Saiju Jacob

Aquaporin-4 antibodies in neuromyelitis optica and longitudinally extensive transverse myelitis.

BACKGROUND There is increasing recognition of antibody-mediated immunotherapy-responsive neurologic diseases and a need for appropriate immunoassays. OBJECTIVES To develop a clinically applicable quantitative assay to detect the presence of aquaporin-4 (AQP4) antibodies in patients with neuromyelitis optica and to characterize the anti-AQP4 antibodies. DESIGN We compared a simple new quantitative fluorescence immunoprecipitation assay (FIPA) with both indirect immunofluorescence and an AQP4-transfected cell-based assay, both previously described. We used the cell-based assay to characterize the antibodies for their immunoglobulin class, IgG subclass, and ability to induce complement C3b deposition in vitro. SETTING United Kingdom and Germany. PARTICIPANTS Serum samples from patients with neuromyelitis optica (n = 25) or longitudinally extensive transverse myelitis (n = 11) and from relevant controls (n = 78) were studied. MAIN OUTCOME MEASURES Comparison of different assays for AQP4 antibodies and characterization of anti-AQP4 antibodies in patients with neuromyelitis optica. RESULTS We found antibodies to AQP4 in 19 of 25 patients with neuromyelitis optica (76%) using FIPA, in 20 of 25 patients with neuromyelitis optica (80%) using the cell-based assay, and in 6 of 11 patients with longitudinally extensive transverse myelitis (55%) with both assays; these assays were more sensitive than indirect immunofluorescence and 100% specific. The antibodies bound to extracellular epitope(s) of AQP4, were predominantly IgG1, and strongly induced C3b deposition. CONCLUSIONS Aquaporin-4 is a major antigen in neuromyelitis optica, and antibodies can be detected in more than 75% of patients. Further studies on larger samples will show whether this novel FIPA is suitable for clinical use. The IgG1 antibodies bind to AQP4 on the cell surface and can initiate complement deposition. These approaches will be useful for investigation of other antibody-mediated diseases.

Myasthenia Gravis Seronegative for Acetylcholine Receptor Antibodies

Antibodies to muscle‐specific kinase (MuSK) are found in a variable proportion of patients with myasthenia without typical acetylcholine receptor (AChR) antibodies, but their characteristics and pathogenic mechanisms are not fully understood. We discuss the incidence and pathogenicity of MuSK antibodies and how clinical studies, animal models, and cultured cell lines can be used to elucidate their pathogenic mechanisms. Patients without either AChR or MuSK antibodies (seronegative myasthenia) appear to present another disease subtype that is highly similar to that of typical myasthenia gravis. We demonstrate a new method that detects AChR antibodies in these patients and show that these low‐affinity AChR antibodies are predominantly IgG1 and can activate complement C3b deposition. Similarly MuSK antibodies, although mainly IgG4, are partially IgG1 and can activate C3b deposition. Overall, these results suggest that complement‐activation may be an important pathogenic mechanism even in patients without conventional AChR antibodies.

Neuromyelitis optica in patients with gluten sensitivity associated with antibodies to aquaporin-4

Neuromyelitis optica (NMO) is a severe inflammatory disorder of the CNS of putative autoimmune aetiology, which predominantly affects optic nerves and spinal cord. Gluten sensitivity refers to an autoimmune condition characterised by the presence of antibodies to tissue transglutaminase usually associated with gastrointestinal symptoms. However, neurological complications associated with gluten sensitivity, ranging from peripheral neuropathy to inflammatory brain lesions mimicking multiple sclerosis (MS), have been described. In a recent case report, published in this journal, some of us reported on the first and, to our knowledge, so far the only cases of serologically and histologically confirmed gluten sensitivity and NMO.1 A major …

Hypothermia in VGKC antibody-associated limbic encephalitis

Voltage-gated potassium channel antibody (VGKC-Ab)-associated limbic encephalitis (LE) is a recently described syndrome that broadens the spectrum of immunotherapy-responsive central nervous system disorders. Limbic encephalitis is typically characterised by a sub-acute onset of disorientation, amnesia and seizures, but the clinical spectrum is not yet fully defined and the syndrome could be under-diagnosed. We here describe the clinical profile of four patients with VGKC-Ab-associated LE who had intermittent, episodic hypothermia. One of the patients also described a prodrome of severe neuropathic pain preceding the development of limbic symptoms. Both of these novel symptoms responded well to immunosuppressive therapy, with concurrent amelioration of amnesia/seizures.

Focal CA3 hippocampal subfield atrophy following LGI1 VGKC-complex antibody limbic encephalitis.

Autoantibodies linked with voltage-gated potassium channel (VGKC)-complex antibody-mediated limbic encephalitis (LE) bind to hippocampal subfields. Miller et al. report that chronic LGI1 antibody VGKC-complex LE is associated with focal CA3 atrophy on 7.0-Tesla neuroimaging and autobiographical episodic amnesia. The results point to antibody-mediated pathogenicity and CA3-mediated impairment of episodic memory.

