Amyotrophic Lateral Sclerosis (ALS),
Lou Gehrig’s Disease, Motor Neuron Disease (MND)
Amyotrophic Lateral Sclerosis (ALS), known also as Motor Neuron Disease (MND) took the name of Lou Gehrig disease in the USA, when a famous baseball player suffered from it. This disease causes the death of the neurons responsible for the control of the voluntary muscles, rendering them stiff with occasional twitching until worsening weakness and finally paralysis. The weakness may start in the legs or the arms with difficulty in ambulation and progressively difficulty in speaking and swallowing. The muscle will lose their size and progressively their functions. Half of the patients suffering from the disease will also present difficulties in thinking and will start experiencing pain until eventually, they lose the ability to walk, or use their hands, to speak, swallow or breathe.
The etiology of this disease is unknown in most of the cases but environmental and genetic factors have been blamed, based on damages to the upper and lower motor neurons relating to the clinical signs and symptoms. ALS is the most common motor neuron disease in adults and the third common neurodegenerative disease after Alzheimer and Parkinson diseases. It is estimated that 1.9% per 100.000 people will develop ALS in any given year while in Europe the incidence is 4.5% per 100.000. Men have a higher risk because of spinal onset ALS is more common in men than women. A 5.2 people per 100.000 with a high incidence in white males over 60 years old was found in the USA. Most of the epidemiology studies have been performed in Europe and there is not enough information on the rates of the disease in Africa, Asia, Russia or South America. A high prevalence of the disease was reported in Guam, Japan, New Guinea but the incidence is unknown. A study in Cuba found that people of mixed race ancestry to be less likely to die from ALS than whites or blacks.
The medical literature mentions the name of Charles Bell as early as 1824, as the first to describe signs of the disease, but it is really Jean Martin Charcot, a French Neurologist who, first coined the term “Amyotrophic Lateral Sclerosis” in 1874 although other scientists may have previously found correlation between symptoms and neurological problems earlier. In the United States, when the famous baseball player Lou Gehrig was diagnosed with the disease in 1939, it became familiarly “Lou Gehrig disease”. Francois Amilcar Aran (1950) named the disease: “Progressive Muscular Dystrophy”. “Flail arm syndrome”, a regional variant of ALS, was described by Alfred Vulpian in 1886 and “Flail leg Syndrome”, a variant of ALS was described by Pierre Marie in 1918. Later, EMG and NCS began to be used in the process of evaluating cases of ALS in 1950 after this decision was taken at a meeting of the Federation of Neurology in El Escorial, Spain. Incidentally, the first ALS gene was discovered in 1993.
Many will remember the way the “ALS Ice Bucket Challenge” become popular in 2014 but, few will make the correlation with the disease itself. A person will challenge you to take a bucketful of iced water while you nominate three individuals of your choice to take part. They will need to dump the bucket of iced water on themselves and contribute to at least $10 for the cause of ALS.
There is no known cure for this disease. The treatment is supportive with mechanical ventilation, feeding tube while others have tried a medication “Riluzole” which may improve the survival rate and increase the life expectancy. Other antiviral drugs, anti-oxidants or growth factors have not shown to be effective in clinical trials. Repeated transcranial magnetic stimulations (2013) have been also used as well as stem cell therapy (2016) were found to be relatively safe and possibly effective. Nowadays, there are insufficient evidence to speculate about efficacy. Other drugs are being studied like Masitinib and Beta-adrenergic agonist are also proposed for their effects on muscle growth and neuroprotection but time will tell about their efficacy.
The disease can affect people at any age but usually starts around the age of 55-60. From the onset of the disease to death a 2 to 4-year survival rate is the norm. 10% may live longer than 10 years. The incidence in Europe 2-3 per 100,000 per year. In the USA, more whites than blacks are affected. A recent study performed in Italy, has demonstrated a higher incidence of ALS in soccer player. I was surprised to read it in the MEDPage today published in February 2019. I was intrigued and this push me to investigate further. We have already mentioned above the low incidence in developing such disease. In fact, in this recent article, it looks like Ettore Beghi MD of the Mario Negri Institute for Pharmacological Research in Milan, reported an incidence of 1.9 times higher for Italian soccer players than the general population. Professional players were found to develop the disease 20 years earlier. We encourage you to read the abstract in the American Academy of Neurology, annual meeting recently held in May 2018.
ALS/Motor Neuron Disease is a group of neurological disorders that selectively affect the motor neuron (cells that control the voluntary Muscles of the body). There are many motor neuron diseases like ALS, notably Primary Lateral Sclerosis (PLS), Progressive Muscular Atrophy (PMA), Progressive Bulbar Palsy, Pseudo bulbar Palsy and Monomeric Amyotrophic (MMA).
