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By Ronald Steriti, NMD, PhD
Amyotrophic lateral sclerosis (ALS) is also known as Lou Gehrig’s Disease, which was one of baseball’s greatest players. He earned the title “Iron Horse” for his record of 2,130 consecutive games. His outstanding record was ended by ALS.
ALS is a rapidly progressive neuromuscular disease caused by the destruction of nerve cells in the brain and spinal cord. This causes loss of nervous control of the voluntary muscles, resulting in the degeneration and atrophy of the muscles. Eventually the respiratory muscles are affected which leads to death from an inability to breath.
ALS symptoms vary from one person to another according to which group of muscles is affected by the disease. Tripping, dropping things, abnormal fatigue in the arms and/or legs, slurred speech, difficulty in talking loudly, uncontrollable bouts of laughing or crying, and muscle cramps and twitches are all symptoms of ALS. ALS usually starts first in the hands and will cause problems in dressing, bathing, or other simple tasks. It may progress to more on one side of the body and generally proceeds up the arm or leg. If it starts in the feet, walking will become difficult. ALS can also start in the throat, causing difficulty with swallowing.
People afflicted with ALS do not lose their ability to see, hear, touch, smell, or taste. The bladder and muscles of the person’s eyes are not affected, nor are sexual drive and function. The disease does not affect the person’s mind.
Men make up the majority of those who contract ALS, although women also get the disease. Race, ethnicity, or socioeconomic boundaries make no difference as to who will come down with ALS. Most of those who get the disease are usually between the ages of 40 and 70, but people in their 20s and 30s can also get it. In most societies, there is an incidence of five in every 100,000 people. [1] [2]
The rate of progression of the symptoms of ALS varies for each person. The average life expectancy for a newly diagnosed person is 2 to 5 years, although improved medical care is resulting in persons living longer. ALS frequently takes its toll before being diagnosed, causing the people who have the disease to be significantly debilitated before they learn they have it.
There are three types of ALS: sporadic, familial, and Guamian. The most common form is sporadic. A small number of cases are inherited genetic disorders (familial). A large number of cases, however, occur in Guam and other Pacific territories.
The familial type of ALS is caused by a genetic defect in superoxide dismutase, an antioxidant enzyme that continuously removes the highly toxic free radical, superoxide. The causes of sporadic and Guamian ALS are unknown. Several hypothesis have been proposed including:
Glutamate is the main excitatory neurotransmitter in the brain. It has been calculated that glutamate is responsible for 75% of excitatory neural transmissions. Glutamate is unique in that it can produce such marked stimulation that neurons die. It has been proposed that the neuronal damage following ischemia (deficiency of blood, for example after a stroke) is due to the action of glutamate, rather than to a lack of oxygen. [3]ALS is highly linked with glutamate. One proposed mechanism is a defective glutamate transport system that permits neurotoxic levels to build up. [2] A recent study published in the Journal Brain Research Bulletin showed significant elevations (by about 70%) of plasma levels of glutamate in ALS patients as compared to controls. [4]
Oxidative stress refers to a shift in the ratio of oxidants to antioxidants in the body. Free radicals are molecules that have an unpaired electron: a highly unstable state. Most free radicals react with molecules that contain oxygen to form reactive oxygen species, such as nitric oxide (NO), superoxide (O2-), and hydroxyl (OH-). Free radical damage is associated with many degenerative conditions, including neurological disorders. [5] [6]
Antioxidants inhibit oxidation by free radicals. There are many types of antioxidants, including:
Inflammation represents a major source of oxidants. Inflammation is often caused by bacterial or viral infections, toxic exposure and trauma. The continuous production of reactive oxidant species during chronic inflammation may deplete the store of antioxidants eventually resulting in a spiral from health to disease. [5]
Mitochondria are the power-generating units of the cell and are most developed where energy-requiring processes take place (for example, in muscles). The outer membrane of the mitochondria is studded with oxidative enzymes that provide raw materials for the reactions occurring inside. In the interior, the citric acid cycle converts carbohydrates into energy releasing carbon dioxide. The energy produced by this reaction is used to form the high-energy phosphate compound ATP (adenosine triphosphate) in a process called oxidative phosphorylation. ATP is the principal energy source for both plants and animals. Mitochondrial DNA is transmitted solely from the mother. [3]
Mitochondrial dysfunction has been linked to neurodegenerative diseases. [7] [8] Defects in mitochondrial DNA have also been proposed as a causative mechanism in sporadic ALS. [9] [10] [11]
One study explored the role of mitochondrial dysfunction by transferring mitochondrial DNA from ALS subjects to normal human neuroblastoma cells (embryonic cells that form nervous tissue) with their mitochondrial DNA removed. The resulting hybrid cells exhibited abnormal electron transport chain functioning, increases in free radical scavenging enzyme activity, perturbed calcium homeostasis, and altered mitochondrial structure.
