Cerebral venous sinus thrombosis and thrombocytopenia after COVID-19 vaccination - A report of two UK cases.

Recent reports have highlighted rare, and sometimes fatal, cases of cerebral venous sinus thrombosis (CVST) and thrombocytopenia following the Vaxzevria vaccine. An underlying immunological mechanism similar to that of spontaneous heparin-induced thrombocytopenia (HIT) is suspected, with the identification of antibodies to platelet factor-4 (PF4), but without previous heparin exposure. This unusual mechanism has significant implications for the management approach used, which differs from usual treatment of CVST. We describe the cases of two young males, who developed severe thrombocytopenia and fatal CVST following the first dose of Vaxzevria. Both presented with a headache, with subsequent rapid neurological deterioration. One patient underwent PF4 antibody testing, which was positive. A rapid vaccination programme is essential in helping to control the COVID-19 pandemic. Hence, it is vital that such COVID-19 vaccine-associated events, which at this stage appear to be very rare, are viewed through this lens. However, some cases have proved fatal. It is critical that clinicians are alerted to the emergence of such events to facilitate appropriate management. Patients presenting with CVST features and thrombocytopenia post-vaccination should undergo PF4 antibody testing and be managed in a similar fashion to HIT, in particular avoiding heparin and platelet transfusions.

Apathy: a practical guide for neurologists.

Apathy is an under-recognised and underestimated problem for people with chronic neurological disorders. Despite being common and disabling, it is seldom volunteered as a symptom by patients or even their caregivers. Yet apathy undoubtedly has an important impact on caregiver stress, functional disability and quality of life. A detailed clinical assessment can distinguish apathy from depression and allow clinicians to make practical suggestions to reduce the impact of symptoms on individual patients and their families. Pharmacological approaches to treatment include cholinesterase inhibitors, dopamine agonists and stimulants. CASE 1A 66-year-old man with progressive supranuclear palsy returned to clinic for review. His wife was upset and finding it difficult to cope. She described him as 'completely lazy', as he just sat in his chair all day watching television, even though he could still do things for himself. She felt that he could not be bothered to speak to her anymore because he was 'obsessed with TV'. He did not seem to engage with the visits to the grandchildren that she arranged. He said that he felt fine apart from the problems with his walking.The neurologist was confident that the patient was not depressed, and that the wife's concerns reflected the apathy that is often very pronounced in progressive supranuclear palsy. By explaining to the man's wife that these problems were due to his disease, their relationship improved and she felt more able to cope with caring for him. CASE 2A 75-year-old man attended clinic with his wife. She had worried about him for over a year, as he had become increasingly withdrawn. He used to enjoy going to the local pub but now stayed at home all day. He seemed less concerned about his personal appearance, about which he used to be meticulous. More recently, she had noticed that he had become forgetful. On examination, he had a mild episodic memory deficit but no impairments in other domains.He was diagnosed with mild cognitive impairment but the presence of apathy suggested a high risk of him developing Alzheimer's disease. He did not improve with a trial of antidepressant treatment but had useful input from an occupational therapist. His apathy improved after he started a cholinesterase inhibitor a year later, when his cognitive symptoms had progressed.

The association between ALS and population density: A population based study.

We aimed to assess whether rural residence is associated with amyotrophic lateral sclerosis in the south-east of England using a population based register. Previous studies in different populations have produced contradictory findings. Residence defined by London borough or non-metropolitan district at time of diagnosis was recorded for each incident case in the South-East England ALS Register between 1995 and 2005. Each of the 26 boroughs or districts of the catchment area of the register was classified according to population density. Age- and sex-adjusted incidence of ALS was calculated for each region and the relationship with population density tested by linear regression, thereby controlling for the underlying population structure. We found that population density in region of residence at diagnosis explained 25% of the variance in ALS rates (r = 0.5, p < 0.01). Thus, in this cohort in the south-east of England, people with ALS were more likely to be resident in areas of high population density at diagnosis.

The sex ratio in amyotrophic lateral sclerosis: A population based study.

Replicable risk factors for ALS include increasing age, family history and being male. The male: female ratio has been reported as being between 1 and 3. We tested the hypothesis that the sex ratio changes with age in a population register covering the south-east of England. The sex ratio before and after the age of 51 years was compared using a Z-test for proportions. Kendall's tau was used to assess the relationship between age group and sex ratio using incidence and prevalence data. Publicly available data from Italian and Irish population registers were compared with results. There was a significant difference in the proportion of females with ALS between those in the younger group (30.11%) and those in the older group (43.66%) (p = 0.013). The adjusted male: female ratio dropped from 2.5 in the younger group to 1.4 in the older group using prevalence data (Kendall's tau = -0.73, p = 0.039). Similar ratios were found in the Italian but not the Irish registry. We concluded that sex ratios in ALS may change with age. Over-representation of younger patients in clinic registers may explain the variation in sex ratios between studies. Menopause may also play a role.

Psychiatrists' Understanding and Management of Conversion Disorder: A Bi-National Survey and Comparison with Neurologists.

