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Tremor syndromes: A review
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.226440
Keywords: Essential tremor, Holmes tremor, orthostatic tremor, palatal tremor, Parkinson disease, tremor
Among the involuntary movement disorders, tremor is a common phenomenology seen in clinical practice.[1] It is defined as an involuntary, rhythmic, oscillatory movements of one or more body parts with relatively fixed frequency and amplitude.[2] Tremor is not only confined to a limb, but can involve any body part, including the head, jaw, tongue and soft palate. It is most common among middle-aged and older adults, although it can occur at any age. The disorder generally affects men and women equally. There are many types of tremor with different etiopathogenesis. Broadly, the important causes of tremors include neurodegenerative diseases, stroke, head injury, drugs and toxins, demyelinating disorders, systemic illnesses, metabolic disorders etc., The important factors that need to be determined while assessing a patient with tremor include the phenomenology of tremor, presence or absence of other neurologic signs, and the effect of medications or alcohol. A good history and detailed neurologic examination will usually help in determining the cause of tremor.[3] This review describes the classification, pathophysiology and the various tremor syndromes commonly seen in clinical practice.
Tremor can be broadly classified based on the circumstances under which it occurs- either at rest or during an action.[2],[4] This distinction helps in grouping tremors according to their pathophysiology and etiology, which in turn is highly relevant in terms of choosing the appropriate therapeutic options. They can also be classified based on the frequency, body part involved and etiology [Table 1].
Classification based on the circumstances Rest tremor Rest tremor is seen in a body part that is relaxed, non-contracting and completely supported against gravity (e.g., when resting an arm on a chair). It is typically enhanced by mental stress (e.g., counting names of the months backward) or while walking. It diminishes or disappears by voluntary movement of the affected body part. In the early period, it is often intermittent and precipitated by stress or anxiety. In most of the rest tremors, the onset is in the upper limbs, often asymmetric. Rest tremors can also be seen in the face and usually involve the lips and jaw. The classical rest tremor is the one seen in Parkinson's disease (PD). Action tremor Action tremors can be further subdivided into postural, isometric and kinetic tremors. Postural tremors appear when the affected body part is held in a particular position against gravity (e.g, arms parallel to the floor) and kinetic tremors are associated with goal directed voluntary movements of the affected body part. Isometric tremors are associated with sustained muscle contraction against a fixed object.[4] Classification based on the body part involved Based on the anatomical distribution, tremors can be classified as head tremors, tongue tremors, jaw tremors, limb tremors, voice tremors, trunk tremors etc. Classification based on the frequency of tremor Tremors can be of a low frequency (<4 Hz), medium frequency (4-7 Hz) and high frequency (≥8 Hz). Physiological tremor is usually a high frequency tremor (8-12 Hz) with low amplitude. The frequency of essential tremor (ET) varies between 6-12 Hz while PD tremor usually has frequencies between 4 and 6 Hz. The cerebellar tremor and Holmes tremor are low frequency tremors (less than 5 Hz). Classification based on the etiology of tremor Tremors are also classified based on the underlying etiologies into various tremor syndromes described below. Pathophysiology of tremor The exact pathophysiology of tremor is still incompletely understood. It was proposed earlier that tremor originates from any of the three sources: mechanical, peripheral and central oscillations. The mechanical oscillations are due to the complex movements occurring at the tendon-muscle-joint system. The peripheral circuit involves the path from muscles to the spinal cord and from the spinal cord to the muscles. On the other hand, the central oscillations involve spinal and suprapinal structures including the basal ganglia, cerebellum and cerebral cortex.