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Our objective was to determine which factors contribute to depression symptoms or increased burden in caregivers of amyotrophic lateral sclerosis (ALS) patients. The five factors assessed were financial status, social support, employment status, religious denomination, and patient disease severity. A prospective, cross-sectional study of 50 caregivers was performed using the Beck Depression Inventory (BDI), Zarit-Burden Interview (ZBI), a demographic survey, and patient ALS functional rating scale, revised (ALSFRS-R) scores. Younger age, female gender, higher financial burden, type of religious denomination, and longer daily hours spent both with the patient and caregiving were associated with BDI scores, indicating they are significant risk factors for depression symptoms. Both younger age and the daily hours spent caregiving, as well as being employed and having less social support, were associated with ZBI scores and higher burden. Adequate social support was the only protective factor in caregivers' lives, having an association with lower burden levels. There was no statistically significant association between a caregiver's BDI or ZBI score and patient ALSFRS-R scores. In conclusion, we identified factors associated with depression symptoms and increased burden in ALS caregivers. Interventions should be designed to target the modifiable factors in order to prevent depression symptoms and minimize burden in caregivers at risk.

Inflammatory myopathy is rare in localized scleroderma. We report 2 new cases of regional inflammatory myopathy associated with localized scleroderma and review 10 reported cases of localized scleroderma associated with an inflammatory myopathy with regional muscle involvement, more often in the upper extremities. Serum creatine kinase was mildly elevated or normal. Histopathology often showed perimysial inflammation and plasma cell infiltration. These cases demonstrate that inflammatory myopathy should be considered in patients with localized scleroderma and regional muscle weakness, pain or atrophy. Muscle biopsy can confirm the diagnosis of myositis, which if identified, will require anti-inflammatory and/or immunosuppressive therapy., (Published by Elsevier B.V.)

Previous diffusion tensor imaging (DTI) studies have shown white matter pathology in amyotrophic lateral sclerosis (ALS), predominantly in the motor pathways. Further these studies have shown that DTI can be used longitudinally to track pathology over time, making white matter pathology a candidate as an outcome measure in future trials. DTI has demonstrated application in group studies, however its derived indices, for example fractional anisotropy, are susceptible to partial volume effects, making its role questionable in examining individual progression. We hypothesize that changes in the white matter are present in ALS beyond the motor tracts, and that the affected pathways and associated pattern of disease progression can be tracked longitudinally using automated diffusion connectometry analysis. Connectometry analysis is based on diffusion spectrum imaging and overcomes the limitations of a conventional tractography approach and DTI. The identified affected white matter tracts can then be assessed in a targeted fashion using High definition fiber tractography (a novel white matter MR imaging technique). Changes in quantitative and qualitative markers over time could then be correlated with clinical progression. We illustrate these principles toward developing an imaging biomarker for demonstrating individual progression, by presenting results for five ALS patients, including with longitudinal data in two. Preliminary analysis demonstrated a number of changes bilaterally and asymmetrically in motoric and extramotoric white matter pathways. Further the limbic system was also affected possibly explaining the cognitive symptoms in ALS. In the two longitudinal subjects, the white matter changes were less extensive at baseline, although there was evidence of disease progression in a frontal pattern with a relatively spared postcentral gyrus, consistent with the known pathology in ALS.

Background/aims: Environmental and occupational exposures are implicated as risk factors for amyotrophic lateral sclerosis (ALS), the etiology of which is largely unknown, although no causal relationships have been established., Objective: The aim of the study was to evaluate the associations of personal risk factors and self-reported environmental and occupational exposures with risk of ALS., Methods: The cases involved ALS patients (n = 66) identified from major neurological centers in Pittsburgh and Philadelphia, Pa., USA, from 2008 to 2010. The age-, race- and sex-matched controls included outpatient hospital and population-based controls (n = 66). A detailed questionnaire obtaining data on occupation, vocational and avocational exposure as well as personal lifestyle factors was administered., Results: Occupational exposure to metals (odds ratio, OR = 3.65; 95% CI: 1.15, 11.60) and pesticides (OR = 6.50; 95% CI: 1.78, 23.77) was related to increased risk of ALS after controlling for smoking and education. No associations were found for occupational exposure to organic or aromatic solvents., Conclusion: Workers exposed to metals and pesticides may be at greater risk of ALS. Future research should involve more accurate exposure assessment through the use of job exposure matrices, confirmation of occupation and biomarkers., (2013 S. Karger AG, Basel)

