severe psychiatric disturbance and abnormalities …severepsychiatric disturbance andabnormalities...

J7ournal of Neurology, Neurosurgery, and Psychiatry 1993;56:85-93

Severe psychiatric disturbance and abnormalitiesof the corpus callosum: review and case series

Anthony S David, Alisa Wacharasindhu,W Alwyn Lishman

AbstractThe association between developmentaldefects of the corpus callosum and majorpsychiatric disturbance is discussed witha review of published cases. Seven newcases are presented, of which four hadclear psychotic symptoms, two receiving adiagnosis of schizophrenia. Of theremainder, one had a developmental dis-order affecting social interaction andspeech which could be classed as Asper-ger's syndrome, one had a personalitydisorder with depressive and conversionsymptoms, and the last was an adolescentboy with severe behavioural problems.The difficulties in determining the preciserelevance of the callosal anomalies tothese clinical manifestations are discussedespecially since the prevalence of suchanomalies in the population is uncertain.

(y Neurol Neurosurg Psychiatry 1993;56:85-93)

Department ofPsychologicalMedicine, Institute ofPsychiatry and King'sCollege Hospital,London, UKA S DavidA WacharasindhuSection ofNeuropsychiatry,Institute of Psychiatry,London, UKW A IishmanCorrespondence to:Dr David, Department ofPsychological Medicine,King's College Hospital,Denmark Hill, London SE59RS, UKReceived 18 December 1991and in revised form3 April 1992.Accepted 13 April 1992

The corpus callosum (CC) contains the largestnerve fibre tract in the human brain, connect-ing the cerebral hemispheres with one another.It is estimated to contain nearly 200 millionfibres. The CC together with the anterior andhippocampal commissures form the forebraincommissures. The tract develops intimately inassociation with the fornix, hippocampal com-missure, hippocampal formation, septum pel-lucidum and cingulate cortex, beginning toform shortly after the anterior commissure.

Details of the anatomy and embryology ofthe CC have been well described.'' Abnormalmorphologies of the CC can be classified intoacquired and congenital defects. Acquiredchanges can result from trauma, tumours,hydrocephalus, vascular accidents and whitematter diseases.' Complete agenesis is a raredevelopmental anomaly ofunknown cause andis associated with a wide variety of geneticdefects, in particular trisomies of chromo-somes, 8, 13 and 18.67 Agenesis has also beenconsidered a marker of intrauterine metabolicupsets such as hyperglycinaemia,8 and mayresult from insults such as intrauterine infec-tions and exposure to toxins.3 - The partialforms of agenesis usually affect the posteriorportions and are presumed to reflect the actionof pathogenic influences occurring after theinitial development of the commissures, that is,after the sixteenth week of gestation.

Agenesis is frequently accompanied by otherdevelopmental defects. These encompass com-

mon midline abnormalities (for example, cleft

palate), although other ocular and spinalabnormalities may occur.6 The associatedbrain anomalies which have been reportedinclude interhemispheric cysts with hydro-cephalus (Dandy-Walker malformation), lipo-mas of the CC or interhemispheric fissure,invariably associated with partial agenesis,absence of the inferior cerebellar vermis, anddisorders of neuronal migration."2 The cingu-late gyrus is invariably abnormal and limbicstructures may also be affected.The main function of the CC is inter-

hemispheric integration: connecting corre-sponding regions of the cerebral cortex in thetwo hemispheres. Crudely, it serves as aconduit for transfer of sensory informa-tion,'3-15 although the precise nature of theinformation transferred and its overall influ-ence on the activity of the hemispheres is atopic of continued research and speculation.'6It has been noted repeatedly that in agenesis ofthe CC there is an absence of most aspects ofthe disconnection symptoms which affect sub-jects who have had surgical separation ofthe commissures-the "split-brain opera-tion"." 1 This has been attributed to thepresence of alternative pathways connectingthe hemispheres such as the anterior com-missure, which is frequently intact despitecallosal agenesis, or subcortical channels.Other compensatory mechanisms may alsoplay a part such as the duplication of thosespecialised functions which are usually dis-tributed asymmetrically between the hemi-spheres, such as speech. Nevertheless, somefailures of interhemispheric communicationhave been noted such as reduced transfer ofmaze learning from one hand to another,'9impaired matching of visual patterns betweenthe right and left visual fields20 and reducedtransfer of incongruent word stimuli in acolour naming task,2' (but see22).The prevalence of callosal agenesis is diffi-

cult to quantify. Widely varying estimates in theliterature, ranging from 0 004% to 2-64%,reflect the different study populations (tables 1and 2). Thus paediatric neurology services willgive higher rates than necropsy studies ofunselected members of the population. Sim-ilarly, the rates of associated abnormalities andclinical problems reflect the setting in whichcases are evaluated. All that can be stated isthat certain presentations, namely learningdisability and epilepsy are rather com-mon,3 17 30 the latter usually estimated ataround 40%. Despite most cases coming tolight because of the need to investigate amanifest neurological syndrome, many series

