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While some regard the flail arm syndrome as a variant of amyotrophic lateral sclerosis (ALS), others have argued that it is a distinct clinical entity. Consequently, the present study applied novel central and peripheral nerve excitability techniques to further explore disease pathophysiology in flail arm syndrome.Cortical and peripheral nerve excitability studies were undertaken in 11 flail arm patients, defined by muscle weakness limited to the proximal aspects of the upper limbs for at least 24 months.Mean age at disease onset (60.3 years) was similar to other ALS phenotypes (58.3 years), with strong male predominance (male:female distribution: flail arm 10:1; ALS 1.5:1; p0.05) and prolonged disease duration (flail arm 62.5 months; ALS 15.8 months; p0.05). There was evidence of cortical hyperexcitability in flail arm patients, similar to findings in ALS, with reduction in short interval intracortical inhibition (flail arm 0.8 (0.6)%; ALS 4.1 (1.1)%; controls 8.5 (1.0)%; p0.0001) and resting motor threshold (flail arm 53.4 (2.8)%; ALS 56.6 (1.8)%; controls 60.7 (1.5)%; p0.05), along with an increase in motor evoked potential amplitude (flail arm 49.5 (9.0)%; ALS 44.4 (4.9)%; controls 25.8 (2.8)%; p0.05). Peripheral nerve excitability studies demonstrated changes consistent with upregulation in persistent Na+ currents and reduction of slow K+ conductances, similar to findings in ALS.This study has demonstrated the presence of cortical hyperexcitability in flail arm syndrome, along with abnormalities in peripheral nerve excitability, findings consistent with previous studies in other ALS phenotypes. By demonstrating the presence of upper motor neuron dysfunction, the present study suggests that the flail arm syndrome is an unusual variant of ALS.

Background: While the incidence of amyotrophic lateral sclerosis (ALS) is similar across the world (range, 1.0 to 2.5/100 000), a latitude gradient from north to south has been observed. Objective: To determine the incidence of ALS in Puglia, a region of south eastern Italy, and to test the latitude gradient hypothesis comparing the present study with findings in studies conducted with the same design in a northern latitude. Methods: Puglia (4 086 613 residents in 2001) is the site of a multicentre-multisource prospective population based registry established in 1997. All incident ALS cases during the period 1998–99 were enrolled and followed up. Cases were classified using the first and the revised El Escorial criteria. Results: During the study period 130 cases were enrolled. The annual crude incidence for ALS in Puglia for the two year period 1998–99 was 1.6/100 000 (95% confidence interval, 1.3 to 1.9). The incidence was higher for men (incidence rate (IR) = 2.1 (1.7 to 2.7) than for women (IR = 1.2 (0.9 to 1.5)) in all age groups, with a male to female ratio of 1.6. For both men and women, the incidence increased through age 75 and declined rapidly afterwards. The mean annual incidence adjusted by age and sex to the 2001 Italian population was 1.7/100 000 (1.4 to 2.0). Conclusions: ALS incidence is within a narrow range across countries, with a peak between 65 and 75 years and a higher incidence in men . A north to south latitude gradient of ALS incidence is not supported by the results of cohort studies.

While patients with amyotrophic lateral sclerosis (ALS) may complain of fatigue, the underlying mechanisms appear complex, with dysfunction of central and peripheral nervous systems independently reported as contributing factors. The aim of the present study was to further delineate the mechanisms underlying increased fatigability in ALS by measuring activity dependent changes in axonal excitability following a maximum voluntary contraction (MVC).Nerve excitability changes were recorded before and after an MVC of the abductor pollicis brevis in 16 patients with ALS and 25 controls.In patients with ALS, there was a greater increase in threshold (36.5 (5.9)%; controls 19.6 (3.5)%; p0.05) as a result of MVC, with reduction in the amplitude of the compound muscle action potential generated by a submaximal stimulus (ALS 49 (7.6)%; controls 41.0 (5.4)%). These changes were associated with an increase in superexcitability (ALS 65.1 (25.4)%; controls 42.3 (5.7)%) and reduction in strength-duration time constant (ALS 20 (4.9)%; controls 10 (2.5)%; p0.01), indicative of axonal hyperpolarisation. The increase in threshold was more pronounced in patients with ALS with predominantly lower motor neuronal involvement.Higher firing rates of surviving motor axons attempting to compensate for neurogenic weakness are likely to explain the greater activity dependent changes in ALS. As such, the present study suggests a further peripheral factor underlying the development of fatigue in ALS.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with severe cervical cord damage due to degeneration of the corticospinal tracts and loss of lower motor neurones. Diffusion tensor magnetic resonance imaging (DT MRI) allows the measurement of quantities reflecting the size (such as mean diffusivity) and orientation (such as fractional anisotropy) of water-filled spaces in biological tissues.Mean diffusivity and fractional anisotropy histograms from the cervical cord of patients with ALS were obtained to: (1) quantify the extent of tissue damage in this critical central nervous system region; and (2) investigate the magnitude of the correlation of cervical cord DT MRI metrics with patients' disability and tissue damage along the brain portion of the corticospinal tracts. Cervical cord and brain DT MRI scans were obtained from 28 patients with ALS and 20 age-matched and sex-matched controls. Cord mean diffusivity and fractional anisotropy histograms were produced and the cord cross-sectional area was measured. Average mean diffusivity and fractional anisotropy along the brain portion of the corticospinal tracts were also measured.Compared with controls, patients with ALS had significantly lower mean fractional anisotropy (p = 0.002) and cord cross-sectional area (p0.001). Mean diffusivity histogram-derived metrics did not differ between the two groups. A strong correlation was found between mean cord fractional anisotropy and the ALS Functional Rating Score (r = 0.74, p0.001). Mean cord and brain fractional anisotropy values correlated moderately (r = 0.37, p = 0.05).Cervical cord DT MRI in patients with ALS allows the extent of cord damage to be graded. The conventional and DT MRI changes found are compatible with the presence of neuroaxonal loss and reactive gliosis, with a heterogeneous distribution of the pathological process between the brain and the cord. The correlation found between cord fractional anisotropy and disability suggests that DT MRI may be a useful adjunctive tool to monitor the evolution of ALS.

