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.

High-frequency chest wall oscillation in ALS: an exploratory randomized, controlled trial.

OBJECTIVES: To evaluate changes in respiratory function in patients with ALS after using high-frequency chest wall oscillation (HFCWO). METHODS: This was a 12-week randomized, controlled trial of HFCWO in patients with probable or definite ALS, an Amyotrophic Lateral Sclerosis Functional Rating Scale respiratory subscale score < or = 11 and > or = 5, and forced vital capacity (FVC) > or = 40% predicted. RESULTS: We enrolled 46 patients (58.0 +/- 9.8 years; 21 men, 25 women); 22 used HFCWO and 24 were untreated. Thirty-five completed the trial: 19 used HFCWO and 16 untreated. HFCWO users had less breathlessness (p = 0.021) and coughed more at night (p = 0.048) at 12 weeks compared to baseline. At 12 weeks, HFCWO users reported a decline in breathlessness (p = 0.048); nonusers reported more noise when breathing (p = 0.027). There were no significant differences in FVC change, peak expiratory flow, capnography, oxygen saturation, fatigue, or transitional dyspnea index. When patients with FVC between 40 and 70% predicted were analyzed, FVC showed a significant mean decrease in untreated patients but not in HFCWO patients; HFCWO patients had significantly less increased fatigue and breathlessness. Satisfaction with HFCWO was 79%. CONCLUSION: High-frequency chest wall oscillation was well tolerated, considered helpful by a majority of patients, and decreased symptoms of breathlessness. In patients with impaired breathing, high-frequency chest wall oscillation decreased fatigue and showed a trend toward slowing the decline of forced vital capacity.

Identification of potential CSF biomarkers in ALS.

BACKGROUND: The clinical diagnosis of ALS is based entirely on clinical features. Identification of biomarkers for ALS would be important for diagnosis and might also provide clues to pathogenesis. OBJECTIVE: To determine if there is a specific protein profile in the CSF that distinguishes patients with ALS from those with purely motor peripheral neuropathy (PN) and healthy control subjects. METHODS: CSF obtained from patients with ALS, disease controls (patients with other neurologic disorders), and normal controls were analyzed using the surface-enhanced laser desorption/ionization time-of-flight mass spectrometry proteomics technique. Biomarker sensitivity and specificity was calculated with receiver operating characteristic curve methodology. ALS biomarkers were purified and sequence identified by mass spectrometry-directed peptide sequencing. RESULTS: In initial proteomic discovery studies, three protein species (4.8-, 6.7-, and 13.4-kDa) that were significantly lower in concentration in the CSF from patients with ALS (n = 36) than in normal controls (n = 21) were identified. A combination of three protein species (the "three-protein" model) correctly identified patients with ALS with 95% accuracy, 91% sensitivity, and 97% specificity from the controls. Independent validation studies using separate cohorts of ALS (n = 13), healthy control (n = 25), and PN (n = 7) subjects confirmed the ability of the three CSF protein species to separate patients with ALS from other diseases. Protein sequence analysis identified the 13.4-kDa protein species as cystatin C and the 4.8-kDa protein species as a peptic fragment of the neurosecretory protein VGF. CONCLUSION: Additional application of a "three-protein" biomarker model to current diagnostic criteria may provide an objective biomarker pattern to help identify patients with ALS.

Quasifree pi0 and pi- electroproduction on 4He in the Delta-resonance region.

The reactions 4He(e, e' p3He)pi- and 4He(e, e' p3He)pi0 were studied simultaneously, and for the first time, in a large kinematical domain including the Delta-resonance region. This was achieved by detecting the recoiling 3He and 3H nuclei instead of the emitted pions. The dependences of the cross section on the recoil momentum p(rec), the invariant mass WpiN, and the direction thetapi,q' and phipi,q' of the produced pion, are globally well described by the results of (quasifree) distorted-wave impulse approximation calculations. However, in the Delta-resonance region there are clear discrepancies, which point to medium modifications of the Delta in 4He.

Inclusion body myositis mimicking motor neuron disease.

