Deep Brain Stimulation in Parkinson’s Disease

Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the cardinal motor features: rest tremor, bradykinesia, rigidity, and loss of postural reflexes. The pathological hallmark of PD is degeneration of dopaminergic neurons in the substantia nigra pars compacta and the presence of alpha synuclein positive neuronal inclusions known as Lewy bodies. It is the second most common neurodegenerative disorder, following Alzheimer’s disease. In the United States over 60,000 individuals are diagnosed with PD every year and there are over 1 million individuals living with the disease ( ). As the size of our elderly population continues to increase, it is expected that the economic burden of chronic diseases such as PD will continue to rise. Given that we have no current treatments to prevent, cure, or slow the progression of PD, it is imperative that we provide treatments to help improve the quality of life of sufferers ( ).

The mainstay of medical therapy is aimed at increasing the availability of striatal dopamine, resulting in symptomatic improvement in most patients with PD. However, the response to dopamine therapy becomes less reliable and predictable over time. After approximately 5 years of therapy, medication-related motor complications develop in most patients with PD, including dyskinesia, wearing off, and “on–off” motor fluctuations characterized by a sudden, unpredictable loss of treatment effect ( ).

Deep Brain Stimulation in Parkinson’s Disease

Deep brain stimulation (DBS) is an established safe and effective surgical alternative for patients with PD who either develop medication-induced side-effects or motor fluctuations. Traditionally DBS has been considered a therapy for advanced PD and has been limited to patients no longer receiving adequate relief of their symptoms; in published studies the mean age of patients who underwent DBS was 58.6 years with mean duration of disease of 12 years ( ). Many clinical trials have demonstrated the effectiveness of DBS therapy in advanced PD ( ). Collectively these trials showed the benefit of neurostimulation in reducing the duration and severity of motor symptoms during the “off” state, providing more consistent and longer “on” time as well as reducing the severity of dyskinesias during the “on” state. Given its effectiveness in advanced PD, DBS has also been considered for the treatment of patients in the earlier stages of the disease. The EARLYSTIM trial assessed the benefit of subthalamic DBS compared to medical treatment in 251 PD patients with mean disease duration of 7.5 years and mean age of 52.4 years. After 2 years subthalamic DBS was found to be superior to medical therapy, with improvements observed in quality of life and motor disability ( ). In 2016, based on the results of the EARLYSTIM trial, the United States Food and Drug Administration expanded the indication for DBS therapy to include patients with PD duration of at least 4 years and at least 4 months of motor complications. It has further been hypothesized that early treatment with DBS might slow the progression of PD, as animal models have shown upregulation of brain-derived neurotrophic growth factor (BDNF) in the substania nigra when the subthalamic nucleus is stimulated ( ). This increased production of BDNF may be neuroprotective and therapeutic.

Selection Criteria for DBS in PD

Patients being considered for DBS should be evaluated for surgical candidacy based on their medical history and PD symptoms, including tremor, dyskinesias, gait, and postural instability. Neurosurgery consistently benefits only patients with idiopathic PD. Atypical PD or “Parkinson plus” syndromes (supranuclear palsy, striatonigral degeneration, etc.) or other disorders with Parkinsonian features have not responded favorably to surgery ( ). The following are presurgical selection criteria for PD patients being considered for DBS.

• 1.

  Idiopathic PD with a historically good response to antiParkinsonian medications.

• 2.

  Surgery is most likely to benefit tremor, rigidity, bradykinesia, dystonia, motor fluctuations, and drug-induced dyskinesia.

• 3.

  Midline symptoms that improve with antiParkinsonian medication also improve with DBS, but those symptoms that do not respond to antiParkinsonian medication generally do not respond to DBS, i.e., postural instability, gait, and speech.

• 4.

  The best indicator of the potential benefit achieved with DBS is the levodopa response: patients who demonstrate a significant improvement in the motor subscore (III) of the Unified Parkinson’s Disease Rating Scale (UPDRS) during “off” versus “on” levodopa medication state are most likely to benefit from surgery.

• 5.

  The cutoff number is arbitrary, and is in the range of 25%–30% improvement in the on-UPDRS score as compared to off-UPDRS score. Patients with severe medication refractory tremor or asymmetric disease may be exceptions to this rule. Decisions must be made on a case-by-case basis.

• 6.

  Patients having had magnetic resonance imaging (MRI) within 2 years that is not suggestive of alternative causes for PD motor symptoms. Atrophy and white-matter disease are concerns, but do not rule out a patient with a good levodopa response.