Neurosurgery in Parkinson Disease: A Brief History and Look Forward

The first-line treatment for Parkinson disease (PD), levodopa paired with carbidopa, did more than revolutionize treatment for PD when it entered use in the 1960s, it also largely replaced the use of neurosurgeries, especially pallidotomy and thalamotomy, that had been used in PD care since the beginning of the 20th century.¹

When it became evident that patients would experience dyskinesias and on/off periods after long-term use of levodopa, whether from the drug itself or from the disease’s progression, attention returned to pallidotomy and thalamotomy in the 1990s.¹

Deep Brain Stimulation Becomes Standard

However, deep brain stimulation (DBS) became the neurosurgical standard of care for PD because of its reversibility, lower adverse event profile, modifiability, and bilateral option without increased adverse effects. Unilateral pallidotomy improved motor symptoms and reduced levodopa-related dyskinesia, but bilateral procedures often led to corticobulbar syndrome with dysarthria and dysphagia.² Similarly, thalamotomy carries a greater risk of permanent dysarthria and imbalance than DBS: a systematic review suggested up to a 47% rate of adverse effects, including 16% of patients with permanent complications.³

“Today, the technological progress in DBS is still rapid,” wrote Paul Krack, MD, PhD, from the University Hospital of Geneva in Switzerland, and colleagues in a recent review published in Movement Disorders.⁴ “It has become by far the leading stereotactic technique, having marginalized radio frequency lesions in economically developed countries.”

Although DBS, similar to all PD therapies, cannot cure, modify, or slow progression of the disease, some recent research suggests that the symptom alleviation and quality-of-life improvement it provides might lead to mild improvements in longevity, noted Justin Martello, MD, a PD and movement disorders specialist from Christiana Care Neurology Specialists in Newark, Delaware.

“It does improve function, so it may improve morbidity over time,” Dr Martello told Neurology Advisor. “It can improve a patient’s life so they can be more active, and that can infer a longer life.”

Most research is therefore focusing on comparing different DBS targets, refining DBS methods and tools, and exploring other interventions only in early phase or preclinical trials.

Benefits and Limitations of DBS Targets

Unilateral or bilateral targeting of the thalamic ventralis intermediaries nucleus (Vim-DBS) was the first to show greater benefits than unilateral thalamotomy, but the demonstrated 90% improvement in tremor did not extend to bradykinesia or rigidity.⁴ The next 2 developments, however, globus pallidus interna(GPi) DBS and subthalamic nucleus (STN) DBS, showed improvement in the whole parkinsonian triad.⁴

Despite continued uncertainty about the mechanism of action for DBS, plenty of trials have now clarified the most common outcomes and adverse effects for different DBS techniques. In fact, DBS comprises more than half the literature published on neurosurgery for PD, according to a review of publications by Christopher Lozano, BSc, from the University of Toronto, Ontario, Canada, and colleagues.¹

Both STN-DBS and GPi-DPS confer improved quality of life, reduction in off-drug motor symptoms, and overall off-time during the day, but only 2 randomized controlled trials have assessed the methods head to head, and they yielded conflicting findings. Quality-of-life improvement was similar between the methods in both studies, but GPi-DBS showed slightly better dyskinesia improvements and STN-DBS showed greater reduction of medication needs. The effects of both lasted at least 3 years in follow-up.⁴

“Cognition and mood outcome seemed to be better with GPi-DBS than with STN-DBS in one study and equivalent in the other,”^5,6 Krack and colleagues wrote.⁴ STN tends to win out, narrowly, because of its better functional motor outcomes when off drugs compared with GPi, but “neither of the 2 targets can be rejected because of higher incidences of cognitive or behavioral side effects.”

“[T]he available evidence and our accumulated experience lead us to suggest that STN-DBS is usually the target of choice in the PD patient with typical complications and clinical features. GPi-DBS is less demanding: unilateral surgery is possible, no decrease in medication is required, and it entails less time-consuming follow-up in an expert center in the early postoperative period,” they wrote. “These are all arguments that should be considered when taking individual decisions about less classical candidates. In patients suffering mainly from unilateral disabling dyskinesia, GPi-DBS may be the best option.”

Recent Developments in DBS

Several technological advances have improved on DBS methods, especially since 2 long-time medical device makers finally entered the movement disorders field. The arrival of Abbott Medical and Boston Scientific in a field previously dominated by Medtronic has driven some innovation, said Matthew Brodsky, MD, an associate professor of neurology and medical director of the DBS program at Oregon Health & Science University in Portland.

“We’re seeing the emergence of new tech just in the world of DBS in terms of what the implanted leads themselves can provide and the way we can deliver currents through those leads and shape the field,” Dr Brodsky told Neurology Advisor. “One innovation has been segmented leads that allow activation of tissue with greater directionality,” he explained. “If an electrode is placed that is off target by more than just a couple millimeters, it makes a big difference in the usability of that implanted lead.”

