Subthalamic deep brain stimulation for Parkinson’s disease outcome

Subthalamic deep brain stimulation for Parkinson’s disease outcome

The surgical and clinical outcomes of asleep DBS for Parkinson’s disease are comparable to those of awake DBS 1).


Suboptimal targeting within the STN can give rise to intolerable sensorimotor side effects, such as dysarthria, contractions and paresthesias 2) 3) 4). eye movement perturbations, and psychiatric symptoms 5) 6) 7), limiting the management of motor symptoms. The small size of the STN motor territory and the consequences of spreading current to immediately adjacent structures obligate precise targeting. Neurosurgeons therefore rely on a combination of imaging, electrophysiology, kinesthetic responses, and stimulation testing to accurately place the DBS lead into the sensorimotor domain of STN 8) 9) 10).

Deep Brain Stimulation has been associated with post-operative neuropsychology changes, especially in verbal memory.

Deep brain stimulation (DBS) of subthalamic nucleus (STN) is widely accepted to treat advanced Parkinson disease (PD). However, published studies were mainly conducted in Western centers 11).

High frequency subthalamic nucleus (STN) deep brain stimulation (DBS) improves the cardinal motor signs of Parkinson’s disease (PD) and attenuates STN alpha/beta band neural synchrony in a voltage-dependent manner. While there is a growing interest in the behavioral effects of lower frequency (60 Hz) DBS, little is known about its effect on STN neural synchrony.

Low-frequency stimulation of the subthalamic nucleus via the optimal contacts is effective in improving overall motor function of patients with Parkinson Disease 12). In Parkinson’s disease significantly improved important aspects of QoL as measured by PDQ-39. The improvements were maintained at 2 years follow-up except for social support and communication. Sobstyl et al., demonstrated a positive correlation between changes in the off condition of motor UPDRS scores and Unified Dyskinesia Rating Scale in several PDQ-39 dimensions, whereas fluctuation UPDRS scores were negatively correlated with PDQ-39 mobility scores 13).

The degree of clinical improvement achieved by deep brain stimulation (DBS) is largely dependent on the accuracy of lead placement.

A study reports on the evaluation of intraoperative MRI (iMRI) for adjusting deviated electrodes to the accurate anatomical position during DBS surgery and acute intracranial changes 14).


Although dementia is a contraindication in deep brain stimulation for Parkinson’s disease, the concept is supported by little scientific evidence. Moreover, it is unclear whether PD with mild cognitive impairment (PD-MCI) or domain-specific cognitive impairments affect the outcome of DBS in non-demented PD patients.

Baseline cognitive levels of patients with PD who underwent DBS were classified into PD with dementia (PDD) (n = 15), PD-MCI (n = 210), and normal cognition (PD-NC) (n = 79). The impact of the cognitive level on key DBS outcome measures [mortality, nursing home admission, progression to Hoehn&Yahr (HY) stage 5 and progression to PDD] were analyzed using Cox regression models. Park et al. also investigated whether impairment of a specific cognitive domain could predict these outcomes in non-demented patients.

Results: Patients with PDD showed a substantially higher risk of nursing home admission and progression to HY stage 5 compared with patients with PD-MCI [hazard ratio (HR) 4.20, P = .002; HR = 5.29, P < .001] and PD-NC (HR 7.50, P < .001; HR = 7.93, P < .001). MCI did not alter the prognosis in patients without dementia, but those with visuospatial impairment showed poorer outcomes for nursing home admission (P = .015), progression to HY stage 5 (P = .027) and PDD (P = .006).

Conclusions: Cognitive profiles may stratify the pre-operative risk and predict long-term outcomes of DBS in PD 15).

References

1)

Wang J, Ponce FA, Tao J, Yu HM, Liu JY, Wang YJ, Luan GM, Ou SW. Comparison of Awake and Asleep Deep Brain Stimulation for Parkinson’s Disease: A Detailed Analysis Through Literature Review. Neuromodulation. 2019 Dec 12. doi: 10.1111/ner.13061. [Epub ahead of print] Review. PubMed PMID: 31830772.
2) , 9)

Benabid AL, Chabardes S, Mitrofanis J, Pollak P: Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson’s disease. Lancet Neurol 8:67–81, 2009
3) , 10)

Groiss SJ, Wojtecki L, Südmeyer M, Schnitzler A: Deep brain stimulation in Parkinson’s disease. Ther Adv Neurol Disorder 2:20–28, 2009
4)

Zhang S, Zhou P, Jiang S, Wang W, Li P: Interleaving subthalamic nucleus deep brain stimulation to avoid side effects while achieving satisfactory motor benefits in Parkinson disease: a report of 12 cases. Medicine (Baltimore) 95:e5575, 2016
5)

