Corpus Callosum Agenesis and Psychosis in Andermann Syndrome Marie-Jos\l=e'\eFilteau, MD; Emmanuelle Pourcher, MD; Roch H. Bouchard, MD; Philippe Baruch, MD; Jean Mathieu, MD; Fernand B\l=e'\dard,MD; Normand Simard, MD; Pierre Vincent, MD \s=b\ Recent illustrations by cerebral magnetic resonance imaging of anomalies of the corpus callosum in schizophrenics have kindled renewed interest in this association. We studied 62 patients affected by the Andermann syndrome, a polymalformative familial

syndrome combining frequent congenital corpus callosum agenesis, mental retardation, psychotic episodes, peripheral neuropathy, and some dysmorphic features. Twenty of 62 patients presenting with psychosis were compared with 20 nonpsychotic patients matched according to sex and age. The psychotic patients presented an atypical psychosis as defined by the Diagnostic and

Statistical Manual of Mental Disorders, Third Edition, beginning in postadolescence. No significant relationship was observed between corpus callosum agenesis and psychosis. However, a significant association between posterior fossa atrophy and psychosis was established in our study. Although there are limitations in using cross\x=req-\ sectional data for this purpose, the findings suggest an association between cerebellar anomalies and schizophrenialike syndrome and rule out an implication of developmental callosal defects in such psychiatric disorders. (Arch Neurol. 1991 ;48:1275-1280)

"1 he existence of structural anomalies of the corpus callosum in schizo¬ phrenia, first reported by Rosenthal and Bigelow,1 appears of interest in re¬ gard to studies documenting anomalies Accepted for publication August 1,1991. From the Unit\l=e'\de Neuropsychopharmacologie, H\l=o^\pitalde l'Enfant-J\l=e'\suset Centre de Recherche Universit\l=e'\Laval-Robert Giffard (Drs Filteau, Pourcher, Bouchard, Baruch, B\l=e'\dard,and Vincent); H\l=o^\tel-Dieude Chicoutimi (Drs Mathieu and Simard), Q\l=u'\ebec,Canada. Reprint requests to the D\l=e'\partementde Psychiatrie, H\l=o^\pitalde l'Enfant-J\l=e'\sus,1401 18\l=e'\me Rue, Q\l=u'\ebec,Canada (Dr Filteau).

of interhemispheric transfer in this pa¬

thology.2"4 The recent illustration in sev¬

eral studies of cerebral magnetic reso¬ nance imaging of volumetric anomalies ofthe corpus callosum in schizophrenics kindled renewed interest in this associa¬ tion without necessarily orienting to¬ ward a precise etiopathology. Nasrallah et al° reported, in a controlled computed tomographic scan study, a callosal hy¬ pertrophy involving the anterior and median parts (genu and corpus) of the corpus callosum. Conversely, Rossi et al6 observed in magnetic resonance im¬ aging a significantly smaller callosal area in schizophrenics and suggested the hypothesis of structural damage oc¬ curring during fetal life or in the new¬ born. Recently, Swayze et al7 found an increased prevalence of callosal agene¬ sis in schizophrenia using magnetic res¬ onance imaging. Hauser et al,a defining strict neuroradiologic criteria of evalua¬ tion of the callosal areas in magnetic resonance imaging, did not find any hy¬

poplasia or hyperplasia differentiating schizophrenics from control subjects. In summary, neuroradiologic abnormali¬

ties ofthe corpus callosum seem to exist in schizophrenia but are not consistent, nor has the acquired or developmental character of these anomalies been

explained. The existence of subjects that are congenitally acallosal allows the study of the developmental role of the corpus callosum in psychopathology. In Charlevoix-Saguenay county (a region of Quebec well known for its high rate of consanguinity, which facilitates emer¬ gence of recessive autosomal hereditary diseases) a polymalformative familial syndrome first described by Leblanc et al,9 and then by Andermann et al10 in 1971, includes frequent partial or total agenesis ofthe corpus callosum, mental

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retardation, peripheral sensorimotor neuropathy, and certain dysmorphic characteristics, combined under the now

well-known term of Andermann

syndrome. Mathieu

et

al," completing

Andermann's observations by using clinical and neuroradiologic evalua¬ tions, studied an impressive cohort of 64 patients affected by this syndrome. Oc¬ currence of this syndrome in more than one member of either sex in certain fam¬ ilies, the absence of the syndrome in their direct ancestry, and the identifica¬ tion of a common ancestral couple, mar¬ ried in Quebec in 1657, indicate an auto¬ somal recessive transmission from the original founder. The frequent occur¬ rence of a psychotic syndrome in the course of the disease makes the Ander¬ mann syndrome an interesting model of association between corpus callosum agenesis and psychosis. These patients constitute the greatest cohort of family cases of agenesis ofthe corpus callosum described in the literature, to our knowledge; Menkes et al12 reported only five cases over two generations, and most other studies on familial agenesis described two cases observed in sib¬

lings.13"15

In this study, we revised the psychi¬ atric presentation of this cohort and fo¬ cused on 20 patients whose evolution was complicated by a psychotic syn¬ drome. The relationship between the corpus callosum and psychosis is de¬ scribed in the light of results obtained from this study. SUBJECTS AND METHODS

