Novel Autoantibodies in Idiopathic Small Fiber Neuropathy.

OBJECTIVE: Small fiber neuropathy (SFN) is clinically and etiologically heterogeneous. Although autoimmunity has been postulated to be pathophysiologically important in SFN, few autoantibodies have been described. We aimed to identify autoantibodies associated with idiopathic SFN (iSFN) by a novel high-throughput protein microarray platform that captures autoantibodies expressed in the native conformational state. METHODS: Sera from 58 SFN patients and 20 age- and gender-matched healthy controls (HCs) were screened against >1,600 immune-related antigens. Fluorescent unit readout and postassay imaging were performed, followed by composite data normalization and protein fold change (pFC) analysis. Analysis of an independent validation cohort of 33 SFN patients against the same 20 HCs was conducted to identify reproducible proteins in both cohorts. RESULTS: Nine autoantibodies were screened with statistical significance and pFC criteria in both cohorts, with at least 50% change in serum levels. Three proteins showed consistently high fold changes in main and validation cohorts: MX1 (FC = 2.99 and 3.07, respectively, p = 0.003, q = 0.076), DBNL (FC = 2.11 and 2.16, respectively, p = 0.009, q < 0.003), and KRT8 (FC = 1.65 and 1.70, respectively, p = 0.043, q < 0.003). Further subgroup analysis into iSFN and SFN by secondary causes (secondary SFN) in the main cohort showed that MX1 is higher in iSFN compared to secondary SFN (FC = 1.61 vs 0.106, p = 0.009). INTERPRETATION: Novel autoantibodies MX1, DBNL, and KRT8 are found in iSFN. MX1 may allow diagnostic subtyping of iSFN patients. ANN NEUROL 2022;91:66-77.

Clinical profile and impact of comorbidities in patients with very-late-onset myasthenia gravis.

INTRODUCTION/AIMS: The purpose of this study was to evaluate the clinical profile of myasthenia gravis (MG) in older patients and determine the impact of medical comorbidities on their MG status and outcome. METHODS: This was a retrospective chart review of patients with a symptom onset of MG at or after 65 years of age. Correlations were made between demographics, clinical characteristics, the Myasthenia Gravis Foundation of America (MGFA) severity scale scores, and Myasthenia Gravis Impairment Index (MGII) scores with two outcome measures: MGFA Post-Intervention Status (MGFA-PIS) and Simple Single Question (SSQ). RESULTS: The study population included 109 patients, with 90 of them having more than one follow-up visit. Their mean age was 75.3 ± 6.9 years and sex distribution was even. Of these patients, 67.7% had generalized MG. Nine-one percent of patients had one comorbidity. None of the demographic factors or comorbidities showed an association with MGFA-PIS, SSQ, or MGII after correction for multiple comparisons. Seventy-one percent of the patients improved with treatment, 12.4% remained unchanged, and 16.6% showed worsening at their last follow-up visit. DISCUSSION: Our study shows that patients with very-late-onset MG had a good prognosis and treatment response. None of the comorbidities had an impact on the severity of myasthenic symptoms or on outcome in these patients.

Telephone consultation for myasthenia gravis care during the COVID-19 pandemic: Assessment of a novel virtual myasthenia gravis index.

INTRODUCTION/AIMS: The aim of the study was to determine the association between the virtual Myasthenia Gravis Impairment Index (vMGII) with other patient-reported outcomes (PROs) of myasthenia gravis (MG) and its usefulness in telephone consultations with MG patients. METHODS: This was a retrospective case series in which vMGII score along with virtual Single Simple Question (vSSQ), virtual Patient-Acceptable Symptom State PASS (vPASS) response, and patient disease status based on Myathenia Gravis Foundation of America postintervention status were collected during telephone consultation along with the MGII, SSQ, and PASS responses during the preceding in-person clinic visits. RESULTS: In 214 patients, the mean difference of vMGII between the vPASS "Yes" and "No" groups was -14.2 ± 1.4 (95% confidence interval, -16.9 to -11.3; P < .001) with mean vMGII for vPASS "Yes" group being 6.4 ± 7.7 and vPASS "No" being 20.5 ± 11.5. A vMGII of 11.5 or higher predicted vPASS "yes" response with a sensitivity of 78.7% and specificity of 81.4%. A strong negative correlation was found between the vMGII and vSSQ (r = -.667; P < .001). The mean vMGII was 0.48 ± 1.42 for patients in remission, and 9.31 ± 10.93 for improved, 9.32 ± 8.79 for stable, and 22.58 ± 14.04 for worsened groups (P < .001). These associations were the same as those obtained during the preceding in-person clinic visit and the direction of change in MGII scores also indicated change in disease status. DISCUSSION: vMGII is an effective measure to assess an MG patient's disease status in telephone consultations and relates well with other PRO measures. The vMGII remains reliable for assessing MG disease status even with removal of the physical examination component.

