Cognitive Side Effects Research Articles

T-495, a novel low cooperative M1 receptor positive allosteric modulator, improves memory deficits associated with cholinergic dysfunction and is characterized by low gastrointestinal side effect risk.

M1 muscarinic acetylcholine receptor (M1R) activation can be a new therapeutic approach for the treatment of cognitive deficits associated with cholinergic hypofunction. However, M1R activation causes gastrointestinal (GI) side effects in animals. We previously found that an M1R positive allosteric modulator (PAM) with lower cooperativity (α‐value) has a limited impact on ileum contraction and can produce a wider margin between cognitive improvement and GI side effects. In fact, TAK‐071, a novel M1R PAM with low cooperativity (α‐value of 199), improved scopolamine‐induced cognitive deficits with a wider margin against GI side effects than a high cooperative M1R PAM, T‐662 (α‐value of 1786), in rats. Here, we describe the pharmacological characteristics of a novel low cooperative M1R PAM T‐495 (α‐value of 170), using the clinically tested higher cooperative M1R PAM MK‐7622 (α‐value of 511) as a control. In rats, T‐495 caused diarrhea at a 100‐fold higher dose than that required for the improvement of scopolamine‐induced memory deficits. Contrastingly, MK‐7622 showed memory improvement and induction of diarrhea at an equal dose. Combination of T‐495, but not of MK‐7622, and donepezil at each sub‐effective dose improved scopolamine‐induced memory deficits. Additionally, in mice with reduced acetylcholine levels in the forebrain via overexpression of A53T α‐synuclein (ie, a mouse model of dementia with Lewy bodies and Parkinson's disease with dementia), T‐495, like donepezil, reversed the memory deficits in the contextual fear conditioning test and Y‐maze task. Thus, low cooperative M1R PAMs are promising agents for the treatment of memory deficits associated with cholinergic dysfunction.

The effect of erythropoietin on electroconvulsive stimulation induced cognitive impairment in rats

Electroconvulsive therapy (ECT) is the most effective and fast-acting treatment for severe depression but associated with troublesome cognitive side-effects. Systemically administered erythropoietin (EPO) crosses the blood-brain-barrier and is a promising treatment for cognitive dysfunction in a wide array of neuropsychiatric and neurological disorders. In this study we trained rats to locate a submerged platform in a water maze and then subjected them to electroconvulsive stimulations (ECS, the rodent equivalent to ECT) and EPO treatment. We then analysed their ability to remember and relearn the location of the platform. In addition, we examined “wall-clinging” (thigmotaxis), a behavioural indicator of stress. ECS caused significant deficit in a probe trial administered after three weeks (nine stimulations) as well as one week (six stimulations) of treatment, indicative of induction of retrograde amnesia. ECS had no effect on relearning of the water maze task or performance in a subsequent probe trial. EPO treatment did not ameliorate the ECS-induced retrograde amnesia, but after nine ECS stimulations the animals that had received EPO relearned the position of the hidden platform faster than the animals that had not. We also found EPO to decrease “wall-clinging” behaviour, suggesting an effect of EPO on the stress response in rats. Thus, we establish the Morris Water Maze as a suitable model for ECS-induced memory loss in rats and provide some evidence for potential beneficial effects of EPO.

Utilization of Medications With Cognitive Impairment Side Effects and the Implications for Older Adults' Cognitive Function.

Objectives: Many medications have cognitive impairment, memory loss, amnesia, or dementia as side effects ("cognitive side effects" hereafter), but little is known about trends in the prevalence of these medications or their implications for population-level cognitive impairment. Method: We use data from the National Health and Nutrition Examination Survey (1999-2016) to describe trends in the use of medications with cognitive side effects among adults aged 60+ (N = 16,937) and their implications for cognitive functioning (measured using word learning and recall, animal fluency, and digit symbol substitution assessments). Results: Between 1999 to 2000 and 2015 to 2016, the prevalence of older adults taking one, two, and at least three medications with cognitive side effects increased by 10.2%, 57.3%, and 298.7%, respectively. Compared to non-users, respondents who simultaneously used three or more medications with cognitive side effects scored 0.22 to 0.27 standard deviations lower in word learning and recall (p = .02), digit symbol substitution (p < .01), and the average standardized score of the three assessments (p < .001). Limitation: Dosage of medications associated with cognitive side effects was not measured. Discussion: Concurrent use of medications with cognitive side effects among older adults has increased dramatically over the past two decades. The use of such medications is associated with cognitive impairment and may explain for disparities in cognitive function across subgroups. These findings highlight the need for cognitive screenings among patients who consume medications with cognitive side effects. They also highlight the synergic effects of polypharmacy and potential drug-drug interactions that result in cognitive deficits.