Sixty-two patients of Mathieu and coworkers'11 group were included in our study (31 females and 31 males, 3 to 36 years of age; mean age, 21.0 ±8.9 years). Neurologic data were obtained from the neuromuscular disease clinic of the Hôtel-

Dieu de Chicoutimi Hospital, Quebec City, and from two specialized centers for severe¬ ly handicapped patients located in the vicini¬ ty. Patients were submitted to a complete physical examination and the diagnosis of Andermann syndrome was established by a neurologist, an orthopedist, and a pediatri¬ cian for patients younger than 18 years. Family and genealogie data were collected from the clinic's family history question¬ naires, Charlevoix's marriage registry, and certain genealogie files from the Montreal (Quebec) Neurological Institute. Psychiatric examination of 20 patients who had experienced one or more psychotic epi¬ sodes was performed, using a semistruc¬ tured interview according to the Diagnostic and Statistical Manual ofMental Disorders, Third Edition Revised (DSM-III-R), crite¬ ria. The developmental and functional pro¬ files were assessed using Harvey's develop¬ mental scale,lb which evaluates five categories of observable behavior: motoricity, autonomy, speech, drawing, and gener¬ al knowledge. This scale has been in use for the past 10 years in these centers, making possible the comparisons ofthe past and pre¬ sent functioning of patients. All subjects were scanned with a fourth-generation com¬ puted tomographic scanner (Picker), with a 256 256-pixel matrix; slice thickness was 10 mm, obtained at +15° to the canthomeatal line. The tomographic criteria used for diag¬ nosis of total agenesis ofthe corpus callosum were the ascension, the interposition and di¬ latation of the third ventricle, the enlarge¬ ment ofthe anterior interhemispheric fissure and the letter's contact with the anterior por¬ tion of the third ventricle, and the distance between the parallelism ofthe lateral ventri¬ cles. Among other anomalies, atrophy of the posterior fossa is diagnosed by an enlarge¬ ment ofthe fourth ventricle, the prominence of vermian and hemispheric arachnoid sulci, or the enlargement of the quadrigeminal cistern. To study the association between corpus callosum agenesis and psychosis, 20 nonpsychotic patients were matched with 20 psy¬ chotic subjects, according to sex and age. The absence of psychosis in this group was assessed using the same diagnostic interview used for the psychotic subjects. Statistical analysis used 2 and Mann and Whitney tests. values of .05 or less were considered

statistically significant. RESULTS

The 62

patients,

31 women and 31 all born to healthy parents with common ancestors between the first and fifth generation in some cases. Ofthe 62 patients, 18 belonged to seven family units. men,

were

Psychomotor Development

Psychomotor development appeared

normal for the first year of life, after which the parents began to notice retar¬ dation or other abnormalities. The ma¬ jority of patients only crawled until the age of 2.5 years and were only able to walk with support or braces. Slight to

Table 1.—Characteristics of

Subjects Matched

Nonpsychotic,

Psychotic, =

(female/male) Age, y (mean ± SD) Age at onset of psychosis All psychotic subjects Sex

10/10

males

17.7 ± vs

females

42

21/21

Nonpsychotic, =

20

10/10 26.2

Females Males

*P< .05.

20

-

3.5*

(Mann-Whitney L/test).

moderate mental retardation impeded normal school learning. Eleven ofthe 62 patients presented with convulsive epi¬ sodes of the grand mal type at various ages, without relationship to a subse¬ quent appearance of psychosis, which eliminates an organic psychotic syn¬ drome complicating a chronic psycho¬ motor epilepsy, active from childhood on. Most patients lived within their fam¬ ilies until caring for them became oner¬ ous due to their physical and/or psycho¬ logic handicaps, the latter appearing typically at adolescence. In fact, after a period of moderate autonomy, most pa¬ tients became confined to a wheelchair after 20 years due to worsening of sen¬ sorimotor neuropathy. In addition, the appearance of psychotic and behavioral problems led to the need for temporary hospital admission and, more often, per¬ manent confinement in an institution that specializes in caring for these

patients.

