Vigabatrin In Patients Research Articles

Effectiveness of vigabatrin for infantile epileptic spasm syndrome categorized by etiologies

PurposeWe aimed to assess the effectiveness of vigabatrin (VGB) in patients diagnosed with infantile epileptic spasm syndrome (IESS) and categorize these patients based on their etiologies. MethodsThis retrospective study included patients diagnosed with IESS who exhibited epileptic spasms before the age of 2 years between January 1, 2015, and October 31, 2023 at Saitama Children's Medical Center. Patients with tuberous sclerosis as the identified etiology were excluded. The effectiveness of VGB was assessed based on the resolution of ES for three months with the absence of hypsarrhythmia on interictal electroencephalogram. ResultsThis study analyzed 41 patients (26 boys). The etiologies included genetic, congenital structural, acquired structural, and unknown in 12, 11, 10, and 8 patients, respectively. Patient characteristics did not significantly differ among the four groups. The overall effectiveness of VGB for IESS was 39.0 % (16/41). Categorized based on etiology, VGB was effective in 41.7 % (5/12), 9.1 % (1/11), 50 % (5/10), and 75 % (6/8) in the genetic, congenital structural, acquired structural, and unknown groups, respectively. Statistical analysis revealed a significant difference in effectiveness among the four groups (p = 0.03). Categorized based on diseases, VGB was effective in 28.6 % (2/7) and 50 % (4/8) in trisomy 21 and perinatal brain injury, respectively. ConclusionThe effectiveness of VGB in patients with IESS varied with etiology. Further investigations into the effectiveness of VGB in etiological subtypes of IESS could facilitate the development of tailored treatment algorithms for each etiology, representing valuable guidelines for future medical practice.

Management of seizures in patients with primary mitochondrial diseases: consensus statement from the InterERNs Mitochondrial Working Group.

Primary mitochondrial diseases (PMDs) are common inborn errors of energy metabolism, with an estimated prevalence of one in 4300. These disorders typically affect tissues with high energy requirements, including heart, muscle and brain. Epilepsy may be the presenting feature of PMD, can be difficult to treat and often represents a poor prognostic feature. The aim of this study was to develop guidelines and consensus recommendations on safe medication use and seizure management in mitochondrial epilepsy. A panel of 24 experts in mitochondrial medicine, pharmacology and epilepsy management of adults and/or children and two patient representatives from seven countries was established. Experts were members of five different European Reference Networks, known as the Mito InterERN Working Group. A Delphi technique was used to allow the panellists to consider draft recommendations on safe medication use and seizure management in mitochondrial epilepsy, using two rounds with predetermined levels of agreement. A high level of consensus was reached regarding the safety of 14 out of all 25 drugs reviewed, resulting in endorsement of National Institute for Health and Care Excellence guidelines for seizure management, with some modifications. Exceptions including valproic acid in POLG disease, vigabatrin in patients with γ-aminobutyric acid transaminase deficiency and topiramate in patients at risk for renal tubular acidosis were highlighted. These consensus recommendations describe our intent to improve seizure control and reduce the risk of drug-related adverse events in individuals living with PMD-related epilepsy.

Vigabatrin-Related Magnetic Resonance Imaging Abnormalities in an Infant with Tuberous Sclerosis Complex and Infantile Spasms

