Gordon Holmes reported in 1904 a series of patients with focal brain damage presenting tremors. Holmes tremor can present at rest or with movement (intention), usually with a sustained posture. It is slow (< 4.5 Hz) but with a large amplitude.[1] It has also been referred to as rubral tremor, midbrain tremor, thalamic tremor, post-traumatic tremor, or complex tremor because of the affected areas in the brain. The tremor was mostly associated with lesions in the midbrain, but now many other regions have been recognized.[2]
Holmes tremors can be caused by a number of conditions:
There are few reports in the literature for Holmes tremor. This could be because due to misdiagnosis as it can be categorized as another type of tremor or because single case reports have not been published. A study in 2016 identified only 155 patients reported since the original 1904 description until 2016.[3] This small amount of cased proves that Holmes tremor is a rare manifestation.
In a series of twenty patients, the average age at diagnosis is 30.6 years (range 8-64), with a female to male ratio of 2:1.[3] The median time from the lesion occurrence and the tremor is 3.6 months, but it can range from one month until two years.[3] Another series of 23 patients found that the median time from the lesion occurrence and the tremor is 29 days, with a range of 2 days to 20 months.[4]
Neuroimaging techniques had helped to uncover the pathophysiology of many tremors.[5] In Holmes tremor, functional MRI has pointed to lesions in a commonly connected brain circuit involving the cerebellum (vermis, lateral cerebellar cortex, and flocculonodular areas), globus pallidus pars internus (GPi), thalamus (ventralis oralis posterior (VOP) and pulvinar nucleus), red nucleus, and pontomedullary junction.[6][7]
Several other circuits have been associated with the tremor, including the dopaminergic nigrostriatal system, dentatorubro-olivary pathways, and the cerebellothalamic system. Physician-scientists propose that a "two-hit" lesion that includes the nigrostriatal and other regions, as mentioned, is necessary to produce the symptoms.[1][8][9][10][11] The involvement of the GPi and VOP implies a pallidal–thalamic circuit.[12][13] The involvement of the pulvinar nucleus suggests posterior thalamic lesions involved in the tremor.[14][15] The presence of a combination of tremors is explained by the multiple regions involved, thus producing a resting, intention, and postural tremor. The GPi influences the pedunculopontine nucleus via the descending reticulospinal tract, controlling posture by acting on the axial and proximal appendicular musculature.[16] The thalamostriatal connections are involved in the interaction of basal ganglia pathways with cerebellar pathways making the GPi one of the targets for treatment.[1][17][18][19]
Most injuries are irreversible, but reversible cases of Holmes tremor had been reported after the resolution of spontaneous intracranial hypotension[20] or nonketotic hyperglycemia[21]. Distortion and swelling of the midbrain can produce functional disruption of the connected brain circuits.
Tremor diagnosis is based on a careful clinical examination, neurophysiological studies, and radiological assessment.
A neurological examination will show a unilateral resting, intention, and postural tremor affecting the extremity symmetrically, which is usually greater proximally than distally. It has a high amplitude at resting, which may worsen with intention. The frequency is generally below 4.5 Hz. Prolong or sustain posture will accentuate the tremor.
The Fahn-Tolosa-Marin tremor rating scale is used to measure tremor severity.[22] The pre-treatment score will be used to assess the results of medical/surgical treatment if there is evidence of a change in the post-treatment score.
Laboratories are usually nondiagnostic. An electromyogram is used to measure the frequency of tremor activity.
A Head computed tomographic (CT) scan will be useful for acute cases in which hemorrhage is identified. The gold standard study is a brain magnetic resonance imaging (MRI) with and without contrast, which will show ischemic lesions, neurodegenerative/inflammatory lesions, traumatic sequela, and tumoral/vascular pathologies. The brain MRI will also be used for the treatment coordination when fused to the head CT scan.