[5] However, recently, two basic principles have been postulated in the genesis of tremors. In one hypothesis, there is functional hyperexcitability and rhythmic oscillation of the neuronal loops without any structural changes. Resolution of tremors in some cases with alcohol lends evidence to this functional disturbance hypothesis. Others hypothesize that there is a permanent structural pathology with features of neurodegeneration.[3] Generation of tremor is associated with the dysfunction of two main circuits-the basal ganglia-cerebello-thalamic and the dentate-olivary circuits.[6] The globus pallidus internus (GPi) sends inhibitory projections (GABAergic) to the anterior part of the ventrolateral thalamus (VLa; also known as ventro intermedial nucleus, Vim), and then the projections connect to the motor cortex. Increased activity of the GPi inhibits motor cortical activity. On the other hand, the cerebellar nuclei (dentate in particular) sends glutaminergic excitatory projections to the posterior part of the ventrolateral thalamus (VLp) nucleus and then to the motor cortex.[7] Cerebellar activity causes facilitation of the motor cortical activity. The involvement of this circuit is thought to be associated with tremor generation in patients with PD, ET, dystonic tremor, orthostatic tremor and Holmes tremor. The other circuit (dentato-olivary pathway) involves the red nucleus, inferior olivary nucleus (ION), and the dentate nucleus, forming the triangle of Guillain and Mollaret (Guillain-Mollaret triangle). The dentate nucleus is connected to the contralateral ION by GABAergic inhibitory projections, which in turn send excitatory projections to the Purkinje cells of the cerebellum. The ION receives projections from the red nucleus. ION plays an important role in the genesis of tremors. The neurons within the ION are connected by gap junctions and can thereby act as asynchronized neuronal ensemble.[3],[8] Normally, the ION neurons demonstrate regular oscillatory depolarizations mediated by calcium channels.[9] These oscillations serve as pacemakers in timely processing, temporal coordination and cerebellar motor learning. All these three circuits are interlinked by the subthalamic nucleus (STN), which forms a major junction in the tremor circuit.[10] Lesions in any of these two circuits produce tremor. Quantification of tremors There are several ways to measure or quantify the tremors. Quantification is important to assess the severity, response to therapy and in clinical studies. The assessment of tremor can be divided into clinical and biomechanical techniques. Clinically, rating scales are used to assess the severity of tremors. The commonly used scales are the “Fahn–Tolosa–Marín tremor rating scale” (FTMTRS) and the “essential tremor rating assessment scale” (TETRAS).[11],[12] MDS-UPDRS is another scale used to assess the tremors in addition to rigidity, bradykinesia and postural instability in PD patients. The biomechanical analysis of the tremor involves electromyography (EMG), accelerometers, gyroscopes and spirography. Subsequent to data aquisition by EMG and accelerometers, the signal processing and analysis of tremor often involves the spectral analysis, based on Fast Fourier Transformation (FFT). Drawing the Archimedes spiral helps in quantifying action tremors and several digitalized tablets are now available.
Essential tremor Essential tremor (ET) is the one of the most common tremor disorders encountered in clinical practice.[13] It is often hereditary and transmitted in an autosomal dominant pattern with high penetrance.[2] The prevalence of ET is estimated to be 4% - 5.6% in people aged 40 years and above.[14] Age, ethnicity and family history of ET have been found to be risk factors.[14] Three genetic loci on chromosome 3q (ETM1), chromosome 2p (ETM2), chromosome 6p (ETM 3) have been identified in some families.[15] However, this has not been reproduced in other studies. There is evidence that environmental factors could serve as modifiers of the underlying susceptibility.[16] Genome wide association studies (GWAS) have found an association with LINGO1 gene and SLC1A2 gene. ET can occur both in children and adults and advancing age has been found to be a risk factor. It usually appears in the second decade, but a second peak is seen in adults older than 35 years. It is a slowly progressive postural tremor and in its classic form involves predominantly both the hands symmetrically. The frequency of ET ranges from 4-12 Hz and varies inversely with the age.[14] The tremor affects the patient's activities of daily living such as writing, eating, pouring, holding objects etc. However other body parts can also be involved such as head, jaw, voice, tongue, trunk and lower limbs.