A newborn with hypopigmented skin macules, cardiac rhabdomyomas, and cerebral magnetic resonance imaging (MRI) demonstrating cortical tubers and subependymal nodules (Figure, A) was diagnosed with tuberous sclerosis complex (TSC). Clusters of flexor spasms began at 3 months of age, infantile spasms was diagnosed. Treatment was commenced with vigabatrin, an irreversible inhibitor of γ-aminobutyric acid transaminase, and the spasms ceased within 1 week. Routine follow-up MRI demonstrated the interval development of asymptomatic abnormalities, including restricted diffusion in the bilateral brainstem, basal ganglia, and thalami (Figure, B). After 1 year of successful treatment, the vigabatrin was discontinued and follow-up MRI demonstrated full resolution of these abnormalities (Figure, C).TSC is a genetic disorder characterized by hamartomatous lesions in multiple organ systems. Infantile spasms are common in TSC, occurring in one-third of patients. Vigabatrin is considered first-line therapy for infantile spasms in patients with TSC due to its remarkable effectiveness (>95%). These striking drug-related MRI abnormalities due to vigabatrin therapy occur primarily in infancy, are dose dependent, and are apparently asymptomatic and fully reversible.1Pearl P.L. Vezina L.G. Saneto R.P. McCarter R. Molloy-Wells E. Heffron A. et al.Cerebral MRI abnormalities associated with vigabatrin therapy.Epilepsia. 2009; 50: 184-194Crossref PubMed Scopus (125) Google Scholar, 2Wheless J.W. Carmant L. Bebin M. Conry J.A. Chiron C. Elterman R.D. et al.Magnetic resonance imaging abnormalities associated with vigabatrin in patients with epilepsy.Epilepsia. 2009; 50: 195-205Crossref PubMed Scopus (93) Google Scholar The pathophysiology is not known, but studies in animals suggest the contribution of intramyelinic edema, and the high risk confined to infancy suggests a developmental role of brain maturation.Bilateral MRI abnormalities in a similar distribution (brainstem, basal ganglia, thalami) can also be seen in metabolic, ischemic, infectious, and toxic etiologies. The patient history, to include concurrent medications, is especially pertinent in the clinical interpretation of these MRI findings. A newborn with hypopigmented skin macules, cardiac rhabdomyomas, and cerebral magnetic resonance imaging (MRI) demonstrating cortical tubers and subependymal nodules (Figure, A) was diagnosed with tuberous sclerosis complex (TSC). Clusters of flexor spasms began at 3 months of age, infantile spasms was diagnosed. Treatment was commenced with vigabatrin, an irreversible inhibitor of γ-aminobutyric acid transaminase, and the spasms ceased within 1 week. Routine follow-up MRI demonstrated the interval development of asymptomatic abnormalities, including restricted diffusion in the bilateral brainstem, basal ganglia, and thalami (Figure, B). After 1 year of successful treatment, the vigabatrin was discontinued and follow-up MRI demonstrated full resolution of these abnormalities (Figure, C). TSC is a genetic disorder characterized by hamartomatous lesions in multiple organ systems. Infantile spasms are common in TSC, occurring in one-third of patients. Vigabatrin is considered first-line therapy for infantile spasms in patients with TSC due to its remarkable effectiveness (>95%). These striking drug-related MRI abnormalities due to vigabatrin therapy occur primarily in infancy, are dose dependent, and are apparently asymptomatic and fully reversible.1Pearl P.L. Vezina L.G. Saneto R.P. McCarter R. Molloy-Wells E. Heffron A. et al.Cerebral MRI abnormalities associated with vigabatrin therapy.Epilepsia. 2009; 50: 184-194Crossref PubMed Scopus (125) Google Scholar, 2Wheless J.W. Carmant L. Bebin M. Conry J.A. Chiron C. Elterman R.D. et al.Magnetic resonance imaging abnormalities associated with vigabatrin in patients with epilepsy.Epilepsia. 2009; 50: 195-205Crossref PubMed Scopus (93) Google Scholar The pathophysiology is not known, but studies in animals suggest the contribution of intramyelinic edema, and the high risk confined to infancy suggests a developmental role of brain maturation. Bilateral MRI abnormalities in a similar distribution (brainstem, basal ganglia, thalami) can also be seen in metabolic, ischemic, infectious, and toxic etiologies. The patient history, to include concurrent medications, is especially pertinent in the clinical interpretation of these MRI findings.

Vigabatrin and Mental Retardation in Tuberous Sclerosis

Tuberous sclerosis complex is a genetic disorder resulting in epilepsy and mental retardation. Vigabatrin has shown efficacy in the treatment of infantile spasms caused by tuberous sclerosis complex, but its effects on focal seizures caused by tuberous sclerosis complex have not been determined. We compared the efficacy of vigabatrin in patients with tuberous sclerosis complex-induced focal seizures and infantile spasms and assessed the mental outcomes in both groups. We retrospectively evaluated 31 children with tuberous sclerosis complex and epilepsy, who were treated with vigabatrin in a single tertiary center in Seoul, Korea. Vigabatrin treatment resulted in spasms cessation in 16 of 18 (88.9%) patients with infantile spasms, whereas 6 of 13 (46.2%) patients with focal seizures became seizure free. Initial response to vigabatrin had no effect on intellectual disability. Vigabatrin was highly effective in eliminating infantile spasms caused by tuberous sclerosis complex but was less effective in patients with focal seizures.

