A Course on Mood, Memory, and Brain Disorders
Case # 1
A 31-year-old woman presented with disabling chronic fatigue of 4-year duration which developed after a highly stressful personal circumstances. She was an active, healthy teenager. Her menarche was at 15, and her menstrual cycles were regular during the first few years. She was prescribed an oral contraceptive (exact type unknown to the patient) for severe PMS after a negative laparoscopy for suspected endometriosis. One year after the onset of disabling fatigue, she developed speech difficulty and facial numbness one week after receiving dental braces. Her neurologic symptoms subsided 6 weeks later. However, an MRI scan showed early demyelinating lesions. She discontinued wearing he braces 5 months later and remained free of symptom for one year. Her personal life became highly stressful again. Her neurologic symptoms recurred after dental “bleaching.” She consulted two neurologists who prescribed variously neurontin, carbamazapine, betaserone and interon at different times. Notwithstanding multiple attempts to control her progressive neurologic symptoms with drugs, her general condition deteriorated to a point that walking became very difficult, and had frequent falls. Other pertinent features of her past history included recurrent episodes of sinusitis, chronic constipation, dizzy spells, and cognitive difficulties. Soon after her cycles became irregular, occurring every five to seven months, with some periods of amenorrhea.
The pertinent laboratory data included the following: WBC, 5800; Hb, 15 g/dL; estradiol, 46.45 pg/mL; FSH, 3.6 mU/mL; LH, 5.7 mU/mL; prolactin, 5.3 ng/mL (all hormones values represent 12th day of the cycle); testosterone, 53 ng/dL; serum potassium, 3.2 mEq/L; ALT, 56 IU/L; PLF, 3+; (1+ four months after beginning the program); antinuclear and lyme antibodies, negative; T4, 6.7 ug/dL; T3 uptake, 1.02 uptake units; TSH, 1.12 uU/mL; cobalamine, 714 pg/mL; ferritin, 60.55 ng/mL; folate, 10.7 ng/mL;
A 24-hour urinary steroid analysis revealed markedly low to nondetectable values of several metabolites. Table 6 shows the steroid profile before and eight months after beginning an integrative plan.
Clinical Management and Outcome
Her intravenous therapies included the following: 23 hydrogen peroxide infusions, each with an intramuscular injection ( IM 6 or IM5 on alternate basis); 7 fatigue IV infusions; and 18 EDTA chelation infusions. After eighteen months of the program, she reported a “near complete” control of her neurologic symptoms and disabling fatigue. Her premenstrual symptoms were markedly reduced and her cycles approached a monthly rate. In spring of 1997, a 31-year-old woman was seen at the Institute for progressive fatigue, persistent muscle spasms, bladder control difficulties, numbness in legs and arms, dizziness, recurrent vaginitis, and oligomenorrhea. She had suffered from chronic constipation and mentioned that during her childhood and teenage years, “she was always sick with something.” In 1994, an MRI of head showed multiple white patches interpreted as demyelinating lesions. She had been given betaserone and interferone therapies which she tolerated poorly and without clinical benefits. Repeat MRI scans in 1995 and 1996 showed persistence of demyelinating lesions. Her mentation was well preserved. The examination of the head and neck and abdominal visceral was not remarkable.
Case # 2
In summer of 1992, a 46-year-old engineer came to the Institute in a wheel chair. He had a near total loss of muscle power in left arm and progressive muscular weakness of right arm and legs. His health had been generally very good until 15 months prior to the onset of his illness. He had been athletic, travelled extensively for his company, and lived an active life with his wife and two children before his illness. Muscles of both arms, hands, legs and feet showed moderate to advanced changes of muscle atrophy. His mentation was well preserved. The examination of the had and neck and abdominal visceral was not remarkable.
Questions for case 1 and 2
1. What are the differential diagnoses in case 1?
2. What are the differential diagnoses in case 2?
3. What is demyelination? Is it reversible?
4. How is the anterior horn cell disease diagnosed?
5. What are the salient histopathologic changes observed at autopsy when patients succumb to diffuse demyelination in the brain?
6. What are the salient histopathologic changes observed in the brain at autopsy when patients succumb to diffuse demyelination in the brain?
