Oral Levetiracetam Research Articles

Safety, tolerability, and efficacy outcomes of the Investigation of Levetiracetam in Alzheimer's disease (ILiAD)study: a pilot, double-blind placebo-controlled crossover trial.

To assess whether the antiseizure medication levetiracetam may improve cognition in individuals with Alzheimer's disease who have not previously experienced a seizure. We performed a randomized, double-blind, placebo-controlled crossover pilot study in individuals with mild-to-moderate Alzheimer's disease. Electroencephalography was performed at baseline and those with active epileptiform discharges were excluded. Eligible participants were randomized to placebo for 12 weeks or an active arm of oral levetiracetam (4 weeks up-titration to levetiracetam 500 mg twice daily, 4 weeks maintained on this dose followed by 4 weeks down-titration to nil). Participants then crossed over to the other arm. The primary outcome was change in cognitive function assessed by the Oxford Memory Task, a task sensitive to hippocampal memory binding. Secondary outcomes included tolerability, other neuropsychological scales, and general questionnaires. Recruitment numbers were severely limited owing to restrictions from the COVID-19 pandemic at the time of the study. Eight participants completed both arms of the study (mean age 68.4 years [SD = 9.2]; 5 females [62.5%]). No participants withdrew from the study and there was no significant difference between reported side effects in the active levetiracetam or placebo arm. Measures of mood and quality of life were also not significantly different between the two arms based on participant or carer reports. In limited data analysis, there was no statistically significant difference between participants in the active levetiracetam and placebo arm on the memory task. This pilot study demonstrates that levetiracetam was well tolerated in individuals with Alzheimer's disease who do not have a history of seizures and has no detrimental effect on mood or quality of life. Larger studies are needed to assess whether levetiracetam may have a positive effect on cognitive function in subsets of individuals with Alzheimer's disease. Abnormal electrical activity within the brain, such as is seen in seizures, might contribute to memory problems in people with dementia. We completed a clinical trial to see if an antiseizure medication, levetiracetam, could help with memory difficulties in people with Alzheimer's disease (the most common cause of dementia). In this pilot study, we could not prove whether levetiracetam helped memory function. We did show that the drug is safe and well tolerated in people with dementia who have not had a seizure. This work, therefore, offers a platform for future research exploring antiseizure medications in people with dementia.

Dyke-Davidoff-Masson syndrome – A dainty spectrum with a diligent diagnosis

ABSTRACT Dyke-Davidoff-Masson syndrome is a rare condition of unknown frequency resulting from brain injury, especially in early life, due to a multitude of causes. We present the case of a 2-year-old, developmentally normal female who presented with one episode of unprovoked generalized tonic-clonic seizures. This child had a history of complex febrile seizures at 1.5 years of age and was started on levetiracetam (20 mg/kg/day). During the current evaluation, a magnetic resonance imaging (MRI) brain showed left hemi cerebral atrophy. The literature review revealed that these findings are consistent with Dyke-Davidoff-Masson syndrome. The child was discharged with oral levetiracetam (30 mg/kg/day) and counseling from parents regarding the need for long-term treatment and follow-up. Due to its rarity, Dyke-Davidoff-Masson syndrome may easily be missed by the treating physician. Knowledge of its radio-imaging features enables timely and accurate diagnosis, allowing appropriate management.

Successful use of intravenous and oral levetiracetam in a goat to control refractory seizures secondary to suspected polioencephalomalacia.