In amyotrophic lateral sclerosis (ALS), a recent double-blind placebo-controlled trial of acetyl-L-carnitine along with riluzole showed probable benefit in 42 patients compared with 40 patients who received placebo. Using an electrophysiologic measure devised to differentiate ALS from other neuromuscular conditions, a "splint-hand index" was devised and is reviewed. Analysis of skin in ALS may also be of interest, and there was a report of accumulation of fused in sarcoma protein in the epidermis of ALS patients. With regard to myasthenia gravis, there is another report that early treatment of ocular symptoms with corticosteroids may prevent the development of generalized symptoms. A new study of thymus histopathology in muscle-specific tyrosine kinase (MuSK) myasthenia gravis is covered and another article on the use of thymectomy. In Duchenne muscular dystrophy, the best method of administrating corticosteroids is still being debated, and a long-term study of daily versus intermittent prednisolone is reviewed. The study showed less sustained benefit from the intermittent prednisolone but with a better side effect profile. According to 2 recent reports, it seems that titin mutations may be an underrecognized cause of myopathy with early respiratory failure in adults. Keeping with the respiratory failure theme, there was also an interesting article on the long-term benefits and side effects of cyclosporine in patients with interstitial lung disease from antisynthetase syndrome. Finally, the spectrum of small fiber neuropathy may be expanding to include a causative role in some patients with fibromyalgia syndrome and in juveniles with diffuse pain and a possible autoimmune predisposition.

To promote clinical and patient oriented research, as part of the Second International ALS Conference in Tarrytown, NY, USA, seven pairs of clinicians and scientists were asked to lead discussions with meeting attendees on six major topics (one of which was discussed by two groups); each one the focus of a 90-min Breakout Session. Approximately 25 meeting attendees participated in each session. The Breakout Sessions considered six major themes: 1) Approaches to encourage clinicians to engage in more clinical research to discover the pathogenesis and cause of ALS; 2) Exploring avenues to build more effective partnerships between basic scientists and ALS physicians; 3) Increasing patient interest and commitment to participating in non-trial clinical research; 4) Brainstorming about factors that are most critical to the discovery of the pathogenesis and cause of ALS; 5) Finding ways to incorporate clinical research projects into clinical trials; and 6) Developing state-of-the-art epidemiological studies to solve the mystery of ALS. In this paper, we present the reports from each of the Breakout Sessions; and we provide a wrap-up of the entire conference.

Introduction: Neuromuscular disorders, predominantly critical illness myopathy (CIM) and critical illness polyneuropathy (CIP) occur in approximately one-third of patients in intensive care units. The aim of this study was to review the important role of electrophysiology in this setting., Results: In CIM, sarcolemmal inexcitability causes low amplitude compound muscle action potentials (CMAPs) that may have prolonged durations. Needle electrode examination usually reveals early recruitment of short duration motor unit potentials, often with fibrillation potentials. In CIP, the findings are usually those of a generalized axonal sensorimotor polyneuropathy. Direct muscle stimulation aids in differentiating CIP and CIM and in identifying mixed disorders along with other electrodiagnostic and histopathologic studies. Identifying evolving reductions in fibular CMAP amplitudes in intensive care unit (ICU) patients predicts development of neuromuscular weakness., Conclusions: Knowledge of the various neuromuscular disorders in critically ill patients, their risk factors, and associated electrodiagnostic findings can lead to development of a rational approach to diagnosis of the cause of neuromuscular weakness in ICU patients., (Copyright © 2013 Wiley Periodicals, Inc., a Wiley company.)

Background: Therapies designed to decrease the level of SOD1 are currently in a clinical trial for patients with superoxide dismutase (SOD1)-linked familial amyotrophic lateral sclerosis (ALS)., Objective: To determine whether the SOD1 protein in cerebral spinal fluid (CSF) may be a pharmacodynamic marker for antisense oligonucleotide therapy and a disease marker for ALS., Design: Antisense oligonucleotides targeting human SOD1 were administered to rats expressing SOD1G93A. The human SOD1 protein levels were measured in the rats' brain and CSF samples. In human CSF samples, the following proteins were measured: SOD1, tau, phosphorylated tau, VILIP-1, and YKL-40., Participants: Ninety-three participants with ALS, 88 healthy controls, and 89 controls with a neurological disease (55 with dementia of the Alzheimer type, 19 with multiple sclerosis, and 15 with peripheral neuropathy)., Results: Antisense oligonucleotide-treated SOD1G93A rats had decreased human SOD1 messenger RNA levels (mean [SD] decrease of 69% [4%]) and decreased protein levels (mean [SD] decrease of 48% [14%]) in the brain. The rats' CSF samples showed a similar decrease in hSOD1 levels (mean [SD] decrease of 42% [14%]). In human CSF samples, the SOD1 levels varied a mean (SD) 7.1% (5.7%) after additional measurements, separated by months, were performed. The CSF SOD1 levels were higher in the participants with ALS (mean [SE] level, 172 [8] ng/mL; P<.05) and the controls with a neurological disease (mean [SE] level, 172 [6] ng/mL; P<.05) than in the healthy controls (mean [SE] level, 134 [4] ng/mL). Elevated CSF SOD1 levels did not correlate with disease characteristics in participants with ALS or controls with dementia of the Alzheimer type, but they did correlate with tau, phosphorylated tau, VILIP-1 and YKL-40 levels in controls with dementia of the Alzheimer type., Conclusions: SOD1 in CSF may be an excellent pharmacodynamic marker for SOD1-lowering therapies because antisense oligonucleotide therapy lowers protein levels in the rat brain and rat CSF samples and because SOD1 levels in CSF samples from humans are stable over time.

