Abbott Educational Supplement

April 2019 | Educational Supplement

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This educational supplement has been sponsored by Abbott

Evolution of DBS

The evolution of directional DBS and the pilot data that pioneered its advancement

The evolution of directional leads to utilise deep brain stimulation (DBS) therapy has accelerated as the challenges with conventional (omnidirectional) DBS have been brought to light. For example, prior research evaluating the impedance levels of subthalamic (STN) DBS throughout the course of Parkinson’s disease revealed a continuous decrease of therapeutic impedance values within 10 years of therapy.1 The investigators of this study highlight that as the stimulation settings remained constant, “a progressive neurodegeneration may be hypothesised as a possible explanation.”

THE PROGRESSION OF PARKINSON’S disease is observed through an increase in the duration of “off” periods—where the medication stops working—relative to “on” periods, involving a reduction in motor fluctuations. To accommodate this physical deterioration, prior research and literary reviews highlight the steady increase in the electrical parameters of DBS necessary to control symptoms and dyskinesias.2,3 Further, prior studies point to how certain side effects of stimulation can limit therapeutic benefit and can contribute to long-term complications.4 For instance, in ventral intermediate (ViM) DBS, balance problems have been reported in 3–7.5% of patients. In terms of speech dysfunction, the prevalence of this impediment following STN DBS was found to range from 4–17%, with dysarthria (unclear articulation) being the most common adverse effect of ViM DBS. The latter stimulation has also been found to produce dysesthesia (an unpleasant sensation when touched) in patients, while eyelid opening apraxia has been reported following STN DBS in several studies, with a prevalence between 1.8–30%.

In light of compromised clinical outcomes and complications associated with stimulation therapies, an analysis of data from multiple North American databases was carried out in 2016.5 Over 28,000 cases of DBS electrode placement, revision and removal indicated that such neurostimulation therapies have a rate of revision and removal higher than previously reported, between 15.2% and 34%.

Moreover, the complex regional anatomy of the brain only reinforces the need for precise stimulation. Through patient-specific approaches, prior research has aimed to identify the intersection between the volume of tissue activated (by DBS) and surrounding anatomical structures in order to compare the associated activation of these

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structures with clinical outcomes.6 Although the investigators found that specific motor symptoms such as bradykinesia and rigidity improved when a specific volume of tissue activation was generated, they alluded to the fact that: “The application of DBS technology to various neurological disorders has preceded scientific characterisation of the volume of tissue directly affected by the simulation.”

Now, the challenges parallel to conventional DBS are in the process of being alleviated, through advancing DBS therapy with the use of directional leads.

Although conventional DBS leads contained cylindrical contacts, producing a “relatively uniform” current spread in all directions, Christopher Buston and Lalit Venkatesan postulated that dividing each circumferential contact into two or more segments may provide additional control over the direction of current flow. As hypothesised, the segmented lead design with a single directional electrode contact was found to generate volume of tissue activations that were 60% larger than their cylindrical predecessors.7 Since intraoperative clinical studies suggested that directional activation may provide therapeutic benefit to Parkinson’s disease patients, the authors also theorised that this method of directional activation allows for a more precise activation of target

regions during DBS. Therefore, through pioneering pilot data published in 2014, the evolution of directional DBS commenced. When one study intraoperatively tested three different directions of stimulation against omnidirectional stimulation, it was found that the therapeutic window (the current difference between efficacy and adverse event threshold) in the best direction was 41% wider (p=0.037) compared to omnidirectional stimulation.8 Further, the same study outlined that the average therapeutic current in the best direction was 43% lower than omnidirectional therapy (p=0.002).

In 2014, a performance and safety study detailing the application of steering DBS in awake patients undergoing DBS found no adverse events related to the device, while steering DBS current was shown to be well tolerated and increased the threshold for side effects.9 Through secondary analyses, further pilot research was able to strengthen the support for the notion of a larger therapeutic window with directional DBS.10 The analyses compared the amplitude range between efficacy and adverse event threshold of optimal current steering at the most effective level compared to ring mode. Interestingly, the investigators found that the change in therapeutic window was “driven only by an increase in adverse event threshold at the most effective level”. In contrast, at the least effective level, it was reported that both efficacy and adverse event thresholds changed in favour of optimal direction. The authors noted that after follow-up at three to six months, all patients have remained programmed in the directional mode.