ALS can be sub-classified by the way the disease progress, by its inheritance or by the way it starts. In 25% of cases, the muscles of the face and the throat are affected due to a bulbar onset. In 5% of cases, it involves the muscles of the trunk and a few may have symptoms localized on one side of the spinal cord region bringing to the picture a better prognosis.
So ALS can be classified in a classical form (70%), affecting the upper neurons in the brain or inna spinal-onset ALS involving the lower motor neuron in the spinal cord with weakness in the arms and legs (2/3 cases). A bulbar ALS will affect the muscles for speech, chewing and swallowing (1/3 cases). PLS (Progressive Lateral Sclerosis) involves only the upper neurons and represent 5% of all cases while PMA (Progressive Muscular Atrophy) involves only the lower neurons and account for as well a 5% of all cases. PMA is associated to a longer survival rate, but still will progress to the spinal region over time, leading to respiratory failure and death.
Many regional variants of ALS can be seen when one side of the spine is involved like a flail arm syndrome or a flail leg syndrome (Diaplegia) or with a gradual onset of difficulty in speech (dysarthria), swallowing and breathing. Studies have shown that people with isolated bulbar onset ALS may live longer.
These neurological variants of ALS, cause muscle weakness, atrophy and muscles spasms due to the degeneration of the upper motor and lower motor neurons and individuals affected by the disorder may ultimately lose the ability to control and initiate any voluntary movements although bladder and bowel movement and extraocular muscles may be usually spared until the final stages of the disease.
30-50% of patients with ALS, will present signs of behavior or cognitive dysfunction. Another 50% will only present with mild changes. In the worse cases, 10-15% will demonstrate signs of temporal and frontal dementia while patients will keep repeating gestures and phrases as well as exhibiting signs of apathy and loss of inhibition. They generally present with a dysfunctional language and difficulty in social cognition and verbal memory. They demonstrate a language dysfunction with inability to take decisions. There is apparently no relation between the level of dysfunction of language and the severity of the disease contrarily to the cognitive and behavior dysfunctions which were found to be directly related to a reduced survival rate with emotional lability rendering caregiving a little more challenging. Many may experience emotional lability, easily crying or laughing for no apparent reasons especially with the bulbar onset of ALS. Often, ALS presents with neuropathic pain due to nerve damage resulting in muscle cramps and spasticity to cause muscle weakness and contractures, joint pain and even pressure sores and ulcerations.
The autonomic system and the sensory nerves remained unaffected allowing patients to be able to touch, smell, taste, hear and keep their sight. One has to remember that the earlier symptoms of ALS are muscle weakness or muscle atrophy associated to problems in swallowing, breathing, cramping or stiffness involving an arm or a leg, a slurred or nasal speech depending on which motor neuron in the body is damaged.
In limb-onset ALS, the legs and arms will be affected first forcing the patients to trip or stumble while walking or running. Soon they will present with a dropped-foot modifying the gait pattern or they will experience a lack of manual dexterity with difficulty in buttoning a shirt or turning a key in a lock.
In bulbar-onset ALS, we will find difficulty in swallowing and in speaking. The speech will progress to slurring with a loss of tongue mobility. A respiratory-onset ALS will show intercostal muscles inability to support breathing. Finally, overtime, patient will demonstrate difficulty in swallowing (dysphagia), in moving and speaking or simply in forming words (Dysarthria).
The upper neuron will translate in stiff muscles (spasticity), associated to hyperreflexia including the gag reflex. A Babinski’s reflex will be also present in face of muscle weakness, atrophy due to upper neuron damage while with a lower neuron involvement muscle weakness and cramps are more often associated to twitches of muscles (fasciculations).
Manifestation of ALS and progression of the symptoms vary from person to person. As we already discussed, most people will eventually become unable to walk or use their hands or to talk, swallow, or breath/cough on their own. The younger the patient (less than 40), the slower the progression of the disease as demonstrated in a survey based-study among clinicians, using the ALS Functional Rating Scale Revised (ALSFRS-R). Patient obese have been found to have the disease restricted to one limb or to the upper neurons exhibiting a slower progression while others with the bulbar onset ALS, Respiratory-onset ALS, Frontotemporal onset ALS. progressed faster with a poorer prognosis.