Background: To assess whether the premorbid dietary intake of fatty acids, cholesterol, glutamate or antioxidants was associated with the risk of developing amyotrophic lateral sclerosis (ALS). Methods: Patients referred to our clinic during 2001–2002, who had definite, probable or possible ALS according to El Escorial criteria, without a familial history of ALS, were asked to participate in a case–control study (132 patients and 220 healthy controls). A food-frequency questionnaire was used to assess dietary intake for the nutrients of interest. Multivariate logistic regression analysis was performed with adjustment for confounding factors (sex, age, level of education, energy intake, body mass index and smoking). Results: A high intake of polyunsaturated fatty acid (PUFA) and vitamin E was significantly associated with a reduced risk of developing ALS (PUFA: odds ratio (OR) = 0.4, 95% confidence interval (CI) = 0.2 to 0.7, p = 0.001; vitamin E: OR = 0.4, 95% CI = 0.2 to 0.7, p = 0.001). PUFA and vitamin E appeared to act synergistically, because in a combined analysis the trend OR for vitamin E was further reduced from 0.67 to 0.37 (p = 0.02), and that for PUFA from 0.60 to 0.26 (p = 0.005), with a significant interaction term (p = 0.03). The intake of flavonols, lycopene, vitamin C, vitamin B 2 , glutamate, calcium or phytoestrogens was not associated with the risk of developing ALS. Conclusion: A high intake of PUFAs and vitamin E is associated with a 50–60% decreased risk of developing ALS, and these nutrients appear to act synergistically.

To determine the relationship of cerebral degeneration with survival in amyotrophic lateral sclerosis (ALS).Patients with probable or definite ALS underwent magnetic resonance spectroscopic imaging (MRSI) of the brain between July 1996 and May 2002, and were followed prospectively until March 2004. Creatine (Cr), choline (Cho) and the neuronal marker N-acetylaspartate (NAA) were quantified as ratios in the motor cortex.In 63 patients compared with 18 healthy people, NAA/Cho was reduced by 13% (p0.001), NAA/Cr was reduced by 5% (p = 0.01) and Cho/Cr was increased by 8% (p = 0.01). NAA/Cho was used for survival analysis, given its larger effect size and superior test accuracy (a sensitivity of 67% and a specificity of 83%). Median survival after MRSI was 24 months. Multivariate analysis showed reduced survival for lower NAA/Cho (hazard ratio (HR) 0.24, 95% confidence interval (CI) 0.08 to 0.72, p = 0.01), older age (HR 1.03, 95% CI 1.00 to 1.06, p = 0.04) and shorter symptom duration (HR 0.96, 95% CI 0.93 to 0.99, p = 0.01). Patients with NAA/Cho2.11 had a reduced survival of 19.4 v 31.9 months (HR 2.05, 95% CI 1.12 to 4.03, p = 0.02).Cerebral degeneration is predictive of reduced survival in ALS.

Background: Excitotoxicity is one pathogenic mechanism proposed in amyotrophic lateral sclerosis (ALS), and loss of cortical inhibitory influence may be contributory. Patients with ALS who are homozygous for the D90A superoxide dismutase-1 (SOD1) gene mutation (homD90A) have a unique phenotype, associated with prolonged survival compared with patients with sporadic ALS (sALS). In this study, transcranial magnetic stimulation (TMS) was used to explore cortical excitation and inhibition. Flumazenil binds to the benzodiazepine subunit of the GABAA receptor, and 11C-flumazenil positron emission tomography (PET) was used as a marker of cortical neuronal loss and/or dysfunction, which might in turn reflect changes in cortical inhibitory GABAergic mechanisms. Methods: Cortical responses to single and paired stimulus TMS were compared in 28 patients with sALS and 11 homD90A patients versus 24 controls. TMS measures included resting motor threshold, central motor conduction time, silent period, intracortical inhibition (ICI), and facilitation. 11C-flumazenil PET of the brain was performed on 20 patients with sALS and nine with homD90A. Statistical parametric mapping was used to directly compare PET images from the two patient groups to identify those areas of relatively reduced cortical 11C-flumazenil binding that might explain differences in cortical excitability seen using TMS. Results: Increased cortical excitability, demonstrated by reduction in ICI, was seen in the patients with sALS but not the homD90A patients. A relative reduction in cortical 11C-flumazenil binding was found in the motor and motor association regions of the superior parietal cortices of the patients with sALS. Conclusions: A cortical inhibitory deficit in sALS was not demonstrable in a homogeneous genetic ALS population of similar disability, suggesting a distinct cortical vulnerability. 11C-flumazenil PET demonstrated that neuronal loss/dysfunction in motor and motor association areas may underlie this difference. The corollary, that there may be relative preservation of neuronal function in these areas in the homD90A group, has implications for understanding the slower progression of disease in these patients.

