This article was sent to me by Sarita Agarwal, one of our members in India, and I think it would be useful to add to our archives--an excellent overview. Camilla Flintermann ----------------------------Original message---------------------------- Return-Path: <[log in to unmask]> <snip> ---------------------------------------- FOCUS ON . . . PARKINSON'S DISEASE by Lynn Wilson Understanding Parkinson's disease Parkinson's disease (PD) is a progressive neurological disorder that results from the degeneration of dopamine- containing neurons that project from the substantia nigra to the striatum in the region of the brain (the basal ganglia) involved in motor control. Symptoms -- tremor, muscular rigidity, and bradykinesia (slowness of movement) -- don't develop until the dopamine level has dropped to only 20% of normal. Approximately 500,000 Americans have been diagnosed with PD, and 40,000 new patients are diagnosed each year. Probably a million or more people actually have the disease; in many cases the general "slowness" attributed to old age may be an early symptom of PD. The average age of onset of PD is 57 years, although the distribution of onset follows a bell-shaped curve, with one- third of patients diagnosed before age 50, one-third between 50 and 60, and one-third over age 60. The disease typically starts with weakness in an arm or leg or a slight hand tremor, then progresses inexorably over the next few decades, to end in paralysis and often dementia, with early death. Classic signs include lack of facial expression, weak voice, drooling and choking due to difficulty swallowing, and festination (walking with small, shuffling steps). Patients also suffer from severe muscle pain (due to rigidity), gastrointestinal disturbances, insomnia, depression, and nightmares. Although PD was first identified in 1817, the cause is still unknown. People in rural areas are at higher risk of developing the disease than those in urban areas, perhaps because of exposure to pesticides, fungicides or herbicides through contaminated well water. There is also a microorganism in the soil -- Nocardia -- that may damage dopaminergic neurons. Other high-risk environments include regions surrounding petroleum plants and pharmaceutical manufacturing plants. Epidemiologists have noted that most PD patients have never smoked, and at least one study found a marked increase in the incidence of the disease among individuals with a history of mumps compared with those who never had mumps. PD is not generally regarded as a genetic disease, although patients may inherit a predisposition. Some 14% of PD patients have one or more first-degree relatives who have the disease or a related disorder, compared to 5% of controls. Onset before age 40 is more often associated with a family history. Disorders that may confuse the diagnosis include benign essential or familial tremor, a slowly progressive condition that usually develops in the fourth and fifth decades. Symptoms include a tremulous voice and shaky hands and/or head (the head may bob side to side or up and down). The typical parkinsonian rigidity, stiffness and bradykinesia do not occur. Hyperthyroidism can also cause tremor. Other more serious conditions that may mimic PD include Progressive Supranuclear Palsy, Shy-Drager Syndrome, and a series of strokes. Drugs that can induce parkinsonism include the antiemetic metoclopramide, the antiarrhythmic amiodarone, the antipsychotic agents haloperidol and chlorpromazine, and the antihypertensive agents reserpine, methyldopa, and certain calcium channel blockers (in particular cinnarizine and flunarizine, which are not available in the US). There was one case of captopril-induced parkinsonism that resolved on drug withdrawal. (Quinn N. Br Med J 1995;310:447-452. Calne DB. Calne DB. N Engl J Med 1993;329:1021-1027. Ed. UPF Newsl. 1995[1]:3.) --------------------- Pharmacotherapy of PD The mainstay of therapy for PD is levodopa combined with carbidopa (Sinemet/MSD); levodopa is converted into dopamine within the brain, while carbidopa prevents the peripheral breakdown of levodopa, thus effectively extending the duration of drug action. (Two related compounds in clinical trial -- entacapone and tolcapone -- also prolong the duration of levodopa action.) Unfortunately, levodopa almost always loses its efficacy over time (primarily because of disease progression) and administration is associated with significant side effects, including response fluctuations ("on-off" phenomenon), involuntary movements, peak-dose chorea, severe end-of-dose symptoms, and psychosis and hallucinations. The timed-release preparation of levodopa (Sinemet CR/MSD) helps smooth the response, although poor absorption of the first dose in the morning is not uncommon. Using the regular (short-acting) Sinemet in the morning followed by Sinemet CR later in the day may circumvent this problem. Second-line PD therapy involves the use of dopamine receptor agonists--bromocriptine (Parlodel/Sandoz), pergolide (Permax/Lilly)--which act directly on dopamine receptors. These agents may reduce the on-off oscillations, although therapeutic efficacy starts to decline in about six months, particularly in patients with more advanced disease. Using an agonist early in the course of disease allows dosage reduction and helps delay the onset of levodopa side effects. Several dopamine agonists are under clinical investigation, including ropinirole, terguride, talipexole, and cabergoline. Cabergoline is an exceptionally long-acting agonist in Phase III trials. It reduces the dose of dopamine required, and appears to be as effective as bromocriptine or pergolide, possibly with fewer associated side effects. Other dopamine agonists under investigation are (Am Acad Neurology 47th Annual Meeting in Seattle, 1995. Ed. UPF Newsl. 