest as cortical masses that are hypointense on T1-weighted images and hyperintense on T2-weighted images without surrounding vasogenic edema.

Some lesions may appear as an enlarged gyrus, producing a soap bubble appearance at the cortical margin.

Approximately one-third of dysembryoplastic neuroepithelial tumors enhance following intravenous administration of contrast material.

DIAGNOSIS: DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOUR ASSOCIATED WITH CORTICAL DYSPLASIA

DISCUSSION:

Dysembryoplastic neuroepithelial tumor [DNET] is a benign tumor of neuroepithelial origin arising from the cortical or deep gray matter. Since the description of 39 cases in 1988 by investigators from Paris and the Mayo Clinic, there are now more than 300 cases on record (1,2). These tumors virtually always manifest in patients with medically refractory partial seizures. The vast majority of patients are younger than 20 years, and males are more commonly affected (3). In contrast to other brain neoplasms, neurologic deficits are not common with dysembryoplastic neuroepithelial tumors unless they occur in the presence of complex congenital abnormalities (3). The temporal lobe is the most common site (62%), followed by the frontal lobe (31%) (3). Although the vast majority of dysembryoplastic neuroepithelial tumors are confined to the cortical gray matter, they may also arise within the caudate nucleus, cerebellum, or pons (4,5). Patients with cerebellar dysembryoplastic neuroepithelial tumors present with symptoms (eg, ataxia, vertigo, gait problems) related to this location rather than seizure activity (2). The locations of these tumors support the hypothesis that these lesions are derived from secondary germinal layers (1).

Dysembryoplastic neuroepithelial tumors appear to be remarkably stable in terms of biologic behavior. Despite only partial resection of many of these lesions, complete cessation of all seizure activity is a common result following neurosurgical intervention (1). Recurrence is also very rare (3). However, there is one recent report in the literature of malignant transformation of a dysembryoplastic neuroepithelial tumor that showed a higher degree of mitotic activity than is commonly seen in these tumors (6). The tumor in this case recurred 11 years after the initial surgical resection (6). This case emphasizes

DIAGNOSIS:

DISCUSSION

Figure 1. Dysembryoplastic neuroepithelial tumor

69


the need for long-term follow-up of patients with atypical dysembryoplastic neuroepithelial tumors.

Figure 2. Dysembyroplastic neuroepithelial tumor. Coronal proton density-weighted image (A) and postcontrast (B) images demonstrate a peripherally based lesion (arrow) with trabeculated enhancement. Based solely on these images, it appears that the lesion is extra-axial because gray matter can be seen surrounding the lesion, especially in (A). However, it is not uncommon for an intra-axial neoplasm causing chronic epilepsy to appear extra-axial because it is situated within or replaces the cortex and has the appearance of being outside the cortex in some cross-sectional planes. Thin section imaging allowed visualization of the multicystic nature of this lesion on the enhanced image (B).

The original description of 39 dysembryoplastic neuroepithelial tumors in 1988 resulted from a retrospective review of nearly 300 tumors initially diagnosed as low-grade astrocytomas in patients with medically refractory seizures (1). These 39 specimens shared common histologic features: a multinodular architecture, a "specific glioneuronal element" in a columnar pattern oriented perpendicular to the cortical surface, and focal areas of cortical dysplasia (1). Since that initial description, neuropathologists have noted that these three characteristics may not always be present. This observation has led to the latest classification scheme, which divides these tumors into a "simple form" (without a nodular architecture) and a "complex form" (with a multinodular appearance) (3). They are characterized by an admixture of astrocytes and oligodendroglial elements, in association with "floating neurons" and mucinous degeneration. The tumors generally have a low growth potential as measured by certain metabolic indexes (3). There are several reports of composite neoplasms with both ganglioglioma and dysembryoplastic neuroepithelial tumor components. Since cortical dysplasia is commonly seen with both of these tumors, perhaps they represent the tumoral form of cortical dysplasia or neoplastic transformation of a dysplastic area (7,8,9,10,11).

Figure 3. Dysembryoplastic neuroepithelial tumor in a 14-year-old girl who experienced a seizure while sleeping. (a) Axial CT image shows a hypoattenuating mass of the right parietal lobe. Note the remodeling of the adjacent inner table of the skull. (b) Axial T2-weighted MR image shows marked high signal intensity of the mass, which extends beyond the normal cortical margin ("soap bubble" appearance) and directly remodels the skull. There is no evidence of vasogenic edema associated with the mass. (c) Contrast-enhanced axial T1-weighted MR image shows no evidence of enhancement within the mass.

70


Figure 4. Photomicrograph (original magnification, x120; hematoxylineosin stain) of a dysembryoplastic neuroepithelial tumor shows neuronal elements surrounded by prominent vacuoles, which represent so-called floating neurons (arrows).

SUMMARY

Dysembryoplastic Neuroepithelial Tumor (DNT) is a recently recognized, benign tumor associated with medically intractable, partial complex seizures. Mean age of onset of symptoms is nine years (range 1-19 years). All reported DNT's have been supratentorial, most often involving the temporal lobe (approximately 2/3) followed in frequency by the frontal lobe (1/3). The tumors are primarily cortical in location, although they may extend to involve the subcortical white matter. On CT scans, DNT's are well-defined, low-attenuation lesions which may be mistaken for cysts. The tumors tend to be low signal on T1-weighted MR images and high signal on T2-weighted images, i.e., similar to CSF, but on proton-density images, they are slightly higher in signal than CSF, allowing them to be differentiated from simple cysts. Less than 25% calcify or enhance. There is associated calvarial remodeling in approximately 1/3 of cases.

Differential diagnoses include ganglioglioma and low-grade astrocytoma. A ganglioglioma, however, is more likely to be located within the white matter. Calvarial remodeling, if present, is a helpful differentiating feature in that it would be unlikely for either a ganglioglioma or a low-grade astrocytoma to cause such changes.

The prognosis for patients with DNT is excellent. 70-81% of patients are seizure-free following surgery, and the tumor does not recur, even in cases where resection is considered incomplete.

Addendum





details. Screen resolution is better set at 1024*768 pixel screen area for optimum display.

SUMMARY

71


For an archive of the previously reported cases go to www.yassermetwally.net, then under pages in the right panel, scroll down and click on the text entry "downloadable case records in PDF format"

Also to view a list of the previously published case records follow the following link (http://wordpress.com/tag/case-record/) or click on it if it appears as a link in your PDF reader

References

1.Daumas-Duport C, Scheithauer BW, Chodkiewicz JP, Laws ER, Jr, Vedrenne C. Dysembryoplastic neuroepithelial tumour: a surgically curable tumour of young patients with intractable partial seizures. Neurosurgery 1988; 23:545-556.

2.Fujimoto K, Ohnishi H, Tsujimoto M, Hoshida T, Nakazato Y. Dysembryoplastic neuroepithelial tumor of the cerebellum and brainstem. J Neurosurg 2000; 93:487-489.

3.Daumas-Duport C, Pietsch T, Lantos PL. Dysembryoplastic neuroepithelial tumour. In: Kleihues P, Cavenee WK, eds. Pathology and genetics of tumours of the nervous system. Lyon, France: IARC, 2000; 103-106.

4.Cervera-Pierot P, Varlet P, Chodkiewicz JP, Daumas-Duport C. Dysembryoplastic neuroepithelial tumors located in the caudate nucleus area: report of four cases. Neurosurgery 1997; 40:1065-1070.

5.Kuchelmeister K, Demirel T, Schlorer E, Bergmann M, Gullota F. Dysembryoplastic neuroepithelial tumour of the cerebellum. Acta Neuropathol (Berl) 1995; 89:385-390.

6.Hammond RR, Duggal N, Woulfe JMJ, Girvin JP. Malignant transformation of a dysembryoplastic neuroepithelial tumor. J Neurosurg 2000; 92:722-725.

7.Prayson RA. Composite ganglioglioma and dysembryoplastic neuroepithelial tumor. Arch Pathol Lab Med 1999; 123:247-250.

8.Koeller KK, Dillon WP. MR appearance of dysembryoplastic neuroepithelial tumors (DNT). AJNR Am J Neuroradiol 1992; 13:1319-1325.

9.Kuroiwa T, Kishikawa T, Kato A, Ueno M, Kudo S, Tabuci K. Dysembryoplastic neuroepithelial tumors: MR findings. J Comput Assist Tomogr 1994; 18:352-356.

10.Ostertun B, Wolf HK, Campos MG, et al. Dysembryoplastic neuroepithelial tumors: MR and CT evaluation. AJNR Am J Neuroradiol 1996; 17:419-430.

11.Abe M, Tabuchi K, Tsuji T, Shiraishi T, Koga H, Takagi M. Dysembryoplastic neuroepithelial tumor: report of three cases. Surg Neurol 1995; 43:240-245.

12. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 10.4a October 2009

REFERENCES

72


CLINICAL PICTURE

15 years old female patient presented clinically with mental subnormality and Lennox Gastaut syndrome. The patient's mother gave a history that when the patient was few months of age she had attacks suggestive of west syndrome.


CASE OF THE WEEK


CLINICAL PICTURE


73


Figure 1. A,B CT scan precontrast and C, CT scan postcontrast study, D,E,F precontrast MRI T1 images, G,H,I MRI T2 images. Notice the calcified cortical tuber in the left frontal region. The tuber is hyperdense in CT scan studies and hypointense on the MRI T2 studies (due to calcification). The precontrast T1 hyperintensity observed in the subcortical white matter in (E,F,G) could be due to defective myelination. The cerebral cortex appears lissencephalic and pachygyric especially over he frontal lobes. The cortical tubers surface is smooth but depressed due to degenerative phenomena with cellular loss in the affected cortex. The subcortical white matter adjacent to the cortical tubers shows the characteristic radial white matter lesions, they are wedge-shaped white matter lesions with their apex near the ventricle and their base at the cortex or at the cortical tuber. These white matter lesion are hyperintense on the T2 MRI images and hypointense on the MRI T1 images. They can also be seen as hypodense regions in CT scan studies. Radial white matter lesions are dysplastic heterotopic neurons seen as migration lines running though the cerebral mantle to a normal cortex or a cortical tuber. Subependymal nodules are also seen in (F) forming what is called candle guttering.

Figure 2. MRI T1 images (A,B,C,D) and MRI T2 images (E,F). A case of tuberous sclerosis, notice that cortical tubers have broad, irregular, and slightly depressed surface and most marked in the frontoparietal regions. The brain is lissencephalic and pachygyric. Also notice the characteristic radial white matter lesions, they are wedge-shaped white matter lesions with their apex near the ventricle and their base at the cortex or at the cortical tuber. These white matter lesion are hyperintense on the T2 MRI images and hypointense on the MRI T1 images. Radial white matter lesions are dysplastic heterotopic neurons seen as migration lines running though the cerebral mantle to a normal cortex or a cortical tuber. The precontrast T1 hyperintensity observed in the subcortical white matter in (E) could be due to defective myelination or hypercellularity (Normal neurons and normal glial cells are scanty and abundant undifferentiated neuroepithelial cells and atypical neuron-like cells are seen as migration lines running though the cerebral mantle to a normal cortex or a cortical tuber, these neurons might have a high nuclear to cytoplasmic ratio, with little extracellular water resulting in precontrast T1 hyperintensity and T2 hypointensity)

DIAGNOSIS: TUBEROUS SCLEROSIS

DISCUSSION

DIAGNOSIS:

DISCUSSION

74


Tuberous sclerosis is a hereditable disorder characterized by the development of early in childhood of hamartomas, malformations and congenital tumours of the CNS, skin and viscera. The pathological changes of tuberous sclerosis are widespread and include lesions in the brain, skin, bone, retina, skin and others. Clinically it is characterized by the occurrence of epilepsy, mental retardation and adenoma sebaceous in various combination.

Tuberous sclerosis (TS) is one of the most common phakomatoses. Its occurrence is around 1-20:500,000 births 1, and Donegani et al. 2, based on autopsy records, estimate its prevalence at 1:10,000. Ahlsen et al. 3 in a study carried out in Sweden on a population up to 20 years old, observed a prevalence of 1: 12,900 with a peak of 1:6,800 in the 11-15-year age group. TS is inherited as an autosomal dominant disorder with high penetrance and variable expressivity, with no racial or sexual predilection. As many as 60% of cases have been described as sporadic, resulting from spontaneous genetic mutations in the offspring of healthy parents.4 The number of true sporadic cases is now decreasing as the parents of affected children undergo ocular fundoscopy and renal and cardiac echography.5

TS, like every phakomatosis, can be defined as a primary cytologic dysgenesis.6 The genetic disorder has been identified, with the TSCI and TSC2 genes localized respectively on chromosome 9 band q 34.3 and chromosome 16 band p 13.3.7,8 Nevertheless, a specific molecular marker that would allow recognition of the asymptomatic and quasi-asymptomatic cases has not yet been found.9 TS is a multiorgan disease (skin, retina, lungs, heart, skeleton, and kidneys) involving the embryonic ectoderm, mesoderm, and endoderm. The central nervous system (CNS) is always affected, and CNS disease is often the first indicator of the disorder.10 The primary anomaly of TS is an abnormal differentiation and growth of the neuronal and glial cells, associated with migration anomalies and disorganization of the cortical architecture, formation of tumor-like cell clusters [hamartias or hamartomas according to Gomez 11], and rarely neoplasia. The presence of cell dysplasia, however, differentiates phakomatoses from CNS malformations.6

Genetic causes

TSC is inherited in an autosomal dominant pattern. An affected parent has a 50% chance of transmitting the disease to offspring. There are a significant number of sporadic mutations, estimated to occur in approximately two thirds of cases. 9

Two genes, TSC1 and TSC2, have been identified. TSC1 is located on chromosome 9 and was identified in 1997. This gene encodes for the protein hamartin. The protein tuberin is encoded by the gene TSC2. TSC2, located on chromosome 16, was the first TSC gene discovered in 1993. Approximately 50% of cases are due to TSC1, and the remaining 50% are due to TSC2. Of sporadic cases, 75% are due to a mutation in the TSC2 gene.9

Table 1. Genetics of tuberous sclerosis

At the present time, TSC is a clinical diagnosis, because genetic testing currently is not routinely available. Genetic mutation analysis is available on a research basis. Family members may also be tested on a clinical basis if a mutation is detected. Information regarding this topic is available at the following website: www.geneclinics.org

Criteria for germline mosaicism have recently been outlined. Parents who have no evidence of either major or minor criteria of TSC and also have 2 or more children affected with TSC are said to meet the criteria for germline mosaicism. For this reason, parents who have none of the manifestations of TSC but do have 1 child affected with TSC should be counseled about a 1-2% chance of having another child affected with TSC. The incidence of germline mosaicism is estimated to be approximately 10-25%. 9

RADIOLOGICAL PATHOLOGY OF TUBEROUS SCLEROSIS

Pathologically tuberous sclerosis is characterized by the presence of Cortical tubers. Subependymal nodule, Giant cell astrocytoma, White matter lesions and Deep white matter lesions.

