Tremor, defined as involuntary rhythmic oscillatory movements of a body part produced by alternating or synchronous contractions of reciprocal agonist and antagonist muscles, is the most common movement disorder that neurologists encounter in clinical practice [1,2,3]. According to the 2018 Consensus Statement from the Task Force on Tremor of the International Parkinson and Movement Disorders Society, tremor is currently classified along 2 axes: clinical features that determine tremor syndromes in Axis 1, and underlying etiology in Axis 2 [1]. Careful history-taking and comprehensive physical examination of tremor characteristics and additional neurological signs are essential for the syndromic identification for Axis 1 [4, 5]. The clinical phenotypes of various tremor syndromes are complex and overlapped, often making the diagnosis challenging [6,7,8]. The lack of validated clinical diagnostic criteria and biomarkers for diagnosis of each tremor syndrome adds to the diagnostic difficulty.
This review article will provide a step-by-step clinical approach to common tremor situations that are usually misdiagnosed in real-life practice. The first step is to confirm that the movements are actually tremors and to exclude tremor mimics [9, 10]. The second step is to assess the tremor during rest, postural holding in different positions, kinetic movements, and task-specific situations. Determination of tremor amplitude, frequency, distribution, and evaluation of the associated systemic and neurological signs can lead to categorizing the tremor into an isolated or combined tremor syndrome [1, 2]. Using a pen and paper for spiral, line, and sentence writing can be useful [11]. Ancillary investigations including laboratory testing, neuroimaging, and neurophysiological study would be necessary to diagnose unclear tremor syndromes and search for the specific etiology [1, 10].
The key feature of tremor is involuntary rhythmic oscillatory movement. Rhythmicity means regular and recurrent, while oscillation refers to a back-and-forth movement, resulting in a sinusoidal movement at a joint [2]. One mimic is rhythmic myoclonus, including cortical tremor, frequent asterixis (negative myoclonus), and polyminimyoclonus [10]. Myoclonus is usually manifested as a sudden, irregular, and shock-like jerky movement. However, high-frequency (8–18 Hz) repetitive myoclonus, called cortical tremor, can be a difficult diagnosis [10, 12,13,14]. In addition, some tremors are not totally rhythmic and may present as an irregular movement such as dystonic tremor (DT) (tremor that appears in the dystonic part), Holmes tremor (HT), and tremor with different amplitudes in various situations, which could clinically overlap with myoclonus [7, 15,16,17]. When the clinical evaluation is in doubt, a neurophysiological study with polymyography (poly-EMG) is indicated to determine “rhythmicity of movement” that might favor tremor over myoclonus [9]. Both tremor and cortical myoclonus could be observed during rest, postural, and kinetic, but tremor is not sensitive to touch unlike myoclonus. Tremor can occur at the distal or proximal limbs unilaterally or bilaterally, while myoclonus mostly presents in the distal limb bilaterally or multifocally [18]. Epilepsia partialis continua (EPC) that looks regular and rhythmic at a low frequency (2–3 Hz) could also be misinterpreted as unilateral jerky tremor. The tonic and clonic components, however, are the main characteristics of EPC. EPC is also always observed at rest and its distribution is limited to the distal part of one limb as opposed to tremor (
Differentiation of tremor from tremor mimics
Movement | Oscillatory | Shock-like or jerky | Tonic/clonic |
Single or repetitive | Repetitive | ||
Rhythmicity | Regular but sometimes looks irregular in dystonic tremor syndromes or with some variability in amplitude of tremor | Irregular but can be rhythmic with repetitive myoclonus (8–18 Hz) | Regular and rhythmic (2–3 Hz) but can be irregular |
