Neuropsychiatric symptoms can be related to less common underlying neuropsychiatric conditions – in this case report, the condition discussed is that of grey matter heterotopia (GMH). The patient presented with a history of prominent aggression, impulsivity and manipulative and attention-seeking behaviour. Episodes of depression and incidents of deliberate self-harm and suicide attempts had been reported. Neuropsychiatric symptoms included anxiety, a labile mood, delusional thinking and auditory hallucinations. Testing revealed some cognitive difficulties and severe impairment of frontal lobe functions. A magnetic resonance imaging (MRI) scan of his brain revealed the presence of GMH, which had previously been misdiagnosed as tuberous sclerosis. An MRI scan of the brain is the special investigation of choice for the correct diagnosis of GMH. The pathognomonic finding is that of heterotopic grey matter abnormally located within areas of white matter. Defective foetal neuronal migration between the third and fifth month of pregnancy can lead to GMH, which can present later on in childhood or adolescence with epilepsy, intellectual impairment or reading difficulties. During the late teenage years or early adulthood, a wide variety of neuropsychiatric symptoms may be present, which can lead to diagnostic difficulties.
A 39-year-old, unemployed Caucasian male was arrested for assault with intent to cause grievous bodily harm involving an incident of extreme violence which occurred in a psychiatric ward where he was being treated as an involuntary mental health care user under the
During the 13 years preceding the observation, he had regularly been engaged with psychiatric services and had presented with multiple, wide-ranging psychiatric symptoms. Most prominent was his impulsivity and difficulty in controlling his aggression, which had led to multiple documented incidents of physical aggression. He had also regularly displayed manipulative and attention-seeking behaviour. He had been suffering from anxiety and a labile mood. He presented with episodes of depression, and there were incidents of deliberate self-harm and suicide attempts. Delusional thinking and perceptual disturbances in the form of auditory hallucinations were less prominent. Because of the complexity of his clinical presentation, he had been diagnosed with a number of different psychiatric disorders including borderline personality disorder; antisocial personality disorder; major depressive disorder; bipolar disorder; schizophrenia and schizoaffective disorder, bipolar type.
The patient had been a breech presentation during pregnancy and developed hydrocephalus secondary to an occipital encephalocoele. Normal flow of cerebrospinal fluid was restored with the resection of the encephalocoele. Early developmental milestones were normal. He completed primary schooling in a mainstream school but presented with learning difficulties. He was bullied and teased by other learners and had no friends. His aggression started at a young age with destruction of property and assaults of fellow learners being reported. Because of his poor academic performance, he attended a special high school where he completed his schooling.
There was also a history of alcohol and cannabis abuse:
At age 5, he was diagnosed with epilepsy, which continued into adulthood and resulted in him being diagnosed with psychotic disorder due to epilepsy at a later stage. The patient’s biological father also has epilepsy and a cousin on the paternal side of the family suffers from intellectual disability. The patient had had a computerised tomography (CT) scan of his brain 11 years ago, and was subsequently misdiagnosed with TS. A psychiatric diagnosis of personality change due to TS was also subsequently made.
During the observation period, demanding and attention-seeking behaviour was observed, but there were no episodes of physical aggression. He displayed a distinct lack of remorse for the assault for which he had been charged, and he held the victim responsible for what had transpired. His mood was labile, but he was not depressed. He was objectively angry at times and admitted to feeling anxious. Subtle persecutory and grandiose delusions were identified, and he admitted to experiencing thoughts of reference.
Some cognitive impairment was apparent. He scored 25 out of 30 on the Folstein Mini Mental State Examination, and specific sifting revealed severe impairment of frontal lobe functions. Attention, judgement, planning and response inhibition were very poor. He also presented with impairment in constructional, sequencing and set-shifting abilities. Intelligence quotient (IQ) testing revealed a score within the range of borderline intellectual functioning.
A neurological examination revealed no motor, sensory, cranial nerve or cerebellar abnormalities.
A physical examination during the observation period revealed none of the characteristic dermatological lesions associated with TS, so the diagnosis was queried (also because specific genetic testing for TS had not been done).
