Consumption of coffee or caffeine and serum concentration of inflammatory markers: A systematic review.

Coffee consumption is associated with reduced risk of conditions that share low-grade inflammation as their physiopathological basis. We therefore summarized the effects of coffee or coffee components on serum levels of inflammatory markers. Clinical trials assessing the effect of coffee, caffeine or other coffee components on inflammatory markers were searched without restriction to publication date. Fifteen studies (8 involving coffee and 7 caffeine) were included. Increased adiponectin levels were found in four of seven trials comparing filtered coffee/caffeinated coffee with placebo or comparing its levels at baseline and after consumption of medium or dark roasted coffee, but no change was seen in caffeine trials. None of the five studies assessing the effects of coffee found changes in C-reactive protein (CPR), but one out of three trials found decreased CPR levels in response to caffeine. Interleukin (IL)-6 was increased by caffeinated coffee compared with placebo in one of four coffee trials, and by caffeine in three out of five studies. Caffeine increased IL-10 levels in two of three trials. These data suggest a predominant anti-inflammatory action of coffee but not of caffeine consumption. Moreover, the proinflammatory and anti-inflammatory responses to caffeine point to its complex effects on the inflammatory response.

Guillain-Barré syndrome associated with resistant cytomegalovirus infection after face transplantation.

A 39-year-old male, who received a facial allograft (cytomegalovirus [CMV] donor-seropositive, recipient-seronegative), developed multidrug-resistant CMV infection despite valganciclovir prophylaxis (900 mg/day) 6 months post transplantation. Lower extremity weakness with upper and lower extremity paresthesias developed progressively 11 months post transplantation, coinciding with immune control of CMV. An axonal form of Guillain-Barré syndrome was diagnosed, based on electrophysiological evidence of a generalized, non-length-dependent, sensorimotor axonal polyneuropathy. Treatment with intravenous immunoglobulin led to complete recovery without recurrence after 6 months.

Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy.

Miyoshi myopathy (MM) is an adult onset, recessive inherited distal muscular dystrophy that we have mapped to human chromosome 2p13. We recently constructed a 3-Mb P1-derived artificial chromosome (PAC) contig spanning the MM candidate region. This clarified the order of genetic markers across the MM locus, provided five new polymorphic markers within it and narrowed the locus to approximately 2 Mb. Five skeletal muscle expressed sequence tags (ESTs) map in this region. We report that one of these is located in a novel, full-length 6.9-kb muscle cDNA, and we designate the corresponding protein 'dysferlin'. We describe nine mutations in the dysferlin gene in nine families; five are predicted to prevent dysferlin expression. Identical mutations in the dysferlin gene can produce more than one myopathy phenotype (MM, limb girdle dystrophy, distal myopathy with anterior tibial onset).

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment.

The non-dystrophic myotonias are an important group of skeletal muscle channelopathies electrophysiologically characterized by altered membrane excitability. Many distinct clinical phenotypes are now recognized and range in severity from severe neonatal myotonia with respiratory compromise through to milder late-onset myotonic muscle stiffness. Specific genetic mutations in the major skeletal muscle voltage gated chloride channel gene and in the voltage gated sodium channel gene are causative in most patients. Recent work has allowed more precise correlations between the genotype and the electrophysiological and clinical phenotype. The majority of patients with myotonia have either a primary or secondary loss of membrane chloride conductance predicted to result in reduction of the resting membrane potential. Causative mutations in the sodium channel gene result in an abnormal gain of sodium channel function that may show marked temperature dependence. Despite significant advances in the clinical, genetic and molecular pathophysiological understanding of these disorders, which we review here, there are important unresolved issues we address: (i) recent work suggests that specialized clinical neurophysiology can identify channel specific patterns and aid genetic diagnosis in many cases however, it is not yet clear if such techniques can be refined to predict the causative gene in all cases or even predict the precise genotype; (ii) although clinical experience indicates these patients can have significant progressive morbidity, the detailed natural history and determinants of morbidity have not been specifically studied in a prospective fashion; (iii) some patients develop myopathy, but its frequency, severity and possible response to treatment remains undetermined, furthermore, the pathophysiogical link between ion channel dysfunction and muscle degeneration is unknown; (iv) there is currently insufficient clinical trial evidence to recommend a standard treatment. Limited data suggest that sodium channel blocking agents have some efficacy. However, establishing the effectiveness of a therapy requires completion of multi-centre randomized controlled trials employing accurate outcome measures including reliable quantitation of myotonia. More specific pharmacological approaches are required and could include those which might preferentially reduce persistent muscle sodium currents or enhance the conductance of mutant chloride channels. Alternative strategies may be directed at preventing premature mutant channel degradation or correcting the mis-targeting of the mutant channels.

