Colleen B. Litof

Solid information about the causes and underlyingmechanisms of epilepsy is as jumbled asthe disorder itself. This is partially becauseso many diverse events can cause localizedor diffuse clusters of nerve cells to fireabnormally, triggering an epileptic seizure.

Contributing to the problem is the relative unreliability of EEG tracings recorded from patients during the interictal period. Although these tracings can reveal certain abnormalities that are characteristic of epilepsy, such as spikes, they tend to be relatively nonspecific. Interictal spikes, for instance, occur inconsistently; they are present in some persons who do not have epilepsy and absent in others who do. For this reason, they have no value for predicting the onset of a seizure. Furthermore, the magnitude of these spikes does not necessarily correlate with the severity of the patient's epilepsy.

A noninvasive, accurate electrophysiological or neuroimaging marker would be of tremendous value for profiling a patient's risk, diagnosing epilepsy, developing new treatments, planning treatment, and monitoring the response to that treatment. A clinically accessible surrogate marker that reliably predicted seizures also could help a patient manage his or her life to minimize the impact and potential damage of epileptic episodes or, better yet, thwart or blunt an impending attack.

Epilepsy can develop in any person at any stage of life. Children appear to be at greatest risk for developing new-onset epilepsy until about the age of 10 years.

After that, the potential for epilepsy stabilizes until it increases again around the age of 55 to 60, when the incidence of strokes, brain tumors, and Alzheimer disease starts to escalate. Risk factors for epilepsy are summarized in Table 1.

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Contributing to the problem is the relative unreliability of EEG tracings recorded from patients during the interictal period. Although these tracings can reveal certain abnormalities that are characteristic of epilepsy, such as spikes, they tend to be relatively nonspecific. Interictal spikes, for instance, occur inconsistently; they are present in some persons who do not have epilepsy and absent in others who do.

Frontiers in Imaging Markers for Epileptogenesis

Thus, a young woman describes her ex-boyfriend who had Tourette syndrome (TS), the impact of which caused their breakup. TS affects approximately 1 in 100 Americans and is marked by a fluctuating course of multiple motor and phonic tics,

 which can have devastating social, physical, and psychological consequences for the patient.

TS commonly first appears as tics between the ages of 7 and 15 years and is more common in boys, explained Shubhangi Chitnis, MD, assistant professor of pediatric neurology at West Virginia University School of Medicine in Morgantown. Typically, TS intensifies during adolescence and subsides by adulthood, but a small group of persons-fewer than 20%-remain afflicted into their adult years.

Evidence collected by Harvey Singer, MD, of the Division of Pediatric Neurology at Johns Hopkins University School of Medicine in Baltimore, suggests that TS is caused by a defect involving the dopamine system and its effect on the corticostriatothalamocortical circuits.

"Dopaminergic neurons directly influence cortical and striatal neurons as well as presynaptic glutamatergic corticostriatal terminals that synapse in the striatum. Whether dopamine's influence is inhibitory or excitatory depends on the type of receptors it interacts with," Singer explained.

 Dopamine can either depress or potentiate corticostriatal transmissions.

 Its effect on the resting potentials of striatal neurons could account for the waxing and waning pattern of tics noted in persons with TS.

Most dopamine innervation to the cortex is in the frontal region, especially the striatum.

 report that the brain of adults with TS is structured differently from that of others in that it has fewer D2 receptors in extrastriatal regions. The TS-affected brain also has reduced distribution volume ratio values in the orbitofrontal and motor cortex, hippocampus, anterior cingulate gyrus, and mediodorsal thalamus, suggesting reduced D2 or D3 receptor density. In his view, the thalamus may play a crucial role in sensory, cognitive, limbic, and behavioral difficulties in TS.

Singer and his group also are studying the brain structure of patients with TS. In 1 study, the team performed a postmortem analysis of brain tissue to determine whether the defect might be located in the frontal lobe.

 "The frontal lobe is integral to the circuits that connect cortical regions to basal ganglia, and it is a site where tics and associated comorbidities could originate," explained Dustin Yoon, a teaching assistant at Johns Hopkins and the study's lead author.

The investigators analyzed tissue samples for several neurochemical markers: dopamine (D1, D2), serotonin (5HT-1A), a-adrenergic (a

) receptors, dopamine transporter (DAT), and vesicular docking and release proteins.

 While the sample size was small-3 patients with TS and 3 matched controls-DAT and D2 receptor densities were consistently increased in 5 of 6 frontal regions in all the patients with TS. Density values for persons with TS versus controls ranged from 133% to 276% for DAT, and from 132% to 182% for the D2 receptor.