1995([2]:4. Calne DB. N Engl J Med 1993;329:1021-1027.) ---------------------------------------- Pharmacotherapy of ancillary PD symptoms PD patients have trouble with muscular function in general, which contributes to a variety of symptoms other than tremor, rigidity and bradykinesia. PD patients are particularly bothered by dysphagia (drooling, difficulty swallowing), nausea, delayed gastric emptying, and constipation. Foot cramps are another debilitating condition. There are a number of remedies for these problems, some pharmacologic, some not. For drooling and difficulty swallowing, sucking hard candy or chewing gum may facilitate the swallow reflex. Anticholinergics are not recommended because they make the saliva sticky. Nausea, delayed gastric emptying and constipation may respond to cisapride (Propulsid/Janssen), a prokinetic agent that accelerates gastric emptying and colonic transit. Exercise and a high-fiber diet also help. There are dopamine receptors in the gut, so delayed gastrointestinal transit may be due the same disease process on a local level. For foot cramps, muscle relaxants such as cyclobenzaprine (Flexeril/Merck) and baclofen (Lioresal/Geigy) may ease the pain. Since cramping can be due to either too much or too little dopamine (a peak-dose dystonia or a wearing-off effect), changing the Sinemet dose or dosage schedule or using the sustained release formulation may help. Some patients respond to the monoamine-oxidase B inhibitor selegiline (Eldepryl/Somerset) or to the dopamine agonists bromocriptine or pergolide. Injections of botulinum toxin (Botox/Allergan) into the cramping muscle can provide months of relief. Another common, and disabling, condition is depression. Some 40% of PD patients develop depression, whether endogenous (due to an imbalance of neurotransmitters) or exogenous (due to the stress of having a chronic debilitating illness). While often responsive to antidepressants, the drug of choice may be the antischizophrenic agent clozapine (Clozaril/Sandoz). Clozapine has proved to be highly effective in PD patients, reducing not only depression but also hallucinations and confusion. The drug is a dopaminergic antagonist but does not appear to interfere with antiparkinson drugs;, its antipsychotic effect is thought to be due to the blockade of a different configuration of the dopamine receptor than the one involved in PD. Side effects include sedation and orthostatic hypotension. Clozapine also causes bone marrow suppression (in 2% of patients), so weekly blood counts are necessary. Dosage reduction will reduce the risk of blood disorders, and low-dose therapy is still effective for psychotic depression. (Am Acad Neurology 47th Annual Meeting in Seattle, 1995. Ed. UPF Newsl. 1995([2]:4. Pfeiffer RF. UPF Newsl. 1994[4]:5-6. LeWitt PA. UPF Newsl.1993[3]:3-4. Gonski PN. Aust NZ J Med 1994;24:585. Gonski P. Lancet 1995 345:516-517.) ----------------------------------------------- Surgery: the remarkable efficacy of pallidotomy The most promising approach to the management of PD since the advent of levodopa therapy is a stereotactic surgical procedure called a pallidotomy. It involves destroying a sliver of neural tissue in the globus pallidus, a paired structure that serves as a relay station deep within the brain, coordinating signals from various parts of the brain that control movement and sensation. The globus pallidus on the left side of the brain controls the right side of the body, while the right pallidus controls the left side of the body. Decades ago, physicians noted that patients with tremor who suffered from a stroke located near a globus pallidus showed relief of tremor. An early pioneer, Russell Meyers, tried to treat 38 PD patients by severing nerve tracts near the globus pallidus; 25 patients showed improvement in PD symptoms, and six died. During the 1950s, Swedish neurosurgeon Lars Leksell found that by threading a probe into a specific part of the globus pallidus he could markedly improve all PD symptoms. Leksell did not publish his findings, but his protege Lauri Laitinen did. In 1992 Laitinen reported in the Journal of Neurosurgery that 92% of 38 patients who underwent pallidotomy had complete or almost complete relief of rigidity, while 81% had excellent or good long-lasting relief of tremor. (Laitinen LV et al. J Neurosurg 1992;76:53-61.) The report was enthusiastically received by the PD community and dozens of patients flew to Sweden for the operation. By mid-1995, Laitinen had performed more than 350 pallidotomies, with similar excellent results, particularly among the younger patients. A recent follow-up of Laitinen's first ten pallidotomy patients from 1985-1986 showed that nine were doing well. Recently, neurosurgeons in centers across the United States have begun offering pallidotomies, at a cost of $20,000 to $40,000 per operation (not covered by major Medicare contractors or HMO insurers). Despite the cost, there are year-long waiting lists at many centers. Robert Iacono of Loma Linda University in California has done around 500 operations, and