Paediatric antibody prevalence in seizure score to predict autoimmune aetiology in seizure disorders.

AIM: To modify the antibody prevalence in epilepsy (APE) score of children with suspected autoimmune central nervous system disease with seizures. METHODS: We retrospectively analysed the cerebrospinal fluid of 157 children (aged 0-18 years) with suspected autoimmune central nervous system disease for antineuronal antibodies in our laboratory from 2016 to 2023. Participants were randomly divided into the development cohort (n = 79, 35 females; median 7 years, SD 4 years 7 months, range 4-11 years) and validation cohort (n = 78, 28 females; median 7 years, SD 4 years 5 months, range 4-12 years). A paediatric antibody prevalence in seizure (PAPS) score was created for one cohort and evaluated in the other. Seven variables were selected through univariate and multivariate analysis to create a PAPS score. RESULTS: One hundred and fifty-seven children who fulfilled the inclusion criteria were enrolled; 49 tested positive for antineuronal antibodies. The sensitivity and specificity of an APE score of 4 and greater were 92% and 22.2% respectively; the sensitivity and specificity of a PAPS score of 2.5 and greater were 83.3% and 77.8% respectively. The area under the curve was 0.832 (95% confidence interval = 0.743-0.921), which was significantly better than that for the APE score (p < 0.001). INTERPRETATION: The APE score had high sensitivity but low specificity in children. The PAPS score may be useful for determining the need for antineuronal antibody testing.

Vagus Nerve Stimulation Therapy for Drug-Resistant Epilepsy in Children-A Literature Review.

Vagus nerve stimulation (VNS) is a palliative treatment for drug-resistant epilepsy (DRE) that has been in use for over two decades. VNS suppresses epileptic seizures, prevents emotional disorders, and improves cognitive function and sleep quality, a parallel effect associated with the control of epileptic seizures. The seizure suppression rate with VNS increases monthly to annually, and the incidence of side effects reduces over time. This method is effective in treating DRE in children as well as adults, such as epilepsy associated with tuberous sclerosis, Dravet syndrome, and Lennox-Gastaut syndrome. In children, it has been reported that seizures decreased by >70% approximately 8 years after initiating VNS, and the 50% responder rate was reported to be approximately 70%. VNS regulates stimulation and has multiple useful systems, including self-seizure suppression using magnets, additional stimulation using an automatic seizure detection system, different stimulation settings for day and night, and an automatic stimulation adjustment system that reduces hospital visits. VNS suppresses seizures and has beneficial behavioral effects in children with DRE. This review describes the VNS system, the mechanism of the therapeutic effect, the specific stimulation adjustment method, antiepileptic effects, and other clinical effects in patients with childhood DRE.

Focal tonic seizures with asymmetrical posturing could allow voluntary movements: A lesson to not be misled for a non-epileptic event.

This report documents the clinical features of supplementary motor area seizures with voluntary movements in two patients. The first case describes a 13-year-old boy with a 2-year history of nocturnal seizures, characterized by an asymmetrical brief tonic posture followed by bilateral rapid hand shaking, but without impaired awareness. Magnetic resonance imaging revealed no abnormalities. Video electroencephalogram indicated interictal focal spikes and ictal activity 2 s before clinical onset in the frontal midline area. The patient stated that he purposely shook his hands to lessen the seizure-induced upper limb stiffness. The second case describes a 43-year-old man with a 33-year history of nocturnal seizures, characterized by an asymmetric brief tonic posture, with the right hand grabbing to hold this posture, but without impaired awareness. Video electroencephalogram indicated that he voluntarily moved his right hand during the latter part of the seizures; however, no clear ictal electroencephalogram change was noted. Magnetic resonance imaging revealed a mass lesion in the right medial superior frontal gyrus. Fluorodeoxyglucose-positron emission tomography and ictal single-photon emission computed tomography indicated ictal focus in the mesial frontal area, as confirmed by invasive electroencephalogram and seizure freedom after surgery. Both patients had typical supplementary motor area seizures, except they could perform voluntary movements in the body parts. The co-occurrence of supplementary motor area seizures and voluntary movements is clinically useful, as it may help avoid the inaccurate and misleading diagnosis of non-epileptic events such as psychogenic non-epileptic seizures.

Loss-of-function mutations in SGCE found in Japanese patients with myoclonus-dystonia.

