Prognosis and clinical varieties of ALS disease

210 cases of ALS disease in the period 1955–1979 are considered. Different parameters such as sex, age, duration and clinical course have been correlated with four clinical types: conventional, pseudopolyneuritic, pyramidal and bulbar. The age distribution shows a peak in the fifth decade of life. The sex ratio is 2.08∶1. Considering together all the clinical types, the mean duration of the disease is 27.05 months. The bulbar variety has the poorest prognosis (19.6 months) and the pyramidal variety the best (37.59 months). Familiarity is evidenced in only 3 cases. All our data are discussed and compared with those of the literature.

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Sommario Sono stati considerati 210 casi di Sclerosi Laterale Amiotrofica nel periodo dal 1955 al 1979. Sono stati messi in relazione ai 4 tipi clinici della malattia: tipo convenzionale, pseudopolinevritico, piramidale e bulbare, vari parametri quali sesso, età, durata e decorso clinico. La distribuzione per età mostra un picco di incidenza nella 5^a decade di vita. Il rapporto maschi/femmine è di 2,08∶1. La durata mediana di malattia per tutti i 4 tipi è di 27,05 mesi. La varietà bulbare ha la prognosi peggiore (19,6 mesi) mentre quella piramidale ha la prognosi migliore (37,59 mesi). Solamente in 3 casi è stata messa in evidenza una storia familiare. Tutti i nostri dati sono discussi e confrontati con quelli della letteraura.

     

Increased fragility of erythrocytes from amyotrophic lateral sclerosis (ALS) patients provoked by mechanical stress

Erythrocytes from patients with amyotrophic lateral sclerosis (ALS) and controls were suspended in an electrolyte-substrate medium and subjected to mechanical stress by centrifugation under standardized conditions. Subsequent spectrophotometric analysis of the medium disclosed a significantly higher degree of haemolysis in samples from ALS-patients than from controls. The observation gives further evidence for the existence of an abnormality of the red cells in the disease. The nature and possible significance of this abnormality in relation to the pathogenesis of ALS is as yet unknown, but notably there was no significant correlation between the degree of cell abnormality as manifested by haemolysis and the duration of the disease in the individual patient.     

High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study

Summary. Increasing evidence has suggested that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of the paralysis in transgenic mice expressing a mutation in the superoxide dismutase gene found in certain forms of familial ALS. The current study, a double blind, placebo-controlled, randomised, stratified, parallel-group clinical trial, was designed to determine whether vitamin E (5000mg per day) may be efficacious in slowing down disease progression when added to riluzole. Methods. 160 patients in 6 German centres with either probable or definite ALS (according to the El Escorial Criteria) and a disease duration of less than 5 years, treated with riluzole, were included in this study and were randomly assigned to receive either alpha-tocopherol (5000mg per day) or placebo for 18 months. The Primary outcome measure was survival, calculating time to death, tracheostomy or permanent assisted ventilation, according to the WFN-Criteria of clinical trials. Secondary outcome measures were the rate of deterioration of function assessed by the modified Norris limb and bulbar scales, manual muscle testing (BMRC), spasticity scale, ventilatory function and the Sickness Impact Profile (SIP ALS/19). Patients were assessed at entry and every 4 months thereafter during the study period until month 16 and at a final visit at month 18. Vitamin E samples were taken for compliance check and Quality Control of the trial. For Safety, a physical examination was performed at baseline and then every visit until the treatment discontinuation at month 18. Height and weight were recorded at baseline and weight alone at the follow-up visits. A neurological examination as well as vital signs (heart rate and blood pressure), an ECG and VEPs were recorded at each visit. Furthermore, spontaneously reported adverse experiences and serious adverse events were documented and standard laboratory tests including liver function tests performed. For Statistical Analysis, the population to be considered for the primary outcome measure was an intent-to-treat (ITT) population which included all randomised patients who had received at least one treatment dose (n=160 patients). For the secondary outcome measures, a two way analysis of variance was performed on a patient population that included all randomised patients who had at least one assessment after inclusion. Results. Concerning the primary endpoint, no significant difference between placebo and treatment group could be detected either with the stratified Logrank or the Wilcoxon test. The functional assessments showed a marginal trend in favour of vitamin E, without reaching significance. Conclusion. Neither the primary nor the secondary outcome measures could determine whether a megadose of vitamin E is efficacious in slowing disease progression in ALS as an add-on therapy to riluzol. Larger or longer studies might be needed. However, administration of this megadose does not seem to have any significant side effects in this patient population.     

Return of the cycad hypothesis – does the amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) of Guam have new implications for global health?

