Electrodiagnostic subtyping in Guillain-Barré syndrome: Use of criteria in practice based on a survey study in IGOS.

Electrodiagnostic (EDx) studies are helpful in diagnosing and subtyping of Guillain-Barré syndrome (GBS). Published criteria for differentiation into GBS subtypes focus on cutoff values, but other items receive less attention, although they may influence EDx subtyping: (a) extensiveness of EDx testing, (b) nerve-specific considerations, (c) distal compound muscle action potential (CMAP)-amplitude requirements, (d) criteria for conduction block and temporal dispersion. The aims of this study were to investigate how these aspects were approached by neuromuscular EDx experts in practice and how this was done in previously published EDx criteria for GBS. A completed questionnaire was returned by 24 (of 49) members of the electrophysiology expertise group from the International GBS Outcome Study. Six published EDx criteria for GBS subtyping were compared regarding these aspects. The indicated minimal number of motor nerves to study varied among respondents and tended to be more extensive in equivocal than normal studies. Respondents varied considerably regarding usage of compression sites for subtyping (median/wrist, ulnar/elbow, peroneal/fibular head): 29% used all variables from all sites, 13% excluded all sites, and 58% used only some sites and/or variables. Thirty-eight percent of respondents required a minimal distal CMAP amplitude to classify distal motor latency as demyelinating, and 58% did for motor conduction velocity. For proximal/distal CMAP-amplitude ratio and F-wave latency, a requisite minimal CMAP amplitude was more often required (79%). Also, the various published criteria sets showed differences on all items. Practical use of EDx criteria for subtyping GBS vary extensively across respondents, potentially lowering the reproducibility of GBS subtyping.

Nitrous oxide-induced neurological disorders: an increasing public health concern.

BACKGROUND: Neurological presentations resulting from nitrous oxide (N2 O) abuse are increasing in Australia and worldwide. Despite known neuropsychiatric sequelae, N2 O canisters remain readily available and its use unregulated. AIMS: To examine the demographics, clinical and electrophysiological findings of patients presenting with neurological complications of N2 O abuse, and thus inform clinicians and public health decision-makers of the significant public health concerns of this increasing practice. METHODS: Consecutive patients presenting to a tertiary referral metropolitan hospital were included in this series. Patients were identified by a search of discharge summaries of patients admitted with acute or subacute neuropathy or myelopathy and a history of N2 O abuse, and from the electrophysiology database. RESULTS: Thirteen patients were identified, most presenting with subacute paraesthesia, sensory ataxia and lower limb weakness. Eleven had low serum vitamin B12 . Spinal magnetic resonance imaging was consistent with subacute combined degeneration in eight. Nerve conduction studies revealed a motor or sensorimotor axonal neuropathy (three with motor predominance). There was a bimodal demographic distribution consisting of socially isolated, international university students and local residents with a history of mental illness and polydrug abuse. CONCLUSIONS: Recreational N2 O use is an emerging health problem in Australia. International university students and patients with pre-existing mental illness or polydrug use appear to be at increased risk. A severe motor neuropathy may emerge following vitamin B12 replacement. Public health measures are required to limit the availability of N2 O and to educate adolescents and young adults about the potential for significant harm.

Oromandibular parafunction in chronic graft-versus-host disease: novel association and treatment approach.

Chronic graft-versus-host disease (cGVHD) complicating allogeneic haemopoietic stem cell transplantation rarely involves the nervous system; oromandibular parafunction has not been previously reported. We describe five patients with cGVHD, presenting with bruxism, limitation of mouth opening, jaw locking, pain and masseter hypertrophy. Pathophysiological mechanisms are discussed. Targeted botulinum toxin injections were an effective treatment with minimal side-effects.

Distal acquired demyelinating symmetric (DADS) neuropathy associated with colorectal adenocarcinoma.

INTRODUCTION: Paraneoplastic neuropathies are well recognized as a remote effect of cancer, and subacute sensory neuronopathy is a recognized syndrome. Demyelinating neuropathies are relatively rare. Distal acquired demyelinating symmetric (DADS) neuropathy associated with lymphoproliferative disease has been reported previously. We present the association of DADS neuropathy with solid tumor. METHODS: We report the clinical presentation, electrophysiology, and progress of DADS neuropathy in a patient later found to have colorectal adenocarcinoma. RESULTS: A patient presented with subacute onset of symmetric distal sensory and motor symptoms. Electrophysiology was typical of DADS neuropathy. Anti-MAG antibodies were initially positive at low titer, and indirect immunofluorescence analysis for anti-nuclear antibodies revealed autoantibodies to centromere nuclear protein-F (CENP-F). There was clinical and electrophysiologic resolution after tumor resection. CONCLUSIONS: This case describes the presentation of DADS neuropathy as a paraneoplastic syndrome in a patient later found to have colorectal adenocarcinoma.

