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essential tremor

Epidemiology: 1) 0.3-5.6% of the general population - most common movement disorder 2) men & women equally affected 3) prevalence increases with age 4) mean age at onset 35-45 years - most often appears in late adolescence or middle age 5) virtually always presents by age 70 years Pathology: - abnormally functioning central oscillator located in the Guillain Mollaret triangle near the brain stem - involves the inferior olivary nucleus - cerebellar-brainstem-thalamic-cortical circuits probably involved - progressive & disabling disorder [2] Genetics: - type 1 is autosomal dominant - susceptibility loci a) FET1 gene at 3q13 identified in 75 members of 16 Icelandic families b) locus 2p25-22 identified in 15 members of 4 generations & 3 other families c) DRD3 gene - 50-70% of patients with family history of essential tremor [2] Clinical manifestations: - onset in adolescence or middle-age - low or moderate amplitude, high-frequency (6-12 Hz) action tremor - most evident during active use of affected muscles - more prominent with finger-to-nose testing - may be worse when holding arms in outstreched position - generally blilateral & symmetrical - progression is generally slow [2] - asymmetric tremor predicts more rapid progression of tremor [6] - often presents as bilateral upper extremity action tremor & postural tremor - may involve head & neck, upper extremities. voice - yes-yes bobbing of head - tremulous voice - movement is flexion-extension - mild cogwheeling without rigidity may be present - aggravated by emotions, hunger, fatigue & temperature extremes - functional impairment may be significant - alleviation by alcohol [2] Laboratory: 1) comprehensive chemistry panel a) serum electrolytes b) serum urea nitrogen (BUN) c) serum creatinine d) liver function tests 2) thyroid function tests 3) serum ceruloplasmin & 24 hour urine copper (for Wilson disease < 40 years) Radiology: - CT & MRI of the head are normal - MRI helps exclude structural & inflammatory lesions (including multiple sclerosis) & Wilson disease - MRI should be performed if the tremor has acute onset or stepwise progression Differential diagnosis: - distinguished from tremor of Parkinson's disease by absence of: rigidity, bradykinesia, postural instability, resting tremor - physiologic tremor - low-amplitude action tremor in fingers & hands - often associated with medications, stress, caffeine, or other triggers - fluctuating course the resolves with removal of underlying triggers - no improvement with alcohol - little or no functional impairment occurs - cerebellar tremor - of lower frequency than essential tremor (< 5 Hz) - often associated with dysmetria, hypotonia, ataxia Complications: - may be associated with increased mortality for unclear reason(s) [7] - 3-fold increased risk of dementia [14] - conversion rate from mild cognitive impairment to dementia is 12%, about 3-fold the rate in the general population, & similar to the rate in patients with Parkinson disease [15] Management: 1) avoidance of caffeine & other stimulants 2) alcohol in small amounts 3) beta blockers a) propranolol* considered effective agent [8] 1] start 20 mg PO TID 2] titrate to effect 3] response rate 50-67% [8] b) other beta blockers probably effective [8] - naldolol, atenolol, sotalol c) non cardiac beta-2 adrenergic receptors may be involved or a central effect is possible [3] 4) primidone* (Primaclone, Mysoline) considered effective agent [8] a) start 50 mg QHS b) gradually increase to 250-300 mg/day in divided doses c) response rate 50-67% [8] 5) topiramate* (Topamax) effective [2,8] 6) gabapentin (Neurontin) 400 mg TID a) comparable to propranolol 40 mg TID [4] b) probably effective [8] 7) methazolamide [2] 8) alprazolam (Xanax) may be useful [4,8] 9) mirtazapine (Remeron) may be useful [4] 10) botulinum toxin (Botox) 11) non-invasive nerve stimulation device worn on wrist may reduce hand tremors [12] 12) stereotactic thalamic stimulation should be considered for more severe tremors not responsive to medical management a) deep brain stimulation more effective with fewer adverse effects (dysarthria, sensory dysfunction, gait disorder) than thalamotomy [2] - indicated for medication-refractory essential tremor [2] b) radiosurgery c) MRI-guided focused ultrasound [10,11] 13) transcranial image-guided focused ultrasound * propranolol, primidone & topiramate most effective [2]

