Schizencephaly and the Neurodevelopmental Model of Psychosis
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.344662
Source of Support: None, Conflict of Interest: None
Keywords: Neuroanatomical model, neurodevelopmental model, psychosis, schizencephaly
Adult onset behavioral disturbances can be one of the common manifestations of congenital neurological conditions. Most often these patients seek help of psychiatrist for behavioral symptoms. Schizencephaly, one such rare congenital disorder of cerebral cortical development, prominently manifests as motor deficits, seizures, and cognitive impairment. Schizencephaly is defined as a gray matter-lined cleft extending from the pial surface to the ventricle. It has an estimated incidence of 1.5 in 100,000 live births. It can present as two types: closed lip or open lip, based on the apposition of the cleft lips. The MRI has been the diagnostic modality of choice. Till now, a handful of case reports associating schizencephaly with psychiatric manifestations have been reported. Here, we report a man in his 50s presenting with longstanding behavioral problems and found to have schizencephaly. We have attempted to do a brief topical review on existing literature on schizencephaly and psychiatric diagnosis.
A 50-year-old married right-handed gentleman, eldest of the three siblings born of nonconsanguineous marriage, presented with family history of psychiatric illness in the second degree relative, diabetes mellitus and hypertension in multiple first and second degree relatives. He is an agricultural landlord, hailing from rural background of Southern India. He presented with complaints of excessive anger outbursts, overspending, intrusiveness, apathy, inability to take independent financial decisions with multiple financial losses over the years. He had overvalued ideas of infidelity leading to verbal and physical aggression towards wife; however, this was not a fixed firm belief. Wife had noticed above symptoms since the time of marriage (patient was 24 years of age at marriage), but they were infrequent and milder in nature. However, wife noticed a significant worsening of the symptoms in the past 7 years with the patient becoming more suspicious of her and other family members, increase in aggression, irritability, and restlessness, leading to impaired bio-socio-occupational functioning. She also reports excessive and repetitive talk on the topics which are irrelevant to the context. History regarding premorbid personality was unavailable due to lack of reliable informant. The patient had history of tobacco use for the past 24 years in the form of smoking 20 cigarettes/day. The patient also had comorbid diabetes mellitus for the past 10 years and is on oral hypoglycaemics (metformin 2000 mg and sitagliptin 100 mg). The patient has been treated for his behavioral problems with adequate trials of ziprasidone, aripiprazole, and valproate with no significant improvement. Available reports with the patient suggested dull normal intelligence.
On physical examination, his body mass index was 35. Mental status examination showed agitation, circumstantiality, tangentiality, poverty of content of speech, perseveration of themes, overvalued ideas of infidelity, overvalued ideas of persecution, hyper religiosity, poor emotional reciprocity (apathy), and absent insight. There were no delusions and hallucinations. Cognitive assessment showed impaired attention, category fluency, verbal learning, abstract thinking, and perseveration. Primitive reflexes were absent. He had dysarthria and bilateral upper limb postural tremors. Other neurological examination was normal.
Routine biochemical examination (complete hemogram, blood sugar, electrolytes, liver function tests, kidney function tests, thyroid function test, lipid profile) were within normal limits except elevated serum creatine kinase (409 U/L). Both ECG and EEG were normal.
MRI brain [Figure 1] showed absent septum pellucidum and gray matter heterotopia with cleft-like appearance seen extending from the left frontal cortex till lateral ventricle with small dimple in the left lateral ventricle suggestive of closed lip schizencephaly.
Neuropsychological assessment revealed significant impairment in executive functions, learning, and memory suggestive of predominantly bilateral frontal lobe (both DLPFC and right orbitofrontal cortex) and temporal lobes (Left > Right) involvement.
Taking into consideration the patient's previous behavioral complaints, there were noticeable recent set of symptoms. These symptoms were observed cross sectionally during the inpatient care with overvalued ideas of infidelity, persecution being prominent with aggression, irritability, and restlessness as acting out behavior. However due to the speech abnormalities (dysarthria), it was difficult to explore further. Hence, the clinical impression of Schizencephaly with psychosis NOS (unspecified nonorganic psychosis) was made. There were some features suggestive of organic psychosis as well, like impaired attention and perseveration. Hence, a differential diagnosis of organic psychosis was also entertained. He was initiated on Tab Trifluoperazine 2.5 mg HS for management of aggression along with oral hypoglycaemics and dietary modifications. Nicotine replacement therapy (nicotine gums) was offered, which he reluctantly agreed to take. Family was educated regarding his neurological condition and behavioral techniques to manage his anger outbursts. The patient showed improvement in aggression, irritability, and restlessness over a period of 4 weeks; however, overvalued ideas of infidelity and persecution remained.
