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DIAGNOSIS AND MANAGEMENT OF THEPATIENT WITH TREMOR

Tremor, the most common formf abnormal involuntary movementIM), is a rhythmic oscillation of a

ody region produced by alternatingtractions of reciprocally innervatedscles.I,llt occurs across awide spec-

um of neurological disorders and issily distinguished from other AIMsch as chorea, tics, and myoclonus bys rhythmic, repetitive and stereotypi-l appearance. Tremor causesnot onlyscomfort and social embarrassmentr patients, but also disability. Sinceccessful treatment depends on therrect diagnosis, it isimportant for theinician to recognize the various pre-ntations of tremor and associatedmptoms. This article describes theneral clinical approach to the patientho presents with tremor and reviewse most common tremor syndromesd their management.LASSIFICATION OF

When evaluating a patient whoresents with tremor, first categorizee tremor based on its positional prop-ties. Tremor can be divided into twoain types: rest and action. Restemor occurs in a body part that islaxed or supported against gravityd not involved in purposeful activi-es, for example, a hand tremor evi-ent when the upper limb rests on therm of a chair. When intermittent orinimal, a rest tremor can be broughtut or enhanced on examination byving the patient concentrate on othersks, such asperforming arithmetic orpening and closing the contralateraland. The presence of a rest tremor isirtually synonymous with parkin-nism, a condition with multiple eti-logies, including drug-induced (dueainly to neuroleptics) and othereurodegenerative disorders such asultiple system atrophy (MSA) orogressive supranuclear palsy (PSP).arkinson's disease (PD), however" is

KELVIN L. CHOU, MDkinsonism, comprising approximatelythree quarters of all casesseen in move-ment disorders centers.3

Action tremor ispresent during thevoluntary contraction of muscles, andcan be subdivided into four types: pos-tural, kinetic, isometric, and task-spe-cific. Postural tremor is seen during themaintenance ofan anti-gravity posture,such aswhen a patient holds a newspa-per up to read, whereas kinetic tremorhappens during voluntary movement.Often brought out using the finger-nose-finger test, a kinetic tremor canoccur at the beginning of the move-ment, during the course of the move-ment, or when approaching a target. Inthe latter condition, it is also known asan intention tremor, commonly seenwith cerebellar lesions. Isometric trem-ors are present during voluntary musclecontractions not accompanied bymove-ment, for example, when standing orwhen making a fist. Task-specific trem-ors, as the name implies, occur onlyduring specific activities, such as writ-ing, singing, or playing an instrument.The postural and kinetic tremor sub-types are seen far more frequently thanthe isometric and task-specific subtypes.

Just as each tremor type has mul-tiple etiologies, more than one tremortype can occur in the same condition.For example, PO patients often have anaction component in addition to theirclassic rest tremor, while the posturaltremor seenin essential tremor (ET) cansometimes persist when the hands restin the patient's lap. Though this overlapcan sometimes cause difficulty for thediagnosing clinician, a tremor that di-minishes with voluntaty movement islikelyto be a rest tremor, while a tremorthat is present at rest but worsens withmovement isprobably an action tremor.CLUES TO THE DIAGNOSISOF TREMOR

Once the predominant type oftremor is identified, a short differen-

1) and narrowed down based on cluesobtained from the clinical history andneurological examination. Historicalelements that are important to elicitinclude: 1) age at onset of the tremor,2) mode of onset (sudden vs. gradual),3) anatomical site(s) affected by thetremor, 4) rate of progression to othersites, 5) exacerbating and remitting fac-tors (such as alcohol responsiveness),6) histoty of alcohol abuse, and 7) fam-ily history of tremor. Furthermore,many pharmacologic agents can causetremor (Table 2), so a thorough reviewof the patient's medications is essen-tial. Associated examination findingsthat may shed light on the underlyingetiology of the tremor include bradyki-nesia or rigidity (PO); nystagmus, scan-ning speech, ataxia (cerebellar lesion);and a wide variation in tremor fre-quency (psychogenic).

