Background:
Neuromyelitis optica (NMO, Devic syndrome) and myasthenia gravis (MG) are rare antibody-mediated autoimmune disorders. Concurrent incidence has been reported in only few patients, mostly ...non-Caucasians.
Objective:
To report on ten Caucasian patients with NMO spectrum disorders (NMOSD) and MG and to provide a comprehensive review of the literature.
Method:
Retrospective study.
Results:
In total, 26 patients (m:f = 1:12; Caucasian in 12) with MG (generalized in 17) and NMOSD (NMO in 21, longitudinally extensive transverse myelitis in five) were identified from the authors’ own files (n = 10) and the previous literature (n = 16). MG preceded NMOSD in 24/25 cases (96%). AQP4-Ab were tested in 20 patients and were positive in 17 (85%). Twenty out of 25 patients (80%) had been treated with thymectomy or thymic irradiation, which preceded NMOSD in all cases (median latency, 12 years; range, 0.3–32). At last follow-up, complete remission of MG was reported in 15/22 (68%), and MG was well controlled with pyridostigmine in three. Co-existing autoimmune disorders or autoimmune antibodies were reported in 17 patients.
Conclusion:
Our study demonstrates that i) AQP4-Ab-positive NMOSD are more commonly associated with MG in Caucasians than previously thought; ii) MG precedes NMOSD in most cases, often by more than a decade; iii) NMOSD almost exclusively occur in females with juvenile or early-onset MG; and iv) MG frequently takes an unusually mild course in patients with NMOSD. A history of thymectomy could be a possible risk factor for the later development of NMOSD. We recommend testing for AQP4-Ab in MG patients presenting with atypical motor or optic symptoms.
Autoantibodies, in particular those against aquaporin-4 and myelin-oligodendrocyte glycoprotein (MOG), aid as biomarkers in the differential diagnosis of demyelination. Here, we report on discovery ...of autoantibodies against flotillin in patients with multiple sclerosis (MS).
The target antigen was identified by histo-immunoprecipitation using the patients' sera and cryosections of rat or pig cerebellum combined with mass spectrometrical analysis. Correct identification was ascertained by indirect immunofluorescence and neutralization tests using the target antigens recombinantly expressed in HEK293 cells.
Serum and CSF of the index patient produced a fine-granular IgG indirect immunofluorescence staining of the hippocampal and cerebellar molecular layers. Flotillin-1 and flotillin-2 were identified as target autoantigens. They also reacted with recombinant human flotillin-1/2 co-expressed in HEK293 cells, but not with the individual flotillins in fixed- and live-cell assays. Moreover, neutralization using flotillin-1/2, but not the single flotillins, abolished the tissue reactivity of patient serum. Screening of 521 patients, for whom anti-aquaporin-4 testing was requested and negative, revealed 8 additional patients with anti-flotillin-1/2 autoantibodies. All eight were negative for anti-MOG. Six patients ex post fulfilled the revised McDonald criteria for MS. Vice versa, screening of 538 MS sera revealed anti-flotillin-1/2 autoantibodies in eight patients. The autoantibodies were not found in a cohort of 67 patients with other neural autoantibody-associated syndromes and in 444 healthy blood donors.
Autoantibodies against the flotillin-1/2 heterocomplex, a peripheral membrane protein that is involved in axon outgrowth and regeneration of the optic nerve, are present in 1-2% of patients with bona fide MS.
Abstract Neuromyelitis optica (NMO; also termed Devic’s disease) is a severely disabling autoimmune disorder of the central nervous system (CNS), which predominantly affects the optic nerves and ...spinal cord. In up to 80% of cases, NMO is associated with antibodies to aquaporin-4 (AQP4-IgG), the most abundant water channel in the CNS. AQP4-IgG have been demonstrated to be directly pathogenic. Gamma-aminobutyric acid A receptor (GABAA R) agonists are frequently used in patients with NMO, e.g., for symptomatic treatment of spasticity or epilepsy or for non-NMO-related indications such as treatment of insomnia. However, GABAA R signaling has recently been shown to strongly promote AQP4 expression. This is of potential clinical importance since any increase in AQP4 membrane expression during acute NMO attacks may enhance the complement-mediated humoral immune reaction against AQP4-expressing cells characteristic for NMO and, thus, result in more severe CNS damage. We therefore hypothesize that GABAA R agonist-induced AQP4 upregulation may be a potential risk factor in NMO. This would also include a potential role for (GABAA R-enhanced) damage to the subependymal zone neural stem cells, the major source of both glial cells and neuroblasts in the adult brain, in NMO. We also make proposals on how to test that hypothesis and underline the general need for evaluating possible detrimental effects of commonly used drugs affecting AQP4 expression in NMO.