"We found that the actual density of DAT and D2 exceeded 150% of control values. A lot of things can contribute to this. It may be that patients with TS have an intrinsic regulatory defect that causes receptor density to increase, or there may be frontal dopaminergic hyperinnervation from the ventral tegmental area," explained Yoon. But he and his colleagues cautioned that their findings must be considered within the context of the effect of medications on the brain. "Treatment with neuroleptics- including dopamine antagonists-increases D2 dopamine receptors in the striatum. It's entirely possible that our findings were the result of patients being treated chronically with neuroleptics," Yoon said.

The uncontrollable urge to perform a tic suggests that TS might be related to the inability to effectively regulate-or gate-sensory information. Effective gating requires the body to sustain neural oscillations in the basal ganglia and cortex that work to filter out motor, somatic, and perceptual stimuli from the surrounding environment. In this model, TS can be seen as a condition in which the ability to ignore constant environmental stimuli is impaired.

In support of this theory, studies have shown that persons with TS are deficient in a key γ-aminobutyric acidergic interneuron that orchestrates filtering oscillations.

 Loss of these cells in the dorsal lateral striatum can lead to tics; losses in other striatal areas can contribute to comorbidities seen in TS, such as obsessive-compulsive disorder (OCD) and attention-deficit hyperactivity disorder (ADHD).

 Deficiency of γ-aminobutyric acidergic interneurons also explains why persons with TS are often disinhibited.

A problem with the oscillatory system also may contribute to tha- lamocortical dysrhythmia.

 Resolving this dysrhythmia would ease tics and might explain why deep brain stimulation (DBS) directed at either the midline thalamic nuclei or the internal globus pallidus alleviates symptoms in some patients.

Some investigators think that serotonin plays a role in TS, although the mechanism of action is unclear.

 Studies have shown decreased levels of serum serotonin and tryptophan in affected patients.

 Levels of serotonin metabolites (5-hydroxyindoleacetic acid) also are diminished in the basal ganglia and cerebrospinal fluid of persons with TS.

Generally speaking, treatment is recommended when tics are causing pain; are jeopardizing safety; or are compromising the patient's physical, mental, or social quality of life or ability to function educationally and professionally.

Several medications are available, but those recommended as first-line treatment-clonidine and guanfacine-are not necessarily the strongest, according to Gilbert. "The Tourette Syndrome Association's medical board has found dopamine-blocking agents-haloperidol, pimozide [Orap], and risperidone [Risperdal]-to be the most compelling.

 But the problem with these medications is that they cause bothersome adverse effects. Patients don't appreciate the weight gain, sedation, and anxiety that can accompany treatment. So, while these drugs might look really good on paper, they're not the most palatable choice at the clinical level," Gilbert explained. He also pointed out that second- and third-line medication choices depend on the patient's tolerance. His recommendation is to individualize treatment.

Chitnis starts his patients with clonidine, 0.1 mg/d, which is titrated upward as needed. Patients who do not respond are switched to guanfacine, starting at 1 mg/d and titrated as necessary to control tics. "Haloperidol is another option, but I rarely resort to it," Chitnis said.

Gilbert advises physicians to be realistic with the patient and family about expectations. "Persons who want to try medical treatment can expect to have their tics reduced to some extent, but those tics are not going to be totally eliminated," Gilbert said. Chitnis added that he will "always treat the patients who are suffering from social or functional impairment as a result of their tics. But I must be honest here: I find that the success rate of treatment is low."

DBS has been found useful for treatment of many movement disorders, including dystonia and Parkinson disease.

 Early reports also indicate that DBS works for adults with OCD and TS, although more study is needed. "DBS is used at my facility for adults who have movement disorders, but we don't use it in children, nor are we using it for TS," explained Chitnis.

In DBS, electrodes are surgically implanted in the brain near the known or suspected site of an abnormality, making implantation for TS challenging because the precise site of abnormality is not known. (Most reported cases of DBS have targeted the centromedian-parafascicular complex of the thalamus, the internal segment of the globus pallidus, or the anterior limb of the internal capsule.

When the electrodes are in place, the battery-powered implanted pulse generator (IPG) to which they are connected is inserted either beneath the patient's clavicle or in his abdomen. The IPG, which must be expertly calibrated, sends electrical impulses to the brain to modify neural activity. Perfecting the calibration can take up to a year and is one of the drawbacks of DBS use. Other potential problems include manic conversion and sudden exacerbation of symptoms when DBS is discontinued. The IPG batteries also need to be replaced every 3 to 5 years.

