Essential Tremor Case File

Essential Tremor Case File

Eugene C. Toy, MD, Ericka Simpson, MD, Pedro Mancias, MD, Erin E. Furr-Stimming, MD

CASE 1

A 65-year-old, right-handed man is being evaluated for a tremor that has been present for approximately 20 years. The tremor began insidiously and has progressed gradually. It involves both hands, although he feels the tremor is asymmetric, with his right-hand tremor being worse. His handwriting, drinking coffee and other liquids from a cup, and any activity that requires fine motor dexterity are affected. His tremor is not present at rest, and he has noticed that drinking a glass of beer or wine often improves his symptoms. His mother and daughter have a similar tremor, though to a lesser degree. On examination, he has a regular tremor of approximately 6 to 8 cycles per second (Hz) that is most prominent when extending his hands outward and during finger-to-nose testing. Occasional tremor is also noted of his head, and his voice has a tremulous quality. The remainder of his examination is unremarkable.

▶ What is the most likely diagnosis?

▶ What is the next diagnostic step?

▶ What is the next step in therapy?

ANSWERS TO CASE 1:

Essential Tremor                                                            

Summary: A 65-year-old, right-handed man has a 20-year history of tremor predominantly limited to actions such as writing, drawing, or holding objects. There is also head tremor, although to a lesser degree. The history is significant for similar signs and symptoms in his family members, and alcohol use improves symptoms.

• Most likely diagnosis: Essential tremor (ET).
• Next diagnostic step: Depending on clinical suspicion based on a detailed neurologic examination, magnetic resonance imaging (MRI) of brain and cervical spine may be warranted. A medication trial may be warranted if clinical suspicion of ET is high.
• Next step in therapy: Consider primidone or propranolol.

ANALYSIS

Objectives

1. Understand the differential diagnosis of tremor.
2. Describe the clinical manifestations of ET.
3. Be aware of the available treatment modalities for patients with ET.

Considerations

This case is typical for ET, although at this age, Parkinson disease (PD) should also be considered. ET is the most common movement disorder and may be 10 to 20 times more prevalent than idiopathic PD. Although ET is not generally thought of as a neurodegenerative disease, it can be bothersome and debilitating, negatively impacting quality of life. The diagnosis of ET is clinical, and several aspects help to distinguish between these two disorders. The tremor associated with PD may occur upon assuming a posture; if it occurs after a latent period of several seconds, it is called a reemergent tremor. PD patients can have jaw and tongue tremor (usually at rest), and head tremor is rare. Tremors from PD are most prominent when the hands are at the sides or resting in the lap. This type of tremor typically decreases with movement of the hands. In addition, PD is associated with rigidity, bradykinesia or slow movement, and postural instability. PD patients may also have a stooped posture, shuffling gait, sleep disturbance, hypophonic speech, autonomic dysfunction, hyposmia, mood disturbances, and subcortical cognitive decline (Table 1–1).

Data from DeLong MR, Luncos JL. Parkinson’s disease and other movement disorders. In: Kasper DL, et al, eds.

Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill; 2005:2406-2418.

APPROACH TO:

Tremor                                                            

DEFINITIONS

COGWHEEL RIGIDITY: “Ratchety” periodic resistance to passive movement.

LEAD-PIPE RIGIDITY: Velocity-independent resistance felt throughout range of motion.

BRADYKINESIA: Slowed ability to start and continue movements and impaired ability to adjust the body’s position.

ACTION TREMOR: Tremor that occurs during voluntary muscle contraction and may include postural, kinetic, or task- or position-specific tremor.

POSTURAL TREMOR: Tremor that occurs while voluntarily maintaining antigravity position.

KINETIC TREMOR: Action tremor that occurs with voluntary movements, including visually or nonvisually guided actions, including speaking or finger-to-nose testing.

PHYSIOLOGIC TREMOR: A very low-amplitude fine tremor (between 8 and 12 Hz) that is rarely visible to the naked eye. It is present in individuals while maintaining a posture or movement and is nonpathologic. It is often enhanced by stress, caffeine, or thyroid dysfunction.

DYSTONIC TREMOR: Dystonia is defined as sustained involuntary movements caused by contraction of agonist and antagonist muscles producing “twisting or turning” movements. A dystonic tremor is usually not rhythmic or oscillatory, but instead it is irregular with rhythm and amplitude and may be accompanied by additional dystonic features.