Evaluation and treatment of inflammatory myopathies.

The major types of idiopathic inflammatory myopathy include dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) and immune mediated necrotising myopathy (NM). These myositides appear clinically, histologically and pathogenically distinct. DM, PM and immune mediated NM are responsive to immunosuppressive therapy, in contrast with IBM which is generally refractory to therapy. Greater understanding of the pathogenic bases of these disorders should hopefully lead to better treatment. We need well designed, prospective, double blind, placebo controlled trials in order to determine the best therapeutic options for these different disorders.

Inclusion body myositis: old and new concepts.

Inclusion body myositis (IBM) is the most common idiopathic inflammatory myopathy occurring in patients over the age of 50 years and probably accounts for about 30% of all inflammatory myopathies. Muscle biopsy characteristically reveals endomysial inflammation, small groups of atrophic fibres, eosinophilic cytoplasmic inclusions and muscle fibres with one or more rimmed vacuoles. However, any given biopsy may lack these histopathological abnormalities; the clinical examination is often the key to diagnosis. Early and often asymmetrical weakness and atrophy of the quadriceps and flexor forearm muscles (ie, wrist and finger flexors) are the clinical hallmarks of IBM. The pathogenesis of IBM is unknown. It may be autoimmune inflammatory myopathy or a primary degenerative myopathy with a secondary inflammatory. A prevailing theory is that there is an overproduction of beta-amyloid precursor protein in muscle fibres that is somehow cleaved into abnormal beta-amyloid, and the accumulation of the latter is somehow toxic to muscle fibres. However, there are many problems with this theory and more work needs to be done. Unfortunately, IBM is generally refractory to therapy. Further research into the pathogenesis, along with both preliminary small pilot trials and larger double blind, placebo controlled efficacy trials, are needed to make progress in our understanding and therapeutic approach for this disorder.

Immunosuppressive treatment of motor neuron syndromes. Attempts to distinguish a treatable disorder.

OBJECTIVE: To determine if response to immunosuppressive treatment in motor neuron syndromes could be predicted on the basis of clinical features, anti-GM1 antibodies, or conduction block. DESIGN: Prospective, uncontrolled, treatment trial using prednisone for 4 months followed by intravenous cyclophosphamide (3 g/m2) continued orally for 6 months. SETTING: All patients were referred to university hospital medical centers. PATIENTS: Sixty-five patients with motor neuron syndromes were treated with prednisone; 11 patients had elevated GM1 antibody titers, and 11 patients had conduction block. Forty-five patients received cyclophosphamide, eight of whom had elevated GM1 antibodies and 10 had conduction block. RESULTS: One patient responded to prednisone, and five patients responded to cyclophosphamide treatment. Only patients with a lower motor neuron syndrome and conduction block improved with either treatment. Response to treatment did not correlate with GM1 antibodies. CONCLUSIONS: GM1 antibodies did not serve as a marker for improvement in patients with motor neuron syndrome treated with immunosuppressive drugs. Patients with amyotrophic lateral sclerosis failed to improve irrespective of laboratory findings.

Chronic cryptogenic sensory polyneuropathy: clinical and laboratory characteristics.

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.

Inclusion body myositis in twins.