Although DBS has been used successfully in persons with movement disorders, only about 10 published reports of DBS in persons with TS exist.

 Joohi Shahed, MD, assistant professor of neurology and an associate at the Parkinson's Disease Center and Movement Disorders Clinic at Baylor College of Medicine in Houston, reported good results with bilateral DBS of the globus pallidus interna in a 15-year-old boy with severe symptoms (including coprolalia, screaming, grabbing others, self-injury, anxiety, depression, and impulsivity) that had not responded to pharmacotherapy.

"We found that comorbidities and quality of life improved considerably. On follow-up testing, this patient had improvement in verbal reasoning, psychomotor speed, mental flexibility, and visual perception," said Shahed.

 the Tourette Syndrome Association recommends DBS as an option for patients with severe tics that persist despite adequate trials of 3 different classes of medications. The guidelines also recommend that before performing a DBS procedure, the psychological condition of the patients be  evaluated to rule out OCD, ADHD, and mood disorders, and that physicians get a sense about whether the patient is capable of taking care of himself after surgery.

The guidelines recommend standard neuroimaging mapping with MRI 1 month before the procedure. They also recommend that patients be followed up at 3, 6, and 12 months after surgery, then annually thereafter, to evaluate long-term effects of DBS.

 National Institute of Neurological Disorders and Stroke. Scientists discover first gene for Tourette syndrome. Available at: 

www.ninds.nih.gov/news_and_events/news_articles/news_article_Tourette_gene_121505.htm

 Leckman JF, Bloch MH, Scahill L, King RA. Tourette syndrome: the self under siege. 

 Singer HS, Minzer K. Neurobiology of Tourette syndrome: concepts of neuroanatomical localization and neurochemical abnormalities. 

 Harris K, Singer HS. Tic disorders: neural circuits, neurochemistry, and neuroimmunology. 

 Ronesi J, Lovinger DM. Induction of striatal long-term synaptic depression by moderate frequency activation of cortical afferents in rat. 

 Mink JW. Basal ganglia dysfunction in Tourette's syndrome: a new hypothesis. 

 Wise RA. Dopamine, learning, and motivation. 

 Bressan RA, Crippa JA. The role of dopamine in reward and pleasure behavior-review of data from preclinical research. 

Gilbert DL, Christian BT, Gelfand MJ, et al. Altered mesolimbocortical and thalamic dopamine in Tourette syndrome. 

 Yoon DY, Gause CD, Leckman JF, et al. Frontal dopaminergic abnormality in Tourette syndrome: a postmortem analysis. 

 Ziemann U, Paulus W, Rothenberger A. Decreased motor inhibition in Tourette's disorder: evidence from transcranial magnetic stimulation. 

 Llinas R, Ribary U, Jeanmonod D, et al. Thalamocortical dysrhythmia: a neurological and neuropsychiatric syndrome characterized by magnetoencephalography. 

 Mink JW, Walkup J, Frey KA, et al. Patient selection and assessment guidelines for deep brain stimulation in Tourette syndrome. 

 Cobb WS, Abercrombie ED. Differential regulation of somatodendritic and nerve terminal dopamine release by serotonergic innervation of substantia nigra. 

 Comings DE. Blood serotonin and tryptophan in Tourette syndrome. 

 Anderson GM, Pollak ES, Chatterjee D, et al. Postmortem analysis of subcortical monoamines and amino acids in Tourette syndrome. 

 Gilbert D. Treatment of children and adolescents with tics and Tourette syndrome. 

 Tourette Syndrome Medical Advisory Board. Coffey B, Berlin C, Naarden A. Medications and Tourette's disorder: combined pharmacotherapy and drug interactions. Available at: 

Thus, a young woman describes her ex-boyfriend who had Tourette syndrome (TS), the impact of which caused their breakup. TS affects approximately 1 in 100 Americans and is marked by a fluctuating course of multiple motor and phonic tics, which can have devastating social, physical, and psychological consequences for the patient.

Understanding Tourette Syndrome    and Providing Relief

Elvis Presley might have found it exciting to be "all shook up," but for the millions of persons with essential tremor (ET), the story is just the opposite. Eighty-five percent of affected persons report that ET significantly compromises their professional and personal lives.

Furthermore, a study of persons with hereditary ET found that 60% were unemployed; 25% changed jobs or retired early; 65% did not dine out; 30% avoided parties, participating in sports, or solo shopping; and 20% stopped driving.

