Social cognition in cervical dystonia.

Background: Whilst traditionally considered a movement disorder, it is now generally accepted that cervical dystonia (CD) presents with additional non-motor symptoms which significantly impact quality of life. Our study primarily aimed to explore social cognition and levels of psychological distress in individuals with CD, in comparison to age- and sex-matched healthy controls. Methods: 20 participants with CD attending a specialist movement disorders clinic were recruited. 20 age and sex matched neurologically healthy controls were recruited in parallel. Participants completed the Hospital Anxiety and Depression Scale, and two novel social cognition tasks: The Cambridge Mindreading Face-Voice Battery (CAFMB) and the Edinburgh Social Cognition Test (ESCoT). Results: Participants with CD exhibited poorer complex emotion recognition abilities for visual and auditory stimuli, compared to controls on the CAFMB task. Participants with CD did not differ significantly from controls on performance on cognitive or affective Theory of Mind tasks, or interpersonal or intrapersonal understanding of social norms, as measured by the ESCoT. The proportion of depressive symptoms was significantly higher for participants with CD than controls. 40% of participants with CD reported clinically elevated depressive symptoms, and 60% reported clinically elevated anxiety. Poorer understanding of emotional facial expressions was associated with higher levels of depression in the CD group. Conclusions: Significant between-group differences between participants with CD and controls suggests socio-cognitive dysfunction is an important aspect of the non-motor syndrome of CD. Findings highlight the need for assessment of and intervention for both social cognitive difficulties and psychological distress in individuals with CD.

Word finding, prosody and social cognition in multiple sclerosis.

BACKGROUND: Impairments in speech and social cognition have been reported in people with multiple sclerosis (pwMS), although their relationships with neuropsychological outcomes and their clinical utility in MS are unclear. OBJECTIVES: To evaluate word finding, prosody and social cognition in pwMS relative to healthy controls (HC). METHODS: We recruited people with relapsing MS (RMS, n = 21), progressive MS (PMS, n = 24) and HC (n = 25) from an outpatient MS clinic. Participants completed a battery of word-finding, social cognitive, neuropsychological and clinical assessments and performed a speech task for prosodic analysis. RESULTS: Of 45 pwMS, mean (SD) age was 49.4 (9.4) years, and median (range) Expanded Disability Severity Scale score was 3.5 (1.0-6.5). Compared with HC, pwMS were older and had slower information processing speed (measured with the Symbol Digit Modalities Test, SDMT) and higher depression scores. Most speech and social cognitive measures were associated with information processing speed but not with depression. Unlike speech, social cognition consistently correlated with intelligence and memory. Visual naming test mean response time (VNT-MRT) demonstrated worse outcomes in MS versus HC (p = .034, Nagelkerke's R2  = 65.0%), and in PMS versus RMS (p = .009, Nagelkerke's R2  = 50.2%). Rapid automatised object naming demonstrated worse outcomes in MS versus HC (p = .014, Nagelkerke's R2  = 49.1%). These word-finding measures showed larger effect sizes than that of the SDMT (MS vs. HC, p = .010, Nagelkerke's R2  = 40.6%; PMS vs. RMS, p = .023, Nagelkerke's R2  = 43.5%). Prosody and social cognition did not differ between MS and HC. CONCLUSIONS: Word finding, prosody and social cognition in MS are associated with information processing speed and largely independent of mood. Impairment in visual object meaning perception is potentially a unique MS disease-related deficit that could be further explored and cautiously considered as an adjunct disability metric for MS.

Interpreting the clinical importance of the relationship between subjective fatigue and cognitive impairment in multiple sclerosis (MS): How BICAMS performance is affected by MS-related fatigue.