Gene Gene Location Gene product Comment

TSC1 Chromosome 9 Hamartin Recent findings support the hypothesis that the TSC2 gene and perhaps the TSC I gene act as tumor suppressors. When the TSC mutation occurs, the defective gene product of the TSC mutation is unable to suppress the tumor growth caused by a random somatic cell mutation that produces an oncogene stimulating the formation and growth of hamartomas.9

TSC2 Chromosome 16 Tuberin

75


Table 2. Pathology of tuberous sclerosis

Cortical tubers In tuberous sclerosis, the most common clinical presentation is seizure, occurring in more than 80% of cases. 9 The brain characteristically reveals multiple nodules ("tuber") in the crest of cerebral gyri. The

nodules are generally most abundant in the frontal lobe. The involved cortex is firm in consistency and shows some blurring of the junction between the cortex and white matter. Histologically, the subpial area is thickened by proliferating astrocytes that may be large and bizarre with abundant processes. Laminar organization of the cortex is obscured by numerous large, irregularly oriented neurons with coarsely granular Nissl substance. In addition, there are, large cells with abundant, pale cytoplasm and large, round nuclei with prominent nucleoli. These cells are free of Nissl substance and some seem to be of astrocytic lineage because of their GFAP immunopositivity. They are more frequently found in the white matter, occasionally arranged in clusters. Overall, these features are not dissimilar to those of cortical dysplasia of Taylor. In tuberous sclerosis, however, severe gliosis may be noted in the subpial area. 9

Pathology Comment Cortical tubers

They involve gray matter and contiguous white matter. Sometimes two or more adjacent gyri are affected. They may cause gyral broadening and thickening. At histologic examination the laminar architecture of affected cortex is completely disorganized. Normal neurons and normal glial cells are scanty and abundant undifferentiated neuroepithelial cells and atypical neuron-like cells are observed, with rare clusters of abnormal bizarre glial cells. The subcortical white matter adjacent to a cortical tubers is abnormal, and is usually with defective myelination of neural fibers and gliosis.13 The cortical tubers surface is smooth but becomes depressed due to degenerative phenomena with cellular loss in the affected cortex. Dystrophic calcifications are infrequently present in cortical tubers

Subependymal nodule

Typically located in the subependymal walls of the lateral ventricles, usually bilateral and mainly at the foramina of Monro. subependymal nodules have never been observed in the third ventricle.9,11 Their number and size are quite variable. Subependymal nodules contain the same kind of cell abnormalities as cortical tubers, but with very many large, bizarre glial cells, fusiform cells, and undifferentiated neuroectodermal cells. However, neuron-like cells are scant. Much vascular and fibroglial stroma with accumulations of calcium deposits is often found. Focal hemorrhages and necrosis have also been reported.9,11,16

Giant cell astrocytoma

Subependymal Giant-Cell Astrocytomas are clinically and histopathologically benign.20 They grow slowly, have no surrounding edema, are noninvasive, and rarely show malignant degeneration.21 There are no qualitative histopathologic differences between subependymal nodules and Subependymal Giant-Cell Astrocytomas. Like subependymal nodules, Subependymal Giant-Cell Astrocytomas contain large amounts of undifferentiated giant cells or abnormally differentiated cells resembling astrocytes or spongioblasts, together with a few abnormal neurons. The fibrovascular stroma contains dystrophic calcifications and cystic or necrotic areas of degeneration.22 Subependymal Giant-Cell Astrocytomas may originate from subependymal nodules located near the foramen of Monro. Recent findings support the hypothesis that the TSC2 gene and perhaps the TSC I gene act as tumor suppressors. When the TSC mutation occurs, the defective gene product of the TSC mutation is unable to suppress the tumor growth caused by a random somatic cell mutation that produces an oncogene stimulating the formation and growth of hamartomas.9

White matter lesions

Radial curvilinear bands, straight or wedge-shaped bands, and nodular foci were found. Radial white matter lesions run from the ventricle through the cerebral mantle to the normal cortex or cortical tuber, wedge-shaped white matter lesions have their apex near the ventricle and their base at the cortex or at the cortical tuber, and nodular foci are located in the deep white matter. White matter lesions are composed of clusters of dysplastic giant and heterotopic cells, with gliosis and abnormal nerve fiber myelination.1 These anomalies are almost identical to those of the inner core of the cortical tubers. The site, shape, and histopathologic findings of white matter lesions confirm that TSC is a disorder of both histogenesis and cell migration.

Deep white matter lesions

These are focal, single or multiple lesions, always in the deep or periventricular white matter.9

Tuberous sclerosis histopathological features are not dissimilar to those of cortical dysplasia. In tuberous sclerosis, however, severe gliosis may be noted in the subpial area.

76


Figure 3. Postmortem specimens showing cortical tubers, the affected gyri are abnormally broad and flat.

Cortical tubers involve gray matter and contiguous white matter. Sometimes two or more adjacent gyri are affected. They may cause gyral broadening and thickening. On MRI, the affected cortex is frequently pseudopachygyric, but the gray matter does not show signal abnormalities on both short and long TR SE images. At histologic examination the laminar architecture of affected cortex is completely disorganized. Normal neurons and normal glial cells are scanty and abundant undifferentiated neuroepithelial cells and atypical neuron-like cells are observed, with rare clusters of abnormal bizarre glial cells.6 The high cortical cellularity implies a free water loss in gray matter, and this explains the normality of the MR signal.12However, the subcortical white matter MR signal is abnormal adjacent to a cortical tuber, and is usually hyperintense on long TR SE images. This is due to defective myelination of neural fibers and gliosis.13 The subcortical white matter in newborns and very young infants appears hyperintense on TIWI and hypointense on T2WI. This can be explained by a greater amount of free water in the unmyelinated white matter compared to the inner core of the cortical tubers.14 The cortical tubers surface is smooth but becomes depressed due to degenerative phenomena with cellular loss in the affected cortex. Dystrophic calcifications cause marked focal hypointensity on T2WI. 11This is not common in cortical tubers. Signal enhancement on TIWI after GD-DTPA administration is reported in less than 5% of cases.15 Follow-up MRI might show an increase in the number and/or size, or increase of signal enhancement after GD-DTPA of cortical tubers.

Subependymal nodule

Typically located in the subependymal walls of the lateral ventricles, usually bilateral and mainly at the foramina of Monro. subependymal nodules have never been observed in the third ventricle.9,11eir number is quite variable in each patient, and their size from a few millimeters to over I cm. subependymal nodules contain the same kind of cell abnormalities as cortical tubers, but with very many large, bizarre glial cells, fusiform cells, and undifferentiated neuroectodermal cells. However, neuron-like cells are scant. Much vascular and fibroglial stroma with accumulations of calcium deposits is often found. Focal hemorrhages and necrosis have also been reported.9,11,16

Figure 4. Postmortem specimens showing cortical tubers with flat surface

77


Figure 5. Postmortem specimens showing cortical tubers in A and subependymal tubers in B

Figure 6. CT scan precontrast showing subependymal calcified nodules projecting into the ventricular cavity (candle guttering)

Figure 7. MRI T1 images showing cortical tuber, radial white matter lesions and subependymal nodules forming candle guttering. The cerebral cortex appears lissencephalic and pachygyric especially over he frontal lobes.

The brain is usually normal in size, but several or many hard nodules occur on the surface of the cortex or along the subependymal covering of the ventricular system. These nodules are smooth, rounded or polygonal and project slightly above the surface of the neighboring cortex. They are whitish in colour and firm.

78


Figure 8. CT scan precontrast in two cases of tuberous sclerosis showing subependymal noncalcified nodules projecting into the ventricular cavity (A,B) and a calcified nodule at the foramen of monro (C)

On MRI, the subependymal nodules appear to impinge on the ventricular cavity from the subependymal walls. Their signal depends mainly on the presence and amount of mineral deposits. If calcifications are widespread, subependymal nodules are very hypointense in all pulse sequences, occasionally surrounded by a hyperintense rim

on long TRI; otherwise, they are usually isointense to white matter on short TR and slightly hyperintense on long TRI.9,12 Calcifications are rare in newborns and infants, making diagnosis difficult both by CT and MRI.14

However, in children over I year and in adults, calcification of the stroma is usual, and CT, owing to its greater ability to detect calcium, has been considered best for assessment of subependymal nodules.17 Nevertheless, MR gradient echo pulse sequences with short flip angle are equally useful because of the magnetic susceptibility of calcified lesions, which appear profoundly hypointense.18 After contrast medium, subependymal nodules do not enhance on CT, whereas on MRI they show nodular or annular hyperintensity.16 This may be due to higher MRI sensitivity and also to enhancement of uncalcified gliovascular stroma after GD-DTPA administration, while the calcified component remains markedly hypointense.15,25

Figure 9. (A,B) In tuberous sclerosis the lining of the lateral ventricles is frequently the site of numerous small nodules that project into the ventricular cavity (candle gutterings) (blue arrows in A). Also notice cortical tubers (black arrow in A)


The subependymal giant cell astrocytoma (SGCA) is another low-grade (WHO grade 1) astrocytic neoplasm. 13 This

Histopathologically, the nodules are characterized by the presence of a cluster of atypical glial cells in the center and giant cells in the periphery. The nodules are frequently, but not necessarily, calcified. These nodules occasionally give rise to giant cell astrocytoma when they are large in size.

The tuberous sclerosis nodules are variable in size and might attain a huge size. On sectioning the brain, sclerotic nodules may be found in the subcortical gray matter, the white matter and the basal ganglia. The lining of the lateral ventricles is frequently the site of numerous small nodules that project into the ventricular cavity (candle gutterings). Sclerotic nodules are characteristically found in or near the foramen of monro and commonly induce hydrocephalus. The cerebellum, brain stem, and spinal cord are less frequently involved.

79


neoplasm is most commonly seen (>90%) in association with clinical or radiologic evidence for tuberous sclerosis. 13

Tuberous sclerosis is an autosomal dominant phakomatosis, characterized by disseminated hamartomas of the CNS, kidneys, skin, and bone. True neoplasms also occur, with approximately 15% of patients developing SGCA. The tumor is sometimes called the intraventricular tumor of tuberous sclerosis. The lesion usually presents in the teens or 20s.25

Subependymal Giant-Cell Astrocytomas are clinically and histopathologically benign 20. They grow slowly, have no surrounding edema, are noninvasive, and rarely show malignant degeneration.21 There are no qualitative histopathologic differences between subependymal nodules and Subependymal Giant-Cell Astrocytomas. Like subependymal nodules, Subependymal Giant-Cell Astrocytomas contain large amounts of undifferentiated giant cells or abnormally differentiated cells resembling astrocytes or spongioblasts, together with a few abnormal neurons. The fibrovascular stroma contains dystrophic calcifications and cystic or necrotic areas of degeneration.22 Subependymal Giant-Cell Astrocytomas may originate from subependymal nodules located near the foramen of Monro.25

On MRI, uncalcified Subependymal giant-cell astrocytomas are isointense to white matter on short TR images: calcified components are hypointense. On long TR images the signal increases in the parenchymal component of the lesion, whereas calcifications become profoundly hypointense on T2WI. Serpentine, linear, or punctate signal voids believed to be due to dilated tumor vessels. 9 Subependymal Giant-Cell Astrocytomas enhance on CT after iodinated contrast medium administration, whereas subependymal nodules do not increase in density. This was believed to be due to a breakdown of the blood-brain barrier in the Subependymal Giant-Cell Astrocytomas 14, and therefore CT was considered best for differential diagnosis. Both Subependymal Giant-Cell Astrocytomas and subependymal nodules located at the foramen of Monro show nodular enhancement on MRI after GD-DTPA.15 Recent findings support the hypothesis that the TSC2 gene and perhaps the TSC I gene act as tumor suppressors. When the TSC mutation occurs, the defective gene product of the TSC mutation is unable to suppress the tumor growth caused by a random somatic cell mutation that produces an oncogene stimulating the formation and growth of hamartomas.25

Figure 11. Giant cell astrocytoma.

Figure 10. Close-up view of the frontal horn of the left lateral ventricle, showing a giant cell astrocytoma filling the anterior horn in a 15-year-old boy with tuberous sclerosis.

80


Grossly the lesion is a well-demarcated mass. It is almost always in the lateral ventricle, near the foramen of Monro. The lesion is fixed to the head of the caudate nucleus but does not spread through it. As the name implies, an intact layer of ependyma covers the tumor. Thus cerebrospinal fluid dissemination and spread through the brain are not typical. Histologically the lesion contains giant cells that have been variously described as astrocytes, neuronal derivatives, or something in between. The histology is distinctive and may suggest not only this particular tumor, but also the association with tuberous sclerosis that is so common. Calcification is frequent. 9,25

The appearance of SGCA on imaging studies is usually typical, characteristic, and almost pathognomonic. First, most patients show other features of tuberous sclerosis, including cortical tubers and subependymal modules. Second, the tumor location is almost unique-intraventricular, near the foramen of Monro, and attached to the head of the caudate nucleus. Enhancement is often present on both CT and MR. Calcification is common and may be in the form of irregular chunks and nodules. The lesion has a polypoid shape as it protrudes into the lumen of the lateral ventricle. Secondary changes of hydrocephalus, from obstruction of the foramen of Monro, are frequent. Ventricular enlargement may be unilateral (on the side of the tumor) or bilateral.25

White matter lesions Radial curvilinear bands, straight or wedge-shaped bands, and nodular foci are found. Radial white matter lesions run from the ventricle through the cerebral mantle to the normal cortex or cortical tuber, wedge-shaped white matter lesions have their apex near the ventricle and their base at the cortex or at the cortical tuber, and nodular foci are located in the deep white matter. White

matter lesions are composed of clusters of dysplastic giant and heterotopic cells, with gliosis and abnormal nerve fiber myelination.1 These anomalies are almost identical to those of the inner core of the cortical tubers. Therefore, on MRI, the white matter lesions are similarly hyperintense on long TR and isointense or hypointense on short TR images. No signal enhancement with GD-DTPA contrast WAS found. The site, shape, and histopathologic findings of white matter lesions confirm that TSC is a disorder of both histogenesis and cell migration. Heterogeneous gray structures in the white matter without calcification may also be present. 9

Figure 12. Subependymal giant cell astrocytoma. Axial T1-weighted gadolinium-enhanced MR image (A) and postcontrast CT scan (B) show a well-demarcated intraventricular mass in the left frontal horn at the foramen of Monro. The lesion is growing into the ventricle as a polypoid lesion, attached to the head of the caudate nucleus.

Figure 13. Subependymal giant cell astrocytoma.

White matter lesions are dysplastic heterotopic neurons seen as migration lines running from though the cerebral mantle to a normal cortex or a cortical tuber. They are wedge-shaped with their apex near the ventricle and their base at the cortex or at the cortical tuber. Gliosis is commonly present in white matter lesion of tuberous sclerosis. 9

81



These are focal, single or multiple lesions, always in the deep or periventricular white matter. On MRI they are isointense to the cerebrospinal fluid in all pulse sequences, sometimes surrounded by a hyperintense rim on T2WI, without mass effect.

Tuberous sclerosis as a disorder of neuronal cell proliferation, differentiation and migration

Tuberous sclerosis is a primary cell dysplasia resulting from embryonic ectoderm, mesoderm, and endoderm anomalies. In the CNS they involve neuroepithelial cells, which also show disordered cell migration and organization. All the lesions are hamartias or hamartomas, and histologic differences among them are slight and quantitative; therefore, all of these lesions may change with time. The arrest of cell migration at different stages explains the different sites of the various anomalies. Subependymal nodules and periventricular white matter anomalies reflect a failure of migration, white matter lesions an interruption, and cortical tubers an abnormal completion of migration with disordered cortical architecture. Subependymal giant-cell astrocytomas are the only neoplastic growth, and they derive from subependymal nodules that have some proliferative potential. 9

Disorders such as tuberous sclerosis, in which both tumor development and areas of cortical dysplasia are seen, might be a differentiation disorder. The brain manifestations of this disorder include hamartomas of the subependymal layer, areas of cortical migration abnormalities (tubers, cortical dysgenesis), and the development of giant-cell astrocytomas in upwards of 5% of affected patients. Two genes for tuberous sclerosis have been identified: TSCI (encodes for Hamartin) has been localized to 9q34 25, and TSC2 (encodes for Tuberin) has been localized to 16pl3.3 .25

Table 4. Tuberous sclerosis as a disorder of neuronal cell proliferation, differentiation and migration

Table 3. Summary of radiological signs in tuberous sclerosis

MRI or CT scan of the brain

An MRI of the brain is recommended for the detection and follow-up of cortical tubers, Subependymal nodule, and giant cell astrocytoma. Perform MRI during the initial diagnostic work-up and also every 1-3 years in children with TSC. The MRI may be performed less frequently in adults without lesions and as clinically indicated in adults with lesions. Also, perform an MRI in family members if their physical examinations are negative or not definitive for a diagnosis. MRI is preferred over CT scan due to improved visualization and no risk of radiation with repeat examinations.

Cortical tubers, best detected on T2-weighted images, often occur in the gray-white junction. On T2-weighted images, they have increased signal and often are in wedged (tuber) or linear shapes (radial migration lines). Conversely, they have decreased signal uptake on T1-weighted imaging. Previously thought to be pathognomonic, they no longer are considered specific for TSC since isolated cortical dysplasia may have a similar radiographic appearance. There appears to be a correlation between the number of tubers on MRI and severity of mental retardation or seizures.

Subependymal nodules (SEN) are located in the ventricles and often become calcified. The lesions are detected best by CT scan, although they sometimes are noted on MRI or plain film if calcified. They give a candle-dripping appearance.

Subependymal nodule may grow and give rise to a giant cell astrocytoma. A giant cell astrocytoma may cause obstruction with evidence of hydrocephalus or mass effect in some patients. These lesions usually appear in the region of the foramen of Monro, are partially calcified, and often are larger than 2 cm. Detection of a giant cell astrocytoma is slightly more sensitive with MRI than CT scan.

Pathology Comment Subependymal nodules and periventricular white matter anomalies.

Failure of migration.

White matter lesion An interruption of migration.

