Background: Neonatal hypoxic ischemic encephalopathy (HIE) is a clinical phenomenon, that often results from pre or perinatal reduced cerebral blood flow and/or hypoxemia. However, in some cases, neonates present with HIE without significant risk factors or have an unusual clinical course. With the advent of advanced genetic testing, we aimed to explore if such infants had genetic risk factors predisposing them to an HIE-phenotype. Methods: We reviewed 206 charts of infants meeting local protocol criteria for moderate to severe HIE at Level III NICU’s in Calgary, Alberta. Of these, 27 patients had genetic testing such as microarray, whole exome sequencing, or gene panels. Results: Six/twenty-seven patients had genetic mutations; two CDKL5 mutations (protein kinase), one CFTR mutation (cystic fibrosis), one PDH deficiency, one CYP21A2 mutation (congenital adrenal hyperplasia), and one ISY1 (VUS; pre-mRNA splicing). Two patients had noted difficult deliveries and four had minor complications, but all were out of keeping with the severity of presumed HIE. Conclusions: This preliminary study demonstrates a possible association between genetic co-morbidities and predisposition towards HIE in the context of a relatively uneventful pre/perinatal course. Earlier identification of genetic etiology, recognized by a discrepancy between risk factors and clinical presentation, could aid in treatment decisions and outcome prognostication.

Background: Tuberous sclerosis complex (TSC) is characterized by growth of benign tumors in the skin, brain, kidneys, lung and heart. Prognosis is mostly determined by the extent of brain involvement as tumors in the brain lead to seizures and cognitive problems. Epilepsy is highly associated with the cognitive abnormalities in TSC and recent evidence suggests anti-epileptic treatment before onset of seizures reduces epilepsy severity and risk of mental retardation. Screening and potential identification of TSC in utero via ultrasound would allow for prophylactic seizure management in these children. The sensitivity of antenatal ultrasound in the identification of brain abnormalities associated with TSC has not yet been published. In this case, we review the antenatal ultrasounds of a child with TSC for evidence of brain abnormalities in utero. Methods: Retrospective review Results: Retrospective review of antenatal ultrasounds showed some evidence of intracranial abnormalities. Ultrasound at 34 weeks and 4 days gestation revealed an echogenic density in the right ventricle that correlates with SEGA on post-natal MRI brain at 12 days of life. Post-natal brain ultrasound at 37 weeks revealed multiple cranial abnormalities not seen in utero. Conclusions: There are limitations to antenatal neurosonography in the detection of intracranial abnormalities associated with TSC.

Background: Acute flaccid myelitis (AFM) is a condition which causes acute paralysis in pediatric patients. Although awareness of AFM is increasing, the pathophysiology and full spectrum of clinical, biochemical, and radiographic features remain to be fully elucidated. Methods: We report a 5 year-old, previously healthy, male patient who presented with acute right upper extremity weakness following a two day history of fever, cough, and fatigue. The patient underwent extensive inflammatory and infectious workup in addition to MRI imaging of the brain, spinal cord, and bilateral brachial plexuses. Results: Infectious and inflammatory workup did not identify a causative agent. The patient was seen to have bilateral asymmetric (R>L) thickening and enhancement of the anterior horn cells of his cervical (C3-C7) spine, consistent with the spinal grey matter lesions previously described in patients with AFM. Enhancement of the corresponding anterior nerve rootlets and bilateral brachial plexuses was also seen. Conclusions: Patients with acute flaccid myelitis may demonstrate grey matter enhancement extending beyond the spinal cord to the peripheral nerves and plexuses, a radiographic finding which has not previously been published.

