Myasthenic crisis.

Myasthenic crisis is a life-threatening medical emergency requiring early diagnosis and respiratory assistance. It can affect between one-fifth and one-third of all patients with generalized autoimmune myasthenia gravis. Myasthenic crisis is to be distinguished from other causes of acute neuromuscular paralysis which in most cases, can be achieved clinically. High dose corticosteroids in combination with plasma exchange or immunoglobulin are the cornerstone of treatment for this fully reversible cause of neuromuscular paralysis.

Treatment of multiple sclerosis: beyond the NICE guidelines.

Multiple sclerosis (MS) is a common, disabling neurological condition whose pathogenesis is not clearly understood. Although current treatment recommendations assume an immunopathogenic disease mechanism, MS may not be an autoimmune disorder. Long-term immunological therapy for MS is in our view an untested approach, guided by uncritical acceptance of data from drug trials. We do not believe that there is convincing evidence that any of these immune-based treatments prevents long-term disease progression, or has much effect on common disabilities such as fatigue, pain, depression and cognitive impairment. The recent recommendations of the National Institute of Clinical Excellence did not address important issues regarding disease modification, management of paroxysmal symptoms and the likely therapeutic candidates for future treatment trials. We discuss treatment options for MS beyond the NICE guidelines.

In vivo magnetic resonance spectroscopy in chronic fatigue syndrome.

The pathogenic mechanisms of chronic fatigue syndrome (CFS) are not clearly known. Fatigue, poor short-term memory and muscle pain are the most disabling symptoms in CFS. Research data on magnetic resonance spectroscopy (MRS) of muscles and brain in CFS patients suggest a cellular metabolic abnormality in some cases. 31P MRS of skeletal muscles in a subset of patients indicate early intracellular acidosis in the exercising muscles. 1H MRS of the regional brain areas in CFS have shown increased peaks of choline derived from the cell membrane phospholipids. Cell membrane oxidative stress may offer a common explanation for the observed MRS changes in the muscles and brain of CFS patients and this may have important therapeutic implications. As a research tool, MRS may be used as an objective outcome measure in the intervention studies. In addition, regional brain 1H MRS has the potential for wider use to substantiate a clinical diagnosis of CFS from other disorders of unexplained chronic fatigue.

Molecular mimicry in type 1 diabetes: immune cross-reactivity between islet autoantigen and human cytomegalovirus but not Coxsackie virus.

Type 1 diabetes is caused by a T cell-mediated autoimmune destruction of the pancreatic beta cells. Molecular mimicry between viral pathogens and beta cell protein has been a popular theory to explain loss of tolerance in type 1 diabetes. However, functional data in support of this hypothesis have been lacking, presumably because the homologies were defined on the basis of linear similarities in peptide sequences, which ignores the criteria of HLA versus T cell receptor contact residues in peptide epitopes required for T cell recognition. We applied a HLA-binding dedicated peptide microarray analysis using autoreactive T cell clones specific for the autoantigen GAD65 to determine the algorithm of T cell recognition by this given T cell clone. The subsequent database search identified a 100% fit with cytomegalovirus peptide, which was subsequently shown to be recognized by these clonal T cells. However, T cell clones reactive with linear homologies previously described as putative candidates for T cell cross-reactivity between GAD65 and Coxsackie virus peptide were unable to recognize the homologous counterparts.

Antiviral pathway activation in patients with chronic fatigue syndrome and acute infection.

Gene expression of key enzymes in 2 antiviral pathways (ribonuclease latent [RNase L] and RNA-regulated protein kinase [PKR]) was compared in 22 patients with chronic fatigue syndrome (CFS), 10 patients with acute gastroenteritis, and 21 healthy volunteers. Pathway activation in the group of patients with infections differed significantly from that of the other 2 groups, in whom there was no evidence of upregulation. Therefore, assay of activation is unlikely to provide the basis for a diagnostic test for CFS.

Cytomegalovirus in autoimmunity: T cell crossreactivity to viral antigen and autoantigen glutamic acid decarboxylase.

Antigens of pathogenic microbes that mimic autoantigens are thought to be responsible for the activation of autoreactive T cells. Viral infections have been associated with the development of the neuroendocrine autoimmune diseases type 1 diabetes and stiff-man syndrome, but the mechanism is unknown. These diseases share glutamic acid decarboxylase (GAD65) as a major autoantigen. We screened synthetic peptide libraries dedicated to bind to HLA-DR3, which predisposes to both diseases, using clonal CD4(+) T cells reactive to GAD65 isolated from a prediabetic stiff-man syndrome patient. Here we show that these GAD65-specific T cells crossreact with a peptide of the human cytomegalovirus (hCMV) major DNA-binding protein. This peptide was identified after database searching with a recognition pattern that had been deduced from the library studies. Furthermore, we showed that hCMV-derived epitope can be naturally processed by dendritic cells and recognized by GAD65 reactive T cells. Thus, hCMV may be involved in the loss of T cell tolerance to autoantigen GAD65 by a mechanism of molecular mimicry leading to autoimmunity.

