~Amyotrophic Lateral Sclerosis (ALS), Part 2 - Diagnosis and Treatment

~Amyotrophic Lateral Sclerosis (ALS), Part 2 - Diagnosis and Treatment
Differential Diagnosis
  • Physical Causes
  • Infectious Diseases
  • Enzyme Disorders
  • Other Neurological Diseases
  • Endocrine Disorders
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 SOD, hexosaminidase A, and alpha-glucosidase
  • Other neurologic al diseases such as Pick's disease and Kennedy's syndrome
  • Endocrine disorders including diabetic amyotrophy and thyrotoxicosis
Physical Causes

Compression of the Cervical Spinal Cord

An 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.

Infectious Diseases
  • Lyme Disease
  • Post-Poliomyelitis
  • HIV Infection
  • Neurosyphilis
Lyme Disease. 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 burgdorferi) spread by a deer tick (Ixodes dammini). The first stage of Lyme disease is present with a fever, enlarged lymph glands, and a characteristic bulls-eye pattern around the bite (Hansel et al. 1995).

Post-Poliomyelitis. 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 that there is a malfunction in the medulla oblongata, a structure important for collections of nerve cells lying anterior to the cerebellum (Roos et al. 1980; Onion 1998).

HIV Infection. 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 et al. 2000).

Neurosyphilis. 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.

Enzyme Disorders
  • Superoxide Dismutase
  • Hexosaminidase A
  • Alpha-Glucosidase
Superoxide Dismutase (SOD). Familial ALS is an autosomal dominant genetic disorder. It is caused by a defect on the gene encoding SOD on chromosome 21 (SOD1).

Hexosaminidase A. 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 (Eisen et al. 1987; Harrison 1998).

Alpha-Glucosidase. 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 ( Harrison 1998).

Other Neurological Diseases
  • Pick's Disease
  • Kennedy's Syndrome
Pick's Disease. 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. Kennedy's syndrome is an X 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.

Endocrine Disorders
  • Diabetic Amyotrophy
  • Thyrotoxicosis
Diabetic Amyotrophy. 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 the numbness and paresthesia of the hands and feet. Diabetic amyotrophy causes progressive muscle wasting, usually of the pelvic girdle and large muscles in the upper leg. Anorexia and depression may accompany amyotrophy.

Thyrotoxicosis. Thyrotoxicosis refers to the effects of excessive quantities of thyroid hormones in tissues found in patients with severe hyperthyroidism and Graves 's disease. Symptoms include feeling hot and sweaty, palpitations, frequent diarrhea from impaired digestion of fats, and a prominent essential tremor.

Assessment

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 thyroid-stimulating hormone (TSH), T3 and T4
  • Hormone panel, including testosterone, dehydro-epiandrosterone (DHEA) and pregnenolone
  • Hexosaminidase A in urine warranted when adult Tay-Sachs is suspected
  • Vitamin B12 levels 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
Treatment

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 independent for as long as possible.

Counseling can 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 his/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 15-30 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 hook-up to a ventilator should be considered.

Medications
  • Baclofen (Lioresal)
  • Tizanidine (Zanaflex)
  • Tricyclic Antidepressants
  • Rilutek (Riluzole)
Various medications can be given to the patient as ALS progresses.

Baclofen (Lioresal). Baclofen (Lioresal) is used to relieve stiffness in the limbs and throat. Patients with seizure disorder or impaired renal function should use caution. Serious adverse reactions include somnolence and stupor, cardiovascular collapse, seizures, and respiratory depression. Common adverse effects include headaches, dizziness, blurred vision, slurred speech, rash, weight gain, pruritus, constipation, and increased perspiration. Excessive dosing may lead to weakness. Baclofen may interact with alcohol, monoamine oxidase inhibitors (MAOI), narcotics, antipsychotics, tricyclic antidepressants, oral hypoglycemics, or insulin.

Tizanidine (Zanaflex). Tizanidine (Zanaflex) is a centrally acting muscle relaxant. Zanaflex may interact with alcohol (to increase somnolence, stupor) and oral contraceptives (to decrease its clearance). Zanaflex can increase hypotensive effects when administered concurrently with diuretics. Elderly patients and patients with impaired renal function should use caution. Serious reactions include hallucinations, severe bradycardia, and liver toxicity. Common adverse effects include dryness of mouth, somnolence and sedation, dizziness, malaise, constipation, increased spasms, and hypotension.

Tricyclic Antidepressants. Tricyclic antidepressants may be used to control the production of excess saliva.

Rilutek (Riluzole). Rilutek (Riluzole), the only FDA-approved drug to treat ALS, reduces the presynaptic release of glutamate. Riluzole is metabolized in the liver. It is contraindicated with active liver disease or elevated liver function tests (serum glutamic pyruvate transaminase [SGPT] or alanine aminotransferase [ALT] and glucose tolerance test [GTT]). Theophylline and caffeine may affect rate of elimination. Riluzole treatment may be associated with mild blood pressure elevation (Scelsa et al. 2000).

