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Tremor: Sorting Through the Differential Diagnosis Paul Crawford, MD, and Ethan E. Zimmerman, MD, Mike O’Callaghan Military Medical Center, Nellis Family Medicine Residency, Nellis Air Force Base, Nevada

Tremor is an involuntary, rhythmic, oscillatory movement of a body part. It is the most common move- ment disorder encountered in primary care. The diagnosis of tremor is based on clinical information obtained from the history and physical examination. The most common tremors in patients present- ing to primary care physicians are enhanced physiologic tremor, , and parkinsonian tremor. All persons have low-amplitude, high-frequency physiologic tremors at rest and during action that are not reported as symptomatic, but can be enhanced by , medication use, intake, or fatigue. Features consistent with psychogenic tremor are abrupt onset, spontaneous remission, changing tremor characteristics, and extinction with distraction. Other types of tremor include cere- bellar, dystonic, and drug- or metabolic-induced. The first step in evaluating a patient with tremor is to categorize the tremor based on its activation condition, topographic distribution, and frequency. Resting tremors occur in a body part that is relaxed and completely supported against gravity. Action tremors occur with voluntary contraction of a muscle and can be further subdivided into postural, isometric, and kinetic tremors. The most common pathologic tremor is essential tremor, which affects 0.4% to 6% of the population. In one-half of cases, it is transmitted in an autosomal-dominant fashion. More than 70% of patients with Parkinson disease have tremor as the presenting feature. This tremor is typically unilateral, occurs at rest, and becomes less prominent with voluntary movement. If there is diagnostic uncertainty, single-photon emission computed tomography can be used to visualize the integrity of the in the brain, and transcranial ultrasonography may be useful to diagnose Parkinson disease. (Am Fam Physician. 2018;97(3):180-186. Copyright © 2018 American Academy of Family Physicians.)

Tremor is an involuntary, rhythmic, oscillatory move- parkinsonian tremor.1,3-6 All tremors are more common ment of a body part and is the most common movement in older age.7 disorder encountered in primary care practices.1-3 Aside from careful clinical examination and imaging when Classification needed, there is no standard test to distinguish between Tremors are classified as resting or action(Table 1).1,8,9 A common types of tremor, which can make the evalua- resting tremor occurs in a body part that is relaxed and tion challenging. However, establishing the underlying completely supported against gravity (e.g., when resting cause is important because prognosis and specific treat- on the arm of a chair). It is typically enhanced by mental ment plans vary considerably. The most common trem- (e.g., counting backward) or movement of another ors in patients presenting to primary care physicians body part (e.g., walking), and diminished by voluntary are enhanced physiologic tremor, essential tremor, and movement.3,10,11 Most tremors are action tremors, which occur with voluntary . Action tremors are subdivided into postural, isometric, and kinetic trem- CME This clinical content conforms to AAFP criteria for ors.8,10 A postural tremor is present while maintaining a continuing medical education (CME). See CME Quiz on page 167. position against gravity (e.g., arm elevation). An isometric tremor occurs with muscle contraction against a rigid sta- Author disclosure: No relevant financial affiliations. tionary object (e.g., when making a fist). A kinetic tremor Patient information: A handout on this topic, written by the authors of this article, is available at http://www.aafp. is associated with voluntary movement and includes org/afp/2011/0315/p703.html. , which is produced with target-directed movement.2