The most common movement disorder in the United States, ET is estimated to affect 0.3% to 5.6% of the general population, or roughly 5 to 10 million persons.

 Men and women appear to be equally affected.

 A 45-year population-based study of persons from Rochester, Minnesota, reported an age-adjusted annual ET incidence of 18.3 and 17.1 per 100,000 for men and women, respectively.

While it is tempting to think of tremor as a geriatric issue, ET targets 2 age groups: those aged 15 to 20 years and those aged 50 to 70 years.

 It is not unusual, however, for ET to appear in persons aged 35 to 45 years. Rarely, newborns and infants are affected.

 No evidence suggests that the earlier ET begins, the more severe and disabling it becomes,

although its characteristics may change over time. Similarly, there is no evidence to indicate that ET has any effect on mortality.


By definition, tremor is "an involuntary, rhythmic oscillation of a body part within a fixed plane, involving alternating or simultaneous contractions of agonist and antagonist muscles entrained by a signal pattern originating from a central oscillator."

 Everyone has physiologic tremor, which is an asymptomatic, small-amplitude tremor that probably originates from spontaneous oscillatory activity within the olivocerebellar system of the brain.

 Physiologic tremor is influenced by such factors as myocardial contraction and motor neuron firing and can be enhanced under certain circumstances, including exercise, emotional stress, metabolic abnormalities, and exposure to some drugs (eg, sympathomimetic agents, lithium).

Tremor is generally classified as being either resting or action.

 Resting tremor, which includes that seen in parkinsonism, is present when the body is fully supported in a way that requires no voluntary activation of skeletal muscles-sitting in a chair with hands resting in the lap, for instance. Resting tremor is suppressed by voluntary movement of the affected body part. If you were to evaluate someone with resting tremor, you would notice that his or her hands were shaky at rest but became steady when reaching out to pick up a book or perform some other intentional activity.

Action tremor occurs during voluntary muscle contraction and can be postural, kinetic, or isometric. ET falls into the postural and kinetic categories. Postural tremor occurs when a person voluntarily tries to maintain a position against the pull of gravity, while kinetic tremor occurs during an intended movement such as drawing or pointing. One type of kinetic tremor, intention tremor, worsens as the person is almost done with his activity or task. Another type of action tremor, task-specific tremor, occurs only during specific, skilled activities-writing or playing the piano, for instance. Isometric tremor occurs when a person voluntarily contracts a muscle against a rigid stationary object, as when squeezing a stick.


The sine qua non of ET is a bilateral postural or kinetic tremor affecting the distal upper extremities. Occasionally, patients have ET affecting the head. Tremor can involve the lips, chin, voice, palate, and tongue-which all affect speech.

 Head tremor can occur alone, but more often follows upper extremity involvement. Alexander Rajput, MD, of the University of Saskatchewan in Canada, in describing a cross section of his patients with ET, notes that about 75% of patients have tremor that originates in an upper extremity; 20% have tremor that starts in an upper extremity and the head, lips, jaw, or vocal cords; and 5% have tremor limited to the head alone.

 There is some thought that hand tremor is more common in men, while women tend to have head involvement, but this is speculative.

 Isolated leg tremor is not a presenting finding of ET and suggests that tremor is related to something else. "We have not found leg tremor to be an initial sign of ET," observes Rajput.

 However, Rajput does point out that he and others have seen that ET can extend to the lower extremities over time.

The onset of ET is gradual. As the person ages, the frequency of tremor declines but its amplitude increases. This makes it increasingly more difficult for the patient to function normally. Elan Louis, MD, of the Gertrude H. Sergievsky Center of Columbia University in New York City, notes that as function declines, persons with ET tend to become increasingly anxious and depressed.

Classically, ET occurs alone, unaccompanied by any other neurological disorders. However, you might occasionally encounter a patient who has subtle signs of ataxia or cognitive impairment.

 Some patients with ET also have migraine headache or report being unable to hear or smell as acutely as before the tremor started.


Because no brain lesion is associated with ET, the diagnosis is based on a comprehensive history and physical examination. Sophisticated imaging studies and extensive laboratory testing are generally unnecessary except to rule out other causes for tremor. The most notable include hyperthyroidism and Wilson disease.

 The diagnostic criteria for ET, as established by the Movement Disorder Society, are listed in Table 1.

Begin by asking the patient about his tremor. When did he first notice the shaking, and what areas of his body were affected? ET typically begins in one arm or hand and, over time, "spreads" to other areas.

 About a third of patients will have head involvement, which may occur alone or develop subsequent to upper extremity tremor.

