Parkinson's disease: Making the diagnosis, selecting drug therapies Douglas W. Scharre, MD Michael E. Mahler, MD -------------------------------------------------------------------- Parkinson's disease is a progressive neurodegenerative con- dition of unknown cause and with no known cure. The diagnosis is based on clinical findings of rest tremor, muscle rigidity, bradykinesia, and gait instability. Over 40% ofpatients develop a dementia syndrome that is largely distinct from Alzheimer's disease. Depression is common, also occurring in more than 40% ofpatients with PD. Careful evaluation is neces- sary to help distinguish Parkinson's disease from secon causes of parkinsonism. Carbidopa/levodopa, dopamine ago- nists, and monoamine oxidase type B inhibitors are the main- stays of treatment. Anticholinergics and other agents may also be useful, Pharmacologic treatment must be carefully titrated to control symptoms and to avoid side effects. In advanced disease, dose-related dyskinesias, end-of-dose wearing-off effect, and unpredictable sudden motor fluctuations become very disabling and difficult to manage. Scharre DW, Mahler ME. Parkinson's disease: Making the diagnosis, selecting drug therapies, Geriatrics 1994; 49 (Oct):14-23 -------------------------------------------------------------------- Dr. Scharre was a neurobehavior fellow and clinical instructor, UCLA School of Medicine, when this article was written. He is now assistant professor of neurology, department of neurology, Ohio State University, Columbus. Dr. Mahler is director, Neurobehavior Unit, West Los Angeles VA Medical Center and associate clinical professor of neurology, UCLA School of Medicine, Reed Neurological Research Center, Los Angeles. This article was supported by a National Institute on Aging training grant and the Department of Veterans Affairs. ----------------------------------------------- Mrs. Cavanaugh is only 55, but as she shuffles into the examination room you can see there's something wrong. Her face seems frozen without expression, and you have to lean closer to hear her faint answer to your greeting. You glance at her name and address on the patient history form and note that her handwriting is small and cramped. Your first impression: Parkinson's disease (PD). Parkinsonism is a clinical syn- drome comprised of a tremor at rest, rigidity, bradykinesia, and gait instability. When this syndrome results from a specific degenerative disorder, it is called PD; when it results from other definable dis- eases, it is called secondary or symptomatic parkinsonism. In this article, we discuss the clinical workup of the patient with suspected PD-what to look for and how to exclude other diag- noses. Once the diagnosis is con- firmed, we discuss the challenge of tailoring drug therapy to control symptoms and avoid side effects in both the newly-diagnosed and later-stage patient. > Parkinson's disease: > Clinical background Parkinson's disease affects about 1 million Americans, most over the age of 50, according to the Ameri- can Parkinson Disease Association, Inc. The age-specific incidence peaks around age 70 and then declines,(1) whereas the age-specific prevalence increases almost expo- nentially for ages beyond 65, affecting 1 to 2% of the population over age 80. Men and women are equally likely to develop PD. For secondary parkinsonism, incidence and prevalence rates vary widely according to the under- lying disorders (table 1). Drug- induced parkinsonism and arterio- sclerotic parkinsonism are the most common, whereas many of the neurodegenerative diseases are rare. Clinical course. PD is a pro- gressive degenerative condition resulting in a gradual worsening of symptoms. The progressive immobility of PD patients makes them susceptible to infection and inanition. Untreated PD patients progress to death within 8 to 10 years, whereas treatment extends their survival to about 15 years fol- lowing diagnosis. Etiology. The etiology of PD is unknown. Viral infections, prema- ture aging, environmental toxins, and genetic factors have all been suggested as potential causes. Von Economo's encephalitis, an epi- demic caused by a viral agent that occurred in the early 20th centu- ry, often resulted in a syndrome that was very simi- lar to PD. Early onset of PD has been associated with living in rural areas of industrial- ized nations, suggesting exposure to an environmen- tal toxin .2 An example of a toxin causing parkinsonism methylphenyltetrahydropyridine (MPTP), a byproduct of a syn- thetic narcotic.