To assess the clinical efficacy and plasma concentrations of levetiracetam in a goat with seizures. A 5-month-old doeling. The goat was referred because of progressive anorexia and lethargy over 3 days. Clinical signs consisted of weakness, obtundation, opisthotonos, anisocoria, and cortical blindness. Initial evaluation was most consistent with polioencephalomalacia. Neurologic improvement occurred within 4 hours of thiamine administration, with appetite returning over 12 hours. On day 3 of hospitalization, the goat suffered acute onset repetitive seizures that were incompletely responsive to standard interventions over 3 hours. Administration of IV levetiracetam (60 mg/kg) produced resolution of seizure activity within 20 minutes. Levetiracetam was continued twice daily IV, then PO after day 6. Plasma concentrations were above or within therapeutic ranges (5 to 45 μg/mL) as previously established for other species, following both IV and PO levetiracetam. Oral administration (60 mg/kg, PO, q 12 h) resulted in plasma levetiracetam concentrations of 48.1 μg/mL 2 hours after a dose and 23.4 μg/mL 2 hours prior to the next dose. Levetiracetam is a newer anticonvulsant commonly used in humans and small animals due to its efficacy, cost, and wide safety margin. Its use has not previously been reported in domestic small ruminants. In this case, levetiracetam showed excellent clinical efficacy in the face of refractory seizures, with no apparent side effects. Plasma concentrations during oral administration were at the high end of the therapeutic range, indicating absorption in a nonmonogastric species. Further studies are warranted to determine optimal dosing in small ruminants.

Investigating Hematological and Renal Effects of Levetiracetam Versus Lamotrigine in Children With Epilepsy: A Randomized Clinical Trial

Objectives: Alterations in hematological and renal parameters have been reported with antiepileptic drugs. This study evaluates the effects of lamotrigine (LTG) and levetiracetam (LEV) on these parameters in children with epilepsy. Methods: This randomized clinical trial included children with a first-time diagnosis of epilepsy referred to Bandar Abbas Children’s Hospital, Bandar Abbas, Iran, from 2017 to 2018. The participants’ age, gender, and family history of epilepsy were recorded. The patients in the LTG group received 0.6 mg/kg oral LTG in two divided doses for two weeks which continued with 1.2 mg/kg for another two weeks and then with a maintenance dose of 5-15 mg/kg daily. The patients in the LEV group received 10 mg/kg oral LEV twice a day. When necessary, the dosage is increased to a maximum of 30 mg/kg twice a day. The treatment continued until seizures were controlled. Hematological and renal parameters were measured at baseline and 3 months after treatment. The total duration of treatment with each drug was also noted. Results: From the 66 children evaluated in this study with a mean age of 8.51±2.11 years, 31 (47%) were male. Age, gender, family history of epilepsy, treatment duration, and baseline hematological and renal parameters did not differ between the LTG group (n=26) and the LEV group (n=40). The patients in both groups were comparable in terms of all the parameters after treatment. Also, no significant change was observed after treatment compared to baseline in either group. Discussion: LTG and LEV have no significant effect on the hematological and renal parameters of children with epilepsy.

Isolation of Salmonella enterica Serovar Typhi from Infected Intracranial Dermoid Cyst: A Case Report

Salmonella Typhi is a versatile pathogen that can infect almost all organs of its host. There has been an increase in the number of cases of extraintestinal infection caused by Salmonella species during the past decade. Present case is of a 17-year-old immunocompetent female admitted to the hospital with complaints of a general tonic-clonic seizure and diagnosed with a Suprasellar hypodense lesion with Hydrocephalus (HCP) documented on a Computed Tomography (CT) scan of the head. Magnetic Resonance Imaging (MRI) revealed signs of an intracranial dermoid cyst. Placement of a right Ventriculoperitoneal (VP) Shunt was performed, followed by a right craniotomy with decompression, during which 5 mL of pus was collected from the lesion. The pus was received in the Department of Microbiology and subjected to culture, which grew Salmonella enterica serovar Typhi. The patient had been empirically receiving injection cefoperazone-sulbactam 2g/2g twice daily and injection vancomycin 1g 12 hourly before the isolation of Salmonella Typhi. She had also been receiving injection levetiracetam 500 mg i.v. twice a day and inj. phenytoin 500 mg i.v. thrice a day. Following the positive culture report, injection ceftriaxone 2 g daily was started. The patient was discharged on the fifth postoperative day while on injection ceftriaxone, oral levetiracetam 500 mg, and phenytoin 100 mg and was asked to report to the neurosurgery department after seven days for follow-up. On follow-up, she showed improvement, and there were no complaints of fever, seizure, or loss of consciousness. In conclusion, proper clinical, radiological, and microbiological evaluation is very much necessary, and clinicians should be aware of the relatively rare manifestations of Salmonella Typhi infections.

