A prospective international multi-center study on safety and efficacy of deep brain stimulation for resistant obsessive-compulsive disorder.

Deep brain stimulation (DBS) has been proposed for severe, chronic, treatment-refractory obsessive-compulsive disorder (OCD) patients. Although serious adverse events can occur, only a few studies report on the safety profile of DBS for psychiatric disorders. In a prospective, open-label, interventional multi-center study, we examined the safety and efficacy of electrical stimulation in 30 patients with DBS electrodes bilaterally implanted in the anterior limb of the internal capsule. Safety, efficacy, and functionality assessments were performed at 3, 6, and 12 months post implant. An independent Clinical Events Committee classified and coded all adverse events (AEs) according to EN ISO14155:2011. All patients experienced AEs (195 in total), with the majority of these being mild (52% of all AEs) or moderate (37%). Median time to resolution was 22 days for all AEs and the etiology with the highest AE incidence was 'programming/stimulation' (in 26 patients), followed by 'New illness, injury, condition' (13 patients) and 'pre-existing condition, worsening or exacerbation' (11 patients). Sixteen patients reported a total of 36 serious AEs (eight of them in one single patient), mainly transient anxiety and affective symptoms worsening (20 SAEs). Regarding efficacy measures, Y-BOCS reduction was 42% at 12 months and the responder rate was 60%. Improvements in GAF, CGI, and EuroQol-5D index scores were also observed. In sum, although some severe AEs occurred, most AEs were mild or moderate, transient and related to programming/stimulation and tended to resolve by adjustment of stimulation. In a severely treatment-resistant population, this open-label study supports that the potential benefits outweigh the potential risks of DBS.

Deep brain stimulation for refractory obsessive-compulsive disorder (OCD): emerging or established therapy?

A consensus has yet to emerge whether deep brain stimulation (DBS) for treatment-refractory obsessive-compulsive disorder (OCD) can be considered an established therapy. In 2014, the World Society for Stereotactic and Functional Neurosurgery (WSSFN) published consensus guidelines stating that a therapy becomes established when "at least two blinded randomized controlled clinical trials from two different groups of researchers are published, both reporting an acceptable risk-benefit ratio, at least comparable with other existing therapies. The clinical trials should be on the same brain area for the same psychiatric indication." The authors have now compiled the available evidence to make a clear statement on whether DBS for OCD is established therapy. Two blinded randomized controlled trials have been published, one with level I evidence (Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score improved 37% during stimulation on), the other with level II evidence (25% improvement). A clinical cohort study (N = 70) showed 40% Y-BOCS score improvement during DBS, and a prospective international multi-center study 42% improvement (N = 30). The WSSFN states that electrical stimulation for otherwise treatment refractory OCD using a multipolar electrode implanted in the ventral anterior capsule region (including bed nucleus of stria terminalis and nucleus accumbens) remains investigational. It represents an emerging, but not yet established therapy. A multidisciplinary team involving psychiatrists and neurosurgeons is a prerequisite for such therapy, and the future of surgical treatment of psychiatric patients remains in the realm of the psychiatrist.

Deep brain stimulation in Lesch-Nyhan disease: outcomes from the patient's perspective.

AIM: To provide insight into outcome and long-term safety and efficacy of deep brain stimulation (DBS), from the perspective of individuals with Lesch-Nyhan disease (LND) and their families. METHOD: We used patient-centered outcome measures to assess long-term outcomes of DBS for 14 individuals (mean [SD] age 10y 10mo [5y 6mo], range 5-23y, all males) with LND, after an average duration of 5y 6mo (range 11mo-10y 5mo) after surgery. We compared these results with a comprehensive review of previously published cases. RESULTS: Patients and their families reported that DBS of the globus pallidus can be effective both for motor and behavioral disturbances in LND. However, outcome measures were often not significantly changed owing to substantial variability among individuals, and were overall less positive than in previous reports based on clinician assessments. In addition, there was an unexpectedly high rate of adverse events, tempering overall enthusiasm for the procedure. INTERPRETATION: Although DBS might be an effective treatment for LND, more research is needed to understand the reasons for response variability and the unusually high rates of adverse events before DBS can be recommended for these patients. What this paper adds Individuals with Lesch-Nyhan disease and their families report variable efficacy of deep brain stimulation. Long-term outcomes are associated with a high adverse event rate.

Hyperbaric Oxygen Therapy as Adjuvant Treatment for Hardware-Related Infections in Neuromodulation.

