Non-recurrent SEPT9 duplications cause hereditary neuralgic amyotrophy.

BACKGROUND: Genomic copy number variants have been shown to be responsible for multiple genetic diseases. Recently, a duplication in septin 9 (SEPT9) was shown to be causal for hereditary neuralgic amyotrophy (HNA), an episodic peripheral neuropathy with autosomal dominant inheritance. This duplication was identified in 12 pedigrees that all shared a common founder haplotype. METHODS AND RESULTS: Based on array comparative genomic hybridisation, we identified six additional heterogeneous tandem SEPT9 duplications in patients with HNA that did not possess the founder haplotype. Five of these novel duplications are intragenic and result in larger transcript and protein products, as demonstrated through reverse transcription-PCR and western blotting. One duplication spans the entire SEPT9 gene and does not generate aberrant transcripts and proteins. The breakpoints of all the duplications are unique and contain regions of microhomology ranging from 2 to 9 bp in size. The duplicated regions contain a conserved 645 bp exon within SEPT9 in which HNA-linked missense mutations have been previously identified, suggesting that the region encoded by this exon is important to the pathogenesis of HNA. CONCLUSIONS: Together with the previously identified founder duplication, a total of seven heterogeneous SEPT9 duplications have been identified in this study as a causative factor of HNA. These duplications account for one third of the patients in our cohort, suggesting that duplications of various sizes within the SEPT9 gene are a common cause of HNA.

Enteral tube feeding for amyotrophic lateral sclerosis/motor neuron disease.

BACKGROUND: Enteral feeding (tube feeding) is offered to many people with amyotrophic lateral sclerosis/motor neuron disease experiencing difficulty swallowing (dysphagia) and maintaining adequate nutritional intake leading to weight loss. OBJECTIVES: The aim of this review is to examine the efficacy of percutaneous endoscopic gastrostomy placement or other tube feeding placement on: (1) survival; (2) nutritional status; (3) quality of life. Another aim is to examine the minor and major complications of percutaneous endoscopic gastrostomy. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register (June 2005), MEDLINE (from January 1966 to June 2005), and EMBASE (from January 1980 to June 2005) for randomized controlled trials. In addition we searched MEDLINE (January 1966 to June 2005) and EMBASE (January 1980 to June 2005) to identify non-randomized studies that might be worthy of review and discussion. We checked references in published articles, proceedings of scientific meetings, and enlisted personal communications to identify any additional references. SELECTION CRITERIA: All randomized and quasi-randomized controlled trials were to have been selected. Since no such trials were discovered, all prospective and retrospective controlled studies were reviewed in the 'Background' or 'Discussion' sections of the review. DATA COLLECTION AND ANALYSIS: We independently assessed study methodological design and extracted data. We considered the following outcomes: (1) survival rate in months (of primary interest), (2) nutritional status measured by weight change, change in body mass index, or other quantitative index of nutritional status, and (3) self-perceived quality of life We were also interested in reports of safety of the procedure as indicated by (4) minor and major complications of percutaneous endoscopic gastrostomy or other feeding tube placement. MAIN RESULTS: We found no randomized controlled trials comparing the efficacy of enteral tube feeding with those people who continued to eat orally, without enteral feeding. We summarized the results of retrospective and prospective case controlled studies in the 'Discussion' section of this review. AUTHORS' CONCLUSIONS: There are no randomized controlled trials to indicate whether enteral tube feeding is beneficial compared to continuation of oral feeding for survival. The 'best' evidence to date, based on controlled prospective cohort studies, suggests an advantage for survival in all people with amyotrophic lateral sclerosis/motor neuron disease, but these conclusions are tentative. Evidence for improved nutrition is also incomplete but tentatively favorable. Quality of life has only been addressed by a few researchers and needs more serious attention.

The effects of executive and behavioral dysfunction on the course of ALS.