A decision was made to refer him for a magnetic resonance imaging (MRI) scan of his brain, and the findings proved to be invaluable in making the correct diagnosis; we were fortunate that this form of imaging was available, as there is a limited availability of MRI facilities outside of the major cities in South Africa. The scan revealed the presence of bilateral, diffuse subependymal nodules along the walls of the lateral ventricles, which had the same signal intensity as grey matter on T1W, T2W, FLAIR and IR sequences, with no blooming artefact on T2W FFE and no enhancement post contrast (
MRI scan sections of the patient’s brain indicating the presence of GMH. (a) A T1W IR SENSE axial section of the brain with arrows indicating bilateral and asymmetrical PNH with heterotopic grey matter stretching all along the ventricular walls, even present anterior to the anterior horns. Note that the shade of grey is the same as that of the cortical grey matter (the same signal intensity), which confirms that it is grey matter – the pathognomonic finding in GMH. (b) The arrows point towards the PNH where the typical nodular appearance of the heterotopic grey matter can be seen on this T2W TSE SENSE axial section of the brain. (c) On this T2W CLEAR SENSE GAD enhanced axial section of the brain, one can see how the subependymal nodules cause bulging of the ventricular walls, as pointed out by the arrows. GMH – grey matter heterotopia; T1W – Tau 1 weighted; T2W – Tau 2 weighted; FLAIR – fluid-attenuated inversion recovery; IR – inversion recovery; FFE – fast field echo; SENSE – sensitivity encoding; TSE – turbo spin echo; CLEAR – constant level appearance; GAD – gadolinium; PNH – periventricular nodular heterotopia.
Following the findings and reports related to his observation, he was referred to Weskoppies Hospital as a State Patient in terms of Section 42 of the
Permission to report on this case was granted by the Research Ethics Committee of the Faculty of Health Sciences of the University of Pretoria. The patient signed informed consent for the case report to be published after having been assessed to have had the capacity to do so.
GMH is a neuronal migration disorder characterised by the presence of normal grey matter neurons and glial cells, which are abnormally located in clusters within areas of white matter.
During embryonic development of the brain, neuroblasts migrate away from the germinal layer of the ventricular neuroepithelium, mostly along the tracks of radial glial fibres.
GMH can be classified as being laminar or nodular. Both types have been described as occurring in the same patient.
Five different groups of PNH have been identified: (1) bilateral and symmetrical; (2) bilateral single-noduled; (3) bilateral and asymmetrical; (4) unilateral and (5) unilateral with extension to neocortex.
GMH is more common than was once thought. Heterotopic tissue cannot always be seen on a CT scan,
Specific genetic mutations have been identified in patients with certain types of PNH, and indeed other forms of GMH, some of which even have differing heritance patterns.
The development of GMH is thought to be due to a combination of this underlying genetic susceptibility coupled with an environmental insult caused by, for example, toxins of viral infections during the time of foetal brain development in the form of neuronal migration between the third and fifth month of pregnancy.
Preliminary findings indicate that GMH is more common in patients with schizophrenia with a prevalence rate of 1.8% being found in a study where none of the normal individuals in the control group were found to have the disorder.
The two disorders have a similar proposed aetiopathogenesis of an underlying genetic susceptibility coupled with an environmental insult.
Psychiatric disorders where grey matter heterotopia has been discovered.
Intellectual disability
Schizophrenia
Unspecified schizophrenia spectrum disorder
Schizoaffective disorders
Major depressive disorder
Bipolar disorder
Delirium
Language disorder
Autism spectrum disorder
Attention-deficit hyperactivity disorder
Somatic symptom disorder
The most common neuropsychiatric clinical picture is that of intellectual disability, which ranges from mild to severe in nature, even though many patients with GMH present with normal intellectual functioning.
Certain types of GMH have also been found to be associated with metabolic disorders such as neonatal adrenoleukodystrophy, connective tissue disorders such as Ehlers-Danlos syndrome and a number of central nervous system malformations such as Chiari II malformations, agenesis of the corpus callosum, encephalocoeles and myelomeningocoeles.