BACKGROUND: In neuromodulation therapies, hardware-related infections are a major challenge often leading to hardware removal. OBJECTIVE: To investigate the role of adjuvant hyperbaric oxygen therapy (HBOT) in hardware-related infections. METHODS: Fourteen hardware-related infection events in 12 consecutive patients between 2002 and 2015 were treated with antibiotics and adjuvant HBOT at the Karolinska University Hospital (Stockholm, Sweden). Two time-independent infection events related to hardware replacements occurred in 2 patients. Infection resolution and the need for hardware removal were assessed. RESULTS: Twelve out of 14 events of hardware-related infection were successfully treated without hardware removal (86%). The 2 patients treated twice with HBOT on 2 time-independent occasions could retain their hardware in both cases. Hardware was removed following HBOT failure in 2 infection events, with long-term infection control achieved in all patients. Further, an intrathecal pump malfunction caused by HBOT at 2.8 bars was observed, leading to a change in the manufacturer's guidelines. CONCLUSIONS: This study indicates a potential benefit of adjuvant HBOT in the treatment of hardware-related infections in neuromodulation, diminishing the need for hardware removal and treatment interruption. Prospective studies are warranted to establish the role of adjuvant HBOT in the treatment of hardware-related infections in neuromodulation.

Predictive factors for decompressive hemicraniectomy in malignant middle cerebral artery infarction.

BACKGROUND: The mortality rate of patients with brain oedema after malignant middle cerebral artery (MCA) infarction approaches 80 % without surgical intervention. Surgical treatment with ipsilateral decompressive hemicraniectomy (DHC) has been shown to dramatically improve survival rates. DHC currently lacks established inclusion criteria and additional research is needed to assess the impact of prognostic factors on functional outcome. The aim of this study was to assess the impact of prognostic factors on functional outcome. METHOD: A retrospective cohort study was carried out including 46 patients who underwent DHC at the Karolinska University Hospital between 2004 and 2014. The maximum time to surgery was 5 days after symptom debut. The primary endpoint was a dichotomised score on the modified Rankin Scale (mRS) 3 months after surgery, with favourable outcome defined as mRS ≤ 4. RESULTS: When the study population was dichotomised according to the primary endpoint, a significant difference between the groups was seen in preoperative Glasgow Coma Score (GCS), blood glucose levels and the infarction's involvement of the basal ganglia (p < 0.05). In a logistic regression model, preoperative GCS contributed significantly with a 59.6 % increase in the probability of favourable outcome for each point gained in preoperative GCS (p = 0.035). CONCLUSIONS: The results indicate that preoperative GCS, blood glucose and the infarction's involvement of the basal ganglia are strong predictors of clinical outcome. These factors should be considered when assessing the probable outcome of DHC, and additional research based on these factors may contribute to improved inclusion criteria for DHC.

Hyperbaric oxygen therapy in spontaneous brain abscess patients: a population-based comparative cohort study.

BACKGROUND: There is a need to improve outcome in patients with brain abscesses and hyperbaric oxygen therapy (HBOT) is a promising treatment modality. The objective of this study was to evaluate HBOT in the treatment of intracranial abscesses. METHOD: This population-based, comparative cohort study included 40 consecutive adult patients with spontaneous brain abscess treated surgically between January 2003 and May 2014 at our institution. Twenty patients received standard therapy with surgery and antibiotics (non-HBOT group), while the remaining 20 patients also received adjuvant HBOT (HBOT group). RESULTS: Resolution of brain abscesses and infection was seen in all patients. Two patients had reoperations after HBOT initiation (10 %), while nine patients (45 %) in the non-HBOT group underwent reoperations (p = 0.03). Of the 26 patients who did not receive HBOT after the first surgery, 15 (58 %) had one or several recurrences that lead to a new treatment: surgery (n = 11), surgery + HBO (n = 5) or just HBO (n = 1). In contrast, recurrences occurred in only 2 of 14 (14 %) who did receive HBOT after the first surgery (p < 0.01). A good outcome (Glasgow Outcome Score [GOS] of 5) was achieved in 16 patients (80 %) in the HBOT cohort versus 9 patients (45 %) in the non-HBOT group (p = 0.04). CONCLUSIONS: HBOT was associated with less treatment failures and need for reoperation and seemingly with improved long-term outcome. Further, HBOT was well tolerated and safe. Prospective studies are warranted to establish the role of HBOT in the treatment of brain abscesses.

Consensus on guidelines for stereotactic neurosurgery for psychiatric disorders.

