Journal of , , and Psychiatry 1997;63:373–375 373 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.373 on 1 September 1997. Downloaded from

SHORT REPORT

Schizencephaly associated with psychosis

Robert C Alexander, Ashwin A Patkar, Jocelyne S Lapointe, Sean W Flynn, William G Honer

Abstract found to be mentally retarded. started is a rare disorder of brain at the age of 7 and she was treated with development resulting in the formation of with good eVect. abnormal unilateral or bilateral clefts in She had her first admission to psychiatric the cerebral hemispheres. It is often hospital at the age of 18 after she began to hear accompanied by partial seizures, mental voices, which were accompanied by religious retardation, and . Two pa- preoccupation and grandiosity. She was given tients are described with clear psychotic the diagnosis of schizophreniform disorder and symptoms with either unilateral or bilat- treated with neuroleptic drugs. Her symptoms eral schizencephaly. The implications of improved but her social functioning remained the association between schizencephaly impaired. Over the next nine years the patient and psychosis in these patients for under- was admitted to hospital eight times at different standing the biology of the psychoses are institutions. The admissions were mainly for discussed. depressive symptoms, suicidal ideation, social withdrawal, and abnormalities of thought (J Neurol Neurosurg Psychiatry 1997;63:373–375) processes. She was treated at diVerent times with therapeutic doses of haloperidol, loxapine, copyright. Center for Studies of Keywords: schizencephaly; psychosis; brain diseases fluphenazine, perphenazine, nortriptyline, ser- Addiction, Department of traline, and benztropine either singly or in Psychiatry, University combination. Her symptoms were usually tem- Originally described by Wilmarth1 and later by of Pennsylvania, 23 porarily alleviated but not eliminated during Philadelphia, PA Yakolev and Wadsworth, the schizen- psychiatric admissions. 19104, USA cephalies are rare abnormal unilateral or bilat- During her most recent admission, she R C Alexander eral clefts in the cerebral mantle arising during displayed depressed mood, feelings of hope- early prenatal development. The clefts most lessness, sleep and appetite disturbances, Department of commonly involve the parasylvian regions and Psychiatry and Human religious and persecutory delusions, and audi- Behavior, JeVerson have been divided into two subtypes. Type 1 tory hallucinations. On physical examination schizencephalies are clefts with fused lips,2 Medical College, she had dysarthria, left sided strabismus, brisk http://jnnp.bmj.com/ Thomas JeVerson whereas type 2 schizencephalies have separated reflexes in her left limbs, and gait disturbances University, lips and accompanying .3 Schi- Philadelphia, PA consistent with . The results of all zencephaly usually presents in childhood with blood tests, chest radiography, and ECG were 19107, USA seizures, motor dysfunction, and intellectual A A Patkar 4–7 within normal limits. impairment. The degree of intellectual and The Wechsler adult intelligence scale— Department of motor dysfunction seems to be related to the 5 revised (WAIS-R) gave scores in the mentally Radiology amount of brain involved. retarded range, with a full IQ score of 63, a J S Lapointe Psychotic symptoms have been reported in performance IQ score of 60, and a verbal IQ on September 28, 2021 by guest. Protected association with a wide array of brain abnor- score of 67. She was also impaired on the wide Department of malities or injuries,89 but there have been no Psychiatry, University range achievement test—revised (WRAS-R) previous reports of psychotic symptoms in of British Columbia, and Bender gestalt visual-motor test with diY- Vancouver, Canada, patients with schizencephaly. We describe culties in arithmetic and timed tasks. V6H 326 below two patients with schizencephaly who Brain MRI disclosed bilateral schizen- S W Flynn had a psychotic disorder. W G Honer cephaly of the closed lip (type 1) variety with clefts in the frontal lobes extending from the Correspondence to: Case reports lateral frontal cortex deep into the Dr Robert C Alexander, PATIENT 1 to the level of the ventricles (fig 1). The clefts Medical Research Service (151), Department of This woman had had several admissions to were superficially surrounded by . Veterans AVairs Medical psychiatric hospitals for either psychotic epi- There was also irregular thickened grey matter Center, University and sodes or depressive states accompanied by sui- aligning the lateral ventricular walls consistent Woodland Avenues, Philadelphia, PA 19104, cide attempts. She was born with left sided with grey matter heterotopias. The septum pel- USA. weakness, reduced vision, and strabismus in lucidum was absent, consistent with septo- her left eye. She had delayed developmental optic dysplasia. The corpus callosum was nor- Received 2 July 1996 and in revised form 7 January 1997 milestones, received the diagnosis of cerebral mal and fully developed. The pituitary, Accepted 7 March 1997 palsy at the age of 2, and was subsequently parasellar, and pineal regions were unremark- 374 Alexander, Patkar, Lapointe, Flynn, Honer J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.373 on 1 September 1997. Downloaded from