BACKGROUND: There is evidence that subjective fatigue can influence cognitive functioning in multiple sclerosis (MS). DeLuca et al.'s (2004) Relative Consequence Model proposes that impairments to other high-level cognitive functions, such as memory, result from the disease's effect on information processing speed. OBJECTIVE: The primary aims of the study were to investigate both 1) the relationship between subjective fatigue and cognitive functioning, as measured by the widely used Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) in MS; and 2) the consequential effect of fatigue on information processing speed as predicted by the Relative Consequence Model. METHODS: 192 participants with MS attending tertiary referral MS centre completed the Modified Fatigue Impact Scale and BICAMS. RESULTS: Multiple correlation analyses determined that there were statistically significant relationships between all domains assessed by the BICAMS and levels of fatigue, such that higher levels of self-reported fatigue were associated with lower performance on information-processing, and visual and verbal learning. After controlling for information processing speed, the strength of correlation between fatigue and learning performance weakened. Linear regression analysis showed that fatigue predicted the most variance in verbal learning and 11.7% of the overall variance in BICAMS performance. CONCLUSION: Subjective fatigue and objective cognitive performance in MS are related. Caution is advised in the interpretation of BICAMS scores in cases where high levels of fatigue are present, and more detailed neuropsychological assessments may be required in order to accurately identify objective cognitive impairment independent of subjective fatigue.

Association between speech rate measures and cognitive function in people with relapsing and progressive multiple sclerosis.

Background: Cognitive impairments are well-documented in multiple sclerosis (MS), while speech impairments are often overlooked despite their significant effect on quality of life. For effective clinical management of multisystem conditions such as MS, consideration should be given to the interaction between deficits in multiple domains, such as speech and cognition. To evaluate speech rate measures of spontaneous and read speech, in people with MS and to examine the link between speech and cognition. Methods: Forty-five people with MS and 25 controls underwent an extensive cognitive battery, including executive functioning, information processing and memory tasks, and completed two speech tasks: a reading task and a picture description task, from which speech rate measures were derived. Results: The progressive MS cohort had reduced articulation (p < 0.04) and speech rate (p < 0.02) compared to controls and those with relapsing MS. Regression models also revealed information processing speed accounted for 18% to 30% of the variance of spontaneous speech rate measures, and 27% of read speech. Executive functioning accounted for a further 10% of the variance of speech rate in those with MS. Conclusions: The present study suggests that speech production is contingent on cognitive ability, with information processing speed and executive functioning linked with speech timing patterns.

Five-year follow up of the original Irish BICAMS validation cohort.

INTRODUCTION: Cognitive impairment is common in multiple sclerosis at all stages of the condition. The natural history of cognition in multiple sclerosis has been considered to be deterioration of cognitive functioning over time. The development of the Brief International Cognitive Assessment for Multiple Sclerosis(BICAMS) has allowed standardization of a screening tool for cognitive impairment which can be easily performed in the neurology clinic. Cross-sectional and validation studies using BICAMS have been widely reported, however minimal longitudinal assessment of cognition using BICAMS has taken place to date. OBJECTIVES: The objective of this study was to evaluate the prevalence of cognitive impairment at a five-year interval in participants of an original BICAMS validation study. We will also evaluate change of the BICAMS subtests over time. MATERIALS AND METHODS: Participants of the original BICAMS validation study were invited to participate in the study. Demographic and clinical details were collected. BICAMS subtests, anxiety, depression and fatigue questionnaires were completed. RESULTS: Fifty out of the original 67 participants completed BICAMS five years post original assessment. The prevalence of cognitive impairment in this cohort with a mean age of 49 and a median EDSS of 2.5 (EDSS of 2.0 at initial BICAMS testing) remained stable five years following initial BICAMS screening assessment, X2(1)=0.36, p=.548. There was no significant difference in SDMT scores between 2014 and 2019 t(48) = 1.08, p=.15. There was an improvement in CVLT-II, t(49)=-3.03; p=.004 and BVMT-R, t(49)=-3.38; p=.001. CONCLUSIONS: This study demonstrates overall stability in the prevalence of cognitive impairment as assessed by the BICAMS. The interval of five years between assessment reduces the possibility of practice effects, although familiarity with the testing protocol may exert an influence.

Vaccine hesitancy among people with multiple sclerosis.