If the diagnosis can be establishedon clinical criteria and the patient re-sponds to treatment, ancillaty studies areusually unnecessary. However, in youngpatients 50 years of age)with tremor,Wilson's disease (WD) should alwaysbe excluded, because it is devastatingand potentially life-threatening if leftuntreated. WD is a rare, autosomal re-cessive disorder believed to be causedbymutations in a gene encoding a cop-per transporting ATP-ase, resulting inabnormal deposition ofcopper in brain,liver and other organs of the body.Although classically described as"wing-beating", the tremor inWO canoccur in any pattern and is the mostcommon neurological manifestation ofthe disease.4 Most cases can be ruledout with a normal serum ceruloplas-min and 24-hour urinary copper ex-cretion. Other groups of patients inwhom investigational studies may behelpful include those with asymmetri-cal, cerebellar, or postural tremors.Asymmetrical or cerebellar tremorsmay result from focal lesions such asneoplasm, stroke, hemorrhage or de-

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tected with a magnetic resonance im-aging stUdy of the brain. Patients whopresent with postural tremor may havehyperthyroidism as an underlying eti-ology and should have their thyroidfunction checked.COMMON TREMORSYNDROMES AND THEIRMANAGEMENT

The most common tremor syn-dromes encountered in clinical prac-tice are ET and PD. Althoughcerebellar and psychogenic tremors arelessfrequently seen, they are importantfor the general clinician to be aware ofand will be briefly reviewed. Iatrogeniccauses of tremor are common, and mayeven mimic ET or PD. If a patient istaking a medication known to inducetremor (Table 2), that medicationshould be discontinued before initiat-ing other therapy.ESSENTIAL TREMOR (ET)

ET is the most common move-ment disorder.2 The diagnosiscan bemade when a persistent, bilateral,mainly symmetrical, postural and/orkinetic tremor of the hands or arms ispresent, without other neurologicalsigns or exposure to drugs that maycause tremor.5 A head tremor can alsobe part of the syndrome, either in ad-dition to the hand tremor or in isola-tion, as long as there is no dystonicpostUring. Clinical or historical fea-tures consistent with a diagnosis ofETinclude a positive family history andimprovement of the tremor with alco-

hol, but these features are not presentin every patient. Although ET canoccur at any age, its prevalence gener-ally increases with age.

ET tends to start distally in thearms with a typical flexion-extensionmotion at the wrists or abduction-ad-duction movement of the fingers. Al-though it may be unilateral in onset,both sides will eventually be involved.The most common anatomical sites ofinvolvement after the hands are (indecreasing order) the head, voice, legs,and chin.6 The tremor tends to in-creasewith stress, anxiety, excitement,emotional upset, fatigue or cold tem-perature. Although ET is sometimespreceded by the term "benign", manypatients dispute the adjective. ETcauses both physical and social disabil-ity. Simple tasks such as signing acheck, eating, drinking from a cup,shaving, brushing teeth, and dressingcan become frustrating ordeals, andembarrassed patients often avoid socialsitUations.

Primidone (Mysoline) and propra-nolol (Inderal) continue to be themainstays of treatment for ET.Primidone, an anticonvulsant, may bethe more effective agent, with approxi-mately 70% of patients experiencingbenefit, compared to 50% of patientson propranoloU Though dosages be-tween 50 and 250 mg of primidonedaily are usually needed to reducetremor,8 this medication should bestarted at a low dose and titrated slowlyup in order to minimize adverse effects.Primidone is usually prescribed in one

single daily dose at bedtime, bwith 25 mg, and increased bweekly until the desired treeffect is obtained or side effeDrowsiness is the most comeffect, but patients may also enausea, vertigo and unsteadinpranolol, a beta-blocker, is ufective between 240 and 320Patients are frequently refmovement disorders centersbeled as having "failed" protreatment, when in fact, andose was never administered.primidone, propranolol shstarted at low doses and increweeks, while monitoring blosure and pulse. Contraindicatthe use of propranolol includconduction block, heart failurand diabetes; side effectslightheadedness, fatigue, nadepression.

