Regulatory Framework for Implantable Neurostimulation Devices: Comparison of Systems in the US and European Union.

BACKGROUND: Implantable neurostimulation devices must be authorized before they are placed on the market. For this purpose, requirements, and processes for assessing their fulfillment, have been defined in different jurisdictions. OBJECTIVE: In this study, we aimed to address differences between the US and European Union (EU) regulatory systems and their relationship to innovation. MATERIALS AND METHODS: A literature review and analysis were conducted using legal texts and guidance documents. RESULTS: The US system has one central body, the Food and Drug Administration, whereas the EU system has several bodies with different responsibilities. The devices themselves are divided into risk classes, which are based on the vulnerability of the human body. This risk class determines the intensity of the review by the market authorization body. In addition to the requirements for development, manufacture, and distribution, the device itself must meet technical and clinical requirements. Compliance with technical requirements is indicated by nonclinical laboratory studies. Proof of efficacy is provided by means of clinical investigations. Procedures are defined for reviewing these elements. Once the market authorization process has been completed, the devices can be placed on the market. In the postmarketing phase, the devices must continue to be monitored, and measures must be initiated, if necessary. CONCLUSIONS: Both US and EU systems are intended to ensure that only safe and effective devices find their way to and remain on the market. The basic approaches of the two systems are comparable. In detail, however, there are differences in ways these goals are achieved.

Targeting of the Subthalamic Nucleus for Deep Brain Stimulation: A Survey Among Parkinson Disease Specialists.

BACKGROUND: Deep brain stimulation within or adjacent to the subthalamic nucleus (STN) represents the most common stereotactic procedure performed for Parkinson disease. Better STN imaging is often regarded as a requirement for improving stereotactic targeting. However, it is unclear whether there is consensus about the optimal target. METHODS: To obtain an expert opinion on the site regarded optimal for "STN stimulation," movement disorder specialists were asked to indicate their preferred position for an active contact on hard copies of the Schaltenbrand and Wahren atlas depicting the STN in all 3 planes. This represented an idealized setting, and it mimicked optimal imaging for direct target definition in a perfectly delineated STN. RESULTS: The suggested targets were heterogeneous, although some clustering was observed in the dorsolateral STN and subthalamic area. In particular, in the anteroposterior direction, the intended targets differed to a great extent. Most of the indicated targets are thought to also result in concomitant stimulation of structures adjacent to the STN, including the zona incerta, fields of Forel, and internal capsule. CONCLUSIONS: This survey illustrates that most sites regarded as optimal for STN stimulation are close to each other, but there appears to be no uniform perception of the optimal anatomic target, possibly influencing surgical results. The anatomic sweet zone for STN stimulation needs further specification, as this information is likely to make magnetic resonance imaging-based target definition less variable when applied to individual patients.

Multiple-source current steering in subthalamic nucleus deep brain stimulation for Parkinson's disease (the VANTAGE study): a non-randomised, prospective, multicentre, open-label study.