Clinical Examination

On the physical level, all patients either confined to bed or a wheel¬ chair. Skeletal abnormalities could be observed and the following dysmorphic features associated with Andermann syndrome were also noted: brachycephaly, a long asymmetric face, more or less were

pronounced drooping eyelids, an ogival palate, abnormal posture of hands with deviation, and partial syndactyly or lax¬ ity of the fingers as well as a pigeon

chest deformation of the thorax. The clinical and electrophysiologic charac¬ teristics of their polyneuropathy have been described previously.10,11 On the mental level, contact and col¬ laboration were difficult to maintain in the majority of cases due to a minimal attention span. All patients examined exhibited, at the time ofthe psychiatric interview, psychotic manifestations of the paranoid type with terrifying and horrible visual hallucinations, often de¬ scribed as monsters or persecutors. Au¬ ditory hallucinations were also report¬ ed, and many patients argued with these voices during the interview. Para¬ noid delusions were also noted. Staff or

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family members present at the inter¬ view reported behavioral disorders

such as bouts of anger or tears but also self-mutilation that have been difficult to relate to psychotic manifestations. According to the DSM-III-R, these pa¬ tients met atypical psychosis criteria. The presence of both hallucinations and delusions precluded the possibility of using the DSM-III-R diagnosis of or¬ ganic delusional disorder or organic hal¬ lucinosis. The antipsychotic medication used (haloperidol, chlorpromazine, trifluoperazine) modified the picture in a rather inconsistent way. The patients quieted down, but still hallucinated. At the time ofthe study, 20 (10 men and 10 women) among the 62 patients exhib¬ ited psychotic symptoms. This high prevalence of psychosis possibly under¬ estimates the final proportion of poten¬ tial psychotic disturbances in our co¬ hort. The psychotic syndrome appears at the end of adolescence and 13 ofthe 42 nonpsychotic patients (21 men and 21 women) were younger than the youn¬ gest age of onset of psychosis in our sample, which was 13 years of age. A significant difference was observed (P .0413) between males and females for age of onset of psychosis (Table 1). Contrasting with the hypothesis sug¬ gesting a protective effect of estrogens on psychosis onset,17 females in our sam¬ ple became psychotic at a younger age than males (17.7 ±3.5 years vs 21.3 ± 4.1 years). For the whole group of patients, the average age for onset of psychosis was 19.5 ± 4.1 years. A comparison with Harvey's scales permitted us to note a clear deteriora¬ tion in autonomy as well as psychomotor regression. This deterioration was pro¬ ceeded by a period of apathy and social withdrawal, often misdiagnosed as a de¬ pressive episode and indicating the start of a psychotic disorder. The distri¬ bution of mental retardation in our sam¬ ple differed in severity from that in the general population of the mentally re¬ tarded (85% mild and 10% moderate, DSM-III-R), by showing a larger pro¬ portion of moderate retardation. How¬ ever, the proportion of psychosis in our =

Table

2.—Computed Tomographic (CT) Scan Characteristics Nonpsychotic Subjects* No.

CT Scan Abnormalities

Corpus callosum agenesis Dilatation of lateral ventricles Dilatation of third ventricle Posterior fossa

*NS indicates tx2 test.

atrophy not significant.

The evolution of the illness is charac¬ terized by a progressive deteriora¬ tion—both physical and psychologic. Patients often develop an extreme de¬ gree of scoliosis, and the majority of them die during their 30s from neuro¬

pathic or respiratory complications. REPORT OF A CASE

The patient was a young woman, 25 years old, with complete agenesis ofthe corpus callosum and sensorimotor po¬ lyneuropathy. Her parents were unre¬ lated. Her gestation and birth were nor¬ mal. She was the third in a family of five

children. The four girls suffered from the Andermann syndrome with psycho¬ sis. The only boy of the family was spared from the disease. The patient's psychomotor development was normal during her first year of life after which the parents noted that, like her sisters, she crawled about without being able to walk. She started to walk, with the use of braces, between 3 and 4 years of age and was able to walk with crutches until the age of about 18 years, when the neuromuscular disorder made walking impossible. The patient has been con¬ fined to a wheelchair since then. The patient showed mild mental retarda¬ tion. Psychotic symptoms appeared at age 16 years. At 18 years she was admit¬ ted for atypical psychosis. At that time the patient was half-mute, spoke to her¬ self, had nightmares, had visual and au¬ ditive hallucinations, and shouted as soon as she was touched. The psychotic symptoms improved slightly with anti¬ psychotic medication (haloperidol) but the patient remained autistic. Other psychotic episodes led to hospitaliza¬ tion, and the patient was finally institu¬ tionalized at the age of 22 years. A com-

On the other hand, a significant rela¬ tionship (P=.0285) between posterior

vs

Nonpsychotic (n 20) 13 (65) 4(20) 13 (65) 2(10)

Pt

-

=

Linaker and Nitter,18 about 18% ofthe mentally retarded show psychotic dis¬ turbances. In our sample, these prob¬ lems were actually present in 33% (20/62) ofthe patients.

Psychotic

(%)

Psychotic (n 20) 11 (55) 8 (40) 16 (80) 8 (40)

sample, which mostly consisted of men¬ tally retarded individuals, was higher than that of the general population of the mentally retarded. According to

of

puted tomographic

NS NS NS

performed in 1986 showed a total agenesis ofthe cor¬ pus callosum, with a moderate enlarge¬ ment ofthe third ventricle, and marked enlarged lateral ventricles at the occipi¬ tal and temporal horn levels. The fourth scan

ventricle was at the upper normal limit, suggesting a slight posterior fossa

atrophy.

