Parkinson's DiseaseIntroduction
Clinical types
Management
Conclusion
References

 

Introduction

Tremor is a hyperkinetic movement disorder characterised by rhythmic oscillations of one or more body parts. It can be disabling and may impair quality of life. Various aetiological subtypes of tremor are recognised, with Parkinsonian tremor and essential tremor being the most common. Other types may include dystonic tremor, orthostatic tremor, tremor due to multiple sclerosis (MS) and functional (psychogenic) tremor. Several tremor syndromes can already be treated with success. Drug therapy mostly depends on the clinical manifestation. However, new drugs specifically designed for tremor treatment are needed.1

Various medications have been used, as monotherapy or in combination, for the management of PD tremor and other types of tremor. Combination therapy with carbidopa and levodopa remains the first-line approach for PD tremor. Surgical options, such as thalamotomy or pallidotomy, should be considered when medical therapy fails to control the tremor, and thalamic stimulation has been used in some severe cases.

 

Clinical types

Tremor is one of the most frequent neurological signs and the diagnosis is based mainly on clinical assessment. Tremor is primarily classified on the basis of when it occurs, either with a certain posture, at rest or during action.2 Tremor in Parkinson’s disease usually occurs at rest and is classically referred to as a “pill rolling” tremor of the hands, but can also affect the head, trunk, legs, jaw and lips. However, the most frequent tremor is essential tremor and it manifests itself as a postural and kinetic tremor.3 Tremor in ET may occur not only in the hands, but also in the head and voice. Orthostatic tremor mainly manifests itself in the legs and gives rise to postural instability. Dystonic tremor is an action tremor of the affected region of the body (Table 1). Rhythmicity distinguishes tremor from disorders in which tremor may be a component, such as choreo-athetosis and dystonia.2

Parkinson’s disease tremor

Rest tremor is one of the hallmarks of PD, and its association with rigidity and bradykinesia typically makes the distinction of PD and ET quite straight-forward.4 However, rest tremor can be present in ET patients with advancing disease and approximately one quarter of ET patients without clinical or pathologic signs of PD exhibit rest tremor together with kinetic tremor.5 The presence of rest tremor during walking can be helpful to support the diagnosis of PD because rest tremor associated with ET tends to disappear with gait.5 Asymmetry of the disease is another common feature suggesting the diagnosis of PD. Indeed, diagnostic criteria for definite ET require the presence of symmetrical postural and kinetic tremor.6 However, strictly unilateral kinetic tremor may be found in 10–20% of patients with presumed ET, and, thus, the involvement of only one arm does not rule out the diagnosis of ET.5

Another confounding factor is the actual overlap of both disorders, and these patients tend to have a tremor-dominant PD subtype. There is an ongoing debate whether this is by chance or ET represents a risk factor for PD.4 Dopamine transporter scintigraphy (DAT) using single-photon emission computed tomography (SPECT) imaging can confirm intact presynaptic nigrostriatal dopaminergic innervations in ET patients, particularly those with rest tremor.5 Normal DAT imaging in patients with rest tremor can be also classified as SWEDDs (subjects with scans without evidence of dopaminergic deficits), but these patients tend to have dystonic tremor, and it has been suggested that SWEDDS represent a subtype of dystonia rather than ET.7 In patients with PD, as a consequence of neuronal degeneration in the substantia nigra pars compacta, the ventral intermediate nucleus of the thalamus becomes overactive, possibly producing the tremor. The neurons in the ventral intermediate nucleus of the thalamus fire at a rate that matches the tremor.2

Essential tremor

ET is one of the most common neurologic movement disorders affecting 0.5% to 5% of the general population.5 The relatively high variability of estimated prevalence reflects the lack of uniform diagnostic criteria or a reliable biomarker. Although the pathophysiology of ET remains unknown, abnormal oscillations in the central nervous system have been suggested as crucial to the pathogenesis, as the clinical presentation of tremor involves a rhythmic motor activity. This could be due to functional aberrations in the structures serving as central oscillators.8 A positive family history of ET can be found in 30–80% of all affected patients, suggesting a strong genetic contribution to its aetiology. The diagnosis of ET remains exclusively clinical and several sets of diagnostic criteria have been proposed. The consensus criteria of the Movement Disorders Society’s Tremor Investigation Group are probably most widely used.6

Occurrence of bilateral, largely symmetrical postural tremor with or without kinetic tremor affecting hands or forearms lasting for more than five years and presenting with a gradual onset is typically considered definite ET. Tremor may affect also other body segments, including neck or vocal cords. Recent exposure to tremorogenic drugs, significant traumatic brain injury, and a convincing evidence of sudden onset or stepwise deterioration are the most important exclusion criteria for ET (Table 1).

