AbstractAmyotrophic Lateral Sclerosis(ALS) has remained a terminal disease without a clear underlying pathogenesis for the majority of patients. It is known to cluster around heavily polluted environments. I began evaluating patients with ALS in 2003 finding they all had evidence of immunosuppression with Hypogammaglobulinemia, Lymphopenia and Anergy on skin testing. They all had evidence of a toxic exposure with elevated Protoporphyrins with adequate Iron Stores. They all had developed a Metabolic Acidosis with an elevated Anion Gap. They all had elevated Kreb Cycle Intermediates on urine screen for Organic Acids consistent with Mitochondrial Damage. Muscle biopsies were positive for only ALS. Screens for the standard poisonings, lead, arsenic, mercury were negative. Studies for the Mycotoxin, Trichothecene were positive. Given the evidence of Immunosuppression the patients were given Gammaglobulin. They were given trials of Amphotericin and Fluconazole without an apparent effect. Trials of Voraconazole routinely corrected the Protoporphyrinemia and the Anion Gap Metabolic Acidosis. In addition, the Krebs Cycle Intermediates returned to normal. On stopping Voraconazole, the findings recurred. There was no apparent improvement in the patients neurologic deficits. The patients were given Plasma Exchange as a 5 day procedure similar to the procedure for Guillain-Barre along with Voraconazole. Again the Protoporphyrinemia and Anion Gap Metabolic Acidosis resolved. In addition, the patients began to show reversal of their neurologic deficits confirmed with Maximum Pressure Inspiratory measurements. In one patient paralyzed from the waist down for over a year, he began walking documented in the hospital. In another patient with Bulbar ALS his pulmonary function returned to normal on the fifth day of plasma exchange.
In 1993 I reported to the Tennessee Department of Health that there was a cluster of patients with amyotrophic lateral sclerosis (ALS) living around and working at the nuclear weapons facility in Oak Ridge, TN. This was confirmed by representatives of the Tennessee Department of Health. 1
More than 10 years later, I began managing the care of a patient with terminal ALS paralyzed from the neck down and ventilator dependent. She was immunosuppressed as evidenced by having hypogammaglobulinemia, lymphopenia, anergy to skin testing to Candida and Trichophyton and with yeast cultured routinely from urine and a tracheostomy. Her labs showed persistently elevated protoporphyrins without iron deficiency. She had persistently low CO2 consistent with a metabolic acidosis with elevated anion gap. A urine screen for organic acids found multiple elevated Kreb cycle intermediates consistent with a mitochondrial injury. Analysis of a muscle biopsy was consistent with only ALS. Due to the secondary porphyria, tests for a toxin were done, but were uniformly negative including lead, arsenic, mercury and other metals. Given the findings of immunosuppression she was given gammaglobulin and an infectious etiology was considered to explain the porphyrins and metabolic acidosis. Trials of anti-fungal agents including Amphotericin and Fluconazole were without effect. However, Voraconazole treatment resulted in normalization of the patients porphyrins and metabolic acidosis. There was no evidence of any clinical improvement with respect to the paralysis. A trial of plasma exchange was done following a protocol similar to that for Guillain-Barre with 5 days of 1.5 liters/day along with the Voraconazole and gammaglobulin. She began to recover functions in her right hand and again her porphyrins and metabolic acidosis resolved.
Based on the findings from this case, other ALS patients were evaluated. All had evidence of immunosuppression, involving both humeral and cellular mechanisms, as well as secondary porphyria. The extent of the paralysis paralleled the degree of immunosuppression. The patients had lymphopenia, anergy to skin testing, hypogammaglobulinemia, depressed lymphocyte mitogen stimulation to candida and depressed natural killer cell function. The pattern of porphyrins was most consistent with secondary etiology due to toxins with elevated protoporphyrins and coproporphyrins. Many had low CO2 levels and metabolic acidosis, but even without this, they had elevated organic acid levels due to Kreb cycle intermediates consistent with a mitochondrial injury. Trials of voraconazole and gammaglobulin with plasma exchange consistently corrected the porphyria and the acidosis and resulted in either stabilization or recovery of motor function.
Review of Literature:
Amyotrophic lateral sclerosis/motor neuron disease is a neurodegenerative disorder causing progressive, relentless muscle weakness with eventual death with median survival of 3-5 years.2, 3 4, 5 The etiology has remained obscure for the majority of patients. The pathology of the disease finds selective motor neuron degeneration2, 3. Studies of signal transduction pathways in patients with ALS using immunohistochemical analysis show abnormalities in c-Jun-JNK/SAPK kinase6, and evidence of oxidative stress7, 8.