Other medications for ETerally not proven to be as efprimidone or propranolol,topiramate was recently showduce tremor in a double-blicebo-con trolledBenzodiazepines such as alpraclonazepam may alsohelp ifthhas concurrent anxiety.When the medications fatrol the tremor, surgery shouldsidered. Stereotactic ablatioventral intermediate nucleusthe thalamus used to be thesurgical procedure for controtremor, but has become obsothe advent of deep brain stim

Table 1. Common Tremor Types, Characteristics, and ExamplesType of TremorRest

Clinical CharacteristicsOccurs when body part is supportedagainst gravity and not engaged in activity

ActionPostural Occurs when body part is maintained

against gravityKinetic Occurs during voluntary movement

Intention Occurs toward the end of a goal-directedmovement

Common ExamplesParkinson's disease, drug-inducedparkinsonism, multiple system atropprogressive supranuclear palsyPhysiologic, essential tremor, drug-induced, alcohol withdrawal, post-traumatic, psychogenicPhysiologic, essential tremor, drug-induced, post-traumatic, psychogencerebellar lesionsCerebellar lesions

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(DBS) of the thalamus.]] ThalamicDES involves the placement of an elec-trode in the Vim nucleus. This elec-trode is connected to a wire, which istunneled under the skin and attachedto an implantable pulse generator lo-cated in the subcutaneous tissue over-lying the pectoralis muscle. This pulsegenerator can then be switched on oroff and programmed using a portablecomputer. The clinical effect of DESisidentical to that of ablation, but DBSholds an advantage over ablation inthat turning the stimulator off can re-verse its effects. Thalamic stimulationcan also be performed bilaterally withfewer side effects than thalamotomy.PARKINSON'S DISEASE (PD)

PD is a slowly progressiveneurodegenerative disorder character-ized clinically by the classic triad of resttremor, bradykinesia and rigidity. Al-though a fourth feature, postural in-stability, is sometimes included amongthe cardinal manifestations, this symp-tom isoften absent until the later stagesof disease. The diagnosis ofPD ismadeclinically, based on the presence of twoout of the three cardinal features andan unequivocal, sustained response todopaminergic therapy.3 PD isuncom-mon under the age of 40 and increasesrapidly in incidence above the age of60 for both males and females, with amean age at diagnosis of70.5 yearsY

Approximately 70% of PD pa-tients will have tremor as the initialsymptom.!3 The rest tremor in PD hasa frequency of 4-6 Hz and a character-istic "pill-rolling" action when the armand hands are involved. Asmentionedearlier, it is not unusual to see an ac-tion or postural tremor with PD, es-pecially in the later stages of disease,although this action component gen-erally has a higher frequency (~7 to 12Hz). In addition to the arms, PDtremor can also affect the legs, lips, jaw,chin, and tongue, but rarely involvesthe head, differentiating it from ET.The tremor tends to start intermit-tently in one arm, but gradually be-comes more constant, and generallyprogresses to the contralateral side a fewyears into the course of the disease.Similar to ET, factors that exacerbate

tremor in PD include anxiety,stress, or emotional states or ex-tremes in temperature.The treatment of PD re-mains symptomatic. Althoughresearch efforts are focusing onneuroprotective strategies andtreatment, there are no therapiesthat unequivocally slowthe pro-gressionof PD. Therefore, ifthepatient's symptoms are not lim-iting, treatment does not needto be initiated. Nevertheless,most patients with prominentrest tremor will opt for treat-ment because the tremor is an-noying or embarrassing.Unfortunately, the response ofparkinsonian tremor to pharma-cologic treatment ishighly vari-able.!

