Thalamic‐Caudal Zona Incerta Deep Brain Stimulation for Refractory Orthostatic Tremor: A Report of 3 Cases

Abstract

Orthostatic tremor (OT) is a rare, disabling movement disorder characterized by the development of a high‐frequency tremor of the lower limbs and feelings of unsteadiness upon standing, which compel the patient to sit down or walk. Medical therapy is often unsatisfactory. Previous reports suggest that deep brain stimulation of the ventral intermediate nucleus of the thalamus may improve clinical outcomes. The authors report 3 patients who had intractable orthostatic tremor treated with bilateral deep brain stimulation of the ventral intermediate nucleus of the thalamus‐caudal zona incerta, resulting in improved and sustained clinical improvements in symptoms, although there were no apparent changes in the underlying tremor frequency or onset.

First reported in 1970 by Pazzaglia and colleagues, the term orthostatic tremor (OT) was coined by Heilman in 1984 to describe a tremor of the legs or trunk induced by standing, causing feelings of unsteadiness or shakiness, compelling patients to sit or walk.1, 2 Although falls are uncommon, symptoms invariably progress and can cause considerable distress to quality of life. Development of a concurrent upper‐limb tremor is not uncommon, and 11% to 15% of patients have additional neurological features, such as parkinsonism or ataxia, termed “OT‐plus.”3, 4 Electromyography (EMG) reveals a characteristic, high‐frequency tremor of 13 to 18 Hz in the lower limbs that demonstrates high intermuscular coherence, which can be used to differentiate it from other types of tremor. Clinical examination may reveal a barely detectable ripple of leg muscles, although auscultation with a stethoscope over the thigh, quadriceps, and hamstrings can reveal a repetitive thumping sound—the so‐called helicopter sign.5 Although anecdotal evidence suggests that treatment with clonazepam, gabapentin, and other antitremor drugs may offer some benefit to patients, the results are often unsatisfactory.3, 6 The pathophysiology of OT is unclear; OT is generally thought to originate from a central oscillator, but involvement of the spinal cord has also been postulated, and surgical treatment for refractory OT has been reported in a small number of patients. Deep brain stimulation (DBS) of the ventral intermediate (ViM) nucleus of the thalamus has been reported in 8 patients, and spinal cord dorsal column stimulation also has been reported in 3 patients (Table 1).

Table 1.

Deep Brain and Spinal Cord Stimulation for the Treatment of Orthostatic Tremor^a

Patient	Patient Age, y	Symptom Duration, y	Previous Medications	DBS Target	Clinical Outcome	EMG Correlate (Reference)
1	54	11	Propranolol, clonazepam, gabapentin, levitiracetem, primidone, trihexyphendyl	Bilateral ViM of thalamus	Tremor free for 4 wk post‐op; symptoms returned but increased latency to symptom onset > 12 mo; drug free	Reduction in amplitude; no change in frequency (Gerschlager et al., 20046)
2	73	28	Clonazepam, valproate, primidone	Bilateral ViM of thalamus	Increased latency to symptom onset sustained > 18 mo; reduction in drugs	Reduction in amplitude; no change in frequency (Guridi et al., 20087)
3	67	30	Gabapentin, atenolol, clonazepam	Unilateral ViM of thalamus	Symptom free for 3 mo, but returned to presurgical level of severity	Reduction in amplitude; no change in frequency (Guridi et al., 20087)
4	68	—	Propranolol, gabapentin, clonazepam, primidone, ropirinole	Bilateral ViM of thalamus	Increased latency to symptom onset sustained > 12 mo; drug free	Reduction in amplitude; no change in frequency (Espay et al., 20088)
5	82	5	Clonazepam, gabapentin, topiramate, l‐dopa, pregabalin, phenobarbital, zonisamide	Bilateral ViM of thalamus	Increased latency to symptom onset sustained > 6 mo; improvement in associated arm tremor	— (Magarinos‐Ascone et al., 20109)
6	75	10	Acetazolamide, primidone, clonazepam, topiramate, gabapentin, valproate	Bilateral ViM of thalamus	Post‐op infection of IPG; increased latency to symptom onset sustained > 30 mo; drug free	Less rhythmic tremor, intermittent slowing of frequency (Yaltho and Ondo, 201110; Lyons et al., 201211)
7	—	—	—	Bilateral ViM of thalamus	—	— (Muthuraman et al., 201312)
8	70	20	Clonazepam, gabapentin, pramipexole	Bilateral ViM of thalamus	Increased latency to symptom onset; electrodes repositioned at 12 mo due to decreased efficacy; decreasing efficacy at 5 y	Reduction in amplitude; slight shift in frequency to 14 Hz (Lyons et al., 201211)
9	58	10	Primidone, clonazepam, l‐dopa	Bilateral dorsal column D11/D12	Increased latency to symptom onset sustained > 36 mo	Reduction in amplitude; no change in frequency (Krauss et al., 200614)
10	72	8	Primidone, clonazepam, l‐dopa	Bilateral dorsal column D11/D12	Increased latency to symptom onset > 12 mo	Reduction in amplitude; no change in frequency (Krauss et al., 200614)
11	73	26	—	“Spinal cord stimulator”	Increased latency to symptom onset at 19 mo; repeated infections induced removal of device; symptoms returned to pre‐op severity	— (Ganos et al., 20163)