Nerve ultrasound in electrophysiologically verified tarsal tunnel syndrome.

INTRODUCTION: Tarsal tunnel syndrome (TTS) arises from tibial nerve damage under the flexor retinaculum of the fibro-osseus tunnel at the medial malleolus. It is notoriously difficult to diagnose, as many other foot pathologies result in a similar clinical picture. We examined the additional value of nerve ultrasound in patients with tarsal tunnel syndrome confirmed by nerve conduction. METHODS: We performed a retrospective analysis of nerve ultrasound changes in electrophysiologically confirmed TTS spanning our records from 2007 to 2015. RESULTS: Nine feet with TTS were identified, all of which showed abnormal nerve ultrasound findings, which in 6 feet, led to identification of the underlying cause. CONCLUSIONS: This study shows that nerve ultrasound is abnormal in all cases of electrophysiologically verified TTS. The pattern of nerve abnormality is varied. This, and the fact that in the majority of patients causation was identified, suggests nerve ultrasound should form part of standard work-up for TTS. Muscle Nerve 53: 906-912, 2016.

Role of plaque inflammation in symptomatic carotid stenosis.

Objective: Prior studies have shown that plaque inflammation on FDG-PET and the symptomatic carotid atheroma inflammation lumen-stenosis (SCAIL) score were associated with recurrent ischemic events, but the findings have thus far not been widely validated. Therefore, we aimed to validate the findings of prior studies. Methods: A single-center prospective cohort study that recruited patients with (1) recent TIA or ischemic stroke within the past 30 days, (2) ipsilateral carotid artery stenosis of ≥50%, and (3) were not considered for early carotid revascularization. The (1) maximum standardized uptake value (SUVmax) of the symptomatic carotid plaque, (2) the SCAIL score, and (3) stenosis severity of the symptomatic carotid artery were measured for all patients. The outcomes were (1) a 90-day ipsilateral ischemic stroke and (2) a 90-day ipsilateral symptomatic TIA or major adverse cardiovascular event (MACE). Results: Among the 131 patients included in the study, the commonest cardiovascular risk factor was hypertension (95 patients, 72.5%), followed by diabetes mellitus (77 patients, 58.8%) and being a current smoker (64 patients, 48.9%). The median (IQR) duration between the index cerebral ischemic event and recruitment to the study was 1 (0, 2.5) days. The median (IQR) duration between the index cerebral ischemic event and FDG-PET was 5 (4, 7) days. A total of 14 (10.7%) patients had a 90-day stroke, and 41 (31.3%) patients had a 90-day TIA or MACE. On comparison of the predictive performances of the SCAIL score and SUVmax, SUVmax was found to be superior to the SCAIL score for predicting both 90-day ipsilateral ischemic stroke (AUC: SCAIL = 0.79, SUVmax = 0.92; p < 0.001; 95% CI = 0.072, 0.229) and 90-day TIA or MACE (AUC: SCAIL = 0.76, SUVmax = 0.84; p = 0.009; 95% CI = 0.020, 0.143). Conclusion: Plaque inflammation as quantified on FDG-PET may serve as a reliable biomarker for risk stratification among patients with ECAD and recent TIA or ischemic stroke. Future studies should evaluate whether patients with significant plaque inflammation as quantified on FDG-PET benefit from carotid revascularization and/or anti-inflammatory therapy.

Normative Value of the Cross-Sectional Area of the Median Nerve at the Carpal Tunnel Inlet and Distal Forearm in the Singapore Population.

Background: Ultrasonography is often used in the diagnosis of carpal tunnel syndrome (CTS). However, we were unable to find normative data regarding the cross-sectional area (CSA) of the median nerve in the Singapore population as measured by ultrasound. The aims of this study were to establish normative values of the CSA of the median nerve at the carpal tunnel inlet in a healthy population, 5 cm proximal to the carpal tunnel inlet, and to determine if the CSA correlated with side, age, gender or race. Methods: Sixty-nine wrists of 36 healthy subjects with no history of wrist injury or any signs and symptoms of CTS were examined. The CSA of the median nerve at the carpal tunnel inlet and 5 cm proximal to the carpal tunnel inlet was determined using ultrasound by a trained operator. Results: The mean CSA of the median nerve at the carpal tunnel inlet was 6.41 mm2 (SD 2.18 mm2). These were not significantly different from the values for mean CSA obtained 5 cm proximal to the carpal tunnel inlet. We did not find any correlation between the CSA of the median nerve and age, gender or race. Conclusions: The mean CSA of the median nerve at the carpal tunnel inlet in normal subjects in Singapore was found to be lower than other Asian populations. Wide variations of the median nerve CSA at the carpal tunnel inlet exists in the literature, and this is probably due to the heterogeneity of the study methodology and population. Level of Evidence: Level III (Diagnostic).