In accordance, the clinical benefit of directional DBS has since been maintained.

Specifically, stimulation in the individual best direction has been shown to result in significantly larger therapeutic windows, higher side-effect thresholds.11 Most recently, however, Rebelo and colleagues from the University of Oxford (UK) have found significant gains in therapeutic window—91%—as well reductions in the therapeutic current strength (31%) through using directional stimulation.12 The authors concluded that with directional DBS, a significant reduction in disability can be sustained without the need for additional reprogramming visits.

Moreover, when averaged across the patient cohort, power output and predicted device lifespan was not impacted by the use of directional stimulation. Unsurprisingly, it was these findings that paved the way for the onset of the PROGRESS trial.

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PROGRESS

DBS Therapy, Upgraded

PROGRESS ensues with superiority of therapeutic window using directional DBS Although the field of neuromodulation is typically fast-moving, deep brain stimulation (DBS) has used leads with circumferential electrodes to treat movement disorders for the last 30 years. Now, findings from the largest multicentre study to evaluate the clinical performance of directional DBS supports the superiority of therapeutic window in directional leads.

LEAD AUTHOR OF PROGRESS, ALFONS Schnitzler (Heinrich Heine University of Düsseldorf, Germany) and colleagues report that 89.4% of the study's first cohort (n=66)—patients with Parkinson’s disease— have a wider therapeutic window when directional DBS was used, compared to omnidirectional.13 Carried out at 37 sites in seven countries, the prospective, single-arm crossover, blinded-observer/blinded-subject multicentre clinical trial aimed to investigate the percentage of subjects with a wider therapeutic window at three months. The study enrolled up to 234 subjects with subthalamic nucleus DBS for Parkinson’s disease and used a >60% superiority margin for the primary endpoint.

The primary endpoint was performed at the point at which 66 subjects completed 12 months of follow-up, with an evaluable primary endpoint at three months. Additional endpoints were wider therapeutic window in >40% using directional stimulation to show non-inferiority as well as comparison of Unified Parkinson Disease Rating Scale (UPDRS) part III motor examination at three and six months. Blind to the stimulation type, subjects received conventional stimulation for 0–3 months, followed by directional stimulation for 3–6 months. Beyond this, the 6–12 month stimulation type was programmed at clinician discretion.

Here, Schnitzler and Rajesh Pahwa (University of Kansas Medical Center, Kansas City, USA) outline the findings of PROGRESS and address both the clinical and patient benefits of this evolving approach to deep brain stimulation.

What were the main findings of PROGRESS? Schnitzler: The main finding was the clear achievement of the primary endpoint with 89.4% (59/66) of patients showing a wider therapeutic window with directional as compared to conventional stimulation (p<0.001).

What additional analyses were done in regards to descriptive endpoints?

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The finding that single segment activation produced wider therapeutic windows suggests that SSA may be recommended as a first-line approach in clinical practice.”

the two methods. In addition, clinicians preferred directional over conventional stimulation in four times as many patients when compared sequentially. In 83% preference was due to additional symptom relief, and 7% due to side effect avoidance.

In total, twice as many patients preferred the directional over conventional stimulation option when compared sequentially. Single Segment Activation (SSA) produced a wider therapeutic window than conventional stimulation in 84.8% patients. Furthermore, the therapeutic current threshold (TCS) to achieve meaningful therapeutic benefit was 30% less with directional as compared to conventional stimulation.

Schnitzler: On average, the therapeutic window was 35% wider with directional stimulation, and the results were significant.

Both conventional and directional stimulation showed significant reduction in UPDRS III scores without a statistical difference between

What impact do these findings have on the way physicians will practice clinically?

