Medication dose reductions after pallidal versus subthalamic stimulation in patients with Parkinson's disease

Evidente VGH, Premkumar AP, Adler CH, Caviness JN, Driver‐Dunckley E, Lyons MK. Medication dose reductions after pallidal versus subthalamic stimulation in patients with Parkinson’s disease.
Acta Neurol Scand: 2011: 124: 211–214.
© 2010 John Wiley & Sons A/S. Objective – To compare the medication dose reduction between deep brain stimulation (DBS) of the globus pallidus interna (GPi) vs subthalamic nucleus (STN) in matched patients with Parkinson’s disease (PD). Materials and methods – Records of 12 patients with PD who underwent GPi‐DBS at our institution from 2002 to 2008 were matched by pre‐operative PD medication doses and pre‐operative motor Unified Parkinson’s Disease Rating Scale (UPDRS) scores to 12 cases of STN‐DBS. PD medication doses were converted to levodopa equivalent doses (LEDs). Results – GPi and STN groups had similar mean pre‐operative LEDs and motor UPDRS scores. At 6 months post‐DBS, there was no significant difference in percent reduction in LEDs between the GPi (47.95%) and STN (37.47%) groups (P = 0.52). The mean post‐operative ‘medication off/stimulation on’ motor UPDRS scores did not differ significantly between GPi (15.33) and STN (16.25) groups (P = 0.74). The mean percent reduction in motor UPDRS scores was also similar between GPi (58.44%) and STN (58.98%) patients (P = 0.94). Conclusions – We conclude that in disease‐matched patients with PD undergoing DBS, both GPi and STN may result in similar reduction in PD medication doses.     

Parkinson‐related genetics in patients treated with deep brain stimulation

Johansen KK, Jørgensen JV, White LR, Farrer MJ, Aasly JO. Parkinson‐related genetics in patients treated with deep brain stimulation.
Acta Neurol Scand: 2011: 123: 201–206.
© 2010 John Wiley & Sons A/S. Objectives – To analyze the frequency of mutations associated with Parkinson’s disease (PD) in a general PD population compared to patients with PD selected for deep brain stimulation (DBS) and evaluate the outcome of surgery. Material and methods – A total of 630 consecutive patients with PD were genetically screened, and 60 had DBS surgery, 37 subthalamic nucleus (STN), 21 ventrointermediate nucleus of thalamus (VIM), and two globus pallidus internus (GPi). Results – Mutations in LRRK2, PRKN, and PINK1 were found: the first two of these being overrepresented in STN‐operated patients, but none being found in VIM‐operated patients. Clinical outcome of the surgery was similar in patients with mutations compared to those without. Conclusions – In a consecutive PD population, patients treated with STN‐DBS are overrepresented for PD‐related mutations and they seem to benefit from DBS as well as patients without mutations.     

Change of the melanocortin system caused by bilateral subthalamic nucleus stimulation in Parkinson's disease

Escamilla‐Sevilla F, Pérez‐Navarro MJ, Muñoz‐Pasadas M, Sáez‐Zea C, Jouma‐Katati M, Piédrola‐Maroto G, Ramírez‐Navarro A, Mínguez‐Castellanos A. Change of the melanocortin system caused by bilateral subthalamic nucleus stimulation in Parkinson’s disease.
Acta Neurol Scand: 2011: 124: 275–281.
© 2011 John Wiley & Sons A/S. Objectives – Determine whether bilateral subthalamic nucleus stimulation (STN–DBS) in Parkinson’s disease (PD) is associated with an increase in neuropeptide Y (NPY) and/or resistance to inhibition by leptin in relation to post‐surgery weight gain. Materials and Methods – This prospective study included 20 patients who underwent bilateral STN–DBS and 17 who refused surgery. Data were obtained at baseline, 3 and 6 months on neurological and nutritional status, including determination of body mass index (BMI) and serum NPY and leptin levels. Results – NPY and leptin levels changed over time, with a distinct pattern. The BMI increase at 6 months was greater in the surgical group (5.5 ± 6.3% vs 0.5 ± 3.5%; P = 0.035). Medical group exhibited a reduction in leptin level (−2.0 ± 4.3 ng/ml) and a consequent increase in NPY level (72.4 ± 58.7 pmol/ml). However, STN–DBS patients showed an increase in leptin (3.1 ± 5.0 ng/ml; P = 0.001 vs medical group) and also in NPY (12.1 ± 53.6 pmol/ml; P = 0.022 vs medical group) levels, which suggests resistance to inhibition by leptin. Rise in NPY level correlated with higher stimulation voltages. Conclusions – Bilateral STN–DBS causes disruption of the melanocortin system, probably related to diffusion of the electric current to the hypothalamus. This mechanism may in part explain the weight gain of patients with PD after surgery.     

