Chronic Neurotoxic Syndromes

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The Detox System...

Detoxification of Bio-toxins in Chronic Neurotoxic Syndromes

 

By , M.D., Kane, Ph.D., Neal Speight, M.D.

Chronically ill individuals suffering from neurotoxin exposure impacts patient

populations with CFIDS, Fibromyalgia, MS, Autism, Cardiovascular Disease,

Depression, Rheumatoid Arthritis, IBS, Infertility, ALS, Parkinsons, Lyme, Toxic

Building Syndrome, Estuary Associated Syndrome, Psychosis, Diabetes without

family Hx, Optic Neuritis, Refractory Heavy Metal Toxicity, Pulmonary

Hemorrhage, Stroke. Patients diagnosed with these chronic illnesses may be

potentially classified as 'Neurotoxic Membrane Syndrome' (NMS) with the

endothelial cell membrane as the target of degeneration.

While hypercoagulation involves a myriad of proteins, it is ultimately a

membrane event, essentially disrupting the phospholipids that structure the

membrane. Agglomeration (blocked cellular exposure to blood flow/nutrients and

impaired cell-to-cell communication) indicates elevation of phospholipase A2 and

the uncoupling of eicosanoids from the cell membrane causing inflammation. The

agglomeration that eventually occurs is, in essence, a product of a weakened

membrane, and ultimately a disturbed red cell fatty acid profile.

Clinical Research

We have established a biomedical protocol in our clinics, The Haverford Wellness

Center in Havertown, PA and The Center for Wellness in Charlotte, NC for

patients with neurotoxic illness. Our biomedical approach is an attempt to reach

the systemic nature of these tenacious neurotoxic syndromes and provide

clinically proven methods that eradicate neurotoxins. Our course of action is

that of freeing the patient of pervasive symptoms of neurotoxic illness in a

non-invasive manner that heals the membrane, and ultimately the body and brain.

The recent pioneering work of Ritchie Shoemaker, M.D., as communicated in his

book Desperation Medicine and his peer reviewed papers (Shoemaker 2001), lends

strong support to a connection between Chronic Fatigue Syndrome, Fibromyalgia,

Lyme Disease, Pfiesteria infection and that of numerous Neurotoxic Syndromes.

Biotoxins as Neurotoxins

The presentation of biotoxin exposure often parallels neurological and

psychological impairment due to the interrelationship between the ENS (Enteral

Nervous System) and the CNS. The biliary tree, gall bladder, and bile formation

within the liver serve in the vital processes of detoxication (disposal of waste

products bilirubin, heavy metals, biotoxins, xenobiotics), lipid metabolism,

transport and digestion (bile acids). Abnormalities of the hepatobiliary system

may involve biliary stasis whereby infectious material or biotoxins reside

within the liver, biliary tree and gall bladder, as a viscous suspension in

biliary sludge.

Biotoxins as bacteria, viruses, parasites, spirochetes, dinoflagelletes, and

fungus may be within biliary sludge often creating neurotoxins impacting the CNS

via the ENS, or the Second Brain (gut). The occurrence of biliary sludge may be

due to prolonged fasting, low fat intake, high carbohydrate diets or exposure to

pathogens. Restriction of dietary fat may impair biliary flow which would be

contraindicated in attempting to clear toxicity as bile is paramount to

cleansing the body and getting biotoxins and heavy metals excreted into the

fecal matter.

Neurotoxins are minute compounds between 200-1000 KD (kilodaltons) that are

comprised of oxygen, nitrogen and sulfate atoms arranged in such a way as to

make the outside of the molecule fat loving and water hating. As such, once it

enters the body, it tends to bind to structures that are rich in fat such as

most of our cells, especially the liver, kidney, and brain. Neurotoxins are

capable of dissolving in fatty tissue and moving through it, crossing cell

membranes (transporting against a gradient, particularly with potassium)

disrupting the electrical balance of the cell itself.

