Caffeine intake interacts with Asian gene variants in Parkinson's disease: a study in 4488 subjects.

Background: Caffeine intake reduces risk of Parkinson's disease (PD), but the interaction with genes is unclear. The interaction of caffeine with genetic variants in those at high PD risk has healthcare importance. We investigate interactions of caffeine intake with risk variants found in Asians, and determine PD risk estimates in caffeine-drinkers carrying these variants. Methods: PD patients and controls without neurological disorders were included. Caffeine intake was assessed using a validated evaluation tool. Leucine rich repeat kinase 2 (LRRK2) risk variants were genotyped. Statistical analysis was conducted with logistic regression models. Gene-caffeine interactions were quantified using attributable proportion (AP) due to interaction (positive interaction defined as AP >0). Findings: 5100 subjects were screened and 4488 subjects (1790 PD, 2698 controls) with genetic data of at least one LRRK2 variant were included. Risk-variant-carriers who were non-caffeine-drinkers had increased PD odds compared to wildtype carriers who were caffeine-drinkers for G2385R [OR 8.6 (2.6-28.1) p < 0.001; AP = 0.71], R1628P [OR 4.6 (1.6-12.8) p = 0.004; AP = 0.50] and S1647T [OR 4.0 (2.0-8.1) p < 0.001; AP = 0.55] variants. Interpretation: Caffeine intake interacts with LRRK2 risk variants across three different groups of gene carriers. Asymptomatic risk-variant-carriers who are non-caffeine-drinkers have four to eight times greater PD risk compared to wildtype-caffeine-drinkers. Lifestyle modifications to mitigate PD risk in asymptomatic healthy risk variant carriers have potential roles in our Asian cohort. Funding: This study was supported by the National Medical Research Council (STaR and PD OF LCG 000207 grants) and Duke-NUS Medical School.

COVID-19 infection after two doses of SARS-CoV-2 mRNA vaccine in multiple sclerosis, AQP4-antibody NMOSD and MOGAD.

BACKGROUND: In pre-vaccinated people with multiple sclerosis (MS), certain disease-modifying therapies (DMTs), particularly the anti-CD20 treatments, appear to be associated with an increased risk of COVID-19 infection and indeed with severe infection. It is still not known if such observations extend to vaccinated individuals and there have been considerably fewer studies in aquaporin-4-antibody neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein-antibody associated disease (MOGAD) patients. In this study, we investigated the rates of symptomatic COVID-19 infection in adult patients with MS, AQP4-NMOSD and MOGAD who had received 2 doses of SARS-CoV-2 mRNA vaccine. METHODS: This was a prospective observational study conducted at the 2 main neuroimmunology referral centres in Singapore. Only patients on active follow-up were recruited to ensure robust data collection. Data on demographics, disease history, DMTs and SARS-CoV-2 mRNA vaccinations were recorded, and for those infected with COVID-19, data on COVID-19 infection was collected. RESULTS: Nineteen (13 MS, 5 AQP4-NMOSD, 1 MOGAD) out of 365 (231 MS, 106 AQP4-NMOSD, 28 MOGAD) patients had COVID-19 infection despite 2 doses of SARS-CoV-2 mRNA vaccine. Amongst the infected patients, 11 patients were on DMTs (3 rituximab, 2 interferons, 1 azathioprine, 1 mycophenolate, 1 prednisolone, 1 cladribine, 1 alemtuzumab, 1 fingolimod), while 8 patients were untreated. The crude infection rate was calculated using time-at-risk analysis, revealing that rituximab had the highest infection rate amongst all the DMTs. A lower crude infection rate was observed in patients who received a third vaccination. The majority of infections were mild and no patients required oxygen supplementation. CONCLUSION: Our findings suggest that patients on rituximab are still at risk of COVID-19 infection after 2 vaccinations and the receipt of a third vaccination may help to prevent infection. Future large scale studies will be required to better delineate the infection risk of different DMTs after the second and subsequent vaccinations.