Guillain-Barré syndrome following pandemic (H1N1) 2009 influenza A immunisation in Victoria: a self-controlled case series.

OBJECTIVES: To determine the relative incidence (RI) of Guillain-Barré syndrome (GBS) in a single Australian state following pandemic (H1N1) 2009 influenza A immunisation (monovalent vaccine or seasonal trivalent influenza vaccine [TIV]) in 2009-2010. DESIGN, SETTING AND PARTICIPANTS: Active GBS surveillance (cases assessed by two neurologists according to the Brighton criteria) from 30 September 2009 to 30 September 2010, conducted at 10 hospitals in Victoria, Australia. MAIN OUTCOME MEASURES: The RI of GBS in the risk window of 0-42 days after vaccination. RESULTS: Sixty-six potential GBS cases were identified, with complete data on 50 confirmed cases. The Victorian annual incidence of GBS was 1.7 per 100 000 population. Three cases had received monovalent vaccine and one case had received seasonal TIV within 42 days of symptom onset. The RI of GBS following monovalent vaccination was 3.4 (95% CI, 0.8-15.0). For TIV, there was one case in the risk period (RI, 0.69; 95% CI, 0.08-5.64). CONCLUSIONS: This is the first published study reviewing GBS after a trivalent and/or monovalent influenza vaccine containing the pandemic (H1N1) 2009 strain, with only a small proportion of GBS cases occurring after influenza immunisation. H1N1-containing vaccines were not statistically associated with GBS, but this study could not exclude smaller increases in the RI. Active surveillance of adverse events following immunisation is required to maintain public and health care professional confidence in mass vaccine implementation programs.

Efficacy of botulinum toxin type a in the targeted treatment of sleep bruxism: a double-blind, randomised, placebo-controlled, cross-over study.

Background: Intramuscular injections of botulinum toxin A (BTX-A) have been used in the treatment of sleep bruxism (SB) however controlled trials are limited and the optimal injection strategy and dose is not known. Methods: This double-blind, randomised, placebo-controlled, cross-over study evaluated the efficacy and safety of BTX-A in participants with SB. Average bruxism events per hour of sleep (Bruxism Index, BI) was calculated using surface electromyography. Participants with BI >5 were included and randomised by order of injection (active or placebo with the opposite 20 weeks later) and into one of three differing treatment groups: bilateral masseter (60 units(U)), bilateral masseter and temporalis (90U) and bilateral masseter, temporalis and medial pterygoid muscles (120U). Change in BI and subjective measures of headache, pain, and bruxism at 4 and 12 weeks was calculated following intervention, and differences between treatment groups analysed. Results: 41 participants were recruited, 35 randomised and data from 22 participants (14 female) were analysed. BI was significantly lower at 4 weeks after active treatment when compared with placebo (mean=-1.66, p=0.003), not sustained at 12 weeks. The difference was greater with higher doses injected and among those with greater baseline BI. There was no difference in subjective measures at any time point. Five participants injected had mild, transient side effects. Discussion: Targeted BTX-A injection is a safe and effective treatment for SB. A greater benefit may be achieved by administering BTX-A into more muscles and at higher total doses and among those with higher baseline BI. Trial registration number: ACTRN12618001430224.

Guillain-Barré syndrome temporally associated with COVID-19 vaccines in Victoria, Australia.

