Biomedical subjects
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The authors report 10 patients with idiopathic dermatomyositis treated with mycophenolate mofetil in combination with corticosteroids. Successful steroid taper without disease relapse was achieved in six patients; however, in three patients, treatment was associated with opportunistic infections, leading to death in one patient. The disproportionately high rate of opportunistic infections in this group is considered.
BACKGROUND: Previous immunohistochemical studies of muscle from patients with inclusion body myositis and polymyositis found many more T cells than B cells, suggesting a role for intramuscular cell-mediated immune mechanisms rather than humoral mechanisms. METHODS: Microarray studies were performed on muscle biopsy specimens from 40 patients with inclusion body myositis (IBM; n = 23), polymyositis (PM; n = 6), and without neuromuscular disease (n = 11). Reverse transcription PCR of selected immunoglobulin gene transcripts was performed on two patient samples. Qualitative immunohistochemical studies for B-cell lineage cell surface markers were performed on 28 muscle specimens and quantitative studies performed on a subset of 19 untreated patients with IBM or PM. CD138+ cells were isolated from muscle using laser capture microdissection, and immunoglobulin transcripts were PCR amplified to determine the presence or absence of immunoglobulin gene rearrangements unique to the B-cell lineage. RESULTS: Immunoglobulin gene transcripts accounted for 59% in IBM and 33% in PM of the most stringently defined highest differentially expressed muscle transcripts compared with normal. Plasma cells, terminally differentiated B cells expressing CD138 but not CD19 or CD20, are present in IBM and PM muscle in numbers several times higher than B cells. CONCLUSIONS: There are differentiated B cells in the form of CD138+ plasma cells within the muscle of patients with inclusion body myositis and polymyositis. The principle of linked recognition of B-cell activation predicts several strategies for autoantigen discovery that could not otherwise be pursued through the study of the infiltrating T-cell population alone.
OBJECTIVE: To describe the use of large-scale gene expression profiles to distinguish broad categories of myopathy and subtypes of inflammatory myopathies (IM) and to provide insight into the pathogenesis of inclusion body myositis (IBM), polymyositis, and dermatomyositis. METHODS: Using Affymetrix GeneChip microarrays, the authors measured the simultaneous expression of approximately 10,000 genes in muscle specimens from 45 patients in four major disease categories (dystrophy, congenital myopathy, inflammatory myopathy, and normal). The authors separately analyzed gene expression in 14 patients limited to the three major subtypes of IM. Bioinformatics techniques were used to classify specimens with similar expression profiles based on global patterns of gene expression and to identify genes with significant differential gene expression compared with normal. RESULTS: Ten of 11 patients with IM, all normals and nemaline myopathies, and 10 of 12 patients with Duchenne muscular dystrophy were correctly classified by this approach. The various subtypes of inflammatory myopathies have distinct gene expression signatures. Specific sets of immune-related genes allow for molecular classification of patients with IBM, polymyositis, and dermatomyositis. Analysis of differential gene expression identifies as relevant to disease pathogenesis previously reported cytokines, major histocompatibility complex class I and II molecules, granzymes, and adhesion molecules, as well as newly identified members of these categories. Increased expression of actin cytoskeleton genes is also identified. CONCLUSIONS: The molecular profiles of muscle tissue in patients with inflammatory myopathies are distinct and represent molecular signatures from which diagnostic insight may follow. Large numbers of differentially expressed genes are rapidly identified.
BACKGROUND: Conduction block is considered an essential finding for the distinction between motor neuropathies and lower motor neuron disorders. Only a small number of reports describe patients with multifocal motor neuropathies who lack overt conduction block, although in these cases other features of demyelination still suggest the presence of a demyelinating disorder. In contrast, a purely axonal multifocal motor neuropathy has not been described. METHODS: This report describes nine patients with slowly or nonprogressive multifocal motor neuropathies who had purely axonal electrodiagnostic features. RESULTS: GM1 antibodies titers were normal in all nine cases. Six patients were treated with either prednisone or IV immunoglobulin and three showed convincing improvement. CONCLUSIONS: These findings suggest an immune-mediated motor neuropathy with axonal electrophysiologic features that appears to be distinct from both multifocal motor neuropathy and established motor neuron disorders.