An increasing incidence of myasthenia gravis (MG) has been reported in the elderly, but the full clinical ramifications of late-onset myasthenia gravis (LOMG) remain unclear. We describe the clinical features of our cohort of patients with MG with an emphasis on an onset after the age of 50. This was a retrospective analysis of medical records of a cohort of patients followed in two tertiary neuromuscular clinics and comparison of early onset MG (EOMG) versus LOMG. There were 174 patients with a mean age of onset of 55.2 ± 19.1 years, and 44 % were women. Late onset of myasthenia gravis after age 50 was reported in 114 patients (66 %). Anti-AChR antibody titers were elevated in 78 % of patients (65 % with EOMG vs. 85 % with LOMG; p = 0.003), and frequency of elevated titers of anti-MuSK antibodies was similar in both groups (present in 38 % of all tested seronegative patients). Myasthenic crisis was equally common in generalized EOMG and LOMG (13 %). Ocular MG was more common in LOMG compared to EOMG (40 vs. 18 %, p = 0.021). Diabetes was more prevalent with LOMG (27 vs. 5 %; p = 0.0002). Overlapping clinical features of EOMG and LOMG are consistent with a continuous clinical spectrum of a single condition, with more frequent occurrence of seropositive and ocular MG with a late onset. A higher burden of comorbidities, such as diabetes mellitus, may warrant a modified approach to treatment of myasthenia in LOMG. However, overall disease severity may not be higher with aging. These observations have implications for design of MG clinical trials and outcomes studies.

Electrodiagnostic testing is a useful component of the approach to a patient with suspected myopathy. It follows the history and is guided by the neurologic examination findings. Uncovering various electrodiagnostic patterns (eg, fibrillation potentials with short-duration motor unit potentials, short-duration motor unit potentials without fibrillation potentials, myotonic discharges, and short-duration motor unit potentials with complex repetitive discharges) can lead to more targeted laboratory testing and a refined differential diagnosis. Electromyography may also be used to detect subclinical myopathy, assess disease activity, and help select a suitable muscle for biopsy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Neurosarcoidosis is an uncommon but potentially serious manifestation of sarcoidosis. While the cranial nerves are most frequently affected, neurosarcoidosis can involve other nervous system tissues including the meninges, brain parenchyma (especially the hypothalamic region), spinal cord, peripheral nerve, and muscle. Diagnosis may be particularly challenging when neurosarcoidosis occurs in isolation. Diagnostic criteria usually include histologic identification of a noncaseating granuloma, supportive laboratory or imaging tests or both, and a compatible clinical course. Treatment has not been subjected to rigorous study, but corticosteroids are typically the first line of therapy and approximately half of patients have substantial benefit. For patients who are refractory to or intolerant of corticosteroid therapy, second-line agents include azathioprine, methotrexate, cyclosporine, cyclophosphamide, mycophenolate, and even cranial irradiation. The combination of infliximab and mycophenolate mofetil is under study as well. Treatment options will likely evolve as well-designed studies are undertaken.

Neuromuscular disorders that are diagnosed in the intensive care unit (ICU) usually cause substantial limb weakness and contribute to ventilatory dysfunction. Although some lead to ICU admission, ICU-acquired disorders, mainly critical illness myopathy (CIM) and critical illness polyneuropathy (CIP), are more frequent and are associated with considerable morbidity. Approximately 25% to 45% of patients admitted to the ICU develop CIM, CIP, or both. Their clinical features often overlap; therefore, nerve conduction studies and electromyography are particularly helpful diagnostically, and more sophisticated electrodiagnostic studies and histopathologic evaluation are required in some circumstances. A number of prospective studies have identified risk factors for CIP and CIM, but their limitations often include the inability to separate CIM from CIP. Animal models reveal evidence of a channelopathy in both CIM and CIP, and human studies also identified axonal degeneration in CIP and myosin loss in CIM. Outcomes are variable. They tend to be better with CIM, and some patients have longstanding disabilities. Future studies of well-characterized patients with CIP and CIM should refine our understanding of risk factors, outcomes, and pathogenic mechanisms, leading to better interventions.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disease with an average survival of 3 years from symptom onset. Rapid and conclusive early diagnosis is essential if interventions with disease-modifying therapies are to be successful. Cytoskeletal modification and inflammation are known to occur during the pathogenesis of ALS. We measured levels of cytoskeletal proteins and inflammatory markers in the CSF of ALS, disease controls and healthy subjects. We determined threshold values for each protein that provided the optimal sensitivity and specificity for ALS within a training set, as determined by receiver operating characteristic analysis. Interestingly, the optimal assay was a ratio of the levels for phosphorylated neurofilament heavy chain and complement C3 (pNFH/C3). We next applied this assay to a separate test set of CSF samples to verify our results. Overall, the predictive pNFH/C3 ratio identified ALS with 87.3% sensitivity and 94.6% specificity in a total of 71 ALS subjects, 52 disease control subjects and 40 healthy subjects. In addition, the level of CSF pNFH correlated with survival of ALS patients. We also detected increased pNFH in the plasma of ALS patients and observed a correlation between CSF and plasma pNFH levels within the same subjects. These findings support large-scale prospective biomarker studies to determine the clinical utility of diagnostic and prognostic signatures in ALS., (© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.)