7. What are the salient histopathologic changes observed in the spinal cord at autopsy when patients succumb to anterior horn cell degeneration?
8. How detailed should be the study of an integrative physician of pathologic lesions in the above two disorders?
9. The patient in case 2 was enrolled in a drug trial for sixteen weeks. He reported that he was the only patient in a group of 13 patients he responded positively to the drug, though for a period of some weeks. He asks you if EDTA chelation that he received during that time might have something to do with that. How would you respond to him?
10. What prognosis would you offer to the patient in case 1?
11. What prognosis would you offer to the patient in case 2?
12. Write an integrative management plan for case 1.
13. Write an integrative management plan for case 2.
Case # 3
A 73-year-old man consults you for a stroke which left him with weakness of left side of the face, left arm, and left leg.
Questions for case 3
1. What are the differential diagnoses in case 3?
2. What changes in tendon reflexes would you expect?
3. What is encephalomalacia?
4. What is cerebral infarction?
5. What is cerebral ischemia?
6. What is reactive gliosis?
7. How do you clinically differentiate between cerebral hemorrhage and thrombosis?
8. Which one generally carries a better prognosis, cerebral hemorrhage or cerebral thrombosis??
9. What prognosis would you offer the patient if he came to you within 24 hours of his illness?
10 What prognosis would you offer the patient if he came to you within 7 days of his illness?
11. What prognosis would you offer the patient if he came to you after six months of his illness?
12 Would you recommend growth hormone for this patient? If so, why?
13. Write an integrative management plan for the patient in case 3.
Patterns of Neuronal Injury
Neurones are cells located in the gray matter and are either aggregated in nuclei, in layers as in six-layered cerebral cortex, or in columns. Neuronal reactions to injury occur as:
- axonal reaction after the axon is cut or otherwise injured represents a healing response characterized by rounding and enlargement of the cell, enlargement of the nucleus, and dispersion of the Nissl substance
- acute cell necrosis (red neurone) due to anoxia or dysoxygenosis
- atrophy of cells surrounded by areas of gliosiss (proliferation of the connective tissue of the brain parenchyma)
- neuronal degeneration surrounded by areas of gliosiss accumulation of oxidized and denatured lipid, protein, and carbohydrate complexes (i.e., lipofuscin)
Patterns of Glial Reactions
Glia is the stroma (the connective tissue scaffolding) of the brain parenchyma. It includes four types of cells:
- astrocytes are large cells with round to ova nuclei
- oligodendrocytes are smaller denser cells
- ependymal cells are columnar in shape, have ciliate borders, and line the inner surfaces of ventricles
- microglial cells that elongated, irregular nuclei.
In neuropathology and neurology texts, glia is delegated a largely structurally supportive role with participation in repair reactions. In my view, such thinking is very limited and is wholly inconsistent with the profound regulatory roles of the matrix in other tissues. In my view, glia foundational regulatory roles in health as well as in all pathophysiologic phenomena affecting the brain parenchyma. Though there is no direct evidence at this time to support my view, it seems safe to predict that future research will clearly show that to be the case.
Patterns of Neuronal Regeneration
Until recently, the prevailing belief in neurology was that neurone once damaged cannot repair themselves. Indeed, of all the body’s cells, neurones seem least capable of repair and regeneration when injured by neurotoxins, infectious diseases, stroke, or degenerative disorders. A spate of recent studies have clearly demonstrated the ability of neurones to regenerate. Still, neurones of neocortex—the region of the brain of greatest interest from the standpoint of functions involving mood, memory, and mentation—appeared not to participate in repair and regenerative functions. Now that also is changing. Consider the following:
“…when they induced certain neurones in the neocortex of adult mice to self-destruct, the loss triggered the formation of replacement neurons by brain stem cells. What’s more, the newly formed neurones migrated to the same position as their deceased predecessors.”
In the experimental cited above, opoptosis of neocortex cells was selectively induced with light-activated compound. The death of neocortical cells then triggered the multipotential neural precursor (stem) cells located in the subventricular zones to produce new neurons which then travelled to find their home in the area of dead cells and replaced them. The tracking of the new neurons was done by labelling those cells with a tracer chemical (5-bromodeoxyuridine). Further experiments with a dye demonstrated that the newly formed neocortical cells established the same functional axon connections to thalamus as the original cells.