Medical
The most commonly used drugs are levetiracetam, trihexyphenidyl, levodopa, dopamine agonists, anticholinergics, and topiramate.[23][24] Very good results have been shown with levetiracetam. Also, the anticholinergics drug trihexyphenidyl has shown good results. Response to levodopa has been approximately 54%.[3][25] Second-line drugs that may help with some of the symptoms include clonazepam, bromocriptine, amantadine, biperiden, or botulinum toxin injections.[4][23][26]
Surgical
Stereotactic lesions (radiofrequency, thermal), principally at the thalamus, have produced partial improvement.[27][28][29] The effect may also wane with time.[1][29]
Gamma knife thalamotomy at Vim nucleus with a 130 Gy dose at the 100% isodose line; the 30% isodose line was kept lateral to the medial margin of the internal capsule with partial results.[30]
Classical targets for deep brain stimulation (DBS) in the VIM produced a good clinical response with partial results in only 31% of patients with Holmes tremor.[31] DBS to the GPi or VOP has been thought of as a target given the areas involved in Holmes tremor.[6] Areas located slightly more medial to the GPi target provide good results. DBS to the thalamic ventralis intermedius nucleus (VIM) in 57.8% of the patients and the GPi 32.8% of the patients provided better tremor suppression than medical treatment.[10] DBS to the GPi provides better control of the resting tremor component and overall tremor improvement.[1][23][32] Some consider that stimulation of the GPi is more effective than thalamic stimulation when there is a midbrain lesion.[2] The postural tremor component had better surgical results, but rest tremor and intention tremor results are similar.[23] GPi stimulation improves the proximal tremor while the Vim stimulation improves the distal tremor.[10] Results have been sustained after several years of follow up.[32] Sometimes a planned target can not be used as it is seriously affected by the etiology.[32]
Other areas of DBS have provided good single case improvement, including the prelemniscal radiations (inferior to the caudal zona incerta)[33] and the posterior subthalamic (three patients)[34]. The ventralis oralis anterior (VOA) and posterior (VOP) produces sustained improvement.[12] Other areas include zona incerta, lenticular fasciculus, subthalamic nucleus, sometimes bilateral with a variable degree of improvement.[31][35] Because of the multiple structures involved, a combination of two targets for DBS can be considered.[31][36] Other studies have not found benefits among patients treated with multiple targets.[10][23] A patient with a midbrain hemorrhage who had stimulation of Vim, GPi, and VOA was found that only the GPi stimulation improved the tremor; none of the other two did not result in further tremor reduction.[1] The presurgical planning of two targets provides the surgeon to choose the best target with optimal results.[32] Stimulation is probably a life-long requirement as a report in which the system was removed after four years produced the tremor's reappearance similar to the preimplantation status.[37]
Focused ultrasound in deep brain targets for movement disorders and some types of tremors have been used and are now under clinical trials for Holmes tremor.[38][39][40][41][42]
Several tremors disorders are included in the differential diagnosis.[43][44]
DBS offers a more significant improvement in overall tremor control, especially in postural tremor.[23] This effect is better with GPi, VOP, or VOA stimulation compared to the classic Vim stimulation.
Here are a few complications:
The consultations from the following departments:
Holmes tremor is significantly incapacitating as the patient presents tremor in resting and intention activities, as with posture. This is in addition to the primary insult producing the tremor. There is no specific treatment. Medication and DBS have been the mainstay to control it. However, results can be incomplete. Initial treatment with levetiracetam, trihexyphenidyl, or levodopa should be tested for an adequate response. Those unresponsive patients should be offered DBS, understanding that results may be incomplete and that multiple targets may be required. Patients have to understand that the original neurological deficits will not benefit from the DBS procedure. This is important, so they do not have false expectations from the procedure.
Management of Holmes tremor is particularly challenging as it involves resting, intention, and postural tremors. The quality of life of patients is very affected in those untreated or unresponsive. Collaboration shared decision making, and communication is a crucial element for a good outcome. The interprofessional care provided to the patient by the neurologist, neurosurgeons, and nurses must use an integrated care pathway combined with an evidence-based approach for the evaluation, diagnosis, and treatment planning. This will improve patient satisfaction and provide better outcomes.
