Declining trend in valproate use in Finland among females of childbearing age in 2012-2016 - a nationwide registry-based outpatient study.

BACKGROUND AND PURPOSE: Documented teratogenic effects of valproate (VPA) prompted restrictions of its use in females of childbearing age in 2014. We investigated possible annual changes in the outpatient use of VPA in Finland during 2008-2016 with a special focus on women. METHODS: We identified all outpatients with VPA purchases between 2008 and 2016 categorizing users due to epilepsy, bipolar disorder or miscellaneous indications. Temporal trends in the annual prevalence rates of VPA use were estimated using Poisson regression analyses. RESULTS: Between 2012 and 2016, the prevalence of VPA use among women aged 15-44 years decreased by 19%, from 50/10 000 to 40/10 000 (prevalence rate ratio, 0.81; 95% confidence intervals, 0.77-0.91; P < 0.001). The use of VPA due to epilepsy decreased significantly in females aged 15-24 and 25-34 years and that due to bipolar disorders decreased significantly in females aged 25-34 and 35-44 years. The use of VPA in the miscellaneous indication group decreased by 32% after 2014 in females aged 15-44 years and, most strikingly, by 56% among those aged 15-25 years. In women with epilepsy, the use of VPA increased among those over the age of 44 years. CONCLUSIONS: The rates of female VPA users with childbearing potential have decreased in all three major indication groups in Finland during recent years, especially after the European Medicines Agency restrictions were published in 2014. However, it still remains open to question as to whether the practice of VPA use follows current guidelines. A special concern is the relatively high prevalence of off-label use of VPA in fertile-aged females.

Idiopathic generalized epilepsies: a follow-up study in a single-center.

OBJECTIVE: To characterize adult patients with idiopathic generalized epilepsies (IGEs) with precise evaluation and to assess factors related to refractoriness. MATERIALS AND METHODS: Hospital records of all our patients with IGEs (n = 128) were evaluated in 2005 and followed-up until 2008. RESULTS: In 2005, 76% of patients were 1-year seizure-free. Seizure freedom increased to 82% during the 3-year follow-up. Seizure freedom was not significantly associated with age, age at diagnosis, epilepsy duration, exposure to inappropriate initial antiepileptic drug (AED), or delay time between starting initial AED and appropriate AED. Women constituted 78% of patients with merely provoked seizures. In 58% of women with recent seizure, one to two avoidable precipitating factors, such as lack of sleep, alcohol, and forgetting to take AED, were observed. In 2008, all patients with no medication, 91% of monotherapy patients, 60% of patients on two AED, and 14% of patients on three AED were seizure-free. CONCLUSIONS: Most of patients with IGEs can be successfully treated with monotherapy. Refractory seizures in some patients may be because of avoidable factors, especially in young women.

Hippocampal sclerosis in refractory temporal lobe epilepsy is associated with gluten sensitivity.

BACKGROUND: Previous studies have associated coeliac disease (CD) and gluten sensitivity (defined as the presence of anti-gliadin antibodies and positive immunogenetics) with cerebellar degeneration and epilepsy with occipital calcifications. Hippocampal sclerosis (HS) in temporal lobe epilepsy (TLE) is a potentially progressive disorder with unknown aetiology; however, autoimmunity has been implicated as one of the possible mechanisms leading to HS. The purpose of this study is to analyze CD-associated antibodies and gluten sensitivity in a well-characterised group of patients with refractory focal epilepsy. METHODS: We measured anti-gliadin, anti-tissue-transglutaminase and anti-endomysium antibodies, and coeliac-type human leukocyte antigen (DQ2 and DQ8), in 48 consecutive patients with therapy-resistant, localisation-related epilepsy. The patients were categorised into the following three groups on the basis of ictal electro-clinical characteristics and the findings of high resolution MRI: TLE with HS (n = 16), TLE without HS (n = 16) and extratemporal epilepsy (n = 16). Patients with suspected CD or gluten sensitivity underwent duodenal biopsies. RESULTS: Seven patients in total were gluten sensitive; all of these patients fell in the TLE with HS group. On the other hand, none of the TLE without HS patients or those with extratemporal epilepsy were gluten sensitive (p<0.0002). The results of duodenal biopsies showed that three of the seven gluten-sensitive patients had histological evidence of CD and four had inflammatory changes consistent with early CD without villous atrophy. Four of the patients with gluten sensitivity had evidence of dual pathology (HS+another brain lesion), whereas none of the remaining patients did (p<0.0002). CONCLUSIONS: The present study demonstrates a previously unrecognised link between gluten sensitivity and TLE with HS. This association was very robust in this well-characterised group of patients; thus gluten sensitivity should be added to the list of potential mechanisms leading to intractable epilepsy and HS.