SGCE myoclonus-dystonia is a monogenic form of dystonia with an autosomal dominant mode of inheritance that co-occurs with a myoclonic jerk. In this study, we present 12 Japanese patients from nine families with this disease. Targeted next-generation sequencing covering major causative genes for monogenic dystonias identified nine distinct SGCE mutations from each of the families: three nonsense, two frameshift, two missense, one in-frame 15 bp deletion, and one splice donor site mutations, of which four were previously unreported. One missense mutation (c.662G>T, p.Gly221Val) was located at the 3' end of exon 5 (NM_001099400), which was predicted to cause aberrant splicing according to in silico predictions. Minigene assays performed together with the c.825+1G>C mutation demonstrated complete skipping of exon 5 and 6, respectively, in their transcripts. The other missense (c.1345A>G, p.Met449Val) and 15 bp deletion (c.168_182del, p.Phe58_Leu62del) mutations showed a significant reduction in cell membrane expression via HiBiT bioluminescence assay. Therefore, we concluded that all the detected mutations were disease-causing. Unlike the other detected mutations, p.Met449Val affects only isoform 3 (NP_001092870 encoded by NM_001099400) among the variously known isoforms of SGCE. This isoform is brain-specific and is mostly expressed in the cerebellum, which supports recent studies showing that cerebellar dysfunction is a key element in the pathophysiology of SGCE myoclonus-dystonia.

CDKL5 deficiency causes epileptic seizures independent of cellular mosaicism.

OBJECTIVE: In a study using a mouse model of CDKL5 deficiency disorder (CDD), seizures are specific to female mice heterozygous for Cdkl5 mutations and not observed in hemizygous knockout males or homozygous knockout females. The aim of this study was to examine whether the clinical phenotype of patients with CDD can be impacted by the type of genetic variant. METHODS: Eleven CDD patients (six females and five males) were included in this study. The molecular diagnosis of hemizygous male patients was performed using digital PCR and their clinical phenotypes were compared with those of patients with mosaic or heterozygous CDKL5 variants. The severity of clinical phenotypes was graded by using CDKL5 Developmental Score and the adapted version of the CDKL5 Clinical Severity Assessment. The effect of cellular mosaicism on the severity of CDD was studied by comparing the clinical characteristics and comorbidities between individuals with hemizygous and mosaic or heterozygous CDKL5 variants. RESULTS: One of the five male patients was mosaic for the CDKL5 variant. All patients developed seizures irrespective of their genetic status of the pathogenic variant. However, cellular mosaicism of CDKL5 deficiency was associated with lesser severity of other comorbidities such as feeding, respiratory, and visual functional impairments. SIGNIFICANCE: This study provided evidence that cellular mosaicism of CDKL5 deficiency was not necessarily required for developing epilepsy. CDD patients not only exhibited clinical features of epilepsy but also exhibited the developmental consequences arising directly from the effect of the CDKL5 pathogenic variant.

Association of early-onset epileptic encephalopathy with involuntary movements - Case series and literature review.

Epileptic-dyskinetic encephalopathies are rare epilepsies characterized by early-onset epileptic encephalopathies (EOEEs) with involuntary movement. Herein, we investigated the impact of gene variants in epileptic-dyskinetic encephalopathies. Four independent patients from four families who exhibited involuntary movements were recruited from Tokyo Metropolitan Neurological Hospital. The inclusion criteria were as follows: onset within 1 year after birth, frequent seizures, severe developmental delay and accompanying involuntary movements. We detected four genetic mutations, including STXBP1, GNAO1, CYFIP2, and SCN8A variants. The involuntary movements were drug-resistant. However, pallidal electrocoagulation followed by gabapentin were partially effective in treating chorea and ballismus of the extremities in patients with GNAO1 variants, and perampanel partially suppressed seizures and involuntary movements in one patient with a SCN8A variant. Movement disorders are common to many neurodevelopmental disorders, including a variety of EOEEs. Although we could not establish a definitive correlation using genetic variants in patients with EOEE and movement disorders, involuntary movements in patients with EOEEs may be a key diagnostic finding. The usage of genetic variants could prove beneficial in the future as more patients are investigated with epileptic-dyskinetic encephalopathies.

Lister hooded rats as a novel animal model of attention-deficit/hyperactivity disorder.