Schnitzler: The results of the PROGRESS study convincingly demonstrate the superiority of directional over conventional

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Twice as many patients preferred directional over conventional stimulation.” stimulation with respect to the width of the therapeutic window. The potential benefits associated with a wider therapeutic window strongly argue in favour of offering directional stimulation to all our patients eligible for DBS. The finding that single segment activation produced wider therapeutic windows in the vast majority of patients suggests that SSA—instead of coactivation of segments—may be recommended as a first-line approach in clinical practice.

How does the data shape the way you view the benefits of directional programming?

Schnitzler: Importantly, the wider therapeutic window of directional stimulation translates into a clinically meaningful benefit because both patients and clinicians preferred directional over conventional stimulation when compared sequentially.

What may these results mean for patients with Parkinson’s disease?

Schnitzler: Directional stimulation offers an important programming consideration in patients with Parkinson’s disease. Widening the therapeutic window carries the potential for an increase in clinical benefits and

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the ability to reduce therapeutic current thresholds may offer additional longevity for recharge-free impulse generators.

How does the data shape the way you view the benefits of directional programming?

Pahwa: While conceptually, we expected the technology to have a clinical impact, it's critical to see this play out in larger trials.

The more options we have to manage these patients chronically, the better. Based on the PROGRESS trial data, directional leads appear to bolster our ability to do so.

How does Informity benefit your clinic in particular?

Pahwa: Informity creates a uniform and prescriptive programming workflow across our clinic from physicians to clinical nurses.

This optimises patients in clinic, and also captures data to answer our future questions that will continue driving this therapy forward.

Informity creates a uniform and prescriptive programming workflow across our clinic from physicians to clinical nurses.”

April 2019

Technology

DBS Therapy, Upgraded

Simplified programming, low-maintenance IPG’s and upgradability: A patientcentric approach to innovation

Abbott’s latest upgrade to the St. Jude Medical InfinityTM Deep Brain Stimulation (DBS) system helps to unlock and uncover the true benefits of directional DBS, all while enabling patients access to full-body magnetic resonance imaging within approved parameters.

THE INFORMITYTM PROGRAMMING Software offers streamlined programming alongside an automated documentation workflow. This facilitates the automatic calculation of the therapeutic window, given that symptom relief and side effect thresholds can be easily recorded.

Through using therapeutic window percentage-based ranking, the technology can also identify electrodes that have a relatively higher therapeutic window at a lower therapeutic current strength. Subsequently, the programme displays the optimal electrodes that achieve desired therapeutic window percentage while minimising power consumption. When combined with total electrical energy delivered (TEED), a power consumption measure, clinicians can easily sort programmes by balanced threshold.

Balanced threshold accounts for the most optimal therapeutic window percentage and then sorts by power consumption to produce the best programme for symptom control and battery longevity.

Furthermore, the segmented directional leads help optimise patient outcomes and April 2019

limit any associated side effects. Research supporting the use of directional stimulation indicates that compared to ring electrodes, a greater volume of tissue can be activated with the same amplitude when directional deep brain stimulation (DBS) is used. Initial results from the international, multicentre PROGRESS study confirms that directed segment activation can broaden the therapeutic window and reduce stimulation strength.

Specifically, the directional lead is built with a 1-3-3-1 segmented configuration. Both 0.5 and 1.5mm spacing options are available, while the lead is designed with enhanced tensile strength for improved durability. A stiff distal tip and strengthened stylet facilitates minimal deviations from the intended trajectory, while a directional orientation marker allows for the identification of contacts under fluoroscopy.

The flexible coiled extension structure of the system is also designed for durability—taking into account tensile strength while increasing patient comfort. With a low profile 1.4mm diameter, the proprietary coiled technology allows for 10% stretch along the entire body of

the extension. Extensions with ExtendTM lead technology feature a single set screw with a built-in Bal Seal, available in three lengths: 50, 60 and 90cm, to accommodate different implant locations. To ensure secure lead fixation, the GuardianTM Burr Hole Cover enables autolocking technology, while conforming to skull curvature with flexible screw tabs. The autolocking clip can be deployed on the guide tube or directly on the lead.