The title “Iron Horse” given to Lou Gehrig is quite appropriate in a biochemical sense. The energy forming process of oxidative phosphorylation relies heavily upon transferring electrons between several iron molecules that form the electron transport chain. The oxidative phosphorylation process also requires coenzyme Q, NAD (nicotinamide or niacinamide adenide dinucleotide) and FAD (flavin adenide dinucleotid). Niacin (vitamin B3) is used to form NAD or Riboflavin (vitamin B2) is used to form FAD.
Autoimmunity may play a role in ALS. In this disease, the immune system becomes confused and begins attacking tissues in the body. Under normal conditions, the body’s immune system produces proteins called immunoglobulins which attach to their target antigen. An antigen is a substance that produces an immune response and is usually something foreign to the body. The immunoglobulins attach to and surround the target antigen forming an antigen-antibody complex. This complex is then ingested by phagocytes such as macrophages in a process called phagocytosis.
In autoimmune disease, antibodies are produced that attach to the tissues of the body, instead of foreign substances. The following are examples of diseases with an autoimmune basis:
In autoimmune hemolytic anemia, the body produces autoantibodies to red blood cell membrane proteins.
In diabetes mellitus, autoantibodies are formed against insulin receptors.
Grave’s disease is associated with autoantibodies to thyroid stimulating hormone (TSH) receptors.
Pernicious anemia can be caused when autoantibodies are formed against intrinsic factor which is needed for vitamin B12 absorption.
Researches have proposed that ALS may have an autoimmune basis. The following are the basis for their hypothesis:
Analyses of ALS patient sera have identified circulating antibodies secreted by denervated muscle. These antibodies inhibit the stimulation of the sprouting of axons, the long arms of neurons which conduct nervous impulses to other neurons throughout the body. [2]
Researchers have found an immunoglobulin that affects the conductance of neuronal voltage-activated calcium channels which may induce an excessive release of glutamate from nerve endings. [2]
Several studies of ALS patients found the presence of antibodies that interact with motor neurons. [12] [13-15]
Immune complexes have been found in spinal cords of patients with ALS.
It has been proposed that T cells, activated microglia, and immunoglobulin G (IgG) within the spinal cord lesions may be the primary event that leads to tissue destruction in ALS.
The increased prevalence in Guam is associated with a decreased delayed hypersensitivity. The secondary response, which occurs with the second exposure to the antigen, is normally quicker and usually produces more antibodies than the primary response. The major reason for the enhanced secondary response is the formation of B memory cells during the primary response. [2]
In a recent study, a family history of thyroid disease was present in 19% of ALS patients, and an additional 21% of patients described family members with other possible autoimmune disorders. In 19% of the patients with ALS, either past or present thyroid disease was documented. Eleven of 47 additional patients with ALS had significant elevations of microsomal and/or thyroglobulin antibody levels. [16]
Amyotrophic lateral sclerosis was once thought to be caused by persistent viral infection. [17] This hypothesis fell out of favor when researchers could not isolate a single causative agent. Recently, however, many researchers are reconsidering infectious agents, particularly since many neurodegenerative disorders are associated with chronic infections, particularly latent viruses. Support for the continued investigation of infectious agents in ALS include:
People with a history of exposure to agricultural chemicals, including fertilizers and pesticides used in gardening and lawn care, may be at twice the risk for developing ALS. [22] [23]
Chemicals foreign to the body are called xenobiotics. They include toluene, xylene, hexanes, benzene, trichloroethane, styrene, phylates and pesticides. Most xenobiotics are lipophilic, which means that they are attracted to the fats (lipids) which comprise cell membranes. Since the brain is full of lipids, xenobiotics are able to rapidly diffuse across cell membranes into the brain and cause neurological symptoms.
Many pesticides are specifically designed as neurotoxins (toxins that affect the nervous system.) Pesticides are generally odorless and can cause progressive symptoms weeks after an exposure. [24] [25] [26]
Xenobiotics are removed from the body by a process called detoxification, which takes place in two phases. Phase I takes place inside the cell and changes the toxic chemicals into less toxic forms by means of the chemical processes of oxidation, reduction and hydrolysis. Phase II detoxification then attaches molecules such as glutathione, methionine and sulfur compounds in a process called conjugation. The body is then able to excrete these modified toxins in stool, urine or sweat.