Kulisevsky J, Berthier ML, Gironell A, Pascual-Sedano B, Molet J, Parés P: Mania following deep brain stimulation for Parkinson’s disease. Neurology 59:1421–1424, 2002
6)

Mallet L, Schüpbach M, N’Diaye K, Remy P, Bardinet E, Czernecki V, et al: Stimulation of subterritories of the subthalamic nucleus reveals its role in the integration of the emotional and motor aspects of behavior. Proc Natl Acad Sci U S A 104:10661–10666, 2007
7)

Raucher-Chéné D, Charrel CL, de Maindreville AD, Limosin F: Manic episode with psychotic symptoms in a patient with Parkinson’s disease treated by subthalamic nucleus stimulation: improvement on switching the target. J Neurol Sci 273:116–117, 2008
8)

Abosch A, Timmermann L, Bartley S, Rietkerk HG, Whiting D, Connolly PJ, et al: An international survey of deep brain stimulation procedural steps. Stereotact Funct Neurosurg 91:1–11, 2013
11)

Chiou SM, Lin YC, Huang HM. One-year Outcome of Bilateral Subthalamic Stimulation in Parkinson Disease: An Eastern Experience. World Neurosurg. 2015 Jun 10. pii: S1878-8750(15)00709-3. doi: 0.1016/j.wneu.2015.06.002. [Epub ahead of print] PubMed PMID: 26072454.
12)

Khoo HM, Kishima H, Hosomi K, Maruo T, Tani N, Oshino S, Shimokawa T, Yokoe M, Mochizuki H, Saitoh Y, Yoshimine T. Low-frequency subthalamic nucleus stimulation in Parkinson’s disease: A randomized clinical trial. Mov Disord. 2014 Jan 21. doi: 10.1002/mds.25810. [Epub ahead of print] PubMed PMID: 24449169.
13)

Sobstyl M, Ząbek M, Górecki W, Mossakowski Z. Quality of life in advanced Parkinson’s disease after bilateral subthalamic stimulation: 2 years follow-up study. Clin Neurol Neurosurg. 2014 Sep;124:161-5. doi: 10.1016/j.clineuro.2014.06.019. Epub 2014 Jun 23. PubMed PMID: 25051167.
14)

Cui Z, Pan L, Song H, Xu X, Xu B, Yu X, Ling Z. Intraoperative MRI for optimizing electrode placement for deep brain stimulation of the subthalamic nucleus in Parkinson disease. J Neurosurg. 2016 Jan;124(1):62-9. doi: 10.3171/2015.1.JNS141534. Epub 2015 Aug 14. PubMed PMID: 26274983.
15)

Park KW, Jo S, Kim MS, et al. Cognitive profile as a predictor of the long-term outcome after deep brain stimulation in Parkinson’s disease [published online ahead of print, 2020 Jul 28]. J Neurol Sci. 2020;417:117063. doi:10.1016/j.jns.2020.117063

Asleep subthalamic deep brain stimulation for Parkinson’s disease

Asleep subthalamic deep brain stimulation for Parkinson’s disease

Deep brain stimulation (DBS) implantation under general anesthesia (GA) is of great importance for patients with disabling off-medication symptoms or medical comorbidities. However, the relative advantages/disadvantages of routine local anesthesia (LA) surgery versus GA regarding clinical outcomes are controversial, and the safety of DBS implantation under GA is debatable.

Meta-Analysis

Liu et al. systematically reviewed the literature to compare the efficacy and safety of awake and asleep deep brain stimulation surgery. They identified cohort studies from the Cochrane libraryMEDLINE, and EMBASE (January 1970 to August 2019) by using Review Manager 5.3 software to conduct a meta-analysis following the PRISMA guidelines. Fourteen cohort studies involving 1,523 patients were included. The meta-analysis results showed that there were no significant differences between the GA and LA groups in UPDRSIII score improvement (standard mean difference [SMD] 0.06; 95% CI -0.16 to 0.28; p = 0.60), postoperative LEDD requirement (SMD -0.17; 95% CI -0.44 to 0.12; p = 0.23), or operation time (SMD 0.18; 95% CI -0.31 to 0.67; p = 0.47). Additionally, there was no significant difference in the incidence of adverse events (OR 0.98; 95% CI 0.53-1.80; p = 0.94), including postoperative speech disturbance and intracranial hemorrhage. However, the volume of intracranial air was significantly lower in the GA group than that in the LA group. In a subgroup analysis, there was no significant difference in clinical efficacy between the microelectrode recording (MER) and non-MER groups. We demonstrated equivalent clinical outcomes of DBS surgery between GA and LA in terms of improvement of symptoms and the incidence of adverse events. Key Messages: MER might not be necessary for DBS implantation. For patients who cannot tolerate DBS surgery while being awake, GA should be an appropriate alternative 1).