Retention rates of new antiepileptic drugs in localization-related epilepsy: a single-center study.

OBJECTIVES: We evaluated long-term retention rates of newer antiepileptic drugs (AED) in adults with localization-related epilepsy retrospectively. METHODS: We estimated retention rates by Kaplan-Meier method in all 222 patients (age > or = 16) with localization-related epilepsy exposed to new AED at the Tampere University Hospital. RESULTS: There were 141 patients exposed to lamotrigine, 78 to levetiracetam, 97 to topiramate, 68 to gabapentin, and 69 to tiagabine. Three-year retention rate for lamotrigine was 73.5%, levetiracetam 65.4%, topiramate 64.2%, gabapentin 41.7%, and tiagabine 38.2%. The most common cause for withdrawal of these AED was lack of efficacy. CONCLUSIONS: Our study suggests that there are clinically significant differences among gabapentin, lamotrigine, levetiracetam, tiagabine, and topiramate as treatment for focal epilepsy in everyday practice. Gabapentin and tiagabine seem to be less useful than the other three AED. Furthermore, our study supports the value of retention rate studies in assessing outcome of the drugs in clinical practice.

Clinical predictors in patients with refractory epilepsy exposed to levetiracetam: a single-center study.

OBJECTIVES: This aim of the study was to ascertain the importance of clinical parameters on the response to treatment in refractory epilepsy patients on levetiracetam (LEV). MATERIALS AND METHODS: We retrospectively evaluated medical records of 132 patients aged 17-78 years with refractory epilepsy (defined as a failure of at least two antiepileptic drugs due to the lack of efficacy) exposed to LEV. We analyzed the response (seizure freedom or continuing LEV) using logistic regression. RESULTS: Of 132 patients exposed to LEV, 103 cases continued the drug. Of the discontinuations (29/132), 75% were for lack of efficacy and 25% for tolerability problems. Twenty-three percent of the previously refractory patients achieved seizure freedom for at least 1 year with LEV in combination therapy. The dose of LEV in 80% of seizure-free patients was 1000 mg/day or less. The duration of epilepsy, age and sex were not associated with response to LEV. Seizure freedom was associated with epileptic syndrome or etiology. If no specific syndrome was recognized, there was a significantly greater chance for response compared with temporal lobe epilepsy (OR 20.76; 95% CI 2.12-203.61). CONCLUSIONS: Our study was based on the careful clinical evaluation of the patients with extensive use of video EEG (50%) and MRI scans (95%). These clinical predictors were evasive in previous studies. This study showed that they are worth pursuing but significantly larger groups of patients need to be investigated to reach significant findings.

Severe epilepsy: diagnostic and epidemiological aspects.

Epidemiological parameters of epilepsy have been estimated in a large number of studies. Reported annual incidence rates for recurrent seizures vary between 30 and 50/100,000, and prevalence rates in most studies between 500 and 1000/100,000. Varying findings are mostly due to different case ascertainment methods and definitions of epilepsy applied in different surveys. These aspects will be discussed in this paper. A special emphasis is laid on differential diagnosis of seizure disorders, and on the prevalence and causes of complex partial epilepsy. This epileptic disorder is one of the most common forms of epilepsy, and also difficult to treat in many cases. Many recent reports show that prognosis of seizures in patients with epilepsy is better than suggested in earlier studies. However, 25-30% of epileptics seem to have frequent (greater than 1/month) seizures. Our own study, in accordance with earlier findings suggests that prevalence of patients with severe complex partial epilepsy is about 80-90/100,000. Available literature provides several predictive factors for the prognosis of seizures and assessment of prognosis is possible quite early after the onset of seizures. Treatment choices for patients with intractable epilepsy will be discussed.

Side effects of carbamazepine, valproate and clonazepam during long-term treatment of epilepsy.

Side effects of carbamazepine (CBZ), valproate (VPA) and clonazepam (CZP) are rare during long-term use but rather common and usually transient during the early phases of treatment. The usual side effects of CBZ are drowsiness, dizziness, and diplopia, which are dose dependent in long-term use, but CBZ does not seem to cause cognitive disturbances, as do phenobarbital and phenytoin. Other reactions to CBZ may include leukopenia, hyponatremia, disturbances of vitamin D metabolism and fortunately rarely, agranulocytosis and hepatitis. Use of VPA can lead to gastrointestinal discomfort, weight gain, hair loss, tremor and sedation, but these side effects are rather uncommon, mild, and transient during VPA monotherapy. Potentially hazardous reactions such as hepatitis and pancreatitis have occurred in a few patients on VPA, generally with multidrug therapy. Some of the side effects are dose related. They infrequently lead to withdrawal of VPA. Side effects limited to initiation of CZP therapy include drowsiness, ataxia, and behavioral changes; they are usually transient but can lead to dose reduction or even withdrawal of the drug. Except for development of tolerance, CZP seems to be practically free of long-term side effects.

