Severe hematologic toxicity of valproic acid. A report of four patients

Four patients with severe cerebral palsy, mental retardation, and seizures who were treated with valproic acid showed a broad spectrum of hematologic toxicity, which included thrombocytopenia, macrocytic red cells with or without anemia, and the Pelger-Huet anomaly in the segmented neutrophils, along with elevated vitamin B12 levels, normal serum folic acid levels, and elevated fetal hemoglobin values (two cases). Bone marrow findings in all four patients were abnormal, suggestive of a myelodysplastic syndrome. These hematologic findings have not been previously reported and are important for monitoring a patient on valproic acid therapy. The Pelger-Huet anomaly may be mistaken for an elevated band count, the macrocytic anemia appears not to be secondary to a vitamin B12 or folate deficiency, and the thrombocytopenia may be sensitive to drug dosage. The bone marrow changes appear to be a drug-related myelodysplastic phenomenon.     

Severe valproic acid intoxication is associated with atrial tachycardia: secondary detoxication by hemoperfusion

Valproic acid is an anticonvulsant drug which is associated with serious toxicity including fatal outcome in case of severe intoxication. Secondary detoxication by hemodialysis or hemoperfusion has been employed successfully in valproic acid intoxication. Cardiac arrhythmias have only been described rarely in valproic acid intoxication in humans. We report on a 15 year-old boy with severe valproic acid intoxication (valproic acid plasma level on admission: 1 150 mg/l) who presented with coma, hypernatremia and atrial tachycardia. The patient was successfully treated with hemoperfusion and intensive supportive care without implementation of a specific antiarrhythmic therapy. We conclude that patients with severe valproic acid intoxication may benefit from secondary detoxication. In addition to generally known symptoms valproic acid intoxication may also be associated with cardiac arrhythmias.     

Valproic acid prenatal exposure. Association with lipomyelomeningocele

Valproic acid is an anticonvulsant that has been associated with open neural tube defects. We report a family in which the maternal use of valproic acid, and other anticonvulsants, during pregnancy resulted in different malformations in two siblings, one of which had a lipomyelomeningocele. The association of valproic acid and closed neural tube defects has not previously been reported. A brief review of the teratogenic effects of valproic acid is included as well as the implications for early surgical management of lipomyelomeningocele.     

Pancreatitis associated with valproic acid therapy

Four patients had pancreatitis associated with valproic acid therapy. Three patients received valproic acid at usual doses, and all were free of other symptoms of toxic reactions, with serum levels of valproic acid in the usual therapeutic range. Two patients underwent exploratory laparotomy prior to diagnosis. Complications included pseudocyst, pericardial effusion, laparotomy wound infection, and coagulopathy. All patients recovered with discontinuation of valproic acid therapy and enteral feeding and administration of intravenous fluids. After recovery, a valproic acid regimen was restarted uneventfully (in one patient). All were asymptomatic with normal serum amylase levels after five to 14 months. Pancreatitis is a serious complication of valproic acid therapy that must be considered in any patient receiving valproic acid who experiences severe abdominal pain and vomiting.     

Evaluation of bone mineral metabolism in children receiving carbamazepine and valproic acid

Dual energy X-ray absorptiometry (DXA) was used to assess lumbar spine (L2-4) and femoral neck bone mineral density (BMD) in 36 children taking either carbamazepine or valproic acid for longer than one year, for generalized idiopathic epilepsy. Patients were matched with controls. Biochemical parameters of bone mineral metabolism were also measured. BMD values at both the femur neck and lumbar spine in both the carbamazepine and valproic acid groups were not significantly different from that of the control group. Serum levels of calcium were subnormal and alkaline phosphatase levels were high in the carbamazepine group. Urinary calcium levels were significantly lower in both groups than in the control group (p< or =0.05) and also significantly lower in the valproic acid group than in the carbamazepine group (p< or = 0.05). There were no other significant biochemical changes in either group. In conclusion, the results suggest that valproic acid and carbamazepine monotherapies have minimal effects on bone mineral metabolism, but routine monitoring of risk and consideration of prophylactic vitamin D supplementation is important.     

