Valproate Restrictions in Sweden and Norway: Online survey suggests implementation deficit.

OBJECTIVES: To assess knowledge among neurologists in Sweden and Norway on the restrictions issued by the European Medicines Agency (EMA) regarding use of valproic acid (VPA) to female patients of childbearing potential, their use of the pregnancy prevention programme and their VPA prescription habits. MATERIALS & METHODS: We conducted an online survey from May through September 2021 inviting neurologists in Sweden and Norway to participate. The questions assessed familiarity with the EMA restrictions, knowledge and use of the information material issued by Market Authorization Holders (MAH) of VPA, and experience of VPA prescriptions to women of childbearing age in the last 2 years. RESULTS: The survey received 202 responses (response rate ≈ 20%). Of the responders, 51% were well acquainted with the EMA restrictions, and 49% were aware of the MAH-issued educational material. Eighty-eight (44%) had prescribed VPA to women of childbearing age in the last 2 years, and of these, only a small minority (n = 13) regularly used the information brochure for patients, and even fewer (n = 8) the VPA risk acknowledgement forms. CONCLUSIONS: We found limited penetrance of the new EMA restrictions on VPA use as well as limited acceptance and use among prescribers of the current company-issued information material and risk acknowledgment forms. More information campaigns and closer collaboration with treating physicians are likely needed.

Seizure control after late introduction of anakinra in a patient with adult onset Rasmussen's encephalitis.

Neuroinflammation has been considered an important pathophysiological process involved in epileptogenesis and may provide possibilities for new treatment possibilities. We present the case of a 45-year-old female with drug resistant epilepsy and progressive right-sided cerebral hemiatrophy associated with adult onset Rasmussen's encephalitis. Over a period of 26 years, she was treated with 14 different antiseizure medications, intravenous immunoglobulins, glucocorticosteroids, underwent two operations with focal resection and subpial transections, and tried out trigeminal nerve stimulation. Extensive blood tests, including antibodies relevant for autoimmune encephalitis, and brain biopsy did not show any signs of neuroinflammation. Eventually, the patient received the interleukin-1 receptor antagonist, anakinra. Within 1-2 days after injection, seizure frequency decreased significantly, and, after one week, the seizures stopped completely. Anakinra treatment was continued for 2 months. Stopping medication led to a relapse of seizures after 2 weeks, with a frequency of up to 45 seizures per day. Reintroduction of anakinra led to rapid recovery. Treatment with anakinra was continued for 7 months. The treatment was discontinued in April 2020, and the patient has been completely seizure free since then. There have been no other changes in antiseizure medication.

Interactions between antiepileptic drugs and hormones.

Antiepileptic drugs (AEDs) are known to have endocrine side effects in both men and women. These can affect fertility, sexuality, thyroid function, and bone health, all functions of major importance for well-being and quality of life. The liver enzyme inducing antiepileptic drugs (EIAEDs), like phenobarbital, phenytoin, and carbamazepine, and also valproate (VPA), a non-EIAED, are most likely to cause such side effects. AED treatment can alter the levels of different sex hormones. EIAEDs increase sex hormone binding globulin (SHBG) concentrations in both men and women. Over time, this elevation can lead to lower levels of bioactive testosterone and estradiol, which may cause menstrual disturbances, sexual problems, and eventually reduced fertility. VPA can cause weight gain in both men and women. In women, VPA can also lead to androgenization with increased serum testosterone concentrations, menstrual disturbances, and polycystic ovaries. Lamotrigine has not been shown to result in endocrine side effects. The newer AEDs have not yet been thoroughly studied, but case reports indicate that some of these drugs could also be suspected to cause such effects if endocrine changes commence after treatment initiation. It is important to be aware of possible endocrine side effects of AEDs as they can have a major impact on quality of life, and are, at least partly, reversible after AED discontinuation.

The impact of seizures on pregnancy and delivery.

PURPOSE AND METHODS: The treatment of women with epilepsy during pregnancy is known to increase the risk of teratogenic effects. Whether seizures during pregnancy have a deleterious effect on the developing child is difficult to determine, but recent animal studies, case studies, cohort studies and population studies have provided useful insights. RESULTS AND CONCLUSION: Seizures before pregnancy are a predictor for seizures during pregnancy, and catamenial epilepsy may also predict the course of seizures during pregnancy. A first epileptic seizure may also have implications for the pregnancy, depending on the seizure aetiology. Seizures affecting maternal awareness and responsiveness may have cardiac effects on the foetus and may impact on the weight of the newborn. Status epilepticus in pregnancy is rare, but isolated cases of perinatal death and malformations after status epilepticus have been reported in women on antiepileptic drugs. Seizures during delivery occur in about 2% of pregnancies of women with epilepsy, and case studies indicate that the foetal heart may be affected. However, a diagnosis of epilepsy is not an indication per se for caesarean delivery. A well-planned pregnancy can reduce the likelihood of seizures occurring.