Autoantibodies to glutamic acid decarboxylase in patients with therapy-resistant epilepsy.

BACKGROUND: Autoantibodies to glutamic acid decarboxylase (GAD-A) are present in type 1 diabetes and stiff man syndrome (SMS), and have also been reported in cerebellar ataxia. Epilepsy was present in 4 of 19 patients with SMS and GAD-A, implying that epilepsy sometimes is associated with anti-GAD autoimmunity. METHODS: The authors investigated the prevalence of GAD-A in patients with therapy-resistant localization-related epilepsy (n = 51) and generalized epilepsy (n = 49) by a radiobinding assay. The positive samples were confirmed by immunohistochemistry and immunoblotting of recombinant human GAD65. RESULTS: GAD-A were found in eight patients with localization-related epilepsy, whereas none of the patients with generalized epilepsy, other neurologic disorders (n = 38), or the control subjects (n = 48) had GAD-A. Two patients had high levels of GAD-A, similar to SMS, whereas six patients had significantly lower titers, characteristic of type 1 diabetes. The two patients with high levels of GAD-A had GAD-A both in serum and CSF by immunohistochemistry and immunoblotting. Both of them had longstanding therapy-resistant temporal lobe epilepsy but did not have diabetes. One had a history of autoimmune disease, whereas the other had serologic evidence of multiple autoantibodies without any clinical signs of autoimmune disease. CONCLUSIONS: GAD autoimmunity may be associated with refractory localization-related epilepsy.

Antiphospholipid and antinuclear antibodies in patients with epilepsy or new-onset seizure disorders.

PURPOSE: The increased prevalence of autoantibodies in patients with epilepsy has been traditionally regarded to be a consequence of antiepileptic drugs. The purpose of this study was to measure autoantibodies in well-defined groups of patients with seizures to determine the effects of epilepsy and antiepileptic medications on the presence of autoantibodies. PATIENTS AND METHODS: We studied the frequency of antinuclear antibodies, anti-beta2-glycoprotein I antibodies, and anticardiolipin antibodies in 50 patients with therapy-resistant localization-related epilepsy, 50 patients with generalized epilepsy syndromes, 52 patients with a newly diagnosed seizure disorder but no antiepileptic medication, and 83 healthy controls. RESULTS: Compared with controls, newly diagnosed patients had a significantly greater prevalence of immunoglobulin (Ig) G class anticardiolipin antibodies (21% versus 7%); the prevalence was 14% in patients with localization-related epilepsy and 8% in patients with generalized epilepsy. The prevalence of IgM class anticardiolipin antibodies was significantly greater in all seizure groups (60% in localization-related epilepsy, 42% in generalized epilepsies, and 33% in newly diagnosed patients) compared with controls (7%). Antinuclear antibodies were significantly more common in newly diagnosed patients (21%) and localization-related epilepsy (24%) compared with controls (12%). When patients with generalized epilepsy (8%) were used as the reference group, antinuclear antibodies were also significantly more frequent in localization-related epilepsy (relative risk [RR] = 2.9, 95% confidence interval [CI]: 1.1 to 8.2) and newly diagnosed seizures (RR = 3.4, 95% CI: 1.2 to 9.3). There were no consistent associations between autoantibodies and specific antiepileptic medications. CONCLUSIONS: The prevalence of autoantibodies is greater in patients with epilepsy, including newly diagnosed seizure disorder. The increased prevalence of autoantibodies is more strongly associated with epilepsy than with antiepileptic drugs, perhaps indicating that immune dysregulation may be commonly associated with epilepsy.

Regulation of IL-6 system in cerebrospinal fluid and serum compartments by seizures: the effect of seizure type and duration.

Experimental studies suggest that cytokine production may be triggered by seizure activity. Here we determined the levels of interleukin-6 (IL-6) and its soluble receptor components (sIL-6R and sGp130) in CSF and serum from control subjects and patients after different types of seizures. IL-6 levels were increased after seizures, whereas sIL-6R levels were decreased. Interestingly, the levels of IL-6 were strongly increased after recurrent generalized tonic-clonic seizures (GTCS), whereas after single tonic-clonic or prolonged partial seizures IL-6 levels were increased to lesser extent. These results provide further support for a hypothesis of cytokine production induced by seizure activity per se.

