Parkinsonism And Movement Disorders

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Dopaminergic

Since degeneration of the nigrostriatal system occurs in all parkinsonian disorders, drugs targeting the principal transmitter deficiency, DA, remain the treatment of choice for associated motor dysfunction, especially rigidity and bradykinesia. Positron emission tomography (PET) studies have shown decreased striatal 18flourodopa uptake and decreased striatal regional blood flow indicative of the loss of nigral dopaminergic neurons (1,2). Moreover, a preferential loss of postsynaptic DA-D2 receptors in the posterior putamen occurs in relation to levodopa resistance, suggesting the additional degeneration of striatal spiny neurons (3,4). Similarly, 123I-iodobenzamide (IBZM) single photon emission computed tomography (SPECT) studies indicate lower mean striatal DA-D2 receptor binding in patients with atypical parkinsonian disorders than in those with PD (5). A comparison using [123I]p-CIT SPECT reveals a reduction of striatal DA transporter density in parkinsonian disorders, including PD (6-8), but long-term studies have shown a more rapid decline in the atypical disorders; in MSA and PSP putamen-caudate nucleus ratios are reduced and in CBD there is an increase in binding asymmetry (9).

In MSA, analyses of 203 pathologically proven cases indicated that although the overall response to levodopa was poor, some patients might initially respond well (10). Indeed, response rates reported for levodopa range from 33% up to 68% (11,12). As striatal degeneration occurs, receptor sites for the postsynaptic activity of DA produced by levodopa treatment declines, and thus clinical efficacy consequently fades, leaving only supportive measures for later-stage patients. Those enjoying good response may develop levodopa-induced axial, orofacial, and limb dyskinesias of the dystonic or choreiform type (10,13). In general, DA agonists are no more effective than levodopa, although an open-label evaluation on apomorphine, the most potent dopamine agonist, suggested some motor benefit in patients with MSA (14). Uncontrolled studies of bromocriptine (10-80 mg) also noted benefit (15), whereas evaluations of pergolide yielded inconsistent results (16). A controlled trial of lisurude (up to 2.4 mg per day) observed improvement in one (who was also levodopa responsive) out of seven patients (17).

In PSP, local cerebral blood flow (LCBF) using xenon-enhanced computed tomography reveal lower striatal baseline values and no increase following the intravenous administration of levodopa compared to PD (18). Extensive degeneration of downstream basal ganglia structures may account for levodopa-unresponsive motor dysfunction (19). Thus, a review of 12 pathologically proven cases of PSP indicated that one-third of the patients had modest, but nonsustained, improvement while receiving levodopa with a peripheral decarboxylase inhibitor (20). Similarly, a retrospective review of clinically diagnosed cases showed that 54% had mild to moderate improvement with levodopa (21). Reports on dopamine agonists appear to be even more negative. Pramipexole (4.5 mg daily) for 2 mo was not effective (22), and lisuride (mean daily dose of 2.5 mg) provided no overall benefit when used alone and in combination with levodopa (23). Dyskinesias and other side effects are rare, with only isolated cases of levodopa-induced oromandibular dystonia, dyskinesia, and apraxia of eyelid opening (24-26).

A review of 14 pathologically proven CBD cases found that virtually all developed asymmetric or unilateral akinetic-rigid parkinsonism and gait disorder, and that none had a dramatic response to levodopa therapy (27). A chart review of 147 clinically diagnosed CBD patients from eight major movement disorders centers noted that 92% received some kind of dopaminergic medication, specifically levodopa with a peripheral decarboxylase inhibitor (87%), bromocriptine or pergolide (25%), and selegiline (20%) (28). Overall, clinical improvement occurred in 24% receiving any of these dopaminergic agents, with levodopa being the most effective drug given at a median dose of 300 mg and ranging from 100 to 2000 mg. Dopamine agonists (pergolide and bromocriptine) and selegiline were less successful, producing 6% and 10% benefit, respectively. Parkinsonian signs improved the most, and dyskinesias were not observed even with high-dose levodopa. Side effects included drug-

associated worsening of parkinsonism, dystonia, myoclonus, and gait dysfunction, whereas nonmotor side effects included gastrointestinal complaints, confusion, somnolence, dizziness, and hallucinations. A relative failure or lack of efficacy of dopaminergic therapy in a parkinsonian patient with cortical dysfunction should raise the suspicion of CBD.

