Delegato

Provinciale

di Cosenza

Lametia Terme

24 Giugno 2011

Bruno Mazzei

FMSI

SCLEROSI LATERALE AMIOTROFICA o malattia dei motoneuroni

Il nome di questa malattia ne sintetizza le sue caratteristiche più salienti:

indurimento (Sclerosi) della porzione laterale del midollo spinale (Laterale) e riduzione della massa muscolare (Amiotrofica)

E’ una grave malattia dell’età adulta, caratterizzata dalla progressiva compromissione dei neuroni di moto centrali (corticali) e periferici (nuclei dei nervi cranici motori somatici e corna anteriori del midollo)

La malattia non

coinvolge la

funzionalità del

cuore, del sistema

digerente, della

vescica, anch’essi

muscoli ma i cui

movimenti non

avvengono sotto il

controllo volontario

SCLEROSI LATERALE

AMIOTROFICA

La malattia viene definita anche come:

• Malattia di Charcot (Neurologo francese che per primo la indentificò e la descrisse)

• Malattia di Lou Gehrig (Famoso giocatore di baseball americano che ne fu colpito all’età di 36 anni, nel 1939, all’apice della sua carriera agonistica)

1990 Jan;47(1):38-41.

Amyotrophic lateral sclerosis. A case-control study following detection of a cluster in a small Wisconsin

community.

Sienko DG, Davis JP, Taylor JA, Brooks BR.

Source

Bureau of Community Health and Prevention, Wisconsin Division of Health, University of Wisconsin School of

Medicine, Madison.

Abstract

From 1975 to 1983, six cases of amyotrophic lateral sclerosis (ALS) were diagnosed in long-term residents of

Two Rivers, Wis; the probability that this occurred due to chance was less than .05. To investigate potential

risk factors for ALS, we conducted a case-control study using two control subjects matched to each case

patient for age, gender, and duration of residence in Two Rivers. Physical trauma, the frequent consumption

of freshly caught Lake Michigan fish, and a family history of cancer were reported more often by case

patients than control subjects. These findings support previous studies proposing a role for trauma in ALS

pathogenesis and suggest that the causative role of diet should be further explored. Continued surveillance

for and epidemiologic investigation of ALS clusters with subsequent retrospective analysis may provide

clues concerning the cause of ALS.

2007 Nov;163(11):1021-30.

[Exogenous risk factors in sporadic ALS: a review of the literature].

[Article in French]

Gil J, Funalot B, Torny F, Lacoste M, Couratier P.

Source

EA 3174, faculté de médecine, Université de Limoges, Limoges, France.

Abstract

The latest reviews of the literature devoted to the epidemiology of ALS all agree that exogenic risk

factors play a role in sporadic ALS. Nevertheless, there is no convincing evidence demonstrating in

a reproducible manner an association between an environmental risk factor and ALS. This

discordance is mainly explained by methodological skews. Over the last ten years, exogenic factors

have been analyzed within the framework of specific lifestyle factors such as place of residence,

smoking or not, or certain eating practices. The most recent work suggests that interactions

between genetic and environmental factors depend on the age at exposure and the duration of

exposure. The objectives of this general review is: to analyze the principal case-control studies,

historical cohort studies or mortality studies which looked at the associations between an

environmental factor and ALS, to present main results of studies having analyzed lifestyles in

relation to one or more exogenic factors, and to discuss the limitations of epidemiologic studies on

ALS.

2009 Aug-Sep;165(8-9):627-40. Epub 2009 Jun 13.

[Epidemiology of amyotrophic lateral sclerosis].

[Article in French]

Soriani MH, Desnuelle C.

Source

Centre de référence maladies neuromusculaires, SLA, hôpital Archet, CHU de Nice, France.

soriani.mh@chu-nice.fr

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. Loss of pyramidal and

anterior horn motor neurons leads to progressive limb weakness, disability, dysarthria, dysphagia and

respiratory insufficiency with a progressive fatal course. The incidence of ALS ranges between 1.5 to 2.5 for

100,000 per year. Although there are familial cases of ALS, about 90% are sporadic and of unknown

etiology. Several exogenous risk factors have been documented. However, no convincing evidence has

demonstrated in a reproducible manner an association between an environmental or lifestyle risk factor and

ALS. Disease duration varies considerably, ranging from a few months to 10-15 years with a mean survival

of about 36 months. Prognostic factors such as age, site of disease onset, nutritional, functional and

respiratory status at the diagnosis or delay between beginning of the disease and diagnosis have been

reported but they appear to be insufficient to explain prognostic variability. These last 15 years, development

of supportive care for ALS patients and management in ALS centers may have contributed to improve

survival. Finally, ALS centres, and particularly French ALS centres, have developed databases to improve

our knowledge of ALS, phenotypic characterization, more accurate phenotype-genotype correlations and

thus contribute to new therapeutics developments.

