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Management of Tremor
 

Management of Tremor

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This presentation was made from Vinken and Bruyn's Handbook of Clinical Neurology, Marsden's Book of Movement Disorder, Movement Disorder Society

This presentation was made from Vinken and Bruyn's Handbook of Clinical Neurology, Marsden's Book of Movement Disorder, Movement Disorder Society

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  • Stanly Fan, VB
  • PathophysiologyThere is a poor correlation between tremor and nigrostriataldopaminergic deficit in PD (8,9).  Considerable evidence exists to suggest that a central oscillator is involved in the generation of tremor (5). The central oscillator involved in generation of PD rest tremor may potentially be located in the thalamus, cerebellum, globuspallidus, or subthalamic nucleus (5,10) and the presence or severity of tremor in PD may be related to the loss of particular subgroups of mesencephalic neurons (8,11).A midbrain lesion near the red nucleus can involve the nigrostriatal pathway in addition to cerebellar outflow tracts and cause a tremor at rest as well as an action tremor, known as a Holmes, or rubral, tremor. (5)
  • TreatmentIn PD, rest tremor can be treated most effectively with dopaminergic medications such as levodopa, dopamine agonists, and MAO-B inhibitors, and anticholinergics (5,12).  At least 50% of patients experience a reduction in tremor with levodopa (13).  Amantadine (14), clozapine (15,16), propranolol (17) and mirtazapine (18) have also been used with some success (12).  Botulinum toxin has been found to effective for some patients with PD hand tremor (19,20) and jaw tremor (21).  The subthalamic nucleus is the most common surgical target for medically refractory PD-related tremor (8) but lesioning or deep brain stimulation of the thalamic nucleus ventralis intermedius can also be performed. A lack of major benefit has been observed with gamma knife thalamotomy (22).ReferencesDeuschl G, Bain P, Brin M.  Consensus statement of the Movement Disorder Society on tremor.  Ad Hoc Scientific Committee.  MovDisord.  1998;13(Suppl 3):2-23.Puschmann A and ZK Wszolek.  Diagnosis and treatment of common forms of tremor.  Semin Neurol.  2011 Feb;31(1):65-77.Elble RJ, Koller WC.  The definition and classification of tremor.  In: Tremor.  Eds.  The Johns Hopkins University Press, Baltimore and London, 1990:1-9.Findley LJ, Koller WC.  Definitions and behavioural classifications.  In Handbook of tremor disorders.  Eds: Findley LJ, Koller WC.  Marcel Dekker Inc, New York, 1995:371-385.Fahn S, Jankovic J, Hallett M (Eds).  Tremors: diagnosis and treatment.  In: Principles and Practice of Movement Disorders, 2ndedition.  Saunders, New York, 2011;389-414.Alty JE, Kempster PA.  A practical guide to the differential diagnosis of tremor.  Postgrad Med J.  Published online June 20, 2011.Lang AE, Zadikoff C.  Parkinsonian Tremor.  In: Handbook of Essential Tremor and Other Tremor Disorders.  Eds: Lyons KE, Pahwa R. Taylor & Francis Group, Boca Raton, 2005:227-41.Dalvi A, Premkumar A.  Tremor: Etiology, phenomenology, and clinical features.  Dis Mon. 2011;57:109-126.Vingerhoets FJ, Schulzer M, Calne DB, Snow BJ.  Which clinical signs of Parkinson’s disease best reflects the nigrostriatal lesion? J Neural Transm Suppl.  1999;56:1-29.Bergman H, Deuschl G.  Pathophysiology of Parkinson’s disease: from clinical neurology to basic neuroscience and back.  MovDisord.  2002;17(Suppl 3):S28-40.Paulus W, Jellinger K.  The neuropathologic basis of different clinical subgroups of Parkinson’s disease.  J neuropathol Exp Neurol.  1991;50:743-55.Marjama-Lyons J, Koller W.  Tremor-predominant Parkinson’s disease: approaches to treatment.  Drugs Aging.  2000;16(4):273-8.Koller WC.  Pharmacologic treatment of parkinsonian tremor.  Arch Neurol.  1986;43:126-7.Fahn S, Isgreen W.  Long term evaluation of amantadine and levodopa combination in parkinsonism by double-blind crossover analyses.  Neurology.  1985;25:603-6.Thomas AA, Friedman JH.  Current use of clozapine in Parkinson disease and related disorders.  ClinNeuropharmacol.  2010 Jan-Feb;33(1):14-6.Bonuccelli U, Cerevolo R, Salvetti S, D’Avino C, Del Dotto P, Rossi G, Murri L.  Clozapine in Parkinson’s disease tremor.  Effects of acute and chronic administration.  Neurology.  1997;49(6):1587-90.Koller WC, Herbster G.  Adjuvant therapy of parkinsonian tremor.  Arch Neurol.  1987;44:921-3.Pact V, Giduz T.  Mirtazapine treats resting tremor, essential tremor, and levodopa-induced dyskinesias.  Neurology.  1999;53(5):1154.Pullman SC, Greene P, Pahn S et al. Approach to the treatment of limb disorders with botulinum toxin A: experience with 187 patients. Arch. Neurol. 53, 617-624 (1996).Sheffield JK, Jankovic J.  Botulinum toxin in the treatment of tremors, dystonias, sialorrhea and other symptoms associated with Parkinson’s disease.  Expert Rev Neurother.  2007;7(6):637-47.Schneider SA, Edwards MJ, Cordivari C, Macleod WN, Bhatia KP. Botulinum toxin A may be efficacious as treatment for jaw tremor in Parkinson's disease. Mov. Disord. 21(10), 1722-1724 (2006).Lim S, Hodaie M, Fallis M, Poon Y, Mazzella F, Moro E.  Gamma knife thalamotomy for disabling tremor: a blinded evaluation.  Arch Neurol.  2010;67(5):584-8.
