Long-term Valproate Therapy Research Articles

Unusual cause of hyperammonemia in two cases with short-term and long-term valproate therapy successfully treated by single dose carglumic acid

Valproic acid (VPA) is an antiepileptic drug which is used in the treatment of various seizure disorders including tonic-clonic, myoclonic, absence, partial seizures and psychiatric disorders. VPA is usually well tolerated, but severe adverse effects may occur. Hyperammonaemic encephalopathy (HE) is a rare and potentially fatal complication of VPA treatment. The mechanism by which valproate induces hyperammonemia remains incompletely understood but is likely to relate to the urea cycle. Herein we present two cases with valproate-induced hyperammonemia at therapeutic valproate levels without signs of liver failure and were successfully treated by a single dose of carglumic acid.

Valproato de sódio: efeitos colaterais em crianças

OBJETIVO: O valproato de sódio é um fármaco anticonvulsivante usado com frequência no manejo dos quadros epilépticos refratários na infância e habitualmente apresenta boas taxas de resposta e toxicidade aceitável. O objetivo deste artigo é destacar os efeitos colaterais secundários ao uso prolongado de valproato de sódio em uma criança e alertar para a importância do acompanhamento dos pacientes em uso crônico de anticonvulsivantes. DESCRIÇÃO DO CASO: Criança do sexo masculino, com quatro anos e oito meses, portadora de síndrome de West, em uso de valproato de sódio desde os seis meses de idade, admitida no hospital com anemia, macrocitose, plaquetopenia, deficiência de vitamina B12, hipoalbuminemia e hiponatremia. Durante a internação e o acompanhamento ambulatorial, relacionou-se o quadro clínico ao uso do valproato de sódio. COMENTÁRIOS: A toxicidade hematológica do valproato de sódio é bem conhecida e comum, podendo variar em relação à época de instalação e gravidade. Os achados mais frequentes são a plaquetopenia e a macrocitose. Além das alterações hematológicas, a literatura relata outros efeitos colaterais relacionados ao uso do fármaco. Destaca-se a importância do conhecimento e monitorização dos eventos adversos nos pacientes submetidos a esse tipo de terapia, para que eles possam ser detectados e tratados o mais precocemente.