BACKGROUND: The current severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic has raised awareness of vaccine hesitancy. Specific reasons for vaccine hesitancy among people with multiple sclerosis (pwMS) have not been fully described. Notably, pwMS may experience higher morbidity from vaccine-preventable diseases such as influenza, pneumococcal disease, and human papillomavirus (HPV)-associated warts and malignancies. Furthermore, screening for immunity against measles, mumps and rubella (MMR) is not standard practice, despite a resurgence of measles and mumps outbreaks in Europe and worldwide. We aimed to evaluate general vaccination status among pwMS to better inform vaccine practices in this cohort. METHODS: This was a prospective audit of pwMS attending an Irish tertiary referral MS centre. We designed a questionnaire that explored awareness, uptake, and hesitancy for the influenza, pneumococcal, SARS-CoV-2, HPV, and MMR vaccines. The clinician administered the questionnaire during the outpatient MS clinic. RESULTS: One-hundred-and-five pwMS participated in the audit, mean (SD) age 47.3 (12.8) years, mean MS disease duration 14.1 (9.5) years, median Expanded Disability Severity Scale (EDSS) score 2.0 (IQR 1.0-6.0), forty-nine (46.7%) were taking either maintenance immunosuppressive or immune reconstitution therapies. SARS-CoV-2 vaccine willingness among pwMS was higher (90.5 vs 60-80%) than that reported in other Western countries, and higher than that for the influenza and pneumococcal vaccines (∼80%) for which perceived unnecessity and unfamiliarity respectively were the main limiting factors. The primary reason for SARS-CoV-2 vaccine hesitancy was safety concern. PwMS who were explicitly advised by a healthcare professional to obtain the influenza vaccine were more likely to do so than those who were not (odds ratio, 8.1, 95% CI 2.8 - 23.4, p<0.001). Of pwMS currently receiving B-cell therapy (ocrelizumab/rituximab, n=12), all but one (n=11, 91.7%) have never received the pneumococcal vaccine, and a quarter (n=3) were uncertain whether to obtain this in the future. Patient-reported uptake of HPV (1.0%) and MMR (51.4%) vaccines were suboptimal. Prevalence of vaccine promotion among healthcare professionals was low (influenza vaccine, 4.8 - 32.4%; pneumococcal vaccine, 0 - 18.1%). CONCLUSIONS: Vaccine hesitancy is common (10-20%) in pwMS, consequent to insufficient knowledge and misconceptions about vaccination among pwMS and suboptimal vaccine promotion by healthcare professionals who manage pwMS. Conscientious and context-specific vaccination counselling is necessary to tackle vaccine hesitancy among pwMS, including (i) avoiding infection-associated disability accrual during MS relapses, (ii) reducing the potentially higher risk of life-threatening/treatment-refractory complications that may be observed in those who develop vaccine-preventable infections while receiving certain DMTs, and (iii) avoiding attenuated vaccine responses or delayed/interrupted DMT with early pre-treatment vaccine delivery where possible.

Postural stability is a valid and meaningful disability metric in progressive MS with potential for use in neuroprotective therapy trials.