OBJECTIVE: To determine whether patients with ALS-frontotemporal lobar dementia (FTLD) have a shorter survival and are less compliant with recommended treatments than those with ALS who have normal executive and behavioral function (classic ALS). METHODS: Survival analysis from ALS symptom onset to death included 81 of 100 consecutive patients who could be classified definitely as ALS with abnormal executive or behavioral function or as classic ALS. Criteria were defined for compliance with noninvasive positive-pressure ventilation (NPPV) and percutaneous endoscopic gastrostomy (PEG). RESULTS: Median survival was 2 years 4 months for the 28 patients with FTLD and 3 years 3 months for the 53 patients with classic ALS (relative hazard for death 1.93, CI 1.09 to 3.43; p = 0.024). However, the relative hazard associated with FTLD (1.49) in the multivariate model was diminished by the association of FTLD with bulbar onset and older age and was not significant in this sample size. With bulbar onset, median survival was 2 years 0 months for the 14 with ALS-FTLD and 2 years 10 months for the 10 with classic ALS (relative hazard for death 2.78, CI 1.02 to 7.55; p = 0.045), and older age was not a significant risk. Noncompliance with NPPV and PEG were 75% and 72% in ALS-FTLD, respectively, vs 38% and 31% in classic ALS (relative risks 2.00 and 2.34; p = 0.013 and 0.022). CONCLUSIONS: Survival is significantly shorter among patients with ALS-FTLD than with classic ALS. Furthermore, patients with ALS-FTLD are twice as likely to be noncompliant.

Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial.

BACKGROUND: Patients with ALS commonly exhibit pseudobulbar affect. METHODS: The authors conducted a multicenter, randomized, double-blind, controlled, parallel, three-arm study to test a defined combination of dextromethorphan hydrobromide (DM) and quinidine sulfate (Q) (AVP-923) for the treatment of pseudobulbar affect in ALS. Q inhibits the rapid first-pass metabolism of DM. The effects of AVP-923 (30 mg of DM plus 30 mg of Q) given twice daily for 28 days were compared with those of its components. Patients were evaluated on days 1, 15, and 29. The primary efficacy variable was the change from baseline in the Center for Neurologic Study Lability Scale (CNS-LS) score. Secondary efficacy variables were laughing/crying episode rates and changes in Visual Analog Scales for Quality of Life (QOL) and Relationships (QOR). Efficacy was evaluated in intention-to-treat subjects who were not poor metabolizers of DM (n = 65 for AVP-923, n = 30 for DM, and n = 34 for Q). Safety was assessed in all randomized subjects (n = 140). RESULTS: AVP-923 patients experienced 3.3-point greater improvements in CNS-LS than DM patients (p = 0.001) and 3.7-point greater improvements than Q patients (p < 0.001). AVP-923 patients exhibited lower overall episode rates, improved QOL scores, and improved QOR scores (p < 0.01 for all endpoints). Adverse effects were mostly mild or moderate; treatment-related discontinuation was 24% for AVP-923, 6% for DM, and 8% for Q. CONCLUSIONS: AVP-923 palliates pseudobulbar affect in ALS. Overall benefits of treatment are reflected in fewer episodes of crying and laughing and improvements in overall quality of life and quality of relationships.

Are amyotrophic lateral sclerosis patients cognitively normal?

BACKGROUND: Patients with ALS are often told that the disease spares cognition; however, recent evidence suggests deficits in frontal executive skills occur in a sizable minority of ALS patients. In many instances, the frontal executive deficits represent the co-occurrence of frontotemporal lobar dementia (FTLD) and ALS. METHODS: Word generation, a simple frontal task that takes <2 minutes, was tested in 100 consecutive patients with ALS seen in the authors' multidisciplinary clinic. Any patient with a prior dementia diagnosis was excluded from the study. A subset of 44 patients agreed to undergo further neuropsychological testing and clinical interview to confirm or deny a diagnosis of dementia. RESULTS: Diminished word generation was found in one-third. Of the patients with abnormal word generation who agreed to further evaluation, nearly all were shown to meet research criteria for FTLD. In addition, one-quarter of the patients with normal word generation who agreed to further evaluation met research criteria for FTLD; these patients had new-onset personality changes. CONCLUSIONS: This study suggests that frontal executive deficits are present in half of ALS patients, many of whom meet strict research criteria for FTLD. Word generation tests are a useful screening tool in this cohort.