Abstract Background Gamma-aminobutyric-acid B (GABA-B)-receptor encephalitis represents a novel entity among autoimmune CNS disorders. Most cases are characterised by limbic encephalitis. Case report ...A 63-year-old patient presented with acute vertigo, nausea and vomiting, facial palsy and dysarthria. He developed dysphagia, gait ataxia and, finally, respiratory failure. Antibodies to GABA-B receptors were positive and declined under treatment with intravenous methylprednisolone and plasma exchange, followed by clinical improvement and stabilisation. Broad tumour screening revealed oesophageal carcinoma. Conclusion The spectrum of neurological manifestations and tumours associated with the paraneoplastic variant of anti-GABA-B-receptor encephalitis may be broader than previously reported.
Abstract Background Several assays have been developed to detect antibodies to aquaporin-4 (NMO-IgG/AQP4-Ab). However, many of these assays require sophisticated techniques and are thus only ...available at specialized laboratories. This is problematic since NMO-IgG/AQP4-Ab testing has important prognostic and therapeutic implications. Objective To evaluate a newly developed, commercial, enzyme-linked immunosorbent assay (ELISA) for detecting NMO-IgG/AQP4-Ab. Methods Serum samples from 261 patients with NMO spectrum disorders (NMOSD; n = 108) and controls (n = 153) were tested for AQP4-Ab by using ELISA. Of these patients, 207 were tested in parallel using a standard immunohistochemical (IHC) assay. Results Fifty of 66 (75.8%) patients with NMO, 17/25 (68%) with LETM, 3/14 (21.4%) with ON, 2/3 (66.7%) with ON and non-extensive transverse myelitis, and 2/153 (1.3%) controls tested positive in the ELISA. Of those NMOSD patients tested by both ELISA and IHC, 10 were positive only in the ELISA and 3 exclusively in the IHC assay, suggesting that the overall sensitivity of the ELISA was higher than that of the standard IHC assay. The ELISA yielded very good intra- and inter-run reproducibility with regard to AQP4-Ab detection and good intrarun, but only moderate inter-run reproducibility with regard to AQP4-Ab quantification. Anti-AQP4 serum concentrations correlated with disease activity (p < 0.00001), but did not differ between patients with NMO and patients with isolated LETM or ON. Conclusion The ELISA evaluated here provides a relatively sensitive and easy-to-use diagnostic tool for detecting antibodies to AQP4 and could make AQP4-Ab testing, which is of high clinical relevance, more widely available.
Objectives – SOX1 antibodies have been described in patients with Lambert–Eaton myasthenic syndrome (LEMS) in association with voltage‐gated calcium channel antibodies as serological markers of ...small cell lung cancer (SCLC). This study was aimed to screen for additional SOX1 autoimmunity in onconeural antibody‐positive sera from patients with paraneoplastic neurological syndromes (PNS) other than LEMS and to identify the clinical–immunological profile and associated tumours of patients with coexisting SOX1 antibodies. Methods– We retrospectively analysed sera from 55 patients with different PNS positive for well‐characterized antineuronal antibodies for the presence of SOX1 antibodies by recombinant ELISA and immunoblot. Results– Eight (14.5%) patients showed additional SOX1 antibodies in the ELISA and the recombinant immunoblot. Five patients had coexisting Hu antibodies, while the other three showed coexisting CV2/CRMP5, amphiphysin, and coexisting CV2/CRMP5 and Hu antibodies, respectively. PNS included (partially overlapping) subacute sensory neuropathy, subacute sensorimotor neuropathy, cerebellar degeneration, brainstem encephalitis, encephalomyelitis and limbic encephalitis. No tumour was detected in two patients, while the others had lung cancer (four SCLC and two non‐SCLC). One patient showed SOX1‐specific intrathecal antibody synthesis. Conclusions– We describe SOX1 reactivity for the first time overlapping with CV2/CRMP5 and amphiphysin antibodies. SOX1 reactivity is predominantly associated with Hu antibodies and SCLC, but can occur also in other types of lung cancer. Neurological manifestations present in patients with coexisting SOX1 antibodies and well‐characterized antineuronal antibodies do not differ from those previously described in patients positive for antineuronal antibodies but no SOX1‐specific anti‐glial antibodies.