Cholinergic

Cholinergic neuronal depletion (29,30) as well as reductions in such enzymatic markers as cholineacetyltransferase (31-33) and acetylcholinesterase (33) occur in the atypical parkinsonian disorders, although with differences in the degree and distribution of affected neurons. For example, several cholinergic nuclei undergo degeneration in PSP (32,34,35), whereas immunohistochemical analyses of autopsy material indicate that in CBD the forebrain cholinergic system is more vulnerable than the midbrain (36). The generalized loss of striatal cholinergic interneurons accounts for observed reduction in DA-D2 receptors (37) and thus the ineffectiveness of dopaminergic drugs in PSP. Unfortunately, cholinergic replacement therapy alone has been no more effective in palliating symptoms, secondary to the severity of cholinergic deficits and the more widespread impairment of monoaminergic systems in PSP (38).

In patients with PSP, cholinergic stimulation by intravenous physostigmine had no significant motor or neurobehavioral effects at any dose, whereas cholinergic blockade by intravenous scopola-mine, in low and medium doses, impaired memory performance in PSP patients as well as normal individuals and exacerbated gait disability in some patients (39). Similarly, controlled trials of orally administered physostigmine failed to benefit any of the motor functions tested (40,41). An open study of the acetylcholinesterase inhibitor, donepezil, lasting 3 mo also did not appear to improve cognitive dysfunction or activities of daily living (38). A controlled trial of donepezil in 21 PSP patients did, however, suggest modest benefit in some cognitive measures but worsened mobility scores (42). The effect of donepezil on motor dysfunction ranges from none (38) to deleterious (42). Similarly, the direct cholinergic agonist RS-86 did not improve motor function, eye movements, or psychometric performance in a controlled trial in 10 PSP patients (43).

In clinically diagnosed CBD cases, 27% received anticholinergics, which briefly benefited some individuals but were often poorly tolerated (28).

Adrenergic, Serotoninergic, GABAergic, Glutamatergic

Neurotransmitter systems downstream from the degenerating nigrostriatal dopaminergic pathway have also been targeted therapeutically. The rationale for these pharmacological interventions parallels that for DA replacement, i.e., the restoration of transmitter function, lost as a consequence of the degenerative process.

Adrenergic system dysfunction occurs in atypical parkinsonian disorders and could contribute to clinical disability. For example, there is degeneration of the locus ceruleus in PSP, where quantitative autoradiographic analysis of tissue sections shows a dramatic reduction in a-2 adrenoceptor density compared to controls (44). Nevertheless, a randomized blinded study revealed that the a-2 adrenergic antagonist idazoxan improved balance and manual dexterity in about half of PSP patients (45), whereas a similarly designed evaluation of efaroxan, another potent a-2 antagonist, did not significantly alter any of the assessed measures of motor function (46).

The effect of serotoninergic drugs in the atypicals has not been extensively studied. Open-label evaluations suggested methysergide, a serotonin 5HT2 receptor antagonist that blocks the facilitatory effects of raphe stimulation on bulbospinal neurons, affords relief to some PSP patients when used alone or in combination with antiparkinsonian agents (47,48); marked improvement was reported in patients with severe dysphagia (48). These studies, however, have not been replicated, and methysergide is no longer being used owing to its clear side effects (e.g., retroperitoneal fibrosis).

y-Aminobutyric acid (GABA) system function has been assessed in the atypical parkinsonian disorders using PET with [11C]flumazenil. GABA-type A/benzodiazepine receptor binding appears to be decreased in the brainstem and cerebellum of MSA patients with MSA-C, but not in MSA-A syndrome; however, binding still remains largely preserved in the cerebral hemispheres, basal ganglia, thalamus, and brainstem as well as cerebellum in both MSA groups compared to normal controls (49). Results from a randomized blinded study of vigabatrin, an irreversible inhibitor of GABA-tran-saminase, given to patients with MSA-C at a daily oral dose of 2-4 g for 4 mo, indicate that agents that increase central GABA concentrations are unlikely to confer symptomatic benefit (50).

