Cerebrospinal fluid neurofilament light predicts longitudinal diagnostic change in patients with psychiatric and neurodegenerative disorders.

OBJECTIVE: People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown. METHODS: We collected longitudinal diagnostic information (mean = 36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other) and PSY. We pre-specified NfL > 582 pg/mL as indicative of ND/MCI/other. RESULTS: Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone. CONCLUSIONS: CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.

Time to diagnosis in younger-onset dementia and the impact of a specialist diagnostic service.

OBJECTIVES: While early diagnosis of younger-onset dementia (YOD) is crucial in terms of accessing appropriate services and future planning, diagnostic delays are common. This study aims to identify predictors of delay to diagnosis in a large sample of people with YOD and to investigate the impact of a specialist YOD service on this time to diagnosis. DESIGN: A retrospective cross-sectional study. SETTING: The inpatient unit of a tertiary neuropsychiatry service in metropolitan Victoria, Australia. PARTICIPANTS: People diagnosed with a YOD. MEASUREMENTS AND METHODS: We investigated the following predictors using general linear modeling: demographics including sex and location, age at onset, dementia type, cognition, psychiatric diagnosis, and number of services consulted with prior to diagnosis. RESULTS: A total of 242 inpatients were included. The mean time to diagnosis was 3.4 years. Significant predictors of delay included younger age at onset, dementia type other than Alzheimer's disease (AD) and behavioral-variant frontotemporal dementia (bvFTD), and increased number of services consulted. These predictors individually led to an increased diagnostic delay of approximately 19 days, 5 months, and 6 months, respectively. A specialized YOD service reduced time to diagnosis by 12 months. CONCLUSION: We found that younger age at onset, having a dementia which was not the most commonly occurring AD or bvFTD, and increasing number of services were significant predictors of diagnostic delay. A novel result was that a specialist YOD service may decrease diagnostic delay, highlighting the importance of such as service in reducing time to diagnosis as well as providing post-diagnostic support.

A description of the components of a specialist younger-onset dementia service: a potential model for a dementia-specific service for younger people.

OBJECTIVES: This narrative paper describes the influences behind the development of, and key components of a specialist younger-onset dementia service located in metropolitan Victoria, Australia. CONCLUSION: The Melbourne Young-Onset Dementia Service was established in 2013 and provides diagnosis and ongoing care for people with younger-onset dementia and their families, through collaboration with other medical units, allied health and community services. It is potentially a model for other younger-onset dementia services nationally and internationally.

A pilot study of the utility of cerebrospinal fluid neurofilament light chain in differentiating neurodegenerative from psychiatric disorders: A 'C-reactive protein' for psychiatrists and neurologists?

OBJECTIVE: Neurofilament light has shown promise as a biomarker for diagnosis, staging and prognosis in a wide range of neurological and neurodegenerative disorders. This study explored the utility of cerebrospinal fluid neurofilament light in distinguishing primary psychiatric disorders from neurodegenerative and neurological disorders, a common diagnostic dilemma for psychiatrists and neurologists. METHODS: This cross-sectional retrospective pilot study assessed cerebrospinal fluid neurofilament light on patients referred to a tertiary neuropsychiatry service from 2009 to 2017 for diagnostic assessment of neuropsychiatric and neurocognitive symptoms, where a neurodegenerative disorder was a differential diagnosis, who received lumbar punctures as part of a comprehensive workup. The most recent gold-standard clinical consensus diagnosis was categorised into psychiatric disorder or neurodegenerative or neurological disorder. Data from healthy controls were available for comparison. Data extraction and diagnostic categorisation was blinded to neurofilament light results. RESULTS: A total of 129 participants were included: 77 neurodegenerative or neurological disorder (mean age 57 years, including Alzheimer's dementia, frontotemporal dementia), 31 psychiatric disorder (mean age 51 years, including schizophrenia, major depressive disorder) and 21 healthy controls (mean age 66 years). Neurofilament light was significantly higher in neurodegenerative or neurological disorder (M = 3560 pg/mL, 95% confidence intervals = [2918, 4601]) compared to psychiatric disorder (M = 949 pg/mL, 95% confidence intervals = [830, 1108]) and controls (M = 1036 pg/mL, 95% confidence intervals = [908, 1165]). Neurofilament light distinguished neurodegenerative or neurological disorder from psychiatric disorder with an area under the curve of 0.94 (95% confidence intervals = [0.89, 0.98]); a cut-off of 1332 pg/mL was associated with 87% sensitivity and 90% specificity. CONCLUSION: Cerebrospinal fluid neurofilament light shows promise as a diagnostic test to assist with the often challenging diagnostic dilemma of distinguishing psychiatric disorders from neurodegenerative and neurological disorders. Further studies are warranted to replicate and expand on these findings, including on plasma neurofilament light.

