Pallidal stimulation for Holmes tremor: clinical outcomes and single-unit recordings in 4 cases

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OBJECT

Holmes tremor (HT) is characterized by irregular, low-frequency (< 4.5 Hz) tremor occurring at rest, with posture, and with certain actions, often affecting proximal muscles. Previous reports have tended to highlight the use of thalamic deep brain stimulation (DBS) in cases of medication-refractory HT. In this study, the authors report the clinical outcome and analysis of single-unit recordings in patients with medication-refractory HT treated with globus pallidus internus (GPi) DBS.

METHODS

The authors retrospectively reviewed the medical charts of 4 patients treated with pallidal DBS for medication-refractory HT at the University of California, San Francisco, and San Francisco Veterans Affairs Medical Center. Clinical outcomes were measured at baseline and after surgery using an abbreviated motor-severity Fahn-Tolosa-Marin (FTM) tremor rating scale. Intraoperative microelectrode recordings were performed with patients in the awake state. The neurophysiological characteristics identified in HT were then also compared with characteristics previously described in Parkinson's disease (PD) studied at the authors' institution.

RESULTS

The mean percentage improvement in tremor motor severity was 78.87% (range 59.9%–94.4%) as measured using the FTM tremor rating scale, with an average length of follow-up of 33.75 months (range 18–52 months). Twenty-eight GPi neurons were recorded intraoperatively in the resting state and 13 of these were also recorded during contralateral voluntary arm movement. The mean firing rate at rest in HT was 56.2 ± 28.5 Hz, and 63.5 ± 19.4 Hz with action, much lower than the GPi recordings in PD. GPi unit oscillations of 2–8 Hz were prominent in both patients with HT and those with PD, but in HT, unlike PD, these oscillations were not suppressed by voluntary movement.

CONCLUSIONS

The efficacy of GPi DBS exceeded that reported in prior studies of ventrolateral thalamus DBS and suggest GPi may be a better target for treating HT. These clinical and neurophysiological findings help illuminate evolving models of HT and highlight the importance of cerebellar–basal ganglia interactions.

ABBREVIATIONSAC-PC = anterior commissure–posterior commissure; DBS = deep brain stimulation; FTM = Fahn-Tolosa-Marin; GPi = globus pallidus internus; HT = Holmes tremor; PD = Parkinson's disease; STN = subthalamic nucleus; VIM = ventralis intermedius nucleus; VOA = ventral oralis anterior; VOP = ventral oralis posterior.

Abstract

OBJECT

Holmes tremor (HT) is characterized by irregular, low-frequency (< 4.5 Hz) tremor occurring at rest, with posture, and with certain actions, often affecting proximal muscles. Previous reports have tended to highlight the use of thalamic deep brain stimulation (DBS) in cases of medication-refractory HT. In this study, the authors report the clinical outcome and analysis of single-unit recordings in patients with medication-refractory HT treated with globus pallidus internus (GPi) DBS.

METHODS

The authors retrospectively reviewed the medical charts of 4 patients treated with pallidal DBS for medication-refractory HT at the University of California, San Francisco, and San Francisco Veterans Affairs Medical Center. Clinical outcomes were measured at baseline and after surgery using an abbreviated motor-severity Fahn-Tolosa-Marin (FTM) tremor rating scale. Intraoperative microelectrode recordings were performed with patients in the awake state. The neurophysiological characteristics identified in HT were then also compared with characteristics previously described in Parkinson's disease (PD) studied at the authors' institution.

RESULTS

The mean percentage improvement in tremor motor severity was 78.87% (range 59.9%–94.4%) as measured using the FTM tremor rating scale, with an average length of follow-up of 33.75 months (range 18–52 months). Twenty-eight GPi neurons were recorded intraoperatively in the resting state and 13 of these were also recorded during contralateral voluntary arm movement. The mean firing rate at rest in HT was 56.2 ± 28.5 Hz, and 63.5 ± 19.4 Hz with action, much lower than the GPi recordings in PD. GPi unit oscillations of 2–8 Hz were prominent in both patients with HT and those with PD, but in HT, unlike PD, these oscillations were not suppressed by voluntary movement.

CONCLUSIONS

The efficacy of GPi DBS exceeded that reported in prior studies of ventrolateral thalamus DBS and suggest GPi may be a better target for treating HT. These clinical and neurophysiological findings help illuminate evolving models of HT and highlight the importance of cerebellar–basal ganglia interactions.

In 1904 Gordon Holmes described a syndrome characterized by a low-frequency rest tremor (< 4.5 Hz), which was accentuated by posture and intentional movements.20 Holmes tremor (HT) usually arises 4 weeks to 2 years after an acute brain event. It is characterized by a large and irregular amplitude tremor often affecting predominantly proximal upper extremities. Holmes tremor is the preferred term, as other terms such as rubral or midbrain tremor are considered to be anatomically misleading because injury to multiple cortical and subcortical areas has been reported to cause HT.7 The exact pathophysiology of HT remains unknown, but lesions involve the cerebello-thalamo-cortical and dentato-rubro-olivary pathways. Superimposed dysfunction in the nigrostriatal pathway may account for the rest tremor component,8,45,53 but not all investigators agree on this point.16 Holmes tremor may arise secondary to cerebral hemorrhage, tumors, cavernomas, infection, multiple sclerosis, or traumatic brain injury.5,14,24,26,27,30,32,33,40,41,44,64,67,68 Medical treatment for HT is often unsatisfactory. Several case reports of patients successfully treated with lesioning procedures as well as deep brain stimulation (DBS) have previously been reported (Table 1). Most commonly thalamic (ventralis intermedius nucleus [VIM]) DBS has been used. In a previous publication we reported the use of unilateral globus pallidus internus (GPi) DBS in a patient with HT due to a midbrain cerebral infarction with a remarkable improvement in functional outcome.33 In this paper we report the long-term outcomes of 4 patients who underwent GPi DBS for medically refractory HT treated at our institution, as well as pallidal single-unit discharge characteristics.