Guillain-Barré syndrome (GBS) is an adverse event of special interest (AESI) for surveillance systems monitoring adverse events following immunisation (AEFI) with COVID-19 vaccines. Emerging data support a temporal association between GBS and adenovirus-vector COVID-19 vaccines. We present a case series of GBS reports submitted between February and November 2021 to our enhanced spontaneous surveillance system (SAEFVIC) in Victoria, Australia, following vaccination with either the adenovirus-vector vaccine Vaxzevria ChadOx1-S (AstraZeneca) or an mRNA vaccine (Comirnaty BNT162b2 [Pfizer-BioNTech] or Spikevax mRNA-1273 [Moderna]). For each report, Brighton Collaboration case definitions were used to describe diagnostic certainty. Severity was graded using the GBS Disability Score. The observed incidence of GBS following immunisation against COVID-19 was compared to expected background ICD10-AM G61.0 coded hospitalisations. There were 41 total cases of GBS reported to SAEFVIC following Vaxzevria (n = 38), Comirnaty (n = 3), or Spikevax (n = 0) vaccines. The observed GBS incidence rate exceeded the expected background rate for Vaxzevria only, with 1.85 reports per 100,000 doses following dose 1, higher than the expected rate of 0.39 hospital admissions per 100,000 adults within 42 days of vaccination. Of 38 GBS reports following Vaxzevria, the median age at vaccination was 66 years and median onset of symptoms was 14 days following immunisation. There was one death. Four cases initially categorised as GBS were later reclassified as acute-onset chronic inflammatory demyelinating polyneuropathy. Fatigue was the predominant persisting symptom reported at follow up. Additional global studies are required to characterise risk factors, clinical variability, and to provide precision and generalizability regarding AEFI risks such as GBS associated with different vaccine platforms, which will help inform communication of the potential benefits and risks of COVID19 vaccination.

Electrodiagnosis of Guillain-Barre syndrome in the International GBS Outcome Study: Differences in methods and reference values.

OBJECTIVE: To describe the heterogeneity of electrodiagnostic (EDx) studies in Guillain-Barré syndrome (GBS) patients collected as part of the International GBS Outcome Study (IGOS). METHODS: Prospectively collected clinical and EDx data were available in 957 IGOS patients from 115 centers. Only the first EDx study was included in the current analysis. RESULTS: Median timing of the EDx study was 7 days (interquartile range 4-11) from symptom onset. Methodology varied between centers, countries and regions. Reference values from the responding 103 centers were derived locally in 49%, from publications in 37% and from a combination of these in the remaining 15%. Amplitude measurement in the EDx studies (baseline-to-peak or peak-to-peak) differed from the way this was done in the reference values, in 22% of motor and 39% of sensory conduction. There was marked variability in both motor and sensory reference values, although only a few outliers accounted for this. CONCLUSIONS: Our study showed extensive variation in the clinical practice of EDx in GBS patients among IGOS centers across the regions. SIGNIFICANCE: Besides EDx variation in GBS patients participating in IGOS, this diversity is likely to be present in other neuromuscular disorders and centers. This underlines the need for standardization of EDx in future multinational GBS studies.

Multifocal Motor Neuropathy Presenting as Pseudodystonia.

Multifocal motor neuropathy (MMN) is an immune-mediated neuropathy. Wasting and weakness typically dominate the clinical presentation. We describe four cases presenting with prominent cramping resembling a primary movement disorder. All cases had features of focal motor conduction block on neurophysiological studies. The involuntary movements resolved in all four patients following treatment with intravenous immunoglobulin. The presented cases highlight an unusual presentation of MMN and emphasize that peripheral nerve pathology can present with movement disorders mimicking central nervous system disease. Furthermore, the movement disorder appears particularly sensitive to standard therapy.

Diagnostic and cost utility of whole exome sequencing in peripheral neuropathy.

OBJECTIVE: To explore the diagnostic utility and cost effectiveness of whole exome sequencing (WES) in a cohort of individuals with peripheral neuropathy. METHODS: Singleton WES was performed in individuals recruited though one pediatric and one adult tertiary center between February 2014 and December 2015. Initial analysis was restricted to a virtual panel of 55 genes associated with peripheral neuropathies. Patients with uninformative results underwent expanded analysis of the WES data. Data on the cost of prior investigations and assessments performed for diagnostic purposes in each patient was collected. RESULTS: Fifty patients with a peripheral neuropathy were recruited (median age 18 years; range 2-68 years). The median time from initial presentation to study enrollment was 6 years 9 months (range 2 months-62 years), and the average cost of prior investigations and assessments for diagnostic purposes AU$4013 per patient. Eleven individuals received a diagnosis from the virtual panel. Eight individuals received a diagnosis following expanded analysis of the WES data, increasing the overall diagnostic yield to 38%. Two additional individuals were diagnosed with pathogenic copy number variants through SNP microarray. CONCLUSIONS: This study provides evidence that WES has a high diagnostic utility and is cost effective in patients with a peripheral neuropathy. Expanded analysis of WES data significantly improves the diagnostic yield in patients in whom a diagnosis is not found on the initial targeted analysis. This is primarily due to diagnosis of conditions caused by newly discovered genes and the resolution of complex and atypical phenotypes.

