Question: Which medications are good for benign primary tremors?

Essential tremor


Essential tremor (ET, also referred to as benign tremor, familial tremor, or idiopathic tremor) is a progressive[7][8][9] neurological disorder that is also the most common movement disorder. The cause of the condition is currently unknown. It typically involves a tremor of the arms, hands or fingers but sometimes involves the head, vocal cords or other body parts during voluntary movements such as eating and writing.[5] It is distinct from Parkinson's disease—and often misdiagnosed as such—although some individuals have both conditions.[5] Essential tremor is commonly described as an action tremor (i.e., it intensifies when one tries to use the affected muscles) or postural tremor (i.e., present with sustained muscle tone) rather than a resting tremor, such as is seen in Parkinson’s, which is usually not included among its symptoms.[10]
Classification
This type of tremor is often referred to as "kinetic tremor".
Essential tremor has been known as "benign essential tremor", but the adjective "benign" has been removed in recognition of the sometimes disabling nature of the disorder.[11][12]
Signs and symptoms
In mild cases, ET can manifest as the inability to stop the tongue or hands from shaking, the ability to sing only in vibrato, and difficulty doing small precise tasks such as threading a needle. Even simple tasks like cutting in a straight line or using a ruler can range from difficult to impossible, depending on the severity of the condition. In disabling cases, ET can interfere with a person's activities of daily living, including feeding, dressing, and taking care of personal hygiene. Essential tremor generally presents as a rhythmic tremor (4–12 Hz) that occurs only when the affected muscle is exerting effort. Any sort of physical or mental stress will tend to make the tremor worse.[3]
The tremor may also occur in the head (neck), jaw and voice as well as other body regions, with the general pattern being that the tremor begins in the arms and then spreads to these other regions in some people. Women are more likely to develop the head tremor than are men. Other types of tremor may also occur, including postural tremor of the outstretched arms, intention tremor of the arms and rest tremor in the arms.[13] Some people may have unsteadiness and problems with gait and balance.
ET-related tremors do not occur during sleep, but people with ET sometimes complain of an especially coarse tremor upon awakening that becomes noticeably less coarse within the first few minutes of wakefulness. Tremor and disease activity/intensity can worsen in response to fatigue, strong emotions, low blood sugar, cold and heat, caffeine, lithium salts, some antidepressants, and other factors. It is typical for the tremor to worsen in "performance" situations, such as when writing a check for payment at a store or giving a presentation.
Parkinson's disease and Parkinsonism can also occur simultaneously with ET.[5]  A study found that the degree of tremor, rigidity, and functional disability did not differ from patients with idiopathic Parkinson's disease. Hand tremor predominated (as it did in Parkinson’s disease), and occurred in nearly all cases, followed by head tremor, voice tremor, neck, face, leg, tongue and trunk tremor. Most other tremors occurred in association with hand tremor. Another study found more severe tremors, a lower sleep disorder frequency, and a similar prevalence of other non-motor symptoms.[14]
Walking difficulties in essential tremor are common. About half of patients have associated dystonia, including cervical dystonia, writer's cramp, spasmodic dysphonia, and cranial dystonia, and 20% of the patients had associated parkinsonism. Olfactory dysfunction (loss of sense of smell) is common in Parkinson’s disease, and has also been reported to occur in patients with essential tremor. A number of patients with essential tremor also exhibit many of the same neuropsychiatric disturbances seen in idiopathic Parkinson's disease.[15]
Essential tremor with tremor onset after the age of 65 has been associated with mild cognitive impairment[16] as well as dementia; although the link between these conditions, if any, is still not understood.[17][18]
Cause
The underlying cause of essential tremor is not clear but many cases seem to be familial.[19] Approximately one-half of the cases are due to a genetic mutation and the pattern of inheritance is most consistent with autosomal dominant transmission. No genes have been identified yet but genetic linkage has been established with several chromosomal regions.[20][21]
A number of environmental factors, including toxins, are also under active investigation as they may play a role in the disease's cause.[22] Harmane or harmaline has been implicated not only in essential tremors, but is also found in greater quantities in the brain fluid of Parkinson's disease sufferers as well as cancer.[23][24][25] Higher levels of the neurotoxin are associated with greater severity of the tremors.[2][26] Exposure is primarily found from meat consumption of beef, pork, and especially chicken, even when cooked.[27][28][29] Indeed, the greatest meat consumers were significantly more likely to have essential tremor.[29] Harmaline's high lipid solubility enables accumulation in the brain tissue upon consumption from these environmental sources.[2]
In terms of pathophysiology, clinical, physiological and imaging studies point to an involvement of the cerebellum and/or cerebellothalamocortical circuits.[30] Changes in the cerebellum could also be mediated by alcoholic beverage consumption. Purkinje cells are especially susceptible to ethanol excitotoxicity.[31] Impairment of Purkinje synapses is a component of cerebellar degradation that could underlie essential tremor.[31] Some cases have Lewy bodies in the locus ceruleus.[32][33][34] ET cases that progress to Parkinson's disease are less likely to have had cerebellar problems.[35]