CLINICAL APPROACH

ET is considered a monosymptomatic disease; that is, it generally causes tremor alone, although some patients also experience difficulty with tandem gait. The tremor usually begins gradually and will likely increase in severity over time. More often, tremors begin in mid-to-late life, with a mean age of onset of 45. The most common sign is an oscillatory movement of the hands or, more precisely, at the wrist joint where flexion and extension can be seen. The tremor may also occur in the legs, head, or voice. Symptoms of ET are typically bilateral, although some patients describe an asymmetric tremor. Tremors usually occur only when the patient engages in a voluntary movement, such as drinking a glass of water, writing, or threading a needle. Actions requiring fine motor skills, such as using utensils or small tools, can be especially difficult. Fatigue, anxiety, and temperature extremes may exacerbate symptoms, but tremors usually disappear when asleep or at rest. Low doses of alcohol, such as a glass of beer or wine, can dramatically decrease the tremor in approximately one-half of cases. Besides tremor, there can be mild impairments of balance. There is no confirmatory imaging or laboratory test to definitively diagnose the disorder; the diagnosis is made clinically using functional assessments such as writing, drawing spirals, or pouring water from one cup to another while performing a complete neurologic examination to rule out other potential diagnoses.

Pathogenesis

Approximately half of all cases of ET are associated with an autosomal dominant inheritance pattern. The cause of ET in patients without identifiable genetic abnormality remains unclear. Histopathologic changes, including loss of Purkinje cells and presence of Lewy bodies (alpha-synuclein aggregates), have been described but are of uncertain significance.

Diagnosis

In addition to ET and PD, other etiologies for tremors should be considered. Tremor as part of dystonic conditions is typically more asymmetric than ET and may have a jerky quality. Purely kinetic (occurring with action or voluntary movement) and intention tremors (when attempting a precise movement) are sometimes seen with disruption of cerebellar output tracts or damage to the red nucleus, which is involved in cerebellar motor pathways. Hyperthyroidism and other metabolic conditions associated with increased adrenergic activity can cause enhanced physiologic tremors that may resemble ET.

ET is a clinical diagnosis and requires thorough evaluation to rule out other conditions. Laboratory studies, including thyroid function tests (thyroid-stimulating hormone [TSH]) and serum copper or ceruloplasmin levels (Wilson disease), should be considered based on the clinical picture. Neuroimaging may be indicated if diagnosis of ET is unclear or another neurologic condition is suspected.

ET may be difficult to distinguish from tremor-dominant parkinsonian syndromes, including idiopathic PD. Traditional computed tomography (CT) or MRI of the brain may not show differences between the two conditions. 123I-FP-CIT SPECT (DaTscan) imaging can differentiate ET from idiopathic

PD and other primary parkinsonian disorders. DaTscan allows measurement and visualization of dopamine transporters (DaT) in the brain. In the setting of idiopathic PD, DaTscan will show asymmetric basal ganglia uptake, indicative of diminished dopamine transporter density in the striatum, whereas it is often normal in ET.

Management

If there is an underlying medical cause such as hyperthyroidism, addressing it can alleviate the symptoms of the tremor. In addition, counseling the patient about lifestyle changes such as limiting caffeine intake, ensuring adequate rest, and employing stress-coping strategies can help tremor exacerbation secondary to external stimuli. Medications provide relief from tremors roughly half of the time. The mainstay of pharmacologic treatment for ET is with beta-blockers or primidone.

Beta-blockers, such as propranolol, may provide relief from symptoms in many ET patients. Their common side effects include dizziness, confusion, and memory loss, particularly in older patients. They should be avoided in patients who are hypotensive or have a resting heart rate of less than 60 beats/min. There is also a relative contraindication in their use in patients with asthma, due to beta-blockade.

