Wasted leg syndrome: An atypical slowly-progressive form of lower motor neuron disease.

We describe four male patients with wasted-leg syndrome, with predominant asymmetric thigh atrophy and weakness that stabilized after a period of slow progression (follow-up 7-18 years). Two patients had an Indian ethnic background and two were Portuguese, without known Indian ancestry. Other mimicking disorders were excluded, but one Indian patient was later diagnosed with CADASIL. Electromyography (EMG) revealed severe chronic neurogenic changes in proximal leg muscles, and mild changes in distal leg muscles, but EMG of the upper limbs was normal. Upper motor neuron signs were absent clinically and on transcranial magnetic stimulation. This seems to represent a variant of the common wasted-leg syndrome presentation.

Muscular cramp: causes and management.

Muscular cramp is a common symptom in healthy people, especially among the elderly and in young people after vigorous or peak exercise. It is prominent in a number of benign neurological syndromes. It is a particular feature of chronic neurogenic disorders, especially amyotrophic lateral sclerosis. A literature review was undertaken to understand the diverse clinical associations of cramp and its neurophysiological basis, taking into account recent developments in membrane physiology and modulation of motor neuronal excitability. Many aspects of cramping remain incompletely understood and require further study. Current treatment options are correspondingly limited.

Diagnostic criteria for amyotrophic lateral sclerosis: A multicentre study of inter-rater variation and sensitivity.

OBJECTIVE: This study assesses inter-rater agreement and sensitivity of diagnostic criteria for amyotrophic lateral sclerosis (ALS). METHODS: Clinical and electrophysiological data of 399 patients with suspected ALS were collected by eleven experienced physicians from ten different countries. Eight physicians classified patients independently and blinded according to the revised El Escorial Criteria (rEEC) and to the Awaji Criteria (AC). Inter-rater agreement was assessed by Kappa coefficients, sensitivity by majority diagnosis on 350 patients with follow-up data. RESULTS: Inter-rater agreement was generally low both for rEEC and AC. Agreement was best on the categories "Not-ALS", "Definite", and "Probable", and poorest for "Possible" and "Probable Laboratory-supported". Sensitivity was equal for rEEC (64%) and AC (63%), probably due to downgrading of "Probable Laboratory-supported" patients by AC. However, AC was significantly more effective in classifying patients as "ALS" versus "Not-ALS" (p < 0.0001). CONCLUSIONS: Inter-rater variation is high both for rEEC and for AC probably due to a high complexity of the rEEC inherent in the AC. The gain of AC on diagnostic sensitivity is reduced by the omission of the "Probable Laboratory-supported" category. SIGNIFICANCE: The results highlight a need for initiatives to develop simpler and more reproducible diagnostic criteria for ALS in clinical practice and research.

Plasma level of club-cell (CC-16) predicts outcome in amyotrophic lateral sclerosis.

OBJECTIVES: The club cell protein (CC-16) is a biomarker associated with respiratory distress and pulmonary inflammation. We evaluated CC-16 as a candidate biomarker for respiratory failure in amyotrophic lateral sclerosis (ALS). MATERIALS AND METHODS: We studied 81 ALS patients and 30 matched controls. We used an ALS-related measure of functional capacity, and tested forced vital capacity (FVC) and the amplitude of the diaphragmatic response by phrenic nerve stimulation (PhrenAmpl). Plasma CC-16 levels were measured in venous blood. Kaplan-Meier survival curves were plotted to evaluate risk to non-invasive ventilation and death in patients with abnormal CC-16 levels. RESULTS: CC-16 levels were significantly raised in ALS patients (10.56 ng/mL ± 6.84 vs 8.34 ng/mL ± 3.10, P = .02), and in 17% of them, CC-16 level was above the upper cutoff value (mean + 2.5SD). CC-16 levels did not correlate with age, onset region, disease duration, functional status, FVC, and PhrenAmpl. In patients with increased CC-16 level, the risk of non-invasive was greater in the following 6 months (P = .01) and tended to have higher mortality in the following 30 months (P = .07). CONCLUSIONS: We propose that increased CC-16 levels is a marker of lung inflammatory response that associated with ventilatory insufficiency are related to impending respiratory failure, not fully predicted by conventional respiratory tests. The latter are limited by the moment of testing.

Congenital myopathy with focal loss of cross-striations revisited.

In 1977 Wijngaarden et al. reported a Dutch family with a congenital myopathy characterized by external ophthalmoplegia and a remarkable histological feature, focal loss of cross-striations. A small number of other families with similar clinical and pathological features led to the consideration of this congenital myopathy as a distinct entity. Here we present more than 30years of follow-up from the Dutch family and report recently identified compound heterozygous mutations in the skeletal muscle ryanodine receptor (RYR1) gene, c.10627-2A>G and p.Arg3539His (c.10616G>A). Focal loss of cross-striations on muscle biopsy is another histopathological feature that should raise the possibility of RYR1 involvement.