(3) MPTP is trans- formed by monoamine oxidase type B to the free radical species MPP+, which selectively enters and destroys cells in the substantia nigra and locus ceruleus. It is pos- sible that similar environmental toxins may produce PD in individ- uals who have an inherited vul- nerability to these toxins.(4) Finally, despite the fact that PD appears to be a sporadic disease with occasional familial incidence, genetic factors may play a role, pos- sibly through the mitochondrial DNA.(5) Pathology. In PD, there is a loss of pigmented neurons and the appearance of intraneuronal Lewy bodies in the pars compacta of the substantia nigra and in the ven- tral tegmental area (VTA). These changes result in the denervation of both the nigrostriatal and VTA- mesocortical dopaminergic path- ways. Denervation in noradrenergic pathways to the cortex also occur secondary to neuronal loss in the locus ceruleus. However, dopa- mine deficiency in the striatum is the major factor in the pathogen- esis of PD and secondary parkin- sonism. Clinical symptoms begin ----------------------------------------------------------------------------- Parkinson's disease is caused by deplefion of the neurotransmitter dopamine, due to the loss of pigmented neurons from the substantia nigra and other brainstem cells. Clinical symptoms, such as the 'pill-rolling' hand tremor, begin with approximately 80% depletion of dopamine from the striatum. ----------------------------------------------------------------------------- ------- TABLE 1 ------- Causes of secondary parkinsonism CAUSE EXAMPLES --------------------------------- ---------------------------------------- Atherosclerosis Degeneration Basal ganglia calcification (Fahr's disease) Cortical Lewy body disease Olivopontocerebellar atrophy Parkinson-dementia complex (of Guam) Progressive supranuclear palsy (PSP) Shy-Drager syndrome Striatonigral degeneration Wilson's disease Drug-induced Antipsychotics Lithium Metoclopramide Methyldopa Reserpine Endocrine Hypoparathyroidism Hypothyroidism Hydrocephalus, normal pressure Infection AIDS Jakob-Creutzfeldt disease Pbsi-encephalitic (Von Economo's) Intoxication Carbon monoxide Manganese Methylphanyltetrahydropyridine (MPTP) Traumatic encephelopathy Tumors, basal ganglia Arteriovenous malformations Neoplasms >Source: Prepared for Geriatrics by Douglas W. Scharre, MD, and Michael E. Mahler, MD ------------------------------------------------------------------------------------------- when there is approximately 80% depletion of the striatal dopamine. >Diagnosis of PD: >The cardinal signs The diagnosis of PD is based on clinical findings. The cardinal signs of PD are the resting tremor, rigid- ity, bradykinesia, and gait insta- bility. Although more than one-half of all PD patients present with a tremor, the other features of the disease are usually present at the time of diagnosis. PD is often mildly asymmetric at the outset, but it generally evolves to affect both sides of the body relatively equally. The tremor frequency is typically between 4 and 7 Hz and consists of coarse, alternating agonist-antagonist muscle movements. It is a rest tremor that is present when the patient is alert but not moving volitionally. With purposeful move- ments, the tremor decreases. In addition, it is not uncommon for some PD patients to have a high frequency, low amplitude action tremor. To test for tremor, have the patient rest his arms on his legs while sitting. Observe for resting tremor on one or both sides. Note the frequency and amplitude, and watch for changes when the arms are then lifted straight away from the body. Muscle rigidity, an increase in resistance to passive stretching, occurs throughout the range of motion. The cog-wheel phe- nomenon results from the resting tremor superimposed on the mus- cle rigidity. Rigidity is also evident in the typical posture of PD patients: flexion of the neck and trunk, flexion of the arms, hips, and knees. Despite the rigidity, there is no loss of muscle strength. In the patient examination, check the muscle tone in all four extremities and the neck to assess the degree of rigidity and to feel for "cogwheeling." The rigidity becomes more pronounced with activating procedures. Ask the patient to draw a large square in the air with a finger or toe while you are assessing muscle tone in the opposite extremity. Bradykinesia literally means slow-moving and is probably the earliest and most disabling feature of PD.