Can statins induce ALS (amyotrofic lateral sclerosis)?/nThe question concerns four patients, who af

Fråga: Can statins induce ALS (amyotrofic lateral sclerosis)?

The question concerns four patients, who after several years of statin therapy have developed ALS.

The first patient was a 67-year-old man treated with atorvastatin who developed cramps in both hands, that later spread to his neck and back. Later a progressive weakness developed in his left arm and hand. It was suspected that the patient had developed ALS and atorvastatin was withdrawn. He was also treated with ezetimibe (Ezetrol), acetylsalicylic acid (Trombyl) and metoprolol (Seloken ZOC).

The second patient was a 69-year-old man treated with atorvastatin who developed dysphagia, dysarthria and problems to hold his head up. It has been shown that the patient has ALS. Atorvastatin was withdrawn, but he has been further impaired. No other drugs were taken.

The third patient was a 64-year-old woman who developed dysarthria after several years of treatment with simvastatin. ALS was suspected, and simvastatin was withdrawn. She was also treated with levothyroxin (Levaxin).

The last patient was a 68-year-old man who after several years of simvastatin treatment develops progressive weakness in his arms, cramps in his fingers and dysarthria. He was diagnosed with ALS and simvastatin was withdrawn. The patient was also treated with several other drugs.

Sammanfattning: The WHO international monitoring centre found, among the individual adverse drug reactions reports in its database, an over representation of upper motor neuron lesions in connection to statin therapy, and has investigated these cases. There are in total 50 cases of ALS (amyotrophic lateral sclerosis) in connection to statin therapy in the WHO adverse drug reactions database. No further reports have been found. Statins can cause an increasing number of regulatory T cells, which down-regulate Th1-cells (which usually minimize glutamate induced neuronal damage) and may therefore impair neuroprotective autoimmunity. However, it has also been shown that statins may be protective of neurodegenerative disease. A causal relationship between statins and ALS cannot be established, but awareness of this possible association can be recommended.

Svar: Amyotrophic lateral sclerosis (ALS) is a deadly disorder characterised by the degeneration of motor neurons. It is estimated that 2-3 persons per 100 000 develop ALS in Sweden every year (1). The median age for ALS diagnosis is 55 years (2), and it is more common in men. The aetiology of ALS is unknown. One theory is that it may develop when nerve cells are highly stimulated by glutamate. Virus, an immunological mechanism, poisoning and lack of trace elements have also been discussed as causative factors (1).

In the WHO adverse drug reactions database (Vigibase) it was found that statins were overall the most frequent reported drugs suspected to cause upper motor neuron lesions (which includes ALS). The WHO international monitoring centre therefore published an analysis of these cases, which describes 43 cases of ALS in connection to statin therapy. Since the cases were sometimes atypical, the authors used the term ALS-like syndrome. Three cases were excluded (two cases were due to possible duplicates and one due to listing of more than 60 adverse reactions), and the remaining 40 were further evaluated. In 34 of the reports, the statin was the only reported drug. In 14 of the reports the time of onset could be determined, and duration of therapy before onset varied between one month and two years. Twenty-five patients had not recovered at the time of reporting, five had made some recovery (with sequale), one had recovered and seven had died (one death was unrelated to the ALS-like syndrome). The clinical outcome of the rest was unknown. The authors conclude that the association between statins and the ALS-like syndrome may be a chance finding and a causal relationship cannot be established. However, an increased awareness of this is important (3).

No further studies or case reports have been found. In the Swedish adverse drug reactions register, there are no reports of ALS for any of the statins (4). In the WHO adverse drug reactions database there are today 50 reports of ALS in connection to statin use (5).

In a corresponding letter to the study above, a possible mechanism of statin induced ALS-like syndrome is discussed. It is known that elevated extracellular glutamate concentration in the CNS promote excitotoxicity, and this has been implicated in chronic neurodegenerative diseases such as ALS. Self reactive T helper 1 cells (Th1-cells) minimize the glutamate induced neuronal damage. Regulatory T cells down-regulate Th1-cell mediated protection and thereby may potentially impair the neuroprotective immune response. It is described that statins can increase the number of regulatory T cells, which may stabilize atherosclerotic plaques but therefore also may impair neuroprotective autoimmunity (6).

However, there have also been suggestions that statins may be protective of neurodegenerative diseases. In one in vitro study it was shown that atorvastatin protected neurons from glutamate excitotoxicity (7). In another in vitro study, pretreatment with statins on cultured neurons produced resistance to NMDA (a glutamate receptor agonist)-induced excitotoxic death (8). It has also been discussed whether statins could therapeutically useful in neurological diseases, such as multiple sclerosis and Alzheimer´s disease (9). Amyotrofisk lateralskleros. Information from the National Board of Health and Welfare (Socialstyrelsen). Available via: http://www.socialstyrelsen.se/ovanligadiagnoser/Amyotrofisk+lateralskleros.htm Amyotrofisk lateralskleros. Information from Wikipedia. Available via: http://sv.wikipedia.org/wiki/ALS Edwards IR, Star K, Kiuru A. Statins, neuromuscular degenerative disease and an amyotrophic lateral sclerosis-like syndrome: an analysis of individual case safety reports from vigibase. Drug Saf 2007;30(6):515-525 Swedis (The Swedish Drug Information System) (2008-01) Vigibase. WHO:s adverse drug reactions database (2008-02-12) Goldstein MR, Mascitelli L, Pezzetta F. Statins, regulatory T cells and amyotrophic lateral sclerosis. Drug Saf 2008;31(2):181-182 Bosel J, Gandor F, Harms C, Synowitz M, Harms U, Djoufack PC et al. Neuroprotective effects of atorvastatin against glutamate-induced excitotoxicity in primary cortical neurones. J Neurochem 2005;92(6):1386-1398 Zacco A, Togo J, Spence K, Ellis A, Lloyd D, Furlong S et al. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors protect cortical neurons from excitotoxicity. J Neurosci 2003;23(35):11104-11111 Reiss AB, Wirkowski E. Role of HMG-CoA reductase inhibitors in neurological disorders : progress to date. Drugs 2007;67(15):2111-2120