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David, Wacharasindhu, Lishman

Table 1 Proportion (%) of individuals with callosal agenesis from necropsy and invasiveencephalography

Authors Proportion (%) Setting

Carpenter and 7/3770 (0 2%) PaediatricDruckniller (1953)23

Thierffry et al,(1958)24 8/1349 (0-6%) Paediatric

Gross and Hoff(1959)25 12/455 (2-64%) Severely mentally retarded

institutionalisedGrogono (1968)26 50/6450 (0 7%)

1/19000 (0 0053%) - Paediatric- Necropsy series (unselected)

Courville (1950)2' 2/40000 (0 005%) - Necropsy series (unselected)cited in 1/20074 (0.005%) WHO studyMyrianthopoulos (1987)28 - Czechoslovakia: case had multiple

congenital abnormalities1/24700 (0.004%) - Mexico City: stillbirth3/40100 (0.0075%) NCPP (Collaborative Perinatal

Project)- 1 child with multiple abnormalitiesand 2 cases detected during 7 yearfollow up

Table 2 Proportion of individuals with callosal agenesisfrom CT and MRI scanning

Authors Proportion (%) Setting

McLeod(1987)'5 10/450 (2 22%)

- 2 complete agenesis Neurology- 5 partial agenesis- 3 callosal cysts

Aicardi et al(1987)3 3/4097 (0 073%) Paediatric neurology

Swayze et al(1990)29 8/7240 (0-11%) Adult neuroradiology

- 5 agenesis- 3 lipoma

include a number of "asymptomatic" cases.

Slager et al3' collected 23 asymptomatic cases

from 170 reviewed in the literature (13-5%),and a recent survey from a children's hospitalreported 23/105 (21%) such individuals.12Nowadays, most cases are identified from CT,MRI brain scans or ultrasonography in preg-nancy. Since the "threshold" for carrying outthese non-invasive investigations is much lower

than invasive studies such as air encephalog-raphy (AEG), we would anticipate a increase inthe identification of relatively symptom-freecases.

A male preponderance of cases has beenclaimed especially in developmentally disabledgroups6 though some large series have failed to

confirm this.3 12

Another related problem is case definition.Surveys differ as to whether they accept partia!agenesis as "cases". Again, this issue is liable toresult in differences between early and latestudies since "focal attenuation" is especiallylikely to be identified using modern neuroim-aging techniques, in particular MRI. McLeodet al,5 report that as many as 112/450 (24X8%)of their patients who were scanned had sig-nificant attenuations, defined as a 50% or

greater thinning of the CC.This paper considers the association

between developmental abnormalities of theCC and severe psychiatric disturbances.

MethodsA review of the literature based upon IndexMedicus and review articles published sincethe 1969 edition of the Handbook of Neurologywas carried out. Four cases of schizophrenia,one of an atypical psychosis and two in whomsignificant depression is mentioned, have beenreported to date. Four out of the seven were

female. The cases are summarised in table 3. Inaddition, Njiokiktjien,7 mentions 4 children inhis personal series with behavioural distur-bances leading to psychiatric care and men-

tions one in whom there was a "temporarypsychosis". Of the cases in table 3 described indetail, at least 4 could be regarded as havingnormal or near normal intelligence and none

had epilepsy, although Lehmann and Lampe'ssecond case had paroxysmal activity in her

Table 3 Summary ofpublished reports on psychiatric patients with callosal abnormalities

Age Age of Psycho- EpilepsyAuthors (years) Sex onset Clinicalfeatures Diagnosis metry IEEG CT/MRI scan

Lehmann andLampe(1970)'9 Case 1 60 F 47 Recurrent Depression VIQ 88 Normal complete

episodes PIQ 90 agenesis(AEG)

Case 2 50 F 49 Insomnia Depression VIQ 85 Paroxysmal h completeSuicidal PIQ 83 both temporal agenesisFamily history regions (AEG)

MacPherson 18 M ? Midline Admitted with ? ? Lipoma of CCet al (1987)32 facial defects psychosis Calcification of