As a general rule, ifthe pa-tient is young 70 yearsof age)andhas other features of PD such asbradykinesia or rigidity in addition totremor, most PD experts would recom-mend initiating treatment with adopamine agonist such aspramipexole(Mirapex) or ropinirole (Requip).!4Although carbidopa/levodopa(Sinemet) is clearly the most effectiveanti-parkinsonian drug overall, it isassociated with long term motor com-plications such as fluctuations anddyskinesias, which can be delayed byinitiating therapy with a dopamineagonist.!5,!6The dopamine agonists areadministered three times a day; com-mon side effects include nausea, dizzi-ness, confusion and excessivesleepiness. In order to minimize theseadverse effects, the agonists should bestarted at a low dose and increasedweekly until a therapeutic dose isreached.

When the patient presentswith PDsymptoms at a more advanced age (>70years of age), carbidopa/levodopa is amore appropriate choice. Carbidopa/levodopa comes in both standard andcontrolled releaseformulations, but pa-tients tend to respond less predictablyto the controlled releaseformulation. Itis reasonable to begin with the 25/100mg dose of carbidopa/levodopa two tothree times a day, and then increase thedosage asneeded for the patient to func-

Table 2. Drugs that commonlycause tremorAlcohol (chronic use or withdrawal)Anti-arrhythmic drugsAmiodarone

ProcainamideAntiepileptic agents

CarbamazepineValproic acidBenzodiazepine withdrawal

CyclosporineLithiumNeurolepticsStimulants

AlbuterolAmphetaminesCaffeineCocaineTheophylline

tion independently.The anticholinergic trihexyphenidyl

hydrochloride (Artane) can improvetremor in PD, but isineffective in con-trolling the other cardinalmotor featuresof PD. Therefore, its use is limited tothe PD patient who presents with a pre-dominant tremor, but minimal bradyki-nesiaand rigidity,orasadjunctivetherapyfor a tremor that is resistant to thedopaminergic medications mentionedearlier. Sedation is the main side effectin addition to anticholinergic symptomssuch as blurred vision, dry mouth andurinary retention, and isusually the lim-iting factor in the use of this agent.Trihexyphenidylshould alsobe used cau-tiously in elderly patients because theyare more prone to developing cognitivedifficulties. Dosages needed to suppresstremor can range from 2 to 12 mg daily(maximum dosage 32 mg); again, it iswise to start at a low dose and titrate upfor effect. If trihexyphenidyl is ineffec-tive or poorly tolerated, propranolol(Inderal) or amantadine hydrochloride(Symmetrel) can be tried.

If the tremor is refractory to phar-macologic modalities, DES should beconsidered. The three anatomical sitesin which stimulation has been studiedfor PD include the thalamus, globuspallidus interna (GPi) and the sub-thalamic nucleus (STN). Thalamicstimulation is effective only for tremor,

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and therefore ishelpful for only a smallproportion of PO patients. Both GPiand STN stimulation have been shownto improve all cardinal features of PO,-including tremor,17 and either wouldbe an appropriate option for the ma-jority of patients.CEREBELLAR TREMOR

Cerebellar tremor most often pre-sents as a kinetic tremor with a promi-nent intention component.5 Theipsilateral arm or leg isusually affectedwhen a cerebellar hemisphere in in-volved. Lesions of the cerebellar ver-mis, or midline, often cause an isolatedpostural tremor of the trunk and head,commonly referred to as "titubation".Multiple sclerosis (MS) is the mostcommon cause; other causes includetumors, ischemic or hemorrhagicstrokes, alcoholic cerebellar degenera-tion, vitamin E deficiency, orparaneoplastic syndromes. Treatmentof the underlying cause (i.e.immunomodulatory therapy in MS,resection of a tumor) can sometimesresolve the tremor. For persistent cer-ebellar tremor, however, no medicationhas been proven to be helpful. A sen-sible approach is first to try the agentsthat are helpful for ET. If these fail torelieve the tremor, isoniazid or DBScan be considered. Isoniazid resultedin mild improvement in one small ran-domized crossover trial of six patientswith severepostural cerebellar tremor, 18while thalamic DBS showed some ben-efit for cerebellar tremor in a smallnumber of patients with MS.19PSYCHOGENIC TREMOR

Although there are no precise es-timates of the incidence and prevalenceof psychogenic tremors, clinical expe-rience suggeststhat it isnot rare. Whileit can be difficult to differentiate be-tween psychogenic and organic trem-ors, the characteristic that allpsychogenic tremors have in commonis variability in the tremor amplitudeand frequency.2 Because of this vari-ability, the tremor often cannot be eas-ily classified. Psychogenic tremorsfrequently increase in severitywith at-tention, and decrease when the patientis forced to concentrate on other tasks.