^aSearch criteria: PubMed was searched for articles published between September 1970 and December 2015. Medical Subject Heading (MeSH) search terms were “orthostatic tremor” alone and in combination with “deep brain stimulation,” “spinal cord stimulation,” “review,” “thalamic,” and “case report.” Only full articles in English were reviewed. Articles were selected for their relevance. Note that the individual listed as patient 7 in this table is included for completeness, although insufficient data exist in the published article to describe the outcome from surgery.

DBS, deep brain stimulation; EMG, electromyography; ViM, ventral intermediate nucleus of the thalamus; l‐dopa, levodopa; post‐op, postoperative; IPG, implantable pulse generator; pre‐op, preoperative.

In this report, we describe the clinical and electrophysiological effects of high‐frequency DBS of the ViM nucleus of the thalamus‐caudal zona incerta in 3 patients suffering from refractory OT.

Cases

Patient 1 (a 46‐year‐old woman) complained of a 20‐year history of unsteadiness during standing that was relieved on sitting, leaning, or walking. The latency between standing and the onset of unsteadiness remained at 30 seconds since onset, although, in the year preceding assessment, she also developed an alcohol‐responsive kinetic tremor of the right hand and subjective worsening unsteadiness, resulting in difficulties performing activities of daily living such as cleaning and cooking. Various medications, including clonazepam, primidone, levodopa (l‐dopa), gabapentin, ropinirole, and levetiracetam, were tried at tolerable doses but were uniformly ineffective. A surface EMG revealed a 16‐Hz lower‐limb tremor, which was coherent across 3 leg muscles (Fig. 1) and appeared as the patient rose to stand, which induced her to sit down after 30 seconds. Neurological examination revealed an action tremor of the right hand but no other signs of neurological disease. She underwent bilateral ViM‐caudal zona incerta implantation of DBS electrodes (model 3389; Medtronic, Minneapolis, MN) using our standard magnetic resonance imaging (MRI)‐guided, MRI‐verified stereotactic procedure.15 Immediate postoperative stereotactic MRI confirmed accurate electrode placement (Fig. 2A) and an implantable pulse generator (Activa PC; Medtronic) was connected 7 days later. All drugs were withdrawn after surgery; and, following resolution of an initial microlesioning effect, stimulation was programmed (left: 1[+], 2[−], 3[+], 1.7 V, 60 microseconds [μsec], 130 Hz; and right: 9[+], 10[−], 11[+], 1.7 V, 60 μsec, 130 Hz). Nine months after surgery, gait analysis and EMG evaluation of the tibialis anterior, gastronimius, rectus femoris, biceps femoris, and paraspinal muscles revealed no change in tremor frequency or time of initiation of tremor ON or OFF stimulation. However, after switching the stimulation on, she noticed a marked clinical improvement in symptom latency and was able to stand for greater than 3 minutes (Fig. 3). The patient reported sustained improvement at regular clinical assessments at 6‐month intervals postoperatively. Although tingling in the leg precluded increases in voltage, at 24 months postsurgery, she continues to report almost complete resolution of her symptoms with significant improvements in her activities of daily living and follows advice to switch off stimulation at night to prevent tolerance to stimulation.

Figure 1.

Neurophysiological electromyography (EMG) findings demonstrate phase‐locking of EMG burst in 3 leg muscles: 2 from 1 limb and 1 homologous muscle from the other. R indicates right; TA, tibailis anterior; Quad, quadriceps; L, left.