Effect of recording window and stimulation variables on the statistical technique of motor unit number estimation.

A variety of methods are used for the selection of recording window sizes and stimulation current levels for statistical motor unit number estimation (MUNE). This study compares different recording window sizes and stimulation current levels within those windows in the same subjects to determine the effect on MUNE value and reproducibility. Four recording windows of 10% size were compared with four of 5%, with the stimulation current set in the lower quarter, middle half, and upper quarter of the recording window. MUNE for stimulation current set in the lower quarter of the window was 81 (62-103) for 10% recording windows and 120 (108-135) for 5% recording windows, and 91 (61-123) and 133 (120-154) for stimulation current set in the middle half. Increasing the recording window size from 5 to 10% lowers the MUNE value in controls, but tends to improve reproducibility; and setting the stimulation current in the lower quarter of the window, changes the MUNE value minimally, while tending to improve further reproducibility. Excellent reproducibility of MUNE was obtained when applied to a pilot group of 10 amyotrophic lateral sclerosis patients. Based on this study, we conclude that the ideal method for statistical motor unit estimation involves using 10% recording windows and setting the stimulation current in the lower quarter of the recording window.

Comparison of multiple point and statistical motor unit number estimation.

This study compares two common techniques for motor unit number estimation, multiple point stimulation and statistical method, to determine which is more reproducible. Surface recorded motor unit action potentials (SMUPs) of the left hypothenar muscle group were measured on 20 controls and 10 ALS patients. For multiple point, 10 different threshold SMUPs were recorded. For statistical method, mean SMUP amplitude was measured at several stimulus levels, typically spanning >40% of CMAP amplitude range. Both techniques were performed twice, results averaged, electrodes changed, and all recording repeated. For controls, mean of two motor unit number estimation (MUNE) (+/- standard deviation) was 60 (+/-5) for statistical method, and 108 (+/-38) for multiple point. For ALS patients, these values were 21 (+/-16) for statistical method and 55 (+/-39) for multiple point. Test-retest correlation coefficients and coefficients of variation for mean of two MUNE were 0.98 and 7% for statistical method, and 0.90 and 12% for multiple point, respectively. Statistical method was more reproducible and faster than multiple point, supporting its utility in monitoring rates of MUNE change.

Statistical motor unit number estimation: reproducibility and sources of error in patients with amyotrophic lateral sclerosis.

The reliability of motor unit number estimation (MUNE) for assessment of the long-term course of ALS is dependent on the reproducibility of the technique. We report our results with the statistical method of MUNE on the ulnar nerve/hypothenar muscle in 16 ALS patients who were studied on 52 occasions. On each occasion, MUNE was performed twice with one electrode placement and once with a different placement. For each MUNE, mean surface motor unit potential amplitude was determined within three different recording ranges or windows at different stimulus intensities. The MUNE results had excellent reproducibility with coefficients of variation of 19% and test-retest correlation coefficients from 0.75 to 0.86. With examination of sources for variability, the reproducibility of statistical MUNE is not affected by minor variation in stimulation and recording electrode placement but may be improved by modifying methods for recording window selection. The high reproducibility of statistical MUNE supports its reliability for estimating the rate of motor unit loss in ALS.

Motor unit number estimation (MUNE): how may it contribute to the diagnosis of ALS?

Motor unit number estimation (MUNE) is a type of electrophysiological technique that measures the approximate number of lower motor neurons (LMNs) innervating a single muscle or a small group of muscles. Low MUNE counts provide evidence of LMN degeneration, but a single MUNE study does not determine if this loss is ongoing, recent or remote in time. Sequential change of MUNE count provides evidence for ongoing degeneration. Furthermore, sequential change in MUNE from a normal to abnormally low count provides evidence for progressive spread of signs within a region or to another region. MUNE has no established ability to identify other diseases that may provide a non-ALS explanation for the signs of LMN degeneration. If MUNE studies were to be incorporated into a future revision of the diagnostic criteria for ALS, prospective studies will be important to define more clearly the sensitivity and specificity of MUNE in patients with ALS and in patients with weakness that does not involve LMN degeneration. In addition to its potential contributions toward the diagnosis of ALS, MUNE may have greater potential in quantifying the rate of progression in studies of the natural history of ALS and the response to experimental treatment.