Other medications include antiseizure medications, such as primidone (Mysoline) or topiramate (Topamax), which may be effective in patients who do not respond to beta-blockers; they are given at lower doses than those given to treat epilepsy. These medications should be initiated at low doses and increased slowly; this is particularly important for primidone, in which 25% of patients can experience acute ataxia and nausea upon starting the medications at higher doses. Topiramate can cause transient peripheral paresthesias, word-finding difficulty, weight loss, and can increase the risk for nephrolithiasis. Sedative-hypnotic agents such as the benzodiazepines diazepam (Valium) and alprazolam (Xanax) are sometimes used to treat patients whose tremors are exacerbated by tension or anxiety. Side effects can include confusion, imbalance, and sedation. It is important to note that the majority of medications used to treat patients with ET are used in an off-label manner. Botulinum toxin type A (Botox) injections can also be useful in treating some types of tremors, especially of the head and voice and dystonic tremors. Patients with refractory, functionally disrupting, or disabling tremor despite medical management may be candidates for deep brain stimulation (DBS) surgery. DBS involves surgical placement of an electrostimulator in the thalamus or subthalamic nucleus (STN) and has been shown to effectively decrease tremor in patients with ET as well as tremor-dominant PD. DBS should be avoided in patients with concurrent or preexisting psychiatric disorders, as it may worsen these conditions.

COMPREHENSION QUESTIONS

1.1 A 59-year-old man is diagnosed with probable ET. A DaTscan is performed. In the case of true ET, which of the following is most likely to show abnormal uptake?

A. Cerebellum

B. Cerebral cortex

C. Striatum

D. None of the above

1.2 A 45-year-old woman is noted to have a distinct tremor with voluntary activity. Multiple family members also are noted to have tremors. If ET is diagnosed, what pattern of inheritance is most likely?

A. Autosomal dominant

B. Autosomal recessive

C. X-linked dominant

D. X-linked recessive

E. Y-linked recessive

1.3 A 58-year-old man is noted to have a noticeable tremor that has progressed over 5 years. The tremor occurs in both hands while eating and drinking; there are mild problems with tandem gait, and there is also presence of tremor of the head. Of the following, which is more supportive of ET rather than idiopathic PD?

A. Gait disturbance

B. Male gender

C. Slow progression of the tremor over 5 years

D. Tremor in the head

ANSWERS

1.1 D. Although DaTscan may reveal diminished signal of basal ganglia structures in PD, it is generally unremarkable in ET. It has been Food and Drug Administration (FDA) approved to radiographically differentiate ET from PD.

1.2 A. An apparently autosomal dominant history of tremor is often seen in ET. A familial tendency may also be seen in PD. With autosomal dominant inheritance, half of offspring are affected, and males and females are equally affected.

1.3 D. The tremor involving the head is more typical of ET. There can be gait problems and also slow onset of tremor in both ET and PD. In general, ET is an isolated finding of tremor, whereas PD is associated with stooped posture, shuffling gait, and memory loss.

    CLINICAL PEARLS    

▶ Essential tremor (ET) is the most common movement disorder and affects up to 10 million adults. ▶ ET may be hereditary in half of patients and exhibits an autosomal dominant inheritance pattern in those cases. ▶ DaTscan may help distinguish ET from primary parkinsonian syndromes. ▶ ET is often relieved with low doses of alcohol and can be treated with beta-blockers, primidone or topiramate. ▶ Refractory, disabling ET may warrant consideration of surgical intervention such as DBS.

REFERENCES

Benamer TS, Patterson J, Grosset DG, et al. Accurate differentiation of parkinsonism and essential tremor using visual assessment of [123I]-FP-CIT SPECT imaging: the [123I]-FP-CIT study group. Mov Disord. 2000;15:503-510. 

Louis ED. Essential tremor. Lancet Neurol. 2005;4:100-110. 

Louis ED. Essential tremor: evolving clinicopathological concepts in an era of intensive post-mortem enquiry. Lancet Neurol. 2010;9:613-622. 

Louis ED. Diagnosis and management of tremor. Continuum (Minneap Minn). 2016;22(4):1143-1158. 

Lyons K, Pahwa R, Comella C, et al. Benefits and risks of pharmacological treatments for essential tremor. Drug Saf. 2003;26:461-481. 

Pahwa R, Lyons KE, Wilkinson SB, et al. Comparison of thalamotomy to deep brain stimulation of the thalamus in essential tremor. Mov Disord. 2001;16:140-143. 

Tolosa E, Borght TV, Moreno E. Accuracy of DaTSCAN (123I-Ioflupane) SPECT in diagnosis of patients with clinically uncertain parkinsonism: 2-year follow-up of an open-label study. Mov Disord. 2007;22(16):2346-2351. 

Zesiewicz TA, Elble RJ, Louis ED, et al. Evidence-based guideline update: treatment of essential tremor. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2011;77:1752-1755.

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