Current Literature In Clinical Science

Responsive Neurostimulation and Cognition

Differential Neuropsychological Outcomes Following Targeted Responsive Neurostimulation for Partial-Onset Epilepsy. Loring DW, Kapur R, Meador KJ, Morrell MJ. Epilepsia 2015;56(11):1836–1844.

OBJECTIVE: Responsive neurostimulation decreases the frequency of disabling seizures when used as an adjunctive therapy in patients with medically refractory partial-onset seizures. The effect of long-term responsive neurostimulation on neuropsychological performance has not yet been established. METHODS: Neuropsychological data were collected from subjects participating in the open-label arm of a randomized controlled trial of responsive neurostimulation with the RNS® System. Primary cognitive outcomes were the Boston Naming Test (BNT) and Rey Auditory Verbal Learning (AVLT) test. Neuropsychological performance was evaluated at baseline and again following 1 and 2 years of RNS System treatment. Follow-up analyses were conducted in patients with seizure onset restricted to either the mesial temporal lobe or neocortex. RESULTS: No significant cognitive declines were observed for any neuropsychological measure through 2 years. When examined as a function of seizure onset region, a double dissociation was found, with significant improvement in naming across all patients (p < 0.0001), and for patients with neocortical seizure onsets (p < 0.0001) but not in patients with mesial temporal lobe (MTL) seizure onsets (p = 0.679). In contrast, a significant improvement in verbal learning was observed across all patients (p = 0.03), and for patients with MTL seizure onsets (p = 0.005) but not for patients with neocortical onsets (p = 0.403). SIGNIFICANCE: Treatment with the RNS System is not associated with cognitive decline when tested through 2 years. In fact, there were small but significant beneficial treatment effects on naming in patients with neocortical onsets and modest improvements in verbal learning for patients with seizure onsets in MTL structures. These results suggest that there are modest cognitive improvements in some domains that vary as a function of the region from which seizures arise.

Commentary Cognition can suffer collateral damage in the battle against seizures. This is unsurprising because antiseizure therapy, directed against aberrant neuronal activity, may affect normal neuronal function. Although simplistic, an analogy can be made with antibiotic therapy for infection or chemotherapy for cancer: treatment exploits differences between host and bacterium or tumor cells, but shared characteristics of host and target may result in toxicity. Similarly, antiseizure therapy imperfectly targets rapidly firing neurons and may have spillover effects on normal neuronal function. Adverse cognitive effects of antiepileptic drug (AED) therapy are common, can be substantial, and have been well demonstrated in people with epilepsy and in healthy individuals who are assessed while on therapy (1, 2). Other treatments for epilepsy are also known to have a potential cognitive cost. Surgical treatment of epilepsy involves resection of an epileptogenic zone that may often include functional tissue. For example, a decline in verbal memory is often noted following dominant temporal lobe surgery, Epilepsy Currents, Vol. 16, No. 2 (March/April) 2016 pp. 98–100 © American Epilepsy Society

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particularly when markers of preserved function such as normal hippocampal size and high preoperative verbal memory scores are present. Still, successful epilepsy surgery can have positive cognitive benefits. Seizure freedom may arrest the accelerated decline in cognition seen with chronic refractory epilepsy. Observed improvements in some cognitive domains following surgery may be a consequence of the release of relatively normal connected networks from the influence of the resected nociferous cortex. Neurostimulation, working by modulating rather than ablating epileptogenic tissue, would seem to have neurocognitive advantages over resection. Yet there have been mixed signals with regard to the cognitive effects of neurostimulation. Approximately 15 to 20 percent of Parkinson disease patients treated with deep brain stimulation (DBS) of the subthalamic nucleus experience negative neuropsychological or neurobehavioral sequelae (3, 4). In the pivotal trial of DBS of the anterior nucleus of the thalamus for treatment of epilepsy, there were significantly more reports of memory impairment and depression in the active stimulation than sham stimulation group (5). However, objective neuropsychological assessment of cognition and mood did not differ between the groups at the end of the blinded phase. Recent work has suggested that disruption of sleep by thalamic stimulationinduced arousals might explain the possible negative effects