Clinical trials for polyneuropathy: the role of nerve conduction studies, quantitative sensory testing, and autonomic function testing.

Clinical trials to assess the treatment of diabetic and other forms of polyneuropathy are becoming increasingly common. Nerve conduction studies, quantitative sensory testing, and autonomic function testing are often used in these trials. This article reviews the sensitivity and reproducibility of these measures to detect change in peripheral nerve function during long-term trials. The attributes of nerve conduction studies that are likely to be most useful are summated or averaged sensory nerve action potential amplitudes and averaged motor nerve conduction velocities. Summated or averaged compound muscle action potential amplitude and mean F-wave latencies are also highly informative. Vibratory detection thresholds are sensitive, specific, and highly reproducible for assessment of large myelinated sensory fibers, with cooling and warming detection thresholds also having good sensitivity for small myelinated sensory fibers. Although less well validated for longitudinal trials, visual analogue scale scoring of heat pain provides assessment of unmyelinated sensory fibers. Heart rate variation to deep breathing, Valsalva, or standing are useful to assess cardiac autonomic function. Based on these data that are reviewed and consistent with the conclusions of previous consensus conferences, a combination of these studies is recommended.

Neuropathies associated with connective tissue disease.

Neuropathies are a common neurologic manifestation of diffuse connective tissue disease. Vasculitic neuropathy requires prompt diagnosis and treatment to improve its outcome. It is commonly multifocal but may be confluent and symmetrical. Vasculitic neuropathy needs to be distinguished from the more common syndromes of compression neuropathy, which may also be multifocal, and nonvasculitic distal axonal polyneuropathy. Sensory neuronopathy is a distinctive syndrome unique to Sjögren's syndrome among the connective tissue diseases. Trigeminal sensory neuropathy may be the presenting feature of systemic sclerosis or may develop during the course of other connective tissue diseases. This article reviews the clinical and diagnostic features of neuropathies associated with the common diffuse connective tissue diseases.

Longitudinal study of fiber density and motor unit number estimate in patients with amyotrophic lateral sclerosis.

We examined fiber density, compound muscle action potential (CMAP) amplitude, and motor unit number estimate (MUNE) of the abductor digiti minimi and grip strength longitudinally. We sought to determine the effects of ALS on these measurements and to evaluate which of these tests may be more sensitive in evaluating progression of ALS and possibly predicting survival. Ten patients were examined at months 0, 3, and 6. A significant decrease in MUNE and increase in fiber density were observed at months 3 and 6 (p < 0.02) compared with baseline (month 0). Mean CMAP and grip strength declined, but not significantly. The decrease in MUNE over 6 months was significantly greater than that of CMAP and grip strength (p < 0.025). The significant changes in MUNE and fiber density over time suggest that they are more sensitive in measuring the rate of progression of ALS. To evaluate further the utility of these tests, we arbitrarily divided the patients into equal groups based on length of survival. MUNE declined significantly in the group with shorter survival (p < 0.01). Conversely, fiber density increased significantly in patients with longer survival (p < 0.01). With similar statistical analysis there were no significant differences in decline of CMAP or grip strength in either subgroup over 6 months. Our study suggests that MUNE and fiber density are more sensitive than CMAP and grip strength in detecting progression of ALS. Furthermore, we raise the hypotheses that a greater increase in fiber density identifies a group of patients with ALS who will have longer survival, and that a greater decline in MUNE identifies a group with a worse prognosis.

Serum IgM monoclonal autoantibody binding to the 301 to 314 amino acid epitope of beta-tubulin: clinical association with slowly progressive demyelinating polyneuropathy.