Sporadic inclusion body myositis (s-IBM) is characterized by late onset of slowly progressive weakness that involves the quadriceps and volar forearm muscles early in the course of the disease. There are hereditary forms of inclusion body myopathy (h-IBM) that histologically resemble s-IBM. The lack of inflammation on biopsy and the different ages at onset and patterns of muscle weakness distinguish s-IBM from h-IBM. We report twin brothers with the typical clinical and histologic features of s-IBM. The occurrence of s-IBM in these twins suggests the possibility of a genetic susceptibility to developing s-IBM.

Treatment of stiff-man syndrome with intravenous immunoglobulin.

Stiff-man syndrome (SMS) is a rare disorder characterized by progressive rigidity, stiffness, and spasms of axial and extremity muscles. The etiology of SMS is unknown, but evidence suggests a possible autoimmune basis. The recent successful use of intravenous immunoglobulin (IVIG) in treating various autoimmune neuromuscular disorders led us to try IVIG in an uncontrolled pilot study on three patients. All three showed subjective and objective improvement.

Myofibrillar myopathy: no evidence of apoptosis by TUNEL.

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.

Inclusion body myositis: explanation for poor response to immunosuppressive therapy.

We treated eight patients who had inclusion body myositis (IBM) with oral prednisone therapy, and we performed muscle biopsies before and after treatment. We documented the patients' clinical response to therapy and changes in serum CK. Although the serum CK level fell, muscle strength worsened after prednisone treatment. In addition, while inflammation decreased in the muscle biopsy specimens, the number of vacuolated and amyloid-positive fibers increased after oral prednisone therapy. These observations indicate that the inflammatory response in IBM may play a secondary role in the pathogenesis of IBM. The unique findings of intracellular amyloid deposits and rimmed vacuoles distinguishing IBM from other inflammatory myopathies, and recognition that suppression of inflammation has no effect on the clinical course, suggest that IBM may represent a degenerative muscle disorder.

Polyneuropathy complicating bone marrow and solid organ transplantation.

We report a generalized polyneuropathy coincident with the occurrence of graft-versus-host disease in four patients undergoing bone marrow transplantation and accompanying solid organ rejection (heart and kidney) in two patients. The neuropathy affected proximal and distal muscles, demonstrated hyporeflexia or areflexia, and usually had elevated CSF protein. Electrophysiologic studies did not meet strict criteria for demyelination. The signs of neuropathy improved after immunosuppressive treatment or simultaneous to the resolution of graft-versus-host disease or tissue rejection. Polyneuropathy must be considered as a potential complication of tissue transplantation.

Kennedy's disease: a clinicopathologic correlation with mutations in the androgen receptor gene.

We confirmed a mutation of the androgen receptor gene as the cause for Kennedy's disease, also called "X-linked recessive spinal and bulbar muscular atrophy" or "bulbospinal neuronopathy." The mutation is characterized by an increased size of a polymorphic tandem CAG repeat within the first exon of the gene. The study population consisted of 17 patients from seven families (five distinct kinships and two isolated cases). Two patients were as yet asymptomatic and had normal examinations. Four carrier females showed the mutant as well as the normal allele; none showed clinical features of Kennedy's disease. There was no large expansion of the mutation observed in three generations of one family. Phenotypic expression between and within families was variable and not related to the size of the mutation. This contrasts with the gene mutations found in myotonic dystrophy and fragile X syndrome, where increased severity of disease correlates with the number of tandem triplet repeats. The findings reported here appear to explain the failure to find genetic anticipation in Kennedy's disease. The DNA test for Kennedy's disease can now be used for definitive diagnosis and carrier detection. In addition, mutation analysis allows early detection, which has implications for potential treatment.

Distal acquired demyelinating symmetric neuropathy.

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.

Molecular profiles of inflammatory myopathies.

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.

Electrophysiologic findings in multifocal motor neuropathy.

We performed detailed electrophysiologic studies on 16 patients with clinically defined multifocal motor neuropathy and found a wide spectrum of demyelinating features. Only five patients (31%) had conduction block in one or more nerves. However, in 15 patients (94%) at least one nerve showed other features of demyelination. We also noted a significant degree of superimposed axonal degeneration in 15 patients. Eight patients (50%) had individual nerves with pure axonal injury, despite the presence of demyelinating features in other nerves. Antiganglioside antibodies were elevated in four of five patients with conduction block and five of 11 patients without conduction block. We conclude that multifocal motor neuropathy is characterized electrophysiologically by a wide spectrum of axonal and demyelinating features. Diagnostic criteria requiring conduction block may lead to underdiagnosis of this potentially treatable neuropathy.