 Approximately 20% of patients will have tremor at rest.

Does anyone else in the family have tremor? About 50% to 70% of persons will mention that ET runs in the family (see "Essential Tremor: Is It All in the Family?" page 15).

Find out if the patient has noticed a pattern to the tremor. A tremor that started intermittently, before becoming worse or more constant with time, is typical of ET. Patients with ET will often report that their tremor intensifies when they become emotional, fatigued, cold, hot, or hungry.

Inquire about any activities or conditions that decrease the patient's tremor. Persons with ET are tremor-free during sleep and after having a cocktail, glass of wine, a beer, or other drink containing alcohol. The general medical history may yield clues to other possible causes for tremor, such as kidney, thyroid, or liver disease.

A tremor that started suddenly "out of the blue," or that is accompanied by other neurological symptoms could be a cerebellar tremor.

The presence of a movement disorder suggests that the tremor is not ET.

Persons who are heavy drinkers can experience transient tremor when they suddenly stop drinking.

Medications and toxins that can induce tremor are listed in Table 2.

You might consider having the patient complete a tremor questionnaire such as that developed by Abe Lieberman, MD, of the National Parkinson Foundation, Inc. The questionnaire, which can be accessed at 

www.essentialtremor.org/research/questionnaire/index.php

, is informal, not scientifically documented, and is solely intended to help clinicians determine whether the patient has ET. It is not intended to be used in place of a visit to the physician, but patients can be asked to fill out the form either before or during the initial visit.

 This procedure facilitates the evaluation and also helps ensure that no information about the tremor is overlooked.


During the physical examination, you'll want to further exclude other possible causes for tremor. This is also a good time to get additional information about the nature of the patient's tremor.

Asking the patient to perform a few simple maneuvers will quickly reveal the nature of the tremor:

If the patient's hands and/or arms shake as he extends his fingers and maintains this position against gravity, then the tremor is postural.

If the tremor occurs during such voluntary movements as pointing his finger to his nose, signing his name, writing a sentence, drinking water from a cup, or drawing freehand spirals, the tremor is kinetic and tends to be more serious than a postural tremor.

 To further investigate kinetic tremor, challenge the patient with more difficult tasks: pouring water from one cup to another, raising an almost full cup of water from lap to lips, signing his name, applying lip balm, and using a spoon to drink water. The patient should do these tests with both arms.

DIFFERENTIATING ET FROM PARKINSONIAN TREMOR


A logical question is whether patients with ET are predisposed to other neurological problems, primarily Parkinson disease (PD). Current data are conflicting-while some studies report that parkinsonism is more common in persons with ET,

 there is no evidence to show that persons with ET consistently have Lewy bodies or lesions in the substantia nigra.

 in reporting on a series of 20 patients with ET, noted Lewy body pathology in only 1 of 6 patients who had clinical evidence suggesting parkinsonism (bradykinesia, rigidity, and resting tremor). Until biologic markers become available, the precise relationship between ET and PD remains speculative, and there is no reason to suspect that PD will develop later in life in a person who presents with ET.

Nonetheless, the ET evaluation cannot be considered complete until PD is ruled out. Persons with ET often have a palpable, cogwheel-like tremor of the arm or hand that is pronounced during voluntary movement of the opposite limb. This so-called Froment sign is distinct from the cogwheel-like rigidity of PD.

Patients with parkinsonism often have a pill-rolling resting tremor of the hand, as well as postural tremor. The presence of rigidity, bradykinesia, and a shuffling gait confirms PD and rules out ET.

As another quick simple test, David M. Swope, MD, of the Movement Disorders Clinic at Loma Linda University Medical Center, Loma Linda, California, suggests asking the patient to extend his arm. ET begins instantly, while a parkinsonian tremor takes several seconds to start.


Other tests become important only when there are no findings in the history and physical examination to suggest that the patient's symptoms are indeed ET. When there is a question, consider ordering laboratory studies, including a standard electrolyte panel, thyroid function tests, blood urea nitrogen, measurement of creatinine, and liver function tests, and ceruloplasmin levels (to rule out Wilson disease).

Imaging studies, such as MRI, are useful for ruling out an inflammatory process or Wilson disease or if the patient's tremor started suddenly or progressed incrementally. Procedures (electromyography, accelerometry) that measure tremor amplitude are not part of the routine clinical evaluation.


The extent of the patient's functional or psychosocial impairment determines the approach to treatment. Many patients with mild or intermittent disability respond well to medications. When medication is ineffective and tremor is hindering the patient's ability to eat, write, speak, remain employed, or otherwise enjoy a satisfactory quality of life, surgery becomes an option. Patients with tremor of the head or voice have the option of botulinum toxin type A (Botox [BTX-A]) therapy.