Clinical Characteristics of Bipolar Disorder Patients with Mood Stabilizer-Induced Cognitive Side Effects findings from the REAP-BD Survey in Korea

Clinical Characteristics of Bipolar Disorder Patients with Mood Stabilizer-Induced Cognitive Side Effects findings from the REAP-BD Survey in Korea

Recent developments in cognitive fMRI for temporal lobe epilepsy

AbstractEpilepsy is frequently accompanied by severe cognitive side effects. Temporal lobe epilepsy (TLE), and even successful surgical treatment, may affect cognitive function, in particular language as well as verbal and visual memory function. Epilepsy arising from the temporal lobe can be controlled surgically in up to 70% of patients. The goals of epilepsy surgery are to remove the brain areas generating the seizures without causing or aggravating neuropsychological deficits. This requires accurate localization of the brain areas generating the seizures (“epileptogenic zone”) and the areas responsible for motor and cognitive functions, such as language and memory (“essential brain regions”) during presurgical evaluation. In the past decades, functional magnetic resonance imaging (fMRI) has been increasingly used to noninvasively lateralize and localize not only primary motor and somatosensory areas, but also brain areas that are involved in everyday language and memory processes. The imaging modality also shows potential for predicting the effects of temporal lobe resection on language and memory function. Together with other MRI modalities, cognitive fMRI is a promising tool to improve surgical strategies tailored to individual patients with regard to functional outcome, by virtue of definition of epileptic cerebral areas that need to be resected and eloquent areas that need to be spared.The aim of this review is to provide an overview of recent developments and practical recommendations for the clinical use of cognitive fMRI in TLE.

Accelerated magnetic seizure therapy (aMST) for treatment of major depressive disorder: A pilot study

Background: Magnetic Seizure therapy (MST) is an emerging treatment for major depressive disorder (MDD) that is associated with fewer cognitive side effects compared to electroconvulsive therapy. The present pilot study sought to investigate whether daily MST treatments were associated to antidepressant effect and assess cognitive side effects associated with an accelerated MST (aMST) treatment schedule. Methods: Fifteen MDD patients underwent a six-day course of MST treatment to the vertex following assessment of symptom severity and neuropsychological testing. The primary outcome was severity on the Hamilton Rating Scale for Depression 17-item (HRSD-17). Patient also underwent neuropsychological assessment with the RBANS and Stroop Colour-Word test. Results: There were no instances of delirium or disturbance of consciousness following aMST sessions. Patients showed significant decreases on indices of depression and anxiety symptoms, with 9 (60%) patients showing a clinical response and 7 (47%) patients experiencing remission. Significant improvements were reported in RBANS total score, as well as indices of immediate memory and delayed memory. No changes at follow-up were reported for visuospatial/constructional, language, and attention RBANS indices, nor for Stroop Colour/Word performance. Limitations: The results should be interpreted with caution as they are part of a non-randomized, open-label pilot study. Further, the short duration of the study does not provide longitudinal follow-up to determine whether treatment response lasts a meaningful duration of time. Conclusions: aMST well tolerated without significant evidence of cognitive side effects and rapid improvement in symptoms. Further research is required to fully characterize these changes and replicate them in independent samples.

International Consortium on the Genetics of Electroconvulsive Therapy and Severe Depressive Disorders (Gen-ECT-ic).