reports restoring almost complete function to dozens of totally disabled patients. In an informal interview of 113 Iacona patients, 80% reported marked improvement after pallidotomy, with symptoms reduced by up to 100%. Only nine patients showed no response. Surgery is remarkably safe, recovery is rapid (1-2 days in hospital), and benefits are seen immediately. For the procedure, the head is immobilized in a cage-like frame, the globus pallidus is located by brain scan, the scalp is anesthetized, the skull is opened at the top through a hole in the frame, and a probe is inserted deep into the brain. An ultrashort-acting anesthetic is used for the mechanical portions of the procedure, but for the most part the patient is awake. Various techniques are used to pinpoint the globus pallidus. One technique uses sound. The patient is asked to make a movement (arm, hand or leg) that sounds a note through a loudspeaker. The sounds tell the neurosurgeons when they have hit the target, a bundle of neurons that connect the globus pallidus with the thalamus. (The thalamus is another relay center that directs signals to various regions of the brain and spinal cord. Thalamotomy is also an effective surgical procedure for PD, although benefits appear to be limited to tremor). When the probe is on target, the tip is electronically heated and it burns a tiny hole, producing an immediate improvement in symptoms. During surgery patients report that they feel a sudden release after being in a state of total rigidity, or that limbs that flopped continuously are suddenly stilled. Risks include brain hemorrhage (2-5% incidence), loss of speech, full or partial loss of vision (the lesion must be placed near to the visual tract), paralysis, and death. Not all patients respond to surgery, and in some patients the improvement is only temporary. Often symptoms are reduced rather than eliminated. Because the operation takes such a long time (up to 10 hours) pallidotomy is performed on one side at a time. Interestingly, 75% of patients report that a pallidotomy on one side of the brain benefits both sides of the body. However, patients are usually so pleased with results from unilateral pallidotomy that they opt to have surgery on the other side as well. At a recent annual meeting of the American Academy of Neurology in Seattle, neurosurgeons Enrico Tazzini (New York University), Jerrold Viteck (Emory University), and Anthony Lang (Toronto University) agreed that pallidotomy is highly efficacious, with nearly all patients showing long-lasting improvement. It is more effective in patients under age 70 who respond to levodopa but show severe fluctuations in response and disabling dyskinesias. It is less effective for freezing. One side effect is an increased incidence of falls, since surgery so improves function in one side of the body that the patient is assymetrical. Because pallidotomy offers relief of symptoms but is not a cure, patients remain on medication, although often at lower doses. In light of these new findings, researchers have speculated that dopamine is involved in a complicated inhibitory feedback loop. Lack of dopamine results in the loss of inhibition of neurons involved in the control of movement. A clinical study underway at Emory University will attempt to evaluate the risk/benefit ratio, determine what part of the globus pallidus should be destroyed for maximum relief, and find out how long benefits last. At Stanford University, researchers are working on a new "spatially correct" magnetic resonance imaging (MRI) scanner with pinpoint accuracy. Pallidotomy has been described as "a miracle." Patients report that for the first time in years, they can turn over in bed, shower, dress themselves, and eat normally. Many can walk, write, drive a car, and even go back to work. (Iacono RP, Lonser RR. Lancet 1994;343:418-419. Giller CA, Dewey RB. West J Med 1995;162:255-256. Am Acad Neurology 47th Annual Meeting in Seattle, 1995. Ed. UPF Newsl. 1995([2]:4. Joyce L Stanford Univ Med Cen Report 1995[3/15]:1,11. Stipp D. WSJ 1995[2/22]:A-1, A-10.) ------------------------------------------------- New technology: transcranial magnetic stimulation Transcranial magnetic stimulation (TMS) is a new noninvasive technique that involves the application of a pulsating magnetic wave to the brain through the cranium. Alvaro Pascual-Leone (Spain) and his colleagues at National Institutes of Health (Washington) are using TMS to improve motor function in PD patients. The technique is thought to increase the threshold for activation of neurons, and can be targeted to a particular area of the brain to relieve specific motor symptoms. A brief course of TMS has been shown to improve motor performance in PD patients for up to four hours. Studies are underway to determine whether continuous application of TMS can provide sustained control of symptoms. (Am Acad Neurology 47th Annual Meeting in Seattle, 1995. Ed. UPF Newsl. 