Appropriate animal models are necessary to determine the molecular and cellular mechanisms underlying attention-deficit/hyperactivity disorder (ADHD). This study used a battery of behavioral tests to compare Lister hooded rats (LHRs), an old outbred strain frequently used for autistic epilepsy research, with Wistar rats and spontaneously hypertensive rats (SHRs), a commonly used ADHD model. The open field, elevated plus maze, light/dark box, and drop tests demonstrated that LHRs were the most hyperactive animals and displayed the most inattentive- and impulsive-like behaviors, which are characteristics of ADHD. The radial arm maze, social interaction, and Morris water maze tests showed that LHRs did not display deficits characteristic of autism or intellectual disability. Although LHRs did not show different monoamine contents, the mRNA expression levels of various genes linked to ADHD (Cdh13, Drd5, Foxp2, Maoa, Sema6d, Slc9a9, and St3gal3) and tyrosine hydroxylase protein expression levels were lower in the prefrontal cortex of LHRs compared with that of Wistar rats or SHRs. c-Fos, synapsin I, and tau protein expression levels in the prelimbic region of the medial prefrontal cortex were also increased in LHRs compared with Wistar rats. Atomoxetine and guanfacine, commonly used non-stimulant treatments for ADHD, ameliorated ADHD-like behaviors in LHRs. These results suggest that LHRs can serve as a better ADHD model to develop novel pharmacological interventions.

IVIG in childhood primary angiitis of the central nervous system: A case report.

Aggressive immunosuppressive therapies have been proposed to treat primary angiitis of the central nervous system (PACNS). Here, we report the first successfully stabilized case of childhood, small-vessel PACNS with intravenous immunoglobulin (IVIG) therapy. A 12-year-old boy was admitted to our hospital complaining of recurrent headaches and upper-left homonymous quadrantanopia, since the age of 11 years. Brain computed tomography scans revealed fine calcification in the right temporal and occipital lobes. Brain magnetic resonance imaging scans revealed white matter lesions, with gadolinium enhancement, which waxed, waned, and migrated for 1 year, without immunomodulatory therapies. A cerebrospinal fluid study showed pleocytosis (12 cells per µl). No clinical or serological findings suggested systemic inflammation or vasculitis. Brain angiography was unremarkable. Brain biopsy revealed thickened and hyalinized small vessels, with intramural infiltration of inflammatory cells, which confirmed the diagnosis of small-vessel PACNS. Because the patient developed surgical site infection following biopsy, the administration of monthly IVIG (2 g/kg) was prescribed, instead of immunosuppressive agents. After IVIG therapy, the patient remained stable, except for a single episode of mild radiological exacerbation at 16 months, which occurred when the IVIG interval was expanded. Oral prednisone was added and gradually tapered. At 50 months, his intellectual abilities and motor functions were normal, although he showed residual upper-left homonymous quadrantanopia and post-exercise headache. A temporary headache, associated with the immunoglobulin infusion, was resolved by slowing the infusion rate. PACNS should be treated aggressively to improve prognosis. However, when immunosuppressants are contraindicated, IVIG may be an alternative therapeutic option.

Survey of patients with spinal muscular atrophy on the island of Shikoku, Japan.

BACKGROUND: Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder associated with spinal motor neuron loss and characterized by generalized muscle weakness. Only a few reports exist on SMA epidemiology in Japan. Additionally, nusinersen recently became available as a treatment for this condition. We estimated the prevalence of each type of SMA on Shikoku, Japan's fourth-largest major island. METHODS: We sent a questionnaire to all 131 hospitals in Shikoku that have pediatrics or neurology departments from March to September 2019, asking whether each hospital had SMA patients at that time. If so, we sent a second questionnaire to obtain more detailed information on the clinical data and treatment of each patient. RESULTS: A total of 117 hospitals (89.3%) responded to our first questionnaire, and 21 SMA patients were reported, 16 of whom had homozygous deletion of SMN1. Of the 21, nine had SMA type 1, five were type 2, five were type 3, one was type 4, and one was unidentified. The estimated prevalence for all instances of SMA and 5q-SMA was 0.56 and 0.43 per 100,000 people, respectively. Thirteen patients had received nusinersen therapy. Its outcomes varied from no obvious effects and being unable to sit to being able to sit independently. CONCLUSION: Our data showed the prevalence of SMA types 2 and 3 was relatively low on Shikoku compared with previous reports from other countries, suggesting delayed diagnosis may affect the results. Remaining motor function may be one predicting factor. Greater awareness of SMA among clinicians and patients seems necessary for more accurate epidemiological studies.

Renal dysfunction can occur in advanced-stage Duchenne muscular dystrophy.