Acute cervical hyperextension-hyperflexion injury may precipitate and/or exacerbate symptomatic multiple sclerosis.

We report here 39 cases in which definite multiple sclerosis (MS) was precipitated or exacerbated by specific hyperextension-hyperflexion cervical cord trauma. The worsening or onset of the symptomatic disease bore a striking temporal relationship to the focal injury. Our data suggests that central nervous system (CNS)-specific acute physical trauma such as cervical cord hyperextension-hyperflexion injury may aggravate latent clinical symptoms in MS. The deterioration of MS bore no direct relationship with the severity of neck injury. Possible pathogenic mechanisms of focal CNS-specific trauma aggravating the course of asymptomatic or benign MS are discussed. This may have implications in improving our understanding of the factors that may modify the clinical course of MS.

DXA body composition studies are not affected by extracellular water measurements using stable sodium bromide dilution.

Body composition studies using dual energy x-ray absorptiometry (DXA) are being increasingly reported in the literature. When DXA body composition measurements are combined with body water studies, stable bromide is often administered to measure extracellular water. Bromine attenuates x-rays significantly more than soft tissue and so could affect DXA body composition analysis. DXA scans were performed on 26 adults (12 F, 14 M) before and after the intravenous injection of 3 g sodium bromide (NaBr). No significant differences were noted pre- and post-NaBr infusion for whole-body fat mass, fat-free soft tissue mass and bone mineral content. These findings were supported by a simple mathematical analysis of the likely effect of the sodium bromide infusion. This showed that when 3 g NaBr was introduced into the body, the effect on fat mass estimates was expected to be marginally less than the precision of the DXA technique.

Fatigue and basal ganglia.

Fatigue is a common symptom in neurology and occurs in the diseases of the central and peripheral nervous system. In order to understand the mechanism of fatigue, it is important to distinguish symptoms of peripheral neuromuscular fatigue from the symptoms of physical and mental fatigue characteristic of disorders like Parkinson's disease or multiple sclerosis. We have introduced and defined the concept of central fatigue for the latter disorders. We have further proposed, with supportive neuropathological data, that central fatigue may occur due to a failure in the integration of the limbic input and the motor functions within the basal ganglia affecting the striatal-thalamic-frontal cortical system.

The symptoms of chronic fatigue syndrome are related to abnormal ion channel function.

The pathogenesis of chronic fatigue syndrome (CFS) is unknown but one of the most characteristic features of the illness is fluctuation in symptoms which can be induced by physical and/or mental stress. Other conditions in which fluctuating fatigue occurs are caused by abnormal ion channels in the cell membrane. These include genetically determined channelopathies, e.g. hypokalemic periodic paralysis, episodic ataxia type 2 and acquired conditions such as neuromyotonia, myasthenic syndromes, multiple sclerosis and inflammatory demyelinating polyneuropathies. Our hypothesis is that abnormal ion channel function underlies the symptoms of CFS and this is supported also by the finding of abnormal cardiac-thallium201 SPECT scans in CFS, similar to that found in syndrome X, another disorder of ion channels. CFS and syndrome X can have identical clinical symptoms. CFS may begin after exposure to specific toxins which are known to produce abnormal sodium ion channels. Finally, in CFS, increased resting energy expenditure (REE) occurs, a state influenced by transmembrane ion transport. The hypothesis that ion channels are abnormal in CFS may help to explain the fluctuating fatigue and other symptoms.

The effect of anti-alpha4 integrin antibody on brain lesion activity in MS. The UK Antegren Study Group.

OBJECTIVE: To determine the effect of humanized monoclonal antibody against alpha4 integrin (reactive with alpha4beta1 integrin or very-late antigen-4) on MRI lesion activity in MS. METHODS: A randomized, double-blind, placebo-controlled trial in 72 patients with active relapsing-remitting and secondary progressive MS was performed. Each patient received two IV infusions of anti-alpha4 integrin antibody (natalizumab; Antegren) or placebo 4 weeks apart and was followed up for 24 weeks with serial MRI and clinical assessment. RESULTS: The treated group exhibited significantly fewer new active lesions (mean 1.8 versus 3.6 per patient) and new enhancing lesions (mean 1.6 versus 3.3 per patient) than the placebo group over the first 12 weeks. There was no significant difference in the number of new active or new enhancing lesions in the second 12 weeks of the study. The number of baseline-enhancing lesions (i.e., lesions that enhanced on the baseline scan) that continued to enhance 4 weeks following the first treatment was not significantly different between the two groups. The number of patients with acute MS exacerbations was not significantly different in the two groups during the first 12 weeks (9 in the treated group versus 10 in placebo) but was higher in the treatment group in the second 12 weeks (14 versus 3; p = 0.005). The study was not, however, designed to look definitively at the effect of treatment on relapse rate. Treatment was well tolerated. CONCLUSIONS: Short-term treatment with monoclonal antibody against alpha4 integrin results in a significant reduction in the number of new active lesions on MRI. Further studies will be required to determine the longer term effect of this treatment on MRI and clinical outcomes.