David Swope, MD, finds that education, lifestyle/behavioral modification, and support are worthwhile for all patients with ET.

 Indeed, such measures may be the primary treatment for persons with very mild ET who do not want to take medications.

Patients can learn to avoid situations that trigger or worsen tremor.

They can eat "safe" foods that do not spill or slop easily and avoid eating or drinking substances that cause or intensify tremor.

Many telephones have voice-activated dialing and are an excellent choice for persons with hand tremor.

Patients can choose clothing and shoes that slip on or fasten easily.

These and other simple lifestyle modifications can help persons manage more effectively. Persons with intermittent tremor that occurs primarily in social settings might benefit from a light cocktail as their primary protection against ET, although alcohol is not a first-line therapeutic mainstay-especially for persons with daytime or frequent tremor.


Medications can blunt tremor amplitude and improve the patient's functional ability but tend not to affect tremor frequency.

 A frank discussion before starting treatment can help ensure that the patient's expectations about medications are realistic.

The primary drugs used to manage ET are Ã-blockers, anticonvulsants, and benzodiazepines. For most patients, treatment begins with either propranolol or primidone.

 When deciding which of these medications to prescribe, the patient's age should be taken into consideration.

Younger persons tend to tolerate Ã-blockers better than the elderly, so typically start out with propranolol. Ã

-agonists, although both have been shown to be better than placebo in clinical trials.

-agonist is a viable option for patients with conditions that preclude the use of propranolol.

 Propranolol, at a dosage ranging from 60 to 240 mg/d, can reduce tremor by 50% to 60% in 75% of patients treated.

Older patients are good candidates for primidone, which has a mildly sedating effect that can be annoying or even detrimental for younger persons, especially those who attend school or work. Primidone is also an effective option for patients in whom propranolol is contraindicated.

The general approach is to start at a low dosage and increase as needed. If you find that the patient responds well to a given dosage of medication and maintains that response, consider changing to a long-acting formulation. If there is no improvement at maximum dosage, gradually discontinue the medication and try a different drug. To test the patient's response to treatment, ask him to perform some of the manual tasks performed during the initial evaluation-writing, drawing a circle, or lifting a glass of water to his lips.

If the patient notices some improvement but needs more control, he might respond well to combination therapy with a Ã-blocker and an anticonvulsant (continue the first medication as you add the second). Increase the dosage of combination therapy as needed to control tremor satisfactorily. If the patient is not responding as you hoped, gradually discontinue the treatment and try a different medication.

Robert A. Hauser, MD, professor in the departments of neurology, pharmacology, and experimental therapeutics at the University of South Florida in Tampa, observes that some patients respond well to mirtazapine as a second-line agent.

 Other choices are a benzodiazepine if the tremor is more of a nuisance than a disability or clozapine if the tremor is disabling.

The American Academy of Neurology Quality Standards Subcommittee has released their recommendations concerning treatment approaches to ET.

 Their suggestions, based on a review of the literature, are summarized in Table 3.


Injections of BTX-A are useful for persons with voice or head tremors, which tend to respond poorly to medications. BTX-A is not generally used to treat hand or upper extremity trauma because the toxin can cause weakness, compromising function.

A single treatment involves multiple point injections of BTX-A at a dose ranging from 1.25 U for voice tremor to 400 U for head tremor. Injections are repeated every 3 to 4 months. Serious adverse reactions to BTX-A are rare. The agent is contraindicated for patients with myasthenia gravis, postpolio syndrome, or motor neuron disease; those who are pregnant; and those being treated with aminoglycoside antibiotics.


When patients have disabling ET that is not controlled by medications, surgery becomes a consideration and is usually definitive. The primary procedures used to control ET are stereotactic thalamotomy and deep brain stimulation (DBS) of the thalamus. Hauser notes that both procedures offer high rates of tremor reduction in the contralateral arm.

 In this procedure neurons in the ventralis intermedius are ablated with thermocoagulation, creating a lesion that disrupts tremor. Thalamotomy is usually performed unilaterally, on the side of the brain contralateral to the most severely affected limb.

Bilateral thalamotomy is performed under local anesthesia and takes about 2 to 3 hours. Evidence indicates that the procedure is effective. Jankovic and colleagues

 examined the results of thalamotomy in 60 patients with various forms of tremor. Over the course of follow-up, which extended to 13 years, the investigators noted significant to complete reduction in tremor in 86% of patients with parkinsonism, 50% of patients with post-traumatic tremor, 67% of patients with cerebellar tremor, and 83% of patients with ET.

