Brain Electrodes Help Early PD, But Still Risky and Costly

Electrodes inserted into specific brain areas can help some people with advanced Parkinson’s disease (PD) who no longer respond well to medication. Now, research in the February 14 New England Journal of Medicine suggests that the therapy, known as deep-brain stimulation (DBS), can also help at earlier stages—before motor complications get out of control. In a two-year trial of 251 PD patients, those who received brain implants had fewer motor symptoms, better quality of life, and similar rates of adverse events as participants receiving medical therapy alone. Günther Deuschl of University Hospital Schleswig-Holstein, Kiel, Germany, was the study’s corresponding author; he led the work with Schleswig-Holstein colleague Karina Knudsen; Joern Rau and Carmen Schade-Brittinger of Philipps University, Marburg, Germany; and Michael Schüpbach and Yves Agid of University Pierre et Marie Curie and INSERM, Paris, France.

The new findings should “make patients and physicians consider the option of DBS surgery earlier in the course of Parkinson’s disease, before patients become disabled and before their work and social lives suffer too much,” noted Andres Lozano of Toronto Western Hospital, Canada, a DBS expert who was not involved in the study. However, because the analysis did not address long-term DBS risks, some clinicians said they would be reluctant to recommend the technology to early-stage PD patients.

Nobody quite understands how DBS helps the 2 to 5 percent of PD patients who opt for the procedure. Scientists think it may work by activating GABAergic inhibitory neurons, thereby normalizing a basal ganglia circuit that becomes hyperactive as dopamine neurons die off in PD, Deuschl said. Typically, patients who receive DBS have battled the disease for more than a decade and reached a point where dopamine-boosting medicines no longer relieve the worst motor symptoms. DBS candidates also tend to be younger, with no or little cognitive impairment.

In two previous six-month randomized trials, neurostimulation relieved symptoms more effectively than medical management alone in people with advanced PD and severe motor complications (Deuschl et al., 2006; ARF related news story on Weaver et al., 2009). The implants also improved symptoms and quality of life in early-stage PD, though that trial had just 20 participants (Schüpbach et al., 2007).

For the current study, first author W. Michael Schüpbach and colleagues enrolled 251 patients at 17 sites in Germany and France. The participants were on the young side (mean age 52-53 years), had had Parkinson’s for an average of 7.5 years with early signs of motor complications, and no dementia or major depression. They were randomized to receive neurostimulation of the subthalamic nucleus or medical therapy alone, with assessments at five, 12, and 24 months.

Quality of life—the trial’s main endpoint—improved by 26 percent in DBS-treated patients, but hardly changed in the control group. The researchers saw clear improvement with DBS at the five-month timepoint, and the benefit persisted. “There was no worsening of life quality across two years,” Deuschl said. Neurostimulation also improved daily function and mobility, and relieved complications from dopaminergic drugs.

“This study is especially important because it demonstrates that DBS can be used earlier in the course of Parkinson’s disease, rather than saving it as a last resort,” wrote Kenneth Follett, University of Nebraska Medical Center, Omaha, in an e-mail to Alzforum. Jerrold Vitek of University of Minnesota School of Medicine, Minneapolis, agreed, calling this “an impact paper that makes people think about [using DBS] earlier.” For patients who start developing complications with medications, DBS would improve quality of life, he said.

Frances Weaver of Hines Veterans Affairs Hospital, Illinois, found the data compelling, but wondered if they apply to the bulk of PD patients, who tend to be older. Based on their disease duration and average age at baseline, most trial participants would have been in their forties at the time of diagnosis, she noted. “I’m not sure how applicable the findings would be for PD patients diagnosed when older, which is more common,” Weaver said. Only 11 percent of PD cases are diagnosed before age 60. Moreover, 30 percent of PD patients, particularly older ones, have dementia, which would have excluded them from the current study, noted Caroline Tanner of Stanford University School of Medicine, Palo Alto California, in an accompanying editorial. The current study cannot tell if DBS would work for older PD patients, she wrote.

The study also does not address long-term DBS complications, which some see as an important consideration. The risks “associated with implantation and non-physiological electrical stimulation on diverse neural brain circuitries are not known,” noted Ole Isacson of Harvard Medical School’s McLean Hospital, Belmont, Massachusetts, in an e-mail to Alzforum (see full comment below). Furthermore, he thinks the trial is “too short to address the most important caveat—loss of DBS efficacy over time.” In prior studies looking at DBS patients five to 10 years post-surgery, patients showed sustained improvement in muscle rigidity, tremor, and dyskinesias, whereas gait and speech seemed to worsen with time (Fasano et al., 2010; Moro et al., 2010; Castrioto et al., 2011).