  • PathophysiologyPhysiologic tremor has a mechanical-reflex component, described as passive mechanical oscillation due to underdampened inertial, viscous, and elastic properties of the limbs and other body parts, as well as a smaller 8-12 Hz component associated with modulation of motor unit activity (15).  In enhanced physiologic tremor there is participation of the stretch reflex pathways as the response of this pathway to oscillation increases in times of stress and with certain medications (15).
  • The most common causes of postural tremor are physiologic tremor, essential tremor (ET), and drug-induced tremor, which is a type of enhanced physiologic tremor that can result from the use of numerous medications including beta-agonists, dopaminergic drugs, stimulants, valproic acid, carbamazepine, verapamil, epinephrine, psychiatric drugs, methylxanthines (coffee, tea), cyclosporine, interferon, and flunarizine.(5-7)  Other enhanced physiologic tremor etiologies include stress, endocrine disturbance (eg. hypoglycemia, thyrotoxicosis, pheochromocytoma, adrenocorticosteroids), and toxin use (mercury, lead, alcohol withdrawal). 
  • Postural tremor can also be associated with other neurological conditions such as dystonia, parkinsonism, myoclonus, Kennedy syndrome, and other neuropathic conditions including Roussy-Levy syndrome. (5)  Parkinson’s disease as well as other Parkinsonian syndromes may have a postural component, known as a reemergent tremor, and postural tremor may also be due to a midbrain lesion or cerebellar dysfunction (titubation) (5).  Postural tremor may also be psychogenic. 
  • Essential TremorEssential tremor (ET) is a chronic progressive neurological disease that features postural and action tremor of the arms. The term was first used by European physicians towards the end of the nineteenth century to describe an inherited, constitutional malady characterized by kinetic tremor in the absence of other neurological signs.1     ET is among the most prevalent movement disorders; a meta-analysis of 28 population-based prevalence studies indicated a prevalence across all ages of 0.9%.2 Prevalence increases markedly with age, and especially with advanced age; in some studies, the prevalence among persons aged >95 years was >20%.2 On an etiological level, both environmental (toxic) 3 and genetic factors4 are currently under investigation, although no susceptibility genes have yet been identified.Clinical Features of Essential TremorET is the most common form of pathological postural tremor (8).  It can be hereditary or sporadic and has a bimodal age at onset (5).  Postural and action tremor may be mistaken as ET, but is actually Fragile X-associated tremor/ataxia syndrome.  Careful examination for cerebellar features and gait disturbance in addtion to corroborating family history are required.  The frequency of ET varies widely, from 4-12 Hz, and has an inverse relationship with amplitude.  It typically involves an adduction-abduction movement of the fingers and flexion-extension movement of the hands (14), and tends to start unilaterally but affects both sides over time.  The tongue, head, or voice can be solely affected but tend to occur with hand tremor, and the legs and trunk are infrequently involved (14). ET often also has a kinetic component and severe ET may occur at rest as well.Kinetic arm tremor (i.e., tremor that occurs during voluntary movement) is a common feature of ET. This tremor is usually slightly asymmetric and may be apparent during a broad range of daily activities (e.g., writing, pouring, and eating). Patients may also have postural tremor (e.g., arms outstretched in front of body), though the amplitude of kinetic tremor exceeds that of postural tremor5 and the converse pattern should raise a diagnostic red flag. In approximately one-half of ET patients, the kinetic tremor may have an intentional component as well (i.e., during finger-nose-finger maneuver, tremor terminally worsens when approaching the target).6 The amplitude of the kinetic tremor increases over time, with recent estimates indicating a median annual increase of  ~2.0%.7 Studies have shown that more than 90% of ET patients who come to medical attention report disability 8 and severely-affected end-stage patients are physically unable to feed or dress themselves.9Tremor may additionally involve other body regions. Most common among these is head tremor, which more typically is a side-to-side (”no-no”) tremor, and is particularly prevalent among women with ET.10 Jaw and voice tremors are also common in ET.11 A characteristic feature of ET is the somatotopic spread of tremor over time such that head tremor typically evolves several years after the onset of arm tremor, and the converse pattern raises another diagnostic red flag.9Patients with ET can also develop a tremor at rest without other features of Parkinson’s disease.12   Aside from tremors, a variety of additional (i.e., accessory) motor features have been described in patients with ET and these features all point towards an underlying abnormality of the cerebellum or of the cerebellar system. The most clinically-evident of these features is gait ataxia, which is generally but not always mild.10, 13
  • The origin of essential tremor is unknown.  A centrally-located oscillator has been suggested by electrophysiologic studies and the inferior olive and cerebellum have been implicated by positron electron topography studies (16).      
