Mechanisms and Emerging Therapies in Tremor Disorders (Contemporary Clinical Neuroscience)

Checkout Your Cart Price. Description Details Customer Reviews Tremor is intimately linked to the numerous interactions of the central and peripheral nervous system components tuning motor control, from the cerebral cortex up to the peripheral effectors. Activities of central generators, reflex loop delays, inertia, stiffness and damping are all factors influencing features of tremor.

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This book discusses the pathophysiology of tremor including membrane mechanisms and rodent models, the advances in genetics and the musculoskeletal models pertinent to body oscillations. The main forms of tremor encountered during clinical practice are considered, taking into account neuroimaging aspects. The book covers recent advances in methodologies and techniques of assessment, and provides practical informations for the daily management. In addition to pharmacological treatments, neurosurgical approaches such as deep brain stimulation DBS and thalamotomy are discussed.

Emerging techniques under development are also introduced. Future challenges are also presented. Review This Product No reviews yet - be the first to create one! The other main tremor type, action tremor, includes all tremor manifestations in body parts that are not at rest, and comprises postural tremor and kinetic tremor Table 2. In most cases, action tremor can be easily distinguished from tremor at rest. However, patients with PD may display a tremor that reoccurs when arms are maintained stretched out for some seconds reemerging tremor.

From a physiologic standpoint, this can be considered a tremor at rest, as the body part has been held motionless in this position for a period of time. Thus, tremor that reemerges after a short period should not be classified as true postural tremor. Adapted from Bhidayasiri R. Differential diagnosis of common tremor syndromes. Postgrad Med J ;81 Other tremor characteristics are the location or distribution in the different body parts, the tremor frequency, the presence of exacerbating or alleviating factors, and the presence of other neurologic signs or symptoms Table 1.

These characteristics are rarely specific for a certain cause of tremor. For example, essential tremor may or may not improve after alcohol ingestion, but also other types of tremor may improve with alcohol. The frequency of a tremor can be approximated by observation with the naked eye, and more accurately measured with surface electromyography. The most often encountered tremors have frequencies between 4 and 12 Hz. However, although there may be general differences in average tremor frequency among different types of tremors, the frequencies overlap considerably between different disorders.

Thus, the exact determination of tremor frequency rarely adds decisive new information when the cause of a tremor in an individual patient is uncertain. Exceptions are unusually fast or slow tremor frequencies, which may help to establish a correct diagnosis. The nomenclature of tremors is not standardized and sometimes confusing, and some terms may have different meanings. However, the term is also sometimes used to describe more irregular, ataxic movements. Both represent a disturbance in the fine-tuning of goal-directed movements and point toward the cerebellum or its inflow- and outflow tracts.

Patients may display several types of tremor and it can be challenging to separate the single components.

Mechanisms and Emerging Therapies in Tremor Disorders (Book)

A general rule is to name the predominant tremor after the position in which the largest amplitude occurs. A diagnostic problem may arise when action tremor persists at rest. If an action tremor persists with the same amplitude during rest, by convention the tremor is considered an action tremor. When assessing a patient with tremor, the type of tremor Table 2 is characterized and other manifestations of a possible underlying neurologic disorder are actively sought.

A thorough neurologic examination of a patient presenting with tremor includes the following:. Tremor at rest may be seen when observing the patient with the affected body part neither voluntarily activated nor supported against gravity. It can become more pronounced when the patient is concentrating on other tasks, e. Postural tremor that was not seen in other parts of the examination can become visible when the patient holds the upper extremities in an outstretched position with the hands supine, prone, and in the wing position i.

Irregular hand or finger movements in these positions are not tremor. Sudden loss of muscle tone with a sudden drop of a finger or hand, succeeded by a corrective movement back to the initial position, indicates negative myoclonus. Intention tremor is characterized by overshooting movements of increasing amplitude when approaching a goal. It can be elicited in goal-directed activities, such as finger-to-nose, heel-to-shin, and toe-to-finger movements. Observing a patient while drawing e. Action tremor is increased during writing or drawing, and a task-specific tremor may become obvious.

