Hospital Medicine

Tremor

Tremor

I. Problem/Condition.

Tremor is a type of Movement Disorder (see that Chapter for where tremor fits in overall Movement Disorder phenomenology) characterized by rhythmic involuntary oscillatory movement of part of the body, typically involving an extremity or the head. Tremor is one of the most common disorders seen in the hospital setting for a number of reasons. First, many medications and metabolic abnormalities can exacerbate physiologic tremor. Second, all forms of tremor are more pronounced in the setting of physical or emotional stress, and hospitalization for inpatient treatment certainly causes this.

Tremor may have abrupt onset but more commonly worsens gradually over months or years. Most types of tremor (like all movement disorders) disappear during sleep. Tremor can occur with other abnormal movements such as ataxia, dystonia, or myoclonus, and if any of these are present, this may help with the diagnosis. Organic neurologic causes of tremor have static unchangng frequencies.

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

Tremor is organized both by causes and by location/description of the tremor. Tremor is either in the head or in the limbs, and limb tremor is either a rest tremor or a postural/action tremor. Head tremor, resting limb tremor, and postural/action limb tremor each have primary and secondary causes, all of which are listed below.

Rest Tremor:

Causes: Parkinson's disease or other forms of parkinsonism like vascular parkinsonism or drug-induced parkinsonism.

Postural/Action Tremor:

Causes: Enhanced physiologic tremor (medication-induced, anxiety, endocrine/metabolic abnormalities), benign essential tremor, orthostatic tremor, dystonic tremor, cerebellar tremor, and other rare obscure causes of tremor beyond the scope of hospital medicine.

**Additionally, there is the possibility that the tremor being observed is psychogenic. Psychogenic tremor is the most common psychogenic movement disorder and has features that are not easily categorized (unusual patterns of body segment involvement or unusual combinations of rest and action/postural tremor). This will be discussed further below.

B. Describe a diagnostic approach/method to the patient with this problem.

First, assess if the movement isrhythmicor not. If not, it may not be tremor at all (myoclonus, ataxia, etc).

Second, determine thetypeof tremor based on history and physical. Is the tremor predominantly a rest tremor or a postural/action tremor? What part of the body is involved? Then, determine the cause based on the above breakdown of primary and secondary causes of rest and postural/action tremors. Rest tremor is defined as tremor that occurs when the area of the body involved is completely relaxed. Postural tremor is tremor that occurs when the limb sustains a particular posture (such as hands outstretched). Action tremor is tremor that occurs with activation and movement of that limb (such as finger to nose task). As a point of clarification, the term intention tremor refers to a subtype of action tremor where the tremor worsens as the target is approached.

Third, determine thelocationof the tremor -

Head tremor:

Tremor in the head rarely occurs for the first time in the hospital but can be worsened due to the stress of hospitalization. If the tremor involves the whole head, it is usually a nodding yes-yes type tremor or a lateral no-no type tremor. If the head tremor is accompanied by a postural/action tremor in the hands and/or tremor of the voice, this is most likely to be essential tremor. Dystonic tremor of the head classically has a 'null point' (described below under physical examination), and presence of any noticeable cervical dystonia helps to point toward dystonia as the etiology of the head tremor. As above, tremor isolated to the chin/jaw area is classically the head region tremor that is seen in Parkinson's disease.

Arm tremor:

Rest tremor = Parkinson's and Postural/Action tremor = Essential tremor, but it is not always that easy. The key is observing all aspects of the tremor (exam tips below). Start by observing at rest and make sure the patient is completely relaxed. Patients with essential tremor can appear to have rest tremor in the arms if their arms are not completely relaxed (i.e., they are activating their arms muscles to sustain theposture of holding their arms on the armrests of the chair).

Parkinsonian rest tremor can re-emerge with sustaining an outstretched posture, but the key is the latency at which it does so. In essential tremor, the tremor should begin in the hands almost immediately upon holding out the hands. In Parkinson's disease the re-emergent postural tremor begins only after a few seconds of holding out the arms. The other key differentiating point is that there are no other parkinsonian features in essential tremor (rigidity, bradykinesia, gait problems).

If the tremor is postural/action and is a very high frequency but low amplitude tremor (like anxious trembling), then this points to a secondary cause such as medication-induced or withdrawal-related. If the tremor was abrupt in onset, then consider neuroimaging to look for an underlying structural cause.

Leg tremor:

Tremor is uncommon in the legs, but if present in one leg and at rest, think Parkinson's disease. Orthostatic tremor can often be auscultated by placing the stethoscope on the same thigh as the tremor to hear the rhythmic firing of the leg muscles.

1. Historical information important in the diagnosis of this problem.

  • Essential tremor does not involve the legs, but Parkinson's disease can.

  • Did the tremor start on one side of the body? Parkinson's disease is classically asymmetric whereas essential tremor is much more symmetric. Though there may be mild asymmetry in essential tremor, the asymmetry seen in Parkinson's is more classically the type that causes tremor (and other Parkinson's symptoms) on one side of the body for months-years before developing on the other side of the body.

  • Does the tremor resolve with even small amounts of alcohol intake? This is commonly seen in essential tremor.

