Movement Disorders: Overview and Treatment Options

Transcription

1 Movement Disorders: Overview and Treatment Options Ali Samii, MD, and Bruce R. Ransom, MD, PhD Educational Objectives Review the terminology used to describe movement disorders. Discuss individual movement disorder syndromes, including essential tremor, Parkinson s disease, dystonia, myoclonus, chorea, tic disorders, tardive dyskinesia and akasthisia, restless limbs syndrome, and Wilson s disease. Review current treatment options for individual movement disorders. Introduction The area of movement disorders is a subspecialty of neurology focusing on a variety of conditions that are characterized by hypokinetic, hyperkinetic, or abnormally coordinated movements. These conditions include tremor, parkinsonism, dystonia, myoclonus, chorea, ballismus, ataxia, tic disorders, dyskinesia, akathisia, restless limbs, and others. The term movement disorders may be used to refer to either abnormal movements or to syndromes that cause these abnormal movements. The classification of movement disorders is based on phenomenology, individual syndromes, or etiology. In this article, we will first review the terminology used to describe movement disorders, then briefly discuss individual movement disorder syndromes. The focus of this article is on treatment options. Terminology A tremor is a rhythmic oscillation of a body part by alternating or synchronous contraction of agonist and antagonist mus- Dr. Samii is Associate Professor and Dr. Ransom is Warren Magnuson Professor and Chair, both in the Department of Neurology at the University of Washington School of Medicine in Seattle, Washington. Dr. Samii is Director of the Seattle Parkinson Disease Research, Education and Clinical Center (PADRECC) at the Seattle Veterans Affairs Puget Sound Health Sciences Center. Dr. Ransom is a member of P&T s editorial board. cles. 1 Usually, the hands are involved, but the head, jaw, voice, tongue, and the lower limbs may also be affected. A resting tremor occurs while a limb is not active or when it is at complete rest against gravity. The resting tremor in Parkinson s disease (PD) affects the upper limbs asymmetrically. An action tremor, such as that seen in essential tremor (the most common movement disorder), can be: postural, as when a limb maintains position against gravity (e.g., with the hands in the outstretched position). intention (terminal), as observed in the finger-to-nose-tofinger test. task-specific (observed while a person is performing a certain activity, such as writing). Parkinsonism is a nonspecific term that refers to a combination of signs seen in PD. These include tremor, rigidity, bradykinesia, and postural instability. PD is defined more specifically, with gradations of diagnostic certainty (Table 1). 2 Dystonia is an abnormal sustained muscle contraction causing twisting or turning around one or multiple joints. 3 It may affect the neck (cervical dystonia or torticollis), eyelids (blepharospasm), limbs, trunk, or vocal cords (spasmodic dysphonia). Dystonia can be focal, segmental, or generalized. Writer s cramp is a focal hand dystonia. With segmental dystonia, an entire limb or trunk is involved. Generalized or multifocal dystonia affects multiple body parts. Myoclonus may be positive or negative. Positive myoclonus is a sudden, brief muscle contraction; a negative myoclonus (e.g., asterixis) is an interruption of muscle contraction in the extended arm and wrist that causes inhibition of the activated muscle. 4 Chorea, meaning dance in Greek, resembles exaggerated fidgetiness. The movements are usually generalized and purposeless. In mild cases, chorea may be blended into natural movements and may appear purposeful. Choreoathetosis refers to slow and writhing movements. Ballismus is a large-amplitude, sometimes violent, proximal chorea. It usually occurs acutely on one side of the body (hemiballismus) after an infarct in the contralateral subthala- 228 P&T April 2005 Vol. 30 No. 4

2 mic nucleus (STN) or with STN stimulation for the treatment of PD. Ataxia refers to impaired motor coordination that is usually related to disorders of the cerebellum or its connections with the brain and spinal cord. It is characterized by slurred speech, nystagmus, dysmetria (undershooting or overshooting a target with trajectory limb movements), poor dexterity, and a wide-based gait. There are no proven drug treatments for ataxia caused by primary degenerative cerebellar syndromes. The therapy for secondary ataxia syndromes (e.g., toxic/metabolic, drug-induced, paraneoplastic, or Wilson s disease) would involve treatment of the primary condition. Tics are temporarily suppressible, abnormal movements or vocalizations. 5 Simple motor tics are isolated, brief, sudden movements that involve one body part. Complex motor tics may involve more than one body part and may have a component of dystonia, other complex movements, or even obscene gestures (copropraxia). A simple vocal tic may be a grunt or a throat clearing. Complex vocal tics are more elaborate vocalizations, words or phrases, even profanity (coprolalia). Dyskinesia literally means abnormal movement. However, the term has evolved to refer to abnormal drug-induced involuntary movements, usually choreatic, dystonic, or a combination of both. Dyskinesia in PD patients results from the long-term complications of levodopa therapy. 6 Tardive dys- Table 1 Diagnosis of Idiopathic Parkinson s Disease (PD) Clinical Diagnostic Criteria Clinically possible PD One of asymmetrical resting tremor, asymmetrical rigidity, or asymmetrical bradykinesia Clinically probable PD Any two of asymmetrical resting tremor, asymmetrical rigidity, or asymmetrical bradykinesia Clinically definite PD Criteria for clinically probable PD Definitive response to antiparkinson medications Exclusion Criteria Exposure to drugs that can cause parkinsonism, such as neuroleptic agents, some antiemetic medications, tetrabenazine, reserpine, flunarizine, and cinnarizine Cerebellar signs Corticospinal tract signs Eye-movement abnormalities other than slight limitation of upward gaze Severe dysautonomia Early moderate-to-severe gait disturbance or dementia History of encephalitis, recurrent head injury, or a family history of PD in two or more family members Evidence of severe subcortical white-matter disease, hydrocephalus, or other structural lesions on magnetic resonance imaging that might explain parkinsonism kinesia refers to choreodystonic movements secondary to the long-term use of neuroleptic or antiemetic medications that have dopamine antagonist activity. 7 Akathisia is excessive motor activity that is intended to relieve a sensation of inner restlessness, which occurs either acutely or as a late complication of neuroleptic medications. 