82


Overview of normal neuronal migration

At the most rostral end of the neural tube in the 40- to 41 -day-old fetus, the first mature neurons, Cajal-Retzius cells, begin the complex trip to the cortical surface. Cajal-Retzius cells, subplate neurons, and corticopetal nerve fibers form a preplate.25 The,neurons generated in the proliferative phase of neurodevelopment represent billions of cells poised to begin the trip to the cortical surface and to form the cortical plate. These neurons accomplish this task by attaching to and migrating along radial glial in a process known as radial migration or by somal translocation in a neuronal process.25 The radial glia extend from the ventricle to the cortical surface. In the process of migration, the deepest layer of the cortical plate migrates and deposits before the other layers. Therefore, the first neurons to arrive at the future cortex are layer VI neurons. More superficial layers of cortex then are formed-the neurons of layer V migrate and pass the neurons of layer VI; the same process occurs for layers IV, III, and II. The cortex therefore is formed in an inside-out fashion.25

A possible mode of movement in neuronal migration on glia would be the attachment of the neuroblast to a matrix secreted by either the glia or the neurons. The attachment of the neuron would be through integrin receptors, cytoskeletal-linking membrane-bound recognition sites for adhesion molecules. That attachment serves as a stronghold for the leading process and soma of the migrating neuron. Neuron movement on radial glia involves an extension of a leading process, neural outgrowth having an orderly arrangement of microtubules. Shortening of the leading process owing to depolymerization or shifts of microtubules may result in movement of the soma relative to the attachment points. This theory of movement of neurons also must include a phase of detachment from the matrix at certain sites, so that the neuron can navigate successfully along as much as 6 cm of developing cortex (the maximum estimated distance of radial migration of a neuron in the human). Finally, the movement of cells must stop at the appropriate location, the boundary between layer I and the forming cortical plate. Therefore, some stop signal must be given for the migrating neuron to detach from the radial glia and begin to differentiate into a cortical neuron. Perhaps that signal is reelin, a protein that is disrupted in the mouse mutant Reeler and is expressed solely in the Cajal Retizius cells at this phase of development. 25

Tuberous sclerosis complex (TSC) is the second most common neurocutaneous disease. It is inherited in an autosomal dominant fashion, although the rate of spontaneous mutation is high. Formerly characterized by the clinical triad of mental retardation, epilepsy, and facial angiofibromas, it is now recognized that TSC may present with a broad range of clinical symptoms due to variable expressivity. TSC may affect many organs, most commonly the brain, skin, eyes, heart, kidneys, and lungs. Common features include cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytomas (SEGAs), facial angiofibromas, hypomelanotic lesions (ash-leaf spots), cardiac rhabdomyomas, and renal angiomyolipomas. Two genes, TSC1 and TSC2, have recently been identified. The current diagnostic criteria, however, continue to be based upon clinical manifestations.

Addendum


To download the current version follow the link "http://pdf.yassermetwally.com/case.zip". You can also download the current version from within the publication or go to my web site at

"http://yassermetwally.com" to download it. Screen resolution is better set at 1024*768 pixel screen area for optimum display

Cortical tubers. An abnormal completion of migration with disordered cortical architecture.

Subependymal giant-cell astrocytomas ( the only neoplastic growth)

They derive from subependymal nodules that have some proliferative potential.

SUMMARY

83


References

1. Braffman BH, Bilaniuk LT, Zimmermann RA. The central nervous system manifestation of the phakomatoses. Radiol Clin North Am 1988;26: 773-800.

2. Donegani G, Grattarola FR, Wildi E. Tuberous sclerosis. In: Vinken PJ, Bruyn GB, eds. The phakomatoses. Vol. 14. Handbook of clinical neurology. Amsterdam: Elsevier, 1972.

3. Ahlsen G, Gilberg IC, Lindblom R, Gilberg G. Tuberous sclerosis in western Sweden. Arch Neurol 1994;51:76-81.

4. Sampson JR, Schahill SJ, Stephenson JBP, Mann L, Connor JM. Genetic aspects of tuberous sclerosis in the west of Scotland. J Med Genet 1989; 26:28-31.

5. Perelman R. Pgdiatrie pratique: pathologie du systeme nerveux et des muscles. Paris: Maloine, 1990.

6. Sarnat HB. Cerebral dysgenesis. Embryology and clinical expression. New York, Oxford: Oxford University Press, 1992.

7. Fryer AE, Chalmers AH, Connor JM, et al. Evidence that the gene for tuberous sclerosis is on chromosome 9. Lancet 1987;1:659-61.

8. Kandt RS, Haines L, Smith S, et al. Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease. Nature Genet 1992;2:37-41.

9. Braffman BH, Bilaniuk LT, Naidich TP, et al. MR imaging of tuberous sclerosis: pathogenesis of this phakomatosis, use of gadopentetate dimeglumine, and literature review. Radiology 1992;183:227-38.

10. Roach ES, Smith M, Huttenlocher P, Bhat M, Alcorn D, Hawley L. Diagnostic criteria of tuberous sclerosis complex. J Child Neural 1992;7:221-4.

11. Gomez MR. Tuberous sclerosis. New York: Raven Press, 1989.

12. Nixon JR, Houser OW, Gomez MR, Okazaki H. Cerebral tuberous sclerosis: MR imaging. Radiology 1989; 170:869-73.

13. Nixon JR, Okazaki H, Miller GM, Gomez MR. Cerebral tuberous sclerosis: postmortem magnetic resonance imaging and pathologic anatomy. Mayo Clin Proc 1989;64:305-1 1.

14. Altmann NR, Purser RK, Donovan Post MJ. Tuberous sclerosis: characteristics at CT and MR imaging. Radiology 1988;167:527-32.

15. Martin N, Debussche C, De Broucker T, Mompoint D, Marsault C, Nahum H. Gadolinium- DTPA enhanced MR imaging in tuberous sclerosis. Neuroradiology 1990;31:492-7.

16. Wippold FJ 11, Baber WW, Gado M, Tobben PJ, Bartnicke BJ. Pre- and postcontrast MR studies in tuberous sclerosis. J Comput Assist Tomogr 1992; 161:69-72.

17. Inoue Y, Nakajima S, Fukuda T, et al. Magnetic resonance images of tuberous sclerosis. Further observations and clinical correlations. Neuroradiology 1988;30:379-84.

18. Berns DH, Masaryk TJ, Weisman B, Modic MT, Blaser SI. Tuberous sclerosis: increased MR detection using gradient echo techniques. J Comput Assist Tomogr 1989;13:896-8.

19. Abbruzzese A, Bianchi MC, Puglioli M, et al. Astrocitomi gigantocellulari nella scierosi tuberosa. Rivista Neuroradiol 1992;5(suppi 1):11-116.

20. Morimoto K, Mogami H. Sequential CT study of subependymal giant-cell astrocytoma associated with tuberous sclerosis. J Neurosurg 1986;65: 874-7.

21. Fitz CR, Harwood-Nash DC, Thompson JR. Neuroradiology of tuberous sclerosis in children. Radiology

REFERENCES 84


1974;110:635.

22. Russell DS, Rubinstein LJ. Pathology of tumors of the nervous system, 5th ed. Baltimore: Williams & Wilkins, 1989.

23. The European Chromosome 16 Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993;75: 1305-15.

24. Pont MS, Elster AD. Lesion of skin and brain: modern imaging of the neurocutaneous syndromes. AJR 1992;158:1193-7.

25. Metwally, MYM: Textbook of Neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 9.1a January 2008

85


CLINICAL PICTURE

9 years old female patient presented clinically with mental subnormality, and Lennox Gastaut syndrome. The patient's familygave a history of west syndrome when the child was few months of age.


Figure 1. Precontrast MRI T1 images showings bilateral subependymal nodules affecting the frontal horns and body of the lateral ventricles. A Cortical tuber can be seen in the occipito-parietal junction, it is hypointense, wedge shaped and involve gray matter and contiguous white matter. The wedge-shaped white matter lesions have their apex near the ventricle and their base at the cortex or at the cortical tuber. Two or more adjacent gyri are affected and appeared lissencephalic, notice gyral broadening and thickening. At histologic examination the laminar architecture of affected cortex is completely disorganized. Some scattered focal hypointense white matter changes are seen.

CASE OF THE WEEK


CLINICAL PICTURE


86


Figure 2. MRI FLAIR images showing bilateral subependymal nodules affecting the frontal horns and body of the lateral ventricles. Bilateral wedge shaped, hyperintense cortical tubers can be seen in the occipito-parietal junction and the frontal area. The tubers involve gray matter and contiguous white matter. Two or more adjacent gyri are affected and appeared lissencephalic, notice gyral broadening and thickening. At histologic examination the laminar architecture of affected cortex is completely disorganized. Some scattered focal hyperintense white matter changes are seen. The wedge-shaped white matter lesions have their apex near the ventricle and their base at the cortex or at the cortical tuber.

Figure 3. MRI FLAIR images showing bilateral subependymal nodules affecting the frontal horns and body of the lateral ventricles. Bilateral wedge shaped, hyperintense cortical tubers can be seen in the occipito-parietal junction and the frontal area. The tubers involve gray matter and contiguous white matter. Two or more adjacent gyri are affected and appeared lissencephalic, notice gyral broadening and thickening. At histologic examination the laminar architecture of affected cortex is completely disorganized. Some scattered focal hyperintense white matter changes are seen. The wedge-shaped white matter lesions have their apex near the ventricle and their base at the cortex or at the cortical tuber.

87


Figure 4. MRI FLAIR images showing bilateral cortical tubers in the temporal lobes. The tubers are wedge shaped, hyperintense and involve the cortical gray matter and the adjacent white matter. The cortex is broadened, thickened, lissencephalic and pachygyric. Notice the periventricular, periaqueductal white matter changes. The wedge-shaped white matter lesions have their apex near the ventricle and their base at the cortex or at the cortical tuber.

Figure 5. MRI T2 images showing bilateral cortical tubers in the temporal lobes. The tubers are wedge shaped, hyperintense and involve the cortical gray matter and the adjacent white matter. The cortex is broadened, thickened, lissencephalic and pachygyric. Notice the periventricular, periaqueductal white matter changes. The wedge-shaped white matter lesions have their apex near the ventricle and their base at the cortex or at the cortical tuber.

88


Figure 6. MRI T2 (A) and FLAIR (B) images showing bilateral cortical tubers in the temporal lobes. The tubers are wedge -shaped, hyperintense and involve the cortical gray matter and the adjacent white matter. The cortex is broadened, thickened, lissencephalic and pachygyric. Notice the scattered focal and diffuse white matter changes. The wedge-shaped white matter lesions have their apex near the ventricle and their base at the cortex or at the cortical tuber.

Box 1. The white matter changes seen in tuberous sclerosis are of two types

DIAGNOSIS: TUBEROUS SCLEROSIS

DISCUSSION

Tuberous sclerosis is a hereditable disorder characterized by the development of early in childhood of hamartomas, malformations and congenital tumours of the CNS, skin and viscera. The pathological changes of tuberous sclerosis are widespread and include lesions in the brain, skin, bone, retina, skin and others. Clinically it is characterized by the occurrence of epilepsy, mental retardation and adenoma sebaceous in various combination.

Tuberous sclerosis (TS) is one of the most common phakomatoses. Its occurrence is around 1-20:500,000 births 1, and Donegani et al. 2, based on autopsy records, estimate its prevalence at 1:10,000. Ahlsen et al. 3 in a study carried out in Sweden on a population up to 20 years old, observed a prevalence of 1: 12,900 with a peak of 1:6,800 in the 11-15-year age group. TS is inherited as an autosomal dominant disorder with high penetrance and variable expressivity, with no racial or sexual predilection. As many as 60% of cases have been described as sporadic, resulting from spontaneous genetic mutations in the offspring of healthy parents.4 The number of true sporadic cases is now decreasing as the parents of affected children undergo ocular fundoscopy and renal and cardiac echography.5 TS, like every phakomatosis, can be defined as a primary cytologic dysgenesis.6 The genetic disorder has been identified, with the TSCI and TSC2 genes localized respectively on chromosome 9 band q 34.3 and chromosome 16 band p 13.3.7,8 Nevertheless, a specific molecular marker that would allow recognition of the asymptomatic and quasi-asymptomatic cases has not yet been found.9 TS is a multiorgan disease (skin, retina, lungs, heart,

1. Radial curvilinear bands, straight or wedge-shaped bands, and nodular foci are found. Radial white matter lesions run from the ventricle through the cerebral mantle to the normal cortex or cortical tuber, wedge-shaped white matter lesions have their apex near the ventricle and their base at the cortex or at the cortical tuber, and nodular foci are located in the deep white matter. White matter lesions are composed of clusters of dysplastic giant and heterotopic cells, with gliosis and abnormal nerve fiber myelination.1 These anomalies are almost identical to those of the inner core of the cortical tubers. The site, shape, and histopathologic findings of white matter lesions confirm that TSC is a disorder of both histogenesis and cell migration.

2. These are focal, single or multiple lesions, always in the deep or periventricular white matter.9

DIAGNOSIS:

DISCUSSION

89


skeleton, and kidneys) involving the embryonic ectoderm, mesoderm, and endoderm. The central nervous system (CNS) is always affected, and CNS disease is often the first indicator of the disorder.10 The primary anomaly of TS is an abnormal differentiation and growth of the neuronal and glial cells, associated with migration anomalies and disorganization of the cortical architecture, formation of tumor-like cell clusters [hamartias or hamartomas according to Gomez 11], and rarely neoplasia. The presence of cell dysplasia, however, differentiates phakomatoses from CNS malformations.6

Genetic causes

TSC is inherited in an autosomal dominant pattern. An affected parent has a 50% chance of transmitting the disease to offspring. There are a significant number of sporadic mutations, estimated to occur in approximately two thirds of cases. 9

Two genes, TSC1 and TSC2, have been identified. TSC1 is located on chromosome 9 and was identified in 1997. This gene encodes for the protein hamartin. The protein tuberin is encoded by the gene TSC2. TSC2, located on chromosome 16, was the first TSC gene discovered in 1993. Approximately 50% of cases are due to TSC1, and the remaining 50% are due to TSC2. Of sporadic cases, 75% are due to a mutation in the TSC2 gene.9

Table 1. Genetics of tuberous sclerosis

At the present time, TSC is a clinical diagnosis, because genetic testing currently is not routinely available. Genetic mutation analysis is available on a research basis. Family members may also be tested on a clinical basis if a mutation is detected. Information regarding this topic is available at the following website: www.geneclinics.org

Criteria for germline mosaicism have recently been outlined. Parents who have no evidence of either major or minor criteria of TSC and also have 2 or more children affected with TSC are said to meet the criteria for germline mosaicism. For this reason, parents who have none of the manifestations of TSC but do have 1 child affected with TSC should be counseled about a 1-2% chance of having another child affected with TSC. The incidence of germline mosaicism is estimated to be approximately 10-25%. 9

RADIOLOGICAL PATHOLOGY OF TUBEROUS SCLEROSIS

Pathologically tuberous sclerosis is characterized by the presence of Cortical tubers. Subependymal nodule, Giant cell astrocytoma, White matter lesions and Deep white matter lesions.

Table 2. Pathology of tuberous sclerosis

Gene Gene Location Gene product Comment TSC1 Chromosome 9 Hamartin Recent findings support the hypothesis that the TSC2 gene and perhaps

the TSC I gene act as tumor suppressors. When the TSC mutation occurs, the defective gene product of the TSC mutation is unable to suppress the tumor growth caused by a random somatic cell mutation that produces an oncogene stimulating the formation and growth of hamartomas.9

TSC2 Chromosome 16 Tuberin

Pathology Comment Cortical tubers

They involve gray matter and contiguous white matter. Sometimes two or more adjacent gyri are affected. They may cause gyral broadening and thickening. At histologic examination the laminar architecture of affected cortex is completely disorganized. Normal neurons and normal glial cells are scanty and abundant undifferentiated neuroepithelial cells and atypical neuron-like cells are observed, with rare clusters of abnormal bizarre glial cells. The subcortical white matter adjacent to a cortical tubers is abnormal, and is usually with defective myelination of neural fibers and gliosis.13 The cortical tubers surface is smooth but becomes depressed due to degenerative phenomena with cellular loss in the affected cortex. Dystrophic calcifications are infrequently present in cortical tubers

Subependymal nodule

Typically located in the subependymal walls of the lateral ventricles, usually bilateral and mainly at the foramina of Monro. subependymal nodules have never been observed in the third ventricle.9,11 Their number and size are quite variable. Subependymal nodules contain the same kind of cell abnormalities as cortical tubers, but with very many large, bizarre glial cells, fusiform cells, and undifferentiated neuroectodermal cells. However, neuron-like cells are scant. Much vascular and fibroglial stroma with accumulations of calcium deposits is often found. Focal hemorrhages and necrosis have also been reported.9,11,16


Subependymal Giant-Cell Astrocytomas are clinically and histopathologically benign.20 They grow slowly, have no surrounding edema, are noninvasive, and rarely show malignant degeneration.21 There are no qualitative histopathologic differences between subependymal nodules and Subependymal Giant-Cell

90


Cortical tubers In tuberous sclerosis, the most common clinical presentation is seizure, occurring in more than 80% of cases. 9 The brain characteristically reveals multiple nodules ("tuber") in the crest of cerebral gyri. The nodules are generally most

abundant in the frontal lobe. The involved cortex is firm in consistency and shows some blurring of the junction between the cortex and white matter. Histologically, the subpial area is thickened by proliferating astrocytes that may be large and bizarre with abundant processes. Laminar organization of the cortex is obscured by numerous large, irregularly oriented neurons with coarsely granular Nissl substance. In addition, there are, large cells with abundant, pale cytoplasm and large, round nuclei with prominent nucleoli. These cells are free of Nissl substance and some seem to be of astrocytic lineage because of their GFAP immunopositivity. They are more frequently found in the white matter, occasionally arranged in clusters. Overall, these features are not dissimilar to those of cortical dysplasia of Taylor. In tuberous sclerosis, however, severe gliosis may be noted in the subpial area. 9

Figure 7. Postmortem specimens showing cortical tubers, the affected gyri are abnormally broad and flat.