Antiplatelets or anticoagulants? Secondary prevention in cervical artery dissection: an updated meta-analysis.

BACKGROUND: Extracranial artery dissection involving either internal carotid artery or vertebral artery is a major cause of stroke in adults under 50 years of age. There is no conclusive evidence whether antiplatelets or anticoagulants are better suited in the treatment of extracranial artery dissection. OBJECTIVES: To determine whether antiplatelets or anticoagulants have advantage over the other in the treatment of extracranial artery dissection for secondary prevention of recurrent ischemic events or death. METHODS: Present meta-analysis followed Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 statement. Database search was done in Medline, Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov from inception to May 2021 using pre-defined search strategy. Additional studies were identified from reference lists from included studies, reviews and previous meta-analyses. Outcome measures were ischaemic stroke, ischaemic stroke or transient ischaemic attack (TIA), and death. RESULTS: Two RCTs and 64 observational studies were included in the meta-analysis. While the outcome measures of stroke, stroke or TIA and death were numerically higher with antiplatelet use, there were no statistically significant differences between antiplatelets and anticoagulants. CONCLUSION: We found no significant difference between antiplatelet and anticoagulation treatment after extracranial artery dissection. The choice of treatment should be tailored to individual cases.

Vogt-Koyanagi-Harada Syndrome - A Neurologist's Perspective.

Vogt-Koyanagi-Harada (VKH) syndrome is an immune-mediated granulomatous disease which affects melanin-rich organs like eyes, skin, nervous system, and ears. Neurological and auditory manifestations usually precede the involvement of other sites. Patients may manifest with "complete" or "incomplete" syndrome. We report two patients who presented with acute headache and impaired vision. Fundus examination revealed optic disc hyperemia and exudative retinal detachment which provided a clue for the diagnosis at the bedside. Fundus fluorescein angiogram (FFA) revealed abnormal dye leakage, whereas B scan showed choroid thickening. Cerebrospinal fluid (CSF) pleocytosis contrasted with unremarkable brain magnetic resonance imaging and lack of meningeal signs. Melanophagocytosis was evidenced by melanin-laden macrophages in CSF and skin biopsy. This finding is specific for VKH syndrome and helps to clinch the diagnosis even when the complete syndrome is not present cross-sectionally. VKH syndrome should be suspected in patients with aseptic meningitis if tests for common infectious and immune-mediated diseases are negative.

Neutrophil-to-Lymphocyte Ratio Predicts Development of Immune-Related Adverse Events and Outcomes from Immune Checkpoint Blockade: A Case-Control Study.

The utility of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) utility in predicting immune-related adverse events (irAEs) and survival have not been well studied in the context of treatment with immune checkpoint inhibitors (ICIs). We performed a case-control study of cancer patients who received at least one dose of ICI in a tertiary hospital. We examined NLR and PLR in irAE cases and controls. Logistic and Cox regression models were used to identify independent risk factors for irAEs, progression-free survival (PFS), and overall survival (OS). The study included 91 patients with irAEs and 56 controls. Multiple logistic regression showed that NLR < 3 at baseline was associated with higher occurrence of irAEs. Multivariate Cox regression showed that development of irAEs and reduction in NLR from baseline to week 6 were associated with longer PFS. Higher NLR values at baseline and/or week 6 were independently associated with shorter OS. A reduction in NLR from baseline to week 6 was associated with longer OS. In this study of cancer patients treated with ICIs, NLR has a bidirectional relationship with adverse outcomes. Lower NLR was associated with increased occurrence of irAEs while higher NLR values were associated with worse clinical outcomes.

Limb Hypothermia for Preventing Paclitaxel-Induced Peripheral Neuropathy in Breast Cancer Patients: A Pilot Study.

BACKGROUND: Peripheral neuropathy (PN) due to paclitaxel is a common dose-limiting toxicity with no effective prevention or treatment. We hypothesize that continuous-flow limb hypothermia can reduce paclitaxel-induced PN. PATIENTS AND METHODS: An internally controlled pilot trial was conducted to investigate the neuroprotective effect of continuous-flow limb hypothermia in breast cancer patients receiving weekly paclitaxel. Patients underwent limb hypothermia of one limb for a duration of 3 h with every paclitaxel infusion, with the contralateral limb used as control. PN was primarily assessed using nerve conduction studies (NCSs) before the start of chemotherapy, and after 1, 3, and 6 months. Skin temperature and tolerability to hypothermia were monitored using validated scores. RESULTS: Twenty patients underwent a total of 218 cycles of continuous-flow limb hypothermia at a coolant temperature of 22°C. Continuous-flow limb hypothermia achieved mean skin temperature reduction of 1.5 ± 0.7°C and was well tolerated, with no premature termination of cooling due to intolerance. Grade 3 PN occurred in 2 patients (10%), grade 2 in 2 (10%), and grade 1 in 12 (60%). Significant correlation was observed between amount of skin cooling and motor nerve amplitude preservation at 6 months (p < 0.0005). Sensory velocity and amplitude in the cooled limbs were less preserved than in the control limbs, but the difference did not attain statistical significance. One patient with a history of diabetes mellitus had significant preservation of compound muscle action potential in the cooled limb on NCS analysis. CONCLUSION: This study suggests that continuous limb hypothermia accompanying paclitaxel infusion may reduce paclitaxel-induced PN and have therapeutic potential in select patients and warrants further investigation. The method is safe and well tolerated.

