Lipidomics study of plasma from patients suggest that ALS and PLS are part of a continuum of motor neuron disorders.

Motor neuron disorders (MND) include a group of pathologies that affect upper and/or lower motor neurons. Among them, amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle weakness, with fatal outcomes only in a few years after diagnosis. On the other hand, primary lateral sclerosis (PLS), a more benign form of MND that only affects upper motor neurons, results in life-long progressive motor dysfunction. Although the outcomes are quite different, ALS and PLS present with similar symptoms at disease onset, to the degree that both disorders could be considered part of a continuum. These similarities and the lack of reliable biomarkers often result in delays in accurate diagnosis and/or treatment. In the nervous system, lipids exert a wide variety of functions, including roles in cell structure, synaptic transmission, and multiple metabolic processes. Thus, the study of the absolute and relative concentrations of a subset of lipids in human pathology can shed light into these cellular processes and unravel alterations in one or more pathways. In here, we report the lipid composition of longitudinal plasma samples from ALS and PLS patients initially, and after 2 years following enrollment in a clinical study. Our analysis revealed common aspects of these pathologies suggesting that, from the lipidomics point of view, PLS and ALS behave as part of a continuum of motor neuron disorders.

Prevalence of fatigue and depression in ALS patients and change over time.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) patients report both fatigue and depression. It is not clear how frequently each occurs, to what extent they occur together, how each relates to ALS disease status, or their stability over time. OBJECTIVE: To assess frequency and persistence of fatigue and depression, and relationship to ALS disease status, for patients attending an ALS interdisciplinary centre for routine 3-month visits. METHOD: Measures included the Fatigue Severity Scale, Patient Health Questionnaire-9. ALS Functional Rating Scale -- Revised and forced vital capacity, rate of disease progression, and bulbar/nonbulbar disease onset. RESULTS: 223 patients completed the ratings once; of these, 113 completed them twice, and 65 on three visits. At baseline, 44% (99/223) had clinically significant fatigue, including 34 patients who also had a depressive disorder; 7% (16/223) had major or minor depression only, and 48% (108/223) had neither condition. Fatigue was associated with greater ALS severity, but depression was not. Among the 113 patients seen 3 months later, 75% (33/44) who were fatigued at Time 1 remained fatigued, while 48% (10/21) remained depressed. New-onset fatigue was reported by 22% (25/113), and new-onset depression by 6% (7/113). For the 65 patients seen a third time, rates remained nearly the same. CONCLUSION: Fatigue was more prevalent and persistent than depression, although 15% (34/223) of patients had both conditions. Fatigue but not depression was associated with ALS severity. The two conditions appear to be independent, although sometimes co-occurring, and both warrant consideration in evaluating patient functioning and treatment.

Arrest of motor neuron disease in wobbler mice cotreated with CNTF and BDNF.

Ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) each promote the survival and differentiation of developing motor neurons, but do so through distinct cellular signaling pathways. Administration of either factor alone has been shown to slow, but not to arrest, progression of motor neuron dysfunction in wobbler mice, an animal model of motor neuron disease. Because CNTF and BDNF are known to synergize in vitro and in ovo, the efficacy of CNTF and BDNF cotreatment was tested in the same animal mode. Subcutaneous injection of the two factors on alternate days was found to arrest disease progression in wobbler mice for 1 month, as measured by several behavioral, physiological, and histological criteria.

WITHDRAWN: Amino acids for amyotrophic lateral sclerosis / motor neuron disease.

BACKGROUND: Amyotrophic lateral sclerosis, also known as motor neuron disease, is a progressive neuromuscular disease that causes disability and eventual death. Various amino acid preparations, the three branched-chain amino acids (L-leucine, L-valine and L-isoleucine) or, alternatively, L-threonine have been used as experimental therapy. OBJECTIVES: To examine the efficacy of amino acid therapies in prolonging survival and/or slowing the progression of amyotrophic lateral sclerosis/motor neuron disease. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (searched February 2003), MEDLINE (from January 1966 to December 2002) and EMBASE (from January 1980 to December 2002) databases and reports of specialist conferences. Authors of known studies were contacted. SELECTION CRITERIA: We included randomised or quasi-randomised trials of participants with a clinical diagnosis of amyotrophic lateral sclerosis/motor neuron disease treated with all combinations of amino acids. Our primary outcome measure was survival determined by a pooled hazard ratio of all studies. Our secondary outcome measures were (in order of priority): survival at six and 12 months, muscle strength, any validated rating scale of physical function, quality of life, proportion of patients completing therapy and proportion of patients reporting adverse events attributable to treatment. DATA COLLECTION AND ANALYSIS: We identified six eligible trials and rejected a further seven because of incomplete data or inadequate duration. Eligible studies were rated for methodological quality and missing data sought from the authors. After this examination two studies were excluded from analysis. Our pooled survival analysis was performed by the Parmar method, other statistical calculations were done using the Review Manager 4.2 software package. MAIN RESULTS: No benefit could be demonstrated for either branched-chain amino acids or L-threonine in improving survival in amyotrophic lateral sclerosis/motor neuron disease. Neither could we find evidence of an effect of either treatment on muscle strength or disability as measured by functional rating scales. No study assessed quality of life. Both branched-chain amino acids and L-threonine appeared well tolerated and caused a degree of adverse events comparable to that of the control medication. AUTHORS' CONCLUSIONS: There is no evidence to support a beneficial effect of either branched-chain amino acids or L-threonine in amyotrophic lateral sclerosis/motor neuron disease.

