Hemimegalen- cep ha ly: h l Diagnosis and Treatment J . Q. Trounce N . Rutter D. H . Mellor

Hemimegalencephaly is a rare congenital anomaly of brain development resulting in severe neurological sequelae and often death in early childhood. The purpose of this report is to illustrate several of the features of the condition and its diagnosis.

Case reports CASE 1 This boy was born at term, and left-sided facial hemihypertrophy was noted at birth and subsequently (Fig. I) . He suffered neonatal convulsions and was treated with phenobarbitone. There was no family history of note. Air encephalogram performed at age seven months showed midline displacement to the right, suggesting a left-sided hemimegalen- cephaly. His development was severely retarded and he attended an ESN(S)* school. When first seen at this hospital, aged 10 years 7 months, his seizures were frequent and did not improve with the addition of phenytoin, but nitrazepam resulted in a con- siderable improvement. His EEG showed almost continuous 2 to 2.5Hz spike and wave paroxysmal activity, which was of greater amplitude on the left side. Other significant findings were a head circum,ference of 58cm (above 98th centile) and pigmented linear naevi on the left side of the neck, but there were no neurocutaneous skin marker!;. He had severe optic atrophy of the right eye, with acuity of 1/60, but reasonable vision with the left eye. Skin fibroblasts obtained from the neck at the time of dental treatment showed a normal male karyotype on both sides. His fits remained infrequent over the next four years while on phenobarbitone and nitrazepam, and he was discharged from further hospital follow-up.

NOW aged 26 years, the air encephalogram diagncisis of hemimegalencephaly has been con- firmed with CT (Fig. 2) and MRI imaging (Fig. 3).

CASE 2 This boy presented with generalised convulsions at the age of seven months. He had been born at I.erm, following a normal pregnancy. There was no family history of note. Examination was unremarkable; there was no cranial or body asymmetry and Wood’s light examination was negative. Occipitofrontal

*‘Educationally subnormal (severe)’

Fig. 1. Facial view of case I , showing enlarged lefr side.

Fig. 2. Axial CT scan of case I , showing enlarged left cerebral hemisphere.

circumference (OFC) was 45.3 cm (50th centile). EEG was very abnormal, with frequent bursts of irregular paroxysmal activity bilaterally and occasional single spike and wave complexes; the recording showed no asymmetry. CT showed the left cerebral hemisphere to be slightly larger than the right, with no significant ventricular enlargement, but slight widening of the left Sylvian fissure and

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Fig. 3. TI-weighted MRI scan of case I , showing (upper) axial view (TR = 700ms, TI = 40ms) and (lower) coronal view (TR-I66Oms, TI = 400ms). These con firm enlarged left cerebral hemisphere, including cerebellum, and also show pachygyric change with loss of sulcation posteriorly.

frontal sulci. The diagnosis was a mild left hemi- megalencephaly. All tests for metabolic disturbance (including amino acids and organic acids) were normal, as was the karyotype.

His seizures have been well controlled by sodium valproate. Now aged two years, he shows significant developmental delay, most evident in his speech, with both comprehension and expression at a nine to 12 month level. He is hyperactive, with a very poor attention span. There is no specific hand preference and no evidence of right-sided weakness.

CASE 3 This boy was born at term, with a birthweight of 3880g and OFC of 37.0cm (98th centile). At five days his OFC had increased to 39.0cm (above 98th

L? centile) and it was noted that the occiput was

Fig. 4. Coronal ultrasound scan of case 3, showing enlargement of left hemisphere and lateral ventricle (v). with marked shift of interhemispheric fissure to right (arrow).

Fig. 5. Axial CT scan of case 3, showing enlargement of left cerebral hemisphere and lateral ventricle. Loss of grey-white matter differentiation on left suggests grey matter heterotopia.

prominent. Cranial ultrasound showed a marked enlargement of the left lateral ventricle, with the midline shifted to the right (Fig. 4). The diagnosis was thought to be left hemimegalencephaly, or possibly unilateral hydrocephalus.

At eight days of age he was re-admitted to hospital with generalised convulsions, and phenobarbitone was commenced. EEG showed continuous high- amplitude sharp and slow waves, much more marked on the left side. The ultrasound findings were unchanged and CT confirmed dilatation of the left lateral ventricle, with enlargement of that hemi- sphere (Fig. 5 ) ; a diagnosis of left hemimegalen- cephaly was made. Cerebral angiography excluded a vascular malformation. TORCH screen was negative and karyotype was 46XY.