[1] | Kilbane C,Ramirez-Zamora A,Ryapolova-Webb E,Qasim S,Glass GA,Starr PA,Ostrem JL, Pallidal stimulation for Holmes tremor: clinical outcomes and single-unit recordings in 4 cases. Journal of neurosurgery. 2015 Jun; [PubMed PMID: 25794341] |
[2] | Starr PA, Deep brain stimulation for other tremors, myoclonus, and chorea. Handbook of clinical neurology. 2013; [PubMed PMID: 24112895] |
[3] | Raina GB,Cersosimo MG,Folgar SS,Giugni JC,Calandra C,Paviolo JP,Tkachuk VA,Zuñiga Ramirez C,Tschopp AL,Calvo DS,Pellene LA,Uribe Roca MC,Velez M,Giannaula RJ,Fernandez Pardal MM,Micheli FE, Holmes tremor: Clinical description, lesion localization, and treatment in a series of 29 cases. Neurology. 2016 Mar 8; [PubMed PMID: 26865524] |
[4] | Liu ZQ,Wan ZR,Jia XT,Yang XZ,Fang XX,Zhang ZY, [Clinical features and short-term prognosis of Holmes' tremor]. Zhonghua yi xue za zhi. 2019 Mar 19; [PubMed PMID: 30893720] |
[5] | Fox MD, Mapping Symptoms to Brain Networks with the Human Connectome. The New England journal of medicine. 2018 Dec 6; [PubMed PMID: 30575457] |
[6] | Joutsa J,Shih LC,Fox MD, Mapping holmes tremor circuit using the human brain connectome. Annals of neurology. 2019 Dec; [PubMed PMID: 31614012] |
[7] | Madelein van der Stouwe AM,Nieuwhof F,Helmich RC, Tremor pathophysiology: lessons from neuroimaging. Current opinion in neurology. 2020 Aug; [PubMed PMID: 32657888] |
[8] | Deuschl G,Bergman H, Pathophysiology of nonparkinsonian tremors. Movement disorders : official journal of the Movement Disorder Society. 2002; [PubMed PMID: 11948754] |
[9] | Deuschl G,Raethjen J,Lindemann M,Krack P, The pathophysiology of tremor. Muscle [PubMed PMID: 11360255] |
[10] | Aydin S,Abuzayed B,Kiziltan G,Gunduz A,Yagci S,Mengi M,Kizilkilic O,Uzan M,Hanci M, Unilateral thalamic Vim and GPi stimulation for the treatment of Holmes' tremor caused by midbrain cavernoma: case report and review of the literature. Journal of neurological surgery. Part A, Central European neurosurgery. 2013 Jul; [PubMed PMID: 23319330] |
[11] | Seidel S,Kasprian G,Leutmezer F,Prayer D,Auff E, Disruption of nigrostriatal and cerebellothalamic pathways in dopamine responsive Holmes' tremor. Journal of neurology, neurosurgery, and psychiatry. 2009 Aug; [PubMed PMID: 18450789] |
[12] | Foote KD,Okun MS, Ventralis intermedius plus ventralis oralis anterior and posterior deep brain stimulation for posttraumatic Holmes tremor: two leads may be better than one: technical note. Neurosurgery. 2005 Apr; [PubMed PMID: 15794849] |
[13] | Krack P,Dostrovsky J,Ilinsky I,Kultas-Ilinsky K,Lenz F,Lozano A,Vitek J, Surgery of the motor thalamus: problems with the present nomenclatures. Movement disorders : official journal of the Movement Disorder Society. 2002; [PubMed PMID: 11948749] |
[14] | Ghika J,Bogousslavsky J,Henderson J,Maeder P,Regli F, The [PubMed PMID: 7799002] |
[15] | Lehéricy S,Grand S,Pollak P,Poupon F,Le Bas JF,Limousin P,Jedynak P,Marsault C,Agid Y,Vidailhet M, Clinical characteristics and topography of lesions in movement disorders due to thalamic lesions. Neurology. 2001 Sep 25; [PubMed PMID: 11571334] |
[16] | Shepherd GM,Tauböll E,Bakke SJ,Nyberg-Hansen R, Midbrain tremor and hypertrophic olivary degeneration after pontine hemorrhage. Movement disorders : official journal of the Movement Disorder Society. 1997 May; [PubMed PMID: 9159743] |
