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Aylin Yaman, MD; Melahat Akdeniz, MD; How best to address these Hakan Yaman, MD, MS Antalya Training and Research Hospital, common movement disorders Clinic, Antalya, Turkey (Dr. A. Yaman); Akdeniz University, This review describes how to manage everything from Department of Family Medicine, Parkinson’s disease and disorders to restless legs Antalya, Turkey (Drs. syndrome and . Akdeniz and H. Yaman) hakanyaman@akdeniz. edu.tr

The authors reported no potential conflict of interest ovement disorders often require consultation with a relevant to this article. This Practice article was supported by the neurologist, and a working knowledge of established Akdeniz University Research recommendations and novel treatments can set the stage for optimal Management Unit. M 1 › Initiate neuroprotective long-term cooperative management. In this article, we review therapy with a monoamine therapeutic options for common movement disorders, including oxidase B inhibitor to slow the hypokinetic, hyperkinetic, and dyskinetic disturbances. progression of Parkinson’s dis- ease. With onset of functional impairment, give levodopa at Parkinson’s disease treatment: the lowest effective dose. A MAO-B inhibitor, levodopa are mainstays › Give for Parkinson’s disease, the most common hypokinetic move- essential causing ment disorder, is a chronic, progressive, neurodegenerative a patient distress, starting disease. It affects 1% of individuals older than 65 years and 4% at 20 to 40 mg twice daily to 5% of individuals older than 85 years. Its cardinal symptoms and increasing the dose (to a maximum of 320 mg/d) are resting tremor, bradykinesia, rigidity, a flexed posture, and until relief is achieved. B loss of postural reflexes. Resting tremor, referred to as “pill roll- ing” tremor, is 4 to 6 Hz and usually begins unilaterally.2,3 Asso- › Consider giving a dopa- ciated symptoms can include , , psychiatric mine receptor blocker for disorders, sleep disorders, and autonomic symptoms. or other tic z disorder; alternative agents Neuroprotective therapy is used to slow the pro- are clonidine or a newer gression of the disease, particularly in its early stage. The agent, . B monoamine oxidase B (MAO-B) inhibitor selegiline has proven effective in this regard2 (strength of recommendation Strength of recommendation (SOR) [SOR]: A). In randomized controlled studies, selegiline has A Good-quality patient-oriented delayed the need for levodopa for 9 to 12 months4 (SOR: A). evidence B  Inconsistent or limited-quality Another MAO-B inhibitor, rasagiline, has demonstrated neu- patient-oriented evidence roprotective effects as well5 (SOR: B). These medications may C  Consensus, usual practice, opinion, disease-oriented also be used with levodopa for symptom control and as adju- evidence, case series vant therapy in patients with motor fluctuations.2 A conven- tional dose of selegiline is 10 mg/d (5 mg at breakfast; 5 mg at lunch). Rasagiline is given at 1 mg/d. Concomitant use of cip- rofloxacin or other CYP1A2 inhibitors limits its effectiveness.6,7 z Symptomatic therapy is indicated at the onset of func- tional impairment. The dopamine precursor levodopa is the most widely used and effective drug for Parkinson’s disease

jfponline.com Vol 60, No 12 | DECEMBER 2011 | The Journal of Family Practice 721 symptoms, especially bradykinesia and rigid- Treating nonmotor symptoms of Parkin- ity. Use the lowest possible dose to control son’s disease can be challenging. For demen- symptoms (eg, 100 mg twice daily) and pro- tia in these patients, consider cholinesterase tect against motor complications of the drug7-9 inhibitors6,8 (SOR: C). For depression, selective (SOR: A). To prevent conversion of levodopa serotonin reuptake inhibitors are effective6,8,9 to dopamine outside the blood-brain barrier, (SOR: C). For , preferred agents combine it with the decarboxylase inhibitor are low-dose or quetiapine6,8-10 carbidopa. Dietary restriction of proteins may (SOR: C). Plan for supportive and symptom- be needed, because amino acids can interfere atic management of constipation, dysphagia, with the absorption of levodopa. sialorrhea, orthostatic hypotension, sleep