ALS is one of the least understood, least treatable and most invariably fatal diseases in neurology.
Lou Gehrig (1903-1941)
The "Iron Horse" played continuously for the Yankees from 6/1/25 to 4/30/39, 2130 games, .340 average. Some studies have found an association between exceptional athleticism (lifetime sweating*, actually) and ALS.
Also called Lou Gehrig's Disease, the neurologist who diagnosed it in the famous baseball player patiently watched the athlete's back for twenty minutes, noted the fasciculations which vary so much from muscle to muscle and moment to moment. Gehrig died two years after diagnosis.
From the SF Chronicle, February 7 1987
Three football players all on the same 1964 49er's team, subsequently developed ALS.
The recent news of Catfish Hunter's diagnosis underscores the fact that otherwise vigorous healthy men, especially atheltic men in their prime, seem to be the most vulnerable. The Chronicle article underscores the yearning to understand the disease and the association with toxins
Fasciculations may be subtle or severe to the point of "vermiculation" giving a "bag of worms" appearance, for example, the infamous "scrotal tongue" when the motor neurons of the 12th Cranial Nerve in the brainstem are affected.
ALS is a system disease analagous to Parkinson's: that is, the neurons affected all participate in a related function. In ALS that function is muscle strength. In Parkinson's (see Parkinson's Disease) the function is muscle coordination, initiation and sequencing of activity and entirely different parts of the brain are affected in the two diseases.
Note the sparing of sensory
nerve roots and the atrophy
of the motor nerve roots
(they should be of the same or larger thickness)
The relative success in Parkinson's which resulted from orally supplementing the precursor (levo DOPA) of the disappearing neurotransmitter (dopamine) has stimulated hopeful pharmacological efforts in finding something for ALS and Alzheimer's without notable results to date (9/98).*
Another source for pharmacological optimism was the unfortunate self-experiment of various intravenous opiate users back in the 1970's. Overnight they came down with an exaggerated form of Parkinson's (from the videos I've seen it was Parkinson's plus) after a bad batch of designer Fentanyl.
The culprit chemical turned out to be a neurotoxin abbreviated MPTP which was then used to produce model Parkinson's in laboratory animals. MPTP is an oxidant and one of its many effects is to nitrate the amino acid tyrosine in the proteins of motor neurons. Some motor neurons have so much tyrosine because tyrosine is one precursor of dopamine which in turn is a precursor of norepinephrine.
Inactivation of that pathway, in 6% of cases due to a genetic malfunction of the enzyme involved, is the best theory of causation I've come across to date. The oxidative stresses may be many and toxins have been associated with a few clusters. Unfortunately, anti-oxidants including the drug Selegiline (Eldepryl) and Vitamin E haven't been breakthroughs.
So one by one, these metabolic dynamos, the biggest, most awesome cells in the entire body, located normally in the brain and spinal cord disappear with minimal signs of struggle (minimal inflammatory response.). Their largest straightest filament, called the axons which transports nutrients the length of the spinal cord, others the length of the arm and leg, shrivel up and disappear. The inexorable and selective loss of the huge Alpha Motor Neurons leads to denervation excitability in muscles:
Identifying denervation potentials is exactly what the Electromyogram (EMG) does best and it can be helpful in diagnosing ALS. Denervation potentials should be found in all four extremities, even in the absence of visible fasciculations.
Denervation potentials occur when muscle cells lose their nerve input and become hyper-excitable, twitching at a microscopic level before they are visible on the surface. Denervation potentials are visualized on a CRT (Cathode Ray Tube - TV) and include
Positive Sharp Waves
(negative is up)
REFERENCES
Anyone familiar with ALS knows the passion for answers this tantalizingly mysterious killer inspires. In spite of the relative rarity, (1-2/100,000 per year incidence) large case control studies have been done and the findings are intriguing.
6% of cases of ALS are inherited in dominant fashion meaning sons and daughters both have a 50% chance of getting it. These pedigrees have been studied genetically recently and it turns out they all have one or another mutation of the gene for Superoxide Dismutase, our body's main anti-oxidant. Some clusters of an ALS like illness once occurred on Guam caused by flour ground from a cycad nut. Solvents have been implicated in a few clusters. So maybe a failure of our defenses causes ALS.