TABLE 1

Case reports and series of DBS in patients with HT

Authors & YearHT EtiologyNo. of PatientsClinical Outcome ScaleStimulation TargetOutcomeFollow-Up
Kudo et al., 2001Rt midbrain cavernous malfor-mation1NoneBilat VIMTremor suppressionNot specified
Pahwa et al., 2002Midbrain cavernous heman-gioma1NoneRt VIMSignificant improvement in postural & resting tremor, kinetic compo-nent persisted24 mos
Romannelli et al., 2003No obvious MRI abnormality1UPDRS-tremor subscoreLt VIM and lt STNTremor component improved2 yrs
Samadani et al., 2003Left midbrain cavernous angioma1Improved speed of specific task, functional disability score of FTM scaleLt VIM4-point decrease in functional disabilityNot specified
Piette et al., 2004Pontine tegmental hemorrhage1NoneRt VIMFunctional improvement1.5 yrs
Nikkhah et al., 2004Rt midbrain infarct2Accelerometer & EMGRt VIMAlmost complete tremor improvement7 mos
Lt AVM w/ midbrain & thalamic hemorrhageLt VIM80% clinical & EMG improvement6 mos
Foote & Okun, 2005Posttraumatic1TRS & tremor disability scores2 rt VIM (border VIM/VOP & border VOA/VOP)Total TRS improvement 37%, dis-ability score improvement 80%1 yr
Foote et al., 2006Posttraumatic tremor3TRS2 VIM (border VIM/VOP & border VOA/VOP)Total TRS improvement of 38.46%, 48.33%, & 66.67%1 yr, 6 mos, & 8 mos
Diederich et al., 2008Lt venous angioma pons Rt hemiatrophy midbrain2CGI-Global ImprovementLt VIM Rt VIMSubstantially ameliorated posturalrest > intention component Postural > rest tremor> 7 yrs 5 yrs
Bandt et al., 2008Lt midbrain cerebral infarction1WHIGET Tremor Rating ScaleLt lenticular fasciculusMild intermittent residual tremors16 mos
Plaha et al., 2008No obvious MRI abnormality1FTM tremor rating scaleCaudal zona incerta70.2% improvement in total tremor rating scale1 yr
Peker et al., 2008Rt thalamic abscess1NoneRt VIM90% improvement30 mos
Sanborn et al., 2009Multilobulated, multiseptated brainstem lesion (thalamus/ pons)1CGI-Global ImprovementRt VIMFull tremor suppression at last follow-up24 mos
Acar et al., 2010Subarachnoid hemorrhage1CGI-Global ImprovementBilat VIMModerate improvement3 mos
Follett et al., 2014Motor vehicle accident, encephalomalacia bilateral anterior & inferior frontal & anterior frontal areas, in ad-dition to 2 thalamic lacunes1TETRASBilat VIMSignificant tremor reduction12–18 mos
Issar et al., 2013“Severe diffuse axonal injuries”5FTM scale3 patients received unilat VIM, 1 received bilat VIM, 1 bilat GPi DBS (had dystonic tremor)14%-36% improvement in tremor rating scale noted in 3 patients w/ VIM2–3 yrs, but follow-up tremor scales unavailable for 2 patients
Kobayashi et al., 2014Lesions of cerebellum, mid-brain, or thalamus4FTM scaleAll 4 patients received dual subthalamic area & thalamic DBS (VO/VIM)93%–100% improvement in tremor rating scale2 yrs

AVM = arteriovenous malformation; CGI = Clinical Global Impression; EMG = electromyography; TETRAS = The Essential Tremor Rating Assessment Scale; TRS = Tremor Rating Scale; UPDRS = Unified PD Rating Scale; WHIGET = Washington Heights–Inswood Genetic Study of Essential Tremor.

Methods

We retrospectively reviewed the medical records of 4 patients who underwent GPi DBS for management of intractable HT at the University of California, San Francisco, and San Francisco Veterans Affairs hospital between August 2006 and February 2009. Baseline clinical characteristics were recorded. An abbreviated Fahn-Tolosa-Marin (FTM) scale was used for tremor rating and was the primary outcome measure.11 Tremor scores from the FTM tremor rating scale parts A, B, and C were summed to obtain a single FTM tremor rating scale score at baseline and last follow-up visit. Stimulation was delivered in a monopolar mode in all but 1 patient, and programming was performed using parameters similar to those used for GPi DBS in Parkinson's disease (PD; Table 2).

TABLE 2

Clinical demographics and FTM tremor rating scale scores at baseline and at last clinical follow-up

Case No.Age at Time of Surgery (yrs)*Neuroimaging FindingsPharmacotherapy TrialsFTM Scale Score% ImprovementLength of Follow-Up (mos)DBS Programming Parameters (V/μsec/Hz)GPi Lead Tip Location (x/y/z [mm])§
BaselineLast Follow-Up
143Rt midbrain hemorrhage from cavernous malformationBenzodiazepines, pramipexole, carbidopa/levodopa, baclofen562359.952Bipolar: 0 + 1– 2.5/90/185‡19.6/0.34/−5.4
265Multiple lt multicystic midbrain tegmentum lesionsPropranolol, lorazepam, pramipexole, trihexy-phenidyl, carbidopa/levodopa581082.836Monopolar: 1– 2.8/90/18519.1/2.5/−5.0
329Lt temporal lobe encephalomalacia & residual lt thalamic bullet fragmentGabapentin, topiramate, phenytoin54394.429Monopolar: 1– 4.5/90/145‡19/2.1/−6.0
450Rt thalamic/ subthalamic infarctionCarbamazepine, trihexyphenidyl, amantadine, olanzapine, quetiapine, clonazepam, re-serpine, gabapentin, lamotrigine, botulinum toxin, carbidopa/levodopa4598018Monopolar: 1– 2.0/120/14519.5/4.0/−7.5
Mean53.2511.2578.8733.75

All patients were male.

Given as voltage (V)/pulse width (msec)/frequency (Hz).

Thalamic leads were “off” after 8 months of multiple programming sessions with lack of additional symptomatic benefit.

DBS lead tip locations (in mm) with respect to the midcommissural (AC-PC) point.

All patients underwent implantation of DBS leads in the GPi using microelectrode-guided stereotactic surgery.57 Prior to recording, all patients were sedated with propofol for placement of the stereotactic frame as well as the surgical incision. Propofol is known to suppress basal ganglia discharge,23 but is cleared rapidly, and prior studies in PD and dystonia suggest no neuronal effect of propofol following 30–60 minutes of washout time.56,58 Propofol was thus stopped 30 or more minutes prior to neuronal recordings. The Medtronic 3387 lead was used in all patients.