[17] ET is known to worsen with mental stress, anxiety, activity and subsides or improves with alcohol intake. In almost all of the familial cases of ET, the tremor onset is before the age of 65 years. Sometimes, tremor can be associated with cogwheel rigidity. In the initial stages, the tremor amplitude is low but as the disease progresses, the amplitude increases and can be seen at rest also. ET is a progressive disorder and patients with advanced ET demonstrate intention tremors and impaired tandem gait that are suggestive of cerebellar involvement.[18] At this stage, patients are physically unable to feed or dress themselves, leading to loss of independence. ET is also associated with cognitive impairment and personality disturbances.[19] There is some evidence that a subset of ET patients develop PD and Alzheimer's dementia.[20] Some experts believe that ET is a neurodegenerative disease, in fact, that it starts insidiously and is slowly progressive and is associated with other neurodegenerative diseases. Pathological studies have demonstrated loss of Purkinje cells of the cerebellum, cerebellar cortical sclerosis and proliferation of Bergmann glia.[21],[22] The exact etiology is not known, however electrophysiological studies have shown that ET is caused by a central oscillator. ET disappears with lesions of the thalamus and cerebellum suggesting the location of the central oscillator.[23],[24],[25] Some experimental data have suggested olivocerebellar system as the site of central oscillator.[26],[27],[28],[29] Evidence suggests that ET is associated with abnormal functioning of the inhibitory neurotransmitter GABA.[30],[31] Hence, there are three hypotheses that has been proposed to explain the generation of tremors. These include the GABA hypothesis, cerebellar degeneration hypothesis and oscillating network hypothesis.[6] There are many criteria for the diagnosis of ET among which the Tremor Investigation Group criteria (TRIG) and Movement Disorder Society Consensus criteria are the ones most useful. ET should be differentiated from PD tremor and enhanced physiological tremor. Asymmetric onset of tremors with associated features such as rigidity, bradykinesia and postural instability suggests the presence of PD tremor. The frequency of enhanced physiological tremor is usually greater than ET. Electrophysiological studies have shown almost simultaneous bursts of muscle activity in both the agonist and antagonist muscles (co-activation) [Figure 1]. In patients with low frequency tremor, alternating patterns of muscle activity are seen, similar to the ones seen in PD tremor. In ET, the tremor frequency does not reduce on weight loading, whereas in enhanced physiological tremor, the tremor frequency reduces with weight loading of the limb.
Treatment can be offered on an intermittent/as-needed basis and a regular basis. Intermittent treatment is recommended when the patient is symptomatic only in social gatherings or prior to an important social activity.[32] Propranolol 20mg about 30 minutes to 1 hour prior to the social encounter has been found to be effective. Although the routine use of alcohol is not recommended, in patients with alcohol responsive tremors, the judicial use of a small amount of alcohol prior to select social activities, such as a social dinner, can be considered.[32] Long term therapy is indicated for patients who have distressing symptoms that are persistent most of the times. Propranolol and primidone are the initial drugs of choice. Propranolol should be started at 10mg once a day and gradually increased up to a maximum of 120-240mg/day in divided doses. Primidone is started if there is no response to propranolol, with a starting dose of 12.5mg/day and increased up to 750 mg/day. Other drugs such as clonazepam, gabapentin, topiramate, zonisamide have been found to be effective. In medically refractory cases, botulinum toxin injections can be useful when administered in carefully selected muscles and improvement has been observed in hand, head and voice tremors.[33],[34],[35] Surgical treatment in the presence of ET is reserved for those selected patients who have severe tremor not adequately controlled by medical therapy. Contralateral thalamotomy (Vim nucleus) or deep brain stimulation (DBS) of the thalamus are highly effective in reducing the tremor.[36] Bilateral thalamotomy is not recommended due to its adverse side effects. Unilateral thalamotomy contralateral to the most severely affected side is recommended for patients who cannot afford the DBS procedure.