Unilateral cortical FLAIR-hyperintense Lesions in Anti-MOG-associated Encephalitis with Seizures (FLAMES): characterization of a distinct clinico-radiographic syndrome.

OBJECTIVE: To characterize the clinical symptoms and magnetic resonance imaging (MRI) findings of unilateral cortical FLAIR-hyperintense Lesions in Anti-MOG-associated Encephalitis with Seizures (FLAMES). METHODS: This is a case report and systematic review of the literature to identify cases of unilateral cortical FLAMES. Cases were reviewed to determine the frequency of clinical symptoms (seizures, headache, fever and cortical symptoms referable to FLAMES location), and to determine whether MRI abnormalities are restricted to the unilateral cortex in this syndrome. RESULTS: We identified 20 cases of unilateral cortical FLAMES for review. Among them, 17/20 (85%) had seizures, 14/20 (70%) had headache, 13/20 (65%) had fever, 11/20 (55%) reported cortical symptoms referable to the FLAMES location, and 19/20 (95%) reported at least two of these four findings. On MRI 4/20 (20%) had some contralateral hemispheric cortical signal abnormality, and 6/20 (30%) had MRI findings concerning for meningeal inflammation. CONCLUSIONS: In patients with unilateral cortical FLAMES, the clinical symptoms of seizures, headache, fever and cortical symptoms referable to the FLAMES location are frequent. Although initially described as a unilateral cortical encephalitis, bilateral cortical involvement and possible meningeal inflammation could indicate a broader disease spectrum. Recognition of this distinct clinico-radiographic syndrome may facilitate prompt diagnosis and treatment.

Sleep and neuromuscular disease.

Sleep disorders in patients with neuromuscular disease are common, but underrecognized by health care providers, and sometimes by patients themselves. Their symptoms may be confused with those of the underlying disease. Their recognition is an important part of the management of patients with neuromuscular disorders, improving quality of life, and sometimes increasing survival. Inadequate ventilation underlies many sleep disorders, and sleep-related disorders may presage daytime ventilatory disorders with disease progression. Involvement of the central or peripheral nervous system, or both, may disrupt sleep, with the relative contribution of each depending on the specific disorder. The pertinent anatomy, physiology, and clinical features of sleep disorders in neuromuscular diseases and a basic approach to their assessment is discussed. Specific neuromuscular disorders in which sleep is commonly affected are reviewed and the principles of management of sleep disorders summarized.

An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis.

BACKGROUND: This prospective, randomized, double-blind, placebo-controlled, phase III trial assessed the efficacy, safety, and tolerability of mycophenolate mofetil (MMF) as a steroid-sparing agent in patients with myasthenia gravis (MG). METHODS: Patients with acetylcholine receptor antibody-positive class II-IVa MG (MG Foundation of America [MGFA] criteria) taking corticosteroids for at least 4 weeks were randomized to MMF (2 g/day) or placebo for 36 weeks. The primary endpoint was a composite measure defined as achievement of minimal manifestations or pharmacologic remission (MGFA post-intervention status), with reduction of corticosteroid dose on a set schedule. Secondary endpoints included disease severity, quality-of-life scores, and safety. RESULTS: A total of 44% of MMF-treated (n = 88) and 39% of placebo-receiving (n = 88) patients achieved the primary endpoint (p = 0.541). Improvements in mean quantitative MG, MG activities of daily living, and 36-item Short-Form health survey scores were similar in both groups. Numbers of adverse events were similar in both groups. The most commonly reported adverse events in the MMF-treated group were headache (12.5%) and worsening of MG (11.4%), and in the placebo group, worsening of MG (20.5%) and diarrhea (10.2%). CONCLUSIONS: Initiation of mycophenolate mofetil (MMF) treatment was not superior to placebo in maintaining myasthenia gravis (MG) control during a 36-week schedule of prednisone tapering. There were no significant differences in the primary or secondary endpoints between the study groups. MMF was well tolerated and adverse events were consistent with previous studies. Experience from this large, international, multicenter, phase III study employing full MG Foundation of America guidelines will aid the design of future MG studies.

Sleep apnea in patients with myasthenia gravis.

To assess the prevalence of obstructive sleep apnea (OSA) in myasthenia gravis, the authors identified patients at risk of OSA using the multivariable apnea prediction index. OSA was diagnosed with polysomnography. The prevalence of OSA was 36% compared to an expected prevalence of 15 to 20% in the general population. When including the presence of daytime sleepiness (OSA syndrome), the prevalence was 11% compared to 3% in the general population.