  • Numerous studies have now demonstrated mild cognitive differences between ET patients and controls, 14 indicating that this is a disease characterized not only by motor but also by non-motor features. The clinical import of these cognitive deficits is not entirely clear, although, studies now indicate that these cognitive features are not without clinical correlates.15 A broad array of neuroimaging studies (functional magnetic resonance imaging, positron emission tomography, [1H] magnetic resonance spectroscopic imaging, diffusion tensor imaging, voxel based morphometry) now indicate the presence not only of functional and metabolic abnormalities in the ET cerebellum, but of structural abnormalities in both the cerebellar gray and white matter.16 In postmortem studies, the degenerative changes in ET are thus far all localized to the cerebellum itself (esp. to Purkinje cells) or to a set of brainstem neurons that synapse directly with Purkinje cells,16 further reinforcing the notion that the disease seems to be one that is centered in the cerebellum and its fiber tracts.Propranolol, which is a nonselective β-adrenergic receptor antagonist, and primidone, an anticonvulsant, remain the two standard treatments for ET. Studies show that a limited number of other agents, including topiramate, gabapentin and several other β-adrenergic receptor antagonists are also beneficial. Surgical interventions, such as thalamic deep brain stimulation, play a role when pharmacological treatment is not satisfactory. References essential tremorLouis ED, Broussolle E, Goetz CG, Krack P, Kaufmann P, Mazzoni P. Historical underpinnings of the term essential tremor in the late 19th century. Neurology 2008;71(11):856-859.Louis ED, Ferreira JJ. How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor. Mov Disord;25(5):534-541.Louis ED. Environmental epidemiology of essential tremor. Neuroepidemiology 2008;31(3):139-149.Deng H, Le W, Jankovic J. Genetics of essential tremor. Brain 2007;130(Pt 6):1456-1464.Brennan KC, Jurewicz EC, Ford B, Pullman SL, Louis ED. Is essential tremor predominantly a kinetic or a postural tremor? A clinical and electrophysiological study. MovDisord 2002;17(2):313-316.Deuschl G, Wenzelburger R, Loffler K, Raethjen J, Stolze H. Essential tremor and cerebellar dysfunction clinical and kinematic analysis of intention tremor. Brain 2000;123 ( Pt 8):1568-1580.Louis ED AA, Gillman A, Gerbin M, Viner AS. Estimating annual rate of decline: Prospective, longitudinal data on arm tremor severity in two groups of essential tremor cases. J Neurology Neurosurg Psychiatry 2010 (in Press).Louis ED, Barnes L, Albert SM, et al. Correlates of functional disability in essential tremor. MovDisord 2001;16(5):914-920.Critchley M. Observations of essential (heredofamilial) tremor. Brain 1949;72:113-139.Hubble JP, Busenbark KL, Pahwa R, Lyons K, Koller WC. Clinical expression of essential tremor: effects of gender and age. MovDisord 1997;12(6):969-972.Louis ED, Rios E, Applegate LM, Hernandez NC, Andrews HF. Jaw tremor: prevalence and clinical correlates in three essential tremor case samples. MovDisord 2006;21(11):1872-1878.Rajput AH, Rozdilsky B, Ang L, Rajput A. Significance of parkinsonian manifestations in essential tremor. Can J NeurolSci 1993;20(2):114-117.Stolze H, Petersen G, Raethjen J, Wenzelburger R, Deuschl G. The gait disorder of advanced essential tremor. Brain 2001;124(Pt 11):2278-2286.Benito-Leon J, Louis ED, Bermejo-Pareja F. Population-based case-control study of cognitive function in essential tremor. Neurology 2006;66(1):69-74.Louis ED. Functional correlates of lower cognitive test scores in essential tremor. Mov Disord;25(4):481-485.Louis ED. Essential tremor: evolving clinicopathological concepts in an era of intensive post-mortem enquiry. Lancet Neurol;9(6):613-622.Treatment postural tremorTreatment of postural tremor may involve discontinuing a culprit medication or treating an underlying metabolic condition if an enhanced physiologic tremor is diagnosed.  A practice parameter for treatment of ET has been published by the American Academy of Neurology (17).  Propranolol (160-320 mg/d, starting dose 20-80 mg/d) and primidone (250-750 mg/d, starting dose 25mg/d) have been shown to have equivalent efficacy for limb tremor and a combination of both may be more effective than each one alone (18,19).  Gabapentin, topiramate, alternative beta-blockers, and benzodiazepines may also be helpful (5,20) and botulinum toxin has shown benefit for essential hand tremor (21) as well as vocal (22) and head tremor (23).  Alcohol has a beneficial effect for treatment of ET but its use is limited by the short duration of response, potential for tolerance, and risk of alcoholism (20,24).  Finally, stereotactic surgery including deep brain stimulation of the thalamic nucleus ventralis intermedius (Vim) and Vim thalalmotomy for medically intractable moderate to severe ET may reduce tremor by up to 90%.  