[32] Parkinson's disease tremor Parkinson's disease (PD) is one of the most common neurodegenerative diseases and tremor is one of the cardinal symptoms. The typical PD tremor occurs at rest, is asymmetric in onset, with a frequency of 4 - 6Hz, classically described as the “pill rolling tremor” and seen in distal part of the limbs.[37] The tremor usually manifests in the hand and fingers as with flexion-extension, pronation-supination or oscillatory movements of the hand and forearm. In the leg, the tremors manifest as flexion-extension movement at the ankle. Asymmetric rest tremors seen in the leg are almost always due to PD unless proved otherwise. The tremors markedly increase in amplitude during situations that are stressful or require concentration.[38] In addition to the tremors of the upper or lower limbs, these patients can also have tremors of the lips and lower jaw. The tremor can reappear with almost the same frequency as rest tremor after a delay of 2 or more seconds once the limb has assumed a new posture (action tremor). This is termed as re-emergent tremor.[39] It is an interesting phenomenon as it represents suppression of the tremor on voluntary activity. Re-emergent tremor is not seen in ET. In some PD patients, isolated postural and kinetic tremors are observed. The frequency of these tremors may vary between 5-10 Hz. Postural tremors are more frequent in the akinetic rigid variant of PD. Some authors believe that kinetic (intention) tremor in PD may be a variant of ET or enhanced physiological tremor.[40] In ET, the tremor usually involves the upper limbs, whereas in PD, the tremor can involve both upper and lower limbs. The tremor in PD is asymmetric and associated with rigidity, bradykinesia which is not seen in ET. There is micrographia in PD patients, whereas in ET, there is tremulousness while writing. PD patients sometimes complain of “internal tremors” that are not visible externally. Pathological studies have demonstrated that patients with tremor dominant PD have more neuronal loss in the retrorubral area of the midbrain as compared to those with non-tremor PD. The latter patients have more cell loss in the substantia nigra pars compacta and locus ceruleus.[41],[42] Loss of dopaminergic neurons of the retrorubral area cause dysfunction of the globus pallidus with depletion of dopamine within the striatum.[42] Abnormalities in the serotonergic system have also been observed with reduced serotonin transporters in the thalamus.[43] These neurotransmitter abnormalities have been hypothesized in the generation of tremor. Intraoperative and other electrophysiological studies have shown that the firing patterns of the VLp neurons of the thalamus are highly synchronous with the tremor rather than that of the striatum, supporting the role of the cerebello-thalamo-cortical circuit in the generation of the tremor.[44] However, some authors believe that the tremor is triggered in the GPi and is maintained or amplified in the cerebello-thalamo-cortical circuit (Dimmer switch hypothesis).[6] Electrophysiologically, the duration of EMG bursts is 50-100 msec with an alternating pattern of contraction of the agonist and antagonist muscles, with no effect on the tremor status following weight loading suggesting the presence of a central oscillator [Figure 2].
Tremor in PD is often more difficult to treat than rigidity and bradykinesia.[45] It is less responsive to dopaminergic therapy as the extent of dopamine deficiency is less in tremor predominant PD when compared to non-tremor PD. Moreover, the degree of disease progression and dopamine deficiency correlate well with rigidity and bradykinesia but not with tremor. Levodopa (LD) alleviates tremor in some PD patients but to a lesser extent. Dopamine agonists have not been found to be superior to LD in reducing tremors. Nevertheless, LD significantly improves the motor symptoms of PD and is the drug of choice. In younger patients, dopamine agonists may be tried. Other treatment options for the treatment of tremor include anticholinergic agents (trihexypheidyl, benzhexol), β-blocker (propranolol) and DBS. Anticholinergic drugs were formerly used with the rationale that these medicines would neutralize the presence of a relative excess of acetylcholine in the striatum subsequent to dopaminergic deficiency, and thus, may restore the balance. These drugs can be used for younger patients and should be avoided in the elderly population due to its side effects. β-blockers improve tremors marginally but in a Cochrane review, they were not found to be beneficial and also, they were often found to be causing bradykinesia.