Ramon Mocellin

Hashimoto's Encephalopathy Epidemiology, Pathogenesis and Management

Hashimoto’s encephalopathy is a term used to describe an encephalopathy of presumed autoimmune origin characterised by high titres of antithyroid peroxidase antibodies. In a similar fashion to autoimmune thyroid disease, Hashimoto’s encephalopathy is more common in women than in men. It has been reported in paediatric, adult and elderly populations throughout the world. The clinical presentation may involve a relapsing and remitting course and include seizures, stroke-like episodes, cognitive decline, neuropsychiatric symptoms and myoclonus. Thyroid function is usually clinically and biochemically normal.Hashimoto’s encephalopathy appears to be a rare disorder, but, as it is responsive to treatment with corticosteroids, it must be considered in cases of ‘investigation negative encephalopathies’. Diagnosis is made in the first instance by excluding other toxic, metabolic and infectious causes of encephalopathy with neuroimaging and CSF examination. Neuroimaging findings are often not helpful in clarifying the diagnosis. Common differential diagnoses when these conditions are excluded are Creutzfeldt-Jakob disease, rapidly progressive dementias, and paraneoplastic and nonparaneoplastic limbic encephalitis. In the context of the typical clinical picture, high titres of antithyroid antibodies, in particular antithyroid peroxidase antibodies, are diagnostic. These antibodies, however, can be detected in elevated titres in the healthy general population. Treatment with corticosteroids is almost always successful, although relapse may occur if this treatment is ceased abruptly. Other forms of immunomodulation, such as intravenous immune-globulin and plasma exchange, may also be effective.Despite the link to autoimmune thyroid disease, the aetiology of Hashimoto’s encephalopathy is unknown. It is likely that antithyroid antibodies are not pathogenic, but titres can be a marker of treatment response. Pathological findings can suggest an inflammatory process, but features of a severe vasculitis are often absent. The links between the clinical pictures, thyroid disease, auto-antibody pattern and brain pathology await further clarification through research. It may be that Hashimoto’s encephalopathy will be subsumed into a group of nonvasculitic autoimmune inflammatory meningoencephalopathies. This group may include disorders such as limbic encephalitis associated with voltage-gated potassium channel antibodies. Some authors have suggested abandoning any link to Hashimoto and renaming the condition ‘steroid responsive encephalopathy associated with autoimmune thyroiditis’ to better reflect current, if limited, understanding of this condition.

Frontotemporal dementia presenting as schizophrenia-like psychosis in young people: clinicopathological series and review of cases

BACKGROUND Few studies have investigated the relationship between schizophrenia and frontotemporal dementia. AIMS To investigate this relationship through a clinicopathological investigation of young-onset frontotemporal dementia and a review of the case literature. METHOD Cases of young-onset frontotemporal dementia were identified within the local brain bank. The clinical course and pathological findings were collated. For the literature review, cases of frontotemporal dementia identified through Medline were selected according to defined criteria. The demographic, clinical, pathological and genetic characteristics of cases presenting with a psychotic illness were identified. RESULTS In the case series, 5 of 17 patients with frontotemporal dementia had presented with a psychotic illness (schizophrenia/schizoaffective disorder n=4, bipolar disorder n=1) an average of 5 years prior to the dementia diagnosis. Patients with schizophrenia exhibited changes consistent with TDP-43 and ubiquitin-positive frontotemporal dementia. In the cases review, a third of patients aged 30 years or under and a quarter of those aged 40 years or under had been diagnosed with psychosis at presentation. CONCLUSIONS Patients with young-onset frontotemporal dementia may be diagnosed with a psychotic illness years before the dementia diagnosis is made. These findings have implications for clinicians and for our further understanding of the neurobiology of psychotic illness.

Clinical characteristics and outcome in patients with psychogenic nonepileptic seizures.

