Motor cortex glutathione deficit in ALS measured in vivo with the J-editing technique.

This study compared in vivo levels of the antioxidant glutathione (GSH) in the motor cortex of 11 ALS patients with those in 11 age-matched healthy volunteers (HV). Using the standard J-edited spin-echo difference MRS technique, GSH spectra were recorded on a 3.0 T GE MR system from a single precentral gyrus voxel. GSH levels expressed as ratios to the unsuppressed voxel tissue water (W) were 31% lower in ALS patients than in HV (p=.005), and 36% lower in ALS than in HV (p=.02) when expressed as ratios to the total creatine peak (tCr), supporting a role for oxidative stress in ALS. Levels of the putative neuronal marker N-acetylaspartate (NAA) relative to W did not differ between ALS and HV (p=.26), but were lower by 9% in ALS than in HV (p=.013) when expressed as ratios relative to tCr. This discrepancy is attributed to small but opposite changes in NAA and tCr in ALS that, as a ratio, resulted in a statistically significant group difference, further suggesting caution in using tCr as an internal reference under pathological conditions.

Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.

OBJECTIVE: To systematically review evidence bearing on the management of patients with amyotrophic lateral sclerosis (ALS). METHODS: The authors analyzed studies from 1998 to 2007 to update the 1999 practice parameter. Topics covered in this section include breaking the news, multidisciplinary clinics, symptom management, cognitive and behavioral impairment, communication, and palliative care for patients with ALS. RESULTS: The authors identified 2 Class I studies, 8 Class II studies, and 30 Class III studies in ALS, but many important areas have been little studied. More high-quality, controlled studies of symptomatic therapies and palliative care are needed to guide management and assess outcomes in patients with ALS. RECOMMENDATIONS: Multidisciplinary clinic referral should be considered for managing patients with ALS to optimize health care delivery and prolong survival (Level B) and may be considered to enhance quality of life (Level C). For the treatment of refractory sialorrhea, botulinum toxin B should be considered (Level B) and low-dose radiation therapy to the salivary glands may be considered (Level C). For treatment of pseudobulbar affect, dextromethorphan and quinidine should be considered if approved by the US Food and Drug Administration (Level B). For patients who develop fatigue while taking riluzole, withholding the drug may be considered (Level C). Because many patients with ALS demonstrate cognitive impairment, which in some cases meets criteria for dementia, screening for cognitive and behavioral impairment should be considered in patients with ALS (Level B). Other management strategies all lack strong evidence.

Randomized controlled phase II trial of glatiramer acetate in ALS.

The authors conducted a randomized controlled trial to test the safety and immunology of glatiramer acetate in ALS. Twenty treated patients were randomly assigned to daily or biweekly injections. Ten control patients were selected from another trial and followed up concurrently. Injection reactions were the only common adverse event (p = 0.01). Treated patients showed enhanced lymphocyte proliferation (p = 0.02). The safety profile and immune effects support conducting larger trials of dose selection and efficacy.

Incidence and predictors of PEG placement in ALS/MND.

In the Project on Death in America ALS cohort, 121 patients were followed to examine the timing of key milestones in the course of the disease, such as tracheostomy and PEG placement. During the 2- to 4-year follow-up period, 26.5% of patients received PEG, yielding a cumulative incidence of 48%. PEG placement occurred, on average, 16 months after patients received confirmation of the diagnosis at our Center. Patients who received PEG were more likely to have tracheostomies than patients not using PEG (p<0.01). In multivariate proportional hazard models that included both sociodemographic and disease indicators, the strongest predictor of PEG use was a patient's baseline preference for PEG: 57.1% of patients "absolutely in favor" went on to have PEG, compared to only 9.3% of those "absolutely against" (p<0.01). PEG users were more likely to have initiated health care proxies. These findings suggest that patients who use PEG may be consistently proactive in the face of the disease.

Novel mutations in spastin gene and absence of correlation with age at onset of symptoms.

Autosomal dominant hereditary spastic paraplegia is genetically heterogeneous, with at least five loci identified by linkage analysis. Recently, mutations in spastin were identified in SPG4, the most common locus for dominant hereditary spastic paraplegia that was previously mapped to chromosome 2p22. We identified five novel mutations in the spastin gene in five families with SPG4 mutations from North America and Tunisia and showed the absence of correlation between the predicted mutant spastin protein and age at onset of symptoms.