[46] DBS of the STN or Vim nucleus of the thalamus have been found to be effective in treating the tremor.[47],[48] Orthostatic tremor Orthostatic tremor (OT), also known as “shaky leg syndrome”, is a rare syndrome and was first coined by Heilman.[49] The patients suffering from OTs usually report a feeling of unsteadiness on standing but not while sitting or lying down. OT is characterized by high frequency tremor of the legs (13-18 Hz) that appears on standing and is relieved by sitting, walking or leaning against a wall. OT can be idiopathic without any associated features (primary OT) in about 75% of patients; and, about 25% have additional neurological features (OT plus) such as PD, cerebellar degeneration, restless leg syndrome, peripheral neuropathy, head injury and aqueduct stenosis.[50],[51],[52] In majority of the patients, the onset of OT occurs above the age of 60 years; however, the age range for the occurrence of these tremors is 13-85 years. [53,54] Primary OT affects female patients slightly more frequently than the males ones. Idiopathic OT is a progressive disorder, and with time, the symptoms increase. This fact has been confirmed objectively.[55] In more advanced stages, the patients may demonstrate features of cerebellar involvement in the form of impaired tandem gait. Some patients, in addition, demonstrate tremors of the hands, head and trunk.[56] Primary OTs have been classified into those with and without postural tremors.[54] The association of postural tremors of the hand with OT has been estimated to be between 77.4% and 92.3%.[54],[56] The postural tremor is indistinguishable from ET and has a frequency of 5-10 Hz. Clinical examination reveals a rapid tremor of the legs on standing. These tremors are best appreciated by palpation of leg muscles (gastrocnemius or quadriceps) rather than being seen visually. Sometimes, auscultation using a stethoscope of the calf muscles reveals a characteristic sound of distant rotor blades of a helicopter.[57] Surface EMG recordings reveals rhythmic activation of lower limb muscles on standing, with frequencies between 13 and 18 Hz. This rhythmic activity disappears when the patient walks or sits. Frequencies less than 13 Hz have also been observed associated with other clinical features that are supportive of OTs and these types of tremors have been termed as slow OTs [Figure 3]. Slow OTs have been associated with familial essential tremor, multiple sclerosis, Graves' disease, PD and parkinsonism.
Orthostatic myoclonus is one of the important differential diagnoses. It is characterized by unsteadiness and jerky movements of the leg muscles on assuming an upright posture. EMG shows short duration bursts that are nonrhythmic and irregular. There is evidence to suggest that there is a central oscillator that includes the cerebellum-brainstem-thalamic pathways in the generation of OT.[58],[59],[60] Unilateral transcranial magnetic stimulation of the leg area also resets OTs in both the legs suggesting the presence of a supraspinal oscillator.[61] The tremor frequency shows a strong coherence between the muscles of leg and arm pointing to a central oscillator. OT has also been considered as a progressive neurodegenerative condition as some patients who initially presented with isolated OT subsequently develop PD.[54],[62] As it is a rare disorder, there is inadequate data on the pharamacotherapy. Alcohol and propranolol do not have any effect in OT.[50] Clonazepam is the first line medication that can be started at 0.5mg in the night and gradually increased up to 2mg three times per day.[63] The other second line drugs that can be used are gabapentin, primidone, valproic acid and carbamazepine.[52],[64],[65] Bilateral Vim thalamic nucleus stimulation has been shown to improve the symptoms in some patients with medication-resistant OT.[53],[66] Deep brain stimulation of the Vim nucleus has been found to be safe and well tolerated, yielding sustained benefit in selected patients with medically refractory orthostatic tremor.[67] Tremor in dystonia The association between tremor and dystonia is known for more than 100 years.[68] It has been observed that primary dystonias can present with pure action tremors.[69] In some conditions, the dystonia is very mild and the abnormal posturing is often overlooked as a compensatory phenomenon.[69],[70] Dystonic tremor (DT) can occur at rest, in sustained postures, as well as during voluntary movements, and can also be focal and task specific.