Abbott’s upgradeable and recharge-free internal pulse generators (IPGs) provide existing patients access to future innovation upgrades as they are approved, without the need for surgery. Two battery sizes (7.5 and 5.3 amp hours) are available, based on individual patient needs. The constant current pulse delivery produces consistent therapy by automatically compensating for impedance changes. The IPGs offer low pulse width, which provides options to broaden the therapeutic window, as well as shared or independent frequencies to stimulate each cerebral hemisphere. Given that movement disorders are rarely symmetrical, these independent frequencies allow for the finetuning to a specific hemisphere and may limit side-effects while further decreasing the power consumption of the device.

Further options for current DBS patients include MultiStimTM Programming Software: providing complex field shaping for patients who require interleaving. Header M (compatible with some Medtronic systems) allows for the ability to upgrade patients needing a generator change to Abbott innovation, without the need for pocket adapters.

During surgery, the Bluetooth connectivity on a consumer-friendly interface permits programming outside of the sterile environment. In the office, physicians are able to utilise the wireless programming during motor skill assessments like gait testing.

The iOS platform also enables patients to experience a more discreet and personalised form of therapy.

In relation to the advances at present, the array of upgrades to Abbott’s St. Jude Medical InfinityTM DBS system, including the directional lead, low-maintenance IPGs, upgradeable technology, familiar consumer iOS interface and wireless Bluetooth® communications—all aim to support patient experience by enabling them to focus on their lives instead of their disease. Now with Invisible TherapyTM, this patient-centric approach, which remains the core of Abbott’s approach to advancing DBS therapy, helps to avoid daily reminders of what the patients have lost; instead allowing them to discreetly monitor their therapy without a compromised quality of life.

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Psychosocial implications

Minimising the psychosocial spiral in Parkinson’s disease Over 10 million people worldwide are currently living with Parkinson’s disease. Through a communication breakdown within the central nervous system, the disease manifests into a progressive loss of muscle control, involuntary movement and reduced coordination. Advancing therapy options for patients with Parkinson’s disease not only addresses these physical symptoms of the condition, but allows patients to focus on their lives instead of their disease.

A RECENT STUDY THAT LOOKED into the factors that determine quality of life in patients with idiopathic Parkinson’s disease concluded that depression, disability, postural instability and cognitive impairment have the greatest influence on quality of life in Parkinson’s disease.14 The authors, Anette Schrag and colleagues (UCL Queen Square Institute of Neurology, London, UK) put forward that the correlation of quality of life with depression is maintained throughout other studies, and accounts for up to 60% of impairment of Parkinson’s Disease Questionnaire (PDQ-39) scores.

Schrag and colleagues also highlighted that a better quality of life was found to be reported in tremor dominant Parkinson’s disease, a subtype with a slower rate of progression compared with the akinetic rigid subtype; a finding which echoes throughout the literature.

With the initial (n=66) PROGRESS results showing that directional deep brain stimulation (DBS) with Abbott's St. Jude Medical InfinityTM DBS system increased the therapeutic window by 35%—satisfying both the non-inferiority and superiority objectives for therapeutic window—a significant reduction in disability may be achieved in Parkinson's disease patients.

As the relationship between prognosis and quality of life has been thoroughly established, a reduction in physical symptoms shows promise for improved patient well-being throughout the course of Parkinson’s disease.

Regardless, the prevalence of depression in Parkinson’s disease is not to be underestimated. “Depression is common […] with over one third having a depressive disorder, subsyndromal depressive symptomatology or significant psychological distress,” emphasised Camille L Julien and colleagues from King's College London (London, UK).15 Although explanations for depression in Parkinson’s disease have typically focused on potential biologicalbased mechanisms with disturbances of brain monoamine systems, Julien and colleagues put forward evidence indicative of an association between psychological and social

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factors, and the presence and severity of depression in Parkinson’s disease.15 Through the 104 participants that completed the questionnaire, Julien et al were able to measure the contribution of mood, motor disability and core psychological variables to the presence and degree of depressive symptoms. The latter variables included maladaptive assumptions, rumination, cognitive-behavioural avoidance, illness representations and cognitivebehavioural responses to symptoms.