EPIDEMIOLOGIA

• E’ una malattia dell’età adulta-anziana (età di insorgenza tra 50 e 70 anni)

• Prevalenza 5-10/100.000, con rapporto

/

=1.5/1

• In alcune aree del Pacifico (isole Marianne, Guam, Nuova Guinea) l’incidenza sembra essere 10 volte superiore e la patologia presenta delle caratteristiche particolari (associazione SLA-Parkinson-Demenza)

• Solo nel 10% dei casi la SLA è ereditaria di tipo autosomico dominante ed, in questi casi, l’età d’esordio è più bassa (40 aa circa); solo nel 10% dei casi di SLA familiare è stato identificato il difetto genico sul cr. 21 (gene della superossido dismutasi SOD).

PERSONAGGI COLPITI DA

SLA

Calciatori malati dal morbo di Gehrig: li colpisce fino a 12 volte di più.

Lo studio di due ricercatori italiani su 24 mila atleti tra il '60 e il '96 con un terribile sospetto :

nel mirino l'uso elevatissimo degli aminoacidi ramificati usati come integratori.

Gianluca Signorini, ex capitano del Genoa, deceduto per SLA nel 2002

DECESSI PER SLA

SLA E SPORT

Sono 57 i calciatori o ex calciatori italiani affetti da Sclerosi Laterale Amiotrofica, un numero venti volte superiore la media della popolazione mondiale! SEMPLICE COINCIDENZA?

Uno studio epidemiologico commissionata dal giudice Guarinello (1999), condotto su un campione di 24 mila calciatori che hanno giocato tra il 1960 ed il 1996, ha messo in evidenza due importanti aspetti: • L’elevata incidenza della malattia nel campione selezionato • L’età media d’esordio, sensibilmente inferiore rispetto a quella della popolazione generale

Calciatori malati dal morbo di Gehrig: li colpisce fino a 12 volte di più.

Lo studio di due ricercatori italiani su 24 mila atleti tra il '60 e il '96 con un terribile sospetto :

nel mirino l'uso elevatissimo degli aminoacidi ramificati usati come integratori.

Gianluca Signorini, ex capitano del Genoa, deceduto per SLA nel 2002

DECESSI PER SLA

Source: The Lancet Neurology 2003; 2:656-657 (DOI:10.1016/S1474-4422(03)00579-9)

Terms and Conditions

The sinister side of Italian soccer

Simone Beretta, Maria Teresa Carrì, Ettore Beghi, Adriano Chiò and Carlo Ferrarese

The Lancet Neurology

Volume 2, Issue 11, Pages 656-657 (November 2003)

DOI: 10.1016/S1474-4422(03)00579-9

2006 Jun;12(5):327-9. Epub 2006 Feb 3.

Amyotrophic lateral sclerosis in an Italian professional soccer player.

Vanacore N, Binazzi A, Bottazzi M, Belli S.

Source

National Centre of Epidemiology, Surveillance and Health Promotion, National Institute of Health, Via Giano

Della Bella, 34, 00161 Rome, Italy. vanacore@iss.it

Abstract

Amyotrophic lateral sclerosis (ALS) is a rare devastating neurodegenerative disease of unknown etiology. Two

recent epidemiological studies showed a high risk for ALS among Italian male soccer players. We present the

clinical and occupational history of an Italian professional soccer player affected by sporadic ALS. The early

onset of ALS (45 years), the bulbar form, the playing position (midfielder) and the duration of the job as

professional soccer (17 years) are four characteristics of this patient that are in good agreement with the

findings in the previous epidemiological studies. This patient reports the frequent consumption of fructose 1,6

biphosphate, extracts of suprarenal cortex, crotetamide and cropropamide, and dietary supplements (branched

chain amino acids and creatine) during his playing career. Some hypotheses have been proposed to explain

this high excess of deaths for ALS among soccer players: (a) vigorous physical activity; (b) soccer specific

trauma or microtrauma; (c) use of illegal toxic substances or chronic misuse of drugs (most often anti-

inflammatory) and dietary supplements; and (d) exposure to pesticides used on playing fields. The overall

available clinical and epidemiological evidence supports the possible relation between the specific occupational

environment (soccer) and the occurrence of ALS in this patient.