In PD, there usually is no tremor during writing, but other signs can be seen, such as increasing micrographia and slow movements. Pouring water from one cup into another shows the degree of disability due to kinetic tremor in a practical situation. Important clues about an underlying neurologic disorder in patients presenting with a tremor can be found during the examination of the cranial nerves, speech, gait, balance, and muscle tone. Torticollis, blepharospasm, or orofacial twitching may indicate dystonia. These signs can be very mild, in which case the patient may not be aware of any disturbance.

Several movement disorders affect the fine-tuned movements of the tongue, where possible abnormal findings include fasciculations or slowness of tongue movements. Slow and irregular speech with increased separation of syllables or explosive sounds may indicate cerebellar dysarthria. Dystonia can manifest as spasmodic dysphonia, with effortful, jerky, strained sounds in the adductor type of spasmodic dysphonia, or a breathy, whispering voice with sudden breaks in the abductor type of spasmodic dysphonia.

Typical parkinsonian or cerebellar gait may be noted, and muscular rigidity in combination with a tremor at rest is typical for PD, whereas spasticity may develop in multiple sclerosis. Although the opposite may be true, generally action tremors will be more severe during an office visit which usually is accompanied by some uneasiness or anxiety , and tremors at rest will become less obvious or not visible at all.

Thus, observations made during a short office visit may be misleading, and information from the patient or proxy is important. The list of medications and toxins that can cause tremor is long. A comprehensive history must include all medications that a patient is taking, as well as possible exposure to toxins. Table 3 summarizes the most common medications and toxins that cause tremor. For most of these medications, tremor is a dose-dependent side effect and will disappear as the dose is decreased or the medication discontinued. In a patient who is treated with lithium or valproate sodium and who develops tremor, the serum concentrations of these substances should be determined.

Some individuals may consume coffee, tea, or other stimulants in unusually high amounts, which can be a sufficient explanation for pronounced tremors. Hyperthyroidism and hypoglycemia may also cause tremor. In the outpatient setting, the clinical features and neurologic examination findings are the most important assessment tools in evaluating patients with tremor. Extensive laboratory testing is usually not necessary. For routine evaluation, thyroid function tests are performed in most or all patients with tremor to exclude hyperthyroidism.

Various nonpharmacologic treatment options for tremor are available, most of which are not specific for a tremor of a certain etiology. Coping strategies form an integral part in the care of a tremor patient. Simple advice may sometimes be helpful, such as avoiding the use of a computer mouse or laser pointer, which magnify tremor movements, in situations where this is embarrassing. The patient can be encouraged to inform others openly about his or her propensity to tremors and about their benign nature.

Some patients may seek medical advice because of concerns that the tremor may be the first sign of a severe disorder such as PD, amyotrophic lateral sclerosis, or a brain tumor. Such patients may not need medical treatment, but feel comfortable after reassurance that their tremor does not herald a more severe disorder. Counseling should include stressing the benign natural course of a particular tremor when appropriate.

Agents that are suspected to cause or worsen a tremor should be removed whenever possible.

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Nonpharmacologic symptomatic treatment options include the use of larger utensil handles or wrist weights, or occupational assessments and advice. This section describes the types of tremor that are most commonly encountered in an outpatient setting and rarer, but important differential diagnoses that require specific treatment. Slight, usually bilateral postural or kinetic action tremor, particularly in the hands and fingers, is a normal phenomenon and does not indicate a disorder physiologic tremor.

Physiologic tremor is more intense in situations of stress or anxiety, after strenuous physical work or exercise, or after ingestion of caffeine or other stimulants. More pronounced cases of easily visible and usually reversible tremor without evidence of neurologic disease reflect enhanced physiologic tremor 1. Usually, nonpharmacologic treatment options are sufficient. However, for some patients, even mild physiologic tremor can lead to large degrees of embarrassment and functional disability, such as the violinist at a decisive audition, or any professional giving an important presentation.

Essential tremor is the most common form of tremor, and probably the most common movement disorder in general.

Unfortunately, there is no uniformly accepted definition of essential tremor. Probably, essential tremor reflects a clinical syndrome rather than a single disease entity. Symptom severity often increases over time, but the progression can be very slow. Several lines of evidence suggest that cerebellar function is disturbed in essential tremor. This is consistent with clinical observations of cerebellar signs, such as slight dysmetria, an ataxic gait, or a component of intention tremor within a subgroup of patients with essential tremor.