Translocation-positive acute myeloid leukemia associated with valproic acid therapy

Valproic acid is an effective anti-epileptic medication often used for long-term control of seizure disorders that has been implicated in hematological toxicities, including rare reports of myelodysplasia and acute leukemia. Here, we report a case of valproic acid-related leukemia-like syndrome with a t(8;16) chromosomal translocation. After discontinuing valproic acid, the hematological findings completely resolved.     

Aplasia cutis congenita of the scalp in an infant exposed to valproic acid in utero

We report a newborn with isolated aplasia cutis congenita of the scalp whose mother was treated with valproic acid during pregnancy. Aplasia cutis congenita has been described in infants exposed in utero to antithyroid drugs, but has not been related to other tetratogenic agents. Fetal exposure to valproic acid is known to increase the risks of spina bifida and other midline defects. Interestingly, aplasia cutis congenita of the scalp is regarded as a cutaneous marker for neural dysraphism. However, this defect of the scalp and valproic acid intake during pregnancy may be a random association and similar observations are needed to suggest causality.     

Bone marrow suppression induced by high dose valproic acid.

A girl with intractable epilepsy who received high dose valproic acid showed bone marrow suppression, which improved after the end of valproic acid treatment and the administration of supportive treatments. Valproic acid markedly suppressed the in vitro colony growth in this patient. It is believed that high dose valproic acid treatment directly suppressed the growth of haematopoietic progenitors, resulting in bone marrow failure.     

Carnitine as an antidote for acute valproate toxicity in children

PURPOSE OF REVIEW: Valproic acid is a widely used anticonvulsant that has recently been approved for stabilization of manic episodes in patients with bipolar disorder. As the use of valproic acid increases, the number of both accidental and intentional exposures increases. This is paralleled by more reports of valproic-acid-induced toxicity. The purpose of this article is to review the pathophysiology and toxicology of valproic acid and determine whether the literature supports the use of carnitine as a treatment for acute valproic-acid-induced toxicity. RECENT FINDINGS: Recent literature documents no cases of allergic reactions or serious side effects associated with the administration of carnitine when given patients with acute ingestions of valproic acid. Other findings suggest that carnitine increases the survival rate of patients who develop valproic-acid-induced hepatotoxicity. Early intervention with intravenous rather than enteral L-carnitine was associated with the greatest hepatic survival. Isolated pediatric case reports show that carnitine administration may reverse toxic metabolic pathways but may not hasten clinical improvement. SUMMARY: Based on this recent literature, it seems reasonable to use carnitine for documented severe valproic acid toxicity, particularly in cases where patients present with coma, rising ammonia level, or valproic acid levels greater than 450 mg/l.     

Carnitine deficiency and hyperammonemia associated with valproic acid therapy

Plasma carnitine and blood ammonia concentrations were measured in 25 severely handicapped patients, ages 3 to 21 years, and 27 age-matched control subjects. Fourteen of the handicapped patients were treated with anticonvulsant drugs including valproic acid; the remaining 11 patients were treated with drugs excluding valproic acid. Plasma carnitine concentrations were lower and blood ammonia values were higher in patients treated with valproic acid than in the untreated patients and control subjects. A significant inverse relationship was found between plasma carnitine concentrations and the dosage of valproic acid, and between plasma carnitine and blood ammonia values. After oral administration of D,L-carnitine (50 mg/kg/day) for four weeks, both carnitine deficiency and hyperammonemia were corrected.     

Pancreatitis associated with valproic acid therapy.

The development of acute pancreatitis in an 8-year-old boy being treated with valproic acid for simple absence spells is documented. A brief discussion of the other previously reported complications with valproic acid is included.     

Omphalocele in a newborn baby exposed to sodium valproate in utero

We report on a newborn baby, exposed to valproic acid in utero, with the typical dysmorphic features of the fetal valproate syndrome and omphalocele. One identical case has already been reported after valproic acid exposure in utero.Conclusion Intra-uterine valproate exposure may be responsible for midline defects of the abdominal wall.     