Neurogenic orthostatic hypotension - management update and role of droxidopa.

Orthostatic hypotension (OH) is defined as a significant decrease in blood pressure (BP) during the first 3 minutes of standing or a head up on a tilt table. Symptoms of OH are highly variable, ranging from mild light-headedness to recurrent syncope. OH occurs due to dysfunction of one or more components of various complex mechanisms that interplay closely to maintain BP in a normal range during various physiological and associated disease states. Various biochemical and electrophysiological studies are often undertaken to assess the severity and etiology of OH. In addition to the lifestyle modifications, various medications that stimulate the adrenergic receptors or increase central blood volume are used in patients with OH. Droxidopa is a newer agent that increases the levels of norepinephrine in postganglionic sympathetic neurons. Management strategies for OH are presented, including the mechanism of action of droxidopa and various studies performed to assess its efficacy.

Role of combined B-mode and Doppler sonography in evaluating neurolymphomatosis.

OBJECTIVE: To highlight the potential usefulness of nerve ultrasonography to identify lymphomatous peripheral nerve infiltration in patients with lymphoma. METHODS: We performed electrodiagnostic studies and nerve ultrasonography in 3 patients with lymphoma presenting with focal peripheral neuropathy. RESULTS: In all 3 patients, electrodiagnostic studies proved focal involvement of the peripheral nerves. Ultrasonography showed nerve thickening at sites of electrodiagnostic abnormality. All enlarged nerves showed increased blood flow within the area of nerve thickening. Abnormal sonographic studies prompted focused imaging and histologic studies, which confirmed the diagnosis of neurolymphomatosis. CONCLUSIONS: Nerve ultrasonography should be considered when evaluating focal neuropathic symptoms in patients with lymphoma. Demonstration of neural enlargement and increased blood flow in symptomatic and electrophysiologically abnormal nerves suggests a diagnosis of neurolymphomatosis, probably reflecting infiltration and neovascularization. Further sonographic studies on the detection and quantification of nerve abnormality in neurolymphomatosis will be of additional value. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with lymphoma and focal neuropathies, nerve ultrasound aids in identifying those with lymphomatous peripheral nerve infiltration on biopsy.

An unhappy patient following successful sonothrombolysis in vertebrobasilar thrombosis: dilemma with final diagnosis.

Acute vertebrobasilar thrombosis is often associated with high mortality and prolonged disability. Therapeutic route and the time window for systemic thrombolysis in acute settings remain uncertain. We describe a case of severe acute ischemic stroke due to vertebrobasilar thrombosis who achieved rapid arterial recanalization and remarkable clinical recovery during ultrasound enhanced intravenous thrombolysis, initiated at 4.5 hours after the symptom-onset. We discuss some important issues, related to the final diagnosis, that arise due to the complete clinical recovery, rapid arterial recanalization and absence of any acute infarction on subsequent neuroimaging.

High resolution ultrasonography in the diagnosis of ulnar nerve lesions with particular reference to post-traumatic lesions and sites outside the elbow.

OBJECTIVE: Recent studies suggest that high resolution ultrasonography (HRU) is useful in evaluating ulnar neuropathy (UN) at the elbow. These studies do not include UN outside the elbow and lesions related to previous trauma. We investigate diagnostic utility of HRU in UN at any location of traumatic and non-traumatic etiology. METHODS: Patients with clinically suspected and electrophysiologically defined UN at the elbow and outside the elbow were included. Nerve conduction studies (NCS) were compared with HRU. HRU defined UN in terms of change in cross-sectional area. RESULTS: Our retrospective analysis included 46 UN. In 25 cases both NCS and HRU localised neuropathy to the elbow. In 15 where NCS was abnormal but non-localising, HRU localised the lesion in 14, 7 outside the elbow. In three of these, HRU characterised further pathology (synovial osteochondromatosis (n=2), myositis ossificans (n=1). Cross-sectional area of the ulnar nerve at the sulcus significantly correlated with distal NCS parameters. CONCLUSIONS: HRU is of greater use than NCS in the localisation of UN both at the elbow and outside the elbow and in UN related to previous trauma. SIGNIFICANCE: HRU is useful for the localisation of ulnar neuropathy.