Place of newer antiepileptic drugs in the treatment of epilepsy.

There are several new antiepileptic drugs undergoing extensive clinical investigation. Five new drugs--vigabatrin, lamotrigine, gabapentin, felbamate and oxcarbazepine--appear to be the most widely tested and promising agents. Vigabatrin is most effective in drug-resistant partial epilepsy. Vigabatrin is also effective in infantile spasms, but seems to have negative effects on myoclonic epilepsies and absence seizures. Lamotrigine and felbamate seem to be effective in partial epilepsy and in Lennox-Gastaut syndrome. In addition, lamotrigine and felbamate seem to have efficacy in idiopathic generalised epilepsies. Oxcarbazepine appears to be equally as effective as carbamazepine, but less toxic. Gabapentin has few adverse effects and has efficacy in some patients with drug-resistant partial epilepsy. Some of the new antiepileptic drugs modify excitatory or inhibitory amino acid transmission, but some of them may employ new, still unknown mechanisms of action. Depending on the mechanism of action, the therapeutic effectiveness of the antiepileptic drugs may differ in specific epileptic syndromes. Future antiepileptic drugs may thus give us the possibility to design rational polypharmacy for individual patients by combining agents with different spectra of effectiveness. Considering the goal of good tolerability in the development of the new antiepileptic drugs, polypharmacy with these agents is not expected to increase adverse effects significantly.

Expression of cytokines and cytokine receptors in the rat brain after kainic acid-induced seizures.

We have previously shown that IL-6 protein levels are increased in cerebrospinal fluid in humans after recent tonic-clonic seizures with unchanged levels of IL-1beta and TNFalpha. Here we studied the expression of cytokines IL-6, LIF, IL-1beta and TNFalpha and cytokine receptors IL-6R, LIFR and Gp130 in the rat brain after kainic acid-induced status epilepticus using Northern blot analysis and in situ hybridization histochemistry. After seizures, IL-6 mRNA was induced in the hippocampus, cortex, amygdala and meninges, and IL-6R was up-regulated in the hippocampus. LIF was up-regulated in the hippocampus, cortex and meninges after seizures, and LIFR mRNA was induced in the hippocampus and cortex. Gp130 was constitutively expressed in the brain. After seizures, Gp130 transcription was rapidly induced in the meninges. In thalamus, cortex, amygdala and hippocampus Gp130 mRNA was induced in a delayed fashion. IL-1beta transcription was induced in the temporal lobe cortex and thalamus, and TNFalpha in the hippocampus. In general, the cytokine and their receptor mRNA levels were low in intact rat brain, but were induced by seizures. Since IL-6 and LIF transcripts were induced in the meninges after seizures, the protein products of these transcripts may be more readily released in cerebrospinal fluid after seizures. In addition, the activity of IL-6 and LIF signaling pathways may be influenced by increased expression of their receptors after seizures.

Trigeminally triggered epileptic hemifacial convulsions.

We present whole-head magnetoencephalographic recordings from a patient suffering from trigeminally triggered left-sided hemifacial convulsions. The patient was a candidate for surgical treatment, but regardless of extensive scalp EEG, videotelemetry and PET recordings, an epileptic focus could not be identified. Magnetic signal distribution during a seizure suggested focal epileptic activity in the face area of the right primary motor cortex. A secondary focus was activated 22 ms later in the left hemisphere. Discharges could be triggered by sensory stimulation of the left lower gum. The similarities of this seizure production mechanism to trigeminal neuralgia and kindling are discussed.

Prolonged cortical somatosensory evoked potential latencies in progressive myoclonus epilepsy.

In 9 mildly affected and 7 severely affected patients with progressive myoclonus epilepsy, we observed a distinct slowing in the short-latency median nerve SEP components N 19 (5.2% and 24.7%), P 22 (14.6% and 37.1%) and N 30 (4.8% and 17.1%, respectively). The P 22-N 30 amplitude increased in mild but decreased again in severe disease. These findings are indicative of mild affection of the peripheral and spinal sensory connections, and more severe involvement of the thalamocortical pathways. In controls, a clear correlation between the height and the latency of the N 19 and P 22 components was observed. We also often observed a small additional negative SEP component adjoining the P 22 component.

Normal CSF neuron-specific enolase and S-100 protein levels in patients with recent non-complicated tonic-clonic seizures.