At two months of age, the fits changed to a salaam

pattern. A repeat EEG showed little change, except that now there was no paroxysmal activity on the right, and during a ipasm a focal discharge was identified in the left posterior temporal and central areas. His seizures remained intractable despite varied combinations of phenobarbitone, carbam- azepine, nitrazepam and sodium valproate. Repeat EEG at 3 years 10 months showed almost con- tinuous slow spike and wave activity, thought to represent the Lennox-Gastaut syndrome. Clonazepam was commenced, and his fits have been well controlled for the last six months on a dose of 0 . Img/kg/day.

Now aged 4 years 5 months, he shows severe developmental delay; he pulls to standing, but cannot walk unaided; vocalises, but has no words with meaning; and he is unable to feed himself. He also has mild right-sided hemiparesis and a right convergent squint, with decreased visual acuity. His head circumference is 53.2cm (98th centile).

Discussion Hemimegalencephaly is a rare condition and was first reported by Sims (1835), who described a woman in whom the left cerebral hemisphere occupied about two- thirds of the cranium. However, the term hemimegalencephaly is rather simplistic, since the anomaly is more typically a hamartomatous malformation than a simple hypertrophy (Bignami et al. 1968, Townsend el al. 1975). Not only is there excessive proliferation of neurons i2nd astrocytes, but also disordered migration and cortical organisation. Macroscopically, the gyri may be enlarged, firm in con- sistency, and have an indistinct boundary between the cortex and white matter (Townsend et al. 1975, Tjiam et al. 1978, King et al. 1985, Robain et al. 1988). Microscopically, there are areas of poly- microgyria and pachygyria, heterotopic neurons and foci of calcification in the subcortical white matter, an increased number of glial cells and a three-fold increase in neuronal size (Bignami et al. 1968, Townsend et al. 1975, Tjiam el al. 1978, Robain et al. 1988). Some of the giant cells resemble those seen in tuberous sclerosis (Tjiam et al. 1978, Robain el al. 1988). In the latter condition, the giant neurons are characteristically nodular and periventricular in distribution, whereas in hemimegalencephaly they are more diffuse. Townsend and colleagues (1975) considered it unlikely that the condition represented a forme fruste of tuberous sclerosis. A review of the literature shows an equal distribution of right- and left-

sided lesions (King et al. 1985, Robain et al. 1988), and it would seem to be a coincidence that in all three of our cases the left hemisphere was involved.

The cause of the disordered develop- ment is uncertain, but it probably originates around the third month of fetal life, i.e. the time o f cortical neuronal migration (Fitz et al. 1978). Sampling the superior frontal gyri, Bignami and col- leagues (1968) demonstrated a 30 per cent increase of DNA content in the affected side. Based on the previous demon- stration that corporal hemihypertrophy may be related to triploid-diploid mosaicism, they postulated that hemi- megalencephaly might be a result of localised heteroploidy. This has yet to be confirmed or refuted. In our first case, we demonstrated normal chromosomal analysis in corporal tissue of the hypertrophic side, but we have not had access to affected brain.

The marked abnormality of the affected hemisphere explains the high incidence of neurological abnormality. Seizures predominate, often starting in the neonatal period, and may become intractable to standard therapy. Severe developmental delay is a common accom- paniment, contralateral hemiparesis may occur (Townsend el al. 1975, Kalifa et al. 1987), and contralateral hemianopia has also been reported (Vigevano et al. 1989). The association of left hemimegalen- cephaly with right optic atrophy in our first case is interesting. Each eye has bilateral cortical connections and we postulate that the area of occipital cortex supplying the right eye was more severely dysgenetic than that of the left. There has never been clinical evidence of raised intracranial pressure and we do not consider this important in causing optic atrophy. A large head circumference, especially in early life, and skull asymmetry are also commonly reported (Laurence 1964, Townsend et al. 1975, King et a/. 1985).

Extracranial manifestations may also occur, most notably an ipsilateral hemi- hypertrophy, which may be total or

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confined to the facial region, as in our first case (Warkany et al. 1981). Other reported associations are hypomelanosis of Ito (Peserico et al. 1988), linear naevus 263

* (II sebaceous of Jadassohn syndrome (Vigevano et al. 1989), cafe au lait spots B

3 ET (Warkany et al. 1981) and renal haem- 3 angioma. Of the 21 reported cases whose

sex is given, 15 have been boys (King et a/ . 1985, Robain et al. 1988, Towbin et a/. 1988, Vigevano et a/. 1989); our three cases, all male, would support this bias.

The EEG is typically very abnormal, with a pattern of spikes and slow waves; the changes may be asymmetrical, being more marked over the abnormal hemi- sphere (Townsend et al. 1975, Tjiam et al. 1978).

