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ObjectivesAutoantibodies against the extracellular domains of the voltage-gated potassium channel (VGKC) complex proteins, leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-2 (CASPR2), are found in patients with limbic encephalitis, faciobrachial dystonic seizures, Morvan's syndrome and neuromyotonia. However, in routine testing, VGKC complex antibodies without LGI1 or CASPR2 reactivities (double-negative) are more common than LGI1 or CASPR2 specificities. Therefore, the target(s) and clinical associations of double-negative antibodies need to be determined.MethodsSera (n=1131) from several clinically defined cohorts were tested for IgG radioimmunoprecipitation of radioiodinated α-dendrotoxin (125I-αDTX)-labelled VGKC complexes from mammalian brain extracts. Positive samples were systematically tested for live hippocampal neuron reactivity, IgG precipitation of 125I-αDTX and 125I-αDTX-labelled Kv1 subunits, and by cell-based assays which expressed Kv1 subunits, LGI1 and CASPR2.ResultsVGKC complex antibodies were found in 162 of 1131 (14%) sera. 90 of these (56%) had antibodies targeting the extracellular domains of LGI1 or CASPR2. Of the remaining 72 double-negative sera, 10 (14%) immunoprecipitated 125I-αDTX itself, and 27 (38%) bound to solubilised co-expressed Kv1.1/1.2/1.6 subunits and/or Kv1.2 subunits alone, at levels proportionate to VGKC complex antibody levels (r=0.57, p=0.0017). The sera with LGI1 and CASPR2 antibodies immunoprecipitated neither preparation. None of the 27 Kv1-precipitating samples bound live hippocampal neurons or Kv1 extracellular domains, but 16 (59%) bound to permeabilised Kv1-expressing human embryonic kidney 293T cells. These intracellular Kv1 antibodies mainly associated with non-immune disease aetiologies, poor longitudinal clinical–serological correlations and a limited immunotherapy response.ConclusionsDouble-negative VGKC complex antibodies are often directed against cytosolic epitopes of Kv1 subunits and occasionally against non-mammalian αDTX. These antibodies should no longer be classified as neuronal-surface antibodies. They consequently lack pathogenic potential and do not in themselves support the use of immunotherapies.

Stiff person syndrome (SPS) is a highly-disabling neurological disorder of the CNS characterized by progressive muscular rigidity and spasms. In approximately 60-80% of patients there are autoantibodies to glutamic acid decarboxylase (GAD), the enzyme that synthesizes gamma-amino butyric acid (GABA), the predominant inhibitory neurotransmitter of the CNS. Although GAD is intracellular, it is thought that autoimmunity to GAD65 may play a role in the development of SPS. To test this hypothesis, we immunized mice, that expressed enhanced green fluorescent protein (EGFP) under the GAD65 promoter, with either GAD65 (n = 13) or phosphate buffered saline (PBS) (n = 13). Immunization with GAD65 resulted in autoantibodies that immunoprecipitated GAD, bound to CNS tissue in a highly characteristic pattern, and surprisingly bound not only to GAD intracellularly but also to the surface of cerebellar neurons in culture. Moreover, immunization resulted in immunoglobulin diffusion into the brainstem, and a partial loss of GAD-EGFP expressing cells in the brainstem. Although immunization with GAD65 did not produce any behavioral abnormality in the mice, the induction of neuronal-surface antibodies and the trend towards loss of GABAergic neurons in the brainstem, supports a role for humoral autoimmunity in the pathogenesis of SPS and suggests that the mechanisms may involve spread to antigens expressed on the surface of these neurons.