BACKGROUND: High-frequency deep brain stimulation (DBS) with a single electrical source is effective for motor symptom relief in patients with Parkinson's disease. We postulated that a multiple-source, constant-current device that permits well defined distribution of current would lead to motor improvement in patients with Parkinson's disease. METHODS: We did a prospective, multicentre, non-randomised, open-label intervention study of an implantable DBS device (the VANTAGE study) at six specialist DBS centres at universities in six European countries. Patients were judged eligible if they were aged 21-75 years, had been diagnosed with bilateral idiopathic Parkinson's disease with motor symptoms for more than 5 years, had a Hoehn and Yahr score of 2 or greater, and had a Unified Parkinson's disease rating scale part III (UPDRS III) score in the medication-off state of more than 30, which improved by 33% or more after a levodopa challenge. Participants underwent bilateral implantation in the subthalamic nucleus of a multiple-source, constant-current, eight-contact, rechargeable DBS system, and were assessed 12, 26, and 52 weeks after implantation. The primary endpoint was the mean change in UPDRS III scores (assessed by site investigators who were aware of the treatment assignment) from baseline (medication-off state) to 26 weeks after first lead implantation (stimulation-on, medication-off state). This study is registered with ClinicalTrials.gov, number NCT01221948. FINDINGS: Of 53 patients enrolled in the study, 40 received a bilateral implant in the subthalamic nucleus and their data contributed to the primary endpoint analysis. Improvement was noted in the UPDRS III motor score 6 months after first lead implantation (mean 13·5 [SD 6·8], 95% CI 11·3-15·7) compared with baseline (37·4 [8·9], 34·5-40·2), with a mean difference of 23·8 (SD 10·6; 95% CI 20·3-27·3; p<0·0001). One patient died of pneumonia 24 weeks after implantation, which was judged to be unrelated to the procedure. 125 adverse events were reported, the most frequent of which were dystonia, speech disorder, and apathy. 18 serious adverse events were recorded, three of which were attributed to the device or procedure (one case each of infection, migration, and respiratory depression). All serious adverse events resolved without residual effects and stimulation remained on during the study. INTERPRETATION: The multiple-source, constant-current, eight-contact DBS system suppressed motor symptoms effectively in patients with Parkinson's disease, with an acceptable safety profile. Future trials are needed to investigate systematically the potential benefits of this system on postoperative outcome and its side-effects. FUNDING: Boston Scientific.

Oscillatory subthalamic nucleus activity is modulated by dopamine during emotional processing in Parkinson's disease.

Dopaminergic denervation in Parkinson's disease (PD) leads to motor deficits but also depression, lack of motivation and apathy. These symptoms can be reversed by dopaminergic treatment, which may even lead to an increased hedonic tone in some patients with PD. Here, we tested the effects of dopamine on emotional processing as indexed by changes in local field potential (LFP) activity of the subthalamic nucleus (STN) in 28 PD patients undergoing deep brain stimulation. LFP activity from the STN was recorded after the administration of levodopa (ON group) or after overnight withdrawal of medication (OFF group) during presentation of an emotional picture-viewing task. Neutral and emotionally arousing pleasant and unpleasant stimuli were chosen from the International Affective Picture System. We found a double dissociation of the alpha band response depending on dopamine state and stimulus valence: dopamine enhanced the processing of pleasant stimuli, while activation during unpleasant stimuli was reduced, as indexed by the degree of desynchronization in the alpha frequency band. This pattern was reversed in the OFF state and more pronounced in the subgroup of non-depressed PD patients. Further, we found an early gamma band increase with unpleasant stimuli that occurred when ON but not OFF medication and was correlated with stimulus arousal. The late STN alpha band decrease is thought to represent active processing of sensory information. Our findings support the idea that dopamine enhances approach-related processes during late stimulus evaluation in PD. The early gamma band response may represent local encoding of increased attention, which varies as a function of stimulus arousal.

Usability of therapy controllers in elderly patients with deep brain stimulation.

BACKGROUND: Technical devices are becoming more prevalent in society and also in medical care. Older adults need more support to learn new technologies than younger subjects. So far, no research has been done on the usability of patient controllers in deep brain stimulation in an elderly population. The aim of the study was to investigate the factors influencing the performance of elderly DBS patients with respect to usability aspects of Medtronic Access therapy controllers. METHODS: Time, mistakes and frequency of use of the controller were compared in 41 elderly DBS patients who prior to the study had already owned a therapy controller for more than six years. One group (n = 20, mean age = 66.4 years) was watching an instructional video and then completed practical assignments on a model implantable pulse generator (IPG). The other group (n = 21, mean age = 65.9 years) completed the tasks without having seen the video before. Any errors that patients made were documented and also corrected so that all of them received hands-on training. After six months all patients were re-evaluated on the dummy IPG in order to compare the effects of hands-on alone vs. video-based training combined with hands-on. RESULTS: The group that had seen the video before significantly outperformed the control group at both assessments with respect to number of errors. Both groups performed faster after six months compared to baseline and tend to use the controller more often than at baseline. CONCLUSION: Our results indicate that elderly DBS patients who have been using the controller for several years still have various difficulties in operating the device. However, we also showed that age-specific training may improve the performance in older adults. In general, the design of DBS patient controllers should focus on the specific needs of the end-users. But as changes to medical devices take a long time to be implemented, video instructions with age-specific content plus hands-on training may improve learning for older adults.

