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Autoimmune Autonomic Ganglionopathy (AAG) is an uncommon immune-mediated neurological disease that results in failure of autonomic function and is associated with autoantibodies directed against the ganglionic acetylcholine receptor (gnACHR). The antibodies are routinely detected by immunoprecipitation assays, such as radioimmunoassays (RIA), although these assays do not detect all patients with AAG and may yield false positive results. Autoantibodies against the gnACHR exert pathology by receptor modulation. Flow cytometric analysis is able to determine if this has occurred, in contrast to the assays in current use that rely on immunoprecipitation. Here, we describe the first high-throughput, non-radioactive flow cytometric assay to determine autoantibody mediated gnACHR immunomodulation. Previously identified gnACHR antibody seronegative and seropositive sera samples (RIA confirmed) were blinded and obtained from the Oxford Neuroimmunology group along with samples collected locally from patients with or without AAG. All samples were assessed for the ability to cause gnACHR immunomodulation utilizing the prototypical gnACHR expressing cell line, IMR-32. Decision limits were calculated from healthy controls, and Receiver Operating Characteristic (ROC) curves were constructed after unblinding all samples. One hundred and ninety serum samples were analyzed; all 182 expected negative samples (from healthy controls, autonomic disorders not thought to be AAG, other neurological disorders without autonomic dysfunction and patients with Systemic Lupus Erythematosus) were negative for immunomodulation (<18%), as were the RIA negative AAG and unconfirmed AAG samples. All RIA positive samples displayed significant immunomodulation. There were no false positive or negative samples. There was perfect qualitative concordance as compared to RIA, with an Area Under ROC of 1. Detection of Immunomodulation by flow cytometry for the identification of gnACHR autoantibodies offers excellent concordance with the gnACHR antibody RIA, and overcomes many of the shortcomings of immunoprecipitation assays by directly measuring the pathological effects of these autoantibodies at the cellular level. Further work is needed to determine the correlation between the degree of immunomodulation and disease severity.

Complement inhibition is a highly effective strategy for preventing relapse and disability accumulation in neuromyelitis optica spectrum disorder (NMOSD). Invasive infection with Neisseria meningitidis, the principal risk of complement inhibition, is largely mitigated by adequate vaccination. However, vaccination in the context of treatment sequencing from other immunosuppressive therapies, in particular rituximab, presents unique challenges. We present a 17-year-old woman with a severe NMOSD relapse despite B-cell depletion, who subsequently developed meningococcal sepsis after treatment with ravulizumab, despite prior vaccination; and we propose strategies to manage risk in this patient population.

BackgroundChronic inflammatory demyelinating polyneuropathy (CIDP) is a common yet underdiagnosed cause of potentially treatable chronic sensorimotor neuropathy. The classical form of the disease is characterised by symmetrical weakness in both distal and proximal muscle groups accompanied by sensory dysfunction and diminished tendon reflexes lasting more than 2 months.MethodThe diagnosis of CIDP is supplemented by electrodiagnostic studies and biopsy findings confirming demyelination, in accordance with well-established diagnostic criteria. Atypical presentations of CIDP often pose a diagnostic challenge.ResultsIn this paper, we present a case of isolated lower limb involvement due to CIDP to raise awareness of this focal lower limb variant. Of particular, significance is the use of lumbosacral plexus MRI to assist in the diagnosis.ConclusionFocal CIDP is an atypical presentation that should be considered in patients presenting with chronic monomelic neuropathy and should be investigated with electrodiagnostic studies, lumbar puncture, nerve biopsy and MRI of the nerve roots and plexuses.

Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis. We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18–60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972. Between Dec 26, 2018, and Aug 30, 2019, 605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0·20 (95% CI 0·07–0·63) in the once every 6 weeks group and 0·05 (0·01–0·22) in the once every 4 weeks group (mean lesion ratio 4·24 [95% CI 0·86–20·85]; p=0·076) under the primary estimand, and 0·31 (95% CI 0·12–0·82) and 0·06 (0·01–0·31; mean lesion ratio 4·93 [95% CI 1·05–23·20]; p=0·044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (≥25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic. We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab. Biogen.

Background/ObjectivesA minority of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have autoantibodies against components of nodal and paranodal structures in peripheral nerves. These autoantibodies are associated with lower likelihood of response to intravenous immunoglobulin (IVIg) treatment and increased responsiveness to B cell depletion. An easily available, reliable diagnostic assay for the detection of nodo-paranodal antibodies is a major unmet need.MethodsWe tested serum samples from patients with CIDP and healthy controls for the presence of antibodies against neurofascin 155 (NF155), neurofascin 186 (NF186), contactin-1 (CNTN1) and the contactin1/contactin-associated protein 1 (CNTN1/CASPR1) complex using a commercial transfected HEK-293 cell-based indirect immunofluorescence immunoassay (EUROImmun). We modified the manufacturer’s staining protocol using an additional incubation step to increase analytical sensitivity of the assay.ResultsWe detected nodo-paranodal antibodies in four out of 22 CIDP patients, including three who had previously tested positive for nodo-paranodal antibodies using enzyme-linked immunosorbent assay (ELISA), with no positive tests in 52 healthy controls. The modified staining protocol successfully increased the analytical sensitivity of the assay. Our modified assay demonstrated robustness in the presence of common interfering substances and serum with high nonspecific background immunofluorescent staining.ConclusionWe successfully modified and validated a commercial indirect immunofluorescence immunoassay for the qualitative detection of antibodies against NF155, CNTN1 and CNTN1/CASPR1. This could lead to more rapid diagnosis of patients with these autoantibodies, avoiding costly and ineffective treatments. Evaluation of the assay in a larger CIDP cohort and disease control group is ongoing. Testing is now available in Australia.

