Neurostimulation Augments Medical Therapy in Earlier Stage of Parkinson’s Disease

Written by on April 1, 2015 in Research & Technology - No comments

Neurostimulation is a recognized therapeutic option for advanced stages of Parkinson’s disease   typically reserved for cases in which medication has become less effective or has induced motor complications. Would neurostimulation be beneficial at an earlier stage by augmenting medical therapeutic response before the onset of motor complications or disability?

Parkinson’s disease is a debilitating progressive neurodegenerative disease afflicting a significant proportion of the older population. The most recognizable aspect of Parkinson’s are motor symptoms of tremors, rigidity and bradykinesia (extreme slowness of movement and reflexes). These motor symptoms are disabling if left untreated. The cognitive, emotional and autonomic symptoms including depression, anxiety, memory loss, constipation, urinary changes, sleep disorders also negatively impact daily life.

NeurostimulationWEBParkinson’s disease stems from the reduced production of the neurotransmitter dopamine by dopaminergic neurons in the midbrain and hypothalamus. Established pharmaceutical treatment act on divergent pathways by supplementing dopamine production with its chemical precursor (levodopa), blocking the enzymatic breakdown of dopamine with MAO-B inhibitors (rasagiline and selegiline) or mimicking dopamine at the receptor level with dopamine agonists (pramipexole, rotigotine, ropinirole). Levodopa is the most effective therapy for the motor symptoms but over time, patients may develop motor complications from the levodopa itself, specifically dyskinesias (involuntary rocking, twisting, writhing movements and grimacing facial expressions) and motor fluctuations (on-off mobility transition periods).1

Deep brain neurostimulation has been a FDA approved neurosurgical procedure for the treatment of Parkinson’s disease and essential tremor since 1977. Electrodes are stereotactically guided and implanted into deep brain targets, specifically subthalamus, globus pallidus or thalamus, and an impulse generator is implanted in the chest wall near the clavicle. The impulse generator modulates an electrical current that interferes and blocks neural signal impulses. Subthalamic neurostimulation is effective for all major Parkinson’s motor symptoms, consequently reducing medication dose reduction and alleviating dyskinesias. Globus pallidal neurostimulation is effective for Parkinson’s symptoms without change in average medication dose and may be safer for language and cognition. Thalamic neurostimulation alleviates essential tremor.2,3

A randomized multicenter European trial showed that neurostimulation combined with medical therapy significantly alleviated symptoms in patients at a relatively early stage of Parkinson’s disease compared with medical therapy alone.4 Because of subthalamic neurostimulation’s efficacy in advanced Parkinson’s disease, the EARLYSTIM researchers hypothesized that neurostimulation would improve quality of life at an earlier stage of Parkinson’s disease by optimizing dopaminergic treatment response.

A total of 251 patients in Germany and France with mean disease duration of 7.5 years, mean age of 52 years and relatively mild parkinsonian motor signs were enrolled for a 2 year period and randomized to the neurostimulation plus medication group and medication only group. Medical therapy conformity with practice guidelines was confirmed by an independent expert panel. Motor scores by video recordings were graded by reviewers who were blinded to study assignments in order to offset the lack of blinding in the neurostimulation group.

Quality of life change from baseline to 2 years was the primary end point as assessed by the Parkinson’s Disease Questionnaire (PDQ-39) summary index. Since quality of life is a complex variable, PDQ-39 addresses cognitive and psychosocial factors in addition to motor function. Quality of life improved by 26% in the neurostimulation group and worsened by 1% in the medication group. Motor disability, activities of daily living, levodopa-induced motor complications, off-medication motor signs and time with good mobility and no dyskinesia were significantly improved in the neurostimulation group compared to the medication group. Substantial medication changes occurred in both groups. Levodopa-equivalent daily dose decreased by 39% in the neurostimulation group and increased by 21% in the medication group.

Compared to a prior randomized trial of neurostimulation in advanced Parkinson’s disease,5 the EARLYSTIM group had greater improvement in activities of daily living, emotional well-being and cognition.

Serious adverse events were more frequent in the neurostimulation group (54.8%) than the medication group (44.1%). Postoperative adverse events occurred in 17.7% of neurostimulation patients with all but one resolving completely. Mobility and medication related side effects were more frequent in the medication group and major depression in the neurostimulation group. Suicidal behavior had equivalent frequency in both groups.

“We found that neurostimulation was superior to medical therapy alone at a relatively early stage of Parkinson’s disease, before the appearance of severe disabling motor complications. Neurostimulation may be a therapeutic option for patients at an earlier stage than current recommendations suggest,” concluded the researchers.

The EARLYSTIM trial was described as “one of the most rigorously conducted trials of neurostimulation” in the accompanying editorial.6 However, there are caveats to consider for wider clinical applications. The study patient population is not representative of the majority of Parkinson’s patients. Neurostimulation is effective in selected motor symptoms and does not change the progression of other symptoms. The experience of large, multidisciplinary teams impact the surgical benefits. Therefore, whether the trial results could be replicated in older Parkinson’s patients or in less experienced medical centers is unknown. Nevertheless, “for carefully chosen, highly functioning patients, [neurostimulation] may provide many additional years of good functioning.” 6

REFERENCES

1 Valeo T. Parkinson’s with fewer side effects. Neurology Now Oct/Nov 2014; 10:7-12. doi: 10.1097/01.NNN.0000455749.86977.7e

2 Deep brain stimulation for Parkinson’s disease. WebMD. http://www.webmd.com/parkinsons-disease/guide/deep-brain-stimulation. Accessed March 16, 2015.

3 Surgical treatment options: deep brain stimulation. National Parkinson Foundationhttp://www.parkinson.org/parkinson-s-disease/treatment/surgical-treatment-options/deep-brain-stimulation. Accessed March 16, 2015.

4 Schuepbach W, Rau J, Knudsen K, et.al.  Neurostimulation for Parkinson’s Disease with Early Motor Complications. N Engl J Med 2013; 368:610-622. doi: 10.1056/NEJMoa1205158

5 Deuschl G, Schade-Brittinger C, Krack P, et. al. A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med 2006; 355:896-908. doi: 10.1056/NEJMoa060281

6 Tanner C. A second honeymoon for Parkinson’s disease? N Engl J Med 2013; 368:675-676. doi: 10.1056/NEJMe1214913

By Marina Liem M.D.

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