1995([2]:3-4.) ------------------------------------------------------------- New research: neurotrophic factors, brain implants, apoptosis PD was the focus of several recent scientific meetings and conferences. Researchers described their studies with nerve growth factors, neural tissue implants, progenitor cells, apoptosis, and genetically engineered cells capable of making, storing and releasing dopamine. They also reported the results of experiments to introduce viruses into the CNS that can infect nerve cells and inject dopamine-coding DNA into neurons. Barry Hoffer at the University of Colorado and researchers at Synergen are studying glial-derived neurotrophic factor (GDNF), which can protect animals against neurotoxins known to cause PD. Louis Ptek and Paul Carvey (Rush-Presbyterian- St. Luke's, Chicago) are studying progenitor cells, cells that are capable of developing into dopaminergic cells when given the appropriate signals. Paul Sanberg at the University of South Florida has implanted Sertoli cells (testicular cells that provide nutrients and support to developing sperm) into the striatum of parkinsonian rats. These cells significantly improved motor function, and improvement was correlated with sprouting of dopaminergic neurons. Nerve tissue implants -- in the striatum or the substantia nigra -- have shown some efficacy in animal studies and are showing promise in clinical studies. Implantation into the substantia nigra, followed by withdrawal of the needle along a path from the nigra to the striatum, may be effective for reconstructing the normal nigrostriatal pathway. Kordower et al described significant clinical improvement in a 59-year old patient who received bilateral fetal nigral implants. Improvement was correlated with enhanced dopaminergic signal on a PET scan in the months following surgery. The patient died of unrelated causes 18 months after the procedure, and autopsy revealed that each implant was viable and dense clusters of dopaminergic neurons had integrated into the host striatum. (Kordower JH et al. N Engl J Med 1995;332:1118- 1124. Hoffer BJ, Van Horne C. N Engl J Med 1995;332:1163- 1164.) One of the most intriguing avenues of research is apoptosis, or programmed cell death. Early brain development is a dynamic process with billions of neurons growing rapidly and competing with other neurons to make connections. Those that don't make enough connection die. In fact, it appears that these cells commit suicide. They actually synthesize proteins that destroy their own DNA. Glial cells promptly engulf the dying cell, in response to some sort of signal. A number of studies indicate that apoptosis may play a role in PD. Several factors thought to be involved in neuron death -- including free radicals, iron, stress, lack of growth factors -- have been shown to induce apoptosis. Levodopa itself induces apoptosis in tissue cultures. During fetal development, apoptosis is important to weed out excess neurons, but it is disastrous in the aging brain. Researchers are trying to detect apoptosis in parkinsonian brains (a difficult task as glial cells eliminate dying cells within 24 hours) and they are trying to determine how to block the suicide attack. (Winter Conference on Neural Plasticity [Grenada]; Conference on Neurodegenerative Disorders: Common Molecular Mechanisms conference [Jamaica]; Annual meeting of the American Society for Neural Transplantation [Clearwater Florida].) Parkinsonism with metoclopramide -------------------------------- Metoclopramide is a dopamine antagonist approved for treating gastroesophageal reflux and disorders of gastric emptying (such as diabetic gastroparesis) and for preventing chemotherapy-induced nausea and vomiting. Since it blocks dopamine receptors in the brain, metoclopramide would be expected to cause extrapyramidal (parkinsonian) side effects. Yet according to the manufacturer, at usual daily doses of 30-40 mg, parkinsonism occurs only rarely (0.2%), most often in children and young adults. Recently Avorn et al published the results of their study of medication use in 17,000 elderly medicaid patients. They found that elderly patients who were using metoclopramide for gastric problems were three times more likely to begin taking drugs specific for Parkinson's disease (levodopa) than patients who were not on metoclopramide. The risk of developing parkinsonian symptoms increased with increasing doses of metoclopramide (to a five-fold increase in patients taking more than 20 mg/day.) These results suggest not only that metoclopramide induces parkinsonism more often than previously suspected, but also that physicians may be misdiagnosing patients with parkinsonism and prescribing drugs for Parkinson's disease, rather than looking at medication history to rule out drug-induced parkinsonism. (Avorn J et al. JAMA 1995;274:1780-1782.) Parkinson's disease and parkinsonism are fairly common in older people, and may be even more common than suspected. Bennett et al conducted a community study of common health problems in the elderly, and found parkinsonian signs in a substantial number of people over age 65. A total of 464 patients underwent structured neurological examinations, neuropsychological performance testing, and laboratory testing. In addition, medications were identified, medical history taken, and an interview conducted. Almost 15% of those surveyed in the age group 65-74 had two or more signs of parkinsonism--bradykinesia, gait disturbances, rigidity, and tremor--while 29.5% of those aged 75-84 had parkinsonism, and 52.4% of those 85 and older had parkinsonism. Adjusted for age and sex, patients with parkinsonism had twice the risk of death of patients without symptoms of Parkinson's disease, particularly when a gait disturbance was present. (Bennett DA et al. N Engl J Med 1996;334:71-76.) It would be interesting to find out how many patients with parkinsonism were taking drugs that could induce such symptoms.