The process of detoxification requires several nutritional cofactors including magnesium, zinc and manganese. The glutathione, methionine and sulfur molecules used in conjugation are used up in the process. As the detoxification pathways become overloaded any further toxic challenge, however slight, can cause symptoms. This is often referred to as chemical sensitivity.
Chemically sensitive people experience symptoms to a variety of chemical insults. Caffeine (the active component of coffee), aspirin and acetaminophen (Tylenol) are often used to assess the functional capacity of the detoxification system. Alcohol is metabolized in Phase I by aldehyde dehydrogenase. Gasoline fumes, deodorizers, rubber, and solvents are sources of benzene. Trichloroethylene, if blocked from the normal Phase I pathway, will form a toxic secondary metabolite called chloral hydrate, the so-called “Mickey Finn”, which causes disorientation and dizziness.
Toxic chemical exposure may be one reason why there is a higher incidence of ALS diagnosed in soldiers that participated in Operation Desert Storm. On April 6, 2000, the Associated Press reported that the Veterans Administration announced a year-long study to determine whether there is a higher incidence of Lou Gehrig's disease (amyotrophic lateral sclerosis or ALS) among the veterans of the Gulf War. At least 28 Gulf veterans have been diagnosed with this deadly disease. Researchers are interested in locating other veterans diagnosed with ALS or other motor neuron diseases that were actively serving duty between August 2, 1990 and July 31, 1991, regardless of location. Those who did not go to the gulf area will serve as part of the control group. Eligible veterans may call 1-877-342-5257 [27]
Because there are high numbers of ALS patients in Guam, Western New Guinea, and Japan, there is a theory that ALS might be caused by environmental problems. These areas have large amounts of heavy metals such as lead, mercury, and aluminum. These metals can poison the body and cause ALS symptoms. [28] [29] [30]
Lead was used as an additive to gasoline and in many paints. Absorption of lead is enhanced by dietary deficiencies in calcium, iron, and zinc. Lead toxicity is most likely related to its affinity for cell membranes and mitochondria, where it interferes with several important enzymes.
In adults, systemic lead poisoning causes abdominal and joint pain, fatigue, anemia, and neurologic symptoms including headaches, irritability, peripheral motor neuropathy, short-term memory loss and an inability to concentrate. Chronic subclinical lead exposure affects the kidneys causing interstitial nephritis, renal tubular damage (with tubular inclusion bodies), hyperuricemia (with an increased risk of gout), and a decline in glomerular filtration rate and chronic renal failure.
An article published in the journal Neurology suggests that there may be an association between ALS in men and exposure to lead vapor. [29]
Mercury exposure is thought to occur from ingestion of contaminated fish, particularly tuna and swordfish, which can concentrate methyl mercury at high levels; inhalation of mercury vapor from dental amalgams; and possibly from drinking water contaminated by toxic waste sites.
Chronic mercury exposure produces a characteristic intention tremor and a constellation of findings including excitability, memory loss, insomnia, timidity, and sometimes delirium. The neurotoxicity resulting from organic mercury exposure is characterized by paresthesia (an abnormal touch sensation often in the absence of external stimulus); impaired peripheral vision, hearing, taste, and smell; slurred speech; unsteadiness of gait and limbs; muscle weakness; irritability; memory loss; and depression. Dentists with occupational exposure to mercury score below normal on neurobehavioral tests of motor speed, visual scanning, verbal and visual memory, and visual-motor coordination. [1]
Amyotrophic lateral sclerosis was diagnosed in one patient after accidental injection of mercury. [31]
It is well known that the selenium decreases the toxicity of mercury in the human body. After measuring the mercury and selenium content in the hair of 13 ALS cases, one study concluded that mercury with low content of selenium might be one of the environmental factors involved in producing ALS. [32, 33] [34]
High levels of aluminum are found in the delicate threads running through the cytoplasm of nerve cells (neurofibrillary tangles) in the cerebral cortex and hippocampus of patients with Alzheimer’s disease. High levels of aluminum has also been found in the drinking water and soil of areas with an unusually high incidence of Alzheimer’s disease. [1]
Aluminum and calcium deposits were found in the neurons of patients with amyotrophic lateral sclerosis of Guam. [35]
Manganese toxicity can cause a Parkinson-like syndrome within 1 to 2 years, including gait disorders; postural instability, a masked, expressionless face; tremor; and psychiatric symptoms.
