DIAGNOSIS AND MANAGEMENT OF THEPATIENT WITH TREMOR

Tremor, the most common form

of abnormal involuntary movement(AIM), is a rhythmic oscillation of abody region produced by alternatingcontractions of reciprocally innervatedmuscles.I,llt occurs across a wide spec-trum of neurological disorders and iseasily distinguished from other AIMssuch as chorea, tics, and myoclonus byits rhythmic, repetitive and stereotypi-cal appearance. Tremor causes not onlydiscomfort and social embarrassment

for patients, but also disability. Sincesuccessful treatment depends on thecorrect diagnosis, it is important for theclinician to recognize the various pre-sentations of tremor and associated

symptoms. This article describes thegeneral clinical approach to the patientwho presents with tremor and reviewsthe most common tremor syndromesand their management.

CLASSIFICATION OFTREMOR

When evaluating a patient whopresents with tremor, first categorizethe tremor based on its positional prop-erties. Tremor can be divided into two

main types: rest and action. Resttremor occurs in a body part that isrelaxed or supported against gravityand not involved in purposeful activi-ties, for example, a hand tremor evi-dent when the upper limb rests on thearm of a chair. When intermittent or

minimal, a rest tremor can be broughtout or enhanced on examination byhaving the patient concentrate on othertasks, such as performing arithmetic oropening and closing the contralateralhand. The presence of a rest tremor isvirtually synonymous with parkin-sonism, a condition with multiple eti-

ologies, including drug-induced (duemainly to neuroleptics) and otherneurodegenerative disorders such asmultiple system atrophy (MSA) orprogressive supranuclear palsy (PSP).Parkinson's disease (PD), however" is

by far the most common cause of par-

KELVIN L. CHOU, MD

kinsonism, comprising approximatelythree quarters of all cases seen in move-ment disorders centers.3

Action tremor is present 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 of an anti-gravity posture,such as when 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 as

an intention tremor, commonly seenwith cerebellar lesions. Isometric trem-

ors are present during voluntary musclecontractions not accompanied by move-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 seen in essential tremor (ET) can

sometimes 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 islikely to be a rest tremor, while a tremorthat is present at rest but worsens withmovement is probably an action tremor.

CLUES TO THE DIAGNOSIS

OF TREMOR

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

tial diagnosis can be generated (Table

1) and narrowed down based on clues

obtained 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 established

on 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 caused

by mutations in a gene encoding a cop-per transporting ATP-ase, resulting inabnormal deposition of copper in brain,liver and other organs of the body.Although classically described as"wing-beating", the tremor in WO canoccur in any pattern and is the mostcommon neurological manifestation ofthe disease.4 Most cases can be ruled

out 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-myelinating disease and may be de-

135VOL. 87 No.5 MAY 2004

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 areless frequently 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 is

present, without other neurologicalsigns or exposure to drugs that maycause tremor.5 A head tremor can also

be 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 of

involvement after the hands are (in

decreasing order) the head, voice, legs,and chin.6 The tremor tends to in-

crease with 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 be

started at a low dose and titrated slowlyup in order to minimize adverse effects.Primidone is usually prescribed in one

single daily dose at bedtime, beginningwith 25 mg, and increased by 25 mgweekly until the desired tremorlyticeffect is obtained or side effects occur.Drowsiness is the most common side

effect, but patients may also experiencenausea, vertigo and unsteadiness. Pro-pranolol, a beta-blocker, is usually ef-fective between 240 and 320 mg daily.9Patients are frequently referred tomovement disorders centers and la-

beled as having "failed" propranololtreatment, when in fact, an adequatedose was never administered. As with

primidone, propranolol should bestarted at low doses and increased over

weeks, while monitoring blood pres-sure and pulse. Contraindications forthe use of propranolol include cardiacconduction block, heart failure, asthmaand diabetes; side effects include

lightheadedness, fatigue, nausea anddepression.

Other medications for ET are gen-erally not proven to be as effective asprimidone or propranolol, thoughtopiramate was recently shown to re-duce tremor in a double-blind, pla-cebo-con trolled trial. 10

Benzodiazepines such as alprazolam orclonazepam may also help if the patienthas concurrent anxiety.