In the whole sample (62 subjects), 40 corpus callosum ageneses were re¬ ported (65%). Thirty-five were total agenesis and five were partial agenesis. The search for correlations between neuroradiologic abnormalities and pres¬ ence of a psychosis was performed on the 20 psychotic subjects and 20 nonpsy¬ chotic patients matched according to sex and age. For statistical analysis, partial and total corpus callosum ageneses were grouped together. Only four partial ageneses were observed, two in each group. No significant relationship was found between agenesis of the corpus callosum and psychosis (Table 2). How¬ ever, when tomographic anomalies were examined separately, a tendency to more pronounced anomalies in psy¬ chotic subjects was noted. Eight (40%) of 20 psychotic subjects showed a dilata¬ tion of the lateral ventricles, while only four (20%) of 20 nonpsychotic subjects showed this dilatation (Table 2). Simi¬ larly, 16 (80%) of 20 psychotic subjects showed a dilatation of the third ventri¬ cle compared with 13 (65%) of 20 for nonpsychotic subjects. The results are comparable with regard to the enlarge¬ ment of the interhemispheric fissure (60% vs 65%). The dilatation ofthe lat¬ eral ventricles, and especially of the third ventricle, may represent a sign of subcortical atrophy that would tend to be more pronounced in psychotic pa¬ tients. Verification of this tendency would require use of more precise plani¬ metrie measurements by computed or

magnetic

patients were psychotic. Interestingly,

the patients' age distribution showed that atrophy ofthe posterior fossa is not detected in young patients and thus, atrophy of the posterior fossa may rep¬

progressive secondary phe¬ rather than a congenital hypoplasia. None of the nonpsychotic subjects presented either an agenesis of the cor¬ resent

a

nomenon

pus callosum

COMPUTED TOMOGRAPHIC SCAN FINDINGS

tomographic scan nance imaging.

fossa abnormalities and psychosis was established (Table 2). Radiologie crite¬ ria for posterior fossa atrophy were ob¬ served in 10 of the 40 patients. Eight (80%) of 10 of these patients were psy¬ chotic. However, these eight patients constitute only eight (40%) of 20 of the psychotic subjects. Considering the whole sample (62), 12 patients showed a posterior fossa atrophy with (in nine cases) a superior or inferior atrophy of the vermis. Eight (66%) of 12 of these

reso¬

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or

abnormalities of the

posterior fossa, and only two psychotic patients had the two abnormalities si¬ multaneously. Therefore, these two phenomena seem unrelated. COMMENT

The limits of this

study must first be

emphasized. From a clinical point of view, the dichotomy psychotic/nonpsychotic subdivision does preclude possi¬ ble doubtful cases. The psychiatric dis¬ turbance exhibited by psychotic patients does not represent a typical schizophrenic syndrome. In particular, psychotic deficit would have been im¬ possible to assess in the presence of mental retardation. However, positive symptoms of psychosis (hallucinations, delusions, psychomotor disturbances) are frank, meeting DSM-III-R criteria of atypical psychosis. Concerning the neuroradiologic examinations, the diag¬ nosis of total or partial agenesis of the corpus callosum, in the absence of plani¬

metrie measurement, is to

some

extent

dependent on the accuracy of the neu¬ roradiologist. However, the interpreta¬ tions were all made by the same neuro¬ radiologist, who was blinded to the diagnosis of psychosis. Moreover, the tomographic examinations were not all

carried out with the same age group, and it can then be imagined that, while agenesis of the corpus callosum is ob¬ servable at any age, an atrophy of the posterior fossa could subsequently de¬ velop in some patients who did not pre¬ sent the anomaly at the time the exami¬ nation was made. Moreover, some of these younger patients will perhaps de¬ velop a psychosis. A longitudinal, rath¬ er than cross-sectional, and partially retrospective study would eliminate

this bias. Finally, even if the abovedescribed sample regroups the greatest number of patients with corpus callo¬ sum agenesis that has ever been pub¬ lished to date, the statistical analysis deals with a small number of individuals as far as some of the results are concerned.

than the corpus callosum cannot be ruled out: at the forebrain level, the anterior commissure, usually spared in callosal agenesis, or at the brain-stem level, the raphe nuclei projections to the

