Theory of ALS
- Immunization Event
- Initiation Event
- Dexamethasone (DEX)
- Blood Brain Barrier (BBB)
- Microglia vs Systemic Macrophages
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The key to my theory of ALS is the Blood Brain Barrier (BBB). This barrier keeps antibodies and systemic immune cells from entering the brain.
Systemic immune cells called “neutrophils” and “macrophages” ingest other cells, like bacteria, to fight infection. These systemic macrophages move freely out of systemic capillaries through ameboid motion, squeezing between body cells to get to the site of an infection.
The brain is protected from these systemic macrophages by the BBB. The brain has its own, more delicate immune cells called microglia. But when the microglia are overwhelmed by a serious infection such as viral encephalitis, they release chemicals that trigger the BBB to open up, allowing antibodies and systemic macrophages to enter the brain to fight the infection.
My theory is that ALS occurs when auto-immune, anti-neuron antibodies are present in the systemic circulation and enter the brain when the BBB opens up. These antibodies then attack the motor neurons, causing them to stop functioning. Over time, systemic macrophages attack these neurons, destroying them completely. In the tightly packed spinal cord motor tracts, adjacent axons are also damaged, attracting more antibodies and macrophages, and leading to the eventual destruction of most of the motor axons in the spinal cord tracts.
Dexamethasone rapidly heals the BBB so it can again block systemic antibodies and macrophages from entering the brain. Motor neurons that were recently attacked by antibodies, but haven’t died yet (shocked neurons) may regain functionality over a few days. This leads to a slight reduction in ALS symptoms, which may not be noticeable.
Continuing dexamethasone at very low doses (i.e. 0.04 mg daily) prevents the “opening” of the BBB in the future without toxic steroid side effects. This prevents any further progression of ALS from systemic antibodies and macrophages.
My theory is that ALS is started by an injury to motor neurons. Motor neurons are the longest and most metabolically active nerve cells in the body. Furthermore, the intensity of a muscle contraction is determined by the rate of firing (action potentials) of these motor neurons. Prolonged, intense muscle contractions require rapid firing of motor neurons. Each time a neuron fires, it uses energy, so motor neurons firing at maximum intensity need lots of energy.
Energy production in brain cells requires a large supply of glucose, oxygen, and a good blood supply along the entire length of the neuron, including the spinal cord. Also, intense energy metabolism produces waste products, including “free radicals.” These molecules contain oxygen with unpaired electrons, similar to carbon monoxide produced in fires. Free radicals, left unchecked, steal electrons from DNA and other components of cells, causing damage and cell death.
To neutralize free radicals, the body contains a wide variety of anti-oxidant compounds that prevent this cell damage and death. When free radical production overwhelms antioxidant production, this is called “oxidative stress.” Antioxidant production can also be impaired by genetic mutations, such as the SOD1 gene present in some types of familial ALS.
So ALS can be triggered by extreme voluntary overuse of muscles for a prolonged period (sporadic ALS), or defective genes that produce antioxidants (familial ALS). The result is massive motor neuron cell death.
Massive motor neuron cell death then triggers the immune reaction that opens up the Blood Brain Barrier (BBB) and presents the systemic immune system with dead nerve cell antigens that sometimes triggers an autoimmune reaction. This includes the production of antibodies within 2 weeks, similar to a vaccination (immunization). I call this the “Immunization Event.”
To understand this, it’s useful to study a disease called “Sympathetic Opthalmia.” In this disease, a penetrating injury to one eye can lead to the autoimmune destruction of the other eye, sometimes after a prolonged delay.
Sympathetic ophthalmia (SO) is a bilateral diffuse granulomatous intraocular inflammation that occurs in most cases within days or months after surgery or penetrating trauma to one eye. The incidence of SO ranges from 0.2 to 0.5% after penetrating ocular injuries and 0.01% after intraocular surgery. Vitreoretinal surgery and cyclodestructive procedures are considered risk factors. The time from ocular injury to onset of SO varies greatly, ranging from a few days to decades, with 80% of the cases occurring within 3 months after injury to the exciting eye and 90% within 1 year.
With sporadic ALS, the cell death presumably is caused by overuse of voluntary motor neurons. Cell damage is more likely in older age groups because of reduced blood supply, and reduced muscle mass (sarcopenia).
