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ORIGINAL CONTRIBUTIONS

Received: November 2^nd 2015

Judged: May 2^nd 2016

Deep brain stimulation in Parkinson’s disease. Preliminary outcomes

Ramiro Antonio Pérez-de la Torre,^a Alejandra Calderón-Vallejo,^b Hugo Morales-Briceño,^b David Gallardo-Ceja,^a Raúl Carrera-Pineda,^b Gerardo Guinto-Balanzar,^a Eduardo Magallón-Barajas,^c Irma Corlay-Noriega,^d Carlos Cuevas-García^e

^aServicio de Neurocirugía

^bServicio de Neurología

^cDirección Médica

^dServicio de Psiquiatría

^eDirección General

Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México

Communication with: Ramiro Antonio Pérez de la Torre

Telephone: (55) 4055 0089

Email: neuropraxis@icloud.com; ramirop8@gmail.com

Background: Parkinson’s disease justifies the use of deep brain stimulation (DBS) in certain patients who suffer from this condition. We present mid-term and long-term post-surgical outcomes in a cohort of 60 patients, who underwent DBS in the Hospital de Especialidades at Centro Médico Nacional Siglo XXI, in Mexico City.

Methods: Patients underwent conventional stereotactic surgery with FrameLink software (Medtronics Inc). This technique consisted in the presurgical evaluation, the placement of stereotactic frame, imaging studies, preoperative planning procedure, microrecording, macrostimulation, as well as the placement of electrodes and generators in two phases. The variables were included in a data platform for Excel management. It was also included a variety of measurement instruments for data comparison. As a standard measure, it was used the Unified Parkinson Disease Rating Scale (UPDRS) before the surgery and at 3, 12, and 36 months.

Results: 60 patients underwent surgery: 41 men and 19 women, with an average age of 56.5 years (39-70). There were good results in the majority of patients with preoperative UPDRS and at 3, 12 and 36 months of 79.57, 66.85, 65.29 and 58.75, respectively (p < 0.0001). There were complications in nine patients (15 %) and they were managed in a conservative manner.

Conclusions: Postsurgical outcomes were from good to excellent in the majority of patients. Complications were minimal and conservatively managed. We propose the use of this procedure in a selected group of Parkinson’s patients.

Keywords: Deep brain stimulation; Parkinson disease

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Parkinson's disease is the second cause of so-called abnormal movements only after essential tremor, with a prevalence of 1601 individuals in North America, Europe, and Australia, compared with 646 in Asia.^1,2 The age of onset is usually in the sixth decade of life; however, recent data place it at a much earlier onset. That is because of the current definition of non-motor signs and symptoms that precede the disease even decades before motor manifestations. The cardinal symptoms of the disease are tremor, rigidity, and bradykinesia, and changes in posture and gait. The presence of two of three clinical criteria means a high possibility of disease. Clinical progression is inexorable and unpredictable, and some patients are severely affected after the onset of illness, with disability at an early age.³ Medical management remains the gold standard of treatment of patients diagnosed with the disease; levodopa in some of its presentations is the treatment of choice in most cases. However, with the progress of the disease and the chronic use of levodopa, its therapeutic effect becomes lower, and secondary and undesirable side effects within the central nervous system (CNS) are added, including dyskinesia, on-off phenomena, shortening of the therapeutic effect, fluctuations in motor function, and neuropsychiatric disorders, which are sometimes more disabling than the disease itself and which necessitate the search and selection of new management alternatives, such as innovative surgical procedures. In this regard, management by surgical techniques such as deep brain stimulation (DBS) is set as the cornerstone of current surgical management, displacing ablative lesion as a management modality.^4-6 Food and Drug Administration (FDA) approval has been achieved for focus on the main targets.

The origins of deep brain stimulation are located in the middle of the last century. Alim Benabid’s work, initially with the use of the subthalamic nucleus, documented improvement in patients during stimulation.7 The use of certain nuclei as DBS targets has been a hot topic in the development of stereotaxy with three extensively studied nuclei approved for use in Parkinson's disease, including ventral intermediate nucleus (VIM), globus pallidus interna (GPi), and the subthalamic nucleus (STN) (Figure 1).^8-12

The mechanism of action of deep brain stimulation is complex and includes a number of local, regional and remote actions. In the first, the local production of dopamine, the release, or a combination thereof.¹³ Regional actions include fiber stimulation and, finally, the remote actions include suprasegmental stimulation known from patients undergoing deep brain stimulation. In the latter category, the stimulation of the prefrontal and frontal cortex is a well-documented mechanism of action.

The clinical results of DBS published in the literature are encouraging and important, with substantial improvements in the tremor, rigidity and bradykinesia in patients, but especially in reducing the percentage of dyskinesia, motor fluctuations, improvements in on time, and specific assessment scales, such as the UPDRS.