In PSP, PET studies revealed a 13% global reduction in [nC]flumazenil binding, particularly in the anterior cingulate gyrus (51), and a reduced density of GABA neurons was seen in the caudate nucleus, ventral striatum, and internal and external pallidum (52). A controlled study of Zolpidem, a hypnotic with putative GABA-A receptor agonist activity, at doses of 5-10 mg, found improvement in parkinsonian signs (>20% improvement), dysarthria, and eye movements, although sedation appeared at the highest dose (53). In clinically diagnosed CBD, benzodiazepines, primarily clonazepam, reportedly improves myoclonus (23%) and dystonia (9%) (28), whereas clinical experience suggests that baclofen and tizanidine can have a modest beneficial effect on rigidity and tremor (54).

Possible involvement of glutamatergic systems in the atypical parkinsonian syndromes has been little explored, although some studies have addressed the therapeutic efficacy of drugs purporting to inhibit glutamate receptors of the N-methyl-D-aspartate (NMDA) type. For example, an uncontrolled study of the NMDA antagonist, amantadine, in eight patients with MSA-C lasting on average for over 40 mo suggested improved performance on measures of reaction and movement time (55). On the other hand, a short-term pilot study of amantadine at relatively high doses (400-600 mg/d) failed to find consistent benefit (56). Nevertheless, a salutatory response was observed in a blinded and controlled study involving 30 MSA-C patients that used lower doses of amantadine (200 mg/d) for 34 mo (57). Amantadine is neither much used nor very effective in patients with CBD (28).

Others

Tricyclics

A blinded trial of amitriptyline, a norepinephrine and serotonin reuptake blocker, beginning at 25 mg at bedtime and increasing to 50 mg in a week or two as needed, showed modest benefit in gait (58).

Botulinum Toxin

Dystonia can be a disabling feature in at least a third of CBD cases (28,59) as well as in other atypical parkinsonian disorders. Open-label studies of botulinum toxin (BTx)-A injections suggest that the treatment of limb dystonia depends on the severity of the deformity and degree of contractures (60), temporarily improving hand and arm function in early disease, while reducing pain, facilitating hygiene, and preventing secondary contractures in more advanced stages (61). BTx-A also reportedly improved orofacial dystonia using clinical and electromyogram (EMG) examinations as outcome measures (61), and can be particularly effective in the relief of blepharospasm and PSP-associated retrocollis (61), and apraxia of eyelid opening (62). Adverse effects are generally mild and transient, although severe dysphagia has been reported, with onset a few days after treatment and persisting for several months (63).

Neurosurgical Approaches

Stereotactic procedures, such as pallidotomy or pallidal/subthalamic nucleus (STN) stimulation, have had limited success in the atypical parkinsonian disorders (64), and are not generally recommended. On the other hand, bilateral STN stimulation reportedly benefited rigidity and akinesia in four MSA patients (65). Neural transplantation approaches are currently being explored in the atypicals, although beset by the same methodological and ethical issues associated with these procedures in PD. A placebo-controlled study is under way to assess the safety, tolerability, and efficacy of glial cell-derived neurotrophic factor (GDNF) continuously infused directly into striatum on motor dysfunction in PSP patients.

Electroconvulsive Therapy (ECT)

ECT appeared to improved motor signs in five PSP patients after nine treatments, although treatment-induced confusion and prolonged hospitalization limit the usefulness of this technique (66).

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