We describe 2 cases of acute demyelination in the context of immune reconstitution, following rituximab. CSF studies were negative for JC virus, and common neurotropic viruses, bacteria, and fungi. None of the patients had aquaporin-4 or MOG antibodies. Rituximab was given to treat an autoimmune neurological disease in one case and a systemic autoimmune disease in the other. Notably, blood B cell numbers had reconstituted, and IgG levels were normal after rituximab treatment.A 19-year-old female, with a diagnosis of Myasthenia Gravis and Systemic Lupus Erythematosus, presented with acute left upper limb paraesthesia and weakness. 4 months prior, she received rituximab for a flare of Lupus, with good effect. Imaging showed a right frontal and left splenial white matter lesion. One month later, she developed right-sided limb weakness and altered sensation, along with dysphasia. Imaging showed progression of the splenial lesion and several new white matter lesions, in keeping with demyelination.A 24-year-old female, with quiescent NMDA-Receptor autoimmune encephalitis, presented with acute onset left visual loss, ophthalmoplegia and right-hand paraesthesia. She had received rituximab 4 months before. Her scan showed acute multifocal demyelinating lesions, affecting the parahippocampal gyrus, basal forebrain, corpus callosum, cerebellum, cerebellar peduncles, and anterior pons.Both patients were pulsed with IV methylprednisolone and a weaning oral steroid course with good clinical and imaging responses. Idiopathic immune reconstitution-related demyelination should be considered as a differential diagnosis to PML-IRIS.

Objective Limbic encephalitis (LE) associated with antibodies to the voltage-gated potassium channel complex (VGKC) is a potentially reversible cause of cognitive impairment. Despite the prominence of cognitive dysfunction in this syndrome, little is known about patients’ neuropsychological profile at presentation or their long-term cognitive outcome. Methods We used a comprehensive neuropsychological test battery to evaluate cognitive function longitudinally in 19 patients with VGKC-LE. Results Before immunotherapy, the group had significant impairment of memory, processing speed and executive function, whereas language and perceptual organisation were intact. At follow-up, cognitive impairment was restricted to the memory domain, with processing speed and executive function having returned to the normal range. Residual memory function was predicted by the antibody titre at presentation. Conclusions The results show that, despite broad cognitive dysfunction in the acute phase, patients with VGKC-LE often make a substantial recovery with immunotherapy but may be left with permanent anterograde amnesia.

Background Myositis is a recognised complication of numerous systemic viral infections including influenza. In adults the typical pattern is characterised by myalgia and marked proximal muscle weakness in upper and lower limbs and resolves slowly over weeks rather than days. Case presentation Here, we describe two male patients with myositis with an unusual distribution of weakness in the distal upper limbs, which both followed a flu-like illness and resolved spontaneously. Both patients had moderate elevations in creatine kinase, extensive negative serological investigations, normal nerve conduction studies and myopathic changes on electromyography. Conclusions In the para-infectious context, myositis is an important differential of acute distal upper limb weakness. This unusual pattern of acute muscle weakness should be recognised to avoid unnecessary in treatments. Similar cases in the recent literature in male patients between the ages of 25 to 55 are reviewed and suggest an emerging pattern of para-infectious myositis.

ObjectivesDescribe the outcomes of patients treated at the Myasthenia Centre at Oxford University Trust who developed COVID-19 during the first year of the pandemic.MethodsRetrospective audit of patients diagnosed with COVID-19 between 31st January 2020 – 31st January 2021. Outcomes of COVID-19 complications, including relapse of myasthenia gravis (MG), were analysed.ResultsThe Myasthenia Centre treated 487 patients, including 370 with acetylcholine receptor (AChR) MG, 74 sero-negative MG, 20 MuSK MG and 23 Lambert-Eaton Myasthenic Syndrome (LEMS). COVID-19 was diagnosed in a total of twelve patients (2.5%) including ten AChR, one MuSK and one LEMS patient, with a mean age of 63.8 years (range 20 – 92 years). Five patients were asymptomatic of MG prior to the diagnosis of COVID-19. Treatments prior to diagnosis included pyridostigmine (8/12), prednisolone (7/12), azathioprine (3/12), mycophenolate (1/12) and rituximab (1/12). The majority (8/12) had at least one other co-morbid risk factor for severe COVID-19.COVID-19 resulted in hospital admission in six patients, with three requiring intensive care treatment. One patient with AChR MG (with NHL and NMO treated with rituximab) died from COVID-19 without MG relapse. Two elderly patients developed moderate COVID-19 after a single dose BioNTech vaccination without MG relapse.MG relapse occurred in four patients post COVID-19, with two requiring inpatient management including IVIG.ConclusionCOVID-19 disease was associated with relapse of MG, with all patients in this group surviving. Further research is required to establish if COVID-19 precipitates MG relapse at a different rate compared to other infectious diseases.