Single-Unit Recording and Analysis

Single-unit recordings were obtained using glass-coated platinum/iridium microelectrode electrodes with impedance of 0.4–1.0 mΩ (Microprobe, or FHC). Signals were band-pass filtered (300 Hz to 4 kHz), amplified, played on an audio monitor, displayed on an oscilloscope, and digitized (20-kHz sampling rate) using the Guideline System 3000 or 4000 (FHC) or Microguide system (Alpha Omega). Cells were recorded approximately every 300–800 μm along each trajectory. Pallidal neurons were screened for movement-related activity based on audible changes in the action potential discharge evoked by passive movements of the contralateral limb. The joints tested were the ankle, knee, hip, shoulder, elbow, and wrist. Once a movement-responsive neuron was identified, cell discharge was recorded both during voluntary movements of the related contralateral joint as well as “at rest.” Cells encountered between the internal medullary lamina and the optic tract were considered GPi cells. Digitized spike trains were imported into offline spike-sorting software (Plexon) for discrimination of single populations of action potentials by principal components analysis. Spike times were used to calculate discharge rate, detect oscillations in neuronal discharge, and evaluate the data stream for occurrence of bursting discharge. Neuronal action potentials were only included in this study if they could be discriminated with a high degree of certainty, as measured by a clear refractory period in the interspike interval histogram (> 3 msec) and if spontaneous activity was recorded for more than 20 seconds. Neurons whose action potential morphology varied with the cardiac cycle were excluded. Analysis was performed using Matlab software (The MathWorks). The quantification of bursting discharge was performed using the Poisson “surprise” method of Legéndy and Salcman,31,65 with a “surprise” value of 5. Oscillations in the spike train at 2–35 Hz were evaluated using the “global spike shuffling” method.47 GPi unit discharge characteristics were compared with findings in patients with PD previously studied at our center.35,55 Statistically significant differences between HT and PD were determined using the Mann-Whitney U-test for continuous data and the chi-square or Fisher exact tests for categorical data.

Lead Locations

Electrode location was measured by postoperative MRI, according to published safety guidelines for performing MRI in patients with implanted DBS systems (http://professional.medtronic.com/pt/neuro/dbs-md/ind/mri-guidelines/#.VOe4MsJ0zcs).46 The MR images were computationally reformatted to be orthogonal to the anterior commissure–posterior commissure (AC-PC) line and midsagittal plane57 (Framelink software, version 4.1, Medtronic), and lead tip locations were measured with respect to the midcommissural point (Table 2, Fig. 1).

FIG. 1.
FIG. 1.

Axial T1-weighted MR images of brain pathology in our patient cohort: multiple tegmental cystic lesions (A), temporal lobectomy and posterior midbrain encephalomalacia (B), and GPi lead location (C).

Results

The clinical characteristics of the patients are summarized in Table 2 and Fig. 1. The mean age at the time of surgery was 47 years (range 29–65 years). At last follow-up after chronic unilateral GPi DBS therapy, the FTM tremor rating scale score improved from a mean of 53.25 ± 5.73 points before surgery to a mean of 11.25 ± 8.42 points, reflecting a 78.87% improvement. Mean length of follow-up was 33.7 months (range 18–52 months). The time course of clinical improvements varied among patients but we observed meaningful improvement of tremor within the first 6 months of therapy in all patients. Additionally, patients reported subjective improvement in other activities of daily life and in social and work environments.

Details of stimulation settings are shown in Table 2. No surgical complications occurred in our cohort. Transient stimulation-induced side effects were observed during programming and resolved after adjusting DBS parameters; the most commonly observed were corticospinal and/ or corticobulbar side effects. Three of the 4 patients were stimulated in a single monopolar fashion, all with a standard pulse width of 90 μsec and a frequency of 145–185 Hz. A postoperative MR image showing a typical electrode location is shown in Fig. 1 (Case 4).

Case Reports

Case 1

The patient in Case 1 was a 43-year-old man who experienced a midbrain hemorrhage due to a cavernous malformation. Approximately 1 month after his stroke, he developed left HT and severe head tremor unresponsive to medical management. He underwent placement of a right thalamic (VIM) DBS lead for tremor control. One month after continuous VIM simulation the patient reported minimal improvement in his tremor. Subsequently he underwent placement of 2 additional right leads: 1 in the ventral oralis anterior (VOA) thalamic nucleus and 1 in the right GPi. At 2 months postoperatively, the patient reported that his left-hand tremor was controlled with GPi stimulation, even when his VIM stimulator was off. Activation of the VOA lead did not result in further tremor reduction. Three months later, he reported he could now drive a car using his left hand, swing a bat, and pick up marbles individually with his affected hand. Eight months after the GPi/VOA surgery, it was determined that there was no tremor benefit with thalamic stimulation (either VIM or VOA) and only his GPi stimulator was left on. At 4 years follow-up, the patient reported sustained benefit in tremor control, he was still able to drive unassisted, able to hold a cup with his left hand, and cut meat. He notices marked worsening of tremor when his stimulator is turned off. The short-term outcome of this patient has been previously published.33

Case 2

This patient was a 65-year-old man with no prior medical history who developed insidious-onset gait difficulties, imbalance, tremor, urinary urgency, and incontinence. He noticed continuous right-arm, and to a lesser extent, right-leg tremor at rest and with action. Brain MRI demonstrated the presence of a complex, multiloculated, noncontrast-enhancing cyst in the left midbrain tegmentum extending up to the ipsilateral thalamus with evidence of mild hydrocephalus. A ventriculoperitoneal shunt was placed, with initial improvement of his symptoms, including tremor, but then gradually he developed worsening symptoms again of his right-sided tremor, leading to marked functional disability. No improvement was obtained with pharmacotherapy. Stereotactic surgical aspiration of the midbrain cyst was accomplished without tremor improvement. Pathological examination of the cyst ruled out neoplastic, inflammatory, or infectious etiologies. He was diagnosed with cystic brainstem degeneration.50 His neurological examination was remarkable for proximal, large-amplitude, low-frequency severe tremor at rest, with action and posture. Five years after tremor onset he underwent unilateral GPi DBS. He had an excellent response to stimulation 2 months postoperatively. He noticed almost complete tremor resolution, with only occasional exacerbations associated with stress, not interfering with daily activities. He was able to drink from a cup using only 1 hand, able to write legibly with minimal assistance, button clothing, open mail, and hold reading material (Video 1).

VIDEO 1. Clip showing tremor examination before and with pallidal DBS in 1 of our 4 patients with HT. Copyright Jill L. Ostrem. Published with permission. Click here to view with Media Player. Click here to view with Quicktime.

Case 3

This patient was a 29-year-old right-handed man with a history of traumatic brain injury secondary to an occipital gunshot injury at the age of 17. He underwent surgical debridement of occipital bone fragments, followed by an excellent recovery with resolution of initial motor and sensory deficits. He developed slowly progressive and functionally debilitating kinetic, postural, and rest tremor in his right hand. His neurological examination revealed right upper extremity HT. He had great difficulty writing with his dominant hand and was unable to drink from a cup, cut food, or button his shirt. A head CT scan showed bullet fragments and encephalomalacia in the left temporal region and a small hyperdensity in the left thalamus, likely representing a small bullet fragment. The patient underwent stereotactic placement of 2 DBS leads, 1 in the left GPi and 1 in the left VIM thalamus. His tremor almost completely disappeared once stable GPi stimulation parameters were achieved. Independent thalamic DBS resulted in only minor improvement in the postural component. When thalamic stimulation was added to pallidal stimulation, there was no additional tremor control beyond using GPi alone. For this reason, only the GPi lead has been used for chronic neuromodulation. He reported almost no observable tremor in any position, with no limitations in activities of daily living. He is able to write legibly, hold his baby confidently, and drink liquids with 1 hand. He was able to return to work as a handyman 6 months after surgery.