(6) PD patients have difficulty initiating movements and are slowed in all volitional and many involuntary acts. Bradykinesia and paucity of movements cause: > the mask-like, expressionless face (decreased eye-blink and emo- tional grimace) > drooling (the result of de- creased swallowing) > hypophonia (soft, mumbled speech) > micrographia (small, illegible handwriting). Abnormal gait and pos- tural instability occur fre- quently. The typical gait for a patient with PD con- sists of- > a forward stooped posture > shortened, shuffling steps (marche a petits pas) > decreased arm-swing > tendency to propel forwards with increasing speed (Destination). To test for postural instability, stand behind the patient and quickly pull backward on his shoulders. The appropriately pre- pared patient will typically start to fall or adjust the feet in order to maintain an upright posture. When turning, the patient does not pivot but takes several small steps and turns en bloc. The bal- ance is unsteady when turning and numerous falls may result. This imbalance can be severe enough to impair standing and even unsup- ported sitting. Patients may also experience autonomic nervous system dys- function resulting in hyperhidro- sis, orthostatic hypotension, impotence, constipation, and incon- tinence. Many PD patients also complain of insomnia. > Neurobehavioral symptoms: > Dementia, depression Although James Parkinson origi- nally wrote that "the senses and intellects [are] uninjured" in PD, most contemporary investigations demonstrate that many patients exhibit cognitive decline. PD pathology without evidence of any concurrent Alzheimer features is sufficient to cause the intellectual ----------------------------------- Depression is common in PD and is thought to be related to the loss of frontal dopaminergic projections ----------------------------------- decline. More than 40% of PD patients have an obvious demen- tia syndrome, whereas more than 90% have subtle but measurable neuropsychological deficits.(7) Dementia is most common in patients with postural instability and gait disturbance and least common in patients with marked tremor.(8) Although the pattern of cognitive deficits can be varied, this dementia is largely distinct from Alzheimer's dementia.(9) Many of those with intellectual loss display a subcortical demen- tia syndrome characterized by poor retrieval memory, slowing of information processing, difficulty with frontal lobe-executive tasks, and sparing of language function. The intellectual decline is insidi- ous and gradual. Some PD patients probably have Alzheimer's disease as well.(10) Depression is common, affect- ing 40 to 60% of PD patients. It is often highlighted with anxiety but does not correlate well with dis- ease severity or disability. In some cases, the depression could repre- sent a psychological response to disability. However, many studies suggest that depression in PD is related to the loss of frontal dopaminergic projections. Depression in PD patients typi- cally responds to treatment with conventional tricyclic antidepres- sants or electroconvulsive thera- py. Nortriptyline HCI (Aventyl, Pamelor), desipramine HCI (Norpramin, Pertofrane), and imipramine HCI (Janimine, Tofranil) have all proven to be effi- cacious. The usual dose is about one-half that used in depressed patients without PD. Medications should be continued for 9 to 12 months for maximal effectiveness. The anticholinergic properties of the tricyclics may improve tremor and rigidity symptoms in some patients but may cause wors- ening of cognition in those who are also demented. Trazodone HCI (Desyrel) may be useful for patients with both depression and dementia. > Differential diagnosis: > Secondary causes Secondary causes of parkinsonism may be difficult to differentiate from PD. Resting tremor is less prominent or absent in many of these conditions. Although the diagnosis of PD is based on clini- cal findings, laboratory evaluations including serum chemistries, thy- roid function tests, heavy metal screens, and brain