A 25-year-old woman had childhood-onset muscle weakness and dilated cardiomyopathy. She exhibited predominantly distal weakness with early toe walking. Dilated cardiomyopathy required cardiac transplantation at age 15 years. We identified a de-novo, heterozygous, missense mutation, c.2348G>C (p. Arg783Pro), in exon 21 of the MYH7 gene, which encodes slow skeletal muscle fiber/β-cardiac myosin heavy chain protein, that replaces a highly conserved arginine with a proline. This novel mutation that results in the unusual combined cardiac and skeletal muscle phenotype localizes to the essential light chain binding area, a region only previously shown to be mutated in hypertrophic cardiomyopathy., (Published by Elsevier B.V.)

Amyotrophic lateral sclerosis (ALS) is a fatal neurologic disease characterized by progressive motor neuron degeneration. Clinical disease management is hindered by both a lengthy diagnostic process and the absence of effective treatments. Reliable panels of diagnostic, surrogate, and prognostic biomarkers are needed to accelerate disease diagnosis and expedite drug development. The cysteine protease inhibitor cystatin C has recently gained interest as a candidate diagnostic biomarker for ALS, but further studies are required to fully characterize its biomarker utility. We used quantitative enzyme-linked immunosorbent assay (ELISA) to assess initial and longitudinal cerebrospinal fluid (CSF) and plasma cystatin C levels in 104 ALS patients and controls. Cystatin C levels in ALS patients were significantly elevated in plasma and reduced in CSF compared to healthy controls, but did not differ significantly from neurologic disease controls. In addition, the direction of longitudinal change in CSF cystatin C levels correlated to the rate of ALS disease progression, and initial CSF cystatin C levels were predictive of patient survival, suggesting that cystatin C may function as a surrogate marker of disease progression and survival. These data verify prior results for reduced cystatin C levels in the CSF of ALS patients, identify increased cystatin C levels in the plasma of ALS patients, and reveal correlations between CSF cystatin C levels to both ALS disease progression and patient survival.

Recent studies using mass spectrometry have discovered candidate biomarkers for amyotrophic lateral sclerosis (ALS). However, those studies utilized small numbers of ALS and control subjects. Additional studies using larger subject cohorts are required to verify these candidate biomarkers. Cerebrospinal fluid (CSF) samples from 100 patients with ALS, 100 disease control, and 41 healthy control subjects were examined by mass spectrometry. Sixty-one mass spectral peaks exhibited altered levels between ALS and controls. Mass peaks for cystatin C and transthyretin were reduced in ALS, whereas mass peaks for posttranslational modified transthyretin and C-reactive protein (CRP) were increased. CRP levels were 5.84 +/- 1.01 ng/ml for controls and 11.24 +/- 1.52 ng/ml for ALS subjects, as determined by enzyme-linked immunoassay. This study verified prior mass spectrometry results for cystatin C and transthyretin in ALS. CRP levels were increased in the CSF of ALS patients, and cystatin C level correlated with survival in patients with limb-onset disease. Our biomarker panel predicted ALS with an overall accuracy of 82%.

Protein-based biomarkers for amyotrophic lateral sclerosis (ALS) and other motor neuron diseases (MNDs) have many potential clinical utilities, including diagnostic, prognostic, and drug development indications. During the past decade a number of potential protein biomarkers have been proposed for MNDs. Further verification studies, followed by large validation and qualification studies, are required to advance these initial discoveries toward clinical use. Study of additional patient populations, including disease mimics, is required during the validation phase of biomarker development. Important regulatory issues are discussed that will affect the timing and strategy for biomarker assay development in ALS and other MNDs. The continued development of protein biomarkers for MNDs requires extensive collaboration between academic clinicians and scientists in conjunction with the biotechnology and pharmaceutical industries.

Monoclonal proteins (paraproteins) may be detected in the sera in approximately 1% of the general population and are frequently associated with peripheral neuropathy. Paraproteinemic neuropathy (PPN) is most commonly associated with monoclonal gammopathy of undetermined significance, and may also occur in the context of multiple myeloma, amyloidosis, cryoglobulinemia, and other hematologic malignant and nonmalignant conditions. Possible malignant conversion of underlying benign monoclonal gammopathy should be closely monitored, and risk factors include progression of neuropathy and rising titers of monoclonal protein. PPN is frequently associated with autoantibodies targeting peripheral nerve antigens, including anti-MAG and anti-GM1 antibodies. Therapy is mostly based on the treatment of the underlying hematologic disorder. Risks and benefits should be carefully evaluated as treatment may be associated with considerable morbidity. Rituximab may be helpful in treatment of IgM-PPN, and paraproteinemic multifocal motor neuropathy usually responds to IVIG. Plasmapheresis is more effective with IgG/IgA paraproteinemic neuropathies. At this time it is not clear whether mere presence of neuropathy warrants more aggressive treatment of otherwise quiescent hematologic malignances (e.g. smoldering myeloma).