Recent genome-wide association studies have demonstrated that the genetic burden associated with depression correlates with depression severity. Therefore, conducting genetic studies of patients at the most severe end of the depressive disorder spectrum, those with treatment-resistant depression and who are prescribed electroconvulsive therapy (ECT), could lead to a better understanding of the genetic underpinnings of depression. Despite ECT being one of the most effective forms of treatment for severe depressive disorders, it is usually placed at the end of treatment algorithms of current guidelines. This is perhaps because ECT has controlled risk and logistical demands including use of general anaesthesia and muscle relaxants and side-effects such as short-term memory impairment. Better understanding of the genetics and biology of ECT response and of cognitive side-effects could lead to more personalized treatment decisions. To enhance the understanding of the genomics of severe depression and ECT response, researchers and ECT providers from around the world and from various depression or ECT networks, but not limited to, such as the Psychiatric Genomics Consortium, the Clinical Alliance and Research in ECT, and the National Network of Depression Centers have formed the Genetics of ECT International Consortium (Gen-ECT-ic). Gen-ECT-ic will organize the largest clinical and genetic collection to date to study the genomics of severe depressive disorders and response to ECT, aiming for 30,000 patients worldwide using a GWAS approach. At this stage it will be the largest genomic study on treatment response in depression. Retrospective data abstraction and prospective data collection will be facilitated by a uniform data collection approach that is flexible and will incorporate data from many clinical practices. Gen-ECT-ic invites all ECT providers and researchers to join its efforts.

Effects of magnetic seizure therapy on anterograde and retrograde amnesia in treatment-resistant depression.

Electroconvulsive therapy (ECT) is the gold standard for treatment-resistant depression (TRD). However, cognitive side effects, mainly anterograde and retrograde amnesia, frequently occur. Magnetic seizure therapy (MST) is tested using more focal seizure induction. However, the suggestion MST may be more beneficial than ECT because it causes fewer amnesia have not yet been comprehensively investigated using common neuropsychological testing specifically for ECT. We aimed to examine whether MST causes anterograde and retrograde amnesia. Ten patients with TRD were treated with MST (8.9 [2] treatments) at 100% machine output, a frequency of 100 Hz and 657.4 (62) pulses per train. The short form of the Autobiographical Memory Inventory was administered to test retrograde amnesia. Furthermore, an extended neuropsychological test battery, including verbal and nonverbal recall as well as recognition tasks, was used. We observed changes in retrograde amnesia, although they were not clinically relevant (mean: -0.42 ± 0.14). Furthermore, no anterograde amnesia as well as no effects on global cognitive status, attention, language, and executive functions after MST were measured. The cognitive safety and efficacy of MST in patients with TRD were indicated. However, the main limitations of the present study were the small sample and as a consequence, the low statistical power to detect changes after treatment. Therefore, our findings require replication in further studies. In addition, a direct comparison between MST and ECT in a larger sample should be performed before MST can be discussed as an alternative treatment approach to ECT in clinical practice.

C1-C3 unilateral dorsal root entry zone rhizotomy for the treatment of persistent postherpetic occipital neuralgia

Background:Postherpetic occipital neuralgia (PHON) is a neuropathic pain condition that usually presents as paroxysmal pain that is stabbing in nature.[5,7] It involves the occiput and posterior scalp in the distribution of the greater and/or lesser occipital nerves. It usually develops after an episode of shingles.[5,7] Treatment usually first consists of medical therapy and then progresses to invasive treatment (e.g., peripheral nerve stimulation, spinal cord epidural stimulation, C2-C3 ganglionectomy, or dorsal root entry zone [DREZ] rhizotomy).[1-4,6] Here, we present a case of persistent PHON that was treated with C1-C3 DREZ.Case Description:A 37-year-old female had a history of several episodes of shingles involving the left neck and occiput; they resolved after treatment with valacyclovir. Subsequently, however, she developed severe lancinating pain of the neck and the occiput and was diagnosed with PHON. Initially, she was treated with oxcarbazepine but was stopped due to cognitive side effects. She then had a cervical spinal cord stimulator implanted which produced relief for several years; it was later removed due to breakage of the electrodes. She then underwent a left- sided C1-C2 hemilaminectomy with a C1-C3 DREZ procedure.[1] Postoperatively, she had immediate resolution of her pain, but developed a new left hemiparesis (4+/5), accompanied by imbalance, decreased sensation to light touch, and loss of proprioception. On 6 weeks follow up, the pain was still relieved, and she exhibited significant improvement in her left-sided hemiparesis and hemisensory deficit to which returned to baseline. Similar outcome was maintained at four months follow up.Conclusion:Although high cervical DREZ lesions may effectively treat post herpetic/occipital neuralgia that fails other measures, there may be associated major neurological morbidity that makes this procedure acceptable as a salvage option, and after clearly explaining the risks to the patient.