L eye enucleated falxLewis et al 55 M 30 Paranoia Schizophrenia VIQ 75 Normal Agenesis(1988)33 Hallucinations PIQ 93 L fronto-

Violent and suicidal temporal cystbehaviourTreatment responsive

Velek et al 24 F 24 Persecution Schizophrenia VIQ 103 Normal Subtotal(1988)34 Passivity (acute) PIQ 97 agenesis

Auditory R > LhallucinationPartial responseto treatment

Swayze et al(1990)29 Case 1 39 F 33 Hallucinations Schizophrenia "border- Normal "Nearly

since childhood line" completeDelusions agenesis"Refractory totreatment

Case 2 33 F 24 Persecution Schizophrenia College Normal LipomaAuditory student replacinghallucination CCRefractory totreatment

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Severe psychiatric disturbance and abnormalities of the corpus callosum: review and case series

EEG. The two cases described by Swayze etal 29 were poorly responsive to treatment whilethe cases of Lewis et al33 and Velek et al34 didrespond to some extent. The symptom profilesof these cases do not point to any cleardistinguishing characteristics which clinicianscould identify.

Case seriesA register of abnormal CT scans from theMaudsley hospital radiology unit was used totrace all psychiatric cases with agenesis orpartial agenesis of the CC over a 7 year period(see table 4). Six were referred to a specialistneuropsychiatric unit at the Maudsley hospital.One of these was investigated for possiblepseudo-seizures when unsuspected callosalagenesis was revealed. The seventh case wasseen in the children's department of theMaudsley hospital. Only one was female.

Case 1 A 35 year old man. Childhood anddevelopment were unremarkable. He attendednormal schooling and left at the age of 15 withno qualifications but was numerate and liter-ate. He held casual jobs between the age of 15and 16 but has not worked subsequently. Therewas no clear family history of psychiatricdisorder although his mother had multiplesclerosis and was said to suffer from moodswings.

Psychiatric history started at age 17 when hewas diagnosed as having "an adolescentidentity crisis", and was treated with out-patient psychotherapy. The first psychiatricadmission was at age 19, when the patient wasnoted to be vague, perplexed, hallucinated andwas treated with phenothiazines. There was afurther admission in the same year when hewas depressed and deluded and possiblythought disordered. Antipsychotic medicationand ECT were given with good response.There were 3 further admissions yearly due tosimilar problems. He was noted early on tohave a destructive propensity.At the age of 25 he had his sixth admission

when he was compulsorily detained followingan assault on a police officer. Since then he hasrequired almost continuous inpatient care andhas received various forms of antipsychoticmedication and further courses of ECT. Theintroduction of carbamazepine showed a mar-ginal effect on his outbursts of aggression. Themental state has fluctuated although thoughtdisorder, persecutory delusions and bizarrehypochondriacal delusions have all been prom-inent. At the age of 30 he was transferred to asecure unit because of serious aggressiontowards staff. The mental state examination atthis time showed disordered thinking withmany shifting persecutory themes, for exam-ple, "People make me do things I don't wantto... to kill... I'm going... what's thisbacktracking ... TV and radio". He had ideasof persecution and bizarre somatic delusionssuch as, "All the bones in my hands arecrushed and broken". His attention and con-centration were poor. He is now undergoingcontinued treatment and rehabilitation butremains symptomatic and a danger to others. A

diagnosis of chronic paranoid schizophreniawas made.

Neuropsychological investigations testingwith the WAIS-R at age 30 showed a full scaleIQ of 72, a fall of 32 IQ points compared withhis score at age 21. Tachistoscopic testingshowed normal cross-field matching of coloursand simple line drawings. Detailed assessmentwas repeated when his mental state improvedbut the IQ remained unchanged. He hadscored poorly on the similarities sub-test indi-cating poor ability to form abstract concepts.Memory testing, using the Weschler logicalmemory test, paired associate learning, Rey-Osterrieth and the Benton Visual Retentiontest were carried out. The results showedoverall poor memory especially spatial mem-ory. The performance on the Trail MakingTestwas also poor while performance on wordfluency showed minor impairment. Perform-ance on the Wisconsin Card Sort test wasabnormal with a high number of preserverativeerrors, suggesting frontal lobe impairment.CT showed a lipoma in the posterior aspect

of the corpus callosums (figure 1). An EEGwas performed twice at age 30; the first showedno abnormalities while the second showedsome minor dysfunction (see table 4).