Background and Purpose: Hemorrhage is known to occur in posterior reversible encephalopathy syndrome (PRES), but the characteristics have not been analyzed in detail. The purpose of this study was to evaluate the imaging and clinical features of hemorrhage in PRES., Materials and Methods: Retrospective assessment of 151 patients with PRES was performed, and 23 patients were identified who had intracranial hemorrhage at toxicity. Hemorrhage types were identified and tabulated, including minute focal hemorrhages (<5 mm), sulcal subarachnoid hemorrhage, and focal hematoma. Clinical features of hemorrhage and nonhemorrhage PRES groups were evaluated, including toxicity blood pressure, coagulation profile/platelet counts, coagulation-altering medication, and clinical conditions associated with PRES. Toxicity mean arterial pressure (MAP) groups were defined as normal (<106 mm Hg), mildly hypertensive (106-116 mm Hg), or severely hypertensive (>116 mm Hg)., Results: The overall incidence of hemorrhage was 15.2%, with borderline statistical significance noted between the observed clinical associations (P = .07). Hemorrhage was significantly more common (P = .02) after allogeneic bone marrow transplantation (allo-BMT) than after solid-organ transplantation. The 3 hemorrhage types were noted with equal frequency. A single hemorrhage type was found in 16 patients, with multiple types noted in 7. Patients undergoing therapeutic anticoagulation were statistically more likely to develop hemorrhage (P = .04). No difference in hemorrhage incidence was found among the 3 blood pressure subgroups (range, 14.9%-15.9%)., Conclusions: Three distinct types of hemorrhage (minute hemorrhage, sulcal subarachnoid hemorrhage, hematoma) were identified in PRES with equal frequency. The greatest hemorrhage frequency was seen after allo-BMT and in patients undergoing therapeutic anticoagulation. Hemorrhage rate was independent of the toxicity blood pressure.

Objective: Juvenile dermatomyositis (DM) is an autoimmune disease of childhood characterized by lesions in skin and muscle that are populated by plasmacytoid dendritic cells (PDCs) and lymphocyte infiltrates. We undertook this study to examine the cellular composition, organization, and molecular milieu of the cellular infiltrates in muscle in juvenile DM and to correlate the infiltrates with clinical disease manifestations., Methods: Since PDCs and lymphocyte foci express CCL19 and CCL21, we investigated for in situ formation of lymphoid microstructures that could be sites of extranodal immune activation., Results: Analyses of muscle biopsy samples from children with new-onset juvenile DM showed 3 categories of lesions: diffuse infiltrates, lymphocytic aggregates lacking follicle-like organization, and follicle-like structures. The last of these exhibited elements of classic lymphoid follicles, including networks of follicular dendritic cells and high endothelial venules. They also expressed high levels of CXCL13 and lymphotoxins known to support lymphoid organogenesis. There were also resident naive CD45RA+ T cells and maternally derived B cells and PDCs. Patients with diffuse infiltrates or lymphocytic aggregates were responsive to standard therapy with steroids and methotrexate, but those with follicle-like structures tended to have severe disease that required additional agents such as intravenous Ig or rituximab., Conclusion: These data suggest that lymphoneogenesis is a component of the early disease process in juvenile DM. Ectopic lymphoid structures could indicate a severe course of disease; their early detection could be a tool for disease management.

Hydroxychloroquine causes a vacuolar myopathy that is usually of mild to moderate severity. The myopathy may be underrecognized, especially in patients who receive multiple other medications for complex illnesses. We report two patients with connective tissue diseases and unusually severe, histopathologically proven hydroxychloroquine myopathy. Both had ventilatory failure; one also had primary pulmonary disease associated with scleroderma, but the other lacked a pulmonary etiology. The ventilatory failure and subsequent medical complications led to death despite discontinuation of hydroxychloroquine, thereby underscoring the potential severity of hydroxychloroquine myopathy and the need for its early recognition.