Defecation 1: Testing a hypothesis for pelvic striated muscle action to open the anorectum.

BACKGROUND: We conducted an observational study to assess the hypothesis that the pelvic muscles actively open the anorectal lumen during defecation. METHODS: Three groups of female patients were evaluated with video imaging studies of defecation using a grid or bony reference points. Eight patients with idiopathic fecal incontinence had video myogram defecography; eight with obstructive defecation had magnetic resonance imaging (MRI) defecating proctograms; and four normal patients had video X-ray or MRI defecating proctogram studies. RESULTS: In all three groups, the anorectum was stretched bidirectionally by three directional muscle force vectors acting on the walls of the rectum, effectively doubling the diameter of the rectum during defecation. The anterior rectal wall was pulled forwards, and the posterior wall backwards and downwards opening the anorectal angle, associated with angulation of the anterior tip of the levator plate (LP). These observations are consistent with a staged relaxation of some parts of the pelvic floor during defecation, and contraction of others. First, the puborectalis muscle relaxes. Puborectalis muscle relaxation frees the posterior rectal wall so that it can be stretched and opened by contraction of the LP and conjoint longitudinal muscle of the anus. Second, contraction of the pubococcygeus muscle pulls forward the anterior rectal wall, further increasing the diameter of the rectum. Third, when the bolus has entered the rectum, the external anal sphincter relaxes, and the rectum contracts to expel the fecal bolus. CONCLUSIONS: Our results are consistent with the hypothesis that pelvic striated muscle actively opens the rectal lumen, thereby reducing internal anorectal resistance to expulsion of feces. Controlled studies of electromyographic activity would be useful to further test this hypothesis.

Defecation 2: Internal anorectal resistance is a critical factor in defecatory disorders.

BACKGROUND: The aim of this study was to test our hypothesis that the reason why imaging is of little assistance in diagnosing "constipation" causes may be related to the high sensitivity of internal anorectal flow resistance in defecation to small changes in geometry. We applied a mathematical model to describe the effects on flow mechanics of observed changes in the shape of the rectum and anus during defecation. METHODS: Three groups of patients were studied with video proctograms. Group 1 comprised 4 patients with normal defecation studied with video proctography or magnetic resonance imaging (MRI). Group 2 comprised 8 patients with fecal incontinence, studied by video X-ray electromyography. Group 3 comprised 8 patients with constipation evaluated by video MRI. RESULTS: Three muscle vectors open the anorectal angle prior to defecation, causing the anorectal luminal diameter to increase to approximately twice its resting size. These vectors are forwards (anterior wall), backwards and downwards (posterior wall). Resistance to passage of a fecal bolus through the anorectum is determined by viscous friction against the anorectal wall and by the energy required to deform the bolus as it flows. The observed changes in anorectal geometry serve to reduce both the viscous friction in the anus and the deformation of the bolus, which reduces the force required to facilitate its passage through the anus. For example, if the effective diameter of the anus is doubled during defecation, the frictional resistance is reduced by a factor of 8. CONCLUSIONS: The sensitivity of flow resistance to geometry explains why MRI or computed tomography (CT) scans taken during defecation are not often helpful in diagnosing causation. Small changes in geometry can have a disproportionate affect on flow resistance. Combining accurate directional measurements during dynamic MRI or CT scans taken during defecation with observations of bolus deformation, and if possible, simultaneous anorectal manometry, may provide clinically helpful insights on patients with anorectal evacuation disorders.

Phase II/III randomized trial of TCH346 in patients with ALS.

BACKGROUND: TCH346 exerts antiapoptotic effects by binding to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and blocking the apoptotic pathway in which GAPDH is involved. Apoptosis is considered to be a key pathogenic mechanism in neurodegenerative diseases including ALS. METHODS: Patients were randomly assigned in a double-blind fashion to receive either placebo or one of four doses of TCH346 (1.0, 2.5, 7.5, or 15 mg/day) administered orally once daily for at least 24 weeks. The primary outcome measure was the rate of change in the revised ALS functional rating scale (ALSFRS-R). The trial design included a 16-week lead-in phase to determine each patient's rate of disease progression. The between treatment comparison was adjusted for the individual pretreatment rates of progression. The study was powered to detect a 25% reduction in the rate of decline of the ALSFRS-R as compared with placebo. Secondary outcome measures included survival, pulmonary function, and manual muscle testing (MMT). RESULTS: Five hundred ninety-one patients were enrolled at 42 sites in Europe and North America. There were no differences in baseline variables. There were no significant differences between placebo and active treatment groups in the mean rate of decline of the ALSFRS-R or in the secondary outcome measures (survival, pulmonary function, and MMT). CONCLUSION: The trial revealed no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS.