Case 4

This patient was a 50-year-old man with a history of complex partial seizures who underwent right anterior temporal lobectomy in 1997 complicated by a right posterior cerebral artery infarction. Approximately 8 months after surgery, he developed slowly progressive involuntary movements involving his left upper extremity, consisting of left-arm coarse resting and kinetic tremor, associated with intermittent choreiform movements. He reported abnormal sustained hand postures, triggered by specific hand positions suggestive of focal limb dystonia. His neurological examination demonstrated a distal and proximal left upper extremity, low-frequency, high-amplitude, coarse, resting, postural, and kinetic tremor. Brain MRI showed postsurgical changes from the prior right temporal lobectomy, and a right parietooccipital and right posterior thalamic and subthalamic area of encephalomalacia consistent with his history of a prior right posterior cerebral artery stroke. The patient underwent unilateral right GPi DBS placement. Initial programming in monopolar mode resulted in partial improvement of his hyperkinetic movements 5 weeks after surgery. He obtained almost complete control of his symptoms and improvement in limb function after optimal neuromodulation parameters were achieved. He has regained skilled use of his hand. He is able to hold and drink from a cup, tie his shoes, cut his food, and use keys normally.

Neurophysiological Findings

Twenty-eight GPi neurons recorded in the resting state were analyzed and 13 of these were also analyzed during contralateral voluntary arm movement. Example recordings and their power spectra are shown in Fig. 2, and neuronal discharge data are summarized in Table 3. The mean firing rate in HT was 56.2 ± 28.5 Hz at rest, and 63.5 ± 19.4 Hz with action. The mean firing rate in HT was significantly lower than that for a PD patient cohort recorded and analyzed with identical techniques at our institution (p < 0.001). Bursting discharge was prominent in both HT and PD, but quantitatively greater in HT. Of note, the frequency of spike discharge within identified bursts was higher in PD, consistent with the recently published finding that elevated intraburst discharge rate is one of the most sensitive markers of the parkinsonian state.51 Neuronal oscillations at or near tremor frequency (2–8 Hz) were prominent in both HT and PD in the resting state (no voluntary movement). The major distinguishing feature of oscillatory discharge in HT was its persistence during active movement, in contrast to PD, for which movement totally suppresses 2–8 Hz neuronal oscillations (Fig. 2 and Table 3).

FIG. 2.
FIG. 2.

Oscillatory single-unit GPi discharge in HT. Images on the left side represent discharge at rest, while those on the right represent discharges during voluntary continuous self-paced flexion-extension elbow movements. A segment of neuronal discharge is shown at the top, and below it the corresponding power spectrum for the entire recording. Tremor frequency discharge is present during both rest and voluntary movement. PSD = power spectral density.

TABLE 3

Globus pallidus internus single-unit discharge characteristics in HT compared with PD

GPi Single-Unit Discharge CharacteristicAt RestDuring Voluntary Movement
HTPD Cohortp ValueHTPD Cohortp Value
No. of neurons281321323
Mean firing rate ± SD (spikes/sec)56.2 ± 28.594.8 ± 23.7< 0.00163.5 ± 19.4102.1 ± 24.1< 0.001
Proportion of spikes in bursts0.110.06< 0.0010.130.040.004
Mean intraburst firing rate ± SD (spikes/sec)182.4 ± 63.6245.3 ± 46.5< 0.001214.7 ± 47.9270.4 ± 43.00.008
Proportion of cells w/ significant oscillations (Hz)
 2–3543%28%0.1146%9%0.008
 2–8*43%27%0.1046%0%< 0.001
 13–35*4%3%0.910%9%0.29
Median frequency of oscillations between 2 and 35 Hz4.8%4.4%0.493.2%21.4%0.07

A unit may have significant oscillations in multiple frequency bands.

Statistically significant p values (< 0.05) in bold.

Discussion

In this article, we report the long-term outcomes of 4 patients who underwent GPi DBS for medically refractory HT treated at our institution. All patients experienced significant improvement in tremor control, with a mean tremor improvement of 79% at the last follow-up appointment. These results are, in general, superior to those reported for other thalamic surgeries in patients with medically intractable HT.

Prior Surgical Approaches to HT

Holmes tremor may respond to levodopa, trihexyphenidyl, clonazepam, cabergoline, levetiracetam, bromocriptine, and piribedil, as well as zonisamide,2,5,12,53,59–61,63 but pharmacotherapy is often unsatisfactory. The success of thalamotomy and chronic thalamic stimulation in essential tremor and parkinsonian tremor led to their application in HT6,52 and other uncommon tremors. In contrast to the small VIM lesions that are effective for parkinsonian tremor, HT requires large lesions, which may have significant permanent adverse effects.19 The effectiveness of thalamotomy in HT often wanes with time.3,27,29 Over the course of weeks to months, despite continuous thalamic stimulation, tremor is often refractory or recurs.18,21,62,66 The effectiveness of ventrolateral thalamic DBS in HT remains uncertain due to the limited number of cases, relatively short follow-up, and diverse outcome scales used1,13,42,50 (Table 1).

Other targets have been proposed as alternatives to achieve better tremor control, including stimulation with multiple leads. Romanelli et al. performed unilateral stimulation of both the VIM nucleus and the subthalamic nucleus (STN) in a single patient with HT as the resting component was not improved after VIM DBS.48 Foote et al. implanted unilateral twin cerebellar receiving area (VIM) and pallidal receiving area (VOA/ventral oralis posterior [VOP]) thalamic DBS leads.15 Dual thalamic stimulation resulted in significant improvement in tremor scales without rebound after 6 months of follow-up. Thalamic and dorsal or posterior STN DBS has been described in multiple case reports in patients with HT secondary to pontomesencephalic lesions with variable short-term results.4,9–11,25,27,29,30,33,34,37–40,43,49,50 Recently Kobayashi et al. reported 2-year outcome with dual thalamic and subthalamic area stimulation in 4 patients with HT, with significant benefit.28

Based on the suboptimal results of thalamic stimulation for HT in the literature and in our own experience, we sought alternative targets for chronic stimulation. We hypothesized that modulation of the basal ganglia outflow pathways (GPi) might be superior to that of thalamic DBS. This concept is supported by 2 case reports showing a beneficial effect of pallidal lesioning on HT.17,36 Two of our cases used combined thalamic and GPi DBS, but GPi DBS alone proved to be effective and the thalamic leads were eventually not used, prompting us to implant only GPi leads in the subsequent cases.