A randomized, double-blinded, placebo-controlled phase II trial of recombinant human leukemia inhibitory factor (rhuLIF, emfilermin, AM424) to prevent chemotherapy-induced peripheral neuropathy.

PURPOSE: To determine whether recombinant human leukemia inhibitory factor (rhuLIF, AM424, emfilermin) can prevent or ameliorate the development of chemotherapy-induced peripheral neuropathy (CIPN) after treatment with carboplatin (AUC 6) and paclitaxel (175 mg/m(2) over 3 hours). EXPERIMENTAL DESIGN: Randomized double-blind placebo-controlled phase II clinical trial. Eligible patients had solid tumors for which treatment with carboplatin/paclitaxel was appropriate. The primary end point was a standardized composite peripheral nerve electrophysiology (CPNE) score, based on nerve velocities and amplitudes, measured at baseline and after four cycles of chemotherapy. Secondary efficacy end points included CPNE score at last cycle and at exit evaluation, vibration perception threshold, H-reflex latency, symptom scores, and quantitative assessment of neurologic signs. Study drug was given s.c. daily for 7 days starting the day before chemotherapy. Patients were randomized to receive low-dose rhuLIF (2 microg/kg), high-dose rhuLIF (4 microg/kg), or placebo. RESULTS: Patients (n = 117) were randomized across seven neurology test centers. Thirty-six patients received low dose rhuLIF (2 microg/kg), 39 received high dose rhuLIF (4 microg/kg) and 42 received placebo. rhuLIF was well tolerated with 95% compliance and no adverse effects on quality of life. No differences between groups in CPNE or any of the individual neurologic testing variables were observed between baseline and cycle 4 or by the secondary efficacy variables. CONCLUSIONS: rhuLIF is not effective in preventing CIPN caused by carboplatin and paclitaxel. CPNE is a reliable and valid tool that was sensitive to the onset and progression of CIPN.

Stimulation of the Neurovascular Bundle Results in Rhabdosphincter Contraction in a Proportion of Men Undergoing Radical Prostatectomy.

OBJECTIVE: To use nerve conduction studies to clarify the functional innervation of the male urethral rhabdosphincter (RS). In particular, to test the hypothesis that in some men, fibers of the neurovascular bundle supply the RS. These fibers may be at risk during radical prostatectomy. MATERIALS AND METHODS: Men undergoing robot-assisted radical prostatectomy for clinically localized prostate cancer were included. Men with a history of pelvic surgery and/or radiation and/or trauma, obesity, or neurological diseases were excluded. Nerve conduction studies were performed before and after prostate removal. The St. Mark's pudendal electrode was used for pudendal (control) stimulation. The ProPep Nerve-Monitoring System (ProPep Surgical, Austin, TX) was used to stimulate the neurovascular bundle at the level of the prostate base, mid, and apex. ProPep needle electrodes inserted into the RS were used to measure evoked compound motor action potential response. Results were only included if a valid pudendal control was elicited. RESULTS: Seventeen men in total underwent investigation. Valid measurements were obtained after initial quality control in seven. In two cases, evidence of sphincteric activation was observed, providing evidence to support neurovascular bundle innervation of the RS. In the other five patients, no intrapelvic nerve supply was demonstrated. CONCLUSION: Somatic nerve supply to the RS is variable. Direct intrapelvic supply to the RS may exist in some men. This may be one explanation as to why some patients unexpectedly develop severe urinary incontinence postoperatively despite technically satisfactory surgery. Further research is required to validate our findings.

Immunomodulation of inflammatory leukocyte markers during intravenous immunoglobulin treatment associated with clinical efficacy in chronic inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVE: The objective of the study was to profile leukocyte markers modulated during intravenous immunoglobulin (IVIg) treatment, and to identify markers and immune pathways associated with clinical efficacy of IVIg for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with potential for monitoring treatment efficacy. METHODS: Response to IVIg treatment in newly diagnosed IVIg-naïve and established IVIg-experienced patients was assessed by changes in expression of inflammatory leukocyte markers by flow cytometry. The adjusted INCAT disability and Medical Research Council sum scores defined clinical response. RESULTS: Intravenous immunoglobulin modulated immunopathogenic pathways associated with inflammatory disease in CIDP. Leukocyte markers of clinical efficacy included reduced CD185+ follicular helper T cells, increased regulatory markers (CD23 and CD72) on B cells, and reduction in the circulating inflammatory CD16+ myeloid dendritic cell (mDC) population and concomitant increase in CD62L and CD195 defining a less inflammatory lymphoid homing mDC phenotype. A decline in inflammatory CD16+ dendritic cells was associated with clinical improvement or stability, and correlated with magnitude of improvement in neurological assessment scores, but did not predict relapse. IVIg also induced a nonspecific improvement in regulatory and reduced inflammatory markers not associated with clinical response. CONCLUSIONS: Clinically effective IVIg modulated inflammatory and regulatory pathways associated with ongoing control or resolution of CIDP disease. Some of these markers have potential for monitoring outcome.