Neurotrophic factors and neuromuscular disease: I. General comments, the neurotrophin family, and neuropoietic cytokines.

Neurotrophic factors are growth factors or cytokines that are inducible polypeptides and permit intercellular communication. An explosion of information about neurotrophic factors is setting the stage for significant advances in neural disease therapy in the next century. The effects of these trophic factors are overlapping and pleiotropic, acting on many cell types and tissues to control proliferation and differentiation of developing neurons and to exert a variety of functions on mature neurons. Studies of receptors unique to several neurotrophic factor families have revealed exquisite mechanisms of signal transduction. Preclinical trials in neuromuscular disease were promising, but results from initial clinical trials have been disappointing; new and better designed clinical trials are under way. Laboratory investigators also are exploring techniques to deliver factors directly to the central nervous system by means of viral vectors or to exert neurotrophic signals on the nervous system using novel small molecules that stimulate neurotrophic factor or neuroimmunophilin receptors. Combination therapies, refined delivery techniques, and treatment timing may be the key for successful treatment with neurotrophic factors. In this two-part review, we discuss the neurobiology of neurotrophic factors, the characteristics of the major neurotrophic factors, and their therapeutic potential in neuromuscular disease.

Exon 5 encoded domain is not required for the toxic function of mutant SOD1 but essential for the dismutase activity: identification and characterization of two new SOD1 mutations associated with familial amyotrophic lateral sclerosis.

Two new mutations in the gene encoding cytoplasmic Cu,Zn superoxide dismutase (SOD1) have been discovered in patients with familial amyotrophic lateral sclerosis (FALS). These mutations result in the truncation of most of the polypeptide segment encoded by exon 5, one by the formation of a stop codon in codon 126 (L126Z) and the other by inducing alternative splicing in the mRNA (splicing junction mutation). These two mutants of SOD1 result in a FALS phenotype similar to that observed in patients with missense mutations in the SOD1 gene, establishing that exon 5 is not required for the novel toxic functions of mutant SOD1 associated with ALS. These mutant enzymes are present at very low levels in FALS patients, suggesting elevated toxicity compared to mutant enzymes with single site substitutions. This increased toxicity likely arises from the extreme structural and functional changes in the active site channel, beta-barrel fold, and dimer interface observed in the mutant enzymes, including the loss of native dismutase activity. In particular, the truncation of the polypeptide chain dramatically opens the active site channel, resulting in a marked increase in the accessibility and flexibility of the metal ions and side chain ligands of the enzyme active site. These structural changes are proposed to cause a decrease in substrate specificity and an increase in the catalysis of harmful chemical reactions such as peroxidation.

Intermittent esotropia associated with rippling muscle disease.

PURPOSE: We report a rare myopathy known as rippling muscle disease, with the unique feature of extraocular muscle involvement, presenting as a variable esotropia. METHODS: Chart review with a review of the literature. RESULTS: Neurologic and neuro-ophthalmic examinations as well as electromyography and muscle biopsy confirm that this case closely resembles those described in the literature with the additional feature of a variable esotropia. CONCLUSION: Rippling muscle disease may be associated with intermittent esotropia. The pathophysiology of this disorder is unknown, but the intermittent esotropia is likely related to "rippling" of the medial recti.

Treatment of myasthenia gravis by immunoadsorption of plasma.

We treated 16 patients with moderately severe to severe generalized myasthenia gravis (MG) by immunoadsorption (perfusion through a resin that adsorbs proteins) of 2,500 ml plasma on each of four alternate days. Fourteen patients who completed treatment all had significant improvement in strength (6 excellent, 6 good, and 2 fair), which began a mean of 42 hours after the first immunoadsorption, reached a maximum 4 days after the fourth immunoadsorption (mean, 250% of baseline strength), and returned to baseline over a mean of 2 months. Thirty-seven grams of plasma proteins were removed during each immunoadsorption, which required no replacement, compared with 175 grams during plasma exchange, which requires replacement with albumin. Serum or plasma concentration of all proteins fell, more so for most of the larger proteins than for the smaller ones: acetylcholine receptor antibody (AChR Ab) fell to a mean of 23% of original level, fibrinogen to 26%, C4 to 29%, IgM to 33%, IgG to 35%, CH50 to 41%, C3 to 42%, IgA to 54%, and albumin to 76%. All proteins, including AChR Ab, returned to their original levels within 1 to 3 weeks after the last immunoadsorption, while improvement in strength lasted a mean of 6 weeks longer. One seronegative patient had excellent improvement lasting more than a month. Activated complement C5a and white blood cell count rose during each immunoadsorption, while activated complement C3a fell, and each returned to its original level within hours. Eight patients had transient symptomatic hypotension attributable to withdrawal of blood more rapidly than it was returned; this hypotension was prevented or ameliorated by intravenous saline.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of cocaine on the contracture response to 1% halothane in patients undergoing diagnostic muscle biopsy for malignant hyperthermia.