8 Patients display agitation, with an inability to remain seated, and are usually shifting their weight, or pacing. Restless limbs syndrome occurs as a distressing desire to move the limbs (usually the legs) while sitting or lying down. The disorder is relieved by walking. Symptoms worsen in the evening, and periodic limb movements may occur during sleep. 9 Treatment of Movement Disorder Syndromes Essential Tremor Essential tremor is a prevalent movement disorder. 10 The tremor is present during action, and the hands, head, and voice are affected to variable degrees. A family history is positive in most patients, with a dominant inheritance pattern and variable penetrance. 11 The occurrence of a family history is more common if the patient s relatives are examined. 12 Tremors are worsened by caffeine, stress, and associated medical disorders, such as hyperthyroidism, and they are relieved by alcohol. Medical Therapy The initial medication for essential tremor is usually either primidone (Mysoline, Xcel) or propranolol (e.g., Inderal, Wyeth). 13 The starting dose of primidone is 50 mg at bedtime, with the doses gradually increasing up to 750 mg daily. Side effects include somnolence, fatigue, cognitive problems, and ataxia. Propranolol should be started at 10 mg daily and titrated as tolerated to 320 mg daily. Adverse drug effects (ADEs) include bradycardia, hypotension, fatigue, bronchospasm, depression, and impotence. Primidone and propranolol can be administered together. Topiramate (Topamax, Ortho-McNeil), gabapentin (Neurontin, Pfizer), and the benzodiazepines (e.g., diazepam [Valium, Roche]) may also relieve tremors. Injections of botulinum toxin may also be helpful. 14,15 Surgical Options Thalamotomy When severe essential tremor is intractable to medical therapy, unilateral thalamotomy (surgical destruction of a small part of the thalamus) improves the contralateral tremor. Bilateral thalamotomy is rarely performed, because it can result in cognition and gait disturbances. Deep-Brain Stimulation Although the exact mechanism of deep-brain stimulation is unknown, the technique is thought to suppress neuronal activity in the target (in this case, the same part of the thalamus that would be destroyed in thalamotomy) by stimulating it at high frequency. Thalamic deep-brain stimulation is considered safer Vol. 30 No. 4 April 2005 P&T 229

3 than thalamotomy, 16 presumably because there is no significant destruction of brain tissue, the effects are considered reversible, and the degree to which the target is suppressed can be adjusted. Serious surgical complications include symptomatic brain hemorrhage (usually fewer than 3% of patients) and death (fewer than 1%). Parkinson s Disease The cardinal features of PD are resting tremor, rigidity, and bradykinesia. Postural instability is sometimes considered a cardinal feature, but this is a nonspecific finding that is usually absent in early PD, especially in younger patients. Nonmotor features may occur in PD, including autonomic dysfunction, cognitive and psychiatric changes, sensory symptoms, and sleep disturbances. The diagnostic criteria for PD have become more rigorous with gradations of diagnostic certainty (Table 1). 17,18 The prevalence of PD in industrialized countries is estimated at 0.3% of the general population; approximately 1% of people over 60 years of age are affected. 19,20 The prevalence is slightly higher in men than in women. 21 The mean age of onset is about 60 years, 22 but 5% of patients experience their first symptom before age The etiologic mechanism of PD is unknown, but aging, environmental factors, and a genetic predisposition probably all play a role. 24 The recent discovery of several genetic loci related to familial PD has led to the hypothesis that failure of the ubiquitin proteasome system and protein misfolding are the final common pathways in the pathogenesis of PD. 25 Medical Therapy There is no unequivocal neuroprotective agent currently available for PD. Vitamin E was not beneficial in a large multicenter trial in patients with early PD. 26 The efficacy of selegiline (Eldepryl, Watson), a monoamine oxidase-b (MAO-B) inhibitor, in delaying the initiation of levodopa is at least partially a consequence of symptomatic relief of motor symptoms rather than neuroprotection. 27 Patients with early PD who were treated for a year with rasagiline (Teva Pharmaceuticals), another MAO-B inhibitor, showed less functional decline than patients whose treatment with rasagiline was delayed for six months. 28 The issue of possible neuroprotection by MAO-B inhibitors remains unresolved. One pilot study suggested that high-dose coenzyme Q10 might slow symptom progression in early PD. 29 These results have yet to be confirmed in larger studies with longer followup periods. Controlled trials of dopamine agonists versus levodopa in early PD using functional imaging of the dopaminergic system have claimed a slower rate of disease progression in PD patients who were started on dopamine agonists. 30,31 However, these results are are still being debated, in part because of issues surrounding the accuracy of functional neuroimaging techniques as markers of disease progression. 32 In a controlled trial of intraventricular infusion of glial cell line derived neurotrophic factor (GDNF) in PD patients, GDNF did not improve motor symptoms. 33 In an open-label study, five PD patients who received GDNF infusions via catheters directly into the putamen improved after a year. 34 A larger controlled trial of bilateral intraputamenal GDNF infusion sought to confirm these findings, but no benefits over placebo were observed. 35 Treatment is initiated when motor symptoms cause disability. Anticholinergic agents are rarely used in younger patients, in whom tremor is the major symptom. The more definitive treatment of early PD consists of either a dopamine agonist or levodopa. Because dopamine agonists cause less dyskinesia than levodopa, 36,37 they are usually the initial therapy for younger patients. Side effects of dopamine agonists include nausea, hypotension, leg edema, vivid dreams, hallucinations (especially in elderly people with cognitive deficits), somnolence, and sleep attacks. 38 Dopamine agonists have less antiparkinson efficacy than levodopa does, but agonist monotherapy can sometimes control motor symptoms for the first two to five years. The nonergot agonists, such as pramipexole (Mirapex, Pfizer) and ropinirole (Requip, GlaxoSmithKline) may help to prevent rare ergot-related retroperitoneal, pulmonary, and cardiac valve fibrosis. Levodopa remains the most potent antiparkinson drug and is the backbone of therapy throughout much of the course of the disease. 