Neurodevelopmental outcomes after prenatal exposure to lamotrigine monotherapy in women with epilepsy: a systematic review and meta-analysis.

BACKGROUND: Lamotrigine has become one of the most commonly prescribed antiseizure medications (ASM) in epileptic women during pregnancy and therefore requires regular updates regarding its safety. The aim of this study was to estimate the association between in utero exposure to lamotrigine monotherapy and the occurrence of neurodevelopmental outcomes. METHODS: All comparative studies assessing the occurrence of neurodevelopmental outcomes after epilepsy-indicated lamotrigine monotherapy exposure during pregnancy were searched. First, references were identified through a snowballing approach, then, through electronic databases (Medline and Embase) from 2015 to June 2022. One investigator evaluated study eligibility and extracted data and a second independent investigator reviewed the meta-analysis (MA). A systematic review and random-effects model approach were performed using a collaborative WEB-based meta-analysis platform (metaPreg.org) with a registered protocol (osf.io/u4gva). RESULTS: Overall, 18 studies were included. For outcomes reported by at least 4 studies, the pooled odds ratios and 95% confidence interval obtained with the number of exposed (N1) and unexposed children (N0) included were: neurodevelopmental disorders as a whole 0.84 [0.66;1.06] (N1 = 5,271; N0 = 22,230); language disorders or delay 1.16 [0.67;2.00] (N1 = 313; N0 = 506); diagnosis or risk of ASD 0.97 [0.61;1.53] (N1 = at least 5,262; N0 = 33,313); diagnosis or risk of ADHD 1.14 [0.75;1.72] (N1 = at least 113; N0 = 11,530) and psychomotor developmental disorders or delay 2.68 [1.29-5.56] (N1 = 163; N0 = 220). The MA of cognitive outcomes included less than 4 studies and retrieved a significant association for infants exposed to lamotrigine younger than 3 years old but not in the older age groups. CONCLUSION: Prenatal exposure to lamotrigine monotherapy is not found to be statistically associated with neurodevelopmental disorders as a whole, language disorders or delay, diagnosis or risk of ASD and diagnosis or risk of ADHD. However, the MA found an increased risk of psychomotor developmental disorders or delay and cognitive developmental delay in less than 3 years old children. Nevertheless, these findings were based exclusively on observational studies presenting biases and on a limited number of included children. More studies should assess neurodevelopmental outcomes in children prenatally exposed to lamotrigine.

Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial.

We sought to determine whether high-dose folinic acid improves verbal communication in children with non-syndromic autism spectrum disorder (ASD) and language impairment in a double-blind placebo control setting. Forty-eight children (mean age 7 years 4 months; 82% male) with ASD and language impairment were randomized to receive 12 weeks of high-dose folinic acid (2 mg kg-1 per day, maximum 50 mg per day; n=23) or placebo (n=25). Children were subtyped by glutathione and folate receptor-α autoantibody (FRAA) status. Improvement in verbal communication, as measured by a ability-appropriate standardized instrument, was significantly greater in participants receiving folinic acid as compared with those receiving placebo, resulting in an effect of 5.7 (1.0,10.4) standardized points with a medium-to-large effect size (Cohen's d=0.70). FRAA status was predictive of response to treatment. For FRAA-positive participants, improvement in verbal communication was significantly greater in those receiving folinic acid as compared with those receiving placebo, resulting in an effect of 7.3 (1.4,13.2) standardized points with a large effect size (Cohen's d=0.91), indicating that folinic acid treatment may be more efficacious in children with ASD who are FRAA positive. Improvements in subscales of the Vineland Adaptive Behavior Scale, the Aberrant Behavior Checklist, the Autism Symptom Questionnaire and the Behavioral Assessment System for Children were significantly greater in the folinic acid group as compared with the placebo group. There was no significant difference in adverse effects between treatment groups. Thus, in this small trial of children with non-syndromic ASD and language impairment, treatment with high-dose folinic acid for 12 weeks resulted in improvement in verbal communication as compared with placebo, particularly in those participants who were positive for FRAAs.

Resting state perfusion in the language network is linked to formal thought disorder and poor functional outcome in schizophrenia.