Unfortunately Riluzole, although described in medical journals as an effective treatment for ALS, provides almost no benefit and is associated with significant side effects in most patients. One journal noted, "It is often said that the benefits of riluzole are marginal but the side effects are major. " One writer commented, " c C learly, Riluzole does succeed at one important task. It allows treating physicians to end the day assured that they did something for the ALS patients they were treating since a prescription was written--an obligation was thus fulfilled" (Rowland 1996; Ludolph et al. 1999; Perlmutter 2000).

Drug Research
  • NMDA receptor antagonists
  • Growth Factors
  • Other Drugs
Several drugs are being studied for treatment of ALS (Hurko et al. 2000). These include:
  • N-methyl-D-aspartate (NMDA) receptor antagonists m e i mantine and dextr o a methorphan
  • Growth factors such as insulin-like growth factor-I, nerve growth factor, leukemia inhibiting factor, ciliary growth factor, pigment epithelium-derived factor, neurturin, and transforming growth factor-beta
  • TR500, a glutathione-repleting agent
  • Deprenyl, a selective monoamine oxidase B inhibitor
  • Pimozide, a voltage-dependent calcium channel blocker
  • Gabapentin, an antiseizure drug made from gamma-aminobutyric acid (GABA)
NMDA receptor antagonists
  • Memantine
  • Dextroamethorphan
Memantine. Memantine is an NMDA receptor antagonist that has been approved for use in the treatment of dementia in Germany for more than 10 years. NMDA receptor antagonists have therapeutic potential in numerous CNS disorders. Memantine does not have the side effects common to other NMDA receptor antagonists such as dizocilpine (Parsons et al. 1999; Jain et al. 2000). Memantine will be available in the U.S. in 2004 pending FDA approval. is not available in the United States.

Dextroamethorphan. Dextroamethorphan is an NMDA receptor antagonist that is being explored for use in ALS. Preliminary studies, however, did not find positive effect (Askmark et al. 1993).

Growth Factors
  • Insulin-like Growth Factor I
  • Nerve Growth Factor
  • Leukemia Inhibitory Factor
  • Ciliary Neurotrophic Factor
  • Pigment Epithelium-derived Factor
  • Neurturin
  • TGF-Beta
Insulin-like Growth Factor I. Some authors have reported decreased IGF-I in patients with ALS (Eisen et al. 1993; Dore et al. 1996; Torres-Aleman et al. 1998). IGF-I receptors are present in the spinal cord where they mediate signal transduction via tyrosine kinase. IGF-I was found to prevent the loss of choline acetyltransferase activity in embryonic spinal cord cultures, as well as to reduce the programmed cell death of motor neurons in vivo during normal development or following axotomy or spinal transection. Clinical trials of recombinant human IGF-I have been initiated for patients with ALS (Lewis et al. 1993).

One study examined the cost effectiveness of treatment with recombinant human insulin-like growth factor I (rhIGF-I) in patients with ALS. They conclude that treatment with rhIGF-I is most cost effective in ALS patients who are either in earlier stages of the disease or progressing rapidly. The cost effectiveness of rhIGF-I therapy compares favorably with treatments for other chronic progressive diseases (Ackerman et al. 1999).

A double-blind, placebo-controlled, randomized study of 266 patients was conducted at eight centers in North America . The authors concluded that rhIGF-I slowed the progression of functional impairment and the decline in health-related quality of life in patients with ALS with no medically important adverse effects (Lange et al. 1996; Lai et al. 1997). A European placebo-controlled trial of IGF-I in ALS, however, showed no significant difference between treatment groups (Borasio et al. 1998).

Nerve Growth Factor. A moderate reduction in beta-nerve growth factor (beta-NGF) levels was seen in the serum of patients with ALS and multiple sclerosis. There was a statistically significant reduction in the patients who were carriers of Parkinson's disease and Huntington's disease (Lorigados et al. 1998).

Leukemia Inhibitory Factor. Leukemia inhibitory factor (LIF) was named after its effect on hemopoietic (blood-forming) cells. Studies have demonstrated a powerful effect of LIF in the survival of both motor and sensory neurons, while reducing denervation-induced muscle atrophy. LIF will also stimulate muscle regeneration in vivo when applied exogenously after injury. A human recombinant form of LIF (AM424) entered human clinical trials during 1998 (Kurek et al. 1998).

Ciliary Neurotrophic Factor. Ciliary neurotrophic factor is currently in clinical trials for the potential treatment of motor neuron disease or ALS (Lindsay 1994).