BACKGROUND: For patients with psychiatric illnesses remaining refractory to 'standard' therapies, neurosurgical procedures may be considered. Guidelines for safe and ethical conduct of such procedures have previously and independently been proposed by various local and regional expert groups. METHODS: To expand on these earlier documents, representative members of continental and international psychiatric and neurosurgical societies, joined efforts to further elaborate and adopt a pragmatic worldwide set of guidelines. These are intended to address a broad range of neuropsychiatric disorders, brain targets and neurosurgical techniques, taking into account cultural and social heterogeneities of healthcare environments. FINDINGS: The proposed consensus document highlights that, while stereotactic ablative procedures such as cingulotomy and capsulotomy for depression and obsessive-compulsive disorder are considered 'established' in some countries, they still lack level I evidence. Further, it is noted that deep brain stimulation in any brain target hitherto tried, and for any psychiatric or behavioural disorder, still remains at an investigational stage. Researchers are encouraged to design randomised controlled trials, based on scientific and data-driven rationales for disease and brain target selection. Experienced multidisciplinary teams are a mandatory requirement for the safe and ethical conduct of any psychiatric neurosurgery, ensuring documented refractoriness of patients, proper consent procedures that respect patient's capacity and autonomy, multifaceted preoperative as well as postoperative long-term follow-up evaluation, and reporting of effects and side effects for all patients. INTERPRETATION: This consensus document on ethical and scientific conduct of psychiatric surgery worldwide is designed to enhance patient safety.

Health economics and surgical treatment for Parkinson's disease in a world perspective: results from an international survey.

BACKGROUND: Most studies in the field of neurosurgical treatment for movement disorders have been published by a small number of leading centers in developed countries. This study aimed to investigate the clinical practice of stereotactic neurosurgery for Parkinson's disease (PD) worldwide. METHODS: Neurosurgeons were contacted via e-mail to participate in a worldwide survey. The results obtained are presented in order of the countries' economic development according to the World Bank, as well as by the source of financial support. RESULTS: A total of 353 neurosurgeons from 51 countries who had operated on 13,200 patients in 2009 were surveyed. Surgical procedures performed in high-income countries were more commonly financed by a public health care system. In contrast, in lower-middle-income and upper-middle-income countries, patients frequently financed surgeries themselves, and ablative surgeries were most commonly performed. Unexpectedly, ablative surgery is still used by about 65% of neurosurgeons, regardless of their country's economic status. CONCLUSIONS: This study provides a previously unavailable picture of the surgical aspects of PD across the globe in relation to health economics and sociodemographic factors. Global educational and training programs are warranted to raise awareness of economically viable surgical options for PD that could be adopted by public health care systems in lower-income countries.

Subthalamic stimulation for essential tremor. Short- and long-term results and critical target area.

BACKGROUND/AIMS/METHODS: In order to explore the usefulness and long-term result of subthalamic nucleus (STN) stimulation for the treatment of essential tremor (ET), we evaluated 3 groups of patients undergoing deep brain stimulation (DBS) for ET. RESULTS: Group 1 consisted of 3 patients who 9 years ago at intra-operative testing had good tremor reduction from STN stimulation. The second group consisted of 10 patients treated with DBS in the ventral intermediate (Vim) nucleus of the thalamus. The third group comprised 9 patients subjected to STN stimulation for ET with 1-3 years of follow-up. The 3 ET patients with STN stimulation in group 1 have continued to have excellent tremor reduction for up to 9 years. The second group, with Vim stimulation, showed less favourable long-term results. All of the recent STN stimulation group experienced good tremor reduction, but some of the patients above 70 years of age reported troublesome side effects. CONCLUSION: Provided that intra-operative test stimulation produces satisfactory tremor control, STN is a good target for long-term treatment of ET. For patients above the age of 70 years, however, the Vim is a preferable target.

[Deep brain stimulation can break vicious circle in obsessive-compulsive disorder]. / Djup hjärnstimulering kan bryta ond cirkel vid tvångssyndrom.

Obsessive-compulsive disorder (OCD), characterized by repetitive intrusive thoughts and ritualized behaviors, is a highly debilitating disorder with an estimated lifetime prevalence of about 2 %. Approximately 10 % of these patients have severe symptoms despite having received all available treatments, thus considered treatment refractory. Deep brain stimulation (DBS), a reversible, safe and adaptive method widely used for movement disorders, enables specific targeting of deep brain structures of relevance in OCD. About 60% of the patients with treatment refractory OCD show ameliorated symptoms and improved quality of life with DBS. Taking ethical aspects into consideration DBS is a viable option for patients with treatment refractory OCD though further studies are needed to fully understand and individualize this treatment.

Gabapentin and pregabalin suppress tactile allodynia and potentiate spinal cord stimulation in a model of neuropathy.