Condition | Rest, postural, kinetic | Rest, postural, kinetic | Rest |
Stimulus sensitivity | No reflex sensitivity | Can be triggered with sensory stimulation | No reflex sensitivity |
Distribution | Bilateral or unilateral | Bilateral, symmetrical | Unilateral |
Distal or proximal | Distal > proximal | Distal > proximal | |
Upper limb > lower limb | Upper limb ~ lower limb | Upper limb > lower limb |
The approach to patients with tremor is based on clinical features. History-taking includes age of onset, clinical progression/evolution, activation of tremor during rest, postural, kinetic or certain tasks or positions, body distribution, site of tremor onset, aggravating and relieving factors, family history of tremor and other movement disorders, and associated systemic and neurological illness [1, 20]. The step-by-step tremor examination with provocation tests and specific observations are essential for a syndromic approach (
Step-by-step description of tremor examination
- Semi-prone - Complete prone - Hanging down from the armrests with forearm supported - Hanging down on sides of a chair |
- Count backwards - Calculation (100-7) - Sequential fingers (1–4) tapping or alternating toes tapping on the contralateral side |
Parkinsonism Dystonic posture |
|
- Hands supported by pillows - Legs supported on the bed - Head supported by pillows |
*Observe characteristics of tremor* *Unilateral vs bilateral* * |
||
- Outstretched arms with hands pronated and fingers spread - Outstretched arms with hands supinated and fingers spread - Outstretched arms with palms or dorsum of hands facing each other - Wing position (elbows flexed, hands underneath the chin, not touching each other) - Outstretched leg with knee extended - Head unsupported while turning head to the extreme side |
Putting a slip of paper on top of hands (visualize fine tremor) |
Parkinsonism Dystonic posture Cerebellar sign Neuropathy |
|
Putting the weight on the dorsum of hands | |||
*Observe *Observe *Observe null point, sensory trick* |
Systemic signs (hyperthyroidism) Kayser-Fleischer (KF) ring |
||
*Listening to high frequency tremor with stethoscope* | |||
- Finger-to-nose test (hands) - Heel-to-knee test (legs) - Simple maneuvers (pouring water from a glass, drinking water, using utensils) - Writing (spiral, lines, sentences) - Specific tasks (from history) - Jaw: open a month - Tongue: protrude a tongue - Voice: Say “Ahh and Eee) |
*Observe simple kinetic vs intentional tremor *Observe |
Parkinsonism Dystonic posture Cerebellar sign Neuropathy |
|
*Observe axis, size* *Observe occurrence of tremor at rest vs action* |
Systemic signs (hyperthyroidism) KF ring |
||
Keep the position that elicits tremor | |||
- Cognitive test and motor test with the contralateral/less affected side - Tapping with different frequencies with the contralateral/less affected side - Ballistic movements of the contralateral/less affected side - Passively move tremulous limb before the onset of tremor |
* *Observe *Observe a pause of tremor* |
||
*Observe co-activation sign* |
The examination starts with techniques to elicit tremor according to the activation of tremor (see
Using a pen and paper for writing tasks is a useful bedside examination that may aid in tremor classification. The writing tasks may include asking the patient to draw an Archimedes spiral of at least 10 cm long with hands held off the paper (
The second step is to determine the distribution of tremor. Upper limb tremor is often the primary focus during the examination. Tremor in other body parts including face, chin, lip, jaw, voice, head, and legs should also be determined during rest, posture, and kinetic conditions. All body parts should be activated for the evaluation of action tremor such as opening a mouth (jaw), protruding a tongue (tongue), speaking (voice), and standing (legs). Involvement of tremor in certain body parts can point to different tremor syndromes. The details of tremor distribution in each tremor syndrome will be described in the next section.