OBJECTIVE: Formal thought disorder (FTD) is a core symptom in schizophrenia. Here, we focus on resting state cerebral blood flow (rCBF) linked to dimensions of FTD. METHODS: We included 47 schizophrenia spectrum patients and 30 age- and gender-matched healthy controls. We assessed FTD with the assessment of thought, language, and communication (TLC) and imaging on a 3T MRI scanner. Within patients, we tested the association of FTD dimensions and in a subgroup (n = 27) the association of functional outcome after 6 months with whole brain rCBF. RESULTS: Negative FTD was most prominently associated with perfusion within the superior temporal gyrus, while positive FTD was associated with perfusion within the supplementary motor area, and inferior frontal gyrus. Perfusion within the left supramarginal gyrus was associated with social functioning after 6 months. CONCLUSIONS: Distinguishable associations of rCBF with FTD dimensions point to distinct underlying pathophysiology. The location of aberrant perfusion patterns suggests that negative FTD might reflect defective access to semantic memory while positive FTD likely reflects defective suppression of irrelevant information during increased speech production. Finally, the neural correlates of thought block were also predictive of poor functional outcome. Thus, functional outcome and distinct FTD dimensions may share some pathophysiology.

The treatment of juvenile/adult GM1-gangliosidosis with Miglustat may reverse disease progression.

Juvenile and adult GM1-gangliosidosis are invariably characterized by progressive neurological deterioration. To date only symptomatic therapies are available. We report for the first time the positive results of Miglustat (OGT 918, N-butyl-deoxynojirimycin) treatment on three Italian GM1-gangliosidosis patients. The first two patients had a juvenile form (enzyme activity ≤5%, GLB1 genotype p.R201H/c.1068 + 1G > T; p.R201H/p.I51N), while the third patient had an adult form (enzyme activity about 7%, p.T329A/p.R442Q). Treatment with Miglustat at the dose of 600 mg/day was started at the age of 10, 17 and 28 years; age at last evaluation was 21, 20 and 38 respectively. Response to treatment was evaluated using neurological examinations in all three patients every 4-6 months, the assessment of Movement Disorder-Childhood Rating Scale (MD-CRS) in the second patient, and the 6-Minute Walking Test (6-MWT) in the third patient. The baseline neurological status was severely impaired, with loss of autonomous ambulation and speech in the first two patients, and gait and language difficulties in the third patient. All three patients showed gradual improvement while being treated; both juvenile patients regained the ability to walk without assistance for few meters, and increased alertness and vocalization. The MD-CRS class score in the second patient decreased from 4 to 2. The third patient improved in movement and speech control, the distance covered during the 6-MWT increased from 338 to 475 m. These results suggest that Miglustat may help slow down or reverse the disease progression in juvenile/adult GM1-gangliosidosis.

Piracetam for Aphasia in Post-stroke Patients: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Aphasia is a common symptom in post-stroke patients. Piracetam is a commonly used nootropic agent that promises various benefits to brain function, including language improvement. OBJECTIVE: We performed a systematic review and meta-analysis to assess whether piracetam facilitates the rehabilitation of language performance in post-stroke patients. METHODS: Randomized controlled trials (RCTs) of piracetam treatment in post-stroke patients published in any language were included, excluding those involving pre-existing cognitive disorders such as dementia and mood disturbances. We searched several databases including PubMed, EMBASE, Cochrane Central, CINAHL, Web of Science, and PsycINFO for RCTs published up to 31 December 2015. We conducted a meta-analysis using RevMan (version 5.3), with standardized mean differences (SMDs) and fixed-effect models, and used StataSE (version 13) for the detection of publication bias. This study has been submitted to PROSPERO, and its registration number is CRD42016034088. RESULTS: We identified 1180 titles and abstracts, and finally included seven RCTs in this meta-analysis. The number of participants in each study ranged from 19 to 66, summing up to 261 patients overall. The dose of piracetam was consistent while the frequency and time of therapy varied. The assessment of the language at the end of trials showed no significant improvement in overall severity of aphasia [SMD 0.23, 95 % confidence interval (CI) -0.03 to 0.49, P = 0.08], but written language (SMD 0.35, 95 % CI 0.04 to 0.66, P = 0.03) showed pronounced improvement. Subgroup analyses indicated a dissociation of effectiveness between short- and long-term assessment in overall severity (P = 0.008, I (2) = 85.6 %) in terms of tests for subgroup differences, and a mild trend toward dissociation in written subtests (P = 0.30, I (2) = 5.1 %). Funnel plots and Egger's test identified no obvious publication bias in the primary variable. CONCLUSIONS: Piracetam plays a limited role in the rehabilitation of overall language impairment and only benefits written language ability at the end of trials. Its effect on overall linguistic level and written language tends to emerge within a short period and declines thereafter.