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BACKGROUND: Preclinical and clinical studies of gabapentin in patients with ALS led the authors to undertake a phase III randomized clinical trial. METHODS: Patients were randomly assigned, in a double-blinded fashion, to receive oral gabapentin 3,600 mg or placebo daily for 9 months. The primary outcome measure was the average rate of decline in isometric arm muscle strength for those with two or more evaluations. RESULTS: Two hundred four patients enrolled, 196 had two or more evaluations, and 128 patients completed the study. The mean rate of decline of the arm muscle strength was not significantly different between the groups. Moreover, there was no beneficial effect upon the rate of decline of other secondary measures (vital capacity, survival, ALS functional rating scale, timed walking) nor was there any symptomatic benefit. In fact, analysis of the combined data from the phase II and III trials revealed a significantly more rapid decline of forced vital capacity in patients treated with gabapentin. CONCLUSION: These data provide no evidence of a beneficial effect of gabapentin on disease progression or symptoms in patients with ALS.
A number of presentations of chronic demyelinating polyneuropathy have been identified, each distinguished by its phenotypic pattern. In addition to classic chronic inflammatory demyelinating polyneuropathy (CIDP), which is characterized clinically by symmetric proximal and distal weakness and sensory loss, several regional variants can be recognized: multifocal motor neuropathy (MMN: asymmetric and pure motor), multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy (asymmetric, sensory, and motor), and distal acquired demyelinating symmetric (DADS) neuropathy (symmetric, distal, sensory, and motor). There are also temporal, pathological, and disease-associated variants. This review describes a clinical scheme for approaching the chronic acquired demyelinating polyneuropathies that leads to a rational use of supportive laboratory studies and treatment options. In addition, we propose new diagnostic criteria for CIDP that more accurately reflect current clinical practice.
Diabetic radiculoplexopathy is commonly viewed as a condition affecting the lower extremities. However, other regions may also be affected and the presence of upper extremity involvement has rarely been emphasized. Our goal was to illustrate the clinical features of arm involvement in this condition. Of 60 patients with diabetic lumbosacral radiculoplexopathy, we identified 9 who also had upper extremity involvement. The study included 8 men and 1 woman, ranging in age from 36 to 71 years. Upper limb involvement developed simultaneously with the onset of lower limb disorder in 1 patient, preceded it by 2 months in another patient, and occurred between 3 weeks and 15 months later in the remaining 7. In 5 cases, arm involvement developed after symptoms in the legs began to improve. The upper extremity weakness affected the hands and forearms most severely. It was unilateral in 5 patients and bilateral but asymmetric in 4. Pain was often present, but it was not a prominent feature. In most patients, neurologic deficits in the arms improved spontaneously after 2-9 months. We conclude that diabetic radiculoplexopathy may involve the cervical region before, after, or simultaneously with the lumbosacral syndrome. The upper limb process is similar to that in the legs, with subacutely progressive weakness and pain followed by spontaneous recovery.
Although most muscle disorders produce proximal weakness, some myopathies may manifest predominantly or exclusively distal weakness. Although several congenital, inflammatory, or metabolic myopathies may produce mainly distal weakness, there are several distinct entities, typically referred to as distal myopathies. Most of these are inherited conditions. The distal myopathies are rare, but characteristic clinical and histological features aid in their identification. Advances in molecular genetics have led to the identification of the gene lesions responsible for several of these entities and have also expanded our understanding of the genetic relationships of distal myopathies to other inherited disorders of muscle. This review summarizes current knowledge of the clinical and molecular aspects of the distal myopathies.
Mixed connective tissue disease is a rheumatological syndrome with neuromuscular manifestations that may include inflammatory myopathy and carpal tunnel syndrome. We report a patient who presented with an inflammatory myopathy and bilateral carpal tunnel syndrome prior to the diagnosis of a connective tissue disorder. Early in the course of treatment, a syndrome of acute renal failure developed. Knowledge of this syndrome, scleroderma renal crisis, and its possible relation to corticosteroid treatment is important to clinicians involved in the management of patients with inflammatory myopathies.