Epidemiologic data have for years implicated an environmental event. There is a 2 fold increase in ALS in young US Gulf War veterans9, 10. As noted above, there is a cluster of ALS in workers from the Oak Ridge Nuclear Weapons facility 1. There is a high prevalence of ALS in the Western Pacific especially Guam, Western New Guinea and Kii Peninsula of Japan2. Studies at UCLA were done of tissue cultures with murine anterior horn cells11, 12. Serum from patients with 17 different neurologic disorders had no negative effects on the cultures, but in the cultures using serum from ALS patients in 70% there was accelerated death of the anterior horn cells 11, 13, 14. Based on the epidemiology and lab studies, ALS patients were treated with plasma exchange with uniformly negative results.15, 16
Immunodeficiency was documented in all the patients involving both cellular and humeral immunity. The same environmental exposures reported in clusters of ALS could also be responsible for immunodeficiency. Radiation causes a profound lymphopenia and can cause immune deficits at subclinical levels17. Natural killer cell function deficiency can be due to corticosteroids, alcohol, salicylates, theophylline as well as environmental toxin 18 predisposing to herpes infections 19. The patients had anergy on skin testing to candida and trichophytin as well as had depressed lymphocyte mitogen stimulation to candida predisposing to mycobacteria and fungi 19. Certain opportunistic fungi such as the fusarium species have become prominent problems in immunocompromised patients.
The mycotoxins released from opportunistic infections could be responsible for the pathology found in ALS. Trichothecene is a mycotoxin from fusarium and several other species. It causes findings similar to ALS on a molecular level6, 20, 21 with oxidative stress and mitochondrial damage. The key moiety is the epoxide ring 9, 22 which targets peptidyltransferasse, an enzyme in the 60 S ribosomal subunit linking amino acids and generating ATP. This would explain the elevated Kreb cycle intermediates in the patients. In addition trichothecenes cause immunosuppression 21. Fusarium is ubiquitous in the worldwide food chain21, 23 Trichothecenes are lipophilic, low molecular weight toxins (MW 250-550) with the structure of a sesquiterpenoid 9. The epoxide moiety is critical to the pathogenesis and if removed leaves the molecule harmless. It generates free radicals which could explain the success of free radical scavengers in ALS research. Trichothecenes rapidly form a covalent bond to proteins. They are cytotoxic to most eukaryotic cells rapidly shutting down protein synthesis. This triggers ribotoxic stress response that activates JNK1, stress-activated MAP kinase and apoptosis 6.
Below are summarized the findings with 4 patients. Similar findings have been observed with others.
1. MP- ventilator dependent, paralyzed from the neck down, lymphopenia, hypogammaglobulinemia, elevated RBC protoporphyrin, elevated anion gap metabolic acidosis. Treatment: All the labs for the patient were corrected with treatment by Voraconazole and/or plasma exchange.
2. JY- ventilator dependent, paralyzed from neck down, porphyria, metabolic acidosis, lymphopenia, hypogammaglobulinemia. Treatment: The patient responded to Voraconazole and plasma exchange with recovery of leg function and overbreathing on the ventilator along with correction of acidosis and porphyria
3. EH- paralyzed from the waist down with intense spasticity in the legs, porphyria, metabolic acidosis, hypogammaglobulinemia, and lymphopenia. Treatment with plasma exchange and Voraconazole resulted in correction of hypogammaglobulinemia, porphyria, and acidosis and also resulted in a remarkable recovery of motor function
4. CM- early phase ALS. The patient was given mesenchymal stem cell therapy, a treatment known to cause immunosuppression, and it resulted in accentuation of the paralysis and with labs showing RBC Protoporphyrin 100, CO2 12, Anion Gap 20, natural killer cell deficiency 5 (normal >8), hypogammaglobulinemia subclass IgG2 280(normal >350) , mitogen stimulation for Candida depressed. Treatment with gammaglobulin, Voraconazole and plasma exchange resulted in elevation of natural killer cells to 12 and stabilization of the paralysis.
5. JH- patient with Bulbar ALS with impending respiratory failure. He refused intubation but agreed to Plasma Exchange and Voraconazole. After 5 days of plasma exchange with Voraconazole his Maximum Inspiratory Pressure rose to normal from zero.
Immunosuppression of both humeral and cellular mechanisms is evident in all the ALS patients studied. The severity of immunosuppression correlated with the extent of the ALS. It is hypothesized that the immunosuppression leads to infections with opportunistic microbes that leads to the release of toxins responsible for the findings in ALS with the toxin targeting the mitochondria in skeletal muscle. The response to Voraconazole implicates a fungus such as fusarium which releases an array of mycotoxin including trichothecene. Voraconazole penetrates the cerebral spinal fluid (CSF) well. This could be interpreted as evidence of a focus of infection in the CSF. The failure of plasma exchange in the past could be due to the persistent production of toxins by an infection. The addition of gammaglobulin and Voraconazole to plasma exchange appears to have succeeded in inducing recovery of motor function. ]
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I do believe this is real.
I have started my mother in law (ALS) on this protocol. There are two crucial steps (after blood work).
1) Take the Voriconazole, the antifungal (this is cheap)
2) Plasma Exchange
Most doctors will read "Plasma Exchange for ALS" and say "Oh that isn't approved for ALS, or has been proven not to work." But they are missing the point. The plasma exchange isn't for "ALS" per se, it is for the toxins in the blood. And you need to try to kill it first with step 1.