Background: Histopathological studies of amyotrophic lateral sclerosis (ALS) are of end stage disease. Diffusion tensor imaging (DTI) provides the opportunity to investigate indirectly corticospinal tract pathology of ALS in vivo. Methods: DTI was used to study the water diffusion characteristics of the corticospinal tracts in 21 patients with ALS and 14 normal controls. The authors measured the fractional anisotropy (FA) and mean diffusivity (MD) along the pyramidal tracts from the internal capsules down to the pyramids. A mixed model regression analysis was used to compare FA and MD between the ALS and control groups. Results: FA showed a downward linear trend from the cerebral peduncles to the pyramids and was lower in the ALS group than controls at multiple levels of the corticospinal tract. At the internal capsules, FA was higher on the right. MD showed an upward trend, progressing caudally from the internal capsules to the pyramids. MD was higher at the level of the internal capsule in the ALS group, but caudally this difference was not maintained. No correlations were found between clinical markers of disability and water diffusion indices. Conclusions: These findings provide insights into the pathological processes of ALS. Differences in diffusion characteristics at different anatomical levels may relate to underlying tract architecture or the distribution of pathological damage in ALS. Further development may permit monitoring of progression and treatment of disease.

Background: In recent years, there has been a paradigm shift in the method of healthcare delivery to amyotrophic lateral sclerosis (ALS) patients with the emergence of multidisciplinary ALS clinics that cater exclusively for patients with this condition. The impact of multidisciplinary management has not been previously evaluated. Methods: Using data from the Irish ALS Register, we conducted a prospective, population based study of all ALS cases diagnosed in Ireland over a five year period to evaluate the effectiveness of a multidisciplinary clinic on ALS survival. Results: Eighty two (24%) patients attended the multidisciplinary ALS clinic, with the remaining 262 (76%) cases followed in a general neurology clinic. The ALS clinic cohort was an average of five years younger (60.1 v 65.6 years) and were more likely to receive riluzole than the general neurology cohort (99% v 61%). The median survival of the ALS clinic cohort was 7.5 months longer than for patients in the general neurology cohort (logrank = 15.4, p < 0.0001). Overall, one year mortality was decreased by 29.7%. Prognosis of bulbar onset patients was extended by 9.6 months if they attended the ALS clinic. Using multivariate analysis, attendance at the ALS clinic was an independent covariate of survival (HR = 1.47, p = 0.02). Conclusions: ALS patients who received their care at a multidisciplinary clinic had a better prognosis than patients attending a general neurology clinic. The data suggest that active and aggressive management enhances survival, particularly among ALS patients with bulbar dysfunction. The effect of clinic type must be considered in future clinical trials design.

Objectives: To use statistical procedures, operationalising what is known as item response theory (IRT), to assess the unidimensionality of the 40 item Amyotrophic Lateral Sclerosis Assessment Questionnaire, and consequently to develop a single index figure from the measure. A secondary objective is to compare scores gained on the ALSAQ-40 with a five item short form (the ALSAQ-5). Methods: Postal survey of patients diagnosed with motor neurone disease (MND) on the MND Associations database. Copies of the ALSAQ-40 and, nested within it, the ALSAQ-5 were completed on two occasions. At time one, the survey contained the ALSAQ-40 and demographic questions. In addition, patients were asked to indicate if they were willing to take part in the follow up. Those who agreed to do so were sent another copy of the questionnaire after a period of three months. Respondents were also asked to indicate how much change they had experienced since baseline on each of the five domains of the questionnaire. Rasch analysis, a form of IRT methodology, was used to determine if the 40 items in the ALSAQ-40 tapped an underlying “latent trait”, and were consequently measuring a unidimensional construct. The results from the ALSAQ-40 single index were then compared with those gained from the ALSAQ-5. Results: Analyses indicated that, at both baseline and follow up, all items on the ALSAQ-40 fitted the Rasch model. Consequently the 40 items were summed to create a single index. Results on this instrument were compared with those gained by summing the five items of the ALSAQ-5. Results on the instruments were found to be highly correlated. Conclusions: Evidence from the analyses suggests that 40 item ALSAQ does contain a unidimensional scale, and can, therefore be summed to create a single index. Furthermore the ALSAQ-5 closely replicates the results of the patient measure.