Aging and technology in medical care: using the example of patient controllers in deep brain stimulation.

Deep brain stimulation is a neurosurgical therapy for patients with advanced movement disorders (e.g., Parkinson's disease). This therapy involves the use of a patient controller for home-use. So far, there are four different patient controllers available on the European market. However, use and acceptance of the patient controller is relatively low. The main end-user group is patients above the age of 60 years. This article compares the design of the different interfaces, with a special focus on gerotechnological aspects (display, acoustic signals, coloring, lettering, cognitive load and haptics). We suggest strategies to optimize the use and acceptance of these devices, which have already entered the market. Moreover, future directions of deep brain stimulation and the usability of patient controllers are discussed.

Predictability of thermo-lesions using electrodes for deep brain stimulation - an in vitro study.

BACKGROUND: Typically, electrodes for Deep Brain Stimulation (DBS) are used for chronic stimulation. However, there are conditions where this therapy has to be discontinued. In such cases using the DBS electrodes as a tool for thermo-lesioning (coagulation) could be used for an alternative treatment. The aim of this study was to determine if it is possible to generate coagula with a predictable geometry and to define their dimensions as a function of power and time in an in vitro model (egg white at room temperature). Furthermore, we tested if repetitive (cumulative) coagulation has an impact on the overall form and size of the clot. FINDINGS: Coagulation-growth was achieved as a function of power and duration of coagulation; reproducible well-formed thermocoagulations could be achieved. When using two adjacent electrodes a power range between 1.25 Watt and 2.00 Watt resulted in homogenous ovoid coagula. After two minutes of coagulation the clots reached a maximum in size and further growth could not be achieved. It was also possible to increase the size of a preformed clot by repetitive coagulation either by increasing the power level or the duration of the coagulation process. CONCLUSIONS: We could show that it is possible to obtain predictable coagula in-vitro when using DBS electrodes for thermocoagulation even though they have not been developed for that specific purpose. However, until in-vivo safety and efficacy of DBS electrodes for ablation purposes is properly assessed, only approved electrodes should be used for brain ablation.

Technical analysis of dual channel pulse generators used in deep brain stimulation; a safety evaluation.

BACKGROUND: A sudden failure of implantable pulse generators (IPG) occurred in 15 out of 143 units during the last 4 years in our patients. This corresponds to a failure rate of 10.5%. In all cases, the connection between the causes of battery and electronic circuit was found defective in the destructive analysis. In order to better understand the failure causes we proceeded to an analysis of explanted IPGs which had reached their normal life span due to depletion of the battery. METHOD: A functional test and an intensive destructive analysis were carried out in 14 units. The internal parts of the IPG were inspected by light and electron microscopy. FINDINGS: Deformations of the connection between battery and electronic circuit could be found in 12 out of 14 IPGs. The epoxy bonds, which achieve the mechanical fixation between the two contact areas of the bond wires, were found separated in 86%. Additionally, in six out of 14 devices the bond wires were either found lifted or with cracks as a sign of material fatigue. CONCLUSION: Based on these results we conclude that the IPGs of the affected series did have a technical weak spot. We presume that this issue appears systematically and not randomly or triggered by an unusual action of the patient.