Vacuolated anterior horn cells in wobbler mouse motor neuron disease: peripheral axons and regenerative capacity.

We investigated whether vacuolated cervical anterior horn cells of the wobbler mouse maintain axons to the periphery, and if these morphologically abnormal neurons are capable of supporting axonal regeneration. Using retrograde axonal transport, we applied horseradish peroxidase (HRP) to peripheral nerves or muscles and with electron microscopy sought evidence for perikaryal labeling in vacuolated neurons in 23 wobbler mice. When HRP was injected into forelimb muscles, 12 of 36 vacuolated neurons became positively labeled indicating that these neurons have axons in continuity with the periphery. In regeneration studies, after nerve crush at the brachial plexus, 23 out of 85 vacuolated neurons were labeled after HRP application at the elbow level. However, after a sufficient regeneration period, none of the 36 vacuolated neurons were labeled if HRP was applied in muscles below the elbow. In all experiments, morphologically normal neurons were always labeled. Our studies indicate that some vacuolated neurons of wobbler mice not only maintain axons into the periphery, but are also capable of supporting regeneration. However, the overall function of these vacuolated neurons appears marginal compared with the majority of morphologically normal neurons in this motor neuron disease.

Amyotrophic lateral sclerosis. Recent advances in pathogenesis and therapeutic trials.

We reviewed the current status of pathogenesis and therapeutic trials in amyotrophic lateral sclerosis (ALS). Clinical studies have identified several rare but definable causes for apparent ALS. Certain clinical features previously considered unlikely to occur in ALS are found on careful examination. Epidemiologic surveillance and recent studies of neurotoxic plant seeds used in Guam have shed light on the pathogenesis of endemic ALS. Extensive analyses of biochemical, metabolic, immunologic, viral, and toxic factors have provided provocative results requiring further studies. Reflecting on some of these hypotheses, therapeutic trials have been performed more vigorously than ever. Amyotrophic lateral sclerosis is now investigated at the molecular genetic level. Human autopsy and experimental animal studies have expanded our understanding of basic mechanisms involving motoneuronal degeneration. In the future, we must continue a relentless search for the pathogenesis of ALS, prospective clinical studies to define the limits of ALS, and well-designed, controlled therapeutic trials.

Focal EEG abnormalities in Heidenhain's variant of Jakob-Creutzfeldt disease.

Serial EEGs obtained during a six-week period from a patient with Heidenhain's variant of Jakob-Creutzfeldt disease demonstrated periodic complexes confined to the occipital regions that at no time became generalized. The focal character of the discharges correlated with the site of maximal disease in the occipital cortex, suggesting that cortical damage is a necessary substrate for the production of periodic complexes in Jakob-Creutzfeldt disease.

McArdle disease: phosphorylase activity in regenerating muscle fibers.

Phosphorylase activity was found histochemically in regenerating muscle fibers in biopsied muscle from a patient with otherwise typical McArdle disease. Phosphorylase activity, shortly after episodes of muscle necrosis, was identified in this patient and in others reported in the literature. Detection of phosphorylase activity accompanied histologic evidence of regenerating muscle fibers and excessive glycogen accumulation. The biopsied muscle had virtually no biochemical enzyme activity. The present study supports a recently introduced hypothesis stating that in McArdle disease there is a lack of "mature" phosphorylase, but skeletal muscle cells are able to manufacture "fetal" phosphorylase isoenzyme during muscle regeneration.

Paroxysmal "nightmares". Sequel of a stroke responsive to diphenylhydantoin.

A 65-year-old man had nightmares a few weeks after a right temporal lobe infarction. Electroencephalography showed no epileptic activity. Therapy with diphenylhydantoin produced complete remission of his symptoms. On the bases of their acute onset, their association with sleep, their occasional occurrence while the patient was awake, the lack of effect of diazepam and flurazepam, and the good response to diphenylhydantoin, we propose that these episodes were partial seizures secondary to the right temporal lobe lesion.

