Recent Advances in the Treatment of Parkinson's Disease
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Recent advances in the treatment of Parkinsonism Parkinsons disease RICHARD J. MARTOCCI, D.O. Highland Park, Michigan ticholinergic drugs conventionally used to treat par- kinsonism, levodopa was three-and-a-half times as Although there are both medical and effective in relieving symptoms. However, the surgical methods of treating treatment of paralysis agitans, whether medical or parkinsonism, medical therapy should surgical, remains purely palliative and never is cura- be tried first and surgical measures tive. reserved for patients who do not respond. Anticholinergic drugs may be Pathophysiologic and biochemical aspects combined with an antihistamine when The pathologic alterations in parkinsonism the symptoms are mild, and levodopa (paralysis agitans) most consistently affect the zona used alone or with another drug when compacta2 of the substantia nigra with formation of the disease is moderate to severe. The Lewy bodies, or inclusion bodies, and neurofibril- side effects of levodopa are lary tangles3 such as those in Alzheimers disease and troublesome, and the clinical program other forms of senile atrophy. Histochemical studies must be adjusted constantly to achieve using fluorescent techniques have shown that maximum benefits and minimum side dopamine is almost nonexistent in the neostriatum effects. Pyridoxine reverses side effects and substantia nigra. Dopamine, a catecholamine, but also the benefits of levodopa. Use of has proved to be a neurohumeral transmitter. This a peripheral decarboxylase inhibitor suggests that in parkinsonism there is a decrease in may permit reduction in the dose of ability of affected brain tissue to form dopamine, levodopa to a point that side effects can and from 80 to 90 percent of dopamine in the brain be minimal. is situated in the nerve ending granules of the cau- date nucleus, substantia nigra, and putamen. Dopamine, formed in the large cells of the zona compacta of the substantia nigra, appears to be con- veyed to the neostriatum (caudate nucleus and pu- tamen) via the nigrostriatal nerve fibers (Fig. 1). Re- When Parkinson described paralysis agitans in ciprocal relations appear to exist between the neo- 1817, he probably did not suspect that it would take striatum and the substantia nigra in what appears to 150 years for an effective treatment to be found. be a closed-loop feedback system, in which The demonstration that administration of reserpine striatonigral fibers (cholinergic) constitute the af- in prolonged and sometimes high doses produces a ferent component, and nigro-neostriatal fibers, state resembling parkinsonism in animals and man, concerned with the transmission and distribution of and that dextro-levodopa reverses this activity in dopamine, form the efferent limb. The output of human beings, led to the clinical use of levodopa in the corpus striatum is principally to the globus pal- treatment of parkinsonism. This was a much needed lidus (mainly cholinergic output); pallidofugal fi- medical breakthrough. After this discovery, be- bers in turn transmit impulses to thalamic nuclei tween 1965 and 1967, large-scale treatment trials which can modify the activity of cortical motor were begun at several medical centers. In general, neurons. The thalamic relay nucleus of greatest im- the akinesia and rigidity responded early in the portance is the ventrolateral (VLo), and surgical course of treatment, and tremor control came with ablation of this area along with the medial portion prolonged use. In comparison with the an- of the globus pallidus has greatly ameliorated the Journal A0A/vol. 74, April 1975 730/105 Treatment of Parkinsons disease defect of the disease. Norepinephrine, another catecholamine widely distributed in the brain, in greatest concentrations in the hypothalamus and Caudate nucleus lower part of the brainstem and much more diffuse Putamen Ventral lateral than dopamine, has not been shown to be affected posterior nucleus consistently in patients with Parkinsons disease. Globus pallidus Levels in the brain have been found to be decreased, Striatonisral increased, and normal. The hypokinesia and rigid- Ni9rostriatal ity induced by reserpine and other related drugs (a-methyldopa and members of the phenothiazine Substantia nigra family) almost invariably affect all limbs equally, Red nucleus whereas the symptoms of Parkinsons disease may be Cerebral peduncle confined to one limb or one side of the body. It can Midbrain be inferred from this that a decrease in dopamine may be secondary to neuronal cell loss in the sub- Fig. 1. Diagram of striatonigral extrapyramidal projective system. stantia nigra and nuclei of the basal ganglia. Clinical features The cardinal signs of Parkinsons disease