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.

Cerebellar Transcranial Magnetic Stimulation (TMS) Impairs Visual Working Memory.

An increasing body of evidence points to the involvement of the cerebellum in cognition. Specifically, previous studies have shown that the superior and inferior portions of the cerebellum are involved in different verbal working memory (WM) mechanisms as part of two separate cerebro-cerebellar loops for articulatory rehearsal and phonological storage mechanisms. In comparison, our understanding of the involvement of the cerebellum in visual WM remains limited. We have previously shown that performance in verbal WM is disrupted by single-pulse transcranial magnetic stimulation (TMS) of the right superior cerebellum. The present study aimed to expand on this notion by exploring whether the inferior cerebellum is similarly involved in visual WM. Here, we used fMRI-guided, double-pulse TMS to probe the necessity of left superior and left inferior cerebellum in visual WM. We first conducted an fMRI localizer using the Sternberg visual WM task, which yielded targets in left superior and inferior cerebellum. Subsequently, TMS stimulation of these regions at the end of the encoding phase resulted in decreased accuracy in the visual WM task. Differences in the visual WM deficits caused by stimulation of superior and inferior left cerebellum raise the possibility that these regions are involved in different stages of visual WM.

Headache Related to PPE Use during the COVID-19 Pandemic.

PURPOSE OF REVIEW: Personal protection equipment (PPE)-associated headache is an unusual secondary headache disorder that predominantly occurs in healthcare workers as a consequence of the donning of protective respirators, face masks and/or eyewear. The appreciation of this entity is important given the significant ramifications upon the occupational health of healthcare workers and could additionally have an impact on persons living with pre-existing headache disorder(s). RECENT FINDINGS: There has been a renewed interest and recognition of PPE-associated headaches amongst healthcare professionals, largely brought about by the ongoing COVID-19 pandemic which has besieged healthcare systems worldwide. De novo PPE-associated headaches may present with migrainous or tension-type features and can be viewed as a subtype of external compression headache. The prognosis of the disorder is generally favourable, given that most headaches are short-lived without long-term sequalae. Several aetiologies have been postulated to account for the development of these headaches. Notably, these headaches can affect the occupational health and work performance of healthcare workers. In this review, we discuss the epidemiology, clinical characteristics, probable etiopathogenesis, management and prognosis of PPE-associated headaches in the context of the COVID-19 pandemic. Future directions for research and PPE development are proposed.

Electrodiagnosis of reversible conduction failure in Guillain-Barré syndrome.

INTRODUCTION: In this study we propose electrodiagnostic criteria for early reversible conduction failure (ERCF) in axonal Guillain-Barré syndrome (GBS) and apply them to a cohort of GBS patients. METHODS: Serial nerve conduction studies (NCS) were retrospectively analyzed in 82 GBS patients from 3 centers. The criteria for the presence of ERCF in a nerve were: (i) a 50% increase in amplitude of distal compound muscle action potentials or sensory nerve action potentials; or (ii) resolution of proximal motor conduction block with an accompanying decrease in distal latencies or compound muscle action potential duration or increase in conduction velocities. RESULTS: Of 82 patients from 3 centers, 37 (45%) had ERCF, 21 (26%) had a contrasting evolution pattern, and 8 (10%) had both. Sixteen patients did not show an amplitude increase of at least 50%. CONCLUSION: Our proposed criteria identified a group of patients with a characteristic evolution of NCS abnormality that is consistent with ERCF. Muscle Nerve 56: 919-924, 2017.

Medical Undergraduate Survey on Headache Education in Singapore: Knowledge, Perceptions, and Assessment of Unmet Needs.