Valproate-Induced Subclinical Hypothyroidism

Back to table of contents Previous article Next article LETTERFull AccessValproate-Induced Subclinical HypothyroidismPallavi Rao M.D.D.S., M.D.Shanker Madhav Natu M.Sc., Ph.D.Madhu Mati Goel M.B.B.S., M.D.Bashir Ali M.Sc., Ph.D.,Pallavi Rao M.D.D.S., M.D.Search for more papers by this authorShanker Madhav Natu M.Sc., Ph.D.Search for more papers by this authorMadhu Mati Goel M.B.B.S., M.D.Search for more papers by this authorBashir Ali M.Sc., Ph.D.Search for more papers by this author,Published Online:1 Jan 2008AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Drug-induced hypothyroidism has been well established in the literature with drugs like lithium, iodine, and amiodarone. We report a rare case of subclinical hypothyroidism in a patient on long-term valproate therapy. A 30-year-old patient undergoing treatment for manic-depressive bipolar disorder presented with complaints of increasing fatigue and weakness. He was on sodium valproate and olanzapine therapy for 8 years before his clinical presentation. His laboratory findings revealed a raised thyrotropin (TSH) of 27.61 microIU/ml (normal range=4–7 microIU/ml) with normal T3 and T4, on two consecutive occasions. His liver function tests showed a raised SGPT (60U/liter). His renal function tests and basic hematological parameters were within normal limits. Subsequent tests for antithyroid antibodies were negative. There was no past history or family history of any thyroid disease. Subclinical hypothyroidism is manifested by raised TSH with normal T3 and T4 levels. The prevalence of subclinical hypothyroidism is approximately 14% and is more frequently observed in females. 1 The main causes of hypothyroidism are autoimmune disorders, inflammation, iodine deficiency, drugs, radio ablated thyroid gland, post surgical resection, and pituitary disorders. Patients with subclinical hypothyroidism may occasionally present with signs and symptoms of clinically apparent hypothyroidism, such as fatigue, weight gain, and dry skin. The association of hypothyroidism with drugs like lithium, amiodarone, and iodine is well established in the literature. Antiepileptic drugs, however, have been recently added to the list. Sodium valproate is commonly used in the treatment of epilepsy and bipolar disorder. It acts by destroying γ-aminobutyric acid (GABA) antagonist thereby increasing the levels of GABA, which is said to have an antimanic effect. The well-known side effects of valproate therapy are weight gain, dyspepsia, headache, and hepatotoxicity. Studies in children undergoing long-term valproate therapy have shown a significantly higher level of TSH compared to controls. 2 Higher levels of TSH, with normal T3 and T4, were also seen in girls undergoing valproate monotherapy. 3 Contradictory to this, some reports suggest that though antiepileptic drugs like carbamazepine and phenytoin have been found to induce hypothyroidism—due to their hepatic enzyme induction properties which lead to increased clearance of thyroid hormones—valproate did not seem to have the same effect on thyroid function as it was not a hepatic enzyme inducer. 4As our patient presented with excessive fatigue, we evaluated his thyroid function tests, which revealed a subclinical hypothyroid state. Increased SGPT levels noted in the patient may be due to hepatotoxic potential of valproate. The patient had no history of radioiodine therapy or any surgical procedure which might have accounted for this clinical state. The patient had negative antithyroid antibody screens ruling out autoimmune causes. As there was no evidence in the literature to support the role of olanzapine in induction of hypothyroidism, we attribute the hypothyroid state of our patient to long-term valproate therapy.This case report highlights the importance of routine thyroid function tests in patients undergoing long-term valproate therapy, which may lead to early detection of subclinical hypothyroid state and thereby prevent subsequent complications.King George Medical University, Lucknow, IndiaReferences1 . Díez JJ, Iglesias P: Spontaneous subclinical hypothyroidism in patients older than 55 years: an analysis of natural course and risk factors for the development of overt thyroid failure. J Clin Endocrinol Metab 2004; 89:4890–4897Google Scholar2 . Eiris-Punal J, Del Rio-Garma M, Del Rio-Garma MC, et al: Long-term treatment of children with epilepsy with valproate or carbamazepine may cause subclinical hypothyroidism. Epilepsia 1999; 40:1761–1766Google Scholar3 . Vainionpaa LK, Mikkonen K, Rattya J, et al: Thyroid function in girls with epilepsy with carbamazepine, oxcarbazepine, or valproate monotherapy and after withdrawal of medication. Epilepsia 2004; 45:197–203Google Scholar4 . Isojarvi JI, Pakarinen AJ, Myllyla VV: Thyroid function with antiepileptic drugs. Epilepsia 1992; 33:142–148Google Scholar FiguresReferencesCited byDetailsCited BySevere fatigue due to valproate-induced hypothyroidism in a case of bipolar disorder5 September 2020 | Annals of General Psychiatry, Vol. 19, No. 1Effect of antiepileptic drugs on the thyroid gland in adult albino ratsThe Egyptian Journal of Histology, Vol. 38, No. 1 Volume 20Issue 1 Winter, 2008Pages 111-112 Metrics PDF download History Published online 1 January 2008 Published in print 1 January 2008

Sodium Valproate, Hyperandrogenism and Altered Ovarian Function in Indian Women with Epilepsy: A Prospective Study

To assess the association of long-term sodium valproate therapy with reproductive endocrine disorders in Indian women with generalized epilepsy. Clinical parameters, ovarian morphology, and serum reproductive hormone concentrations were evaluated in 30 clinically normal and eumenorrheic reproductive age women with generalized epilepsy who were newly initiated on valproate. Longitudinal evaluations were done in 25 of these women after 1 year, and in some of them after 2 and 3 years of therapy. Of the 25 women who completed 1 year follow-up, we observed clinically relevant weight gain in 40%, hirsutism in 20%, menstrual abnormalities in 24%, polycystic ovaries (PCO) in 16%, polycystic ovarian syndrome (PCOS) in 20%, and a significant increase in mean serum testosterone (p=0.046). A significant positive correlation existed between weight gain and the development of menstrual abnormalities (r=0.66, p<0.0001), hirsutism (r=0.53, p=0.006) and PCO (r=0.51, p=0.012). No correlation existed between weight change and serum reproductive hormonal changes. Yearly follow-up for next 2 years in some of these women revealed persistence of menstrual abnormalities, hirsutism and PCO, a significant linear increase in mean body weight, body mass index, and serum testosterone concentrations, and an increase in serum LH levels from second year onwards. Limitations include small sample size and a high dropout rate on follow-up. Long-term valproate therapy in Indian women with generalized epilepsy is associated with development of hirsutism, significant weight gain, stable or progressive alterations in reproductive hormonal function, and ultimately a higher occurrence of PCOS.