Background: SMA1 is a rapidly progressing disease resulting in death/permanent ventilation by 2 years. This study compared clinical trial data evaluating the relationship between treatment timing, time to treatment effect, and clinical outcomes in SMA1 patients Methods: A post-hoc indirect treatment comparison was conducted to measure time-to-effect differences in AVXS-101 (CL-101, NCT02122952, cohort 2) vs nusinersen (ENDEAR, NCT02193074) or risdiplam (FIREFISH, NCT02913482) using CHOP-INTEND scores. Results: Compared with nusinersen, AVXS-101 more rapidly increased mean CHOP-INTEND score from baseline (9.8- and 14.9-point increase at 1- and 2-months post-AVXS-101 vs ≤5-point increase at 2-months post-nusinersen). Greater survival benefits and lower rates of permanent ventilatory support were also observed in AVXS-101- vs nusinersen-treated patients. Compared with risdiplam treatment, AVXS-101 improved median CHOP-INTEND scores (14.0-point increase at 2-months post-AVXS-101 vs 5.5-point increase at ~2-months post-risdiplam). Treatment differences were maintained through 8-months with additional improvements at all time-points. Conclusions: Although patients in these 3 cohorts are not entirely matched (e.g. age, disease severity), useful comparisons can still be made. Based on CHOP-INTEND scores, the treatment effect of AVXS-101 appears to be more rapid vs nusinersen or risdiplam. These findings suggest that timely restoration of SMN protein may be essential for maximizing outcomes in SMA1 patients.

Background: SMA1, a rapidly progressing disease, results in muscle weakness, respiratory failure, hospitalization, and early death. This study highlights the value of onasemnogene abeparvovec (AVXS-101) gene-replacement therapy for SMA1. Methods: Twelve SMA1 patients received a one-time intravenous proposed therapeutic dose of AVXS-101 (CL-101; NCT02122952). Event-free survival (no death/permanent ventilation), pulmonary/nutritional interventions, swallow function, hospitalization rates, CHOP-INTEND, motor milestones, and safety were assessed (2-year follow-up). Results: By study end, all 12 patients survived event-free; 7 did not require non-invasive ventilation; 11 had stable/improved swallowing function (6 exclusively fed by mouth); 11 spoke. On average, patients experienced 1.4 (SD=0.41, range=0–4.8) respiratory hospitalizations/year. The mean proportion of time hospitalized was 4.4% (range=0–18.3%); mean unadjusted rate of hospitalization/year was 2.1 (range=0–7.6), with a mean hospital stay of 6.7 (range=3–12.1) days. CHOP-INTEND increased by 9.8 (SD=3.9) and 15.4 (SD=6.4) points at 1- and 3-months post-treatment. At long-term follow-up, 11 patients sat unassisted, 4 stood with assistance, and 2 walked. Adverse events included elevated serum aminotransferase levels, which were attenuated by prednisolone. Conclusions: AVXS-101 in CL-101 resulted in dramatic survival and motor function improvements. The reduced healthcare utilization in treated infants could decrease cost and alleviate patient, caregiver, and societal burden.

Background: In this retrospective claims analysis, real-world healthcare resource use (HRU) and costs among SMA type 1 (SMA1) patients were assessed. Methods: SMA1 patients were identified from Symphony Health’s Integrated Dataverse® (09/01/2016–08/31/2018). The study period spanned from the index date (date of first SMA1 diagnosis after nusinersen approval [12/23/2016]) until death/end of available data. HRU and costs per-patient-per-year (PPPY; 2018USD) were described during the study period for all patients and after treatment initiation for nusinersen-treated patients. Results: A total of 349 SMA1 patients (median age=1 year; 55.6% female) with median follow-up of 7.9 months were included. The proportion of patients receiving mechanical ventilation, nutritional support, and physical therapy/rehabilitation was 46.4%, 46.1%, and 22.6%. Patients had, on average, 59.4 days with medical visits/year (14.1 inpatient, 13.4 respiratory failure-related). The 45 nusinersen-treated patients had, on average, 56.6 days with medical visits/year (4.6 inpatient, 11.4 respiratory failure-related). Excluding nusinersen-related costs, mean healthcare costs PPPY were $137,627 (median: $43,167) for all patients and $92,618 ($29,425) for nusinersen-treated patients. Mean nusinersen-related costs were $191,909 ($144,487) per month for the first 3 months post-initiation and $36,882 ($16,132) per month thereafter. Conclusions: HRU and costs associated with SMA1 are substantial, even among patients treated with nusinersen.