Distinct effects of cocaine and cocaine + cannabis on neurocognitive functioning and abstinence: A six-month follow-up study

Background and AimsCannabis use is frequent among individuals with cocaine use disorder. Despite recent non-controlled studies advocating a therapeutic role of smoked cannabis, there is a paucity of evidence-based data on potential therapeutic and cognitive side-effects of this association. MethodsWe examined 63 cocaine-addicted subjects who used cannabis more than 50 times in lifetime (COC + CAN), 24 cocaine-addicted patients who use cannabis less than 50 times (COC), and 36 controls (CON). Participants were evaluated with an extensive battery of neurocognitive tests after two weeks of supervised detoxification in an inpatient treatment program. Patients were followed up in one, three, and six months after discharge. ResultsBoth groups of patients performed worse than CON on working memory, processing speed, inhibitory control, mental flexibility, and decision making. COC + CAN performed worse than COC on speed processing, inhibitory control and sustained attention, while COC performed worse than COC + CAN on mental flexibility. Concomitant cannabis use did not decrease relapses to cocaine use after one, three and six months. Among COC + CAN, earlier cocaine and cannabis use, and impaired executive functioning were predictive of relapse on cocaine after six months. ConclusionOur results did not support the recommendation of smoked cannabis as a safe therapeutic approach for cocaine-addicted patients due to significant negative cognitive side-effects and absence of efficacy. Further studies investigating frontal brain morphology, neuromaturation, and prescription of the non-psychoactive constituent of cannabis sativa cannabidiol among cocaine-addicted patients who use cannabis are warranted.

Effects of\xa0the\xa0monoamine stabilizer (-)OSU6162 on\xa0cognitive function in\xa0alcohol dependence

IntroductionAlcohol dependence (AD) is associated with a dysregulated mesolimbocortical dopamine system—a pathway which is also implicated in both reward and cognition. The monoamine stabilizer (-)-OSU6162 (OSU) is a novel pharmacological compound with the ability to reduce ethanol intake and ethanol seeking in long-term drinking rats as well as reducing alcohol craving in AD patients. Dopaminergic drugs can both impair and improve cognitive functions, and the aim of the current study was to investigate the effect of OSU treatment on cognitive functioning in AD patients.MethodIn a randomized double-blind placebo-controlled study, 56 individuals with AD received 14 days of OSU or placebo treatment. Neuropsychological tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB®) and other tasks were used to evaluate treatment effect on executive function/impulsivity, working memory, attention, emotional recognition, and divergent thinking.ResultsTreatment with OSU did not impair neuropsychological function in any of the cognitive domains investigated (all p > 0.1). In fact, OSU treatment did, compared to placebo, improve future planning ability (F(1,46) = 6.9; p = 0.012; Cohen’s d = 0.54), verbal divergent thinking (F(1,44) = 10.1; p = 0.003; d = 0.96), and response time for emotional recognition (F(1,47) = 6.7; p = 0.013; d = 0.44).ConclusionOSU treatment did not cause short-term cognitive side effects, further supporting the potential of OSU as a clinically feasible pharmacological treatment in AD patients. OSU treatment might improve future planning, verbal divergent thinking, and emotional recognition latency, which in turn may have a beneficial impact on alcohol use outcomes. Future studies are needed to confirm these preliminary findings.