Valproate-induced hyperammonemic encephalopathy with normal liver function

Hyperammonemic encephalopathy with normal liver function is an uncommon serious adverse effect of valproate therapy. We retrospectively analyzed the case records of 5 patients of epilepsy on valproate with hyperammonemic encephalopathy. Of the 5 patients, 3 were on monotherapy. The mean valproate dose was 1250 mg/day and the duration of therapy ranged between 4 and 90 days. Alteration in the sensorium was the presenting clinical feature. The risk factors included high initial dose (2), long-term valproate therapy (1), and long-term valproate therapy with concomitant topiramate (1). There was good correlation between the fall in serum ammonia levels and clinical improvement. Hyperammonemic encephalopathy should be suspected in patients on valproate with altered sensorium. Response to treatment is rewarding.

A case of valproate-associated hepatotoxicity treated with l-carnitine

Valproate is a major broad-spectrum anti-epileptic drug that is effective against many different types of epileptic seizures and that is usually well tolerated. Nevertheless, serious side effects can occur, including hepatotoxicity. This side effect is rare but often fatal, and it has been hypothesized that long-term valproate therapy may induce a carnitine deficiency and cause non-specific symptoms of hepatotoxicity and hyperammonemia. These factors suggest that l-carnitine supplementation may play a role in preventing hepatotoxicity. We report a case of valproate-induced acute liver injury with a favorable evolution after l-carnitine therapy.

Influence of valproate monotherapy on platelet activation and hematologic values.

Valproate (VPA) has been linked to coagulation disturbances, with both impaired and exaggerated clotting, which has been attributed to an effect of VPA on platelets or hemostatic proteins. Additional thrombocytic function testing may help to identify patients at risk of increased bleeding caused by platelet dysfunction. We evaluated the influence of VPA on hematologic routine values and platelet activation by using immunostaining and flow cytometry in 30 patients receiving long-term VPA therapy and in 30 controls. The fraction of activated platelets was similar in both groups; however, the general extent of platelet activation was significantly lower in the patient group, with considerable interindividual variability. In addition, patients had a significantly lower platelet count, prolonged thrombin time, and higher mean corpuscular hemoglobin. Our data confirm the previously reported hematologic changes caused by VPA and additionally suggest that VPA impairs procoagulatory thrombocytic function, which is reflected by reduced platelet activation and increased thrombin time. Possible mechanisms of VPA-platelet interaction are discussed.

Haematological disturbances during long-term valproate therapy

A 14-year-old boy with mental retardation presented with severe thrombocytopenia, macrocytic anaemia and allergic dermatitis. He had been treated with valproate for seizures since the age of 2 years. Clinical examination showed severe purpura, mucous bleeding and extensive dermatitis. Tests to detect serum direct antiplatelet antibodies were positive and bone marrow examination revealed myelodysplastic abnormalities. Valproate was discontinued and both dermatitis and general condition of the child improved with normalization of the full blood count. This report suggests that valproate may produce both peripheral immune thrombocytopenia and severe bone marrow depression several years after the initiation of the therapy.

Haematological disturbances during long-term valproate therapy

Haematological disturbances during long-term valproate therapy

Hematologic manifestations of long-term valproate therapy.

Sixty patients receiving long-term valproate (VPA) monotherapy were studied for hematologic side effects. All were patients in a long-term care facility and ranged in age from 2 to 29 years (mean 14.6 years). Twenty developed at least one prominent hematologic abnormality. Thrombocytopenia and macrocytosis were the most common findings. In patients with macrocytosis, platelet counts were inversely related to VPA levels. Serum B12 levels were increased in 51 of the patients. In 12 patients with macrocytosis who were extensively studied, no etiology for the increased MCV could be identified. An increased number of Pelger-Huet-like cells was noted in these 12 patients. None of the patients demonstrated hepatic dysfunction. Hematologic toxicity was never severe enough to discontinue therapy and always responded to small decrements in VPA therapy. VPA was discontinued in only 1 patient, owing to poor seizure control.

Edema Associated with Long‐Term Valproate Therapy

Scattered reports of facial and limb edema have been reported, predominantly in the context of valproate (VPA)-induced hepatic injury. We report seven patients with edema associated with long-term VPA therapy in the absence of hepatic disease.