Essential tremor

The etiology of essential tremor (ET) is unknown, but evidence exists implicating aging, genetics, and environmental toxins. For example, the severity and prevalence of ET are associated with aging.[21][22] Although genetics are recognized as a contributory factor, the degree of involvement is uncertain or variable.[23][24][25] A positive family history has been found in 17% to 100% of patients.[25] There are several research projects under way to delineate the gene defects in people with ET. In two genome-wide association studies, polymorphisms of LINGO1 and SLC1A2/EAAT2 were associated with ET.[26][27] The mechanism by which these genetic polymorphisms may confer risk of ET is being investigated; however, they were not confirmed in a larger study, in which the new genes PPARGC1A, CTNNA3, and STK32B were identified.[28]

At present there is no reliable genetic test to diagnose ET or to predict its development. However, the relative risk of a first-degree relative of an ET patient is 4.7, a number that is too low to ascribe to simple Mendelian genetics.[29] While they have not been systematically investigated, the following environmental toxins have been suggested as risk factors: organochlorine pesticides, lead, mercury, and beta-carboline alkaloids (e.g., harmane or harmaline, which are found in several medicinal plants).[30] In particular, harmane has been found to be elevated in the blood and brain of patients with ET.[31][32][33]

The pathophysiology of essential tremor (ET) has not been defined, but various lines of evidence implicate the involvement of the cerebellum, brainstem, and thalamus.[30] Often patients have abnormal cerebellar function. Also, an acute cerebellar stroke has been reported to abolish ET.[34] Imaging studies have shown increased blood flow in the cerebellum, red nuclei, and inferior olivary nuclei, suggesting their involvement as either a cause or a result of the tremor.[35][36][37] Magnetoencephalogram and functional magnetic resonance imaging (MRI) studies also revealed the cerebellum as part of the tremor circuitry.[38][39][40]

An ET-like tremor has been reported in animals exposed to harmaline, a neurotoxin that injures cerebellar Purkinje cells by excessive activation of climbing fibers.[41][42][43][44] Immunohistochemical studies have identified climbing-fiber synaptic pathology in ET cerebellum; this pathologic feature is associated with tremor severity, and climbing fiber pathology is specific to ET.[45][46][47][48] Interestingly, deep brain stimulation in ET patients seems to be able to modulate climbing fiber pathology.[49] Collectively, these studies highlight the relationship between climbing fiber and tremor.

To further study the role of climbing fiber synaptic pathology and tremor, a mouse model, Grid2dupE3, has been established that develops ET-like climbing fiber synaptic pathology along with age-related kinetic tremor that responds to primidone, propranolol, and alcohol. This helps understanding of the causal relationship between climbing fiber synaptic pathology and action tremor in ET.[50]

Genetic polymorphisms of LINGO1 and SLC1A2/EAAT2 have been implicated in ET from genome-wide association (GWA) studies.[26][27] Abnormal LINGO1-expressing basket cell terminals have been found in ET cases, which, given that LINGO1 is particularly enriched in the basket cell terminals surrounding Purkinje cell axons, could potentially affect Purkinje cell transmission.[51] In addition, the expression of EAAT2 is decreased in the ET cerebellar cortex, which might predispose Purkinje cells to excitotoxicity from excessive climbing fiber activity.[52] Purkinje cell loss and/or associated cerebellar pathology may contribute to disease progression in ET.[53][54][55] On the other hand, EAAT2 levels are decreased in the ET dentate nucleus, suggesting that imbalance of excitatory neurotransmission between the cerebellar cortex and the dentate nucleus might play a role in tremor.[56]

ET is suppressed by multiple medications that affect gamma-aminobutyric acid (GABA)-ergic systems, including alcohol, benzodiazepines, barbiturates, and gabapentin.[57] This is why many patients report that their tremor is abated following alcohol consumption. In ET, the lack of GABA-ergic tone in the dentate nucleus may be a consequence of Purkinje cell terminal loss.[58] GABA(A)-receptor alpha-1 subunit knockout mice exhibited tremor characteristics typical of ET that responded to primidone, propranolol, and gabapentin, highlighting the role of GABA-ergic dysfunction in ET.[59] Purkinje cell-specific GABA(A)-receptor knockout mice exhibit similar tremor, demonstrating the role of the GABA dysfunction in the cerebellum in tremor.[60] However, a 2018 study using magnetic spectroscopy to study GABA content in the cerebellum of patients with ET did not find any GABA deficiency.[61]