Heart rate variability in Parkinson's disease unaffected by deep brain stimulation

Trachani E, Constantoyannis C, Sakellaropoulos GC, Stavrinou ML, Nikiforidis G, Chroni E. Heart rate variability in Parkinson’s disease unaffected by deep brain stimulation.
Acta Neurol Scand: 2012: 126: 56–61.
© 2011 John Wiley & Sons A/S. Objectives – Our aim was to investigate the impact of subthalamic nucleus deep brain stimulation (STN‐DBS) on the cardiovagal control of patients with advanced Parkinson’s disease. Materials and methods – Twenty‐four patients (mean age: 62.1 ± 9.4 years) were examined 3 days before and 6 months after DBS by a questionnaire, blood pressure monitoring and a battery of neurophysiological tests: time domain analysis of RR interval variation during normal and deep breathing (DB), Valsalva manoeuvre, and tilt test. By off‐line, performed frequency domain analysis of heart rate variation, total power (TP), low frequency band (LF) band, high‐frequency (HF) band, and their normalized units were estimated. The neurophysiological measurements were compared to those of 24 healthy controls. Results – The values of time domain variables were pre‐ and postoperatively lower in patients than in controls. A significant reduction was found in LF band after the implantation. Orthostatic hypotension was present in 45.8% of the patients preoperatively and 12.5% postoperatively. There was no correlation between DBS‐related changes of motor function and corresponding neurophysiological measurements, but patients with more than 60% motor improvement had higher time domain parameters’ values than the others. Conclusions – STN‐DBS offered no considerable impact on autonomic cardiovascular control.     

Protection of nigral cell death by bilateral subthalamic nucleus stimulation

In Parkinson disease (PD), the subthalamic nucleus (STN) becomes hyperactive (disinhibited), which is reported to cause excitotoxic damage to midbrain dopaminergic neurons. Here, we examined whether silencing of the hyperactive STN by chronic bilateral deep brain stimulation (DBS) increased the survival of midbrain dopaminergic neurons in a rat model of PD. High-precision design-based stereologic examination of the total number of neurons and tyrosine tydroxylase (TH) immunoreactive neurons in the substantia nigra pars compacta revealed that STN DBS resulted in a significant survival of these neurons. These data provide the first evidence in vivo that bilateral STN DBS is useful for protecting midbrain dopaminergic neurons from cell death in PD.     

Combined deep brain stimulation and thalamotomy for tremor-dominant Parkinson’s disease

Although deep brain stimulation (DBS) is an established treatment for Parkinson’s disease, the long-term suppression of tremor is still a challenging issue. We report two patients with tremor-dominant Parkinson’s disease (PD) treated with unilateral thalamotomy of the ventralis intermedius nucleus (Vim) combined with the subthalamic nucleus (STN)-DBS or the posterior subthalamic area (PSA)-DBS. One year after the surgery, thalamotomy of the area from the Vim to the PSA showed improvement not only in tremor but also in rigidity and akinesia. PSA- or STN-DBS with low intensity stimulation eliminated residual PD symptoms. Combined DBS and thalamotomy may provide long-term improvement of the majority of PD symptoms using lower therapeutic stimulation voltages.     

微电极记录与影像技术联合应用对帕金森病脑深部电刺激最佳刺激治疗位置的研究

目的探讨帕金森病(PD)患者脑深部电刺激(DBS)术最佳刺激靶点的位置。方法 40例PD患者接受立体定向双侧丘脑底核(STN)脑深部电刺激术。术中通过微电极记录采集神经元电活动,埋置脑深部电刺激器,术后复查电极位置,通过影像资料和电生理数据,确定电极尖端坐标,并计算电极各触点坐标,以及电极针道中STN上下边界和中心点的坐标。结果最佳刺激触点中心坐标的平均位置与STN上边界坐标的平均位置的差异无统计学意义。结论 STN上边界区域为DBS治疗PD的最佳刺激位置。     

Emergence of restless legs syndrome during subthalamic stimulation for Parkinson disease

The authors systematically studied the emergence of restless legs syndrome (RLS) after subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson disease (PD). Postoperatively, 11 of 195 patients with STN DBS reported new problematic symptoms of RLS. The mean reduction in antiparkinsonian medication was 74%. The mean RLS score at diagnosis was 15 (+/-5.9) of a possible 24 points and after symptomatic drug therapy 4.3 (+/-3.1) points. Reduction of antiparkinsonian medication during STN DBS may unmask symptoms of RLS and complicate therapy of both RLS and PD.     