Pathophysiology of HT Reconsidered

The major long-term benefit of GPi DBS in HT shown here is consistent with emerging concepts of the connectivity between cerebellar and basal ganglia systems. Although HT was originally conceptualized as a disorder of the cerebellothalamic system, there has recently been a greater appreciation of the interaction of cerebellar and basal ganglia pathways, especially via thalamostriate connections.22 We propose that this interaction is critical to the genesis of tremor in HT, and that neuromodulation of thalamic targets has been relatively ineffective due to the anatomically dispersed nature of thalamic projections to the striatum,54 involving both medial and lateral thalamic nuclei. In addition, some HT cases may have a component of direct basal ganglia damage via involvement of the midbrain substantia nigra compacta. However, the mean pallidal firing rates, as well firing rates within neuronal bursts, were much lower than those of PD and were consistent with nonparkinsonian disorders.56 An elevation in basal ganglia output, and in the firing rate within burst discharges, would be expected if nigrostriatal denervation was a major contributor to the pathophysiology of HT.51

Limitations of the Study

The present study has some limitations. The clinical data were collected in a retrospective nonblinded fashion. The neurophysiological and clinical results presented only include 4 patients. Isolation of single units is challenging due to high neuronal density and periodic loss of unit isolation in synchrony with the cardiac cycle. As a result, the number of stable, well-isolated units recorded from each study participant was small. Given the absence of prior reports of neurophysiological characteristics in HT, however, we believe that these results represents an important contribution to the understanding of this tremor disorder.

Conclusions

Globus pallidus internus DBS provided excellent tremor control in a series of 4 patients with HT of diverse etiologies. The clinical and neurophysiological findings of this study support evolving models of HT that emphasize the interconnectedness between cerebellothalamic and basal ganglia pathways in its pathophysiology.

Acknowledgment

We would like to thank Leslie Markun, BS, for her help with creating and editing the patient video.

Author Contributions

Conception and design: Ostrem. Acquisition of data: Kilbane, Ramirez-Zamora, Ryapolova-Webb, Qasim, Glass, Starr. Analysis and interpretation of data: Ostrem, Kilbane, Ramirez-Zamora, Starr. Drafting the article: Kilbane, Ramirez-Zamora. Critically revising the article: Ostrem, Ryapolova-Webb, Qasim, Glass, Starr. Reviewed submitted version of manuscript: Ostrem, Glass, Starr. Approved the final version of the manuscript on behalf of all authors: Ostrem. Statistical analysis: Kilbane, Ramirez-Zamora, Ryapolova-Webb, Qasim, Glass, Starr.

Supplemental Information

Previous Presentation

Part of this work was previously presented in poster form at the American Society for Stereotactic and Functional Neurosurgery in San Francisco, California, in May 2012.

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  • 16

    Gajos ABogucki ASchinwelski MSołtan WRudzińska MBudrewicz S: The clinical and neuroimaging studies in Holmes tremor. Acta Neurol Scand 122:3603662010

  • 17

    Goto SYamada K: Combination of thalamic Vim stimulation and GPi pallidotomy synergistically abolishes Holmes' tremor. J Neurol Neurosurg Psychiatry 75:120312042004

  • 18

    Hassan AAhlskog JERodriguez MMatsumoto JY: Surgical therapy for multiple sclerosis tremor: a 12-year follow-up study. Eur J Neurol 19:7647682012

  • 19

    Hirai TMiyazaki MNakajima HShibazaki TOhye C: The correlation between tremor characteristics and the predicted volume of effective lesions in stereotaxic nucleus ventralis intermedius thalamotomy. Brain 106:100110181983

  • 20

    Holmes G: On certain tremors in organic cerebral lesions. Brain 27:3273751904

  • 21

    Hooper JTaylor RPentland BWhittle IR: A prospective study of thalamic deep brain stimulation for the treatment of movement disorders in multiple sclerosis. Br J Neurosurg 16:1021092002

  • 22

    Hoshi ETremblay LFéger JCarras PLStrick PL: The cerebellum communicates with the basal ganglia. Nat Neurosci 8:149114932005

  • 23

    Hutchison WDLang AEDostrovsky JOLozano AM: Pallidal neuronal activity: implications for models of dystonia. Ann Neurol 53:4804882003

  • 24

    Inci SCelik OSoylemezoglu FOzgen T: Thalamomesencephalic ossified cavernoma presenting with Holmes' tremor. Surg Neurol 67:5115162007

  • 25

    Issar NMHedera PPhibbs FTKonrad PENeimat JS: Treating post-traumatic tremor with deep brain stimulation: report of five cases. Parkinsonism Relat Disord 19:110011052013

  • 26

    Kim DGKoo YHKim OJOh SH: Development of Holmes' tremor in a patient with Parkinson's disease following acute cerebellar infarction. Mov Disord 24:4634642009

  • 27

    Kim MCSon BCMiyagi YKang JK: Vim thalamotomy for Holmes' tremor secondary to midbrain tumour. J Neurol Neurosurg Psychiatry 73:4534552002

  • 28

    Kobayashi KKatayama YOshima HWatanabe MSumi KObuchi T: Multitarget, dual-electrode deep brain stimulation of the thalamus and subthalamic area for treatment of Holmes' tremor. J Neurosurg 120:102510322014

  • 29

    Krauss JKMohadjer MNobbe FMundinger F: The treatment of posttraumatic tremor by stereotactic surgery. Symptomatic and functional outcome in a series of 35 patients. J Neurosurg 80:8108191994

  • 30

    Kudo MGoto SNishikawa SHamasaki TSoyama NUshio Y: Bilateral thalamic stimulation for Holmes' tremor caused by unilateral brainstem lesion. Mov Disord 16:1701742001

  • 31

    Legéndy CRSalcman M: Bursts and recurrences of bursts in the spike trains of spontaneously active striate cortex neurons. J Neurophysiol 53:9269391985

  • 32

    Lekoubou ANjouoguep RKuate CKengne AP: Cerebral toxoplasmosis in Acquired Immunodeficiency Syndrome (AIDS) patients also provides unifying pathophysiologic hypotheses for Holmes tremor. BMC Neurol 10:372010

  • 33

    Lim DAKhandhar SMHeath SOstrem JLRingel NStarr P: Multiple target deep brain stimulation for multiple sclerosis related and poststroke Holmes' tremor. Stereotact Funct Neurosurg 85:1441492007