BACKGROUND: There have been no prior studies assessing the status of undergraduate headache training and education in Singapore. Unmet needs of undergraduate medical students in terms of knowledge-practice gaps pertaining to diagnosis and management of headache disorders are unknown. The possible underemphasis of this aspect of the curriculum as compared to other chronic conditions such as diabetes mellitus has also not been ascertained. OBJECTIVE: The aim of this article is to assess the knowledge base and perceptions, thereby identifying the unmet needs of headache disorder education in undergraduate medical students. Students reported their perceived time that was devoted to the subject matter and this was recorded and reported. In order to provide a comparative indication on the level of prioritization, the total duration within the syllabus dedicated to headache education vs other chronic diseases (using diabetes mellitus as a surrogate) was sought. METHODS: A comprehensive survey consisting of questions assessing the headache curriculum, knowledge, and perceptions was developed. The questionnaire was distributed to final year medical students attending a full-day Neurology review course in their last semester. Attendees were given the duration of the course to complete the questionnaire, and forms were collected at the end of the day. RESULTS: About 127 final year medical students completed our survey. More than half (55.1%) did not receive formal teaching on how to take a complete headache history. The majority (90.6%) have not attended a headache sub-specialty clinic. The mean total number of hours exposed to headache disorders was 5.69h (SD ± 5.19). The vast majority (96.1%) were unfamiliar with locally published clinical practice guidelines, and a significant proportion (74.0%) were unfamiliar with the third edition (beta) of the International Classification of Headache Disorders. Nearly half (47.2%) were unfamiliar with 'medication overuse headache' as a disease entity. Only one (0.8%) respondent was able to correctly classify all listed primary and secondary headache disorders correctly. Only 37.0% were able to identify all 4 indications (headaches that were new, worsening, and unresponsive to treatment or associated with neurological symptoms) that warranted neuroimaging in a patient with a pre-existing diagnosis of migraine. The antidepressants were the most frequently reported incorrect option for the abortive treatment of migraine (16.5%). Nearly one-fifth (18.9%) were unable to name a single abortive treatment correctly, while a significant proportion (39.4%) could not identify a single correct prophylactic migraine treatment. A large proportion (62.2%) opined that their exposure to 'headache diagnosis and management' was inadequate, with a minority (3.1%) being 'very comfortable' in the diagnosing migraine. A significant proportion felt uncomfortable in treating special population groups diagnosed with migraine - pregnant (79.5%), elderly (48.0%), those with cardiac conditions (51.2%). CONCLUSIONS: The current medical undergraduate curriculum on headache disorders in Singapore may harbor significant unmet needs. A review of the syllabus to increase headache education may be one method to address this gap. Further studies in this area are required.

Immunotherapy for diabetic amyotrophy.

BACKGROUND: People with diabetes mellitus (DM) sometimes present with acute or subacute, progressive, asymmetrical pain and weakness of the proximal lower limb muscles. The various names for the condition include diabetic amyotrophy, diabetic lumbosacral radiculoplexus neuropathies, diabetic femoral neuropathy or Bruns-Garland syndrome. Some studies suggest that diabetic amyotrophy may be an immune-mediated inflammatory microvasculitis causing ischaemic damage of the nerves. Immunotherapies would therefore be expected to be beneficial. This is the second update of a review first published in 2009. OBJECTIVES: To review the evidence from randomised trials for the efficacy of any form of immunotherapy in the treatment of diabetic amyotrophy. SEARCH METHODS: On 5 September 2016 we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE and Embase. We also contacted authors of relevant publications and other experts to obtain additional references, unpublished trials, and ongoing trials. SELECTION CRITERIA: We intended to include all randomised and quasi-randomised trials of any immunotherapy in participants with the condition fulfilling all the following: diabetes mellitus as defined by internationally recognised criteria; acute or subacute onset of pain and lower motor neuron weakness involving predominantly the proximal muscles of the lower limbs; weakness that is not confined to one nerve or nerve root distribution; and exclusion of other causes of lumbosacral radiculopathies and plexopathy. DATA COLLECTION AND ANALYSIS: Two authors independently examined all references retrieved by the search to select those meeting the inclusion criteria. MAIN RESULTS: We found only one completed placebo-controlled trial (N = 75) using intravenous methylprednisolone in diabetic amyotrophy (Dyck 2006). The results have not been fully published and were not available for analysis. The risk of bias was unclear because there was too little information to make a judgement, but we considered the trial at high risk of selective reporting. The published abstract did not report adverse events. We found no additional trials when the searches were updated in September 2016. AUTHORS' CONCLUSIONS: There is presently no evidence from randomised trials to support a positive or negative effect of any immunotherapy in the treatment in diabetic amyotrophy.