Rare Coexistence of SLC6A9 and TOR1A Gene Mutations in a Neonate Presenting with Hereditary Hyperekplexia and Arthrogryposis Multiplex Congenita

Background: Neonatal hyperekplexia is a rare nonepileptiform disorder characterized by an exaggerated startle reflex associated with generalized hypertonia. We report a newborn with mutation in the glycinergic inhibition pathway resulting in hyperekplexia, associated with features of arthrogryposis multiplex congenita. Clinical Description: A 3-day-old newborn born at term vaginally cried immediately after birth and presented with lethargy, poor cry, and abnormal clonic movements of all four limbs. On examination, there was hyperreflexia and hypertonia in all four limbs along with dislocation of the right knee joint. Blood investigations, including tandem mass spectrometry, serum ammonia, serum, and cerebrospinal fluid glycine levels, were normal, ruling out inborn errors of metabolism responsible for hyperekplexia and arthrogryposis. The magnetic resonance imaging (MRI) brain and electroencephalogram were normal, while the MRI spine showed kyphosis. The genetic evaluation showed heterozygous missense mutation in exon 6 of the SLC6A9 gene and homozygous mutation in the TOR1A gene, which explained the hyperekplexia and the arthrogryposis multiplex congenita. Management and Outcome: The patient received supportive care. Oral clonazepam and levetiracetam were started in view of hypertonia and clonic spasms. Feeding was given by intragastric tube as he had poor suck–swallow coordination. Conclusions: This case highlights an interesting and extremely rare combination of hereditary hyperekplexia and arthrogryposis multiplex congenita existing together in the same patient, confirmed by the corroborating genetic mutations. Awareness of such conditions among pediatricians is essential to order appropriate genetic evaluations and treatment accordingly.

Comparison of Efficacy and Safety of Levetiracetam Versus Phenytoin for Post-craniotomy Seizure Prophylaxis.

Background: Superiority of levetiracetam over phenytoin for postcraniotomy seizure prophylaxis in patients with a supratentorial brain tumor is controversial. We aimed to evaluate the efficacy of levetiracetam versus phenytoin for postcraniotomy seizure prophylaxis in supratentorial brain tumor. Methods: In a randomized controlled trial study, 80 patients with a supratentorial brain tumor who underwent craniotomy were allocated to levetiracetam or phenytoin group, 40 patients each. Seizure prophylaxis was started 5 days before the surgery and continued until 90 days after surgery. Phenytoin group received 100 mg oral phenytoin 3 times a day. The levetiracetam group received 500 mg oral levetiracetam 2 times a day. The primary outcome was the incidence of postcraniotomy seizures. The secondary outcome measure was the safety profile of the drugs. Results: All patients of the phenytoin group and 39 patients of levetiracetam completed the study. Two seizures developed in the study population, 1 in the phenytoin group (2.5%) and 1 in the levetiracetam group (2.6%) (P = 0.710). Renal or hepatic dysfunction was not observed in any patients. Wound hematoma was seen in 5 patients (12.5%) of the phenytoin and 6 patients (15.4%) of the levetiracetam group (P = 0.481). Skin rash developed in 3 patients (7.5%) of the phenytoin group and no patient of the levetiracetam group (P = 0.132). Thrombocytopenia was detected in 1 patient of the phenytoin group (2.5%) and no patient of the levetiracetam group (P = 0.511). None of the adverse events led to drug withdrawal. Conclusion: These results reveal no superiority of levetiracetam over phenytoin for postcraniotomy seizure prophylaxis in supratentorial brain tumor.

A case of glossopharyngeal neuralgia successfully treated with levetiracetam

BackgroundGlossopharyngeal neuralgia is a condition that causes severe pain in the throat during swallowing. Although carbamazepine is a viable option for treating glossopharyngeal neuralgia, there are minimal data regarding the effect of alternative agents to treat it. We report on glossopharyngeal neuralgia, which is successfully controlled by levetiracetam.PresentationA woman in her 70s checked into our hospital with a chief complaint of neck pain lasting 5 years. She had a history of carbamazepine-induced interstitial pneumonia. As a result, we prescribed oral levetiracetam 1000 mg daily in addition to mirogabalin, which was previously prescribed. This effectively reduced the numerical rating scale from 9 to 1 with no adverse effects. Finally, she underwent microvascular decompression, and her symptoms were resolved.ConclusionLevetiracetam may be an option for patients with glossopharyngeal neuralgia who cannot receive carbamazepine. However, levetiracetam is for off-label use according to the Japanese medical system.