imaging may be indicated in newly-diagnosed patients to differentiate those with secondary parkinsonism. Marked asymmetry of symp- toms, limb weakness, and abnor- mal reflexes are likely to be present in arteriosclerotic parkinsonism. In progressive supranuclear palsy (PSP), patients have supranuclear ophthalmoplegia, pseudobulbar palsy, and axial rigidity in addition to parkinsonism. Some of the other degenerative conditions are multisystem disor- ders that display combinations of extrapyramidal, corticospinal, spinocerebellar, and autonomic dysfunction. The multisystem atrophies generally have a more rapid progression, a tendency for familial inheritance, and a poor response to levodopa.(11) In drug- induced parkinsonism, the symp- toms may linger as long as 6 months after removal of the offending agent. > Drug therapy: Symptom > control and side effects Antiparkinson pharmacologic treatment is necessary when the tremor and bradykinesia begin to interfere with the patient's occu- pational and social functioning, independence, and self-care activ- ities. Drug therapy must be care- fully titrated to control symptoms and to avoid side effects (table 2). Anticholinergics. For patients younger than age 65 with mild symptoms, anticholinergic medi- cations help to restore the balance between the decreased dopamine levels and the normal levels of acetylcholine within the striatum. Anticholinergics help with drool- ing and are more effective for the resting tremor than for rigidity or bradykinesia. Amantadine (Symadine, Sym- metrel) increases the release of dopamine in the brain. In the treatment of early PD, both aman- tadine and anticholinergic medi- cations have been used alone or in combination with carbidopa/lev- odopa (Sinemet) for additive effects. However, because of the high incidence of serious side effects from anticholinergics and amantadine, these agents should be used with caution-if at all-in patients age 65 and older. Selegiline. The secondary parkinsonism seen with MPTP sparked the development of neu- roprotective therapy for PD. Selegiline HCI (Eldepryl) selec- tively inhibits monoamine oxidase type B and protects pretreated ani- mals then exposed to MPTP from developing parkinsonism by block- ing its conversion to the toxic free radical MPP+. Several randomized placebo- controlled studies in humans have concluded that selegiline delays the need for levodopa for up to 9 months in early PD.(12,13) It is not clear yet whether this benefit will be apparent throughout the course of the illness. (14) All newly diagnosed PD patients should be started on selegiline for its potential neuroprotective effect, and levodopa should be added later only if symptoms are disabling. The effective dose of selegiline is 5 mg bid, with the second dose in the early afternoon to avoid insom- nia. No dietary restrictions are necessary. Carbidopa/levodopa. Dopa- mine replacement has been the mainstay of treatment for PD. The combination of levodopa and car- bidopa (Sinemet) is the most effi- cient way to get dopamine into the brain. Dopamine does not pass the blood-brain barrier, but levodopa does, and it is converted in the brain to dopamine through decar- boxylation. Carbidopa inhibits only the peripheral decarboxylation of levodopa, thereby reducing the peripheral side effects and enhanc- ing the availability of dopamine in the brain. Levodopa is dramati- cally effective; bradykinesia and rigidity improve markedly, where- as tremor responds variably. The usual initial dose of car- bidopa/levodopa for middle-age adults is a 25/100 tablet three times a day. However, elderly patients-who are most sensitive to side effects-should start with one-half tablet twice a day and increase the dose every week by increments of one-half to one tablet. The serum half-life of levodopa is 3 hours, so a more frequent schedule is necessary as the daily dose increases while titrating to an optimal effect. Substitute the 10/100 or 25/250 carbidopa/lev- odopa tablets when the dose exceeds six of the 25/100 tablets a day, because only 75 to 100 mg/day of carbidopa is needed to maxi- mally inhibit peripheral decar- boxylation. The immediate side effects of levodopa include nausea, dizziness, confusion, and psychosis. These are limited by careful titration of the dose. After several years of therapy, the response to levodopa changes and dose-related dyski- nesias (chorea, dystonia, myo- clonus), end-of-dose wearing-off effect, and unpredictable sudden fluctuations between mobility and immobility (the "on-off" phe- nomenon) can emerge.