PATHOLOGICAL CASE OF THE MONTH: SUDDEN DEATH IN A CHILD AS A RESULT OF PANCREATITIS DURING VALPROIC ACID THERAPY

Valproic acid is a widely used drug in the treatment of epilepsy and, compared to other anticonvulsant drugs, is considered safe. The most common side effects of valproic acid ingestion or therapy are transient nausea, vomiting, abdominal cramps, and diarrhea. Most of these complaints are mild. However, more serious adverse reactions can occur such as hepatotoxicity and pancreatitis. It has been proposed that, whenever possible, valproic acid not be used in the younger child, the child with a severe seizure disorder or other neurological disorders, mental retardation, developmental delay, organic brain disease, congenital abnormalities, or the child who is taking multiple anticonvulsant drugs, as these factors may increase the likelihood of hepatotoxicity and/or pancreatitis. In the present report, we describe a fatal case of acute hemorrhagic pancreatitis in a four and a half-year-old Hispanic female child who was receiving valproic acid in combination with another anticonvulsant drug for control of focal seizures. The patient also received the macrolide antibiotic azithromycin. For pediatricians and forensic pathologists valproic acid-induced pancreatitis can be a challenging diagnosis which must not be mistaken for abdominal trauma. We discuss the workup of the patient and differential diagnosis.     

Vitamin K and Thrombotest values in full term infants.

The vitamin K dependent clotting factors were measured by the ''Thrombotest'' on the second day of life in 72 healthy full term babies, half of whom had received vitamin K at birth. Forty eight of these were breast fed, and those not given vitamin K had significantly lower Thrombotest values than those who had received vitamin K. By contrast, administration of vitamin K did not affect the Thrombotest values in bottle fed babies, the values in treated and untreated babies being the same and of the same order as the level in those breast fed babies treated with vitamin K. Serial study of 18 normal breast fed babies tested at day 0 and day 2 showed a pronounced drop in the Thrombotest values in this period, which was prevented by one intramuscular dose of 1 mg vitamin K at birth. Although none of the neonates in this study showed haemorrhagic disease, nine of the 24 untreated breast fed infants had Thrombotest values below 10% on day 2, at which level bleeding has been reported.     

Effect of carbamezapine and valproic acid on bone mineral density, IGF-I and IGFBP-3

OBJECTIVE: To examine the effect of carbamezapine and valproate on bone mineral density (BMD), IGF-I and IGFBP-3 levels in children. METHODS: The effects of at least 2 years valproic acid and carbamazepine therapy on BMD were evaluated in a cross-sectional and retrospective study. All children were ambulatory, prepubertal, and had normal activity and nutritionally adequate diets. Ambulatory epileptic patients were divided into two groups. Thirty-three patients (group 1; 17 boys, 16 girls; mean age: 8.8 +/- 2.0 years) were treated with valproic acid and 33 patients were treated with carbamazepine (group 2; 20 boys, 13 girls; mean age: 9.7 +/- 1.6 years). The control group consisted of 22 healthy children (13 boys, 9 girls; mean age: 8.9 +/- 2.3 years), who were age- and sex-matched with the patient groups. Children with metabolic bone disease, growth and neurological impairment, signs of malnutrition, or any chronic disease were excluded from the study. RESULTS: BMD values at lumbar spine in both the carbamazepine (-1.69 +/- 0.85 mean L1-4 BMD z-scores, mean 35.5 +/- 12.8 months treatment, and 19,478.6 +/- 6,301.3 mg/kg cumulative dose) and valproic acid (-1.28 +/- 0.80 mean L1-4 BMD z-scores, mean 33.7 +/- 15.0 months treatment, and 22,852.4 +/- 12,477.4 mg/kg cumulative dose) groups were significantly lower than that of the control group (-0.23 +/- 0.87 mean L1-4 BMD z-score). Serum ALP and PTH levels were significantly higher in the carbamazepine-treated group (65.4 +/- 21.1 pg/ml, 767 +/- 267 U/l, respectively) than those of the valproic acid-treated (39.1 +/- 12.8 pg/ml, 561 +/- 166 U/l, respectively) and control groups (36.3 +/- 4.9 pg/ml, 487 +/- 82 U/l, respectively). Serum 25-hydroxyvitamin D of the carbamazepine-treated group (9.8 +/- 3.2 microg/l) was significantly lower than the other groups (15.1 +/- 3.5, 16.6 +/- 4.7 microg/l, respectively). There were eight and 13 patients with plasma intact PTH above reference values in groups 1 and 2, respectively. Valproic acid and carbamazepine therapy results in a hyperparathyroid state and altered vitamin D metabolism, respectively. CONCLUSION: BMD values at lumbar spine were significantly reduced in both carbamezapine and valproic acid treated groups. Valproic acid and carbamazepine therapy do not change IGF-I and IGFBP-3 levels. Altering the hepatic conversion of vitamin D may be the mechanism of carbamazepine-associated reduction in BMD, but the mechanism of decreased BMD in valproate therapy remains unclear.     