The new ability to direct that current away from parts of the brain that might cause adverse effects enhances the therapy’s effectiveness while lowering the risk profile.

Contraindications and Adverse Events

One of the biggest reasons DBS took over neurosurgery treatment for PD was its stronger safety profile than previous surgical interventions. In a review of 38 studies involving 471 patients undergoing DBS, 1% to 2% experienced severe adverse events, such as death or permanent neurological deficits from intracerebral hemorrhage, and 9% experienced hardware-related problems, such as infections or lead and pulse generator issues.⁷ An additional 19% experienced reversible adverse effects from the stimulation. In the 6 largest controlled studies on STN and GPi, involving 1096 patients, death was extremely rare, at 0.3% caused by hemorrhage and 0.5% caused by pneumonia.⁸

That said, speech, gait and balance difficulties might be aggravated over the long-term in those treated with DBS, and disease progression eventually overtakes much of the benefit, Krack and colleagues noted.

“[T]he benefit of surgery on motor manifestations seems to remain, but patients’ overall state worsens as a result of disease progression with axial features or the appearance of nonmotor symptoms such as cognitive impairment that partly neutralize the effect of stimulation,” they wrote. The primary reasons to recommend DBS to patients include increasing levodopa-induced dyskinesias (or similar adverse effects) or increasing off periods.

“Either we’re running out of options for good meds or the good meds aren’t working anymore,” Dr Martello told Neurology Advisor. He also questioned the common practice of holding off on DBS until it is one of the last resorts. “I’d argue we’re trying to get away from that line of thinking and moving toward determining whether this is what’s right for a particular patient,” Dr Martello said. “We know that patients do better when they get it done earlier. They usually have fewer comorbidities with other problems like heart disease.”

He also challenged the belief that cognitive decline is a contraindication for DBS based on recent evidence suggesting otherwise, but uncontrolled depression and inadequate response to levodopa remain contraindications.

What Is on the Horizon

Several experimental therapies for PD have so far dead-ended. Gamma-knife thalamotomy enjoyed brief interest but has now fallen by the wayside for PD nearly everywhere because of its high-risk adverse effect profile, Dr Martello said. Stem cell transplantation has similarly shown too many adverse effects, and gene therapy simply has not shown much benefit.

“Parkinson’s is a tough disease and a tough model to try to use cell-based therapies, since there are so many changes occurring in the brain,” Dr Brodsky told Neurology Advisor. “Trying to repair or replace just that 1 part of the circuitry is oversimplifying things and really a big challenge.” In terms of medication, Dr Brodsky expects to see immunotherapy become an option, especially with phase 2 trials underway for PD. Dr Martello similarly sees disease-modifying drugs on the horizon.

In terms of surgery, however, Dr Martello believes the next frontier is focused ultrasound, which he was surprised did not receive more attention in Dr Krack’s paper. “It’s a new technique based off old principles, and it’s more of a hot topic now,” he told Neurology Advisor. The magnetic resonance imaging-guided procedure directs sound waves to 1 place enough to upheave and damage the cells before then killing them. Although only currently approved by the FDA for central tremor, Dr Martello expects approval for PD in the next year or 2.

References

1. Lozano CS, Tam J, Lozano AM. The changing landscape of surgery for Parkinson’s Disease. Mov Disord. 2018;33(1):36-47.
2. Merello M, Starkstein S, Nouzeilles MI, Kuzis G, Leiguarda R. Bilateral pallidotomy for treatment of Parkinson’s disease induced corticobulbar syndrome and psychic akinesia avoidable by globus pallidus lesion combined with contralateral stimulation. J Neurol Neurosurg Psychiatry. 2001;71:611-614.
3. Zesiewicz TA, Elble R, Louis ED, et al. Practice parameter: therapies for essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2005;64:2008-2020.
4. Krack P, Martinez-Fernandez R, Del Alamo M, Obeso JA. Current applications and limitations of surgical treatments for movement disorders. Mov Disord. 2017;32(1):36-52.
5. Follett KA, Weaver FM, Stern M, et al. Pallidal versus subthalamic deep-brain stimulation for Parkinson’s disease. N Engl J Med. 2010;362:2077-2091.
6. Odekerken VJ, van Laar T, Staal MJ, et al. Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinson’s disease (NSTAPS study): a randomised controlled trial. Lancet Neurol. 2013;12:37-44.
7. Hamani C, Richter E, Schwalb JM, Lozano AM. Bilateral subthalamic nucleus stimulation for Parkinson’s disease: a systematic review of the clinical literature. Neurosurg. 2005;56:1313-1321.
8. Deuschl G, Paschen S, Witt K. Clinical outcome of deep brain stimulation for Parkinson’s disease. Handb Clin Neurol. 2013;116:107-128.