There is currently insufficient evidence to recommend gamma knife thalamotomy as a treatment for ET (25).References postural tremorDeuschl G, Bain P, Brin M.  Consensus statement of the Movement Disorder Society on tremor.  Ad Hoc Scientific Committee.  MovDisord.  1998;13(Suppl 3):2-23.Puschmann A and ZK Wszolek.  Diagnosis and treatment of common forms of tremor.  Semin Neurol.  2011 Feb;31(1):65-77.Elble RJ, Koller WC.  The definition and classification of tremor.  In: Tremor.  Eds.  The Johns Hopkins University Press, Baltimore and London, 1990:1-9.Findley LJ, Koller WC.  Definitions and behavioural classifications.  In Handbook of tremor disorders.  Eds: Findley LJ, Koller WC.  Marcel Dekker Inc, New York, 1995:371-385.Fahn S, Jankovic J (Eds).  Tremors: diagnosis and treatment.  In: Principles and Practice of Movement Disorders, 2nd edition.  Saunders, New York. 2007;389-414.Alty JE, Kempster PA.  A practical guide to the differential diagnosis of tremor.  Postgrad Med J.  Published online June 20, 2011.Crawford P, Zimmerman EE.  Differentiation and diagnosis of tremor.  Am Fam Physician. 2011;83(6):697-702.Dalvi A, Premkumar A.  Tremor: etiology, phenomenology, and clinical features.  Dis Mon.  2011;57:109-26.Lou JS, Jankovic J.  Essential tremor: clinical correlates in 350 patients.  Neurology.  1991;41:234-8.Elble RJ, Koller WC.  Tremor.  The Johns Hopkins University Press, Baltimore.Sanes JN, Hallett M.  Limb positioning and magnitude of essential tremor and other pathological tremors.  MovDisord.  1990;5(4):304-9.Leehey MA. Fragile X-associated tremor/ataxia syndrome: clinical phenotype, diagnosis, and treatment.  J Investig Med.  2009;57:830-6.Louis ED, Faust PL, Vonsattel JP, . Neuropathological changes in essential tremor: 33 cases compared with 21 controls.  Brain.  2007;130:3297-307.Koller WC and Busenbark KL.  Essential tremor.  In: Movement Disorders: Neurologic Principles and Practice.  Eds: Watts RL, Koller WC. McGraw-Hill. New York:365-85.Elble RJ.  The pathophysiology of tremor.  In: Neurologic Disorders: Principles and Practice.  McGraw-Hill, New York, 2004:481-493.Deuschl G, Elble RJ.  The pathophysiology of essential tremor.  Neurology.  2000;54(11):S14-20.Zesiewicz TA, Elble R, Louis ED, Hauser RA, Sullivan KL, Dewey Jr RB, Ondo WG, Gronseth GS, Weiner WJ.  Practice parameter: therapies for essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology.  Neurology.  2005;64:2008-20.Gorman WP, Cooper R, Pocock P, Campbell MJ.  A comparison of primidone, propranolol, and placebo in essential tremor, using quantitative analysis.  JNNP.  1986;49:64-8.Koller WC, Royse VL.  Efficacy of primidone in essential tremor.  Neurology. 1986;36:121-4.Dalvi A.  Medical treatment of tremor.  Dis Mon.  2011;57:135-141.Brin MF, Lyons KE, Doucette J, Adler CH, Caviness JN, Comella CL, Dubinsky RM, Friedman JH, Manyam BV, Matsumoto JY, Pullman SL, Rajput AH, Sethi KD, Tanner C, Koller WC.  A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor.  Neurology.  2001;56:1523-8.Pahwa R, Busenbark K, Swanson HE, et al. Botulinum toxin treatment of essential head tremor. Neurology 1995;45: 822-824.Kendall KA, Leonard RJ.  Interarytenoid muscle botox injection for treatment of adductor spasmodic dysphonia with vocal tremor.  J Voice.  2011;25(1):114-9.Schroeder D, Nasrallah HA.  High alcoholism rate in patients with essential tremor.  Am J Psychiatry.  1982;139:1471-3.Deuschl G, Raethjen J, Hellriegel H, Elble R.  Treatment of patients with essential tremor.  Lancet Neurol.  2011;10:148-61.
  • Clinical Features of Kinetic TremorKinetic tremor is typically proximal but can be distal (9).  It tends to be irregular with high amplitude and low frequency.  The frequency of kinetic tremor is commonly reported as 3-5 Hz (10) but it may range between 3-8 Hz in the arms and is usually 3 Hz in the legs (11).  It is often called an intention tremor since the tremor usually increases as the tremulous limb approaches a visually-guided target (8).  The axis of the tremor depends upon limb position and the movement executed (11), usually perpendicular to the direction of movement (5).
  • PathophysiologyCerebellar kinetic tremor may be due to dysfunction of cerebellar-based motor control affecting multiple oscillatory mechanisms, which include mechanical oscillation of joints and their muscles, stretch reflex oscillations through afferent muscle spindle pathways to the brain, and centrally-located oscillatory neuronal groups (5).  Cerebellar tremor tends to occur ipsilateral to a lesion of the deep cerebellar nuclei or outflow tracts through the superior cerebellar peduncle (5).  It is likely injury to these outflow tracts through the midbrain that cause the kinetic component of a Holmes, or rubral, tremor.