OBJECTIVE: To determine the sensitivity and specificity of superficial peroneal nerve (SPN)/peroneus brevis muscle (PBM) biopsy in a cohort of patients with suspected peripheral nerve vasculitis. BACKGROUND: In patients with suspected vasculitic neuropathy, combined nerve and muscle biopsies have been advocated as a way to increase the diagnostic yield, but the sensitivity and specificity of this approach have not been evaluated. Pathologic predictors of biopsy-proven peripheral nerve vasculitis have also not been analyzed in a systematic fashion. METHODS: The clinical, laboratory, and pathologic data for all patients undergoing SPN/PBM biopsy for possible vasculitis from 1986 through 1996 were analyzed. Biopsies were classified as positive, negative, or suspicious for vasculitis. Patients were then divided into vasculitis and nonvasculitis cohorts by final clinical diagnosis. RESULTS: Of 70 SPN/PBM biopsies, 22 (30%) showed definite vasculitis; nerve was diagnostic in 90% (n = 20) and muscle in 50% (n = 11). Nerve biopsy had a higher yield than muscle in patients with nonsystemic vasculitic neuropathy (p = 0. 0047) but not in those with systemic vasculitis. The estimated sensitivity of a positive SPN/PBM biopsy for vasculitis was 60%. Considering biopsies either positive or suspicious for vasculitis increased the sensitivity to 86% with a corresponding specificity of 85%. Pathologic features associated with necrotizing vasculitis were muscle fiber necrosis/regeneration (relative risk 18.1; 95% CI 3.4 to 96.1), predominant axonal nerve pathology (>8.8; >1.0 to 77.4), Wallerian-like degeneration (5.6; 1.4 to 21.9), and asymmetric nerve fiber loss (4.6; 1.4 to 15.9). CONCLUSIONS: These findings establish the yield, sensitivity, and specificity of SPN/PBM biopsy for diagnosing vasculitic neuropathy and validate the use of suggestive pathologic features for diagnosing cases lacking definite necrotizing vascular changes.
OBJECTIVE: To characterize an acquired, symmetric, demyelinating neuropathic variant with distal sensory or sensorimotor features. BACKGROUND: Classic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients have prominent proximal and distal weakness. However, chronic demyelinating neuropathies may present with different phenotypes. An approach that distinguishes these disorders primarily according to the pattern of weakness may be useful to the clinician. METHODS: A total of 53 patients with acquired symmetric demyelinating polyneuropathies were classified primarily according to the pattern of the neuropathy and secondarily according to the presence and type of monoclonal protein (M-protein) in this retrospective review. The authors distinguished between patients with distal sensory or sensorimotor involvement, designated as distal acquired demyelinating symmetric (DADS) neuropathy, from those with proximal and distal weakness, who were designated as CIDP. RESULTS: M-proteins were present in 22% of patients with CIDP. There were no features that distinguished clearly between CIDP patients with or without an M-protein, and nearly all of these patients responded to immunomodulating therapy. In contrast, nearly two-thirds of the patients with DADS neuropathy had immunoglobulin M (IgM) kappa monoclonal gammopathies, and this specific combination predicted a poor response to immunomodulating therapy. Antimyelin-associated glycoprotein (anti-MAG) antibodies were present in 67% of these patients. CONCLUSION: Distinguishing acquired demyelinating neuropathies by phenotype can often predict the presence of IgM kappa M-proteins, anti-MAG antibodies, and responses to immunomodulating therapy.
There are 11 glycogen diseases (GSD), nine of which are associated with myopathy. Most of these glycogen storage myopathies are associated with dynamic symptoms and signs in that the major neuromuscular complaints are exercise-induced muscle pain, cramps, and myoglobinura (e.g., GSD V or McArdle's disease associated with myophosphorylase deficiency). The other types of glycogen storage myopathies are considered static in that they are associated with fixed weakness rather than dynamic symptoms and signs. The static glycogen storage myopathies include: GSD I or Pompe's disease (acid maltase or (-glucosidase deficiency), GSD II or Cori-Forbes disease (debranching enzyme deficiency), and GSD IV or Andersen's disease (branching enzyme deficiency). This article reviews the clinical, laboratory, electrophysiologic, histopathologic, and pathogenesis of these static GSD myopathies.
The pathogenesis of myofibrillar myopathy (MFM) is not known. Muscle biopsy specimens demonstrate increased expression of cell cycle regulatory proteins as well as the ectopic expression of lamin B and nuclear matrix protein in the cytoplasm, suggesting the possibility of apoptosis. The authors investigated for apoptosis using the TUNEL method in six muscle biopsy specimens from patients with MFM. There was no evidence of apoptotic myonuclei in any of the MFM muscle biopsies. Further studies regarding the pathogenesis of MFM and the possible role of mitotic catastrophe are needed.