Our case highlights the presentation of psychosis NOS (unspecified nonorganic psychosis) as symptoms of schizencephaly. Till date, nine cases of schizencephaly with psychiatric manifestations have been reported in literature, of which seven are psychosis and two are bipolar disorder. [Table 1] shows a psychiatric diagnosis in reported cases available in the literature. In our patient, impairment in cognitive functions were prominent features along with symptoms suggestive of psychosis. The presence of perseveration, apathy, and gross cognitive deficits on the bedside clinical examination prompted us to investigate further on details neuropsychological testing and neuroimaging. The presence of schizencephaly helped us to explain the longstanding psychiatric symptoms, cognitive impairment, and poor response of these thought abnormalities and overvalued ideas to psychotropic medications. Due to lack of reliable informants regarding his perinatal, developmental, and childhood history, we could not get any clear onset and progression of his symptoms. However, current neuropsychological examination revealed significant cognitive deficits involving frontal and temporal regions.
Table 1 shows all the cases of schizencephaly reported in the literature with psychiatric manifestations. The age at presentation of psychiatric symptoms varied from 21 to 46 years. It is quite possible from the psychiatric history of our patient that he might have developed symptoms in the second decade. Three reported cases,, have family history of psychiatric illness which was similar in our patient. Neurological symptoms were a common manifestation in all the reported cases, most commonly unilateral hemiplegia on the contralateral side to the lesion, followed by speech difficulties, dystonia, chorea, and reduced vision. Unlike the reported cases, our patient had slurred speech and postural tremors. Similar to our patient having history of dull normal intelligence, low intelligence or learning disability was one of the consistent finding in cognitive domain among all the reported cases. Detailed neuropsychological tests were done in one of the patients with reports of cognitive deficits in verbal memory, verbal fluency, whereas in our patient there were findings of cognitive deficits involving both frontal and temporal regions. Except for one patient which showed EEG findings of repetitive single sharp waves and spikes in frontal region, were reported in one case and rest were normal including our patient. Imaging findings of MRI revealed that most of the lesions were unilateral (4 left, 3 right, 1 bilateral), as was the case in our patient. In terms of treatment response, three of the psychotic patients responded to risperidone monotherapy, while other showed responses to haloperidol, carbamazepine, trifluoperazine, or amisulpride combinations.,, The two patients with mood disorders showed good response to loxapine—carbamazepine combination and imipramine-haloperidol-lithium combination., In line to patients responding to antipsychotic monotherapy, we also saw a good response to behavioral symptoms in our patient to low-dose trifluoperazine; however, thought abnormalities and overvalued ideas persisted.
Schizencephaly is a neuronal migration anomaly, caused by insults to migrating neuroblasts during third to fifth gestational months. Because the corpus callosum and septum pellucidum are developing in the midline of the prosencephalon during the second to third month, the concurrence of schizencephaly and the absence of the corpus callosum or septum pellucidum may be based upon a common event that damages both the germinal matrix and the midline structures. Ischaemia, germline mutations, intrauterine infections, and exposure to drugs have been implicated in the aetiology of schizencephaly. While some patients with schizencephaly have been found to have mutations in the EMX2 gene, some investigators believe that it is very rare etiology.
Weinberger, Murray, & Lewis framed the neurodevelopmental hypothesis of schizophrenia nearly quarter of a century ago. Recent research indicates genetic overlap between schizophrenia and neurodevelopmental disorders. Though neuroimaging studies shows structural brain abnormalities at the onset of psychotic illness, postmortem studies failed to demonstrate an apparent evidence for neurodegeneration. It has been noted that cognitive and motor abnormalities develop much earlier than frank behavioral symptoms in psychosis. The importance of cognitive impairment in psychosis has been rediscovered and it is now very certain that many individuals with psychosis have a generalized cognitive impairment as well as a heterogeneous pattern of more specific impairments.,
This case report and review of existing literature on psychiatric manifestations of schizencephaly helps us to understand the developmental origin of psychosis. Subtle cognitive impairment with or without behavioral symptoms must prompt the clinician to evaluate further using detailed neurocognitive and neuroimaging assessments. To understand the specific association of schizencephaly with psychosis, systematic research is challenging due to low prevalence rates of schizencephaly.
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