SLA E SPORT

Molte sono le ipotesi: •Elevato uso (abuso) di antinfiammatori e di antidolorifici? •Doping? •Uso dei pesticidi nei campi di calcio?

2004 Apr;20(4):505-8.

Soccer, neurotrauma and amyotrophic lateral sclerosis: is there a connection?

Piazza O, Sirén AL, Ehrenreich H.

Source

Max-Planck-Institute for Experimental Medicine Goettingen, Germany.

Abstract

Trauma has long been hypothesized but never proven to be a risk factor for amyotrophic lateral sclerosis

(ALS). This hypothesis may now have a renaissance due to recent reports in the lay press on 'the Italian

motoneuron mystery', i.e. the disclosure of 33 diagnosed ALS cases in a subpopulation of 24000 soccer

players of the top three Italian divisions from the 1960s to 1996. Could the repetitive brain trauma that

soccer players experience for controlling and advancing the ball with their heads represent an

environmental risk factor for developing ALS in genetically predisposed individuals? By critically reviewing

the scarce literature and 'surrounding evidence' (Medline, CDC, lay press, Italian health officials), we have

looked for a potential relationship between (1) soccer and head trauma and (2) head trauma and

subsequent development of amyotrophic lateral sclerosis. Whereas the brain traumatizing effect of soccer

seems to be out of the question, the findings of the few retrospective studies on ALS and neurotrauma are

conflicting. Taken together, however, the literature would still support the concept of soccer, head trauma,

and ALS being interrelated, with high levels of athleticism/physical activity perhaps playing an additive

part. To further clarify this issue, extensive prospective epidemiological investigations on ALS following

neurotrauma as well as carefully designed animal studies will have to be conducted.

2005 Mar;12(3):223-5.

Amyotrophic lateral sclerosis and sports: a case-control study.

Valenti M, Pontieri FE, Conti F, Altobelli E, Manzoni T, Frati L.

Source

Section of Medical Statistics and Epidemiology, Faculty of Human Movement and Sports Science,

University of L'Aquila, L'Aquila, Italy. valenti@cc.univaq.it

Abstract

An increased incidence of amyotrophic lateral sclerosis (ALS) amongst soccer players in Italy has

recently been reported. A case-control study (300 cases and 300 matched controls) was

conducted to explore the association between ALS and physical/sports activities, with specific

reference to trauma-related risk. Neither the practice of competitive sports nor sports-related

traumas were found to be associated with an increased risk of ALS. The practice of physical

activities or sports is not per se a risk factor for ALS. Our results exclude sports-related

microtraumas as etiopathogenic factors in the natural history of ALS

2007 Nov 15;262(1-2):45-53. Epub 2007 Aug 2.

Sports and trauma in amyotrophic lateral sclerosis revisited.

Armon C.

Source

Tufts University School of Medicine, Boston, MA, USA.

Abstract

An evidence-based review was undertaken of the literature published between 2002 and 2006

about sports, trauma and ALS in order to see if there were new data to modify the conclusions of a

previous review (2003). The new data support the previous conclusions that physical activity and

trauma are probably ("more likely than not") not risk factors for ALS (Level II conclusions). This

review concludes also that the reports of an apparent excess of ALS in Italian soccer players likely

reflect incorrect analysis of the data. The appearance of excess relies on accepting as valid

estimation methods resulting in improbably low numbers of expected cases. A different method is

proposed: it generates more plausible numbers of expected cases, compared to which there is no

excess of total cases (Level C conclusion). A theoretical framework is developed to analyze the

possible influence of a "healthy worker effect" on incidence of neurodegenerative diseases in

cohorts of employed or formerly employed individuals. In lieu of theoretical speculations, data are

needed to measure this effect, while controlling for known lifestyle factors and accounting for the

effect of loss of competing causes of mortality.

2007 Oct 1;166(7):810-6. Epub 2007 Jul 19.

Head injury and amyotrophic lateral sclerosis.

Chen H, Richard M, Sandler DP, Umbach DM, Kamel F.