Cortical tubers involve gray matter and contiguous white matter. Sometimes two or more adjacent gyri are affected. They may cause gyral broadening and thickening. On MRI, the affected cortex is frequently pseudopachygyric, but the gray matter does not show signal abnormalities on both short and long TR SE images. At histologic examination the laminar architecture of affected cortex is completely disorganized. Normal neurons and normal glial cells are scanty and abundant undifferentiated neuroepithelial cells and atypical neuron-like cells are observed, with rare clusters of abnormal bizarre glial cells.6 The high cortical cellularity implies a free water loss in gray matter, and this explains the normality of the MR signal.12However, the subcortical white matter MR signal is abnormal adjacent to a cortical tuber, and is usually hyperintense on long TR SE images. This is due to defective myelination of neural fibers and gliosis.13 The subcortical white matter in newborns and very young infants appears hyperintense on TIWI and hypointense on T2WI. This can be explained by a greater amount of free water in the unmyelinated white matter compared to the inner core of the cortical tubers.14 The cortical tubers surface is smooth but becomes depressed due to degenerative phenomena with cellular loss in the affected cortex. Dystrophic calcifications cause marked focal hypointensity on T2WI. 11This is not common in cortical tubers. Signal enhancement on TIWI after GD-DTPA administration is reported in less than 5% of cases.15 Follow-up MRI might show an increase in the number and/or size, or increase of signal enhancement after GD-DTPA of cortical tubers.

Astrocytomas. Like subependymal nodules, Subependymal Giant-Cell Astrocytomas contain large amounts of undifferentiated giant cells or abnormally differentiated cells resembling astrocytes or spongioblasts, together with a few abnormal neurons. The fibrovascular stroma contains dystrophic calcifications and cystic or necrotic areas of degeneration.22 Subependymal Giant-Cell Astrocytomas may originate from subependymal nodules located near the foramen of Monro. Recent findings support the hypothesis that the TSC2 gene and perhaps the TSC I gene act as tumor suppressors. When the TSC mutation occurs, the defective gene product of the TSC mutation is unable to suppress the tumor growth caused by a random somatic cell mutation that produces an oncogene stimulating the formation and growth of hamartomas.9

White matter lesions

Radial curvilinear bands, straight or wedge-shaped bands, and nodular foci were found. Radial white matter lesions run from the ventricle through the cerebral mantle to the normal cortex or cortical tuber, wedge-shaped white matter lesions have their apex near the ventricle and their base at the cortex or at the cortical tuber, and nodular foci are located in the deep white matter. White matter lesions are composed of clusters of dysplastic giant and heterotopic cells, with gliosis and abnormal nerve fiber myelination.1 These anomalies are almost identical to those of the inner core of the cortical tubers. The site, shape, and histopathologic findings of white matter lesions confirm that TSC is a disorder of both histogenesis and cell migration.


These are focal, single or multiple lesions, always in the deep or periventricular white matter.9

Tuberous sclerosis histopathological features are not dissimilar to those of cortical dysplasia. In tuberous sclerosis, however, severe gliosis may be noted in the subpial area.

91


Subependymal nodule

Typically located in the subependymal walls of the lateral ventricles, usually bilateral and mainly at the foramina of Monro. subependymal nodules have never been observed in the third ventricle.9,11eir number is quite variable in each patient, and their size from a few millimeters to over I cm. subependymal nodules contain the same kind of cell abnormalities as cortical tubers, but with very many large, bizarre glial cells, fusiform cells, and undifferentiated neuroectodermal cells. However, neuron-like cells are scant. Much vascular and fibroglial stroma with accumulations of calcium deposits is often found. Focal hemorrhages and necrosis have also been reported.9,11,16

Figure 9. Postmortem specimens showing cortical tubers in A and subependymal tubers in B

Figure 8. Postmortem specimens showing cortical tubers with flat surface

Figure 10. CT scan precontrast showing subependymal calcified nodules projecting into the ventricular cavity (candle guttering)

92


Figure 11. MRI T1 images showing cortical tuber, radial white matter lesions and subependymal nodules forming candle guttering. The cerebral cortex appears lissencephalic and pachygyric especially over he frontal lobes.

Figure 12. CT scan precontrast in two cases of tuberous sclerosis showing subependymal noncalcified nodules projecting into the ventricular cavity (A,B) and a calcified nodule at the foramen of monro (C)

On MRI, the subependymal nodules appear to impinge on the ventricular cavity from the subependymal walls. Their signal depends mainly on the presence and amount of mineral deposits. If calcifications are widespread, subependymal nodules are very hypointense in all pulse sequences, occasionally surrounded by a hyperintense rim on long TRI;

otherwise, they are usually isointense to white matter on short TR and slightly hyperintense on long TRI.9,12 Calcifications are rare in newborns and infants, making diagnosis difficult both by CT and MRI.14 However, in children over I year and in adults, calcification of the stroma is usual, and CT, owing to its greater ability to detect calcium, has been considered best for assessment of subependymal nodules.17 Nevertheless, MR gradient echo pulse sequences with short flip angle are equally useful because of the magnetic susceptibility of calcified lesions, which appear profoundly hypointense.18 After contrast medium, subependymal nodules do not enhance on CT, whereas on MRI they show nodular or annular hyperintensity.16 This may be due to higher MRI sensitivity and also to enhancement of uncalcified gliovascular stroma after GD-DTPA administration, while the calcified component remains markedly hypointense.15,25

The brain is usually normal in size, but several or many hard nodules occur on the surface of the cortex or along the subependymal covering of the ventricular system. These nodules are smooth, rounded or polygonal and project slightly above the surface of the neighboring cortex. They are whitish in colour and firm.

Histopathologically, the nodules are characterized by the presence of a cluster of atypical glial cells in the center and giant cells in the periphery. The nodules are frequently, but not necessarily, calcified. These nodules occasionally give rise to giant cell astrocytoma when they are large in size.

The tuberous sclerosis nodules are variable in size and might attain a huge size. On sectioning the brain, sclerotic nodules may be found in the subcortical gray matter, the white matter and the basal ganglia. The lining of the lateral ventricles is frequently the site of numerous small nodules that project into the ventricular cavity (candle gutterings). Sclerotic nodules are characteristically found in or near the foramen of monro and commonly induce hydrocephalus. The cerebellum, brain stem, and spinal cord are less frequently involved.

93


Figure 13. (A,B) In tuberous sclerosis the lining of the lateral ventricles is frequently the site of numerous small nodules that project into the ventricular cavity (candle gutterings) (blue arrows in A). Also notice cortical tubers (black arrow in A)


The subependymal giant cell astrocytoma (SGCA) is another low-grade (WHO grade 1) astrocytic neoplasm. 13 This neoplasm is most commonly seen (>90%) in association with clinical or radiologic evidence for tuberous sclerosis. 13 Tuberous sclerosis is an autosomal dominant phakomatosis, characterized by disseminated hamartomas of the CNS, kidneys, skin, and bone. True neoplasms also occur, with approximately 15% of patients developing SGCA. The tumor is sometimes called the intraventricular tumor of tuberous sclerosis. The lesion usually presents in the teens or 20s.25

Subependymal Giant-Cell Astrocytomas are clinically and histopathologically benign 20. They grow slowly, have no surrounding edema, are noninvasive, and rarely show malignant degeneration.21 There are no qualitative histopathologic differences between subependymal nodules and Subependymal Giant-Cell Astrocytomas. Like subependymal nodules, Subependymal Giant-Cell Astrocytomas contain large amounts of undifferentiated giant cells or abnormally differentiated cells resembling astrocytes or spongioblasts, together with a few abnormal neurons. The fibrovascular stroma contains dystrophic calcifications and cystic or necrotic areas of degeneration.22 Subependymal Giant-Cell Astrocytomas may originate from subependymal nodules located near the foramen of Monro.25

On MRI, uncalcified Subependymal giant-cell astrocytomas are isointense to white matter on short TR images: calcified components are hypointense. On long TR images the signal increases in the parenchymal component of the lesion, whereas calcifications become profoundly hypointense on T2WI. Serpentine, linear, or punctate signal voids believed to be due to dilated tumor vessels. 9 Subependymal Giant-Cell Astrocytomas enhance on CT after iodinated contrast medium administration, whereas subependymal nodules do not increase in density. This was believed to be due to a breakdown of the

Figure 14. Close-up view of the frontal horn of the left lateral ventricle, showing a giant cell astrocytoma filling the anterior horn in a 15-year-old boy with tuberous sclerosis.

94


blood-brain barrier in the Subependymal Giant-Cell Astrocytomas 14, and therefore CT was considered best for differential diagnosis. Both Subependymal Giant-Cell Astrocytomas and subependymal nodules located at the foramen of Monro show nodular enhancement on MRI after GD-DTPA.15 Recent findings support the hypothesis that the TSC2 gene and perhaps the TSC I gene act as tumor suppressors. When the TSC mutation occurs, the defective gene product of the TSC mutation is unable to suppress the tumor growth caused by a random somatic cell mutation that produces an oncogene stimulating the formation and growth of hamartomas.25

Figure 15. Giant cell astrocytoma.

Grossly the lesion is a well-demarcated mass. It is almost always in the lateral ventricle, near the foramen of Monro. The lesion is fixed to the head of the caudate nucleus but does not spread through it. As the name implies, an intact layer of ependyma covers the tumor. Thus cerebrospinal fluid dissemination and spread through the brain are not typical. Histologically the lesion contains giant cells that have been variously described as astrocytes, neuronal derivatives, or something in between. The histology is distinctive and may suggest not only this particular tumor, but also the association with tuberous sclerosis that is so common. Calcification is frequent. 9,25

The appearance of SGCA on imaging studies is usually typical, characteristic, and almost pathognomonic. First, most patients show other features of tuberous sclerosis, including cortical tubers and subependymal modules. Second, the tumor location is almost unique-intraventricular, near the foramen of Monro, and attached to the head of the caudate nucleus. Enhancement is

Figure 16. Subependymal giant cell astrocytoma. Axial T1-weighted gadolinium-enhanced MR image (A) and postcontrast CT scan (B) show a well-demarcated intraventricular mass in the left frontal horn at the foramen of Monro. The lesion is growing into the ventricle as a polypoid lesion, attached to the head of the caudate nucleus.

Figure 17. Subependymal giant cell astrocytoma.

95


often present on both CT and MR. Calcification is common and may be in the form of irregular chunks and nodules. The lesion has a polypoid shape as it protrudes into the lumen of the lateral ventricle. Secondary changes of hydrocephalus, from obstruction of the foramen of Monro, are frequent. Ventricular enlargement may be unilateral (on the side of the tumor) or bilateral.25

White matter lesions Radial curvilinear bands, straight or wedge-shaped bands, and nodular foci are found. Radial white matter lesions run from the ventricle through the cerebral mantle to the normal cortex or cortical tuber, wedge-shaped white matter lesions have their apex near the ventricle and their base at the cortex or at the cortical tuber, and nodular foci are located in the deep white matter. White matter lesions are composed of

clusters of dysplastic giant and heterotopic cells, with gliosis and abnormal nerve fiber myelination.1 These anomalies are almost identical to those of the inner core of the cortical tubers. Therefore, on MRI, the white matter lesions are similarly hyperintense on long TR and isointense or hypointense on short TR images. No signal enhancement with GD-DTPA contrast WAS found. The site, shape, and histopathologic findings of white matter lesions confirm that TSC is a disorder of both histogenesis and cell migration. Heterogeneous gray structures in the white matter without calcification may also be present. 9


These are focal, single or multiple lesions, always in the deep or periventricular white matter. On MRI they are isointense to the cerebrospinal fluid in all pulse sequences, sometimes surrounded by a hyperintense rim on T2WI, without mass effect.

Tuberous sclerosis as a disorder of neuronal cell proliferation, differentiation and migration

Tuberous sclerosis is a primary cell dysplasia resulting from embryonic ectoderm, mesoderm, and endoderm anomalies. In the CNS they involve neuroepithelial cells, which also show disordered cell migration and organization. All the lesions are hamartias or hamartomas, and histologic differences among them are slight and quantitative; therefore, all of these lesions may change with time. The arrest of cell migration at different stages explains the different sites of the various anomalies. Subependymal nodules and periventricular white matter anomalies reflect a failure of migration, white matter lesions an interruption, and cortical tubers an abnormal completion of migration with disordered cortical architecture. Subependymal giant-cell astrocytomas are the only neoplastic growth, and they derive from subependymal nodules that have some proliferative potential. 9

Disorders such as tuberous sclerosis, in which both tumor development and areas of cortical dysplasia are seen, might be a differentiation disorder. The brain manifestations of this disorder include hamartomas of the subependymal layer, areas of cortical migration abnormalities (tubers, cortical dysgenesis), and the development of giant-cell astrocytomas in upwards of 5% of affected patients. Two genes for tuberous sclerosis have been identified: TSCI (encodes for Hamartin) has been

White matter lesions are dysplastic heterotopic neurons seen as migration lines running from though the cerebral mantle to a normal cortex or a cortical tuber. They are wedge-shaped with their apex near the ventricle and their base at the cortex or at the cortical tuber. Gliosis is commonly present in white matter lesion of tuberous sclerosis. 9

Table 3. Summary of radiological signs in tuberous sclerosis

MRI or CT scan of the brain

An MRI of the brain is recommended for the detection and follow-up of cortical tubers, Subependymal nodule, and giant cell astrocytoma. Perform MRI during the initial diagnostic work-up and also every 1-3 years in children with TSC. The MRI may be performed less frequently in adults without lesions and as clinically indicated in adults with lesions. Also, perform an MRI in family members if their physical examinations are negative or not definitive for a diagnosis. MRI is preferred over CT scan due to improved visualization and no risk of radiation with repeat examinations.

Cortical tubers, best detected on T2-weighted images, often occur in the gray-white junction. On T2-weighted images, they have increased signal and often are in wedged (tuber) or linear shapes (radial migration lines). Conversely, they have decreased signal uptake on T1-weighted imaging. Previously thought to be pathognomonic, they no longer are considered specific for TSC since isolated cortical dysplasia may have a similar radiographic appearance. There appears to be a correlation between the number of tubers on MRI and severity of mental retardation or seizures.

Subependymal nodules (SEN) are located in the ventricles and often become calcified. The lesions are detected best by CT scan, although they sometimes are noted on MRI or plain film if calcified. They give a candle-dripping appearance.

Subependymal nodule may grow and give rise to a giant cell astrocytoma. A giant cell astrocytoma may cause obstruction with evidence of hydrocephalus or mass effect in some patients. These lesions usually appear in the region of the foramen of Monro, are partially calcified, and often are larger than 2 cm. Detection of a giant cell astrocytoma is slightly more sensitive with MRI than CT scan.

96


localized to 9q34 25, and TSC2 (encodes for Tuberin) has been localized to 16pl3.3 .25

Table 4. Tuberous sclerosis as a disorder of neuronal cell proliferation, differentiation and migration

Figure 18. A,B CT scan precontrast and C, CT scan postcontrast study, D,E,F precontrast MRI T1 images, G,H,I MRI T2 images. Notice the calcified cortical tuber in the left frontal region. The tuber is hyperdense in CT scan studies and hypointense on the MRI T2 studies (due to calcification). The precontrast T1 hyperintensity observed in the subcortical white matter in (E,F,G) could be due to defective myelination. The cerebral cortex appears lissencephalic and pachygyric especially over he frontal lobes. The cortical tubers surface is smooth but depressed due to degenerative phenomena with cellular loss in the affected cortex. The subcortical white matter adjacent to the cortical tubers shows the characteristic radial white matter lesions, they are wedge-shaped white matter lesions with their apex near the ventricle and their base at the cortex or at the cortical tuber. These white matter lesion are hyperintense on the T2 MRI images and hypointense on the MRI T1 images. They can also be seen as hypodense regions in CT scan studies. Radial white matter lesions are dysplastic heterotopic neurons

Pathology Comment Subependymal nodules and periventricular white matter anomalies.