The clinical picture is determined by the type of GMH and the location of the heterotopic tissue. Most of the presenting symptoms are common to all types of GMH but may differ in severity among the different types. Certain symptoms have been described only in certain types of GMH. For the purposes of this overview of the subject, presenting symptoms of GMH are discussed as a whole.
The most common initial symptoms are those of epileptic seizures.
An overview of the literature reveals that most publications have concentrated on the neurological presentations (especially epilepsy), radiological findings and the genetics of GMH. Neuropsychiatric symptoms are less well researched and possibly underrecognised.
Neuropsychiatric symptoms of grey matter heterotopia.
Dyslexia and other learning difficulties Deficits in:
Reading fluency Spatial orientation Planning Constructional abilities Attention Processing speed Adaptive skills Other areas of executive functioning Problems in areas of:
Social skills Leadership Functional communication Hyperactivity Rage Aggression Violence Lack of remorse for problematic behaviour
Mood lability Depressive symptoms
Low mood Low self-esteem Insomnia and nightmares Social withdrawal Hopelessness Deliberate self-harm Suicidal ideation and suicide attempts Manic symptoms
Elevated mood Racing thoughts Decreased need for sleep Distractibility Irritability Agitation Impulsivity Sexual inhibition and sexually inappropriate behaviour Financial and social indiscretions
Thought form disorder Auditory and visual hallucinations Paranoid ideation Referential thinking Vague delusions (more so than systematised delusions) Inappropriate affect
Anxiety Panic attacks Obsessive-compulsive symptoms Phobias Disorientation and ‘confusion’
The findings on the MRI scan of the patient in the case report are consistent with that of GMH. The bilateral, diffuse subependymal nodules along the walls of the lateral ventricles suggest a diagnosis of PNH.
An absence of the typical dermatological signs of TS – hypomelanotic macules or ash leaf spots (found in up to 90% of patients with TS), confetti lesions, poliosis, facial angiofibromas or adenoma sebaceum, shagreen patches and ungual fibromas
Examining his background history and the clinical findings again, retrospectively, after the new diagnosis of GMH was made, reveals interesting findings, some of which are unique to this case, and others that are consistent with what has been described in the literature.
This patient with PNH being born with an encephalocoele is noteworthy since a concurrent development of the two anomalies has been described.
His developing epilepsy at age 5 is earlier than the usual second decade of life reported in the literature for this patient population.
The patient has presented with a large number and a varying spectrum of neuropsychiatric symptoms over the years. Probably, the most prominent features of his presentation are aggression, impulsive violence, inability to control anger and lack of remorse for his violent acts. All of these symptoms have been described in patients with GMH.
‘Mood swings’ have been described in patients with GMH.
His episodes of depression and his history of previous deliberate self-harm and suicide attempts, all of which have been reported in relation to GMH,
His prominent anxiety, even in the absence of mood abnormalities, is noteworthy and can be present in patients with the same condition.
Intellectual disability of varying severity (including that which is mild in nature), specific learning disorder and executive dysfunction have been associated with GMH.
His vague, subtle, mild paranoia and referential thinking are similar to what has been described in other patients with GMH.
From a diagnostic point of view, there was never a clear period of him having experienced auditory hallucinations during a period in which he was not abusing cannabis and he was also not experiencing these hallucinations during the observation period and had not abused substances in the months leading up to the observation. With him presenting only with non-bizarre delusions, his symptoms did not meet the criteria for a diagnosis of schizophrenia. A case has been described where such a patient with GMH was diagnosed with, in Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) terminology,
GMH is a neuronal migration disorder which is more common than was once thought in the time before MRI scans were regularly used. The condition most frequently presents with epilepsy but intellectual disability of varying severity is also commonly found. GMH has not only been associated with schizophrenia, but also with a wide range of neuropsychiatric symptoms, many of which may be present in the same patient. When that is the case, diagnosis may be difficult.
This case highlights that when patients present with many different neuropsychiatric symptoms, a possible diagnosis of GMH should be considered and that they should be referred for an MRI scan, where possible, to look for the pathognomonic findings of heterotopic grey matter abnormally located within areas of white matter.
The author declares that he has no financial or personal relationships which may have inappropriately influenced him in writing this article.