ET has been traditionally viewed as a monosyptomatic disorder, where tremor is the only clinical sign with the exception of Froment’s sign, “cog wheeling” on passive manipulations of affected limbs.5 The absence of additional signs or symptoms is, therefore, helpful to distinguish ET from other disorders causing mostly action (postural and kinetic) tremor. However, even patients with “pure” ET commonly develop signs of mild, but definitive cerebellar dysfunction, including midline ataxia with a wide-based gait and impaired tandem gait.5 Cerebellar hemispheric dysfunction is also common, and many patients in the advanced stages of the disease manifest intention tremor, defined as a crescendo increase in tremor amplitude during a visually guided movement towards the end of the task.4 This is the result of abnormal activation of antagonistic muscles stopping the movement as it approaches the target. These subtle cerebellar signs further support the role of the cerebellum in ET pathogenesis.5 Some variants of ET may also be associated with other neurologic manifestations.

 

Clinical Feature Essential tremor Parkinson's Disease tremor Dystonic tremor Cerebellar tremor Drug-induced tremor Psychogenic tremor Physiologic tremor
Type of tremor Postural and kinetic tremor
Rest tremor in advanced ET
Rest tremor
Postural and kinetic in some patients
Postural and kinetic tremor, with irregular amplitude and variable frequencies Kinetic “action” tremor
Postural tremor in some patients
Postural and kinetic tremor Variable:
Postural, kinetic or rest
Postural with low amplitude and high frequency
Distribution and symmetry Typically bilateral and symmetrical
In about 10% unilateral tremor
Asymmetric onset is typical, even preserved in bilateral disease
Rest tremor persists during walking
Directionality, with the increasing amplitude in one particular direction Bilateral in degenerative ataxias.
Unilateral in acquired ataxias (MS* =, stroke + hemibalisum)
Bilateral and symmetric Variable with positive entrainment# Variable.
It increases under direct observation, decreases with distraction, and changes with voluntary movement of contralateral limb.
Clinical characters Postural and kinetic
Rest tremor disappears during walking.
Positive family history in 30%-80%
Tremulous handwriting and shaky voice.
Rest tremor with other features of PD:
Bradykinesia, rigidity and postural instability.
Micrographia with monotonous speech.In about 10% unilateral tremor
Co-exist of tremor and dystonia in the same body segment Kinetic, postural and intentional.
Cerebellar signs: Dysmetria, dysdiadochokinesis, gaze-evoked nystagmus and dysarthria
DIP** features in anti-dopaminergic agents.
Temporal association between new drug and onset/worsening of tremor
Inconsistent, irregular and oscillatory with sudden onset
Distractibility, suggestibility, entrainment
Provoking circumstances:
Anxiety, stress.
Applying small weights (0.5– 1.5 lbs.) to affected limb will reduce amplitude/frequency.
Associated neurological features Subtle midline ataxia / cerebellar signs.
May coexist with focal dystonia
Rigidity, bradykinesia, postural instability responsive to dopaminergic therapy Dystonia affecting other areas, blepharospasm.
No response to typical ET medications
Ataxia Pyramidal and extrapyramidal features (in neurodegenerative cases) Typically no other neurologic features Multiple somatization signs, previous psychiatric history, and possible secondary gain Typically no other neurologic features
Location Mainly hands, fore-arms with titubation.
Also eyelids, lip and tongue, vocal cords.
Arms, legs, chin (jaw), and tongue or lip.
Classically, no titubation (head tremor
Mainly arms and neck Arms, legs infrequently, neck Arms, other body segments may be affected in severe cases Variable
Mainly hand and forearms
Variable
Mainly, hand and forearms
Frequency 5-10 Hz 3–5 Hz 7 Hz 2–7 Hz 5–12 Hz 2–12 Hz Variable, could be 5-9 Hz
*MS: Multiple sclerosis
**DIP: Drug-induced parkinsonism.
# Entrainment: The change in frequency of psychogenic tremor in adaption to voluntary tasks with determined frequency and performed with contralateral arm.