Preemptive Levetiracetam Decreases Postoperative Pain: A Double-Blind, Randomised, Control Trial.

Background Previously many studies have found the use of anti-epileptic drugs such as pregabalin, carbamazepine, and gabapentin in pain management. In addition, levetiracetam (LEV), an effective anti-epileptic drug, has shown analgesic effects in animal models. We aimed to evaluate the effect of oral LEV as pre-emptive analgesia in patients who underwent laparoscopic cholecystectomy under general anaesthesia and postoperative fentanyl requirements. Material and methods Forty-two patients of the American Society of Anaesthesiologists (ASA) grade I and II of either gender posted for elective laparoscopic cholecystectomy surgery were included in this double-blind, randomised, placebo-controlled study. Patients were divided into two equal groups of 21 each to receive either tablet LEV 500 mg or a matching placebo tablet, given 1 hour before surgery. Postoperative pain was assessed by a visual analogue scale (0-100 mm), where 0 meant no pain and 100, worst pain. In addition, patients received IV fentanyl as rescue analgesia during the first 24 hours of the postoperative period. Results Nineteen patients in the LEV group and 20 in the placebo group completed the study. Patients in the LEV group had significantly lower pain scores at all time intervals except 0 hours and reduced fentanyl consumption postoperatively in the first 24 hours (p<0.05). Side effects were comparable in both groups. Conclusion A single, preoperative dose of oral LEV 500 mg significantly decreases post-surgical pain and fentanyl demand as rescue analgesia in elective laparoscopic cholecystectomy.

Case Report and Review: An Unusual Case of Fetal Traumatic Brain Injury

We herein report an unusual case of maternal road traffic accident with blunt trauma to the abdomen at 34 weeks of gestation followed by delivery of severely encephalopathic baby and also a brief review of similar previous reports.The baby had near normal transition, then progressively developed severe encephalopathy and multiple organ dysfunction attributed mainly to the intrauterine traumatic injury. The baby had multiple intra and extra axial bleeds,cerebral edema and diffuse axonal injury, as revealed by the CT scan. The baby was managed conservatively with various neuroprotective strategies similar to management in older children and thus cerebral edema/ hematomas subsided. The baby required ventilatory support, prolonged assisted ventilation/oxygen and the metabolic derangements were managed accordingly. The baby was discharged on oral Levetiracetam, multivitamins and nasogastric tube feeds. Baby was followed up sequentially till day 74 and on physical examination had poor head growth and increased muscle tone of the extremities. Neuroimaging revealed diffuse multicystic leukoencephalomalacia, hydrocephalus ex vacuo with cortical thinning. Intrauterine fetal brain injury is an uncommon incidence which causes mortality and significant morbidity in the child. Neuroimaging of the fetus after trauma to the mother can lead to early diagnosis and anticipation. Early vigorous neuroprotective measures and management may prevent mortality and reduce further brain insult in theseneonates. There is paucity of information on management of such cases thus they should be reported in detail forstudy and future references.