Laparoscopic Catheter Implantation for Targeted Therapy Delivery in the Treatment of Pudendal Neuralgia and Other Intrapelvic Causes Of Neuropathic Pain

Video Objective To describe the technique and propose a tentative care pathway for the use of the targeted delivery of ropivacaine via implanted catheter to alleviate post-decompression neuropathic pain in patients with intrapelvic nerve entrapments (INE) in four successful initial cases. Setting Tertiary care center: specialized Neuropelveology center; this video features an initial proof-of-concept case series. Interventions Despite the high success rate of laparoscopic neuronavigation (LANN) in the surgical treatment of INE, 52% of patients experience residual pain, likely resulting from axon demyelination and Schwann cell degeneration. During axonal injury, sodium channels are upregulated, resulting in a massive influx of sodium, causing neuralgia, mechanosensitivity, and hyperalgesia. Genetic/pharmacologic blockade of these channels has neuroprotective and analgesic effects. Building on these insights, we hypothesized that the inhibition of sodium channels with ropivacaine in the entrapped nerve may alleviate post-decompression pain in patients undergoing LANN. Four patients (one male, three female) diagnosed with INE in our Neuropelveology clinic in Sao Paulo and undergoing LANN detrapment were included. The first three cases had a catheter implanted at the site where the INE was relieved; the catheter was connected to a medication pump or a subcutaneous port. The fourth case was a salvage procedure, in which the patient had failed to experience pain relief following one prior hip replacement, one hip prosthesis revision, and one previous LANN detrapment of the intrapelvic portion of the sciatic nerve. Optimal pain control was obtained in all the four patients. A proposed care pathway for INE is presented and discussed. Conclusion Preliminary observations indicate that the targeted delivery of ropivacaine via implanted catheter and pump/port may effectively control post-decompression neuropathic pain and completely obviate the use of opioid analgesics without the risk of dependence or cognitive side effects.

CN1 - Patients’ usage and perception of an interactive app for symptom management and self-care during cancer treatment

BackgroundEmploying apps in assessment of symptoms during cancer treatment facilitates detection of adverse events and may improve patient outcomes. Our interactive app Interaktor supports patients’ symptom management by regular symptom reporting, alerts for rapid access to staff in case of severe symptoms and continual access to relevant self-care advice. The aim of this study was to describe usage and explore perceptions of using Interaktor during cancer treatment. MethodsThe study includes the participants from the intervention arms of two separate randomized controlled trials (RCT) on patients with breast cancer (n=74) during neoadjuvant chemotherapy and locally advanced prostate cancer (n=75) during radiotherapy. It comprises usage metrics analysed by descriptive statistics and interviews analyzed by conventional content analysis. ResultsAdherence to daily reporting during treatment was in median above 80 %. Most patients viewed the information pages with self-care advice numerous times. The app was perceived user-friendly, faciliating interaction with health care professionals and supporting self care. Symptom reporting was a quick and comfortable way to access help. Using the app generated feelings of being monitored, involved and cared for. Further it supported attentiveness to and reflection of own well- being but could also serve as a reminder of illness. Some patients described that vigor, comorbidity, and cognitive side effects from the treatment influenced the motivation for and ability to symptom report. The information pages with self care advice were useful and appreciated and gave an idea of what was to be expected during treatment. Patients requested added and more comprehensive information on psychological symptoms and dietary advice. ConclusionsThe Interaktor app is a userfriendly and convenient alternative for patients contact and involvement with health care that aided symptom management, self-care and further enhanced patients participation in their care. Clinical trial identificationNCT02479607 and NCT02477137. Legal entity responsible for the studyKarolinska Institutet. FundingSwedish Cancer Foundation, Swedish Research Council, Swedish Research Council for Health, Working Life and Welfare and Karolinska Institutet. DisclosureAll authors have declared no conflicts of interest.

CN79 - Cognitive function changes and associated factors in patients receiving chemotherapy

