Spinal cord stimulation significantly decreased pain and reduced motor symptoms associated with Parkinson’s disease

A team of researchers in the United States and Japan reports that spinal cord stimulation (SCS) measurably decreased pain and reduced motor symptoms of Parkinson’s disease, both as a singular therapy and as a “salvage therapy” after deep brain stimulation (DBS) therapies were ineffective.

Writing in the September 28, 2020 issue of Bioelectronic Medicine, first author Krishnan Chakravarthy, MD, PhD, assistant professor of anesthesiology at University of California San Diego School of Medicine, and colleagues recruited 15 patients with Parkinson’s disease, a neurodegenerative disorder that is commonly characterized by physical symptoms, such as tremors and progressive difficulty walking and talking, and non-motor symptoms, such as pain and mental or behavioral changes.

The mean age of the patients was 74, with an average disease duration of 17 years.

All of the patients were experiencing pain not alleviated by previous treatments. Eight had undergone earlier DBS, a non-invasive, pain therapy in which electrical currents are used to stimulate specific parts of the brain. Seven patients had received only drug treatments previously.

Researchers implanted percutaneous (through the skin) electrodes near the patients’ spines, who then chose one of three types of electrical stimulation: continuous, on-off bursts or continuous bursts of varying intensity.

Following continuous programmed treatment post-implantation, the researchers said all patients reported significant improvement, based on the Visual Analogue Scale, a measurement of pain intensity, with a mean reduction of 59 percent across all patients and stimulation modes.

Seventy-three percent of patients showed improvement in the 10-meter walk, a test that measures walking speed to assess functional mobility and gait, with an average improvement of 12 percent.

And 64 percent of patients experienced improvements in the Timed Up and Go (TUG) test, which measures how long it takes a person to rise from a chair, walk three meters, turn around, walk back to the chair and sit down.

TUG assesses physical balance and stability, both standing and in motion. Average TUG improvement was 21 percent.

The authors said the findings suggest SCS may have therapeutic benefit for patients with Parkinson’s in terms of treatment for pain and motor symptoms, though they noted further studies are needed to determine whether improved motor function is due to neurological changes caused by SCS or simply decreased pain.

“We are seeing growing data on novel uses of spinal cord stimulation and specific waveforms on applications outside of chronic pain management, specifically Parkinson’s disease,” said Chakravarthy, pain management specialist at UC San Diego Health.

“The potential ease of access and implantation of stimulators in the spinal cord compared to the brain suggests that this is a very exciting area for future exploration.”

Co-authors include: Rahul Chaturvedi and Rajiv Reddy, UC San Diego; Takashi Agari, Tokyo Metropolitan Neurological Hospital; Hirokazu Iwamuro, Juntendo University, Tokyo; and Ayano Matsui, National Center Hospital of Neurology and Psychiatry, Tokyo.

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Parkinson’s disease (PD) is a progressive neurodegenerative disease with an incidence of 0.1 to 0.2% over the age of 40 and a prevalence of over 1 million people in North America (Kalia and Lang 2015). The most common symptoms include tremor, bradykinesia, rigidity, pain, and postural instability, with significant impact in quality of life (Ha and Jankovic 2012; Martinez-Martin 2011) and mortality (Forsaa et al. 2010).

A report of 618 patients with PD found that the transition from disease impairment to disability as defined by loss of independent function occurred generally between three and 7 years after the onset of PD (Shulman et al. 2008). Intervention targeting the impairments caused by PD is a crucial aspect of disease management.

The pathological mechanisms of the motor symptomology of PD center around the dysfunction of the substantia niagra pars compacta (SNc) and depletion of dopamine neurons.

The reduction of dopamine in the nigrostriatal pathway to the caudate and putamen subsequently results in reduced inhibition of the thalamus and thus reduced excitatory input to the motor cortex, ultimately expressing as bradykinesia and other parkinsonian signs.

Related to these physiological changes is the altered electrical communication within the nigrostriatal pathway. It was found that synchronized oscillatory activity at 10–35 Hz, as measured by deep brain electrodes, may mediate certain parkinsonian features and can be reduced by treatments using both dopamine agonists or by disruption of synchronized oscillatory impulses with direct electrical current stimulation (Gatev et al. 2006; Silberstein et al. 2005).

As such, the primary modes of management of PD includes dopamine replacement therapy and bioelectric implantation using deep brain stimulation (DBS), which can directly disrupt the pathological synchronized oscillations.

Dopamine agonists are the gold standard for the treatment of PD. However, dopamine agonisms may be associated with loss of efficacy with prolonged use, necessitating increased dosing frequency, as well as issues with absorption (LeWitt et al. 2019). Invasive procedures like DBS have been utilized more recently with significant improvements in PD symptoms (Mills-Joseph et al. 2019; Okun 2012).