We identified five patients with IgM monoclonal autoantibodies that bound to human brain tubulin. In a companion study, we found that IgM in these sera selectively recognized one of three epitopes on tubulin. IgM from three patients bound selectively to a small epitope on human beta-tubulin comprising amino acids 301 to 314. The other two sera recognized tubulin amino acids 215 to 235 and 315 to 336. In this study, we compared the clinical syndromes in these patients with the tubulin epitope recognized by their serum IgM. The three patients with IgM binding to tubulin amino acids 301 to 314 all had chronic inflammatory demyelinating polyneuropathy (CIDP) syndromes with slowly progressive weakness, hyporeflexia, and electrophysiologic studies consistent with demyelination. Two of these patients had significant asymmetry to their weakness. The two other patients had diagnoses of polyradiculopathy and amyotrophic lateral sclerosis with no evidence of peripheral nerve demyelination. We conclude that IgM monoclonal anti-tubulin antibodies have some association with demyelinating polyneuropathy syndromes, but may occur in patients with other clinical syndromes as well. A stronger association with demyelinating polyneuropathies may occur if the anti-tubulin antibodies recognize the 301 to 314 amino acid epitope on tubulin. This tubulin epitope, or a similar one on another molecule, could play an important antigenic role in the development of demyelinating polyneuropathies with features of CIDP.

Reduced corticomotoneuronal excitatory postsynaptic potentials (EPSPs) with normal Ia afferent EPSPs in amyotrophic lateral sclerosis.

We studied excitatory postsynaptic potentials (EPSPs) arising in single spinal motoneurons (composite EPSPs) induced by Ia afferent and magnetic cortical stimulation in 28 normal subjects ranging in age from 24 to 84 years and 28 patients with amyotrophic lateral sclerosis (ALS) aged 34 to 82 years. The subjects voluntarily recruited single motor units of the first dorsal interosseous muscle. Using peristimulus time histograms, we determined changes in the firing probability of the first dorsal interosseous motor units and measured the magnitude of the EPSP. An early period of increased firing probability (primary peak) occurred at approximately 30 msec after la afferent and 25 msec after cortical stimulation, reflecting underlying EPSPs arising in spinal motoneurons induced by either projection. The latency of the primary peaks for both Ia afferent and cortical stimulation was mildly prolonged in ALS, suggesting a loss of the fastest-conducting spinal motoneurons. Patients with ALS had la afferent-driven EPSPs whose amplitude and rise time were equivalent to those of normal subjects. However, the ratio of cortical to la afferent-driven composite EPSPs in ALS was significantly lower than that for normal subjects. Fourteen of 28 ALS motor units had cortically driven EPSPs that were small or large only because of a prolonged rise time. The findings suggest that in ALS, corticomotoneuronal attrition or dispersion of the descending volley occurs in the presence of normally functioning spinal motoneurons to which they project.

Peptide T in the treatment of painful distal neuropathy associated with AIDS: results of a placebo-controlled trial. The Peptide T Neuropathy Study Group.

OBJECTIVE: To assess the safety and efficacy of Peptide T in the treatment of painful distal symmetrical polyneuropathy (DSP) associated with human immunodeficiency virus (HIV) infection. BACKGROUND: Painful DSP is a frequent complication of HIV infection, although its etiology and optimal treatment are unknown. Peptide T (D-(alpha 1)-Peptide T-amide) has been found in phase I trials and anecdotal reports to relieve neuropathic pain in AIDS patients. DESIGN/METHODS: In this multicentered, double-blind, randomized study, subjects received intranasal Peptide T 6 mg/day or placebo for 12 weeks. The primary outcome measure was change in the modified Gracely pain score. Secondary efficacy variables were results of neurologic examination, neuropsychological and electrophysiologic studies, global evaluation, and CD4 lymphocyte counts. RESULTS: Of 81 evaluable subjects, 40 received Peptide T and 41 received placebo. The change in pain scores was not significantly different (p = 0.32) in the Peptide T group (-0.24) as compared to placebo (-0.39). Group comparisons were not significantly different for change in any clinical examination or neuropsychologic measure, sural nerve amplitude or conduction velocity, or CD4 lymphocyte count. No significant drug-related adverse effects occurred in either group. CONCLUSION: Intranasal Peptide T is safe but ineffective in the treatment of painful DSP associated with AIDS.