Jan 16 2007

Stephen Hawking and Motor Neuron Disease (Part II)

Yesterday I discussed the nature of disease, disorder, and syndrome – all as a prelude to the discussion of motor neuron disease, and the fact that it is not a disease. It is better understood as a clinical syndrome.

There are basically two types of motor neurons – the upper motor neurons which have their cell bodies in the motor cortex of the brain and send their axons down to the spinal cord to synapse on the lower motor neuron; and the lower motor neuron, which has its cell body in the anterior horn of the spinal cord and sends its axon out of the spinal cord to become part of a peripheral nerve and eventually synapse on a collection of muscle fibers. There are also interneurons that regulate motor function, but we won’t consider these for now.

A disruption anywhere in the motor system results in weakness. If the upper motor neurons die or stop functioning, or their axons are disrupted, then the result is an upper motor neuron syndrome. The signs of this are increased deep tendon reflexes (like when a doctor bangs on your knee with a small rubber hammer and your leg jumps), increased muscle tone, and the presence of certain abnormal reflexes. If the lower motor neuron dies or its axon is damaged then the result is a lower motor neuron syndrome, with signs of decreased deep tendon reflexes, decreased muscle tone, and in addition the muscles that have lost their nerve supply will become twitchy producing fasciculations (the muscles contract spontaneously giving an appearance that has been compared to a bag of wiggly worms) and fibrillations (small electrical discharges that can only be measured by placing a needle electrode within the muscle tissue.

So motor neuron disease is really a category of diseases that is further divided into upper motor neuron diseases, lower motor neuron diseases, and diseases that involve both the upper and lower motor neurons. Within this category there are some specific pathophysiological diseases. For example, spinal muscular atrophy is a genetic disease that results in the death of the lower motor neuron.

What Stephen Hawking has is a motor neuron syndrome called amyotrophic lateral sclerosis (ALS – in America it is also referred to as Lou Gehrig’s disease after the famous ball player who died from it). ALS is a combined upper and lower motor neuron syndrome. But ALS is not a specific disease either, because there are multiple underlying diseases that can cause this syndrome. ALS is defined at this time as any disease that causes the death of upper and lower motor neurons. It is defined by the target cell populations – not the underlying cause.

ALS is further divided in familial ALS (FALS – where there is a family history of others with the disease) and sporadic ALS (where there is no family history). FALS is a genetic disorder, about 15% of patients with FALS have a mutation in the superoxide dismutase (SOD1) gene. Normally this protein is a powerful anti-oxidant, and the mutant protein does not fulfill its anti-oxidant function and is also directly toxic to motor neurons – a double whammy.

At present we do not know what causes sporadic ALS, or in fact how many different causes there are. There are many theories, lots of clues, but no smoking gun. But it is probably many diseases, all with the common end result of death of upper and lower motor neurons.

Historically, when the cause or causes of a syndrome are unknown attempts are made to describe and even categorize the different ways in which the syndrome presents. So people have tried to classify ALS based upon where it starts (in the arms and legs, or in the muscles of speech and swallowing, for example) how it progresses, and other signs that may accompany it. But no one knows if these different flavors of ALS are different expressions of one disease or in fact different diseases. This debate won’t be resolved until more is known about the pathophysiology.

Getting back to Stephen Hawking, he first started having symptoms at age 18-19, and is now 65 years old. So he has survived with ALS for over 40 years, when the average life expectancy is about 2-3 years. (To be clear, this is the life expectancy unless someone is placed on full mechanical ventilation, then they can survive for as long as they are cared for.) But now that we know ALS is just a clinical syndrome, likely with many underlying causes, this makes more sense. It is probable that Hawking has ALS from some cause that tends to stop progressing at some point (although he has functionally progressed due to aging, it is unlikely that he has an active disease process killing more motor neurons). So he has survived much longer than the average ALS patient because he probably has it from a different underlying cause. In other words, although he has a similar syndrome to other ALS patients, he probably has a different disease.

Hopefully during my career we will learn more about the causes of this dreadful neurological syndrome. When that happens the old fuzzy categories will likely fade, and a new categorization scheme will emerge – one based on actual disease entities. And that will complete the typical historical life-cycle that diseases go through from first clinical description to eventual pathophysiological understanding.

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