OBJECTIVE: To describe the clinical and electrophysiologic features of patients with inclusion body myositis that was misinterpreted as motor neuron disease. PATIENTS AND METHODS: We retrospectively retrieved the medical records of 70 patients with a pathologic diagnosis of inclusion body myositis. From this group, we selected those who had been first diagnosed as having motor neuron disease or amyotrophic lateral sclerosis. We reviewed the clinical, electrophysiologic, laboratory, and morphologic studies. RESULTS: Nine (13%) of 70 patients with inclusion body myositis had been diagnosed as having motor neuron disease. Six of the 9 patients had asymmetric weakness; in 4 the distal arm muscles were affected. Eight patients had finger flexor weakness. Tendon reflexes were preserved in weak limbs in 6, hyperactive in 2, and absent in 1. Four patients had dysphagia. Fasciculation was seen in 2 patients. None had definite upper motor neuron signs or muscle cramps. Routine electromyographic studies showed fibrillation potentials and positive sharp waves in all 9. Fasciculation potentials were seen in 7 and long-duration polyphasic motor unit potentials were seen in 8. There was no evidence of a myogenic disorder in these 9 patients. Muscle biopsy was done because of slow progression or prominent weakness of the finger flexors and was diagnostic of inclusion body myositis. A quantitative electromyogram was myopathic in 4 of the 5 patients studied. CONCLUSIONS: Inclusion body myositis may mimic motor neuron disease. Muscle biopsy and quantitative electromyographic analysis are indicated in patients with atypical motor neuron disease, especially those with slow progression or early and disproportionate weakness of the finger flexors.

Unexpectedly severe sleep and respiratory pathology in patients with amyotrophic lateral sclerosis.

Daytime fatigue and sleep disturbance are frequent complaints in patients with amyotrophic lateral sclerosis (ALS). However, polysomnographic data are sparse. Nocturnal respiratory insufficiency may occur despite nearly normal daytime pulmonary function. We describe the clinical presentation and polysomnographic findings in two patients with clinically and electrophysiologically confirmed ALS with minimal weakness but excessive daytime sleepiness. Polysomnography in the first patient showed a respiratory disturbance index of 43.5, and profound oxygen desaturations to 62%. The second patient had prolonged periods of hypoventilation, with oxygen saturations oscillating between 86 and 83%. Both patients showed severe sleep maintenance insomnia with a sleep efficiency < 40% and frequent arousals while asleep. Application of continuous positive airway pressure (CPAP) restored normal nocturnal ventilation, blood oxygenation and sleep parameters in the first patient; compliance, however, was poor. The second patient was unable to tolerate CPAP. We conclude that ALS patients with excessive daytime sleepiness or insomnia should undergo polysomnography to adequately diagnose nocturnal respiratory insufficiency and sleep disturbance. Compliance with treatment, however, may be poor.

Motor neuron diseases: comparison of single-voxel proton MR spectroscopy of the motor cortex with MR imaging of the brain.

PURPOSE: To evaluate single-voxel proton magnetic resonance (MR) spectroscopy in detection of abnormality of the upper motor neuron in patients with motor neuron diseases. MATERIALS AND METHODS: In 43 of 50 patients with motor neuron disease and 14 of 14 control subjects, matching sets of MR spectra were obtained in the left and right motor cortex. The ratio of N-acetylaspartate (NAA) to creatine (Cr) was derived from peak area measurements. Mean ratios were calculated for control subjects and several patient groups, including patients with amyotrophic lateral sclerosis (ALS) or primary lateral sclerosis (PLS). MR images were evaluated for corticospinal tract hyperintensity and central sulcus dilatation. RESULTS: Mean NAA/Cr values were significantly different between control subjects and the ALS or PLS groups (P < .05). With an optimal cutoff of 2.5, NAA/Cr values were abnormal in 15 (79%) of 19 patients with ALS, 12 (67%) of 18 patients with PLS, and one (7%) of 14 control subjects. Corticospinal tract hyperintensity, central sulcus enlargement, or both were found in 43% of the ALS group, 24% of the PLS group, and 7% of the control group. CONCLUSION: NAA/Cr values determined at single-voxel proton MR spectroscopy are more sensitive than are standard findings at MR imaging in the detection of upper motor neuron disease.

Amyotrophic lateral sclerosis in an adult following acute paralytic poliomyelitis in early childhood.

About 30% of polio survivors develop a post-polio syndrome. Some of these patients develop slowly progressive muscle weakness known as post-poliomyelitis muscular atrophy (PPMA). We describe an unusual form of amyotrophic lateral sclerosis (ALS) in a patient with acute poliomyelitis in childhood. An 80-year-old woman had acute poliomyelitis at 2 years of age and developed weakness limited to the lower extremities. Residual weakness was stable until the age of 75 when she developed rapidly progressive weakness that first affected her left arm and subsequently the right arm. Neurological examination revealed both upper and lower motor neuron signs. These clinical features were more consistent with ALS than PPMA. At autopsy, there was marked atrophy of the precentral gyrus. Microscopic examination revealed a severe loss of all nerve cells and pronounced fibrillary astrocytosis of the lumbar ventral horns in the spinal cord, presumably a result of poliomyelitis. Superimposed on these spinal cord alterations were the pathological features of ALS, consisting of loss of Betz cells, corticospinal tract degeneration and loss of motor neurons of other levels of the spinal cord. The findings included some atypical features for ALS, namely, sparing of the hypoglossal nucleus, absence of Bunina bodies and absence of ubiquitin-immunoreactive inclusions. Although poliomyelitis and ALS may be coincidental, the unusual pathological expression of ALS raise the possibility that it is related to the antecedent poliomyelitis.