Corpus Callosum Agenesis and Psychosis

Posterior Fossa Atrophy Abnormalities and Psychosis

In our cohort, we did not find any correlation between agenesis of the cor¬ pus callosum and presence of a psycho¬ sis. Previous articles on the psychiatric disturbances observed in patients with corpus callosum agenesis from different causes did show mental retardation and seizures to be the most frequent clinical features (see Parrish et al19 and Jeret et al2" for review). In our study, psychosis is frequent but corpus callosum agene¬ sis does not appear to play a determi¬ nant influence in its apparition. In the case of schizophrenia, there is a general lack of consensus over morphologic anomalies ofthe corpus callosum.1"6'8 As recently observed by Swayze et al,7 two of 140 schizophrenic patients displayed partial agenesis of the corpus callosum; they suggest the evidence of a higher than control prevalence of callosal and possibly paracallosal limbic abnormali¬ ties that may be significant in the patho¬ genesis of the disease in some subset of schizophrenic patients. While the psy¬ chotic syndrome associated with Ander¬ mann syndrome does not meet the DSM-III-R criteria for schizophrenia because of the association of mental re¬ tardation, it must be noticed that it shares with the two cases of the previ¬ ously quoted article florid visual and au¬ ditory hallucinations refractory to cur¬ rently used antipsychotic medications. Lewis et al21 described another case as¬ sociating schizoparanoid disease with callosal agenesis, but the presence of a left-sided cystic cavity projecting into the frontotemporal region led to cau¬ tious interpretation of the relationship between the two problems. As some au¬ thors (Beaumont and Dimond2 and Doty22) assume that florid symptoms such as perceptual disorder and delu¬ sions arise from a defective integration of the mental activities of each hemi¬ sphere, a lesion or dysfunction of callo¬ sal interhemispheric transfer could hypothetically play a role in the expression of the "first rank" symptoms of delu¬ sions or hallucinations. Our results, however, do not provide any argument to confirm a possible causal role of de¬ velopmental anomalies of the corpus callosum in schizophrenic disorders. On the other hand, anomalies of interhemi¬ spheric processes in other pathways

hypothesized by Doty,22 could both be areas implicated in the genesis of positive symptoms. forebrain,

In

our

as

sample, there exists a signifi¬

cant association between anomalies of

the posterior fossa and psychosis. Cour¬ chesne et al23 have recently reported and confirmed24 a specific hypoplasia of the vermian lobules VI and VII in autism. Gaffney et al2° described enlargement of the fourth ventricle and significantly smaller pons in autism, orienting to¬ ward a brain-stem neuropathology in this complex behavioral syndrome. Our patients did not present any autistic be¬ havior in early childhood; rather, their disease was characterized by a postpuberty psychologic and motor deteriora¬ tion. The association between atrophy of the vermis and schizophrenia was first reported in 1979 by Weinberger et al,26 who found an incidence of 16.6% of atrophy of the vermis in schizophrenic subjects treated with neuroleptics against 0.6% in the general population. In 1980, Weinberger et al27 published a histopathologic study of 12 schizophren¬ ic brains, and found an atrophy of the anterior vermis in five patients (three patients died before being treated by neuroleptic drugs). The studies by Snider et al,28'29 Snider and Snider,3" and Heath et al,31,32 have supported, on an electrophysiologic, biochemical, and clinical basis, a causal relationship be¬ tween dysfunction of the vermis and functional changes of the dopaminergic mesolimbic system that is involved in the genesis of the symptoms of psycho¬ sis. All these results have been heavily questioned in the literature. Other au¬ thors33"31' did not find any significant rela¬ tionship between schizophrenic and cer¬ ebellar atrophy. We must remember that volumetric anomalies of the cere¬ bellum were observed in the older sub¬ jects. This suggests a secondary ac¬ quired atrophy of the vermis rather than a congenital hypoplasia. However, only serial radiologie examinations dur¬ ing the course of development would allow us to confirm this hypothesis. Moreover, if almost all patients with a posterior fossa anomaly were psychotic, only 40% of the subjects exhibited it. Therefore, our study suggests an ag¬ gravating while not causal role of atro¬ phy of the vermis in schizophreniform

psychosis.

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Psychosis in Andermann Syndrome: Involvement of Other Central Nervous System Structures?

The inherited Andermann syndrome of the autosomal recessive type, which combines facial and digital dysmorphia (acrocephalosyndrome), partial or total agenesis of the corpus callosum, and sensorimotor polyneuropathy, and which presents a high incidence of psy¬ chosis, is certainly original. Pure corpus callosum agenesis of the adult has little or no clinical conse¬ quence. This is the conclusion resulting from a study by Slager et al,37 which, based on other observations of callosal agenesis diagnosed in adults,38 did not find any behavioral or neuropsychologic anomaly. The characteristic deficits of acquired callosal disconnection syn¬ dromes, consisting of tactile anomia of objects palpated with the left hand, vi¬ sual anomia of objects presented in the visual left hemifield, ideomotor apraxia, and unilateral left-sided agraphia, are not observed in the congenital absence of the corpus callosum.3" Nor are they observed in a surgical callosotomy per¬ formed before the age of 10 years,4" indi¬ cating the potential role and the plastici¬ ty of other commissural formations, especially in the absence of the corpus callosum.4143 Only a deficit in motor coor¬ dination, observed during special bimanual tasks, is reported in those sub¬ jects with a pure callosal agenesis in