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.

Skin receptors and intradermal nerves do not generate the sensory double peak.

INTRODUCTION: The cause of the double peak observed at submaximal stimulation of sensory nerves is unknown. The first peak is generated under the cathode and the second under the anode. The double peak is thought to arise from intradermal nerves or skin receptors, and in this study we tested this assumption. METHODS: We studied the effect of different stimulus durations on anodal peak latency in volunteers. Biphasic anodal stimulation was used to investigate the latent additive effect of the trailing negative phase on the partial depolarization induced by the initial positive phase. We further tested the maximal amplitude of anode-generated potentials to estimate the number of neural structures involved in their generation. RESULTS: Increased stimulus duration caused anode-generated potential delay. Biphasic stimulation increased anode-generated amplitude 4-fold compared with monophasic stimulation. The anode-generated potential produced up to 85% of the supramaximal cathode-generated amplitude. CONCLUSIONS: The results suggest that the double peak arises from anodal break excitation and not from intradermal nerves or receptors.

Cytoalbuminologic dissociation in Asian patients with Guillain-Barré and Miller Fisher syndromes.

Cerebrospinal fluid (CSF) protein level, cell count, and its relationship to the timing of lumbar puncture were collected from patients with Guillain-Barré syndrome (GBS) and Miller Fisher syndrome (MFS) from various Asian centers. A total of 507 patients with GBS were studied. Overall, 56% had elevated CSF protein level. This was significantly lower than that reported in a recent Dutch study (56% vs 64%). Cytoalbuminologic dissociation was also lower in the Asian cohort (55% vs 64%), with a significantly higher proportion of patients with mild pleocytosis (26% vs 15%). A lower proportion of the 164 patients with MFS had elevated CSF protein level (38% vs 56%), mild pleocytosis (11% vs 26%), and cytoalbuminologic dissociation (41% vs 55%) compared to patients with GBS. In both conditions, cytoalbuminologic dissociation was linked to the timing of lumbar puncture. Cytoalbuminologic dissociation was only observed in half of the Asian patients with GBS and MFS, and it is strongly dependent on the timing of the lumbar puncture.

Polymyxin-induced neuromuscular weakness: a case report.

Polymyxin-induced neuromuscular blockade is a rare but potentially fatal condition, with majority of cases that were reported between 1962 and 1973. We describe a patient who developed hypercapnic respiratory failure after initiation of polymyxin for multi-drug resistant Escherichia Coli bacteremia, due to polymyxin-induced neuromuscular dysfunction. After cessation of polymyxin, he regained full strength, had complete resolution of ptosis, and was successfully extubated. In light of the renewed use of polymyxin in this era of antimicrobial-resistance, this case aims to raise awareness about this rare but life-threatening condition, which is easily reversible with early recognition and prompt discontinuation of the drug.

Atypical Bickerstaff brainstem encephalitis: ataxic hypersomnolence without ophthalmoplegia.

OBJECTIVE: Clinical and immunological evaluation of 'incomplete' Bickerstaff brainstem encephalitis (BBE). METHODS: We studied two patients with postinfectious brainstem syndromes who presented at National University Hospital Singapore. Laboratory work-up included measurement of antiganglioside antibodies. RESULTS: Both patients displayed hypersomnolence and cerebellar-like ataxia in the absence of external ophthalmoplegia and carried high serum titres of IgG anti-GQ1b antibodies, strongly indicative of BBE. CONCLUSIONS: Ophthalmoplegia can be absent or incomplete in BBE, and the absence of this clinical feature should not exclude BBE from the clinicians' differential. Such cases of incomplete BBE could be defined as 'ataxic hypersomnolence without ophthalmoplegia'.