R+ pramipexole (PPX) is a lipophilic cation that concentrates into brain and mitochondria and efficiently scavenges reactive oxygen and nitrogen species (RONS). Under the auspices of a Physician-Sponsor IND, R+PPX was dosed to small numbers of ALS patients for tolerability and safety while efficacy measures were also collected. The purpose of this paper is to describe the outcomes of these initial clinical studies. In a futility design study, 30 patients with early SALS were evaluated monthly for ALSFRS-R scores and FVC measurements for three months during lead-in, followed by open-label dosing at 30 mg/day of R+PPX for the next six months. In the dose escalation study, 10 subjects with early ALS received daily doses of R+PPX from 10 mg t.i.d. to 100 mg t.i.d. over seven weeks. In the open-label extension analysis, subjects from the initial studies were treated with 30 mg/day for at least six months, then switched to 60 mg/day. R+PPX was tolerated well in all studies. In the futility study, slopes of decline in ALSFRS-R scores and neurophysiological index (NI) values yielded non-significant reductions during treatment. In the dose-escalation study, all subjects increased daily R+PPX intake safely to 100 mg t.i.d. Markers of ALS did not change (ALSFRS-R) or improved (FVC). Trough and peak plasma (PPX) increased linearly with dosing, and several subjects achieved plasma (PPX) >1 microM. In the open-label extension protocol, changing from 30 to 60 mg/day caused a non-significant 17% reduction in slope of decline of ALSFRS-R. It was concluded that R+PPX was tolerated well in long-term dosing at 30 and 60 mg/day. Encouraging but non-significant effects of R+PPX on ALS decline were observed. High doses of R+PPX were tolerated well and yielded neuroprotective plasma levels. These findings support longer-term testing of higher R+PPX doses as a potential disease-altering therapy for SALS.

Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), lack definitive diagnostic tests or biomarkers of disease progression. Most studies that investigate protein abnormalities in ALS have used biofluids such as blood or cerebrospinal fluid (CSF), while some have used post mortem tissue or CSF samples. Since ALS disease progression and post mortem effects probably induce significant alterations to protein modifications or proteolysis, we directly examined the CSF proteome from ALS subjects at various lengths of time from symptom onset and at autopsy by mass spectrometry based proteomics. CSF was also obtained from both healthy age-matched control subjects and at autopsy from healthy and Alzheimer's disease (AD) controls. We identified significant differences in the CSF proteome between living and post mortem ALS subjects, as well as living and post mortem control subjects. We also noted differences in the CSF proteome of ALS subjects that have exhibited symptoms for varying lengths of time and between ALS and AD subjects at end-stage of disease. This is the first study describing differences in the CSF proteome from post mortem and living ALS subjects using a mass spectrometric approach. These differences highlight the importance of utilizing CSF from living ALS subjects near the time of symptom onset for the identification of early protein biomarkers, although some protein alterations that occur early in the disease process are maintained throughout the course of disease and in post mortem samples.

Since vasculitic neuropathy is treatable and potentially debilitating, clinicians should develop an approach to neuropathy that increases the likelihood of uncovering existing systemic or nonsystemic vasculitis. The presence of a connective tissue disease, systemic vasculitis, asymmetric or non--length-dependent axonal polyneuropathy, or multiple axonal mononeuropathies should heighten suspicion, but vasculitic neuropathy can also present as a distal symmetric polyneuropathy with or without other organ involvement. Electrodiagnostic testing utilizing extensive nerve conductions may be helpful in identifying features suggestive of vasculitic neuropathy and in selecting an abnormal nerve and muscle for biopsy confirmation. An array of laboratory tests may lead to identification of a systemic disorder that is either characterized by or predisposes to vasculitic neuropathy. The mainstays of treatment are corticosteroids and cyclophosphamide, but other drugs are used in specific conditions. With early diagnosis and careful monitoring of treatment regimens, the prognosis is usually good.

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons. We tested the hypothesis that proteomic analysis will identify protein biomarkers that provide insight into disease pathogenesis and are diagnostically useful. To identify ALS specific biomarkers, we compared the proteomic profile of cerebrospinal fluid (CSF) from ALS and control subjects using surface-enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF-MS). We identified 30 mass ion peaks with statistically significant (p < 0.01) differences between control and ALS subjects. Initial analysis with a rule-learning algorithm yielded biomarker panels with diagnostic predictive value as subsequently assessed using an independent set of coded test subjects. Three biomarkers were identified that are either decreased (transthyretin, cystatin C) or increased (carboxy-terminal fragment of neuroendocrine protein 7B2) in ALS CSF. We validated the SELDI-TOF-MS results for transthyretin and cystatin C by immunoblot and immunohistochemistry using commercially available antibodies. These findings identify a panel of CSF protein biomarkers for ALS.

Histopathologic evaluation of nerve biopsy specimens provides important diagnostic information in some patients with peripheral neuropathy. The role of nerve biopsy is more restricted than that of muscle biopsy. Nerve biopsy is utilized mainly for diagnosis of vasculitis and infiltrative neuropathies. It is also utilized in diagnosis of atypical inflammatory demyelinating neuropathies in which the clinical, electrodiagnostic, and laboratory features are inconclusive. In addition, the study of nerve histopathology can also enhance our understanding of disease pathogenesis.

Fabry's disease is a multisystem disorder that is commonly associated with a painful, debilitating neuropathy. The common coexistence of arthralgias and an elevated erythrocyte sedimentation rate may lead to the misdiagnosis of a rheumatic condition. We report a 38-year-old man who was evaluated for progressive neuropathy and limb pain in the setting of longstanding arthralgias, presumed juvenile rheumatoid arthritis, and past renal transplantation. Histopathologic assessment of nerve and muscle biopsy specimens led to the diagnosis of Fabry's disease, thus allowing the patient to receive enzyme replacement therapy that may slow progression and preserve the transplanted kidney.