Serum inflammatory mediators correlate with disease activity in electrical status epilepticus in sleep (ESES) syndrome.

We aimed to study serum cytokine levels in 11 electrical status epilepticus in sleep (ESES) patients and 20 healthy control children. Patients showed significantly higher levels of interleukin (IL)-1α, IL-6, IL-10, chemokine (C-C motif) ligand (CCL)2 and chemokine (C-X-C motif) ligand (CXCL)8/IL-8 than controls, while macrophage migration inhibitory factor (MIF) and CCL3 were significantly lower. Follow-up analyses in five patients revealed a significant decrease of IL-6 levels after immunomodulating treatment. IL-6 changes were accompanied by clear improvement of electroencephalography (EEG) patterns and neuropsychological evaluation. We hypothesize that IL-6 correlates with disease activity and immunomodulating treatment efficacy.

Effect of propranolol on word fluency in autism.

OBJECTIVE AND BACKGROUND: Autism is characterized by repetitive behaviors and impaired socialization and communication. Preliminary evidence showed possible language benefits in autism from the ß-adrenergic antagonist propranolol. Earlier studies in other populations suggested propranolol might benefit performance on tasks involving a search of semantic and associative networks under certain conditions. Therefore, we wished to determine whether this benefit of propranolol includes an effect on semantic fluency in autism. METHODS: A sample of 14 high-functioning adolescent and adult participants with autism and 14 matched controls were given letter and category word fluency tasks on 2 separate testing sessions; 1 test was given 60 minutes after the administration of 40 mg propranolol orally, and 1 test was given after placebo, administered in a double-blinded, counterbalanced manner. RESULTS: Participants with autism were significantly impaired compared with controls on both fluency tasks. Propranolol significantly improved performance on category fluency, but not letter fluency among autism participants. No drug effect was observed among controls. Expected drug effects on heart rate and blood pressure were observed in both the groups. CONCLUSIONS: Results are consistent with a selective beneficial effect of propranolol on flexibility of access to semantic and associative networks in autism, with no observed effect on phonological networks. Further study will be necessary to understand potential clinical implications of this finding.

Safety and efficacy of rivastigmine in adolescents with Down syndrome: long-term follow-up.

Following the completion of a 20-week, open-label study of the safety and efficacy of liquid rivastigmine for adolescents with Down syndrome, 5 of the 10 adolescents in the clinical trial continued long-term rivastigmine therapy and 5 did not. After an average period of 38 months, all 10 subjects returned for a follow-up assessment to determine the safety and efficacy of long-term rivastigmine use. Rivastigmine was well tolerated and overall health appeared to be unaffected by long-term rivastigmine use. Performance change on cognitive and language measures administered at the termination of the open-label clinical trial was compared between the two groups. No between-group difference in median performance change across the long-term period was found, suggesting that the long-term use of rivastigmine does not improve cognitive and language performance. However, two subjects demonstrated remarkable improvement in adaptive function over the long-term period. Both subjects had received long-term rivastigmine therapy. The discussion addresses the challenge of assessing cognitive change in clinical trials using adolescents with Down syndrome as subjects and the use of group versus individual data to evaluate the relevance of medication effects.

Autism.

INTRODUCTION: Evidence for the efficacy of treatments for autism has improved in recent years. In this systematic review the evidence for both drug and non-drug treatments is appraised and clinical guidance is provided for their use. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of early intensive multidisciplinary intervention programmes in children with autism? What are the effects of dietary interventions in children with autism? What are the effects of drug treatments in children with autism? What are the effects of non-drug treatments in children with autism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2009 (Clinical evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 30 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: applied behavioural analysis; auditory integration training; Autism Preschool Programme; casein-free diet; chelation; Child's Talk programme; cognitive behavioural therapy; digestive enzymes; EarlyBird programme; facilitated communication; Floortime therapy; gluten-free diet; immunoglobulins; melatonin; memantine; methylphenidate; More Than Words programme; music therapy; olanzapine; omega-3 fish oil; picture exchange communication system; Portage scheme; probiotics; relationship development interventions; risperidone; secretin; selective serotonin reuptake inhibitors (SSRIs); sensory integration training; social stories; social skills training; Son-Rise programme; TEACCH; vitamin A; vitamin B6 (pyridoxine) plus magnesium; and vitamin C.