BDNF provides many routes toward STN DBS‐mediated disease modification

The concept that subthalamic nucleus deep brain stimulation (STN DBS) may be disease modifying in Parkinson's disease (PD) is controversial. Several clinical trials that enrolled subjects with late‐stage PD have come to disparate conclusions on this matter. In contrast, some clinical studies in early‐ to midstage subjects have suggested a disease‐modifying effect. Dopaminergic innervation of the putamen is essentially absent in PD subjects within 4 years after diagnosis, indicating that any neuroprotective therapy, including STN DBS, will require intervention within the immediate postdiagnosis interval. Preclinical prevention and early intervention paradigms support a neuroprotective effect of STN DBS on the nigrostriatal system via increased brain‐derived neurotrophic factor (BDNF). STN DBS‐induced increases in BDNF provide a multitude of mechanisms capable of ameliorating dysfunction and degeneration in the parkinsonian brain. A biomarker for measuring brain‐derived neurotrophic factor‐trkB signaling, though, is not available for clinical research. If a prospective clinical trial were to examine whether STN DBS is disease modifying, we contend the strongest rationale is not dependent on a preclinical neuroprotective effect per se, but on the myriad potential mechanisms whereby STN DBS‐elicited brain‐derived neurotrophic factor‐trkB signaling could provide disease modification. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Influence of deep brain stimulation and levodopa on sensory signs in Parkinson's disease

To examine the effects of levodopa (L ‐dopa) and deep brain stimulation of the subthalamic nucleus (STN‐DBS) on sensory symptoms and signs in Parkinson's disease (PD). Seventeen patients with PD were included. (1) Presence of sensory symptoms and (2) effects of L ‐dopa and STN‐DBS on sensory symptoms and signs [assessed by quantitative sensory testing (QST)] were examined 6 months after starting STN‐DBS. In addition, in 12 of these patients, presence of sensory symptoms prior and post STN‐DBS was compared. Pain was most frequently nociceptive. In about 30–40%, pain and sensory symptoms were associated with PD motor symptoms. In most of these cases, pain responded to L ‐dopa. Intensity of pain was reduced post STN‐DBS compared to pre STN‐DBS. L ‐Dopa had no influence on detection thresholds, whereas STN‐DBS improved thermal detection thresholds. However, thermal and mechanical pain thresholds were uninfluenced by L ‐dopa or STN‐DBS. Although some patients reported an improvement of pain with STN‐DBS or L ‐dopa, objectively pain sensitivity as assessed by QST was not altered by STN‐DBS or L ‐dopa suggesting that there is no evidence for a direct modulation of central pain processing by L ‐dopa or STN‐DBS. © 2010 Movement Disorder Society     

Psychiatric and Cognitive Effects of Deep Brain Stimulation for Parkinson’s Disease

Deep brain stimulation (DBS) is effective for Parkinson’s disease (PD), dystonia, and essential tremor (ET). While motor benefits are well documented, cognitive and psychiatric side effects from the subthalamic nucleus (STN) and globus pallidus interna (GPi) DBS for PD are increasingly recognized. Underlying disease, medications, microlesions, and post-surgical stimulation likely all contribute to non-motor symptoms (NMS).     

More than meets the Eye—Myelinated axons crowd the subthalamic nucleus

High frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a successful treatment for patients with advanced Parkinson's disease (PD). Although its exact mechanism of action is unknown, it is currently believed that the beneficial effects of the stimulation are mediated either by alleviating pathological basal ganglia output patterns of activity or by activation of the axons of passage that arise from the cerebral cortex and other sources. In this study, we show that the anatomical composition of the primate STN provides a substrate through which DBS may elicit widespread changes in brain activity via stimulation of fibers of passage. Using quantitative high‐resolution electron microscopy, we found that the primate STN is traversed by numerous myelinated axons, which occupy as much as 45% of its sensorimotor territory and 36% of its associative region. In comparison, myelinated axons occupy only 27% of the surface areas of the sensorimotor and associative regions of the internal segment of the globus pallidus (GPi), another target for therapeutic DBS in PD. We also noted that myelinated axons in the STN, on average, have a larger diameter than those in GPi, which may render them more susceptible to electrical stimulation. Because axons are more excitable than other neuronal elements, our findings support the hypothesis that STN DBS, even when carried out entirely within the confines of the nucleus, mediates some of its effects by activating myelinated axons of passage. © 2013 International Parkinson and Movement Disorder Society     

