[Show abstract][Hide abstract] ABSTRACT: Transient neonatal myasthenia gravis (TNMG) affects a proportion of infants born to mothers with myasthenia gravis (MG). Symptoms usually resolve completely within the first few months of life, but persistent myopathic features have been reported in a few isolated cases.
Here we report 8 patients from 4 families born to mothers with clinically manifest MG or mothers who were asymptomatic but had elevated acetylcholine receptor (AChR) antibody levels.
Clinical features in affected infants ranged from a mild predominantly facial and bulbar myopathy to arthrogryposis multiplex congenita. Additional clinical findings included hearing impairment, pyloric stenosis, and mild CNS involvement. In all cases, antibodies against the AChR were markedly elevated, although not always specific for the fetal AChR γ subunit. There was a correlation between maternal symptoms; the timing, intensity, and frequency of maternal treatment; and neonatal outcome.
These findings suggest that persistent myopathic features following TNMG may be more common than currently recognized. Fetal AChR inactivation syndrome should be considered in the differential diagnosis of infants presenting with unexplained myopathic features, in particular marked dysarthria and velopharyngeal incompetence. Correct diagnosis requires a high degree of suspicion if the mother is asymptomatic but is crucial considering the high recurrence risk for future pregnancies and the potentially treatable nature of this condition. Infants with a history of TNMG should be followed up for subtle myopathic signs and associated complications.
[Show abstract][Hide abstract] ABSTRACT: The field of neuronal surface-directed antibody-mediated diseases of the central nervous system has dramatically expanded in the last few years and now forms an important cluster of treatable neurological conditions. In this review, we focus on three areas. First, we review the demographics, clinical features and treatment responses of these conditions. Second, we consider their pathophysiology and compare autoantibody mechanisms and their effects to genetic or pharmacological disruptions of the target antigens. Third, we discuss areas of controversy within the field, propose possible resolutions, and explore new directions for neuronal surface antibody-mediated diseases.
Journal of Neurology 12/2014; · 3.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In 2007, serum IgG autoantibodies to the NMDAR (NMDAR-Ab) were identified in subjects with an autoimmune encephalopathy responsive to immunotherapy; two thirds of whom present with psychiatric symptoms (Dalmau et al., 2007, Irani et al., 2010 and Titulaer et al., 2013). There is increasing evidence for NMDAR-hypofunction and neuroinflammation in the pathophysiology of first episode schizophrenia (Kahn and Sommer, 2014). Whilst many patients with NMDAR-ab develop a widespread encephalopathy, restricted phenotypes, including isolated psychosis, epilepsy, or movement disorders have also been described (Irani et al., 2010, Zandi et al., 2011, Brenner et al., 2013, Titulaer et al., 2013 and Hacohen et al., 2014). We reported in 2010 for the first time IgG NMDAR, and voltage gated potassium channel-complex (VGKC), antibodies in 3 of 46 (6.5%) patients with a first episode psychosis without other neurological symptoms (Zandi et al., 2011). Pollak and colleagues, found IgG NMDAR-ab in 1.46% (95% CI 0.94–2.23) cases of psychosis and schizophrenia from 7 studies, compared to (5/1598) 0.3% controls, but a variety of assays including fixed assays were compared (Pollak et al., 2013). In their analysis, rates of IgA and IgM antibodies were higher in both cases (7.1%) and controls (10.2%), though IgA and IgM antibodies are of unlikely pathogenic relevance. Dalmau and colleagues found isolated psychotic episodes in 23/571 (4%) patients with NMDAR-Ab encephalitis either in presentation (5) or at relapse (18) (Kayser et al., 2013). One test of clinical relevance of autoantibodies is the immunotherapy response. Here we describe 18 cases of acute psychosis with NMDAR-ab measured by live cell based assay without clear clinical ‘neurological’ involvement, 9 of whom we treated with immunotherapy.
Schizophrenia Research 11/2014; · 4.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The pathogenesis of Guillain-Barré syndrome (GBS) is considered to be, at least in part, mediated by autoantibodies directed against neuronal antigens. Antibodies to contactin-associated protein-like 2 (CASPR2), part of the voltage-gated potassium channel complex (VGKC-complex), are associated with neurological disease predominantly affecting the peripheral nervous system but are not known to be associated with GBS. We report 2 cases of ganglioside antibody-negative paediatric GBS associated with CASPR2 antibodies. Both patients made a full clinical recovery. The tissue distribution and function of CASPR2 make it a biologically plausible autoimmune target in GBS and its clincial relevance in GBS should be determined in further studies.