Efficacy and Safety of Levetiracetam in Refractory Seizures in Children

Objective: To assess efficacy and safety of Levetiracetam (LEV) as add-on therapy in children with refractory seizure. Methodology: This prospective observational cohort study was conducted in the Outpatient Department of Paediatric Neurology, “The Children’s Hospital &amp; Institute of Child Health, Multan”, Pakistan from 15th January 2020 to 14th January 2021. Fifty children of aged 2 months to 14 years of both genders with refractory epilepsy were enrolled and received oral LEV. Data on LEV efficacy and side effects were recorded. The medication was considered as “effective” when all seizures had ceased within 3 months, “partially effective” when seizure frequency was decreased by ≥50% and “ineffective” when seizure frequency was decreased by &lt; 50%.or seizure frequency remain unchanged during a period of 3 month. Results: Out of a total of 50 participants, there were 35 (70.0%) male. Mean age was 4.81±3.79 years while mean age at onset of seizures was 2.51±2.85 years. Most frequent type of seizures was generalized tonic clonic seizures in 19 (38.0%) patients followed by focal clonic seizures in 13 (26.0%) patients. Levetiracetam was effective in 14 (28%) patients, partially effective in 24 (48.0%) and not effective in 12 (24.0%) patients. Conclusion: Levetiracetam as add-on therapy reduced the seizure frequency in 76% of the participants without any significant side effects. Keywords: Levetiracetam, refractory seizure, epilepsy, add-on therapy, efficacy.

Duration of Prophylactic Levetiracetam After Surgery for Brain Tumor: A Prospective Randomized Trial.

Levetiracetam is commonly used as a prophylactic antiseizure medication in patients undergoing surgical resection of brain tumors. To quantitate side effects experienced in patients treated with 1 week vs 6 weeks of prophylactic levetiracetam using validated measures for neurotoxicity and depression. Patients undergoing surgical resection of a supratentorial tumor with no seizure history were randomized within 48 hours of surgery to receive prophylactic levetiracetam for the duration of either 1 or 6 weeks. Patients were given oral levetiracetam extended release 1000 mg during the first part of this study. Owing to drug backorder, patients enrolled later in this study received levetiracetam 500 mg BID. The primary outcome was the change in the neurotoxicity score 6 weeks after drug initiation. The secondary outcome was seizure incidence. A total of 81 patients were enrolled and randomized to 1 week (40 patients) or 6 weeks (41 patients) of prophylactic levetiracetam treatment. The neurotoxicity score slightly improved in the overall cohort between baseline and reassessment. There was no significant difference between groups in neurotoxicity or depression scores. Seizure incidence was low in the entire cohort of patients with 1 patient in each arm experiencing a seizure during the follow-up period. The use of prophylactic levetiracetam did not result in significant neurotoxicity or depression when given for either 1 week or 6 weeks. The incidence of seizure after craniotomy for tumor resection is low regardless of duration of therapy.

Levetiracetam in Alzheimer's Disease: Do Epileptologists Already Have the Cure?

Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity: A Randomized Clinical Trial Vossel K, Ranasinghe KG, Beagle AJ, et al. JAMA Neurol. 2021;78(11):1345-1354. doi:10.1001/jamaneurol.2021.3310.Importance:Network hyperexcitability may contribute to cognitive dysfunction in patients with Alzheimer disease (AD).Objective:To determine the ability of the antiseizure drug levetiracetam to improve cognition in persons with AD.Design, setting, and participants:The Levetiracetam for Alzheimer’s Disease–Associated Network Hyperexcitability (LEV-AD) study was a phase 2a randomized double-blinded placebo-controlled crossover clinical trial of 34 adults with AD that was conducted at the University of California, San Francisco, and the University of Minnesota, Twin Cities, between October 16, 2014, and July 21, 2020. Participants were adults 80 years and younger who had a Mini Mental State Examination score of 18 points or higher and/or a Clinical Dementia Rating score of less than 2 points. Screening included overnight video electroencephalography and a 1-hour resting magnetoencephalography examination.Interventions:Group A received placebo twice daily for 4 weeks followed by a 4-week washout period, then oral levetiracetam, 125 mg, twice daily for 4 weeks. Group B received treatment using the reverse sequence.Main outcomes and measures:The primary outcome was the ability of levetiracetam treatment to improve executive function (measured by the National Institutes of Health Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research [NIH-EXAMINER] composite score). Secondary outcomes were cognition (measured by the Stroop Color and Word Test [Stroop] interference naming subscale and the Alzheimer’s Disease Assessment Scale—Cognitive Subscale) and disability. Exploratory outcomes included performance on a virtual route learning test and scores on cognitive and functional tests among participants with epileptiform activity.Results:Of 54 adults assessed for eligibility, 11 did not meet study criteria, and 9 declined to participate. A total of 34 adults (21 women [61.8%]; mean [SD] age, 62.3 [7.7] years) with AD were enrolled and randomized (17 participants to group A and 17 participants to group B). Thirteen participants (38.2%) were categorized as having epileptiform activity. In total, 28 participants (82.4%) completed the study, 10 of whom (35.7%) had epileptiform activity. Overall, treatment with levetiracetam did not change NIH-EXAMINER composite scores (mean difference vs placebo, .07 points; 95% CI, −.18 to .32 points; P = .55) or secondary measures. However, among participants with epileptiform activity, levetiracetam treatment improved performance on the Stroop interference naming subscale (net improvement vs placebo, 7.4 points; 95% CI, .2–14.7 points; P = .046) and the virtual route learning test (t = 2.36; Cohen f2 = .11; P = .02). There were no treatment discontinuations because of adverse events.Conclusions and relevance:In this randomized clinical trial, levetiracetam was well tolerated and, although it did not improve the primary outcome, in prespecified analysis, levetiracetam improved performance on spatial memory and executive function tasks in patients with AD and epileptiform activity. These exploratory findings warrant further assessment of antiseizure approaches in AD.