Myasthenic crisis is a serious occurrence, affecting up to 27% of patients with myasthenia gravis. In the approach to the patient with myasthenic crisis, (1) the diagnosis of myasthenia gravis is confirmed; (2) respiratory failure is evaluated and treated in the intensive care unit, while potential precipitating factors are identified and managed; (3) immunomodulatory treatment is initiated; and (4) complications are avoided or managed promptly. The mortality rate should be 5% or less, with the elderly being most vulnerable.

Histologically proven sarcoid neuropathy is rare and its features are protean. The objectives of this study were to describe a patient with chronic, stable sarcoidosis and new onset of neuropathy and to review the neuropathic manifestations of sarcoidosis. We conducted a case report and review of the literature. A 59-year-old woman with a 9-year history of quiescent sarcoidosis developed progressive distal leg paresthesias over 12 months. Electrodiagnostic studies showed a mild left peroneal neuropathy, and superficial peroneal nerve biopsy revealed evidence of sarcoidosis with vasculitis. Additional investigations revealed unsuspected, active systemic sarcoidosis involving the lungs, salivary glands, and peripheral lymph nodes. Historically, sarcoid neuropathy could present as focal, multifocal, or diffuse sensorimotor neuropathy with predominant axon loss and sometimes vasculitis. Serologic testing has limited value, particularly in patients with known sarcoidosis. Nerve biopsy is required for diagnosis of sarcoid neuropathy, and positive biopsy could lead to recognition of more extensive subclinical multisystem involvement. Fortunately, most patients improve with oral corticosteroids.

Despite major advances in molecular genetics, histopathologic evaluation of muscle biopsy specimens continues to provide important diagnostic information in patients with suspected muscle diseases and in patients with vasculitic neuropathies. Muscle biopsy specimens are used in diagnosing many inherited as well as inflammatory and toxic myopathies. Furthermore, the study of muscle histopathology can also enhance our understanding of disease pathogenesis.

Objective: To determine the long-term outcome and associated clinical, serologic, and pathologic features in a cohort of patients with connective tissue disease (CTD) and the anti-signal recognition particle (anti-SRP) autoantibody., Methods: Sera and clinical data were collected prospectively from consecutive adult patients with polymyositis (PM; n = 134), dermatomyositis (n = 129), or other CTDs (predominantly systemic sclerosis [SSc; n = 790]). Patients were first evaluated during 1973-2001., Results: Nineteen patients with the anti-SRP autoantibody were identified, 16 (84%) of whom had pure PM and 3 (2 with SSc and 1 with antisynthetase syndrome) had yet to develop features of myositis after a mean followup of 4.5 years (range 2.5-6 years). More SRP-positive PM patients had severe proximal muscle weakness (50%) and muscle atrophy (67%) at initial presentation compared with antisynthetase-positive PM controls. Cardiac involvement occurred in only 2 of 16 SRP-positive PM patients (13%), and interstitial lung disease was noted in 3 of 13 SRP-positive PM patients (23%) and in the 3 SRP-positive nonmyositis patients. There was a relative lack of inflammation in muscle biopsy specimens from the SRP-positive PM cohort. Other autoantibodies in the SRP-positive patients included Ro/SSA (4 patients), Th/To (1 patient), and anti-PL-12 (1 patient). Survival in the SRP-positive PM patients was comparable with that seen in the cohort of SRP-negative PM patients., Conclusion: The anti-SRP autoantibody is not specific for PM. Severe muscle weakness and atrophy were prominent features in PM patients with anti-SRP. Cardiac involvement was less common and survival was better in patients with anti-SRP than has previously been reported.

The distinct distribution of trkA receptors on small neurons and trkC receptors on large neurons in the dorsal root ganglion correlates with the dependence of these two classes of neurons on nerve growth factor and neurotrophin-3, respectively, for survival during development. In adult animals, the distribution of high affinity neurotrophin (trk) is complex and overlapping; neurotrophins are not required for cell survival, but may influence cell phenotype and the response to injury. In order to test the functional activity of trkA receptors in the sensory ganglia of adult animals in vivo, we examined the ability of a nerve growth factor-expressing recombinant replication-defective herpes simplex virus-based vector to prevent the selective degeneration of large sensory fibres caused by intoxication with pyridoxine. Transduction of dorsal root ganglion neurons in vivo by subcutaneous inoculation of the nerve growth factor-expressing vector prevented the development of pyridoxine-induced neuropathy measured by electrophysiological, morphological and behavioural measures. These results demonstrate a functional activity of trkA receptors expressed on large neurons in the dorsal root ganglion in mature animals; this observation has important implications for the choice of neurotrophic factors for treatment of peripheral nerve disease.