Spontaneous infarction in pituitary tumors: neurologic and therapeutic aspects.

In addition to progressive endocrine dysfunction and progressive visual loss, pituitary neoplasms may annouce their presence by the more catastrophic alternative of spontaneous tumor infarction. In two patients reported, illness due to the spontaneous infraction of pituitary tumors was heralded by sudden onset of focal headache associated with diplopia. Stupor, confusion, and evidence of increased intracranial pressure occurred without subarachnoid hemorrhage or massive extrasellar extension of tumor. One patient developed inappropriate antidiuretic hormone secretion with spontaneous infarction in a large but clinically silent chromophobe adenoma. In both patients, skull x-rays suggested a long-standing intrasella mass. Both underwent prompt treatment with endocrinologic replacement therapy and subsequent successful transsphenoidal removal of voluminous, infarcted, pituitary masses.

1H-MRS evidence of neurodegeneration and excess glutamate + glutamine in ALS medulla.

OBJECTIVE: To determine whether short echo-time (TE) proton magnetic resonance spectroscopic imaging (1H-MRSI) can detect in vivo differences in signal intensities of specific metabolites in the medulla of patients with ALS compared with healthy individuals and whether these metabolites could be useful surrogate markers of disease. BACKGROUND: 1H-MRSI can detect N-acetylaspartate + N-acetylaspartylglutamate (abbreviated NAx), which is localized to neurons, and glutamate (Glu) + glutamine (Gln), abbreviated Glx, which may be important in ALS pathogenesis. The medulla is an ideal region to study ALS because of its high density of nuclei and fiber tracts that frequently undergo degeneration, even when more rostral brain regions show minimal pathology. METHODS: Ten patients with ALS and seven healthy control subjects underwent short TE 1H-MRSI on a 1.5 T clinical imaging system. Signal intensities of NAx and Glx were normalized to creatine-phosphocreatine and compared between groups. RESULTS: Compared with normal subjects, the medulla of patients with ALS had 17% lower NAx (p = 0.03) and 55% higher Glx (p = 0.02) signals. Bulbar symptoms, represented by the ALS Functional Rating Scale, correlated with Glx (r = -0.68, p = 0.03) but not NAx (r = 0.22, p = 0.53). CONCLUSION: There is in vivo 1H-MRSI evidence of neuronal degeneration or loss and excess Glu + Gln in the medulla of patients with ALS. Although this cross-sectional study cannot identify which change occurred first, the higher Glx signal in the medulla of patients with more dysarthria and dysphagia is consistent with the hypothesis of Glu excitotoxicity in ALS pathogenesis. Longitudinal 1H-MRSI studies of the medulla (and other brain regions) in more patients with ALS are required to confirm these findings and to determine whether such metabolite changes will be useful in monitoring disease progression, in clinical diagnosis, and in understanding the pathogenesis of ALS.

Chronic progressive external ophthalmoplegia (CPEO): clinical, morphologic, and biochemical studies.

We studied skeletal muscles from eight chronic progressive external ophthalmoplegia patients with ragged-red fibers (group A), five CPEO patients without ragged-red fibers (group B), and five controls. The EM morphometric fraction of structurally abnormal mitochondria was increased in group A, and there was a similarly increased fraction of normal-appearing mitochondria in group B. State 3 respiration and uncoupled respiration were severely decreased in both groups. The morphometric mitochondrial fraction and respiratory functions were inversely related in all three groups. The cytochrome content in group A was normal; cytochromes b and cc1 were decreased in group B. These studies point to a central role of mitochondrial dysfunction in all types of CPEO, but the basic abnormalities remain to be elucidated.

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)

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.

The ALS patient care database: goals, design, and early results. ALS C.A.R.E. Study Group.