“The regression analyses revealed that a small number of psychological factors accounted for the majority of depression variance, over and above that explained by overall disability.” Specifically, it was found that behavioural avoidance of social activities was significantly predictive, when compared to other forms of avoidance.

“Whether because of concerns such as falling in public or fear of negative social evaluation concerning their Parkinson’s symptoms, patients often avoid social situations,” explained Julien and colleagues.

They postulated that this chronic pattern of avoidance can result in isolation and loss of opportunity for rewarding interactions; providing a “plausible mechanism for vulnerability to depression”.

In addition, rumination, which they described as “a trait-like self-reflective cognitive mode that involves repetitively and passively focusing one’s symptoms of distress on the possible causes and consequences,” also emerged as strongly

associated with depression symptom severity and depression status.

Julien and colleagues suggest that continued rumination can give rise to further cognitive deficits, such as attentional difficulties or faulty executive functioning, which, in turn, “may exacerbate individuals’ tendency to ruminate by further inhibiting their ability to switch their attention from such thinking patterns to more adaptive problem solving strategies”.

The burden of these symptom-focused thoughts and the inevitable vulnerability to depression in patients with Parkinson’s disease has been maintained throughout the literature. Abbott’s St. Jude Medical InfinityTM DBS system uniquely empowers physicians to treat the whole patient, addressing their motor symptoms as well as minimalising their attention to their device and disease.

Through the advantages of Invisible Therapy™, such as non-rechargeable, low maintenance internal pulse generators, upgradeable technology and a familiar consumer iOS interface with wireless Bluetooth communication, patients are able to resume their day-to-day activities while discreetly monitoring their therapy.

This patient-centric approach allows the patient to forget about the hardship and the social strain of the condition, and in turn, may help to interrupt the relationship between psychological distress and the presence of depression so commonly observed in Parkinson’s disease.

April 2019

DBS Therapy, Upgraded

References 1. H artmann, CJ, Wojtecki, L, Vesper, J, et al., 2015. Long-term evaluation of impedance levels and clinical development in subthalamic deep brain stimulation for Parkinson’s disease. Parkinsonism & related disorders, 21(10), pp.1247-1250.

2. L imousin, P, Krack, P, Pollak, P, et al., 1998. Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. New England Journal of Medicine, 339(16), pp.1105-1111.

3. L imousin, P and Foltynie, T, 2019. Long-term outcomes of deep brain stimulation in Parkinson disease. Nature Reviews Neurology, p.1.

4. D euschl, G, Herzog, J, Kleiner‐Fisman, G, et al., 2006. Deep brain stimulation: postoperative issues. Movement disorders: official journal of the Movement Disorder Society, 21(S14), pp.S219-S237.

5. R olston, JD, Englot, DJ, Starr, PA and Larson, P.S., 2016. An unexpectedly high rate of revisions and removals in deep brain stimulation surgery: analysis of multiple databases. Parkinsonism & related disorders, 33, pp.72-77.

6. B utson, CR, Cooper, SE, Henderson, JM and McIntyre, CC, 2007. Patientspecific analysis of the volume of tissue activated during deep brain stimulation.

Neuroimage, 34(2), pp.661-670.

7. B utson, C.R. and Venkatesan, L., 2014. comparison of neural activation between standard cylindrical and novel segmented electrode designs: 1179. Movement Disorders, 29, p.433.

8. P ollo, C, Kaelin-Lang, A, Oertel, MF, et al., 2014. Directional deep brain stimulation: an intraoperative double-blind pilot study. Brain, 137(7), pp.20152026.

9. Contarino, MF, Bour, LJ, Verhagen, R, et al., 2014. Directional steering: a novel approach to deep brain stimulation. Neurology, 83(13), pp.1163-1169.

10. Steigerwald, F, Müller, L, Johannes, S, Matthies, C and Volkmann, J, 2016.

Directional deep brain stimulation of the subthalamic nucleus: a pilot study using a novel neurostimulation device. Movement Disorders, 31(8), pp.1240-1243.

