ALS pathophysiology

ALS pathophysiology

As a lot of you have shown interest in ALS, I thought this would be a good time to dwell into its pathophysiology. I shall try to explain what happens in ALS in simple terms. ALS as has been pointed out is a motor neuron disease. What does one mean by motor neuron disease (MND)?

In the human body we have motor neurons and sensory neurons. Motor neurons refer to nerve cells and their bodies which control motor movements for example a motor neuron helps you to move your fingers or move your toes. We have sensory neurons too, these help us to perceive sensations like temperature (when you touch a hot cup of coffee), pain (you step on a nail—ouuuchhh) and touch (you touch a soft coat made of fur).

Each neuron whether motor or sensory has a cell body and then has a process called the axon (think of it as a body and its tail). The motor neurons which control the movements of the arms and legs are located in the spinal cord (we refer to them as the anterior horn cells becuase they lie anterioly in the spinal cord). We also have motor neurons which control other movements like that of swallowing, speech etc. These neurons lie in the brain stem (the lower part of the brain). MND’s like ALS cause the death of these motor neurons in the spinal cord (anterior horn cells) and those in the brain stem. In its classical form, ALS does not affect the sensory neurons hence it is called a motor neuron disease. Once the motor neurons in the anterior horn cells and the brainstem die they do not regenerate again and hence ALS is also a neurodegenerative disease causing progressive relentless degeneration of motor neurons.

So the next question arises what causes the death of these motor neurons? Why suddenly in a healthy person the motor neurons start dying? Why is this death irreversible? Why are only the motor neurons affected why not the sensory neurons? Why are other parts of the brain not affected?

No one quite knows the answers to any of the above question. Why is the death so selective that it only affects the motor neurons and spares everything else. As the disease progresses and more and more motor neurons die, the patient is left paralysed (wheelchair or bed bound) not able to eat or swallow with difficulty in speaking. The higher mental functions remain intact so the memory is as sharp as ever and that is what becomes so difficult both for the patient and the caregivers (you can only imagine what it must feel like been trapped in a body which is paralysed). There is a form of ALS which runs in some families, this has been referred to as familial ALS and is genetic in etiology. Mutations in the copper/ zinc superoxide dismutase (SOD) have been implicated in causing ALS. The role of oxidative stress and free radicals has also been mentioned in its pathophysiology but the disease does not respond even if you treat it with anti-oxidants.

Tremendous research is going on around the world in ALS and there are some very prominent labs here in U.S.A. working on it too.  I would advise all patients and their caregivers to get in touch with an ALS specialist as he or she shall be the best informed if any new therapeutic modalities (medicines etc) become available.The ALS association is also a good organization to be in touch with. They can be reached at www.alsa.org.

Even though there is no cure there are a multitude of devices out there that can ease the life for a patient with ALS. My message hence is one of hope and I keep reading and am inspired by patient’s stories of living and winning the battle against ALS.

 Dr. Sethi

 

ALS

Amyotrophic lateral sclerosis (ALS) is better known in the United States and Canda as Lou Gehrig disease. It comes under the umbrella of a group of progressive neurological disorders collectively known as Motor Neuron Diseases (MNDs. ALS is a devastating neurological condition and is uniformally fatal in its outcome.

As the name suggests ALS involves the motor neurons selectively. What are motor neurons you may ask? Motor neurons are neurons (nerve cells) that control voluntary muscle activity. The motor neurons that control voluntary activity like swallowing, coughing, breathing and speaking lie in the brain stem while those that control voluntary activity like walking and moving your hands lie in the spinal cord.

ALS affects motor neurons of both the brain stem as well as the spinal cord. The disease by defination affects only the motor neurons and spares all sensory neurons. Thus patients with ALS have progressive motor weakness but no sensory findings ( no numbness or sensory loss). The disease also spares other brain functions like memory, cognition, orientation, alertness, ability to calculate, eye movements and bladder/bowel function.

That is why ALS is so devastating: it leaves one quadriplegic (completely paralyzed) having difficulty with swallowing, difficulty speaking and breathing but intact of all higher mental functions. Imagine been in a situation where your mind is completely healthy trapped in a completely paralyzed body.