As fat soluble neurotoxins move through the cells of the body from the GI tract

to sinus to lung to eye to muscle, to joint to nerve, whereby they eventually

enter the liver and the bile. Once neurotoxins bind with bile they have access

to the liver, the body is poisoned over and over again as the bile is

re-circulated (first released into the intestine to digest fats, and then

reabsorbed).

Neurotoxins cause damage by disrupting sodium and calcium channel receptors,

attacking enzyme reactions involved in glucose production thereby disrupting

energy metabolism in the cell, manufacturing renegade fatty acids as saturated

very long chain, odd chain and branched chain fatty acids impairing membrane

function, stimulating enzymes (PLA2) which uncouple essential fatty acids from

the cell membrane and impairing the function of the nuclear receptor PPAR gamma

which partially controls transcription (the conversion of instructions held in

our DNA to RNA which then leads to translation or protein production in the

cell).

Heavy Metals reside in Fatty Tissue with Bio-toxins

Heavy metals are also lipid soluble and often compound the removal of biotoxins

(Aschner et al 1990, 1998; Dutzak 1991). As has been observed by many

clinicians, often as the patients' heavy metal toxicity is addressed they are

faced with the additional complication of the presence of biotoxins. Biotoxins

and heavy metal exposure co-exist within the cell membrane and fatty tissue

requiring consideration for both types of toxicity in regard to patient

intervention.

By stabilizing glutathione we in turn impact metallothionein markers (Nordberb

and Nordberb 2000, Ebadi et al 1995, Sato et al 1995, Kerper et al 1996, to

et al 1998), glycoaminoglycans or GAGS (Klein 1992), methylation, sulfation,

hepatic and renal function as we introduce treatment protocols for detoxication

with gentle, natural modalities that unload cellular toxicity safely. GSH

infusion by fast IV push has been a remarkable tool to unload the body burden of

heavy metals and neurotoxins in both pediatric and adult populations, without

side effects.

Renegade fatty acids as Neurotoxin Markers

Renegade fats as very long chain fats (VLCFAs) that are over expressed, disrupt

the membrane structure. There is a beautiful geometry to the membrane that is

highly sensitive to the size of the lipid chains. The overall width of the fatty

acid portion of the membrane is ~3 ½ nm which must be maintained for stability.

Saturated or monounsaturated fatty acids with a length of 16 or 18 carbons and

polyunsaturated fatty acids of 18 to 22 carbons are preferred to permit the

structure to maintain optimal horizontal fluidity. VLCSFAs that range from 20 to

26 carbons force the parallel dimensions vertically. There simply is not enough

room.

The distortion weakens the phosphate bonds that derive their strong attraction

only as long as the phospholipids are parallel to each other on both sides of

the membrane. The cell weakness is then expressed in leaky attraction to ion

channels and receptors which marginalize cell cytosol fluids and electrolytes

with the only option as early cell death.

The Brain is Comprised of 60% Fat

To view the brain beyond its architecture as a biological orchestration of the

physical and chemical constituents necessary for performance, we cannot begin to

conceptualize without considering the importance of fatty acids as the human

brain is 60% lipid. Dendrites and synapses are up to 80% in lipid content.

Although Arachidonic acid (AA) has been given a negative association, it is the

most prominent essential fatty acid in the red cell and comprises 12% of the

total brain and 15.5% of the body lipid content.

If AA is depleted by overdosing with marine or flax oil establishing the balance

of the EFAs is profoundly impaired. Often both prostaglandin one and two series

relating to omega six metabolism are compromised when flax and marine oils are

overdosed or lipid intake is insufficient. When AA, the lead eicosanoid of the

body, is suppressed due to excess intake of omega 3, toxicity or disease the

control circuitry of the body is impaired as is clearly viewed in the patient's

presentation.

Arachidonic acid is preferentially wasted in states of heavy metal toxicity

(Tiin and Lin, 1998) and has been observed to be sharply suppressed in RBC lipid

analysis in states of heavy metal toxicity (Kane, clinical observation

1997-2002).