After the Immunization Event, systemic immune cells (B lymphocytes) are ready to immediately produce massive numbers of anti motor neuron antibodies the next time there is a large number of neurons dying. When this happens and the BBB opens up again, antibodies start attacking motor neurons. Systemic macrophages rush in through the open BBB to remove the dead neurons. But unlike brain microglia, systemic macrophages also destroy adjacent neurons in the tightly packed spinal cord tracts, starting the vicious cycle of ALS progression.
It’s possible that the Immunization Event can immediately lead to Initiation of ALS if it lasts long enough. I suspect this may be more common with the familial forms of ALS.
The body produces two steroid hormones in the cortex (outer layer) of the adrenal gland, which sits on top of the kidney. Aldosterone, a mineralocorticoid, causes retention of sodium (and excretion of potassium) by the kidney, leading to fluid retention.
Cortisol, a glucocorticoid, raises blood glucose (sugar) by stimulating the breakdown of protein. Cortisol, and most synthetic glucocorticoids, also have mineralocorticoid effects. (Dexamethasone has no mineralocorticoid effects, so it doesn’t cause fluid retention and brain swelling).
My theory is that adrenocorticoids evolved to help animals survive in drought and starvation conditions. Fluid retention is helpful when there is no water to drink, and converting protein to glucose prolongs survival when there is no food to eat.
In addition to triggering the conversion of muscle protein to glucose, glucocorticoids also block the immune system from using scarce protein and energy to create new immune cells. This is what produces the immunosuppressive effects of corticosteroids.
To control infection without immune cells, glucocorticoids also trigger vasoconstriction, reducing blood flow and isolating infections during periods of starvation. This effect can reduce swelling and pain, but when the high glucocorticoid levels are reduced, it leads to increased swelling, inflammation, and increased pain. In other words, glucocorticoids are strong pain relievers with a severe withdrawal syndrome, similar to narcotics.
Thus, treatment of ALS with high doses of glucocorticoids relieves symptoms by relieving pain, swelling and inflammation. But reduction of the dosage causes rebound ALS symptoms that are worse than before treatment. Prolonged high dose corticosteroids don’t work for ALS because the severe side effects eventually become life threatening.
But very low dose corticosteroids have never been tested before. All it does is stop new motor neurons from dying, thus halting the progression of the disease pathology. It doesn’t improve symptoms, and symptoms can still get worse from other factors ( i.e. fear of falling, cold weather, anxiety, depression, prolonged bedrest ).
Triamcinolone, betamethasone, and dexamethasone are “fluorinated” steroids. Only dexamethasone is widely available orally. The fluorine atom disables the mineralocorticoid effects of dexamethasone, which is very important to prevent brain swelling.
Blood Brain Barrier (BBB)
This video clip illustrates how the tight junctions of the BBB endothelial cells open up and let a systemic immune cell into the brain by amoeboid motion.
Steroids Rapidly Restore Blood-Brain Barrier Function After Blast
The photos above show stained ZO-1 BBB tight junction “glue” protein
A) Normal – Note the stained filaments that make up the BBB tight junctions
B) Injured – Note the absence of filaments
C) Injured treated with dexamethasone – Note restored filaments
D) Injured but dexamethasone blocked by RU486 – Note absence of filaments
Development, Maintenance and Disruption of the Blood-Brain Barrier
This article shows that the BBB is damaged in ALS even before any symptoms of ALS are detectable.
“Mice expressing mutant SOD1 have leaky barriers at their blood-brain and blood-spinal cord interfaces at disease onset, and increased neurovascular permeability has also been detected in patients with ALS”
Astrocyte Endothelial Interactions At The Blood Brain Barrier
This article shows the anatomy of the BBB, including the all important tight junctions between endothelial cells lining brain capillaries that prevent systemic immune cells from entering, and damaging the tightly packed brain neurons.
Lipoic Acid Affects Cellular Migration into the Central Nervous System and Stabilizes Blood-Brain Barrier Integrity
This article shows that Alpha Lipoic Acid (ALA) may be helpful in stabilizing the BBB, in addition to dexamethasone. I’ve included ALA in the protocol.
Microglia vs Systemic Macrophages
This video clip shows brain microglia in cell culture attacking bacteria by extending thin filament “arms.” This is a more delicate process that doesn’t damage surrounding neurons.
And the video below shows systemic neutrophils (similar to macrophages but smaller) moving through amoeboid motion to attack bacteria. Note how they shove other cells aside. These systemic cells are normally prevented from entering the brain by the BBB. With ALS, the opening of the BBB allows these cells in, where they destroy adjacent axons in the spinal cord leading to progression of ALS symptoms.