Deep Brain Stimulation (DBS) for Multiple Sclerosis and Severe Tremor

Deep brain stimulation (DBS) is an invasive but reversible method of functional neurosurgery in which electrodes are implanted into deep brain structures and connected to a subcutaneous neurostimulator. High-frequency stimulation modulates abnormal neuronal network activity and allows control of symptoms—primarily tremor and other movement disorders.

History of the Method and Approved Indications

The first description of suppressing severe intention tremor by deep stereotactic thalamic stimulation was published in 1980 (Brice & McLellan, Lancet). In the late 1980s–early 1990s, Alim-Louis Benabid and colleagues demonstrated that high-frequency stimulation of the ventral intermediate nucleus (VIM) of the thalamus effectively reduced tremor in Parkinson’s disease, marking the beginning of the modern era of DBS.

In 1997, the U.S. Food and Drug Administration (FDA) approved stimulation of the VIM nucleus for the treatment of essential tremor and parkinsonian tremor. In 2002, indications were expanded to include Parkinson’s disease (subthalamic nucleus and globus pallidus internus stimulation). In subsequent years, DBS received approvals for dystonia, severe obsessive-compulsive disorder, and epilepsy. DBS gradually replaced irreversible procedures (thalamotomy, pallidotomy) and became the standard surgical treatment for several movement disorders.

According to current estimates, more than 200,000 DBS procedures have been performed worldwide, predominantly for Parkinson’s disease, essential tremor, and dystonia. In Israel, DBS for Parkinson’s disease, essential tremor, and dystonia is performed in major university medical centers (Sheba Tel HaShomer, Ichilov/Sourasky, Rambam, Hadassah, etc.) and is part of standard care for complex movement disorders.

There is no separate regulatory indication for the use of DBS in tremor associated with multiple sclerosis (MS). In this context, the intervention is considered off-label, although the technology itself is formally approved for tremor and movement disorders.

Why DBS Has Been Used in Multiple Sclerosis

Tremor occurs in 25–58% of patients with multiple sclerosis. The most severe group includes individuals with prominent proximal and intention tremor of the upper limbs, resulting in major disability and inability to perform self-care, writing, holding objects, and daily tasks. This tremor is often accompanied by cerebellar ataxia, dysmetria, and reduced muscle tone.

Pharmacological treatment (beta-blockers, primidone, benzodiazepines, isoniazid, cannabinoids, etc.) usually provides limited and unstable benefit. Against this background, the application of DBS in MS became a logical step, mirroring the successful experience in essential and parkinsonian tremor:

• the target (VIM of the thalamus) and stimulation principles are well established in other tremor syndromes;
• the method is reversible and programmable, unlike irreversible thalamotomy;
• in some patients, tremor is driven by functional hyperactivity of thalamocortical and cerebellothalamic circuits, which can be modulated by stimulation.

The first series of interventions for MS-associated tremor were published in the early 2000s (Hooper, Berk, Wishart, and others) and demonstrated that DBS can significantly reduce tremor and improve quality of life in patients refractory to medical therapy.

Extent of Clinical Experience with DBS in MS Tremor

Since the initial reports, a substantial—though heterogeneous—body of evidence has accumulated. According to the meta-analysis by Brandmeir et al. (2020), 261 DBS procedures in MS patients were analyzed. Considering more recent studies, including the large retrospective cohort by Chagot et al. (104 patients), and additional case series, the global literature contains descriptions of at least 300–350 MS patients who underwent DBS for severe, medication-resistant tremor.

No dedicated registry of DBS for MS tremor has been published in Israel. Available data and clinical practice indicate that such interventions are extremely rare and are performed as individual off-label procedures in large neurosurgical centers with established DBS expertise.

DBS Targets in MS-Associated Tremor

The standard target for surgical treatment of tremor remains the ventral intermediate nucleus (VIM) of the thalamus. In MS, several targeting approaches have been attempted:

• unilateral or bilateral VIM stimulation (the most common strategy);
• dual-lead stimulation (e.g., VIM + ventralis oralis posterior/anterior – VOP/VOA) for complex tremor patterns;
• stimulation of the subthalamic region and caudal zona incerta (ZI) in cases with prominent proximal and intention tremor.