[17] | Bostan AC,Strick PL, The basal ganglia and the cerebellum: nodes in an integrated network. Nature reviews. Neuroscience. 2018 Jun; [PubMed PMID: 29643480] |
[18] | Bostan AC,Dum RP,Strick PL, The basal ganglia communicate with the cerebellum. Proceedings of the National Academy of Sciences of the United States of America. 2010 May 4; [PubMed PMID: 20404184] |
[19] | Hoshi E,Tremblay L,Féger J,Carras PL,Strick PL, The cerebellum communicates with the basal ganglia. Nature neuroscience. 2005 Nov; [PubMed PMID: 16205719] |
[20] | Iyer RS,Wattamwar P,Thomas B, Reversible Holmes' tremor due to spontaneous intracranial hypotension. BMJ case reports. 2017 Jul 27; [PubMed PMID: 28754752] |
[21] | Tan JH,Chan BP,Wilder-Smith EP,Ong BK, A unique case of reversible hyperglycemic Holmes' tremor. Movement disorders : official journal of the Movement Disorder Society. 2006 May; [PubMed PMID: 16416414] |
[22] | Pahwa R,Lyons KL,Wilkinson SB,Carpenter MA,Tröster AI,Searl JP,Overman J,Pickering S,Koller WC, Bilateral thalamic stimulation for the treatment of essential tremor. Neurology. 1999 Oct 22; [PubMed PMID: 10534249] |
[23] | Wang KL,Wong JK,Eisinger RS,Carbunaru S,Smith C,Hu W,Shukla AW,Hess CW,Okun MS,Ramirez-Zamora A, Therapeutic Advances in the Treatment of Holmes Tremor: Systematic Review. Neuromodulation : journal of the International Neuromodulation Society. 2020 Jun 24; [PubMed PMID: 32578304] |
[24] | Rojas NG,Cesarini M,Etcheverry JL,Da Prat G,Viera Aramburu T,Gatto EM, Holmes Tremor Partially Responsive to Topiramate: A Case Report. Tremor and other hyperkinetic movements (New York, N.Y.). 2018; [PubMed PMID: 30191084] |
[25] | Alqwaifly M, Treatment responsive Holmes tremor: case report and literature review. International journal of health sciences. 2016 Oct; [PubMed PMID: 27833521] |
[26] | Kreisler A,Bouchain B,Defebvre L,Krystkowiak P, Treatment with Botulinum Neurotoxin Improves Activities of Daily Living and Quality of Life in Patients with Upper Limb Tremor. Tremor and other hyperkinetic movements (New York, N.Y.). 2019; [PubMed PMID: 31413896] |
[27] | Krauss JK,Mohadjer M,Nobbe F,Mundinger F, The treatment of posttraumatic tremor by stereotactic surgery. Symptomatic and functional outcome in a series of 35 patients. Journal of neurosurgery. 1994 May; [PubMed PMID: 8169619] |
[28] | Kim MC,Son BC,Miyagi Y,Kang JK, Vim thalamotomy for Holmes' tremor secondary to midbrain tumour. Journal of neurology, neurosurgery, and psychiatry. 2002 Oct; [PubMed PMID: 12235320] |
[29] | Maki F,Sato S,Watanabe K,Yanagisawa T,Hagiwara Y,Shimizu T,Hasegawa Y, Vim thalamotomy in a patient with Holmes' tremor and palatal tremor - Pathophysiological considerations. BMC neurology. 2015 Mar 11; [PubMed PMID: 25879699] |
[30] | Tripathi M,Mehta S,Singla R,Ahuja CK,Tandalya N,Tuleasca C,Batish A,Mohindra S,Agrahari A,Kaur R, Vim stereotactic radiosurgical thalamotomy for drug-resistant idiopathic Holmes tremor: a case report. Acta neurochirurgica. 2020 Jul 17; [PubMed PMID: 32676689] |
[31] | Artusi CA,Farooqi A,Romagnolo A,Marsili L,Balestrino R,Sokol LL,Wang LL,Zibetti M,Duker AP,Mandybur GT,Lopiano L,Merola A, Deep brain stimulation in uncommon tremor disorders: indications, targets, and programming. Journal of neurology. 2018 Nov; [PubMed PMID: 29511865] |