ALS usually affects people in their late 40’s and above. The disease has been known to occur in the younger age groups but in these rare cases it usually runs in the family an entitiy called familial ALS (FALS). The onset of the disease is very insidious and patients may present to their doctor with complaints of a wrist drop or foot drop ( inability to lift the wrist or the foot). Usually the bulbar symptoms of difficulty in swallowing and speaking come later on in the disease course. There is a constellation of signs and symptoms which physicians look for clinically when trying to secure a diagnosis of ALS. 

Though this is technical let me try to explain it to you. If we as physicians find weakness in an arm or leg and the muscles are visibly atrophic (shrunken) but the reflexes (these are the reflexes which we elict by tapping your tendons with our hammers) are brisk, we think about possible ALS. If we find these signs in 3 different limbs it makes the diagnosis more secure. We also look for fasiculations. Fasiculations are visible involuntary muscle twitches under the skin arising from spontaneous discharge of motor neurons. In ALS one may see widespread fasciculations involving different muscle groups as well as fasciculations in the tongue (remember the tongue is also a muscle).

A word of caution here. A lot of us have visible fasciculations, we all have experienced the feeling when one of our muscle such as the eye-lid or thigh suddenly starts twitching. These are called benign fasciculations and do not protend ALS. Only when fasciculations are accompanied by visible muscle wasting and weakness that one should be worried. Benign fasciculations usually occur when one is tired or after heavy exercise and dehydration.

Other symptoms which commonly occur in patients with ALS include cramping especially of bigger muscle groups like that of the back.

 

If a diagnosis of ALS is been considered, it is imperative that other diseases which can mimic ALS in their presentation be ruled out. Some of these are readily treatable as against ALS for which currently we have no effective treatments. So how is the diagnosis of ALS secured?

When ALS is advanced, the diagnosis is readily apparent on a routine clinical neurological examination. The patient has visible atrophy (wasting) of the muscles of the limbs. Wide-spread fasiculations (muscle twitches) are visible to the naked eye. We as neurologists search for these in the tongue and the big muscle groups on the back. To secure the diagnosis in the earlier stages of the disease when the clinical features are not so florid, your doctor may order a few tests. The most important among these is the EMG (electromyogram). The EMG is a test which is not as bad as it looks. It basically involves putting a recording needle electrode in different muscles of the limbs, back and even the tongue to look for signs of denervation (damage to the motor nerves). There are criteria on EMG that help secure the diagnosis of ALS.

 

Management Issues in an ALS patient: ALS as a disease is incurable as of now. That said there is a lot which can be done to help a patient with ALS. Only one medication by the name of riluzole is approved for the treatment of ALS. That too prolongs the life expectancy by only a few months. Patients with ALS need a multitude of services and their care is best handled by a multi-speciality team consisting of neurologists, respiratory therapists, gastroenterologist, physical and occupational therapists and speech therapists. As the disease progresses and takes its toll, patients are prone to pneumonia and other respiratory tract infections. As their swallowing and speech functions become progressively impaired, nutrition (feeding) may have to be accomplished via either a feeding tube or a tube in the stomach (we call this a PEG tube).  Physical and occupational therapy helps to preserve motor functions. These patients are greatly helped by assist devices like motorized wheel chairs, a simple straw to aid them in drinking water and other liquids etc.

Tremendous research is going on to find a cure for ALS. Your doctor might also prescribe some vitamins and supplements like coenzyme Q 10. Whether these help is doubtful but they most likely do not cause any harm. You should discuss and other experimental therapies with your physician.

Some diseases which may resemble ALS superficially in their presentation:

1) Benign Cramping Fasiculation Syndrome: I explained this above. A lot of people have visible fasiculations (their muscles quiver) and they may also have complaints of cramps. There is no associated muscle weakness or atrophy. Reassurance is all that is needed.

2) Multi-focal motor neuropathy with conduction blocks: an uncommon neurological condition characterized by involvement of multiple motor nerves (thus resulting in weakness). Conduction blocks are present in nerve conduction study. It resembles ALS in that it presents with weakness and does not cause sensory symptoms.

3) High cervico-medullary junction involvement–if there is a high cervical disk herniation, it at times can present just like ALS.

4) X-linked spinal and bulbar muscle atrophy also referred to as Kennedy’s disease: neuromuscular disease due to mutations in the androgen receptor. Presents with cramps and progressive weakness due to degeneration of motor neurons in the brainstem and spinal cord.

 

It is imperative that the above conditions be looked for and ruled out before a diagnosis of ALS is arrived at, as some (multi-motor motor neuropathy with conduction blocks) do respond to therapies like intravenous immunoglobulin.