2 It is the preferred initial drug in older adults and in those with cognitive deficits or serious comorbid conditions. Levodopa is combined with carbidopa (e.g., Sinemet, Bristol-Myers Squibb) or benserazide (e.g., Parlopa in Canada) to prevent peripheral conversion to dopamine by dopa-decarboxylase. Side effects of levodopa are similar to those of dopamine agonists, although somnolence, hallucinations, and leg edema are less common. Complications of long-term levodopa therapy include motor fluctuations, including end-of-dose wearingoff and on off phenomena, and dyskinesia. 39 Dividing protein intake throughout the day may help to reduce motor fluctuations. Controlled-release forms of levodopa may provide a longer duration of benefit, but their absorption is more unpredictable than immediate-release levodopa. Catechol-O-methyl transferase (COMT) inhibitors, such as entacapone (Comtan, Novartis) and tolcapone (Tasmar, Roche), prolong the halflife of circulating levodopa and improve end-of-dose wearingoff. 40 Tolcapone is more potent, but its use has declined significantly because of a few cases of fatal liver failure. 41 Dyskinesia can be alleviated with a lower levodopa dosage but at the expense of worsening motor symptoms. In patients with motor fluctuations and dyskinesia, adding a dopamine agonist to levodopa may help reduce motor fluctuations. It may also allow for levodopa reduction, which in turn alleviates dyskinesia. The subcutaneously injectable dopamine agonist apomorphine is useful for rapid treatment of off periods in PD. 42 However, given the severity of apomorphine-induced nausea, 230 P&T April 2005 Vol. 30 No. 4

4 premedication with domperidone (Motilium, Janssen) or trimethobenzamide (Tigan, King) is needed. Amantadine (Symmetrel, Endo) may also suppress dyskinesia, possibly by N-methyl-D-aspartate (NMDA) receptor antagonism. 43 Nonmotor Symptoms Nonmotor symptoms in PD may occur as part of the disease or as complications of treatment. These include depression, constipation, sleep disturbance, psychosis, cognitive impairment, orthostatic hypotension, drooling, and urinary urgency. Depression in PD is usually treated with a selective serotonin reuptake inhibitor (SSRI). 44 No controlled head-to-head studies have suggested that one SSRI is superior to another in PD. The aggressive use of multiple modalities (e.g., stool softeners, increased fiber intake, and suppositories) is indicated for treating constipation. Disorders of sleep in PD patients include daytime somnolence, sleep attacks, night-time awakenings caused by overnight bradykinesia, rapid-eye movement (REM) behavior disorder, and restless limbs or periodic limb movements. 45 Daytime somnolence and sleep attacks may be associated with dopamine agonists, and the agonist may have to be discontinued. 46 Overnight bradykinesia and restless limbs syndrome may be alleviated with a bedtime dose of long-acting levodopa, sometimes with entacapone, or a dopamine agonist. Clonazepam (Konopin, Roche) is effective in treating REM behavior disorder. Psychosis in PD patients is thought to be mostly druginduced, and it occurs more frequently in patients with dementia. Dopamine agonists are more likely than levodopa to cause hallucinations. 38 First, the agonist or anticholinergic agent should be discontinued, and the lowest dose of levodopa should be used. Adding an atypical neuroleptic drug may be necessary. Quetiapine fumarate (Seroquel, AstraZeneca) is the more popular atypical neuroleptic agent in therapy for PD. It causes fewer extrapyramidal ADEs than risperidone (Risperdal, Janssen) or olanzapine (Zyprexa, Eli Lilly), and there is no need for weekly or biweekly measurements of the complete blood count (CBC), as would be required with clozapine (Clozaril, Novartis). 47 Open-label studies have suggested that dementia and psychosis in PD may be treated with central cholinesterase inhibitors. 48 Rivastigmine tartrate (Exelon, Novartis) has been effective for dementia with Lewy bodies 49 and in treating the dementia associated with PD. 50 Another small randomized, controlled study showed that donepezil (Aricept, Esai/Pfizer) improved cognition in PD patients. 51 Memantine (Namenda, Forest), proven to be effective in moderate-to-severe Alzheimer s dementia, 52 has not been evaluated in a large, controlled study for dementia in PD, but it may prove to be useful. Treatment options for hypotension include reducing the dosage of antiparkinson medications, increasing the salt and fluid intake, and adding fludrocortisone acetate (Florinef, King) or midodrine (ProAmatine, Shire). Drooling may be reduced by the peripheral anticholinergic agent glycopyrrolate (Robinul, First Horizon), but this drug may worsen constipation. Injection of botulinum toxin into the salivary glands reduces drooling. 53 Urinary urgency may be treated with peripheral anticholinergic agents, such as oxybutynin (Ditropan, Ortho-McNeil) and tolterodine tartrate (Detrol, Pfizer) or with alpha-adrenergic blocking agents, such as prazosin (Minipress, Pfizer) and terazosin (Hytrin, Abbott). Unfortunately, the former agents worsen constipation and the latter agents exacerbate hypotension. Surgical Options Deep-Brain Stimulation For more than a decade, deep-brain stimulation of hyperactive nuclei has been used to help relieve motor symptoms in PD patients with severe motor fluctuations and dyskinesia. High-frequency stimulation of deep-brain targets presumably reduces neural activity in the tissue surrounding the electrode contact. The suppression of the target induced by this technique can be sculpted by adjustments of the electrode configuration, stimulation intensity, pulse width, and frequency. Bilateral stimulation of the internal globus pallidus (GPi) or the subthalamic nucleus (STN) helps to relieve PD motor symptoms. 54 Some researchers claim that bilateral STN stimulation is superior to bilateral GPi stimulation in PD patients because it allows a reduction in antiparkinson medications, 55 but the debate continues regarding the optimal stimulation target for PD. A large randomized, multicenter study comparing bilateral STN to bilateral GPi stimulation is currently under way. The adverse effects of deep-brain stimulation include brain hemorrhage, infarct, seizures, and death. Other complications include breakage of the leads, various hardware failures, malfunction of the pulse generator, and infected hardware. Side effects from the stimulation itself include gait disturbances and worsening dyskinesia, paresthesias, cognition, mood, and speech. The stimulation-related side effects may be reversible by adjusting stimulation parameters. The key to a successful outcome is appropriate patient selection. 56 Surgical patients must have clinically definitive PD with documented motor improvement after levodopa therapy. All attempts to optimize drug therapy must have failed to relieve motor fluctuations or dyskinesia. Patients should not have dementia, untreated psychiatric conditions, or serious medical illnesses. Dedication and commitment from patients and their families are essential for maintaining frequent follow-up visits. Restorative (Transplantation) Therapy In the first randomized sham surgery-controlled study of fetal mesencephalic tissue transplantation, younger patients showed some improvement in the medication-off state, but many patients experienced disabling dyskinesia. 57 The second randomized, controlled study found no significant motor improvement. 58 Most transplant recipients developed dyskinesia Vol. 30 No. 4 April 2005 P&T 231

