Professor, Drexel University College of Medicine Department of Neurosurgery, Department of Pharmacology & Physiology, Drexel Neurosciences Institute; Director, Stereotactic, Functional, and Epilepsy Surgery; Co-Director, Philadelphia Voice Tremor Center, Global Neurosciences Institute, LLC

Atom Sarkar, MD, PhD

 have coalesced as communities, beginning nearly 10,000 years ago in the Neolithic period, there has been a fascination with the skull and brain. From here emerged the rudiments of neurosurgery. In regions ranging from the Ensisheim in Alsace, France, to the Peruvian Altiplano, we know trepanation was practiced. In trepanation, a hole is scraped or drilled into the human skull, and it is the oldest documented surgical procedure performed by man. While we can only speculate about the millennia-old reasons for such “procedures”—spanning from the mystical to spiritual and ritual—they must be favored over any current-day notion of medicinal. Nevertheless, such experiences of the shaman and healers of lore should not be discounted, because some of our current neurosurgical practices, in particular the practice of minimal-access surgery, harken back to their legacy of transcalvarial access.

In general, neurosurgical interventions can be considered corrections of structural deformities. For instance, 

 depicts a disc herniation impinging on a nerve root. Here, a right-sided C6/7 disc herniation causes a right C7 radiculopathy, with associated pain and triceps weakness. Since an adequate trial of conservative care failed, our solution was to remove the pathology. In this instance, an anterior cervical discectomy was performed to remove the C6/7 disc, and in the process decompress the afflicted C7 root. An arthroplasty was performed, with immediate relief in symptoms and restoration of normal structural alignments. In some instances, the structural anomaly is far more serious, such as in the 

 example of a patient with Klippel-Feil syndrome. The osseous dyssegmentation spinal anomalies resulted in an ominous situation in which the dens of C2 was being drawn into the foramen magnum, causing a symptomatic pithing of medulla. The solution here was to decompress the suboccipital bone, while stabilizing the occipital-cervical alignment with a titanium plate-screw-rod as well as bone fusion construct. In doing so, the occipital-cervical junction was repositioned back toward a nonpathologic, native axial alignment. Our neurosurgical intervention, which relieved the pressure that had been present at the cervicomedullary junction, was critical in maintaining neurological integrity and averting quadriparesis.

Even tumors can be considered a structural problem for a neurosurgeon to combat. The images in 

 (left panels) demonstrate a temporal-parietal-occipital mass that is impinging on the posterior aspect of the left lateral ventricle. This patient did not even appreciate their visual deficit until it was demonstrated on physical exam; it had instead been the loss of the ability to read that had prompted admission. While the patient could spell and recite letters, the ability to process letters into words had been affected. Two weeks following surgery (right panel), their ability to recognize simple 3- and 4-letter words was starting to return. In contrast to structural problems such as those illustrated above, the movement disorders that afflict some patients are distinctly different. In an individual with essential tremor, Parkinson disease (PD), or dystonia, no particular structural deficit exists. That being said, neurosurgeons have nonetheless been actively seeking to define effective interventions for patients with these diagnoses since the foundation of our specialty, and treatments for PD have been a keen interest for the past 130 years. April is Parkinson Disease Awareness Month, and it has been just over 200 years since James Parkinson, published his 1817 monograph, An Essay on the Shaking Palsy.

 Devotees of James Parkinson will appreciate that only 6 index cases were described, and of these, 3 patients were evaluated from casual observation, or in Parkinson’s own words, “…next noticed was casually met with in the street…” While Parkinson’s keen sense of observation allowed him to identify some of the cardinal features of the then-designated “shaking palsy/paralysis agitans”—tremor, rigidity, and postural instability—it was Jean-Martin Charcot’s meticulous analysis that added the fourth cardinal feature: bradykinesia. It was also Charcot who suggested that such individuals should be designated as patients with Parkinson disease. 