PURPOSE: Increased concentrations of the nervous-system-specific proteins neuron-specific enolase (NSE) and S-100 protein (S-100) have been measured with lesions in the CNS. Elevated levels of serum NSE (s-NSE) have been found in status epilepticus, but also after single epileptic seizures. Because larger studies addressing cerebrospinal fluid (CSF) levels of NSE or S-100 have not been performed, we measured CSF NSE and S-100 after tonic-clonic seizures to search for evidence of neuronal and glial damage. METHODS: 22 consecutive patients with single, previously undiagnosed and untreated tonic-clonic seizures were studied. Serum and CSF samples were collected within 24 h after seizure. 18 serum and CSF samples were measured from a control group. RESULTS: The mean CSF NSE was 8.9 ng/ml (range 0-28 ng/ml) and s-NSE 8.2 ng/ml (range 5-15 ng/ml) in the patient group. The mean concentrations in the control group were 13.1 ng/ml (range 3-24 ng/ml) and 8.0 ng/ml (range 5-12 ng/ml) respectively. The mean CSF S-100 was 3.17 microg/l (range 1.45-7.02 microg/l) and serum S-100 0.05 microg/l (range 0-0.32 microg/l), and in controls 3.19 microg/l (range 1.52-5.13 microg/l) and 0.08 microg/l (range 0-0.28 microg/l). CONCLUSION: There were no significant differences between the mean concentrations of NSE or S-100 in CSF and serum between the epileptic group and controls. These results do not confirm the previous observation of elevated NSE-levels after tonic-clonic seizures, which argues against neuronal or glial damage after uncomplicated tonic-clonic seizures in unmedicated patients.

Late epilepsy after aneurysm operations.

The risk of late epilepsy was analyzed in a consecutive series of 177 patients operated on for supratentorial aneurysms. Late seizures occurred in 25 patients (14%); the seizures were recurrent in 21 patients (12%). Most seizures were partial, secondary generalized, or generalized tonic-clonic (72%). The mean latency between the operation and seizures was 8.4 months (range, 1 to 24 months), and in only 2 patients was the interval more than 12 months. The most important risk factors were preoperative and postoperative complications. Only 2.5% of the 81 Grade I patients developed epilepsy, compared to 33% of the 42 Grade III-IV patients. Other risk factors were location of the aneurysm in the middle cerebral artery, the presence of a large intracerebral hematoma, postoperative spasm with late ischemic infarction, and shunt-dependent hydrocephalus. The timing of operation or intraventricular intracranial pressure monitoring did not change the risk of late epilepsy. The fact that only 2 patients had early epilepsy may have been due to routine treatment with prophylactic anticonvulsants. The value of prophylaxis in late epilepsy is unproven, but prophylactic treatment could be useful in patients with a high risk of epileptic seizures.

Elevated levels of interleukin-6 may occur in cerebrospinal fluid from patients with recent epileptic seizures.

Experimental animal studies suggest the involvement of cytokines in epilepsy. We measured increased concentrations of interleukin-6 in four out of 15 cerebrospinal fluid samples from unmedicated patients with newly developed tonic-clonic seizures; plasma levels were also increased but to a lesser extent. Although the significance of cytokine production in relation to epileptic seizures is not known, it might be important for neuronal survival.

High prevalence of antiphospholipid antibodies in children with epilepsy: a controlled study of 50 cases.

Evidence of immune system aberrations in patients with epilepsy includes antiphospholipid antibody positivity in adult patients with epilepsy with a prevalence of 19-26% and in 13% of children with partial epilepsy. Also immunoglobulin A deficiency has been reported to exist in up to 25% of epilepsy patients. The possible role of immune mechanisms in the pathogenesis of childhood epilepsy is clinically supported by the effectiveness of immunomodulatory treatments in cases with catastrophic childhood epilepsies. We analyzed a set of various autoantibodies in 50 consecutive children with epilepsy and in 20 healthy control subjects. None of the children had any clinical signs of immune system disorders. The main result was a significantly (P=0.011) higher prevalence of antiphospholipid antibodies in the study group (44%) compared with controls (10%). These antibodies were unexpectedly common (71-80%) in children with multiple seizure types associated often with symptomatic etiology, early onset and high frequency of seizures. There was no evidence of the antiphospholipid positivity being induced by certain AEDs (e.g. phenytoin or carbamazepine). Even though the significance of these autoantibodies remains unknown, their increased prevalence indicates that immune system mediated mechanisms may have a role in the manifestation of epilepsy in some children.