Recent post mortem studies have evidenced alterations in LINGO1 (Leucine rich repeat and Ig domain containing 1) gene[36][37] and GABA receptors[38] in the cerebellum of people with essential tremor.  HAPT1 mutations have also been linked to ET, as well as to Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy.[39]
In 2012, the National Toxicology Program concluded that there is sufficient evidence of an association between blood lead exposure at levels <10 μg/dL and essential tremor in adults, and limited evidence at blood lead levels <5 μg/dL.[40]
Diagnosis
Usually the diagnosis is established on clinical grounds. Tremors can start at any age, from birth through advanced ages (senile tremor).[41][42] Any voluntary muscle in the body may be affected, although the tremor is most commonly seen in the hands and arms and slightly less commonly in the neck (causing the person's head to shake), tongue, and legs. A resting tremor of the hands is sometimes present.[15][43] Tremor occurring in the legs might be diagnosable as orthostatic tremor.
ET occurs within multiple neurological disorders besides Parkinson's Disease. This includes migraine disorders, where co-occurrences between ET and migraines have been examined.[44]
Treatment
Not all individuals with ET require treatment, but there are many treatment options depending on symptom severity.[5]  Caffeine and stress should be avoided, and good sleep is recommended.[5]
When symptoms are sufficiently troublesome to warrant treatment, the first medication choices are beta blockers such as propranolol or alternately, nadolol and timolol. Atenolol and pindolol are not effective for tremor.[5]  The anti-epileptic primidone is also effective for ET.[5]
Second-line or third-line medications can be added if the first-line medications do not control the tremor. Second-line medications are the anti-epileptics topiramate, gabapentin (as monotherapy) and levetiracetam, or do in benzodiazepines like alprazolam. Third-line medications are clonazepam and mirtazapine.[5]
Theophylline has been used by some practitioners to treat ET, even though it may also induce tremor.  However, its use is debated due to conflicting data on its efficacy.[45]  There is some evidence that low doses may lead to improvement.[46][47]
Ethanol has shown superior efficacy to that of benzodiazepines in small trials. It improves tremor in small doses and its effects are usually noticeable within 20 minutes for 3–5 hours, but occasionally appears a rebound tremor augmentation later.[48]
When medications do not control the tremor or the person does not tolerate medication, botulinum toxin,[49][50][51][52] deep brain stimulation or occupational therapy can be helpful.[5] The electrodes for deep brain stimulation are usually placed in the  "tremor center" of the brain, the ventral intermediate nucleus of the thalamus.
Additionally, MRI-guided high intensity focused ultrasound is a non-surgical treatment option for people with essential tremor who are medication refractory.[53][54] MRI-guided high intensity focused ultrasound does not achieve healing but can improve the quality of life.[54] While its long-term effects are not yet established, the improvement in tremor score from baseline was durable at 1 year and 2 year following the treatment.[55] To date, reported adverse events and side effects have been mild to moderate. Possible adverse events include gait difficulties, balance disturbances, paresthesias, headache, skin burns with ulcerations, skin retraction, scars and blood clots.[53][54][56] This procedure is contraindicated in pregnant women, persons who have non-MRI compatible implanted metallic devices, allergy to MR contrast agents, cerebrovascular disease, abnormal bleeding, hemorrhage and/or blood clotting disorders, advanced kidney disease or on dialysis, heart conditions, severe hypertension, ethanol or substance abuse, among others.[54] The US Food and Drug Administration (FDA) approved Insightec’s Exablate Neuro system to treat essential tremor in 2016.[54]
Prognosis
Although essential tremor is often mild, people with severe tremor have difficulty performing many of their routine activities of daily living.[11][12]  ET is generally progressive in most cases (sometimes rapidly, sometimes very slowly), and can be disabling in severe cases.[57][58][59]
Epidemiology
ET is one of the most common neurological diseases, with a prevalence of approximately 4% in persons age 40 and older and considerably higher among persons in their 60s, 70s, 80s, with an estimated 20% of individuals in their 90s and over.[60] Aside from enhanced physiological tremor, it is the most common type of tremor and one of the most commonly observed movement disorders.[61]
Society and culture
The actress Katharine Hepburn (1907–2003) had an essential tremor, which she inherited from her grandfather,[62] that caused her head—and sometimes her hands—to shake.[63][64][65] According to Dickens (1990), the tremor was noticeable by the time of her performance in the 1979 film The Corn is Green, when critics mentioned the "palsy that kept her head trembling".[66] Hepburn's tremor worsened in the 1980s, when she was in her 70s to 80s.[64]
In 2010, musician Daryl Dragon of The Captain and Tennille was diagnosed with essential tremor, with the condition becoming so severe that Dragon was forced to retire from music.
Director-writer-producer-comedian Adam McKay was diagnosed with essential tremor. He’s insistent on doing press for his work telling himself, “if I get shaky, I get shaky, who the f*ck cares.”[67]
Research directions
Harmaline is a widely used model of essential tremor (ET) in rodents.[68] Harmaline is thought to act primarily on neurons in the inferior olive (IO). Olivocerebellar neurons exhibit rhythmic excitatory action when harmaline is applied locally.[68]
See also
Intention tremor




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