Two case reports have cited the recreational use of cocaine as possible trigger of a malignant hyperthermia (MH) crisis. We evaluated whether toxic concentrations of cocaine altered the in vitro muscle response to halothane during contracture tests for MH. Twenty-two patients were studied. Muscle biopsies were obtained and first tested for MH susceptibility with 3% halothane and caffeine contracture testing. Ten patients were diagnosed as MH-susceptible and 12 as MH non-susceptible, in accordance with the North American Malignant Hyperthermia Group protocol. Then, muscle strips were exposed to 1% halothane in the presence and absence of 0.1 mmol.L-1 cocaine. Cocaine alone did not affect baseline muscle tension in either group. With 1% halothane, MH non-susceptible muscle showed no contracture with or without cocaine. In contrast, in the presence of 1% halothane, MH-susceptible muscle showed either no change in contracture (six patients), an increase (two patients), or a decrease (two patients) when exposed to cocaine. However, the overall effect of cocaine on muscle contracture in the presence of 1% halothane was insignificant in both groups. We conclude that cocaine, even at toxic levels, does not have a direct effect on skeletal muscle contractility and thus is safe for MH-susceptible patients.

Causes and diagnosis of sensory neuropathies: a review.

Sensory neuropathies are rare but unique peripheral neuropathies that involve only the peripheral sensory system. The diagnosis is made by both clinical and electrophysiological findings. Sensory neuropathies occur predominantly in women. The symptoms begin in the arms more often than the legs and occur asymmetrically. Pain and severe sensory ataxia in varying degrees are the main presenting symptoms. Definable causes of sensory neuropathies are hereditary, paraneoplastic, immunological, metabolic, infectious, and drug-induced disorders. In our experience, however, nearly half of all sensory neuropathies have been idiopathic. The clinical course of these sensory neuropathies is variable. The symptoms clearly worsened in 25% of our patients, but in the rest remained unchanged for many years, resulting in a poor functional prognosis because of intractable pain and ataxia. Most sensory neuropathies are resistant to any treatment. We review the electrophysiological features, laboratory findings, and nerve biopsy results in our patients and discuss in detail the potential underlying diseases included in the differential diagnosis.

Obturator mononeuropathy caused by pelvic cancer: six cases.

OBJECTIVE: To report the clinical and pelvic CT findings in six patients with obturator mononeuropathy caused by cancer. DESIGN: A clinical case series of six patients followed for 2 months to 10 years (one patient lost to follow-up). SETTING: Three referral centers. PATIENTS: Three men and three women, ages 52 to 81 years. Three patients had transitional cell carcinoma of the bladder, and one patient each had pelvic papillary carcinoma, carcinoma of unknown origin, and lymphoma. MAIN RESULTS: In each patient, symptoms of obturator mononeuropathy were the sole presenting sign of new or recurrent pelvic cancer. Three patients had ipsilateral leg edema in addition to the typical sensory and motor findings of obturator mononeuropathy. Tumor sites detected on pelvic CT that correlated with obturator nerve compression or infiltration, singly or in combination, included the posterolateral wall of the upper pelvis or midpelvis, the anterior wall of the lower pelvis, and the external obturator and pectineus muscles extrinsic to the bony pelvis. Antineoplastic treatment provided symptomatic relief in four patients. CONCLUSIONS: Pelvic CT or MRI should be performed to exclude pelvic tumor in patients with obturator mononeuropathy if there is no temporal association with pelvic trauma or intra-abdominal, pelvic, or hip surgery.

Myasthenia gravis therapy: immunoadsorbent may eliminate need for plasma products.