Women with epilepsy and post partum bleeding--Is there a role for vitamin K supplementation?

PURPOSE: Guidelines for women with epilepsy (WWE) are advising those on enzyme inducing drugs EIAEDs to take vitamin K the last month of pregnancy. The primary aim of this study was to investigate whether WWE have a higher frequency of large post partum hemorrhage. Secondary we wanted to see if this was more severe in women taking EIAEDs, and also to evaluate whether those receiving prenatal vitamin K supplementation have a less pronounced risk. METHODS: All patients (n=109), with the diagnosis of epilepsy giving birth at OUS Rikshospitalet from 2006 to 2011 were selected to be in the epilepsy group. They were compared to controls with regard to the amount of post partum hemorrhage, gestational age for the mother, birth weight and APGAR score in the newborns. RESULTS: No significant difference between the groups regarding post partum hemorrhage, gestational age, birthweight or APGAR score in the newborn was found. Also, comparing the WWE using EIAED who received prenatal vitamin K with those who did not receive vitamin K, no significant difference in post partum hemorrhage could be demonstrated. CONCLUSION: In this study, WWE was not found to have increased risk of post partum hemmorrhage including those using EIAED with/without vitamin K supplementation.

Interactions between hormones and epilepsy.

There is a complex, bidirectional interdependence between sex steroid hormones and epilepsy; hormones affect seizures, while seizures affect hormones thereby disturbing reproductive endocrine function. Both female and male sex steroid hormones influence brain excitability. For the female sex steroid hormones, progesterone and its metabolites are anticonvulsant, while estrogens are mainly proconvulsant. The monthly fluctuations in hormone levels of estrogen and progesterone are the basis for catamenial epilepsy described elsewhere in this issue. Androgens are mainly anticonvulsant, but the effects are more varied, probably because of its metabolism to, among others, estradiol. The mechanisms for the effects of sex steroid hormones on brain excitability are related to both classical, intracellularly mediated effects, and non-classical membrane effects due to binding to membrane receptors. The latter are considered the most important in relation to epilepsy. The different sex steroids can also be further metabolized within the brain to different neurosteroids, which are even more potent with regard to their effect on excitability. Estrogens potentiate glutamate responses, primarily by potentiating NMDA receptor activity, but also by affecting GABA-ergic mechanisms and altering brain morphology by increasing dendritic spine density. Progesterone and its main metabolite 5α-pregnan-3α-ol-20-one (3α-5α-THP) act mainly to enhance postsynaptic GABA-ergic activity, while androgens enhance GABA-activated currents. Seizures and epileptic discharges also affect sex steroid hormones. There are close anatomical connections between the temporolimbic system and the hypothalamus controlling the endocrine system. Several studies have shown that epileptic activity, especially mediated through the amygdala, alters reproductive function, including reduced ovarian cyclicity in females and altered sex steroid hormone levels in both genders. Furthermore, there is an asymmetric activation of the hypothalamus with unilateral amygdala seizures. This may, again, be the basis for the occurrence of different reproductive endocrine disorders described for patients with left-sided or right-sided temporal lobe epilepsy.

Overnight response to infliximab in neurosarcoidosis: a case report and review of infliximab treatment practice.

OBJECTIVES: Central nervous system manifestations of sarcoidosis occur in approximately 5% of patients with sarcoidosis, often lead to substantial morbidity, and therefore require immediate treatment. Spinal cord involvement is exceptionally rare. The tumor necrosis factor-α inhibitor infliximab seems to be an effective alternative in severe cases, refractory to other therapies, but a standard concept of treatment is lacking. METHODS: We presented a case of severe corticosteroid-refractory spinal cord sarcoidosis with immediate and dramatic response to infliximab. In addition, we reviewed the literature on infliximab therapy in neurosarcoidosis and drew parallels to other medical fields in order to have a basis for decision making in the initiation and discontinuation of treatment. RESULTS: We identified a total of 34 case reports on effective infliximab treatment of therapy-resistant neurosarcoidosis through PubMed search. Nineteen of the 34 cases reported the duration until treatment response. In accordance with our patient, 14 of the 34 case reports showed improvement between first and third infusion. Eight of the 34 cases reported sustained remission after cessation of infliximab. No definite treatment regimen was used. CONCLUSIONS: Infliximab seems to be a fast-acting and effective drug for severe neurosarcoidosis. No systematic treatment strategy is available because of lack of controlled trials. Until then, therapy regimens may be adapted to those used in other medical fields where infliximab treatment is well established.