Vigabatrin's Complicated Journey—To be or Not to Be?

Visual Fields at School-Age in Children Treated with Vigabatrin in Infancy. Gaily E, Jonsson H, Lappi M. Epilepsia 2009;50(2):206–216. PURPOSE: The use of vigabatrin (VGB) as an antiepileptic drug (AED) has been limited by evidence showing that it causes vigabatrin-attributed visual field loss (VAVFL) in at least 20–40% of patients exposed at school age or later. VGB is an effective drug for infantile spasms, but there are no reports on later visual field testing after such treatment. Our aim was to investigate the risk of VAVFL in school-age children who had received VGB in infancy. METHODS: Visual fields of 16 children treated with VGB for infantile spasms were examined by Goldmann kinetic perimetry at age 6–12 years. Normal fields were defined as the temporal meridian extending to more than 70°, and mild VAVFL between 50 and 70°. Abnormal findings were always confirmed by repeating the test. Exposure data were collected from hospital charts. RESULTS: Vigabatrin was started at a mean age of 7.6 (range, 3.2–20.3) months. The mean duration of therapy was 21.0 (9.3–29.8) months and cumulative dose 655 g (209–1,109 g). Eight children were never treated with other AEDs, five received only adrenocorticotropic hormone (ACTH) in addition to VGB, and three children had been treated with other AEDs. Fifteen children had normal visual fields. Mild VAVFL was observed in one child (6%) who had been treated with VGB for 19 months and who received a cumulative dose of 572 g. CONCLUSIONS: The risk of VAVFL may be lower in children who are treated with VGB in infancy compared to patients who receive VGB at a later age. Magnetic Resonance Imaging Abnormalities Associated with Vigabatrin in Patients with Epilepsy. Wheless JW, Carmant L, Bebin M, Conry JA, Chiron C, Elterman RD, Frost M, Paolicchi JM, Donald Shields W, Thiele EA, Zupanc ML, Collins SD. Epilepsia 2009;50(2):195–205. PURPOSE: Vigabatrin used to treat infantile spasms (IS) has been associated with transient magnetic resonance imaging (MRI) abnormalities. We carried out a retrospective review to better characterize the frequency of those abnormalities in IS and in children and adults treated with vigabatrin for refractory complex partial seizures (CPS). METHODS: Medical records and 332 cranial MRIs from 205 infants (aged ≤24 months) with IS treated at 10 sites in the United States and Canada were collected. Similarly, 2,074 images from 668 children (aged 2–16 years) and adults (aged >16 years) with CPS were re-reviewed. Prespecified MRI abnormalities were defined as any hyperintensity on T2-weighted or fluid-attenuated inversion-recovery (FLAIR) sequences with or without diffusion restriction not readily explained by a radiographically well-characterized pathology. MRIs were read by two neuroradiologists blinded to treatment group. The incidence and prevalence of MRI abnormalities associated with vigabatrin were estimated. RESULTS: Among infants with IS, the prevalence of prespecified MRI abnormalities was significantly higher among vigabatrin-treated versus vigabatrin-naive subjects (22% vs. 4%; p < 0.001). Of nine subjects in the prevalence population with at least one subsequent determinate MRI, resolution of MRI abnormalities occurred in six (66.7%)—vigabatrin was discontinued in four. Among adults and children treated with vigabatrin for CPS, there was no statistically significant difference in the incidence or prevalence of prespecified MRI abnormalities between vigabatrin-exposed and vigabatrin-naive subjects. DISCUSSION: Vigabatrin is associated with transient, asymptomatic MRI abnormalities in infants treated for IS. The majority of these MRI abnormalities resolved, even in subjects who remained on vigabatrin therapy.