Figure 2.

Postoperative, stereotactic, T2‐weighted magnetic resonance images reveal (A–C) electrode placements with the deepest contact of the 3389 electrode in the caudal zona incerta in each of the 3 patients. (E) A T1‐weighted scan shows cerebritis around the electrode in patient 3. (D) A combined electromyogram from right the tibialis anterior (TA) demonstrates high signal during 5 periods of standing, with local field potentials (LFPs) confirming the presence of orthostatic tremor (correlated at about 17 Hz) and its harmonic.

Figure 3.

Neurophysiological electromyography (EMG) findings in the right tibialis anterior (TA) muscle while sitting/standing before surgery and OFF and ON stimulation.

Patient 2 (a 73‐year‐old man) developed slowly progressive shakiness and unsteadiness on standing over 15 years that was relieved by sitting or walking. Latency between rising and onset of unsteadiness progressed from 2 minutes to 10 seconds during the last 10 years of the disease, causing great difficulty in performing activities such as shaving and dressing. He also developed a slow, stumbling gait, hypophonia, and rapid eye movement sleep behavior disorder in the 5 years before assessment. Medications that were tried included clonazepam, gabapentin, l‐dopa, and benzhexol but were ineffective. His medical history included essential tremor (diagnosed at age 20 years), type 2 diabetes, and hypertension. Neurological examination revealed left‐sided, upper‐limb, nonfatigable bradykinesia; bilateral action tremor of the upper limbs; and a mildly ataxic gait but no other signs of cerebellar disease or parkinsonism. Surface EMG revealed a coherent 16‐Hz tremor of his lower limbs (Fig. 1) that appeared on rising, causing him to sit down after 10 seconds, and fluoropropyl–carbomethoxy‐3 β‐(4‐iodopenyltropane) (FP‐CIT) single‐photon emission computed tomography (SPECT) imaging (DaTscan; GE Healthcare, Milwaukee, WI) showed no abnormality of uptake. He underwent bilateral ViM‐caudal zona incerta DBS implantation of electrodes using a procedure identical to that described above for patient 1 (Fig. 2B). After surgery, there was an immediate symptomatic benefit and increase in symptom latency, with the patient reporting being able to stand for 4 minutes both OFF and ON stimulation. Gait analysis 7 months after surgery showed no change in tremor frequency or latency of onset OFF or ON stimulation (Fig. 3). Four months after surgery, his symptoms gradually worsened; however, after adjustments to parameters (left: 2[−]; right: 0[−], 1.5 V, 60 μsec, 130 Hz), he reported prolongation of standing and improvement in gait, which subjectively worsened when the stimulation was switched OFF. Benefits were sustained 12 months after surgery, and the patient continues to report no waning of symptomatic benefits 18 months postoperatively.

Patient 3 (a 66‐year‐old man) developed unsteadiness on prolonged standing due to a tremor in the lower limbs since 16 years. Over the years, symptoms progressed, and he developed an action tremor in his upper limbs that affected the left side more than the right. Latency between rising and onset of unsteadiness progressed from around 45 seconds in the beginning to a few seconds at the time of assessment, causing significant difficulties with walking and balance and necessitating the use of a wheelchair for mobility. In the last 5 or 6 years of the disease, he developed increasing forgetfulness, a tremulous voice, and bilateral upper‐limb slowness and stiffness. He was tested on L‐dopa, which clinically improved the upper‐limb symptoms only. In addition, he was taking gabapentin and baclofen. His past medical history included type 2 diabetes treated with metformin. Neurological examination revealed a mild intention tremor of the left hand, but no ataxia. There was bilateral, nonfatigable bradykinesia and mild rigidity in the upper limbs, but no resting tremor. Upon standing from a sitting position, he developed a marked lower‐limb tremor that was relieved when walking. Gait was slow with poor balance that made him fall if not caught. FP‐CIT SPECT (DaTscan; GE Healthcare) imaging showed no abnormality of uptake, and surface EMG revealed a coherent 17‐Hz tremor that appeared 2 seconds after standing and made him unsteady that was relieved on walking (Fig. 1). He underwent implantation of DBS electrodes in the ViM‐caudal zona incerta bilaterally (Fig. 2C). After surgery, there was immediate symptomatic relief (left: 1[−], 3.0 V, 60 μsec, 130 Hz; right: 9[−], 3.0 V, 60 μsec, 130 Hz) associated with an increase of the latency of symptom onset upon standing from a sitting position, resulting in the patient being able to stand greater than 4 minutes from a sitting position (Fig. 3). These clinical benefits were demonstrated both OFF and ON stimulation; and, similarly, EMG in the month after surgery showed that the frequency of the tremor was unchanged (17 Hz). In addition, thalamic local field potentials were recorded from the bilateral DBS electrodes simultaneously with tibialis anterior surface EMG activity in the postoperative period. Both local field potentials and EMG demonstrated oscillatory activity narrowly tuned to 17 Hz during standing, but not when sitting (Fig. 2D). The 2 signals were coherent, but the phase relationship between them could not be determined by linear regression of phase versus frequency due to the narrow band nature of the common oscillation. One month after the operation, the patient reported a headache accompanied by fever. An MRI showed signs of cerebritis as a result of an infection, and the DBS hardware had to be removed (Fig. 2E). After removal of the system, the patient had 1 generalized seizure. The OT subsequently reverted back to baseline severity; however, the patient declined to have another DBS system implanted.