  • 34

    Louis EDBarnes LWendt KJFord BSangiorgio MTabbal S: A teaching videotape for the assessment of essential tremor. Mov Disord 16:89932001

  • 35

    Martin AJLarson PSOstrem JLSootsman WKTalke PWeber OM: Placement of deep brain stimulator electrodes using real-time high-field interventional magnetic resonance imaging. Magn Reson Med 54:110711142005

  • 36

    Miyagi YShima FIshido KMoriguchi MKamikaseda K: Posteroventral pallidotomy for midbrain tremor after a pontine hemorrhage. Case report. J Neurosurg 91:8858881999

  • 37

    Movement Disorder Society Task Force on Rating Scales for Parkinson's Disease: The Unified Parkinson's Disease Rating Scale (UPDRS): status and recommendations. Mov Disord 18:7387502003

  • 38

    Nikkhah GProkop THellwig BLücking CHOstertag CB: Deep brain stimulation of the nucleus ventralis intermedius for Holmes (rubral) tremor and associated dystonia caused by upper brainstem lesions. Report of two cases. J Neurosurg 100:107910832004

  • 39

    Pahwa RLyons KEKempf LWilkinson SBKoller WC: Thalamic stimulation for midbrain tremor after partial hemangioma resection. Mov Disord 17:4044072002

  • 40

    Peker SIsik UAkgun YOzek M: Deep brain stimulation for Holmes' tremor related to a thalamic abscess. Childs Nerv Syst 24:105710622008

  • 41

    Pezzini AZavarise PPalvarini LViale POladeji OPadovani A: Holmes' tremor following midbrain Toxoplasma abscess: clinical features and treatment of a case. Parkinsonism Relat Disord 8:1771802002

  • 42

    Piette TMescola PHenriet MCornil CJacquy JVanderkelen B: [A surgical approach to Holmes' tremor associated with high-frequency synchronous bursts.]. Rev Neurol (Paris) 160:7077112004. (Fr)

  • 43

    Plaha PKhan SGill SS: Bilateral stimulation of the caudal zona incerta nucleus for tremor control. J Neurol Neurosurg Psychiatry 79:5045132008

  • 44

    Raina GBVelez MPardal MFMicheli F: Holmes tremor secondary to brainstem hemorrhage responsive to levodopa: report of 2 cases. Clin Neuropharmacol 30:951002007

  • 45

    Remy Pde Recondo ADefer GLoc'h CAmarenco PPlanté-Bordeneuve V: Peduncular ‘rubral' tremor and dopaminergic denervation: a PET study. Neurology 45:4724771995

  • 46

    Rezai ARPhillips MBaker KBSharan ADNyenhuis JTkach J: Neurostimulation system used for deep brain stimulation (DBS): MR safety issues and implications of failing to follow safety recommendations. Invest Radiol 39:3003032004

  • 47

    Rivlin-Etzion MRitov YHeimer GBergman HBar-Gad I: Local shuffling of spike trains boosts the accuracy of spike train spectral analysis. J Neurophysiol 95:324532562006

  • 48

    Romanelli PBrontë-Stewart HCourtney THeit G: Possible necessity for deep brain stimulation of both the ventralis intermedius and subthalamic nuclei to resolve Holmes tremor. Case report. J Neurosurg 99:5665712003

  • 49

    Samadani UUmemura AJaggi JLColcher AZager ELBaltuch GH: Thalamic deep brain stimulation for disabling tremor after excision of a midbrain cavernous angioma. Case report. J Neurosurg 98:8888902003

  • 50

    Sanborn MRDanish SFRanalli NJGrady MSJaggi JLBaltuch GH: Thalamic deep brain stimulation for midbrain tremor secondary to cystic degeneration of the brainstem. Stereotact Funct Neurosurg 87:1281332009

  • 51

    Sanders THClements MAWichmann T: Parkinsonism-related features of neuronal discharge in primates. J Neurophysiol 110:7207312013

  • 52

    Schuurman PRBosch DABossuyt PMBonsel GJvan Someren EJde Bie RM: A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. N Engl J Med 342:4614682000

  • 53

    Seidel SKasprian GLeutmezer FPrayer DAuff E: Disruption of nigrostriatal and cerebellothalamic pathways in dopamine responsive Holmes' tremor. J Neurol Neurosurg Psychiatry 80:9219232009

  • 54

    Smith YRaju DVPare JFSidibe M: The thalamostriatal system: a highly specific network of the basal ganglia circuitry. Trends Neurosci 27:5205272004

  • 55

    Starr PAKang GAHeath SShimamoto STurner RS: Pallidal neuronal discharge in Huntington's disease: support for selective loss of striatal cells originating the indirect pathway. Exp Neurol 211:2272332008

  • 56

    Starr PARau GMDavis VMarks WJ JrOstrem JLSimmons D: Spontaneous pallidal neuronal activity in human dystonia: comparison with Parkinson's disease and normal macaque. J Neurophysiol 93:316531762005

  • 57

    Starr PATurner RSRau GLindsey NHeath SVolz M: Microelectrode-guided implantation of deep brain stimulators into the globus pallidus internus for dystonia: techniques, electrode locations, and outcomes. J Neurosurg 104:4885012006

  • 58

    Steigerwald FHinz LPinsker MOHerzog JStiller RUKopper F: Effect of propofol anesthesia on pallidal neuronal discharges in generalized dystonia. Neurosci Lett 386:1561592005

  • 59

    Strecker KSchneider JPSabri OWegner FThen Bergh FSchwarz J: Responsiveness to a dopamine agent in Holmes tremor—case report. Eur J Neurol 14:e9e102007

  • 60

    Striano PElefante ACoppola ATortora FZara FMinetti C: Dramatic response to levetiracetam in post-ischaemic Holmes' tremor. J Neurol Neurosurg Psychiatry 78:4384392007

  • 61

    Suda SYamazaki MKatsura KFukuchi TKaneko NUeda M: Dramatic response to zonisamide of post-subarachnoid hemorrhage Holmes' tremor. J Neurol 259:1851872012

  • 62

    Torres CVMoro ELopez-Rios ALHodaie MChen RLaxton AW: Deep brain stimulation of the ventral intermediate nucleus of the thalamus for tremor in patients with multiple sclerosis. Neurosurgery 67:6466512010

  • 63

    Vélez MCosentino CTorres L: Levodopa-responsive rubral (Holmes') tremor. Mov Disord 17:7417422002

  • 64

    Walker MKim HSamii A: Holmes-like tremor of the lower extremity following brainstem hemorrhage. Mov Disord 22:2722742007