  • Was the tremor sudden in onset? If so, secondary causes should be considered.

  • Was the patient exposed to any of the medications known to induce tremor? See diagnostic criteria below for list of medications that cause tremor.

  • Are there any other associated neurologic signs?

  • Is there a family history of tremor? Essential tremor frequently (~80%) runs in families with multiple family members/generations affected. Less than 5% of all cases of Parkinson's disease are felt to be familial/genetic.

Head tremor causes:

In tremor involving the whole head, the causes are either benign essential tremor or cervical dystonia with dystonic tremor. If the tremor is isolated to the jaw, the cause is Parkinson's disease. Note that Parkinson's disease does not cause tremor of the entire head.

Arm tremor causes:

Resting arm tremor is caused by Parkinson's disease or another form of parkinsonism. Other forms of parkinsonism that may cause resting arm tremor include multiple systems atrophy, vascular parkinsonism, and drug-induced parkinsonism. Drug-induced parkinsonism is exclusively caused by medications that block dopamine such as antipsychotics (all typicals and less commonly all atypicals except for quetiapine and clozapine) and antiemetics (metoclopramide, rarely promethazine).

Postural/action tremor in the arms is caused by benign essential tremor, dystonic tremor, anxiety, sedative withdrawal, cerebellar lesion or degeneration, and drug-induced. Medications that induce tremor are listed below.

Leg tremor causes:

Resting leg tremor is caused by Parkinson's disease or other parkinsonism such as vascular or drug-induced parkinsonism as in resting arm tremor.

Postural/action tremor of the legs is essentially a tremor that occurs with standing/walking, and the primary cause is orthostatic tremor.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Tremor Exam: Have the patient rest their hands in their lap and sit back in their chair relaxed. To elicit a resting tremor, the patient can perform (with eyes closed) a cognitive task for distraction such as stating the months of the year backwards from December to January or reciting the birthdates of his/her children. Observe for tremor in the hands, feet, or face. Then have the patient extend their arms and hold them outstretched, palms down. Occasionally there is a position-specific component, so the patient can be asked to turn their hands over to palms up. Then have patient perform finger to nose task to assess for action tremor.

Assess for dystonia: Start by looking at shoulder height - an asymmetrically elevated shoulder may mean a dystonia. Look to see if the head is naturally deviated to one side or the other. If there is a jerky head tremor, assess for anull point by having the patient turn their head to look to the far left and to the far right. If the head tremor resolves looking in one direction, that is the null point of the tremor and suggests that the tremor is caused by cervical dystonia pulling the head one direction but the patient's natural inclination to straighten/resist this pulling leads to an agonist/antagonist muscle battle which manifests as tremor.

Assess tone, bradykinesia, and gait to look for evidence of parkinsonism in addition to the tremor.

Psychogenic tremor often has variable frequency, and this can be tested by the entrainment maneuver. If the patient has a tremor in a part of the body, and you suspect that it is psychogenic, you can ask the patient to assume whatever position elicits the tremor. Then, ask the patient to use their opposite limb and move it up and down at a very different frequency (either very fast or very slow) from the affected limb.If the frequency of the tremor in the affected limb slows or quickens to the exact frequency of the other limb, then it is exhibiting entrainment, which is a hallmark feature of psychogenic tremor.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Labs: Hb A1C (severe diabetic neuropathy can lead to a mild postural/action tremor), TSH (hyperthyroidism causes an exaggerated physiologic postural/action tremor). Imaging (computed tomography [CT] or magnetic resonance imaging [MRI] brain) can rule out any structural etiologies of tremor (stroke, tumor, etc).

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

All of the above are diagnosed by clinical criteria and do not require any confirmatory ancillary testing.

Parkinson's disease: requires at least two of the four cardinal symptoms (rest tremor, rigidity, bradykinesia, and gait imbalance) to be diagnosed with Parkinson's disease. Parkinson's is so commonly asymmetric that symmetric presentation brings into question whether the diagnosis is correct.

Vascular parkinsonism: Parkinsonian features as above but sudden onset and exclusively affects one hemibody (side contralateral to the stroke), corroborated by imaging documenting infarct in the basal ganglia.

Drug-induced parkinsonism: Again, features of parkinsonism but loss of asymmetry. Must have history of dopaminergic blockade (anti-emetics or antipsychotics save for clozapine and quetiapine).

Essential tremor: Postural/action in the bilateral hands (can be one more affected than the other) and/or head tremor and/or voice tremor, often with positive family history and +/- recognition that alcohol intake improves the tremor.

Dystonic tremor: Almost always from a cervical dystonia, so given the name, a dystonia must also be present. For a dystonic head tremor, the null point should be seen. For dystonic limb tremor, there should be striking asymmetry and task-specificity (executing a certain task brings out the tremor and dystonia).