Figure 2 MRI of patient 2. The image was obtained with an inversion recovery sequence and shows a left sided, unilateral frontal cleft (arrow). and appetite, concentration, and sleep were diminished. Brain CT and MRI were performed. The CT was initially read as normal by a general radiologist; however review with a neuroradi- ologist indicated a deep, left frontoparietal sul- Figure 1 MRI of patient 1. The T2 weighted image shows cus. The inversion recovery sequence of an bilateral CSF clefts and absence of the septum pellucidum. MRI study showed a left sided unilateral schi- zencephalic cleft, lined with grey matter and able. There was no evidence of . with loss of the adjacent white matter (fig 2). A Brain MR angiography was essentially normal, proton density sequence showed an area of with the exception of a fetal origin of the left increased signal over the cleft, consistent with posterior cerebral artery. reduced myelination of nearby white matter. copyright. The patient was treated with trifluoperazine, Patient 2 was unresponsive to haloperidol, trazodone, and carbamazepine. She showed lithium, and carbamazepine, and deteriorated some improvement in her depressive symptoms when given brief trials of nortriptyline and clo- but remained psychotic at the time of discharge. mipramine. He underwent a course of nine electroconvulsive treatments (ECT) aug- PATIENT 2 mented with carbamazepine and pimozide. His Patient 2 was a 29 year old man with a history mood improved significantly after ECT, but he of psychotic symptoms. He was born with right remained psychotic. Since his discharge from sided monoplegia, thought to be secondary to hospital, he has been complying with his treat- cerebral palsy, and had perinatal hyperbilirubi- ment as prescribed by a community psychia-

naemia. Learning problems became evident at trist. He is currently treated with risperidone. http://jnnp.bmj.com/ the age of 8. He was seen by the school At times, he has prominent depressive symp- psychologist at the age of 14 for acting out and toms, and has had intermittent antidepressant poor self care, and was thought to have an treatment. He remains psychotic during his adjustment reaction of adolescence with con- depression free intervals. duct disturbance and depressive traits. Intelli- gence testing showed a normal IQ. His family Discussion psychiatric history was notable for a paternal Schizencephaly is one of a group of malforma-

half uncle who had undiVerentiated schizo- tions, including , , on September 28, 2021 by guest. Protected phrenia. and heterotopia, which are the result of abnor- The patient was first admitted to hospital at mal brain development during the first six the age of 16, after he developed social months of gestation.10 Some lesions classified withdrawal, persecutory delusions, and audi- as schizencephaly may be due to encephalo- tory hallucinations. He displayed an inappro- clastic lesions from intrauterine cerebral infarc- priate aVect and was given the diagnosis of tion leading to .11–13 Yakolov and undiVerentiated schizophrenia. He was treated Wadsworth2 have argued persuasively that with haloperidol and procyclidine but was “true schizencephaly can be distinguished from poorly compliant with his medication. At the porencephaly by its unique neuropathology age of 19 he was taken oV medication and his and associated abnormalities”. They further mental status deteriorated; he did poorly and hypothesised that schizencephaly is the result was eventually transferred to a psychiatric hos- of abnormal neuronal migration occurring pital. On admission, he was grossly psychotic during the first half of the first trimester. Oth- and reported auditory hallucinations, ideas of ers have argued that the presence of polymicro- reference, thought insertion and withdrawal, gyria lining the clefts in schizencephaly indi- persecutory delusions, and suicidal ideation. cates that these abnormalities are formed in the His hygiene was poor, his aVect was blunted, early part of the second trimester.5 Whether Schizencephaly associated with psychosis 375 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.3.373 on 1 September 1997. Downloaded from

schizencephaly represents a primary disorder related to schizophrenia.19 Convincing evi- of neuronal migration or is the consequence of dence of a neurodevelopmental origin to an insult followed by secondary disruption of schizophrenia, however, remains elusive. The neuronal migration is unknown. The recent possible association between psychosis and identification of mutations in the homeobox schizencephaly in the two patients presented gene EMX2 in three patients with type 2 schi- may provide an example of a neurodevelop- zencephaly suggests that genetic factors may be mental abnormality that manifests as psychosis operative in some patients.14 after a long delay. A key question is the importance of the association between schizencephaly and psy- This work was supported in part by a scholarship award from chosis in the two cases presented. The two MRC Canada to WGH. We thank Drs Adam Flanders and patients show some interesting similarities. Daniel R Weinberger for their assistance in the preparation of this manuscript. Both experienced auditory hallucinations, de- lusions, and prominent depressive symptoms and could be given the DSM-IV diagnosis of 1 Wilmarth WA. Presentation to the Philadelphia Neurological Society. J Nerv Ment Dis 1887;14:395–407. schizoaVective disorder. Also, both patients 2 Yakolev PI, Wadsworth RC. Schizencephalies: a study of experienced a relatively early onset of psychosis congenital clefts in the cerebral mantle. I. Clefts with fused lips. J Neuropathol Exp Neurol 1944;5:116–30. and have had a poor response to treatment. 3 Yakolev PI, Wadsworth RC. Schizencephalies: a study of The similarity in phenomenology lends sup- congenital clefts in the cerebral mantle. II. Clefts with hydrocephalus and lips separated. J Neuropathol Exp Neurol port to the hypothesis that schizencephaly is 1944;5:169–206. related in some way to the development of psy- 4 Miller GM, Stears JC, Guggenheim MA, Wilkening G. Schizencephaly: a clinical and CT study. Neurology chosis in these patients. A definitive statement 1984;34:997–1001 that the psychosis in each patient is due to 5 Barkovich AJ, Kjos BO. Schizencephaly: correlation of clini- cal findings with MR characteristics. AJNR Am J Neurora- schizencephaly, however, can obviously not be diol 1992;13:85–94. made. Given the history of seizures which pre- 6 Aniskiewicz AS, Frumkin NL, Brady DE, Moore JB, Pera A. Magnetic resonance imaging and neurobehavioral corre- ceded the psychosis in patient 1, an alternative lates in schizencephaly. Arch Neurol 1990;47:911–6. diagnosis in her case is psychotic disorder due 7 Bird CR, Gilles FH. Type I schizencephaly: CT and 15 neuropathologic findings. AJNR Am J Neuroradiol 1987;8: to . History of schizophrenia in the 451–4. family (albeit distant) of patient 2 could have 8 Davison K. Schizophrenia-like psychosis associated with organic disorders of the central . 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