[32] | Espinoza Martinez JA,Arango GJ,Fonoff ET,Reithmeier T,Escobar OA,Furlanetti L,Alvarez Berastegui GR,Fernandes da Silva FE,Contreras Lopez WO, Deep brain stimulation of the globus pallidus internus or ventralis intermedius nucleus of thalamus for Holmes tremor. Neurosurgical review. 2015 Oct; [PubMed PMID: 25990341] |
[33] | Martinez V,Hu SC,Foutz TJ,Ko A, Successful Treatment of Holmes Tremor With Deep Brain Stimulation of the Prelemniscal Radiations. Frontiers in surgery. 2018; [PubMed PMID: 29904635] |
[34] | Dec-Ćwiek M,Tutaj M,Pietraszko W,Libionka W,Krupa M,Moskała M,Rudzińska-Bar M,Słowik A,Pera J, Posterior Subthalamic Area Deep Brain Stimulation for Treatment of Refractory Holmes Tremor. Stereotactic and functional neurosurgery. 2019; [PubMed PMID: 31600751] |
[35] | Plaha P,Khan S,Gill SS, Bilateral stimulation of the caudal zona incerta nucleus for tremor control. Journal of neurology, neurosurgery, and psychiatry. 2008 May; [PubMed PMID: 18037630] |
[36] | Romanelli P,Brontë-Stewart H,Courtney T,Heit G, Possible necessity for deep brain stimulation of both the ventralis intermedius and subthalamic nuclei to resolve Holmes tremor. Case report. Journal of neurosurgery. 2003 Sep; [PubMed PMID: 12959446] |
[37] | Grabska N,Rudzińska M,Dec-Ćwiek M,Tutaj M,Pietraszko W,Michalski M,Szczudlik A, Deep brain stimulation in the treatment of Holmes tremor - a long-term case observation. Neurologia i neurochirurgia polska. 2014; [PubMed PMID: 25168330] |
[38] | Walters H,Shah BB, Focused Ultrasound and Other Lesioning Therapies in Movement Disorders. Current neurology and neuroscience reports. 2019 Aug 3; [PubMed PMID: 31377876] |
[39] | Fishman PS,Frenkel V, Treatment of Movement Disorders With Focused Ultrasound. Journal of central nervous system disease. 2017; [PubMed PMID: 28615985] |
[40] | Meng Y,Pople CB,Kalia SK,Kalia LV,Davidson B,Bigioni L,Li DZ,Suppiah S,Mithani K,Scantlebury N,Schwartz ML,Hamani C,Lipsman N, Cost-effectiveness analysis of MR-guided focused ultrasound thalamotomy for tremor-dominant Parkinson's disease. Journal of neurosurgery. 2020 Aug 7; [PubMed PMID: 32764177] |
[41] | Paff M,Boutet A,Neudorfer C,Elias GJB,Germann J,Loh A,Kucharczyk W,Fasano A,Schwartz ML,Lozano AM, Magnetic Resonance-Guided Focused Ultrasound Thalamotomy to Treat Essential Tremor in Nonagenarians. Stereotactic and functional neurosurgery. 2020; [PubMed PMID: 32224617] |
[42] | Pineda-Pardo JA,Urso D,Martínez-Fernández R,Rodríguez-Rojas R,Del-Alamo M,Millar Vernetti P,Máñez-Miró JU,Hernández-Fernández F,de Luis-Pastor E,Vela-Desojo L,Obeso JA, Transcranial Magnetic Resonance-Guided Focused Ultrasound Thalamotomy in Essential Tremor: A Comprehensive Lesion Characterization. Neurosurgery. 2020 Aug 1; [PubMed PMID: 31574145] |
[43] | Bhidayasiri R, Differential diagnosis of common tremor syndromes. Postgraduate medical journal. 2005 Dec; [PubMed PMID: 16344298] |
[44] | Bötzel K,Tronnier V,Gasser T, The differential diagnosis and treatment of tremor. Deutsches Arzteblatt international. 2014 Mar 28; [PubMed PMID: 24739887] |
[45] | Gironell A, Holmes' tremor or functional tremor: Neurophysiological criteria can help diagnosis. Clinical neurophysiology practice. 2019; [PubMed PMID: 30793067] |