Background: SMA is characterized by reduced levels of survival of motor neuron (SMN) protein from deletions and/or mutations of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2, produces low levels of functional SMN protein. Risdiplam (RG7916/RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates pre-mRNA splicing of SMN2 to increase SMN protein levels. Methods: SUNFISH (NCT02908685) is an ongoing multicenter, double-blind, placebo-controlled, operationally seamless study (randomized 2:1, risdiplam:placebo) in patients aged 2–25 years, with Type 2/3 SMA. Part 1 (n=51) assesses safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. Pivotal Part 2 (n=180) assesses safety and efficacy of the risdiplam dose level selected based on Part 1 results. Results: Part 1 results showed a sustained, >2-fold increase in median SMN protein versus baseline following 1 year of treatment. Adverse events were mostly mild, resolved despite ongoing treatment and reflected underlying disease. No drug-related safety findings have led to withdrawal (data-cut 06/17/18). SUNFISH Part 1 exploratory endpoint results and Part 2 study design will also be presented. Conclusions: To date, no drug-related safety findings have led to withdrawal. Risdiplam led to sustained increases in SMN protein levels.

Background: SMA is characterized by reduced levels of survival of motor neuron (SMN) protein from deletions and/or mutations of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2, produces low levels of functional SMN protein. Risdiplam (RG7916/RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates pre-mRNA splicing of SMN2 to increase SMN protein levels. Methods: FIREFISH (NCT02913482) is an ongoing, multicenter, open-label operationally seamless study of risdiplam in infants aged 1–7 months with Type 1 SMA and two SMN2 gene copies. Exploratory Part 1 (n=21) assesses the safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. Confirmatory Part 2 (n=40) is assessing the safety and efficacy of risdiplam. Results: In a Part 1 interim analysis (data-cut 09/07/18), 93% (13/14) of babies had ≥4-point improvement in CHOP-INTEND total score from baseline at Day 245, with a median change of 16 points. The number of infants meeting HINE-2 motor milestones (baseline to Day 245) increased. To date (data-cut 09/07/18), no drug-related safety findings have led to patient withdrawal. No significant ophthalmological findings have been observed. Conclusions: In FIREFISH Part 1, risdiplam improved motor function in infants with Type 1 SMA.

Background: SMA is a neurodegenerative disease caused by biallelic deletion/mutation of SMN1. Copies of a similar gene (SMN2) modify disease severity. In a phase 1 study, SMN GRT onasemnogene abeparvovec (AVXS-101) improved outcomes of symptomatic SMA patients with two SMN2 copies (2xSMN2) dosed ≤6 months. Because motor neuron loss can be insidious and disease progression is rapid, early intervention is critical. This study evaluates AVXS-101 in presymptomatic SMA newborns. Methods: SPR1NT is a multicenter, open-label, phase 3 study enrolling ≥27 SMA patients with 2–3xSMN2. Asymptomatic infants ≤6 weeks receive a one-time intravenous AVXS-101 infusion (1.1x1014 vg/kg). Safety and efficacy are assessed through study end (18 [2xSMN2] or 24 months [3xSMN2]). Primary outcomes: independent sitting for ≥30 seconds (18 months [2xSMN2]) or assisted standing (24 months [3xSMN2]). Results: From April–September 2018, 7 infants received AVXS-101 (4 female; 6 with 2xSMN2) at ages 8–37 days. Mean baseline CHOP-INTEND score was 41.7 (n=6), which increased by 6.8, 11.0, 18.0, and 22.5 points at day 14 (n=4), month 1 (n=3), 2 (n=3), and 3 (n=2). Updated data available at the time of the congress will be presented. Conclusions: Preliminary data from SPR1NT show rapid motor function improvements in presymptomatic SMA patients.

Background: SMA is a neurodegenerative disease caused by biallelic deletion/mutation of the survival motor neuron (SMN1) gene. In the phase 1 trial (NCT02122952), SMN GRT onasemnogene abeparvovec (AVXS-101) improved outcomes of 15 symptomatic SMA1 patients (3 at a lower dose [cohort 1] and 12 at the proposed therapeutic dose [cohort 2]). This report describes long-term follow-up study design and data from the phase 1 study. Methods: Patients in the phase 1 study could rollover into a long-term follow-up study (NCT03421977). The primary objective is to collect long-term safety data (serious adverse events, hospitalizations, and adverse events of special interest). Annual follow-up will occur for 15 years. Additionally, patient record transfers from local clinician(s) will be requested. Safety assessments include medical history and record review, physical examination, clinical laboratory evaluation, and pulmonary assessments. Efficacy assessments include physical examination to assess developmental milestones. Results: As of September 27, 2018, the oldest patients are 59.2 (cohort 1) and 52.1 (cohort 2) months old and free of permanent ventilation. Preliminary data, including survival and developmental milestones, will be presented. Conclusions: Patients treated with a one-time dose of AVXS-101 continue to gain strength, develop, and achieve new milestones, demonstrating a long-term, durable response.