Magnetic resonance imaging abnormalities associated with vigabatrin in patients with epilepsy

Vigabatrin used to treat infantile spasms (IS) has been associated with transient magnetic resonance imaging (MRI) abnormalities. We carried out a retrospective review to better characterize the frequency of those abnormalities in IS and in children and adults treated with vigabatrin for refractory complex partial seizures (CPS). Medical records and 332 cranial MRIs from 205 infants (aged <or=24 months) with IS treated at 10 sites in the United States and Canada were collected. Similarly, 2,074 images from 668 children (aged 2-16 years) and adults (aged >16 years) with CPS were re-reviewed. Prespecified MRI abnormalities were defined as any hyperintensity on T(2)-weighted or fluid-attenuated inversion-recovery (FLAIR) sequences with or without diffusion restriction not readily explained by a radiographically well-characterized pathology. MRIs were read by two neuroradiologists blinded to treatment group. The incidence and prevalence of MRI abnormalities associated with vigabatrin were estimated. Among infants with IS, the prevalence of prespecified MRI abnormalities was significantly higher among vigabatrin-treated versus vigabatrin-naive subjects (22% vs. 4%; p < 0.001). Of nine subjects in the prevalence population with at least one subsequent determinate MRI, resolution of MRI abnormalities occurred in six (66.7%)-vigabatrin was discontinued in four. Among adults and children treated with vigabatrin for CPS, there was no statistically significant difference in the incidence or prevalence of prespecified MRI abnormalities between vigabatrin-exposed and vigabatrin-naive subjects. Vigabatrin is associated with transient, asymptomatic MRI abnormalities in infants treated for IS. The majority of these MRI abnormalities resolved, even in subjects who remained on vigabatrin therapy.

Vigabatrin Caused Rapidly Progressive Deterioration in Two Cases With Early Myoclonic Encephalopathy Associated With Nonketotic Hyperglycinemia

Vigabatrin, a structural analogue of gamma-aminobutyric acid (GABA), is used for the treatment of generalized and partial seizures in infants. The drug inhibits the GABA transaminase and elevates the GABA concentration in the brain. Here we present the vigabatrin experience in two patients with early myoclonic encephalopathy owing to nonketotic hyperglycinemia (glycine encephalopathy). Both patients had early infantile seizures characterized by fragmentary myoclonic jerks associated with burst-suppression pattern on electroencephalography. Nonketotic hyperglycinemia was diagnosed with elevated cerebrospinal fluid and plasma glycine levels. The seizures were initially thought to be infantile spasms, and vigabatrin (50 mg /kg/day) was started for the treatment of seizures. Rapidly progressive deterioration was noticed after a few days. Acute encephalopathy associated with sleepiness and respiratory failure developed. Vigabatrin produced acute encephalopathy, which regressed in a few days after vigabatrin was stopped in the first patient. However, in the second case, despite the discontinuation of vigabatrin, there was no recovery of general conditions. Our observations in two cases indicate the risk of using vigabatrin in patients with nonketotic hyperglycinemia. The elevated GABA concentration in the brain can enhance the encephalopathy, together with the elevated levels of glycine. (J Child Neurol 2006;21:82-84).

Randomized trial of vigabatrin in patients with infantile spasms

Infantile spasms are a rare but devastating pediatric epilepsy that, outside the United States, is often treated with vigabatrin. The authors evaluated the efficacy and safety of vigabatrin in children with recent-onset infantile spasms. This 2-week, randomized, single-masked, multicenter study with a 3- year, open-label, dose-ranging follow-up study included patients who were younger than 2 years of age, had a diagnosed duration of infantile spasms of no more than 3 months, and had not previously been treated with adrenocorticotropic hormone, prednisone, or valproic acid. Patients were randomly assigned to receive low-dose (18-36 mg/kg/day) or high-dose (100-148 mg/kg/day) vigabatrin. Treatment responders were those who were free of infantile spasm for 7 consecutive days beginning within the first 14 days of vigabatrin therapy. Time to response to therapy was evaluated during the first 3 months, and safety was evaluated for the entire study period. Overall, 32 of 142 patients who were able to be evaluated for efficacy were treatment responders (8/75 receiving low-dose vigabatrin vs 24/67 receiving high doses, p < 0.001). Response increased dramatically after approximately 2 weeks of vigabatrin therapy and continued to increase over the 3-month follow-up period. Time to response was shorter in those receiving high-dose versus low-dose vigabatrin (p = 0.04) and in those with tuberous sclerosis versus other etiologies (p < 0.001). Vigabatrin was well tolerated and safe; only nine patients discontinued therapy because of adverse events. These results confirm previous reports of the efficacy and safety of vigabatrin in patients with infantile spasms, particularly among those with spasms secondary to tuberous sclerosis.