Deep brain stimulation for severe treatment-resistant obsessive-compulsive disorder: An open-label case series.

OBJECTIVE: Deep brain stimulation can be of benefit in carefully selected patients with severe intractable obsessive-compulsive disorder. The aim of this paper is to describe the outcomes of the first seven deep brain stimulation procedures for obsessive-compulsive disorder undertaken at the Neuropsychiatry Unit, Royal Melbourne Hospital. The primary objective was to assess the response to deep brain stimulation treatment utilising the Yale-Brown Obsessive Compulsive Scale as a measure of symptom severity. Secondary objectives include assessment of depression and anxiety, as well as socio-occupational functioning. METHODS: Patients with severe obsessive-compulsive disorder were referred by their treating psychiatrist for assessment of their suitability for deep brain stimulation. Following successful application to the Psychosurgery Review Board, patients proceeded to have deep brain stimulation electrodes implanted in either bilateral nucleus accumbens or bed nucleus of stria terminalis. Clinical assessment and symptom rating scales were undertaken pre- and post-operatively at 6- to 8-week intervals. Rating scales used included the Yale-Brown Obsessive Compulsive Scale, Obsessive Compulsive Inventory, Depression Anxiety Stress Scale and Social and Occupational Functioning Assessment Scale. RESULTS: Seven patients referred from four states across Australia underwent deep brain stimulation surgery and were followed for a mean of 31 months (range, 8-54 months). The sample included four females and three males, with a mean age of 46 years (range, 37-59 years) and mean duration of obsessive-compulsive disorder of 25 years (range, 15-38 years) at the time of surgery. The time from first assessment to surgery was on average 18 months. All patients showed improvement on symptom severity rating scales. Three patients showed a full response, defined as greater than 35% improvement in Yale-Brown Obsessive Compulsive Scale score, with the remaining showing responses between 7% and 20%. CONCLUSION: Deep brain stimulation was an effective treatment for obsessive-compulsive disorder in these highly selected patients. The extent of the response to deep brain stimulation varied between patients, as well as during the course of treatment for each patient. The results of this series are comparable with the literature, as well as having similar efficacy to ablative psychosurgery techniques such as capsulotomy and cingulotomy. Deep brain stimulation provides advantages over lesional psychosurgery but is more expensive and requires significant multidisciplinary input at all stages, pre- and post-operatively, ideally within a specialised tertiary clinical and/or academic centre. Ongoing research is required to better understand the neurobiological basis for obsessive-compulsive disorder and how this can be manipulated with deep brain stimulation to further improve the efficacy of this emerging treatment.

Clinical update on frontotemporal dementia: diagnosis and treatment.

OBJECTIVES: To provide a clinical update for general psychiatrists on frontotemporal dementias (FTDs) using a selective narrative review of recent findings and advances in conceptualising, diagnosing and treating FTD. CONCLUSIONS: General psychiatrists can apply their skills to support patients, carers, GPs and allied health workers in comprehensive care of persons with FTD.

Comparing neurocognition in severe chronic schizophrenia and frontotemporal dementia.