 

Dystonic tremor

The association of tremor and dystonia is perhaps the most confusing clinical scenario and the term “dystonic tremor” has been inconsistently applied in the medical literature.5 Even though controversies persist, dystonic tremor should be reserved to describe the coexistence of tremor and dystonia in the same body segment. Dystonic tremor is further characterised by directionality, with the increasing amplitude in one particular direction, and by the null point phenomenon, resulting in diminished or absent tremor in certain limb positions.5

Overlap of arm postural and/or action tremor with dystonia affecting other body segments, such as blepharospasm of cervical dystonia, probably represents a variant of ET and should not be classified as dystonic tremor.9 This distinction is clinically relevant because dystonic tremor usually does not respond to typical ET medications, and its pharmacotherapy is similar to the treatment of generalised or focal dystonia.5

Enhanced physiologic tremor

Enhanced physiologic tremor are characterised by predominantly postural tremor with a low amplitude and high frequency.5 This may not represent any central nervous system dysfunctions, as it is experienced by almost every individual under certain circumstances, such as anxiety or strenuous physical activity.5 However, some patients with ET may have prodromal signs more consistent with enhanced physiologic tremor before developing definite ET.5 The intensity of enhanced physiologic tremor may be bothersome for some patients, and, in general, if provoking circumstances cannot be avoided and treatment is warranted, the same medications used for ET are useful for enhanced physiologic tremor. Application of small weights from 0.5 to 1.5 pounds to the affected limb will result in reduction of amplitude and frequency in enhanced physiologic tremor, while it remains relatively constant in ET.10

Cerebellar tremor

Cerebellar tremor is characterised by a low frequency high amplitude tremor that is mostly generated in proximal limb segments during postural or kinetic tasks (Finger-nose test).5 Intention tremor is another feature of cerebellar tremor. Some patients with an advanced ET may develop characteristics of cerebellar tremor, but other signs of cerebellar dysfunction, such as limb dysmetria, dysdiadochokinesis, gaze-evoked nystagmus, and cerebellar dysarthria are absent in ET.11

Wing-beating proximal tremor, appearing while holding semi-flexed outstretched arms may also resemble cerebellar tremor, but is most commonly seen with advanced Wilson’s disease. The diagnosis of Wilson’s disease should be considered even in familial tremor patients younger than 40 years, particularly if additional neurologic signs, such as dysarthria or Parkinsonism, are present. Elevated 24-hour urine copper is diagnostic of Wilson’s disease.

Psychogenic tremor

Psychogenic tremor is the most common nonorganic movement disorder and occasionally can be confused with ET.12 Psychogenic tremor can occur at rest, with posture, or during kinetic tests. Its diagnosis is based on a sudden onset, irregular and inconsistent oscillatory movements with distractibility and suggestibility.5 Entrainment, defined as changing frequency of psychogenic tremor in adaption to voluntary tasks with determined frequency and performed with contralateral arm such as tapping in time to a metronome, can be very helpful in differentiation from ET.12 Multiple somatisation signs, previous psychiatric diagnoses, and possible secondary gain can be also helpful for the diagnosis of psychogenic tremor.5

Drug-induced tremor

Exposure to tremorogenic drugs may mimic PD tremor or ET, and a long list of tremor-inducing medications include tricyclic, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors, neuroleptics, β-2 agonist, theophylline, caffeine, cyclosporine A, tacrolimus, valproic acid, lithium, nicotine, pseudoephedrine, and levothyroxine.5 Temporal association between newly prescribed medications and the onset of tremor or its significant worsening suggests medicationinduced tremor. When medication is suspected as a likely culprit, discontinuation should be attempted to confirm this causality.

Other types

Orthostatic tremor is a rare kind of tremor characterised by coarse shaking of the legs with a feeling of postural instability in standing position. This feeling of instability or being about to fall is experienced on standing up and disappears or improves on walking and is absent when sitting or lying down. It is seen in older women and can lead to fear of falling, which can limit patient mobility. Typically, the symptoms rapidly improve on sitting or walking, and the need to sit down or to move can be so strong that patients avoid situations where they have to stand still.13 The diagnosis is usually confirmed by EMG which reveals a pathognomonic tremor of 13–18 Hz while the patient is standing upright.13

Alcohol can be associated with a variety of movement disorders, including postural tremor due to alcohol withdrawal, action tremor as a result of cerebellar atrophic changes and flapping tremor seen in acute liver failure. Alcohol withdrawal tremor is similar to essential tremor on examination, but with subtle differences and it tends to be more rapid than ET.2

 

Management

Several tremor syndromes can already be treated with success, but new drugs specifically designed for tremor treatment are needed. Symptomatic treatment is tailored to the tremor type. Combination therapy with carbidopa and levodopa remains the first-line approach for parkinsonian tremor.2 Essential tremor may be amenable to propranolol or primidone. Propranolol may be useful in treating alcohol withdrawal tremor, and isoniazid may control the cerebellar tremor associated with multiple sclerosis. Clonazepam may relieve orthostatic tremor.