Journal of the Peripheral Nervous System 11/2014; · 2.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Our aim was to determine the presence and possible role of autoantibodies in epileptic patients with an undetermined etiology. Eighty epilepsy patients, who were referred to the Pediatric Neurology Department at Ankara University between November 2011 and April 2012, were enrolled in the study. Antinuclear antibodies (ANA), anticardiolipin IgG, antiphospholipid, antithyroid peroxidase, paraneoplastic, glutamic acid decarboxylase (GAD), and N-methyl-d-aspartate (NMDA) receptor antibodies were studied in our university laboratory. In addition, NMDA receptor (NMDAR), voltage-gated potassium channel (VGKC)-complex, leucine-rich, glioma inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2) antibodies were studied at the Oxford University Immunology Laboratory. The study included 35 girls (44%) and 45 boys (56%) with a mean symptom age of 8.6 ± 4.53 years. ANA was detected in 15 (18.8%), antiphospholipid Ab in 3 (3.75%), anticardiolipin Ab in 1 (1.25%), and antithyroid peroxidase in 3 (3.75%) epileptic patients. In addition, anti-GAD Ab was detected in 7 (8.75%), anti-Yo Ab in 3 (3.75%), and anti-Ma2 in 3 (3.75%) epileptic patients. Anti-VGKC was positive in 13 (16.25%) epileptic patients. We performed a pioneer study to investigate the association between autoimmunity and pediatric epilepsy and we conclude that autoimmunity should be considered in epileptic patients with an undetermined etiology.
[Show abstract][Hide abstract] ABSTRACT: Des anticorps reconnaissant différentes protéines membranaires de la jonction neuromusculaire incluant le récepteur de l’acétylcholine, la kinase spécifique musculaire (MuSK) et la protéine 4 reliée au récepteur des lipoprotéines de faible densité (LRP4) sont bien identifiés dans la myasthénie autoimmune. Cependant, les mécanismes responsables de la distribution et de la fluctuation de l’atteinte musculaire demeurent incertains et sont discutés ici. De plus, le rôle des anticorps dirigés contre les protéines du complexe du canal potassique aident à mieux comprendre des maladies du système nerveux central sensibles à l’immunothérapie.
[Show abstract][Hide abstract] ABSTRACT: Abstract
Objective There are now a large number of requests for N-methyl-d-aspartate receptor autoantibody (NMDAR-Ab) tests, and it is important to assess the clinical relevance of all results, particularly when they are reported as ‘Low Positive’.
Methods The clinical data of 56 patients found Positive or Low Positive by the Oxford live cell-based assay were reviewed. An autoimmune basis for the condition was assigned as ‘Definite’, ‘Possible’ or ‘Unlikely’. The number of core features (encephalopathy, psychiatric, cognitive, epileptic, extrapyramidal and inflammatory cerebrospinal fluid (CSF)) was tabulated.
Results Twenty-five (44.6%) patients had a Definite NMDAR-Ab encephalitis (eight ovarian teratomas, one Hodgkin's lymphoma), 18 (32.1%) a Possible NMDAR-Ab encephalitis and 13 (23.2%) an Unlikely autoimmune syndrome. Serum NMDAR-Ab levels were higher in patients with tumours. Positive NMDAR-Abs were found not only in patients with three or more core features and a Definite syndrome, but also in five patients classified as Possible. Conversely, Low Positive NMDAR-Abs were present in 7 Definite cases as well as in 13 Possible cases. Unlikely patients had mainly Low Positive antibodies and fewer core features. CSF NMDAR-Abs, only available in 11 pairs and at varying time points, broadly related to serum levels and were Positive in 3/3 patients with tumours but in only 2/5 Definite patients, and none of the Possible or Unlikely cases.
Interpretation Using live cell-based assays, Positive and Low Positive antibodies can be of clinical significance. The number of core clinical features should help to select those patients in whom an immunotherapy intervention might be considered, irrespective of the antibody level.
[Show abstract][Hide abstract] ABSTRACT: Complex Regional Pain Syndrome (CRPS) is a limb-confined post-traumatic pain syndrome with sympathetic features. The cause is unknown, but the results of a randomized crossover trial on low-dose IVIG treatment point to a possible autoimmune mechanism. We tested purified serum immunoglobulin G (IgG) from patients with longstanding CRPS for evidence of antibodies interacting with autonomic receptors on adult primary cardiomyocytes, comparing with control IgG from healthy and disease controls, and related the results to the clinical response to treatment with low-dose intravenous immunoglobulins (IvIG). We simultaneously recorded both single cell contractions and intracellular calcium handling in an electrical field. Ten of 18 CRPS preparations and only 1/57 control preparations (p<0.0001) increased the sensitivity of the myocytes to the electric field and this effect was abrogated by pre-incubation with alpha1a receptor blockers. By contrast, effects on baseline calcium were blocked by pre-incubation with atropine. Interestingly, serum-IgG preparations from all four CRPS patients who had responded to low-dose IVIG with meaningful pain relief were effective in these assays, although 4/8 of the non-responders were also active. To see if there were antibodies to the alpha1a receptor, CRPS-IgG was applied to alpha 1a receptor transfected rat1-fibroblast cells. The CRPS serum IgG induced calcium flux, and FACS showed that there was serum IgG binding to the cells. The results suggest that patients with longstanding CRPS have serum antibodies to alpha 1a receptors, and that measurement of these antibodies may be useful in the diagnosis and management of the patients.