The fatty acid cleaving enzyme PLA2

In states of toxicity via biotoxins or heavy metals there is a dramatic

elevation in Phospholipase A2 (PLA2) activity (Verity et al 1994) Increases in

PLA2 activity result in premature uncoupling of the essential fatty acids (EFAs)

from phospholipids in the cell membrane. Accelerated loss of EFA places the

patient in a severely compromised position as that of inflammation which results

from the promiscuous release of AA in the presence of an overexpression of PLA2.

Carbohydrate consumption, as one of the most profound stimulators of PLA2, must

be restricted to control the insulin response and the subsequent loss of EFAs.

Phospholipids and Neurons

Phospholipids, cholesterol, cerebrosides, gangliosides and sulfatides are the

lipids most predominant in the brain residing within the architectural bilayers

(Bazan et al 1992). The phospholipids and their essential fatty acid components

provide second messengers and signal mediators. In essence, phospholipids and

their essential fatty acid components play a vital role in the cell signaling

systems in the neuron. The functional behavior of neuronal membranes largely

depends upon the ways in which individual phospholipids are aligned,

interspersed with cholesterol, and associated with proteins.

All neurotransmitters are wrapped up in phospholipid vesicles. The release and

uptake of the neurotransmitters depends upon the realignment of the phospholipid

molecules. The nature of the phospholipid is a factor in determining how much

neurotransmitter or metal ion will pass out of a vesicle or be taken back in.

Phospholipid re-modeling may be accomplished by supplying generous amounts of

balanced lipids and catalysts via nutritional intervention and the use of

intravenous Phospholipid Exchange (IV Phosphatidyl choline).

Hypercoagulation and Membrane Integrity

An undesirable course of events in an exposure to biotoxins is agglomeration in

a hypercoagulation state. The distorted membrane with its weakened structure and

almost absolute reduced fluidity is powerless to resist coagulation. A highly

fluid membrane would kick off an accumulation of oxidized cholesterol; it would

not permit it to attach. This is not the case when the membrane is compromised,

as in much of the patient population affected with neurotoxic illness.

Hypercoagulation is predominantly a non-regulated mass of proteins disrupting

function. When referencing the artery; hypercoagulation invariably involves the

plasmic side of the cell and if endothelial cells of the vascular system are

targeted by a toxin (virus, neurotoxin, metal, antibody, etc) , restriction of

blood flow ultimately results. If a neuron is targeted then signaling is

disrupted. The presence of neurotoxins invariably involves PLA2, which is the

" sergeant at arms " monitoring cell membrane health. A membrane

disturbance(unwanted mass) would trigger PLA2, which hydrolyses the release of

eicosanoids, which would then induce inflammation and call to attention the

clean-up committee, i.e. macrophages.

Hypercoagulation is a restrictive agglomeration, (mass) that occurs principally

on the membrane of endothelial cells blocking the flow of vital fluids, blood,

bile, etc., with a high causal relationship to oxidation, and equally to

toxicity, quite often neurotoxins. Oxidized LDL (Sobel et al 2000) is

predominantly a membrane disturbing event agglomerating and attaching to

endothelial cells, while neurotoxins can move through the lipid membrane and

attack the cell itself.

The Liver as the Center of the Storm

Unhealthy bacteria have been known to colonize the liver and its biliary system.

These bacteria as well as viruses, spirochetes, dinoflagellates, and the like

can synthesize very long chain saturated or renegade fats (Harrington et al

1968, Carballerira et al 1998) that lead to liver toxicity, biliary congestion,

impairment of prostaglandin synthesis and the release of glutathione (Ballatori

et al 1990). Lipids vibrate in the cell at millions of times/second. The double

bonds of the omega 6 and omega 3 lipids are the singing backbone of life

expressed through their high energy level.