This theory would be consistent with two other observations consistently over the years: trauma has been significantly associated with onset and exacerbation of ALS as has lifetime perspiration. ALS patients often have a history of pushing themselves physically. It stretches credulity to think that one can wear out one's motor neurons but if they're compromised genetically, by toxic exposures, by trauma...well, the fact is no one knows.
All the clues are enticing. Maybe taking anti-oxidants and/or SOD itself or the precursor tyrosine will cure ALS. Then again, maybe it won't. Charcot identified this unique illness more than 100 years ago (see chronology below) and we're still far from a cure.
Here are the references for these ideas. I encourage anyone interested to investigate for themselves. There is a huge amount of material out there, some utterly contradictory, but there's got to be an answer for this one.
CHRONOLOGY
1830 Charles Bell reports the case of a middle aged woman with progressive paralysis of limbs and tongue, preservation of sensation. The anterior portion of the spinal cord showed degeneration, supporting his brilliant neuroanatomical discovery that "the anterior column...of the spinal marrow is for motion, the posterior column is for sensation..."
1850 Aran describes progressive muscular atrophy (PMA), thought to be a primary disease of muscle.
1855 Cruvelihier attributes PMA to atopy of the anterior horns.
1868 Jean-Marie Charcot recognizes the demyelinating lesions of Multiple Sclerosis.
1870 Fritsch and Hitzig identify the cortical motor strip of the brain by electrical stimulation in dogs.
1874 Charcot, in a series of lectures based on 20 cases and 5 autopsies, establishes the clinical entity, Amyotrophic Lateral Sclerosis (ALS).
1879 Kahler and Pick identify gross atrophy of the motor gyrus in ALS.
1883 Dejerinne relates Progressive Bulbar Palsy (PBP) to ALS.
1884 Kahler unifies cases of PMA, ALS and PBP as "primary degneration of the motor system."
1891 Werdnig and Hoffman identify Infantile Progressive Muscular Atrophy since eponymically called Werdnig Hoffman Disease.
1952 Guamanian ALS
1956 Kugelberg and Welander distinguish juvenile muscvular atrophy from muscular dystrophy.
1959 Engel, Kurland and Klatzo report familial ALS (FALS) with posterior column involvement. The number of ALS cases which are familial is usually given as 6%.
PROGNOSIS
Mulder, D and Howard F: Patient Resistance and Prognosis in ALS. Mayo Clinic Procedings, Vol 51, p 537, September 1976
"Amyotrophic lateral sclerosis is usually considered a disease that will have a fatal termination in 1 to 3 years. A prospective study of 100 patients with this disorder revealed that 20 of them were living 5 years after the onset..."
"Thus it becomes essential for physicians reporting to patients and to relatives about the prognosis of the disease to remember that at least a fifth of the patients who are diagnosed with our present techniques do live for a much longer period than has usually been thought probable."
REFERENCES REGARDING CAUSATION
Roman, G: Neuroepidemiology of amyotrophic lateral sclerosis: clues to etiology and pathogenesis. J Neurol Neurosurg and Psych, 1996 August , p 130-137
TOXINS, OXIDATION AND CYTOTOXICITY
Hyser Cl et al: Three cases of als in a common occupational environment:J Neurol 1987;234: 443-444
Pardo CA et al. Superoxide dismutase is an abundant component in cell bodies, dendrites and axons of motor neurons and in a subset of other neurons. Proc Natl Acad Sci USA 1995;92:954-958
Coyle JT et al. Oxidative stress, glutamate, and neurodegenerative disorders. Science 1993;262:689-694
Damier P et al. Glutathione peroxidase, glial cells and Parkinson's disease. Neuroscience 1993;52:1-6
Establishes that the locus of the protective glutathione peroxidase is not in the neurons themselves but in the supportive or glial cells.
Hawks, CH, Fox, AJ, Motor neurone disease in leather workers (LETTER). lANCET 1981;i;507
Przedborski S et al: Brain superoxide dismutase, catalase and glutathione peroxidase activities in ALS. Ann Neurol 1996;39:158-165
Stadtman ER and Berlett BS: Reactive oxygen mediated protein oxidation in aging and disease. Drug Metabolism Reviews 1998 May, 30(2):225-243
Strong, M and Garruto R: Chronic Aluminum Induced Motor Neuron Degeneration: Clinical, Neuropathological and Molecular Biologcial Aspects. Can J Neurol Sci. 1991;18:428-431
Note that aluminum has no natural biologic function. It is highly toxic to the brain and is used topically on animal brains to induce experimental epilepsy. Aluminum in dialysate baths has caused "dialysis dementia." Aluminum has been implicated in clusters of Alzheimer's in regions where the background levels are high and is also suspect. Besides cookware, aluminum is found in almost all underarm deodorants deodorants and Aluminum, as aluminum hydroxide or alum is used by some communities to clarify their drinking water.