  • 65

    Wichmann TBergman HStarr PASubramanian TWatts RLDeLong MR: Comparison of MPTP-induced changes in spontaneous neuronal discharge in the internal pallidal segment and in the substantia nigra pars reticulata in primates. Exp Brain Res 125:3974091999

  • 66

    Wishart HARoberts DWRoth RMMcDonald BCCoffey DJMamourian AC: Chronic deep brain stimulation for the treatment of tremor in multiple sclerosis: review and case reports. J Neurol Neurosurg Psychiatry 74:139213972003

  • 67

    Yerdelen DKaratas MGoksel BYildirim T: A patient with multiple sclerosis presenting with Holmes' tremor. Eur J Neurol 15:e2e32008

  • 68

    Zhong JLi STXu SQWan L: Holmes' tremor caused by midbrain cavernoma. Chin Med J (Engl) 120:205920612007

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

Correspondence Jill Louise Ostrem, UCSF Surgical Movement Disorder Center, 1635 Divisadero St., Ste. 520-530, San Francisco, CA 94115. email: jill.ostrem@ucsf.edu.

INCLUDE WHEN CITING Published online March 20, 2015; DOI: 10.3171/2015.2.JNS141098.

DISCLOSURE Dr. Ostrem has received support for non–study-related clinical or research effort from St. Jude Medical, Boston Scientific, and MRI Interventions, and has also received a fellowship training grant from Medtronic.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Axial T1-weighted MR images of brain pathology in our patient cohort: multiple tegmental cystic lesions (A), temporal lobectomy and posterior midbrain encephalomalacia (B), and GPi lead location (C).

  • View in gallery

    Oscillatory single-unit GPi discharge in HT. Images on the left side represent discharge at rest, while those on the right represent discharges during voluntary continuous self-paced flexion-extension elbow movements. A segment of neuronal discharge is shown at the top, and below it the corresponding power spectrum for the entire recording. Tremor frequency discharge is present during both rest and voluntary movement. PSD = power spectral density.

References

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Baysal LAcarer ACelebisoy N: Post-ischemic Holmes' tremor of the lower extremities. J Neurol 256:207920812009

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Ferlazzo EMorgante FRizzo VSciarrone GMeduri MMagaudda A: Successful treatment of Holmes tremor by levetiracetam. Mov Disord 23:210121032008

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Follett MATorres-Russotto DFollett KA: Bilateral Deep brain stimulation of the ventral intermediate nucleus of the thalamus for posttraumatic midbrain tremor. Neuromodulation 17:2892912014

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Foote KDOkun 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 56:2 SupplE4452005

15

Foote KDSeignourel PFernandez HHRomrell JWhidden EJacobson C: Dual electrode thalamic deep brain stimulation for the treatment of posttraumatic and multiple sclerosis tremor. Neurosurgery 58:4 Suppl 2ONS-280ONS-2862006

16

Gajos ABogucki ASchinwelski MSołtan WRudzińska MBudrewicz S: The clinical and neuroimaging studies in Holmes tremor. Acta Neurol Scand 122:3603662010

17

Goto SYamada K: Combination of thalamic Vim stimulation and GPi pallidotomy synergistically abolishes Holmes' tremor. J Neurol Neurosurg Psychiatry 75:120312042004

18

Hassan AAhlskog JERodriguez MMatsumoto JY: Surgical therapy for multiple sclerosis tremor: a 12-year follow-up study. Eur J Neurol 19:7647682012

19

Hirai TMiyazaki MNakajima HShibazaki TOhye C: The correlation between tremor characteristics and the predicted volume of effective lesions in stereotaxic nucleus ventralis intermedius thalamotomy. Brain 106:100110181983

20

Holmes G: On certain tremors in organic cerebral lesions. Brain 27:3273751904

21

Hooper JTaylor RPentland BWhittle IR: A prospective study of thalamic deep brain stimulation for the treatment of movement disorders in multiple sclerosis. Br J Neurosurg 16:1021092002

22

Hoshi ETremblay LFéger JCarras PLStrick PL: The cerebellum communicates with the basal ganglia. Nat Neurosci 8:149114932005

23

Hutchison WDLang AEDostrovsky JOLozano AM: Pallidal neuronal activity: implications for models of dystonia. Ann Neurol 53:4804882003

24

Inci SCelik OSoylemezoglu FOzgen T: Thalamomesencephalic ossified cavernoma presenting with Holmes' tremor. Surg Neurol 67:5115162007

25

Issar NMHedera PPhibbs FTKonrad PENeimat JS: Treating post-traumatic tremor with deep brain stimulation: report of five cases. Parkinsonism Relat Disord 19:110011052013

26

Kim DGKoo YHKim OJOh SH: Development of Holmes' tremor in a patient with Parkinson's disease following acute cerebellar infarction. Mov Disord 24:4634642009

27

Kim MCSon BCMiyagi YKang JK: Vim thalamotomy for Holmes' tremor secondary to midbrain tumour. J Neurol Neurosurg Psychiatry 73:4534552002

28

Kobayashi KKatayama YOshima HWatanabe MSumi KObuchi T: Multitarget, dual-electrode deep brain stimulation of the thalamus and subthalamic area for treatment of Holmes' tremor. J Neurosurg 120:102510322014

29

Krauss JKMohadjer MNobbe FMundinger F: The treatment of posttraumatic tremor by stereotactic surgery. Symptomatic and functional outcome in a series of 35 patients. J Neurosurg 80:8108191994

30

Kudo MGoto SNishikawa SHamasaki TSoyama NUshio Y: Bilateral thalamic stimulation for Holmes' tremor caused by unilateral brainstem lesion. Mov Disord 16:1701742001

31

Legéndy CRSalcman M: Bursts and recurrences of bursts in the spike trains of spontaneously active striate cortex neurons. J Neurophysiol 53:9269391985

32

Lekoubou ANjouoguep RKuate CKengne AP: Cerebral toxoplasmosis in Acquired Immunodeficiency Syndrome (AIDS) patients also provides unifying pathophysiologic hypotheses for Holmes tremor. BMC Neurol 10:372010

33

Lim DAKhandhar SMHeath SOstrem JLRingel NStarr P: Multiple target deep brain stimulation for multiple sclerosis related and poststroke Holmes' tremor. Stereotact Funct Neurosurg 85:1441492007

34

Louis EDBarnes LWendt KJFord BSangiorgio MTabbal S: A teaching videotape for the assessment of essential tremor. Mov Disord 16:89932001

35

Martin AJLarson PSOstrem JLSootsman WKTalke PWeber OM: Placement of deep brain stimulator electrodes using real-time high-field interventional magnetic resonance imaging. Magn Reson Med 54:110711142005