Medication-induced tremor: High frequency low amplitude exaggerated physiologic (postural/action) tremoranddocumented history of use of drugs on this list:

  • Antidepressants (TCA's >> SSRI's)

  • Mood stabilizers (valproate, lithium)

  • Cardiac drugs (amiodarone, mexiletene, procainamide)

  • Antibiotics (TMP/SMX)

  • Pulmonary (salmeterol, theophylline)

  • Chemotherapy (tamoxifen, ifosfamide, cytarabine)

Psychogenic tremor: Diagnostic criteria: inconsistent over time, incongruent with classical tremor diagnoses plus one of the following: resolution with psychotherapy or placebo, additional atypical neurologic signs, obvious psychiatric disturbance, multiple somatizations.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Imaging (CT/MRI) is rarely helpful. There are no imaging findings to be seen on CT or MRI for essential tremor and Parkinson's disease.

III. Management while the Diagnostic Process is Proceeding.

A. Management of Clinical Problem Tremor.

Treat the underlying etiology. If it is a medication-induced tremor, remove the offending agent. This includes drug-induced parkinsonism as adding anti-parkinsonian agents when a patient is on risperidone (for example) is not effective, and the antiparkinsonian drugs could worsen the psychosis anyway (see below).

Essential tremor is treated with primidone or propranolol. Other drugs such as topiramate and gabapentin are significantly less effective.

Parkinson's disease is treated with levodopa (comes only in carbidopa/levodopa combination) with or without COMT inhibitors, dopamine agonists, MAO-B inhibitors, amantadine, trihexyphenidyl. The previous are listed in relative efficacy from most to least potent.

Dystonic tremor is treated by treating the dystonia. Oral agents include trihexiphenidyl or other dopaminergic agents such as carbidopa/levodopa. Most effective is the use of injectable botulinum toxin to the muscles affected by the dystonia. Botulinum toxin injections are most easily done for neck muscles (head tremor) and more difficult in limb muscles (arm tremor).

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

Parkinsonism:

- For the tremor of true idiopathic Parkinson's disease, here are some rules for using the drugs above. In general, if a patient is over 65, you can start immediately with Sinemet (carbidopa/levodopa). If under 65, you should start with a dopamine agonist. Though the dopamine agonists are overall less effective than Sinemet for the overall treatment of the disease, for the symptom of parkinsonian tremor, they are perhaps slightly more effective than Sinemet. Trihexiphenidyl, amantadine, and MAO-B inhibitors have some efficacy for parkinsonian tremor as well but to a lesser degree.

- Vascular parkinsonism does not respond to anti-parkinsonian medications. Medication-induced parkinsonism responds very poorly to antiparkinsonian medications, and you quickly drive side effects.

Essential tremor:

- By far the most effective drugs are propranolol and primidone. Choose the agent based on side effect profile and the patient's other comorbidities. If the patient has lung disease (asthma/COPD/etc), then avoid propranolol and choose primidone first. Likewise, if the patient has insulin-dependent diabetes, your first choice should be primidone. If the patient is elderly/demented or young/working/subject to drug screens, you may choose propranolol first. Primidone is a pro-drug for and metabolized to phenobarbital. Titration of propranolol can be limited by bradycardia or hypotension. Other agents can be added to these if this is insufficient.

Dystonic tremor:

- Start with trihexiphenidyl or Sinemet. If these are ineffective, consult neurology for possible botulinum toxin.

Anti-parkinsonian drugs:

-Carbidopa/levodopa. Formulations include Sinemet 10/100, Sinemet 25/100, Sinemet 25/250, Sinemet CR 25/100, Sinemet CR 50/200, Stalevo (Sinemet plus entacapone) in varying doses. If you're going to use Sinemet, use the 25/100 (less nausea due to the higher carbidopa to levodopa ratio), start with one tab daily for a few days then BID for a few days then TID. The main side effect in titration is nausea. It can also cause vivid dreams.

-Dopamine agonists. Currently, these are ropinirole (Requip) and pramipexole (Mirapex). For Requip, start 1mg HS and titrate every 4-7 days to 2-3mg TID. For Mirapex, start 0.125mg daily and titrate every 4-7 days to 0.5mg TID. Max recommended doses of Requip are 24mg/day and for Mirapex are 6mg/day. Side effects to counsel on are pedal edema, sedation/fatigue, and rarely, OCD symptoms like excessive gambling or inappropriate sexual behaviors. You should ask about these at every visit.

-Trihexiphenidyl - start 0.5 or 1mg daily for one week and then titrate weekly to 2mg TID. Side effects are anticholinergic.

-Amantadine - start 100mg daily and titrate over a few weeks to 100mg TID. Side effect to counsel on is livedo reticularis - a netlike discoloration of the skin (not a rash).

-MAO-B inhibitors. These include selegiline and rasagiline. Selegeline has amphetamine metabolites so can be stimulating (good for fatigue) but can also cause delirium, especially if the patient is already demented. Dose starts at 5mg daily then titrates slowly to 10mg AM and noon. Rasagiline does not have amphetamine metabolites and has the most evidence supporting that it may have disease modifying effect.

Essential tremor:

- For propranolol, start at 10-20 mg daily and titrate over 3-4 weeks to effect or tolerability (unusual to see doses above 60mg BID)

- For primidone, it only comes in 50mg or 250mg pills, so start with 25mg (half of the 50) or 50mg, titrating every 2 weeks to effect, usually 100-250mg HS. Doses above 250mg daily are less effective.

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