OBJECTIVE: Previous research has suggested cognitive similarities between schizophrenia and frontotemporal dementia. In the current study, we compared neurocognition in a group of hospitalised patients with chronic schizophrenia, who may have a more severe form of schizophrenia resembling Emil Kraepelin's dementia praecox, with patients with frontotemporal dementia. We hypothesised minimal group differences in cognitive performance, and a large overlap in between-group score distributions in each cognitive domain. METHODS: Retrospective neuropsychological data for 26 patients with severe chronic schizophrenia and 34 patients with frontotemporal dementia (behavioural variant) was collated. Neuropsychological measures were categorised into 16 cognitive domains. Raw scores were converted into standardised z-scores for each measure, which were then averaged across measures within each domain. In addition to difference analysis, equivalence testing was utilised, whereby overlap percentages were computed to reflect the amount of score distribution overlap in each domain between groups. RESULTS: A statistically significant difference was observed only in the executive function sub-domain of Switching. Small-to-moderate and moderate effect sizes were noted in four other domains. Equivalence testing showed more than 85% of overlap in score distribution in most domains. CONCLUSIONS: Our findings suggest that some patients with severe chronic schizophrenia have cognitive deficits similar in degree and pattern to patients with frontotemporal dementia. The few differences observed between both groups of patients are important for differential diagnostic purposes. One limitation is the retrospective nature of the study. Suggestions for future research include longitudinal follow-up studies of these two patient populations and studies of aspects beyond neurocognition. An implication of our findings is that the 'dementia of schizophrenia' concept may be applicable to patients with severe chronic schizophrenia.

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.

Peduncular hallucinosis secondary to central pontine myelinolysis.

Peduncular hallucinations are generally associated with lesions in the midbrain. They have rarely been associated with central pontine myelinolysis, a condition associated with rapid alterations in serum sodium and chronic alcoholism. Described herein is the case of a 46-year-old man who developed typical peduncular hallucinations, whose imaging demonstrated central pontine myelinolysis. After alcohol cessation and neuroimaging resolution, the patient's hallucinatory phenomena abated.

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 (mu, 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.

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.

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 individual's neurodevelopmental stage with both initial interrupted neurodevelopment, and supervening neurodegeneration.

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.

The development and validation of a carer questionnaire to assess cognitive function in neuropsychiatric patients.

OBJECTIVES: The carer history is an integral part of the assessment of patients with cognitive impairment. We aimed to develop a comprehensive yet concise carer questionnaire, the CogRisk, which captures actuarial risk variables for cognitive impairment in addition to key symptoms suggestive of cognitive decline in a number of cognitive domains, and to then assess its validity and reliability in a neuropsychiatric population. METHOD: Carers of patients assessed for cognitive impairment completed the CogRisk, and patients were clinically assessed using the Mini-Mental State Examination (MMSE) and Neuropsychiatry Unit COGnitive assessment tool (NUCOG). Reliability was assessed using test-retest and interrater measures and measures of internal consistency. Construct and concurrent validity was assessed using correlation between total and subscale scores on the CogRisk, total scores on the NUCOG and MMSE, and subscale scores on the NUCOG. Predictive validity was determined using measures of sensitivity and specificity and using receiver operating characteristic (ROC) methods. RESULTS: The CogRisk was completed by all carers in less than 10 min. The total CogRisk score correlated significantly with total MMSE and NUCOG scores (r=-0.511 and -0.563, respectively) and remained highly significant when age and education were controlled for. Internal consistency of CogRisk items was high (alpha=0.943). Intrarater reliability of the CogRisk was high with an intraclass correlation coefficient of .978 (P<.001), and interrater reliability between carers was also high at 0.868 (P<.05). Sensitivity and specificity for the detection of dementia were .70 and .73, respectively, with area under the ROC curve not significantly different from that of the MMSE or NUCOG. CONCLUSION: The CogRisk is a brief carer-rated tool of a patient's cognitive functioning developed for use within a neuropsychiatric setting. It exhibited good concurrent validity, internal consistency, and interrater and intrarater reliability. The CogRisk also demonstrated good sensitivity and specificity for dementia. The CogRisk provides carer information, which complements the clinical assessment and can be used to focus on direct carer interview.

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.

Topiramate for abnormal eating behaviour in frontotemporal dementia.

Topiramate is a sulfamate-substituted monosaccharide anticonvulsant that is associated with anorexia and weight loss and has been used to treat binge eating disorder and bulimia nervosa. This report describes a man with frontotemporal dementia, behavioural variant, associated with abnormal eating behaviour which appeared to respond to topiramate. We review the physiological basis of abnormal eating behaviour in frontotemporal dementia and explore possible mechanisms of action by which topiramate may modify eating behaviour in this condition.