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Enhanced Physiologic Tremor idiopathic Parkinson disease, a chronic neurodegenerative All persons have an asymptomatic physiologic tremor. It is disorder with a prevalence of 1%.17 a low-amplitude, high-frequency tremor at rest and during Approximately 70% of patients with Parkinson disease action. This tremor can be enhanced by anxiety, stress, cer- have resting tremor as the presenting feature.1,11 The classic tain medications, and metabolic conditions. Patients with parkinsonian tremor begins as a low-frequency, pill-rolling a tremor that comes and goes with anxiety, medication use, motion of the fingers, progressing to forearm pronation/ caffeine intake, or fatigue do not need further testing.1,8 supination and elbow flexion/extension. It is typically unilateral, occurs at rest, and fades with voluntary move- Essential Tremor ment. It can reemerge after latency with maintenance of The most common pathologic tremor is essential tremor, posture, which can create diagnostic confusion. Tremor which is an action tremor. Essential tremor has been can involve the leg and jaw as well.3,9 A video example of described as postural, kinetic, and even as a sporadic rest- this tremor can be found at https://www.youtube.com/ ing tremor.3,12 One study found that 95% of patients with watch?v=ZMx07OagyJw. essential tremor had primarily kinetic, rather than pos- tural, characteristics.12 Essential tremor is most obvious Drug- and Metabolic-Induced Tremors in the wrists and hands when patients hold their arms in Dozens of medications can cause or exacerbate any type of front of them; however, it can also affect the head, lower tremor (Table 2).18 Patients with new-onset tremor should extremities, and voice.13 It is generally bilateral, is present have a comprehensive medication review with specific with different tasks, and interferes with activi- ties of daily living.1,5 Essential tremor affects 0.4% to 6% of the TABLE 1 population.4 In about one-half of cases, it is transmitted in an autosomal-dominant fash- Broad Classification of Tremor 8 ion. Although essential tremor can manifest by Tremor type Description early adulthood, most patients do not present for treatment until 60 to 69 years of age because Resting Occurs in a body part that is relaxed and completely it tends to progress slowly. Sometimes called supported against gravity and reduces activation of musculature benign essential tremor, essential tremor often causes social embarrassment, and up to 25% of Most commonly caused by , but may also occur in severe essential tremor those affected retire early or modify their career path.4,8,9 Importantly, 30% to 50% of those ini- Action Occurs with voluntary contraction of muscle tially diagnosed with essential tremor eventually Includes postural, isometric, and kinetic tremors receive an additional tremor diagnosis or a differ- 12 Postural Occurs when the body part is voluntarily maintained ent diagnosis entirely after further evaluation. against gravity The diagnosis of essential tremor is clinical, 2 Includes essential, physiologic, cerebellar, dystonic, based on classic symptoms and tremor features. and drug-induced tremors Persons with essential tremor typically have no other neurologic findings; therefore, it is some- Isometric Occurs as a result of muscle contraction against a times considered a diagnosis of exclusion.13 A rigid stationary object video of this tremor is available at http://www. Kinetic Occurs with any form of voluntary movement youtube.com/watch?v=xVRKO-Sz0x4&NR=1. Includes classic cerebellar, dystonic, and drug- induced tremors; essential tremor can cross over Parkinsonism to this category

Parkinsonism is a clinical syndrome charac- Intention Subtype of kinetic tremor amplified as the target is terized by tremor, bradykinesia, rigidity, and reached postural instability. Many patients also have Presence of this type of tremor implies that there is a micrographia, shuffling gait, and masked disturbance of the or its pathways facies.11,14-16 Various medications cause parkin- Adapted with permission from Leehey MA. Tremor: diagnosis and treatment. sonism by blocking or depleting lev- Primary Care Case Rev. 2001;4(1):34, with additional information from refer- els (e.g., , metoclopramide [Reglan], ences 1 and 9. ).10,11 The most common form is

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attention to any medications started before the onset of tremor. Measurement of serum ceruloplasmin level and tremor.8 Medications that stimulate the sympathetic ner- 24-hour urinary copper excretion should be considered vous system (e.g., , , pseudo- in young patients presenting with tremor to exclude this ephedrine) and psychoactive medications (e.g., tricyclic potentially life-threatening disease.16,22 A video example antidepressants, haloperidol, [Prozac]) are most of this tremor is available at http://www.youtube.com/ likely to cause a postural tremor.1,8,12,13 When the medication watch?v=JgDvQUwUOo0. review reveals a likely culprit, a trial discontinu- ation should be attempted if clinically possible. The features and causes of metabolic tremor TABLE 2 8 are varied. Initial workup of tremor may include Select Medications and Substances blood testing for hepatic (e.g., That May Exacerbate Tremor ammonia level), hypocalcemia, , hyponatremia, hypomagnesemia, hyperthy- Amiodarone Amphetamines (Ritalin) roidism, hyperparathyroidism, and vitamin B12 deficiency.8 Atorvastatin (Lipitor) Metoclopramide (Reglan) Beta- agonists Pseudoephedrine Cerebellar Tremor (e.g., albuterol) Second-generation The classic cerebellar tremor presents as a Caffeine disabling, low-frequency, slow-intention, or Carbamazepine (Tegretol) Terbutaline postural tremor, and is typically caused by mul- Theophylline tiple sclerosis with cerebellar plaques, , or Cyclosporine (Sandimmune) Thyroid hormones tumors. Most patients have other neu- Tricyclic antidepressants rologic signs of cerebellar dysfunction, including Fluoxetine (Prozac) Valproic acid (Depakene) (overshoot on finger-to-nose test- Haloperidol Verapamil ing), (abnormal heel-to-shin test- Hypoglycemic agents ing), and hypotonia.8,19 A video example of this tremor is available at http://www.youtube.com/ Adapted with permission from Crawford P, Zimmerman EE. Differentiation and diagnosis of tremor. Am Fam Physician. 2011;83(6):699. watch?v=GQm8klm6ub8.