Thalamotomy is not without risks; it can cause permanent, severe dysarthria.

 Cerebral hemorrhage, motor weakness, and memory loss are other possible complications but occur in fewer than 2% of cases.

 Thalamic DBS may work by providing chronic artificial "noise" that disrupts tremor activity within the motor circuit pathway. The ventralis intermedius remains relatively intact, and impulse variables can be changed to reduce adverse effects and increase efficacy. Evidence indicates that thalamic DBS is very effective: Ondo and colleagues

 reported an average 83% reduction in contralateral arm tremor in 14 patients with ET. Other studies report similar efficacy rates.

Thalamic DBS is preferred to thalamotomy because it does not involve ablation, and stimulation can be adjusted according to the severity of tremor. Another advantage is that DBS can be done bilaterally, without exposing the patient to risk of severe adverse effects. Disadvantages include expense and the need to implant hardware in the brain-hardware that requires periodic maintenance and replacement of batteries.

 Burke D. Essential tremor. Available at: 

 Bain PG, Findley LJ, Thompson PD, et al. A study of hereditary essential tremor. 

 Louis ED, Ottman R, Hauser WA. How common is the most common adult movement disorder? Estimates of the prevalence of essential tremor throughout the world. 

 Chen JJ, Swope DM. Essential tremor: diagnosis and treatment. 

 Rajput AH, Offord KP, Beard CM, et al. Essential tremor in Rochester, Minnesota: a 45-year study. 

 Louis ED, Zheng W, Jurewicz EC, et al. Elevation of blood beta-carboline alkaloids in essential tremor. 

 Mally J, Baranyi M, Vizi ES. Change in the concentration of amino acids in CSF and serum of patients with essential tremor. 

 Boecker H, Brooks DJ. Functional imaging of tremor. 

 Rajput AH, Hornykiewicz O, Deng Y, et al. Increased noradrenaline levels in essential tremor brain. 

 Rajput AR, Robinson CA, Rajput AH. Essential tremor course and disability: a clinicopathologic study of 20 cases. 

 Louis ED, Barnes L, Albert SM, et al. Correlates of functional disability in essential tremor. 

 Elble RJ. Essential tremor is a monosymptomatic disorder. 

 Biary N, Koller W, Langenberg P. Correlation between essential tremor and migraine headache. 

 Louis ED, Bromley SM, Jurewicz EC, et al. Olfactory dysfunction in essential tremor: a deficit unrelated to disease duration or severity. 

 Ondo W, Jankovic J. Hearing loss in essential tremor. 

 Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. 

 Cohen O, Pullman S, Jurewicz E, et al. Rest tremor in patients with essential tremor. 

 Louis ED, Ottman R. Study of possible factors associated with age of onset in tremor. 

 Rehman HU. Diagnosis and management of tremor. 

. Louis ED, Ford B, Frucht S, et al. Risk of tremor and impairment from tremor in relatives of patients with essential tremor: a community-based family study. 

 Tanner CM, Goldman SM, Lyons KE, et al. Essential tremor in twins: an assessment of genetic vs environmental determinants of etiology. 

 Louis ED, Jurewicz EC, Applegate L, et al. Association between essential tremor and blood lead concentration. 

 Lieberman A. Essential tremor questionnaire. International Essential Tremor Foundation. Available at: 

 Pahwa R, Koller WC. Is there a relationship between Parkinson's disease and essential tremor? 

Essential tremor significantly compromises patients' professional and personal lives.

Essential Tremor: Tips for Managing a Disquieting Problem

When it comes to disease risk, not all of us are created equal. Genetics, culture, diet, education, occupation, income, environment, or a combination of these factors can predispose some persons and ethnic groups to certain illnesses. For instance, diabetes mellitus is rampant among Pima Indians, and black populations have a higher incidence of hypertension than do white populations. Does this phenomenon also apply to persons with disorders affecting the CNS? Data are accumulating to suggest that racial and ethnic components need to be seriously considered when addressing certain neurologic conditions.