Other agents are also available for the treatment of tremor. Botulinum toxin can improve head and voice tremor in ET. When medical therapy fails to control the tremor, surgical options such as thalamotomy, pallidotomy and thalamic stimulation should be considered in severe cases.2 Thalamic stimulation, the most recent of these surgical approaches, offers the advantage over ablative procedures of alleviating tremor without the creation of a permanent lesion.2,5The US Food and Drug Administration has approved thalamic stimulation as an accepted therapy for unilateral suppression of uncontrolled essential tremor or parkinsonian tremor in an upper extremity in patients who failed to respond to medical therapies.2

Treatment of PD tremor

Combination therapy with carbidopa and levodopa remains the first-line approach for parkinsonian tremor. In addition to modulating the tremor associated with Parkinson’s disease, levodopa improves bradykinesia, rigidity and other commonly associated symptoms. When tremor is the predominant presenting symptom of Parkinson’s disease or when tremor persists despite adequate control of other parkinsonian symptoms with low dosages of levodopa, an anticholinergic agent such as trihexyphenidyl (Artane) or benztropine (Cogentin) may be considered as an alternative treatment.2

In most patients, however, anticholinergics do not significantly improve bradykinesia and rigidity. Trihexyphenidyl dosages necessary to improve tremor are between 4–10mg per day (maximum: 32mg), and useful benztropine dosages range from 1–4mg per day.2 The side effects of these agents are their limiting factor, particularly in older people.14 Side effects include memory impairment, hallucinations, dry mouth, urinary difficulties and blurred vision.14

Other antiparkinsonian drugs—for example, amantadine (Symmetrel), and dopamine agonists such as ropinirole (Requip) and pramipexole (Mirapex)—are most helpful in patients whose tremor responds poorly to levodopa alone.2

Surgical therapy for tremor should only be considered if drug therapy fails to produce adequate relief. Before the introduction of levodopa, thalamotomy was an often-selected option in the treatment of Parkinson’s disease. However, problems associated with bilateral thalamotomy, such as dysphagia and dysarthria, limit its use. Catastrophic complications in the perioperative period include bleeding in the thalamus or the subdural or epidural area, which can lead to death, paralysis, aphasia or significant cognitive deficits.2 Producing lesions in the globus pallidus by means of pallidotomy used to be an alternative to thalamotomy in the treatment of parkinsonian tremor. The side effects associated with the procedure are similar to those of thalamotomy and include visual field defects, such as lower central visual field scotomas, and hemiparesis. Thalamic stimulation or deep brain stimulation (DBS) involves implanting an electrode in the thalamic area found to be responsible for the tremor. In the first study of this technique, as many as 88% of the patients with Parkinson’s disease had either good or excellent relief of tremor.15

Treatment of ET

Therapy for ET remains purely symptomatic, and virtually all medications used for the reduction of tremor have initially been developed and approved for other indications.5 Anti-tremorogenic action of these compounds was discovered incidentally.5

There are a number of agents supported by various levels of clinical evidence that have become standard of care for the symptomatic control of ET. These available medications can be divided into first line (propranolol and primidone), second (gabapentin, pregabalin, topiramate and beta-adrenergic receptor antagonists other than propranolol), and third line therapy, which includes nimodipine and clozapine. The classification is based on the level of clinical evidence and risk-benefit ratio. Both groups, first and second line therapies, are supported by double-blinded, placebo controlled studies and those for the first-line therapy would meet the criteria for the class I evidence.