  • TreatmentTreatment of kinetic tremor is often unsuccessful or suboptimal.  Removal of the underlying cause by cessation of a culprit substance or management of a tumor or abscess can lead to tremor improvement or resolution.  Behavioral modifications may help to dampen kinetic tremor.  For example, significant functional improvement has been demonstrated when wrists weights were used by patients with kinetic tremor while eating (12).  No drugs have been shown to reduce cerebellar kinetic tremor satisfactorily and reproducibly (6).  Small trials have indicated that carbamazepine may reduce tremor amplitude (13) and that levetiracetam may be effective (14).  Propranolol use has had varying results (15,16) and treatment with primidone in two patients with multiple sclerosis showed a reduction in cerebellar tremor with improved hand control (17).  Evidence for isoniazid has been mixed (5) and its side effect profile may limit its use.  An open trial of Glutethimide showed improvement in kinetic tremor due to multiple sclerosis and traumatic brain injury (18).  Benzodiazepines and baclofen have both been reported to elicit an improvement in kinetic tremor (19-21) and on open label study of buspirone also showed effectiveness in mild to moderate cerebellar tremor (22).  Botulinum toxin type A has been tried for cerebellar kinetic tremor due to multiple sclerosis and no significant improvement was demonstrated (23).  Patients with cerebellar tremor who underwent thalamotomy or deep brain stimulation of the nucleus ventralis intermedius (Vim) have experienced improvement (5,24,25).ReferencesDeuschl G, Bain P, Brin M.  Consensus statement of the Movement Disorder Society on tremor.  Ad Hoc Scientific Committee.  MovDisord.  1998;13(Suppl 3):2-23.Puschmann A and ZK Wszolek.  Diagnosis and treatment of common forms of tremor.  Semin Neurol.  2011 Feb;31(1):65-77.Elble RJ, Koller WC.  The definition and classification of tremor.  In: Tremor.  Eds.  The Johns Hopkins University Press, Baltimore and London, 1990:1-9.Findley LJ, Koller WC.  Definitions and behavioural classifications.  In Handbook of tremor disorders.  Eds: Findley LJ, Koller WC.  Marcel Dekker Inc, New York, 1995:371-385.Seeberger LC, Hauser RA.  Cerebellar Tremor.  In: Handbook of Essential Tremor and other Tremor Disorders.  Taylor & Francis, Boca Raton, 2005:227-41.Fahn S, Jankovic J, Hallet M (Eds).  Tremors: diagnosis and treatment.  In: Principles and Practice of Movement Disorders.  Saunders, New York, 2011;389-414.Manyam BV.  Uncommon forms of tremor.  In: Movement disorders: neurological principles and practice 2nd Ed.  Eds: Watts RL, Koller WC.  McGraw-Hill, New York, 2004:459-80,Alty JE, Kempster PA.  A practical guide to the differential diagnosis of tremor.  Postgrad Med J.  Published online June 20, 2011.Liu x, Miall RC, Aziz TZ, Palace JA, Stein JF.  Distal versus proximal arm tremor in multiple sclerosis assessed by visually guided tracking tasks.  J NeurolNeurosurg Psychiatry. 1999 Jan;66(1):43-7.Dalvi A, Premkumar A.  Tremor: etiology, phenomenology, and clinical features.  Dis Mon.  2011;57:109-26.Elble RJ, Koller WC.  Cerebellar tremor.  In: Tremor.  Eds.  The Johns Hopkins University Press, Baltimore and London, 1990:109-17.Aisen ML, Arnold A, Baiges I, Maxwell S, Rosen M.  The effect of mechanical damping loads on disabling action tremor.  Neurology.  1993;43(7):1346-50.Sechi GP, Zuddas M, Piredda M, Agnetti V, Sau G, Piras ML, Tanca S, Rosati G.  Treatment of cerebellar tremors with carbamazepine: a controlled trial with long-term follow-up.  Neurology.  1989;39:1113-5.Saponara R, Greco S, Proto G, Trubia T, Domina E.  Levetiracetam improves intention tremor in fragile x-associated tremor/ataxia syndrome.  ClinNeuropharmacol. 2009;32(1):53-4.Braham J, Sadeh M, Turgman J, Sarova-Pinchas I.  Beneficial effect of propranolol in familial ataxia. Ann Neurol.  1979;5(2):207.Koller WC.  Pharmacologic trials in the treatment of cerebellar tremor.  Arch Neurol.  1984;41:280-1.Henkin Y, Herishanu YO.  Primidone as a treatment for cerebellar tremor in multiple sclerosis – two case reports.  Isr J Med Sci.  1989;25(12):720-1.Aisen ML, Holzer M, Rosen M, Dietz M, McDowell F.  Glutethimide treatment of disabling action tremor in patients with multiple sclerosis and traumatic brain injury.  Arch Neurol.  1991;48(5):513-5.Trelles L, Trelles JO, Castro C, Altamirano J, Benzaquen M.  Successful treatment of two cases of intention tremor with clonazepam.  Ann Neurol.  1984;16(5):621.Brunberg JA, Jacquemont S, Hagerman RJ, Berry-Kravis EM, Grigsby J, Leehey MA, Tassone F, Brown WT, Greco CM, Hagerman PJ.  Fragile X premuation carriers: characteristic MR imaging findings of adult male patients with progressive cerebellar and cognitive dysfunction.  AJNR Am J Neurol.  2002;23(10)1757-66.Weiss N, North RB, Ohara S, Lenz FA.  Attenuation of cerebellar tremor with implantation of an intrathecal baclofen pump: the role of gamma-aminobuytricacidergic pathways.  Case report.  J Neurosurg.  2003;99(4):768-771.Lou JS, Goldfarb L, McShane L, Gatev P, Hallet M.  Use of buspirone for treatment of cerebellar ataxia  An open-label study.  Arch Neurol.  1995;52(10)982-8.Clarke CE.  Botulinum toxin type A in cerebellar tremor caused by multiple sclerosis.  Eur J Neurol.  1997;4(1):68-71.Shahzadi S, Tasker RR, Lozano A.  Thalamotomy for essential and cerebellar tremor.  StereotactFunctNeurosurg.  1995;65:11-7.Schulder M, Sernas TJ, Karimi R.  Thalamic stimulation in patients with multiple sclerosis: long-term follow-up.  StereotactFunctNeurosurg.  2003;80:48-55.