Other criteria useful in the diagnosisof this tremor include sudden or abruptonset, variable course with spontane-ous remissions, ability to perform somefunctions despite severe tremors, andunresponsiveness to anti-tremor medi-cations.2OOften, "false" signs will ap-pear on the neurologic examination,such as give-way weakness or bizarresensory findings. Psychotherapy is themain treatment approach.SUMMARY

Tremor isa common and disablingsymptom that isassociated with a largenumber of neurological disorders, in-cluding ET and PD. The positionalproperties of the tremor allow the clini-cian to generate a short list of diagnos-tic possibilities, which can then benarrowed down based on the clinicalhistory and the neurological examina-tion. A number of medical and surgi-caltherapies areavailablefor tremor, buta successful response to treatment de-pends on an accurate diagnosis.REFERENCES1. Wasielewski PG, Burns JM and Koller

We. Mov Disord 1998; 13SuppI3:90-100.2. Zesiewicz TA and Hauser RA. Neurol

Clin 2001; 19:651-680.3. Colcher A and Simuni T. Med ClinNorthAm 1999; 83:327-347.

4. Pfeiffer RF.Wilson's Disease. In WattsRL and Koller WC, ed. MovementDisorders: Neurologic Principles andPractice. New York: McGraw-Hill.1997:623-638.

5. Deuschl G, Bain P and Brin M. MovDisord 1998; 13 SuppI3:2-23.6. Koller WC, Busenbark K and MinerK. Ann Neuro11994; 35:717-723.

7. KollerWC, Busenbark K, Gray C, et al.Clin NeuropharmacoI1992; 15:81-87.

8. Koller WC and Royse VL. Neuro1986; 36:121-124.9. KollerWe. ArchNeurol 1986;43:42-4310. Connor GS.Neuro12002; 59:132-134.11. Benabid AL, Pollak P,Gao D, et al.]

Neurosurg 1996; 84:203-214.12. Van Den Eeden SK, Tanner CMBernstein AL, et al. Am ] Epidemio2003; 157:1015-1022.13. Hoehn MM and Yahr MD. Neuro1967; 17:427-442.

14. Olanow CW, Watts RL and KolleWe. Neuro12001; 56:S1-S88.15. Rascol 0, Brooks DJ, KorczynAD, eal. NE]M2000; 342:1484-1491.

16. Parkinson Study Group. ]AMA 2000284:1931-1938.17. Deep Brain Stimulation for Parkinson'

Disease Study Group. NE]M 2001345:956-963.18. Hallett M, Lindsey JW, Adelstein BDet al. Neuro11985; 35:1374-1377.19. Montgomery EB,Jr., Baker KB, KinkeRP,et al. Neuro11999; 53:625-628.20. Koller W, Lang A, Vetere-Overfield Bet al. Neuro11989; 39:1094-1099.

Kelvin L. Chou,MD, isa Movement DisordersFellowat theParkinsonDisease and Movement Disorders Center,PennsylvaniaHospital, UniversityoPennsylvania School of Medicine, andwill bejoining theDepartment ofClini-cal Neurosciences at Brown MedicalSchool as an Assistant Professorof Neurology in July.

CORRESPONDENCE:Kelvin L. Chou, MDParkinson's Disease and MovementDisorders Center330 South Ninth StreetPhiladelphia, PA 19107Phone: (215) 829-8593Fax: (215) 829-7552e-mail: chouk@uphs.upenn.edu

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