RNS and Cognition

(6). Vagus nerve stimulation therapy has been purported to show mildly positive neurocognitive effects (7), and preliminary work has suggested the potential for cognitive benefit from neurostimulation in several conditions including traumatic brain injury, stroke, and Alzheimer disease (8–10). Likely, cognitive risk or benefit depends on where, how, and in whom neurostimulation is performed. Responsive neurostimulation (RNS) has emerged as a promising approach to treatment of refractory focal epilepsy in patients with one or two epileptogenic regions. Therapy is delivered by a cranially implanted neurostimulator connected with two four-contact leads that are placed at identified seizure foci. Through an iterative process, the device is programmed to recognize epileptiform activity that precedes seizures and to deliver brief bursts of neurostimulation to the seizure focus. A randomized controlled trial demonstrated a significant benefit of RNS for seizure control during the blinded period (11), and long-term open-label studies suggest increasing benefit over time (12). Does RNS therapy come at a cognitive cost from disruption of normal neuronal function at the site of stimulation? Or, conversely, does RNS enhance cognitive function? The present report from Loring et al. of neurocognitive assessments in patients participating in the open-label phase of the randomized controlled trial of RNS addresses these questions. In the open-label phase of the study, all patients received RNS. Prespecified neuropsychological assessments were administered at baseline, 1 year, and 2 years following device implantation. Testing focused on language (Boston Naming Test, BNT) and verbal memory (Rey Auditory Verbal Learning Test, AVLT) and included other secondary measures. Change over time was carefully assessed to avoid spurious findings from practice effects or measurement error. One challenge that faced the researchers was the inherent heterogeneity of the population under study. All patients were adults with refractory epilepsy who averaged three or more focal seizures per month, but in contrast to thalamic DBS therapy for epilepsy, which targeted a single site for neurostimulation, RNS stimulation was tailored to the individual’s seizure focus. Included in the study were patients with a frontal, temporal, parietal, or occipital neocortical focus, as well as many with limbic foci. However, rather than a liability, this heterogeneity offered an opportunity to examine the regional effects of stimulation on cognition. The researchers grouped subjects into those with exclusively mesial temporal (N = 86; 62 bilateral) or exclusively neocortical leads (N = 76; 25 frontal, 25 temporal neocortical). The results of cognitive assessments varied by group. Neocortical, but not medial temporal, patients showed significant improvements in the BNT over time; while medial temporal, not neocortical, patients registered significant improvements in the Auditory Verbal Learning Test (AVLT). In addition to group differences, region-specific improvements were also seen at the individual patient level. Improvements in BNT were seen in 32.3% of the neocortical patients, but only 16.7% of the mesial temporal patients. Less striking findings were seen on the AVLT, in which more mesial temporal subjects (8.5%) than neocortical patients (6.5%) showed improvement. Laterality of stimulation might be expected to influence results, but