Selegiline is ineffective in a collaborative double-blind, placebo-controlled trial for treatment of amyotrophic lateral sclerosis.

BACKGROUND: The cause of amyotrophic lateral sclerosis (ALS) is not known, and there is no effective treatment. Cell death may be caused by oxidative damage. Selegiline hydrochloride (Eldepryl) is a monoamine oxidase-B inhibitor with antioxidant properties. OBJECTIVE: To determine if selegiline affects the clinical course of patients with ALS. DESIGN: Six-month, double-blind, placebo-controlled study of 133 patients with classical ALS and symptoms for less than 3 years. The primary end point to indicate effectiveness was the rate of change of the Appel ALS total score, an index of disease severity that incorporates strength and function in limbs, respiratory function, and bulbar function. RESULTS: Of the 133 patients, 67 were randomized to receive selegiline and 66 to receive placebo. One hundred four patients (53 in the selegiline group and 51 in the placebo group) completed the 6-month trial. Both groups were comparable for baseline characteristics and mean Appel ALS total score (70.5 points for the selegiline group and 70.6 for the placebo group). There was no difference in the rate of progression as measured by the Appel ALS total score, showing an average increase of 22 points in 6 months. The monthly rate of change was 3.4 for the selegiline group and 3.5 for the placebo group. There was 1 adverse reaction: worsening depression. Seven patients died during the study (4 in the selegiline group and 3 in the placebo group). CONCLUSION: Selegiline treatment had no significant effect on the rate of clinical progression or outcome of ALS.

Diagnostic biopsy of the motor nerve to the gracilis muscle. Technical note.

A biopsy specimen of the motor nerve to the gracilis muscle was obtained in 151 patients to aid in the diagnosis of neuromuscular disorders. The procedure is simple, safe, and has low morbidity and complication rates. The surgical technique is described. Indications for the use of this technique are motor neuropathy, motor neuron disease, Guillain-Barre syndrome, and mixed neuropathy with prominent motor symptoms.

Lymphoproliferative disorders and motor neuron disease: an update.

We studied 26 patients with both motor neuron disease and lymphoproliferative disease (LPD). Twenty-three patients had definite or probable upper motor neuron signs; none had electrophysiologic evidence of motor neuropathy. LPD syndromes comprised Waldenström's macroglobulinemia, multiple myeloma, chronic lymphocytic leukemia, follicular cell lymphoma, and Hodgkin's disease. In all but one patient, the cause of disability or death was neurologic. LPD was confined to bone marrow in 14 patients; eight of 14 had monoclonal paraproteinemia. One patient had LPD discovered at autopsy. Treatment of LPD in 20 patients resulted in neurologic improvement in 1 patient and arrest in another; both had progressive spinal muscular atrophy. Eleven patients were worse and 13 died. At least 30 cases have been reported from other centers, bringing the total to 56. Among the unusual reported concomitants were POEMS (polyneuropathy, organomegaly, endocrinopathy, myeloma, and skin changes) syndrome of myeloma and angiotropic lymphoma.

Impact of health care reform on the business and practice of ophthalmology.

This study examines the attitudes and opinions of 122 Texas ophthalmologists facing the health care reform movement. It illustrates the commercial practice of ophthalmology today, how practitioners would like it to be, and what they see as the future trends. The study also explores the options and future plans of ophthalmologists for maintaining practice revenues.

The role of quantitative electromyography in inclusion body myositis.

OBJECTIVE AND METHODS: Inclusion body myositis is said to have both myopathic and neurogenic features on electrophysiological tests. Twenty one studies from 20 patients with biopsy defined inclusion body myosis, 13 of whom had quantitative electromyography (qEMG), were reviewed to determine if this technique added diagnostic specificity (one patient had both needle EMG and a later study with qEMG before muscle biopsy). RESULTS: Excessive numbers of polyphasic motor unit potentials (MUPs) (> 12% per muscle) were seen in 11 of the 13 patients. In 10 of 13 patients, mean MUP duration was abnormally reduced (26% to 48%). In three patients, mean MUP duration was abnormally reduced only after polyphasic MUPs were excluded. In all 13 patients, the simple MUP duration was reduced. Myopathy was unequivocally diagnosed in all 13 studies that included qEMG; of the remaining eight patients, the conclusions of the electrophysiological studies without qEMG was myopathy (one), neurogenic (four) or non-diagnostic (three). CONCLUSIONS: There is no evidence of a neurogenic component in inclusion body myosis if qEMG is used. Quantitative EMG is often necessary to make an electrophysiological diagnosis of a myogenic disorder in patients with inclusion body myosis.