As with any treatment, the benefits of DBS must be weighed against cost and risk. The new data “aren’t compelling enough for me to recommend surgery to an early PD patient,” said Warren Olanow of Mount Sinai Hospital in New York. “The procedure carries risk of infarction, infection, and side effects, not to mention cost.” A DBS device costs $20,000-$30,000. The therapy can also affect a person’s mood and emotions (see Part 2 of a four-part DBS series). Nevertheless, DBS is gaining international credibility as a suitable treatment for some high-functioning PD patients (ARF related news story). The therapy is also starting to show its mettle in other disorders. The procedure looked safe in a small Phase 1 trial in people with Alzheimer’s disease (ARF related news story on Laxton et al., 2010), is currently being tested in a Phase 2 AD trial (see ARF related news story), and appears to improve functional connectivity in AD patients (ARF related news story on Smith et al., 2012). In a prospective study published this month in the journal Neurosurgery, researchers report that DBS improves quality of life in people with neuropathic pain (Boccard et al., 2013).—Esther Landhuis

Comments

  1. I think the trial is too short (two years) to address the most important caveat: the loss of DBS efficacy over time. Hence, the trial is not well conceived, in my opinion.

    Another issue is that the actual rationale for DBS use—as the authors themselves state in the introduction—is to deal with serious dyskinetic side effects that develop with extended use of pharmacological therapies.

    Given that DBS is not a restorative treatment—such as replacing or restoring the original neurons—this effort may drive up the use of this technology to new patient groups who are less likely to benefit from this treatment over a decade than they might from pharmacological or other therapies. And DBS brings significant risks for complications. The use of DBS, and the risks associated with the implantation and the non-physiological electrical stimulation on diverse neural brain circuitries are not known.

    View all comments by Ole Isacson

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References

News Citations

  1. PD Studies Highlight Deep Brain Stimulation, New Role for α-Synuclein
  2. Deep-Brain Stimulation: Steadies the Body, But What About the Mind?
  3. DBS Draws Consensus Nod for Parkinson’s, But Not Other Conditions
  4. DBS Update: Attempting to Stimulate Memory in Alzheimer’s
  5. A Day in the OR: Surgeons Zap Neurons for Parkinson’s, AD
  6. Deep-Brain Stimulation Improves Connectivity in AD

Paper Citations

  1. Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schäfer H, Bötzel K, Daniels C, Deutschländer A, Dillmann U, Eisner W, Gruber D, Hamel W, Herzog J, Hilker R, Klebe S, Kloss M, Koy J, Krause M, Kupsch A, Lorenz D, Lorenzl S, Mehdorn HM, Moringlane JR, Oertel W, Pinsker MO, Reichmann H, Reuss A, Schneider GH, Schnitzler A, Steude U, Sturm V, Timmermann L, Tronnier V, Trottenberg T, Wojtecki L, Wolf E, Poewe W, Voges J, . A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med. 2006 Aug 31;355(9):896-908. PubMed.
  2. Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ, Rothlind J, Sagher O, Reda D, Moy CS, Pahwa R, Burchiel K, Hogarth P, Lai EC, Duda JE, Holloway K, Samii A, Horn S, Bronstein J, Stoner G, Heemskerk J, Huang GD, . Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA. 2009 Jan 7;301(1):63-73. PubMed.
  3. Schüpbach WM, Maltête D, Houeto JL, du Montcel ST, Mallet L, Welter ML, Gargiulo M, Béhar C, Bonnet AM, Czernecki V, Pidoux B, Navarro S, Dormont D, Cornu P, Agid Y. Neurosurgery at an earlier stage of Parkinson disease: a randomized, controlled trial. Neurology. 2007 Jan 23;68(4):267-71. PubMed.
  4. Fasano A, Romito LM, Daniele A, Piano C, Zinno M, Bentivoglio AR, Albanese A. Motor and cognitive outcome in patients with Parkinson's disease 8 years after subthalamic implants. Brain. 2010 Sep;133(9):2664-76. PubMed.
  5. Moro E, Lozano AM, Pollak P, Agid Y, Rehncrona S, Volkmann J, Kulisevsky J, Obeso JA, Albanese A, Hariz MI, Quinn NP, Speelman JD, Benabid AL, Fraix V, Mendes A, Welter ML, Houeto JL, Cornu P, Dormont D, Tornqvist AL, Ekberg R, Schnitzler A, Timmermann L, Wojtecki L, Gironell A, Rodriguez-Oroz MC, Guridi J, Bentivoglio AR, Contarino MF, Romito L, Scerrati M, Janssens M, Lang AE. Long-term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson's disease. Mov Disord. 2010 Apr 15;25(5):578-86. PubMed.
  6. Castrioto A, Lozano AM, Poon YY, Lang AE, Fallis M, Moro E. Ten-year outcome of subthalamic stimulation in Parkinson disease: a blinded evaluation. Arch Neurol. 2011 Dec;68(12):1550-6. PubMed.
  7. Laxton AW, Tang-Wai DF, McAndrews MP, Zumsteg D, Wennberg R, Keren R, Wherrett J, Naglie G, Hamani C, Smith GS, Lozano AM. A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease. Ann Neurol. 2010 Oct;68(4):521-34. PubMed.
  8. Smith GS, Laxton AW, Tang-Wai DF, McAndrews MP, Diaconescu AO, Workman CI, Lozano AM. Increased Cerebral Metabolism After 1 Year of Deep Brain Stimulation in Alzheimer Disease. Arch Neurol. 2012 May 7; PubMed.
  9. Boccard SG, Pereira EA, Moir L, Aziz TZ, Green AL. Long-term Outcomes of Deep Brain Stimulation for Neuropathic Pain. Neurosurgery. 2013 Feb;72(2):221-31. PubMed.

