Essential tremors (ET), is a one of the commonest progressive tremor disorder. Traditionally it is viewed as a monosymptomatic disorder, however off late has been noted as a more complex and heterogeneous entity.
In extensive prevalence literature, crude estimates of ET prevalence ranges from 0.008% to 22%(Louis ED et al, Mov Disord 1998). However, this wide range has been refined to 0.4% to 3.9%, from population based and definition criteria of ET( Deuschl G et al, 2010). Meta-analysis of epidemiological studies has found prevalence rates of 0.01% to 20.5%, with pooled prevalence of 0.9%. The prevalence in people over 65 years has been 4.6% and may be as high as 21.7% in people older than 95 years (Louis ED et al, 2010). However, in relation to the prevalence studies, there is paucity of data in regards to incidence due to difficulties of long term data acquisition. In prospective, population based studies to look for incidence of ET it has been noted that about 616/100,000 person years develops ET over the age of 65 years( Benito-Leon J et al, 2005) In another retrospective 45 year study performed in Rochester, New york, the age adjusted incidence was estimated to be 17.5/100,000/year, however this study could be an underestimate of true incidence due to entry of ET into medical records would have required severe enough symptoms to be recognized and treated ( Rajput AH et al, 1984)
A family history of tremors has been reported in 17% to 100% of patients with ET.( Busenbark K et al, 1996; Louis ED et al, 1996) The families where in hereditary inheritance has been noted are mostly characterized by autosomal dominant inheritance with an almost complete penetrance at age 60-70 years. However still about 20 to 40% of patients are sporadic, and this has been attributed to reduced or age depended penetrance of autosomal dominant mutations, new mutations and phenocopies, or due to polygenic, mitochondrial, autosomal recessive or X-linked inheritance (Deuschl G et al, 2010). Currently till dates, various loci has been found to be linked to the familial ET and include
- ETM1 – 3q13.1, a Ser9Gly variant in the DRD3 gene noted from 75 affected relatives of definitive case of ET from 16 Icelandic families (Gulcher JR et al, 1997). It encodes for dopamine D3 receptor, expressed in Purkinje cells. It has been noted that Gly9 variant represent a gain of function.
- ETM2 – 2p41.1, established in 3 pure ET families, and one family with ET parkinsonism.(25) It encodes the hematopoietic lineage cell specific protein 1 binding progein 3 (HS1-BP3), which binds to motor neurons and Purkinje cells and regulates the Ca2+/Calmodulin dependent protein kinase activation of tyrosine and tryptophan hydroxylase. This association has not been confirmed by other studies (Deng H et al, 2005; Shatunov A et al, 2005).
- 3 – 24.1 linkage has been confirmed in two families ( Shatunov A et al, 2006).
- LINGO – 1 gene on chromosome 15q24.3 has been found to significantly associated with ET from a genome wide scan of 452 ET patients, as compared to 14,378 controls( Stefansson H et al, 2009).
Although ET was one of the earliest recognized tremor disorders, there has been a considerable controversy in relation to its criteria for diagnosis. There have been various criteria described and among them the criteria described by movement disorder society has been most widely accepted for clinical application and the Washington Heights-Inwood genetic study of ET criteria is used mainly for genetic and epidemiological studie ( Findley LJ et al, 1995; Deuschl G et al, 1998; Benito-Leon J et al, 2006; Louis ED et al, 1997) These criteria’s have been summarized in Table -2.
The topographic distribution of ET shows that hand tremors are noted in 94% of patients followed by head tremors (33%), voice tremor (16%), jaw tremor (8%), facial tremor (3%), leg tremor (12%) and trunk tremor (3%).(32;33) About 50-90% of patients show reduction tremor with ingestion of alcohol (Louis ED et al, Mov Disord 1998). Usually, the ET starts with a postural tremor later evolving to have all forms of phenomenological descriptions, including rest tremors. As the disease progress, the intention tremors become more apparent and are also accompanied by other features of cerebellar dysfunction, although most of them would be subtle in nature. Recent studies have described various non-motor features associated with ET and include, subtle attentional and executive dysfunction in the form of deficits on verbal fluency, naming, mental set shifting, verbal and working memory, complex auditory attention, visual attention and response inhibition (Gasparini M et al, 2001; Lombardi WJ et al, 2001; Benito-Leon J et al, 2006). There have also been reports of mild but definite olfactory impairment (Applegate LM et al, 2005; Hawkes C et al, 2003).
The clinical process may begin in childhood, but the incidence dramatically increases after the age of 40 years. Intention tremor develops at various interval between 3 and 30 years after the onset of postural tremor( Deuschl G et al, 2000). The disease related disability depends on the severity of tremor and many times, patients may not seek medical attention also.
There has been paucity of consistent literature on pathological changes in ET till about a decade back. Since then, the published literature proposes two different pathological patterns based upon Lewy bodies either predominantly in brainstem or reduction in number of purkinje cells in the cerebellum (Louis ED, 2006 & 2007).
Anatomical imaging such as CT scans and MRI have provided only a modest insight into diagnostic or functional changes in brain of patients with ET. However, the functional imaging with PET and SPECT studies has shown abnormalities in dopaminergic system and the cerebellar connections. In addition ultrasonography has shown hyperechognenecity of the substantianigra. However, these changes have not been universal (Jenkins IH et al, 1993; Louis ED et al, 2002; Martinelli P et al, 2007; Stockner H et al, 2007).
Although there is paucity of disease modifying therapies for ET, there have been various pharmacological and non-pharmacological therapies available for the symptomatic therapy. The non-pharmacological therapies include, behavioural relaxation training, speech therapy, physical therapies and weights which have been shown to help ET to some extent. In pharmacological therapies, both medical and surgical management have been shown to be effective for managing symptomatic tremors. There have been various drugs used in the management and include, beta adrenergic antagonists (propranolol, metoprolol, nadolol, atenolol, sotalol…), anticonvulsants (Primidone, topiramate, gabapentin, levericitam), benzodiazepines, botulinum toxin, calcium channel antagonists, atypical antipsychotics(clozapine, queitpaine), and antidepressants (mirtazapine). Even though alcohol is considered as to benefit ET, prescribing it as a therapeutic agent is generally avoided as the dose required for significant benefit has been noted to approach intoxication. The most commonly used drugs and their dosages are given in table-3. The quality standards subcommittee of American Academy of Neurology recognizes propranolol and Primidone as the cornerstone therapies. Following these the first line drugs also include gabapentin and topiramate. Botulinum toxin has been proposed as a treatment for ET and reduces tremor by weakening of muscles. Botulinum toxin is used only in those patients who don’t respond to conventional oral therapies and the efficacy therapy is also limited due to narrow range for therapeutic benefits vs. adverse effects due to weakness. Surgical therapy is accepted treatment for patients with severe disability and resistance to medical treatment. The various surgical modalities used include lesionectomies, deep brain stimulation (DBS) and gamma knife surgery and target the thalamus (Vim nucleus). Both lesionectomies and DBS have shown to be considerable effective in management, but DBS remains the first choice due to its advantages. Gamma knife surgery even though helpful, is limited by its slow clinical benefits and sometimes due to loss of efficacy, but is most commonly reserved for elderly patients in whom lesionectomies or DBS is contraindicated (Zesiewicz TA et al, 2005; Findley LJ et al, 1985; Findley LJ et al, 1985; Gironell A et al, 1999; Connor GS, 2002; Handforth A et al, 2004 ; Adler CH et al, 2004; Brin MF et al, 2001; Ondo W et al, 2001; Pahwa R et al, 1999; Koller WC et al, 1999; Ohye C et al, 2005)