Recently published work provides evidence in support of the cycad hypothesis for Lytico--Bodig, the Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC), based on a new understanding of Chamorro food practices, a cyanobacterial origin of beta-methylaminoalanine (BMAA) in cycad tissue, and a possible mechanism of biomagnification of this neurotoxic amino acid in the food chain. BMAA is one of two cycad chemicals with known neurotoxic properties (the other is cycasin, a proven developmental neurotoxin) among the many substances that exist in these highly poisonous plants, the seeds of which are used by Chamorros for food and medicine. The traditional diet includes the fruit bat, a species that feeds on cycad seed components and reportedly bioaccumulates BMAA. Plant and animal proteins provide a previously unrecognized reservoir for the slow release of this toxin. BMAA is reported in the brain tissue of Guam patients and early data suggest that some Northern American patients dying of Alzheimer's disease (AD) have detectable brain levels of BMAA. The possible role of cyanobacterial toxicity in sporadic neurodegenerative disease is therefore worthy of consideration. Recent neuropathology studies of ALS/PDC confirm understanding of this disorder as a 'tangle' disease, based on variable anatomical burden, and showing biochemical characteristics of 'AD-like' combined 3R and 4R tau species. This model mirrors the emerging view that other neurodegenerative disease spectra comprise clusters of related syndromes, owing to common molecular pathology, with variable anatomical distribution in the nervous system giving rise to different clinical phenotypes. Evidence for 'ubiquitin-only' inclusions in ALS/PDC is weak. Similarly, although there is evidence for alpha-synucleinopathy in ALS/PDC, the parkinsonian component of the disease is not caused by Lewy body disease. The spectrum of sporadic AD includes involvement of the substantia nigra and a high prevalence of 'incidental'alpha-synucleinopathy in sporadic AD is reported. Therefore the pathogenesis of Lytico-Bodig appears still to have most pertinence to the ongoing investigation of the pathogenesis of AD and other tauopathies.     

Emotional responding in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal disease, leaving the patient in a partially or completely deafferented state. In an explorative study, we investigated responses to visual socio–emotional stimuli in ALS patients. Pictures from the International Affective Picture System (IAPS) were verbally judged by 12 moderately affected ALS patients with a spinal onset and a slow progression and 18 age–matched controls, and data were compared with psychophysiological responses. Verbal emotional judgments of patients were more positive than ratings of controls. Regarding arousal, patients neutralized extreme pictures, in that they rated calm pictures as more exciting than controls and exciting pictures as more calm. These changes of emotional processing were unrelated to depression or frontal lobe dysfunction. There were no major differences between patients and controls concerning physiological responses to emotional stimuli. We conclude that emotional responses of ALS patients tend to be altered towards positive valence and towards a more balanced arousal state in early stages of the disease. These findings contradict assumptions of a generally negative impact of the disease on the emotional disposition and may indicate compensatory cognitive or neuroplastic changes.     

The ALS/MND prevalence in Sweden estimated by riluzole sales statistics

OBJECTIVES: To determine whether sales statistics for riluzole can be used as a marker for the prevalence of amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND) in Sweden. MATERIALS AND METHODS: A questionnaire was sent to all neurological units in Sweden asking about the numbers of patients with ALS/MND and whether these patients were treated with riluzole. Sales statistics for riluzole were obtained from the 906 public pharmacies and 89 hospital pharmacies in Sweden. RESULTS: Eighty percent of the neurological units answered the questionnaire. The estimated prevalence in September 2003 from the questionnaire was 5.4/100,000 inhabitants. The sales expressed in defined daily dose/100,000 inhabitants/day was 3.8. For the counties the correlation between these two parameters was 0.83. CONCLUSION: Estimated prevalence is highly correlated with sales statistics for riluzole. Riluzole sales statistics could be used as a crude marker for the prevalence of ALS/MND in Sweden.     

Temporal profiles of neuronal degeneration, glial proliferation, and cell death in hNFL(+/+) and NFL(-/-) mice

Neurofilament (NF) aggregate formation within motor neurons is a pathological hallmark of both the sporadic and familial forms of amyotrophic lateral sclerosis (ALS). The relationship between aggregate formation and both microglial and astrocytic proliferation, as well as additional neuropathological features of ALS, is unknown. To examine this, we have used transgenic mice that develop NF aggregates, through either a lack of the low-molecular-weight NF subunit [NFL (-/-)] or the overexpression of human NFL [hNFL (+/+)]. Transgenic and wild-type C57bl/6 mice were examined from 1 month to 18 months of age, and the temporal pattern of motor neuron degeneration, microglial and astrocytic proliferation, and heat shock protein-70 (HSP-70) expression characterized. We observed three overlapping phases in both transgenic mice, including transient aggregate formation, reactive microgliosis, and progressive motor neuron loss. However, only NFL (-/-) mice demonstrated significant astrogliosis and HSP-70 upregulation in both motor neurons and astrocytes. These in vivo models suggest that the development of NF aggregates in motor neurons leads to motor neuron death, but that the interaction between the degenerating motor neurons and the adjacent non-neuronal cells may differ significantly depending on the etiology of the NF aggregate itself.