External Citations

  1. two-year trial
  2. Phase 1 trial
  3. Phase 2 AD trial

Further Reading

Papers

  1. Schüpbach WM, Maltête D, Houeto JL, du Montcel ST, Mallet L, Welter ML, Gargiulo M, Béhar C, Bonnet AM, Czernecki V, Pidoux B, Navarro S, Dormont D, Cornu P, Agid Y. Neurosurgery at an earlier stage of Parkinson disease: a randomized, controlled trial. Neurology. 2007 Jan 23;68(4):267-71. PubMed.
  2. Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ, Rothlind J, Sagher O, Reda D, Moy CS, Pahwa R, Burchiel K, Hogarth P, Lai EC, Duda JE, Holloway K, Samii A, Horn S, Bronstein J, Stoner G, Heemskerk J, Huang GD, . Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA. 2009 Jan 7;301(1):63-73. PubMed.
  3. Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schäfer H, Bötzel K, Daniels C, Deutschländer A, Dillmann U, Eisner W, Gruber D, Hamel W, Herzog J, Hilker R, Klebe S, Kloss M, Koy J, Krause M, Kupsch A, Lorenz D, Lorenzl S, Mehdorn HM, Moringlane JR, Oertel W, Pinsker MO, Reichmann H, Reuss A, Schneider GH, Schnitzler A, Steude U, Sturm V, Timmermann L, Tronnier V, Trottenberg T, Wojtecki L, Wolf E, Poewe W, Voges J, . A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med. 2006 Aug 31;355(9):896-908. PubMed.
  4. Laxton AW, Tang-Wai DF, McAndrews MP, Zumsteg D, Wennberg R, Keren R, Wherrett J, Naglie G, Hamani C, Smith GS, Lozano AM. A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease. Ann Neurol. 2010 Oct;68(4):521-34. PubMed.

Primary Papers

  1. Tanner CM. A second honeymoon for Parkinson's disease?. N Engl J Med. 2013 Feb 14;368(7):675-6. PubMed.
  2. Schuepbach WM, Rau J, Knudsen K, Volkmann J, Krack P, Timmermann L, Hälbig TD, Hesekamp H, Navarro SM, Meier N, Falk D, Mehdorn M, Paschen S, Maarouf M, Barbe MT, Fink GR, Kupsch A, Gruber D, Schneider GH, Seigneuret E, Kistner A, Chaynes P, Ory-Magne F, Brefel Courbon C, Vesper J, Schnitzler A, Wojtecki L, Houeto JL, Bataille B, Maltête D, Damier P, Raoul S, Sixel-Doering F, Hellwig D, Gharabaghi A, Krüger R, Pinsker MO, Amtage F, Régis JM, Witjas T, Thobois S, Mertens P, Kloss M, Hartmann A, Oertel WH, Post B, Speelman H, Agid Y, Schade-Brittinger C, Deuschl G, . Neurostimulation for Parkinson's disease with early motor complications. N Engl J Med. 2013 Feb 14;368(7):610-22. PubMed.

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