Frequency matters: beta‐band subthalamic nucleus deep‐brain stimulation induces Parkinsonian‐like blink abnormalities in normal rats

The synchronized beta‐band oscillations in the basal ganglia‐cortical networks in Parkinson's disease (PD) may be responsible for PD motor symptoms or an epiphenomenon of dopamine loss. We investigated the causal role of beta‐band activity in PD motor symptoms by testing the effects of beta‐frequency subthalamic nucleus deep‐brain stimulation (STN DBS) on the blink reflex excitability, amplitude, and plasticity in normal rats. Delivering 16 Hz STN DBS produced the same increase in blink reflex excitability and impairment in blink reflex plasticity in normal rats as occurs in rats with 6‐hydroxydopamine lesions and patients with PD. These deficits were not an artifact of STN DBS because, when these normal rats received 130 Hz STN DBS, their blink characteristics were the same as without STN DBS. To demonstrate that the blink reflex disturbances with 16 Hz STN DBS were frequency specific, we tested the same rats with 7 Hz STN DBS, a theta‐band frequency typical of dystonia. In contrast to beta stimulation, 7 Hz STN DBS exaggerated the blink reflex plasticity as occurs in focal dystonia. Thus, without destroying dopamine neurons or blocking dopamine receptors, frequency‐specific STN DBS can be used to create PD‐like or dystonic‐like symptoms in a normal rat.     

Neuroleptic malignant syndrome (parkinsonism–hyperpyrexia syndrome) after deep brain stimulation of the subthalamic nucleus

Neuroleptic malignant syndrome (NMS), also called parkinsonism–hyperpyrexia syndrome (PHS), is a severe, general, sometimes fatal, physical reaction, induced by sudden and strong blockade of dopamine receptors. When subthalamic nucleus (STN)–deep brain stimulation (DBS) is used on patients with Parkinson disease (PD), dopaminergic medications are transiently stopped prior to the procedure, and a reduction in the use of drugs is routinely attempted after the procedure. Although a sudden stop or abrupt reduction of dopaminergic medications may set the stage for NMS/PHS, only three cases have been reported after STN–DBS surgery. Here, we describe a 75-year-old woman with PD who experienced delayed onset, yet fatal, PHS after STN–DBS. Although STN–DBS might prevent or suppress PHS, its protective effect is not always complete. We must be aware that fatal PHS can occur when the use of medication for PD is reduced or altered, even when patients are under continuous STN stimulation.     

丘脑底核脑深部电刺激治疗帕金森病临床SPECT随访

目的探讨丘脑底核脑深部电刺激(STN DBS)治疗帕金森病(PD)患者症状的改善及单光子放射计算机断层扫描(SPECT)的影像学变化。方法4例施行单侧STN DBS患者术前和给予电刺激后进行帕金森病综合评分(UPDRS)和SPECT测定。结果STN DBS术后临床症状明显改善,UPDRS运动评分缓解60%。3例改善良好的患者SPECT检查提示纹状体区域多巴胺转运体(DAT)含量较术前提高,另1例疗效欠佳的患者DAT含量降低,所有的患者多巴胺D2受体(D2R)检测与术前无明显差异。结论STN DBS可以明显改善PD患者的临床症状,SPECT检查显示刺激侧纹状体区DAT含量的升高提示STN DBS可能改善了多巴胺的代谢,而这种改善可能是STN DBS缓解PD症状的作用机制之一。     

Apraxia of eyelid opening after subthalamic deep brain stimulation may be caused by reduction of levodopa

Apraxia of eyelid opening (ALO) is an infrequent side effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's disease (PD). However, the pathogenesis of ALO after STN DBS is not well understood. We report on two patients who suffered from disabling ALO after bilateral STN DBS. Their ALO improved by resuming the levodopa medication that had been discontinued after the surgery. Although ALO after STN DBS is considered as an adverse effect of STN stimulation, postoperative modification of dopaminergic medication may be a cause of ALO after STN DBS.     