Hematological and Renal Effects of Levetiracetam Versus Lamotrigine in Children With Epilepsy: A Randomized Clinical Trial

Background: Alterations in hematological and renal parameters have been reported with antiepileptic drugs (AEDs). This study aimed to evaluate the effects of lamotrigine (LTG) and levetiracetam (LEV) on these parameters in children with epilepsy. Materials and Methods: This randomized clinical trial included children with a first-time diagnosis of epilepsy referred to Bandar Abbas Children’s Hospital, Bandar Abbas, Iran, from 2017 to 2018. Participants’ age, gender, and family history of epilepsy were recorded at the time of admission. Patients in the LTG group received 0.6 mg/kg of oral LTG in two divided doses for two weeks which continued with 1.2 mg/kg for another two weeks and then with a maintenance dose of 5-15 mg/kg daily. Patients in the LEV group received 10 mg/kg of oral LEV twice a day. When necessary, the dosage was increased to a maximum of 30 mg/kg twice a day. Treatment continued until seizures were controlled. Hematological and renal parameters were measured at baseline and 3 months after treatment. The total duration of treatment with each drug was noted as well. Results: Of the 66 children evaluated in this study with a mean age of 8.51±2.11 years, 31 (47%) were males. Age, gender, family history of epilepsy, treatment duration, and baseline hematological and renal parameters did not differ between the LTG (n=26) and LEV (n=40) groups. Patients in both groups were comparable regarding all the parameters after treatment. Finally, no significant change was observed after treatment compared to baseline in either group. Conclusion: Overall, LTG and LEV appear to have no significant effect on the hematological and renal parameters of children with epilepsy.

64-Year-Old Woman With Aphasia and Troponin Elevation

64-Year-Old Woman With Aphasia and Troponin Elevation

Decreased Systemic Busulfan Exposure After Oral Dosing With Concomitant Levetiracetam Compared With Phenytoin.

Busulfan (Bu) conditioning used in hematopoietic stem cell transplantation may induce seizures, and prophylactic antiepileptic treatment is recommended. Following updated guidelines, in August 2019, the adult hematopoietic stem cell transplantation department of the Rambam Health Care Campus (Haifa, Israel) switched the antiepileptic prophylaxis protocol from phenytoin to oral levetiracetam during oral Bu conditioning. The aim of this study was to compare the pharmacokinetic parameters of Bu after oral dosing between patients receiving phenytoin and those receiving levetiracetam prophylaxis. This study was a retrospective cohort study in adults undergoing myoablative conditioning with oral Bu between August 2018 and August 2020. Bu pharmacokinetic parameters (AUC0-6, C0, Cmax, and Tmax) were compared in patients treated with phenytoin comedication (during the year before the change in policy) and levetiracetam comedication (during the year after the change). Potential confounders were accounted for including age, azole comedication, and body weight. There were no significant differences in demographic and clinical parameters or weight-corrected Bu dose between the phenytoin group (n = 28) and the levetiracetam group (n = 25). There was no difference in the rate of voriconazole comedication, but fluconazole was more common in the phenytoin group (P = 0.026). The median AUC0-6 was significantly lower in the levetiracetam group (949 μM*min; IQR = 806 to 1101 μM*min) than in the phenytoin group (1208 μM*min; IQR = 1087 to 1389 μM*min; P < 0.001). This is a clinically significant difference of 258 μM*min (21%). Azole use was not associated with Bu exposure. The findings suggest that, after treatment with oral Bu, oral levetiracetam comedication is associated with reduced systemic exposure compared with phenytoin comedication, possibly because of decreased bioavailability.