These bonds are their vibratory song, and they absolutely carry a tune befitting

every act and function in the exercise of life, providing all 70 trillion of our

cells their flexible nature. When renegade fats are over represented in the cell

membrane they result in off key expression, and if strong enough, may spell

cellular death and apoptosis. Healing the outer leaflet of the membrane

(Schachter et al 1983), comprised primarily of phosphatidylcholine, with

phospholipid therapy, is our highest priority in addressing chronic illness and

hypercoagulation.

The Visual Contrast Sensitivity Test

Our clinical approach is to first confirm that neurotoxin mediated illness could

in fact be a problem for the patient via the Visual Contrast Sensitivity test

that isolates deficits in velocity of flow in retinal capillaries. If the

patient scores poorly on this test then the evaluation may include screening for

cytokine elevations followed by coagulation and red blood cell lipid testing

through s Hopkins/interpretation through BodyBio. (For pediatric patients

the Heidelberg Retinal Tomogram Flow Meter Evaluation may be performed in place

of the Visual Contrast Test by an ophthalmologist.)

Neurotoxins and Cytokines

Once neurotoxins enter the cell they move toward the nucleus turning on

indirectly the production of cytokines such as TNF alpha, IL6, and IL-1Beta

(Shrief and 1993, Tsukamoto 1995, Abordo et al 1997,Rajora et al 1997,

Brettelal 1989, Hassen et al 1999, son 2001). TNF alpha will stimulate

macrophages in the body (macrophages) to become active. The white cells are also

induced to gather in the area of the cytokine (TNF alpha) release.. In addition,

TNF alpha induces endothelial cell adhesion.

Endothelial cells which line the blood vessels of the body become " sticky " in

conjunction with the increase in white cells. Increased blood viscosity results

in restricted blood flow in neurotoxic patients leading to fatigue and

discomfort, and quite possibly disturbed toxic photoreceptor lipid structures

that become compromised with subsequent reduction in visual performance.

The cellular impact of biotoxin and heavy metal burdens results in disturbed

prostaglandin synthesis, poor cellular integrity, decreased GSH levels (DeLeve

and Kaplowitz 1990, Dentico et al 1995, Hayter et al 2001, Miles et al 2000,

Nagai et al 2002, Zalups and Barfuss 1995, Watanabe et al 1988, Fernandez-Checa

et al 1996), significant suppression of omega 6 arachidonic acid and marked

elevation of Renegade fats and ultimately with demyelination (depressed DMAs).

The presence of VLCFAs are evidence of peroxisomal dysfunction and suppression

of the beta oxidation of lipids and cellular respiration.

Renegade fats (VLCSFAs, Odd Chains, Branched Chains) are represented as an

increase in fat content in the brain as discovered in stroke patients examined

by Stanley Rapoport, Chief of the Laboratory of Neuroscience at the NIH..

Biotoxins and heavy metals are lipid soluble thus the effect upon cellular

processes and hepatobiliary function is often gravely deranged. Often, patients

do not possess a gross burden of toxins but rather a burden that has a finite

impact upon the cell by blocking receptor sites such as G proteins, which act as

a relay system through the cell.

Peroxisomes, most prevalent in the liver and kidney, are organelles within the

cell that play a crucial role in clearing xenobiotics and the third phase of

detoxification. Peroxisomes are intimately involved in cellular lipid metabolism

(Bentley et al 1993, Mannaerts and Van Veldhoven 1992, Luers et al 1990, Leiper

1995) as in the biosynthesis of fatty acids via ß-oxidation involving

physiologically important substrates for VLCFAs, thromboxanes, leukotrienes and

prostaglandins.

The creation of a prostaglandin is an oxidative event (Diczfalusy 1994).

Inappropriate use of antioxidants (mega-dosing) will inhibit ß-oxidation, the

production of prostaglandins and cellular metabolism, thus the liberal use of

potent antioxidants would be contraindicated in the buildup of Renegade fats as

VLCFAs, Odd Chain and Branched Chains (Akasaka et al 2000) which are the

hallmark of toxicity (Kane and Kane 1997, Kane 1999, Kane 2000, Roels et al

1993, Rustan et al 1992).