Case 2 A 29 year old man was bom six weeksprematurely, experienced lack of oxygen atbirth and was of low birth weight. Motordevelopment was slow: at twelve months hehad to be propped up to sit and was noticed byhis mother to sit with his legs in a scissoredposition. The diagnosis of cerebral palsy wasmade. He could not crawl until aged five, andhad surgical operations on leg tendons at theages of 10 and 12 enabling him to walk withcrutches. The patient had episodes of febrileconvulsions between the ages of 2 and 4 whichwere characterised by generalised twitching.He attended schools for the physically handi-capped. Academically he was hampered by"severe spatial problems" and he was poor atmaths and woodwork.

Epileptic fits began at age eight. He wastreated with a combination of phenytoin andphenobarbitone and achieved relatively goodcontrol. During adolescence he began toexperience more complex seizures. Thesebegan when he saw a vision of the "judgementday" and occasionally, the "whole world'sgrave opening". This was associated with thethought that he was dying and a sense of losingcontact with reality. The fits began with thepatient calling out followed by twitching of theleft side of the mouth, then eyelids, and finallygeneralised jerking of all four limbs. He wouldalso shout quotations from the Bible or pleadto God to take him. These occurred approx-imately monthly.

Psychiatric illness began in adolescence. At13 he was noted to be anxious and havingdifficulty "distinguishing reality and unreal-ity". At 15, he was admitted to hospitalexperiencing auditory hallucinations, and pre-occupied with religious and sexual ideas. Hewas treated with a combination of antidepres-sants and neuroleptics. When assessed at age

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25 he believed that he had been chosen by Godand described the experience of God speakingto him.

Physical examination showed a divergentsquint and a defect in his iris. There was facialasymmetry and he had marked spastic diplegiawith tendon reflexes increased bilaterally.Mental state examination at age 29 revealed ananxious and irritable man, occasionally over-familiar. He showed some thought disorderand was incoherent at times with circum-stantial and tangential speech. There wasmarked interpenetration of themes reflecting apreoccupation with religious and grandiosedelusions. He reported no auditory and visualhallucination apart from those at the time ofseizures.

Cognitive testing showed good orientationbut some difficulty with concentration. He wasunable to do serial 7s but could perform bothserial 3s and naming the months of the yearbackward slowly and accurately. Digit spanwas 5 forwards and 4 backwards. He couldname 16 T-words and 3 four-legged animals ona test of verbal fluency. His writing was poorlyformed and done with great difficulty. He wasunable to write a sentence of his own creation.His verbal memory was unimpaired but therewas some impairment of visual memory withevidence of constructional apraxia. There wassome evidence of concrete thinking on wordassociation and proverbs. Comprehension wasnormal. There was no nominal aphasia, right-

Figure I Case I CT axial brain scan showing lipoma immediately to the right of themidline within the posterior aspect of the corpus callosum.

left disorientation or finger agnosia.The diagnoses were: cerebral palsy, complex

partial seizures with secondary generalisationand chronic schizophrenia.CT scan at age 25 showed agenesis of the

corpus callosum and left hemiatrophy affectingprincipally the anterior hemisphere wherethere was a CSF-containing cyst within the leftfrontal lobe. Adjacent to this there was someatrophy of the sulci extending into the insularregion. In addition there was relative dilatationof the posterior horns and bodies of theventricles adjacent to the upward extension ofthe widened third ventricle. The EEG wasdiffusely abnormal with sharp waves over bothtemporal regions particularly on the right.Case 3 A 41 year old man. He was a twin,born 3 weeks premature after a forceps deliveryand needed oxygen for one week. The birthwas also complicated by Rhesus incompatibil-ity. His co-twin died at one week. Macroceph-aly was noted during early childhood. Hisparents reported that he had temper tantrumsand breath holding attacks, but no convulsions.He was said to be a happy child with friends inthe local village. He left school at age 17 with 5CSEs and then worked as a clerk for 6 months.He began basic training for the armed forcesbut failed and left after 2 months. Since thenhe has had several unskilled jobs, each lastingshort periods, followed by long periods ofunemployment due to psychiatric illness.There is no family history of psychiatric illnessor epilepsy.From age 18 he has experienced brief,

bifrontal headaches of moderate severity. Inaddition he has had a total of 6 seizures. Theseare stereotyped, starting with an abrupt loss ofconsciousness, followed by tonic-clonicmovements.