1. Lasley EN. Death leads to brain neuron birth. Science 2000;288:2111-2.
2. Magavi S, Leavit B, Macklis J. Nature June 22, 2000
Oxidative-Dysregulative Perspective on the Patterns of Neuronal Degeneration
In my view, the molecular underpinnings of all types of toxic, metabolic, ischemic, degenerative, and infectious injuries to brain parenchyma involve oxidative-dysoxygenative phenomena. I draw this conclusion from the examination of experimental and clinical observations reported about the various clinicopathologic entities concerning the central nervous system. For example, the the genetic locus on chromosome 21 in familial AML appears to be the Cu/Zn-binding superoxide dismutase. Monoamine oxidase inhibitors are of limited benefits in the early stages. As for the common stroke, Alzheimer’s disease, and heavy metal toxicity, the oxidative-dysoxygenative nature of the nature is self-evident.
From the standpoint of integrative medicine, this is of paramount importance since it means all effective integrative therapies for brain disorders must be sharply focused on issues of oxidosis and dysoxygenosis.1
1. Ali M. Darwin, oxidosis, dysoxygenosis, and integration. J Integrative Medicine 1999;3:11-16.
The cranium has very limited expansible capacity. Furthermore, the brain has few, if any, demonstrable functioning lymphatic channels under ordinary conditions. Thus, the presence of very small amounts of excess fluid puts into serious jeopardy the physiologic as well as compensatory pathophysiologic processes. The junctions between the capillary endothelial cells and glial surfaces are tight and closely regulate the to and fro movement of fluid and solutes between the two compartments. That is the morphologic underpinning of the brain-blood barrier (BBB).
Cerebral edema is of three main types:
- vasogenic due to changes in permeability
- cytotoxic due to intracellular and extracellular fluid regulations
- interstitial edema that is regarded as transudate. All three types occur in acute oxidative-dysoxygenative lesions associated with infectious, toxic reactions, metabolic derangement, and malignant neoplasms.
As in the case of the pathophysiologic roles of the glia, there are major differences in the prevailing opinions in neurology and neuropathology on one hand and integrative medicine on the other. I believe cerebral edema plays a significant contributory role in the pathogenesis of many neurologic symptoms seen in fatigue/fibromyalgia complex and those associated with allergic reactions, chemical sensitivity syndrome, and environmental exposures as well as in hormone disorders, such as severe PMS, endometriosis, and others. The concept of brain allergy usually draws derogatory comments from most neurologists.
Perinatal Brain Injury
Cerebral palsy is an inclusive descriptive term for all forms of nonprogressive motor deficit of neurologic origin that develop during the perinatal period. It does not connote any etiologic factors. Some such cases are due to hemorrhage in the brain parenchyma, the region between the thalamus and cuadate nucleus being often involved. In other cases, microinfarcts occur in the periventricular white matter (periventricular leukomalacia).
encephalopathyudewith neurologic The cranium has very limited expansible capacity. Furthermore, the brain has few, if any, demonstrable functioning lymphatic channels under ordinary condition
Cerebral Ischemia and Infarction
The common term stroke refers to loss of neurologic function caused by death of brain cells due to hemorrhagic infarction (cerebral hemorrhage) or ischemic infarction (cerebral thrombosis). The term TIA (transient ischemic attacks) refers to temporary loss of some brain functions due to reversible ischemia, often caused by a spasm of cerebral arteries.
are characterized by damage to myelin sheath while the axon structure and function is relatively preserved (at least in the early stages), and include the following:
1. Multiple sclerosis
2. Neuromyelitis optica (Devic’s disease), mostly in Asians
3. Acute disseminated encephalomyelitis (ADEM)
4. Central pontine myelinolysis (thought to be related to rapid correction of hyponatremia)
Multiple Sclerosis (MS)
is the most common demyelinating disorders, and is an intermittent disorder characterized by episodes of neurologic deficits associated with discrete and noncontiguous demyelinating lesions of the white matter. In MRI scans, such lesions appear as “white” lesions. Most MS patients show monoclonal bands of proteins in cerebrospinal fluid specimens. There are known associations with several MHC antigens, including A3, B7, DR2, Dqwl, DQB1, and DQA1. Some reports point to polymorphims involving the alpha and beta subunits of the T-cell receptors. Both CD4+ and CD8+ lymphocytes are present in MS lesions.