Source

Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of

Health, Research Triangle Park, NC 27709, USA. chenh2@niehs.nih.gov

Abstract

Recent data showed that soccer players in Italy had an unusually high risk of amyotrophic lateral

sclerosis (ALS) and that repeated head trauma might have contributed to this increase. The

authors examined whether head injury was related to ALS risk in a case-control study of 109 New

England ALS cases diagnosed in 1993-1996 and 255 matched controls. They also conducted a

meta-analysis of the published literature. Overall, ever having experienced a head injury was

nonsignificantly associated with a higher ALS risk. When compared with persons without a head

injury, a statistically significant ALS risk elevation was found for participants with more than one

head injury (odds ratio (OR) = 3.1, 95 percent confidence interval (CI): 1.2, 8.1) and patients who

had had a head injury during the past 10 years (OR = 3.2, 95 percent CI: 1.0, 10.2). For participants

who had had multiple head injuries with the latest occurring in the past 10 years, risk was elevated

more than 11-fold. The meta-analysis also indicated a moderately elevated risk of ALS among

persons with previous head injuries (OR = 1.7, 95 percent CI: 1.3, 2.2). In this study population,

physical injuries to other body parts, including the trunk, arms, or legs, were not related to ALS

risk. These data support the notion that head injury may increase the risk of ALS.

2010 Jan 15;288(1-2):45-8. Epub 2009 Oct 30.

Head and other physical trauma requiring hospitalisation is not a significant risk factor in the development of

ALS.

Turner MR, Abisgold J, Yeates DG, Talbot K, Goldacre MJ.

Source

Oxford University Department of Clinical Neurology, John Radcliffe Hospital, Oxford, OX3 9DU, UK.

martin.turner@clneuro.ox.ac.uk

Abstract

The pathogenesis of ALS is not fully understood but, as an overwhelmingly sporadic disorder, it is likely to result from a

complex mixture of polygenic and environmental risk factors operating in the context of an ageing nervous system.

Physical trauma, in particular head injury, has been variably associated with both Alzheimer's and Parkinson's disease,

and largely discounted in relation to multiple sclerosis. Several case-control studies in ALS have reported an association

with physical trauma or head injury, but such studies are greatly limited by recall bias. The Oxford Record Linkage Study

(ORLS) includes brief statistical abstracts of records of all hospital admissions, including day cases, and all deaths for a

defined region of UK National Health Service hospitals. We used ORLS spanning a 36year period to study the relationship

between recorded head, upper and lower limb trauma both before and after a diagnosis of ALS. Overall the adjusted rate

ratio for ALS after head injury, compared with a control group, was 1.5 (95% confidence interval 1.1-2.1); but this elevation

of risk was only found within the first year after injury, and we speculate that this is most likely to be a consequence of

incipient ALS causing a tendency to fall. We conclude that there is no association between antecedent injury requiring

hospitalisation, and the later development of ALS. The high risk of head injury observed in the immediate post-diagnosis

period may be amenable to primary prevention.

1999;18(2):101-10.

Physical trauma and family history of neurodegenerative diseases in amyotrophic lateral sclerosis: a population-

based case-control study.

Cruz DC, Nelson LM, McGuire V, Longstreth WT Jr.

Source

Department of Health Research and Policy, Stanford University School of Medicine, Stanford, Calif. 94305-5405,

USA.

Abstract

This population-based case-control study was conducted in three counties in western Washington state (USA)

between 1990 and 1994 to assess the association between amyotrophic lateral sclerosis (ALS) and several

hypothesized risk factors, including a family history of neurodegenerative diseases, physical trauma (fractures,

electrical shocks, and surgeries), rural residence, travel, and medical history. One hundred seventy-four cases with

ALS, newly diagnosed by neurologists, were identified through several case-finding methods. Two controls (n =

348), who were matched to each case by gender and age (+/-5 years), were identified through random digit

telephone dialing or Medicare lists. Exposure data were collected through structured in-person interviews. A

greater proportion of cases (2. 3%) than controls (0.9%) reported a first-degree relative with ALS, resulting in an

odds ratio of 3.1 (95% CI, 0.6-15.7). For a positive family history of ALS among second-degree relatives, the odds

ratio was 4.0 (95% CI, 1.0-16.6). Overall, reports of first- or second-degree relatives with ALS yielded a significantly

elevated odds ratio of 3.3 (95% CI, 1.1-9.9). No association was found with a family history of Alzheimer's disease or

Parkinson's disease, or with a family history of the neurodegenerative diseases as a group. No significant

associations were demonstrated for any of the other factors analyzed, including a history of fractures, electrical

shocks, or surgeries, a history of residence in rural areas, a history of travel to areas in the western Pacific where

ALS is endemic, and a medical history of polio, polio immunization, or tetanus immunization.