James Parkinson was a man of many talents, both medical and nonmedical. Like his father, John, he was an apothecary. His nonmedical interests included geology and paleontology as well as political activism. What is perhaps often forgotten with the passage of time is that Parkinson was a surgeon, and his affiliation as a member of the Royal College of Surgeons is prominently evident on his landmark publication. However, Parkinson was most certainly not a neurosurgeon, because, historic trephination notwithstanding, neurosurgery as an emerging field wouldn’t occur for nearly 70 years, when the neurologist Sir William Gowers, MD, collaborated with the pioneering neurosurgeon Sir Victor Horsley, MD. As such, Parkinson’s advocacy was for solutions that were in keeping with the times: bloodletting and blistering. While the methods were antiquated, his belief that such maneuvers would relieve inflammatory pressure away from the medulla, while incorrect, was prescient at least in suggesting subcortical pathology. 

 Scans of Mass in Brain. Left panels: Temporal-parietal-occipital mass. Right panel: Two weeks post-surgery.

Approximately 10 million individuals globally carry the diagnosis of PD. The disease is neurodegenerative and is second only to Alzheimer disease with regard to neurodegenerative prevalence. The hallmark pathology of PD occurs in the ventral midbrain. Specifically, it is the selective loss of dopaminergic neurons in the pars compacta of the substantia nigra. The mechanism of deterioration is not entirely clear, aside from its association with selective neuronal loss and the prevalence of aggregates of the intrinsically unstructured, otherwise soluble protein, alpha-synuclein. Ninety percent of PD is idiopathic. Although its cause is unknown, certain risk factors are recognized: 

Age: Infrequently, PD can affect young adults. The frequency for individuals aged over 60 years is estimated to be 1%, increasing to 5% in individuals aged over 85 years.

Heredity: Having close relatives with PD increases one’s chances of developing the disease, although the genetic understanding of PD is murky at best.

Sex: Men are 1.5 times more likely to develop PD than women.

Environmental: Exposure to such toxins as herbicides and pesticides may slightly increase the risk of developing PD.

Patients lose autonomy as the disease progresses, which is incalculable in terms of personal loss. Economically, the estimated annual cost to the health care system in the United States alone is more than $50 billion.

Movement disorders, in general, fascinated neurosurgeons from the start, perhaps because their associated debilitation was so obvious. Conditions such as hemiballism, Huntington chorea, and PD offered opportunities to create therapeutic ameliorations surgically by disrupting the motor pathways. All points of contact were explored, from the cortex to the internal capsule, from the basal ganglia to the cerebral pyramids, and even the spinal cord. 

As early as 1890, Horsley resected the motor cortex, and while this operation was performed with some frequency in the 1920s, over the ensuing 20 years, it became clear that such an approach to treating movement disorders was risky and ineffective; it frequently left the patient far worse off. For instance, in patients with PD, while the immediate postoperative period saw a disappearance of the tremor due to motor paresis, the tremor would relapse, with the extrapyramidal rigidity being substituted for pyramidal spasticity. Even more disappointing was with progression of disease. Patients with PD who had undergone such cortical extirpations were left with a paretic limb contralateral to their surgery, and a tremulous or rigid limb heralded the march of neurodegeneration in their other extremity. 

Marching caudally, hope remained that subcortical surgery focused on the pyramidal tracts might hold promise over the unpromising cortical interventions. In the late 1940s, E. Jefferson Browder, MD, advocated for the frontal transventricular approach. His surgery involved resecting the caudate nucleus as a means to trace the anterior limb of the internal capsule fibers back toward the genu to induce a subcortical paresis. Unsurprisingly, the outcomes here were no better than those of the cortical resections, with the added downside that ventricular entry increased risks and complications. Additionally, behavioral changes from the destruction of the internal capsule’s anterior limb left patients neuropsychiatrically altered. 

Around the same time as Browder, also in the quest to find a subcortical pyramidal tract target suitable for destruction, A. Earl Walker, MD, proposed sectioning the pyramidal tracts at the level of the mesencephalon. Such a surgery was subtemporal, thereby avoiding the complications that were then associated with intraventricular surgery. Pedunculotomy was a technical feat and had its proponents, but compromising the pyramidal tracts, whether supratentorially or infratentorially, was typically unsuccessful and left the patient worse off than they began. 