The age onset of ET is bimodal. Early-onset ET cases more commonly have a family history of tremor, whereas late-onset ET cases seem to have a faster rate of tremor progression and a higher risk for dementia.[62][63][64][65] The term “age-related tremor” has been proposed for late-onset ET cases.[64] Early-onset and late-onset ET cases might also differ in the tremor brain circuitry, specifically regarding involvement of the cerebellum, as shown in one electroencephalogram study.[66] However, cerebellar pathology is similar between early-onset and late-onset ET cases.[67]

Tremor syndromes according to the 2018 consensus statement[4]

Action or rest tremor

ET and ET plus
Isolated segmental action tremor
Isolated rest tremor
Enhanced physiologic tremor

Focal tremors

Voice, head, jaw, face, others
Essential palatal tremor

Task- and position-specific tremors

Writing, sports, music

Orthostatic tremors

Primary orthostatic
Pseudo-orthostatic

Tremor with prominent additional signs

Dystonic tremors
Parkinsonism-associated tremors
Intention tremor
Holmes tremor
Myorhythmia
Symptomatic palatal tremor

Others

Functional tremor
Indeterminate tremor

Clinical definitions[5][6]

Rest (or resting) tremor

Occurs when the affected body part is completely supported against gravity (e.g., hands resting in the lap). Amplitude increases during mental stress (e.g., counting backward) or with general movement (e.g., walking), and diminishes with target-directed movement (e.g., finger-to-nose test).

Action tremor

Produced by voluntary muscle contraction and includes postural, isometric, or kinetic tremors.
- Postural tremor: occurs when the affected body part maintains position against gravity (e.g., extending arms in front of body), but isn't actively moving.
- Isometric tremor: results from muscle contraction against stationary objects (e.g., squeezing the examiner's fingers or pushing against a wall).
- Kinetic tremor: occurs with voluntary movement and can be classified as either simple kinetic tremor or intention tremor. Simple kinetic tremor is associated with movement of extremities. Intention tremor occurs during visually guided movement toward a target (e.g., finger-to-nose or finger-to-finger testing), with significant amplitude fluctuation on approaching the target, typically with the tremor amplitude increasing as a function of proximity to the target.

Types of action tremor[5][6]

Essential tremor

Bilateral, largely symmetric postural or kinetic tremor involving hands and forearms that is visible and persistent. May also include tremor of head and voice.

Enhanced (or exaggerated) physiologic tremor

May be present equally in the outstretched arms and legs; signs of the underlying cause may be present (e.g., thyrotoxicosis, hypoglycemia, use of certain drugs, or withdrawal from extended use of alcohol or benzodiazepines). Caffeine, tobacco withdrawal, and exercise-induced tremors are classified as enhanced (or exaggerated) physiologic tremor.

Parkinson disease

Rest tremor is a classical Parkinson disease tremor and, along with rigidity, bradykinesia, and postural instability, constitutes a core feature of the disease. Occasionally postural tremor can be present, particularly when there is a latent period between changing hand posture and tremor onset (re-emergent tremor).

Adult-onset idiopathic dystonia

Tremor is often irregular and jerky rather than regular and oscillatory; may be task-specific. Other dystonic features are often present such as sustained, patterned muscle contractions.

Wilson disease

A neurologic disorder characterized by dystonia; dystonic tremor and/or action and rest tremor may be present. Other neurologic abnormalities present (e.g., dysarthria and parkinsonism).

Cerebellar outflow tremor

Characterized by irregular tremor associated with goal-directed movements; includes an ataxic component. Present in cerebellar degenerative disorders, especially when the disease becomes severe. Usually associated with other cerebellar signs such as slurred speech, eye findings, or gait abnormality.

Holmes (rubral) tremor

Irregular, coarse proximal upper-extremity tremor with large amplitude. Rest, postural, and action tremor may also be present. Usually seen with midbrain injuries, typically strokes, but can also occur in cerebellar disorders.[7]

Orthostatic tremor

A rare condition, often not even producing visible tremor, but reported as an inability to stand still. A uniquely high frequency (14 Hz to 16 Hz) tremor, usually affecting the legs, it is best proven by surface electromyography (EMG) recording from the quadriceps femoris and fast Fourier transform (FFT) analysis showing a characteristic peak around 15 Hz. There is often no visible tremor as the frequency is too fast to be visualized.

Psychogenic tremor

Typically seen as action tremor but can also present as postural, kinetic, or intention tremor, or any combination thereof. The main exam features that distinguish this tremor from all organic ones and help positively confirm/identify psychogenic etiology are distractibility, suggestibility, and entrainability.

Pathophysiology

Classification

Tremor syndromes according to the 2018 consensus statement[4]

Clinical definitions[5][6]

Types of action tremor[5][6]