Psychiatric history started at age 24 withalternating periods of "up" and "down" moodswings. "Up" swings manifest as restless,overactive, irritable and noisy behaviour withpressure of speech. "Down" swings manifestas feeling tired, listless, low in mood, tearful,anhedonic and retarded. He has had numeroushospital admissions due to mood disorder andepilepsy and has been treated with a variety ofanticonvulsants, antidepressants, mood stabi-lisers, antipsychotics, and ECT.Mental state examination at age 39 revealed

tearfulness, low mood and early morningwakening. Speech was odd, pedantic, circum-locutory and metaphorical, but there was noclear evidence of thought disorder and heshowed neither delusions nor hallucinations.Cognitive testing was reported to show noabnormalities. At that time his epilepsy waswell controlled.The diagnoses were, manic depressive psy-

chosis, epilepsy and tension headaches. Also,in view of some obsessional features, socialavoidance, and his use of language, the possi-bility of the diagnosis of Asperger's syndrome(or "schizoid personality") was suggested butfelt to be inconsistent with his sociability as achild.

Psychometric testing at age 39 revealed aWAIS-R full scale IQ of 86. Verbal score was

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89Severe psychiatric disturbance and abnormalities of the corpus callosum: review and case series

the same as previous testing at age 26 butperformance showed a significant fall of 20points. Sub-test scores showed that he per-formed well on tasks involving rote learningand poorly on tasks involving abstract reason-ing.CT and MRI scans showed agenesis of the

anterior part of the corpus callosum (fig 2). Hehad a series of EEGs which showed bursts ofgeneralised rhythmic delta activity and someevidence of left anterior quadrant dysfunc-tion.

Case 4 A 33 year old man. Birth was normalbut he showed slow development, only learn-ing to walk at the age of 3. There were alsosome behavioural disturbances. At age 5 he setfire to an armchair and at other times heattacked neighbours. He was described as"slow" at school and was advised to havespecial education. He had no friends and wasconstantly bullied and "in trouble". He left atage 15 with no qualifications, and had severaldifferent menial jobs; the longest period ofemployment was three and a half years. All hisjobs terminated in him being sacked, mostlydue to incompetence. He was involved inseveral heterosexual and homosexual relation-

Figure 2 Case 3 Coronal MRI scan showing dysgenesis of the anterior part of thecorpus callosum and deformity of the frontal horns.

ships. There is no history of drug or alcoholabuse. The only family history of psychiatricdisorder is alcohol dependence in the patient'smother.

Psychiatric history started at age 24 follow-ing the end of a long homosexual relationship.He started attending a monastery and on oneoccasion while he was praying he heard "thevoice of god" talking close to him saying"Heaven". He felt from that point that he hadbeen chosen as a disciple of Christ. He alsodescribed waking one morning with a terrify-ing sensation of strangulation and the feeling ofan evil presence. He had a strange feeling thathe was "meant to commit suicide". He rushedout of bed, looked in the mirror and saw a facewhich seemed not to belong to him. Hedescribed hearing loud noises which he feltrepresented good and evil coming into conflict.He also described second person auditoryhallucinations and symptoms of acute deper-sonalisation.Mental state examination during his admis-

sion revealed some mannerisms: repeated rais-ing his eyebrows, flapping his hands around.He showed a combination of fear and anxietybut occasionally seemed to be unconcernedand confused. Grandiose religious delusionswere elicited as well as hallucinations of "voi-ces", and visual hallucinations of seeing brightlights flashing in the sky and hallucinations ofthe smell of oranges. Cognitive testing showedgood orientation in time and place but poorconcentration tested by digit span and serial7s. He showed good immediate memory butpoor recent memory when tested by usingname and address. Within a week of admissionhis symptoms had improved completely withno medication except occasional anxiolytics.The diagnosis was of an acute anxiety state

although schizophreniform psychosis must beconsidered. He was felt to have a dependentpersonality, with difficulty in relating to otherpeople. Follow up over 2 years showed onlydiscrete episodes of acute anxiety occurringonce every 3 to 4 weeks, lasting an hour or so.These were precipitated by interpersonal stres-ses or vivid images in magazines or on tele-vision, and responded to behaviour therapy.

Psychometric test gave a full scale IQ of 78.The score of Mill Hill was 82 and Progressivematrices was 92. Neuropsychological testsshowed some incoordination involving finemotor control and opposing hand movements.Somato-sensory evoked potentials showed nosignificant abnormality or delay between rightand left impulses.CT scan showed partial agenesis of the

anterior part of the corpus callosum. EEGwhich was done twice, showed no significantabnormality (table 4).