dis- Especially with prolonged use, levodopa turbances, and urinary urgency.2,3 can cause disturbing adverse effects, such as nausea, vomiting, psychosis, cardiac ar- rhythmia, and orthostatic hypotension. Tremor Dyskinesias and motor fluctuations are Tremor is a common form of hyperkinesia, complications of long-term treatment presenting either as a primary disorder or as and are irreversible. Adding a cathecol-O- a symptom of another condition.11 By defini- methyltransferase (COMT) inhibitor, such as tion, it is a rhythmical, involuntary, oscillatory entacapone, to increase levodopa’s effective- movement of 1 or more body parts. Propranolol ness has been shown to reduce motor fluctu- are classified as rest or action tremors, with is more ations2,3,10 (SOR: B). Dopamine agonists such the latter being further categorized as pos- effective for as bromocriptine, ropinirole, and pramipex- tural (occurring while the patient maintains a hand and ole used in early Parkinson’s disease can also position against gravity) or kinetic (occurring forearm tremor reduce dyskinesias and motor fluctuations. during voluntary movement).2,10 than for head Dopamine agonists may be preferred to le- and voice vodopa in early Parkinson’s disease because Physiologic tremor: tremor. they are better tolerated and cause fewer ad- Pharmacologic Tx is usually not needed verse effects. Or they may be used as adjuncts Physiologic tremor is benign, high frequency for patients whose response to levodopa is (8-12 Hz), low amplitude, and postural. An ex- deteriorating or fluctuating3,7,8 (SOR: B). In aggerated form of this tremor may result from advanced disease, motor complications can anxiety, , pheochromocytoma, also be managed by augmenting levodopa hypoglycemia, excessive consumption, therapy with a dopamine agonist, MAO-B in- fever, withdrawal from opioids and sedatives, hibitor, or COMT inhibitor7,8 (SOR: A). and some medications. No drug treatment is , mainly benztropine necessary unless symptoms become bother- and trihexyphenidyl, may be used as symp- some. Correct the underlying cause or have tomatic treatment, especially in young peo- the patient avoid the triggering factor, and ple with early Parkinson’s disease and severe offer reassurance that the condition is not tremor. However, they are not the first drugs pathological or progressive.2,12 For anxiety, con- of choice due to limited efficacy and the sider cognitive-behavioral/relaxation therapy potential for neuropsychiatric side effects8 or (if tremor did not result (SOR: C). can reduce dyskinesia from withdrawal of benzodiazepines) or beta- in people with advanced Parkinson’s disease8 adrenergic antagonists (eg, propranolol).12,13 (SOR: C). For patients who have Parkinson’s disease with severe motor complications, : intermittent apomorphine injections can Try propranolol or first help reduce “off time” periods in the daily Essential tremor (ET) is the most common treatment cycle when the efficacy of drugs . It often results in func- wanes9 (SOR: B). tional disability and leads to many physical of the subtha- and emotional difficulties. ET is bilateral, lamic nucleus has only SOR C support for re- usually symmetric (although mild asymmetry ducing dyskinesias and off time.9 is possible), and postural or kinetic, typically

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affecting hands and forearms. The frequency term outcomes are lacking. ’s side of ET is 4 to 12 Hz. Cranial musculature may effects include weight loss and paresthesias. be involved in 30% of cases, affecting the Additionally, alprazolam, clonazepam, clozap- head and voice.3 Prevalence ranges from 4 to ine, , atenolol, sotalol, nadolol, and 40 cases per 1000 people. The age-adjusted nimodipine may reduce limb tremor2 (SOR: C). incidence is 17.5/100,000 per year; it peaks Alcohol reduces tremor amplitude in 50% to during the teen years and the fifth decade.2,3 90% of patients, but tremor may worsen after Autosomal dominant type of inheritance the effect of alcohol has worn off.15 is common, and a family history of ET is often For patients with essential hand tremor present, particularly with younger patients. that fails to respond to oral agents, consider