The long-term use of gabapentin, lamotrigine, and vigabatrin in patients with chronic epilepsy.

To compare the long-term retention of gabapentin (GBP), lamotrigine (LTG), and vigabatrin (VGB) by patients with chronic epilepsy and the reasons for treatment discontinuation. To assess the likelihood of seizure freedom, seizure-related injury/hospital admission and mortality after these drugs were commenced. This was a retrospective case-records survey in five tertiary referral epilepsy centres in the U.K. The retention times on treatment (from initiation to discontinuation) for the different antiepileptic drugs (AEDs) were compared by using Kaplan-Meier survival analysis and Cox regression. Incidences of seizure freedom and seizure-related injury/hospital admissions and standardised mortality ratios were calculated. There were 1,375 patients with chronic epilepsy included; 361 were taking GBP, 1,050 LTG, and 713 VGB. The retention of GBP, LTG, or VGB was <40% at 6 years. Fewer than 4% of patients become seizure free while taking one of the drugs. There was no reduction in mortality or seizure-related injury/admission. The impact of these new AEDs on chronic epilepsy can be described only as modest. This view may be revised, however, as more experience is gained with new drugs in previously untreated patients.

The post-marketing surveillance of gabapentin, lamotrigine and vigabatrin in patients with chronic epilepsy

The post-marketing surveillance of gabapentin, lamotrigine and vigabatrin in patients with chronic epilepsy

Lamotrigine-related rash: an audit

s 423 Lamotrigine-related rash: an audit I. Wang*, G. Mawer? J University of Bradford, Bradford, UK; t David Lewis Centre for Epilepsy Cheshire, UK; $ institute of Neurology National Hospital for Neurology and Neurosurgery, London, UK Purpose: 1. To estimate the incidence of serious and non-serious rashes associated with lamotrigine (LTG) treatment. 2. To identify risk factors for LTG-related rash. 3. To assess the effectiveness of the recommendation by the manufacturers to reduce starting dose. Methods: Case records were surveyed in five tertiary referral epilepsy centres in the UK. The causality of the rash was assessed using the WHO method. Risk factors for LTG-related rash were identified by logistic regression. The incidences of rash before and after reduction in starting dose were compared by Chi-square. Results and discussion: 1050 patients were included. The incidences of serious and non-serious rash were 1.1% (95% CI = 0.5% to 1.8%) and 7% (95% CI = 5.5% to 8.6%). This study confirms previous reports that concurrent sodium valproate and a high starting daily dose increase the risk of LTG-related rash, while concurrent enzyme inducers reduce it. Furthermore, female patients were twice as likely to develop rash than males. Some clinicians ignored the recommendation to start LTG at a lower dose, consequently, there was no reduction in the incidence of LTG-related rash since the manufacturer recommended reducing the starting dose of LTG. The post-marketing surveillance of gabapentin, lamotrigine and vigabatrin in patients with chronic epilepsy I. Wang*, G. Mawet-+ & J. Sander* *School of Pharmacy, University of Bradford, Bradford, UK; + David Lewis School of Epilepsy Cheshire, UK; $ Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, UK Purpose: A post-marketing surveillance study of gabapentin (GBP), lamotrigine (LTG) and vigabatrin (VGB) investigated adverse drug reactions (ADRs) and mortality. Methods: Case records were surveyed in five tertiary referral epilepsy centres in the UK. Adverse events were recorded and compared within and between the drugs. All deaths were followed and standardized mortality ratios (SMRs) calculated. Serious ADRs were assessed individually. Results and discussion: 1375 patients were included in the statistical analyses. ADRs to GBP were generally mild but one case of leucopenia was identified. Skin rash was the major ADR to LTG but rare cases of hepatic failure, acute exacerbation of ulcerative colitis, disseminated intravascular coagulation and renal failure were also identified. Psychiatric/behavioural disturbance was the major ADR to VGB but one case of visual field constriction was identified. No death could be directly attributed to the use of the new drugs. The SMRs were slightly higher than that reported in the literature. This probably reflects the severity of epilepsy in the study population. Beneficial effect of levetiracetam (UCB L059) on juvenile myoclonic epilepsy resistant to valproate and lamotrigine Kate Smith, Tim Betts & Cathy Fox Birmingham University Seizure Clinic, Queen Elizabeth Psychiatric Hospital, Birmingham B 15 2QZ, UK Levetiracetam (UCB L059) is a new antiepileptic drug (an enantiomer of piracetam) currently undergoing evaluation and already of proven efficacy in patients with partial onset epilepsy. We have examined the effect of this drug on a sub-group of nine patients with juvenile myoclonic epilepsy resistant to conventional therapy with sodium valproate and lamotrigine. Seven of these patients have become totally seizure-free-the other two almost completely so (still in dose escalation). This intriguing result is worthy of further study particularly because Levetiracetam has an acceptable side effect profile.