[69],[71] Focal and segmental dystonias are often associated with tremors that appear like ETs. Using a multichannel EMG, it was shown that patients with dystonia had phasic muscle contractions.[72] These long duration bursts of muscle activity occur at a frequency of 1.0-6.5 Hz and are irregular [Figure 4].[73] However, sometimes the DT can be rhythmic and can be mistaken for ET. The Consensus Statement of the Movement Disorder Society (MDS) on Tremor has recognized two types of tremor in patients with dystonia: (1) dystonic tremor (tremor in a dystonic body part); and, (2)tremor associated with dystonia (tremor in a body part with no dystonia, but the patient has dystonia elsewhere).[2] There is no clear pathophysiological difference between these two types of tremors. DT is often suppressed by sensory tricks (geste antagoniste) and may exhibit null points (body positions with no tremor), irregular jerky rhythm and amplitude, task or position specificity, persistence at rest, and overflow to neighboring body segments.[73] Medical management includes the use of clonazepam, baclofen, and anticholinergics (trihexyphenidyl). Botulinum toxin injections usually ameliorate dystonia and dystonic tremor, and are accepted as the treatment of choice in medically refractory cases.[37] Vim DBS may be beneficial in medically refractory cases with transient and modest benefit.[74]
Palatal tremor Palatal tremor (PT) is a rare clinical syndrome and is characterized by rhythmic movements of the soft palate with a frequency of 1-3 Hz.[75] Two types of PT are recognized. The term 'essential palatal tremor' (EPT) is used when no cause is identifiable; and, the term 'symptomatic palatal tremor' (SPT) is used when a lesion is found in the brainstem and superior cerebellar peduncle (Guillian Mollarett triangle).[76] The soft palate contraction can be unilateral or bilateral. In EPT, there is an objective complaint of ear click, which is due to the contraction of the tensor veli palatine; and, in SPT, there is contraction of the levator veli palatine.[77] Both these muscles contract the soft palate. Eye movement abnormalities in the form of bilateral vertical nystagmus and asymmetric jerky nystagmoid movements are observed in SPT but not in EPT.[78] Other uncommon symptoms associated with SPT include head or limb tremors, limb myoclonus, dysphonia and breathing difficulty.[79],[80] The exact cause of EPT is not known and even the MRI does not show any abnormality. MRI of the brain in patients with SPT shows olivary hypertrophy.[81] Lesions of the cerebellum or brainstem along the dentato-olivary pathway lead to hypertrophic degeneration of the olivary nucleus. The tremor is thought to be generated by the cells of the inferior olive. The neurons in the olivary nucleus are enlarged with cytoplasmic vacuolation.[82] Hypertrophic olivary degeneration typically develops in about 3 weeks after the appearance of the lesion. [81] Transoral or transnasal endoscopy usually helps in establishing the diagnosis of PT.[75] Psychogenic palatal tremors have been described by some authors.[75] Very few treatment options are available. Phenytoin, carbamazepine and sumatriptan have been useful in some patients.[83] Injection of botulinum toxin in the levator and tensor veli palatini muscles is used in severe cases.[84],[85] Holmes tremor Holmes tremor (HT) was first described by Gordon Holmes in 1904.[86] It is also known as midbrain (mesencephalic), rubral or cerebellar outflow tremor. However, these terms are no longer used as experimental lesions in these areas have failed to induce persistent tremors.[87],[88],[89] These tremors occur at rest and also have an intention component. The tremor frequency is usually 3-4 Hz and often these tremors are not rhythmic.[2] HT usually results due to the disruption of the dentato-rubro-thalamic circuit and also the nigro-striatal circuit and is most often due to stroke, trauma, vascular malformations or tumors.[90] In most of the cases, the imaging is abnormal, but in some cases no lesions can be demonstrated.[91] It has been observed that HT develops between 1 and 24 months after the insult and this delay is thought to be due to neuroplasticity changes.[89] Some researchers believe that a double lesion is required for HT to develop, with lesions involving both the dopaminergic nigrostriatal system and the cerebello-thalamo-cortical or dentato-rubro-olivary pathways.[87] In a study of 29 patients with HT, an MRI brain abnormality was seen in 28 patients. These lesions were mostly vascular in etiology. MRI showed lesions in the thalamus, midbrain or cerebellum in 82.7% of the patients.[92] HT is difficult to treat. EMG shows alternate pattern of agonist and antagonist muscle contractions with long duration bursts of 125-250 msec. Dopaminergic agents and levetiracetam are reported to be beneficial.[93],[94] Drug induced tremor [Table 2]
