Riluzole
Since 1996 riluzole (Rilutek®) has been licensed as the first and so far the only medication of an international standard against ALS. This medication was shown to have a positive effect on the course of the disease. In two large studies, a prolongation of life for 3 months in a study period of 18 months was achieved. The daily dose is 50 mg twice a day.
One tablet should be taken at an interval of about 12 hours (e.g. morning and evening) one hour before or two hours after meals. Meals high in fat delay absorption of the drug. The adverse drug effects are mild and lead to premature cessation of the treatment in only a small number of patients. The controlled studies yielded evidence that patients especially in the early stages of the disease benefited from the neuroprotective treatment. Riluzole intervenes at several sites in the process of signal transmission by the messenger glutamate. It is known that it reduces the release of glutamate into the synaptic gap and thus glutamate mediated activation of glutamate receptors (see Fig. 6, mechanism A). The drug thus counteracts the toxic effects of the neurotransmitter glutamate.
Another neuroprotective mechanism is direct interaction with and inhibition of the glutamate receptors
(see Fig. 6, mechanism B).
A further effect is probably inactivation of so called voltage dependent sodium channels, which are important in the excitability of neurons and release of the neurotransmitter glutamate
(see Fig. 1, mechanism C).
Fig. 1
Mechanisms of action of riluzole.
Vitamin E
The therapeutic effect of vitamin E (alpha tocopherol) in ALS was investigated in a clinical study and published in the British journal “ALS“ in March 2001 (Desnuelle et al.). In this study in 298 ALS patients, one group was given 1000 mg vitamin E /day while another group of patients was treated with a placebo. Analysis showed a slight slowing of the disease in the early course of ALS but no influence on the middle and late phases of the disease and ALS patient survival. Thus, it was not possible to confirm that life was prolonged by vitamin E in a dose of 1000 mg/day. In September 2003 a high dose study with 5000 mg vitamin E/day was reported at the annual conference of the German Neurology Society. This was a multicentre and placebo controlled study in several European ALS centres, which was published by M. Graf and colleagues in late 2004. The results show that no statistically significant influence on the survival of ALS patients was achieved at a dosage of 5000 mg/day either. The delay in disease progression in the early stages of ALS was not investigated separately. On the basis of recent studies, a recommendation of vitamin E treatment cannot be made.
Lithium
On 04.02.2008 the results of the Italian Lithium Study in ALS were published for the first time (Fornai et al. PNAS;105:2052 2057). These are the results of research by neurobiology teams and a neurology department in Pisa, Rome and Novara. The article is a summary of the experiences of a randomised and open ALS therapy study in 44 ALS patients, which started in October 2005 and was conducted for 15 months. 16 patients were treated with a combination of riluzole and lithium carbonate, while 28 patients were treated with riluzole monotherapy. The lithium carbonate dosage was 300 mg (150 mg twice a day) with a possible increase in dose up to 450 mg/day. The target serum level was 0.4 to 0.8 mmol/l. The study groups (riluzole + lithium vs. riluzole monotherapy) showed similar baseline values with regard to the severity of the ALS (ALS FRS R), muscle strength (MRC scale) and respiratory function (forced vital capacity, FVC). As regards the age of the patients, there was a non significant difference between the lithium group (66.9 years) and the riluzole group (70.3 years). The authors report a positive treatment effect in the lithium group compared with riluzole monotherapy. In the lithium group, there was a reduction of 14.3% in the ALS FRS R score, whereas a reduction of 39.8% of this score was recorded with riluzole monotherapy. The Italian researchers also report that there was no death in the lithium group while 29% of the patients in the riluzole group died. The authors concluded that lithium may represent an effective treatment option in ALS.