2005 Jan 25;64(2):241-5.

Physical activity and the association with sporadic ALS.

Veldink JH, Kalmijn S, Groeneveld GJ, Titulaer MJ, Wokke JH, van den Berg LH.

Source

Department of Neurology of the Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands.

Abstract

OBJECTIVE:

To assess whether lifetime physical activity during work and leisure time is associated with an increased risk of developing

ALS and to determine the association between physical activity and duration or age at onset of disease.

METHODS:

Patients referred to our clinic during the 1-year period 2001 to 2002 who had definite, probable, or possible ALS according to El

Escorial criteria, without a familial history of ALS, were asked to participate in the study. A case-control study was performed

taking into account all occupational and leisure time activities of patients (n = 219) and controls (n = 254). Multivariate analysis

included confounding factors (sex, age, level of education, body mass index, alcohol use, and smoking). Three quantitative

measures of cumulative physical activity were calculated: until 1 year before the onset of disease (total physical activity), the

last 10 years before the onset of disease (late physical activity), and until the age of 25 (early physical activity). In addition, a

systematic review of all published data is presented.

RESULTS:

Smoking and alcohol use were independently associated with ALS (current smoking increased risk, OR = 1.8, 95% CI = 1.0 to

3.0, p = 0.03, ever/current alcohol use decreased risk, OR = 0.6, 95% CI = 0.3 to 0.9, p = 0.04). No significant association with

occupational or leisure time physical activity was found (all ORs < or = 1.7), which was in agreement with most studies with the

highest level of evidence in the systematic review. Higher leisure time activities were associated with an earlier age at onset:

activity levels before age of 25 (p < 0.001, 7 years earlier), and activity during the last 10 years (p < 0.001, 3 years earlier).

CONCLUSIONS:

There is no association between physical activity and the risk of developing ALS.

Ipotesi SLA e SPORT Alcuni studi epidemiologici hanno evidenziato un’associazione fra sla ed

esposizione ad agenti tossici. Tra quelli maggiormente chiamati in causa vi

sono i pesticidi e i fertilizzanti. In effetti, secondo uno studio

epidemiologico condotto in Sardegna, l’incidenza della malattia tra gli

agricoltori è doppia rispetto alla popolazione generale. Tali sostanze,

utilizzate anche per la manutenzione del campo da gioco, potrebbero

seriamente essere responsabili dell’insorgenza della malattia tra i

calciatori. Dallo studio epidemiologico condotto su 24.000 calciatori che

avevano giocato tra il 1960 e il 1996 sembra emergere che la sclerosi

laterale amiotrofica abbia nei giocatori di calcio una prevalenza venti volte

superiore a quella della popolazione in generale.

Alcuni studiosi hanno proposto invece la patogenesi autoimmunitaria,

dimostrando la presenza di disordini linfoproliferativi e anticorpi anticanali

del calcio “L-type voltage-gated” in alcuni casi di ALS.

In una rassegna apparsa su “Current Medical Research and Opinion” gli

autori parlano di “Motor Neurone Mystery”, frase usata per la prima volta

da Tom Kington in un articolo comparso il 25 febbraio 2003 sul sito internet

dell’ UEFA, nel quale si faceva riferimento ad inchieste giornalistiche e

giudiziarie italiane sull’abuso di farmaci nello sport.

Nel 1998, in Italia sono stati venduti 109.600.000 kg di pesticidi chimici: 23.100.000 di diserbanti, 29.000.000 di insetticidi, 47.600.000 di anticrittogamici, 9.900.000 di altri prodotti

La maggior parte è stata irrorata sui campi dell'Italia

settentrionale (54.1%)

(fonte Greenpeace)

2009 Oct-Dec;10(5-6):302-9.

Exposure to chemicals and metals and risk of amyotrophic lateral sclerosis: a systematic review.

Sutedja NA, Veldink JH, Fischer K, Kromhout H, Heederik D, Huisman MH, Wokke JH, van den Berg LH.

Source

Department of Neurology, University Medical Centre Utrecht, Utrecht, The Netherlands.

Abstract

Environmental exposure to chemicals and metals may contribute to the risk of sporadic amyotrophic lateral

sclerosis (ALS). Two systematic reviews of the literature on these topics performed according to the well-

established MOOSE guidelines are presented. Literature cited in MEDLINE, EMBASE, CINAHL, and Cochrane

databases (up to March 2007) as well as references of relevant articles were screened for case-control or cohort

studies investigating the associations between sporadic ALS and exposure to chemical agents or metals.