5 Table 2 Drug Therapy for Movement Disorders Condition Essential tremor Parkinson disease (motor symptoms) Parkinson disease (non-motor symptoms) REM behavior disorder Psychosis Medication Propranolol (beta blocker) Primidone (anticonvulsant) Topiramate (anticonvulsant) Immediate-release carbidopa/ levodopa (levodopa is a precursor to dopamine, and carbidopa blocks conversion of levodopa to dopamine in the periphery) Controlled-release carbidopa/levodopa Ropinirole (non ergot-derived dopamine agonist) Pramipexole (non ergotderived dopamine agonist) Pergolide (ergot-derived dopamine agonist) Entacapone (catechol-o-methyl transferase inhibitor) Tolcapone (catechol-o-methyl transferase inhibitor) Selegiline (selective monoamine oxidase-b inhibitor) Trihexyphenidyl (central anticholinergic agent) Amantadine (N-methyl-Daspartate receptor inhibitor) Apomorphine (non ergotderived injectable dopamine agonist) Clonazepam (benzodiazepine) Quetiapine (antipsychotic agent) Clozapine (antipsychotic agent) Dose Range mg daily mg daily mg daily 25/100 or 25/250 from 1/2 tablet t.i.d. to as high as tolerated, depending on motor symptoms 25/100 and 50/200 1/2 tablet t.i.d. to as high as tolerated 0.25 mg t.i.d. to 5 mg q.i.d mg t.i.d. 1.5 mg q.i.d mg t.i.d. 1 mg q.i.d. 200 mg with each dose of carbidopa/levodopa 100 mg t.i.d. 5 mg b.i.d mg daily 100 mg b.i.d. t.i.d. 1 6 mg SQ injection for severe "off" episodes mg mg daily mg daily Side Effects Hypotension, bradycardia, fatigue, impotence, bronchospasm, depression Somnolence, cognitive impairment Somnolence, cognitive impairment, weight loss, paresthesias Nausea, somnolence, dyskinesia, hypotension, hallucinations Nausea, somnolence, dyskinesia, hypotension, hallucinations Nausea, more somnolence than levodopa, less dyskinesia than levodopa, sleep attacks, leg edema, hallucination, hypotension Nausea, more somnolence than levodopa, less dyskinesia than levodopa, sleep attacks, leg edema, hallucination, hypotension Same as ropinirole and pramipexole, plus cardiac valve, retroperitoneal and pulmonary fibrosis Exacerbates levodopa s side effects; diarrhea and bright-orange urine Exacerbates levodopa s side effects; diarrhea, rare liver failure (liver enzyme monitoring required) Nausea, insomnia, interaction with other monoamine oxidase inhibitors Dry mouth, dry eyes, constipation, hypotension, cognitive impairment, urinary retention Nausea, hypotension, hallucinations, confusion, edema Severe nausea, abdominal cramps, yawning, somnolence, hallucinations, hypotension Residual daytime somnolence, impaired cognition, worsening of sleep apnea Somnolence, worsening of motor symptoms, confusion Same as quetiapine plus possible agranulocytosis requiring frequent blood count measurements 232 P&T April 2005 Vol. 30 No. 4

6 Table 2 Drug Therapy for Movement Disorders, continued Condition Medication Dose Range Side Effects Dementia Rivastigmine (central cholinesterase inhibitor) mg b.i.d. Nausea and abdominal cramps Donepezil (central cholinesterase inhibitor) 5 10 mg daily Nausea and abdominal cramps Galantamine (central cholinesterase inhibitor) 4 12 mg b.i.d. Nausea and abdominal cramps Levodopa- and dopamine agonistinduced nausea Domperidone (peripheral dopamine antagonist) mg with each dose of carbidopa/levodopa or dopamine agonist No common side effects Levodopa-induced nausea Carbidopa alone (Lodosyn ) 25 mg with each dose of carbidopa/levodopa No common side effects Depression SSRIs SSRI adverse effects vary among individual drugs Orthostatic hypotension Fludrocortisone (mineralocorticoid) mg daily Hypertension, edema, fluid retention Midodrine (peripheral alphaagonist) mg daily Hypertension, piloerection, urinary retention Drooling Glycopyrrolate (peripheral anticholinergic agent) 2 8 mg daily Dry mouth, dry eyes, constipation, hypotension, urinary retention Botulinum toxin injections units Dry mouth, difficulty chewing or swallowing Urinary urgency Peripheral anticholinergic agents (e.g., tolterodine, oxybutynin) Dry mouth, dry eyes, constipation, hypotension, urinary retention Alpha-adrenergic blocking agents (e.g., prazosin, terazosin) Hypotension Dystonia Trihexyphenidyl 2 10 mg daily Dry mouth, dry eyes, constipation, hypotension, cognitive impairment, urinary retention Benztropine (central anticholinergic agent) 2 8 mg daily Dry mouth, dry eyes, constipation, hypotension, cognitive impairment, urinary retention Carbidopa/levodopa Smaller doses than for Parkinson s disease Nausea, somnolence, dyskinesia, hypotension, hallucinations Botulinum toxin injections for focal dystonia Depends on body part injected Depends on body part injected Myoclonus Valproic acid (anticonvulsant) 500 2,000 mg daily Somnolence, cognitive impairment, tremor, hair loss, weight gain, thrombocytopenia, elevated ammonia Clonazepam 1 4 mg daily Somnolence, cognitive impairment, fatigue Levetiracetam (anticonvulsant) 500 3,000 mg daily Somnolence, cognitive impairment, fatigue Primidone mg daily Somnolence, cognitive impairment, fatigue Vol. 30 No. 4 April 2005 P&T 233

7 Table 2 Drug Therapy for Movement Disorders, continued Condition Medication Dose Range Side Effects Chorea Neuroleptic (antipsychotic) agents Somnolence, cognitive impairment, parkinsonism, plus others Reserpine (monoamine depleter) mg daily Hypotension, depression, parkinsonism Tetrabenazine (monoamine vesicular transporter inhibitor) mg daily Hypotension, depression, parkinsonism Tic disorder Clonidine (central alphaadrenergic agonist) mg daily Hypotension Neuroleptic agents (quetiapine, risperidone, olanzapine, pimozide, haloperidol) Somnolence, cognitive impairment, dystonic reaction, parkinsonism, tardive dyskinesia Reserpine and tetrabenazine Hypotension, depression, parkinsonism Tardive dyskinesia Stop the offending drug first Dystonic dyskinesia only Trihexyphenydil or benztropine Dry mouth, dry eyes, constipation, hypotension, cognitive impairment, urinary retention Clozapine or quetiapine Somnolence, confusion, and agranulocytosis with clozapine Reserpine or tetrabenazine Hypotension, depression, parkinsonism Akathisia Stop the offending drug first No definitive drug therapy (see text) Restless limbs Ropinirole mg qhs, or more often Nausea, somnolence, leg edema, hypotension, hallucinations Pramipexole mg qhs, or more often Nausea, somnolence, leg edema, hypotension, hallucinations Controlled-release carbidopa/levodopa 50/200 1/2 tablet qhs, or more often Nausea, hypotension, somnolence Gabapentin (anticonvulsant) mg qhs or more often Somnolence, cognitive impairment, fatigue Clonazepam 0.25 mg 1 mg qhs or more often Somnolence, cognitive impairment, fatigue Wilson s disease Zinc acetate (blocks copper absorption) Trientene (heavy metal chelator) Penicillamine (heavy metal chelator) 50 mg t.i.d. 250 mg t.i.d. or q.i.d. 250 mg t.i.d. or q.i.d. Gastrointestinal upset and rarely pancreatitis Initial neurological worsening, bone marrow suppression, proteinuria, dermatitis Similar to trientene b.i.d. = twice daily; q.i.d. = four times daily; mg = milligrams; qhs = at bedtime; REM = rapid-eye movement; SQ = subcutaneous; SSRI = selective serotonin reuptake inhibitor; t.i.d. = three times daily. 234 P&T April 2005 Vol. 30 No. 4