The aim of this paper is to present the first results of a series of patients with Parkinson's disease who underwent DBS as part of their management, and the experience this medical center had in the comprehensive and multidisciplinary management of this severe disease.

Methods

The integration of multidisciplinary centers for patient selection provides a consensus. The Hospital de Especialidades of the Centro Médico Nacional Siglo XXI of the Instituto Mexicano del Seguro Social consensually and collaboratively selects patients with Parkinson's disease who are candidates to receive with DBS starting in November 2011. For this, the following criteria are applied:

1. Patients have a definitive diagnosis of Parkinson's disease according to the guidelines of the Brain Bank of the UK Parkinson's Disease Society.¹⁴
2. More than five years of diagnosis of Parkinson's disease.
3. Patients present motor fluctuations, dyskinesia, and on-off phenomenon by the time of disease progression, which interfere or incapacitate the patient to carry out their activities of daily living.
4. A minimum of one year of medical treatment with levodopa.
5. Medical management that is stabilized and optimized at least one to three months before deciding to make the assessment for the DBS procedure.
6. Parkinson's disease is classified as complicated or early onset and difficult to control, with dyskinesia, on-off phenomenon, or neuropsychiatric disorders secondary to levodopa.

DBS Surgical Technique  

The surgical technique consists of an interactive planning process in which imaging studies are made before the procedure in order to indirectly locate anomalies, based on magnetic resonance imaging and cranial computed tomography. The direct method can be used when the structure can be located in the imaging method. Once the anterior and posterior commissures are located, these can be imported to a planning system to convey a set of coordinates to a stereotactic transformation method (Figure 2).

Planning has as its ultimate object locating a target in physical space to generate a defined location point. The patient is operated on while awake, using a methodology of asepsis and antisepsis permitting its direct monitoring. When hygiene is complete, an incision is made into the cerebral convexity 1 cm before the coronal suture to make an incision of 6 cm in length; subsequently, two drills are made. At this point an electrode anchoring system is used. The critical part of the procedure involves placing the electrodes. These are nanostructure designs in which a set of four electrodes are located in turn, which can operate independently (Medtronics 3387 and 3389) (Figure 3). 

Functional patient monitoring starts with the microrecording procedure, then microstimulation and finally macrostimulation. The microrecording procedure involves placing a microelectrode in a stereotactic assembly to individually or collectively explore a nucleus in order to locate a specific structure. Each nucleus in particular can exhibit unique basal and stimulation patterns, which can confirm the position of the microelectrode. 

Once the progressive scan of selected nuclei shows a characteristic pattern of interest in the selected region, we proceed to do microstimulation of the nucleus (Figure 4). The patient is examined by Neurology to confirm clinical improvement in the outstanding symptoms. In such case, the patient undergoes replacement for a final electrode (Medtronic 3387 or Medtronic 3389), and monitoring with the microelectrode continues. This is subjected to a circuit through a screener in which different pacing modalities are tested again until a satisfactory clinical response is obtained without complications. The electrodes are fixed to a fastening system, and the incision is closed conventionally. Next, a detailed postoperative study allows visualization of the final position of the electrode.

In a second phase, the procedure is performed with the patient in general anesthesia to continue the asepsis and antisepsis of the head region, the neck, and the clavicular region. A subcutaneous pocket is made in both hemithorax to the thoracic fascia, and the incision in the skull is reopened, exposing the microelectrode; the tunneling of the extensions is then continued, connecting them to the electrode with a single clamping system. Similarly the generator is inserted in the thorax (Medtronics, Soletra, Activa SC, PC) to continue the respective connection. The incisions are closed in two layers and the patient is woken up (Figure 5). The initial programming of the generator is done a day later and then every two months during the first year.

The removal of stitches is done two weeks after the procedure. With the increasing use of data management platforms, it is evident that a series of clinical scales have been designed to serve as a universal tool for comparison.

Evaluations

The Hospital de Especialidades has a selection committee that evaluates patients with Parkinson's disease who are candidates for DBS. All patients were rated with international scales validated for this purpose, such as the unified scale for assessing Parkinson's disease (UPDRS) (note that in the case of deep brain stimulation, this scale has been extensively validated¹⁵ as a clinical comparison tool), the Hoehn and Yahr scale and the Schwab and England scale. Evaluations were performed preoperatively and at 3, 12, and 36 months follow-up, in order to compare of results. The percent change of scales was assessed as a standard measurement, and these were registered as an improvement parameter. The percentage of time patients spent on, off, and the presence of dyskinesia and neuropsychiatric manifestations related to the chronic use of levodopa was also quantified.

Statistical analysis was performed using SPSS version 19.