When FT is suspected from historical clues such as sudden onset with a precise moment, triggered by a minor injury or surgery, fluctuation course, and inconsistency over time, then the specific signs for FT should be determined by an examination [31]. Observation of variability in tremor frequency, amplitude, axis, and distribution are very suggestive of FT [32, 35, 36]. However, frequency variability can also be found in DT [15,16,17]. The combination of tremor variability with other positive clinical signs including distractibility (tremor suppression or attenuation) with cognitive loading or sequential motor tasks, a brief pause of tremor with a contralateral quick movement, entrainment (adopting the tapping frequency) with contralateral tapping with three different frequencies, and tonic coactivation (co-contraction of antagonistic muscle) at the tremor onset are helpful in supporting a diagnosis for FT. However, the sensitivity and specificity of these features may be biased due to the unblinded nature of the assessment in most FT studies [31, 32, 36]. Increased tremor amplitude when weight is applied to the affected limb is another sign of FT. These specific signs for FT should be evaluated to distinguish FT from other tremor syndromes. All details about techniques for tremor examination are listed in
The final step for evaluation of tremor is to look for relevant neurological signs associated with tremor. These could be either prominent parkinsonism, cerebellar signs, clear dystonic posture, brainstem signs, and neuropathy or signs of uncertain significance such as mild parkinsonian sign, impaired tandem gait, questionable dystonia, and memory impairment, which could increase diagnostic discrepancies among neurologists [37,38,39,40,41]. Subtle dystonic posture of a body part is often difficult to determine except when it accompanies overflow and mirrors dystonia [42]. The presence of clear associated signs is essential because tremor can be classified into isolated tremor syndrome (tremor occurs in isolation) and combined tremor syndromes where tremor is accompanied by neurological signs. Some tremor syndromes such as HT can present with a combination of cerebellar and brainstem attributes as well as dystonia [43]. Each tremor syndrome in both the isolated and combined groups can be diagnosed based on its clinical features and pattern recognition [6]. Tremor diagnosis can change with time if additional signs develop [7].
Action tremor of the bilateral upper limbs is one of the most common tremors [10]. For diagnosis, it is important to categorize whether patients have an isolated or combined tremor syndrome (
Clinical features of essential tremor and enhanced physiological tremor
Activation | Kinetic (intentional component) > postural | Postural or kinetic |
(amplitude of kinetic > postural) | (amplitude of postural > kinetic) | |
Rest (in severe cases with action tremor) | Intentional component uncommon | |
Distribution | Hands (flexion/extension of wrist, bilateral) | Fingers > hands (+/− voice) |
Head, voice, jaw (with hands) | NOT head, jaw | |
Frequency | 4–10 Hz (decrease with age) | 8–12 Hz |
Changes with different tasks and different body parts | ||
Amplitude | Fine to large | Fine |
Aggravating /relieving factors | Alcohol responsiveness | Increase with stress, exercise, fatigue, caffeine |
Pathophysiology | Central oscillator in the cerebello-thalamo-cortical pathway | Sympathetic overactivity and increase sensitivity of peripheral components |
Weighting | Similar frequency | Decrease frequency |
Treatment | Beta-blocker, primidone, topiramate | Beta-blocker |
Surgery (DBS, MRI FUS thalamotomy) | Decrease aggravating factors | |
Assistive devices |
Clinical characteristics of Parkinson’s disease, dystonic tremor, and essential tremor
Symmetry | Asymmetry | Asymmetry | Symmetry (mostly) |
Activation | R > P > K | P ~ K > R | K > P >>> rest |
(Not intentional) | (Not intentional) | (Intentional) | |
**Suppression of rest tremor with movements** | Rest (can be early) | Rest (in severe cases with action tremor) | |
**Re-emergent tremor** | **position or task specific** | ||
Distribution | Hands (pill-rolling, rotation of wrist, forearm) > jaw, tongue > leg > head | Head > Hands > jaw Isolated head, voice, jaw | Hands >> head > voice > jaw (with hands in severe cases) |
Frequency | 4–7 Hz | 5–7 Hz | 4–10 Hz |
Amplitude | Large, waxing & waning | Large, irregular, jerky | Fine to large |
Association | Parkinsonism | Dystonic posture | Mild ataxia |
Non-motor symptoms: RBD, anosmia, constipation, depression | Null point (head), overflow/mirror dystonia, sensory trick | Non-motor symptoms: anxiety, depression, cognitive impairment | |
Family history | Usually absent in late onset | Sometimes present | Present in early onset |
Treatment | Dopaminergic agent (response 50%) | Anticholinergics | Beta-blocker, primidone, topiramate |
Anticholinergics | Botulinum toxin injection | Surgery (DBS, MRI FUS thalamotomy) | |
Surgery (DBS, FUS) | Assistive devices |
DBS; deep brain stimulation, FUS; focus ultrasound, MRI; magnetic resonance imaging, R; rest, P; postural, K; kinetic.