Propranolol and primidone are considered drugs of first choice with a mean effect size of approximately 50% tremor reduction.1 The daily dose of propranolol varied from 60 to 800mg/day with an average dose of 182.5mg/day.16 There is no convincing evidence that doses higher than 320mg/ day provide any additional benefit.16

Overall, other beta-blockers are inferior in efficacy to propranolol.5 Nadolol is a nonselective β-blocker, and, unlike other members of this therapeutic class, it does not undergo hepatic metabolism and is renally excreted unmetabolised. It has also the longest half-life up to 24 hours, allowing once-daily dosing.5 Primidone is minimally bound to protein and penetrates the blood-brainbarrier (BBB) well. Several double-blinded, placebo controlled studies demonstrated reduction of tremor in patients treated with doses ranging from 50mg/ day to 1000mg/day and the average dose was around 500mg/day.17 The efficacy of topiramate is also supported by a large double-blind placebocontrolled trial, while other drugs in the second-line therapy have less supporting evidence.5

Gabapentin was developed as a structural analog of gamma-aminobutyric acid (GABA), but it does not directly bind to GABAA or GABAB receptors.18 Gabapentin does not undergo any metabolisation and is excreted unchanged in urine. At best, the benefit in ET is modest, and the likelihood of gabapentin being helpful in patients who have failed primidone or propranolol is very low.

Pregabalin is another structural derivative of GABA, and similar to gabapentin, it does not display any affinity to GABA-ergic receptors.19 Clozapine is an atypical antipsychotics that mainly blocks dopamine D1 and D4 receptors with relatively less affinity to the dopamine D2 receptors and, thus, a low potential for extrapyramidal side effects. Clozapine reduced tremor up to 50% from the baseline in two small studies using doses of 25mg to 75mg/day.20,21 The most common problem in these studies was sedation; however, the main risk of clozapine is agranulocytosis that can be seen in up to 1% and neutropenia in 3% of all treated patients.

Non-pharmacological therapies for ET, including chemo-denervation with botulinum toxin and surgical approaches, including deep brain stimulation(DBS), may be considered in severe cases that failed to respond to medical therapies.5 Stereotactic thalamotomy is the surgical procedure most often used to quell essential tremor.2 DBS of the nucleus ventralis intermedius (VIM) is used as an alternative to pharmacological therapy of ET in patients who fail to adequately respond to medical therapy. The magnitude of effect from DBS is greater than from medical management, but more severe side effects are possible with surgery.22

Botulinum toxin improves head and voice tremor. Ethanol is a potent suppressant of ET in many patients, but it has obvious limitations in the chronic treatment of the disorder. It has been reported that alcohol reduces tremor amplitude in 50–90% of cases, but tremor may temporarily worsen after the effects of alcohol have worn off.23

Treatment of other types of tremor

The treatment of dystonic tremor matches the treatment of dystonia and there are no specific therapeutic trials evaluating treatment efficacy on dystonic tremor. Dystonic limb tremor may respond to anticholinergics. In addition, dystonic tremor may be successfully treated by injecting botulinum toxin.3 However, the toxin injection in forearm muscles produces little if any improvement in most patients, and finger or wrist weakness is a common side effect.21

Gabapentin and clonazepam are often recommended for orthostatic tremor.1,3 In addition, a walking aid may help in improving postural instability on standing still and reducing the fear of falling.13 Postural and action tremors respond to beta blockers, primidone, some anti-epileptics and benzodiazepines. Multiple sclerosis (MS) tremor responds only poorly to drug treatment and those with severe MS tremor, thalamic deep brain stimulation may be considered.

Local injections of botulinum toxins and surgical interventions such as thalamic deep brain stimulation play a role as alternative options when pharmacological treatment is not satisfactory. With a mean effect size of about 90% deep brain stimulation (DBS) in the nucleus ventralis intermedius (VIM) or the subthalamic nucleus may be the most potent treatment; however, there are no controlled trials and it is reserved for severely affected patients.1 Patients with functional tremor may benefit from antidepressants and are best treated in a multidisciplinary setting.1,3 Several uncontrolled studies have reported favourable results with gamma knife thalamotomy. However, delayed complications have been observed and clinical improvement may take weeks to months.24 Several tremor syndromes can already be treated with success, but new drugs specifically designed for tremor treatment are needed.5

 

Conclusion

Tremor is one of the most frequent neurological signs and the diagnosis is based mainly on clinical assessment. Various aetiological subtypes of tremor are recognised, with Parkinsonian tremor and essential tremor being the most common. Several tremor syndromes can already be treated with success. Controlled trials outside ET are rare and hence most of the recommendations are based on a low level of evidence.

Therapy for PD tremor, ET, and tremor in general, remains purely symptomatic, and virtually all medications used for the reduction of tremor in ET have initially been developed and approved for other indications. In patients with severely disability, implantation of thalamic stimulation electrodes may be considered. Botulinum toxin can improve head and voice tremor in ET. New therapies specifically designed for tremor treatment are needed.

 

Dr N Aly Consultant Physician, University Hospital Aintree, Liverpool
Conflict of interest: none declared

 

References

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