Case 5 A 22 year old man. Birth was normalbut he was noted to be slow to develop incomparison with his sister. At school at the ageof five years he was reported by the teacher tobe an odd and lonely boy, who was teasedfrequently. He finished schooling with 2 CSEs.During work training he showed poor initiativeand failed because of poor concentration,

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turning up in the wrong places and inability tocommunicate. He was described as a lonerwho had poor social skills, drive and motiva-tion. He was in good physical health.

Family history revealed that his father hadbeen a quiet and self-contained man but"rather aloof'. Maternal grandfather had aphobic disorder.At the age of 6 he was referred to a Child

Guidance Clinic. He showed anxiety aboutschool, self-absorption, wandering, an "odd"manner, "in a daydream most of the time". Hewas solitary and enjoyed being on his own withimaginary friends. At the age of 10 he devel-oped obsessional and manneristic symptoms.His talk was difficult to follow and he hadparanoid ideas about school as well as hypo-chondriacal preoccupations. The diagnosis ofschizoid personality was made and he wastreated with social skills training.At age 18 he was referred for psychiatric

treatment and has attended a day hospitalsince then. He was noted to be withdrawn,mumbling, smiling to himself, picking uplitter, bumping into walls, trees and fences, andwandering.

Mental state examination showed some odd-ities of manner and social interaction. Talk washesitant and hard to understand at timesbecause of disjointedness and mumbling. Writ-ten productions were similarly disordered.There was no evidence of abnormal mood,delusions or hallucinations. He was competentin all aspects of self-care.The diagnosis was uncertain. Asperger's

syndrome or simple schizophrenia were con-sidered. He was treated with antipsychoticmedication, attended day hospital with occu-pational therapy, individual and group activ-ities.

Neuropsychological testing showed a fullscale IQ of 85 by the WAIS-R. This was felt tobe lower than expected from his reading abilityand educational history. Memory for bothverbal and visual-spatial material was alsofound to be poorer than expected.CT scan at age 18 showed a lipoma in the

splenium of the corpus callosum. EEG showedan excess of slow activity, more over the leftside but there were neither specific abnor-malities nor evidence of epileptogenic activ-ity.

Case 6 A 12 year old boy. He was born bynormal delivery. He was fostered at the age oftwo and had several different foster homes. Heattended school regularly though he requiredextra tuition. His mother was emotionallydisturbed when he was taken into care. Shehad been an inpatient in a psychiatric hospitalfor a few years and had a diagnosis of possibleHuntington's disease. The maternal grand-mother died from a similar disorder. Thepatient had two sibs who were well but also incare.At age eight he was referred to a child

psychiatrist. On physical examination he wasjust below average weight and height. Therewas macrocephaly (head circumference58.5cms above the 99th centile). Vision in his

right eye was poor - 6/24 (left, 6/6). There wasa short metacarpal, a long thin upper lip andlong philtrum. Tone on his left side was mildlyincreased in a cogwheel pattern resulting inpoor coordination. Power and sensation werenormal, and reflexes normal and symmet-rical.Mental state examination revealed a cooper-

ative boy with normal speech. He was sociableand smiled occasionally. Short and long termmemory appeared normal but writing andcopying skills were poor. He played imag-inatively.He has had severe behavioural problems. At

times he appeared vacant and was destructiveat home. His conduct had become progres-sively more disruptive to family life. He wouldnot join in family activities such as games andmeals and set himself apart from the others. Inaddition he destroyed his belongings includingfavourite toys. Feeding had been messy, and hehad the habit of eating anything he could gethold of, such as soil, rubbish, and grass. Hesoiled and wet himself deliberately on occa-sion.

Diagnosis was of a non-progressive congeni-tal neurological lesion. His behaviour prob-lems were treated by standard behaviouraltechniques for 8 weeks during which time therewas some improvement.

Psychological testing revealed a full scale IQof 88 (WISC-R). He scored below his age levelon the Oseretsky motor test35 and had diffi-culty with fine motor movements and biman-ual co-ordination.CT scan showed partial agenesis of the

corpus callosum with a moderately largelipoma. The caudate nuclei were small andpoorly defined. There was also dilation of boththe temporal and posterior horns of the thirdventricle. EEG was normal. No chromosomalabnormalities (including fragile X) weredetected.