adults.41

The authors who

reported Ander¬

syndrome1"11 described clinical and epidemiologie characteristics to dis¬ mann

it from other inherited syn¬ dromes of polymalformation with agen¬ esis of the corpus callosum; it clearly differs, for example, from Menkes and coworkers' observations,12 where epi¬ lepsy and mental retardation prevail and seem to be inherited in an X-linked recessive manner, or from the cases of callosal agenesis observed in less than 20% of other diseases with a known ge¬ netic marker such as trisomia 18, mucopolysaccharidosis ofthe Hurler type, or tuberous sclerosis. However, this syn¬ drome may share, along with other polymalformative syndromes with agene¬ sis of the corpus callosum, the diffusion of central nervous system defects. In their review ofthe literature, referring to 42 cases of callosal agenesis "plus," Parrish et al1" recorded nervous system abnormalities in 85% of the cases, and an unexpectedly high incidence of hypo¬ plasia ofthe pyramidal tracts; they con¬ sider that corpus callosum agenesis may be part of a widespread developmental disturbance of the major myelinated pathways of cortical origin. In a recent

tinguish

extensive review by Jeret et al,20 re¬ grouping all cases described in the liter¬ ature (660 cases) proven by necropsy, pneumoencephalography, or computed tomography, a high percentage of asso¬ ciated extracallosal anomalies and, in¬ terestingly, up to 32% of anomalies of cortical development abnormalities (polymicrogyria or heterotopia) was ob¬ served. Clinically, 85% of acallosal pa¬ tients were classified as mentally re¬

tarded and seizures were recorded in 42% of the cases. Convulsive episodes were, however, much less common in our

sample (15%).

De Leon et al,44 in an autopsy study of Apert's syndrome, associated with agenesis of the corpus callosum, hippo¬ campal hypoplasia, skeletal malforma¬ tions ofthe craniofacial massif, and syn-

dactylies (acrocephalosyndactylia type 1), described a high incidence of limbic abnormalities associated with total

or

partial agenesis of the corpus callosum and the difficulty of histopathologic def¬

inition of these defects in midline struc¬ tures extending from the basal telencephalon to the mesodiencephalic junction. The callosal and hippocampal commissures derive from the lamina terminalis from which they differenti¬ ate between the 10th and 12th week of gestation.40 The corpus callosum follows its development in a rostrocaudal gradi¬ ent with the septoammonic formations while remaining encircled by them. On the other hand, the rostrocaudal devel¬ opment ofthe fornix allows the develop¬ ment of the psalterium or hippocampal commissure. The teratologie involve¬ ment of limbic structures in corpus cal¬ losum agenesis resulting from a central nervous system insult occurring after

the 10th week of gestation is highly probable because ofthis chronologic and topographic synchronism. Before this period, agenesis of the corpus callosum is only part of a more extensive manifes¬ tation of midline dysgenesis as seen in holoprosencephaly.46 These data could suggest that most of the psychopathologic manifestations observed in the An¬ dermann syndrome are related primari¬ ly to the paracallosal limbic develop¬ mental defects. Several authors suggest an involve¬ ment of the limbic system in chronic schizophrenia. For Bogerts et al,47 hy¬ poplasia ofthe limbic structures may be a histopathologic indication of a predis¬ position to schizophrenia, whether in¬ herited or acquired in the course of em¬ bryonic development, due to the action of one or another toxic or infectious agent, in this specific vulnerable area; the precocious "lesion" ofthe limbic sys¬ tem and the abnormalities of the septohippocampal connections that derive from them, and the maturation of the central nervous system, are likely to explain the predisposition to psychosis observed in postadolescence when the mesocorticolimbic adaptation systems and their dopaminergic targets are fully active, as recently suggested by Wein¬ berger.48 Since Scheibel and Kovelman49 first observed orientation anomalies of the dendritic arborization of the hippo¬ campal pyramidal cells, anomalies have also been described in the medial struc¬ tures of the limbic system using mor¬

phometric techniques statistically

con¬

trolled in histopathology.47'5"01 These observations support the hypothesis, in the chronic schizophrenic subject, of a hypotrophy of the amygdalian forma-

tions and the hippocampal and parahip¬ pocampal cortex, sometimes associated

a dilatation of the inferior horn found in 98% of cases of schizophrenia by Brown et al.50 Relating the high inci¬ dence of psychosis in Andermann syn¬ drome to associated anomalies of the limbic system would require histopath-

with

ologic confirmation, with morphometric techniques adapted to the study of these

areas, but seems, at the actual state of

knowledge, the best hypothesis. Our study associating clinical and neuroradiologic investigation tends to invalidate the hypothesis of a link be¬ tween corpus callosum

agenesis and atypical psychosis, while supporting a

coincidental association between vermian abnormality and psychosis. Confirm¬ ing the link would necessitate prospec¬

tive serial computed tomographic scan studies with planimetrie techniques. Thus, a psychiatric and radiologie pro¬ spective follow-up ofthe patients, espe¬ cially the youngest ones who have not yet developed the psychotic syndrome, will be carried out. A study of chromosomic liaison of these families also remains to be performed, which could link a psy¬ chotic syndrome with a known chromosomic anomaly, similar to the observa¬ tions of Basset and Jones,"2 where facial dysmorphia, mental retardation, and schizophrenia were associated with an anomaly of the short arm of chromo¬ some 5. Andermann syndrome stands out as a unique entity, with both distinct neuroanatomic and clinical features, which allows a reflection on the interac¬ tion between central nervous system le¬ sions and a schizophrenialike syndrome.