8 that persisted after the withdrawal of dopaminergic therapy. Therefore, at present, fetal nigral transplantation is not a treatment option for PD. The negative results from fetal tissue transplantation have dampened the enthusiasm for stem-cell therapy. At present, there are no large-scale stem-cell human clinical trials for PD. Other Movement Disorders Dystonia Dystonia may be classified by the body part affected or by its etiology, including genetic forms. 3,59 Dopa-responsive dystonia is a rare genetic disorder that begins in childhood. Dystonia usually starts in one leg. There is a diurnal fluctuation, and patients respond dramatically to relatively low doses of levodopa. 60 Drug-induced dystonia may occur acutely or as a tardive phenomenon from exposure to neuroleptic agents, antiemetic therapy, and promotility drugs with dopamine antagonist activity, such as prochlorperazine (Compazine, GlaxoSmith Kline), promethazine (Phenergan, Wyeth) and metoclopramide (Reglan, Wyeth). Patients must avoid the offending drug and similar drugs in the future, and they should use centrally acting anticholinergic agents, such as benztropine mesylate (Cogentin, Merck) orally or intravenously. Although focal dystonias may be treated initially with anticholinergic agents, benzodiazepines, or muscle relaxants, these drugs are somewhat ineffective at doses that would not cause side effects. Therefore, botulinum toxin injections are the first line of therapy for most focal dystonias, including torticollis, blepharospasm, and focal limb dystonia. In selected cases, electromyographic guidance helps to localize the muscles targeted for injection. Treatment of generalized dystonia is more challenging, because botulinum toxin cannot be injected at high doses in multiple body parts. Anticholinergic agents, benzodiazepines, muscle relaxants, and anticonvulsants are frequently used. Other options for managing severe generalized dystonia include intrathecal baclofen (Lioresal, Novartis), 61 tetrabenazine (Xenazine or Nitroman, Prestwick), 62 and reserpine. 63 Tetrabenazine and reserpine act as monoamine depleters and may cause depression, hypotension, and druginduced parkinsonism. Bilateral pallidal deep-brain stimulation is effective in severe cases of generalized dystonia. 64 Myoclonus Myoclonus can be classified according to its site of origin, its etiology, or the body part involved. 4 Although the exact site of myoclonus is difficult to determine, cortical, subcortical (brainstem), and spinal (including propriospinal) types of myoclonus are described. Physiological myoclonus occurs in normal subjects and includes jerking movements during sleep as well as anxietyinduced or exercise-induced myoclonus. In essential myoclonus, there is no known cause and there are no gross neurological deficits. In symptomatic myoclonus, a progressive or static encephalopathy exists, and myoclonus is one of the clinical signs. In cortical myoclonus, the sensorimotor cortex is the site of origination; 65 therefore, cortical myoclonus is a fragment of epilepsy, and its treatment frequently involves anticonvulsant agents. The most commonly used drugs are valproic acid, clonazepam, and primidone. Levetiracetam (Keppra, UCB Pharma) has emerged as an effective antimyoclonic drug, 66 and it may also alleviate negative myoclonus, which has traditionally proved challenging to treat. 67 Chorea Chorea can be observed in patients with Huntington s disease, benign hereditary chorea, endocrine-mediated disorders (e.g., hyperthyroidism), or autoimmune-mediated disorders (e.g., Sydenham s chorea and lupus). Chorea is a major component of levodopa-induced dyskinesia in PD and neuroleptic-induced tardive dyskinesia. Therapy for chorea begins with treating the underlying condition or reducing or stopping the drug that is potentially causing it. The next step depends on the cause. In PD patients with levodopa-induced choreatic dyskinesia, drug adjustments are necessary (see Medical Therapy on page 230). In neuroleptic-induced choreatic tardive dyskinesia, the offending neuroleptic agent should be discontinued. If the patient requires antipsychotic therapy, an atypical neuroleptic agent should be used. Clozapine has proved the most efficacious among the neuroleptic drugs in alleviating tardive dyskinesia; however, it may cause agranulocytosis, and CBC monitoring is necessary. 68 Anticholinergic medications are not effective in alleviating chorea. In Huntington disease, treatment of chorea begins with a neuroleptic agent, but monoamine-depleting agents may also be used. Benzodiazepines may help suppress chorea in a variety of disorders. Ballismus, a condition in which the limbs fling violently and involuntarily, is rare. It usually occurs as hemiballismus, with only one side affected, after an infarct in the contralateral STN. The violent nature of ballismus dissipates over time, and the movements become choreatic. Its treatment is similar to that for chorea. Tic Disorders Tourette syndrome is a neuropsychiatric disorder characterized by motor and vocal tics. 5 Depression and obsessivecompulsive traits are common in Tourette syndrome and in tic disorders in general. Therefore, treating the underlying psychiatric conditions is extremely important in conjunction with treating the movement disorder. 69 Two classes of drugs are usually used as first-line therapy to suppress tics: alpha 2 -adrenergic agonists and neuroleptic agents. 70 Guanfacine (Tenex, A. H. Robbins) and clonidine (Catapres, Boehringer Ingelheim) are two alpha 2 -adrenergic agonists that are less effective than neuroleptic drugs in suppressing tics, but they have better side-effect profiles. Clonidine is commonly used in the U.S. with a starting dose of 0.1 Vol. 30 No. 4 April 2005 P&T 235