Treatment effects of Memantine on language in moderate to severe Alzheimer's disease patients.

BACKGROUND: Language impairment is one of the most troublesome manifestations of Alzheimer's disease (AD). The objective of this post hoc analysis was to assess the treatment effects of Memantine on language in patients with moderate to severe AD, using the recently developed Severe Impairment Battery-Language (SIB-L) scale. METHODS: From a combined database including four Memantine clinical trials in moderate-to-severe AD, we analyzed 801 patients with SIB-L scores of <38 and Mini-Mental State Examination scores of <15. Patients were treated with either 20 mg Memantine per day or placebo. Mean changes in SIB-L scores from baseline were calculated. For responder analyses, a change in SIB-L score greater than or equal to the SIB-L measurement error of 3.7 points was considered a clinically relevant response. RESULTS: The mean change from baseline in SIB-L score at week 12 and weeks 24/28 (study end) significantly favored Memantine over placebo treatment (P < .0001 and P = .0182, respectively). Overall, more Memantine-treated patients than placebo-treated patients benefited from treatment. The effect was especially pronounced in patients with substantial language impairment on the SIB-L (baseline score,

Effects of memantine on cognition in patients with moderate to severe Alzheimer's disease: post-hoc analyses of ADAS-cog and SIB total and single-item scores from six randomized, double-blind, placebo-controlled studies.

OBJECTIVES: The post-hoc analyses reported here evaluate the specific effects of memantine treatment on ADAS-cog single-items or SIB subscales for patients with moderate to severe AD. METHODS: Data from six multicentre, randomised, placebo-controlled, parallel-group, double-blind, 6-month studies were used as the basis for these post-hoc analyses. All patients with a Mini-Mental State Examination (MMSE) score of less than 20 were included. Analyses of patients with moderate AD (MMSE: 10-19), evaluated with the Alzheimer's disease Assessment Scale (ADAS-cog) and analyses of patients with moderate to severe AD (MMSE: 3-14), evaluated using the Severe Impairment Battery (SIB), were performed separately. RESULTS: The mean change from baseline showed a significant benefit of memantine treatment on both the ADAS-cog (p < 0.01) and the SIB (p < 0.001) total score at study end. The ADAS-cog single-item analyses showed significant benefits of memantine treatment, compared to placebo, for mean change from baseline for commands (p < 0.001), ideational praxis (p < 0.05), orientation (p < 0.01), comprehension (p < 0.05), and remembering test instructions (p < 0.05) for observed cases (OC). The SIB subscale analyses showed significant benefits of memantine, compared to placebo, for mean change from baseline for language (p < 0.05), memory (p < 0.05), orientation (p < 0.01), praxis (p < 0.001), and visuospatial ability (p < 0.01) for OC. CONCLUSION: Memantine shows significant benefits on overall cognitive abilities as well as on specific key cognitive domains for patients with moderate to severe AD.

Treatment with L-arginine improves neuropsychological disorders in a child with creatine transporter defect.

Creatine transporter deficit (CT1) is an inherited metabolic disorder that causes mental retardation, epilepsy, speech, language and behavioral deficits. Until now, no treatment has been proven to be successful for this condition. We describe 1-year follow-up study of a child, aged 9.6 years, with CT1 defect, on oral supplementation with L-arginine, a precursor of creatine synthesis. Under supplementation, he showed a noticeable improvement of neurological, language and behavioral status and an increase of brain creatine and phosphocreatine documented with magnetic resonance spectroscopy. The results suggest that children with CT1 disorder show some residual adaptive plasticity for certain functions even at quite an advanced age. Further trials with higher L-arginine dosages and more protracted treatment are encouraged.

Word processing in Parkinson's disease is impaired for action verbs but not for concrete nouns.

Recent studies have demonstrated that processing of action words recruits cortical motor regions that are also involved in the planning and execution of the actions words refer to. The functional role of these regions in word understanding remains, however, to be clarified. The present study investigates this issue by examining the impact of Parkinson's disease (PD) on lexical decision performance for action words, relative to concrete nouns, in a masked priming paradigm. Priming effects for the two word categories were measured in non-demented PD patients off and on dopaminergic treatment, and in healthy participants. Our results revealed that although overall performances did not differ between verbs and nouns, priming effects showed a clear dissociation between word categories. While priming for concrete nouns was not affected by Levodopa intake, it dissociated as a function of treatment for action verbs. No priming was actually obtained for action verbs in PD patients off dopaminergic treatment. Following Levodopa intake, this deficit recovered, however, because priming effects for verbs became comparable to those for concrete nouns and similar to performance of healthy participants. Overall, this study thus brings compelling evidence that processing lexico-semantic information about action words depends on the integrity of the motor system.