Methodology of selected studies was appraised according to Armon's classification system for ALS risk factor

studies as well as a newly developed classification system for quality of exposure assessment. Seven of the 38

studies concerning exposure to chemicals and three of the 50 studies concerning exposure to metals fulfilled

the validity criteria. In two independent studies meeting the validity criteria, a significant association with

increased ALS risk was reported for exposure to pesticides. This systematic review demonstrated the difficulty

in attaining a high level of evidence due to lack of high quality of methodological and exposure assessment

components. Although pesticide exposure was identified as candidate risk factor, more well-designed studies

are needed to provide a definitive answer about exogenous factors of ALS.

SLA E SPORT

Molte sono le ipotesi, poche le certezze: •Elevato uso (abuso) di antinfiammatori e di antidolorifici? •Doping? •Uso dei pesticidi nei campi di calcio?

Beretta et al. Lancet Neurology 2003 Cruz DC. Et al. Neuroepidemiology 1999 Sienko DG. Arch Neurology 1990

I ciclisti e i cestisti sono risparmiati. Ruolo dell’EPO?

The role of creatine in the management of amyotrophic lateral sclerosis and other neurodegenerative disorders.

Ellis AC, Rosenfeld J.

Source

Carolinas Neuromuscular/ALS Center, Charlotte, North Carolina 28203, USA. amy.ellis@carolinahealthcare.org

Abstract

Creatine is consumed in the diet and endogenously synthesised in the body. Over the past decade, the ergogenic benefits of

synthetic creatine monohydrate have made it a popular dietary supplement, particularly among athletes. The anabolic

properties of creatine also offer hope for the treatment of diseases characterised by weakness and muscle atrophy. Moreover,

because of its cellular mechanisms of action, creatine offers potential benefits for diseases involving mitochondrial

dysfunction. Recent data also support the hypothesis that creatine may have a neuroprotective effect. Amyotrophic lateral

sclerosis (ALS) is characterised by progressive degeneration of motor neurons, resulting in weakening and atrophy of skeletal

muscles. In patients with this condition, creatine offers potential benefits in terms of facilitating residual muscle contractility

as well as improving neuronal function. It may also help stabilise mitochondrial dysfunction, which plays a key role in the

pathogenesis of ALS. Indeed, the likely multifactorial aetiology of ALS means the combined pharmacodynamic properties of

creatine offer promise for the treatment of this condition. Evidence from available animal models of ALS supports the utility of

treatment with creatine in this setting. Limited data available in other neuromuscular and neurodegenerative diseases further

support the potential benefit of creatine monohydrate in ALS. However, few randomised, controlled trials have been

conducted. To date, two clinical trials of creatine monohydrate in ALS have been completed without demonstration of

significant improvements in overall survival or a composite measure of muscle strength. These trials have also posed

unanswered questions about the optimal dosage of creatine and its beneficial effects on muscle fatigue, a measure distinct

from muscle strength. A large, multicentre, clinical trial is currently underway to further investigate the efficacy of creatine

monohydrate in ALS and address these unresolved issues. Evidence to date shows that creatine supplementation has a good

safety profile and is well tolerated by ALS patients. The purpose of this article is to provide a short, balanced review of the

literature concerning creatine monohydrate in the treatment of ALS and related neurodegenerative diseases. The

pharmacokinetics and rationale for the use of creatine are described along with available evidence from animal models and

clinical trials for ALS and related neurodegenerative or neuromuscular diseases.

2009 Jan 21;(1):CD006153.

Treatment for familial amyotrophic lateral sclerosis/motor neuron disease.

Benatar M, Kurent J, Moore DH.

Source

Neurology Department, Emory University, Department of Neurology, Woodruff Memorial Building , Suite 6000, 100 Woodruff Circle, Atlanta, GA 30322, USA.

michael.benatar@emory.edu

Abstract

BACKGROUND:

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a rare neurodegenerative disease. Approximately 5% to 7% of ALS/MND

patients report a family history of a similarly affected relative. Superoxide dismutase-1 gene mutations are the cause in about 20% of familial cases. In those with

non-familial (sporadic) ALS/MND the cause is unknown. Also unknown is whether patients with familial and sporadic ALS/MND respond differently to treatment.