9 mg daily in adults. The dose may be slowly increased to 0.4 mg daily, and patients should be monitored for hypotension. Haloperidol (Haldol, Ortho-McNeil)and pimozide (Orap, Gate) have been the most commonly used neuroleptic agents for the treatment of tics. However, atypical neuroleptic drugs (e.g., risperidone, olanzapine, and quetiapine) have been also used. The benzodiazepines and even cannabis have also been used with variable success. Monoamine-depleting drugs (e.g., reserpine and tetrabenazine) suppress tics, but they should be used in conjunction with close monitoring for side effects. For patients with dystonic tics, muscle relaxants, anticholinergic agents, and other treatment modalities for dystonia, including botulinum toxin injections, are used. Neuroleptic therapy, which is frequently used to suppress myoclonic tics, should be avoided in those with dystonic tic disorders. Tardive Dyskinesia and Akathisia Tardive dyskinesia is typically choreatic, dystonic, or a combination of the two. It is usually a late complication of neuroleptic therapy, but it may occur rarely after repeated exposure to promotility or antiemetic agents that have dopamine antagonist activity. 68 Of course, it is best to prevent tardive syndromes by using the lowest dose of an atypical antipsychotic agent for the shortest possible duration. Once tardive dyskinesia is present, its treatment can be challenging. The data supporting the use of vitamin E and benzodiazepines are weak, although the sedative and anxiolytic effects of the benzodiazepines may suppress abnormal movements. There are no large-scale head-to-head studies comparing atypical neuroleptic agents among themselves. Clozapine and quetiapine are associated with the lowest reported cases of tardive dyskinesia. 68 Therefore, the offending neuroleptic agent should first be stopped. If the patient requires neuroleptic treatment, quetiapine should be tried initially. However, if psychosis prevails or tardive dyskinesia deteriorates, clozapine therapy with CBC monitoring may be necessary. Centrally acting anticholinergic drugs, such as benztropine or trihexyphenidyl (Artane, Lederle) may alleviate dystonic dyskinesia, but they do little for choreatic dyskinesia. Monoamine-depleting agents may also be used in intractable cases of tardive dyskinesia. 62 Neuroleptic-induced akathisia is characterized by dysphoria and motor restlessness. 8 Treatment of akathisia begins with discontinuation of the offending neuroleptic agent. If the patient requires neuroleptic therapy, using the lowest dose of an atypical antipsychotic agent, preferably quetiapine, is recommended. A number of drugs, including beta blockers, anticholinergics, clonidine, amantadine, and even opiates, have been somewhat successful in alleviating akathisia. Restless Limbs Syndrome Restless limbs syndrome is a common disorder with a prevalence of 5% to 15% in Western countries. 9 It is characterized by a distressing desire to move the legs, with motor restlessness brought on by rest. Symptoms worsen in the evenings and at night, and patients experience periodic limb movements during sleep. Although the syndrome is sometimes observed in patients with peripheral neuropathy, most of the time it is not accompanied by neuropathy. There is an association between restless limbs and a deficiency of brain dopamine and iron deficiency. 71 Therefore, checking iron and ferritin levels is part of the evaluation for this movement disorder. If iron deficiency is detected, it should be evaluated (with an anemia workup) and treated with iron supplementation. If a sleep study reveals sleep apnea together with periodic limb movements during sleep, the apnea should be treated. Symptomatic treatment of restless legs and limb movements during sleep usually begins with a dopamine agonist, such as pramipexole or ropinirole. 72 Dopamine agonists have longer durations of action compared with levodopa, and one or two evening or bedtime doses may suffice. If dopamine agonists are not well tolerated, a controlledrelease formulation of carbidopa/levodopa should be tried next, and the dose should be titrated as tolerated. Other adjunct medications include gabapentin, benzodiazepines, and lowpotency opiates as a last resort. Wilson s Disease Wilson s disease is a rare autosomal recessive disorder of copper metabolism that causes a buildup of the mineral in the liver, brain, eye, and other organs. It is a disease of children, adolescents, and young adults. 73 The neurological manifestations include large-amplitude tremor, dystonia, chorea, and ataxia. 74 Neurological manifestations may occur in the absence of hepatic disease. The diagnosis depends on a high index of suspicion, a low serum ceruloplasmin level, and high urinary excretion of copper. Medical therapies include (1) reducing copper in the diet (foods such as shellfish, liver, mushrooms, some legumes, chocolate, soy, bran, and avocado), (2) supplementing with zinc, and (3) using chelating agents such as penicillamine or trientine. In cases of chronic hepatic failure, liver transplantation is an option. Conclusion Advances in the treatment of PD and other movement disorders continue to provide new strategies in symptomatic management of motor and nonmotor symptoms. Atypical neuroleptic agents have significantly reduced the incidence of tardive dyskinesia. Newer or rediscovered older drugs, as well as functional neurosurgery, have provided better relief of motor fluctuations in PD. However, definitive neuroprotection and effective restorative therapy for degenerative diseases remain elusive. Neuroimaging techniques need to be refined to enhance our ability to follow disease progression at the cellular level. Future drug therapy for PD is focusing as much on neuroprotection as on alleviating motor symptoms. 236 P&T April 2005 Vol. 30 No. 4