INTRODUCTION: With improved treatments, patients with Duchenne muscular dystrophy (DMD) can survive far beyond adolescence. However, advanced-stage DMD patients are at risk of developing renal dysfunction. In this study, long-term renal function outcomes and associated risk factors in advanced stage DMD were analyzed. METHODS: Fifty-one patients were classified into three different age groups (<20, 20-29, and ≥30 years of age), and cystatin C (CysC) levels were compared among groups. RESULTS: Median serum CysC levels were 0.74 mg/L, 0.63 mg/L, and 0.76 mg/L in the age groups of <20, 20-29, and ≥30 years, respectively (P = .003). Five of the nine patients in the ≥30 years age group showed elevated serum CysC and decreased cardiac function compared with the other four in the group (P = .014). DISCUSSION: Our results indicate an association between cardiac and renal dysfunction in patients with advanced-stage DMD.

Nonocclusive Mesenteric Ischemia Rescued by Immediate Surgical Exploration in a Boy with Severe Neurodevelopmental Disability.

BACKGROUND: Nonocclusive mesenteric ischemia (NOMI) defines acute mesenteric ischemia without occlusion of the mesenteric arteries. The most common cause of NOMI is vasoconstriction or vasospasm of a mesenteric artery. NOMI generally affects patients >50 years of age, and few cases have been reported in children. CASE PRESENTATION: A 15-year-old boy with severe neurodevelopmental disability developed sudden-onset fever, abdominal distention, and dyspnea. Laboratory and radiological findings indicated acute intestinal obstruction and prerenal failure. He developed transient cardiopulmonary arrest and hypovolemic shock. Emergent laparotomy was performed, which revealed segmentally necrotic intestine from the jejunum to the ascending colon with pulsation of peripheral intestinal arteries, leading to a diagnosis of NOMI. The necrotic intestine was resected, and stomas were created. He was discharged on postoperative day 334 with short bowel syndrome as a complication. CONCLUSIONS: NOMI should be considered a differential diagnosis for intestinal symptoms with severe general conditions in both adults and children with underlying disease. Immediate surgical exploration is essential with NOMI to save a patient's life.

Incidence of infantile spinal muscular atrophy on Shikoku Island of Japan.

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by homozygous mutations in the SMN1 gene. SMA has long been known to be the most common genetic cause of infant mortality. However, there have been no reports on the epidemiology of infantile SMA (types 1 and 2) based on genetic testing in Japan. In this study, we estimated the incidence of infantile SMA on Shikoku Island, which is a main island of Japan and consists of four prefectures: Ehime, Kagawa, Tokushima and Kochi. METHODS: A questionnaire was sent to 91 hospitals on Shikoku Island to investigate the number of SMA infants born from 2011 to 2015. A second questionnaire was then sent to confirm the diagnoses of SMA based on clinical and genetic features. RESULTS: Responses were received from all of the hospitals, and four patients were diagnosed with infantile SMA among 147,950 live births. We estimated the incidence of infantile SMA patients as 2.7 per 100,000 live births (95% confidence interval, 0.1-5.4). A comparison of the four prefectures indicated that the incidence of infantile SMA was significantly higher in Ehime Prefecture than in the other three prefectures; 5.6 per 100,000 live births (95% confidence interval, -0.7 to 11.9) in Ehime Prefecture and 1.1 per 100,000 live births (95% confidence interval, -1.0 to 3.1) in the other prefectures. CONCLUSION: We estimated the incidence of infantile SMA in an isolated area of Japan. For more precise determination of the incidence of infantile SMA, further studies that include neonatal screening will be needed.

Incidence of childhood epilepsy: A population-based study in rural Japan.

INTRODUCTION: Epilepsy is a common childhood neurological condition and a major public health concern worldwide. A higher incidence of epilepsy is reported in low- and middle-income countries, particularly in rural areas. However, no Japanese reports on the incidence of childhood epilepsy have been published in the past 25 years. We estimated the annual incidence of epilepsy in children aged 1-14 years in Uwajima, a city in a rural, relatively isolated area of Japan. METHODS: Candidates were extracted from Japan's public insurance database following the International Classification of Diseases code for epilepsy. Epilepsy was defined as two or more unprovoked seizures more than 24 hours apart, as per the International League Against Epilepsy definition. The study sample was divided into three cohorts based on age at diagnosis: 1-4, 5-9, and 10-14 years. The incidence of epilepsy was calculated as the number of children with epilepsy divided by the person-years in each cohort. RESULTS: The annual incidence rate of epilepsy in children aged 1-14 years was 70.4/100,000 children (95% confidence interval, 44.8-96.0). There was no significant difference in incidence between boys and girls. This rate was similar to those reported in other countries, although the incidence in children aged 1-4 years was slightly higher in our study than in other countries. CONCLUSION: The annual incidence of childhood epilepsy in rural areas of Japan is generally comparable with rates of childhood epilepsy reported in other countries.