Periodic discharge of adrenocorticotropin and vasopressin associated with focal glomerulosclerosis

We report the first case of the syndrome of periodic adrenocorticotropin (ACTH) and vasopressin (ADH) discharge associated with focal glomerulosclerosis. Approximately 30 cases of this syndrome have so far been reported in Japan, but no cases associated with renal dysfunction have yet been reported. The patient, a 10-year-old Japanese boy, was referred to our hospital because of recurrent attacks of vomiting. He was diagnosed as having this syndrome from clinical and laboratory findings. While various drugs were tried to manage his vomiting attacks, only valproic acid appeared to be effective in reducing the frequency of the attacks. Chronic nephritis was manifested when the patient was 12 years old, which required treatment with continuous ambulatory peritoneal dialysis. Valproic acid was proved to be effective in reducing the number of attacks over 4 months.     

Anti-Epileptic drug treatment in children: Hyperhomocysteinaemia, B-Vitamins and the 677C→T Mutation of the Methylenetetrahydrofolate Reductase Gene

The aim of the study was to observe the influence of carbamazepine and valproic acid on plasma total homocysteine and B-vitamin status and the gene-drug interaction with the 677C-->T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. Plasma total homocysteine concentrations were determined in 136 epileptic children taking anti-epileptic drugs as monotherapy. Nutritional (folate, B12 and B6 vitamins) and genetic (MTHFR 677 C-->T) determinants of plasma homocysteine were studied in a random sample of 59 of the 136 epileptic children. Total homocysteine concentrations were significantly increased (p < 0.05) and folate and vitamin B6 levels were significantly decreased (p < 0.01) in the children taking anti-epileptic drugs compared with our reference ranges. In the carbamazepine-treated group, significantly positive correlation was found between duration of treatment and homocysteine concentration (p < 0.01). Homocysteine concentrations showed a significantly negative correlation with vitamin levels (folate: p = 0.002, and vitamin B12: p = 0.017) only in the carbamazepine treated group. In children treated with carbamazepine up to 3 years, total homocysteine concentration correlated negatively only with folate (p = 0.003), while in patients treated for more than 3 years, total homocysteine correlated negatively only with vitamin B12 values (p = 0.007). The lowering action of carbamazepine treatment on folate levels seems to be associated with hyperhomocysteinaemia, which seems to be related to the homozygous condition for the MTHFR 677C-->T mutation. Valproic acid treatment, although also associated with hyperhomocysteinaemia, only shows a lowering effect on vitamin B6 levels, which seems to be independent of the MTHFR genotype.     