Extending most caudally, surgical approaches reached the spinal cord. Fundamentally, efforts here were coupled with low success and high complication rates and are effectively a remnant of the past, despite the fact that pioneers such as Tracy J. Putnam, MD, investigated spinal pyramidotomy. 

Turning to the concept of surgery upon the basal ganglia and its extrapyramidal motor system, we note that one of the founding fathers of neurosurgery, the preeminent American surgeon Walter Dandy, MD, had posited in the 1920s that the ventral striatum was critical for consciousness and therefore not to be touched during neurosurgery. Colleagues dutifully followed his lead. However, in 1939, Russell Meyers, MD, serendipitously cared for a conscious patient with a horrendous open-skull fracture injury that lay bare for observation a bilaterally injured ventral striata. After this encounter, Meyers hypothesized that he might improve functional outcomes for patients with PD by operating “safely” and selectively on their extrapyramidal system without compromising their consciousness. While there was much to be admired in this bold innovation, the high morbidity and mortality of such a transventricular approach to the basal ganglia rapidly fell out of favor. 

In 1952, serendipity again arose in allowing Irving Cooper, MD, to surmise that a lesion to the globus pallidus/thalamus might be the key toward quelling the extrapyramidal symptoms of PD. During a pedunculotomy operation Cooper was performing on a patient with postencephalitic parkinsonism, a ferocious bleed forced him to ligate what was later determined to be the anterior choroidal artery. What must have undoubtably felt like an intraoperative calamity turned out to be a surprising postoperative success, as the patient’s tremor and rigidity were quelled without hemiparesis. However, as was true of many other innovative operations in the history of functional surgery, early enthusiasm was quashed by complications that included unacceptably high morbidity and mortality. 

What was immediately clear, though, from Meyers’ and Cooper’s independent observations of extirpative and vascularly occlusive surgeries, respectively, was that the future of PD surgery lay in innovative selective ablation of basal ganglia nuclei that could be achieved with minimal morbidity. Also, another point worth emphasizing was that movement disorder surgical investigations, starting with those of Horsley and modified by global pioneers, were able to address only “hemi-parkinsonism.” In other words, although PD manifests bilaterally as it progresses, these pioneers believed that in any surgery to try to ameliorate symptoms of PD, which would result in paresis of 1 side of the body, in turn, limiting the ability to address symptoms on both sides. 

Still, while the definitive surgical therapies emerging from the 1890-1960 period had significant limitations, those surgeons and their teams have to be applauded. It is easy to forget how few resources, relatively, were available at the time. There was certainly little in the way of modern imaging or intraoperative navigation, and for sure, visualization of the operative field was not accompanied by magnification or even illumination. As such, taken in context, the notion of these collective investigations is just simply remarkable. 

At this point, it would be logical to transition to a discussion of stereotactic and modern functional/neuromodulation procedures. We stop here, though, to introduce the work of one physician/scientist—Oleh Hornykiewicz, MD—who is fundamental to any discussion of PD treatment. In July 1961, Hornykiewicz, in collaboration with the neurologist Walther Birkmayer, MD, (head of the neurological ward of Vienna’s largest home for the aged, Wien-Lainz), effectively established the medical and pharmacological practice of transmitter-based therapeutics so widely used today. The dopamine miracle is what happened that day when intravenous levodopa was infused into a patient with PD. In Hornykiewicz’s own recollections, the results were spectacular. Consequently, and not surprisingly, interest in surgery to treat PD quickly waned. 

Human stereotactic surgery found its inception in Philadelphia, which is also the birthplace of many American institutions and ideas. The neurology-neurosurgical collaboration of Ernest A. Spiegel, MD, and Henry T. Wycis, MD, at Temple University heralded the first human stereotactic procedure in 1947. Their device was called the “stereoencephalon,” and their first patient had Huntington chorea. The genius of this approach was that for the first time, internal cerebral landmarks, such as the air outline of the ventricular system, as well as other in situ markers, such as the calcified pineal gland, correlated to a brain atlas that had been developed by the Temple team. This allowed deep intracranial structures to be approached with relative accuracy and safety. 