36

Miyagi YShima FIshido KMoriguchi MKamikaseda K: Posteroventral pallidotomy for midbrain tremor after a pontine hemorrhage. Case report. J Neurosurg 91:8858881999

37

Movement Disorder Society Task Force on Rating Scales for Parkinson's Disease: The Unified Parkinson's Disease Rating Scale (UPDRS): status and recommendations. Mov Disord 18:7387502003

38

Nikkhah GProkop THellwig BLücking CHOstertag CB: Deep brain stimulation of the nucleus ventralis intermedius for Holmes (rubral) tremor and associated dystonia caused by upper brainstem lesions. Report of two cases. J Neurosurg 100:107910832004

39

Pahwa RLyons KEKempf LWilkinson SBKoller WC: Thalamic stimulation for midbrain tremor after partial hemangioma resection. Mov Disord 17:4044072002

40

Peker SIsik UAkgun YOzek M: Deep brain stimulation for Holmes' tremor related to a thalamic abscess. Childs Nerv Syst 24:105710622008

41

Pezzini AZavarise PPalvarini LViale POladeji OPadovani A: Holmes' tremor following midbrain Toxoplasma abscess: clinical features and treatment of a case. Parkinsonism Relat Disord 8:1771802002

42

Piette TMescola PHenriet MCornil CJacquy JVanderkelen B: [A surgical approach to Holmes' tremor associated with high-frequency synchronous bursts.]. Rev Neurol (Paris) 160:7077112004. (Fr)

43

Plaha PKhan SGill SS: Bilateral stimulation of the caudal zona incerta nucleus for tremor control. J Neurol Neurosurg Psychiatry 79:5045132008

44

Raina GBVelez MPardal MFMicheli F: Holmes tremor secondary to brainstem hemorrhage responsive to levodopa: report of 2 cases. Clin Neuropharmacol 30:951002007

45

Remy Pde Recondo ADefer GLoc'h CAmarenco PPlanté-Bordeneuve V: Peduncular ‘rubral' tremor and dopaminergic denervation: a PET study. Neurology 45:4724771995

46

Rezai ARPhillips MBaker KBSharan ADNyenhuis JTkach J: Neurostimulation system used for deep brain stimulation (DBS): MR safety issues and implications of failing to follow safety recommendations. Invest Radiol 39:3003032004

47

Rivlin-Etzion MRitov YHeimer GBergman HBar-Gad I: Local shuffling of spike trains boosts the accuracy of spike train spectral analysis. J Neurophysiol 95:324532562006

48

Romanelli PBrontë-Stewart HCourtney THeit G: Possible necessity for deep brain stimulation of both the ventralis intermedius and subthalamic nuclei to resolve Holmes tremor. Case report. J Neurosurg 99:5665712003

49

Samadani UUmemura AJaggi JLColcher AZager ELBaltuch GH: Thalamic deep brain stimulation for disabling tremor after excision of a midbrain cavernous angioma. Case report. J Neurosurg 98:8888902003

50

Sanborn MRDanish SFRanalli NJGrady MSJaggi JLBaltuch GH: Thalamic deep brain stimulation for midbrain tremor secondary to cystic degeneration of the brainstem. Stereotact Funct Neurosurg 87:1281332009

51

Sanders THClements MAWichmann T: Parkinsonism-related features of neuronal discharge in primates. J Neurophysiol 110:7207312013

52

Schuurman PRBosch DABossuyt PMBonsel GJvan Someren EJde Bie RM: A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. N Engl J Med 342:4614682000

53

Seidel SKasprian GLeutmezer FPrayer DAuff E: Disruption of nigrostriatal and cerebellothalamic pathways in dopamine responsive Holmes' tremor. J Neurol Neurosurg Psychiatry 80:9219232009

54

Smith YRaju DVPare JFSidibe M: The thalamostriatal system: a highly specific network of the basal ganglia circuitry. Trends Neurosci 27:5205272004

55

Starr PAKang GAHeath SShimamoto STurner RS: Pallidal neuronal discharge in Huntington's disease: support for selective loss of striatal cells originating the indirect pathway. Exp Neurol 211:2272332008

56

Starr PARau GMDavis VMarks WJ JrOstrem JLSimmons D: Spontaneous pallidal neuronal activity in human dystonia: comparison with Parkinson's disease and normal macaque. J Neurophysiol 93:316531762005

57

Starr PATurner RSRau GLindsey NHeath SVolz M: Microelectrode-guided implantation of deep brain stimulators into the globus pallidus internus for dystonia: techniques, electrode locations, and outcomes. J Neurosurg 104:4885012006

58

Steigerwald FHinz LPinsker MOHerzog JStiller RUKopper F: Effect of propofol anesthesia on pallidal neuronal discharges in generalized dystonia. Neurosci Lett 386:1561592005

59

Strecker KSchneider JPSabri OWegner FThen Bergh FSchwarz J: Responsiveness to a dopamine agent in Holmes tremor—case report. Eur J Neurol 14:e9e102007

60

Striano PElefante ACoppola ATortora FZara FMinetti C: Dramatic response to levetiracetam in post-ischaemic Holmes' tremor. J Neurol Neurosurg Psychiatry 78:4384392007

61

Suda SYamazaki MKatsura KFukuchi TKaneko NUeda M: Dramatic response to zonisamide of post-subarachnoid hemorrhage Holmes' tremor. J Neurol 259:1851872012

62

Torres CVMoro ELopez-Rios ALHodaie MChen RLaxton AW: Deep brain stimulation of the ventral intermediate nucleus of the thalamus for tremor in patients with multiple sclerosis. Neurosurgery 67:6466512010

63

Vélez MCosentino CTorres L: Levodopa-responsive rubral (Holmes') tremor. Mov Disord 17:7417422002

64

Walker MKim HSamii A: Holmes-like tremor of the lower extremity following brainstem hemorrhage. Mov Disord 22:2722742007

65

Wichmann TBergman HStarr PASubramanian TWatts RLDeLong MR: Comparison of MPTP-induced changes in spontaneous neuronal discharge in the internal pallidal segment and in the substantia nigra pars reticulata in primates. Exp Brain Res 125:3974091999

66

Wishart HARoberts DWRoth RMMcDonald BCCoffey DJMamourian AC: Chronic deep brain stimulation for the treatment of tremor in multiple sclerosis: review and case reports. J Neurol Neurosurg Psychiatry 74:139213972003

67

Yerdelen DKaratas MGoksel BYildirim T: A patient with multiple sclerosis presenting with Holmes' tremor. Eur J Neurol 15:e2e32008

68

Zhong JLi STXu SQWan L: Holmes' tremor caused by midbrain cavernoma. Chin Med J (Engl) 120:205920612007

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