OBJECTIVE: The ALS Patient Care Database was created to improve the quality of care for patients with ALS by 1) providing neurologists with data to evaluate and improve their practices, 2) publishing data on temporal trends in the care of patients with ALS, and 3) developing hypotheses to be tested during formal clinical trials. BACKGROUND: Substantial variations exist in managing ALS, but there has been no North American database to measure outcomes in ALS until now. METHODS: This observational database is open to all neurologists practicing in North America, who are encouraged to enroll both incident and prevalent ALS patients. Longitudinal data are collected at intervals of 3 to 6 months by using standard data collection instruments. Forms are submitted to a central data coordinating center, which mails quarterly reports to participating neurologists. RESULTS: Beginning in September 1996 through November 30, 1998, 1,857 patients were enrolled at 83 clinical sites. On enrollment, patients had a mean age of 58.6 years +/-12.9 (SD) years (range, 20.1 to 95.1 years), 92% were white, and 61% were men. The mean interval between onset of symptoms and diagnosis was 1.2+/-1.6 years (range, 0 to 31.9 years). Riluzole was the most frequently used disease-specific therapy (48%). Physical therapy was the most common nonpharmacologic intervention (45%). The primary caregiver was generally the spouse (77%). Advance directives were in place at the time of death for 70% of 213 enrolled patients who were reported to have died. CONCLUSIONS: The ALS Patient Care Database appears to provide valuable data on physician practices and patient-focused outcomes in ALS.

Amyotrophic lateral sclerosis: effects of acute intravenous and chronic subcutaneous administration of thyrotropin-releasing hormone in controlled trials.

We performed double-blind crossover trials to assess the effects of thyrotropin-releasing hormone (TRH) on amyotrophic lateral sclerosis patients. For acute intravenous trials, 500 mg TRH or placebo with norepinephrine was given at 1-week intervals (16 patients). CSF TRH concentration increased, and clinical side effects appeared with TRH. For chronic studies, 25 mg TRH and a saline placebo were given subcutaneously every day for 3 months (25 patients). CSF TRH level increased 29-fold after a single TRH injection, and mild transient side effects occurred. Vital signs, respiratory function, semiquantitative and quantitative neurologic function, muscle strength by manual and dynamometer testing, and EMG were studied. With daily TRH, 10 patients noted subjective improvement without objective evidence, and 10 patients complained of worsening of the disease with objective decline after TRH was stopped. Statistical analysis, however, showed no beneficial effects from either acute or chronic TRH trials.

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.

Chloroquine neuromyotoxicity. Clinical and pathologic perspective.

Six cases of toxic myopathy and/or neuropathy with chloroquine and/or hydroxychloroquine therapy are described. Two patients had unique clinical and pathologic evidence of cardiomyopathy secondary to chloroquine or hydroxychloroquine therapy. One patient had polyneuropathy secondary to chloroquine toxicity. This may be the first documentation of several features of chloroquine/hydroxychloroquine toxicity: morphologic changes in human peripheral nerve in chloroquine toxicity; chloroquine/hydroxychloroquine cardiomyopathy diagnosed by endomyocardial biopsy; and hydroxychloroquine myotoxicity. Chloroquine is a neuromyotoxin that affects nerves and cardiac and skeletal muscles. Discontinuation of chloroquine and hydroxychloroquine resulted in marked improvement in most cases. The reversibility of the symptoms emphasizes the importance of recognizing potential signs of nerve, muscle, and cardiac toxicity in patients being treated with chloroquine or hydroxychloroquine.

Neuronal pathology in the wobbler mouse brain revealed by in vivo proton magnetic resonance spectroscopy and immunocytochemistry.

Proton magnetic resonance spectroscopy (1H-MRS) was used to measure the in vivo signal of N-acetylaspartate (NAA), a putative neuronal marker, in the brain of the mutant wobbler mouse, a model of motor neuron disease. The ratio of NAA to creatine-phosphocreatine, an internal standard, was significantly lower in five affected wobbler mice (0.79+/-0.05; mean+/-s.d.) than in five unaffected littermates (0.98+/-0.10, p = 0.006). Ubiquitin and phosphorylated heavy neurofilament immunoreactivities were increased in cortical neurons of affected animals. This is the first demonstration of cerebral neuronal pathology in the wobbler mouse, supporting its use as a model of amyotrophic lateral sclerosis. In vivo IH-MRS and correlative postmortem study of wobbler mouse brain will allow temporal monitoring of neuronal degeneration and responsiveness to neuroprotective pharmacotherapies.

The wobbler mouse: amino acid contents in brain and spinal cord.

Reductions in glutamate and aspartate contents, together with increased contents of taurine, have been observed in the autopsied brains and spinal cords of patients who have died with amyotrophic lateral sclerosis (ALS). The wobbler mouse develops an inherited degeneration of motoneurons within the brainstem and spinal cord, and has been proposed as an animal model of ALS. In symptomatic wobbler mice we found brain contents of glutamate, aspartate, and taurine similar to those in unaffected littermates, while brain contents of glutamine were increased, and those of serine and alanine were decreased. Spinal cords of wobbler mice had slightly decreased contents of glutamate, aspartate and glycine compared to normal littermates. Abnormalities of amino acid contents in the nervous system of wobbler mice are dissimilar to those in ALS patients suggesting a different pathogenesis of motoneuron loss.