Management of Tremor Management of Tremor Presentation Transcript

  • TREMOR Compiled by Dr PS Deb MD, DM (Neurology) Director Neurology GNRC Hospitals Guwahati, Assam, India
  • TREMOR  Rhythmical, involuntary oscillatory movement of a body part, produced by either synchronous or alternating contractions of antagonist muscles (1- 3).  Type:  Rest  Action  Postural  Kinetic
  • TREMOR EVALUATION  History  Age of onset, progression  Family history  Systemic symptoms : diaphoresis, palpitations, and bowel irregularities  Association: other neurological disease, Drug use  Examination  Rate : Frequency  Amplitude  Location: Part of the body affected  Modification:  Rest (repose)  Actional  Postural (static)  Movement  Task specific  Other factors: Anxiety, exertion, sleep, drugs  Special tests:  Handwriting  Drawing Archimedes spirals  Ability to transfer water between 2 cups or drink from a cup  Investigation  EMG: Antagonist muscle shows, burst synchronous / asynchronous  Recording: Acceterometer, Goniometer, Computer
  • PATHOPHYSIOLOGY  Due to burst of α motor neuron, synchrony in antagonistic muscle, presumably inadequately in the strength and timing of contraction of opposite muscle group.  Rhythmic burst of discharge of unitary cellular activity in VIM of thalamus synchronous with tremor on contralateral side with stopping of tremor by voluntary or passive movement due to disappearance of burst  The neurons are arranged somatotopically and respond to kinesthetic impulse from the muscle and joint involved  In monkey VIM contains large sized neuron receive dense projection from the cerebellar nuclei and spinocerebellar tract  Tremor can be abolished by lesion of VIM  VIM is key nucleus which is sensory in character as well as interfering motor activity
  • PATHOPHYSIOLOGY  Synchronous burst also occur in sensory-motor cortex, important for tremor generations.  Passive stretching of muscle →  >1Hz Non Parkinsonian  < 1Hz Parkinsonian  Suggest tremor rhythm is strongly influenced by spinal reflex mechanism  Pathway not clear pyramidal / extrapyramidal  Probably tremor is produced in the reticular formation the brain stem or thalamus and is modified and regulated in its rhythm setting by spinal reflex mechanism most prominently by the kinesthetic sence.
  • PATHOPHYSIOLOGY Frequency Site System involved Human form 8-12Hz None Olivocerebellum Physiological 6-8 Hz Dentate N. Olivocerebellum Essential 3-6 Hz Midbrain tegmentum Thalamo-cortical Parkinsonism Lamore 1984 in monkey Hornalive (GABA antagonist) injection
  • Oscillation in Inf- Olive Activation of Purkenji Cells Reticulospinal, vestibulospinal, cerebellothalamic system Tremor Tremor abolished by inf. Olive lesion But, no such lesion found in human except palatal myoclonus
  • PATHOGENESIS OF TREMOR Red- nucleus OliveCerebellum Cortex Basal Ganglion Thalamus Ant. Horn Cells Muscle External Protuberance
  • REST TREMOR  Parkinsonian syndrome  Multiple Systems Atrophy,  Progressive Supranuclear Palsy (PSP),  Corticobasal Syndrome,  Parkinsonism-Dementia-ALS of Guam,  Progressive Pallidal Atrophy,  Diffuse Lewy Body disease  Heredodegenerative disorders  Huntington's disease,  Neuroacanthocytosis,  Neurodegeneration with Brain Iron Accumulation,  Gerstmann-Strausler-Scheinker disease,  Neuronal Ceroid Lipofuscinosis
  • CAUSES OF REST TREMOR  Secondary parkinsonism  Toxins  carbon monoxide,  MPTP,  manganese,  methanol,  cyanide poisoning)  Drugs  neuroleptics,  dopamine depleting drugs,  Antiemetics  Infections  Creutzfeldt-Jakob disease,  Subacute Sclerosing Panencephalitis,  fungal  post-encephalitic  Metabolic disorders  hypothyroidism,  chronic hepatic degeneration,  mitochondrial cytopathies  Other:  vascular events,  head trauma,  neoplastic or  paraneoplastic conditions  Severe essential tremor  Midbrain (rubral) tremor  Psychogenic tremor
  • PARKINSONIAN TREMOR  Incidence: 60-70% at the onset(8).  Rate : 3-7Hz variable  Amplitude: moderate  Location: One of both hand→ feet → jaw → tongue  Type:  Flexion extension of hand , adduction abduction of finger, pronation supination of forearm  Flexion extension of finger + adduction abduction of thumb – pin rolling tremor  Foot flexion extension  Lips and jaw opening and clossing  Tongue in and out  Eyes flutter when closed  Other type: 15-30%  Fast frequency postural or action tremor  Paralysis agitance: gentle distal tremor  Post encephalatic: proximal slow tremor  Elderly my have tremor for long time without other features of parkinsonism which may develop later  Progression:  Modification:  Increased  At the time of repose  Emotional stress  Walking  Reduced  when hand is supported  by willed movement  During deep sleep, relaxation  Rigidity  Functional interference  Does not interfere with voluntary movement  Association: other neurological disease  EMG: Antagonist muscle shows, burst synchronous / asynchronous  Recording: Acceterometer, Goniometer, Computer
  • PAHTOPHYSIOLOGY  Not due to nigrostriatal dopaminergic deficit  Animal lesion of SN, striatopallidal → no tremor  All patients with SN lesion do not have tremor  Central oscillator in thalamus, cerebellum, globus pallidus, or subthalamic nucleus,  Monkey: lesion between SN and RN in midbrain tegmentum → parkinsonian like tremor (Ward)  Severity may correlates with loss of subgroup of mesencephalic neurons  A midbrain lesion near the red nucleus can involve the nigrostriatal pathway in addition to cerebellar outflow tracts and cause a tremor at rest as well as an action tremor, known as a Holmes, or rubral, tremor. (5)
  • RX PD TREMOR  Dopamineric agent : 50% reduction with levodopa , Amantadine, clozapine, propranolol,and mirtazapine,  Botulinum toxin has been found to effective for some patients with PD hand tremor (19,20) and jaw tremor (21).  The subthalamic nucleus is the most common surgical target for medically refractory PD-related tremor (8)  but lesioning or deep brain stimulation of the thalamic nucleus ventralis intermedius can also be performed.  A lack of major benefit has been observed with gamma knife thalamotomy (22).