Immunotherapy for idiopathic lumbosacral plexopathy.

BACKGROUND: Idiopathic lumbosacral plexopathy (ILSP), also called lumbosacral plexitis or non-diabetic lumbosacral (radiculo)plexus neuropathy is a rare clinical entity. The core features are (sub)acute, severe, asymmetrical leg pain, followed by asymmetrical multifocal weakness and atrophy in the subsequent weeks or months. Sensory symptoms include paresthesias, hypesthesia, allodynia, and autonomic dysfunction. ILSP generally runs a monophasic and self limiting course. Recovery starts slowly over months to several years and is nearly always incomplete. Some studies suggest that the condition has an immune-mediated etiology. Biopsies of distal cutaneous nerve segments have shown features suggestive of an inflammatory microvasculitis causing ischemic damage of the nerves. The clinical and pathological findings are similar to those found in diabetic lumbosacral plexus neuropathy and suggest that inflammation may form part of the final common pathway in both conditions. OBJECTIVES: To assess the effects of any form of immunotherapy in the treatment of ILSP. SEARCH METHODS: On 15 October 2013, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, and Index to Theses. We scanned conference abstracts, and searched trials databases for ongoing trials. We checked all references in the identified trials and contacted authors to identify any additional published or unpublished data. SELECTION CRITERIA: We intended to include all randomized controlled trials (RCTs) or quasi-RCTs of any immunotherapy given within six weeks of disease onset, in participants with conditions fulfilling all the following: acute or subacute onset of pain and lower motor neuron weakness involving predominantly the proximal muscles of the lower limbs, weakness that is not confined to one nerve or nerve root distribution, electrophysiological tests showing predominantly axonal neuropathies, exclusion of other causes of lumbosacral radiculopathy and plexopathy as well as patients with plasma sugar in the diabetic range (fasting greater than 7.0 mmol/L, random greater than 11.1 mmol/L). DATA COLLECTION AND ANALYSIS: Two authors independently examined all references retrieved by the search to select those meeting the inclusion criteria, according to standard Cochrane methodology. MAIN RESULTS: We identified no RCTs of any immunotherapy for ILSP. AUTHORS' CONCLUSIONS: There is at present no evidence from randomized trials to support any recommendation on the use of any immunotherapy treatment in ILSP.

Approach to headache disorders and the management of migraine: consensus guidelines from the Headache Society of Singapore, first edition (2023).

Headache disorders, particularly migraine, are one of the most common and disabling neurological disorders. There is a need for high-quality, accessible care for patients with headache disorders across all levels of the healthcare system in Singapore. The role of the Headache Society of Singapore is to increase awareness and advance the understanding of these disorders and to advocate for the needs of affected patients. In this first edition of local consensus guidelines, we focus on treatment approaches for headaches and provide consensus recommendations for the management of migraine in adults. The recommendations in these guidelines can be used as a practical tool in routine clinical practice by primary care physicians, neurologists and other healthcare professionals who have a common interest in headache disorders.

Immunotherapy for diabetic amyotrophy.

BACKGROUND: People with diabetes mellitus (DM) sometimes present with acute or subacute, progressive, asymmetrical pain and weakness of the proximal lower limb muscles. The various names for the condition include diabetic amyotrophy or diabetic lumbosacral radiculoplexus neuropathies. Some studies suggest that it may be due to immune-mediated inflammatory microvasculitis causing ischaemic damage of the nerves. Immunotherapies would therefore be expected to be beneficial. This is an update of a review first published in 2009. OBJECTIVES: We aimed to review the evidence from randomised trials for the efficacy of any form of immunotherapy in the treatment of diabetic amyotrophy. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (7 February 2012), CENTRAL (2012 Issue 1), MEDLINE (January 1966 to January 2012) and EMBASE (January 1980 to January 2012), and contacted authors of relevant publications and other experts to obtain additional references, unpublished trials, and ongoing trials. SELECTION CRITERIA: We intended to include all randomised and quasi-randomised trials of any immunotherapy in participants with the condition fulfilling all the following: diabetes mellitus as defined by internationally recognised criteria, acute or subacute onset of pain and lower motor neuron weakness involving predominantly the proximal muscles of the lower limbs, weakness that is not confined to one nerve or nerve root distribution and exclusion of other causes of lumbosacral radiculopathies and plexopathy. DATA COLLECTION AND ANALYSIS: Two authors independently examined all references retrieved by the search to select those meeting the inclusion criteria. MAIN RESULTS: We found only one completed controlled trial using intravenous methylprednisolone in diabetic amyotrophy (Dyck 2006). The results have not been fully published and were not available for analyses. We found no additional trials when the searches were updated in 2012. AUTHORS' CONCLUSIONS: There is presently no evidence from randomised trials to support any recommendation on the use of any immunotherapy treatment in diabetic amyotrophy.