(15) These complications may be caused by progression of the illness, altered pharmacokinetics, or receptor changes. The use of the lowest dose that controls symptoms early in the disease may forestall the devel- opment of these disabling and dif- ficult-to-manage response fluctu- ations. The controlled-release prepara- tion of carbidopa/levadopa (Sine- met-CR, 50/200), helps to reduce the wearing-off phenomenon but may increase dyskinesias.(16) Because the controlled-release preparation takes longer to reach maximum plasma levels, a stan- dard tablet may also be required to control symptoms, especially with the first dose of the day. Dopamine agonists. When a levodova dosage of 1,000 mg/d is ------- TABLE 2 ------- Drug treatment options in Parkinson's disease DRUG TYPE OF AGENT TYPICAL DOSAGE ADVERSE EFFECTS ----------------------------- ------------------------------ ------------------------------ --------------------------------- Benztropine mesylate Anticholinergic 0.5 to 2 mg at night Dry mouth, constipation, Cogentin urinary retention, blurred vision, impaired memmory hallucination, confusion Biperiden Anticholinergic 2 mg tid or qid As above Akineton Trihexyphenidyl HCI Anticholinergic 1 to 5 mg at night As above Artane, Trihexy Diphenhydramine HCI Antihistaminic and 25 to 50 mg up to Sedation, dizziness, and Benadryl, et al anticholinergic four times daily as above Amantadine HCI Antiviral and 100 mg bid or tid Hallucinations, Symadine, Symmetrel dopaminergic confusion, pedal edema Carbidopa/levodopa Dopaminergic 300 to 1,000 mg levodopa Nausea, orthostasis Sinemet in 3 to 8 divided doses with hallucinations, delusions, 75 to 100 mg/d carbidopa; confusion, dose-related start elderly with 100 mg/d fluctuations and levodopa dyskinsias Controlled-release Dopaminergic As above in 2 to 4 divided As above; may increase carbidopatievodopa doses dyskinsias Sinemet CR Bromocriptine mesylate Dopamine agonist 1.25 mg/d for 3 days, then Orthostasis, dyskinsias, Parlodel increase by 1.25 mg/week psychosis, nausea, up to 15 to 30 mg in 2 cardiac arrhythhmias divided doses with meals Pergolide meslyate Dopamine agonist 0.05 mg/d for 3 days, then As above Permax increase slowly up to 1.5 to 3mg in 3 divided doses Selegiline HCI Monoamine oxidase 5 mg with breakfast and Insomnia, confusion, Eldepryl type B inhibitor lunch nausea, orthostasis >Source: Prepared for Geriatrics by Douglas W. Scharre, MD, and Michael E. Mahler, MD ------------------------------------------------------------------------------------------- not sufficient to control the symp- effect than levodopa, but they have improve efficacy and smooth out toms, add a dlopamine agonist such a longer duration of action. the motor fluctuations that appear as bromocriptine mesylate (Par- In combination with levodopa, after the patient has had PD for lodel) or pergolide mesylate these agents appear no more effec- several years.(18) Dopamine agonists (Permax). Used alone, dopamine tive than levodopa alone in new- and levodopa have similar side agonists have less antiparkinson onset PD." However, they may effects, so dosing them apart in time or reducing their dosage will help decrease these effects. > Nondrug therapies: > Maxiniizing function Dietary factors can affect the clin- ical response to levodopa. Neutral amino acids in proteins compete with levodopa for absorption across the intestinal mucosa and for active transport across the blood- brain barrier. (19) Patients may avoid fluctuating responses to levodopa by taking the dose at least 30 minutes before meals. Reducing protein intake to the minimum daily allowance or eating most of the day's protein at the evening meal-when motor fluctuations are most tolerable- can also be beneficial. Calcium supplementation may be necessary for protein-restricted diets. An alternative to protein restriction or redistribution is a diet with a carbohydrate-to-pro- tein ratio of up to 7 to 1, as carbo- hydrate loads tend to reduce circulating amino acid levels. Other important ways to maxi- mize patient function include: > regular exercise to counteract physical disability > hearing and vision care