Wednesday, March 3, 2021William ReidAmyotrophic Lateral Sclerosis(ALS) remains a terminal disease without an established etiology for the majority of patients. The dominant theory of ALS before 1970’s was the presence of poisons. One of the primary means of treating patients with a toxic exposure has been plasma exchange, but plasma exchange of ALS patients failed to alter the clinical course. The failure of plasma exchange assumes the patient is no longer exposed to the poison. If the toxic exposure continues after plasma exchange, then plasma exchange alone would fail. The world food supply is contaminated by opportunistic fungi that release mycotoxins. There is mounting evidence of the profound neurologic and immunologic toxicity of the most common mycotoxins. Every ALS patient examined had evidence of a toxic exposure. Treatment with antifungals specific to the most common opportunistic fungi led to improvement in laboratory evidence of a poisoning. The pathology of the common mycotoxins mimics the pathology reported in ALS patients. Along with the profound neurotoxicity of mycotoxins, there is profound immune toxicity. If mycotoxins are involved causing ALS, then the immunotoxicity of mycotoxins could be responsible for the recalcitrance of therapy reported in ALS. New forms of treatment for immune deficits, immune tolerance and immune evasion could remarkably improve the treatment of ALS patients.Introduction :The etiology of ALS has remained elusive. The dominant theory before the 1970’s was the presence of neurotoxins1,2. Serum from patients with ALS were toxic to motor neuron cells in culture. Based on this theory multiple institutions treated ALS patients with plasma exchange without apparent improvement3. The conclusion that plasma exchange was ineffective made a critical assumption that there is a finite body burden of neurotoxin and no further exposures. If, instead exposure to neurotoxins persist after plasma exchange then plasma exchange would be inadequate. The source of toxins whether environmental or endogenous would need to be removed. If neurotoxins were generated by an infectious agent colonizing or infecting patients, then treatment would require control of the infection along with plasma exchange.In every ALS patient studied, there was laboratory evidence of a poisoning4. Patients developed secondary porphyria in a pattern typical of a poisoning. They developed anion-gap positive metabolic acidosis. They all had elevated Kreb cycle intermediates consistent with mitochondrial damage typically seen with toxic exposures. Treatment with anti-fungal agents specific to Fusarium species corrected many of the laboratory findings including the elevated protoporphyrins, the anion-gap positive metabolic acidosis and the elevated Kreb cycle intermediates. This is consistent with the presence of mycotoxin generated by a fungus growing in the patient.The literature on mycotoxins is extensive5-7. Mycotoxins are ubiquitous in the human environment and prominent in the world food supply. Globalization has accentuated the problem. Efforts to prevent or remove fungi and their mycotoxins from food and the environment have been difficult to impossible. Humans are routinely colonized by fungi that populate the skin, gastrointestinal tract, lungs and upper airway8,9. The same fungal species contaminating food are the species colonizing the human airways. Surveys of grain supplies found hundreds of fungal species producing over 700 mycotoxins5. Four fungal genera were routinely reported Aspergillus, Penicillium, Alternaria and Fusarium10,11. Of these fungal genera, Fusarium species were especially problematic12. Studies from otolaryngology reported that fungal colonization of the sinus cavity and upper airway is almost ubiquitous13-16. These studies found the same spectrum of fungal species with Aspergillus and Fusarium listed first and second in frequency. Many of these fungal species are highly resistant to anti-fungal agents especially Fusarium. Fusarium species produce a broad spectrum of mycotoxins with Fumonisins and Trichothecenes predominate12. Both these compounds have significant neurologic toxicity17. The problem of contamination of the human food chain by fungi and their mycotoxins has led to a world-wide industry to control the contamination of food (Romer Labs, Vicom Labs division Waters). Mycotoxin levels vary with environmental factors as well as storage techniques. There has been no successful way to prevent or remove these mycotoxins from food. This has left governmental authorities with few options. They have elected to monitor food supplies, set limits of exposure and discard food that exceed limits.Animals fed hay or grain contaminated with mycotoxins develop serious problems that include neurologic deficits18-20. Horses exposed to hay or grain contaminated with Fumonisins develop Equine Leukoencephalomalacia with paralysis of tongue, incoordination, ataxia, blindness, hind limb paralysis and eventual death with pathology finding severe brain damage.The other dominant mycotoxins from Fusarium are Trichothecenes divided into four groups, A,B,C & D12. The key to their toxicity is the presence of an epoxide ring moiety that generates free radicals setting off Oxidative Stress Reactions. They form covalent bonds to DNA, RNA and proteins. They target the 60S ribosome and peptidyl transferase shutting down protein production. The molecular weight of trichothecenes ranges from 200 to 500 Dalton. They are highly lipophilic able to be absorbed through skin, gut, crossing plasma membranes, including the blood brain barrier. Trichothecenes are known to accumulate in nervous tissue17. In surveys of grain, the trichothecene Deoxynivalenol was the most common with T-2/HT-2 Toxins the fourth most common. Studies of Deoxynivalenol found that it could accumulate in tissues even when levels were below the regulatory limit21.