ObjectivesWe have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry.BackgroundNMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established.MethodsCentres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture–recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases.ResultsNMOSD was confirmed in 81/170 (48%) cases referred. Capture–recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD.ConclusionsNMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry.

BackgroundCOVID-19 vaccine-associated peripheral and central neuroimmunological disorders have been well described. We present the case of a 57 year old male who developed α3-ganglionic AChR antibody positive Autoimmune Autonomic Ganglionopathy (AAG) after completion of a two-dose course of mRNA (Cominarty) vaccination for COVID19.ResultsA previously hypertensive 57 year old Vietnamese male presented with the subacute sequential onset of severe constipation, urinary retention, erectile dysfunction, sudomotor failure, sicca symptoms, non-reactive pupils and severe orthostatic hypotension shortly after receiving the second dose of an mRNA vaccine against COVID19. Autonomic testing revealed severe cardiovagal, adrenergic and sudomotor impairment, and tonic ‘half-mast’ pupils with evidence of sympathetic and parasympathetic denervation. Nerve conduction studies were normal. Investigations for common causes of autonomic failure were non-contributory to a diagnosis. Pathological α3-ganglionic ACHR antibodies were positive in serumas detected by a new flow cytometric immunomodulation assay. Malignancy was excluded. The patient was diagnosed with severe, treatment resistant acute pandysautonomia (AAG).ConclusionsWhile autonomic dysfunction has been previously reported post-COVID19 vaccination, to our knowledge this is the first reported case of antibody-positive AAG in this setting. The severity of this case is in marked contrast to the existing literature on idiopathic antibody-positive autoimmune pandysautonomia.

ObjectivesCases of CNS demyelination temporally associated with covid-19 vaccination have been reported in the literature. We report six cases presenting to Royal Prince Alfred Hospital, a tertiary hospital in New South Wales, between May 2021 and January 2022.MethodsWe report clinical and MRI features of six individuals with evidence of an inflammatory CNS disorder temporally associated with receiving the Pfizer (n=2) or AstraZeneca (n=4) SARS-CoV-2 vaccines.ResultsAge ranged from 30 to 68 years (mean 56), four were female. The onset of neurological symptoms was within 1 to 60 days (mean 28 days) of the first (n=4) or the second (n=2) vaccine dose. Presenting symptoms included visual loss, numbness/paraesthesia, facial/limb weakness, speech disturbance, gait instability, and sphincter disturbance. Presentations were transverse myelitis (n=2), acute disseminated encephalomyelitis- (ADEM) like (n=2), and optic neuritis (n=2). No patients had any prior history of autoimmunity. MRI showed enhancing lesions consistent with active demyelination of the optic nerves, brain and/or spinal cord all but one patient. CSF oligoclonal bands were negative where tested (n=4). The final diagnoses included aquaporin-4 positive neuromyelitis optica (n=1), myelin oligodendrocyte glycoprotein antibody disease (MOGAD) (n=1), transverse myelitis (n=1), optic neuritis (n=1), and ADEM (n=2). All patients responded to high dose intravenous methylprednisolone therapy and returned to baseline (n=1) or near baseline (n=5).ConclusionA wide variety of inflammatory CNS syndromes temporally associated with the covid-19 vaccination have been described. Large post-marketing studies are required to investigate any causal relationship.

ObjectivesWe present the largest case series to date of patients with long term follow up who developed clinically significant autonomic dysfunction due to baroreflex failure following neck irradiation for head and neck cancer (HNC) and Hodgkin’s lymphoma.MethodsWe retrospectively collated clinical, radiological, and autonomic testing data on nine patients who were referred to a quaternary institution in Sydney, Australia for evaluation of autonomic function following head and neck irradiation for malignancy.ResultsAll patients demonstrated baroreflex failure and had symptomatic orthostatic hypotension. The average time to symptom onset was 9.1 years (range 0 to 26 years). One patient demonstrated isolated baroreflex failure and two patients displayed baroreflex failure and segmental hypohidrosis, suggestive of local nerve damage involving efferent baroreceptor pathways. Five patients demonstrated significant cardiovagal and adrenergic dysfunction and one patient had severe cardiovagal and adrenergic dysfunction with additional features of a length-dependent neuropathy. Five of the six patients with severe pan-autonomic failure received concomitant chemotherapy. The features of baroreflex failure occurred independently of radiologically significant carotid atherosclerotic disease.ConclusionThis case series highlights the phenomenon of radiotherapy-induced damage to blood pressure regulatory structures and provides further commentary on the pathophysiology of baroreflex failure. The appearance of urinary frequency, gastrointestinal disturbance, or abnormal sweating in addition to postural symptoms was more common in patients with pan-autonomic failure. The constellation of presenting symptoms, as well as the presence of paroxysmal hypertension, can in turn guide pharmacotherapeutic management in these cases.