Failure of migration.

White matter lesion An interruption of migration. Cortical tubers. An abnormal completion of migration with disordered

cortical architecture. Subependymal giant-cell astrocytomas ( the only neoplastic growth)

They derive from subependymal nodules that have some proliferative potential.

97


seen as migration lines running though the cerebral mantle to a normal cortex or a cortical tuber. Subependymal nodules are also seen in (F) forming what is called candle guttering.

Figure 19. MRI T1 images (A,B,C,D) and MRI T2 images (E,F). A case of tuberous sclerosis, notice that cortical tubers have broad, irregular, and slightly depressed surface and most marked in the frontoparietal regions. The brain is lissencephalic and pachygyric. Also notice the characteristic radial white matter lesions, they are wedge-shaped white matter lesions with their apex near the ventricle and their base at the cortex or at the cortical tuber. These white matter lesion are hyperintense on the T2 MRI images and hypointense on the MRI T1 images. Radial white matter lesions are dysplastic heterotopic neurons seen as migration lines running though the cerebral mantle to a normal cortex or a cortical tuber. The precontrast T1 hyperintensity observed in the subcortical white matter in (E) could be due to defective myelination or hypercellularity (Normal neurons and normal glial cells are scanty and abundant undifferentiated neuroepithelial cells and atypical neuron-like cells are seen as migration lines running though the cerebral mantle to a normal cortex or a cortical tuber, these neurons might have a high nuclear to cytoplasmic ratio, with little extracellular water resulting in precontrast T1 hyperintensity and T2 hypointensity)

Overview of normal neuronal migration

At the most rostral end of the neural tube in the 40- to 41 -day-old fetus, the first mature neurons, Cajal-Retzius cells, begin the complex trip to the cortical surface. Cajal-Retzius cells, subplate neurons, and corticopetal nerve fibers form a preplate.25 The,neurons generated in the proliferative phase of neurodevelopment represent billions of cells poised to begin the trip to the cortical surface and to form the cortical plate. These neurons accomplish this task by attaching to and migrating along radial glial in a process known as radial migration or by somal translocation in a neuronal process.25 The radial glia extend from the ventricle to the cortical surface. In the process of migration, the deepest layer of the cortical plate migrates and deposits before the other layers. Therefore, the first neurons to arrive at the future cortex are layer VI neurons. More superficial layers of cortex then are formed-the neurons of layer V migrate and pass the neurons of layer VI; the same process occurs for layers IV, III, and II. The cortex therefore is formed in an inside-out fashion.25

A possible mode of movement in neuronal migration on glia would be the attachment of the neuroblast to a matrix secreted by either the glia or the neurons. The attachment of the neuron would be through integrin receptors, cytoskeletal-linking membrane-bound recognition sites for adhesion molecules. That attachment serves as a stronghold for the leading process and soma of the migrating neuron. Neuron movement on radial glia involves an extension of a leading process, neural outgrowth having an orderly arrangement of microtubules. Shortening of the leading process owing to depolymerization or shifts of microtubules may result in movement of the soma relative to the attachment points. This theory of movement of neurons also must include a phase of detachment from the matrix at certain sites, so that the neuron can navigate successfully along as much as 6 cm of developing cortex (the maximum estimated distance of radial migration of a neuron in the human). Finally, the movement of cells must stop at the appropriate location, the boundary between layer I and the forming cortical plate. Therefore, some stop signal must be given for the migrating neuron to detach

98


from the radial glia and begin to differentiate into a cortical neuron. Perhaps that signal is reelin, a protein that is disrupted in the mouse mutant Reeler and is expressed solely in the Cajal Retizius cells at this phase of development. 25

Tuberous sclerosis complex (TSC) is the second most common neurocutaneous disease. It is inherited in an autosomal dominant fashion, although the rate of spontaneous mutation is high. Formerly characterized by the clinical triad of mental retardation, epilepsy, and facial angiofibromas, it is now recognized that TSC may present with a broad range of clinical symptoms due to variable expressivity. TSC may affect many organs, most commonly the brain, skin, eyes, heart, kidneys, and lungs. Common features include cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytomas (SEGAs), facial angiofibromas, hypomelanotic lesions (ash-leaf spots), cardiac rhabdomyomas, and renal angiomyolipomas. Two genes, TSC1 and TSC2, have recently been identified. The current diagnostic criteria, however, continue to be based upon clinical manifestations.

Addendum

A new version of case record of the week publication is uploaded in my web site every week (every Saturday and remains available till Friday.)

To download the current PDF version of case record of the week publication follow the link "http://pdf.yassermetwally.com/case.pdf".

To download the current software version of case record of the week publication (crow.exe) follow the link: http://neurology.yassermetwally.com/crow.zip

You can also download the current version from my web site at "http://yassermetwally.com". The case is also presented as a short case in PDF format, to download the short case follow the link:


details. Screen resolution is better set at 1024*768 pixel screen area for optimum display Click here for an archive of the previously reported cases in downloadable PDF files. For an archive of the previously reported cases go to www.yassermetwally.net, then under pages in the right panel, scroll

down and click on the text entry "Downloadable case records in PDF format" and "Downloadable short cases in PDF format"

Also to view a list of the previously published case records follow the following link (http://wordpress.com/tag/case-record/).

References

1. Braffman BH, Bilaniuk LT, Zimmermann RA. The central nervous system manifestation of the phakomatoses. Radiol Clin North Am 1988;26: 773-800.

2. Donegani G, Grattarola FR, Wildi E. Tuberous sclerosis. In: Vinken PJ, Bruyn GB, eds. The phakomatoses. Vol. 14. Handbook of clinical neurology. Amsterdam: Elsevier, 1972.

3. Ahlsen G, Gilberg IC, Lindblom R, Gilberg G. Tuberous sclerosis in western Sweden. Arch Neurol 1994;51:76-81.

4. Sampson JR, Schahill SJ, Stephenson JBP, Mann L, Connor JM. Genetic aspects of tuberous sclerosis in the west of Scotland. J Med Genet 1989; 26:28-31.

5. Perelman R. Pgdiatrie pratique: pathologie du systeme nerveux et des muscles. Paris: Maloine, 1990.

6. Sarnat HB. Cerebral dysgenesis. Embryology and clinical expression. New York, Oxford: Oxford University Press, 1992.

7. Fryer AE, Chalmers AH, Connor JM, et al. Evidence that the gene for tuberous sclerosis is on chromosome 9. Lancet 1987;1:659-61.

8. Kandt RS, Haines L, Smith S, et al. Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker

SUMMARY

REFERENCES

99


for polycystic kidney disease. Nature Genet 1992;2:37-41.

9. Braffman BH, Bilaniuk LT, Naidich TP, et al. MR imaging of tuberous sclerosis: pathogenesis of this phakomatosis, use of gadopentetate dimeglumine, and literature review. Radiology 1992;183:227-38.

10. Roach ES, Smith M, Huttenlocher P, Bhat M, Alcorn D, Hawley L. Diagnostic criteria of tuberous sclerosis complex. J Child Neural 1992;7:221-4.

11. Gomez MR. Tuberous sclerosis. New York: Raven Press, 1989.

12. Nixon JR, Houser OW, Gomez MR, Okazaki H. Cerebral tuberous sclerosis: MR imaging. Radiology 1989; 170:869-73.

13. Nixon JR, Okazaki H, Miller GM, Gomez MR. Cerebral tuberous sclerosis: postmortem magnetic resonance imaging and pathologic anatomy. Mayo Clin Proc 1989;64:305-1 1.

14. Altmann NR, Purser RK, Donovan Post MJ. Tuberous sclerosis: characteristics at CT and MR imaging. Radiology 1988;167:527-32.

15. Martin N, Debussche C, De Broucker T, Mompoint D, Marsault C, Nahum H. Gadolinium- DTPA enhanced MR imaging in tuberous sclerosis. Neuroradiology 1990;31:492-7.

16. Wippold FJ 11, Baber WW, Gado M, Tobben PJ, Bartnicke BJ. Pre- and postcontrast MR studies in tuberous sclerosis. J Comput Assist Tomogr 1992; 161:69-72.

17. Inoue Y, Nakajima S, Fukuda T, et al. Magnetic resonance images of tuberous sclerosis. Further observations and clinical correlations. Neuroradiology 1988;30:379-84.

18. Berns DH, Masaryk TJ, Weisman B, Modic MT, Blaser SI. Tuberous sclerosis: increased MR detection using gradient echo techniques. J Comput Assist Tomogr 1989;13:896-8.

19. Abbruzzese A, Bianchi MC, Puglioli M, et al. Astrocitomi gigantocellulari nella scierosi tuberosa. Rivista Neuroradiol 1992;5(suppi 1):11-116.

20. Morimoto K, Mogami H. Sequential CT study of subependymal giant-cell astrocytoma associated with tuberous sclerosis. J Neurosurg 1986;65: 874-7.

21. Fitz CR, Harwood-Nash DC, Thompson JR. Neuroradiology of tuberous sclerosis in children. Radiology 1974;110:635.

22. Russell DS, Rubinstein LJ. Pathology of tumors of the nervous system, 5th ed. Baltimore: Williams & Wilkins, 1989.

23. The European Chromosome 16 Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993;75: 1305-15.

24. Pont MS, Elster AD. Lesion of skin and brain: modern imaging of the neurocutaneous syndromes. AJR 1992;158:1193-7.

25. Metwally, MYM: Textbook of Neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 9.4a October 2008

100


CLINICAL PICTURE:

8 years old male patient presented clinically with right sided hemiplegia since birth, Lennox Gastaut syndrome (with a history suggestive of infantile spasm during the first few months of life) and mental subnormality. The vision in the left eye was completely lost since birth and the vision in the right eye was markedly defective. The child showed evidence of growth and developmental delay.


Figure 1. Postcontrast CT scan images (A,B) and Precontrast MRI T1 images (C). Notice the cleft that extends through the entire thickness of cerebral hemisphere from the ventricular surface (ependyma) to the periphery (pial surface) of the brain, apparently the cleft is lined by gray matter (Open lip schizencephaly). The schizencephalic cleft is appreciated at the parasylvian regions and is seen communicating with an encephalocele externally. The optic nerves are markedly hypoplastic bilaterally. The septum pellucidum is markedly deficient, hypoplastic and can not be appreciated in the presented images. The hypoplastic septum pellucidum resulted in a box- like appearance of the frontal horns. It is difficult to see the pituitary stalk in the presented images. The cerebral cortex is lissencephalic and pachygyric and the corpus callosum is markedly thinned anteriorly. The schizencephalic cleft walls are separated (open-lip or type II schizencephaly).

CASE OF THE WEEK


CLINICAL PICTURE


101


Figure 2. Septo-optic dysplasia. Precontrast MRI T1 images. Notice the cleft that extends through the entire thickness of cerebral hemisphere from the ventricular surface (ependyma) to the periphery (pial surface) of the brain, apparently the cleft is lined by gray matter (Open lip schizencephaly). The schizencephalic cleft is appreciated at the parasylvian regions and is seen communicating with an encephalocele externally. The optic nerves are markedly hypoplastic bilaterally. The septum pellucidum is markedly deficient, hypoplastic and can not be appreciated in the presented images. The hypoplastic septum pellucidum resulted in a box- like appearance of the frontal horns. It is difficult to see the pituitary stalk in the presented images. The cerebral cortex is lissencephalic and pachygyric and the corpus callosum is markedlythinned anteriorly (B,C). The schizencephalic cleft walls are separated (open-lip or type II schizencephaly).

Figure 3. Septo-optic dysplasia. Precontrast MRI T1 images. Notice the cleft that extends through the entire thickness of cerebral hemisphere from the ventricular surface (ependyma) to the periphery (pial surface) of the brain, apparently the cleft is lined by gray matter (Open lip schizencephaly). The schizencephalic cleft is appreciated at the parasylvian regions and is seen communicating with an encephalocele externally. The optic nerves (A) and optic chiasma (B) are markedly hypoplastic bilaterally. The septum pellucidum is markedly deficient, hypoplastic and can not be appreciated in the presented images. The hypoplastic septum pellucidum resulted in a box- like appearance of the frontal horns. It is difficult to see the pituitary stalk in the presented images. The cerebral cortex is lissencephalic and pachygyric and the corpus callosum is markedly thinned anteriorly (A). The schizencephalic cleft walls are separated (open-lip or type II schizencephaly). The pituitary gland appeared vacuolated (B)

102


Figure 4. Septo-optic dysplasia. Precontrast MRI T1 images. Notice the cleft that extends through the entire thickness of cerebral hemisphere from the ventricular surface (ependyma) to the periphery (pial surface) of the brain, apparently the cleft is lined by gray matter (Open lip schizencephaly). The schizencephalic cleft is appreciated at the parasylvian regions and is seen communicating with an encephalocele externally. The optic nerves (A) and optic chiasma (B) are markedly hypoplastic bilaterally. The septum pellucidum is markedly deficient, hypoplastic and can not be appreciated in the presented images. The hypoplastic septum pellucidum resulted in a box- like appearance of the frontal horns. It is difficult to see the pituitary stalk in the presented images. The cerebral cortex is lissencephalic and pachygyric. The schizencephalic cleft walls are separated (open-lip or type II schizencephaly). The pituitary gland appeared vacuolated (B)

The encephalocele and the skull wall expansion that are present at the opening of the open-lip schizencephaly (in the presented case) is believed to result from CSF pulsations from the lateral ventricles transmitted through the cleft. [45]

DIAGNOSIS: SEPTO-OPTIC DYSPLASIA WITH OPEN LIP SCHIZENCEPHALY

DISCUSSION:

Septo-optic dysplasia (de Morsier syndrome)

Septo-optic dysplasia (de Morsier syndrome) is a disorder characterized by the absence of the septum pellucidum, optic nerve hypoplasia, and hypothalamic dysfunction. It may be associated with agenesis of the corpus callosum. This disorder should be considered in any patient who exhibits at least two of the above abnormalities and perhaps even solely hypothalamic dysfunction [2]. Septo-optic dysplasia also appears to involve prosencephalic cleavage and development of anterior telencephalic structures [3]. About 50% of patients with septo-optic dysplasia have schizencephaly [1].

Patients may present with visual disturbance, seizures, mental retardation, hemiparesis (especially if associated with schizencephaly), quadriparesis, or hypothalamic dysfunction. Endocrine abnormalities may include growth hormone, thyroid hormone, or antidiuretic hormone function or levels. The consideration of septo-optic dysplasia necessitates an evaluation of the hypothalamic-pituitary axis because as many as 60% of the children with this disorder might exhibit

Case summary

Open-lip or type II schizencephaly Deficient and hypoplastic septum pellucidum Dysplatic cerebral cortex (The cerebral cortex is lissencephalic and

pachygyric) The pituitary gland appeared vacuolated Hypoplastic optic nerves and optic chiasma Hypoplastic corpus callosum Encephalocele

DIAGNOSIS:

DISCUSSION

103


evidence of a disturbance of endocrine function [4]. This evaluation can include thyroid function studies and electrolytes; these patients are at high risk for growth retardation.