Vigabatrin-associated brain abnormalities on MRI and other neurological symptoms in patients with West syndrome

ObjectivesReport a series of children with West syndrome (WS) treated with vigabatrin (VGB) who developed characteristic MRI alterations. In the majority, these adverse events were asymptomatic; however, some of the patients developed movement disorders and acute encephalopathy. MethodsThis is a retrospective analysis of our epilepsy clinical and EEG database of 288 patients with WS seen between 2014 and 2020. All patients who received VGB alone or with concomitant therapies, such as adrenocorticotropic hormone (ACTH), high-dose oral corticosteroids, ketogenic diet, valproate, levetiracetam, or topiramate, were evaluated. ResultsIn 44 of 288 patients with WS receiving VGB, MRI findings compatible with VGB-associated brain abnormalities were identified; median age at diagnosis was 6.29 months (range, 2 weeks to 11 months). The etiology of WS with vigabatrin-associated brain abnormalities on MRI (VABAM) was unknown in 22 (52.27%), genetic in seven (15.9%), genetic-structural in three (6.8%), structural malformative in three others (6.8%), and structural acquired in eight patients (18.2%). Vigabatrin-associated brain abnormalities on MRI was asymptomatic in 25 of 44 patients. Ten of 44 (22.7%) infants were reported to have had a movement disorder (choreoathetosis, dystonic posturing). Nine of 42 infants exhibited progressive psychomotor deterioration associated with signs and symptoms of encephalopathy. ConclusionMRI abnormalities were observed in infants treated with VGB and they appeared to be dose dependent. In our study common locations for MRI abnormalities included globi pallidi and brainstem, followed by thalami and dentate nuclei. Risk factors for the development of VABAM may include age younger than 11 months and higher VGB dose of VGB (>165 mg/kg/day). Vigabatrin-associated brain abnormalities on MRI usually resolved following VGB discontinuation, probably after a period of 3 months.

Clinical Pharmacology of Levetiracetam in Infants and Children

Levetiracetam inhibits focal and secondary generalized tonic-clonic seizures. The mechanism of levetiracetam action is not fully understood, however the correlation between binding affinity of levetiracetam and its analogues and their potency toward audiogenic seizures suggest that the synaptic vesicle glycoprotein 2A mediates the anticonvulsant effects of levetiracetam. The neural function of the synaptic vesicle 2A protein is not fully understood, but binding of levetiracetam to synaptic vesicle glycoprotein 2A might affect neuronal excitability by modifying the release of glutamate GABA through an action on vesicular function. Synaptic vesicle glycoprotein 2A may plain a role in vesicle recycling following exocytosis of neurotransmitter. In addition, levetiracetam inhibits N-type Ca2+ channels and Ca2+ release from intracellular stores. Levetiracetam may be administered intravenously or orally to infants and children and in children the levetiracetam dose varies according to the child age and body-weight. Levetiracetam is almost completed absorbed after oral administration and levetiracetam is found efficacy and safe in infants and children but it may induce adverse-effects. The levetiracetam elimination half-life is about 6 hours in infants and children, and in children the renal clearance is similar to the non-renal clearance. The prophylaxis, treatment, and trials with levetiracetam have been extensively studied in infants and children. Levetiracetam freely crosses the human placenta and freely migrates into the breast-milk. The aim of this study is to review the levetiracetam dosing, efficacy, safety, adverse-effects, pharmacokinetics, prophylaxis, treatment, and trials and transfer of levetiracetam across the human placenta and levetiracetam migration into the breast-milk.