Background: To attain the most comprehensive view of the quality of life (QoL) of a child with Duchenne Muscular Dystrophy (DMD), the completion of a pediatric QoL measure by the child and his/her parent and the assessment of QoL and health-related quality of life (HRQoL) as separate constructs is crucial. Previous QoL research has not assessed HRQoL as a separate construct. By using the Quality of My Life (QoML) questionnaire, our objective was to describe QoL and HRQoL in boys with DMD based on child-and parent-reports. Methods: Parent and child dyads identified via the Canadian Neuromuscular Disease Registry received QoML questionnaires (2013-2016). Children and parent-proxy each completed the QoL and HRQoL Visual Analog Scales. Responses were marked on a 10-cm line, with higher scores (max=10) reflecting higher QoL and HRQoL. Descriptive statistics were computed for child- and parent-reports of QoL and HRQoL at three time-points. Results: Mean(SD) QoL and HRQoL scores for child- and parent-reports were: 1) Baseline (n=20 dyads), 8.32(1.72) vs. 6.73(2.23) and 7.63(2.51) vs. 6.73(2.19); 2)18-months (n=10 dyads, n=9 dyads), 7.83(2.05) vs 7.66(1.66) and 7.62(2.41) vs 7.41(2.16); 3) 36-months (n=15 dyads) 7.38(2.00) vs. 6.99(1.77) and 7.19(2.70) vs. 6.76(2.26). Conclusions: Boys with DMD report higher QoL and HRQoL compared to their parents.

Background: Spinal muscular atrophy (SMA) is a children’s neuromuscular disorder. Although motor neuron loss is a major feature of the disease, we have identified fatty acid abnormalities in SMA patients and in preclinical animal models, suggesting metabolic perturbation is also an important component of SMA. Methods: Biochemical, histological, proteomic, and high resolution respirometry were used. Results: SMA patients are more susceptible to dyslipidemia than the average population as determined by a standard lipid profile in a cohort of 72 pediatric patients. As well, we observed a non-alcoholic liver disease phenotype in apreclinical mouse model. Denervation alone was not sufficient to induce liver steatosis, as a mouse model of ALS, did not develop fatty liver. Hyperglucagonemia in Smn2B/-mice could explain the hepatic steatosis by increasing plasma substrate availability via glycogen depletion and peripheral lipolysis. Proteomic analysis identified mitochondrion and lipid metabolism as major clusters. Alterations in mitochondrial function were revealed by high-resolution respirometry. Finally, low-fat diets led to increased survival in Smn2B/-mice. Conclusions: These results provide strong evidence for lipid metabolism defects in SMA. Further investigation will be required to establish the primary mechanism of these alterations and understand how they lead to additional co-morbidities in SMA patients.

Background: In 2013, the University of Calgary (UofC) - Mbarara University of Science and Technology (MUST) Pediatric Education Program was established when the Pediatric Department in Mbarara, Uganda identified a need for enhanced education in pediatric subspecialty areas. We report on the experience of developing the pediatric neurology subspecialty curriculum. Methods: Pre-visit meetings established mutually agreed upon objectives and learning activities that were implemented over 2-week periods in 2015 and 2018. Pre and post-tests were administered to MUST Pediatric residents. Mean differences in test scores were compared using a Student t-test. Residents provided written feedback following the end of the second visit. Results: A pediatric neurologist (AM) visited MUST (2015 and 2018) to deliver the curriculum. The second visit was accompanied by a senior UofC Pediatrics resident (LD). Eight and 14 residents at MUST participated in the curriculum in 2015 and 2018, respectively. Neurology test scores improved in 2015 from a mean of 43% to 61% (p = 0.011) and in 2018 from 53% to 84% (p < 0.00001). Teaching sessions were well received by MUST residents. Conclusions: Collaboration between UofC faculty and MUST established an effective pediatric neurology curriculum that was well-received by residents.