Recently, the disappearance of oligoclonal bands (OCBs) from the cerebrospinal fluid (CSF) of a few natalizumab-treated patients with multiple sclerosis (MS) has been reported. This is interesting ...since CSF-restricted OCB are believed to persist in MS. We pooled CSF data from 14 MS centers to obtain an adequate sample size for investigating the suspected changes in central nervous system (CNS)-restricted humoral immune activities in the context of natalizumab therapy. In a retrospective chart analysis, CSF parameters of blood–CSF barrier integrity and intrathecal IgG production from 73 natalizumab-treated MS patients requiring a diagnostic puncture for exclusion of progressive multifocal leukoencephalopathy were compared with CSF data obtained earlier in the course of disease before natalizumab therapy. At the time of repeat lumbar puncture, local IgG production (according to Reibergram) was significantly reduced (p < 0.0001) and OCB had disappeared in 16% of the patients. We therefore conclude that natalizumab therapy interferes with intrathecal antibody production at least in a significant number of patients.
Abstract Background Antibodies to the Rho GTPase-activating protein 26 (ARHGAP26, GRAF1) (also termed anti-Ca) were first described in patients with cerebellar ataxia. However, ARHGAP26 is also ...expressed in some hippocampal neurons. Moreover, some of the previously reported patients showed cognitive and affective symptoms. It is unknown whether those symptoms reflected involvement of the limbic system or were part of the so-called cerebellar cognitive/affective syndrome. Case report Here, we report a newly diagnosed anti-Ca/ARHGAP26-IgG-positive patient who presented with recurrent psychotic symptoms but no cerebellar ataxia. In addition, low-titer acetylcholine receptor antibodies, voltage-gated potassium channel complex antibodies (but no LGI1 or CASPR2 antibodies) and anti-nuclear antibodies of unknown specificity were detected, suggesting a general autoimmune predisposition. Thymectomy revealed mild thymic nodular hyperplasia. Conclusion This case indicates that the clinical spectrum of ARHGAP26-related autoimmunity might be broader than expected. Studies on the prevalence of anti-Ca/ARHGAP26 in patients with suspected limbic encephalitis seem warranted.
Abstract Introduction Antibodies against neurofascin, an axo-glial protein located around the node of Ranvier, have been shown to contribute to axonal pathology both in vitro and in experimental ...autoimmune encephalomyelitis models. Moreover, small case studies have reported anti-NF antibodies in samples from patients with progressive multiple sclerosis (MS). Patients and methods Building up on this observation, we compared the anti-NF reactivity in serum samples from 83 chronic progressive MS (PMS) patients to those with relapsing remitting MS (RRMS, n = 159) and 50 healthy controls. Anti-NF seroreactivity was quantified by enzyme-linked immunosorbent assay using recombinant rat neurofascin. In addition, to identify a potential intrathecal anti-NF antibody synthesis, we calculated the specific antibody index in paired cerebrospinal fluid and serum samples from MS patients with positive anti-NF seroreactivity. Results Prevalence of anti-NF seroreactivity in PMS patients (4.8%; all with primary progressive MS) was significantly higher than that detected in RRMS (0.6%; p = 0.030). However, we found no significant difference between PMS patients and healthy controls (2.0%; p = 0.408). MS patients with positive anti-NF reactivity experienced an above-average progression of disability compared to MS natural-history controls. Anti-NF-specific intrathecal antibody synthesis was not detected in MS patients with positive anti-NF seroreactivity. Conclusions Although present only in a minor subgroup, seroprevalence of anti-NF reactivity was significantly more frequent in patients with PMS than in those with RRMS, but was also occasionally found in healthy controls. Further prospective studies are warranted to investigate whether anti-NF antibodies anticipate disease progression.
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