More recently, relatively slight but distinct pathologic changes in essential tremor have been studied systematically. In one group of essential tremor patients, there were pathologic changes within the cerebellar cortex. Cell loss in the locus ceruleus leads to decreased noradrenergic stimulation of Purkinje celis, which reduces their inhibitory effect on the dentate nucleus and the other components of the triangle of Guillain and Mollaret.

This mechanism is analogous to the severe action tremor characteristic of spinocerebellar ataxia type 2 SCA 2 , whose pathologic correlate is the preferential degeneration of Purkinje cells. These more recent pathologic findings, taken together with the higher incidence of essential tremor observed in relatives of individuals with other neurodegenerative disorders, such as PD and possibly a common genetic background, 33 — 35 have led to suggestions that essential tremor in fact also is a neurodegenerative disorder.

A variety of treatment options for essential tremor are available today which makes it possible, but also necessary, to select the most appropriate solution for the individual patient. Such assessment may be difficult. Studies have shown that on average, physical and mental quality of life measures are lower in essential tremor patients compared with healthy individuals. The nonpharmacologic treatment options outlined above are considered for all patients with essential tremor. Pharmacologic treatment may be utilized either intermittently or daily and is most effective at reducing limb tremor in essential tremor.

In the absence of contraindications, propranolol or primidone are both recommended as first-line choices. Primidone is not approved for the treatment of essential tremor in many countries including the United States , but widely considered effective. It should be initiated gingerly; perhaps If propranolol or primidone do not provide satisfactory tremor relief, guidelines unanimously recommend the combination of propranolol plus primidone.

Gabapentin, topiramate, or lorazepam are considered second- and third-line drugs. Botulinum toxin remains expensive, needs to be administered repeatedly, and there is a risk for weakness in the body parts treated. Overall, the pharmacologic treatment efficacy of essential tremor is unfortunately low. A recent study that included essential tremor patients found that almost one-third of patients discontinued treatment within the first year. Furthermore, tremor may diminish in later stages of the disease, when bradykinesia becomes more prominent.

They include agonist and antagonist activation alternating in a precisely tuned manner, often leading to a stereotypical series of movements, such as the typical pill-rolling tremor. Electrophysiologic surface recording study. All recordings shown were performed simultaneously. The antagonists, anterior tibial and gastrocnemius muscles, are activated in shifted phases, and a slight electrical activity was detected in the quadriceps musculature on the same side.

The frequency in the electrophysiologic activity on the left and on the right side differs slightly, with 13 activations in the left anterior tibial muscle, but only 12 in the right side during the period represented in the figure. This indicates that tremors originate in separate circuits in the left and right sides, and the overall picture underscores the central origin and complex nature. There are descriptions of patients with only a rest tremor who do not subsequently develop PD, and the term monosymptomatic rest tremor has been suggested when this situation has persisted for at least 2 years.

Diagnostic difficulties can arise when a patient only has tremor and no other signs and symptoms are found, when no tremor is visible during the office visit, or when other forms of tremor coexist. Thus, a diagnosis of PD should never be based solely on tremor, but requires the presence of the other cardinal symptoms of PD, notably, bradykinesia. Tremor in PD is often more difficult to alleviate than the hypokinetic PD manifestations bradykinesia and rigidity.

The pathologic hallmark of PD is the loss of dopamine-producing neurons in the substantia nigra pars compacta SNc , especially its ventrolateral portion, which projects to the putamen. Dopaminergic neurons project to striatal cells that form part of the indirect pathway.

These are equipped with inhibitory D 2 receptors. Thus, dopamine exerts an inhibitory net effect on the indirect pathway loop, and the dopaminergic deficit of PD reduces this inhibition. Dopamine also acts on the excitatory D 1 receptors found on inhibitory striatopallidal pathway cells of the direct pathway. More recent findings also show that the anatomic connections between the brainstem nuclei are more complex than previously appreciated.