Results

A total of 85 patients who underwent DBS/DBS were reviewed for this publication; of these, 60 met the criteria to be included. Clinical data of the number of cases are described below (Table I).

There were a total of 60 patients undergoing DBS, 41 men (68.3%) and 19 women (31.7%) with a mean age of 56.5 years (range 39-70). The age of disease onset was 42.21 years (range 26-68), with stiffness/bradykinesia the predominant syndrome. All had side effects with the chronic use of levodopa, particularly dyskinesia, on-off phenomenon, and neuropsychiatric manifestations. The most frequently used target was the GPi with 46 patients, the STN in nine cases, and the VIM in five patients.

With regard to clinical assessments, a reduction was observed in average scores on the UPDRS at indicated cutoff times both at baseline and postoperatively at 3, 12, and 36 months, showing clinical improvement. An average UPDRS of 66.85, 65.75, and 58.29 was obtained at 3, 12, and 36 months, respectively, with significant difference between baseline and 12 months after the procedure (p < 0.0001).   

The postoperative complications were divided into those presented within the first 30 days after surgery that can be considered under the heading of perioperative complications, and those presented after 30 days. Given that it is an implant, monitoring these patients is essential, especially if they come from remote regions of the country. Complications were recorded in nine patients (15%) and were related to the hardware; they consisted of hardware exposure (three patients), electrode migration (two patients), infection (two patients), granuloma, and accelerated battery consumption (in one patient each complication) (Table I).

Regarding other adverse events not related to surgery, three cases of delirium related to the change in medication were reported, which were handled by adjusting antipsychotics for short periods of time.

No deaths were reported in this group of patients.

Discussion

Parkinson's disease remains a daily challenge for neuroscience. Despite being the best known neurological disease in its anatomy, pathophysiology, and biochemical deficit, and besides being the first for which the first specific treatment for such disturbances was developed, even today this has not been enough to control this disease.

The surgical management of Parkinson's disease has been a focus of growing interest in integrated patient management.^4,16,17 The era of deep brain stimulation (DBS) begins with the work of A. Benabid in 1987.6 Deep brain stimulation is a modern concept in the treatment of patients with Parkinson's disease. This research represents a preliminary series that is undoubtedly the largest in Mexico from a single institution. The integration of a data platform is a constant in centers of excellence regarding abnormal movements. To this end, the institutional effort involves monitoring patients closely through the application of longitudinal scales, and the preparation and presentation of their results. The methodology used, as can be noted, is comparable to that used in international reference centers through computed virtual planning with high-resolution images methods, image fusion, and intraoperative methodology, consisting of microrecording and macrostimulation. Certainly, some original results can be seen with the descriptive analysis. The predominance of men in the series may be biased because it is an insured population. The ages of disease onset is noteworthy with an average of 42.21 and 14.3 years of evolution. To this end, there is a growing universal consensus to consider the use of deep brain stimulation therapy in the early stages of the disease to prevent motor complications.^18,19,20 Considering the selection criteria for our series, it is important to note the extensive condition of these patients when compared to reference studies, which may limit the effect of brain stimulation therapy.²¹ In these reported studies, patients had a better response to DBS, probably because they were patients with a better UPDRS score and were thus less clinically affected than the patients reported in our series.

The cohort represents a significant number of implanted cases, because it is 60 patients with the complete protocol. Half are patients diagnosed with juvenile Parkinson's disease (50%), which suggests the possibility of a prolonged evolution. With respect to clinical variables, the UPDRS, Hoehn and Yahr, and Schwab and England scales are referred to preoperatively, and the UPDRS for comparison. Of these, based on the rate of change between pre- and postoperative UPDRS, it was concluded that this remains the individual scale with the best correlation in motor improvement in activities of daily living and motor complications. Preoperative UPDRS in off is 79.57 decreasing to 58.75 (Figure 6). The degree of UPDRS change is 26.17% on average, which is comparable with published studies.²² Complications occurred in nine patients (15%) with a single case of infection that required the extraction of the equipment, electrode migration in two, and hardware exposure, which is managed conservatively.

Conclusions

With deep brain stimulation a series of highly successful techniques are shown in the management of Parkinson's disease that allow adaptability, reproducibility, and efficiency in the medium and long term. It is clear that the availability of resources of such magnitude requires judicious clinical practice with the need to apply neurostimulation to patients severely affected by the disease, with poor response to pharmacological management and related complications. The effectiveness of the procedure is demonstrated in the medium and long term. The complication rate is low compared with the series described. This work reports on initial clinical experience.

Acknowledgments

This study was made possible thanks to the generous support of the Instituto Mexicano del Seguro Social at the respective levels and to the staff of the institution, who encourage the continuity and permanence of the project.

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