A combination of rest and action tremor with various severity is one of the most challenging situations that physicians encounter in clinical practice. These types of tremors include specific clinical features with or without the associated neurological symptoms as given below.
Ancillary tests are not indicated if the clinical assessment is clear. The investigations are different depending on the clinical features of the tremor. Blood tests should be indicated if there is an acute onset or acute worsening of tremor or combined tremor syndromes [1, 4, 8, 86]. If there is bilateral upper limb action tremor, metabolic disturbances including thyroid function test, liver or renal function, glucose, and electrolytes may be considered. If tremor is combined with other neurological signs, cognitive or psychiatric problems, or positive family history of movement disorders, serum ceruloplasmin should be tested as a first screen for Wilson’s disease. Other treatable metabolic disorders that may evoke tremor such as Neimann-Pick disease type C, glutaric aciduria type 1, vitamin E deficiency, dopa-responsive dystonia, and coenzyme Q10 deficiency should be considered, if suspected [10].
Neurophysiological testing is a very important tool to confirm the real tremor and search for the etiology of tremor syndromes, but it is not indicated when a diagnosis can be made from clinical assessment [9]. A 1- to 3-axis accelerometer or gyroscope can be used to measure the movement, and multichannel surface EMG (sEMG) can be used to capture the associated motor unit activity [91]. The accelerometers should be placed on the tremulous limb, while the sEMG should be put on the relevant agonist–antagonist muscles [47]. The accelerometer may be an isolated device or can be embedded in a smartphone or smartwatch to objectively evaluate the tremor and quantify tremor severity [92,93,94,95]. The free software (
Structural neuroimaging should be performed in patients with focal or unilateral tremor, nonclassical manifestation, sudden onset or stepwise deterioration, and positive family history of combined tremor syndrome with cognitive or psychiatric problems. Functional imaging such as DaTscan or F-DOPA PET may be considered in distinguishing between ET, DT, or drug-induced parkinsonian tremor and PD patients who would have dopaminergic denervation when the diagnosis is equivocal particularly from neurophysiological studies [10].
Genetic testing can be considered only in combined tremor syndrome with parkinsonism, dystonia, ataxia, neuropathy, cognitive impairment, psychiatric symptoms, and a positive family history of movement disorders [10]. Patients manifesting with bilateral action tremor with ataxia would point to fragile X-associated tremor and ataxia syndrome (FXTAS) or SCA particularly type 12 [100,101,102,103]. In familial cases with dystonia and tremor with or without neuropsychiatric problems, DYT24 (Anoctamin-3 (ANO3) mutation), DYT3 (Lubag’s disease), and Wilson’s disease should be considered [104]. A relevant family history in autosomal dominant with anticipation, autosomal recessive, or X-linked recessive pattern would be essential to suggest different genetic etiologies. Genetic testing can be performed with whole exome sequencing, whole genome sequencing, or targeted resequencing panel.
The Axis 1 diagnosis of a tremor syndrome can change over time if additional signs develop. For example, the diagnosis would be ET if the patient has bilateral action tremor of the upper limb without other neurological signs for a period of 3 years. Later, if prominent dystonic posture of the head and one arm emerges, the diagnosis could be modified to DT with antecedent ET.
Treatment of tremor depends on the underlying tremor syndrome, tremor-related disability, and the types of tremors as given below.
Diagnosis of patients with tremor is challenging due to the complex and overlapping phenotypes. Careful history-taking and focused tremor examination are essential in the exclusion of tremor mimics, evaluation of clinical features, and recognition of specific tremor syndromes. The step-by-step algorithm proposed here for approaching the diagnosis of tremor will make it easier for neurologists who are in clinical practice (