Case 7 A 31 year old woman. She hadundergone special education because of read-ing problems. Since the age of 12 she reported"'epileptic attacks" and periods of alteredconsciousness. Psychiatric assessment began atage 29 when she was admitted because ofdepression and suicidal thoughts, somemonths after her fiance had died. She des-cribed insomnia, early morning wakening,anorexia, poor concentration and low energy.Mental state examination revealed an

expressionless woman who showed little evi-dence of depression, but at times joked inap-propriately and made fatuous remarks. Therewas no evidence of delusions or hallucinations.Cognitive testing revealed good orientation intime, place and person, normal memory andgeneral knowledge, but poor concentration.The diagnosis was of a personality disorder

in that she had a long history of histrionic andattention seeking behaviour. "Seizures" wereobserved in the absence of EEG abnormality.She had no medication during admission, andfinally discharged herself against advice.The patient had neuropsychological testing

at age 28 (see table 4). She was mildly

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Table 4 Clinical details of psychiatric patients with callosal abnormalities

Age PerinatalCase (years) Sex /development Clinical features Diagnosis Psychometry EpilepsylEEG CT scan

1 35 F Long labour Persecutory and Schizophrenia VIQ 74 No seizures. Lipoma ofbizarre delusions PIQ 73 Excess e, 1 a spleniumHallucinations right temporoViolent behaviour occipital

2 29 M Premature Early onset Schizophrenia "Mild Complex partial Agenesis.Hallucinations mental seizures. L anteriorand delusions Cerebral palsy handicap" Diffuse hemiatrophy

abnormality L frontalCognitive deficits cyst

3 41 M Premature Mood swings Manic depressive VIQ 91 Generalised PartialOdd speech psychosis PIQ 81 epilepsy. agenesis

Macrocephaly Tension headaches ? Lanterior (anterior)Fits as teenager dysfunction

4 33 M "Slow" at Early onset ?Anxiety state VIQ 86 Normal Partialschool Prominent anxiety ?Schizophreniform PIQ 71 agenesis

Psychotic psychosis (anterior)symptoms

5 22 M "Slow Anxiety age 6 Asperger's VIQ 91 Excess slow Lipoma ofdeveloper" Mannerisms syndrome PIQ 79 activity spleniumPoor social Paranoid ideas ?schizophrenia L > Rrelationships

6 12 M Minor Behavioural ?Juvenile WISC- Normal Partialphysical problems, pica Huntington's VIQ 81 agenesis withanomalies soiling. Family Disease PIQ 99 large lipomaMacrocephaly history of HD.* Conduct disorder

7 31 F Reading Pseudo-seizures Personality disorder VIQ 87 "Within normal Agenesisimpairment Depression Conversion PIQ 106 limits"

Parasuicide symptoms

* HD = Huntington's Disease

impaired on tests of verbal memory, immediatespatial recall and memory spans; new learningof verbal and non-verbal materials and long-term spatial memory were intact. She was alsoimpaired in reading with a pattern consistentwith surface dyslexia (L Goldstein, personalcommunication).CT scan showed agenesis of the corpus

callosum. The lateral ventricles were widelyseparated by the continuous upward expansionof the third ventricle between them. EEG waswithin normal limits.

DiscussionSchizophrenia was the most frequent syn-drome reported in the new cases and thosereviewed. However, we cannot make any defin-itive statements about the relative risk ofschizophrenia in callosal agenesis. Firstly, esti-mates of the prevalence of the condition in thegeneral population differ widely (tables 1 and2). Secondly, the reported cases do not comefrom a defined population so it is impossible toknow the "denominator". Even Swayze et al,29who attempted to give some idea of thenumber of callosal abnormalities seen at thesame hospital, were not surveying a definedpopulation and did not take into account theselection factors for MRI scanning in general.One important criterion which will exert amajor influence on the rates of callosal abnor-malities reported is the exclusion from scan-ning of patients with IQ less than 80.29The 7 new cases were all tertiary referrals to

a specialist neuropsychiatric unit and so ourexperience cannot be considered representa-tive. Again, no meaningful calculation of ratescan be made only to mention that agenesis is arare accompaniment of psychosis. However,when criteria for normal intellectual function-ing are relaxed, more cases are to be antici-pated. Two of our cases had mild mentalimpairment (IQ < 80) and three had "border-

line" scores (IQ between 80 and 90)-although evidence for deterioration in IQ,presumably as a consequence of psychosis, waspresent in cases 1 and 3. Similarly, cohorts inwhich psychosis and epilepsy coexist, mayinclude more cases with abnormal callosa. Thesame applies to cerebral palsy and patientswith other obvious neurological disorders.The cases in table 4 show that the psychiat-

