Michael W. Nicolle

Autoimmune T cells in myasthenia gravis: heterogeneity and potential for specific immunotargeting

Abstract The initiation of many autoimmune and allergic responses depends on specific T cells, which could thus be selectively targeted for potential therapeutic benefit. The target autoantigen of myasthenia gravis (MC) has been identified; however, the heterogeneity among T cells that recognize it is much greater in some reports than in others. Here, Simon Hawke and colleagues discuss how the prospects for specific therapeutic intervention depend on the resolution of this controversy.

A prospective assessment of the characteristics of dysphagia in myasthenia gravis.

Fatigable muscle weakness is the clinical hallmark of the human autoimmune disease myasthenia gravis (MG). Weakness of the oropharyngeal muscles produces dysphagia, which continues to be a major source of morbidity in MG. In this study we prospectively assessed 20 patients with myasthenia gravis who described difficulties with swallowing. Videofluoroscopic assessment showed disordered swallowing in all, with abnormalities in oral, pharyngeal, and, to a lesser extent, oral preparatory phases. Of the 20 studied, 7 aspirated, most of whom did so silently. Laryngeal penetration occurred in many more patients. The characteristics of dysphagia in MG are described and compared with other neurological disorders that can produce dysphagia.n

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.

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.

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 ≥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.

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 Wartenbergs migrant sensory neuritis.

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.

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

BACKGROUNDnDiagnostic 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 Graves disease is the occurrence of an enlarged thymus (thymic hyperplasia) on chest CT, or of thymic lymphoid hyperplasia pathologically.nnnCASE STUDYnThis 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.nnnRESULTSnDespite symptoms which strongly suggested MG, subsequent investigations did not confirm the diagnosis, and treatment of Graves lead to a resolution of the symptoms and regression of the thymic enlargement seen on CT.nnnCONCLUSIONSnThe case study highlighted clinical similarities between Graves 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 Graves disease and myasthenia gravis may both produce radiological thymic enlargement.

Cross-restriction of a T cell clone to HLA-DR alleles associated with rheumatoid arthritis - Clues to arthritogenic peptide motifs

OBJECTIVEnTo identify distinctive sequence motifs required for productive peptide presentation by those HLA-DR alleles/DR4 subtypes that predispose to rheumatoid arthritis (RA).nnnMETHODSnWe tested 10 different HLA-DR4 subtypes for presentation of acetylcholine receptor peptides to 8 different DR4-restricted T cell lines/clones in proliferation assays.nnnRESULTSnSeven of the 8 T cells depended absolutely on either the autologous Lys71 (in Dw4) or Arg71 (e.g., Dw14), despite these alleles similar charge and RA associations. In contrast, the PM-A T cell was only mildly affected by this interchange. Moreover, after minor modifications, peptides were presented to this unusual T cell preferentially by all the RA-associated subtypes of DR4 as well as by 2 other DR alleles (DR1 and DR1402) that predispose to RA.nnnCONCLUSIONnThis coincident cross-restriction to all the RA-associated HLA-DR alleles except DR10 shows that there could even be a single arthritogenic peptide; we now suggest a possible consensus motif.

Prediction of aspiration in myasthenia gravis

Prediction of the risk of dysphagia and aspiration is important in the management of myasthenia gravis (MG). We assessed the ability of four bedside clinical tools to predict aspiration in 20 MG patients. Patients completed a self‐directed questionnaire, underwent clinical neurological assessment and a bedside speech pathology assessment, and were assessed with the quantitative myasthenia gravis (QMG) score. The ability of these tools to predict aspiration was compared with the results of a modified barium swallow. Seven patients aspirated, 4 silently. The total self‐directed questionnaire score, two specific questions on the self‐directed questionnaire, the prediction based on clinical neurological assessment, and the QMG bulbar subset score all correlated with aspiration. The speech pathology prediction was highly sensitive but less specific. This pilot study shows that simple clinical tools can predict which MG patients are at risk of aspiration. Muscle Nerve 29: 256–260, 2004