BackgroundDespite the accumulation of knowledge on the cognitive side-effects of chemotherapy, the actual incidence of this impairment is still a subject of research. Estimates of affected patients vary from 17% to 78% across studies.In recent years, growing attention is being paid to the potential adverse effects of chemotherapy on brain and cognitive function. Despite the accumulation of knowledge on the cognitive side-effects of chemotherapy, the actual incidence of this impairment is still a subject of research. Estimates of affected patients vary from 17% to 78% across studies. The aim of the study is to evaluate cognitive function changes experienced by cancer patients who receive chemotherapy and associated factors. MethodsThis is a descriptive study. The data collection phase of the study is ongoing and the results obtained from 47 patients who received chemotherapy have been reported here. The results of the large group will be presented at the congress. Data collection was started on March 2019 and will be continuing until September 2019. This study was conducted in a Research and Training Hospital in Istanbul/Turkey. Data were collected by using the Patient İnformation form and Functional Assessment of Chronic Illness Therapy- Cognitive Function (FACIT-Cog) and The European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30). Mann-Whitney U test, Kruskal-Wallis test, and Spearman Correlation analysis were used to evaluate the data. ResultsThere was statistically significant and positive relationship between FACIT-Cog “perceived cognitive impairments” subscale and EORTC-30 cognitive (r=0,755; p≤0,001), emotional (r=0,505; p=0,001) and social (r=0,504; p=0,001) functioning subscales. There was statistically significant and positive relationship between FACIT-Cog “comments from others on cognitive function” and EORTC-30 emotional (r=0,491; p=0,001), cognitive (r=0,539; p≤0,001), and social (r=0,588; p≤0,001) functioning subscales. FACIT-Cog scores was not significantly differ by patients’ characteristics (p>0,005). ConclusionsCognitive function should be assessed and considered during the care of cancer patients. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Telomere length in depression and association with therapeutic response to electroconvulsive therapy and cognitive side-effects.

Electroconvulsive therapy (ECT) is the most acutely effective treatment for severe treatment-resistant depression. However, there are concerns about its cognitive side-effects and we cannot yet confidently predict who will experience these. Telomeres are DNA-protein complexes that maintain genomic integrity. In somatic cells, telomeres shorten with each cell division. Telomere length (TL) can thus provide a measure of 'biological' aging. TL appears to be reduced in depression, though results are mixed. We sought to test the following hypotheses: (1) that TL would be shorter in patients with depression compared to controls; (2) that TL would be a predictor of response to ECT; and (3) that shorter TL would predict cognitive side-effects following ECT. We assessed TL in whole blood DNA collected from severely depressed patients (n = 100) recruited as part of the EFFECT-Dep Trial and healthy controls (n = 80) using quantitative real-time polymerase chain reaction. Mood and selected cognitive measures, including global cognition, re-orientation time, and autobiographical memory, were obtained pre-/post-ECT and from controls. Our results indicate that TL does not differ between patients with depression compared to controls. TL itself was not associated with mood ratings and did not predict the therapeutic response to ECT. Furthermore, shorter baseline TL is not a predictor of cognitive side-effects post-ECT. Overall, TL assessed by PCR does not represent a useful biomarker for predicting the therapeutic outcomes or risk for selected cognitive deficits following ECT.

Cognitive and Behavioral Changes in Patients Treated With Droxidopa for Neurogenic Orthostatic Hypotension: A Retrospective Review

Droxidopa is a norepinephrine precursor that improves symptoms of neurogenic orthostatic hypotension in conditions such as Parkinson disease, multiple system atrophy, and pure autonomic failure by inducing a pressor effect. Unlike other pressor agents, droxidopa crosses the blood-brain barrier; however, its central effects are, as of yet, uncharacterized. We present the results of a retrospective cohort study examining cognitive and behavioral side effects linked to droxidopa therapy. We performed a review of 101 patients who had been treated with droxidopa at an academic tertiary care center and identified cases of cognitive and behavioral changes associated with the therapy. We identified six patients who had developed cognitive and behavioral symptoms, including memory difficulties, confusion, mania, and irritability, shortly after droxidopa initiation. All six patients displayed symptoms of synucleinopathy, manifesting with autonomic failure, rapid eye movement sleep behavior disorder, and parkinsonism. Patients had no significant cognitive or behavioral symptoms before droxidopa initiation. Behavioral disturbances were observed early in the droxidopa titration period and at relatively low doses. Symptoms resolved with dose reduction in four patients, and droxidopa was discontinued in two patients due to persistent irritability. No other medical comorbidities or alternative etiologies were identified to explain the symptoms. Droxidopa is designed to act peripherally as a pressor agent but may also exert important central effects. We hypothesize that the cognitive and behavioral manifestations observed in the patients with orthostatic hypotension resulted from an "overdose" of key noradrenergic networks linking orbitofrontal and mesolimbic regions.