TRAUMA
Bracco L et al: Study of epidiomological factors of amyotrophic lateral sclerosis in the province of Florence, Italy. Acta Neurologica Scandinavica, 60:2, 1979
"In the present study a surprising observation was the high frequency (31%) of patients who presented anamnestic (personal past history) evidence of trauma....Among 21 patients who presented a trauma, 10 presented the initial symptoms at the same site of the lesions..."
Riggs, J: Trauma, Axonal Injury, and Amyotorophic Lateral Sclerosis: A Clinical Correlate of a neuropharmacologic Model. Clin Neuropharmacol., Vol. 18, No 3, 1995
"Antecedent trauma has been implicated as a precipitating factor for amyotrophic lateral sclerosis in susceptible individuals."
"Case 2: A 38 year old man struck his forehead against the windshield in a near-head-on motor vehicle accident. He immediately began experiencing neck pain radiating down the left arm. He noted weakness in the left hand, and cervical radiculopathy was dfiagnosed clinically. Five months after the injury, fasciculations became evident over shoulder girdle, trunk and proximal leg muscles...a diagnosis of ALS was made."
"Case 3: A 38 year old man fell and sustained a neck injury. MRI demonstrated moderately severe degenerative joint disease of the cervical spine with a large central disc herniation at C4-5 and nerve root compresson on the left by a lateral C6-C7 disc herniation. By EMG evidence of chronic right C5 and C6 radiculopathies was found. At age 42 years, he developed weakness and fasciculations in the right arm. Six months later, diffuse upper and lower motor neuron muscle were present (sic), and a diagnosis of ALS was made. The patient's father and paternal grandfather both died of ALS at age 59 and 62 years."
(Note: Case 6 in this series involves a 29 year old man who suffered a neck extension injury and pain who developed wasting two months after an injury and eventually was diagnosed with ALS. A cousin died of ALS. These two cases appear to be the result of a combination of an inherited predisposition and injury.)
"Discussion: Suspicions regarding a relationship between antecedent trauma and the subsequent development of ALS have existed for more than half a century....Motor neurons in patients with ALS may, be definition, be considered selectively vulnerable to cell death....
Gallagher, JP, Talbert or Motor Neuron Disease After Electric Shock. Acta Neurologica Scandinavica 1990;83:79-82
Kondo K and Tsubaki T: Case-control Studies of Motor Neuron Disease: Association with mechanical injuries. Arch Neurol 1981;38:220-226
"Two case control studies of motor neuron disease that involved 712 cases and 158 cases, respectively, showed that 1) mechanical injuries were to to three times more frequent in both sexes, heralding amyotrophic lateral sclerosis, progressive bulbar paralysis and progressive muscular atrophy; 2) the head, neck and spine, and the extremities were more often traumatized...these results suggested that mechanical injuries were not the cause but probably one of the risk factors of the disease. No association was observed with smoking, drinking, residence, home space, drinking water, animals...."
"These results suggested that mechanical injuries were not the cause, but probably one of the risk factors of the disease."
*Strickland D. et al: Physical activity, trauma and ALS: a case-control study. Acta Neurol Scand 1996: 94: 45-50
"Conclusions: Severe head, neck and back injury showed a strong association with ALS...The frequency of sweating both in work and leisure activity showed significant association with ALS."
THERAPY
Gurney, M et al: Benefit of Vitamin E, Riluzole, and Gabapentin in a Transgenic Model of Familial ALS. Ann Neurol 1996;39:147-157
Bensimon G. et al. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med 1994;330:585-591
Lai EC, et al. Effect of recombinant human insulin like growth factor-I on progressions ofALS: a placebo-controlled study. neurology 997;49:1621-1630
A study of recombinant human insulin-like GROWTH FACTOR I on progression of ALS on 266 patients concluded that the growth hormone SLOWED THE DECLINE OF FUNCTION BY 26% - not a cure but certainly a contribution to quality of life. Unfortunately, even a 26% life extension would only be another 9 months, small consolation.
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