PSYCHOGENIC TREMOR Differentiating between organic and psychogenic TABLE 3 tremor can be difficult. Features consistent with psychogenic tremor are abrupt onset, sponta- Characteristics of Psychogenic Tremor neous remission, changing tremor characteristics Abrupt onset Presence of psychiatric disease (including location and frequency), and extinc- Absence of other neurologic Presence of secondary gain 8,20 18 tion with distraction (Table 3 ). Often, there signs Reported functional distur- 3 is a stressful life event that precedes the tremor. Changing tremor characteristics bances in the past Clinical inconsistencies Responsive to placebo DYSTONIC TREMOR Multiple somatizations Spontaneous remission Dystonic tremor is rare, appearing in 0.03% of Multiple undiagnosed conditions Static course the population. It typically occurs in patients No evidence of disease by Tremor increases with younger than 50 years. The tremor is usually laboratory or radiologic attention and lessens with irregular and jerky, and certain hand or arm investigations distractibility positions extinguish the tremor. Other signs of Patient employed in allied Unclassified tremor (complex (e.g., abnormal flexion of the wrists) health professions tremors) 8,21 are always present. Patient involved in litigation or Unresponsive to antitremor compensation issues medications WILSON DISEASE

Wilson disease is a rare, autosomal-recessive Adapted with permission from Crawford P, Zimmerman EE. Differentiation and disorder that manifests in persons five to 40 diagnosis of tremor. Am Fam Physician. 2011;83(6):699. years of age, sometimes with a wing-beating

182 American Family Physician www.aafp.org/afp Volume 97, Number 3 ◆ February 1, 2018 TREMOR FIGURE 1

Patient with tremor

Diagnostic Approach Is tremor physiologic? The diagnosis of tremor is generally based on clinical information obtained from the history Yes No and physical examination.17 Although there is overlap and variability among tremor syndromes, Enhanced Taking medication physiologic associated with tremor? the intrinsic features of the tremor usually pro- tremor vide key diagnostic clues (Figure 118; Table 418). The first step is to categorize the tremor based Yes No on its activation condition, topographic distri- Drug-induced tremor Relieved with distraction? bution, and frequency. The activation condition should be described as resting, kinetic (or inten- tion), postural, or isometric. The examiner can Trial off medication Yes No have the patient sit with his or her hands in the Psychogenic Organic cause lap to check for rest tremor. A sequential test Evaluate for anxiety, caffeine tremor for postural and kinetic tremors can involve the use; serum glucose level; liver patient stretching his or her arms and hands out, function testing; thyroid- Go to Figure 2 2,3 stimulating hormone level Mental health followed by a simple finger-to-nose test. A rest- evaluation ing tremor is virtually pathognomonic for par- kinsonism, whereas an intention tremor often Diagnostic algorithm for tremor. indicates a cerebellar lesion.11 Frequency is gen- Adapted with permission from Crawford P, Zimmerman EE. Differentiation and erally classified as low (less than 4 Hz), medium diagnosis of tremor. Am Fam Physician. 2011;83(6):700. (4 to 7 Hz), or high (more than 7 Hz). The topo- graphic distribution of the tremor (e.g., limbs,

TABLE 4

Features of Common Tremor Syndromes Tremor syndrome Clinical features Diagnostic tests Treatment

Cerebellar Intention tremor; ipsilateral Head computed tomography or Treat underlying cause; tremor involvement to lesion; abnormal magnetic resonance imaging finger-to-nose test; imbalance; abnormal heel-to-shin test

Enhanced Postural tremor; low amplitude; use History of caffeine use or anxi- Treat underlying cause; physiologic of exacerbating medication ety; glucose (for hypoglycemia), reassurance tremor thyroid-stimulating hormone, liver function testing

Essential tremor Postural tremor; symmetric; involves No specific test; complete blood ; hands/wrists, lower extremities, head, count; thyroid function testing; (Mysoline); surgery or voice; family history; improvement serum chemistry profile may rule with small amount of intake out other disease

Parkinsonian Rest tremor; asymmetric; involves No specific test; positron emission Dopamine agonists; tremor distal extremities; decreases with tomography or single-photon ; surgery; voluntary movement; bradykinesia emission computed tomography deep brain stimulation and rigidity; postural instability for atypical presentation

Psychogenic Abrupt onset; spontaneous remis- Careful history Mental health counseling tremor sion; changing tremor characteristics; extinction with distraction

Adapted with permission from Crawford P, Zimmerman EE. Differentiation and diagnosis of tremor. Am Fam Physician. 2011;83(6):700.