Histological characterisation of visceral changes in a patient with type 2 Gaucher disease treated with enzyme replacement therapy.

Gaucher disease is a lysosomal storage disease caused by deficiency of glucocerebrosidase and accumulation of glucocerebroside. Three major sub-types have been described, type 2 is an acute neurological form that exhibits serious general symptoms and poor prognosis, compared with the other types. This case was a girl diagnosed with type 2 Gaucher disease at 12months of age who presented with poor weight gain from infancy, stridor, hypertonia, hepatosplenomegaly, trismus and an eye movement disorder. Enzyme replacement therapy (ERT) was administered, but she had frequent myoclonus and developmental regression. She needed artificial ventilation because of respiratory failure. She died at 11years of age. An autopsy demonstrated infiltrating CD68-positive large cells containing abundant lipids in alveoli, while in the liver, kidney and bone marrow CD68-positive cells were small and round. In the bone marrow, myelodysplastic changes were present without Gaucher cells. The infiltration of Gaucher cells in alveoli was marked, suggesting that ERT was relatively ineffective in pulmonary involvement, particularly intra-alveolar. Additional treatments are necessary to improve the neurological and pulmonary prognosis of type 2Gaucher disease.

Goreisan Inhibits Upregulation of Aquaporin 4 and Formation of Cerebral Edema in the Rat Model of Juvenile Hypoxic-Ischemic Encephalopathy.

Secondary cerebral edema regulation is of prognostic significance in hypoxic-ischemic encephalopathy (HIE), and aquaporin 4 (AQP4) plays an important role in the pathogenesis of cerebral edema. The traditional Japanese herbal medicine Goreisan relieves brain edema in adults; however, its effect and pharmacological mechanism in children are unknown. We investigated the effects of Goreisan on HIE-associated brain edema and AQP4 expression in a juvenile rat model, established by combined occlusion of middle cerebral and common carotid arteries. Magnetic resonance imaging showed that the lesion areas were significantly smaller in the Goreisan- (2 g/kg) treated group than in the nontreated (saline) group at 24 and 48 h postoperatively. AQP4 mRNA levels in the lesion and nonlesion sides were significantly suppressed in the Goreisan group compared with the nontreated group 36 h postoperatively. Western blotting revealed that levels of AQP4 protein were significantly decreased in the Goreisan group compared with the nontreated group in the lesion side 72 h postoperatively, but not at 12 or 36 h. After 14 days, the Goreisan group had a significantly better survival rate. These findings suggest that Goreisan suppresses brain edema in HIE and improves survival in juvenile rats, possibly via regulation of AQP4 expression and function.

High mobility group box 1 enhances hyperthermia-induced seizures and secondary epilepsy associated with prolonged hyperthermia-induced seizures in developing rats.

Levels of high mobility group box 1 (HMGB1), an important inflammatory mediator, are high in the serum of febrile seizure (FS) patients. However, its roles in FS and secondary epilepsy after prolonged FS are poorly understood. We demonstrate HMGB1's role in the pathogenesis of hyperthermia-induced seizures (HS) and secondary epilepsy after prolonged hyperthermia-induced seizures (pHS). In the first experiment, 14-15-day-old male rats were divided into four groups: high-dose HMGB1 (100 µg), moderate-dose (10 µg), low-dose (1 µg), and control. Each rat was administered HMGB1 intranasally 1 h before inducing HS. Temperature was measured at seizure onset with electroencephalography (EEG). In the second experiment, 10-11-day-old rats were divided into four groups: pHS + HMGB1 (10 µg), pHS, HMGB1, and control. HMGB1 was administered 24 h after pHS. Video-EEGs were recorded for 24 h at 90 and 120 days old; histological analysis was performed at 150 days old. In the first experiment, the temperature at seizure onset was significantly lower in the high- and moderate-dose HMGB1 groups than in the control group. In the second experiment, the incidence of spontaneous epileptic seizure was significantly higher in the pHS + HMGB1 group than in the other groups. Comparison between pHS + HMGB1 groups with and without epilepsy revealed that epileptic rats had significantly enhanced astrocytosis in the hippocampus and corpus callosum. In developing rats, HMGB1 enhanced HS and secondary epilepsy after pHS. Our findings suggest that HMGB1 contributes to FS pathogenesis and plays an important role in the acquired epileptogenesis of secondary epilepsy associated with prolonged FS.