  • OTHER REST TREMORS  Cerebellar rest tremor: also due to striatonigral lesion  Hereditary chin tremor  Paroxysmal tremor  Dystonic disorder with tremor – spasmodic torticollis – 1-6.5 Hz  Shuttering attack of children  Whole body tremor + sympathetic changes  ± Essential tremor or FH of ET  Jittering of new born infent  With other signs of CNS hyperactivity  Hypermobility  Hypertonicity  Easy to startle  Due to pre or post natal insult
  • POSTURAL TREMOR  Physiologic  Essential
  • PHYSIOLOGICAL TREMOR  Asymptomatic oscillation of body  Present even during sleep  Cannot be seen by eyes  Frequency 8-13 Hz  Due to (Marsden)  Mechanical resonance frequency of related joints  Irregularity of muscle contraction in an un-fused tetanus of slow firing motor unit  Reflexion of balistocardiogram  Oscillation in the spinal monosynaptic reflex
  • ENHANCED PHYSIOLOGIC TREMOR  Frequency :8-13Hz (altered by mechanical loading, alpha/beta stimulation)  Due to increased operation of segmental stretch reflex consequent to mechanical changes produced in the muscles by its beta adgrenergic stimulation
  • PHYSIOLOGIC TREMOR  Physiologic tremor enhanced by  Emotion – anxiety stress  Exercise, fatigue  beta-agonists,  dopaminergic drugs,  stimulants,  valproic acid,  carbamazepine,  verapamil,  epinephrine,  psychiatric drugs,  methylxanthines (coffee, tea),  cyclosporine,  interferon, and flunarizine.(5- 7)  stress,  Endocrine: hypoglycemia, thyrotoxicosis, pheochromocytoma, adrenocorticosteroids  Toxin: mercury, lead, alcohol withdrawal
  • OTHER CAUSES OF POSTURAL TREMOR  Dystonia,  Parkinsonism,  Myoclonus,  Kennedy syndrome,  Roussy-Levy syndrome.  Parkinson syndromes may have a postural component, known as a re-emergent tremor,  Midbrain lesion or cerebellar dysfunction (titubation) (5).  Psychogenic.
  • ESSENTIAL TREMOR  Inherited, constitutional malady characterized by kinetic tremor in the absence of other neurological signs  Prevalence – 0.9% increases with age >95years >20%  Onset: childhood or late life  Progression : Unilateral to bilateral and from arm to head after several year, voice, tongue, leg and trunk can be involved rarely, slowly progressive with increased severity  It can be hereditary (30%) with variable penetrance or sporadic and has a bimodal age at onset.  Etiology : Unknown (Genetic, toxic)  Pattern: Kinetic tremor, postural and during action (writing, drinking,), >50% have intention component, rarely rest tremor also
  • ESSENTIAL TREMOR  Frequency : 4-12 Hz inversely related to amplitude  Amplitude more than physiological, increases gradually and large proportion are disabled  Type: Postural action tremor, sometime intentional, rarely rest (frequency 4-12Hz)  Site: Aadduction-abduction movement of the fingers (individual finger can be affected) and flexion-extension movement of the hands-> Head no-no (F>M)-> voice and jaw, lower limbs are rarely affected.  Modification: Forment’s sign: Tremor and cog-wheeling increased voluntary activity even in opposite limbs and reduced by relaxation  Increased by cold, exercise, emotion, sympathetic stimulation  Associated cerebellar features (mild ataxia of gait ), Mild cognitive difference
  • PATHOPHYSIOLOGY  Cerebellum (Purkinje cells) and inferior olive have been implicated by fMRI, PET, diffusion tensor imaging and Pathological studies
  • ASSOCIATED NEUROLOGIC DISEASE  Parkinson’s disease  Higher incidence of PD in ET 24times  In familial PD ET common  Spasmodic torticollis  Torsion dystonia  Essential myoclonus  Peripheral neuropathy  Fredrick's ataxia  Physiological tremor  Other condition  Essential hypertension  CVD  CHD  Alcoholism  Intelligent professional
  • ESSENTIAL TREMOR TYPE (MARSDEN)  Type I – Benign exaggerated essential tremor (8-12Hz)  Type II – Benign pathological essential tremor (5-7Hz)  Type III – Severe pathological essential tremor (4-6Hz) frequently spasmodic, not responsive to therapy  Type IV – Symptomatic essential tremor, associated with other neurological conditions
  • ESSENTIAL TREMOR - RX  Standard Rx: Propranolol, Primidone  Other Rx: Other beta blockers, Topiramate , Gabapentin , benzodiazepine  Deep brain stimulation: in resistance cases  Ventralis intermedius (Vim)  Thalamotomy not recommended
  • KINETIC TREMOR  Kinetic tremor refers to oscillation during a visually-guided voluntary movement (5).  Cerebellar outflow tract disorder  Stroke  Demyelination  Infection or post-infection  Viral, bacterial, fungal, parasitic, prion  Trauma  Neoplastic or paraneoplastic  Endocrinopathies  Hereditary disease  Spinocerebellar ataxias,  Wilson's disease  Medications  Phenytoin, valproate, amiodarone, lithi um  Heavy metals & toxins  Organic mercury, alcohol, toluene  Midbrain (rubral) tremor  Severe essential tremor  Psychogenic tremor
  • CEREBELLAR TREMOR MILD  Mild (simple) rapid 10Hz distal (unresponsive to INH)  Severe (Rubral – Gorden Holmes 1904) – not rubral but upper brain stem lesion involving dentato-thalaminc and dentato-olivary system  Proximal can be distal Arm > Leg, head and trunk can be involved  Irregular low frequency (3-5Hz)  High amplitude, increased amplitude with prolonged posture  Intention tremor, increased with goal directed movement of difficult pathway  Perpendicular to the direction of movement  Associated rest tremor due to involvement of different pathway.