The differential diagnosis includes Parkinson’s A16 (SOR: B). However, it is disease tremor; dystonic, cerebellar, rubral, also associated with dose-dependent hand and psychogenic tremors; and .3 Un- weakness16 (SOR: C). Botulinum toxin may like ET, many of these disorders have associ- reduce head and voice tremor16 (SOR: C), but ated neurologic, psychiatric, or systemic signs. hoarseness and swallowing difficulties may Treatment with propranolol or primi- occur after use for voice tremor.16 done is indicated if ET causes functional im- Invasive therapies may benefit patients pairment or social or emotional problems for with refractory tremor. Deep brain stimula- the patient.2,3,10,13 Both propranolol and prim- tion and are highly effective idone reduce limb tremor2,10,13 (SOR: B), but in reducing limb tremor13 (SOR: C). Each Tic disorders, only propranolol is approved by the US Food carries a small risk of major complications. including and Drug Administration (FDA) for treat- Some deep brain stimulation adverse events Tourette ment of ET. Propranolol is more effective for may resolve with time. Other adverse events syndrome, hand and forearm tremor than for head and may resolve with adjustment of stimulator rarely require voice tremor. Start propranolol at 20 to 40 mg settings. No evidence exists for surgical treat- drugs. twice a day and increase the dose as needed ment for voice and head tremor or for gam- to achieve symptom relief.14 ma-knife thalamotomy.13 A maintenance dose of 240 to 320 mg/d may be needed. Major adverse effects are fa- Drug-induced tremor tigue, sedation, depression, and erectile dys- Drugs with the potential to cause postural function. Contraindications to propranolol tremor, intention tremor, or rest tremor in- include asthma, second-degree atrioventric- clude the following: 15 ular block, and insulin-dependent diabetes. • alcohol (chronic) If starting with primidone alone, pre- • amiodarone scribe at a dose <25 mg at bedtime and in- • amphetamines crease the dose slowly over several weeks to • beta-adrenergic agonists prevent onset of nausea, vomiting, sedation, • caffeine confusion, or ataxia. The maximum allow- • calcitonin able dose is 750 mg/d in 3 divided doses.10 • carbamazepine Primidone and propranolol may be used • cocaine in combination to treat limb tremor when • cyclosporine monotherapy is insufficient (SOR: B).13 • dopamine Thirty percent of patients with ET will not • lithium respond to propranolol or primidone. An alter- • metoclopramide native choice is the gabapen- • neuroleptics tin10,12–14 (SOR: C). However, clinical experience • procainamide with it is limited. Lethargy, fatigue, decreased • steroids libido, dizziness, nervousness, and shortness of • theophylline breath are adverse effects of ; they • thyroid hormones are usually mild and tolerable.13 Topiramate is • tricyclic antidepressants another option that seems to be as effective as • trifluoperazine gabapentin10,13 (SOR: C), but studies of long- • valproic acid CONTINUED

jfponline.com Vol 60, No 12 | DECEMBER 2011 | The Journal of Family Practice 723 With drug-induced tremor, carefully as , , and evaluate a patient’s need for the drug. Dis- are the most effective treatment for tics20 continue the offending agent if possible, or (SOR: B). Tetrabenazine is a promising new try lowering the dose. dopamine-depleting drug; controlled trials are ongoing2,20 (SOR: B). Clonidine, an al- Psychogenic tremor: pha 2-adrenergic agonist, is useful in treat- A history of somatization is a clue ing patients with Tourette syndrome, helping Psychogenic tremor can occur at rest or dur- to improve sleep and attention2,21 (SOR: C). ing postural or kinetic movement. Clinical Medically refractory motor and disabling features include an abrupt onset, a static phonic such as coprolalia can be ame- course, spontaneous remission, and unclassi- liorated by botulinum toxin injections21 fiable tremors.17 Psychogenic tremor increas- (SOR: B). Deep brain stimulation is being used es under direct observation and decreases at an increasing rate for medically refractory with distraction. Patients with psychogenic tics in Tourette syndrome21 (SOR: B). tremor often have a history of