The incidence of MS is 1 per 1000 persons in the United States and Europe and in, general, increases with distance from the equator. After migration, people take on the risk of the new geographic region.
I believe MS is largely a disease produced by mycotoxicity, with heavy metal and other types of toxicities playing secondary roles.
I base my opinion not only on the known geographical distribution of the disease but also on my observation that persons living in true desert environment (where there are no mold overgrowth) do not commonly suffer from MS.
Amyotrophic Lateral Sclerosis (ALS)
ALS is a very serious and a specific type degeneratory disorder characterized by loss of lower and upper motor neurons. Muscular atrophy, weakness, and fasiculations result from the injury to the former while muscle spasticity, hyperreflexia, and positive Babinski sign appear due to involvement of the former. Approximately 10% of cases seem to be familial. The genetic locus on chromosome 21 in such cases appears to be the Cu/Zn-binding superoxide dismutase.
In the nonfamilail types, a high prevalence of HLA-A3 and B12 haplotypes points to an underlying oxidative-immune diathesis. In animal studies, some plant-derived neurotoxins produced an ALT-like state.
I have observed limited clinical results with antioxidant and oxygenative therapies supported by strong bowel, blood, and liver detox measures.
Alzheimer’s Disease (AD)
AD is an insidious and a progressive disorder of intellectual impairment and changes in mood and memory. Severe cortical dysfunction can lead to a immobility and mutism. The incidence rises from the fifth decade of life steadily so that about 20% of persons over 75 years of age and 50% of those over 85 suffer from it. Five to ten percent of cases are thought to be familial in nature.
The salient gross pathologic changes include diffuse cortical atrophy with widened sulci and enlargement of ventricles. The major microscopic changes include:
a. Nurofibrillary tangles (bundles of basophilic filaments within the neuronal cytoplasm that displace the nucleus) and loss of neurones.
b. Neuritic (senile) plaques are composed of dystrophic neurites.
c. Amyloid angiopathy involving deposition in the vessel walls of amyloid beta peptide.
Considerable direct and indirect evidence points to the involvement of amyloid beta peptide and its precursor protein called APPin the pathogenesis of AD. APP has a large extracellular domain, a membrane-spanning region, and a short intracellular domain. Point mutations in genes coding APP have been identified. Under physiologic conditions, processing of APP includes cleavage of beta peptide to prevent production of insoluble aggregatesof mcromolecules that trigger the formation of amyloid material as well as neurofibrillary tangles.
In 1995, I proposed a hypothesis that AD results from oxidative injury to proteins as well as lipid and glycolipids in the brain parenchyma. Specifically, I hold that AD is essentially caused by oxidative injury to beta peptide and APP. Of considerable interest in the context is role of oxidative coagulopathy in pathogenesis of AD. Some isoforms of APP containing a domain called KPI (Kunitz protease domain) that exert regulatory influence in clotting cascades.
The following text reproduced from RDA: Rats, Drugs and Assumption (1995) may be of some general interest to the reader.
Oxidative Theory of Alzheimer’s Disease
Abnormal, oxidatively damaged proteins called beta-amyloid proteins occur in the brains of people who suffer from Alzheimer’s disease. The tangled fibers made up of such proteins literally choke the neurons and nerve fibers trapped in them. Such telltale signs of cell death are called neurofibrillary tangles or plaques. Four years ago, Yankner and co-investigators at Harvard Medical School published an important paper showing that beta-amyloid proteins indeed are toxic to nerve cells. Predictably, that report triggered a flurry of activity in the drug industry to develop drugs that inhibit plaque formation in the brain and prevent Alzheimer’s disease. There were the expected pronouncements of an imminent drug breakthrough for this dreadful disorder.
No one bothered to ask the basic question: If Alzheimer plaques are caused by oxidatively damaged proteins, why would any drug for this disease fare any better than thousands of other drugs that have failed miserably for other oxidative degenerative disorders in the past?