VIM remains the most frequently used target due to its predictable effect on upper-limb tremor and extensive accumulated experience. Alternative targets (VOP/VOA, subthalamic area, ZI) are considered in complex cases, mainly within specialized centers and clinical research settings.

Clinical Effectiveness of DBS in MS Tremor

Systematic reviews and meta-analyses show that, with careful patient selection, DBS produces the following outcomes:

• tremor reduction on the Fahn–Tolosa–Marin (FTM) scale by 30–61% at 6 months postoperatively;
• durable benefit over 2–6 years in a substantial proportion of patients, provided adequate programming and stable MS course;
• improvement in quality-of-life measures (SF-36, ADL scales) by 30–170% compared with baseline;
• significant improvement in upper-limb function—restoration or enhancement of the ability to eat, wash, fasten clothing, write, and use electronic devices.

Importantly, DBS does not affect MS disease activity or modify overall disability measured by EDSS, which reflects the sum of multiple neurological deficits. DBS is a symptomatic treatment for tremor, not a disease-modifying therapy.

Limitations of the Effect

Even with substantial reduction in tremor amplitude, functional improvement may be limited. Factors negatively affecting outcomes include:

• prominent cerebellar ataxia and dysmetria;
• very high baseline disability (EDSS > 6–6.5);
• presence of spasticity, weakness, and other non-tremor motor deficits;
• cognitive impairment and depression.

In such cases, tremor reduction does not necessarily translate into significant gains in self-care or quality of life.

Adverse Effects and Safety of DBS in MS

The safety profile of DBS in MS-associated tremor is comparable to that in essential tremor and Parkinson’s disease. Adverse events are divided into surgical, hardware-related, and functional.

Surgical and Hardware-Related Complications

• intracerebral hemorrhage along the electrode trajectory or around the contact—approximately 1–2% of procedures (overall serious surgical complications estimated at 2–7%);
• infectious complications (generator pocket infection, lead or extension infection)—more common in early series, lower in modern practice;
• hardware problems such as lead migration or fracture, generator malfunction, or connector issues—requiring revision or replacement.

Functional Adverse Effects

• paresthesias or “current-like” sensations in the limb;
• dysarthria (slurred speech) due to stimulation of adjacent fiber pathways;
• imbalance or worsening of ataxia with excessive stimulation amplitude;
• rarely, seizures in the early postoperative period.

Most functional adverse effects are reversible and respond to adjustment of stimulation parameters (amplitude, pulse width, frequency, active contacts).

Available series do not demonstrate increased MS relapse rates, new demyelinating lesions attributable to DBS, or accelerated EDSS progression. DBS is therefore regarded as a symptomatic intervention that does not influence MS immune activity.

Patient Selection for DBS in MS Tremor

Favorable Candidate Characteristics

• severe, disabling tremor of one or both upper limbs that markedly impairs self-care;
• medication-refractory tremor—lack of response to adequate trials of multiple agents;
• relatively stable MS course without frequent relapses in the past 6–12 months;
• absence of marked cerebellar ataxia or gross dysmetria;
• moderate disability (EDSS ≤ 6–6.5), allowing potential functional improvement;
• preserved cognitive status; no severe psychiatric comorbidities;
• absence of large demyelinating lesions in the target region on MRI.

Factors Associated with Poorer Outcomes

• ataxia predominating over tremor;
• very high disability (EDSS ≫ 6–7);
• widespread supra- and infratentorial plaques disrupting major pathways;
• large lesions in the thalamus or marked cerebellar atrophy;
• significant cognitive impairment or psychiatric illness.

The decision to perform DBS is made by a multidisciplinary team (neurologist, neurosurgeon, neuropsychologist, and, if needed, psychiatrist and neuroradiologist) after comprehensive clinical and neuroimaging evaluation.

Comparison of DBS in MS with Other Tremor Syndromes

In essential tremor and Parkinson’s disease, VIM-DBS provides sustained tremor reduction of approximately 48–70%, with long-term benefit lasting 5–10 years or longer, accompanied by significant improvement in activities of daily living.