Multiple sclerosis with intractable vomiting and atypical area postrema lesion.

BACKGROUND: Area postrema syndrome is considered as one of the most typical presentations of neuromyelitis optica spectrum disorders (NMOSDs) (Wingerchuk et al., 2015). The involvement of area postrema is rarely seen in multiple sclerosis (MS). We are here report a case of a young woman with multiple sclerosis, presented with intractable vomiting, and her MRI brain showed acute T2 hyperintense signal over the area postrema. CASE PRESENTATION: A 36-year-old Asian woman who is known to have schizophrenia and multiple sclerosis since 2012. She was noted to have spastic gait, and the MRI brain in 2012 showed multiple perpendicular periventricular T2 lesions suggestive of multiple sclerosis (MS). However, she defaulted her neurologist follow-up and was not on any treatment for MS. She was admitted in 2016 with intractable vomiting, and her MRI brain showed T2 hyperintense signal over area postrema with focal contrast enhancement. Her MRI cervical spine was normal. The visual evoked potential study showed bilateral prolonged P100 latencies. Oligoclonal bands were detected in her CSF analysis. Both the serum aquaporin-4 IgG (AQP4 IgGs) antibody and myelin oligodendrocyte glycoprotein (MOG-IgGs) were negative. Her intractable vomiting resolved after a short course of intravenous methylprednisolone. She was treated as MS with interferon-beta 1a. She has been in remission since 2016, and her functional status also improved from the expanded disability status scale (EDSS) of 2.0 (in 2016) to 1.0 (in 2020). CONCLUSION: We proposed that although area postrema lesion is typically seen in NMOSDs, it may also be seen in MS. Current MRI criteria for MS and NMOSDs are not sufficiently specific, and the diagnostic criteria should only be used in the appropriate clinical context.

18F-FDG PET Brain in a Patient With Fatal Familial Insomnia.

A 57-year-old woman presented with a 3-month history of cognitive impairment, daytime somnolence, and violent sleep behavior. Her first- and second-degree relatives had similar symptoms prior to their premature deaths. Her MRI scan of the brain showed no significant abnormality. Electroencephalogram showed loss of slow-wave activity. Functional brain imaging performed with F-FDG PET was fused with her MRI scans. This demonstrated profound hypometabolism in bilateral thalami and the posterior cingulate cortex, which is pathognomonic for familial fatal insomnia. Hypometabolism in the temporal lobes suggests a long-standing course of the disease. Genetic testing confirmed a mutation of the prion-protein gene (PRNP).

The laterality index in the evaluation of distal sensorimotor neuropathy.

OBJECTIVE: Electrodiagnostic evaluation of distal sensorimotor neuropathy can be technically challenging. Conventional nerve conduction studies (NCS) often include unilateral upper and lower limb evaluation for patients with suspected sensorimotor peripheral neuropathy. For patients with predominantly lower extremity complaints, NCS of both lower limbs are performed occasionally. Side-to-side NCS parameters have not been adequately addressed. METHODS: We performed NCS prospectively on 132 patients presenting with complaints of bilateral numbness or weakness in the extremities and 45 normal controls. The laterality index (LI) was defined as ratio of the smaller to the larger amplitude in a sensory or motor NCS, as a novel side-to-side comparison parameter. RESULTS: Ten patients had at least 1 sensory or motor NCS with LIs exceeding that of normal controls. Patients 1-7 (group 1) had diagnoses of autoimmune or neoplasia-related conditions and all had 3 or more NCS with abnormal LIs. In contrast, patients 8-10 (group 2) had diabetes mellitus and all had 2 or less NCS with abnormal LIs (unpaired t test; P = 0.002). In group 1, patients 1-4, 6, and 7 all had both upper and lower limb LI abnormalities. In contrast, only 1 patient (patient 9) had upper limb LI abnormality in group 2. CONCLUSIONS: Patients with abnormal LIs were uncommon in our cohort. Patients with diabetes mellitus had significantly less abnormal LIs than those with autoimmune or neoplasia-related etiologies. There is evidence of vasculitic inflammation documented in diabetic neuropathy. However, this process may be significantly less prominent compared with the former 2 conditions. Our findings of predominantly lower limb LI abnormalities suggest the presence of a length-dependent distal neuropathic process in diabetes mellitus. The LI is a simple and useful adjunct to detect asymmetrical NCS abnormalities. It may also provide helpful information regarding the underlying etiology.