If your loved one with ALS went to the doctor with a broken foot, would they say "sorry, cant treat her, she has ALS?" No. This is the problem we are having.
If nothing else, have Dr. Reid send you the lab orders for certain porphyrins. When/if the results are off the charts, then turn to your doctor and say "regardless of ALS, what do we do about this evidence of toxins/poison in the blood?"
Some say "But this is only 10 people". My reply is, "would you bet on somebody that is 10 for 10 or 0 for 10,000?"
And lastly, I did get a reply from a well known ALS doctor that said
"Porphyria is a condition known to be associated with a motor nerve disorder. Consulting neurologists expert in ALS diagnosis for your mother in law would help to know if this is relevant to her condition. Autoimmune motor nerve disorders can also simulate ALS and these do respond to plasmapheresis. Again consulting neurologists expert in the diagnosis of ALS would reveal whether your mother in law has an autoimmune motor nerve disorder as opposed to ALS."
So we will be looking into this route as well.
Dear Dr. Reid, I run a program called ALSUntangled (www.alsuntangled.org) which reviews alternative therapies based on requests from patients with ALS. We have requests to review your anti fungal protocol. Would you be willing to talk about it by phone or email (firstname.lastname@example.org)? Any chance I could review the records on the patients you say improved on this treatment?
-Rick Bedlack MD PhD
I believe the immune suppression can be explained by looking at the complement evasion strategies of the microbes. Candida captures Factor H, FHL-1, C4bp and plasminogen(1).
The way complement works is C4 splits into C4a and C4b, and then C4bp is one of the split products from C4b. Each time is splits, more letters are added. Where C4 is in complement is very important. It is the initiation phase, which means in order to get the amplification phase going, not much needs to be expressed as the amplification is like a cascade response. By capturing C4bp the amplification phase and immunity is turned down. More C4 needs to be expressed to turn up innate immunity.
I believe there is a huge problem with over expression of C4 of complement, which is located on chromosome 6. Within C4 is varying amounts of herv-k. Sekar's paper (2) has fantastic information on C4 of complement and shows the correlation of the herv-k to schizophrenia. Blanchong's paper goes into much greater detail about the nature of C4 and the varying lengths of C4 due to different amounts of herv-k in the gene.
There are other microbes that capture C4bp and I did a very simply back of napkin kind of model to predict what would happen to C4 expression and my untested model showed a non-linear increase. In ALS some pALS have been tested to show enormous amounts of herv-k.
Other research I've looked at suggests that herv-k facilitates other viral attacks such as HSV, EBV and Coxsackie Virus.
Factor H is supposed to removed the C3b from the spine but it isn't doing its job and it is also captured by candida and molds and lyme to name a few microbes. The microbe that causes gingivitis also has Factor H and C4bp complement evasion.
Factor h is in balance with properdin(4). Complement is very important in removal of dead cells and C4bp and factor H through its balance with properdin play an important role in regulating this(5).
I believe that excess C4A is correlated to microbial capture of C4bp, although I've not seen research on this, but stoichiometrically, this is what would happen with capture of C4bp.
(1) Luo, Shanshan, et al. "Complement and innate immune evasion strategies of the human pathogenic fungus Candida albicans." Molecular immunology 56.3 (2013): 161-169.
(2) Sekar, Aswin, et al. "Schizophrenia risk from complex variation of complement component 4." Nature 530.7589 (2016): 177.
(3) Blanchong, Carol A., et al. "Deficiencies of human complement component C4A and C4B and heterozygosity in length variants of RP-C4-CYP21-TNX (RCCX) modules in caucasians: the load of RCCX genetic diversity on major histocompatibility complex–associated disease." The Journal of experimental medicine 191.12 (2000): 2183.
(4) Kouser, Lubna, et al. "Properdin and factor h: opposing players on the alternative complement pathway “see-saw”." Frontiers in immunology 4 (2013).
(5) Martin, Myriam, and Anna M. Blom. "Complement in removal of the dead–balancing inflammation." Immunological reviews 274.1 (2016): 218-232.
My mother was diagnosed with ALS in May 2016. Her doctor put her on riluzole, letting her know there was no cure but the medication might provide her a few more months of delayed symptoms. ALS progresses at different rates and affects different body parts first. My mother, being 73 at the time, fell into a category of what they call "fast progression" (older female). Her arms weakened first, then her hands, her mouth, and throat, and finally her lungs. Throughout her two-and-a-half-year ordeal, she was able to walk with assistance nothing was really working to help her condition.I took her off the riluzole (with the doctor’s knowledge) and started her on amyotrophic lateral sclerosis herbal formula i ordered from Health Herbal Clinic, her symptoms totally declined over a 5 weeks use of the ALS disease natural herbal formula. She's now almost 75 and doing very well, the disease is totally reversed!! Visit there website www. healthherbalclinic. net
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