Sorting out tremors

Tremor is defined as

• rhythmic,
• involuntary
• oscillating movement of a body part with a relatively constant frequency and variable amplitude
• occurring in isolation or as part of a clinical syndrome.

No diagnostic standard to distinguish among common types of tremor, which can make the evaluation of tremor more challenging.

Establishing the underlying cause is important because prognosis and specific treatment plans vary considerably.

In clinical practice, characterization of tremor is important for etiologic consideration, establishing the underlying cause, treatment plan as well as for prognosis.

Common types include resting, postural, kinetic, intention, and task-specific tremor.

The most common tremor in patients presenting to general physicians is enhanced physiologic tremor, followed by essential tremor and parkinsonian tremor.

Table 1. Broad Classification of Tremor

Pathophysiology

The pathophysiology of tremor is not fully understood.

Four basic mechanisms are linked to the production of tremor.

It is likely that combinations of these mechanisms produce tremor in different disease states.

1. Mechanical oscillations of the limb can occur at a particular joint, e.g., physiologic tremor.
2. Reflex oscillation is elicited by afferent muscle spindle pathways, e.g., tremor in hyperthyroidism or other toxic states.
3. Central oscillators are by groups of cells in the thalamus, basal ganglia, and inferior olives, which have the capacity to fire repetitively and produce tremor, e.g., Parkinsonian tremors essential tremors (ETs)
4. Abnormal functioning of the cerebellum can produce almost all forms of tremor.

Fig. 1. Pathophysiology of different etiologies of tremor

Neuronal Pathways

Two neuronal pathways are of particular importance in production of tremor.

(a) The corticostriatothalamocortical loop through the basal ganglia. This pathway maintains the ongoing pattern of movement
(b) The “Guillain-Mollaret triangle” pathway connecting the red nucleus, inferior olivary nucleus, and the dentate nucleus. This pathway is involved in fine tuning the voluntary precision of movements.

Fig 2. Schematic and simplified synopsis of the brain regions and pathways involved in tremorogenesis.

Corticostriatothalamocortical loop is indicated with a bold line and Guillain-mollaret triangle is indicated with a dotted line.

D1, dopamine receptor type 1; D2, dopamine receptor type 2; exc., excitatory; GABA, gamma-amino butyric acid; Glu, glutamate; GPe, external globus pallidus; GPi, internal globus pallidus; ICP, inferior cerebellar peduncle; inh., inhibitory; SCP, superior cerebellar peduncle; SNc, substantial nigra, pars compacta; SNr, substantial nigra, pars reticulata; STN, subthalamic nucleus; VIM, ventrointer-mediate nucleus of the thalamus.

In this review, essential tremor will be emphasized.

I. Essential Tremors (ET)

The most common pathologic tremor is essential tremor.

ET is an action tremor, usually postural, but kinetic (action) and even sporadic rest tremors have also been described.

It is most obvious in the wrists and hands when patients hold their arms in front of themselves.

The worldwide estimated prevalence of ET is up to 5% of the population.

Family history can be found in near 50% of cases and in 90% concordance in monozygotic twins.

The incidence of essential tremor increases with age, although it often affects young individuals, especially when it is familial

Most patients do not seek help for it until over 60s years of age because of its progressive nature.

They occur in the absence of other neurological signs (e.g., dystonia, ataxia, parkinsonism).

If other neurological signs develop, diagnosis changes to a combined tremor syndrome.

Cases with tremor less than 3 years duration are labeled as observational tremor. Tremor worsens during activities such as eating, drinking, and writing.

Drinking alcohol may temporarily alleviate ET.

The most commonly affected parts include hands, head, and voice, but can also be seen in the legs, trunk, and face.

Tongue tremor is a rare initial presentation of ET.

ET is exacerbated by conditions as stress, exercise and fatigue, caffeine, certain medications; and improves with relaxation and alcohol.

Other associated symptoms can include mild gait difficulty. This typically is a finding associated with longer disease duration and worsening of tremors.

Some patients have decreased hearing, cognitive slowing and psychiatric nonmotor manifestation, as well as depression and social phobia can be present.

Variants of ET including:

• Task-specific tremor (e.g., primary writing tremor)
• Isolated voice tremor
• Isolated chin tremor

II. Essential Tremors-Plus (ET-P)

Tremors with characteristics of ET and additional neurological signs of uncertain significance that do not suffice to make an additional syndrome.