10 References 1. Elble RJ. Physiologic and essential tremor. Neurology 1986; 36(2): Samii A, Nutt JG, Ransom BR. Parkinson s disease. Lancet 2004; 363(9423): Langlois M, Richer F, Chouinard S. New perspectives on dystonia. Can J Neurol Sci 2003(30 Suppl 1):S34 S Rivest J. Myoclonus. Can J Neurol Sci 2003(30 Suppl 1):S53 S Marcus D, Kurlan R. Tics and its disorders. Neurol Clin 2001; 19(3): , viii. 6. Luquin MR, Scipioni O, Vaamunde J, et al. Levodopa-induced dyskinesias in Parkinson s disease: Clinical and pharmacological classification. Mov Disord 1992;7(2): Llorca PM, Chereau I, Bayle FJ, Lancon C. Tardive dyskinesias and antipsychotics: A review. Eur Psychiatry 2002;17(3): Chung WS, Chiu HP. Drug-induced akathisia revisited. Br J Clin Pract 1996;50(5): Schapira AH. Restless legs syndrome: An update on treatment options. Drugs 2004;64(2): Louis ED. Clinical practice: Essential tremor. N Engl J Med 2001; 345(12): Watner D, Jurewicz EC, Louis ED. 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11 53. Lipp A, Trottenberg T, Schink T, et al. A randomized trial of botulinum toxin A for treatment of drooling. Neurology 2003; 61(9): Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson s disease. N Engl J Med 2001;345(13): Moro E, Scerrati M, Romito LM, et al. Chronic subthalamic nucleus stimulation reduces medication requirements in Parkinson s disease. Neurology 1999;53(1): Lozano AM. Surgery for Parkinson s disease. The five W s: why, who, what, where, and when. Adv Neurol 2003;91: Freed CR, Greene PE, Kordower JH, et al. Transplantation of embryonic dopamine neurons for severe Parkinson s disease. N Engl J Med 2001;344(10): Olanow CW, Goetz CG, Kordower JH, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson s disease. Ann Neurol 2003;54(3): Bressman SB. Dystonia genotypes, phenotypes, and classification. Adv Neurol 2004;94: Furukawa Y. Update on dopa-responsive dystonia: Locus heterogeneity and biochemical features. Adv Neurol 2004;94: Albright AL, Barry MJ, Shafton DH, et al. Intrathecal baclofen for generalized dystonia. Dev Med Child Neurol 2001;43(10): Jankovic J, Orman J. Tetrabenazine therapy of dystonia, chorea, tics, and other dyskinesias. Neurology 1988;38(3): Rojas VM, Davies RK. Reserpine treatment of comorbid Tourette s disorder and tardive dystonia. J Clin Psychiatry 1999;60(10): Kiss ZH, Doig K, Eliasziw M, et al. The Canadian multicenter trial of pallidal deep brain stimulation for cervical dystonia: Preliminary results in three patients. Neurosurg Focus 2004;17(1):E Mima T, Nagamine T, Nishitani N, et al. Cortical myoclonus: Sensorimotor hyperexcitability. Neurology 1998;50(4): Schauer R, Singer M, Saltuari L, et al. Suppression of cortical myoclonus by levetiracetam. Mov Disord 2002;17(2): Gelisse P, Crespel A, Genton P, et al. Dramatic effect of levetiracetam on epileptic negative myoclonus. Acta Neurol Scand 2003; 107(4): Fernandez HH, Friedman JH. Classification and treatment of tardive syndromes. Neurologist 2003;9(1): Jankovic J. Tourette s syndrome. N Engl J Med 2001;345(16): Leckman JF. Tourette s syndrome. Lancet 2002;360(9345): Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med 2004;5(4): Silber MH, Ehrenberg BL, Allen RP, et al. An algorithm for the management of restless legs syndrome. Mayo Clin Proc 2004; 79(7): ; erratum, 79(10): El-Youssef M. Wilson disease. Mayo Clin Proc 2003;78(9): Robertson WM. Wilson s disease. Arch Neurol 2000;57(2): Disclosure Dr. Ransom has no financial relationships to disclose. Dr. Samii has indicated the following relationships: grant/ research support: Allergan, Medtronics. Speaker s Bureau: Boehringer-Ingelheim (unpaid). 238 P&T April 2005 Vol. 30 No. 4

12 Continuing Education for Physicians and Pharmacists P&T 2005;30(4): ACPE Program # H01 Expiration Date: April 30, 2006 TOPIC: Movement Disorders: Over view and Treatment Options CME Accreditation This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Jefferson Medical College and MediMedia USA, Inc. Jefferson Medical College of Thomas Jefferson University, as a member of the Consortium for Academic Continuing Medical Education, is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians. All faculty/authors participating in continuing medical education activities sponsored by Jefferson Medical College are expected to disclose to the activity audience any real or apparent conflict(s) of interest related to the content of their article(s). Full disclosure of these relationships appears on the last page of the article. Continuing Medical Education Credit This CME activity is designed to assist physicians and other health care professionals who are P&T committee members in making formulary decisions. Its goal is to increase participants ability to recognize and treat important medical problems. Jefferson Medical College designates this continuing medical education activity for a maximum of one Category 1 credit toward the Physician s Recognition Award (PRA) of the American Medical Association. Each physician should claim only those credits that he/she actually spent in the educational activity. This credit is available for the period of one year from the date of publication. Although forms will be processed when received, certificates for CME credits will be issued every six months, in February and August. Interim requests for certificates can be made by contacting the Jefferson Office of Continuing Medical Education at (215) or by going online to Continuing Pharmacy Education Credit The Department of Health Policy, Thomas Jefferson University Hospital, is approved by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmaceutical education and complies with the Criteria for Quality for continuing pharmaceutical education programming. This program ( H01) is acceptable for 1.0 hour of continuing education credit (0.1 CEUs) in states that recognize ACPE-approved providers. Statements of Credit indicating hours/ceus will be mailed within six to eight weeks to participants who completed this activity and submitted a completed evaluation with payment. How to Apply for CE Credit 1. Each CE article is prefaced by learning objectives for participants to use to determine whether the article relates to their individual learning needs. 2. Read the article carefully, paying particular attention to the tables and other illustrative materials. 3. Complete the questions and fill in the answers on the evaluation form on the next page. 4. Complete the CE Registration and Evaluation Form. Type or print your full name and address in the space provided, and evaluate the activity as requested. In order for the form to be processed, all information must be complete and legible. 5. Payment of $10 per exam is required for processing and maintenance of records. Make checks payable to P&T. This processing fee is non-refundable. 6. Send the completed form, answer sheet, and $10 payment to: Department of Health Policy Thomas Jefferson University Attn: Continuing Education Credit 1015 Walnut Street, Suite 115 Philadelphia, PA Be sure to mail the Registration, Evaluation Form, and $10 payment within one year of the date of publication. After that date, this article will no longer be designated for credit and forms cannot be processed. Vol. 30 No. 4 April 2005 P&T 239