The recent identification of patients with this condition that harbor mutations in the transcriptional regulator gene HESX1, suggest that the mechanism of this disorder is likely genetic and a patterning or segmental abnormality [5]. Even though the genetic abnormality has been identified for a minority of patients, there exists the possibility that this may not represent an entirely genetic disorder because associations have been made with young maternal age, diabetes, the use of anticonvulsants, phencyclidine, cocaine, and alcohol [6,45]

Pathology of septo-optic dysplasia

Several congenital malformations might be associated with macroscopic malformations of the septal nuclei. Most of them involve the midline structures, including the septum pellucidum. For example, septo-optic dysplasia is a syndrome characterized by the absence of the septum pellucidum and optic nerve hypoplasia It may also be associated with pituitary insufficiency resulting in growth and developmental delay. The septal nuclei abnormalities are often an element of a larger cerebral malformation, such as holoprosencephaly, schizencephaly, or porencephaly. In most cases, other midline structures such as the optic nerves, hypothalamus, and septum pellucidum are involved. Absence of the septum pellucidum may reach 80% to 90% in conditions such as schizencephaly. Focal heterotopias or cortical dysplasias may be associated with epileptic seizures. Severe mental retardation and intractable seizures are typical features of the more common larger cerebral malformations and of the syndromes associated with chromosomal anomalies. In some cases of corpus callosum agenesis, it is possible to discern a few axon bundles in an anteroposterior orientation that attempted to cross posteriorly. These are called Probst's bundles. If the corpus callosum is absent, the subcallosal interhemispheric tracts such as the anterior, posterior, and hippocampal commissure might be enlarged. The presence of Probst's bundles is considered by some to indicate that the agenesis of the corpus callosum is due to a primary cause and not the result of secondary injury such as hypoxia. These primary causes include chromosomal abnormalities, single gene defects, and metabolic defects. Cysts and lipomas may be associated with absence of the corpus callosum. [45]

Large occiput encephaloceles may include significant parts of the brain, inducing hypoplasia of the anterior and middle cranial fossa. The brain in the encephalocele could show ischemia or polymicrogyria or be normal. The hypoplasia of the anterior and middle cranial fossa may stretch the septal nuclei, fornix, and septum pellucidum, among other structures. In contrast, transsphenoidal and sphenoethmoidal encephaloceles may directly involve the septal nuclei because they may be included in the herniated brain. [45]

Neuroendocrine disorders in septo-optic dysplasia

Syndromes that may be associated with pituitary-hypothalamic dysfunction include septo-optic dysplasia, Kallmann's syndrome, and empty sella syndrome. In addition, other developmental anomalies may be associated with pituitary-hypothalamic defects, including agenesis of the corpus callosum, holoprosencephaly, and basal cephaloceles. [45]

Septo-optic dysplasia, a disorder of ventral induction, is considered a mild form of holoprosencephaly. It is a disorder of abnormal induction of the midline mesoderm occurring at the same time as the development of the optic vesicles. Failure of differentiation of the mesoderm into the optic stalk results in aplasia of the stalk. [15] Septo-optic dysplasia is characterized by absence or hypoplasia of the septum pellucidum associated with hypoplasia of the optic nerves as first described by DeMorsier. [12] Associated hypothalamic-pituitary dysfunction occurs in two thirds of patients. [17,18,19] Patients may have hypopituitarism that ranges from panhypopituitarism to growth hormone deficiency, thyroid-stimulating hormone deficiency, elevated prolactin, or ACTH or ADH deficiency. [16] Visual symptoms include nystagmus, amblyopia, or hemianopsia. This syndrome may result from in utero injury or genetic abnormalities. [9] Environmental factors implicated are maternal diabetes, quinidine ingestion, anticonvulsants, alcohol or drug abuse, and cytomegalovirus. [17,45] There may be associated anomalies of neuronal migration, such as schizencephaly and gray matter heterotopias.

On imaging, there is absence or hypoplasia of the septum pellucidum resulting in a box- like appearance of the frontal horns. [8,13,14] Hypoplasia of the optic disks is often diagnosed by an ophthalmologist; however, optic nerve, optic tract, or optic chiasm hypoplasia may be seen in 50% of patients on imaging. [8] Other associated abnormalities include absence of the fornix and callosal dysgenesis. [11,45] On MR imaging, three patterns of involvement have been described in septo-optic dysplasia. [8,11.45]

1. One group has neuronal migration anomalies such as schizencephaly and gray matter heterotopias, hypothalamic-pituitary dysfunction, and partial absence of the septum pellucidum. [45]

2. The other group has complete absence of the septum pellucidum with cerebral white matter hypoplasia. This group may be associated with hypoplasia of the genu of the corpus callosum or hypoplasia of the anterior falx cerebri.

3. Another group of these patients with ectopia of the posterior pituitary has also been described. [11]

Other anomalies that may be associated with complete or partial absence of the septum pellucidum include holoprosencephaly, hydranencephaly, basilar cephaloceles, dysgenesis of the corpus callosum, chronic hydrocephalus,

104


Chiari II malformation, and schizencephaly. [7,10,20]

Optic nerve hypoplasia in septo-optic dysplasia

Optic nerve hypoplasia, a specific clinical entity, is an increasingly common cause of infantile blindness in the United States. It is characterized by a small optic disc surface area and thin optic nerve caused by a congenital nonprogressive decrease in the number of optic nerve axons. Unilateral and bilateral optic nerve hypoplasia occurs with roughly equal frequency. Various pathophysiologic theories have been proposed, including failure of axons to normally develop; a destructive developmental event, such as a vascular insult; exaggerated apoptosis; or a genetic disorder. [45]

All patients with optic nerve hypoplasia show visual field defects; localized defects as well as generalized constriction are seen. The loss of visual acuity is variable depending on the degree of involvement with axons from the macula, the center of sight. [45]

Optic nerve hypoplasia is recognized as part of a spectrum of optic nerve, central nervous system (CNS), and hypothalamic-pituitary axis congenital anomalies [21]. From the ophthalmologist's perspective, optic nerve hypoplasia can be assigned into five sometimes overlapping groups: isolated unilateral or bilateral optic nerve hypoplasia, with absence of the septum pellucidum (septo-optic dysplasia), with posterior pituitary ectopia or absence of the pituitary stalk, with hemispheric migration anomalies, or with intrauterine and/or perinatal hemispheric injuries [22]. Optic nerve hypoplasia is also associated with a variety of ocular and systemic disorders, including aniridia, albinism, maternal diabetes, fetal alcohol syndrome, and other maternal ingestions [23,24,25].

Schizencephaly in septo-optic dysplasia

Schizencephaly is the most complete form of migrational disorders. It is thought to be caused by a complete agenesis of a section of the cerebral tissue, which results in clefts that extend through the entire thickness of cerebral hemisphere. At the margin of the cleft the pial membrane and ependymal lining of the ventricle lie adjacent to each other and form a pial ependymal seam [29] Schizencephaly probably occurs as the end result of a variety of insults occuring at a critical time and in a critical location during brain development. No specific inciting or unusual prenatal events are described. The lesion is most likely related to multiple etiologies including genetic, toxic, metabolic, vascular or infectious disease. Familial cases have been reported. [30] Septooptic dysplasia, also called as De Morsier disease is a syndrome consisting of blindness, hypoplastic optic nerves and absence of septum pellucidum in females. [29] It is known that Schizencephaly and septo-optic dysplasia frequently coexists. [31] Associated anomalies are heterotopias, Dandy Walker malformation, hydrocephalus and polymicrogyria. [28] Cleft may be unilateral or bilateral, symmetrical or asymmetrical. Commonly located near pre/post central gyrus [26.27]] The cleft in Schizencephaly are lined either totally or in part by gray matter and extend from pial surface to ependyma of the lateral ventricle. The clefts can be located anywhere but commonly occur in parasylvian regions. The cavity formed in open lip type varies in size from small to large and may communicate with lateral ventricle. The ventricular system may be enlarged, particularly in-patients with open lip form of Schizencephaly. [30]

Absence of septum pellucidum, dysgenesis of corpus callosum are often associated with open lip Schizencephaly [28,29] Differential diagnosis includes subarachnoid cysts and porencephaly. Using CT diagnosis of Schizencephaly is sometimes difficult particularly in case of type I. CT may show a slight outpouching at the ependymal surface of cleft and a full thickness cleft may be difficult to identify on CT Scan .Secondary findings like hydrocephalus, heterotopia, polymicrogyria, subdural hygromas and arachnoid cysts can be identified. [30] MRI gives most detailed and precise definition of anatomy and anomaly. For anatomy MRI T1 images suffice [28] MRI is the modality of choice. MRI better delineates the gray matter lining the cleft, which is pathognomonic finding in Schizencephaly.MRI also provides superb cortical anatomy detail and multiplanar capacity. Primary findings related to the cleft and secondary findings associated with Schizencephaly are identified using MRI.The ability of MRI pulse sequence to differentiate gray matter and white matter permit demonstration of gray matter heterotopias in the subcortical white matter beneath the cleft, abnormalities involving the cortex (pachygyria and polymicrogyria) and other secondary findings are also identified. Homolateral absence of sylvian vasculature, small medullary pyramids low position of fornix and thinning of the corpus callosum are findings related to absent cerebral cortex and are better demonstrated by MRI than with other studies.

Sonography can be done in neonatal period in-patients in whom this anomaly is suspected. In Schizencephaly type I, a

Groups with optic nerve hypoplasia

Isolated unilateral or bilateral optic nerve hypoplasia Optic nerve hypoplasia with absence of the septum pellucidum

(septo-optic dysplasia) Optic nerve hypoplasia with posterior pituitary ectopia or absence

of the pituitary stalk Optic nerve hypoplasia with hemispheric migration anomalies Optic nerve hypoplasia with intrauterine and/or perinatal

hemispheric injuries

105


hyperechoic line extends from the parasylvian region to the anterior portion of lateral ventricle. The hyperechoic line represents the cortex lining the fused cleft. This type of anomaly is difficult to detect with ultrasound and requires high index of suspicion and highly skilled operator. In Schizencephaly type II an anechoic band or cavity, representing the fluid filled cleft extends from the cortical surface of lateral ventricle. The meeting of the closed lip portion or apex of the cleft with the margin of ventricle may be identified as a ventricular diverticulum or dimple. The size of the caudate, thalamus and lenticular nuclei (subcortical gray matter structures) is decreased. Other associated anomalies such as ventricular enlargement may also be identified. [30]

This case represents a typical association of septo-optic dysplasia with open lip Schizencephaly with all cardinal neurological cardinal features on one hand and a rare form of unilateral open lip cleft on the other. It highlights the importance of MRI in diagnosis of such a condition.

SCHIZENCEPHALY

Schizencephaly is an uncommon disorder of neuronal migrational characterized by a cerebrospinal fluid–filled cleft, which is lined by gray matter. The cleft extends across the entire cerebral hemisphere, from the ventricular surface (ependyma) to the periphery (pial surface) of the brain.

The clefts may be unilateral or bilateral and may be closed (fused lips), as in schizencephaly type I, or separated (open lips), as in schizencephaly type II. Presentation and outcome are variable, but patients typically present with seizures, hemiparesis, and developmental deficits. Usually, the severity of symptoms is related to the amount of brain affected by the abnormality.

Aetiology and types of schizencephaly

Several theories have been proposed to explain the etiology of schizencephaly, although none is universally accepted. The leading theory indicates that schizencephaly results from an early, focal destruction of the germinal matrix and surrounding brain before the hemispheres are fully formed. Schizencephaly probably occurs as the end result of a variety of insults occurring at a critical time and in a critical location during brain development. No specific inciting or unusual prenatal events have been identified, and reported cases are sporadic. The lesion is most likely related to multiple etiologies, including genetic, toxic, metabolic, vascular, or infectious causes. Familial cases of schizencephaly have been reported. Schizencephaly is uncommon; to our knowledge, there are no documented geographical differences in its occurrence. Severity of the symptoms depends on the amount of brain involved. Affected patients typically have seizures, hemiparesis, variable developmental delay, and blindness. Patients also have variable degrees of mental retardation. Patients with open-lip schizencephaly die at an earlier age than patients with the closed-lip form. Usually, death results from failure to thrive, chronic infections, and respiratory problems. Patients with closed-lip schizencephaly may not present clinically until later in infancy or early childhood and may live to early adulthood.

Schizencephaly is divided into 2 types, which have prognostic significance. In closed-lip or type I schizencephaly, the cleft walls are in apposition. In open-lip or type II schizencephaly, the cleft walls are separated. Schizencephaly type II occurs more commonly than type I.

The clefts in schizencephaly are lined either totally or in part by gray matter and extend from the pial surface to the ependyma of the lateral ventricle. The clefts can be located anywhere, but they commonly occur in the parasylvian regions. The clefts can be unilateral or bilateral, and can be either symmetric or asymmetric. The cavity formed in the open-lip type varies in size from small to large and may communicate with the lateral ventricle. The ventricular system may be enlarged, particularly in patients with the open-lip form of schizencephaly.

Gray-matter heterotopia (collections of gray matter in abnormal locations), polymicrogyria, and arachnoid cysts can be associated with schizencephaly. Heterotopias and polymicrogyria typically line the clefts. Microcephaly has been noted in some patients. The septum pellucidum is absent in 80-90% of patients, and schizencephaly may coexist with septo-optic dysplasia.

Clinical picture of schizencephaly

Clinical features of schizencephaly are highly variable. Patients with unilateral clefts with fused lips may have mild hemiparesis and seizures but otherwise have normal development. When the cleft is open, patients present with mild-to-moderate developmental delay and hemiparesis; severity is related to the extent of cortex involved in the defect.

Patients with bilateral clefts present with severe mental deficits and severe motor anomalies including spastic quadriparesis. Frequently, these patients present with blindness, which is often associated with optic nerve hypoplasia. Language development is more likely to be normal in patients with unilateral schizencephaly compared to patients with bilateral clefts.

Intractable seizures frequently are noted in schizencephaly. Several types of seizures have been reported including generalized tonic-clonic, partial motor, and sensory seizures. Infantile spasms have been seen in a few children. Reports

106


have found no correlation between the subtype of schizencephaly and the occurrence or type of seizure disorder. Identification of gray matter lining the cleft is the pathognomonic finding in differentiating schizencephaly from porencephaly; this is best demonstrated on MRIs.

The more complete information obtained by MRI enables a more accurate prediction of neurologic outcome.

Figure 6. Bilateral open lip schizencephaly

Neuroimaging of schizencephaly

CT scan

Using CT, the diagnosis of schizencephaly is sometimes difficult, particularly type I, or closed lip schizencephaly. CT scans of closed-lip schizencephaly may show only a slight outpouching at the ependymal surface of the cleft, and a full-thickness cleft may be difficult to identify on CT scan. The cleft is partially or totally lined by gray matter and extends from the lateral ventricle to the pial surface of the cerebral hemisphere. Secondary findings that can be identified on CT

Figure 5. Open-lip schizencephaly with cortical dysplasia

107


scan include hydrocephalus, heterotopia, polymicrogyria, subdural hygromas, and arachnoid cysts.

MRI

MRI is the modality of choice for evaluating patients with schizencephaly. MRI better delineates the gray matter lining the cleft, which is the pathognomonic finding in schizencephaly. MRI also provides superb cortical anatomy detail and multiplanar capability. Primary findings related to the cleft and secondary findings associated with schizencephaly are identified using MRI.

The ability of MRI pulse sequences to differentiate gray matter and white matter permits demonstration of gray-matter heterotopias in the subcortical white matter beneath the cleft, abnormalities involving the cortex (eg, pachygyria or polymicrogyria), and other secondary findings also identified by using CT scans. Homolateral absence of the sylvian vasculature, small medullary pyramids, a low position of the fornix, and thinning of the corpus callosum are findings related to absent cerebral cortex and are better demonstrated by MRI than with other studies.

Figure 7. A, Schizencephaly. Axial T2-weighted MRI in unilateral closed-lip (type I) schizencephaly. The cleft is lined by gray matter and extends from the pial surface to the lateral ventricle. B, Schizencephaly. Axial T2-weighted (left) and coronal T1-weighted (right) MRIs in bilateral closed-lip (type I) schizencephaly. A ventricular diverticulum defines the meeting of the closed-lip portion of the clefts with the margin of the ventricles. The septum pellucidum is absent, and the clefts are lined by gray matter and extend from the pial surface to the lateral ventricle. C, Schizencephaly. Axial T2-weighted MRI demonstrates a small open-lip schizencephaly. The septum pellucidum is absent. D, Schizencephaly. Axial T2-weighted MRI in unilateral open-lip (type II) schizencephaly. The septum pellucidum is absent, and a large cerebrospinal fluid–filled cleft extends from the lateral ventricle to the cortical surface. The cleft is lined by gray matter. E, Schizencephaly. Coronal sonograms with a corresponding coronal T1-weighted MRI of open-lip bilateral schizencephaly. Extensive bilateral schizencephalic defects with large CSF-filled clefts extend from the lateral ventricles to the cortical surface.

SUMMARY

Schizencephaly is the term describing gray matter-lined clefts that extend through the entire hemisphere from the lateral ventricles to the cortical surface, characterized pathologically by a pial-ependymal continuity [28,29]. The gray matter lining these clefts is dysplastic and has irregular inner and outer surfaces, identical to that of polymicrogyria. The clefts can be unilateral or bilateral and are most commonly located near the pre- and postcentral gyri, locations almost

SUMMARY

108


identical to those in which polymicrogyria occurs [22,23]. It is probable that schizencephaly represents an extreme variant of cortical dysplasia, in which the infolding of cortex extends all the way into the lateral ventricle [22,23]. The lips of the cleft may be fused, in which case the walls are directly apposed, obliterating the CSF space within the cleft at that point. When the lips are separated, CSF fills the cleft from the lateral ventricle to the subarachnoid space surrounding the hemispheres [23,28-30]. As in polymicrogyria, large vessels are often seen in the cleft between the lips of the schizencephaly.

The severity of the clinical symptoms is related to the amount of involved brain [23, 31,32]. Patients with a unilateral cleft with fused lips typically present with mild hemiparesis or epilepsy but are otherwise developmentally normal. Patients with unilateral clefts with separated lips more commonly present with hemiparesis and a mild to moderate developmental delay, depending on the location of the cleft within the brain. Patients with bilateral clefts tend to be severely retarded, with refractory seizures beginning at a very early age and severe motor anomalies, and they may appear to be blind. Optic nerve hypoplasia is seen in up to one-third of affected patients [8,30, 33,34].