somatization.18 Electrophysiologic testing can help confirm the diagnosis. If remission does not occur : spontaneously, patients may find relief with Dopamine agonists are preferred psychotherapy or placebo.19 Restless legs syndrome (RLS) is a disorder Restless legs characterized by sensory symptoms and mo- syndrome can tor disturbances of the legs, mainly during rest. occur secondary Tic disorders: Treatment may not be necessary for patients to iron Opt for dopamine receptor blockers with mild or sporadic symptoms. For moder- deficiency Tics are involuntary or semivoluntary move- ate to severe RLS with significant impairment, and uremia; ments or sounds that are sudden, brief, dopamine agonists are the preferred agents22 correction of intermittent, repetitive, nonrhythmic, unpre- (SOR: A). RLS can also occur secondary to the underlying dictable, and purposeless. Tics can occur in such conditions as iron deficiency and ure- disorder is key. any part of the body.20 mia, and correction of the underlying disor- The most common tic disorder is der is the goal. Prescribe iron replacement Tourette syndrome—a combination of mo- for patients with a ferritin level <50 ng/mL22 tor and phonic tics with onset before age 21. (SOR: C). Medications known to cause or It affects approximately 5 to 10 children out exacerbate the symptoms of RLS are anti- of 10,000. Boys are more commonly affected dopaminergic agents (such as neuroleptics), than girls. Attention deficit hyperactivity dis- diphenhydramine, tricyclic antidepressants, order frequently accompanies this syndrome.2 alcohol, caffeine, lithium, and beta-blockers. If The goal of treatment with any tic disorder a patient is taking medications that exacerbate is to improve social functioning, self-esteem, symptoms of RLS, discontinue them and use and quality of life. Education and support of appropriate substitutes22 (SOR: C). patients is important. Tic disorders, includ- ing Tourette, rarely require drugs. But if tics become too distressing, first-line treatment : would be a dopamine modulator, tetrabena- Clonazepam for essential disorder zine, or clonidine. Randomized controlled Myoclonus is a brief, sudden, shock-like move- trials with various neuroleptics have revealed ment caused by involuntary muscle contrac- dramatic reductions in tic severity. How- tions or lapse of muscle contraction (asterixis). ever, many patients do not tolerate the acute Given the complex origins of myoclonus, adverse effects (most commonly sedation, multiple drugs may be needed. Essential my- weight gain, depression, lethargy, and akathi- oclonus is disabling and can be treated with sia), and prolonged treatment confers a small clonazepam. Start with 0.25 mg orally twice risk of . Behavioral therapy is daily, and increase the dosage over 3 days to an important part of management.20 1 mg/d23 (SOR: C). Most cases of myoclonus Dopamine-receptor blocking drugs such are secondary due to drugs such as lithium,

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toxins, advanced liver disease, infections in- postures. Primary dystonia can be treated cluding human immunodeficiency virus, de- successfully with high doses of trihexyphe- mentia, and brain lesions. Treatment should nidyl alone, starting with 1 mg orally per day also address the underlying disorder.2,23 and increasing gradually to 6 to 80 mg/d until symptoms are controlled; or in combination with , starting with 10 mg orally once daily and increasing to a maximum dose of 30 Chorea is an abnormal involuntary move- to 120 mg/d1,2 (SOR: C). ment disorder described as “a state of exces- Consider botulinum neurotoxin injec- sive, spontaneous movements, irregularly tion for focal upper extremity dystonia and timed, nonrepetitive, randomly distributed, adductor spasmodic dysphonia16 (SOR: B). and abrupt in character.”24 Treatment of chorea is symptomatic, aiming to reduce morbidity and prevent Ataxia complications. Haloperidol and fluphen- Ataxia is an unsteady gait associated with azine are effective but can impair voluntary cerebellar dysfunction, proprioceptive de- movements2,10,25 (SOR: C). The dopamine- fects, or both. Ataxia may be primary (Fried- depleting drugs reserpine and tetrabenazine