Low-Dose Radiation Spillage During Stereotactic Radiosurgery for Brain Metastases is Associated with a Decreased Incidence of New Supratentorial Brain Metastases.

Stereotactic radiosurgery (SRS) for brain metastases is increasingly used in lieu of whole brain radiation (WBRT), with reduced risk of cognitive side effects but at the expense of an increased risk of developing new lesions in non-treated parts of the brain. Here we investigated whether the low dose fall-off during SRS is associated with a lower incidence of brain metastases. We reviewed 130 patients treated with single or fractionated SRS for definitive or post-op brain metastases at our institution during 2016-2017. Patients with MRI findings of local recurrence or new brain metastases within 18 months of the first SRS were selected. WBRT before SRS was an exclusion. MRI or CT simulation for repeat treatment was fused with the initial SRS treatment plan. The new lesions and the corresponding contralateral anatomical site were outlined on the initial planning scan. The mean doses delivered to the site of these new lesions from the initial SRS treatment were tabulated. Comparison of mean doses to the new lesions and contralateral site were performed using t-test, and the difference in number of lesions at varying low dose levels was examined using Z-test for proportion. Thirty-six patients met the inclusion criteria. 24 patients (67%) had lung primary (2 squamous cell carcinoma and 19 adenocarcinoma), 6 breast (17%), 2 renal cell carcinoma (RCC), one each of esophagus, melanoma, cervix and unknown primary. 21 patients (58%) received chemotherapy during the time interval of 18 months, and 20 (56%) received immunotherapy. One hundred sixty-six new brain lesions were evaluated. Three of the 7 cerebellar lesions (43%) showed local recurrence. In patients with initial supratentorial metastasis, only 5 of total 159 lesions (3%) appeared when exposed to >6 Gy from prior SRS. 11 (6.9%), 30 (19%) and 49 (31%) lesions occurred in the >4 Gy, >2 Gy and >1 Gy dose levels, respectively. 14 lesions (9%) had no recurrences in their contralateral comparable site which received >6 Gy (p= 0.033) and 21 lesions had no recurrences in their contralateral comparable site if >4 Gy was received (13%) (p=0.063). Among the lesions that appeared after exposure to >6 Gy and >4 Gy dose, 2/5 (40%) and 5/11 (55%) lesions, respectively, were from RCC primaries. New metastases developed in sites that received less mean dose from prior treatments as compared to mean dose received in the corresponding contralateral hemisphere, where the patients did not experience recurrence. This was true for all dose levels, >1Gy through >6 Gy (all p values ≤0.02). New lesions appeared more often on the side that received lower dose of radiation compared to their contralateral site. Dose levels of >6 Gy or >4 Gy were associated with decreased incidence of new supratentorial brain metastases, less so for RCC primaries. Low dose bath to the non-target brain may be protective. Validation in larger dataset is warranted.

C1-C4 Unilateral Dorsal Root Entry Zone Rhizotomy (Drez) for Treatment of Refractory Post-Herpetic Occipital Neuralgia

Abstract INTRODUCTION Occipital neuralgia (ON) is a neuropathic pain condition that usually present as sharp, stabbing, paroxysmal pain. It involves the occiput and posterior scalp in the distribution of the greater, and/or lesser occipital nerve. Treatment usually takes a stepwise fashion starting with medical therapy then progress to a more invasive methods such as peripheral nerve stimulation, spinal cord epidural stimulation, C2-C3 ganglionectomy, or dorsal root entry zone rhizotomy (DREZ). Here, we present a case of a patient with postherpetic ON that was treated with C1-C4 DREZ due to failure of other therapies. METHODS A 37-yr-old female with history of several episodes of shingles involving the left neck and occiput. The episodes resolved after an extended period of valacyclovir. Subsequently, developed severe lancinating pain of the neck and the occiput. She was treated initially with oxcarbazepine but was stopped due to cognitive side effects. Then the patient underwent implantation of a spinal cord stimulator, which did produce relief for several years; however, it was removed due to breakage of the electrodes. She underwent a left sided C1-C2 hemilaminectomy with C1 C4 DREZ. RESULTS Postoperatively, the patient developed a mild new motor weakness 4 + /5, and decreased sensation to light touch and proprioception. In addition, she had unsteady gait. Six weeks postop the patient endorsed significant improvement in her ON pain, muscle strength, sensation and balance. On exam: she had pronounced numbness of the left side of the occiput and neck down to the clavicle, but the rest of her exam improved to preoperative baseline. CONCLUSION C1-C4 DREZ can be an efficacious treatment option for refractory ON.