Wartenberg's migrant sensory neuritis.

We describe a patient with the sudden onset of a painful, purely sensory, mononeuritis multiplex. Investigations showed no evidence for any underlying systemic condition. A nerve biopsy showed fascicular wallerian degeneration with perineurial thickening, inflammatory cells, and immunoglobulin G (IgG) deposition. His painful sensory deficits persisted, with no improvement after treatment with prednisone. The clinical characteristics in this case were very similar to those originally described by Wartenberg, and subsequently by other investigators. The investigations in our case strongly suggest that there may be an underlying immune pathogenesis for cases of Wartenberg's migrant sensory neuritis.

Conduction block in neuralgic amyotrophy.

We describe two cases of neuralgic amyotrophy with electrophysiological evidence of conduction block across the lower trunk of the brachial plexus. Low-output impedance stimulation of the cervical spinal roots in combination with collision was used to accurately demonstrate the conduction block. Complete electrophysiological recovery of the conduction block occurred within 3 months. Early clinical and electrophysiological recovery in both patients suggests that, in some cases, demyelination may predominate early in the course of neuralgic amyotrophy.

Coma mimicking brain death following baclofen overdose.

Baclofen toxicity can be a cause of profound coma with brainstem dysfunction mimicking brain death, and is mainly a clinical diagnosis. Measuring plasma levels is not always possible and may be misleading. Imaging results are usually normal. Electroencephalography may show a pattern of burst suppression. At present no effective specific therapy is available. However, as demonstrated in our case, the prognosis can be good even in severe cases, provided it is recognized early enough, and appropriate supportive measures are instituted.

A novel sodium channel mutation in a family with hypokalemic periodic paralysis.

OBJECTIVE: To identify the cause of hypokalemic periodic paralysis (HOKPP) in a family whose disease is not caused by a mutation in the dihydropyridine-sensitive (DHP) receptor alpha1-subunit gene (CACNA1S). BACKGROUND: Hypokalemic periodic paralysis is primarily caused by mutations within CACNA1S. Genetic heterogeneity for HOKPP has been reported, but no other locus has been identified. METHODS: Single-stranded conformational polymorphism (SSCP) analysis and PCR direct sequencing were used to screen the skeletal muscle alpha1-sodium channel gene (SCN4A) for a mutation in our family. RESULTS: SSCP analysis showed an abnormally migrating conformer in exon 12. Direct sequencing of the conformer showed a guanine to adenine transition at position 2006 in the cDNA sequence; this results in an amino acid substitution of a highly conserved arginine (Arg) to histidine (His) at position 669. This sequence alteration segregated only with the affected members of the kindred and was not found in a panel of 100 DNA samples from healthy controls. The amino acid substitution alters the outermost positive charge in the membrane spanning segment DII/S4, which is involved in voltage sensing. CONCLUSIONS: The first arginine in DII/S4 and in DIV/S4 within the skeletal muscle sodium channel and the L-type calcium channel genie CACNA1S appear to be critical for normal function. In all four cases, Arg to His mutations result in a disease phenotype. The identification of a mutation within the skeletal muscle sodium channel resulting in hypokalemic periodic paralysis represents a novel finding.

Generation of acetylcholine receptor-specific human T cell lines using heterobifunctional antibody-targeted antigen presentation.

Characterizing AChR-specific T lymphocyte clones is an important step towards the ability to induce antigen-specific tolerance in myasthenia gravis (MG). However, the limited supply of relatively inefficient autologous antigen presenting cells (APCs) makes establishing AChR-specific T lymphocyte lines difficult. In this study we targeted AChR to autologous surface IgM+ (sIgM+) APCs using heterobifunctional antibodies (bi-Ab) consisting of anti-sIgM linked to anti-AChR antibodies. FACScan analysis and whole cell-based radioimmunoassay (RIA) showed binding of bi-Ab/AChR conjugates to sIgM+ APCs. Using antigen targeting, AChR-presentation to a well-characterized AChR-specific T cell clone, and to T cell lines raised de novo from MG thymocytes, was improved. Thus, antigen targeting using bi-Ab improved the efficiency of presentation of the scarce autoantigen AChR, suggesting that this method might allow the use of relatively impure antigen preparations and normally inefficient non-antigen-specific APCs, including those which can be immortalized, to accelerate the characterization of the AChR epitopes recognized by pathogenic T helper lymphocytes.

Repetitive phrenic nerve stimulation in myasthenia gravis.