When the medications fail to con-

trol the tremor, surgery should be con-sidered. Stereotactic ablation of the

ventral intermediate nucleus (Vim) of

the thalamus used to be the preferredsurgical procedure for control of ETtremor, but has become obsolete with

the advent of deep brain stimulation

Table 1. Common Tremor Types, Characteristics, and Examples

Type of Tremor

Rest

Clinical Characteristics

Occurs when body part is supported

against gravity and not engaged in activity

ActionPostural Occurs when body part is maintained

against gravity

Kinetic Occurs during voluntary movement

Intention Occurs toward the end of a goal-directedmovement

Common Examples

Parkinson's disease, drug-induced

parkinsonism, multiple system atrophy,

progressive supranuclear palsy

Physiologic, essential tremor, drug-

induced, alcohol withdrawal, post-

traumatic, psychogenic

Physiologic, essential tremor, drug-

induced, post-traumatic, psychogenic,cerebellar lesions

Cerebellar lesions

MEDICINE AND HEAL TH / RHODE ISLAND

136

(DBS) of the thalamus.]] Thalamic

DES 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 attached

to 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 DESis identical to that of ablation, but DBS

holds an advantage over ablation inthat turning the stimulator off can re-verse its effects. Thalamic stimulation

can 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 is often absent until the later stagesof disease. The diagnosis ofPD is madeclinically, based on the presence of twoout of the three cardinal features and

an unequivocal, sustained response todopaminergic therapy.3 PD is uncom-mon under the age of 40 and increasesrapidly in incidence above the age of60 for both males and females, with a

mean age at diagnosis of70.5 yearsYApproximately 70% of PD pa-

tients will have tremor as the initial

symptom.!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. As mentioned

earlier, 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, PD

tremor 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 slow the pro-gression of PD. Therefore, if thepatient'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 is highly vari-able.!

As a general rule, if the pa-tient is young «70 years of age)andhas other features of PD such as

bradykinesia or rigidity in addition totremor, most PD experts would recom-mend initiating treatment with adopamine agonist such as pramipexole(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 excessive

sleepiness. In order to minimize theseadverse effects, the agonists should bestarted at a low dose and increased

weekly until a therapeutic dose isreached.

When the patient presents with 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. It

is reasonable to begin with the 25/100mg dose of carbidopa/levodopa two tothree times a day, and then increase thedosage as needed for the patient to func-

Table 2. Drugs that commonlycause tremor

Alcohol (chronic use or withdrawal)

Anti-arrhythmic drugsAmiodarone

Procainamide

Antiepileptic agents

Carbamazepine

Valproic acid

Benzodiazepine withdrawal

CyclosporineLithium

NeurolepticsStimulants

Albuterol

AmphetaminesCaffeine

Cocaine

Theophylline

tion independently.The anticholinergic trihexyphenidyl

hydrochloride (Artane) can improvetremor in PD, but is ineffective in con-

trolling the other cardinal motor featuresof PD. Therefore, its use is limited to

the PD patient who presents with a pre-dominant tremor, but minimal bradyki-nesiaand rigidity,or as adjunctivetherapyfor a tremor that is resistant to the

dopaminergic medications mentionedearlier. Sedation is the main side effect

in addition to anticholinergic symptomssuch as blurred vision, dry mouth andurinary retention, and is usually the lim-iting factor in the use of this agent.Trihexyphenidyl should 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 studied

for PD include the thalamus, globuspallidus interna (GPi) and the sub-thalamic nucleus (STN). Thalamic

stimulation is effective only for tremor,

137VOL. 87 NO.5 MAY 2004

and therefore is helpful for only a smallproportion of PO patients. Both GPiand STN stimulation have been shown

to 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 is usually affectedwhen a cerebellar hemisphere in in-volved. Lesions of the cerebellar ver-

mis, or midline, often cause an isolated

postural tremor of the trunk and head,commonly referred to as "titubation".Multiple sclerosis (MS) is the mostcommon cause; other causes include

tumors, 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 sometimes

resolve the tremor. For persistent cer-ebellar tremor, however, no medication

has 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 resulted

in 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 small

number of patients with MS.19

PSYCHOGENIC TREMOR

Although there are no precise es-timates of the incidence and prevalenceof psychogenic tremors, clinical expe-rience suggests that it is not rare. Whileit can be difficult to differentiate be-

tween psychogenic and organic trem-ors, the characteristic that all

psychogenic 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 severity with at-tention, and decrease when the patientis forced to concentrate on other tasks.

138

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.2O Often, "false" signs will ap-pear on the neurologic examination,such as give-way weakness or bizarresensory findings. Psychotherapy is themain treatment approach.

SUMMARY

Tremor is a common and disablingsymptom that is associated 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 clinical

history and the neurological examina-tion. A number of medical and surgi-cal therapies are availablefor tremor, buta successful response to treatment de-pends on an accurate diagnosis.

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Kelvin L. Chou,MD, is a Move-ment DisordersFellow at the Parkinson'sDisease and Movement Disorders Cen-

ter, Pennsylvania Hospital, University ofPennsylvania School of Medicine, andwill bejoining the Department ofClini-cal Neurosciences at Brown Medical

School as an Assistant Professorof Neu-rology in July.

CORRESPONDENCE:Kelvin L. Chou, MDParkinson's Disease and MovementDisorders Center330 South Ninth Street

Philadelphia, PA 19107Phone: (215) 829-8593Fax: (215) 829-7552

e-mail: chouk@uphs.upenn.edu

MEDICINE AND HEALTH I RHODE ISLAND