This in vitro study assessed the effectiveness of a new immunoadsorbent (Asahi IM-TR 350) in removing anti-acetylcholine receptor antibody from plasma with minimal loss of albumin. Plasma procured from a myasthenia gravis patient undergoing routine plasma exchange was perfused through the immunoadsorbent and recirculated in vitro to simulate a clinical treatment. To assess the temperature dependency of sorption, perfusion was performed at various temperatures. Plasma solute concentrations were taken before and after perfusion to calculate solute rejection coefficients. The immunoadsorbent has a high sorption capacity for anti-acetylcholine receptor antibody, while allowing a minimum loss of albumin. For patients with myasthenia gravis, this immunoadsorbent can provide an alternative to plasma exchange that does not require the use of plasma products.

Perineurial cell hypertrophic mononeuropathy manifesting as carpal tunnel syndrome.

A 42-year-old man showed signs and symptoms suggestive of carpal-tunnel syndrome, but EMG showed an isolated motor axon-loss lesion affecting the right median nerve distally. After the MRI revealed a mass in the median nerve, surgical exploration showed a diffusely swollen median motor branch. Biopsy showed a lesion with marked onion-bulb formation composed of perineurial cells as identified by immunohistochemical analyses and electron microscopic examination. Although we previously coined the term "perineurioma" for this condition, re-reviews of our cases do not support the idea that the onion-bulb lesion is a benign tumor; instead, it appears to be reactive hyperplasia. Although rare, electromyographers and neurologists need to be aware of this problem because it is self-limited and does not require surgical resection.

Hypertrophic mononeuritis clinically presenting with painful legs and moving toes.

A 40-year-old woman presented with progressive lower leg pain and spontaneous toe movement. The EMG showed a posterior tibial nerve mononeuropathy and continuous myokymic discharges in posterior tibial-innervated muscles. The MRI revealed a markedly enlarged posterior tibial nerve. Toe movements and myokymia were unaffected by the proximal transection of the lesion but ceased abruptly when the distal end of the fusiform "tumor" was resected, suggesting that spontaneous electrical foci may have been located along the nerve lesion. The markedly enlarged nerve segment contained edematous, swollen fascicles with marked Schwann cell onion-bulb lesions and angiocentric, lymphocytic, and lymphofollicular infiltration. This nerve lesion is an example of a newly recognized entity called hypertrophic mononeuritis.

Fiber-type specific caffeine sensitivities in normal human skinned muscle fibers.

Caffeine sensitivity was studied in chemically skinned muscle fibers from vastus lateralis muscle obtained by biopsy during reconstructive knee surgery from 15 otherwise healthy young individuals. Muscle fiber type was determined by contracture occurring in strontium (slow-oxidative, type I fiber) or calcium (both type I and type II, fast glycolytic fiber) solutions and in several fibers after contracture testing by ATPase enzyme histochemistry. Caffeine sensitivity (mean +/- SD), defined as the threshold concentration inducing more than 10% of the maximal tension obtained with a calcium 3 x 10(-5) mM solution was 2.7 +/- 1.3 mM in 37 type I fibers, whereas it was 6.9 +/- 2.4 mM in 61 type II fibers. A paired t test showed a significantly increased sensitivity to caffeine in type I fibers (P less than 0.001) in 13 individuals in whom the two fiber types were identified. The mean (+/- SD) difference between type I and type II fibers was 4.1 +/- 1.9 mM. Type I fibers contracted with greater tension in response to the increasing concentration of caffeine than did type II fibers (P less than 0.05). These skinned fiber studies showed significantly different caffeine sensitivities between human type I and type II muscle fibers, as previously shown in animal muscles. The findings that human type I muscle fibers have higher caffeine sensitivity than type II muscle fibers should be helpful for the interpretation of the in vitro contracture test done in muscle strips containing type I and type II fibers in varying proportions.

Inclusion body myositis presenting as treatment-resistant polymyositis.

Inclusion body myositis (IBM) has been viewed as a distinct and rare form of inflammatory myopathy. Previously reported findings from series of IBM patients have suggested that clinical and pathologic features are present which readily distinguish it from idiopathic polymyositis. We report 4 cases of IBM presenting clinically and pathologically as polymyositis, each of which was refractory to therapy. Our data suggest that IBM may be a more common and heterogeneous form of inflammatory myopathy than has been previously suggested. Furthermore, IBM may be clinically and electrophysiologically indistinguishable from polymyositis. Reasons for failing to recognize IBM by pathologic studies appear to include: the skip lesion nature of the pathologic findings, failure to examine tissues by electron microscopy, and a low level of suspicion or lack of recognition. Because of its insidious clinical course and its failure to respond to immunosuppressive therapy, IBM may be an important variant of treatment-resistant polymyositis.