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.

Immunotherapy for diabetic amyotrophy.

BACKGROUND: People with diabetes mellitus (DM) sometimes present with acute or subacute, progressive, asymmetrical pain and weakness of the proximal lower limb muscles. The various names for the condition include diabetic amyotrophy, or diabetic lumbosacral radiculoplexus neuropathies. Some studies suggest that it may be due to immune-mediated inflammatory microvasculitis causing ischaemic damage of the nerves. Immunotherapies would therefore be expected to be beneficial. OBJECTIVES: We aimed to review the evidence from randomised trials for the efficacy of any form of immunotherapy in the treatment of diabetic amyotrophy. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register (searched April 2 2009), MEDLINE (searched January 1966 to April 2 2009), EMBASE (searched January 1980 to April 2 2009) and contacted authors of relevant publications and other experts to obtain additional references, unpublished trials, and ongoing trials. SELECTION CRITERIA: We intended to include all randomised and quasi-randomised trials of any immunotherapy in participants with the condition fulfilling all the following: diabetes mellitus as defined by internationally recognised criteria, acute or subacute onset of pain and lower motor neuron weakness involving predominantly the proximal muscles of the lower limbs, weakness that is not confined to one nerve or nerve root distribution and exclusion of other causes of lumbosacral radiculopathies and plexopathy. DATA COLLECTION AND ANALYSIS: Two authors independently examined all references retrieved by the search to select those meeting the inclusion criteria. MAIN RESULTS: We found only one completed controlled trial using intravenous methylprednisolone in diabetic amyotrophy (Dyck 2006). The results have not been fully published and were not available for analyses. AUTHORS' CONCLUSIONS: There is presently no evidence from randomised trials to support any recommendation on the use of any immunotherapy treatment in diabetic amyotrophy.

Electroencephalographic changes and seizures in familial hemiplegic migraine patients with the CACNA1A gene S218L mutation.

The S218L CACNA1A mutation has been previously described in two families with familial hemiplegic migraine. We present three siblings with the mutation with the novel association of childhood seizures, and highlight the dynamic changes seen on electroencephalography during hemiplegic migraine attacks. Depressed activity contralateral to the hemiparesis was seen on electroencephalography during acute hemiplegic migraine attacks, which may be due to changes to calcium channels caused by the S218L mutation. Both parents were asymptomatic and did not carry the S218L mutation in their blood. This suggests the presence of mosaicism in the transmitting parent.

POEMS syndrome--a case for more aggressive treatment.

INTRODUCTION: Patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal or M-protein and skin changes) syndrome exhibit a wide range of clinical manifestations and are often seen by a variety of specialists prior to diagnosis. CLINICAL PICTURE: We describe a case of POEMS syndrome that first presented with significant neuropathy but progressed to develop further manifestations of the condition, including marked gastrointestinal symptoms. TREATMENT: The patient was commenced on localised radiotherapy and chemotherapy in addition to immunomodulatory therapy for the neuropathy. CONCLUSION: We highlight several learning points that may benefit physicians from varied specialties. This case is also unique for its marked gastrointestinal manifestation. To our knowledge, this is the second reported case in the literature with this feature.