DBS procedures are inherently moderate to high risk as they require cranial burr hole, carry a risk of infection, intracranial hemorrhage (up to 5.0%), seizures (up to 2.4%) and also may have diminished magnitude of improvement over time or failure after impantation (Okun 2012). The risk of infection has been reported to range from 1.2 to 15.2% (Okun 2012).

Functional movement disorders can also arise after DBS, including involuntary movement of the extremities, weakness, and impaired balance (Breen et al. 2018). Failure may be related to lead migration, suboptimal patient selection, suboptimal therapy programming, disease progression, and/or development of tolerance or habituation (Okun 2012; Okun et al. 2008).

In one retrospective study, misplaced leads had led to the majority of DBS failure (Okun et al. 2005). Additionally the treatment may only apply to a selective population of 1–4% of patients with PD, thus leaving large groups of patients without further treatment beyond standard conservative care (Morgante et al. 2007).

Another emerging electrical system that may disrupt the pathological neuronal oscillations in the basal ganglia in patients with PD is spinal cord stimulation (SCS) (Fuentes et al. 2009). Spinal cord stimulation of the dorsal columns within the epidural space is an emerging bioelectronic technology that has been extensively studied in multiple painful conditions (Caylor et al. 2019).

More recently, SCS has been shown to improve locomotor symptoms in both animal models and human subjects with PD (Hassan et al. 2013; Santana et al. 2014). As previously mentioned, many patients with PD also have concurrent pain conditions that may also be responsive to the typical use of SCS (Fénelon et al. 2012).

Interestingly, there is also a subgroup of patients whose SCS therapy was used as salvage therapy after loss of efficacy to both dopamine agonists medications and DBS, leading to the possibility that SCS may be a viable alternative or conjunctive therapy to DBS for the management of PD symptoms, as well as pain (Pinto de Souza et al. 2017) (Fig. 1).

This article aims to summarize and discuss preclinical translational data for SCS in PD as well as clinical cases of SCS for PD as both singular bioelectric therapy and salvage therapy after loss of efficacy of DBS.

Data sources for this relevant literature search included PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles with keywords Parkinson’s disease, spinal cord stimulation, and deep brain stimulation.

Conclusion
Motor symptoms and pain in PD can impact quality of life, and lead to disability as well as mortality. Current management includes dopamine therapy and DBS each with its own challenges and decreased efficacy with prolonged use. However, in recent years, it has been demonstrated that SCS for PD can be used as both a singular bioelectric therapy and salvage therapy after loss of efficacy of DBS, although the mechanisms remain shrouded in mystery.

It may be possible that electrical stimulation of spinal cord sends signals to basal ganglia circuits which then in turn increases release of stored dopamine similar to DBS in pigs (Shon et al. 2010). There may also be a neuroprotective component achieved by electrical stimulation that delays progression of dopaminergic neuron loss in the brain.

It is also of note that in combination with SCS, a decreased dose of L- DOPA was enough to produce equivalent locomotion to L-dopa alone in the rat model. A better understanding of how to optimally combine dopamine replacement therapy and electrical stimulation will be a very important future goal in order to develop better strategies to alleviate motor symptoms in PD.

As previously mentioned, the study by Thevathasan et al. showed that SCS failed to relieve akinesia or restore locomotion in PD when leads were placed in the high cervical position, while a recent case report by Fenelon et al. showed SCS was able to improve abnormal posture and gait disorders when the leads were placed at the T9-T10 level (Fénelon et al. 2012).

This variability in data has led to a demand for more studies to definitively conclude if SCS has an improved role compared to DBS in PD patients, and if these modes of neuromodulation could perhaps act synergistically. There remains a paucity of data on the potential synergistic effects of SCS and DBS in PD patients with regards to improvements in gait and postural instability. Certainly, the neuroanatomy of gait function involves all levels of the nervous system, and it can be difficult to pinpoint which single specific area would benefit most from stimulation to improve gait function.

The synergistic effects of SCS and DBS offer a neuromodulatory approach capable of stimulating multiple complementary neuronal areas in gait and postural function and optimizing transmission in spinal locomotor tracts.

Different stimulation patterns and frequencies have been considered when determining efficacy. In the Mazzone et al. study that compared tonic stimulation versus burst stimulation in the high cervical region (C1–2 or C2–3), patients programmed with the burst mode of stimulation showed faster onset of motor improvement as well as required fewer adjustments to programming in a 3-month period.

More research is needed to determine maximum efficacy at specific spinal levels as well as mode of stimulation. There is one clinical trial listed in www.clinicaltrials.gov for a future study on the effects of SCS on freezing of gait in patients with PD (NCT03526991).

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Source: Garvan Institute of Medical Research