Usually referred ET cases that present with “soft neurological signs” such as cognitive impairment, gait difficulty

■ For example, in patients with longstanding ET, resting tremor can sometimes develop due to overflow muscle activation, causing rest tremor look alike, but do not have other cardinal signs of PD.

However, there is controversy about the necessity of this distinction, this ET-P term should not be used routinely.

Table 2. Criteria for diagnosis of essential tremor

Table 3. Symptoms or signs suggestive of tremors other than ET

Treatment approach for ET

In most cases, ET can be managed by family clinicians, beginning with exclusion of secondary causes, and followed by non-pharmacologic measures and, when needed initiation of medical therapy with propranolol or primidone if the tremor is causing disability or affecting activity of daily living.

The decision to refer to a neurologist depends upon the clinician’s confidence in the diagnosis, comfort level with use of the drugs recommended for tremor suppression, and the patient’s response to treatment.

1.Non-Pharmacological treatment of ET

• Find ways to reduce stress and relax.
• Avoid alcohol consumption. While small amounts of alcohol seem to relieve essential tremor in some patients, it may interact with medications used to treat ET and also have negative effects on the body, such as alcohol dependency disorder or liver damage. Most experts do not recommend its use.
• Consider taking a small dose of medication, such as a beta-blocker, before a social outing; this may help to reduce the tremors
• Avoid certain drugs that can aggravate tremor like thyroid or asthma medications before attending a social event. Be sure you check with your doctor first.
• Avoid awkward or uncomfortable positions.
• Add a little weight to hands of patients by wearing a heavy bracelet or watch while holding something in the hands. This may reduce some tremors and restore more control to their hands.
• Drink beverages from half-filled cups or glasses and use a straw.
• Get enough rest and sleep. Fatigue often makes a tremor worse.

2.Pharmacologic treatment of ET

2.1. Whom to treat?

• Drug treatment should be offered to patients with ET who have intermittent or persistent disability caused by tremor.
• Individuals with mild ET and little or no tremor-related disability usually do not require treatment, although some patients are bothered by the cosmetic effect of even the least amount of shaking.
• Patients may not complain of being bothered or embarrassed by the tremor; they should be asked about it directly.

2.2. Intermittent therapy

• Some patients with ET develop exacerbations of tremor triggered by stressful social occasions or public performances.
• Intermittent drug treatment of ET in anticipation of these situations can be useful in such cases.
• For patients with mild ET who have situational exacerbations of tremor that cause concern, use propranolol as needed.
• An alternative option is alcohol in small amounts (e.g., one or two alcoholic drinks).
• Some experts report that primidone also can be effective when used intermittently for ET exacerbated by situational stress or anxiety, but its slow onset of action limits the utility of primidone in this setting.

2.3. Continuous therapy

• Patients with persistent functional or psychological disability (including embarrassment or anxiety) from ET generally need continuous drug therapy.
• In such cases, we recommend monotherapy with propranolol or primidone as initial therapy.
• Propranolol and primidone each may reduce tremor amplitude by approximately 50 percent.
• However, neither drug is effective for all patients with ET.
• In addition, acute adverse reactions with primidone and chronic side effects of propranolol appear to be important limitations to the use of these drugs.
• For ET that is resistant to monotherapy with either propranolol or primidone, the two can be used together.
• Switching from one to the other is also a reasonable strategy if either agent is poorly tolerated.

2.4. Duration of benefit

• The symptomatic benefit of drugs used to treat ET declines over time, probably due to disease progression or the development of drug tolerance.  Propranolol and primidone remain effective for limb tremor reduction in the majority of patients for at least one year.
• Increased doses of both drugs may be needed by 12 months of therapy.

2.5. Treatment failure

• Options for ET that fails continuous treatment with the two primary drugs with addition of second line drugs (e.g., gabapentin, topiramate, nimodipine), and any combinations of agents that do not have additive adverse effects.
• Other beta blockers, anticonvulsants, and miscellaneous drugs may also have a role in the treatment of ET.
• For patients who fail pharmacologic treatment with these agents, options include:
  • surgery with deep brain stimulation (DBS) or thalamotomy to treat persistently disabling limb tremor
  • DBS appears to have fewer adverse events than thalamotomy
  • botulinum toxin injections to treat persistently disabling head or vocal cord tremor

2.6 Propranolol (Beta Blocker)

Dose: Propranolol, 60 to 320 mg/day.