Minimally invasive endovascular stent-electrode array for high-fidelity, chronic recordings of cortical neural activity.

High-fidelity intracranial electrode arrays for recording and stimulating brain activity have facilitated major advances in the treatment of neurological conditions over the past decade. Traditional arrays require direct implantation into the brain via open craniotomy, which can lead to inflammatory tissue responses, necessitating development of minimally invasive approaches that avoid brain trauma. Here we demonstrate the feasibility of chronically recording brain activity from within a vein using a passive stent-electrode recording array (stentrode). We achieved implantation into a superficial cortical vein overlying the motor cortex via catheter angiography and demonstrate neural recordings in freely moving sheep for up to 190 d. Spectral content and bandwidth of vascular electrocorticography were comparable to those of recordings from epidural surface arrays. Venous internal lumen patency was maintained for the duration of implantation. Stentrodes may have wide ranging applications as a neural interface for treatment of a range of neurological conditions.

Analysis of HLA-DRB3 alleles and supertypical genotypes in the MHC Class II region in sporadic inclusion body myositis.

We compared the carriage frequencies of HLA-DRB3 and its major alleles and of HLA-DRB4 and HLA-DRB5 in an Australian sIBM cohort and a population control group who had previously been genotyped for the HLA-DRB1*03:01 risk allele. There was a strong disease association with the carriage of the DRB3*01:01 allele which was accounted for by its linkage disequilibrium with DRB1*03:01. The carriage of HLA-DRB4 was found to be strongly protective and abrogated the risk effect of HLA-DRB1*03:01. The findings indicate that haplotypic combinations of alleles at the HLA-DRB1 and secondary HLA-DRB loci have important risk modifying effects in sIBM.

High-resolution HLA-DRB1 genotyping in an Australian inclusion body myositis (s-IBM) cohort: an analysis of disease-associated alleles and diplotypes.

We performed high-resolution (4-digit) HLA-DRB1 genotyping in an Australian cohort of 105s-IBM patients and 189 controls. Our findings showed that whilst the strongest association was with the HLA-DRB1*03:01 allele and the HLA-DRB1*03:01/*01:01 diplotype, HLA-DRB1*01:01 and HLA-DRB1*13:01 are also risk alleles. A number of other alleles, HLA-DRB1*04:01, *04:04, *07:01, *09:01, *11:01 and *15:01, as well as the HLA-DRB1*03:01/*04:01 and HLA-DRB1*03:01/*07:01 diplotypes were reduced in s-IBM cases and may be protective. The HLA-DRB1*03:01 and HLA-DRB1*13:01 alleles also appear to have an influence on the age at onset of the disease and severity of muscle weakness. Our findings indicate that the influence of HLA-DRB1 in s-IBM is complex and that epistatic interactions at the HLA-DRB1 locus contribute both to disease susceptibility and to the clinical phenotype.

Sporadic inclusion body myositis: HLA-DRB1 allele interactions influence disease risk and clinical phenotype.

Susceptibility to sIBM is strongly associated with the HLA-DRB1*03 allele and the 8.1 MHC ancestral haplotype (HLA-A1, B8, DRB1*03) but little is known about the effects of allelic interactions at the DRB1 locus or disease-modifying effects of HLA alleles. HLA-A, B and DRB1 genotyping was performed in 80 Australian sIBM cases and the frequencies of different alleles and allele combinations were compared with those in a group of 190 healthy controls. Genotype-phenotype correlations were also investigated. Amongst carriers of the HLA-DRB1*03 allele, DRB1*03/*01 heterozygotes were over-represented in the sIBM group (p<0.003) while. DRB1*03/*04 heterozygotes were under-represented (p<0.008). The mean age-at-onset (AAO) was 6.5 years earlier in DRB1*03/*01 heterozygotes who also had more severe quadriceps muscle weakness than the rest of the cohort. The findings indicate that interactions between the HLA-DRB1*03 allele and other alleles at the DRB1 locus can influence disease susceptibility and the clinical phenotype in sIBM.