Autologous haematopoietic stem cell transplantation for the treatment of multiple sclerosis.

INTRODUCTION: Autologous haematopoietic stem cell transplantation (auto-HSCT) has been performed for severe multiple sclerosis (MS) refractory to standard therapy with increasing frequency worldwide. However, experience in Asia employing this modality in MS has been limited. In this review, we explored the pathophysiology of autoimmunity and the underlying rationale for auto-HSCT in treating autoimmune diseases including MS, as well as existing published pre-clinical and clinical data. We aimed thereby to better understand the utility of treating MS with auto-HSCT and the feasibility of this procedure in Singapore. METHODS: A Medline search was performed with the terms "haematopoietic stem cell transplantation", "multiple sclerosis" and "autoimmune diseases" from 1996 to 2005. Both original papers and review articles were considered. MAIN FINDINGS: The majority of publications were from Europe or the United States and most clinical series from single centres had relatively small numbers of patients. Worldwide, the number of patients reported has been less than 300 since 1997. Existing data support the feasibility and promise of this procedure and ongoing Phase III trials may serve to confirm this initial experience. CONCLUSION: Pre-clinical and early clinical data support the rationale for immunoablative therapy for autoimmune disorders. Auto-HSCT for severe MS is a feasible procedure and can be safely performed in centres with experience managing HSCT patients.

Pectoral nerve conduction studies: technique in healthy subjects and evaluation of brachial plexopathy.

OBJECTIVE: To define the optimal nerve conduction study (NCS) technique of the pectoral nerves and evaluate its clinical utility. DESIGN: Prospective electrophysiologic study with healthy controls. SETTING: Electrophysiologic laboratory in a large general hospital. PARTICIPANTS: Thirty healthy controls and 10 patients with cervical root or brachial plexus pathologies. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Correlation of pectoral NCS with electromyography and magnetic resonance imaging. RESULTS: For pectoral NCS, the mean values +/- standard deviation of onset latency, amplitude, and interside amplitude ratio (ratio of smaller over larger amplitude) were 2.01+/-0.22 ms, 11.75+/-2.21 mV, and .95+/-.04 mV, respectively. Subject age correlated significantly with both onset latency (r=.46, P<.001) and amplitude (r=-.34, P<.008). All 5 patients with brachial plexopathy had amplitude ratios below the normal limit of controls (.87). However, this was not seen for all 5 patients with cervical spondylotic radiculopathy. CONCLUSIONS: The pectoral NCS technique is feasible in healthy subjects. It is useful when differentiating brachial plexopathy from cervical root lesions.

Effect of exercise on repetitive nerve stimulation studies: new appraisal of an old technique.

Repetitive nerve stimulation (RNS) is a simple and rapid method for evaluation of neuromuscular transmission defects. Although the effect of exercise in conjunction with RNS is well recognized, it has not been standardized in actual patient and control groups. In a prospective study over a period of 1 year, the authors evaluated the effect of exercise in conjunction with RNS in comparison with conventional 3-Hz RNS at rest in the clinical setting. Fifty-four patients who were referred for possible neuromuscular transmission disorders, in addition to 35 healthy control subjects, were studied. Amplitude and area decremental responses with RNS at rest and after 20 seconds of maximal exercise at 1-minute intervals up to 3 minutes were evaluated. The use of RNS with exercise resulted in additional diagnostic yield of up to 36.4% compared with conventional 3-Hz RNS at rest. The standardized use of exercise with RNS is advocated for increasing its diagnostic yield in the neurophysiologic laboratory.