In late stages, eating will become more difficult with poorer chewing and swallowing, increasing the risks for aspiration pneumonia. Often a feeding tube becomes mandatory. Later once the diaphragm and the intercostal muscles show signs of paralysis most of the patients will present with a reduced lung capacity and a diminished inspiratory pressure and although respiratory support can ease the problems and prolong survival, it does not affect in any way the progression of the disease. Most of ALS patients will die at home, during sleep, in 2-4 years, from the onset of the symptoms, almost always in respiratory failure due to pneumonia. Less than 20% of patient suffering from ALS will survive between 5 and 10 years after the onset of the symptoms.
The exact cause of ALS remains a puzzle for scientists which have shown that genetic factors, although better understood than environmental factors, carry the same importance. The recent study in Italy showing a better prognosis in younger patient and a relation to head injury and soccer activities may bring light to such fascinated disease which challenge us all.
First degree and second degree relatives have been studied to in ALS for possible clues to resolve the mystery but there is no consensus among neurologist on what really how to define familial ALS. More than 20 genes have been isolated especially C9orf72(40%, SOD1(20%)etc. Even an “oligogenic” mode of inheritance has been suggested with possible mutations possibly causing the disease.
90% of ALS cases have no familial history. Some have mentioned military services and smoking with no positive correlation. Other factors like tobacco and alcohol. More exposure to heavy metal like lead, beta-carotene intake or even a head injury (TBI) have also shown weak evidences linking to the disease. A study at the Centers for Disease Control and Prevention in 2017 analyzed death from 1985-2011 in white collar employees. Other factors unconfirmed the possible risks for being exposed to chemical, magnetic fields or pesticides like DDT and toxaphene and even to serum uric acid.
Many reviews found no relation between physical activity and ALS other were of inconclusive evidences. Soccer and Football players have been identified at risk for ALS in numerous studies. A 2012 study found that a professional American football player to be at risk of dying from neurodegenerative causes three times higher than the general US population but this study was based on 2 cases. Those NFL players may have died from chronic traumatic encephalopathy more than from ALS. Soccer players from this recent study from Milan, Italy represented a cohort of 240000 people studied between 1960 and 1996 and in 375 deaths, eight were diagnosed with ALS. So the study proved that soccer players were 11 times more prone to die from ALS than the general Italian population.
Finally, smoking may be associated to ALS. This 2009 study concluded that it was a risk factor and the younger they started smoking, the more they may have ALS. Nerveless, neither the numbers of cigarettes smoked per day, neither the number of the years passed smoking affected the risks to suffer from ALS.
The diagnosis may be made with a MRI study demonstrating a T signal within the posterior part of the internal capsule, consistent with ALS. We will have to supplement the signs already described in the medical records with muscle weakness and atrophy, hyper-reflexia and spasticity and the biomarkers already discussed earlier. One can base the diagnosis on findings in the EMG in the early stages based on the Awaji criteria and be sure to differentiate ALS to ALS like syndrome like in HIV, Syringomyelia, Lyme disease or Syphilis etc.
There is no cure as we already reported but Riluzole may prolong the survival. Other medication like Gabapentin, Tricyclic anti-depressants, Opioids etc. may be helpful. others like Baclofen, Atropine, Scopolamine. Feeding tube, gastrostomy added to a Non-invasive ventilation (NIV) or invasive ventilation bring additional support.
Physical therapy, Occupational Therapy as well as Speech therapy play an important role in the life of an individual suffering from ALS limiting pain, delaying loss of strength, improving speech and swallowing and overall providing functional independence.
Nutrition preserve weight loss. Difficulty in swallowing may require a feeding tube or any kind of gastrostomy until end of life care is necessary with palliative to relieve symptoms and improve quality of life without treating the underlying condition. 90% of ALS patients die peacefully and about 3% of cases may die suffocating. Opioids can be used to treat pain and benzo diazepam to treat anxiety.
Many animal models have been used in researches about Amyotrophic lateral sclerosis (ALS) research like yeast, roundworm, fruit fly, zebrafish, house mouse and common rat in search of mutant genes. New methods to develop animal models including “viral transgenesis” in which viruses are used to deliver mutant genes to an animal model etc. are also implemented.
In conclusion, any physician should learn about Motor neuron disease and remember that can be always a diagnosis of exclusion at time. Remember the symptoms and the clinical findings to avoid confusion. I tried to elaborate on a difficult topic and maybe neurologists of our AMHE association can as well bring their experience and a final touch for the one who read regularly our newsletter and share with us the pearls in they may use in their practice to treat and support patient suffering from this disease which certainly bring death in 2 to 4 years of the diagnosis. Although finally the discovery of other markers like TDP43, FUS, C9orf72 can cause an ALS form of Fronto-Temporal Dementia, scientists are trying to understand how these mutations can explain the disease and even whether or not other protein dysfunction may play a role, like within the methylation of the arginine.
Maxime Coles MD
References:
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