February 1, 2018 ◆ Volume 97, Number 3 www.aafp.org/afp American Family Physician 183 TREMOR FIGURE 2

Tremor with organic cause

Age < 40 years?

Yes No

Serum ceruloplasmin level and Resting or action tremor? 24-hour urinary copper secretion

Resting Action Positive Negative Rigidity, bradykinesia, History of ? Wilson disease Neurologic signs postural instability? or symptoms? Yes No Chelation Yes No therapy Yes No Withdrawal Postural or Parkinsonism Possible or alcohol intention tremor? Various anatomic, Likely parkinsonism tremor metabolic, and essential genetic problems tumor Trial of Postural Intention dopaminergic Monitor agent Essential tremor Cerebellar tremor Appropriate blood Trial of beta or genetic tests blocker with or without Trial of beta Head imaging for head imaging blocker stroke, mass,

Diagnostic algorithm for tremor with an organic cause.

Adapted with permission from Crawford P, Zimmerman EE. Differentiation and diagnosis of tremor. Am Fam Physician. 2011;83(6):701.

head, voice) can also provide useful information. For exam- tremor. Conversely, small amounts of alcohol (30 to 60 g) ple, a high-frequency tremor involving the head is more can temporarily relieve essential tremor and can be a his- likely to be essential tremor than parkinsonian tremor.2,3 torical clue to the diagnosis.2,3 Several historical clues can play important roles in dif- The assessment of tremor also includes examination for ferentiating tremor (Figure 218). Tremor in older patients signs associated with tremor syndromes. Bradykinesia and and gradual onset are more likely to be Parkinson disease postural abnormalities, which are late findings, strongly or essential tremor. Sudden onset of tremor is more likely suggest parkinsonism.22 Difficulty rising from a seated to be caused by medication use, toxins, a psychogenic position, micrographia, reduced arm swing while walking, cause, or, in rare cases, a . A list of clinical and masked facies are also features of bradykinesia.23 Pos- features that help differentiate between essential tremor tural abnormalities can be demonstrated by a positive pull and Parkinson disease is available at http://www.aafp.org/ test, where the patient stands in a neutral position and the afp/2003/1015/p1545.html#afp20031015p1545-t3. examiner causes him or her to become unsteady by pull- Caffeine intake and fatigue are often exacerbating fac- ing on the upper arms from behind. This can help isolate tors in essential tremor with few alleviating factors. Asso- cerebellar tremor and prompt evaluation for multiple scle- ciated conditions and diseases should be identified. For rosis or stroke.24 Similarly, coactivation sign is resistance example, fatigued muscles from disorders amplify during passive movement of a tremulous limb, but with physiologic tremor, and polyneuropathy from lack of disappearance of the tremor, which indicates psychogenic innervations causes small involuntary movements that tremor. If essential tremor and parkinsonism are both pos- may be interpreted as tremor. A family history of neu- sible diagnoses, the patient should be asked to draw a clock- rologic disease or tremor suggests a genetic component, wise spiral. A large, shaky spiral points to essential tremor; which is common in essential tremor. A medication his- however, a small, quivery spiral means that parkinsonism tory should be obtained to rule out drug-induced tremor. is likely.25 The examiner should also look for dystonia (i.e., Patients should be screened for drugs of abuse as well as sustained muscle contraction), cerebellar signs (e.g., , alcohol overuse and withdrawal because these can cause incoordination), pyramidal signs, neuropathic signs, and