OBJECTIVES:

To systematically review the literature and to answer the specific question: 'Is there a difference in the response to treatment between patients with sporadic and

familial forms of ALS?'

SEARCH STRATEGY:

In May 2006 we searched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (January 1966 to May 2006) and EMBASE (January 1980 to

May 2006) for randomized controlled trials (RCTs). Two review authors read the titles and abstracts of all articles and reviewed the full text of all possibly relevant

articles. We scanned references of all included trials to identify additional relevant articles. For all trials eligible for inclusion we contacted the authors to request

the necessary raw data.

SELECTION CRITERIA:

Studies had to meet two criteria: (a) randomized controlled study design, and (b) inclusion of patients with both familial and sporadic ALS/MND.

DATA COLLECTION AND ANALYSIS:

We attempted to contact authors of all trials that met inclusion criteria. We obtained data regarding ALS/MND type (sporadic versus familial), treatment assignment

(active versus placebo), survival and ALS Functional Rating Scale scores for four large RCTs that included 822 sporadic and 41 familial ALS patients. We could

not obtain data from 25 potentially eligible studies (17 trial authors could not be contacted and eight were unwilling to provide data).

MAIN RESULTS:

There was no statistical evidence for a different response to treatment in patients with familial ALS/MND compared to those with sporadic ALS/MND. The pooled

estimate of the hazard ratio for the interaction term (treatment x familial ALS) suggested a more beneficial response with respect to survival among patients with

familial ALS/MND, but the result was not statistically significant. Estimates of the rate of decline on the ALS Functional Rating Scale also suggested a slightly

better response to treatment among those with familial ALS/MND, but the result was not statistically significant.

AUTHORS' CONCLUSIONS:

Future RCTs should document whether patients with familial ALS/MND are included and the presence or absence of a mutation in the superoxide dismutase-1

gene amongst those with familial ALS/MND.

2003 Aug 26;61(4):456-64.

A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis.

Cudkowicz ME, Shefner JM, Schoenfeld DA, Brown RH Jr, Johnson H, Qureshi M, Jacobs M, Rothstein JD, Appel SH, Pascuzzi

RM, Heiman-Patterson TD, Donofrio PD, David WS, Russell JA, Tandan R, Pioro EP, Felice KJ, Rosenfeld J, Mandler RN, Sachs

GM, Bradley WG, Raynor EM, Baquis GD, Belsh JM, Novella S, Goldstein J, Hulihan J; Northeast ALS Consortium.

Source

Neurology Clinical Trials Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

mcudkowicz@partners.org

Abstract

OBJECTIVE:

To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS.

METHODS:

A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were

randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary

outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric

contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced

vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival.

RESULTS:

Patients treated with topiramate showed a faster decrease in arm strength (33.3%) during 12 months (0.0997 vs 0.0748 unit

decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate

was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus,

paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep

venous thrombosis).

CONCLUSIONS:

At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was

associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse

events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a

dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.

2006 Jul;60(1):22-31.

Trial of celecoxib in amyotrophic lateral sclerosis.

Cudkowicz ME, Shefner JM, Schoenfeld DA, Zhang H, Andreasson KI, Rothstein JD, Drachman DB.

Source

Neurology Clinical Trials Unit, Massachusetts General Hospital, Harvard Medical School, Boston, 02172, USA.

mcudkowicz@partners.org

Abstract

OBJECTIVE:

To determine whether chronic treatment with celecoxib, a cyclooxygenase-2 inhibitor that has been shown to be beneficial in

preclinical testing, is safe and effective in amyotrophic lateral sclerosis (ALS).

METHODS:

A double-blind, placebo-controlled, clinical trial was conducted. Three hundred research subjects with ALS were randomized

(2:1) to receive celecoxib (800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper

extremity motor function measured by the maximum voluntary isometric contraction strength. Secondary end points included

safety, survival, change in cerebrospinal fluid prostaglandin E(2) levels, and changes in the rate of decline of leg and grip

strength, vital capacity, ALS Functional Rating Scale-Revised, and motor unit number estimates.

RESULTS:

Celecoxib did not slow the decline in muscle strength, vital capacity, motor unit number estimates, ALS Functional Rating Scale-

Revised, or affect survival. Celecoxib was well tolerated and was not associated with an increased frequency of adverse events.

Prostaglandin E(2) levels in cerebrospinal fluid were not elevated at baseline and did not decline with treatment.