Background: Stroke is a rare neurological disease in children, with an annual incidence of 2 - 13/100,000 children per year. Pediatric stroke is associated with significant morbidity and mortality lasting many decades. Diagnosis of pediatric stroke is challenging and often delayed, limiting options for acute intervention, and the pharmacological and mechanical recanalization strategies that have revolutionized adult stroke remain undefined in children. Clinicians are left to draw conclusions from other retrospective cohort studies or case reports and extrapolate adult guidelines to the pediatric population. The TIPS trial eligibility criteria are often used in clinical practice, despite not being validated for this purpose. We present here the case of a healthy 14 year old male who was treated with intravenous tissue plasminogen activator (IV tPA) for a presumed arterial ischemic stroke without large vessel occlusion on neuroimaging. Methods: Retrospective chart review Results: Not applicable Conclusions: Following the administration of IV tPA, the patient made a full recovery. While we do not recommend the routine use of IV tPA for treatment of presumed large vessel or small vessel in children, we suggest that the decision to proceed with IV tPA be considered on a case-by-case basis.

Background: Genetically-determined leukoencephalopathies comprise a rare group of inherited white matter disorders. The vast majority are associated with a progressive disease course and early death. This study seeks to determine the clinical and demographic correlates of stress in parents of leukodystrophy patients, for future clinical guidance. Methods: A cross-sectional study including 36 families was performed. Children aged 1 month to 12 years with a diagnosed leukodystrophy or genetically-determined leukoencephalopathy were included. 31 mothers and 24 fathers completed the Parental Stress Index, 4th edition (PSI-4). One demographic questionnaire was completed per family. Clinical data was gathered within 6 months of the questionnaires. Statistical analysis was performed with total stress (TS) scores as the primary outcome. Results: Mothers and fathers had comparable TS scores. No clinical or demographic factors predicted the father’s TS score. Greater ambulatory impairment, using the GMFCS scale, correlated to lower TS scores in the mother. Conclusions: The progressive nature of these conditions makes it such that anticipating a child’s inability to walk may cause more stress for mothers than a child’s actual inability to ambulate. The inability of all other variables to predict total stress highlights a need for individualized approaches when addressing stress in these families.

Background: Fetal alcohol spectrum disorder (FASD) is used to describe the spectrum of birth defects due to prenatal alcohol exposure; these include craniofacial abnormalities and intellectual disabilities. The prevalence of FASD is estimated at 1 in 100. Diagnostic criteria include distinct facial features, neurodevelopmental deficits and confirmation of alcohol use during pregnancy. Unfortunately, often criteria are missed or absent. No biochemical marker is available for screening and diagnosis of FASD that is easy, accurate and cost-effective. Methods: Five children are being recruited from both the FASD clinic at the Glenrose Rehabilitation Hospital and the Healthy Infants and Children’s Clinical Research Program (HICUPP) registry. The levels of exhaled nasal NO will be measured and compared between the two groups. Metabolomics analysis on urine samples targeting metabolites of the NO pathway, along with other urinary metabolites is being performed. Bioinformatic statistical tools will be applied to determine whether measured metabolite profiles can provide distinct signatures between healthy children and children with FASD. Results: This project is ongoing. Conclusions: We hope to correlate NO levels with FASD, illustrating the relationship between NO, ciliopathies and development of FASD. As well, we hope to determine whether urinary metabolites may yield diagnostic markers of FASD.