Erroneous diagnosis corrected after 28 years. Not spinal muscular atrophy with ophthalmoplegia but minicore myopathy.

OBJECTIVE: To correct, after 28 years, the previously reported diagnosis of ophthalmoplegia in a patient with presumed childhood spinal muscular atrophy. DESIGN: Clinical follow-up, laboratory, electrophysiologic, and muscle biopsy data are provided. RESULTS: The findings of clinical follow-up examination, electrophysiologic tests, and histologic examination of muscle specimens led to a revised diagnosis of minicore myopathy. CONCLUSIONS: Spinal muscular atrophy was diagnosed in 1967, before histochemical techniques for examining muscle tissue and quantitative electromyography became widely available. Modern laboratory techniques later made the diagnosis of minicore myopathy possible. Progressive external ophthalmoplegia has been described in 24% of patients with minicore myopathy, but there have been only 7 reports of ophthalmoplegia with spinal muscular atrophy since 1954, and some of these diagnoses have been questioned.

Motor neuron disease, lymphoproliferative disease, and bone marrow biopsy.

Some have suggested that nonfamilial motor neuron disease (MND) may be autoimmune, and the neurological disorder may benefit from immunotherapy. There have been reports of over 30 cases of lymphoproliferative disease (lymphoma, multiple myeloma, Waldenström's macroglobulinemia) with MND, and these patients might he offered immunosuppressive therapy. Bone marrow examination might increase the sensitivity of the diagnostic workup for lymphoma and other lymphoproliferative disorders. We examined the bone marrow in our first evaluation of 161 patients with MND seen at Columbia-Presbyterian Medical Center during 1991-1994. Four of 161 patients (2.5%) had lymphoproliferative disease in the marrow; only 1 of these had a monoclonal paraprotein. Routine bone marrow examination of patients with MND increases the diagnostic yield of lymphoproliferative diseases. The frequency of these bone marrow abnormalities in comparison with a group of age-matched control subjects should be studied further.

Complications of intravenous immune globulin treatment in neurologic disease.

Intravenous immune globulin (IVIg) is advocated as a safe treatment for immune-mediated neurologic disease. We reviewed the medical records of 88 patients who were given IVIg for a neurologic illness. Major complications in four patients (4.5%) included congestive heart failure in a patient with polymyositis, hypotension after a recent myocardial infarction, deep venous thrombosis in a bed-bound patient, and acute renal failure with diabetic nephropathy. Other adverse effects included vasomotor symptoms 26, headache 23, rash 5, leukopenia 4, fever 3, neutropenia 1, proteinuria (1.9 g/day) 1, viral syndrome 1, dyspnea 1, and pruritus 1. Fifty-two patients (59%) had some adverse effect of IVIg infusion, most commonly vasomotor symptoms, headaches, fever, or shortness of breath in 40 (45%), which improved with reduced infusion rate or symptomatic medications. Five (6%) had asymptomatic laboratory abnormalities and seven (8%) had other minor adverse effects. Adverse effects led to discontinuation of therapy in 16% and permanent termination of therapy in 10% of patients. There was no mortality or long-term morbidity. Although adverse effects were frequent, serious complications were rare except in patients with heart disease, renal insufficiency, and bed-bound state.

Autopsy-proven amyotrophic lateral sclerosis, Waldenström's macroglobulinemia, and antibodies to sulfated glucuronic acid paragloboside.

Antibodies to myelin-associated glycoprotein (MAG) are found in patients with both monoclonal gammopathy and sensorimotor peripheral neuropathy but almost never in patients with amyotrophic lateral sclerosis (ALS). Ninety percent of patients with anti-MAG activity also have antibodies to sulfated glucuronic acid paragloboside (SGPG). We studied a patient with autopsy-proven ALS who had high titers of anti-SGPG but normal anti-MAG--one more unexplained immunologic abnormality in ALS.

Clinical and electrophysiologic correlates of elevated anti-GM1 antibody titers.

We reviewed the clinical and electrophysiologic features of 36 patients with increased titers of IgM anti-GM1 antibodies. Mildly elevated titers of up to 3,200 were not associated with any particular clinical syndrome or disease. Clinically, 14 of 16 patients with highly elevated titers of 6,400 or higher had progressive weakness with lower motor neuron signs; six had active tendon reflexes and eight had absent reflexes, but none had definite upper motor neuron signs. Electrophysiologic studies showed spontaneous activity in all 14 patients, one or more motor conduction blocks in nine, slowed motor conductions in one, and normal conductions in four patients. None had abnormal sensory conductions. These patients presented with a syndrome that has features of, but is distinct from, both motor neuron disease and demyelinating neuropathy.