BACKGROUND: A 2011 survey of neurologists' attitudes to conversion disorder found a tacit acceptance of the psychological model but significant ambivalence around its relationship to feigning. These issues are under increased scrutiny as the DSM-5 revision removed both the requirement for a psychological formulation and the exclusion of feigning from the diagnostic criteria. Whether those attitudes are shared with psychiatrists is unknown. METHODS: An online survey of the Section of Neuropsychiatry, Royal Australian and New Zealand College of Psychiatrists, and the Faculty of Neuropsychiatry, Royal College of Psychiatrists (UK), on their understanding and management of conversion disorder in February 2019. Statistical comparisons are made with our previous survey of Neurologists. RESULTS: A total of 52 Australian and 131 UK-based members completed the survey which revealed similarities but also clear differences from their neurological colleagues. The psychiatrists strongly endorsed a psychogenic model for conversion disorder, and the conversion model in particular, though many models were employed. They felt a psychiatric assessment was essential to the diagnosis of conversion disorder, and they often disagreed with the diagnosis in neurology referrals of putative conversion disorder. Most felt that a psychiatric formulation was supportive, and many that it was necessary to the diagnosis. They saw feigning as usually present to a degree but were more comfortable with discussing this than neurologists. CONCLUSION: Psychiatrists use psychosocial models for conversion disorder and see an overlap with feigning. They believe psychiatrists are essential for the diagnostic process and would not usually support a diagnosis without a psychiatric formulation.

Geographical clustering of amyotrophic lateral sclerosis in South-East England: a population study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons that causes progressive paralysis and eventually results in death from respiratory failure. Environmental factors that trigger ALS might result in a pattern of geographical clustering of cases. We tested this hypothesis using the South-East England ALS population register, which covers south-east London, Kent and parts of neighbouring counties. METHODS: The register's catchment area was divided into postcode districts and sectors. The expected rates of ALS (adjusted for age and sex) were compared with the observed rates using a standardised residuals method and the SaTScan programme. RESULTS: There were 406 cases of ALS identified in the catchment area during the study period. Four of the 126 postcode districts, all in Greater London, had residuals >2.5 SDs from the mean. Similarly, there were 15 postcode sectors (out of 420) that had residuals >1.96 SDs from the mean. Nine of these were in Greater London. SaTScan identified an area that had a 5.61-km radius in which the relative risk of ALS was 1.70 (p = 0.012). This area overlapped with the postcode districts and some of the sectors identified using the residuals method. CONCLUSIONS: These findings suggest an excess of ALS cases in some postcode districts in south-east England.

Cortical activation during motor imagery is reduced in Amyotrophic Lateral Sclerosis.

The neural correlates of motor execution in Amyotrophic Lateral Sclerosis (ALS) are challenging to investigate due to muscle weakness. Alternatives to traditional motor execution paradigms are therefore of great interest. This study tested the hypothesis that patients with Amyotrophic Lateral Sclerosis (ALS) would show increased cortical activation during motor imagery compared to healthy controls, as seen in studies of motor execution. Functional MRI was used to measure activation during a block design paradigm contrasting imagery of right hand movements against rest in 16 patients with ALS and 17 age-matched healthy controls. Patients with ALS showed reduced activation during motor imagery in the left inferior parietal lobule, and in the anterior cingulate gyrus and medial pre-frontal cortex. This reduction in cortical activation during motor imagery contrasts with the pattern seen during motor execution. This may represent the disruption of normal motor imagery networks by ALS pathology outside the primary motor cortex.

Altered cortical activation during a motor task in ALS. Evidence for involvement of central pathways.

OBJECTIVE: To test the hypothesis that patients with amyotrophic lateral sclerosis (ALS) show increased cortical activation during a motor task compared to both healthy controls and patients with muscle weakness due to peripheral lesions. METHODS: Functional magnetic resonance imaging (fMRI) was used to measure activation during a block design paradigm contrasting right hand movements against rest in sixteen patients with ALS, seventeen healthy controls and nine patients with peripheral lesions. The groups were matched for age and gender and the two patient groups were matched for their degree of upper limb weakness. Analysis used a non-parametric approach to perform a 3 way hypothesis-driven comparison between the groups. RESULTS: During the motor task, patients with ALS showed increased cortical activation bilaterally, extending from the sensorimotor cortex [Brodmann areas (BA) 1, 2, 4] posteriorly into the inferior parietal lobule (BA 40) and inferiorly to the superior temporal gyrus (BA 22) when compared to peripheral lesion patients and controls. In addition, ALS patients showed reduced activation in the dorsolateral prefrontal cortex (DLPFC) extending to anterior and medial frontal cortex (BA 8, 9, 10, 32). CONCLUSIONS: We conclude that alterations in cortical function in ALS differ in sensorimotor and prefrontal regions. Importantly, we have shown that these changes do not reflect confounding by weakness or task difficulty, but are likely to be related to upper motor neuron pathology in ALS.