The lithium in ALS study attracted substantial media attention (e.g. Frankfurter Allgemeine Zeitung of 06.02.2008) and generated a considerable potential for hope in ALS patients. According to assessments to date, the lithium study in ALS is an interesting starting point for further studies. At the same time, it must be emphasised that the complex data were overrated and simplified in the non scientific press and internet publications. The results so far unfortunately do not permit the conclusion that lithium provides a cure or highly effective treatment of ALS. The Italian lithium treatment study has several method related limitations, which should lead to a cautious interpretation of the data. For instance, the number of patients treated with lithium is much lower than the group given riluzole monotherapy (16 vs. 28 patients). In addition, the article does not state whether different observation periods were used in the lithium and riluzole groups. Against this background, the different mortality rates (0 vs. 29%) are not directly comparable. Moreover, it can be seen in the original data that the rate of progression of all the investigated parameters (ALS FRS R, FVC, MRC) was already poorer in the riluzole group at the start of the study and remained unchanged in both groups throughout the study . However, with a high grade medication effect, it would have been expected that there would be an increase in the therapeutic effect with an increase in the duration of treatment. Therefore, it cannot be ruled out that ALS patients with a primarily better disease course were included in the lithium group. Because of these problems, stratification of ALS patients according to their rate of progression was undertaken in other ALS therapy studies even prior to inclusion in the study in order to avoid “distortion effects“ due to uneven allocation of patients with different rates of progression.
The small number of patients so far (n=16) and the method related limitations of the study unfortunately do not permit any general therapy recommendation for lithium in ALS. The risk of toxic effects of lithium in the event of overdose should be pointed out. Cardiac arrhythmias, disorders of consciousness, epileptic seizures, nausea, vomiting and diarrhoea are possible with overdose. Because of the side effect profile, renal function tests, electrocardiography and thyroid function tests are required in every case.
To confirm a therapeutic effect of lithium in ALS, a placebo controlled study is planned, which is being prepared by the Italian research group in 100 ALS patients. Moreover, it can be assumed that the experiences of ALS patients will be communicated via web portals (http://alslithium.atspace.com, www.patientslikeme.com). The self description of individual ALS patients is no alternative to the planned controlled multicentre therapy study but is important for exchanging information about the effects, risks and limits of lithium medication in ALS.
Lithium treatment in ALS was practised repeatedly in previous decades. The previous use of this medication refers to the treatment of motor disinhibition (compulsive laughing and crying). Due to the mood stabilising effects of lithium, the drug was recommended in individual cases (e.g. Amyotrophic Lateral Sclerosis Practice, UNI MED Verlag 2002, editor B. Neundörfer). No effects on the course of the disease were identified from this previous experience with lithium although the dosages corresponded to those of the Italian lithium study.
Lithium is an established symptomatic treatment option for motor disinhibition. In this context, use of this medication is justified when the risk/benefit relationship is considered. Systematic analysis of the course of ALS in this group of patients will also help to assess the status of lithium in the treatment of ALS as fast and comprehensively as possible.
Creatine phosphate
An animal model of ALS produced by genetic engineering methods has been available for a few years, and can be employed in basic and therapy research of ALS. The transgenic mouse model of ALS allows rapid investigation of medications before a decision is made regarding their use in humans. These are mice produced by genetic engineering, which are given the human superoxide dismutase (SOD1) gene including a mutation that causes ALS (SOD1 mouse model of ALS). The mutation carrying animal is born healthy and shows normal development. Only later in life does the SOD1 mouse develop progressive paralysis and disease symptoms that have parallels with the human form of ALS. Even before the onset of the clinical symptoms and at a very early stage of the disease, the ALS mouse exhibits obvious changes in the mitochondria, the components of the nerve cell that can be regarded as the energy producers of the neuron. Due to these findings, it was already suspected several years ago that a disturbance of the energy resources of the nerve cell contributes to the dysfunction and finally degeneration. Based on the hypothesis of a chronic energy deficit, an experimental treatment of the SOD1 animal model was conducted with creatine phosphate, a high energy substance. The results showed that survival of the SOD1 mouse model was prolonged by treatment with creatine phosphate. Biochemical tests yielded evidence that the prolongation of survival is due to neuroprotective effects on the motor neurons and not to strengthening of the musculature. On the basis of the information from the SOD1 mouse model, a therapeutic experiment with creatine phosphate in clinical practice also was recommended. At the international ALS conference in Melbourne, Australia in November 2002, data on the use of creatine phosphate in ALS patients were published for the first time. The results come from a placebo controlled study of creatine in association with riluzole. The research team of van den Berg, a neurologist at the University of Utrecht, Netherlands, found that creatine did not have a statistically significant effect on the survival of ALS patients. The conclusion from these study results was that treatment with this substance is not indicated in ALS.