are trem- or, rigidity, hypokinesia, and disorders of posture parkinsonian tremor and rigidity. It is conceivable and equilibrium. Any one of these may be the initial that interruption of one of the cholinergic pathways symptom, and two or even three of them may be by anticholinergic drugs also could restore the bal- absent for several years, even after illness is estab- ance between the interacting cholinergic and lished. dopaminergic systems. Typical signs of Parkinsons disease are as follows: Neurophysiologic evidence indicates that (1) loss of finger dexterity without weakness; dopamine has an inhibitory effect on single (2) loss of automatic and emotional control of neurons, and this would suggest that in parkin- speech and expression; sonism the neostriatal inhibition that normally acts (3) loss of automatic swallowing of saliva; on the pallidal neurons is impaired. In this concept (4) loss of spontaneous blinking of the eyes; the dyskinesia and increased muscle tone seen in (5) loss of arm swinging in walking and other parkinsonism may be regarded as "release" associated movements; phenomena (removal of inhibitory influences). (6) loss of automatic spontaneous alternate con- This concept provides a rationale for use of traction and extension of limb muscles at rest; levodopa in treatment of parkinsonism. Levodopa, a (7) loss of normal amplitude of continuous mus- precursor of dopamine, can cross the blood-brain cle movement (petit pas, micrographia, and loss of barrier; dopamine cannot. speech volume, and tendency to speed up — festina- There can be little doubt that dopamine plays an tion); important role in the functions of the corpus (8) loss of concurrent hand, face, and body striatum. Beyond this, however, there is no evidence movement and communication; that the depletion of this catecholamine in the brain (9) loss of semiautomatic continuation of move- of patients with parkinsonism is a primary metabolic ment pattern; 731/106 (10) loss of learned automatic motor patterns in Parkinsonian syndromes cooperative movements (example: extending the The term Parkinsons disease refers to what Gilroy wrist in order to get efficient contraction of fingers); and Meyer2 said should be more accurately classified (11) regular resting tremor (4 or 5 per second); as parkinsonian syndromes, a number of conditions (12) cogwheel rigidity; with diverse causes that possess similar clinical (13) muscular weakness; characteristics of rigidity, bradykinesia, and tremor. (14) dystonic flexed posture; These include paralysis agitans, postencephalitic (15) oculogyria, tics, and spasms; parkinsonism, arteriosclerotic parkinsonism, (16) depression of mood; striatonigral degeneration, parkinsonism induced (17) akinesia in all its forms, including "freezing"; by a drug such as reserpine, a phenothiazine, or (18) retropulsion and propulsion; a-methyldopa, such infectious diseases as viral en- (19) bradykinesia; and cephalitis and meningovascular syphilis, toxic par- (20) insidious development of loss of attention, kinsonism due to manganese, carbon monoxide, or memory and interest in surroundings. carbon disulfide, other chronic neurologic condi- On the other hand, 95 percent of patients with tions with features of parkinsonism, including Parkinsons disease do not show the following signs: Huntingtons chorea, Wilsons disease, Alzheimers (1) spasticity of limbs with marked pyramidal disease, and olivopontocerebellar degeneration, tract signs; Shy-Drager syndrome, and the parkinsonian de- (2) epileptic seizures; mentia complex of Guam. 2 Most often parkinsonism (3) sensory defects; is idiopathic (paralysis agitans) or a sequel of en- (4) focal muscle wasting, fasciculations, and fibril- cephalitis. Most cases of postencephalitic disease fol- lations (electromyography) in the muscles; lowed the epidemic of encephalitis lethargica be- (5) papilledema; tween 1916 and 1926; they frequently present with (6) changes in the cerebrospinal fluid (pleo- clinical charactieristics of oculogyria and palilalia. cytosis, increase in total protein, and high pressure); Reference to parkinsonian syndromes is neces- (7) pupillary and ocular palsies; sary, because treatment often is not the same for the (8) hemianopia and other severe visual field de- different types, and the results and clinical course fects; also differ. Two other syndromes with features of (9) nystagmus; parkinsonism also deserve mention: (1) the Shy- (10) aphasia as opposed to dysarthria; Drager syndrome, in which features of parkin- (11) severe headache; sonism are associated with marked orthostatic (12) rapidly increasing dementia; hypotension, anhidrosis, and end-stage muscle wast- (13) severe and rapid personality changes; ing, with fasciculations in the more distal muscles, (14) paranoid delusions; and occasionally with alternating