OBJECTIVE: In patients with MG it may be difficult to determine whether respiratory insufficiency is due to a defect in neuromuscular transmission. We therefore studied the clinical value of repetitive electrical stimulation of the phrenic nerve. METHODS: Repetitive phrenic nerve stimulation at 3 Hz was performed in 25 patients with MG. We recorded from the ipsilateral hemidiaphragm with surface electrodes before and after exercising the diaphragm for 10 and 90 seconds. The percent decrement of the negative peak (NP) area between the first and the fifth or sixth diaphragmatic compound muscle action potential (DCMAP) was analyzed and results compared with those from 10 healthy individuals. RESULTS: The mean +/- standard deviation percent change of the NP area in healthy individuals was -2.1 +/- 4.2%, with a normal cutoff of > or = 11%. Twelve patients (48%) had an abnormal decrement of DCMAP--9 had a decrement when the diaphragm was rested, 3 only after fatiguing of the diaphragm. The mean percent change in the 12 patients was 20% at rest, -18% after 10 seconds of exercise, and -23% after 90 seconds of exercise-a pattern consistent with MG. Repetitive stimulation of the accessory nerve with recording of the trapezius CMAP (TCMAP) was abnormal in nine patients (36%). The three patients with abnormal decrement of the DCMAP despite normal TCMAP had symptoms of dyspnea. CONCLUSIONS: Repetitive phrenic nerve stimulation studies are a promising tool in the diagnosis of respiratory muscle weakness in MG and should be part of electrophysiologic studies in patients with undiagnosed respiratory failure.

Pseudo-myasthenia gravis and thymic hyperplasia in Graves' disease.

BACKGROUND: Diagnostic confusion between thyroid disease and myasthenia gravis (MG) can arise because the two may have similar clinical features, and also because of the more frequent coexistence of these autoimmune disorders in the same individual. In MG, autoantibodies directed against the acetylcholine receptor result in muscle weakness. Thymic pathology is well recognized in MG, with thymic hyperplasia frequent in early onset MG and thymoma more common in later onset MG. In Graves' disease, autoantibodies against thyroid antigens result in hyperthyroidism. A seldom-recognized feature of Grave's disease is the occurrence of an enlarged thymus (thymic hyperplasia) on chest CT, or of thymic lymphoid hyperplasia pathologically. CASE STUDY: This report describes a case in which the discovery of a mediastinal mass during imaging of the thyroid, and the presence of myasthenic-like symptoms, in a patient with Graves' disease prompted investigations into whether the patient also had MG. RESULTS: Despite symptoms which strongly suggested MG, subsequent investigations did not confirm the diagnosis, and treatment of Grave's lead to a resolution of the symptoms and regression of the thymic enlargement seen on CT. CONCLUSIONS: The case study highlighted clinical similarities between Grave's disease and myasthenia gravis which might cause diagnostic confusion, and also the investigations which are useful in order to differentiate the two diseases. In addition to common clinical features, the autoimmune diseases Grave's disease and myasthenia gravis may both produce radiological thymic enlargement.

Diagnostic difficulties in myasthenia gravis.

Four patients with myasthenia gravis presented with severe, largely isolated, bulbar and respiratory muscles weakness. Tensilon tests were positive and antiacetylcholine receptor (anti-AChR) antibody titers were negative in all patients. Only 1 patient had a greater than 10% decremental response during the period of respiratory failure. Although routine nerve conduction studies were normal, all had very low-amplitude diaphragmatic compound muscle action potentials. Three patients had abundant fibrillation potentials and positive sharp waves largely restricted to respiratory muscles. Clinical and electrophysiological findings improved with corticosteroids, and surprisingly, decremental responses became positive in all patients. The assessment of patients with largely isolated bulbar and respiratory muscle weakness due to myasthenia gravis may be difficult and misleading, as anti-AChR antibody titers may be negative, decremental responses may be absent, and electrophysiological assessment atypical. Due consideration of clinical symptomatology, a Tensilon test, and a trial of immunosuppression may be necessary to establish the diagnosis.

Repetitive phrenic nerve stimulation study in normal subjects.