Discussion

The natural history of OT is that clinical symptoms worsen over time (although interestingly without any concurrent changes in electrophysiology).3 Our cases provide further evidence to support the efficacy of bilateral thalamic ViM‐caudal zona incerta DBS for OT and are consistent with previous findings of clear improvements in latency of clinical symptoms and reduced unsteadiness despite no alteration in peripheral tremor rhythm. Previous reports of ViM DBS in OT indicated changes in amplitude as a putative explanation of the beneficial effects, however, it has also been shown that changes in amplitude are independent of objective measures of unsteadiness.16 Although a central tremor generator for OT has been proposed, characteristic oscillatory 16‐Hz tremors have been observed in a patient with paraplegia17; furthermore, spinal cord stimulation can be effective in patients who have intractable OT, indicating that the spinal cord may also be involved in its development or maintenance.14

The pathogenesis of OT remains uncertain, although it is postulated that it is caused by disruption of proprioceptive afferent activity from the lower limbs.17 Our findings would support recent studies suggesting that, of the 2 separated cerebello‐thalamo‐cortical networks thought to contribute to OT,12 DBS may modulate the feedback loop only, leaving the hypothetical brainstem or spinal oscillator active—possibly accounting for the disparity between clinical and EMG correlates. We purposely planned the trajectory of the 3389 quadripolar DBS leads such that the lowermost contact came to lie in the caudal zona incerta (Fig. 1A–C) and the uppermost contact in the thalamic ViM area, with the other electrode contacts activated in the 3 patients lying in the subthalamic area just below the ViM, where the cerebello‐thalamic fibers converge upon their entrance into the ViM thalamus. This is the site of the active contacts delivering the most effective stimulation in the current patients. The efficacy of thalamic‐subthalamic DBS despite the absence of any change in leg tremor, together with the evidence of coupled oscillatory activity in the ViM, suggests that cerebellar input to the thalamus (ViM) may be part of this feedback loop. Although the observation period in these reported cases was short, based on these and previous cases, further long‐term data from controlled clinical trials are needed to examine the efficacy of this approach in OT.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the first draft, B. Review and Critique.

D.A.: 1A, 1B, 1C, 3A

D.G: 1B, 3A

I.A.‐O.: 1C, 3B

A.P.: 1B, 1C

B.D.: 1B, 1C, 3B

P.B.: 1B, 1C, 3B

L.Z.: 1B, 1C, 3B

M.H.: 1B, 1C, 3B

P.L.: 1B, 1C, 3B

T.F.: 1A, 1B, 3B

Disclosures

Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for the previous 12 months: Ludvic Zrinzo has received honoraria for speaking at academic meetings sponsored by St. Jude Medical and Medtronic. Marwan Hariz has received travel expenses and honoraria from Medtronic for speaking at meetings. Patricia Limousin has received honoraria for speaking at academic meetings sponsored by Medtronic and St. Jude Medical. Thomas Foltynie has contracts and received honoraria for speaking at academic meetings sponsored by St. Jude Medical, GlaxoSmithKline, Teva, and Orion Pharma. The remaining authors report no sources of funding and no conflicts of interest.