Objectives: To examine baseline clinical features of psychogenic nonepileptic seizures (PNES) in a large cohort and to investigate outcome over a period of up to 10 years. Studies investigating PNES have been limited by differences in diagnostic criteria, short follow-up periods, and the use of limited outcome measures. Method: Patients with PNES were identified, using strict diagnostic criteria. Baseline neurological, neuropsychiatric, and neuroimaging data were obtained from medical records. Long-term outcome was assessed with ratings of seizures, psychopathology, and quality of life in a subset of the patients. Results: Patients with PNES (n = 221) experienced long delays in diagnosis (&mgr;, 5.6 years; standard deviation, 7.7 years) and high rates (>60%) of prolonged treatment with antiepileptic drugs. Compared with previous studies, a relatively low proportion (8.1% to 17.9%, depending on diagnostic criteria) had comorbid epilepsy. An unexpected finding was that 22.6% of PNES patients had magnetic resonance imaging abnormalities. Patients assessed at follow-up (n = 61) exhibited poor long-term outcomes with ongoing PNES, high rates of psychopathology, low rates of specialist follow-up, poor quality of life, and poor overall levels of functioning. Conclusions: These results demonstrate the need for earlier diagnosis of PNES and comorbidities and highlight the need for diagnostic and therapeutic approaches that combine neurological and psychiatric perspectives. PNES = psychogenic nonepileptic seizures; VEM = video-electroencephalographic monitoring; EEG = electroencephalogram; AEDs = antiepileptic drugs; MRI = magnetic resonance imaging; ES = epileptic seizures; QOL = quality of life.

The neuropsychiatry of inborn errors of metabolism.

A number of metabolic disorders that affect the central nervous system can present in childhood, adolescence or adulthood as a phenocopy of a major psychiatric syndrome such as psychosis, depression, anxiety or mania. An understanding and awareness of secondary syndromes in metabolic disorders is of great importance as it can lead to the early diagnosis of such disorders. Many of these metabolic disorders are progressive and may have illness-modifying treatments available. Earlier diagnosis may prevent or delay damage to the central nervous system and allow for the institution of appropriate treatment and family and genetic counselling. Metabolic disorders appear to result in neuropsychiatric illness either through disruption of late neurodevelopmental processes (metachromatic leukodystrophy, adrenoleukodystrophy, GM2 gangliosidosis, Niemann-Pick type C, cerebrotendinous xanthomatosis, neuronal ceroid lipofuscinosis, and alpha mannosidosis) or via chronic or acute disruption of excitatory/inhibitory or monoaminergic neurotransmitter systems (acute intermittent porphyria, maple syrup urine disease, urea cycle disorders, phenylketonuria and disorders of homocysteine metabolism). In this manuscript we review the evidence for neuropsychiatric illness in major metabolic disorders and discuss the possible models for how these disorders result in psychiatric symptoms. Treatment considerations are discussed, including treatment resistance, the increased propensity for side-effects and the possibility of some treatments worsening the underlying disorder.

Neuropsychiatry of complex visual hallucinations.

Objective: To describe the phenomenology and pathophysiology of complex visual hallucinations (CVH) in various organic states, in particular Charles Bonnet syndrome and peduncular hallucinosis. Method: Three cases of CVH in the setting of pontine infarction, thalamic infarction and temporoparietal epileptiform activity are presented and the available psychiatric, neurological and biological literature on the structures of the central nervous system involved in producing hallucinatory states is reviewed. Results: Complex visual hallucinations can arise from a variety of processes involving the retinogeniculocalcarine tract, or ascending brainstem modulatory structures. The cortical activity responsible for hallucinations results from altered or reduced input into these regions, or a loss of ascending inhibition of their afferent pathways. Conclusions: A significant degree of overlaps exists between the concepts of Charles Bonnet syndrome and peduncular hallucinosis. The fluidity of these eponymous syndromes reduces their validity and meaning, and may result in an inappropriate attribution of the underlying pathology. An understanding of how differing pathologies may produce CVH allows for the appropriate tailoring of treatment, depending on the site and nature of the lesion and content of perceptual disturbance.

Reversible dementia with psychosis: Hashimoto's encephalopathy.

Abstract  A case of presumed Hashimoto’s encephalopathy (HE) is presented. The presentation included memory loss, delusions, functional decline and culminated in a generalized seizure. Anti‐thyroid antibodies were detected and symptoms resolved with prednisolone. Patients with HE may present with prominent neuropsychiatric symptoms, attract psychiatric diagnoses and present to psychiatric services. Primarily a diagnosis of exclusion, HE should be considered in cases of encephalopathy in which standard investigations are negative.

Adolescent obsessive compulsive disorder heralding chorea-acanthocytosis

We describe one male and one female patient who each developed childhood/adolescent obsessive‐compulsive disorder as a prelude to the development of a typical picture of chorea‐acanthocytosis (ChAc). In each patient, the caudate nucleus showed dramatic atrophy. The role of the caudate in compulsive phenomena, and the predilection for neurological disorders with onset in adolescence to present as major mental illness, is discussed. On the basis of the current evidence and previous findings, we suggest that ChAc can be understood as a disorder whose clinical presentation reflects an interaction between the disease process and the individuals neurodevelopmental stage with both initial interrupted neurodevelopment, and supervening neurodegeneration.