The field of stereotactic surgery for the next 40 years would refine itself utilizing 2 principles—progressive minimalism and high-fidelity targeting—which would allow for increasingly finely tuned “lesionectomies.” Lesionectomies were performed in a variety of ways that were sufficient to impart irreversible cellular or tissue injury; they included caustic measures as well as those utilizing thermal/energy means via extreme temperatures, either hyperthermia or hypothermia. The important point to note here is that these therapies were still destructive/ablative. These lesions are irreversible, fixed, and unmodifiable. 

The first half of the 1980s saw a change away from the emphasis on lesionectomies, and the age of functional and neurorestorative surgery was ushered in. Neurosurgeon/physicist Alim-Louis Benabid, MD, PhD, was performing stereotactic operations for movement disorders at the Université Joseph Fourier in Grenoble, France. A unilateral lesion to the ventral intermediate nucleus of thalamus was a reliable way of treating “hemi-parkinsonism.” As Benabid has described, “At the time, the treatment for PD was [levodopa], and that had side effects, and neurosurgery had complications.”

The anatomy of the thalamus is somatotopic, and surgeons use this information to physiologically define critical vital areas to avoid, allowing them to impart lesions while minimizing adverse effects. The motor thalamus is anterior, and the sensory thalamus posterior; the face is represented more medially, while the legs are more lateral in both motor and sensory somatotopy. The internal capsule is lateral and carries the pyramidal motor fibers. Prior to creating a precise thermally ablative lesion in the thalamus, testing with microelectrode stimulation ensued. Using physiologic neuronal firing frequencies ranging from 20 Hz to 50 Hz, the thalamus and adjacent structures could be mapped. Ideally, stimulation would identify a spot just anterior to the somatosensory thalamus, but safely enough medial to the internal capsule, which would be targeted for ablation. By his own admission, curiosity prompted Benabid to stimulate at low frequencies—starting at 1 Hz, and then going up to the maximal stimulation frequency of the electrical pulse generator, 100 Hz, which remarkably stopped the tremor! Much like the “Eureka!” moment that must have flooded Hornykiewicz and Birkmayer more than a quarter-century earlier, Benabid realized that high-frequency stimulation, rather than ablation, might be the solution, and this ushered in our present era of neurorestorative, neuromodulatory, nonablative surgery. The beauty here is that the “currency” of the brain is electricity, and deep brain stimulation (DBS) elegantly offers a solution using electricity as a therapeutic, prompting some to call this manner of intervention “electroceutical” treatment. 

The impact of Benabid’s work and of his realization, as well as its clinical implementation, must not be underestimated. Prior to Benabid’s insight, procedures for PD or any other movement disorder were necessarily unilateral. Even with carefully deployed thalamic ablations, a bilateral procedure carried a risk for dysarthria as high as nearly 30%. The absolute benefit of PD DBS neuromodulation is that bilateral nuclei can be targeted, to afford relief for not just “hemisymptoms” but rather full body control. Additionally, unlike ablative interventions, DBS is dynamic—very important, since PD is not static. While the disease will invariably progress, the ability to program DBS therapy to modify its parameters—current/voltage, pulse width, and frequency—can often combat disease progression, thereby keeping disabling symptoms at bay. 

 Montage of a Patient With Parkinson Disease With Bilateral Globus Pallidus Internal Implants

Typically, bilateral electrode placements that lead to an impulse generator battery are placed in the subclavicular region. The battery may be either rechargeable or nonrechargeable and it can be wirelessly programmed or interrogated. Barring any compromise of intracranial electrodes, they are a permanent fixture; the impulse generator battery will require periodic surgical exchange, depending upon the battery’s demands. All components are subcutaneous and effectively hidden from view. In 

, the montage shows bilateral globus pallidus internal (GPi) implants in one of our patients with PD. The arrows in the brain CT scan show bilateral electrode tips; the skull films give an overall appreciation of the electrodes in relationship to the cranial anatomy, highlighting the deep nature of these implants and the absolute need for precise submillimetric stereotactic accuracy. In this particular patient, 2 impulse generators were placed subclavicularly, and the leads can be seen coursing down each side of the neck, terminating into right and left batteries. 