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If there is diagnostic uncertainty, SORT: KEY RECOMMENDATIONS FOR PRACTICE single-photon emission computed tomography (SPECT) using ioflupane Evidence (123I-FP-CIT SPECT or DaTSCAN), Clinical recommendation rating References in addition to subspecialty consulta- A resting tremor is usually caused by parkinsonism. C 1, 11 tion, can be useful for distinguish- ing Parkinson disease from essential Patients with new-onset tremor should have a com- C 8, 12, 13 tremor, and to a lesser extent from prehensive review of medications (prescribed and over-the-counter), with specific attention to medica- drug-induced tremor, dystonic tremor, tions started before the onset of tremor. psychogenic tremor, or unilateral pos- tural tremor.29,30 When assessing for The diagnosis of tremor is based on clinical information C 2, 17 dopamine transporter dysfunction, obtained from the history and physical examination. 123I-FP-CIT SPECT was 78% sensitive Tremor in children is potentially serious; patients C 26, 27 and 97% specific, with a positive like- should be promptly referred to a neurologist. lihood ratio of 26 and a negative likeli- In select cases when there is significant diagnostic C 29, 30, 32 hood ratio of 0.23 in one case series of uncertainty, single-photon emission computed 99 patients with suspected Parkinson tomography using ioflupane can be useful for distin- disease.31 A positive test can therefore guishing Parkinson disease from other tremor types. rule in a diagnosis of Parkinson dis- A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality ease within three years; however, it is patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert not superior to clinical assessment in opinion, or case series. For information about the SORT evidence rating system, go to http:// the diagnosis of Parkinson disease,29 www.aafp.org/afpsort. and its specific clinical use remains unclear.32 Transcranial ultrasonography can signs of systemic disease (e.g., thyrotoxicosis). A shuffling also predict Parkinson disease by revealing hyperecho- gait is consistent with parkinsonism.2,8,25 genicity of the . A European study of 49 Stanford University has a brief tutorial on the approach patients in a clinic demonstrated that ultraso- to tremor available at https://www.youtube.com/watch?v=​ ​ nography compared favorably vs. 123I-FP-CIT SPECT myQdK6BuBws. for sensitivity (90% vs. 97%), specificity (60% vs. 70%), positive predictive value (77% vs. 82%), and negative pre- TREMOR IN CHILDREN dictive value (80% vs. 93%) for the diagnosis of Parkinson The diagnosis of tremor in children is challenging because disease. Operator inexperience and limited fusion imaging of myriad potential causes, such as Wilson disease, frag- technology, as well as conflicting results from several clini- 33 ile X syndrome, nutritional deficiencies (e.g., vitamin B12), cal studies, limit the use of transcranial ultrasonography. heavy metal poisoning, and essential tremor. Almost one- half of children with experience This article updates previous articles on this topic by Crawford 18 34 35 tremor for up to 18 months.26 All childhood tremors are and Zimmerman ; Smaga ; and Charles, et al. potentially serious and should prompt an in-depth inves- Data Sources: A PubMed search was completed in Clinical tigation to clarify the cause; patients should be promptly Queries using the key terms tremor, movement disorders, referred to a neurologist.27 ultrasound, and SPECT. The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. Also searched were the Agency for Healthcare Research and Quality Imaging evidence reports, Bandolier, Clinical Evidence, FPIN’s Clini- Although the diagnosis of tremor remains primarily clini- cal Inquiry database, the Cochrane database, the Institute for cal, certain imaging modalities can help differentiate some Clinical Systems Improvement, the National Guideline Clear- causes of tremor. Noncontrast magnetic resonance imaging inghouse database, Essential Evidence Plus, EBM Online, and UpToDate. Reference lists of recent review articles were also and computed tomography can rule out secondary causes searched for articles not previously discovered. Search dates: of tremor (e.g., multiple sclerosis, mass lesion, stroke) when January 10 and September 10, 2017. the history and physical examination are suggestive of a The opinions expressed in this article do not represent the structural cause, or in parkinsonism with atypical features official opinions of the U.S. Air Force or the Department of or that is refractory to levodopa.28 Defense.

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The Authors 15. Berardelli A, Wenning GK, Antonini A, et al. EFNS/MDS-ES/ENS [cor- rected] recommendations for the diagnosis of Parkinson’s disease PAUL CRAWFORD, MD, is the program director of the Nellis [published correction appears in Eur J Neurol. 2013;​20(2):​406]. Eur J Family Medicine Residency, Nellis Air Force Base, Nev., and a Neurol. 2013;​20(1):​16-34. professor of family medicine at the Uniformed Services Uni- 16. Bohnen NI, Studenski SA, Constantine GM, Moore RY. Diagnostic per- versity of the Health Sciences, Bethesda, Md. formance of clinical motor and non-motor tests of Parkinson disease: ​ a matched case-control study. Eur J Neurol. 2008;​15(7):​685-691. ETHAN E. ZIMMERMAN, MD, is a faculty member at Nellis 17. Espay AJ, Lang AE, Erro R, et al. Essential pitfalls in “essential” tremor. Family Medicine Residency and an assistant professor of Mov Disord. 2017;​32(3):325-331​ . family medicine at the Uniformed Services University of the 18. Crawford P, Zimmerman EE. 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