Spinal cord stimulation (SCS) is an effective tool in alleviating neuropathic pain. However, a number of well-selected patients fail to obtain satisfactory pain relief. Previous studies have demonstrated that i.t. baclofen and/or adenosine can enhance the SCS effect, but this combined therapy has been shown to be useful in less than half of the cases and more effective substances are therefore needed. The aim of this experimental study in rats was to examine whether gabapentin or pregabalin attenuates tactile allodynia following partial sciatic nerve injury and whether subeffective doses of these drugs can potentiate the effects of SCS in rats which do not respond to SCS. Mononeuropathy was produced by a photochemically induced ischaemic lesion of the sciatic nerve. Tactile withdrawal thresholds were assessed with von Frey filaments. Effects of increasing doses of gabapentin and pregabalin (i.t. and i.v.) on the withdrawal thresholds were analysed. These drugs were found to reduce tactile allodynia in a dose-dependent manner. In SCS non-responding rats, i.e. where stimulation per se failed to suppress allodynia, a combination of SCS and subeffective doses of the drugs markedly attenuated allodynia. In subsequent acute experiments, extracellular recordings from wide dynamic range neurones in the dorsal horn showed prominent hyperexcitability. The combination of SCS and gabapentin, at the same subeffective dose, clearly enhanced suppression of this hyperexcitability. In conclusion, electrical therapy and pharmacological therapy in neuropathic pain can, when they are inefficient individually, become effective when combined.

Subthalamotomy in the treatment of Parkinson's disease: clinical aspects and mechanisms of action.

Parkinson's disease (PD) is a neurodegenerative condition that can be pharmacologically treated with levodopa. However, important motor and nonmotor symptoms appear with its long-term use. The subthalamic nucleus (STN) is known to be involved in the pathophysiology of PD and to contribute to levodopa-induced complications. Surgery is considered in patients who have advanced PD that is refractory to pharmacotherapy and who display disabling dyskinesia. Deep brain stimulation of the STN is currently the main surgical procedure for PD, but lesioning is still performed. This review covers the clinical aspects and complications of subthalamotomy as one of the lesion-based options for PD patients with levodopa-induced dyskinesias. Moreover, the authors discuss the possible effects of subthalamic lesioning.

Factors that influence outcome of percutaneous balloon compression in the treatment of trigeminal neuralgia.

BACKGROUND: Percutaneous balloon compression is an effective, low-cost, simple therapeutic modality with the special advantage of being the only percutaneous technique that can be simply performed with the patient under general anesthesia for the treatment of trigeminal neuralgia. OBJECTIVE: To identify surgical and individual parameters that could influence outcome in patients with trigeminal neuralgia treated with percutaneous balloon compression. METHODS: Within a 5-year period, 66 consecutive percutaneous balloon compressions were performed in 47 patients. The medical and surgical records of all patients were retrospectively reviewed and analyzed for a possible correlation between the following parameters and outcome: balloon shape, balloon volume, compression time, age, sex, type of pain, duration of disease, previous procedures, and trigeminal division affected. Univariate and multivariate analyses were used to test for statistical significance. RESULTS: The initial success rate was 85%, and 36% of the responders are still pain free with a mean follow-up of approximately 20 months, whereas in 33 patients, trigeminal pain recurred after a mean of approximately 17 months. Of the investigated parameters, significant correlations were obtained between balloon shape and all aspects of outcome, previous operations and complication rate, pain type and complication rate, and compression time and postoperative numbness. CONCLUSION: The balloon shape is a parameter with a very strong impact on outcome, and balloon volume should be adjusted to this parameter. Persistent elliptical balloon shapes should raise consideration of aborting the procedure. There were no differences in outcomes between 60 seconds and longer compression times. The number of previous operations did not correlate with pain relief, but seemed to increase the risk of complications. Patients with multiple sclerosis seemed to obtain similar benefit from the procedure as do patients with classic trigeminal neuralgia.

Comparison of percutaneous balloon compression and glycerol rhizotomy for the treatment of trigeminal neuralgia.