Evaluation of neuromuscular symptoms in veterans of the Persian Gulf War.

OBJECTIVE: To comprehensively evaluate complaints of muscle fatigue, weakness, and myalgias in Persian Gulf veterans (PGV). BACKGROUND: Approximately 700,000 American troops were deployed to the Persian Gulf during Desert Shield and Desert Storm. Upon return from the Gulf, some PGV developed unexplained illnesses, and special referral centers were established for the evaluation of these patients. Among the most common symptoms of these PGV are fatigue, weakness, and myalgias. An Institute of Medicine committee recommended further exploration into the possible etiologies of these complaints. METHODS: Twenty PGV with severe muscle fatigue, weakness, or myalgias that interfered with their daily activities were referred for an extensive prospective neuromuscular evaluation. Routine laboratory studies included serum creatine kinase (CK), erythrocyte sedimentation rate, thyroid function tests, and exercise forearm tests. All patients received nerve conduction studies (NCS), repetitive nerve stimulation, quantitative and single-fiber electromyography (EMG), and muscle biopsies. RESULTS: Manual muscle strength examinations were normal in all patients. Six patients had mildly elevated CKs (range 223 to 768 IU/l); otherwise, laboratory tests were unremarkable. NCS were normal except in 2 patients with carpal tunnel syndrome. Quantitative EMGs were normal. One patient had mildly increased jitter on single-fiber EMG. Muscle biopsies demonstrated minor nonspecific abnormalities in 5 patients (i.e., increased central nuclei, rare necrotic fibers, tubular aggregates). CONCLUSIONS: Despite severe subjective symptoms, most of our patients had no objective evidence of neuromuscular disease. Mildly increased CKs or nonspecific histologic abnormalities on muscle biopsy were evident in 8 patients but were not believed to be clinically significant in most. We found no evidence of a specific neuromuscular disorder in any patient. Exposures to toxins during the Persian Gulf War were not likely responsible for our patients' symptoms.

Primary hyperparathyroidism and ALS: is there a relation?

BACKGROUND: An association between primary hyperparathyroidism (PHP) and amyotrophic lateral sclerosis (ALS) has been noted; however, a causal relation between these disorders has not been confirmed. PATIENTS/METHODS: We report five patients (three men, two women) meeting El Escorial criteria for ALS who also had PHP. In three patients, the diagnosis of PHP was made during the laboratory evaluation for motor neuron disease, and in one patient, the diagnosis of PHP preceded the onset of weakness by 5 months and in another by 2 years. Serum calcium levels in all five patients were elevated, ranging from 11.2 to 12.8 mg/dL (normal, <10.4 mg/dL), as were levels of parathyroid hormone (PTH). RESULTS: All five patients underwent parathyroid adenoma resection with subsequent normalization of serum calcium and PTH levels. Each patient had progressive weakness resulting in death 1 to 3 years following parathyroidectomy. CONCLUSION: Resection of parathyroid adenomas in patients meeting El Escorial criteria for ALS did not alter the course of ALS. PHP and ALS appear to be coexisting but unrelated disorders.

Inclusion body myositis: treatment with intravenous immunoglobulin.

We report the results of nine patients with inclusion body myositis treated with intravenous immunoglobulin in an open-label uncontrolled study. None of our patients improved on objective manual muscle testing or functional disability scores. One patient developed mild neutropenia, complicating the intravenous immunoglobulin treatment. Our results do not exclude the possibility that intravenous immunoglobulin could be beneficial in some patients by slowing the rate of deterioration or perhaps stabilizing the disease. However, given the lack of objective improvement and high cost of treatment, we would not recommend intravenous immunoglobulin in the treatment of inclusion body myositis unless a blinded, controlled trial demonstrates clear benefit.