BACKGROUND: Chronic sensory-predominant polyneuropathy (PN) is a common clinical problem confronting neurologists. Even with modern diagnostic approaches, many of these PNs remain unclassified. OBJECTIVE: To better define the clinical and laboratory characteristics of a large group of patients with cryptogenic sensory polyneuropathy (CSPN) evaluated in 2 university-based neuromuscular clinics. DESIGN: Medical record review of patients evaluated for PN during a 2-year period. We defined CSPN on the basis of pain, numbness, and tingling in the distal extremities without symptoms of weakness. Sensory symptoms and signs had to evolve for at least 3 months in a roughly symmetrical pattern. Identifiable causes of PN were excluded by history, physical examination findings, and results of laboratory studies. We analyzed clinical and laboratory data from patients with CSPN and compared findings in patients with and without pain. RESULTS: Of 402 patients with PN, 93 (23.1%) had CSPN and stable to slowly progressive PN syndrome. These patients presented with a mean age of 63.2 years and a mean duration of symptoms of 62.9 months. Symptoms almost always started in the feet and included distal numbness or tingling in 86% of patients and pain in 72% of patients. Despite the absence of motor symptoms at presentation, results of motor nerve conduction studies were abnormal in 60% of patients, and electromyographic evidence of denervation was observed in 70% of patients. Results of laboratory studies were consistent with axonal degeneration. Patients with and without pain were similar regarding physical findings and laboratory test abnormalities. Only a few patients (<5%) had no evidence of large-fiber dysfunction on physical examination or electrophysiologic studies. All 66 patients who had follow-up examinations (mean, 12.5 months) remained ambulatory. CONCLUSIONS: Cryptogenic sensory polyneuropathy is a common, slowly progressive neuropathy that begins in late adulthood and causes limited motor impairment. Isolated small-fiber involvement is uncommon in this group of patients. Management should focus on rational pharmacotherapy of neuropathic pain combined with reassurance of CSPN's benign clinical course.
We report 11 patients with multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy, defined clinically by a multifocal pattern of motor and sensory loss, with nerve conduction studies showing conduction block and other features of demyelination. The clinical, laboratory, and histological features of these patients were contrasted with those of 16 patients with multifocal motor neuropathy (MMN). Eighty-two percent of MADSAM neuropathy patients had elevated protein concentrations in the cerebrospinal fluid, compared with 9% of the MMN patients (P < 0.001). No MADSAM neuropathy patient had elevated anti-GM1 antibody titers, compared with 56% of MMN patients (P < 0.01). In contrast to the subtle abnormalities described for MMN, MADSAM neuropathy patients had prominent demyelination on sensory nerve biopsies. Response to intravenous immunoglobulin treatment was similar in both groups (P = 1.0). Multifocal motor neuropathy patients typically do not respond to prednisone, but 3 of 6 MADSAM neuropathy patients improved with prednisone. MADSAM neuropathy more closely resembles chronic inflammatory demyelinating polyneuropathy and probably represents an asymmetrical variant. Given their different clinical patterns and responses to treatment, it is important to distinguish between MADSAM neuropathy and MMN.
Although muscle disease classically presents with proximal extremity weakness, some myopathic disorders, including several types of muscular dystrophy, result in predominantly, or exclusively, distal muscle involvement. Accurate diagnosis of these relatively uncommon conditions can be challenging for the clinician, because of both the unusual phenotype and the significant overlap in the clinical features of many of these entities. Advances in molecular genetics have permitted a tentative classification of these disorders and have led to the identification of the responsible gene lesion for several of these entities. This review summarizes current understanding of this interesting group of muscular dystrophies and briefly summarizes other myopathies that can present with distal weakness.
Myasthenia gravis (MG) characteristically involves ocular, bulbar, and proximal extremity muscles. Distal extremity muscles are typically spared or less prominently involved. The authors performed a retrospective chart review of MG patients treated at two university-based neuromuscular clinics. From a total population of 236, nine patients (3%) had distal extremity weakness exceeding proximal weakness by at least one Medical Research Council grade during their illness. Hand muscles, particularly finger extensors, were involved more frequently than were distal leg and foot muscles.