In patients with myasthenia gravis (MG), it may be difficult to determine by clinical methods if respiratory insufficiency is due to a defect in neuromuscular transmission. We therefore studied the technique of repetitive electrical stimulation of the phrenic nerve in 6 healthy subjects. It was easily performed and quite reproducible. Responses at 3-Hz stimulation were recorded from surface electrodes of the ipsilateral hemidiaphragm, before and after exercise. We analyzed the percent decrement of the negative peak (NP) amplitude, area, and duration of the diaphragmatic compound muscle action potential (CMAP) between the first and the fifth or sixth potentials. The mean percentage change of the area was -2.2% (+/-4.3), and in all tests the change was <10.6%, yielding a normal range of <11%. The change in the NP amplitude was 12.1% (+/-8.3); in duration, the change was -8.7% (+/-9.6). Producing diaphragm fatigue did not change these results. The increase in amplitude and decrease in duration with little change in area, termed pseudofacilitation, may be due to shifts in the position of the diaphragm affecting volume conduction. The technique is a promising tool in the diagnosis of respiratory involvement from neuromuscular transmission disorders.

Lambert-Eaton myasthenic syndrome presenting with severe respiratory failure.

Two cases of Lambert-Eaton myasthenic syndrome (LEMS) who presented with primary respiratory failure are reported. In each case, although not initially suspected clinically, the electrophysiological findings, which included reduced compound muscle action potential amplitudes, decrement to 3-Hz stimulation, and potentiation after 40-Hz stimulation, led to the diagnosis in the critical care unit. Electrophysiological studies of the respiratory system, including repetitive nerve stimulation of the phrenic nerve, were extremely valuable in management. As shown by these cases, the severe respiratory failure in LEMS is reversible with treatment. Thus, LEMS should be considered in cases of unexplained respiratory failure, other clinical features of the disorder sought, and the electrophysiological hallmarks looked for including studies of the respiratory system.

Differences in processing of an autoantigen by DR4:Dw4.2 and DR4:Dw14.2 antigen-presenting cells.

Variations in antigen processing can influence class II-restricted T cell responses. We now report a highly significant difference (p < 0.001) between the ability of antigen-presenting cells from three HLA-DR4:Dw14.2 (Arg71) and six DR4:Dw4.2 (Lys71) individuals to present recombinant or native acetylcholine receptor antigens to a myasthenia gravis T cell clone. The difference was greatest with longer antigens, and not seen with short synthetic peptides, suggesting that it may result from a difference in antigen processing between the two alleles. The results were not related to the presence of myasthenia gravis or of steroid therapy. They could, however, be of relevance in rheumatoid arthritis where particularly severe disease associates with Dw4.2/Dw14.2 heterozygosity.

Specific tolerance to an acetylcholine receptor epitope induced in vitro in myasthenia gravis CD4+ lymphocytes by soluble major histocompatibility complex class II-peptide complexes.

In autoimmune disorders, inactivation of pathogenic antigen-specific T cells, rather than global immunosuppression, would be highly desirable. One way to achieve this would be to deliver the first antigen-specific signal to the T cell in the absence of the second costimulatory signal. Myasthenia gravis (MG) is a well-characterized autoimmune disease in which T cell-dependent autoantibodies are directed against the acetylcholine receptor (A ChR) at the neuromuscular junction. AChR-specific T cells have been cloned from MG patients, and in this study, we have induced long-lasting tolerance in vitro in one particular clone (PM-A1) with a known peptide epitope (alpha 144-163) and MHC class II restriction (DR4 Dw14.2 or 4.2) by using soluble MHC-class II peptide complexes. Preincubation of PM-A1 T cells with such complexes induced death by apoptosis in < or = 40-50% of the AChR-specific cells. Surviving cells remained refractory to stimulation with AChR-derived synthetic peptides or recombinant polypeptides for < or = 38 d after complex treatment. These effects were highly specific, dose-dependent and required > 2 h preincubation. The T cells could be protected from the tolerizing effects of complex by coincubation with DR-matched or -mismatched antigen-presenting cells. This work shows that antigen-specific T cells can be selectively killed or anergized using soluble MHC class II: peptide complexes. Such an antigen-specific therapy offers a rational approach to the immunotherapy of autoimmune or allergic disease in vivo.

Microangiopathy with retinopathy, encephalopathy, and deafness (RED-M) and systemic features.

The case of a young woman with a rare syndrome of acute encephalopathy followed by deafness and retinopathy developing over 1 year is reported. Unlike previously described similar cases, she had considerable systemic symptoms and signs including polyarthralgia-arthritis, diffuse myalgia, malar rash, livedo reticularis, night sweats, and fatigue suggestive of systemic lupus erythematosus. However, results of most immunological investigations were repeatedly normal, including antinuclear antibodies. Anticardiolipin antibodies were elevated on one occasion. Cyclophosphamide has been the most effective treatment for exacerbations of the disease, which have continued to occur over 6 years. This microangiopathic syndrome more likely relates to an immunologically mediated vasculitis of small blood vessels than to a thromboembolic etiology.