Carnitine-related hypoglycemia caused by 3 days of pivalate antibiotic therapy in a patient with severe muscular dystrophy: a case report.

BACKGROUND: Long-term treatment with antibiotics containing pivalic acid may decrease serum carnitine concentration and can sometimes be associated with severe hypoglycemia and encephalopathy in infants. Little has been reported, however, on severe hypocarnitinemia induced by acute administration in older children. CASE PRESENTATION: We describe a 6-year-old Japanese girl with Fukuyama-type congenital muscular dystrophy who lost consciousness after 3 days of treatment with an antibiotic containing pivalic acid (cefditoren pivoxil). Investigations at the onset of unconsciousness revealed hypoglycemia (free plasma glucose concentration: 31 mg/dL) and hypocarnitinemia (serum free carnitine concentration: 6.2 µmol/L). Intravenous administration of glucose rapidly improved her symptoms without any complications. Serum free carnitine concentration was 29.0 µmol/L immediately prior to the initiation of cefditoren pivoxil. Computed tomography scanning showed severe peripheral skeletal muscle atrophy, indicating the likelihood of decreased carnitine stores in skeletal muscle. CONCLUSIONS: Although serum carnitine concentration can appear deceptively normal, skeletal muscle carnitine stores can be reduced in patients with severe muscular atrophy. Even a short course of a pivalate-containing antibiotic can lead to life-threatening hypocarnitinemia in older children with severe muscular dystrophy.

Spinal fusion in a patient with Fukuyama congenital muscular dystrophy.

Many studies have evaluated surgical treatments for spinal deformities in patients with neuromuscular disease. However, few reports have described patients with Fukuyama congenital muscular dystrophy (FCMD). A 13-year-old boy with FCMD was unable to sit for long periods or sleep in the supine position because of progressive scoliosis. His Cobb angle worsened from 27° to 41° in 5months. He underwent standard posterior spinal fusion and pedicle-screw-alone fixation from T5 to S1. Postoperatively, his Cobb angle improved from 41° to 25° without exacerbation for 2years. After the surgery, he was able to sit for longer periods without pain, and he and his family were satisfied with the efficacy of the spinal fusion. Some patients with mild FCMD can sit at the age of puberty, but progression to scoliosis is possible. Therefore, spinal fusion for progressive scoliosis in patients with FCMD should be considered.

Add-on stiripentol elevates serum valproate levels in patients with or without concomitant topiramate therapy.

OBJECTIVE: Stiripentol (STP), valproate (VPA) and topiramate (TPM) are reported to have efficacy for Dravet syndrome. In this study, we sought to elucidate the mechanisms underlying the increased serum VPA concentrations following STP adjunctive therapy in patients with Dravet syndrome. METHODS: Twenty-eight patients with Dravet syndrome (age range, 1-35 years) undergoing combination therapy with VPA and STP were included in this study. We evaluated VPA and clobazam (CLB) serum concentrations before and after add-on STP. We also investigated potential factors impacting VPA metabolism during add-on STP therapy, including add-on TPM and CYP2C9 and CYP2C19 gene polymorphisms. The effect of STP on the metabolism of concomitantly administered CLB was also investigated. RESULTS: Add-on STP was significantly associated with the serum concentration-to-dose (CD) ratio of VPA. Two patients, who were concomitantly treated with TPM, developed severe anorexia and thrombocytopenia because of marked increases in serum VPA concentrations. Further analysis revealed that the rate of increase in the VPA CD ratio was positively correlated with TPM dose. In patients not receiving TPM, STP enhanced the rate of increase in the VPA CD ratio to a significantly greater extent in CYP2C19 extensive metabolizers than in CYP2C19 poor metabolizers. Add-on STP was also associated with significant increases in CLB and N-desmethyl-CLB serum concentrations. CONCLUSION: Our findings suggest that serum VPA concentrations should be carefully monitored during STP adjunctive therapy, particularly in patients receiving concomitant TPM therapy.