Allergic skin rash with lamotrigine and concomitant valproate therapy - Evidence for an increased risk

Cutaneous rash is one of the commonest adverse events associated with lamotrigine. We assessed whether the risk is increased in patients receiving concomitant valproate therapy in a population of 103 adult patients with intractable epilepsy, who had lamotrigine added to their treatment. Of the 33 patients taking valproate, 10 (30%) developed a rash, whilst of the 70 not taking valproate, only 6 (8%) developed a rash. This suggests a significantly higher risk of cutaneous rash when starting lamotrigine in patients already taking valproate (p<0.02)

Latest clinical recommendations on valproate use for migraine prophylaxis in women of childbearing age. Overview from European Medicines Agency and European Headache Federation

Migraine is a common and burdensome neurological condition which affects mainly female patients during their childbearing years. Valproate has been widely used for the prophylaxis of migraine attacks and is also included in the main European Guidelines. Previous (2014) European recommendations on limiting the use of valproate in women of childbearing age did not achieve their objective in terms of limiting the use of valproate in women of childbearing age and raising awareness regarding the hazardous effect of valproate to children exposed in utero. The teratogenic and foetotoxic effects of valproate are well documented, and more recent studies show that there is an even greater neurodevelopmental risk to children exposed to valproate in the womb. The latest 2018 European review from the European Medicines Agency, with the active participation of the European Headache Federation, concluded that not enough has been done to mitigate the risks associated with in utero exposure to valproate. The review called for more extensive restrictions to the conditions for prescribing, better public awareness, and a more effective education campaign in migrainous women

Teratogenic risk and contraceptive counselling in psychiatric practice: analysis of anticonvulsant therapy

&lt;p&gt;Background: Anticonvulsants have been used to manage psychiatric conditions for over 50 years. It is recognised that some, particularly valproate, carbamazepine and lamotrigine, are human teratogens, while others including topiramate require further investigation. We aimed to appraise the documentation of this risk by psychiatrists and review discussion around contraceptive issues.&lt;/p&gt; &lt;p&gt;Methods: A retrospective review of prescribing patterns of four anticonvulsants (valproate, carbamazepine, lamotrigine and topiramate) in women of child bearing age was undertaken. Documented evidence of discussion surrounding teratogenicity and contraceptive issues was sought.&lt;/p&gt; &lt;p&gt;Results: Valproate was most commonly prescribed (n=67). Evidence of teratogenic risk counselling at medication initiation was sub-optimal – 40% of individuals prescribed carbamazepine and 22% of valproate. Documentation surrounding contraceptive issues was also low- 17% of individuals prescribed carbamazepine and 13% of valproate.&lt;/p&gt; &lt;p&gt;Conclusion: We found both low rates of teratogenic risk counselling and low rates of contraception advice in our cohort. Given the high rates of unplanned pregnancies combined with the relatively high risk of major congenital malformations, it is essential that a detailed appraisal of the risks and benefits associated with anticonvulsant medication occurs and is documented within patients’ psychiatric notes.&lt;/p&gt

Differential treatment of bipolar disorder with old and new antiepileptic drugs

Although lithium remains the preferred medication for bipolar disorders, new investigations suggest that only 60 to 80% of patients have a good response with a classical presentation. The antiepileptics carbamazepine and valproate are important alternatives. Several studies have shown that lithium, carbamazepine and valproate are effective in pure mania. Mixed mania and rapid cycling respond, however, well to valproate. One disadvantage of carbamazepine is its enzyme inducing property with the consequence of a decrease of plasma levels of other psychotropic medications and a worsening of psychopathology. First data indicate a good antimanic and antidepressive efficacy of the new antiepileptic drug lamotrigine

The effect of sodium valproate in Cushing's disease, Nelson's syndrome and Addison's disease

We investigated the effect of sodium valproate on plasma ACTH and serum cortisol concentrations in different pathological states of ACTH hypersecretion. Five patients with pituitary dependent Cushing's syndrome, two patients with Nelson's syndrome and five patients with Addison's disease were studied. Neither a single dose nor long term administration of sodium valproate resulted in a significant decrease of plasma ACTH levels in patients with Cushing's disease and Nelson's syndrome. Furthermore, the response of ACTH and cortisol to stimulation with lysine-vasopressin was unaffected during acute and chronic treatment. Patients with Addison's disease showed a slight attenuation of the ACTH response to lysine-vasopressin as compared to placebo but the difference was not statistically significant. In conclusion: sodium valproate does not appear to be effective in controlling ACTH hypersecretion in pituitary dependent Cushing's syndrome