OBJECT: The aim of this study was to compare percutaneous balloon compression (PBC) and percutaneous retrogasserian glycerol rhizotomy (PRGR) in terms of effectiveness, complications, and technical aspects. METHODS: Sixty-six consecutive PBC procedures were performed in 45 patients between January 2004 and December 2008, and 120 PRGR attempts were performed in 101 patients between January 2006 and December 2008. The PRGR procedures were not completed due to technical reasons in 19 cases. Five patients in the Balloon Compression Group and 9 patients in the Glycerol Group were lost to follow-up and were excluded from the study. The medical records and the intraoperative fluoroscopic images from the remaining cases were retrospectively examined, and the follow-up was completed with telephone contact, when necessary. The 2 groups were compared in terms of initial effect, duration of effect, and rates of complications as well as severity and type of complications. RESULTS: The rates for immediate pain relief were 87% for patients treated with glycerol injection and 85% for patients treated with balloon compression. The Kaplan-Meier plots for the 2 treatment modalities were similar. The 50% recurrence time was 21 months for the balloon procedure and 16 months for the glycerol procedure. When the groups were broken down by the "previous operations" criterion, the 50% recurrence time was 24 months for the Glycerol First Procedure Group, 6 months for the Balloon First Procedure Group, 8 months for the Glycerol Previous Procedures Group, and 21 months for the Balloon Previous Procedures Group. The rates of complications (excluding numbness) were 11% for PRGR and 23% for PBC, and this difference was statistically significant (chi-square test, p = 0.04). CONCLUSIONS: Both PRGR and PBC are effective techniques for the treatment of trigeminal neuralgia, with PRGR presenting some advantages in terms of milder and fewer complications and allowing lighter anesthesia without compromise of analgesia. For these reasons the authors consider PRGR as the first option for the treatment of trigeminal neuralgia in patients who are not suitable candidates or are not willing to undergo microvascular decompression, while PBC is reserved for patients in whom the effect of PRGR has proven to be short or difficult to repeat due to cisternal fibrosis.

Intrathecal clonidine and baclofen enhance the pain-relieving effect of spinal cord stimulation: a comparative placebo-controlled, randomized trial.

OBJECTIVE: Spinal cord stimulation (SCS) is a well-established treatment for neuropathic pain; nevertheless, 40% of patients fail to obtain satisfactory pain relief and in many patients, the effect tends to diminish with time. Based on animal experiments, intrathecal baclofen was previously introduced clinically to enhance suboptimal SCS effects. Later animal experiments demonstrated similar data for clonidine. The aim of this study was to elucidate whether intrathecal clonidine or baclofen enhances the effect of SCS in neuropathic pain patients in whom the pain relieving-effect of SCS is inadequate. METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted with 10 patients experiencing neuropathic pain with insufficient pain relief with SCS alone. Clonidine, baclofen, and saline (control) were intrathecally administered by bolus injections in combination with SCS. RESULTS: Seven of 10 patients reported significant pain reduction when SCS was combined with active drugs. The mean visual analog scale ratings were reduced by more than 50% with either drug combined with SCS. Four patients previously treated with SCS alone later underwent implantation of a pump for long-term administration of clonidine or baclofen. In the 2 patients with clonidine pumps with a mean follow-up of 15 months, the combined therapy produced pain reduction of 55% and 45%, respectively. The corresponding effect with baclofen was 32% and 82%, respectively, at 7 months follow-up. CONCLUSION: A trial with clonidine and baclofen combined with SCS may be warranted in patients who do not obtain satisfactory pain relief with SCS alone or experienced a decreasing therapeutic effect.

Cholinergic mechanisms involved in the pain relieving effect of spinal cord stimulation in a model of neuropathy.

The mechanisms underlying the pain relieving effect of spinal cord stimulation (SCS) on neuropathic pain remain unclear. We have previously demonstrated that suppression of tactile hypersensitivity produced by SCS may be potentiated by i.t. clonidine in a rat model of mononeuropathy. Since the analgesic effect of this drug is mediated mainly via cholinergic mechanisms, a study exploring the possible involvement of the spinal cholinergic system in SCS was undertaken. The effect of SCS was assessed with von Frey filaments in rats displaying tactile hypersensitivity after partial ligation of the sciatic nerve and both SCS-responding and non-responding as well as normal rats were subjected to microdialysis in the dorsal horn. Acetylcholine (ACh) was analyzed with HPLC before, during and after SCS. SCS produced significantly increased release of ACh in the dorsal horn in rats responding to SCS whereas the release was unaffected in the non-responding animals. Furthermore, the basal release of ACh was significantly lower in nerve lesioned than in normal rats. In another group of rats it was found that the response to SCS was completely eliminated by i.t. atropine and a muscarinic M(4) receptor antagonist while a partial attenuation was produced by M(1) and M(2) antagonists. Blocking of nicotinic receptors did not influence the SCS effect. In conclusion, the attenuating effect of SCS on pain related behavior is associated with the activation of the cholinergic system in the dorsal horn and mediated via muscarinic receptors, particularly M(4,) while nicotinic receptors appear not to be involved.