[Pharmacotherapy of the cognitive sequelae secondary to traumatic brain injury]. / Farmacoterapia de las secuelas cognitivas secundarias a traumatismo craneoencefálico.

AIM: To review and correlate the most common cognitive disorders secondary to traumatic brain injuries (TBI), the neurobiology of these deficits and their possible modulation by neuropharmacological means. DEVELOPMENT: As of a complex cascade of injuries to the brain, patients with TBI may experience alterations that affect the cognitive domain on different levels and to varying degrees, the most common being alteration of the level of alertness; slowing of the speed at which information is processed; attention, memory and learning deficits; language and communication disorders; and impaired executive functions. Brain damage may be caused by a range of pathological mechanisms, such as focal bruising, diffuse axonal damage, cytotoxic damage and neurotransmitter excitotoxicity. Certain pharmacological agents have an effect on the cognitive functions. Pharmacological agents that improve cognitive performance include dopaminergic agents, psychostimulants, some antidepressants and cholinesterase inhibitors. CONCLUSIONS: Studies into the pharmacological neuromodulation of the cognitive disorders secondary to TBI are currently in the early stages. The information we have available on the neurochemical bases of cognition and cognitive disorders due to TBI suggest that the most important goals of pharmacological intervention in this group of patients are the stimulation of the catecholaminic and cholinergic functions.

Cognitive function in relapsing multiple sclerosis: minimal changes in a 10-year clinical trial.

BACKGROUND: Although cognitive impairment is common in patients with multiple sclerosis (MS), its value as a clinical trial endpoint remains uncertain. For example, in the randomized, blinded, pivotal trial of glatiramer acetate (GA) in patients with relapsing MS, improvements occurred in neuropsychological test scores during 2 years of treatment regardless of whether patients received GA or placebo, likely due to practice effects. OBJECTIVES: To assess long-term changes in neuropsychological status following 10 years of prospective evaluation in a typical immunotherapy trial cohort. METHODS: Participants in the ongoing open-label GA extension study repeated the Brief Repeatable Battery of Neuropsychological Tests an average of 10.6+/-0.4 years after their initial baseline evaluation. RESULTS: Mean scores on tests of memory and semantic retrieval were not significantly changed over 10 years of follow-up, but tests of attention showed declines for the group as a whole. Using a threshold of a 0.5 SD decline to define significant worsening, individual tests showed declines in 27-49% of participants and a composite score showed worsening in 19%. Controlling for age, gender, and education level, cognitive tests tended to worsen more in participants with better baseline cognitive test scores and higher EDSS scores. Changes in cognitive test scores during the first 2 years of observation were predictive of 10-year changes. CONCLUSIONS: Most patients with relapsing MS had stable cognitive performance during 10 years of prospective evaluation, some of which may be related to a therapeutic effect of GA. Because cognitive changes occur slowly on average, they may not be responsive enough to serve as useful endpoints in studies of course-modifying therapies in relapsing MS.

Disorders of speech and language: aphasia, apraxia and dysarthria.

PURPOSE OF REVIEW: We review recent important papers pertaining to acquired aphasia, apraxia of speech and dysarthria with special attention to clinically significant work published in the last 12 months. RECENT FINDINGS: The role of the contralateral inferior frontal gyrus in language recovery after stroke is controversial, but is an area of active research, particularly in functional imaging studies. Recent treatment studies in poststroke aphasia have shown that intensity of language therapy may be more important than the method of therapy. Some studies have indicated that amphetamines, piracetam and repetitive transcortical magnetic stimulation may be effective adjuncts to speech and language therapy. Treatment studies for poststroke dysarthria indicate that speech supplementation strategies may be effective and deserve further study. SUMMARY: Recent studies of aphasia provide clues regarding language recovery poststroke, but further studies of the role of the ipsi and contralateral inferior frontal gyrus are necessary, and should be longitudinal. There are relatively few recent studies on the treatment of acquired disorders of speech and language, other than poststroke aphasia.