Long-acting propranolol (propranolol LA) is also used

A single starting dose of 10 or 20 mg is suggested in anticipation and may be effective within an hour.

Common side effects are lightheadedness, fatigue, impotence, and bradycardia.

It is relatively contraindicated in the presence of heart block, asthma, or type 1 diabetes mellitus.

Other BBs: None of them is superior to Propranolol and patients who do not respond to adequate doses of one beta blocker for ET are unlikely to respond to another.

2.7. Primidone

It is an antiseizure medication in the group of barbiturate.

Dose up to 750 mg/day, is effective.

Side effects from primidone were typically more severe at treatment initiation they included sedation, drowsiness, fatigue, depression, nausea, vomiting, ataxia, malaise, dizziness, unsteadiness, confusion, vertigo, and an acute toxic reaction.

The mechanism of action of primidone in ET is unknown.

2.8. Other antiseizure medications

Figure 3. Algorithm for management of ET

III. Enhanced Physiologic Tremor

• A physiologic tremor is present in all persons. It is a low-amplitude, high-frequency tremor visible at rest and during certain posture or action (especially when a specific posture is maintained) that is not reported as symptomatic.
• This tremor can be enhanced by anxiety, stress, and certain medications and metabolic conditions.
• Patients with a tremor that comes and goes with anxiety, medication use, caffeine intake, or fatigue do not need further testing.

IV. Drug- and Metabolic-Induced Tremors

• Patients with new-onset tremor should have a comprehensive medication review, specifically attention to any medications started before the onset of tremor.
• Medications particularly prone to inducing or exacerbating tremor are those that stimulate the sympathetic nervous system (e.g., amphetamines, terbutaline, pseudoephedrine) and psychoactive medications (e.g., tricyclic antidepressants, haloperidol, fluoxetine).
• When medication review reveals a likely culprit, a trial off of this medication should be attempted.
• Initial workup of tremor may include blood testing for hepatic encephalopathy, hypocalcemia, hypoglycemia, hyponatremia, hypomagnesemia, hyperthyroidism, hyperparathyroidism, and vitamin B12 deficiency.

Table 3. Selected Toxins, Medications and Substances ThatMay Exacerbate Tremor

V. Parkinson Disease

Parkinson disease is a progressive neurodegenerative disorder that is pathologically defined by degeneration of the dopaminergic neurons in the substantia nigra and development of Lewy bodies in the residual dopaminergic neurons.

Pathologic changes may be detected up to 20 years before the onset of motor symptoms and are accompanied by a clinical prodrome of nonspecific symptoms such as hyposmia, constipation, and fatigue.

The disease affects approximately 1% of older than 60 years, and up to 4% of those older than 80 years.

Parkinson tremor is often characterized by a low-frequency rest tremor prototypically described as a pill rolling tremor.

A characteristic feature of symptoms in PD is the asymmetric nature of symptoms, especially early in the disease.

The most common areas affected include the hands, legs, chin, and jaw.

Patients sometimes complain of the sensation of ‘internal tremors’ that are not visible externally. These may involve the chest and abdomen as well as extremities and often not relieved by typical antiparkinsonian medications, and commonly associated with anxiety when involving PD patients.

Some patients may also have postural and action tremors.

Resting tremors may also be observed in other parkinsonian syndromes.

Table 4. Characteristics of Parkinsonian Versus Essential Tremors

VI. Cerebellar Tremor

Cerebellar tremor is a slow frequency tremor, between 3–5 Hz.

It occurs during the execution of a goal-directed movement.

The amplitude usually increases with movement and by approaching the intended target and can be associated with a postural component.

Signs and symptoms of others cerebellar dysfunction may be present including ataxia, dysmetria (overshoot on finger-to-nose testing), dyssynergia (abnormal heel-to-shin testing), hypotonia, dysdiadochokinesia, and scanning speech dysarthria.

Another tremor associated with a cerebellar etiology is titubation, better described as a rhythmical, slow-frequency bobbing motion of the head or trunk. It is usually seen in conditions such as multiple sclerosis, hereditary ataxia syndromes, brainstem stroke affecting cerebellar pathways, and traumatic brain injury (TBI).