to avoid social and sensory depriva- tion > education concerning disease progression, complications of drug treatments, and neurobehavioral symptoms to help prepare the patient or caregiver for declining or fluctuating abilities > individual psychotherapy or support groups to help patients and family deal with feelings of loss, grief, and guilt. >> Conclusion Because there is no known cure for PD, its management focuses on the control of symptoms and the avoid- ance of drug side effects. By indi- vidualizing therapy and making changes in drugs and dosages as needed, the primary care physi- cian aims to increase the span of independent function. Neurologic consultation should be obtained to assist with proper diagnosis in atypical presentations and to help with management of fluctuating motor responses to treatment and neurobehavioral symptoms. Research for a more definitive treatment of PD continues. Surgical transplantations of adrenal medulla tissue were not very successful and were plagued by comphcations.(20) However, trans- plantation of catecholaminergic cells from fetal brain tissue into the striatum may decrease the severity of PD and increase the effectiveness of levodopa.(21) REFERENCES 1. Schoenberg BS. Epidemiology of move- ment disorders. In: Marsden CD, Fahn S, eds. Movement disorders (2nd ed). London: Butterworth, 1987.-7-32. 2. Stern M, Dulaney E, Gruber S, et al. The epidemiology of Parkinson's disease: A case-control study of young onset and old onset patients. Arch Neural 1991; 48:903-7. 3.Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic parkinsonism in humans due to a product of meperidine- analog synthesis. Science 1983; 219.-979- 80. 4. Jenner P, Schapira AHV, Marsden CD. New insights into the cause of Parkinson's disease. Neurology 1992; 42:2241-50. 5. Jankovic I. Theories on the etiology and pathogenesis of Parkinson's disease. Neurology 1993; 43(suppl 1):21-3. 6. Watts RL, Mandir AS, Ahn KJ, Juncos JL, Zakers GO, Freeman A. Electrophys- iologic analysis of early Parkinson's dis- ease. Neurology 1991; 41(suppl 2):44-8. 7. Cummings JL. Intellectual impairment in Parkinson's disease: Clinical, patho- logic, and biochemical correlates. Geriatr Psychiatry Neural 1988,- 1:24-36. 8. Jankovic 1, McDermott M, Carter J, et al. Parkinson Study Group. Variable expression of Parkinson's disease: A baseline analysis of the DATATOP cohort. Neurology 1990; 40:1529-34. 9. Mahler ME, Cummings JL. Alzheimer disease and the dementia of Parkinson disease: Comparative investigations. Alzheimer Dis Assoc Disord 1990,- 4:133- 49. 10. Hakim AM, Mathieson G. Dementia in Parkinson's disease: A neuropathologic study. Neurology 1979,- 29:1209-14. ll. Langston JW, Koller WC, Giron LT. Etiology of Parkinson's disease. In: Olanow CW, Lieberman AN, eds. The scientific basis for the treatment of Parkinson's disease. Park Ridge, NJ. Parthenon Publishing Group, 1992:33- 58. 12. Myllyla VV, Sotaniemi KA, Vuorinen JA, Heinonen EH. Selegiline as initial treatment in de novo parkinsonian patients. Neurology 1992; 42:339-43. 13. The Parkinson Study Group. Effects of tocopherol and deprenyl on the progres- sion of disability in early Parkinson's disease. N Engl J Med 1993; 328:176- 83. 14. Olanow CW, Caine D. Does selegiline monotherapy in Parkinson's disease act by symptomatic or protective mecha- nisms? Neurology 1991; 42(suppl 4):13- 26. 15. Jankovic J. Natural course and limita- tions of levodopa therapy. Neurology 1993, 43(suppl 1):14-7. 16. Sage JI, Mark M. Comparison of can- trolled-release Sinemet (CR4) and stan- dard Sinemet (25 mg/100 mg) in advanced Parkinson's disease: A dou- ble-blind, crossover study. Clin Neuropharmacol 1988; 11:174-9. 17. Weiner WJ, Factor SA, Sanchez-Ramos JR, et al. Early combination therapy (bromocriptine and levodopa) does not prevent motor fluctuations in Parkin- son's disease. Neurology !993; 43:21-7. 18. Goetz CG. Dopaminergic agonists in the treatment of Parkinson's disease. Neurology 1990; (,@uppl 3):50-4 19. Kempster PA, Wahlquist ML. Dietary factors in the management a Parkinson's disease. Nutr Rev 1994; 52:51-8. 20, Olanow CW, Koller WC, Goetz CG, et al. Autologous transplantation of adrenal medulla in Parkinson's disease: 18- month results. Arch Neural 1990 47:1286-9. 21.Fahn S. Fetal-tissue transplants i Parkinson's disease. N Engl J Med 1992 327:1589-90.