Routine spin-echo MR obtained in at least two planes is usually adequate for imaging of schizencephalies. These studies show full-thickness clefts, lined by gray matter with an irregular inner surface, that extend through the hemisphere from the ventricle to the surface of the brain. The gray matter lining the cleft often extends into the ventricle as a subependymal heterotopia [6,8,23,30,32]. A dimple is usually seen in the wall of the lateral ventricle where it communicates with the cleft. The dimple provides a helpful sign of continuity of the cleft with the ventricle when the lips of the cleft are fused. The gyral pattern of the cortex adjacent to the cleft is usually abnormal, with features characteristic of polymicrogyria. Polymicrogyria may also be present in the hemisphere contralateral to a unilateral schizencephaly [22,23]. Therefore, the contralateral hemisphere should always be scrutinized.

The calvarium is often expanded over the opening of an open-lip schizencephaly. The expansion is believed to result from CSF pulsations from the lateral ventricles transmitted through the cleft. When plagiocephaly is severe, insertion of a ventriculoperitoneal shunt may help to dampen the pulsations and reverse the cranial asymmetry.

Addendum




http://pdf.yassermetwally.com/short.pdf At the end of each year, all the publications are compiled on a single CD-ROM, please contact the author to know

more details. Screen resolution is better set at 1024*768 pixel screen area for optimum display. For an archive of the previously reported cases go to www.yassermetwally.net, then under pages in the right panel,

scroll down and click on the text entry "downloadable case records in PDF format"

References

[1] Aicardi J, Goutieres F. The syndrome of absence of the septum pellucidum with porencephalies and other developmental defects. Neuropediatrics 1981;12:319-29.

[2] Brickman JM, Clements M, Tyrell R, et al. Molecular effects of novel mutations in Hesxl/HESXI associated with human pituitary disorders. Development 2001;128:5189-99.

[3] Ouvier R, Billson F. Optic nerve hypoplasia: a review. J Child Neurol 1986;1:181-8.

[4] Costin G, Murphree AL. Hypothalamic-pituitary function in children with optic nerve hypoplasia. Am J Dis Child 1985;139:249-54.

[5] Dattani MT, Martinez-Barbera JP, Thomas PQ, et al. Mutations in the homeobox gene HESXI/Hesxl associated with septo-optic dysplasia in human and mouse. Nat Genet 1998; 19:125-33.

REFERENCES

109


[6] Patel H, Tze WJ, Crichton JU, et al. Optic nerve hypoplasia with hypopituitarism: septo- optic dysplasia with hypopituitarism. Am J Dis Child 1975;129:175-80.

[7] Aicardi J, Goutieres F: The syndrome of absence of the septum pellucidum with porencephalies and other developmental defects. Neuropediatrics 12:319-329, 1981

[8] Barkovich A, Fram E, Norman D: Septooptic dysplasia: MR imaging. Radiology 171:189-192,1989

[9] Barkovich AJ: Pediatric Neuroimaging, ed 2. New York, Raven Press, 1995, pp 236-237

[10] Barkovich Aj, Norman D: Absence of the septum pellucidum: A useful sign in the diagnosis of congenital brain malformations. AJR Am j Roentgenol 152:353- 360,1989

[11] Brodsky M, Glasier C: Optic nerve hypoplasia: Clinical significance of associated central nervous system abnormalities on magnetic resonance imaging. Arch Ophthalmol 111:66-74,1993

{12] DeMorsier G: Etudes sur les dysraphics cranio-encephaliques 111. Agenese du septum lucidum avec malformation du tractus optique. La dysplasie septo- optic. Schweiz Arch Neurol Neurochir Psychiatry 77:267-292,1956

[13] Fitz C: Holoprosencephaly and related entities. Neuroradiology 25:3-238, 1983

[14] Fitz CR: Holoprosencephaly and septo-optic dysplasia. Neuroimaging Clin North Am 4:263-281, 1994

[15] Hale BR, Rice P: Septo-optic dysplasia: Clinical and embryological aspects. Dev Med Child Neurol 16: 812-817,1974

[16] Izenberg N, Rosenblum M, Parks JS: The endocrine spectrum of septo-optic dysplasia. Clin Pediatr (Phila) 23:632-636, 1984

[17] Morishima A, Aranoff G: Syndrome of septooptic- pituitary dysplasia: The clinical spectrum. Brain Dev 8:233-239,1986

[18] Skarf B, Hoyt C: Optic nerve hypoplasia in children: Association with anomalies of the endocrine and CNS. Arch Ophthalmol 102:62-67,1984

[19] Stanhope R, Preece M, Brook C: Hypoplastic optic nerves and pituitary dysfunction: A spectrum of anatomical and endocrine abnormalities. Arch Dis Child 59:111-114,1984

[20] Harwood-Nash D, Fitz C: Neuroradiology in Infants and Children. St. Louis, CV Mosby, 1976, pp 484-486

[21] Campbell CL. Septo-optic dysplasia: a literature review. Optometry. 2003;74(7):417–426.

[22]Brodsky MC, Glasier CM. Optic nerve hypoplasia. Clinical significance of associated central nervous system abnormalities on magnetic resonance imaging. Arch Ophthalmol. 1993;111(1):66–74.

[23]Brown GC. Optic nerve hypoplasia and colobomatous defects. J Pediatr Ophthalmol Strabismus. 1982;19(2):90–93.

[24]Chan T, Bowell R, O'Keefe M, et al.. Ocular manifestations in fetal alcohol syndrome. Br J Ophthalmol. 1991;75(9):524–526.

[25]Mansour AM, Bitar FF, Traboulsi EI, et al.. Ocular pathology in congenital heart disease. Eye. 2004;19(1):29–34.

[26] S.K.Sethi, R.S.Solanki Radiological Quiz. Indian J. Radiology and Imaging, 2004,14:1:95-96.

[27] D.A Shah, G.D.Rathod, Radiological Quiz Ind J Radiology and Imaging, 2005,15:1:127-128.

[28] Yutaka Sato, Simon C.S.Kao, and Wilbur L.Smith, RCNA, March 1991, Vol. 29,No 2 :179-194,

[29] C.Raybaud Destructive lesions of Brain Neuroradiology 1983; 25:265-291.

[30] Ken R.Close Schizencephaly www emedicine.com/radio/topic622.htm last updated April 7, 2004

[31] AJNR, Mar/Apr, 1988:9:297-302.:MR imaging of Schizencephaly; A.James Barkovich, David Norman.

[32] Barkovich AJ, Norman D: MR imaging of schizencephaly. AJR Am J Roentgenol 1988 Jun; 150(6): 1391-6.

110


[33] Barkovich AJ: Schizencephaly. In: Pediatric Neuroimaging. 2nd ed. Philadelphia: Lippincott-Raven; 1996:219-25.

[34] Barth PG: Schizencephaly and nonlissencephalic cortical dysplasias. AJNR Am J Neuroradiol 1992 Jan-Feb; 13(1): 104-6.

[35] Bird CR, Gilles FH: Type I schizencephaly: CT and neuropathologic findings. AJNR Am J Neuroradiol 1987 May-Jun; 8(3): 451-4.

[36] Byrd SE, Osborn RE, Bohan TP, Naidich TP: The CT and MR evaluation of migrational disorders of the brain. Part II. Schizencephaly, heterotopia and polymicrogyria. Pediatr Radiol 1989; 19(4): 219-22.

[37] Chamberlain MC, Press GA, Bejar RF: Neonatal schizencephaly: comparison of brain imaging. Pediatr Neurol 1990 Nov-Dec; 6(6): 382-7.

[38] Denis D, Chateil JF, Brun M, et al: Schizencephaly: clinical and imaging features in 30 infantile cases. Brain Dev 2000 Dec; 22(8): 475-83.

[39] DiPietro MA, Brody BA, Kuban K, Cole FS: Schizencephaly: rare cerebral malformation demonstrated by sonography. AJNR Am J Neuroradiol 1984 Mar-Apr; 5(2): 196-8.

[40] Komarniski CA, Cyr DR, Mack LA, Weinberger E: Prenatal diagnosis of schizencephaly. J Ultrasound Med 1990 May; 9(5): 305-7.

[41] Lee SH, Rao K, Zimmerman RA: Schizencephaly. In: Cranial MRI and CT. 4th ed. New York: McGraw-Hill; 1999: 163-5.

[42] Miller GM, Stears JC, Guggenheim MA, Wilkening GN: Schizencephaly: a clinical and CT study. Neurology 1984 Aug; 34(8): 997-1001.

[43] Osborne AG: Schizencephaly. In: Diagnostic Neuroradiology. St Louis: Mosby-Year Book; 1994:52-6.

[44] Packard AM, Miller VS, Delgado MR: Schizencephaly: correlations of clinical and radiologic features. Neurology 1997 May; 48(5): 1427-34.

[45] Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 9.2a April 2008

111


CLINICAL PICTURE

A 6 months old male patient presented with macrocephaly, west syndrome, right sided hemiplegia, and severe developmental delay.


Figure 1, A case of hemimegalencephaly. Precontrast MRI T1 images showing a moderately enlarged left cerebral hemisphere with diffuse lissencephaly, pachygyria, and cystic white matter changes. Also noted some precontrast white matter hyperintensity probably due to defective myelination. Subcortical band heterotopias are probably present.

CASE OF THE WEEK


CLINICAL PICTURE


112


Figure 2. A case of hemimegalencephaly. Precontrast MRI T1 images showing a moderately enlarged left cerebral hemisphere with diffuse lissencephaly, pachygyria, and cystic white matter changes. Also noted some precontrast white matter hyperintensity probably due to defective myelination. The ventricular system on the left side are enlarged. The genu of the Corpus callosum is poorly seen in these images. Notice abnormal shape of the brain with bulging on the left side.

Figure 3. A case of hemimegalencephaly. Precontrast MRI T1 images showing a moderately enlarged left cerebral hemisphere with diffuse lissencephaly, pachygyria, and cystic white matter changes. Also noted some precontrast white matter hyperintensity probably due to defective myelination. The ventricular system on the left side are enlarged. The genu of the Corpus callosum is poorly seen in these images. Notice abnormal shape of the brain with bulging on the left

113


side.

Figure 4. MRI T2 image (A) and MRI FLAIR images (B,C) showing diffuse white matter hyperintensity (which correlates with histopathologic findings of poor myelination and early cystic changes) and subependymal nodular heterotopias. Notice abnormal shape of the brain with bulging on the left side.

Figure 5. MRI T2 image (A) and postcontrast MRI sagittal T1 image (B) showing diffuse white matter hyperintensity (which correlates with histopathologic findings of poor myelination and early cystic changes). Notice agenesis of the corpus callosum with hypoplasia of the cerebellum and the brain stem (B). The basal ganglia are poorly visualized. Notice abnormal shape of the brain with bulging on the left side.

114


DIAGNOSIS: A CASE OF HEMIMEGALENCEPHALY

DISCUSSION

Hemimegalencephaly (HME) consists of diffuse unilateral hypertrophy of the brain. This malformation has been the subject of several reports over the past few years (1).

The malformation is strictly unilateral. Computed tomography (CT) and magnetic resonance imaging (MRI) show a characteristic appearance of prominent and diffuse enlargement of one hemisphere with a shift of the midline to the normal side (Fig. 6). In most cases the ventricle on the hypertrophic side is enlarged. T2-weighted MRI sequences usually show an intense signal in the subcortical white matter (2). The gyral pattern is slightly modified, typically with widening of the gyri (Fig. 7) and thickening of the cortical ribbon. In a some cases , the brain surface appeared polymicrogyric.

Hemimegalencephaly or unilateral megalencephaly is a congenital disorder in which there is hamartomatous overgrowth of all or part of a cerebral hemisphere (20,21). The affected hemisphere may have focal or diffuse neuronal migration defects, with areas of polymicrogyria, pachygyria, and heterotopia. Hemimegalencephaly is a rare disorder and was first described by Sims in 1835 after reviewing 253 autopsies (22). Although the cause is unknown, it is postulated that it occurs due to insults during the second trimester of pregnancy, or as early as the 3rd week of gestation, as a genetically programmed developmental disorder related to cellular lineage and establishment of symmetry (20). Hemimegalencephaly may also be considered a primary disorder of proliferation wherein the neurons that are unable to form synaptic connections are not eliminated and are thus accumulated.

Hemimegalencephaly differs from other cerebral dysgeneses because of its extreme asymmetry not corresponding to any normal stage of human brain development. No chromosomal abnormalities have been associated with hemimegalencephaly. There are three types of hemimegalencephaly (20). The isolated form occurs as a sporadic disorder without hemicorporal hypertrophy or cutaneous or systemic involvement. The syndromic form is associated with other diseases and may occur as hemihypertrophy of part or all of the ipsilateral body. It has been described in patients with epidermal nevus syndrome, Proteus syndrome, neurofibromatosis type 1, hypermelanosis of Ito, Klippel-Weber-Trenaunay syndrome, and tuberous sclerosis (21,23). Therefore, the syndromic type may follow a mendelian pattern of inheritance. The third and least common type is total hemimegalencephaly, in which there is also enlargement of the ipsilateral half of the brainstem and cerebellum.

Affected patients may have macrocephaly at birth and in early infancy and often present with an intractable seizure disorder, hemiplegia, and severe developmental delay (21). Males and females are equally affected. Pregnancy is usually uncomplicated, but cesarean section may be required owing to cephalopelvic disproportion. Therefore, macrocephaly is often the first presentation at birth (21). Hemimegalencephaly has a high mortality in infancy unrelated to surgery (24,25). A brain tumor may be suspected when there is rapid enlargement of the head in the first months of life. Patients have been misdiagnosed as having obstructive hydrocephalus and undergone unnecessary ventriculoperitoneal shunting (20). In hemimegalencephaly, the clinical signs of intracranial hypertension such as separation of sutures, bulging fontanels, and the "setting-sun" sign of the eyes are absent. The latter is characteristic of increased intracranial pressure in infants, with both ocular globes deviated downward, the upper lids retracted, and the white sclerae visible

Summary of radiological findings

Abnormal shape of the skull Diffuse unilateral hypertrophy of the brain Migratory disorders (lissencephaly, pachygyria and heterotopias) White matter signal changes which correlates with histopathologic findings of poor myelination, early cystic

changes and gliosis Agenesis of the corpus callosum, hypoplasia of the cerebellum and brain stem Enlargement of the ventricular system

DIAGNOSIS:

DISCUSSION

115


above the iris. Epilepsy is the most frequent neurologic manifestation, occurring in greater than 90% of patients (20). Although progressive hemiplegia and hemianopia are common, some patients do not have focal motor deficits (20). Hemimegalencephaly in association with neurofibromatosis type 1 may be associated with a more favorable clinical course (21,23).

Cortical disorganization characterized as hemilissencephaly has also been reported (3).

HME includes two different histologic abnormalities, neuronal and glial. In the cortex there is lack of alignment in the horizontal layers and an indistinct demarcation between gray and white matter (Fig. 8). Giant neurons scattered throughout the cortex and the subcortical white matter are clearly seen in Fig. 9 a,b. The main morphologic changes in these giant neurons are the abnormal distribution of Nissi bodies and a conspicuous proliferation of the dendritic tree visible after Golgi impregnation (Fig. 10). Glial abnormalities are present in half of the cases. The glial cytoplasm is positive for the periodic acid-Schiff, glial fibrillary acidic protein (GFAP), and vimentin reactions, and contains glial filaments on electron microscopic examination. This type of cell, sometimes called a "balloon cell," belongs to the glial line and can be extensively distributed throughout the cortex and subcortical white matter. Invasion of the molecular layer by multinucleated glial cells is observed in many cases. Bundles of glial fibers, sometimes merging with typical Rosenthal fibers, may also be present (4). Striking demyelination of the centrum semiovale is seen in some cases, giving an appearance similar to that of Alexander's disease (5). This involvement of white matter appears to be associated with many Rosenthal fibers throughout the brain (Fig. 11), and may explain the diffuse, hyperintense signal observed in white matter on T2-weighted MRI images. It also indicates that glial cells are involved in the lesion, a clear difference between agyriapachygyria, and focal dysplasia and HME.

Figure. 6. CT scan showing the midline shift to the normal side and loss of normal gyral pattern of the hypertrophic hemisphere.

Figure 7. Gross appearance of hemimegalencephaly: diffuse hypertrophy of the left hemisphere. The temporal lobe appears macrogyric.