GAD65-Reactive T cells in a non-diabetic stiff-man syndrome patient.

GAD65 (glutamic acid decarboxylase) is an important autoantigen in both type 1 (insulin-dependent) diabetes mellitus (IDDM) and the neurological autoimmune disease stiff-man syndrome (SMS), and is expressed in pancreatic islets as well as the nervous system. Still, only 30% of SMS patients also have type 1 diabetes. To study regulation of T cell responsiveness to GAD65, we investigated a non-diabetic SMS patient with HLA-DR3/7 (predisposing to type 1 diabetes) and high levels of type 1 diabetes-associated autoantibodies against GAD65 and islet cells, and compared the results with those of her diabetic son and two other SMS patients. T cell responses to GAD65 were repeatedly absent in primary stimulation, whereas IA-2, islet antigen and tetanus toxoid induced significant T cell proliferation. However, after in vitro restimulation, GAD65 reactive T cell lines and clones were obtained that were HLA-DR3 restricted, and cross-reactive with a homogenate of purified human pancreatic islets. These T cells produced the immunoregulatory cytokine IL-10 in combination with IFN-gamma and IL-4 (Th0). The dominant T cell epitope was mapped to the central region of GAD65. Although no primary response to whole GAD65 was detectable, the naturally processed GAD65 peptide epitope was recognized vigorously in the primary stimulation assay. The lack of detectable primary T cell responses to GAD65, together with the GAD65-specific cytokine production of restimulated T cells, suggest that GAD65-specific cellular autoimmunity in this patient is suppressed and may be related to the absence of diabetes despite humoral autoreactivity and genetic predisposition.

Genomic and template RNA transcription in a model of persistent enteroviral infection.

Enteroviruses have been implicated in persistent infections of the nervous system and in certain paralytic motor neuron syndromes. Enteroviral persistence may depend on defective transcription, resulting in the abnormal production of equal amounts of genomic and template RNA strands rather than the normal ratio of 60-100:1. An in vitro model of a persistent coxsackie virus in human skeletal muscle cells was investigated using in situ hybridisation and a semiquantitative parallel, complementary, reverse transcriptase polymerase chain reaction. The ratio of genomic to template RNA was found to be approximately 60:1. We conclude that enteroviral persistence in this in vitro model is not dependent on altered transcription. In vivo, other viral and host factors should be considered.

Search for picornaviruses at onset of inflammatory myopathy.

Picornaviruses may not play a role as persistent agents in the inflammatory myopathies, but it is still thought likely that they may act as triggers of an autoimmune process. Forty one muscle biopsy specimens, taken from three weeks to six months (mean four months) after onset, were examined using three different picornaviral primers and PCR. Moderate to severe disease activity was evident in all specimens. The results were compared with those of 18 biopsy specimens examined later in the disease course, and with specimens from 27 patients with non-inflammatory myopathies. All results were negative. Thus, even as early as three weeks after clinical disease appears, picornaviruses are not detectable in these disorders.

Abnormalities of carnitine metabolism in chronic fatigue syndrome.

Carnitine may be involved in the pathogenesis of the chronic fatigue syndrome (CFS). However, no information about the cellular metabolism of carnitine in CFS patients is currently available. Therefore, we aimed to measure the levels of carnitine (total, free and short-chain) in both peripheral blood lymphocytes (PBLs) and sera from patients with CFS. The serum levels of total, free and short-chain were comparable in CFS patients, considered as the whole group, to those in healthy control subjects, even though a trend indicating slightly reduced serum concentrations of free carnitine was observed in male patients with CFS. In contrast, the concentrations of total, free and short-chain carnitine in PBLs from patients with CFS were significantly lower than in cells from healthy controls. Our study indicates that patients with CFS require exogenous carnitine supplementation. The low carnitine concentrations in PBLs from patients with CFS probably reflect the carnitine deficiency occurring in other tissues, including the skeletal muscles. The low cellular concentrations of carnitines may help to explain both the immunological abnormalities and the impaired energy metabolism in skeletal muscles.