References

Bigelow LB. Quantitative brain schizophrenia. Br J Psychiatry. 1987;20:259-264. 2. Beaumont JG, Dimond SJ. Brain disconnection and schizophrenia. Br J Psychiatry. 1973; 1. Rosenthal R,

measurements in chronic

123:661-662. 3. Flor-Henry HP. Gender, hemispheric specialization and psychopathology. Soc Sci Med. 1978; 12:155-162. 4. Green P. Defective interhemispheric transfer in schizophrenia. J Abnorm Psychol. 1978;87:472\x=req-\ 480. 5. Nasrallah NA, Andreasen NC, Coffman JA, et al. A controlled magnetic resonance imaging study of corpus callosum thickness in schizophrenia. Biol Psychiatry. 1986;21:274-282. 6. Rossi A, Stratta P, Gallucci M, Passariello R, Casacchia M. Quantification of corpus callosum and ventricles in schizophrenia with magnetic nuclear resonance imaging, a pilot study. Am J Psychiatry.

1989;146:99-101. 7. Swayze VW, Andreasen NC, Ehrhardt JC, Yuh WTC, Alliger RJ, Cohen GA. Developmental abnormalities of the corpus callosum in schizophrenia. Arch Neurol. 1990;47:805-808. 8. Hauser P, Dauphinais DI, Benehini W, Delisi LE, Geternter J, Dost RM. Corpus callosum dimensions measured by magnetic resonance imag-

ing in bipolar affective disorder and schizophrenia. Biol Psychiatry. 1989;26:659-668. 9. Leblanc G, Morteza\l=i"\MA, Lopez-Pinto CA. Agenesie du corps calleux (12 cas). Neurochirurgie. 1966;7:789. Abstract. 10. Andermann E, Andermann F, Melan\l=c;\eonD, Karpati G, Carpenter S. Three familial midline malformation syndromes of the central nervous system. In: de Grouchy J, ed. Proceedings of the Fourth International Congress of Human Genetics. Amsterdam, the Netherlands: Excerpta Medica International Congress Series; 1971;233:15. 11. Mathieu J, B\l=e'\dardF, Pr\l=e'\vostC, Langevin P. Neuropathie sensori-motrice h\l=e'\r\l=e'\ditaireavec ou sans ag\l=e'\n\l=e'\siedu corps calleux: \l=e'\tuderadiologique et clinique de 64 cas. Can J Neurol Sci. 1990;17:103\x=req-\ 108. 12. Menkes JH, Philippart M, Clark DB. Hereditary partial agenesis of corpus callosum. Neu-

rology. 1964;11:198-208. 13. Dogan K, Dogan S,

Lovren CI.

the corpus callosum in two brothers.

Agenesis of Lijec Vjesn.

1967;89:377-385. 14. Shapira Y, Cohen T. Agenesis of the corpus callosum in two sisters. J Med Genet. 1973;70:266\x=req-\

269. 15. Naiman J, Fraser FC. Agenesis of the corpus callosum: a report of two cases in siblings. Arch

Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/02/2015

Neurol Psychiatry. 1955;74:182-185. 16. Harvey M. Echelle de D\l=e'\veloppement. Alma, Quebec: Bureau d'Etudes Psychosociales; 1974. 17. Hauser P. Risk and protective factors in schizophrenia, clinical and social implications. Mod Med Can. 1985;40:579-584. 18. Linaker OM, Nitter R. Psychopathology in institutionalised mentally retarded adults. Br J

Psychiatry. 1990;156:522-525.

19. Parrish ML, Roessmann U, Levinsohn MD. of the Ann Neurol. 1979;6:349-354. 20. Jeret JS, Serur D, Wisniewski KE, Lubin RA. Clinicopathological findings associated with of the corpus callosum. Brain Dev. agenesis

Agenesis of the corpus callosum: a study frequency of associated malformations.

1987;9:255-264. 21. Lewis SW, Reveley MA, David AS, Ron

Agenesis of the corpus callosum and schizophrenia: a case report. Psychol Med. 1988;18:341\x=req-\ MA.

347. 22.Doty

RW. Schizophrenia: a disease of interhemispheric processes at forebrain and brainstem

level? Behav Brain Res. 1989;34:1-33. 23. Courchesne E, Yeung-Courchesne R, Press

GA, Hesselink JR, Jernigan TL. Hypoplasia of cerebellar vermal lobules VI and VII in autism.

Engl J Med. 1988;318:1349-1354. 24. Courchesne E, Hesselink JR, Jernigan TL, Yeung-Courchesne R. Abnormal neuroanatomy in a non-retarded person with autism: unusual findings with magnetic resonance imaging. Arch Neurol. 1987;44:335-341. 25. Gaffney GR, Kuperman S, Tsai LY, Minchin S. Morphological evidence for brainstem involvement in infantile autism. Biol Psychiatry. N

1988;24:578-586. 26. Weinberger DR, Torrey EF, Wyatt RJ.

