There is often a family history of the disorder and approximately 50% of cases have a genetic link with an autosomal dominant disorder. Thus, genetic factors play much more of a role in
essential tremor than in Parkinson disease. Several susceptibility loci (autosomal dominant gene) recently have been reported to be genetically linked to dominantly inherited essential tremor.
Markers for two genes have been discovered on chromosomes 2 and 3, and additional genes are expected. These include loci in chromosome arm 2p (ETM gene) and band 3q13 (FET1 gene) (11). The cause of essential tremor in people without the genetic
mutation is unknown. Having a parent with the disorder increases the risk (12).
n Workup
In laboratory studies, there are no biological markers exist for ET. If the family history and examination are indicative of ET, no laboratory or imaging studies are required. If the family
history and examination are not indicative of ET, laboratory and imaging studies should be considered. Laboratory investigations include standard electrolyte panel, thyroid function tests, BUN, creatinine, liver function tests, and serum ceruloplasmin (for Wilson disease).
In imaging studies, the CT scan and MR examination must reveal normal imaging without identified lesions. MRI helps exclude structural and inflammatory lesions (including multiple sclerosis) and Wilson disease. MRI should be performed if the tremor has a history of acute onset or stepwise progression.
The electromyography or accelerometry can be used to assess tremor frequency, rhythmicity, and amplitude but are not part of the routine evaluation.
n Pathophysiology
There is no specific diagnostic laboratory test for the early diagnosis of ET and diagnosis is mainly based on the clinical features. Its pathophysiologic mechanisms remain unclear.
There were no consistent lesions have been found at postmortem examinations (13).
Much debate exists on the pathophysiologic basis of ET. The underlying mechanism of essential tremor is not known although several theories have been proposed.
A group of drugs known as beta-adrenergic blockers such as propranolol are known to improve the symptoms associated with ET. Peripheral mechanisms have also been suggested in ET,
mainly because β-blockers that do not easily cross the blood and brain barrier (such as nadolol) can still attenuate tremor. It is possible that these beta-blockers work through peripheral beta2 skeletal muscle adrenoreceptors (receptor mechanisms).
However, beta-blockers may also affect central pathways. There is evidence, however, that β-blockers may work centrally as well as peripherally, as nonselective blockade of β2 receptors may improve tremor control.
It was reported that alcohol suppression of ET is mediated through a reduction in overactivity (cerebellar synaptic), resulting in an increased afferent input to the inferior olivary
nuclei. The ingestion of ethanol led to bilateral decreases of cerebellar blood flow in both tremor patients and normal
subjects, and this was associated with suppression of tremor in the patients. Moreover, alcohol-associated increases of regional cerebral blood flow were observed in the inferior olivary nuclei in the patients but not in the control subjects.
In a study of individuals with ET, results of an advanced imaging technique known as positron emission tomography (PET), which examines the biochemistry of the brain, suggested an abnormality in the olivo-cerebellar tracts of the brain. In addition, PET testing in patients with essential tremor reveals increased activity in one brain region known as the cerebellum even while at rest, a finding that is consistent with the
cerebellum having an important role in the generation of tremor.
Other researchers are investigating the role of stretch loop
circuits as well as circuits within the central nervous system that may become unstable and drive muscle contractions (central
oscillators), or a combination of both to produce tremor as in ET.
A report published in 1997 about the role of clonidine in ET,
lends support the theory of a central oscillating "pacemaker" in ET.
In another study with functional magnetic resonance imaging (fMRI) for patients with ET underwent studies of the brain. The results suggested that ET is mainly associated with an additional contralateral cerebellar pathway activation and overactivity in the cerebellum, red nucleus, and globus pallidus without significant intrinsic olivary activation.
Focal lesions in the brainstem, cerebellum, and cerebellar
projections have also been reported to produce tremor (Figure 2).
Secondary tremor similar to ET is most often associated with lesions in the ventrolateral or posterolateral parts of the
thalamus and disruption of the cerebellothalamic pathway has been suggested to produce postural and action tremor. Further indirect evidence of cerebellothalamic circuit dysfunction in tremor is derived from the accepted observation that modulation of the VIM thalamic nucleus via thalamotomy or deep brain stimulation (DBS) suppresses tremor by altering the abnormal
activity of the oversynchronized nuclei.
The transmission of oscillatory signals to the limb is believed to occur through the influence of the central oscillator on
interconnecting central and peripheral reflex loops. Peripheral loops send alternating impulses to agonistic and antagonistic muscles, resulting in the joint oscillation that characterizes tremor. With current knowledge, it is believed that the primary generator of ET is a central oscillator at the
olivo-cerebellothalamo-cortico-spinal circuit, modulated by a peripheral component (14). More controlled studies are required to further investigate the underlying mechanisms of ET.
Single-unit electrophysiological recordings in monkeys with harmaline-induced tremor have suggested that the inferior olivary nucleus may play a pivotal role in postural tremor generation, which in turn induces a stream of abnormal neural efferents through the ipsilateral cerebellum, and contralateral red nucleus, thalamus and cerebral motor cortex (15). Ipsilateral cerebellar stroke (16) and contralateral stereotactic lesion of the nucleus ventralis intermedius (Vim) of the thalamus (17) can
abolish ET in humans, further strengthening the notion of a central origin for ET.
Cerebral blood flow (CBF) perfusion imaging with radioisotope labeled ligands has been used as a measurement of regional
cerebral blood flow (rCBF) in various conditions, including tremors (18). Previous studies with positron emission
tomography (PET) have revealed an alternation of the rCBF in ET patients (19). However PET is not feasible for routine
clinical use owing to the cost and the lack of availability in most hospitals as compared with SPECT. Recently, technetium 99m ethyl cysteinate dimer (99m Tc ECD) has been developed as a new and reliable marker in quantifying rCBF; without the shortcomings of radiochemical instability and delayed imaging (20, 21). It is intriguing, and mandatory, to investigate whether
the alternation of rCBF can be demonstrated by SPECT with this ligand, so as to construct a feasible method for the study of a possible centrally located circuitry of tremor in patients with ET.