reich ataxia and spinocerebellar ataxia) or are also effective2,10,25 (SOR: C). GABAergic secondary to stroke, trauma, alcoholic de- drugs, such as clonazepam, gabapentin, and generation, multiple sclerosis, vitamin B12 Consider valproate, can be used adjunctively.10,25 deficiency, and hydrocephalus. Treatment, botulinum when possible, should target the underlying neurotoxin cause.1,2 JFP injection for Dystonia focal upper Dystonia is a syndrome involving sustained Correspondence extremity contractions of opposing muscles that cause Hakan Yaman, MD, Akdeniz University, Department of Family Medicine, Antalya, Turkey 07058; hakanyaman dystonia and twisting, repetitive movements and abnormal @akdeniz.edu.tr adductor . References 1. Deuschl G, Bain P, Brin M. Consensus statement of the Move- overview. Accessed May 12, 2010. ment Disorder Society on Tremor. Ad Hoc Scientific Commit- 13. Zesiewicz TA, Elble R, Louis ED, et al. Practice parameter: tee. Mov Disord. 1998;13(suppl 3):2-23. therapies for essential tremor. Neurology. 2005;64:2008-2020. 2. Yaman A, Yaman H, Rao G. Tremors and other movement disor- 14. Elble RJ. Tremor: clinical features, pathophysiology, and treat- ders. In: Mengel MB, et al, eds. Family Medicine Ambulatory Care ment. Neurol Clin. 2009;27:679–695. and Prevention. 5th ed. New York: McGraw-Hill; 2009:400-407. 15. Smaga S. Tremor. Am Fam Physician. 2003;68:1545-1552. 3. Harris MK, Shneyder N, Borazanci A, et al. Movement disor- ders. Med Clin North Am. 2009;93:371-388. 16. Use of botulinum neurotoxin for the treatment of movement disorders. AAN summary of evidence-based guidelines for 4. Palhagen S, Heinonen E, Hagglund J, et al. Selegiline slows the clinicians. 2008. Available at: http://www.aan.com/practice/ progression of the symptoms of Parkinson disease. Neurology. guideline/uploads/280.pdf. Accessed May 25, 2010. 2006;66:1200-1206. 17. Redondo L, Morgado Y, Durán E. Psychogenic tremor: a posi- 5. Olanow CW, Rascol O, Hauser R, et al. A double-blind, tive diagnosis [ in Spanish]. Neurología. 2010;25:51-57. delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med. 2009;361:1268-1278. 18. Schwingenschuh P, Katschnig P, Seiler S, et al. Moving toward 6. Zesiewicz TA, Sullivan KL, Arnulf I, et al. Treatment of nonmotor ‘‘laboratory-supported’’ criteria for psychogenic tremor. Mov symptoms of Parkinson disease. Neurology. 2010;74:924-931. Disord. 2011;Sep 28. [Epub ahead of print]. 7. Suchowersky O, Reich S, Perlmutter J, et al. Practice param- 19. McKeon A, Ahlskog JE, Bower JH, et al. Psychogenic tremor: eter: diagnosis and prognosis of new onset Parkinson disease long-term prognosis in patients with electrophysiologically (an evidence-based review). Neurology. 2006;66:968-975. confirmed disease.Mov Disord. 2009;24:72–76. 8. Rao SS, Hofmann LA, Shakil A. Parkinson’s disease: diagnosis 20. Shprecher D, Kurlan R. The management of tics. Mov Disord. and treatment. Am Fam Physician. 2006;74:2046-2054. 2009;24:15-24. 9. The National Collaborating Centre for Chronic Conditions. 21. Kenney C, Kuo SH, Jimenez-Shahed J. Tourette’s syndrome. Parkınson’s Dısease. National Clinical Guideline for Diagnosis and Am Fam Physician. 2008;77:651-658. Management in Primary and Secondary Care. 2006. Available at: 22. Bayard M, Avonda T, Wadzinsky J. Restless legs syndrome. Am http://www.nice.org.uk/nicemedia/live/10984/30087/30087.pdf. Fam Physician. 2008;78:235-240. Accessed May 12, 2010. 23. Caviness JN. Pathophysiology and treatment of myoclonus. 10. Jankovic J. Treatment of hyperkinetic movement disorders. Neurol Clin. 2009;27:757-777. Lancet Neurol. 2009;8:844-856. 24. Barbeau A, Duvoisin RC, Gerstenbrand F, et al. Classification 11. Kerlsberg G, Rubenstein C, St Anna L, et al. Differential diag- of extrapyramidal disorders. J Neurol Sci. 1981;51:311-327. nosis of tremor. Am Fam Physician. 2008;77:1305-1306. 25. Vertrees SM, Berman SA. Chorea in adults: treatment & man- 12. Burke DA, Hauser RA, McClain T. Essential tremor. Avail- agement. Available at: http://emedicine.medscape.com/ able at: http://emedicine.medscape.com/article/1150290- article/1149854-treatment. Accessed February 12, 2010.

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