Human brain GABA levels rise rapidly after initiation of vigabatrin therapy.

The purpose of this study was to measure changes in brain GABA after a single oral dose (50 mg/kg) of vigabatrin in patients with intractable epilepsy. Vigabatrin is a safe and effective antiepileptic medication designed to increase brain GABA by irreversibly inhibiting GABA-transaminase. Serial measurements showed that brain GABA levels increased from 1.0 (SEM, 0.07) to 2.4 mmol/kg (SEM, 0.09) in patients who were regularly taking vigabatrin (50 mg/kg/day divided into two doses). In vivo measurements of GABA in human brain were made using 1H magnetic resonance spectroscopy. We used a 2.1-T NMR spectrometer and an 8-cm surface coil to measure a 13.5 cm3 volume in the occipital cortex. Brain GABA increased by more than 40% within 2 hours of administration of a single 50 mg/kg oral dose of vigabatrin from 0.95 (SEM, 0.07; n = 7) to 1.34 mmol/kg (SEM, 0.13). By the next day, brain GABA increased further to 1.44 mmol/kg (SEM, 0.08). Levels declined gradually to 1.16 mmol/kg (SEM, 0.14) by day 5 and 1.03 mmol/kg (SEM, 0.10) at day 8. The patients reported no side effects and were calm but not drowsy. A single oral dose of vigabatrin rapidly increased brain GABA without side effects. Once-a-day dosing should be as effective as divided doses.

Six-year follow-up study on the efficacy and safety of vigabatrin in patients with epilepsy.

Twenty-five patients with epilepsy (mostly with partial seizures) who had responded favourably to a short-term trial of add-on vigabatrin entered maintenance treatment. After 52 to 78 months, 15 patients continue to take the drug with good therapeutic response. Median monthly seizure frequency during the last 2 months on vigabatrin in all patients, including drop-outs, was 3.5 (range 0-74) as compared with 10 (range 3-98) during an initial placebo period (p < 0.01). Drop-outs were caused by adverse events in 2 cases (ataxia and psychotic symptoms respectively), seizure breakthrough in 4 cases and reasons unrelated to treatment in 4 patients. In most patients, side effects were absent or mild, the most frequent complaint being weight gain. It is concluded that the antiepileptic efficacy and good clinical tolerability of vigabatrin are generally maintained during long-term treatment for up to 6 years.

Vigabatrin in Pediatric Epilepsy—An Open Study

The antiepileptic effect of vigabatrin in adults has been demonstrated in a number of controlled studies. In children, the effect of vigabatrin has been investigated only to a limited extent. In order to assess the long-term effect and safety of vigabatrin in patients with severe epilepsy, an open, add-on, dose-ranging study was initiated. To date, 27 children with partial epilepsy, two with generalized epilepsy, two with Lennox-Gastaut syndrome, and one with nonclassifiable epilepsy have been enrolled in the trial. Fifty-four percent of patients have experienced a greater than 50% reduction in seizure frequency, and four patients have become seizure free. A significant reduction in seizures was noted across the patient population, although patients who were recorded as seizure free at 3 and 6 months did suffer some recurrence of seizures. However, when seizures recurred, they did so at much lower frequency than recorded at the start of the study. Thirteen patients (39%) reported adverse events attributable to vigabatrin; one was immediately withdrawn from the study, and six had their vigabatrin dose reduced. No physiologic effects were noted on normal growth or clinical physical examination.