In Vitro and In Vivo Bioequivalence Study of 3D-Printed Instant-Dissolving Levetiracetam Tablets and Subsequent Personalized Dosing for Chinese Children Based on Physiological Pharmacokinetic Modeling.

Recently, the development of Binder Jet 3D printing technology has promoted the research and application of personalized formulations, which are especially useful for children’s medications. Additionally, physiological pharmacokinetic (PBPK) modeling can be used to guide drug development and drug dose selection. Multiple technologies can be used in combination to increase the safety and effectiveness of drug administration. In this study, we performed in vivo pharmacokinetic experiments in dogs with preprepared 3D-printed levetiracetam instant-dissolving tablets (LEV-IDTs). Bioequivalence analysis showed that the tablets were bioequivalent to commercially available preparations (Spritam®) for dogs. Additionally, we evaluated the bioequivalence of 3D-printed LEV-IDTs with Spritam® by a population-based simulation based on the established PBPK model of levetiracetam for Chinese adults. Finally, we established a PBPK model of oral levetiracetam in Chinese children by combining the physiological parameters of children, and we simulated the PK (pharmacokinetics) curves of Chinese children aged 4 and 6 years that were administered the drug to provide precise guidance on adjusting the dose according to the effective dose range of the drug. Briefly, utilizing both Binder jet 3D printing technology and PBPK models is a promising route for personalized drug delivery with various age groups.

Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity

Network hyperexcitability may contribute to cognitive dysfunction in patients with Alzheimer disease (AD). To determine the ability of the antiseizure drug levetiracetam to improve cognition in persons with AD. The Levetiracetam for Alzheimer's Disease-Associated Network Hyperexcitability (LEV-AD) study was a phase 2a randomized double-blinded placebo-controlled crossover clinical trial of 34 adults with AD that was conducted at the University of California, San Francisco, and the University of Minnesota, Twin Cities, between October 16, 2014, and July 21, 2020. Participants were adults 80 years and younger who had a Mini-Mental State Examination score of 18 points or higher and/or a Clinical Dementia Rating score of less than 2 points. Screening included overnight video electroencephalography and a 1-hour resting magnetoencephalography examination. Group A received placebo twice daily for 4 weeks followed by a 4-week washout period, then oral levetiracetam, 125 mg, twice daily for 4 weeks. Group B received treatment using the reverse sequence. The primary outcome was the ability of levetiracetam treatment to improve executive function (measured by the National Institutes of Health Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research [NIH-EXAMINER] composite score). Secondary outcomes were cognition (measured by the Stroop Color and Word Test [Stroop] interference naming subscale and the Alzheimer's Disease Assessment Scale-Cognitive Subscale) and disability. Exploratory outcomes included performance on a virtual route learning test and scores on cognitive and functional tests among participants with epileptiform activity. Of 54 adults assessed for eligibility, 11 did not meet study criteria, and 9 declined to participate. A total of 34 adults (21 women [61.8%]; mean [SD] age, 62.3 [7.7] years) with AD were enrolled and randomized (17 participants to group A and 17 participants to group B). Thirteen participants (38.2%) were categorized as having epileptiform activity. In total, 28 participants (82.4%) completed the study, 10 of whom (35.7%) had epileptiform activity. Overall, treatment with levetiracetam did not change NIH-EXAMINER composite scores (mean difference vs placebo, 0.07 points; 95% CI, -0.18 to 0.32 points; P = .55) or secondary measures. However, among participants with epileptiform activity, levetiracetam treatment improved performance on the Stroop interference naming subscale (net improvement vs placebo, 7.4 points; 95% CI, 0.2-14.7 points; P = .046) and the virtual route learning test (t = 2.36; Cohen f2 = 0.11; P = .02). There were no treatment discontinuations because of adverse events. In this randomized clinical trial, levetiracetam was well tolerated and, although it did not improve the primary outcome, in prespecified analysis, levetiracetam improved performance on spatial memory and executive function tasks in patients with AD and epileptiform activity. These exploratory findings warrant further assessment of antiseizure approaches in AD. ClinicalTrials.gov Identifier: NCT02002819.