Drug induced tremor is an important problem encountered in clinical practice. Many drugs have been associated with tremor. Important among them include neuroleptic and dopamine depleting agents (thioridazine, fluphenazine, chlorpromazine, other atypical neuroleptic agents, cinnarizine, flunarizine, tetrabenazine, methyldopa),[95],[96],[97] tricyclic antidepressants (amitriptyline, imipramine),[98],[99] selective serotonin reuptake inhibitors (SSRIs) (fluoxetine),[100] lithium,[101] antiepileptic drugs (valproate, tiagabine, gabapentin, oxcarbazepine, lamotrigine),[102],[103] bronchodilators (salbutamol, salmeterol),[104],[105] antiarrhythmic drugs (amiodarone, mexiletine, procainamide),[106],[107],[108] antimicrobial agents (co-trimoxazole, vidarabine, acyclovir, amphotericin),[109],[110],[111],[112] chemotherapeutic agents (cytarabine, thalidomide, ifosfamide, tamoxifen),[113],[114],[115],[116],[117] drugs of abuse (alcohol, nicotine),[118],[119] gastrointestinal drugs (metoclopramide, cimetidine, misoprostol),[120],[121],[122] immunosuppressants/immunomodulators (cyclosporine, tacrolimus),[123],[124] hormones (levothyroxine, medroxyprogesterone acetate),[125],[126] methylxanthines (caffeine, aminophylline), etc.[127] There are multiple risk factors associated with drug induced tremor such as old age, underlying medical illness (renal failure, liver failure), polypharmacy with drug interactions, structural brain lesions, and mood disorders.[128] A temporal association with the start of pharmacotherapy and onset of tremor is useful in establishing the diagnosis of drug-induced tremor. Most of the drugs cause postural tremor, although many drugs can also cause resting and intention tremors. In majority of the cases, the tremor disappears after stopping the drug. For drug induced parkinsonism with rest tremors, anticholinergic agents such as trihexyphenidyl can be considered.[129] In case of drug induced postural tremors, propranolol may be tried. Acetazolamide and propranolol are useful in valproate induced tremors, whereas primidone and propranolol are useful in lithium induced tremors.[130],[131] Tetrabenazine may be used for neuroleptic induced tardive tremor.[132] Task specific tremor Task-specific tremors are observed during specific activities.[2] Primary writing tremor (PWT) is the most common form. It was initially described by Rothwell in 1979.[133] There are two types of PWTs: Type A and B. Type A is task specific and the tremor is induced by writing, whereas type B tremor appears when the arm is held in the position of writing (position specific). It is a specific action tremor in which pronation of the forearm elicits a pronation/supination tremor during writing that is not seen during the other arm movements.[134] It is still a matter of debate whether PWT represents a type of focal dystonia or a variant of ET.[134],[135] PWT may occur sporadically or may be inherited as an autosomal dominant trait, and in one study, about 33% patients had a family history of PWT.[135] It is generally regarded as non-progressive as many patients have this condition for decades without manifesting any symptoms or remissions.[134] PWT is different from writer's cramp as shown by electrophysiological studies. It was observed that there is an excessive overflow of electromyogram (EMG) activity in the proximal musculature of writer's cramp patients, whereas this overflow of EMG activity is not observed in patients with PWT.[136],[137] The reciprocal inhibition elicited by ipsilateral radial nerve stimulation between 5 and 50 ms before the median nerve, occurred within the normal time in PWT, whereas in the writer's cramp, this phenomenon was diminished.[138] The typical frequency of PWT is 5-6 Hz with alternating pattern or synchronous EMG bursts of 100 msec [Figure 5]. Other task specific tremors includes the primary bowing tremor (PBT) seen in bowed string instrumentalists.[139],[140] Pharmacological therapy includes propranolol, primidone, trihexyphenidyl and botulinum toxin.[134],[141]