Manganese is emitted from the tail pipes of motor vehicles. [36] Occupational exposure can occur in miners, dry-battery manufacturers and arc welders. [1]
A recent study showed that the nitrated manganese-superoxide dismutase level was strikingly elevated in amyotrophic lateral sclerosis patients. The authors also proposed that nitration of manganese superoxide dismutase in cerebrospinal fluids is a marker for oxidative stress in neurodegenerative diseases. [37]
It is proposed that chronic environment deficiencies of calcium and magnesium may result in increased intestinal absorption of toxic metals and lead to the mobilization of calcium and metals from the bone and deposition of these elements in nervous tissue. This hypothesis, called metal-induced calcifying degeneration of CNS, has been supported by experimental studies using several animal species. [38]
Low calcium/magnesium intake with excess amounts of aluminum and manganese are associated with the incidence of amyotrophic lateral sclerosis (ALS) in the Western Pacific. The authors conclude that the high incidence of ALS in the Western Pacific may be due to calcium/magnesium metabolism dysfunction resulting in excess deposition of aluminum. [39, 40]
Over the last 30 years glucose intolerance has been reported in a significant percentage of patients with amyotrophic lateral sclerosis (ALS). Currently, a controversy exists in determining whether the carbohydrate abnormality is disease-specific or secondary to decreased glucose utilization due to muscle atrophy. One study showed that the glucose infusion rate, an estimate of in vivo insulin sensitivity, was significantly diminished in ALS patients compared to both normal and disease controls which suggests that ALS may be associated with a dysfunction in carbohydrate metabolism. [41] [42] [38]
A lack of trophic (growth) factors support has been hypothesized as a probable cause of ALS. Several growth factors have been identified, including insulin-like growth factor 1 (IGF-I), nerve growth factor (NGF), Leukemia inhibitory factor (LIF), and ciliary neurotrophic factor (CNF). More specific information can be found about these growth factors in the New Drug Section.
Because the course of ALS is fatal within 3-5 years, a careful differential diagnosis is needed. The following should be considered (Harrison 1998):
Physical causes such as compression of the cervical spinal cord
Infectious diseases such as Lyme disease, post poliomyelitis, HIV infection
Enzyme disorders in superoxide dismutase, hexosaminidase A, and alpha-glucosidase
Other neurologic diseases such as Pick’s disease and Kennedy’s syndrome
Endocrine disorders including Diabetic amyotrophy and Thyrotoxicosis.
Compression of the cervical spinal cord
A MRI of the head and cervical spine is usually ordered for patients with lower neurological disease to rule out compression of the spinal cord and impingement along the spinal nerves.
The second and third stages of Lyme disease are associated with neurological changes that may cause an axonal, lower motor neuropathy. Lyme disease is caused by the bacterial spirochete (Borrelia burgdorfere) spread by a deer tick (Ixodes dammini). The first stage of Lyme disease presents with fever, enlarged lymph glands and a characteristic bulls-eye pattern around the bite. [43]
Polio is an enterovirus, a genus that preferentially inhabits the intestinal tract. Reactivation of a central nervous system polio infection (post-poliomyelitis) may cause a delayed deterioration of motor neurons and muscular atrophy including difficulty in swallowing (dysphagia) from bulbar involvement. Bulbar involvement indicates there is a malfunction in the medulla oblongata, a structure important for collections of nerve cells lying anterior to the cerebellum (Onion 1998) [44]
HIV infection is associated with extreme immune system dysfunction. HIV-1 proteins Tat and gp120 have been implicated in the pathogenesis of dementia associated with HIV infection. (Jain, Parsons et al. 2000)
Tertiary syphilis is seen 3-4 years after the primary infection with the spirochete Treponema pallidum. It is often seen in AIDS patients. Tertiary syphilis usually presents with hypersensitivity reactions since few organisms are present. Tabes dorsalis is associated motor and sensory losses in the lower extremities which causes difficulties in coordination.
Familial ALS is an autosomal dominant genetic disorder. It is caused by a defect on the gene encoding superoxide dismutase on chromosome 21 (SOD1).