Perhaps the most stunning and clear-cut data on racial influences-and disparity-in disease incidence concern ischemic events. Findings suggest that incidence and mortality are higher among black persons than among white persons,

 black and Hispanic persons are more likely than white persons to have stroke recurrence,

 black and Hispanic persons are more likely to be admitted for hospitalization with a diagnosis of acute brain lesion while white persons are more likely to be admitted for transient ischemic attack (TIA),

The earliest population-based studies on stroke and ethnicity, conducted in the 1990s, pointed out that stroke incidence and associated mortality were higher in black persons than in white persons:


The Northern Manhattan Study compared the incidence of hospitalized and nonhospitalized first strokes in 210,000 black, white, and Hispanic persons living in the same urban community.

 The average age-adjusted stroke incidence per 100,000 population was 223 for black, 196 for Hispanic, and 93 for white persons. Compared with white persons, stroke incidence increased for black persons by 2.4-fold and for Hispanic persons by 2.0-fold.

The Greater Cincinnati/Northern Kentucky Stroke Study-the first large population-based metropolitan study to examine trends in stroke incidence and outcome in black and white persons

-found that most of the 1.3 million persons who died of or were hospitalized for stroke were black. Incidence of stroke among black persons in the Greater Cincinnati area was 288 per 100,000 population, compared with 179 per 100,000 among white persons living in Rochester, Minnesota.

The findings of these studies were confirmed by a recently published report by the CDC.7 The CDC study, like the earlier population-based studies, found that race matters when it comes to risk of stroke and heart disease. The prevalence of having 2 or more risk factors for stroke and heart disease was highest in black persons (48.7%) and Native Americans/Native Alaskans (46.7%), moderate for white persons (35.5%), and lowest for Asians (25.9%) (Table). Other factors, especially employment status and income level, also influenced stroke risk.

 also noted a geographic variation in stroke risk and occurrence, with the highest incidence occurring in the so-called stroke belt: Kentucky (46.2%), Mississippi (45.8%), West Virginia (44.9%), Tennessee (43.2%), Louisiana (41.6%), North Carolina (40.4%), and Georgia (40%). Conjectures about contributors to the high incidence of stroke in the Southeast include softness of the drinking water, decreased antioxidant intake, a high incidence of hypertension, environmental toxins, and/or the low socioeconomic status of many residents in this area.


Besides lifestyle habits and perhaps genetic predisposition, one of the reasons white persons may have an advantage over black or Hispanic persons in relation to stroke mortality and morbidity is that they are likely to have better timing. They are more likely to arrive at the emergency department within 3 hours of symptom onset. This was the finding of a review of data on black and white stroke patients admitted to the University of Cincinnati Medical Center.

 Furthermore, when black and Hispanic persons get to the hospital, they tend to present with more serious conditions than white persons do. A recent study from St Luke's-Roosevelt Hospital Center in New York City showed that white persons were more likely than black and Hispanic persons were to be admitted to the hospital with a diagnosis of TIA and that black and Hispanic persons were more likely to be admitted with a diagnosis of acute brain lesion.

"It is possible that TIA is overdiagnosed in white persons and underdiagnosed in black and Hispanic persons," said the study's lead investigator, Daniel Labovitz, MD, associate professor of neurology and director of the Division of Cerebrovascular Disease in the Department of Neurology at New York University School of Medicine. "I think the 'take-home' message for practicing physicians, however, is that although black and Hispanic persons may show up at the hospital with a TIA less often than white persons, they are more likely to actually have a cerebral lesion. These patients may be more likely than white patients to go on to a full-blown stroke."

Once the patient is admitted to the hospital, does the quality of care vary according to race? Maybe. Jacobs and colleagues

 from the comprehensive stroke program at Wayne State University School of Medicine in Detroit culled data from a statewide hospital-based stroke registry and found that care was similar in many respects; however, a few differences were noted. Black persons were less likely than other persons to get a CT scan within 25 minutes of hospital arrival. They were also less likely to undergo cardiac monitoring or dysphagia screening and to receive smoking cessation counseling.


Researchers are currently studying whether racial differences underlie Alzheimer disease (AD) pathology. Findings suggest that although the neuropathology appears to be similar between black and white persons,

 the rate of cognitive decline is slower in black persons.

 Indeed, a team from Washington University School of Medicine in St Louis was not able to identify a neuropathologic phenotype of AD that differed among races.

 They examined characteristics of AD: neurofibrillary tangles, senile plaques, Lewy bodies, cerebral infarcts, and cerebral amyloid angiopathy in autopsy specimens from 10 black and 10 age-, sex-, and dementia-matched white persons. The investigators found no important differences, however Barnes and colleagues

When it comes to disease risk, not all of us are created equal. Genetics, culture, diet, education, occupation, income, environment, or a combination of these factors can predispose some persons and ethnic groups to certain illnesses.

Author | Colleen B. Litof

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