13 Continuing Education Questions for Physicians and Pharmacists TOPIC: Movement Disorders: Over view and Treatment Options ACPE Program # H01 CE Evaluation: Select the one best answer to each of the following questions, and record your response on the examination answer sheet. Complete the additional requested information. Forward the answer sheet, with appropriate payment, to the Department of Health Policy,Thomas Jefferson University Hospital, at the address indicated. A certificate of completion will be mailed within six to eight weeks of receipt of your exam/payment. (A minimum test score of 70% is required.) Multiple Choice Select the one correct answer. 1. Select the false statement concerning terminology related to movement disorders: a. Action tremor can be postural, intention, or task-specific. b. Signs seen in Parkinson s disease include tremor, rigidity, bradykinesia, and postural instability. c. Negative myoclonus is a sudden, brief muscle contraction, whereas positive myoclonus is an interruption of muscle contraction in the extended arm and wrist that causes inhibition of the activated muscle. d. Chorea resembles exaggerated fidgetiness. 2. Concerning movement disorders, select the false statement: a. Writer s cramp is a focal hand dystonia. b. The term choreoasthetosis refers to slow and writhing movements. c. Impaired motor coordination, ballismus, is characterized by slurred speech, nystagmus, dysmetria, poor dexterity, and a wide-based gait. d. Dyskinesia in patients with Parkinson s disease results from the long-term complications of levodopa therapy. 3. The following statement is false for the treatment of essential tremor: a. The starting dose for primidone is 50 mg at bedtime, with doses gradually increasing up to 750 mg daily. b. Side effects associated with primidone include somnolence, fatigue, cognitive problems, and ataxia. c. Propranolol should be started at 50 mg daily and titrated as tolerated to 320 mg daily. d. Topiramate, gabapentin, benzodiazepine, and botulinum toxin may help relieve tremor. 4. Which of the following statements is true regarding neuroprotective agents for Parkinson s disease? a. There is no unequivocal agent available at this time. b. Coenzyme Q10 may slow symptom progression in early Parkinson s disease. c. Vitamin E was not beneficial in a large multicenter trial in patients with early Parkinson s disease. d. all of the above 5. Which of the following statements concerning dopamine agonists is false? a. Dopamine agonists cause less dyskinesia than levodopa. b. Dopamine agonists have more antiparkinson efficacy than levodopa does. c. Dopamine agonists may be used as monotherapy for the first few years of Parkinson s disease. d. The side effects of dopamine agonists include nausea and hypotension. 6. Which of the following statements is true concerning pharmaceutical treatments of nonmotor symptoms of Parkinson s disease? a. Memantine was found to be effective in treating dementia associated with Parkinson s disease in large studies. b. Risperidone is associated with fewer extrapyramidal adverse drug effects compared with quetiapine in patients with Parkinson s disease. c. Drooling and urinary urgency can be treated with peripheral anticholinergic agents. d. Levodopa is more likely than dopamine agonists to induce hallucinations. 7. Regarding dystonia, which statement is incorrect? a. Botulinum toxin injections are the first line of therapy for most focal dystonias. b. Focal dystonias may first be treated effectively with anticholinergic agents, benzodiazepines, or muscle relaxants at any dose with no insurgence of side effects. c. Botulinum toxin is not appropriate for the treatment of generalized dystonia. d. Anticholinergic agents, benzodiazepines, muscle relaxants, and anticonvulsants are frequently used to treat generalized dystonia. 8. Which of the following statements is incorrect? a. In patients with cortical myoclonus, the most commonly used drugs are valproic acid, clonazepam, and primidone. b. Benzodiazepines may help to suppress chorea in a variety of disorders. c. Anticholinergic medications are very effective in alleviating chorea. d. Clozapine has the most proven efficacy among neuroleptic agents in alleviating tardive dyskinesia; however, it may cause agranulocytosis, and blood count monitoring is necessary. 9. Which of the following classes of drugs is/are used to treat tic disorders? a. alpha 2 -adrenergic agonists b. neuroleptic agents c. benzodiazepines d. all of the above 10. Regarding restless limbs syndrome, which statement is incorrect? a. There is an association between restless limbs and a deficiency of brain dopamine and iron. b. Symptomatic treatment of the syndrome begins with dopamine agonists. c. First-line medications include gabapentin and benzodiazepines. d. If dopamine agonists are not well tolerated, a controlledrelease formulation of carbidopa/levodopa should be tried next. 240 P&T April 2005 Vol. 30 No. 4

14 CE Registration and Evaluation Form Date of publication: April 2005 Title: Movement Disorders: Overview and Treatment Options Authors: Ali Samii, MD, and Bruce R. Ransom, MD, PhD Submission deadline: April 30, 2006 ACPE Program # H01 Pharmacy and Therapeutics A Peer-Reviewed Journal for Managed Care and Hospital Formulary Management Registration Name: Degree: Street address: Last 4 Digits of Social Security No. (Web ID): City: State: Zip: Telephone: Address: Check one: Physician Pharmacist Other Time needed to complete this CE activity in hours: 0.5 hr 1 hr 1.5 hr 2 hr Other Certification: I attest to having completed this CE activity. Signature (required) Date Answer Sheet Please fill in the box next to the letter corresponding to the correct answer 1. a b c d 6. a b c d 2. a b c d 7. a b c d 3. a b c d 8. a b c d 4. a b c d 9. a b c d 5. a b c d 10. a b c d Evaluation Rate the extent to which: Very High High Moderate Low Very Low 1. Objectives of this activity were met 2. You were satisfied with the overall quality of this activity 3. Content was relevant to your practice needs 4. Participation in this activity changed your knowledge/attitudes 5. You will make a change in your practice as a result of participation in this activity 6. This activity presented scientifically rigorous, unbiased, and balanced information 7. Individual presentations were free of commercial bias 8. Adequate time was available for Q&A 9. Which ONE of the following best describes the impact of this activity on your performance: This program will not change my behavior because my current practice is consistent with what was taught. This activity will not change my behavior because I do not agree with the information presented. I need more information before I can change my practice behavior. I will immediately implement the information into my practice. 10. Will you take any of the following actions as a result of participating in this educational activity (check all that apply) Discuss new information with other professionals Discuss with industry representative(s) Consult the literature Participate in another educational activity Other None Send the completed form and $10 payment (make checks payable to P&T) to: Department of Health Policy, Thomas Jefferson University, Attn: Continuing Education Credit, 1015 Walnut Street, Suite 115, Philadelphia, PA Vol. 30 No. 4 April 2005 P&T 241