Severe hepatopathy and neurological deterioration after start of valproate treatment in a 6-year-old child with mitochondrial tryptophanyl-tRNA synthetase deficiency

Background: The first subjects with deficiency of mitochondrial tryptophanyl-tRNA synthetase (WARS2) were reported in 2017. Their clinical characteristics can be subdivided into three phenotypes (neonatal phenotype, severe infantile onset phenotype, Parkinson-like phenotype). Results: Here, we report on a subject who presented with early developmental delay, motor weakness and intellectual disability and who was considered during several years as having a non-progressive encephalopathy. At the age of six years, she had an epileptic seizure which was treated with sodium valproate. In the months after treatment was started, she developed acute liver failure and severe progressive encephalopathy. Although valproate was discontinued, she died six months later. Spectrophotometric analysis of the oxidative phosphorylation complexes in liver revealed a deficient activity of complex III and low normal activities of the complexes I and IV. Activity staining in the BN-PAGE gel confirmed the low activities of complex I, III and IV and, in addition, showed the presence of a subcomplex of complex V. Histochemically, a mosaic pattern was seen in hepatocytes after cytochrome c oxidase staining. Using Whole Exome Sequencing two known pathogenic variants were detected in WARS2 (c. 797delC, p. Pro266ArgfsTer10/c. 938 A > T, p. Lys313Met). Conclusion: This is the first report of severe hepatopathy in a subject with WARS2 deficiency. The hepatopathy occurred soon after start of sodium valproate treatment. In the literature, valproate-induced hepatotoxicity was reported in the subjects with pathogenic mutations in POLG and TWNK. This case report illustrates that the course of the disease in the subjects with a mitochondrial defect can be non-progressive during several years. The subject reported here was first diagnosed as having cerebral palsy. Only after a mitochondriotoxic medication was started, the disease became progressive, and the diagnosis of a mitochondrial defect was made

Management of epilepsy

Figures for the incidence of epilepsy in Malta are not available. The overall figure for epilepsy given by the Royal College of General Practitioners (Reid 1960) is 4.82 per 1,000 population. As there is no reason to expect and difference in the incidence in these Islands, one can expect that there are at least 1,500 epileptics in Malta. This would mean that all general practitioners would, at some time, come across a patient with epilepsy.peer-reviewe

Periodic motor impairments in a case of 48-hour bipolar ultrarapid cycling before and under treatment with valproate

Motor impairments of psychiatric patients can be assessed with digital recordings of handwriting tasks. The investigation of patients with bipolar affective disorders differentiates intraindividual changes related to the patient's fluctuating affective states. An unmedicated 67-year-old male with 48-hour bipolar ultrarapid cycling was investigated during 8 consecutive days of ultrarapid cycling and 4 weeks later, after remission under treatment with valproate. The handwriting skills of the patient followed the same rhythmic changes of the psychopathology in the first part of the study and a steady pattern in the second phase, after remission. Therefore, it can be assumed that the handwriting skills reflect a state marker of the disease. Poorer handwriting skills on the manic days, as compared to the depressive ones, support the hypothesis of a low arousal in manic patients. Copyright (C) 2000 S. Karger AG, Basel

Overexpression of the type 1 adenylyl cyclase in the forebrain leads to deficits of behavioral inhibition

The type 1 adenylyl cyclase (AC1) is an activity-dependent, calcium-stimulated adenylyl cyclase expressed in the nervous system that is implicated in memory formation. We examined the locomotor activity, and impulsive and social behaviors of AC1+ mice, a transgenic mouse strain overexpressing AC1 in the forebrain. Here we report that AC1+ mice exhibit hyperactive behaviors and demonstrate increased impulsivity and reduced sociability. In contrast, AC1 and AC8 double knock-out mice are hypoactive, and exhibit increased sociability and reduced impulsivity. Interestingly, the hyperactivity of AC1+ mice can be corrected by valproate, a mood-stabilizing drug. These data indicate that increased expression of AC1 in the forebrain leads to deficits in behavioral inhibition