Long-term effects of STN DBS on mood: psychosocial profiles remain stable in a 3-year follow-up.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus significantly improves motor function in patients with severe Parkinson's disease. However, the effects on nonmotor aspects remain uncertain. The present study investigated the effects of subthalamic nucleus deep brain stimulation on mood and psychosocial functions in 33 patients with advanced Parkinson's disease in a three year follow-up. METHODS: Self-rating questionnaires were administered to 33 patients prior to surgery as well as three, six, twelve and 36 months after surgery. RESULTS: In the long run, motor function significantly improved after surgery. Mood and psychosocial functions transiently improved at one year but returned to baseline at 36 months after surgery. In addition, we performed cluster and discriminant function analyses and revealed four distinct psychosocial profiles, which remained relatively stable in the course of time. Two profiles featured impaired psychosocial functioning while the other two of them were characterized by greater psychosocial stability. CONCLUSION: Compared to baseline no worsening in mood and psychosocial functions was found three years after electrode implantation. Moreover, patients can be assigned to four distinct psychosocial profiles that are relatively stable in the time course. Since these subtypes already exist preoperatively the extent of psychosocial support can be anticipatory adjusted to the patients' needs in order to enhance coping strategies and compliance. This would allow early detection and even prevention of potential psychiatric adverse events after surgery. Given adequate psychosocial support, these findings imply that patients with mild psychiatric disturbances should not be excluded from surgery.

Subacute brainstem angioencephalopathy: favorable outcome with anticoagulation therapy.

We present a patient who developed progressive neurological disease caused by lesions histologically compatible with those observed in subacute brainstem angioencephalopathy. The patient was treated with low-molecular weight heparin, and treatment response was monitored clinically and with MRI. Anticoagulation therapy stopped progression of the neurological deficit and led to improvement of MRI findings. This report further supports the existence of subacute brainstem angioencephalopathy as a characteristic disease entity and gives insight into possible therapeutic approach with anticoagulation treatment.

Deep brain pulse-generator and lead-extensions: subjective sensations related to measured parameters.

This study analyzed subjective sensations caused by DBS pulse-generator and lead-extensions in relation with objectively measured parameters. In 50 patients implant-related sensations were evaluated. The pulse-generator mobility was video-analyzed. Insufficient lead-extension/pulse-generator tolerability (72%/84%) was documented. Furthermore, 54% of the patients described movement impairments and 48% cosmetic deformity. High body mass index (BMI) was associated with low lead-extension related pain (P < 0.001). High generator mobility resulted in high lead-extension related pain (P < 0.001). Compared with lead-extension type 7482, type 7495 showed less lead-extension related pain (P = 0.0138), we suppose secondary to surgical tunneling instruments with a larger tip diameter. The lead-extension path with one tissue tunnel for both lead-extensions had 36% lead-extension related pain versus 11% for the path with one single tunnel for each lead-extension. Smaller pulse-generators for better cosmetic results, surgical procedures using larger tunneling instruments and one single tunnel for each lead-extension would provide better results for patients with BMI <30.

Sudden failure of implantable pulse generators: cause of failure and examination.

A sudden failure of implantable pulse generators used for spinal cord stimulation occurred in two patients. To identify the cause of this failure, an intensive destructive analysis of the explanted devices was carried out. A functional diagnosis was carried out by inspecting amplitude, pulse width and frequency on each output channel of the implantable pulse generators. Later, the titanium case of the pulse generators was opened by laser cutting to minimise any additional mechanical stress during the opening procedure. The functional test for both pulse generators showed faultless behaviour. Using light and electron microscopy, hairline cracks could be identified in the electrical connection between battery and electronic circuit. In both devices, the cracks spread through the whole bond wire in the connection to the plus pole of the battery and partially also to the minus pole. The analysis showed that both devices failed by broken bond wires. The electrical connection to the battery exists just by the spring characteristic of the wires. A push to the implant causes a short-term disconnection, resulting in a power on reset of the device. Manufacturing or design issues, allowing micromotion between battery and the hybrid part, may be the reason for this problem.