Acute myopathy is a common problem in intensive care units. Those at highest risk for developing critical illness myopathy are exposed to intravenous corticosteroids and paralytic agents during treatment of various illnesses. Diffuse weakness and failure to wean from mechanical ventilation are the most common clinical manifestations. Serum creatine kinase levels are variable. Electrodiagnostic studies reveal findings of a myopathic process, often with evidence of muscle membrane inexcitability. Based on animal model studies, the loss of muscle membrane excitability may be related to inactivation of sodium channels at the resting potential. In addition, human and animal pathologic studies reveal characteristic loss of myosin with relative preservation of other structural proteins. In some patients, there is also upregulation of proteolytic pathways, involving calpain and ubiquitin, in conjunction with increased apoptosis. Fortunately, the disorder is reversible, but there may be considerable morbidity.

Small-fiber neuropathy is a common disorder. It is often "idiopathic" and typically presents with painful feet in patients over the age of 60. Autoimmune mechanisms are often suspected, but rarely identified. Known causes of small-fiber neuropathy include diabetes mellitus, amyloidosis, toxins, and inherited sensory and autonomic neuropathies. Occasionally, small-fiber neuropathy is diffuse or multifocal. Depending on the type of small-fiber neuropathy, autonomic dysfunction can be significant or subclinical. Diagnosis is made on the basis of the clinical features, normal nerve conduction studies, and abnormal specialized tests of small-fiber function. These specialized studies include assessment of epidermal nerve fiber density as well as sudomotor, quantitative sensory, and cardiovagal testing. The sensitivities of these tests range from 59-88%. Each has certain advantages and disadvantages, and the tests may be complementary. Unless an underlying disease is identified, treatment is usually directed toward alleviation of neuropathic pain., (Copyright 2002 Wiley Periodicals, Inc.)

Peripheral neuropathy is a common and debilitating complication of diabetes. In animal models, neurotrophic factors can prevent progression of the neuropathy, but adverse effects prevent systemic administration in adequate doses to treat human disease. We examined whether gene transfer with replication-defective genomic herpes simplex virus (HSV) vectors modified to express nerve growth factor (NGF) could be used to prevent progression of neuropathy in mice. Diabetes induced by streptozotocin (STZ) resulted in a sensory neuropathy manifest by a decrease in the foot sensory nerve amplitude (FSA; control = 20 +/- 0.1 microV, treated = 14 +/- 0.1 microV). Transduction of dorsal root ganglia in vivo with an HSV-based vector expressing NGF under the control of the human cytomegalovirus immediate early promoter (vector SHN) or the HSV latency active promoter 2 (vector SLN) by footpad inoculation 2 weeks after STZ administration protected against the decrease in FSA (22 +/- 1.4 microV and 21 +/- 1.7 microV, respectively) measured 4 weeks later. Injection of SHN into inguinal adipose tissue 2 weeks after onset of diabetes also prevented the decrease in FSA (20 +/- 3.3 microV). These results suggest that gene transfer with an NGF-producing herpes-based vector may prove useful in the treatment of diabetic neuropathy.

Uncovering the cause of a suspected myopathy may be challenging. However, a careful approach starts with utilizing the wealth of available information regarding the clinical and laboratory features of myopathy. Electrodiagnostic testing is then obtained (in most cases). Recognition of the pattern of EMG findings in light of the clinical and laboratory features should narrow the differential diagnosis and dictate the next steps in the evaluation. Histopathologic or molecular studies, or both may follow. Ultimately, this approach usually allows the clinician to make the correct diagnosis.

A 43-year-old man with an 8-year history of hypereosinophilia was evaluated for persistent muscle pain. Methotrexate and corticosteroids were ineffective. Examination, limited by pain even with passive motion, showed only mild weakness. Electromyography and muscle enzymes were normal. A needle muscle biopsy specimen revealed eosinophilic perimyositis. This case illustrates that the diagnosis of eosinophilic perimyositis requires histopathological evaluation, which should be pursued in patients with eosinophilia and persistent myalgia despite normal electromyography and muscle enzymes., (Copyright 2002 Wiley Periodicals, Inc.)

Objectives: To better characterize the clinical, electrodiagnostic, and pathologic aspects of amiodarone-induced neuromyopathy., Methods: We reviewed medical records, performed electrodiagnostic studies, and examined histopathologic specimens of muscle and nerve in three patients with amiodarone-induced neuromuscular toxicity, as well as summarized the relevant literature., Results: Two patients had a slightly asymmetric, mixed, but primarily demyelinating sensorimotor polyneuropathy. One also had a substantial myopathy. The third had an acute neuropathy resembling Guillain-Barré syndrome. Seemingly, creatine kinase levels did not correlate with clinical or electromyographic evidence of myopathy. Histologic evaluations of peripheral nerves revealed demyelination, some axon loss, and a variable number of characteristic lysosomal inclusions. Muscle specimens from two patients showed evidence of a vacuolar myopathy. After discontinuation of amiodarone, two patients improved and one died of cardiac arrhythmia., Conclusions: Although the clinical features and onset times vary, amiodarone neuromuscular toxicity manifests as a mixed polyneuropathy, vacuolar myopathy, or both. Creatine kinase levels may not correlate with the degree of myopathy. Variable numbers of lysosomal inclusions in peripheral nerve, endothelial cells, and muscle are characteristic.