Background Evidence is conflicting about a causal role of inflammation in psychosis and, specifically, regarding antibodies binding to neuronal membrane targets, especially N-methyl-D-aspartate receptors. NMDAR, LGI1 and GABA-A antibodies were found more prevalent in people with psychosis than in healthy controls. We aim to test whether these antibodies are pathogenic and may cause isolated psychosis. The SINAPPS2 phase IIa double-blinded randomised controlled trial will test the efficacy and safety of immunoglobulin and rituximab treatment versus placebo for patients with acute psychosis symptoms as added to psychiatric standard of care. Methods We will screen approximately 2500 adult patients with acute psychosis to identify 160 with antibody-positive psychosis without co-existing neurological disease and recruit about 80 eligible participants to the trial in the period from September 2017 to September 2021 across the UK. Eligible patients will be randomised 1:1 either to intravenous immunoglobulin (IVIG) followed by rituximab or to placebo infusions of 1% albumin followed by 0.9% sodium chloride, respectively. To detect a time-to-symptomatic-recovery hazard ratio of 0.322 with a power of 80%, 56 participants are needed to complete the trial, allowing for up to 12 participants to drop out of each group. Eligible patients will be randomised and assessed at baseline within 4 weeks of their eligibility confirmation. The treatment will start with IVIG or 1% albumin placebo infusions over 2–4 consecutive days no later than 7 days from baseline. It will continue 4–5 weeks later with a rituximab or sodium chloride placebo infusion and will end 2–3 weeks after this with another rituximab or placebo infusion. The primary outcome is the time to symptomatic recovery defined as symptomatic remission sustained for at least 6 months on the following Positive and Negative Syndrome Scale items: P1, P2, P3, N1, N4, N6, G5 and G9. Participants will be followed for 12 months from the first day of treatment or, where sustained remission begins after the first 6 months, for an additional minimum of 6 months to assess later response. Discussion The SINAPPS2 trial aims to test whether immunotherapy is efficacious and safe in psychosis associated with anti-neuronal membrane antibodies. Trial registration ISRCTN, 11177045. Registered on 2 May 2017. EudraCT, 2016-000118-31. Registered on 22 November 2016. ClinicalTrials.gov, NCT03194815. Registered on 21 June 2017.

In patients with nonthymomatous myasthenia gravis, thymectomy plus prednisone was associated with better clinical outcomes than prednisone alone. Patients treated with thymectomy had fewer hospitalizations for exacerbations and required lower prednisone doses. The first reported use of thymectomy in patients with nonthymomatous myasthenia gravis was 75 years ago. 1 Of six patients who underwent surgery, three had a favorable response. Subsequent retrospective studies have shown benefits of thymectomy in patients with nonthymomatous myasthenia gravis but with widely varying rates of clinical improvement or remission. A compilation of retrospective studies comparing surgery with medical management did not show a difference in remission rates. 2 Two studies that showed clinical improvements after thymectomy indicated that benefit occurred in the first few years after the procedure, but after 5 years, rates of clinical improvement were similar among . . .

IntroductionEpidemiological studies conducted in several countries have shown that the incidence of myasthenia gravis in the older population (>50 years) is increasing. We were interested in establishing if there were different clinical and immunological features between early (EOMG) and late onset myasthenia gravis (LOMG).Methods and ResultsWe have recruited 150 patients making this the largest prospective cohort study in MG to date with 100% recruitment rates in the Trent region. Most (72.7%) patients had LOMG. Comparison between MG composite scores shows that disease severity at diagnosis was greater (p=0.0339) and antibody titres higher (p=0.007) in the LOMG group compared to EOMG. This was not entirely because of pure ocular presentation, which was observed at similar rates between both patient groups (48% EOMG, 36% LOMG, p=0.24) There was a significant fall in Acetylcholine receptor Antibody titres with time, in keeping with improved MG composite scores (p<0.0001) both in patients who were and were not given immunosuppression.ConclusionOur prospective cohort study shows that the incidence of LOMG is indeed much higher than EOMG with greater disease severity in LOMG pts at diagnosis. Immunological studies are ongoing and should add to the clinical data already collected.