Peroxisomal oxidation enzymes are suppressed by elevation of cytokines such as

TNFalpha (Beier et al 1992). Individuals with immune, CNS, cardiac, GI and

endocrine disorders often present with complex xenobiotics involving

disturbances in the cytochrome P450 superfamily (hepatic detoxification

difficulties) which parallels disturbances in peroxisomal function.

The cytochrome P450's are responsible for the biotransformation of endogenous

compounds including fatty acids, steroids, prostaglandins, leukotrienes and

vitamins as well as the detoxification of exogenous compounds resulting in

substantial alterations of P450s (Guengerich 1991) as xenobiotics may turn off

or greatly reduce the expression of constitutive isoenzymes (Sharma et al 1988).

Targeted Nutritional Intervention for Toxicity

Inadequate stores of arachidonic acid can compromise P450 function (McGiff

1991). Oral application of hormones such as pregnenolone, DHEA (Di Santo et al

1996, Ram et al 1994, Rao et al 1993) or thyroid stimulate peroxisomal

proliferation and the ß-oxidation of Renegade fats as would nutrients

(riboflavin, pyruvate, manganese) and oxidative therapies.

Anti-oxidants slow cellular metabolism and must remain in the proper balance

with all the essential nutrients and substrates (lipids, protein) to maintain

metabolic equilibrium. Removal of renegade fats in the diet is accomplished by

the avoidance of mustard, canola oil (Naito et al 2000), peanuts and peanut oil

which contain VLCSFAs that can challenge patients with liver and CNS toxicity.

The oral use of butyrate, a short 4-carbon chain fatty acid, is of striking

benefit (Fusunyan et al 1998, Segain et al 1983, Yin et al 2001) in mobilizing

renegade fats, lowering TNFalpha, sequestering ammonia, and clearing biotoxins.

In states of toxicity it is paramount to stabilize omega 6 fatty acids and the

lead eicosanoid (Attwell et al 1993) Arachidonic acid (AA) before introducing

omega 3 lipids. There exists a crucial balance between omega 6 and omega 3 fatty

acids in human lipid metabolism which has only recently been brought into

clearer focus through the work of Yehuda (1993, 1994, 1995, 1998, 2000, 2002).

His development of the SR-3 (specific ratio of omega 6 to omega 3) has revealed

that the optimum ratio of omega 6 to omega 3 FAs is 4:1.

AA, the lead eicosanoid, must be stable first along with the other w6 EFAs

before w3 fatty acids are introduced and balanced. Clinicians are often met with

poor patient outcomes when merely administering omega 3 lipids without first

introducing omega 6 fatty acids, stabilizing the structural lipids, increasing

the fat content of the diet, stimulating the ß-oxidation of renegade fatty

acids, flushing of the gall bladder/biliary tree and supporting digestion of

fats with bile salts and lipase.

The manipulation of lipid distortion involves two basic essential fats: omega 6

and omega 3. The body loses its ability to metabolize fats in states of toxicity

and therefore becomes depleted in the eicosanoids and prostaglandins. Essential

fatty acids are the precursors to the regulatory prostaglandins which are " local

hormones " providing the communication controlling all cell to cell interactions.

The human cell membrane cannot be supported nor its function controlled without

respect to lipid substrate, yet fatty acid metabolism has been poorly delineated

in the medical literature.

An optimum balance of fatty acids make up the dynamic membrane. The membrane of

every living cell and organelle is composed of two fatty acid tails facing each

other. This bilipid layer is so minute (3.5 nanometers) that it would take

10,000 membranes layered on top of each other to make up the thickness of this

paper. Yet the dynamics that occur within this tiny envelope with organelles

prancing up and down the cytoskeleton microtubules is a microcosm that is a

challenge for the human mind to envision. Mercury toxicity damages the

microtubule structure of the cell. All cells must synthesize molecules and expel

waste.