General

action tremor

Database Correlations

OMIM 190300

References

  1. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 1015-16
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2021. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  3. Physician's Desk Reference (PDR) 56th ed, 2002
  4. Gironell A et al A randomized placebo-controlled comparative trial of gabapentin and propranolol in essential tremor. Arch of Neurol 56:475, 1999 PMID: 10199338 - Harrison's Online, 2002
  5. Zesiewicz TA et al, CME Practice Parameter: Therapies for essential tremor Report of the Quality Standards Subcommittee of the American Academy of Neurology Neurology 2005;64:2008-2020 PMID: 15972843 http://www.neurology.org/cgi/reprint/64/12/2008.pdf?ck=nck
  6. Putzke JD, Whaley NR, Baba Y, Wszolek ZK, Uitti RJ. Essential tremor: predictors of disease progression in a clinical cohort. J Neurol Neurosurg Psychiatry. 2006 Nov;77(11):1235-7. PMID: 17043291
  7. Louis ED et al, A population-based study of mortality in essential tremor. Neurology 2007, 69:1982 PMID: 18025392
  8. Zesiewicz TA et al Evidence-based guideline update: Treatment of essential tremor Report of the Quality Standards Subcommittee of the American Academy of Neurology Neurology, October 19, 2011 PMID: 22013182 http://www.neurology.org/content/early/2011/10/18/WNL.0b013e318236f0fd.abstract - Evidence-based guideline update: Treatment of essential tremor Data Supplement http://www.neurology.org/content/early/2011/10/18/WNL.0b013e318236f0fd/suppl/DC1
  9. Prescriber's Letter 19(3): 2012 Drug Treatment for Essential Tremor Detail-Document#: 280336 (subscription needed) http://www.prescribersletter.com
  10. Elias WJ et al. A pilot study of focused ultrasound thalamotomy for essential tremor. N Engl J Med 2013 Aug 15; 369:640. PMID: 23944301 http://www.nejm.org/doi/full/10.1056/NEJMoa1300962 - FDA News Release. July 11, 2016 FDA approves first MRI-guided focused ultrasound device to treat essential tremor. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm510595.htm
  11. Elias WJ et al A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor. N Engl J Med 2016; 375:730-739. August 25, 2016 PMID: 27557301 http://www.nejm.org/doi/full/10.1056/NEJMoa1600159 - Louis ED Treatment of Medically Refractory Essential Tremor. N Engl J Med 2016; 375:792-793. August 25, 2016 PMID: 27557307 http://www.nejm.org/doi/full/10.1056/NEJMe1606517
  12. George J Wrist-Worn Device Reduces Hand Tremor. Neuroperipheral therapy interrupts signal in essential tremor patients. MedPage Today. April 19, 2018 https://www.medpagetoday.com/meetingcoverage/aan/72445 - Pahwa R, et al Non-invasive peripheral nerve stimulation for symptomatic relief of hand tremor in essential tremor. American Academy of Neurology (AAN) 2018.
  13. Haubenberger D, Hallett M. Essential Tremor. N Engl J Med. 2018 May 10;378(19):1802-1810. PMID: 29742376 https://www.nejm.org/doi/full/10.1056/NEJMcp1707928
  14. George J Dementia More Common in People With Essential Tremor. Prevalence greater than normal aging, but not as high as Parkinson's disease. MedPage Today March 6, 2024 https://www.medpagetoday.com/meetingcoverage/aan/109046
  15. Ghanem A et al. Prevalence of and annual conversion rates to mild cognitive impairment and dementia: Prospective, longitudinal study of an essential tremor cohort. Ann Neurol 2024 Jun; 95:1193. https://onlinelibrary.wiley.com/doi/10.1002/ana.26927