Cerebellar cet.

atrophy in chronic schizophrenia. Lan-

1979;1:718-719.

Weinberger DR, Kleinman JE, Luchins DJ, Bigelow LB, Wyatt RJ. Cerebellar pathology in schizophrenia: a controlled postmortem study. Am J Psychiatry. 1980;137:359-361. 28. Snider RS, Maiti A, Snider SR. Cerebellar pathways to ventral midbrain and nigra. Exp Neurol. 1976;53:714-728. 29. Snider SR, Snider RS. Alterations in forebrain catecholamine metabolism produced by cere27.

bellar lesions in the rat. J Neural Transm.

1977;40:115-128.

30. Snider SR, Snider RS. Cerebellar lesion and psychiatric disorders. J Nerv Ment Dis. 1979;167:

760-671. 31. Heath RG, Franklin DE, Shraberg D. Gross pathology in the cerebellum in patients diagnosed and treated as functional psychiatric disorders. J Nerv Ment Dis. 1979;167:585-592. 32. Heath RG, Franklin DE, Walker CF, Keating JW. Cerebellar vermal atrophy in psychiatric patients. Biol Psychiatry. 1982;17:569-583. 33. Coffman JA, Mefferd J, Golden CJ, Bloch S, Graber B. Cerebellar atrophy in chronic schizophrenia. Lancet. 1981;1:666.

34. Nasrallah

HA, Jacoby CG, McCalley-Whit-

ters M. Cerebellar

atrophy in

chronic

schizophre-

nia. Lancet. 1981;1:1102. 35. Mathew RJ, Partain CL. Midsagittal sections of the cerebellar vermis and fourth ventricle obtained with magnetic resonance imaging of schizophrenic patients. Am J Psychiatry. 1985; 142:970-971. 36. Yates W. Cerebellar atrophy in schizophrenia and affective disorder. Am J Psychiatry.

1987;144:465-467.

37. Slager UT, Kelly AB, Wagner JA. Congenital absence of the corpus callosum: report of a case and review of literature. N Engl J Med. 1957; 256:1171-1176. 38. Carpentier MD, Druckemille WH. Agenesis of corpus callosum diagnosed during life: review of literature and presentation of two cases. Arch Neurol Psychiatry. 1953;69:305-322. 39. Lassonde M, Nolin P, Laurencelle L, Geoffroy G. Evaluation neurospychologique d'enfants atteints d'ag\l=e'\n\l=e'\siedu corps calleux. Apprent Soc.

1982;5:115-124.

40. Lassonde M, Saverwein G, Geoffroy G, Decarie M. Effects of early and late transsection of the corpus callosum in children. Neurosci Lett.

1984;18(suppl):407.

41. Lassonde M, Lepore F, Ptito M. Les Fonctions Calleuses: Neuropsychologie Clinique et Neurologie du Comportement. Montr\l=e'\al,Canada: PUM Masson; 1987. 42. Geoffroy G, Lassonde M, Delisle F, Decarie M. Corpus callosotomy for control of intractable seizures in children. Neurology. 1983;33:891-897. 43. Bogen JE, Vogel PJ. Neurological status in the longterm following complete cerebral commissurotomy. In: Michel F, Shott B, eds. Lyon,

Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/02/2015

France: Presses de L'Imprimerie JP. 1975:227-254. 44. De Leon GA, De Leon G, Grover WD, Zaeri N, Alburger PD. Agenesis of the corpus callosum and limbic malformation in Apert syndrome (type 1 acrocephalosyndactyly). Arch Neurol. 1987;44:979\x=req-\ 982. 45. Rakic P, Yakovlev PI. Development of the corpus callosum and cavum septi. J Comp Neurol.

1968;132:45-72. 46. Loeser JD, Alvord EC. Agenesis of the corpus callosum. Brain. 1968;91:553-570. 47. Bogerts B, Meertz E, Sch\l=o"\nfeldt-BauschR. Basal ganglia and limbic system pathology in schizophrenia: a morphometric study of brain volume and shrinkage. Arch Gen Psychiatry. 1985;42:784-790.

Weinberger DR. Implications of normal development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987;44:660-669. 48. brain

49. Scheibel AB, Kovelman JA. Disorientation of the hippocampal pyramidal cell and its processes in the schizophrenic patients. Biol Psychiatry.

1981;16:101-102. 50. Brown R, Colter N, Corsellis N, et al. Post-

changes in Psychiatry. 1986;43:36\x=req-\

mortem evidence of structural brain

schizophrenia.

Arch Gen

42. 51. Suddath RL, Canasova ML, Goldberg TE, Daniel DE, Kel Soe JR, Weinberger DR. Temporal lobe pathology in schizophrenia: a quantitative magnetic resonance imaging study. Am J Psychia-

try. 1989;146:464-472. 52. Basset AS, Jones B. Partial trisomy chromosome

5

cosegregating with schizophrenia.

1988;1:799-800.

Lancet.