[Show abstract][Hide abstract] ABSTRACT: Patients with autoimmune disorders often have low levels of 25-hydroxyvitamin D [25(OH)D3], which correlates with disability or disease activity. Vitamin D may play a role in neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD), as an important factor involved in immunological pathways. We investigated the relationship between vitamin D levels and disease related disability and clinical activity in patients with NMOSD. Blood samples from 51 patients with NMOSD who were positive for anti-aquaporin4-antibody (AQP4-ab) and 204 healthy controls were collected for 25(OH)D3 measurement. Clinical parameters, including expanded disability status scale (EDSS) score, annualized relapse rate (ARR) and time of blood sampling relative to attack, were determined in patients with NMOSD. We found that 25(OH)D3 levels were significantly lower in patients with NMOSD compared to healthy controls. There was no difference between 25(OH)D3 levels in blood samples taken at relapse or remission, and no association between 25(OH)D3 levels and ARR, but there was an inverse correlation between 25(OH)D3 levels and EDSS scores in patients with NMOSD. It remains to be determined whether low vitamin D levels predispose to NMO and/or modify disease severity, or are secondary to neurological disability. In either case the results could also be of relevance to other neurological diseases such as multiple sclerosis as well as NMO.
PLoS ONE 09/2014; 9(9):e107274. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The role of complement has been demonstrated in experimental models of neuromyeltis optica (NMO), however, only few studies have analysed complement components longitudinally in NMO patients. We measured serum or plasma concentrations of anti-C1q antibodies and complement split products C3a, C4a and soluble C5b-9 in patients with NMO, multiple sclerosis and healthy controls. NMO patients had higher levels of C3a and anti-C1q antibodies than healthy controls. C3a levels correlated with disease activity, neurological disability and aquaporin-4 IgG in NMO patients suggesting a role of the alternative pathway of complement in the pathogenesis of NMO and supporting the strategy of therapeutic complement inhibition.
Journal of Neuroimmunology 09/2014; · 2.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Identification of auto antibodies has defined distinct clinico-immuno-pathological subtypes of myasthenia gravis (MG) such as AChR-antibody-positive-MG and MuSK-antibody-positive-MG. The use of more sensitive assays such as the cell-based assay (CBA) is expected to reduce the proportion of seronegative-MG. We studied the seroprevalence of AChR and MuSK antibodies using both radioimmunoprecipitation (RIA) and CBA amongst MG patients in Sri Lanka and related their antibody status to their clinical subtypes and severity.
113 patients with MG attending Neurology units in the district of Colombo were studied. Clinical data were obtained using an interviewer-administered questionnaire and medical records. The severity of MG was assessed according to MGFA clinical grading. RIA and CBA were used to detect serum AChR and MuSK antibodies. Patients with other neurological diseases were recruited as controls.
We detected either AChRAb (85%) or MuSKAb (6.2%) in 91.2% of MG patients. Complementing the RIA with the CBA improved the diagnostic power of detecting AChRAbs by 21% and MuSKAbs by 77%. The clinical characteristics and the occurrence of thymic pathology were similar to other populations except for a male preponderance (1.5:1). The AChRAb titer appeared to parallel the clinical severity. Seven of 11 (63.6%) patients with AChRAb-negative generalized MG had MuSK–MG.
Clinical characteristics of MG in Sri Lanka are similar to other populations. Complementing the RIA with CBA increases the diagnostic power of detecting pathogenic autoantibodies.
Journal of the Neurological Sciences 08/2014; 342(1):82-83. · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is increasing evidence to support the relevance of immune system in the pathogenesis of Alzheimer Disease (AD) and also there is growing evidence for importance of specific antibodies in some neurological disorders. Antibodies against Voltage Gated Potassium Channels (VGKC) and Glutamic Decarboxylase (GAD) are of interest for AD. The presence of these antibodies is thought to be related to cognitive impairment and memory problems. In our study we attempted to find a relationship between these antibodies in individuals with AD compared with healthy controls.