Abnormal hippocampal distribution of TDP-43 in patients with-late onset psychosis

Objective: Young patients with frontotemporal dementia (FTD) may present with schizophrenia-like psychosis. Few studies have investigated whether FTD-like neuropathological changes are present in schizophrenia. The purpose of the present study was therefore to determine whether FTD-like abnormalities in TARDNA binding protein (TDP-43) and ubiquitin are detectable in hippocampal dentate gyrus of patients with schizophrenia and bipolar disorder. A secondary objective was to identify clinicopathological relationships of any such abnormalities. Methods: Hippocampal sections from 12 patients (nine with schizophrenia and three with bipolar disorder) and 11 control subjects Facility from the National Neural Tissue Resource Centre, Melbourne were blindly rated for the presence or absence of normal TDP-43 staining or ubiquitin-positive neuronal inclusions within the dentate gyrus. The clinical files of all subjects were reviewed for demographic and clinical information. Results: In three patients the normal expression of nuclear TDP-43 staining was not detected. Significantly, all three subjects presented after the age of 50 and had an adult child diagnosed with the same psychiatric disorder. Conclusion: Abnormalities in TDP-43 nuclear expression were identified in patients with late-onset psychosis and a positive family history.

Validity and reliability of the Behavioural Assessment Tool for Cognition and Higher Function (BATCH) in neuropsychiatric patients.

Objective: Patients with mental health disorders frequently have difficulties with their cognitive functioning. Assessment of cognition in this population can be complicated by psychiatric symptomatology, making standard written and verbal assessment methods difficult. In these situations, observations by nursing and allied staff of patients’ routine activities provide an important source of information about cognitive ability. The Behavioural Assessment Tool for Cognition and Higher Function (BATCH) was developed to record observations of patients’ daily functioning under subheadings that reflect cognitive domains. Its capacity to provide a measure of cognitive function through observational means was assessed in a neuropsychiatric unit. Method: A consecutive sample of 76 adult neuropsychiatry inpatients were assessed over 6 months using BATCH. BATCH measures the frequency of given behaviours grouped under 10 functional and cognitive domains: orientation, attention/concentration, personal responsibility, volition, adaptation, problem-solving/judgement, executive function, memory, language, and visuospatial function. Data from routine standardized cognitive (Mini-Mental Status Examination, MMSE; Neuropsychiatry Unit Cognitive Screening Tool, NUCOG), psychiatric (Neuropsychiatric Inventory; Health of the Nation Outcome Scale) and functional (Bristol Activities of Daily Living Scale; Barthel Index) instruments were collected to determine the relative contribution of cognitive function to scores on the BATCH. Results: A strong correlation was found between total BATCH scores and total NUCOG and MMSE scores. BATCH and NUCOG subdomains correlated significantly in all subscales. BATCH demonstrated very high internal consistency. Linear regression analysis showed that the strongest determinant of BATCH scores was cognitive function as measured on the NUCOG. A significant subscale×group effect showed lower BATCH scores in memory, orientation, attention, executive function and language in dementia sufferers compared to psychiatric and neurological patient groups. Conclusion: BATCH scores correlated strongly with pencil-and-paper measures of cognitive function. BATCH provides clinicians with a means of assessing cognitive function through behavioural observation, thus enabling assessment of patients with behavioural disturbance or severe psychopathology. This tool has practical application for adult and aged clients across all observational mental health settings.

Neurocognitive similarities between severe chronic schizophrenia and behavioural variant frontotemporal dementia

This study focuses on a group of patients with chronic schizophrenia who have a more severe form of the disorder, as indicated by socio-functional decline, treatment resistance, and recurrent hospitalisation. Previous research has suggested that the pattern and severity of cognitive deficits in people with severe chronic schizophrenia is similar to that observed in behavioural variant frontotemporal dementia (bvFTD). In the current study, we compared neurocognitive performance in 16 cognitive domains in 7 inpatients with severe chronic schizophrenia, 13 community-dwelling outpatients with chronic schizophrenia, 12 patients with bvFTD, and 18 healthy controls. Our findings revealed more similar cognitive profiles between the schizophrenia inpatient and bvFTD groups compared to the schizophrenia outpatient group, who outperformed the former groups. The current results provide preliminary evidence for a distinct schizophrenia subgroup, distinguishable from other chronic schizophrenia patients by poorer clinical and functional status, who have levels of cognitive impairment comparable to those seen in bvFTD patients.