Case series

The objective of a study of Senemmar et al. was to investigate whether asleep deep brain stimulation surgery of the subthalamic nucleus (STN) improves therapeutic window (TW) for both directional (dDBS) and omnidirectional (oDBS) stimulation in a large single-center population.

A total of 104 consecutive patients with Parkinson’s disease (PD) undergoing STN-DBS surgery (80 asleep and 24 awake) were compared regarding TW, therapeutic thresholdside effect threshold, improvement of Unified PD Rating Scale motor score (UPDRS-III) and degree of levodopa equivalent daily dose (LEDD) reduction.

Asleep DBS surgery led to significantly wider TW compared to awake surgery for both dDBS and oDBS. However, dDBS further increased TW compared to oDBS in the asleep group only and not in the awake group. Clinical efficacy in terms of UPDRS-III improvement and LEDD reduction did not differ between groups.

The study provides first evidence for improvement of therapeutic window by asleep surgery compared to awake surgery, which can be strengthened further by dDBS. These results support the notion of preferring asleep over awake surgery but needs to be confirmed by prospective trial2).


Clinical outcome studies have shown that “asleep” DBS lead placement, performed using intraoperative imaging with stereotactic accuracy as the surgical endpoint, has motor outcomes comparable to traditional “awake” DBS using microelectrode recording (MER), but with shorter case times and improved speech fluency 3).


Ninety-six patients were retrospectively matched pairwise (48 asleep and 48 awake) and compared regarding improvement of Unified PD Rating Scale Motor Score (UPDRS-III), cognitive function, Levodopa-equivalent-daily-dose (LEDD), stimulation amplitudes, side effects, surgery duration, and complication rates. Routine testing took place at three months and one year postoperatively.

Results: Chronic DBS effects (UPDRS-III without medication and with stimulation on [OFF/ON]) significantly improved UPDRS-III only after awake surgery at three months and in both groups one year postoperatively. Acute effects (percentage UPDRS-III reduction after activation of stimulation) were also significantly better after awake surgery at three months but not at one year compared to asleep surgery. UPDRS-III subitems “freezing” and “speech” were significantly worse after asleep surgery at three months and one year, respectively. LEDD was significantly lower after awake surgery only one week postoperatively. The other measures did not differ between groups.

Overall motor function improved faster in the awake surgery group, but the difference ceased after one year. However, axial subitems were worse in the asleep surgery group suggesting that worsening of axial symptoms was risked improving overall motor function. Awake surgery still seems advantageous for STN-DBS in PD, although asleep surgery may be considered with lower threshold in patients not suitable for awake surgery 4).

References

1)

Liu Z, He S, Li L. General Anesthesia versus Local Anesthesia for Deep Brain Stimulation in Parkinson’s Disease: A Meta-Analysis. Stereotact Funct Neurosurg. 2019;97(5-6):381-390. doi:10.1159/000505079
2)

Senemmar F, Hartmann CJ, Slotty PJ, Vesper J, Schnitzler A, Groiss SJ. Asleep Surgery May Improve the Therapeutic Window for Deep Brain Stimulation of the Subthalamic Nucleus [published online ahead of print, 2020 Jul 13]. Neuromodulation. 2020;10.1111/ner.13237. doi:10.1111/ner.13237
3)

Mirzadeh Z, Chen T, Chapple KM, Lambert M, Karis JP, Dhall R, Ponce FA. Procedural Variables Influencing Stereotactic Accuracy and Efficiency in Deep Brain Stimulation Surgery. Oper Neurosurg (Hagerstown). 2018 Oct 18. doi: 10.1093/ons/opy291. [Epub ahead of print] PubMed PMID: 30339204.
4)

Blasberg F, Wojtecki L, Elben S, Slotty PJ, Vesper J, Schnitzler A, Groiss SJ. Comparison of Awake vs. Asleep Surgery for Subthalamic Deep Brain Stimulation in Parkinson’s Disease. Neuromodulation. 2018 Aug;21(6):541-547. doi: 10.1111/ner.12766. Epub 2018 Mar 13. PubMed PMID: 29532

Subthalamic nucleus anatomy

Subthalamic nucleus anatomy

The subthalamic nucleus is a small lens-shaped nucleus in the brain where it is, from a functional point of view, part of the basal ganglia system.

Located ventral to the thalamus. It is also dorsal to the substantia nigra and medial to the internal capsule. It was first described by Jules Bernard Luys in 1865, and the term corpus Luysi or Luys’ body is still sometimes used.


Güngör et al., aimed to delineate the 3D anatomy of the STN and unveil the complex relationship between the anatomical structures within the STN region using fiber dissection technique, 3D reconstructions of high-resolution MRI, and fiber tracking using MR diffusion tractography utilizing a generalized q-sampling imaging (GQI) model.