116


It is difficult to decide if HME should be considered a true malformation. Glial and nerve cell abnormalities are so widespread that this disease has sometimes been regarded as a tumor or hamartoma (6,7). It has also been suggested that such cases represent an unusually massive unilateral variant of tuberous sclerosis (8,9). The lack of skin or visceral lesions and the diffuse distribution of neuropathologic changes are the main arguments for distinguishing HME from tuberous sclerosis. This nosologic issue must be considered speculative without precise genetic data on HME: a gene for tuberous sclerosis has been localized to chromosome 9 in some tuberous sclerosis families (10).

The neuronal pattern after Golgi impregnation shows that the increased size of the giant neurons is associated with increased size of their dendritic tree and increased number of dendritic branches. Similar findings have recently been reported in neurons of a tetraploid strain of the frog Xenopus laevis (I 1). This finding lends support to the view that the

Figure 8. Hemimegalencephaly

Figure 9a. Disappearance of horizontal layering, radial organization of neurons, and large hyperchromatic neurons scattered throughout the cortex.

Figure 9b. Giant neurons and small pyramidal cells

117


hypertrophic neurons are polyploid, as suggested by Bignami et al. (12) and by Manz et al. (13), who found an increased amount of DNA in the cells of the hypertrophic hemisphere. The localization of neuronal anomalies to one hemisphere and to one part of the neuronal population suggests mosaicism. Interestingly, hypomelanosis of Ito, a neuroectodermal disease with known mosaicism, can be associated with HME (14,15).

The classical association between Jadas- sohn's linear naevus sebaceus syndrome (sebaceous adenoma) and HME is noteworthy (16-19). These cases are different from isolated HME, and the pathologic similarities to tuberous sclerosis are closer. In our experience, periventricular tumors, including giant cell astrocytomas, can be encountered in Jadassohn syndrome, as well as in tuberous sclerosis, but not in isolated HME, strongly implying that HME is a heterogeneous condition.

Figure 11. A case with hemimegalencephaly. (A) Low-power photomicrograph (hematoxylin-eosin stain) of the cerebral cortex shows a thickened cortex with poor neuronal lamination (between brackets). An increased number of neurons are present in the subcortical white matter (arrow). Large abnormal blood vessels with prominent perivascular spaces are also present in the white matter (arrowheads). (B) High-power photomicrograph (hematoxylin-eosin stain) shows poorly myelinated white matter containing scattered ectopic neurons (solid straight arrow), gliosis with hypertrophic changes (curved arrow), numerous Rosenthal fibers (arrowheads), and vacuolar changes in the white matter. Focally scattered calcifications are also present in the white matter (open arrow).

NEUROIMAGING OF HEMIMEGALENCEPHALY

The diagnosis of hemimegalencephaly can usually be made at cross-sectional imaging. At CT, asymmetry of the cranium may be evident with enlargement of all or part of a cerebral hemisphere and ipsilateral ventricle. There is often focal, small, or extensive calcification in the white and gray matter, and the white matter may have abnormally low attenuation representing heterotopia and dysplasia of neurons. MR is the imaging modality of choice. A characteristic

Figure 10. Typical Rosenthal fiber with a dense osmiophilic core surrounded by many glial filaments, * l3,000.

118


finding is straightening of the ipsilateral frontal horn of the enlarged ventricle (21). However, the ipsilateral ventricle may be small in some patients. In some cases, ventricular enlargement is less severe compared with that of the involved hemisphere. At MR imaging, the white matter shows heterogeneous but frequently high signal intensity and there is often distinction of areas of agyria, pachygyria, and/or polymicrogyria. The white matter of the affected hemisphere may show advanced myelination for age (26). There is a roughly inverse relationship between the severity of the cortical and white matter abnormalities and the size of the cerebral hemisphere. Patients with agyria tend to have mild to moderate hemispheric enlargement, while those with polymicrogyria have more severe hemispheric enlargement (21,23). Prenatal and postnatal cranial sonography may reveal ventricular asymmetry and unilateral ventricular dilatation. Functional imaging with positron emission tomography has had good correlation with CT and MR imaging findings and has disclosed functionally abnormal brain regions in the noninvolved hemisphere that appeared structurally normal at CT and MR imaging (27).

The gross pathologic appearance correlates with the imaging findings of enlargement of the affected cerebral hemisphere. The brain surface may show pachygyria and polymicrogyria. Microscopically, nerve cells are larger and less densely packed than in the normal side of the brain, and the number of glial cells is increased. Areas of polymicrogyria, neuronal heterotopia, and pachygyria occur. Histologically, there is no difference between focal cortical dysplasia and hemimegalencephaly. However, macroscopically, hemimegalencephaly involves the whole hemisphere, whereas focal cortical dysplasia is more limited (28). White matter may show areas of poor myelination, cystic change, and gliosis, which correspond to increased signal intensity on T2-weighted MR images. Some patients have extensive gliosis, microcystic changes, and Rosenthal fibers in the white matter resembling leukodystrophy. Such extensive white matter involvement is unusual in hemimegalencephaly. Delayed myelination was the extent of involvement described by Woo et al (28) in three patients with hemimegalencephaly.

Figure 12. A case with hemimegalencephaly. (A), Axial unenhanced (a) and contrast material-enhanced (B) T1-weighted MR images show enlargement of the right cerebral hemisphere, cavitation in the region of the centrum semiovale (arrowhead), and diffuse gyral thickening (arrows) with diminished sulcation, a finding consistent with pachygyria. There are patchy, linear regions of increased signal intensity in the white matter of the right hemisphere. No pathologic enhancement is seen on the contrast-enhanced image (B).

119


Figure 13. A case with hemimegalencephaly. (A) Axial unenhanced T1-weighted MR image obtained at the level of the basal ganglia shows an enlarged and dysmorphic right cerebral hemisphere. The right basal ganglia are poorly demonstrated. There is moderate mass effect anteriorly (arrow). (B) On a sagittal T1-weighted MR image obtained at the midline, the corpus callosum is poorly seen (arrowhead).

Figure 14. A case with hemimegalencephaly. Axial (A) and coronal (b) unenhanced T2-weighted MR images show enlargement of the right cerebral hemisphere. There is diffuse high signal intensity in the white matter, which correlates with histopathologic findings of poor myelination and early cystic changes. The right lateral ventricle is compressed (arrow in b). The cerebellum is symmetrical and appears normal (arrowhead in A).

120


MANAGEMENT OF HEMIMEGALENCEPHALY

Syndromic hemimegalencephaly has a worse prognosis than the isolated type, and there is generally poor neurologic function in cases of hemimegalencephaly. Seizure control is the principal goal of therapy, and patients often require multiple antiepileptic medications that have adverse side effects. Hemispherectomy was first performed for treatment of refractory epilepsy in 1978 and is considered the best therapeutic choice for patients with intractable seizures (23,24,25). Anatomic or functional hemispherectomy has also been performed with improvement in quality of life (29). Nevertheless, there is a high mortality and morbidity rate associated with hemispherectomy (24,25,20). Complications include subdural hematomas and hydrocephalus, often requiring surgical intervention and ventriculoperitoneal shunting. The age of the patient at the time of surgical intervention is an important factor in development of secondary hydrocephalus, with patients younger than 9 months being more at risk (30). The intracranial space left by resection of a large portion of the brain may be intraoperatively filled with Ringer lactate or may eventually become filled with cerebrospinal fluid, but it remains vulnerable to infection and hemorrhage.

Table 2. Definition of developmental disorders.

Figure 15. A case with hemimegalencephaly. Coronal section through the right frontal hemisphere shows broad gyri and a thick cortex, particularly in the frontal lobe (solid straight arrow). The occipital lobe has a more normal gyral pattern (arrowhead). The white matter is gliotic and shows areas of mucinous and cystic degeneration (curved arrow). The gray matter-white matter junction is indistinct. The basal ganglia and thalami are small and poorly demarcated. Subventricular gray matter heterotopia is also noted (open arrow).

Type Comment schizencephaly

(disorder of segmentation)


Megalencephaly


The terms megalencephaly and hemimegalencephaly refer to disorders in which the brain volume is greater than normal (not owing to the abnormal storage of material); usually, the enlarged brain is accompanied by macrocephaly, or a large head.

Microcephaly The term microcephaly refers to disorders in which the brain volume is smaller than normal

121


The terms megalencephaly and hemimegalencephaly refer to disorders in which the brain volume is greater than normal (not owing to the abnormal storage of material); usually, the enlarged brain is accompanied by macrocephaly, or a large head. Although considered by some to be a migration disorder, the increase in brain size in these disorders appears to be attributable to errors in neuroepithelial proliferation, as the microscopic appearance of the brain is that of an increase in number of cells (both neurons and glia) and in cell size.

Typically, patients are noted to have large heads at birth, and may manifest an accelerated head growth in the first few months of life. Children with megalencephaly or hemimegalencephaly may come to medical attention when presenting with seizures, a developmental disorder (mental retardation), hemihypertrophy, or a hemiparesis (opposite the affected hemisphere). Seizures vary both in onset and in type, and usually are the most problematic symptom. sometimes necessitating hemispherectomy or callosotomy.

(Non-neoplastic disorder of neuronal proliferation) Dysembryoplastic neuroepithelial tumor and ganglioglioma


Lissencephaly


Lissencephaly (smooth brain) refers to the external appearance of the cerebral cortex in those disorders in which a neuronal migration aberration leads to a relatively smooth cortical surface. One should not consider only agyria in making this diagnosis, rather, the full spectrum includes agyria and pachygyria.

Agyria


Extreme end of lissencephaly (sever lissencephaly) spectrum in which gyri are completely absent and the brain surface is completely smooth.

Pachygyria


The other end of lissencephaly spectrum (mild lissencephaly), the brain have a few broad, flat gyri separated by shallow sulci (pachygyria). The cortex is thick in pachygyria.

Polymicrogyria


Polymicrogyria (many small gyri) is a disorder often considered to be a neuronal migration disorder, but alternate theories exist regarding its pathogenesis, The microscopic appearance of the lesion is that of too many small abnormal gyri. The gyri may be shallow and separated by shallow sulci, which may be associated with an apparent increased cortical thickness on neuroimaging. The multiple small convolutions may not have intervening sulci, or the sulci may be bridged by fusion of overlying molecular layer, which may give a smooth appearance to the brain's surface.

Heterotopias


Heterotopias are collections of normal-appearing neurons in an abnormal location, presumably secondary to a disturbance in migration. Heterotopias may be classified by their location: subpial, within the cerebral white matter, and in the subependymal region.

Tuberous sclerosis

(differentiation disorder)

Disorders such as tuberous sclerosis, in which both tumor development and areas of cortical dysplasia are seen, might be a differentiation disorder. The brain manifestations of this disorder include hamartomas of the subependymal layer, areas of cortical migration abnormalities (tubers, cortical dysgenesis), and the development of giant-cell astrocytomas in upwards of 5% of affected patients.

SUMMARY

122


Addendum


To download the current version follow the link "http://pdf.yassermetwally.com/case.pdf". You can also download the current version from my web site at "http://yassermetwally.com". Screen resolution is better set at 1024*768 pixel screen area for optimum display

References

I .Robain 0, Floquet J, Heidt N, Rozemberg F. Hemimegalencephaly: a clinicopathological study of four cases. Neuropathol Appl Neurobiol 1988; 14:125-35.

2. Katifa GL, Chiron C, Sellier N, et al. Hemimegalencephaly MR imaging in five children. Radiology 1987;165:29-33.

3. De Rosa MJ, Secor DL, Barsom M, Fisher RS, Vinters HV. Neuropathologic findings in surgically treated hemimegalencephaly: immunohistochemical, morphometric, and ultrastructural study. Acta Neuropathol (Berl) 1992;84:250-60.

4. Robain 0, Chiron C, Dulac 0. Electron, microscopic and Golgi study in a case of hemimegalencephaly. Acta Neuropathol (Berl) 1989;77:664-6.

5. Squier M. White matter change in hemimegalencephaly. Rev Neurol 1993;149:370.

6. Dom R, Brucher JM. Hamartoblastome (gangliocytome diffus) unilateral de encore cerebrale, Rev Neurol 1969;120:317-8.

7. Townsend JJ, Nielsen SL, Malamud N. Unilateral megalencephaly hamartoma or neoplasm. Neurology 1975;25:448-53.

8. Davis RLM, Nelson E. Unilateral ganglioglioma in a tuberosclerotic brain. J Neuropathol Exp Neurol 1961;21:571-81.

9. Jervis GA. Spongioneuroblastoma and tuberous sclerosis. J Neuropathol Exp Neurol 1954;13:105- 16.

10. Fryer AE, Connor JM, Povey S, et al. Evidence that the gene for tuberous sclerosis is on chromosome 9. Lancet 1987;1:659-61.

II. Szaro BG, Tompkins R. Effects of tetraploidy on dendritic branching in neurons and glial cells of the frog Xenopus laevis. J Comp Neurol 1987;258: 304--16.

12. Bignami A, Palladini G, Zappella M. Unilateral megalencephaly with cell hypertrophy. An anatomical and quantitative histochemical study. Brain Res 1968;9:103-14.

13. Manz H, Phillips T, Rowden G, McCullough DC. Unilateral megalencephaly, cerebral cortical dysplasia, neuronal hypertrophy and heterotopia: cytophotometric fluorometric cytochemical and biochemical analysis. Acta Neuropathol (Berl) 1979; 45:97-103.

14. David TJ. Hypomelanosis of Ito: a neurocutaneous syndrome. Arch Dis Child 1981;56:798-800.

15. Turleau C, Taillard F. Hypomelanosis of Ito (incontinentia pigmenti achromians) and mosaicism for a microdeletion of 15 ql. Hum Genet 1986;74: 185-7.

REFERENCES

123


16. Choi BH, Kudo M. Abnormal neuronal migration and gliomatosis cerebri in epidermal naevus syndrome. Acta Neuropathol (Berl) 1981;53:319-25.

17. Vigevano F, Aicardi J, Lini M, Pasquinelli A. La sindrome del nevo sebaceo lineare presentazione di una casuistica multicentra. Boll Lega It Epil 1984;45-46:59-63.

18. Vles JSH, Degraeuwe P, De Cock P, Casaer P. Neuroradiological findings in Jadassohn's naevus phakomatosis: a report of two cases. Eur J Pediatr 1985;144:290-4.

19. Zaremba J, Wislawski J, Bidzinski J, Kansky J, Bogna S. ladassohn's naevus phakomatosis: a report of two cases. J Ment Deric Res 1978;22:91- 102.

20. Flores-Sarnat L. Hemimegalencephaly. I. Genetic, clinical, and imaging aspects. J Child Neurol 2002; 17:373-384.

21. Barkovich AJ, Chuang SH. Unilateral megalencephaly: correlation of MR imaging and pathologic characteristics. AJNR Am J Neuroradiol 1990; 11:523-531.

22. Sims J. On hypertrophy and atrophy of the brain. Med Quir Trans 1835; 19:315-380.

22. Wolpert SM, Cohen A, Libenson MH. Hemimegalencephaly: a longitudinal MR study. AJNR Am J Neuroradiol 1994; 15:1479-1482.

23. Vigevano F, Bertini E, Boldrini R, et al. Hemimegalencephaly and intractable epilepsy: benefits of hemispherectomy. Epilepsia 1989; 30:833-843.

24. Mathis JM, Barr JD, Albright AL, Horton JA. Hemimegalencephaly and intractable epilepsy treated with embolic hemispherectomy. AJNR Am J Neuroradiol 1995; 16:1076-1079.

25. Yagishita A, Arai N, Tamagawa K, Oda M. Hemimegalencephaly: signal changes suggesting abnormal myelination in MRI. Neuroradiology 1998; 40:734-738.

26. Rintahaka PJ, Chugani HT, Messa C, Phelps ME. Hemimegalencephaly: evaluation with positron emission tomography. Pediatr Neurol 1993; 9:21-28.

27. Adamsbaum C, Robain O, Cohen P, Delalande O, Fohlen M, Kalifa G. Focal cortical dysplasia and hemimegalencephaly: histological and neuroimaging correlations. Pediatr Radiol 1998; 28:583-590.

28. Woo C, Chuang S, Becker L, et al. Radiologic-pathologic correlation in focal cortical dysplasia and hemimegalencephaly in 18 children. Pediatr Neurol 2001; 25:295-303.

29. Carreno M, Wyllie E, Bingaman W, Kotagal P, Comair Y, Ruggieri P. Seizure outcome after functional hemispherectomy for malformations of cortical development. Neurology 2001; 57:331-333.

30. Di Rocco C, Iannelli A. Hemimegalencephaly and intractable epilepsy: complications of hemispherectomy and their correlation with the surgical technique—a report on 15 cases. Pediatr Neurosurg 2000; 33:198-207.

31. Metwally, MYM: Textbook of neurimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publishing, version 9.1a January 2008

124


case of the week: cases presented with cortical dysplasia

Health & Medicine