BACKGROUND: Balance impairment is observed in up to 70% of people with MS (pwMS) and worsens with disease progression. Posturography using a force platform is the current gold standard in the measurement of balance. However, posturography has not been adequately studied or widely accepted for use as a disability outcome measure for pwMS. Importantly, the recent emergence of both successful and failed neuroprotective therapy trials in progressive MS has emphasised the need for new disability outcome measures for people with progressive MS. The main objectives of this study were to evaluate the clinical validity, reliability and feasibility of posturography as a disability metric in progressive MS. METHODS: This was a prospective cross-sectional study. We recruited 73 people with progressive MS (age 18-65 years, EDSS 3.5-6.0). Participants stood in the centre of a force platform, feet comfortably apart, under various conditions: (i) eyes open (EO), (ii) eyes closed (EC) - a single task, each lasting ninety seconds; and simultaneous EO with a cognitive test: (iii) N-Back, a three-minute test whereby participants were instructed to click the mouse when two identical letters were displayed consecutively on a screen, (iv) Sustained Attention Response Task, a five-minute test whereby participants were instructed to click the mouse for every number "1″ to "9″ except "3″ - i.e., dual-tasks. Additionally, we performed a battery of validated physical and cognitive outcome measures. Posturographic data was processed using Matlab. Statistical analysis was performed using SPSS version 26. We used multiple linear regression modelling to determine whether significant univariate correlations between posturography and clinical metrics were independent of covariates that may influence the associations seen. A two-tailed significance level of 0.05 was used. RESULTS: Of 73 participants, mean age 52.4 (8.5) years, mean MS disease duration 13.8 (10.3) years, median EDSS 5.0 (IQR 4.0-6.0), 44 (60.4%) were female. EO-Path-Length independently predicted upper extremity function (9-Hole-Peg-Test) with a larger effect size (adjusted R2=20.0%, p = 0.001) than that for walking measures (Timed 25-Foot Walk, adjusted R2=1.6%, p = 0.01; Two-Minute Walk Test, adjusted R2=7.2%, p = 0.002), while controlling for age, disease duration, height, weight, and sex. The addition of EO-Mediolateral-Displacement to the MS Functional Composite (MSFC) created a four-component z-score that increased the variance explained for quality of life (QOL) by 62.1%. Postural stability was significantly lower with mediolateral vs anteroposterior direction of sway, removal of vision, increased body weight, male sex, and fampridine use. Postural stability improved during dual-tasks compared to EO single task. Posturography detected significant worsening of balance over a single prolonged stance. CONCLUSION: Postural stability independently predicted a wide range of clinical metrics including upper extremity function, walking ability, cognition and QOL, therefore establishing construct and concurrent validity as a disability outcome measure for people with progressive MS. Additionally, posturography is a quantitative, non-invasive, quick-and-easy-to-administer, and highly sensitive device, demonstrating its high feasibility for use as a time- and resource-efficient disability metric in neuroprotective therapy trials for progressive MS.

Multiscale entropy derived complexity index analysis demonstrates significant mediolateral sway in persons with multiple sclerosis compared to healthy controls.

Clinical assessment of Multiple Sclerosis relies heavily on the Expanded Disability Status Scale, a non-linear rating system based on physician assessment of disease progression and walking ability. This inherently makes this method both subjective and limited in repeatability. This study developed a technically derived outcome measure of posture to compare a cohort of Multiple Sclerosis and Control subjects during an Eyes-Open and Eyes-closed task. Analysing traditional sway parameters and a multiscale entropy derived complexity index of posturography showed a significant difference in medio-lateral sway between groups during the Eyes-Open condition. This technically derived outcome measure may be of clinical benefit in the longitudinal assessment of the functional impact of balance in MS cohorts and assist in the evaluation of pharmaceutical and rehabilitation interventions.

Alemtuzumab-related thyroid disease in people with multiple sclerosis is associated with age and brainstem phenotype at disease onset.

BACKGROUND: Autoimmune thyroid disease (AITD) occurs in 40%-50% of alemtuzumab-treated persons with multiple sclerosis (pwMS), most of whom will develop Graves' Disease (GD). OBJECTIVE: To explore contributory factors for alemtuzumab-related AITD in pwMS. METHODS: A retrospective patient chart review was performed. RESULTS: Sixteen out of 52 (30.8%) pwMS developed AITD. GD occurred in 56.3% (n = 9), the majority (n = 7, 77.8%) symptomatic. All but one (85.7%) pwMS with symptomatic GD developed atypical, large and rapid fluctuations in thyroid hormone levels unexplained by effect of anti-thyroid medication alone. All symptomatic GD cases were age ≤32 years when starting alemtuzumab (ɸ = 0.60, p = 0.03). PwMS who started alemtuzumab at a younger age developed thyroid disease earlier (r = 0.51, p = 0.04). PwMS with clinical and radiological evidence of brainstem involvement at onset of multiple sclerosis were 11 times more likely to develop symptomatic GD compared with those with other phenotypes (p < 0.01). CONCLUSION: Alemtuzumab-induced reconstitution GD may result from early and increased cross-reactivity between antigens common to the brainstem and thyroid, or presence of shared Human Leukocyte Antigen (HLA) alleles that determine brainstem and thyroid involvement. We suggest cautious use of alemtuzumab in younger (≤32 years) pwMS with early brainstem involvement, especially those actively planning pregnancy, where alternative therapies are readily available.