ric syndromes associated with callosal abnor-malities are heterogeneous. Case 4 had a highlyatypical disorder characterised by extensiveanxiety and psychotic symptoms. Another(case 3), had a classical bipolar affective illnesswith some features of disordered social inter-action and idiosyncratic use of language. Thepatient described by Lewis et al,33 althoughdiagnosed as suffering from chronic schizo-phrenia, also had experienced marked affectivesymptoms. Unlike case 3, however, he had apositive family history of manic depression.Case 5 had a more striking, pervasive disorderof social development than case 3. This wouldfit into the rubric of Asperger's syndrome36 orschizoid personality disorder.37This syndromehas been described in association with righthemisphere deficits38 but neurological anoma-lies involving the CC could also have apotential aetiological role. Both these cases hadsignificant reductions in performance vs verbalIQ, which, while not unique in our series (seecase 4), are somewhat unusual for "uncompli-cated" agenesis. '7 This may relate to functionalimpairment of the right hemisphere.The finding of agenesis in case 7 who was

finally diagnosed as having a personality dis-order with depressive and conversion symp-toms, may have been a coincidence. However,it is conceivable that the patient's specificlearning disability, possibly a direct conse-quence of callosal agenesis could have contrib-uted to her poor self-esteem through academicfailure35 setting off a chain of negative experi-ences. Other cases in whom early devel-

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opmental problems were noted, ma-y also havesuffered from distorted social and family rela-tionships as a result. This may have influencedthe onset, course, and form of the eventualpsychiatric syndrome, interacting with the"endogenous" brain abnormality. It is notpossible to state with any confidence thepotential influence of CC abnormalities onnon-psychotic psychiatric disorders sincepatients so diagnosed rarely undergo compre-hensive neurological evaluation.Are abnormalities of the CC relevant in the

understanding of severe psychiatric distur-bances? Such disturbances, particularly schizo-phrenia, have been shown to be associated witha number of disparate abnormalities of brainstructure.39-4' Deviant brain development,pre-dating the onset of gross disorder is attract-ing the attention of those who favour a"neurodevelopmental" theory of the origin ofschizophrenia.42 Cases such as those reportedhere, with abnormal premorbid personalities,atypical features, low IQ, early onset and achronic course may be especially likely todemonstrate congenital brain anomalies.43 4Obvious structural anomalies which are occa-sionally identified by neuroimaging studies ofpsychiatric hospital cohorts, though of interestin their own right, may be of value in providingclues as to the location of more prevalentlesions of a subtler kind. They may also givehints as to aetiology. It should be noted thatintrauterine influenza infection and maternalalcohol consumption may cause agenesis of theCC,9 10 and both have been proposed asaetiological factors in schizophrenia.45 46 Themany genetic anomalies found in familial andsporadic cases of callosal agenesis may point tocandidate regions for genetic markers in psy-chotic illnesses. It is conceivable though highlyspeculative, that if the genetic control of thedevelopment of callosal fibres was disrupted ina subtle way, short of agenesis, psychosis mayensue.

Disorders of interhemispheric integrationcan be considered as a plausible model for arange of psychiatric phenomena from "alex-ithymia" to delusions and hallucinations.475'Support comes from some neuropathological52and MRI studies of the CC in psychiatricpatients53 which found differences in compar-ison with normal controls. Another line ofevidence linking psychiatric symptoms and theCC, is the high incidence of such symptoms,54in patients with tumours of that region. Othershave reported series with psychotic and affec-tive symptoms.55 56 This evidence providessome of the rationale for pursuing dysfunc-tional interhemispheric communication incases of psychosis.57 58

Clearly, the CC itself need not be involveddirectly in the causation of psychosis. As well asallowing communication between the hemi-spheres, the CC may be necessary to regulatethe activity within them30 and it may be thelack of this which predisposes to psychosis.49-59Indeed the inhibitory nature of the CC60 issuggested by the high incidence of seizures inagenesis. Similarly, altemative pathways forinterhemispheric communication, which

develop in the absence of a functioning CC,may be especially susceptible to misconnec-tion, a proposed mechanism for producingpsychotic symptoms.6' 62 Finally, the asso-ciated cerebral anomalies such as those involv-ing limbic structures, which occur in tandemwith callosal agenesis, could be of specificaetiological importance for psychiatric illnes-ses. In any event, further studies of psychiatricdisorders in patients with callosal anomaliesshould increase our understanding of thecerebral basis of many psychiatric conditions.

We thank Drs J Bird, P Taylor, P Fenwick and E Taylor for theirpermission to report on their patients, and Dr Laura Goldsteinwho carried out some of the neuropsychological assessments.

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