Perhaps the single most important factor in predicting DBS success for patients with PD is patient selection. Herein lies the importance of assembling a multidisciplinary team. Ever since Horsley and Gowers, neurosurgeons and neurologists have been inextricably linked. Today, in addition to the requisite support staff, a multidisciplinary movement disorder team requires a neuropsychologist, a movement disorder neurologist, and a stereotactic/ functional neurosurgeon. In addition to patient selection, target selection is also key. In patients with PD, either the subthalamic nucleus (STN) or the GPi must be selected as the target, and the choice is typically based on multidisciplinary input from neuropsychologists, neurologists, and neurosurgeons. For instance, concern for postsurgical cognitive impairment would favor implanting the GPi, but a desire to taper medications secondary to adverse effects might favor an STN implant. 

It has been 50 years since Hornykiewicz and Birkmayer experienced the dopamine miracle, and it is certainly reasonable to muse what the next 50 years will bring. For neurosurgeons and neurologists alike, it is perhaps best to reflect back not on the successes but some of the major shortcomings regarding our current treatment paradigm for PD. Of the 4 cardinal features that define PD, postural instability is least likely to improve with this paradigm. In addition, several nonmotor manifestations, including depression, dementia, psychosis, and dysautonomia, do not reliably find relief from DBS or even from polypharmacological therapy. This reality emphasizes that PD is a focal problem in the substantia nigra, with globally distributive effects throughout the central nervous system and protean clinical manifestations. For surgeons, this means that the next challenge is to identify brain targets and networks that might be intervened upon in order to capture and improve a greater number of PD symptoms. 

While DBS surgery is now in its third decade of clinical use, other therapies, all still nascent, will likely one day be carried out in complement, or perhaps even in a staged integrated approach. For instance, it is eminently conceivable to think that a future stereotactic surgeon might deliver stem-cell–based or viral-based gene therapies, or even optogenetics solutions in conjunction with electrical stimulation or otherwise, that would not only treat symptoms but perhaps even afford neuroprotection.

 It’s also obvious that the physical hardware of DBS will no doubt change in coming years. Electrodes will become more sophisticated, and the pulse generator will no doubt become miniaturized and more powerful in its abilities to sense biosignatures of disease and offer therapeutic stimulation. Current DBS therapy is applied as an “open loop,” which means that therapy is always on, much like the “on” and “off” of a light switch. The DBS of the future, however, will incorporate artificial intelligence and deep learning to record, sense, screen and process local field potentials. In other words, the device will not only deliver therapy, but act in the manner of a true brain-machine interface, imparting stimulation in an episodic “closed-loop” manner when preset parameters are met. Such a closed-loop therapeutic already exists for patients with epilepsy, in a device colloquially referred to as a brain pacemaker. 

Finally, DBS therapy as a treatment for PD needs to be embraced much more thoroughly than it has been. Curious neurosurgeons, neurologists, and scientists have collectively spent more than a century both directly and indirectly developing DBS. In the 34 years since the first implant in Grenoble, approximately 200,000 patients have been implanted globally, inclusive of all neuromodulatory applications. To compare that with another neurosurgical technique, there were about 300,000 thoracolumbar fusion operations just in the United States alone in 2020. 

Part of that gaping disparity represents the prevalence of spine disease vs PD, but an even bigger part lies in apprehension on the part of the patients and even their care providers in considering DBS. Innovations in neurobiology, science, technology, engineering, and public awareness will shape the future of DBS in ways that we might not even be able to imagine right now. All the work will have been for naught, though, if DBS continues to enjoy simply a niche status. Surgical care for PD is safe and effective, period. It should no longer be treated as a consideration of last resort, but as a treatment option discussed early in the disease course with the patient and their family. 

REFERENCES 
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Articles

Surgical care for PD is safe and effective, and should no longer be treated as a consideration of last resort, but as a treatment option discussed early in the disease course with the patient and their family.

Atom Sarkar, MD, PhD

Articles

Neurosurgery and Parkinson Disease: Past, Present, and Future of Deep Brain Stimulation