MRI verified STN stimulation site – gait improvement and clinical outcome

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective in alleviating Parkinson’s disease (PD) symptoms (tremor, rigidity and bradykinesia) and may improve gait and postural impairment associated with the disease. However, improvement of gait is not always as predictable as the clinical outcome. This may relate to the type of gait impairment or localization of the active DBS contact. Methods: The active contact was visualized on peri‐operative magnetic resonance imaging in 22 patients with idiopathic PD, consecutively treated with bilateral STN DBS. Stimulation site was grouped as either in the dorsal/ventral STN or medial/lateral hereof and anterior/posterior STN or medial/lateral hereof. The localization was compared with relative improvement of clinical outcome (UPDRS‐III). In 10 patients, quantitative gait analyses were performed, and the improvement in gait performance was compared with stimulation site in the STN. Results: Of 44 active contacts, 77% were inside the nucleus, 23% were medial hereof. Stimulation of the dorsal half improved UPDRS‐III significantly more than ventral STN DBS (P = 0.02). However, there were no differences between anterior and posterior stimulation in the dorsal STN. Step velocity and length improved significantly more with dorsal stimulation compared with ventral stimulation (P = 0.03 and P = 0.02). Balance during gait was also more improved with dorsal stimulation compared with ventral stimulation. Conclusions: Deep brain stimulation of the dorsal STN is superior to stimulation of the ventral STN. Possible different effects of stimulation inside the nucleus underline the need for exact knowledge of the active stimulation site position to target the most effective area.     

Evolution of Deep Brain Stimulation: Human Electrometer and Smart Devices Supporting the Next Generation of Therapy

Deep brain stimulation (DBS) provides therapeutic benefit for several neuropathologies, including Parkinson disease (PD), epilepsy, chronic pain, and depression. Despite well‐established clinical efficacy, the mechanism of DBS remains poorly understood. In this review, we begin by summarizing the current understanding of the DBS mechanism. Using this knowledge as a framework, we then explore a specific hypothesis regarding DBS of the subthalamic nucleus (STN) for the treatment of PD. This hypothesis states that therapeutic benefit is provided, at least in part, by activation of surviving nigrostriatal dopaminergic neurons, subsequent striatal dopamine release, and resumption of striatal target cell control by dopamine. While highly controversial, we present preliminary data that are consistent with specific predications testing this hypothesis. We additionally propose that developing new technologies (e.g., human electrometer and closed‐loop smart devices) for monitoring dopaminergic neurotransmission during STN DBS will further advance this treatment approach.     

Comparison of neuropathology in Parkinson's disease subjects with and without deep brain stimulation

Background : The aim of this postmortem study was to compare, in Parkinson's disease subjects with and without bilateral subthalamic nucleus deep brain stimulation (STN‐DBS), the loss of pigmented neurons within the substantia nigra and pathological alpha‐synuclein density within the SN and other brain regions. Methods : PD subjects were identified from the Arizona Study of Aging and Neurodegenerative Disorders database (STN‐DBS = 11, non‐DBS = 156). Pigmented neuron loss scores within the substantia nigra as well as alpha‐synuclein density scores within the substantia nigra and 9 other brain regions were compared, the latter individually and in summary as the Lewy body brain load score. Results : DBS subjects had higher alpha‐synuclein density scores within the substantia nigra, olfactory bulb, and locus ceruleus, as well as higher total Lewy body brain load scores when compared with non‐DBS subjects. No differences in substantia nigra pigmented neuron loss scores were found. Conclusions : STN‐DBS subjects tend to have higher alpha‐synuclein density scores, but do not have a differential loss of substantia nigra pigmented neurons. © 2016 International Parkinson and Movement Disorder Society     

丘脑底核脑深部电刺激治疗帕金森病的功能显像研究

目的通过单光子放射计算机断层扫描(SPECT)功能显像研究探讨丘脑底核脑深部电刺激(STN DBS)对纹状体多巴胺系统代谢的影响。方法对2只偏侧帕金森病(PD)模型猴及4例临床PD患者在施行单侧STN DBS手术前后给予SPECT检查,测定纹状体区域多巴胺转运体(DAT)及多巴胺D2受体(D2R)含量变化。结果STN DBS电刺激后2只偏侧PD模型猴及3例疗效较好的PD患者纹状体区DAT含量明显增加,2只PD模型猴D2R含量逐渐下降,4例患者D2R检测与术前无统计学意义。结论STN DBS可以明显改善PD症状,SPECT检查显示刺激侧纹状体区DAT含量升高,提示STN DBS可能改善了刺激侧纹状体区多巴胺的代谢,这可能是STN DBS的作用机制之一。