  • CAUSES OF INTENTION TREMOR  Multiple sclerosis  Brainstem tumor  Benedict’s syndrome
  • PATHOPHYSIOLOGY  Dysfunction of cerebellar-based motor control  mechanical oscillation of joints and their muscles,  stretch reflex oscillations through afferent muscle spindle pathways to the brain, and centrally-located oscillatory neuronal groups (5).  Cerebellar tremor tends to occur ipsilateral to a lesion of the deep cerebellar nuclei or outflow tracts through the superior cerebellar peduncle (5).  It is likely injury to these outflow tracts through the midbrain that cause the kinetic component of a Holmes, or rubral, tremor.
  • TREATMENT OF KINETIC TREMOR  Difficult:  CBZ in small trial  Glutethimide in MS  Bnezodiazepine  Baclofen  Botox no use  Tetrahydrocanabinol  5 Hydroxytryptophan  INH 900-1200mg/d with Pyridoxin  Removal of cause  Behavioral modification: wrist weight while eating  Surgical  Thalamotomy or  Deep brain stimulation of the nucleus ventralis intermedius (Vim)
  • CEREBELLAR INTENTION TREMOR  Rhythmic oscillation on reaching the target perpendicular to the direction of movement  Once the target is reached tremor will cease after 1 sec (postural tremor will continue once the target is reached)  Frequency 3-5 Hz  Sometime associated with titubation of head and trunk  Interferes with voluntary act  Drugs ineffective  Stereotaxis improve tremor but not function  Adding wt to the limb  Vigorous friction of the joints
  • PERIPHERAL NEUROPATHY WITH TREMOR  Hereditary motor sensory neuropathy with ET  Chronic relapsing neuropathy after 2-3rd relapse 6-8Hz tremor improve with neuropathy  Paraprotenemia with neuropathy (IgM benign)  Muscles are not weak, motor conduction reduced, proprioception normal  Recovery phase of GBS  Rarely Diabetic neuropathy  Uremic neuropathy  Porphyria
  • PATHOGENESIS OF TREMOR IN PN  Enhanced physiologica tremor by weakness and impairment of stretch reflex (Shid et al)  Loss of large fiber sensory function -> imbalance in the sensory input to the motor neuron pool (Shahani and Yong)  Primary CNS disorder  Spinocerbellar pathway involved -> impaired central function
  • WILSON DISEASE  Postural and intension tremor  3-5Hz severe poximally  Can increase amplitude with time  Wing beating tremor at shoulder when abducted at 90 degree and elbow flexed
  • POST TRAUMATIC  Proximal postural and intentional  Following sever head trauma  Stereotactic VIM lesion  Propranolol
  • ALCOHOLIC TREMOR  Exaggerated physiological  Essential tremor – inherited as different tract  3Hz leg tremor - by standing and closing eyes – ant cerebellar lesion
  • TASK SPECIFIC TREMOR 1. Primary writing tremor  Related to essential tremor, writer’s cramp, dystonia  Alcohol, Propranolol, Anticholinergic improve in some 2. Vocal tremor 1. Related to ET, family history 1. Respond to alcohol, propranolol 2. Not related to ET, no family 1. Does not respond to beta blocker
  • ORTHOSTATIC TREMOR  On standing  Reduced by walking  Clonazepam 4-6mg effective
  • HYSTERICAL TREMOR  Commonly action tremor  May persist in repose  Irregular frequency  Unilateral  Disappear when attention diverted and restart tremor shift to other parts of body
  • ASTERIXIS  Arrhythmic lapses of sustained posture  Sudden interruption of muscular contraction allow gravity or inherent elasticity of muscle to produce a movement when the patient corrects with overshoot  Metabolic encephalopathy  Anticonvulsant  Anticonvulsant  Unilateral Asterixis  Ant. Cerebral occlusion  Thalamotomy  Mid brain lesion
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