11. Dembek, TA, Reker, P, Visser‐Vandewalle, V, et al., 2017. Directional DBS increases side‐effect thresholds—A prospective, double‐blind trial. Movement Disorders, 32(10), pp.1380-1388.

12. Rebelo, P, Green, AL, Aziz, TZ, et al., 2018. Thalamic directional deep brain stimulation for tremor: spend less, get more. Brain stimulation, 11(3), pp.600-606.

13. Schnitzler, A, Mir, P, Brodsky, M, et al., Directional or omnidirectional Deep Brain Stimulation for Parkinson’s Disease: Results of a prospective blindedcomparison multi-center study, Poster, 3rd International Brain Stimulation Conference, 2019.

14. Schrag, A, Jahanshahi, M and Quinn, N, 2000. What contributes to quality of life in patients with Parkinson’s disease?. Journal of Neurology, Neurosurgery & Psychiatry, 69(3), pp.308-312.

15. Julien, CL, Rimes, KA and Brown, RG, 2016. Rumination and behavioural factors in Parkinson’s disease depression. Journal of psychosomatic research, 82, pp.48-53.

Global Indications Brief Summary:

Prior to using these devices, please review the Clinician’s Manual for a complete listing of indications, contraindications, warnings, precautions, potential adverse events, and directions for use. The system is intended to be used with leads and associated extensions that are compatible with the system.

Indications for Use:

US: Bilateral stimulation of the subthalamic nucleus (STN) as an adjunctive therapy to reduce some of the symptoms of advanced levodopa-responsive Parkinson’s disease that are not adequately controlled by medications, and unilateral or bilateral stimulation of the ventral intermediate nucleus (VIM) of the thalamus for the suppression of disabling upper extremity tremor in adult essential tremor patients whose tremor is not adequately controlled by medications and where the tremor constitutes a significant functional disability.

International: Unilateral or bilateral stimulation of the thalamus, internal globus pallidus (GPi), or subthalamic nucleus (STN) in patients with levodopa-responsive Parkinson’s disease, unilateral or bilateral stimulation of the ventral intermediate nucleus (VIM) of the thalamus for the management of disabling tremor, and unilateral or bilateral stimulation of the internal globus pallidus (GPi) or the subthalamic nucleus (STN) for the management of intractable, chronic dystonia, including primary and secondary dystonia, for patients who are at least 7 years old.

Contraindications:

US: Patients who are unable to operate the system or for whom test stimulation is unsuccessful. Diathermy, electroshock therapy, and transcranial magnetic stimulation (TMS) are contraindicated for patients with a deep brain stimulation system.

International: Patients who are unable to operate the system or for whom test stimulation is unsuccessful. Diathermy and magnetic resonance imaging are contraindicated for patients with a deep brain stimulation system.

Warnings/Precautions: Return of symptoms due to abrupt cessation of stimulation (rebound effect), excessive or low frequency stimulation, risk of depression and suicide, implanted cardiac systems or other active implantable devices, magnetic resonance imaging (MRI), electromagnetic interference (EMI), proximity to electrosurgery devices and high-output ultrasonics and lithotripsy, ultrasonic scanning equipment, external defibrillators, and therapeutic radiation, therapeutic magnets, radiofrequency sources, explosive or flammable gases, theft detectors and metal screening devices, activities requiring excessive twisting or stretching, operation of machinery and equipment, pregnancy, and case damage. Patients who are poor surgical risks, with multiple illnesses, or with active general infections should not be implanted.

Adverse Effects: Loss of therapeutic benefit or decreased therapeutic response, painful stimulation, persistent pain around the implanted parts (e.g. along the extension path in the neck), worsening of motor impairment, paresis, dystonia, sensory disturbance or impairment, speech or language impairment, and cognitive impairment. Surgical risks include intracranial hemorrhage, stroke, paralysis, and death. Other complications may include seizures and infection. Clinician’s Manual must be reviewed for detailed disclosure.

All rights reserved. Published by BIBA Publishing, London T:+44 (0)20 7736 8788, publishing@bibamedical.com.

The opinions expressed in this supplement are solely those of Abbott and the featured physicians and may not reflect the views of NeuroNews.

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