Bartonella neuroretinitis (cat-scratch disease).

We report a patient with cat-scratch disease presenting with meningitis and neuroretinitis. This condition, caused by Bartonella henselae, has a worldwide distribution and is among the most common infective causes of neuroretinitis. Bartonella neuroretinitis is a rare but under-recognised mimic of optic neuritis; it should be suspected in a patient with an infective prodrome whose fundus shows optic disc oedema and a macular star. A low-positive initial serological test for Bartonella henselae does not exclude cat-scratch disease if there is high clinical suspicion, and repeat testing is recommended to look for titre rise.

Ryanodine receptor 2 (RYR2) mutation: A potentially novel neurocardiac calcium channelopathy manifesting as primary generalised epilepsy.

PURPOSE: Ryanodine receptor 2 (RYR2) mutation is well-established in the aetiology of an inherited cardiac disorder known as catecholaminergic polymorphic ventricular tachycardia (CPVT). The RYR2 receptor is expressed in cardiomyocytes, and also in the hippocampus. The RYR2 mutation has not been reported as a potential cause of adult-onset genetic generalised epilepsy (GGE). METHOD: Case report. RESULTS: A 32-year-old right-handed female presented with three unprovoked generalised seizures over twelve years. Electroencephalogram showed epileptiform activity which coincided with normal electrocardiogram recording. Her brother survived a cardiac arrest in his 20's and was diagnosed with CPVT and found to be heterozygous for a novel mutation in the RYR2 gene at chromosome 1q43, c.229 G > A p.(Ala77Thr). The patient inherited the same missense variant, predicted to be damaging by numerous in silico analytic tools. This mutation affects the N-terminal domain of the RYR2 receptor which plays a role in channel activation. However, the patient had repeatedly normal cardiac investigations including normal exercise stress tests. CONCLUSION: We propose that the RYR2 mutation is a potentially novel neurocardiac calcium channelopathy that may manifest with either CPVT or GGE depending on selective involvement of RYR2 receptors expressed in the heart or in the brain. RYR2 mutant mice have demonstrated spontaneous EEG-positive seizures independent of cardiac arrhythmia. Whole exome sequencing analyses have identified RYR2 as a candidate gene in GGE. This case is a reminder for careful assessment of episodes of transient loss of consciousness in an individual with CPVT, so as to not mistake possible neurogenic seizure for cardiogenic syncope, carrying obvious implications for treatment.

Alternating hemiparesis and orolingual apraxia as manifestations of methotrexate neurotoxicity in a paediatric case of acute lymphoblastic leukaemia.

A 15-year-old girl with a recent diagnosis of acute lymphoblastic leukaemia was admitted to hospital with pancytopaenia after having received high-dose intrathecal methotrexate 1 day prior. During the next week she had intermittent episodes of alternating hemiparesis associated with speech arrest lasting minutes to hours at a time. The episodes were not associated with altered level of consciousness or headache. MRI of the brain showed features consistent with methotrexate encephalopathy. This report discusses the typical clinical and radiological features of methotrexate neurotoxicity in addition to differential diagnoses and the proposed pathophysiological mechanisms.

Auditory hallucination in basilar occlusion: I heard it was the basilar.

Acute basilar artery occlusion is a neurological emergency. Unlike anterior circulation stroke presenting with hemiparesis, the symptoms of basilar artery occlusion are challenging to recognise in the emergency setting. Basilar artery occlusion can rarely lead to ischaemia of the auditory pathways, resulting in bizarre, positive auditory hallucinations. Here, we report two cases of basilar artery occlusion presenting with positive auditory phenomena; in both cases the auditory phenomenon resolved upon arterial recanalisation. We discuss the phenomenology of this unusual and distinctive neurological symptom. Acute auditory hallucinosis in the setting of sudden vomiting, dizziness, visual disturbance or other posterior circulation symptoms should prompt emergency imaging of the basilar artery, to avoid a potentially devastating posterior circulation stroke.