Titubation may have additional noncerebellar findings due to involvement of nearby brainstem structures by underlying disease process. Unfortunately, these tremors are highly disabling and are difficult to treat.

Deep brain stimulation (DBS) may provide a viable treatment option but has shown inconsistent success compared to PD and ET.

VII. Funtional Tremor

Previously known as psychogenic or hysterical tremors, usually present a challenge in any medical practice.

Psychogenic tremors usually have an irregular frequency and are associated with sudden onset and remissions.

Frequency and amplitude may vary and diminish or disappear with distraction.

“Co-activation sign” may be observed and other somatization history may be present.

VIII. Orthostatic Tremor

Tremors are mostly confined to the legs that occur within a few seconds upon standing and subside with walking and sitting.

There is no problem sitting or lying down.

The tremor rate is between 13–18 Hz (via EMG) and is may not be visible to the naked eye, but could sometimes be “heard” on auscultation, or “felt” (e.g., a vibratory sensation) on palpation, of the leg muscles.

Treatments in their typical order of efficacy include benzodiazepines, beta blockers, and anticonvulsants. It may coexist with other movement disorders, most commonly ET and parkinsonian disorders.

IX. Clinical Examination of the Tremulous Patient

7.1. Observation

1. What is the affected body region?
2. Is there an abnormal body posture?
3. Does the tremor occur at rest, or is it associated with purposeful movement?
4. Are there leg tremors?
5. Is there masked facies?
6. Is there reduced amplitude of movement?
7. Is there voice tremor?
8. Is there shuffling of gait?

7.2. Examination (System focus)

1. With the patient keeping the extremities at rest, distract patient by asking to perform serial sevens
2. Examine extremities in the postural position (hand in front with arms outstretched, parallel to the floor)
3. Finger to nose testing
4. Examine for rigidity and bradykinesia, decreased arm swing
5. Examine for task specific tremor by asking patient to write
6. Examine for orthostatic tremor by asking patient to stand up and put both hands on patient leg
7. Examination of casual gait
8. Tandem Gait
9. Pulsion (retropulsion, propulsion or lateral pulsion )
10. Speech Evaluation

X. Diagnostic Work Up for Tremors

1. Thyroid function tests
2. Liver function studies
3. Complete chemistry
4. Serum ceruloplasmin
5. Toxicology screen
6. Drug levels
7. MRI/CT of the brain
8. FP-CIT SPECT scan

Role of Imaging

• Currently, the diagnosis of tremor remains primarily clinical.
• In difficult cases, single-photon emission computed tomography (SPECT) to visualize the integrity of the dopaminergic pathways in the brain may be useful to diagnose Parkinson disease.
• Plain CT and MRI are good choices to rule out secondary causes of tremor (e.g., multiple sclerosis, stroke) when the diagnosis of tremor is not obvious from history and physical examination.

Summary

Tremors are the most common movement disorder presenting to general practice and family medicine clinic.

Diagnosis is purely clinical, and imaging has limited role in diagnosis.

Tremors can affect functioning and in Parkinson’s disease is associated with increased mortality.

Essential tremors can be disabling and require treatment in patient with disability.

Parkinson’s disease is a disabling progressive neurodegenerative condition requiring specialist follow up.

References

1. Bhatia KP, Bain P, Bajaj N, et al. Consensus Statement on the classification of tremors. from the task force on tremor of the International Parkinson and Movement Disorder Society. Mov Disord. 2018;33(1):75–87.
2. Louis ED, Ferreira JJ. How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor. Mov Disord 2010; 25:534-41.
3. Louis E, Bares M, Benito-Leon J, et al. Essential tremor-plus: a controversial new concept. Lancet Neurol. 2020;19(3):266–270.
4. Morgan JC, Sethi KD. Drug-induced tremors. Lancet Neurol. 2005;4:866–876.
5. Lagrand T, Tuitert I, Klamer M, et al. Functional or not functional; that’s the question. Eur J Neurol. 2020;28:33–39.
6. Puschmann A. Wszolek ZK. Diagnosis and treatment of common forms of tremor. Semin Neurol. 2011;31(1):65–77.

Author Information

Thar Thar Oo,
MBBS, MD, MPH, FAAN <br/Senior Consultant Neurologist>