Imaging is the key to diagnosis. Pneumoencephalography was used in the past, as in our first case (Fitz et al. 1978, King et al. 1985). CT scanning of our other two cases showed midline shift, widening of the Sylvian fissure and frontal sulci in one case, and unilateral ventricular enlargement in the other. More recently, M R I has been shown to give greater precision of detail compared with CT (Kalifa el a/. 1987). Both methods could demonstrate the midline shift and dilated lateral ventricle on the hypertrophic side. However, M R I also showed the excessively wide gyri, the shallow and poorly defined sulci and the thickened cortical ribbon on the abnormal side, with poor differentiation of cortex and subcortex. MRI of our first case showed pachygyric changes in the megalencephalic hemisphere.

Our third case was initially diagnosed by real-time ultrasound scanning, which showed marked midline shift with enlargement of the lateral ventricle on the affected side. King and colleagues (1985) report an ultrasound appearance of increased echodensity on the side of the megalencephaly, with midline shift to the opposite side; we did not see this in our case. We are unaware of any other reports of ultrasound diagnosis. A loculated lateral ventricle might produce a similar appearance on ultrasound scan; this results from obstructed drainage and is usually the sequal to either meningitis or haemorrhage. The former should be clinically obvious and the latter recognised from residual thrombus on the ultrasound scan.

Treatment is largely confined to control 264 of convulsions, which may prove

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extremely difficult. The standard anti- convulsants are the main support, but our experience suggests that benzodiazepines may be particularly useful-our first case responded well to nitrazepam and the third achieved seizure control with clonazepam, following the failure of other drugs in adequate dosage. The intractability of the fits has led others to suggest that hemispherectomy should be considered (Fitz et a/. 1978). Indeed, Towbin and colleagues (1988) join King et al. (1985) in recommending early hemi- spherectomy as the treatment of choice. Vigevano et al. (1989) report seizure control, greater alertness and improved psychomotor development in two children following hemispherectomy performed for intractable epilepsy. The children were aged 2% and three years, and the authors advise against surgery earlier than this. We too would favour a cautious approach, with an extensive trial of medical therapy first.

The prognosis appears to be universally bad. Reviewing the earlier reports of King et a/. (1985) and Robain et al. (1988), eight children died aged six months or less, and a further seven before the fifth birthday. Only one of the cases was still alive, and she was only 1 1 months old at the time of reporting. All five of the children reported by Kalifa and colleagues (1987) were still alive at ages up to nine years, and our experience, especially with the first case, suggests that more pro- longed survival is possible. The earlier reports suggested that death might occur during an episode of status epilepticus (Bignami et al. 1968, Tjiam et a/. 1978); possibly the greater range and efficacy of modern anticonvulsant drugs are reasons for the improved survival. Also, the intro- duction of non-invasive imaging tech- niques could mean that some milder cases, which would have escaped recog- nition in the past, might now be diagnosed. This would apply to our case 2. Survivors have variable but often severe mental impairment, and all three of the children we report show marked developmental delay. Early presentation may augur badly for the prognosis; the three children reported by Kalifa and colleagues (1987), who presented in the neonatal period, had seizures which were

much more difficult to control than the T. Jaspan, Consultant Neuroradiologists, for two who presented at three and nine performing and interpreting the CT and MRI scans. months. o u r experience with our second Authors’ Appointments

*J Q . Trounce, M.B., B.S., M.R.C.P., Senior case would support this; he presented at Registrar Paediatrics; age SE!ven months with fits which were N. Rutter, M.D., F.R.C.P., Senior Lecturer Child more readily controlled than those of the Health;

D. H. Mellor, M.D., F.R.C.P., Consultant other two children. Paediatric Neurologist;

Department of Child Health, University Hospital, Accepted for publication 10th August 1990. Nottingham NG7 2UH.

Ackno rvledgements *Correspondence to first author at Royal Alexandra The authors are grateful for the assistance of Hospital for Sick Children, Dyke Road, Brighton Profess,or B. Worthington, Dr. I . Holland and Dr. BNl 3JN.

SUMMARY Three boys with hemimegalencephaly are reported. Two suffered neonatal convulsions and the third presented with seizures at seven months. In each case the EEG was grossly abnormal, with spike and wave activity. All three have significant developmental delay and demonstrate other manifestations of the condition: macrocephaly in two, contralateral hemiparesis in one and one boy has ipsilateral facial hemihypertrophy and linear naevus. Hemimegalencephaly can be recognised on cranial ultrasonography, and the seizures may respond to benzodiazepine therapy.

RESUME Hemimegalencephalie, diagnostic et traitemmi L’article decrit trois cas masculins d’hemimegalencephalie. II y avait des convulsions neonatales dans deux cas, une comitialite a sept mois dans le troiserne cas. Dans tous les cas, I’EEG etait tres anormal avec une activite de pointes-ondes. On observait chez les trois patients un important retard de developpement et d’autres manifestations de l’affection: macrocephalie dans deux cas, hemiparesie contralaterale dans un cas, hkmihypertrophie facialr: ipsilaterale avec naevus lineaire dans un cas. L’hemimegalencephalie peut Ctre reconnue a l’echographie cranienne et les crises comitiales peuvent repondre au traitement par benzodiazepines.