Fiber dissection was performed in 20 hemispheres and 3 cadaveric heads using the Klingler method. Fiber dissections of the brain were performed from all orientations in a stepwise manner to reveal the 3D anatomy of the STN. In addition, 3 brains were cut into 5-mm coronal, axial, and sagittal slices to show the sectional anatomy. GQI data were also used to elucidate the connections among hubs within the STN region.

The study correlated the results of STN fiber dissection with those of 3D MRI reconstruction and tractography using neuronavigation. A 3D terrain model of the subthalamic area encircling the STN was built to clarify its anatomical relations with the putamen, globus pallidus internus, globus pallidus externus, internal capsule, caudate nucleus laterally, substantia nigra inferiorly, zona incerta superiorly, and red nucleus medially.

They also described the relationship of the medial lemniscus, oculomotor nerve fibers, and the medial forebrain bundle with the STN using tractography with a 3D STN model.

This study examines the complex 3D anatomy of the STN and peri-subthalamic area. In comparison with previous clinical data on STN targeting, the results of this study promise further understanding of the structural connections of the STN, the exact location of the fiber compositions within the region, and clinical applications such as stimulation-induced adverse effects during DBS targeting 1).


Mavridis et al., used cerebral magnetic resonance images (MRIs) from 26 neurosurgical patients and for the anatomic study 32 cerebral hemispheres from 18 normal brains from cadaver donors. They measured and analyzed the STN dimensions (based on its stereotactic coordinates).

At stereotactic level Z = -4, the STN length was 7.7 mm on MRIs and 8.1 mm in anatomic specimens. Its width was 6 mm on MRIs and 6.3 mm in anatomic specimens. The STN was averagely visible in 3.2 transverse MRI slices and its maximum dimension was 8.5 mm. The intercommissural distance was 26.3 mm on MRIs and 27.3 mm in anatomic specimens. They found statistically significant difference of the STN width and length between individuals <60 and ≥60 years old.

The identification of the STN limits was easier in anatomic specimens than on MRIs and easier on T2 compared to T1-weighted MRIs sections. STN dimensions appear slightly smaller on MRIs. Younger people have wider and longer STN 2).

Structure

The principal type of neuron found in the subthalamic nucleus has rather long sparsely dendritic spines.

The dendritic arborizations are ellipsoid, replicating in smaller dimension the shape of the nucleus.

The dimensions of these arborizations (1200,600 and 300 μm) are similar across many species—including rat, cat, monkey and human—which is unusual. However, the number of neurons increases with brain size as well as the external dimensions of the nucleus. The principal neurons are glutamatergic neurons, which give them a particular functional position in the basal ganglia system. In humans there are also a small number (about 7.5%) of GABAergic interneurons that participate in the local circuitry; however, the dendritic arborizations of subthalamic neurons shy away from the border and majorly interact with one another 3).

Divisions

The STN has been divided into three distinct subdivisions, motor, limbic, and associative parts in line with the concept of parallel information processing. The extent to which the parallel information processing coming from distinct cortical areas overlaps in the different territories of the STN is still a matter of debate and the proposed role of dopaminergic neurons in maintaining the coherence of responses to cortical inputs in each territory is not documented.

Afferent axons

The subthalamic nucleus (STN) receives monosynaptic glutamatergic afferents from different areas of the cortex, known as the “hyperdirect” pathway.

The subthalamic nucleus receives its main input from the globus pallidus, not so much through the ansa lenticularis as often said but by radiating fibers crossing the medial pallidum first and the internal capsule.

These afferents are GABAergic, inhibiting neurons in the subthalamic nucleus.

Excitatory, glutamatergic inputs come from the cerebral cortex (particularly the motor cortex), and from the pars parafascicularis of the central complex. The subthalamic nucleus also receives neuromodulatory inputs, notably dopaminergic axons from the substantia nigra pars compacta. It also receives inputs from the pedunculopontine nucleus.

References

1)

Güngör A, Baydın ŞS, Holanda VM, Middlebrooks EH, Isler C, Tugcu B, Foote K, Tanriover N. Microsurgical anatomy of the subthalamic nucleus: correlating fiber dissection results with 3-T magnetic resonance imaging using neuronavigation. J Neurosurg. 2018 Apr 1:1-17. doi: 10.3171/2017.10.JNS171513. [Epub ahead of print] PubMed PMID: 29726781.
2)

Mavridis I, Boviatsis E, Anagnostopoulou S. Anatomy of the human subthalamic nucleus: a combined morphometric study. Anat Res Int. 2013;2013:319710. doi: 10.1155/2013/319710. Epub 2013 Dec 15. PubMed PMID: 24416591; PubMed Central PMCID: PMC3876692.
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