In MS-associated tremor, average improvement is lower and more variable (30–61% FTM), and functional gains are often limited by concomitant neurological deficits (ataxia, spasticity, weakness, cognitive symptoms). The complication profile remains similar, supporting DBS as an effective but more niche intervention for select MS patients.

MR-Guided Focused Ultrasound (MRgFUS) Thalamotomy in MS

Magnetic-resonance-guided focused ultrasound (MRgFUS) thalamotomy is a non-incisional technique that creates a focal lesion in the VIM thalamus using high-intensity ultrasound under MRI control. The method is approved in several countries, including Israel, for essential tremor and parkinsonian tremor, and is used as an alternative to DBS in patients who wish to avoid implanted hardware.

Global Experience of MRgFUS Specifically in MS

Published data on MRgFUS thalamotomy for tremor associated with multiple sclerosis are extremely limited. A review of the literature shows:

• a single case report describing successful MRgFUS thalamotomy in a patient with severe, medication-refractory MS-associated tremor;
• another publication describing two patients with MS and coexisting essential tremor who underwent MRgFUS for essential tremor;
• no dedicated clinical series or randomized trials of MRgFUS specifically for MS tremor;
• MS patients are rarely included in large MRgFUS cohorts for essential or parkinsonian tremor and are not analyzed as a separate subgroup.

Thus, only three MS patients treated with MRgFUS thalamotomy have been documented in the literature (one with MS-associated tremor and two with MS plus essential tremor). This number is insufficient to determine long-term safety, efficacy, or optimal patient selection in MS.

Limitations of MRgFUS in MS

• MRgFUS produces an irreversible thalamic lesion, unlike DBS, which is adjustable and reversible;
• cerebellothalamic pathways in MS are often demyelinated, reducing predictability of lesioning outcomes;
• MRgFUS does not improve cerebellar ataxia and may aggravate imbalance;
• no long-term (>12–24 months) data exist for MRgFUS in MS tremor;
• the impact of high-intensity ultrasound on MS disease activity is unknown.

MRgFUS cannot currently be considered a standard treatment for MS-associated tremor. It may be discussed only in exceptional cases within specialized centers, mainly when MS coexists with essential tremor.

Regulatory Status and Off-Label Use in MS

Regulatory approvals for DBS (FDA, CE marking) include essential tremor, parkinsonian tremor, Parkinson’s disease, dystonia, severe obsessive-compulsive disorder, and epilepsy. There is no dedicated indication for MS-associated tremor, and the procedure is performed off-label.

In practice:

• the decision to perform DBS or MRgFUS in MS is made by a multidisciplinary team and thoroughly documented;
• patients are informed that the intervention is off-label in the context of MS;
• insurance pre-authorization is often required on an individual basis.

In Israel, both DBS and MRgFUS are standard options for essential and parkinsonian tremor. Procedures for MS-associated tremor are rare and considered individually.

Future Directions for DBS and MRgFUS in MS Tremor

• Refinement of selection criteria—standardization of tremor and functional outcome assessment, use of neuroimaging and connectomics to predict response;
• Optimization of targets—further evaluation of the subthalamic area, zona incerta, and combined targeting (VIM + VOP/VOA);
• Adaptive (closed-loop) DBS—systems that adjust stimulation based on neural signals may improve effectiveness and reduce adverse effects;
• Comparative studies with MRgFUS—head-to-head evaluation of DBS vs MRgFUS in MS tremor;
• Integration with modern MS therapy—as disease-modifying treatments improve disease control and life expectancy, high-technology symptomatic therapies become increasingly relevant.

Key Practical Conclusions

• DBS is an effective and relatively safe method for severe, medication-refractory tremor in selected MS patients.
• Best outcomes occur when tremor is the dominant disabling symptom and ataxia is minimal.
• Average tremor improvement is 30–61%, but functional benefit depends on coexisting neurological deficits.
• The complication profile is comparable to DBS for other indications; no specific negative effect on MS has been demonstrated.
• MRgFUS in MS tremor remains experimental: only three cases are reported worldwide.
• The choice between DBS and MRgFUS must be individualized and performed in specialized centers.