Wednesday, March 3, 2021
William Reid
Amyotrophic 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.