A longitudinal study of diffusion tensor MRI in ALS.

In this study, we investigated whether diffusion tensor MRI (DTI) could detect progressive corticospinal tract degeneration in amyotrophic lateral sclerosis (ALS) and whether changes in diffusion variables reflected clinical deterioration. Twenty-three ALS patients and 25 healthy volunteers underwent whole brain DTI. Patients and a subset (n = 12) of controls returned for a second scan. Clinical measures of disease severity were assessed in the ALS group. Changes in fractional anisotropy (FA) and mean diffusivity (MD) were measured along the corticospinal tract using a region of interest approach. Adequate DTI data were available in 11 ALS patients and 11 controls at two time points. FA and MD differed significantly between ALS patients and controls at both time points, but neither changed significantly over time, while global measures of disease severity in patients increased with time. Although we confirmed that DTI detects corticospinal tract damage in ALS, there were no significant changes in diffusion measures over time. The sensitivity of DTI may be improved by advanced data analysis techniques, although the high dropout rate suggests that use of MRI as a biomarker in ALS may be restricted to earlier stages of disease.

Behavioural and emotional symptoms of apathy are associated with distinct patterns of brain atrophy in neurodegenerative disorders.

Apathy is a neurocognitive syndrome of reduced goal-directed behaviour and is an important cause of disability in neurodegenerative disorders. Frontal-subcortical dysfunction is thought to be important in apathy, but the contribution of individual brain regions to different aspects of the apathy syndrome is poorly understood. We aimed to test the hypotheses that apathy in two distinct neurodegenerative disorders would be associated with frontal lobe atrophy and that reduced initiative and emotional blunting would be associated with distinct patterns of atrophy in functionally relevant brain areas. Seventeen patients with progressive supranuclear palsy (PSP) and 17 patients with Alzheimer's disease (AD) underwent structural MRI scanning at 3 T to provide data for voxel based morphometric analysis. Apathy was defined using Robert's 2009 diagnostic criteria and specific symptoms were assessed with the Apathy Inventory. Patients with and without apathy were matched for important demographic and clinical characteristics. Apathy was associated with atrophy of the ventromedial orbitofrontal cortex and left insula in both AD and PSP. Reduced initiative was specifically associated with atrophy of the anterior cingulate and ventrolateral orbitofrontal cortex whilst emotional blunting was specifically associated with atrophy of the left insula. These findings provide further support for the role of medial frontal regions and insular cortex in apathy and suggest that behavioural and emotional aspects of the apathy syndrome may have distinct neuroanatomical bases.

Diffusion tensor imaging in sporadic and familial (D90A SOD1) forms of amyotrophic lateral sclerosis.

BACKGROUND: The basis of heterogeneity in the clinical presentation and rate of progression of amyotrophic lateral sclerosis (ALS) is poorly understood. OBJECTIVES: To use diffusion tensor imaging as a measure of axonal pathologic features in vivo in ALS and to compare a homogeneous form of familial ALS (homozygous D90A SOD1 [superoxide dismutase 1]) with sporadic ALS. DESIGN: Cross-sectional diffusion tensor imaging study. SETTING: Tertiary referral neurology clinic. PATIENTS: Twenty patients with sporadic ALS, 6 patients with homozygous D90A SOD1 ALS, and 21 healthy control subjects. MAIN OUTCOME MEASURE: Fractional anisotropy in cerebral white matter. RESULTS: Patients with homozygous D90A SOD1 ALS showed less extensive pathologic white matter in motor and extramotor pathways compared with patients with sporadic ALS, despite similar disease severity assessed clinically using a standard functional rating scale. Fractional anisotropy correlated with clinical measures of severity and upper motor neuron involvement. CONCLUSION: In vivo diffusion tensor imaging measures demonstrate differences in white matter degeneration between sporadic ALS and a unique familial form of the disease, indicating that genotype influences the distribution of cerebral pathologic features in ALS.

Conversion disorder: towards a neurobiological understanding.

Conversion disorders are a common cause of neurological disability, but the diagnosis remains controversial and the mechanism by which psychological stress can result in physical symptoms "unconsciously" is poorly understood. This review summarises research examining conversion disorder from a neurobiological perspective. Early observations suggesting a role for hemispheric specialization have not been replicated consistently. Patients with sensory conversion symptoms have normal evoked responses in primary and secondary somatosensory cortex but a reduction in the P300 potential, which is thought to reflect a lack of conscious processing of sensory stimuli. The emergence of functional imaging has provided the greatest opportunity for understanding the neural basis of conversion symptoms. Studies have been limited by small patient numbers and failure to control for confounding variables. The evidence available would suggest a broad hypothesis that frontal cortical and limbic activation associated with emotional stress may act via inhibitory basal ganglia-thalamocortical circuits to produce a deficit of conscious sensory or motor processing. The conceptual difficulties that have limited progress in this area are discussed. A better neuropsychiatric understanding of the mechanisms of conversion symptoms may improve our understanding of normal attention and volition and reduce the controversy surrounding this diagnosis.