Frequency-correlated decreases of motor cortex activity associated with subthalamic nucleus stimulation in Parkinson's disease.

According to the classical model of basal ganglia organization, deep brain stimulation (DBS) in the subthalamic nucleus (STN) for the treatment of Parkinson's disease (PD) blocks overactive excitatory projections to inhibitory basal ganglia output structures. This would release the break on thalamofrontal neurons alleviating the poverty of movement, the hallmark of PD. Such parallels to a functional lesion certainly simplify the mechanism of STN DBS. Here, we applied parametric analyses of H2(15)O positron emission tomography (PET) scans at rest while systematically varying stimulation frequency in 6 patients with STN DBS for akinetic PD. A strong positive correlation of rCBF to increasing stimulation frequency was detected around the STN bilaterally. More importantly, we show that gradual increases in STN stimulation frequency are tightly correlated with decreases in motor cortex activity. This demonstrates an active modulation of resting activity within the subcortical stimulation target and within motor cortex by STN DBS. Rather than a possible downstream effect, we propose to consider the tight correlations between DBS frequency and motor cortex activity in the context of an upstream modulation of direct efferents to the STN from primary motor and premotor cortices.

Efficient internal pallidal stimulation in Gilles de la Tourette syndrome: a case report.

The usefulness of deep brain stimulation (DBS) of thalamic nuclei in Gilles de la Tourette syndrome (GTS) has recently been advocated. We report on a 14-month follow-up study of a patient with intractable GTS in whom bilateral DBS of the internal globus pallidus was carried out. Tic frequency per minute decreased by 73% in the postoperative phase and in particular the vocal tics became less intense. Pronation/ supination bradykinesia of the left extremities was a well-tolerated, permanent side effect. Pallidal DBS could become a valuable rescue therapy for otherwise intractable GTS.

Sudden failure of dual channel pulse generators.

We report a series of four sudden hardware failures in dual channel pulse generators implanted for chronic stimulation of the subthalamic nucleus in the treatment of Parkinson's disease. In all cases, a sudden and severe deterioration of the patient's neurological condition occurred with symptoms similar to those present before surgery. In all cases, destructive analysis of the generator revealed a fracture of the wire bonds connecting the battery to the hybrid (electronic) part of the pulse generator. This fracture led to repeated Power On Resets, bringing the parameter settings back to default (factory settings). As a cause, we propose that relative movements between the hybrid and the battery led to low cycle fatigue fractures due to insufficient stiffness of the device. That three of four failures occurred when the implant was in the infracostal region makes it likely that the fractures depend on the mechanical stress applied to the device. The efficacy of the therapy resumed immediately after device replacement. As a corrective measure, the manufacturer has added epoxy between both components, increasing significantly the stiffness of the device.

Dielectric properties of porcine brain tissue in the transition from life to death at frequencies from 800 to 1900 MHz.

Ten experiments on pigs were performed to investigate possible postmortem changes of the dielectric properties of brain gray matter in the frequency range of 800-1900 MHz. After keeping the animals in stable anaesthesia for at least 45 min, they were euthanatised by an intravenous injection of hypertonic potassium chloride (KCl), causing cardiac arrest within 3 min. Measurements of the dielectric properties were performed repeatedly from at least 45 min prior to death to 18 h after euthanasia. The anaesthesia regimen was chosen to minimize influence on brain tissue characteristics such as brain water content, intracranial blood volume, and cerebral blood flow. The data showed a decline of mean gray matter equivalent conductivity of about 15% at 900 MHz and about 11% at 1800 MHz within the first hour after death. The decline in permittivity was less pronounced (about 3-4%) and almost frequency independent. The results indicate that in vitro measurements of dielectric properties of brain tissue underestimate equivalent conductivity as well as permittivity of living tissue. These changes may affect the generally accepted data of dielectric properties of brain tissue widely used in RF dosimetry.