INTERPRETATION:

At the dosage studied, celecoxib did not have a beneficial effect on research subjects with ALS, and it was safe. A biological

effect of celecoxib was not demonstrated in the cerebrospinal fluid. Further studies of celecoxib at a dosage of 800 mg/day in

ALS are not warranted.

2007 Dec;8(6):323-7. Epub 2007 Aug 7.

Young-onset sporadic amyotrophic lateral sclerosis: a distinct nosological entity?

Gouveia LO, de Carvalho M.

Source

Department of Neurology, Hospital de Santa Maria, Lisbon, Portugal.

Abstract

There are few reports describing young-onset amyotrophic lateral sclerosis (ALS). Age at onset is a

prognostic factor in ALS, and thus it is relevant to investigate the clinical features of very young ALS

patients. We describe three young-onset ALS cases and review the literature. SOD1 mutations were not

identified. Our cases and 24 others from the literature indicate that young-onset ALS is characterized by

slowly progressive symmetrical weakness; nevertheless, progression is variable. Young-onset ALS seems

to be a distinct clinical syndrome but its aetiological background is largely unknown.

Journal Club

Lametia Terme

24 Giugno 2011

Bruno Mazzei

FMSI

Incidence of Amyotrophic Lateral Sclerosis in Europe

Abstract

Background—Geographical differences in amyotrophic lateral sclerosis (ALS) incidence have

been reported in the literature, but comparisons across previous studies are limited by different

methods in case ascertainment and by the relatively small size of the studied populations. To address

these issues, the authors undertook a pooled-analysis of European population-based ALS registries.

Methods—All new incident ALS cases in subjects 18 years old and older were identified

prospectively in six population-based registries in three European countries (Ireland, United

Kingdom, Italy) in the two year period 1998-1999 with a reference population of almost 24 million.

Results—Based on 1,028 identified incident cases, the crude annual incidence rate of ALS in the

general European population was 2.16 per 100,000 person-years; 95% CI 2.0-2.3), with similar

incidence rates across all registries. The incidence was higher among men (3.0 per 100,000 personyears; 95%

CI = 2.8 to 3.3) than among women (2.4 per 100,000 person-years; 95% CI=2.2 to 2.6).

Spinal onset ALS was more common among men compared to women, particularly in the 70-80 year

age group. Disease occurrence decreases rapidly after 80 years of age.

Conclusions—ALS incidence is homogeneous across Europe. Sex differences in incidence may

be explained by the higher incidence of spinal onset ALS among males and the age-related disease

pattern suggests that ALS occurs within a susceptible group within the population rather than being

a disease of aging. Corresponding Author: Giancarlo Logroscino, MD, PhD, Department of Neurology and Psychiatry, Piazza Giulio Cesare,

Policlinico,

70121 Bari, Italy. giancarlo.logroscino@neurol.uniba.it; Phone: +39-080-559-2250.

Giancarlo Logroscino and Bryan J. Traynor are both first authors and contributed equally to this paper.

NIH Public Access

J Neurol Neurosurg Psychiatry 2011 Jun;82(6):623-7.

Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis.

Byrne S, Walsh C, Lynch C, Bede P, Elamin M, Kenna K, McLaughlin R, Hardiman O.

Source

Deparment of Neurology, Beaumont Hospital, Beaumont Rd, Dublin 9, Ireland. suabyrne@gmail.com

Abstract

BACKGROUND:

The population rate of familial amyotrophic lateral sclerosis (FALS) is frequently reported as 10%. However, a systematic review

and meta-analysis of the true population based frequency of FALS has never been performed.

METHOD:

A Medline literature review identified all original articles reporting a rate of FALS. Studies were grouped according to the type of

data presented and examined for sources of case ascertainment. A systematic review and meta-analysis of reported rates of

FALS was then conducted to facilitate comparison between studies and calculate a pooled rate of FALS.

RESULTS:

38 papers reported a rate of FALS. Thirty-three papers were included in analysis and the rate of FALS for all studies was 4.6%

(95% CI 3.9% to 5.5%). Restricting the analysis to prospective population based registry data revealed a rate of 5.1% (95% CI

4.1% to 6.1%). The incidence of FALS was lower in southern Europe. There was no correlation between rate of FALS

and reported SOD1 mutation rates.

CONCLUSION:

The rate of FALS among prospective population based registries is 5.1% (CI 4.1 to 6.1%), and not 10% as is often

stated. Further detailed prospective population based studies of familial ALS are required to confirm this rate.