Neuropathic tremor Tremor developing in association with neuropathy is termed as neuropathic tremor.[75] It can be seen in a variety of peripheral neuropathies: Charcot-Marie Tooth (CMT) disease, inflammatory neuropathies such as IgM-monoclonal gammopathy of undetermined significance (IgM-MGUS), chronic inflammatory demyelinating neuropathy (CIDP), multifocal motor neuropathy with conduction block (MMNCB), and recovering Guillian Barre syndrome.[142],[143],[144] The characteristic features are that they are postural or action tremors with a frequency of 3-6 Hz and predominantly involve the upper limbs.[145] Nerve conduction studies usually demonstrate demyelinating neuropathy with slowing of conduction velocity.[146] Electrophysiological studies have demonstrated that the tremor frequency in the hand muscles is lower than that seen in the proximal arm muscles, suggesting a peripheral mechanism.[147] The exact mechanism involved in the generation of tremor is not known. Initially, some authors believed that tremor associated with peripheral neuropathy may be due to enhancement of the physiologic tremor by minimal weakness.[146] Subsequently, it was proposed that there is an altered proprioceptive feedback due to the neuropathy with abnormal central processing.[75] Recently studies have shown the role of central oscillators in the thalamo-cortical networks as the generators of tremors.[148] In most of the patients, the tremors are mild; in some patients, however, they can be severe enough to require surgery. Medical management of symptomatic patients is with propranolol, primidone or pregabalin.[143],[147] Vim DBS has also been shown to be effective in reducing the tremor.[148] Cerebellar tremor These are irregular, often of a high amplitude, postural and action tremors.[4] Rest tremors are not seen. They are predominantly intention tremors and have a tremor frequency of less than 5 Hz (3-5 Hz). Tremors can be seen in the head, trunk and extremities. The tremor frequencies also vary with the part of the body being affected. The tremor frequency in the upper extremities ranges from 3-8 Hz, and in the lower extremities it ranges from 1-3 Hz; and, the frequency is 2 - 4 Hz for the truncal tremors.[4] Involvement of the deep cerebellar nuclei, cerebellar outflow tracts and the cerebro-cerebellar loops has been postulated in the tremor production.[4],[75] The common causes of cerebellar tremor include posterior circulation stroke, degenerative diseases (spinocerebellar ataxias, ataxia telengectasia, Friedreich's ataxia etc.), Wilson's disease, multiple sclerosis, drugs (antiepileptic agents, alcohol), posterior fossa tumors and infective or post infective cerebellar diseases. EMG reveals a long duration burst of muscle activity in an alternating pattern. Management includes treatment of the underlying cause. Propranolol, clonazepam, carbamazepine, and topiramate have been found to be effective.[149] However there is no established therapy till date. Psychogenic tremor Tremor is the commonest manifestation of psychogenic movement disorders and affects up to 55% of the patients.[150],[151] Women are more frequently affected.[151],[152] Tremor can affect any part of the body but is commonly observed in the hands and legs.[152] The characteristic features that help in distinguishing them from organic tremors include their abrupt onset, changing combinations of rest and postural tremors, presence of distractability, suggestibility and entrainability, multiple associated somatisations and spontaneous remissions.[152],[153],[154] Electrophysiological studies are helpful in making the diagnosis [Figure 6].[152] Psychogenic palatal tremor has also been described in the literature. The underlying mechanism is largely unknown; two possible mechanisms have been suggested: coherent oscillations between both the affected limbs, and independent oscillators, suggestive of a clonus mechanism.[155] Another clinical feature described is the coactivation sign that is elicited by passively moving the affected limb and assessing the co-contraction of the antagonist muscle.[154]
The characteristics and therapeutic options of the different tremor syndromes is summarized in [Table 3] and [Table 4].
Tremors are the most common phenomenology seen in movement disorders clinic. A comprehensive knowledge of the various tremor syndromes helps in guiding appropriate management. Electrophysiological methods are valuable in the characterization of tremors. In addition to the pharmacological therapy including botulinum toxin therapy, surgical therapies in form of DBS or lesional surgeries are beneficial in reducing the symptoms. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4]
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