Cortical neurons that activate the STN without any relay in the basal ganglia have been identified, the hyperdirect pathway. Furthermore, feedback neurons from the GPe to the striatum as well as from GPe to GPi have been discovered in different mammals. Several intriguing findings argue against the striatonigral dopaminergic deficit directly causing PD tremor. The extent of dopamine deficiency and the degree of disease progression correlate well with the severity of rigidity and bradykinesia, but not with tremor.

Mechanisms and Emerging Therapies in Tremor Disorders : Giuliana Grimaldi :

Levodopa and dopamine agonists alleviate parkinsonian symptoms including tremor in some patients, but often tremor control is not satisfactory. Although frequently discussed, there is no convincing data showing that dopamine agonists lead to greater improvement of tremor than levodopa. The clinical trials that were performed with this question in mind either did not directly compare a dopamine agonist to levodopa 61 — 65 ; did not asses tremor as primary outcome but in post hoc analyses 62 , 65 ; or the recorded effect sizes, even though statistically significant, were small.

In general, levodopa remains the antiparkinsonian medication producing maximal motor benefit in PD patients, with the fewest side effects. In patients younger than 60 years of age, dopamine agonists may be considered as there is some evidence for a possibly lower risk for dyskinesias in later stages of the disease, compared with when treatment was initiated with levodopa. Beta-blockers have a documented effect also in parkinsonian tremor, but may increase the orthostatic hypotension that often develops in PD, which can have serious consequences. Anticholinergic drugs were formerly used for the treatment of PD.

The rationale behind their use is that the dopaminergic deficit in PD leads to a relative excess of acetylcholine in the striatum, and that anticholinergic drugs can restore a balance on a lower level of both transmitters. In fact, experience shows that anticholinergics can improve tremor in PD. However, there are no modern studies on their use, and side effects can be dramatic. Nevertheless, some authorities recommend anticholinergics as one of several treatment options for younger patients with tremor-dominant PD who do not respond to other medications.

Many other disorders may be encountered in an outpatient clinical practice that can cause tremor or movement disorders with a similar appearance. Tremor can be a presenting or predominant sign of polyneuropathies or other lesions of peripheral nerves neuropathic tremor.

In particular, immunoglobulin-mediated forms, such as IgM-neuropathy or chronic inflammatory demyelinating polyneuropathy, may be associated with tremor. Usually, these disorders develop subacutely within weeks to months; thus, the temporal profile of tremor development is unique. On neurologic examination, other signs of peripheral neuropathy will be present. Serum electrophoresis, electrophysiologic studies, cerebrospinal fluid analysis, and sometimes nerve biopsy, can help establish a diagnosis.

The cause of excessive immunoglobulin production is usually monoclonal gammopathy of unknown significance, but a certain amount of screening tests are conducted to exclude plasmocytoma, amyloidosis, or lymphoreticular malignancy. Lesions of cerebral structures implicated in tremorogenesis Fig.

The lesions may be a consequence of trauma, stroke, tumors, infection, or other disorders. The history and temporal development can provide clues, as these tremors develop within a shorter time. Symptomatic treatments of the tremor include similar options as for other types of tremor.

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Brainstem stroke and trauma are the most common causes. As the dopaminergic system is involved in most cases, treatment with levodopa should be attempted. The tremor may occur in the same body part as the dystonia, or in different areas. Both the frequency and amplitude are often irregular and variable. A typical example is dystonic head tremor in a patient with torticollis. Diagnosis rests on finding other signs or symptoms of dystonia, bearing in mind that some symptoms, such as mild blepharospasm, a subtle voice change of spasmodic dysphonia, or a slight torticollis, may be easily missed as important clues by both the physician and the patient.

Responsiveness to sensory tricks gestes antagonistiques indicates a dystonic tremor. Many dystonias are hereditary, and signs and symptoms of dystonia in a relative may help establish a correct diagnosis. The precise relationship of dystonic tremor to dystonia has been debated. It has been suggested that dystonic movements may be tremulous in nature, or that dystonic tremor results from a more or less conscious attempt of the patient to restore normal body position against the permanent dystonic muscle contraction.

In dystonia, activity in the lentiform nuclei putamen, external and internal globus pallidus at rest is generally disturbed, and there are cortical abnormalities in areas of the sensorimotor circuitry. As most other movement disorder signs, tremor or tremor-like movements may have a psychogenic cause.