Alzheimer’s disease is a dreaded disorder that causes memory loss and dementia. This disease has a very strong link with high aluminum content of the brain tissue. The overload of neurotoxic metals such as mercury, lead, nickel and others can be fully expected to add to the injury caused by aluminum. Most people with Alzheimer’s disease also show evidence of poor circulation due to plaque formation in the brain blood vessels. In view of these considerations, what therapy can be expected to be most beneficial for patients with Alzheimer’s disease? A therapy that takes toxic metals out of the brain tissue and a therapy that improves the blood circulation to the brain. What therapy eminently accomplishes both goals? EDTA chelation therapy. Oops! Those chelation quacks again!
Is beta amyloid protein found in plaques of Alzheimer’s disease a product of oxidative damage to natural proteins present in the brain? Objective scientific evidence for this has not yet been published. So it remains speculative on my part at this time. However, I have absolutely no doubt that such evidence will be forthcoming with future research in this area.
The disease doctors of drug medicine do have a problem. When proteins are oxidatively damaged, they cannot be “un-oxidized” by drugs to undo the tissue damage caused by them. The only real chance we have of reversing such lesions is to prevent further oxidative damage and to facilitate recovery using Nature’s own way of replacing oxidatively damaged proteins with newly synthesized, unoxidized proteins. The problem for drug doctors is that such a philosophic approach is considered unscientific and so unworthy of the scientists at the National Institutes of Medicine (NIH). Why? Because quacks were there first. The NIH syndrome thrives in our universities.
is a clinical syndrome of flat facial affect (diminished expression), sluggish movements, stooped posture , and festinating gait (a “shuffling” walk with progressively shortened, accelerated steps). Following are principle entities included in Parkinsonism:
1. Idiopathic Parkinson’s disease
2. Striatonigral degeneration
3. Shy-Dager syndrome (associated with autonomic dysfunction (oxidative dysautonomia) with orthostatic hypotension).
4. Progressive supranuclear palsy
5. Drug-induced Parkinsonism, especially methyl phenyl tetrahydropyridine (MPTP) produced as a byproduct in illicit production of meperidine analogues
6. Postencephaltic Parkinsonism
The common pathogenetic mechanism in all involves injury to nigrostriatal dopaminergic system. Pathological features include pallor and depigmentation of substantia nigra and locus ceruleus. Histologically, there is loss of pigmented catecholaminergic neurons, gliosis, and presence in neurons of bright eosinophilic Lewy bodies.
Monoamine oxidase inhibitors are of limited benefits in the early stages. Stereotactic implants of fetal mesencephalic tissue into the striatum show some promise. Fetal cell injections with implants into the striatum tissue are also sometimes helpful for variable periods of time. Aggressive integrative detox, nutrient, and chelation therapy in early to moderate cases appear to give the best results.
1. Drilling of the occipital bone to relieve Budd-Chiari compression in fibromyalgia should not be unnecessarily deferred when indicated. F
2. The differential diagnoses of multiple sclerosis must include Lou Gehrig’s disease. F
3. Deep tendon reflexes are increased in areas affected by encephalomalacia. F
4. Deep tendon reflexes are increased in areas affected by cerebral hemorrhage. T
5. Cerebral infarction and cerebral ischemia are synonymous terms. F
6. Reactive gliosis is scarring in the brain parenchyma. T
7. Clinically differentiation between cerebral hemorrhage and thrombosis is sometimes extremely difficult. T
8. Ventricles in Alzheimer’s disease usually show contraction. F
10. Neurofibrillary tangles are pathognomic of Alzheimer’s disease. F
11. In general, cerebral thrombosis carries a better prognosis than cerebral hemorrhage. T
12. The long-term prognosis of patient with CVA likely to better if integrative intervention begins within hours of the stroke. T
13 Growth hormone is beneficial in most patients if administered soon after a CVA occurs. F
14. The neocortex has no demonstrated capacity for regeneration in mammals. F
15. Parkinsonism comprises a spectrum of clinical disorders with the dominant feature of memory loss. F
16. A hallmark of clinical diagnosis of Alzheimer’s disease is festinating gait (a “shuffling” walk with progressively shortened, accelerated steps). F
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