Background: Pediatric neurology referral wait times are increasing, often leading to emergency department (ED) utilization. On average 5% of ED patients present with neurological symptoms and 35% of ED neurological diagnoses are revised after specialist review. A Stollery Rapid Access Neurology (RAN) clinic was created to decrease wait time, and initiate an efficient referral process. Methods: The RAN clinic ran weekly from March 2018 until February 2019. This was a prospective study approved by the University of Alberta ethics board. Inclusion criteria were met. Information was collected for diagnosis, along with confidential patient satisfaction surveys. Results: Seventy-five patients were referred, 49% from the ED. Wait time averaged 6 weeks. The most frequent referral reason was seizures, with 60% of referring diagnosis being correct. Prior to RAN appointment, 61% of patients presented to the ED, whereas only 0.1% returned in the following 3 months. Neurology follow up was required in 81% of patients. Overall satisfaction was ranked 9.6/10. Conclusions: The RAN clinic created an effective urgent triage method. Neurologist review revised 40% of diagnoses. This ongoing study reveals that a RAN clinic can reduce visits to the ED following appointment and initiate appropriate follow up. Future evaluation in cost effectiveness and telehealth appointments are required.

Background: Idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, is an increase in intracranial pressure due to unknown etiology. Presentation in infancy is extremely rare. Little is known about infantile IIH and age-specific treatment guidelines are lacking. Methods: Patient data was obtained from medical records at the Children’s Hospital of Eastern Ontario. A literature review of infantile IIH was performed. Results: A previously healthy 9-month-old boy presented with irritability, decreased appetite, and a bulging fontanelle. CT head imaging and cerebrospinal fluid studies revealed normal results. Symptoms transiently resolved after a lumbar puncture, but 11 days later, his fontanelle bulged again. A second lumbar puncture revealed an elevated opening pressure of 35 cm H2O and led to a diagnosis of IIH in accordance with the modified Dandy Criteria. Treatment with acetazolamide at a dose of 25 mg/kg/day was initiated and the patient remained symptom-free for 6 weeks, followed by another relapse. His acetazolamide was increased to 38 mg/kg/day, with no further relapses to date. Conclusions: A diagnosis of IIH is challenging in infants, since the patients cannot yet verbalize typical IIH-related symptoms, and papilledema is difficult to assess. If undetected and untreated, IIH may result in permanent visual deficits.

Background: Biallelic variants in POLR1C are associated with POLR3-related leukodystrophy (POLR3-HLD), or 4H leukodystrophy (Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism), and Treacher Collins syndrome (TCS). The clinical spectrum of POLR3-HLD caused by variants in this gene has not been described. Methods: A cross-sectional observational study involving 25 centers worldwide was conducted between 2016 and 2018. The clinical, radiologic and molecular features of 23 unreported and previously reported cases of POLR3-HLD caused by POLR1C variants were reviewed. Results: Most participants presented between birth and age 6 years with motor difficulties. Neurological deterioration was seen during childhood, suggesting a more severe phenotype than previously described. The dental, ocular and endocrine features often seen in POLR3-HLD were not invariably present. Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including one individual with clear TCS features. Several cases did not exhibit all the typical radiologic characteristics of POLR3-HLD. A total of 29 different pathogenic variants in POLR1C were identified, including 13 new disease-causing variants. Conclusions: Based on the largest cohort of patients to date, these results suggest novel characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.

Background: Down syndrome (DS) is the most common genetic cause of intellectual disability.Although progress in managing co-morbidities has improved life expectancy, no therapeutic options have showed to significantly improve intellectual deficiencies.The current focus of the pharmacological treatment of DS is on the improvement of the cognitive impairment that is probably due to neurodevelopmental alterations,neurotransmitter alterations and neurodegeneration,and is also targeted to the overexpression of selected genes on HSA21. Methods: We review the clinical trials of the last 5 years focusing on the cognitive improvement of children with DS. Results: We report the results of therapeutic trials concerning selective negative allosteric regulators of the GABAAa5 receptor, NMDA antagonists, Kinase inhibitors of DYRK1A, folinic acid and thyroid hormone supplementation, activators of serotonergic and cholinergic system. Conclusions: The incomplete understanding of individual phenotypic variability, natural history, lack of biomarkers, no adapted neuropsychological tests, placebo effect, epigenetic effect have limited our capacity to succeed, even when promising drugs are tested.We need new tools and models will allow a better understanding of the pathophysiology. We also need to create more sensitive and realistic outcome mesures to quantify disease and therapeutic efficacy. The association of different therapeutic agents (epidrugs included) with cognitive stimulation could be a future strategy.