Immune-mediated rippling muscle disease with myasthenia gravis: A report of seven patients with long-term follow-up in two

We report seven patients with immune-mediated rippling muscle disease (iRMD) and AChR-antibody positive myasthenia gravis (MG) without germline caveolin-3 gene mutations. We describe the follow-up of two patients and the clinical features of five new patients (1 female, 4 male, aged 32 to 69 years). These presented with significant generalized, exercise-induced and electrically-silent muscle rippling with myalgia, combined with generalized MG. In two of the seven patients, MG appeared before iRMD. Mediastinal imaging excluded thymic alterations in all, although two had other coincident tumours. Myalgia and rippling were aggravated by acetylcholinesterase-inhibitor treatment. Generalized MG and iRMD were successfully treated with plasma exchange, steroids and azathioprine in the two patients followed long-term. Muscle morphology of five patients showed a minimal myopathic pattern with rare lymphohistiocytic infiltration. In four patients, sarcolemmal caveolin-3, and dysferlin immunofluorescence staining was moderately reduced in a mosaic pattern, but caveolin-3 protein on Western blots was clearly reduced only in two. Notably, electron microscopy showed that caveolae were almost completely lost at the sarcolemma in the three biopsies examined but not in endothelium. Antibodies targeting high molecular weight muscle proteins, likely associated with the neuromuscular endplate and sarcolemma, were found in the iRMD patients but also in age-matched MG patients without iRMD. Since the generalized MG and iRMD improved with immunosuppressive treatments, it is likely that both are caused by autoantibodies, but the target for pathogenic antibodies in iRMD requires further study.

Myasthenia gravis and other neuromuscular junction disorders

Myasthenia gravis is the most common autoimmune disease affecting the neuromuscular junction and is characterised by painless fatigable muscle weakness. It is caused by autoantibodies against neuromuscular junction proteins, either the nicotinic acetylcholine receptor (AChR) or the muscle specific tyrosine kinase (MuSK). Mutations in neuromuscular junction proteins cause congenital myasthenic syndromes. Other antibody mediated conditions affecting the neuromuscular junction include Lambert Eaton myasthenic syndrome and neuromyotonia. Figure 1 The neuromuscular junction and the proteins involved in neuromuscular transmission. Several of the proteins at the neuromuscular junction are targets for autoimmune disorders (AChR and MuSK in myasthenia gravis, VGCC in Lambert–Eaton myasthenic syndrome and VGKC in neuromyotonia). Genetic mutations can affect several of these proteins (AChR, Rapysn, MuSK, Dok-7, etc) causing congenital myasthenic syndromes. ACh, acetylcholine; AChE, acetylcholinesterase; AChR, acetylcholine receptor; MuSK, muscle specific tyrosine kinase; VGCC, voltage gated calcium channel; VGKC, voltage gated potassium channel; VGSC voltage gated sodium channel.

Correlating extent of neuromuscular instability with acetylcholine receptor antibodies

In a retrospective study of 86 patients with myasthenia gravis (MG), we correlated the acetylcholine receptor (AChR) antibody titers with single‐fiber EMG studies to explore whether a relationship exists between these parameters. We found that the AChR antibody titers correlated significantly with the mean of the mean consecutive difference of orbicularis oculi (OO, P < 0.0001) and extensor digitorum communis (EDC, P < 0.0001). The correlation was found to be stronger in OO. The antibody titers also correlated with the percentage of potential pairs with increased jitter in both muscles and, again, the correlation was more significant in OO (P < 0.0001) than in EDC (P = 0.001). We speculate that this relationship is stronger in OO than in the limb muscles, because the architectural and immunological differences in the motor unit render OO more vulnerable and sensitive to disturbances in neuromuscular transmission. Muscle Nerve, 2009

Limbic encephalitis and Lambert Eaton myasthenic syndrome - An immunological profile of a new syndrome

No abstract available Keywords: Lambert Eaton myasthenic syndrome; Limbic encephalitis; SOX antibodies; VGCC; VGKC.

TUBULAR AGGREGATES AND CYLINDRICAL SPIRALS IN AUTOIMMUNE LIMB-GIRDLE MYASTHENIA

Limb-girdle myasthenia is a rare form of autoimmune myasthenia which presents without the typical ocular or bulbar symptoms. Patients present with proximal muscle weakness and are often misdiagnosed as a myopathy and tests for myasthenia may not always be performed. This 43-year-old lady presented with “legs giving way” while climbing stairs or bending down. She was initially investigated by the rheumatologists who noted a marginally increased creatine kinase level (263). A muscle biopsy which showed tubular aggregates on gomori trichrome staining and cylindrical spirals on electron microscopy. She was referred for a neuromuscular opinion. Neurophysiology showed decremental response (60.7%) on repetitive nerve stimulation and a prolonged jitter (mean MCD –60 mcs) on SFEMG. AChR antibodies were strongly positive at 344 nM (confirmed using multiple assays in different labs). She responded well to pyridostigmine therapy, but no additional response to steroids was noted. In view of the atypical presentation several possible genetic mutations were tested (mitochondrial, GFPT1, DPAGT1) which were all negative. Autoimmune limb-girdle myasthenia is a very rare sub-type of myasthenia which may not respond as well to immunosuppressive therapy. Unusual muscle biopsy findings suggest that there might be non-immunological reasons playing a part in the pathophysiology of this disease.