ZUSAMMENFASSUNG Hemimegalenzephalie-Diagnose und Behandlung Drei Jungen mit Hemimegalenzephalie werden vorgestellt. Zwei hatten neonatale Krampfanfalle und der dritte bekam mit sieben Monaten Krampfe. In allen Fallen war das EEG schwer verandert, mit Spike und Wave Aktivitat. Alle drei hatten eine signifikante Entwicklungsverzogerung und andere Merkmale: Zwei hatten eine Makrozephalie, einer eine kontralaterale Hemiparese und ein Junge hatte eine ipsilaterale faziale Hemihypertrophie und einen linearen Naevus. Hemimegalenzephalie kann bei der cranialen Ultraschalluntersuchung erkannt werden und die Krampfanfalle konnen auf eine Therapie mit Benzodiazepin ansprechen .

RESUMEN Heminiegaencefalia-diagnostic0 y tratamiento Se aportan tres muchachos con hemimegaencefalia. Dos tuvieron convulsionnes neonatales y el tercero tuvo convulsiones a 10s siete meses. En cada caso el EEG era muy anomalo, con actividad de punta-onda. Los tres tenian un retraso significativo de desarrollo y mostraban otras manifestaciones de la anomalia: macrocefalia en dos casos, hemiparesia contralateral en uno y una hemihipertrofia facial ipsilateral en uno, con nevus linear. L,a hemimegaencefalia puede ser reconocida con la ultrasonografia craneana y las convulsiones pueden responder a la terapia con benzodiazepina.

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References Bignami, A., Palladini, G., Zappella, M. (1968)

‘Unilateral rnegalencephaly with nerve cell hypertrophy. An anatomical and quantitative histochemical study.’ Brain Research, 9, 103-1 14.

Fitz, C. R., Harwood-Nash, D. C., Boldt, D. W. (1978) ‘The radiographic features of unilateral megalencephaly.’ Neuroradiology, 15, 145-148.

Kalifa, G. L., Chiron, C., Sellier, N., Demange, P., Ponsot, G., Lalande, G., Robain, 0.. (1987) ‘Hemimegalencephaly: MR imaging in five children.’ Radiology, 165, 29-33.

King, M., Stephenson, J . B. P., Ziervogel, M., Doyle, D., Galbraith, S. (1985) ‘Hemimegalen- cephaly-a case for hernispherectomy?’ Neuro- pediatrics, 16, 46-55.

Laurence, K. M. (1964) ‘A case of unilateral

megalencephaly.’ Developmental Medicine and Child Neurology, 6, 585-590.

Peserico, A,, Battistella, P. A. , Bertoli, P., Drigo, P. (1988) ‘Unilateral hypomelanosis of Ito with hernimegalencephaly . ’ Acta Paediatrica Scandin- avica, 77, 446-441.

Robain, O., Floquet, C., Heldt, N., Rozenberg, F. (1988) ‘Hemimegalencephaly: a clinicopatho- logical study of four cases.’ Neuropathology and Applied Neurobiology, 14, 125-135.

Sims, J. M. (1835) ‘On hypertrophy and atrophy of the brain.’ Medicochirugical Transactions, 19, 315-380.

Tjiarn, A. T., Stefanko, S., Schenk, V. W . D., de Vlieger, M. (1978) ‘Infantile spasms associated with hemihypsarrythmia and hernirnegalen- cephaly.’ Developmental Medicine and Child Neurology, 20, 179-789. 265

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Towbin, R. B., Ball, W. S., Witte, D. P., Han, Claps, D., di Capua, M., di Rocco, C., Rossi, G. B. K. (1988) ‘Pediatric case of the day: F. (1989) ‘Hemimegalencephaly and intractable hemimegalencephaly.’ RadioCraphics, 8, epilepsy: benefits of hemispherectomy.’ Epilepsia, 573-511. 30, 833-843.

Townsend, J. J. , Nielsen, S. L., Malamud, N. Warkany, J., Lemire, R. J., Cohen, M. M. (1981) (1975) ‘Unilateral megalencephaly: hamartoma or Mental Retardation and Congenital neoplasm?’ Neurology, 25, 448-453. Malformations of the Central Nervous System.

Vigevano, F., Bertini, E., Boldrini, R., Bosman, C., Chicago: Year Book Medical Publishers.

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Corrigendum The name of the second author of the letter to the Editor ‘Nimodipine treatment for drug-resistant childhood epilepsy’ (DMCN, 32, 11 14) should have appeared as Antonio Sciarretta (not Antonia Sciaretta as printed).