Pigment Epithelium-derived Factor. Pigment epithelium-derived factor (PEDF), a natural substance produced by the body, was located for the first time in the spinal cord and skeletal muscles of humans, monkeys, and rats. Previously, scientists believed that PEDF was found only in the pigmented layer of cells beneath the retina. Using slices of rat spinal cords kept alive in culture, PEDF showed a dramatic ability to protect cells from the toxic effects of threohydroxyaspartate (THA), a chemical that mimics the effects of ALS, causing slow death of motor neurons. The PEDF-treated sections showed a near normal neuron count compared with untreated cultures. According to Dr. Ralph Kuncl, who led the Johns Hopkins research team, protection of the spinal cord nerves in culture by PEDF was nearly complete. He went on to state that ". .. If we had this same level of protection in patients with ALS, they'd experience slight muscle weakness at most." The effectiveness of PEDF will be tested next on transgenic mouse models.

Neurturin. The same research team reported on another natural compound known as neurturin, a neurotrophic substance that will stimulate regeneration of damaged nerve cells. Neurotrophic factors, including PEDF and neurturin, are believed to protect healthy cells from the damaging effects of glutamate, a neurotransmitter that gluts the spaces between motor nerve cells, causing over - stimulation and contributing to the progression of the disease. Although Riluzole mildly restrains the immediate release of glutamate, it provides minimal protection to motor neurons as do PEDF and neurturin. The researchers predict the development of an "ALS cocktail," drug combinations containing neurotrophic factors, "each working at a different point in the process" (Bilak et al. 1999).

TGF-Beta. In a commentary, Miller and Ragsdale of the University of Chicago discuss the function of transforming growth factor-beta (TGF-beta) in the programmed death, or apoptosis, of nerve cells. TGF-beta is part of a family of growth factors by the same name that are involved in many biological functions in all of the body's tissues, such as embryonic development, reproduction, and wound-healing (Miller et al. 2000).

In a study reported in the same issue, chick embryos were immunized to neutralize the three forms of TGF-beta during the restricted period of embryonic development in which 50% of the neurons that have formed experience apoptosis. Neuron death was halted in all of the cells that were destined to die, which included central nervous system motor neurons and peripheral nervous system autonomic neurons. It is possible that TGF-beta works only on those neurons that will die, acting in a way that permits rather than instructs the cells to die. In other circumstances TGF-betas may enhance neuron survival. Researchers, led by Krieglstein of the University of Saarland at Homburg , Germany, concluded that TGF-beta could function as a molecular switch, which determines the life and death of neurons (Krieglstein et al. 2000).

The authors of the commentary state that the findings may have important implication for diseases, such as ALS, which is characterized by the death of motor neurons and may involve programmed cell death. Spinal cord trauma may involve neuron death by apoptosis as well. The removal of TGF-betas may be able to reduce the death of neurons and prevent some of the disability associated with this and other conditions.

Other Drugs
  • TR500
  • Deprenyl
  • Orap (Pimozide)
  • Neurontin (Gabapentin)
TR500. TR500, a glutathione-repleting agent, is being studied for use in ALS (Hurko et al. 2000).

Deprenyl. Deprenyl (Eldepryl, selegiline hydrochloride), a selective monoamine oxidase B inhibitor, is partially effective in Parkinson's disease and can slow the cognitive deterioration in Alzheimer's disease. Studies of its use in ALS, however, did not show any significant improvement (Kuhn et al. 1996; Lange et al. 1998). Deprenyl is available from offshore pharmacies for personal use only.

Orap (Pimozide). Orap (pimozide) is a voltage-dependent calcium channel blocker that is being explored for use in ALS. One study showed a significant decrease of the index of progression of the disease in Pimozide-treated patients compared to selegiline and vitamin E. In a randomized trial 44 patients, diagnosed as either definite or possible ALS, were treated with 1 mg a day of Pimozide for 3-12 months. Statistical analysis showed a significant decrease of the index of progression of the disease in Pimozide-treated patients as compared to the others (Szczudlik et al. 1998).

Neurontin (Gabapentin). Neurontin (Gabapentin) is derived from GABA. Gabapentin prevents seizures in a wide variety of models in animals, including generalized tonic-clonic and partial seizures. In vitro, Gabapentin modulates the action of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD), and the glutamate synthesizing enzyme, branched-chain amino acid transaminase. Results with human and rat brain NMR spectroscopy indicate that Gabapentin increases GABA synthesis. In vitro, Gabapentin reduces the release of several monoamine neurotransmitters (Taylor 1997; Taylor et al. 1998).

Unfortunately gabapentin was found to provide no evidence of a beneficial effect on disease progression or symptoms in patients with ALS in a Phase III randomized double-blind placebo trial (Miller et al. 2001).

Continued . . .


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