Tay-Sachs disease and Sandhoff’s disease are autosomal recessive genetic disorders resulting from a deficiency of hexosaminidase and the accumulation in lysosomes (small bodies in cells involved in the process of intracellular digestion) of GM2 gangliosides, particularly in the central nervous system. Motor weakness, progressive ataxia and lower motor neuron symptoms predominate in the adult form. The patients often report clumsiness in childhood and motor weakness in adolescence. The diagnosis is established by visualizing cytoplasmic bodies by electron microscopy or by detecting reduced hexosaminidase-A activity in white blood cells. [45] [1]
Accumulation of glycogen in lysosomes in Pompe’s disease is due to deficiency of a specific enzyme, alpha-glucosidase. The juvenile form is characterized by progressive proximal muscle weakness, including impairment of respiratory function. [1]
Pick’s disease exhibits a progressive atrophy of the frontal and temporal lobes of the brain. Swollen neurons called Pick cells and argentophilic (attracted to silver) neuronal inclusions known as Pick bodies affect the frontal and temporal cortical regions.
Kennedy’s syndrome is an X-linked, lower motor neuron disorder in which progressive weakness and wasting of limb and bulbar muscles begins in males in adult life. Kennedy’s syndrome is associated with androgen (testosterone) insensitivity manifested by excessive growth of the male breasts (gynecomastia) and reduced fertility.
Neuropathy is a common clinical manifestation associated with diabetes. The most common presentation is that of peripheral polyneuropathy which is also referred to as “stocking and glove neuropathy” due to numbness and paresthesia of the hands and feet. Diabetic amyotrophy presents with progressive muscle wasting, usually of the pelvic girdle and large muscles in the upper leg. Anorexia and depression may accompany amyotrophy.
Thyrotoxicosis refers to the effects of excessive quantities of thyroid hormones in tissues found in patients with severe hyperthyroidism and Graves disease. Symptoms include feeling hot and sweaty, palpitations, frequent diarrhea from impaired digestion of fats, and a prominent essential tremor.
Neurologists use clinical tests such as blood testing, electromyograms (EMG), magnetic resonance imaging (MRI), CT scans, and nerve biopsies to establish a profile when diagnosing ALS. These profiles will eliminate other possibilities as to what the person might be suffering from. The following labs should be considered in the diagnosis of ALS:
Lyme disease serology
HIV testing
Autoimmune panel.
Thyroid panel, including TSH, T3 and T4
Hormone panel, including testosterone, DHEA and pregnenolone
Hexosaminidase A in urine is warranted when adult Tay-Sachs is suspected.
Vitamin B12 levels are also useful.
After the diagnosis of ALS has been confirmed, additional lab tests can be used to identify the predominant etiology and thus direct appropriate treatment. Additional labs would include:
A Comprehensive Detoxification Profile
Oxidative Stress Analysis
Mineral analysis, including Calcium, Magnesium, Copper and Zinc
Toxin analysis, including heavy metals and chemicals
Amino acid analysis
Many things can be done to improve or maintain the lifestyle of a person who is suffering from the disease. First, the patient should continue his or her usual daily activities, stopping just before getting tired. Physicians often recommend specific exercises, such as breathing exercises and/or exercises to strengthen the muscles that are not affected with the disease. Foot braces, hand splints, or wheelchairs, combined with exercise, will enable the patient to remain as independent as possible for as long as possible.
Counseling can be of help to ease the mental anguish brought on by this disease. Family counseling can also be helpful to the person with ALS as well as the family.
One of the side effects of this disease is uncontrolled muscle contractions or spasms. Physical therapy cannot restore normal muscle function, but may help in preventing painful contractions of the muscles and in maintaining normal muscle strength and function. The physical therapist should show family members how to perform these exercises so they can help maintain this therapy for the person with ALS.
Speech therapy may also be helpful in maintaining the person’s ability to speak. Swallowing therapy is important as well, to assist with the problems of swallowing and drinking. This treatment helps prevent choking. It is recommended that the patient adopt a new head posture and positioning of the tongue. The patient should also change the consistency of the food to aid swallowing accordingly as the disease progresses.
Occupational therapy is also important. The therapist will come to the person’s home and recommend where to move furniture to make it easier for the patient to move around her house. The therapist will also place kitchen appliances in areas where making meals will be easier. The occupational therapist will also bring devices that will help the person in making the telephone, computer, and other devices easier to use.
When the ability to breathe decreases, a respiratory therapist is needed to measure the breathing capacity. These tests should take place on a regular basis. To make breathing easier, the patient should not lie down immediately after eating. The patient should not eat large meals, because they can increase abdominal pressure and prevent the diaphragm from expanding. When sleeping, the head should be elevated 15 to 30 degrees to keep the abdominal organs away from the diaphragm. When breathing capacity falls below 70%, noninvasive respiratory assistance should be provided. This involves a nasal mask connected to a mechanical ventilator. When the breathing capacity falls below 50%, a permanent hookup to a ventilator should be considered.
Continue to Part 2 of the ALS Article
© 2002