A focus on valproate and cognitive deficits in Bipolar Disorders: A mini-review: Special Section on “Translational and Neuroscience Studies in Affective Disorders” Section Editor, Maria Nobile MD, PhD.

BackgroundCognitive deficits represent a core feature of Bipolar Disorder (BD), which seem to characterize this disorder regardless of the mood phase. However, the role of pharmacological treatment in determining cognitive alterations is still not clear. Indeed, although drugs improve cognition by targeting mood symptoms, they could also carry their own cognitive side effects. This is true especially for mood stabilizers as they are the most commonly prescribed drugs in patients affected by BD and they are usually administered also during euthymic phases. MethodsIn this context, the present review aimed at summarizing the results of the studies evaluating the impact of valproate on cognitive functions in patients suffering from BD, as primary or secondary results. The inclusion criteria were met by ten studies. Specifically, we included one double-blind quasi-randomized study and nine cross-sectional or naturalistic studies, which a) used healthy subjects as control group (N = 1), b) compared valproate treated patients with healthy individuals and other treatments (N = 5), and c) compared valproate treated patients just with other treatments, with a specific focus on lithium (N = 3). ResultsOverall the results suggested a negative effect of valproate on cognitive functions in chronically-treated patients affected by BD. Notably, it has been found that the working memory was the most affected cognitive domain. LimitationsFew studies directly explored the effect of valproate on cognition in BD. ConclusionsThese findings seem to suggest that valproate might have a negative effect on cognitive functions, especially on working memory domain. However, the results should be taken cautiously since the limited number of available studies published so far. In conclusion, these evidences seem to point out that the possible cognitive side effects of pharmacological treatments should be carefully taken into account, especially in chronic patients.

Multicenter randomized controlled trial of bifrontal, bitemporal, and right unilateral electroconvulsive therapy in major depressive disorder.

Electroconvulsive therapy (ECT) has been shown to be the most effective and rapid treatment for severe depression. Electrode placement is one of the most important factors that affect ECT's efficacy and side-effects profile. Bifrontal, bitemporal, and unilateral are the three most used electrode placements. Very few studies have directly compared the efficacy and cognitive side-effects of the three placements. The aim of this study was to compare the efficacy and cognitive side-effects associated with bifrontal, bitemporal, and unilateral electrode placements. This multicenter randomized, blinded, controlled trial included 40 patients in each of the three groups. Most of the patients (94.8%) completed six ECT treatments. We used mixed-model analyses to compare differences in 17-item Hamilton Depression Rating Scale (HAMD-17) and Clinical Global Impression (CGI) scores among the three groups and the five times series (baseline, Week 1, Week 2, Week 3, and Week 4). The cognitive outcome was Mini-Mental State Examination (MMSE) score. HAMD-17 and CGI scores did not differ significantly across the groups (HAMD-17 scores: z = -1.13, P = 0.259; CGI scores: z = -0.35, P = 0.729). MMSE scores at pre- and post-ECT were similar across the three groups (F = 2.06, P = 0.133). However, subgroup analysis using paired t-tests showed that MMSE scores improved in the right unilateral and bifrontal groups (t = 2.745, P = 0.0098; t = 2.464, P = 0.0204), but did not change in the bitemporal group (t = 1.188, P = 0.2461). The efficacy of right unilateral and bifrontal ECT placement was similar to that of bitemporal ECT. The physical side-effects were also similar across the three groups. Right unilateral and bifrontal ECT placement were associated with improved cognitive outcomes, but bitemporal ECT placement was not.