Prevention of vitamin K deficiency bleeding with oral mixed micellar phylloquinone: results of a 6-year surveillance in Switzerland

In 1995, a new form of vitamin K prophylaxis with two oral doses of 2 mg mixed micellar phylloquinone (Konakion MM) on the 1st and 4th day of life was introduced in Switzerland. It was hoped that this new galenic preparation of phylloquinone would protect infants with insufficient or absent bile acid excretion from late vitamin K deficiency bleeding (VKDB). Subsequently, the occurrence of VKDB was monitored prospectively between July 1, 1995 and June 30, 2001 with the help of the Swiss Paediatric Surveillance Unit (SPSU). Over a period of 6 years (475,000 deliveries), there were no cases of early (<24 h of age), one case of classical (2–7 days of life), and 18 cases of late (1–12 weeks) VKDB fulfilling standard case definitions. In 13/18 patients with late VKDB there was pre-existing liver disease and in 4/18 patients, parents had refused prophylaxis. The incidence of late VKDB for infants with completed Konakion MM prophylaxis was 2.31/100,000 (95% CI: 1.16–4.14) and for the entire population 3.79/100,000 (95% CI: 2.24–5.98). There was only one case of late VKDB after complete prophylaxis in an infant without underlying liver disease. Conclusion: two oral doses of 2 mg of a mixed micellar vitamin K preparation failed to abolish VKDB. The recommendations for vitamin K prophylaxis in Switzerland have therefore been changed to include a third dose at 4 weeks of age. Starting on January 1, 2004, the incidence of vitamin K deficiency bleeding will again be monitored prospectively by the Swiss Paediatric Surveillance Unit.Abbreviations CI confidence interval - SPSU Swiss Paediatric Surveillance Unit - VKDB vitamin K deficiency bleeding     

Early treatment with erythromycin of Campylobacter jejuni-associated dysentery in children

To evaluate the efficacy of early treatment with erythromycin on the duration of fecal excretion and of diarrhea associated with Campylobacter jejuni, 170 patients, age 3 to 60 months, were randomly assigned in a double-blind fashion to receive either erythromycin ethyl succinate or placebo immediately after being seen at Cayetano Heredia Hospital because of acute dysentery. The groups' pretreatment characteristics were comparable. Of the 30 patients with stools positive for C. jejuni, 12 were in the placebo group and 16 in the treatment group. After 2 days of treatment, none of the patients in the placebo group and 36% of those in the erythromycin group had normal stools (P less than 0.05). After 5 days of treatment, 50% of the patients in the placebo group and 93% of those in the erythromycin group had normal stools (P less than 0.02). Fecal excretion of the organism continued significantly longer in the placebo group (P less than 0.01). There were no treatment failures in the treatment group compared with five (42%) in the placebo group (P less than 0.01). Thus, early administration of erythromycin significantly reduced the duration of both diarrhea and fecal excretion of the organism in infants and children with acute dysentery associated with C. jejuni.     

不同丙戊酸负荷量对癫痫持续状态的治疗效果分析

目的了解不同丙戊酸负荷量对癫痫持续状态患儿的治疗效果。方法收集2013年1月1日至2017年12月31日在浙江大学医学院附属儿童医院重症监护室住院治疗的癫痫持续状态患儿的病例资料,根据丙戊酸负荷量进行分组,了解各组患儿癫痫持续状态的控制情况。结果(1)66例癫痫持续状态患儿,包括癫痫36例(54.5%),颅内感染16例(24.2%),缺氧窒息3例(4.5%),颅内肿瘤2例(3.0%),脑发育异常2例(3.0%),颅内出血2例(3.0%),病因不明确5例(7.6%)。(2)所有癫痫持续状态患儿根据不同的丙戊酸负荷量(0 mg/kg,10~15 mg/kg,16~39 mg/kg,40 mg/kg)分为4组,各组间的性别、年龄差异无统计学意义,癫痫持续状态控制时间和癫痫控制情况差异无统计学意义(P=0.402、0.340)。(3)所有患儿予丙戊酸钠应用后都有监测肝功能,无一例患儿出现肝功能损害的表现。结论不同丙戊酸负荷量对于癫痫持续状态患儿的治疗效果无明显差异,并且接受负荷量为40 mg/kg治疗的癫痫持续状态患儿未出现相关不良反应。