Feb 08 2008
A recent Italian study (full pdf) of the drug lithium in 44 patients with Amyotrophic Lateral Sclerosis (ALS) showed a fairly dramatic effect in slowing progression of this disease. While hopeful, these findings should be considered preliminary.
ALS is a neurodegenerative disease involving motor neurons – those cells in the brain and spinal cord that control voluntary muscles. The motor neurons of ALS patients slowly die, and when they do the muscle fibers they innervate become weak, they begin to twitch and cramp, and then eventually die and atrophy away. Weakness will typically begin in one part of the body but then relentlessly spread to involve all four limbs and the facial and mouth muscles (so-called bulbar or brainstem innervated muscles), and eventually the muscle of breathing. Patient develop arm and leg weakness, difficulty speaking and swallowing, and then eventually become short of breath and then become too weak to breath without a ventilator. On average patients will progress to the point where they cannot breath without a ventilator after 2.5 years from the onset of symptoms, but this can vary greatly in an individual.
Although we have many clues, we do not know what causes ALS. It is likely not a single disease, but multiple entities that all result in the same thing – motor neurons dying. We already divide ALS into familial and sporadic. About 10% of those with ALS inherited the disease, and about 20% of those have a known mutation in the gene for the superoxide dismutase (SOD1) gene.
At present there is no known cure for ALS. There is on approved treatment, the drug riluzole. Riluzole inhibits the action of glutamate, which is a neurotoxic neurotransmitter – meaning that it serves a function as a chemical signal between neurons but in high enough doses it is toxic to neurons and can kill them. Although it seems that glutamate toxicity is probably not the sole cause of ALS in any patients, it is likely a contributing cause. Glutamate may be adding physiological stress to motor neurons, making them more likely to die, and inhibiting glutamate may therefore allow them to survive longer.
Interestingly, other glutamate inhibitors have not been shown to have a beneficial effect in ALS. It is also certainly not the only model we have of motor neuron stress and death in ALS, and drugs with many different activities are under investigation.
Lithium is an element that is used as a drug in its ionic form (Li+). Lithium is widely distributed in the nervous systems and affects various neurotransmitters and enzymes. In animal studies lithium was observed to increase autophagy – a process by which cells eat up and clear away cellular waste or damaged structures. Autophagy is known to help cells lives longer. This observation of lithium’s effects lead the study authors, led by Dr. Fornai, to propose that lithium might have beneficial effects in ALS.
They first studied lithium in the mouse model of ALS (SOD1 mutant mice) and found that it prolongs survival, and when they looked at the spinal cords of these mice they found increased autophagy, increased mitochondria (the energy factories of cells) within motor neurons, and increased motor neuron density. They next conducted the current study in 44 humans with ALS, comparing riluzole alone to riluzole + lithium. After 15 months 29% of the control group (riluzole alone) had died, while none of the lithium group had died. They also report that the lithium group had slower progression as measure by a test of breathing (FVC) and strength.
For ALS, these results are quite impressive. The methods of this study are reasonable – the subjects appear to have been properly randomized to treatment or control group and the methods used to follow their outcome were also standard. However, the weaknesses of this study are that it was not blinded (so the patients and their doctors knew who was getting lithium and who wasn’t) and the number of subjects (44) was quite low.
At this point it is clear, and everyone would agree, that we need to do one or a few follow up studies of lithium in ALS – randomized, placebo-controlled, double-blind studies with about 300 patients followed for at least a year. This will have the methods necessary to produce reliable results and will be powerful enough to detect a meaningful effect with statistical significant (if there is one).
What is not clear is what patients and physicians who treat ALS now should do, until more definitive evidence is available. Lithium is a potentially toxic drug and requires close monitoring of blood levels. If it were more benign then it would be an easy decision – give it to patients until we know for sure what the benefit are, if any. With toxic drugs this choice is much harder, because we do not want to cause more harm than good.
Of course, whenever possible patients who want to take lithium for ALS should do so within the context of a clinical trial. But if no such trial is available to them, we have a dilemma. It is reasonable to argue for compassionate use of an experimental drug to treat a terminal and incurable disease. But unless this is done carefully it is easy to cause more harm to patients.
At this point I think compassionate experimental use of lithium in ALS is reasonable, but I will have to explore this more with my colleagues. Also in these situations I typically will lay out the pros and cons to patients and let them decide if they want to take the chance. I suspect most will, given the alternative. I just hope we can get the follow up clinical trials done quickly – definitive information either way is preferred when making life and death decisions.
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