All cells must create, through gene expression, the proteins needed for cellular

gates embedded in the membrane as ion channels and receptors. The ultimate

control of how those peptides behave rests with the character of the membrane

while the integrity of the membrane rests with the structural (oleic, stearic,

palmitic, cholesterol) and essential lipids (omega 6, omega 3).. Without control

of membrane function through lipid manipulation, detoxication is compromised. In

essence, the life of the cell is intimately tied to health of the membrane and

the health of the entire organism.

Our clinical protocol is to initiate treatment with changing the patients'

overall diet, addressing the lipid balance and especially the outer lipid

leaflet of the cell membrane through fatty acid therapy and the addition of

supplementation targeted towards dissolving fibrin, clearing the liver/biliary

tree, and healing the cell membrane. Patient progress is evaluated through the

Visual Contrast Test and repeat lab evaluation.

Blood thinning agents such as Heparin and Warfarin increase blood flow around

the blocked endothelium, however, reconstituting membrane fluidity can directly

address coagulation in a natural restorative way. Vibrant healthy membranes will

not permit agglomeration. The high polyunsaturated lipids with a preponderance

of phosphatidylcholine on the plasmic surface precludes undesirable clumping to

occur. Treatment modalities should address dissolving fibrin and healing the

cell membrane.

Spreading Infection

It has been suggested that the use of heparin will address hypercoagulation..

Recent data from JAMA (son 2001) indicates that the use of low dose

heparin may transform a 'benign fungal infection into a toxic shock-like

reaction'. This research was presented at the 39th annual meeting of the

Infectious Diseases Society of America in 2001 by Margaret K. Hostetter, M.D. of

Yale University School of Medicine (Hostetter 2001 and San-Blas et al 2000).

Hostetter and colleagues found that Candida albicans can attach to host cells

and form invasive hyphae. Low dose heparin utilized in procedures for

hospitalized patients through the practice of heparin in intravascular catheters

may transform C. albicans into a life-threatening pathogen. Hostetter was able

to identify a gene, INT1, encoding a C. albicans surface protein, Intlp, which

was linked with adhesion, the ability to grow filaments and ultimately virulence

of C. albicans of a systemic nature.

The use of heparin raises the cytokines TNF alpha and IL-6 (son 2001) in

addition to Phospholipase A2 (Mudher et al 1999; Kern et al 2000; Farooqui 1999;

Verity et al 1994). Biotoxins which form neurotoxins, may create a state of

hypercoagulation from the rise in TNF alpha. Consequently, the use of heparin

may exacerbate the hypercoagulation and the neurotoxic condition. The source of

the problem- biotoxins, which have formed neurotoxins creating a state of

hypercoagulation, must be addressed from the context of the underlying

neurotoxic condition and healing the cell membrane.

Evidence Based Clinical Protocols

By stabilizing lipid status with intravenous Phospholipid exchange and oral EFA

supplementation we have remarkable tools to unload the body burden of

neurotoxins ( et al 1982, Cariso et al 1983, Jaeschke et al 1987, Kolde

et al 1992) in both pediatric and adult populations, without side effects. Oral

use of phospholipids in a Liver Flush is also an effective intervention in

addressing neurotoxic syndromes.

Through isolating individual fatty acids and dimethylacetyls in red cells we can

now examine the cellular integrity/structure, fluidity, the formation of

renegade fats that impair membrane function, myelination status, and the

intricate circuitry of the prostaglandins. The systemic health of the individual

patient may reached and targeted nourishment utilized through evidence based

intervention which may yield positive patient outcomes.

Healing the membrane is virtually…healing the brain.

> References for this Article

Neal Speight, M.D. may be reached at Center For Wellness in Charlotte, NC.

Kane, Ph.D. at the Haverford Wellness Center in Havertown, PA. or to

obtain the 'The Detoxx Book: Detoxification of Biotoxins in Chronic Neurotoxic

Syndromes' at 888.320.8338 or 856.825.8338

 

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" I know of nobody who is purely Autistic or purely neurotypical. Even God had

some Autistic moments, which is why the planets all spin. " ~ Jerry Newport