Comparison of the 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) with a short-form five-item version (ALSAQ-5) in a longitudinal survey.

OBJECTIVES: To compare results on the 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) with those gained on the short-form five-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5) in a longitudinal study. DESIGN: Postal survey. Copies of the ALSAQ-40 which incorporates the five items of the ALSAQ-5, were completed on two occasions. Respondents were also asked to indicate how much change they had experienced since baseline on each of the five domains of the questionnaire. SETTING: The database of all patient members of the Motor Neurone Disease Association for England, Wales and Northern Ireland. SUBJECTS: Nine hundred and twenty-seven patient members returned questionnaires at baseline, and 764 completed questionnaires at both baseline and follow-up. RESULTS: Results on the five dimensions of the ALSAQ-40 and ALSAQ-5 were found to be highly correlated, and 95% confidence intervals on mean scores were found to overlap for each dimension. The instruments both provide a similar picture of change in terms of their responsiveness. For example, effect sizes were calculated for patients who claimed their health had deteriorated a little since baseline, and gave almost identical results (e.g. for the Physical functioning domain effect sizes of 0.12 and 0.11 were found on the long and short measures respectively). CONCLUSIONS: Results suggests that the ALSAQ-5 provides similar results to the ALSAQ-40 yet with considerable economy. In instances where a very brief health status measure is required then the ALSAQ-5 may be the instrument of choice.

The onset of amyotrophic lateral sclerosis.

Two patients in whom both the neurological examination and electromyography (EMG) were normal prior to the onset of amyotrophic lateral sclerosis (ALS) are reported. In each patient, the onset of ALS some 18 months later was clearly defined clinically and confirmed by subsequent EMG studies. These unique observations show that ALS commences at a defined time, and that there is early generalisation with an initial phase of rapid progression.

Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene.

BACKGROUND: Minicore myopathy (multi-minicore disease [MmD]) is a congenital myopathy characterized by multifocal areas with loss of oxidative activity on muscle biopsy. MmD is clinically heterogeneous and distinct phenotypes have been associated with recessive mutations in either the selenoprotein N (SEPN1) or the skeletal muscle ryanodine receptor (RYR1) gene, also implicated in central core disease and malignant hyperthermia. External ophthalmoplegia is an additional finding in a subset of patients with MmD. OBJECTIVE: To clinically and genetically examine families with MmD and external ophthalmoplegia. METHODS: The authors investigated 11 affected individuals from 5 unrelated families. Clinical, histopathologic, and imaging studies were performed and RYR1 haplotyping and mutational analysis were carried out. RESULTS: All patients had multiple cores involving the entire fiber diameter on longitudinal sections. Weakness and wasting in the shoulder girdle, scoliosis, moderate respiratory impairment, and feeding difficulties were prominent. In contrast to SEPN1-related myopathies, soleus was more severely affected than gastrocnemius on muscle MRI. Haplotyping suggested linkage to the RYR1 locus in informative families and mutational screening revealed four novel RYR1 mutations in three unrelated families; in addition, functional haploinsufficiency was found in one allele of two recessive cases. CONCLUSION: These findings expand the phenotypic spectrum associated with mutations in the skeletal muscle ryanodine receptor (RYR1) gene. Recessive mutations of domains commonly affected in malignant hyperthermia appear to be particularly prevalent in multi-minicore disease with external ophthalmoplegia and might suggest a different pathomechanism from that involved in central core disease.

Contribution of the pudendal nerve to sensation of the distal rectum.

BACKGROUND: Anal and rectal sensory mechanisms and pudendal nerve function are important in the control of faecal continence. The contribution of the pudendal nerve to sensation of the distal rectum was investigated. METHODS: Heat thresholds in the anal canal, distal and mid rectum were measured using a specially designed thermoprobe. Rectal sensory threshold volumes were measured using the balloon distension method. Needle electrodes were inserted into the external anal sphincter. Pudendal nerve block was performed through a perineal approach, and completeness assessed by loss of electromyographic activity. Heat and rectal volume thresholds were measured again following unilateral and bilateral pudendal nerve block. RESULTS: The technique was successful in four of six volunteers. Bilateral pudendal nerve block produced complete anaesthesia to heat in the anal canal (P = 0.029), but had no effect on heat thresholds in the distal or mid rectum. Rectal sensory threshold volumes were also unaffected by pudendal nerve anaesthesia. CONCLUSION: Anal canal sensation is subserved by the pudendal nerve, but this nerve is not essential to nociceptive sensory mechanisms in the distal or mid rectum. The transition between visceral control mechanisms in the lower rectum and somatic mechanisms in the anal canal may have functional importance in the initiation of defaecation and the maintenance of continence.