the large number of individuals receiving bilateral stimulation precluded this assessment. In the neocortical group, an exploratory subgroup analysis by specific region of stimulation (e.g., frontal vs temporal neocortical) would have been of interest but was not reported, likely because of the small numbers of subjects in some subgroups. In addition to the region-of-stimulation heterogeneity, patients in this longitudinal, open-label study also had substantial heterogeneity in AED treatment and seizure frequency over time. Both of these factors could potentially confound the interpretation of the cognitive findings. The authors attempted to address these variables by looking for associations between cognitive outcomes and rough categories of AED burden (increased, decreased, both increased and decreased, or unchanged) or seizure frequency. No relationship was revealed between cognitive scores and changes in either AEDs or seizure frequency. This suggests that changes in seizure frequency or AED therapy were not the primary driver of changes in cognitive scores but, given the limits of the data and analysis, does not entirely exclude some indirect benefit of stimulation via reduced seizure frequency or AED burden. What does this mean for patients considering RNS therapy? We can counsel patients that RNS therapy over this 2-year interval was not associated with adverse cognitive effects. The authors are appropriately cautious in their interpretation of the positive findings. While a substantial number of patients showed improvements in naming, relatively fewer showed improvements in verbal memory. In both cases, the magnitude of the improvements was modest. In this study, RNS therapy was not designed or optimized for cognitive enhancement. The lack of cognitive deterioration and the signal of region-specific cognitive improvement are encouraging both for patients considering RNS therapy for treatment of epilepsy and for the burgeoning field of neurostimulation and cognition. by David Spencer, MD References 1. 1.Salinsky MC, Storzbach D, Spencer DC, Oken BS, Landry T, Dodrill CB. Effects of topiramate and gabapentin on cognitive abilities in healthy volunteers. Neurology 2005;64:792–798. 2. Eddy CM, Rickards HE, Cavanna AE. The cognitive impact of antiepileptic drugs. Ther Adv Neurol Disord 2011;4:385–407. 3. Volkmann J, Daniels C, Witt K. Neuropsychiatric effects of subthalamic neurostimulation in Parkinson disease. Nat Rev Neurol 2010;6:487– 498. 4. Parsons TD, Rogers SA, Braaten AJ, Woods SP, Troster AI. Cognitive sequelae of subthalamic nucleus deep brain stimulation in Parkinson’s disease: A meta-analysis. Lancet Neurol 2006;5:578–588. 5. Fisher R, Salanova V, Witt T, Worth R, Henry T, Gross R, Oommen K, Osorio I, Nazzaro J, Labar D, Kaplitt M, Sperling M, Sandok E, Neal J, Handforth A , Stern J, DeSalles A, Chung S, Shetter A, Bergen D, Bakay R, Henderson J, French J, Baltuch G, Rosenfeld W, Youkilis A, Marks W, Garcia P, Barbaro N, Fountain N, Bazil C, Goodman R, McKhann G, Babu Krishnamurthy K, Papavassiliou S, Epstein C, Pollard J, Tonder L, Grebin J, Coffey R, Graves N; SANTE Study Group. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 2010;51:899–908.

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RNS and Cognition

6. Voges BR, Schmitt FC, Hamel W, House PM, Kluge C, Moll CK, Stodieck SR. Deep brain stimulation of anterior nucleus thalami disrupts sleep in epilepsy patients. Epilepsia 2015;56:e99–e103. doi:10.1111/ epi.13045. 7. Vonck K, Raedt R, Naulaerts J, De Vogelaere F, Thiery E, Van Roost D, Aldenkamp B, Miatton M, Boon P. Vagus nerve stimulation...25 years later! What do we know about the effects on cognition? Neurosci Biobehav Rev 2014;45:63–71. 8. Plow EB, Machado A. Invasive neurostimulation in stroke rehabilitation. Neurotherapeutics 2014;11:572–582. 9. Nardone R, Holler Y, Tezzon F, Christova M, Schwenker K, Golaszewski S, Trinka E, Brigo F. Neurostimulation in Alzheimer’s disease: From basic research to clinical applications. Neurol Sci 2015;36:689–700.

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10. Shin SS, Dixon CE, Okonkwo DO, Richardson RM. Neurostimulation for traumatic brain injury. J Neurosurg 2014;121:1219–1231. 11. Morrell MJ; RNS System in Epilepsy Study Group. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 2011;77:1295–1304. 12. Bergey GK, Morrell MJ, Mizrahi EM, Goldman A, King-Stephens D, Nair D, Srinivasan S, Jobst B, Gross RE, Shields DC, Barkley G, Salanova V, Olejniczak P, Cole A, Cash SS, Noe K, Wharen R, Worrell G, Murro AM, Edwards J, Duchowny M, Spencer D, Smith M, Geller E, Gwinn R, Skidmore C, Eisenschenk S, Berg M, Heck C, Van Ness P, Fountain N, Rutecki P, Massey A, O’Donovan C, Labar D, Duckrow RB, Hirsch LJ, Courtney T, Sun FT, Seale CG. Long-term treatment with responsive brain stimulation in adults with refractory partial seizures. Neurology 2015;84:810–817.

Responsive Neurostimulation and Cognition.

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