The Croatian Model of Integrative Prospective Management of Epilepsy and Pregnancy

Epilepsy is the most common neurological complication in pregnancy. Women with epilepsy have a higher risk of complications in pregnancy. In Croatia, women with epilepsy are treated by neurologists at tertiary centers according to the place of residence. We prospectively followed-up pregnancies in women with epilepsy and healthy controls, and analyzed the factors responsible for their delivery outcomes and development of their babies. Healthy pregnant women had a higher level of education and economic status, but pregnant women with epilepsy took folic acid in a higher proportion than controls, possibly due to timely preconception counseling. Complications during pregnancy depended on the number of antiepileptic drugs and epilepsy control. We noticed some behavioral and cognitive aspects in children exposed in utero to valproic acid, which required follow up. The rate of congenital malformations was not increased. In conclusion, women with epilepsy should receive preconception counseling about the risk for pregnancy, but also about the possibilities to minimize that risk. We have introduced a model of integrative management of pregnancy and epilepsy based on close collaboration among different clinical experts in Croatia, in order to provide prompt counseling and timely intervention.

[Neurophysiological methods in headache diagnosis]. / Neurofizioloski postupci u dijagnosticiranju glavobolja.

Neurophysiological methods used in the diagnosis of headache, especially migraine are: electroencephalography (EEG), evoked cortical potentials (VEP, BAER, ERP), reflex responses, autonomic tests and transcranial magnetic stimulation (TMS). Interpretation of EEG can be important for the differential diagnosis of some disorders with headache as a presenting symptom. Noninvasiveness, accessibility and ability to repeat the test due to exposure to harmful ionization are the main advantages of EEG. The role of thorough medical history and clinical assessment in patients with headache should not be underestimated. Interictal EEG (between headache attacks) is not significant in routine evaluation of these patients, but can be useful in patients with unusual symptoms suggesting epilepsy or migraine. It is indicated in patients with an abrupt onset of headache, in patients with migraine followed by neurological signs, in basilar migraine, migraine with extended duration of aura and in cases where epilepsy is suspected. Headache as a symptom is present in various brain and systemic diseases and metabolic disorders. EEG changes seen in headache patients are not specific for a particular disorder, but can suggest additional evaluation and accelerate accurate diagnosis and earlier treatment. Visual evoked cortical potentials (VEP) and cognitive evoked potentials (ERP) in patients with migraine in interictal periods have shown differences in sensory processing between patients with headache and healthy controls. Neurophysiological methods (VEP, ERP) between migraine attacks show cortical hyperactivity and predisposition for further attacks. Brainstem auditory evoked responses (BAER) are a sensitive method for the detection of central nervous system damage. Activation of the brainstem during the migraine attack results in an amplitude increment seen soon after the end of the attack. According to recent studies, R2 component of the blink reflex was six times longer during migraine attack as compared to interictal values. This is thought to be a response to sensitization of the skin nociceptive afferent arch or other neurons in the trigeminal nucleus. In patients with cluster headache, autonomic tests generate cardiovascular and pupillary response suggesting systemic sympathetic hyperactivation connected to concurrent pupillary sympathetic hypofunction and modified opioid modulation. TMS is shown to be very useful for the detection of pathophysiological changes of numerous disorders including migraine, due to its excitatory and inhibitory effects. Recent studies have shown changes in motor and occipital cortex during TMS interictal excitability. Neurophysiological tests are used in differential diagnosis of headache, follow up of possible complications in patients with symptomatic headache as well as in neurorehabilitation. In addition, electrophysiological diagnostic test can contribute to better understand the headache pathophysiology.

[Association of epilepsy and headache from the patient perspective]. / Povezanost epilepsija i glavobolje iz perspektive bolesnika.

Headache occurs more frequently in patients with epilepsy as compared to the general population. Current studies in patients with epilepsy and migraine show that this increased frequency is independent of the seizure type, etiology or age at onset. People with epilepsy are 2.4 times more likely to be diagnosed with migraine. In our study, we evaluated patients' attitudes toward comorbidity of epilepsy and all headache types. Study results showed a significant number of patients to have experienced headaches after being diagnosed with epilepsy, and some of them assumed it was a side effect of their antiepileptic drug. Based on these data, we propose a more detailed assessment of the history of epilepsy including questions on headache, and offer the epilepsy patient a newer antiepileptic drug. In this way, we can significantly decrease the comorbidity of these two neurologic disorders and improve the quality of life in epilepsy patients.

Epilepsy in patients with pineal gland cyst.

OBJECTIVE: The aim of the study is to describe types of epileptic seizures in patients with pineal gland cyst (PGC) and their outcome during follow up period (6-10 years). We wanted to determine whether patients with epilepsy differ in PGC volume and compression of the PGC on surrounding brain structures compared to patients with PGC, without epilepsy. PATIENTS AND METHODS: We analyzed prospectivelly 92 patients with PGC detected on magnetic resonance (MR) of the brain due to various neurological symptoms during the period 2006-2010. Data on described compression of the PGC on surrounding brain structures and size of the PGC were collected. RESULTS: 29 patients (16 women, 13 men), mean age 21.17 years had epilepsy and PGC (epilepsy group). 63 patients (44 women, 19 men), mean age 26.97 years had PGC without epilepsy (control group). Complex partial seizures were present in 8 patients, complex partial seizures with secondary generalization in 8 patients, generalized tonic clonic seizures (GTCS) in 10 and absance seizures in 3 patients. Mean PGC volume in epilepsy group was 855.93 mm3, in control group 651.59 mm3. There was no statistically significant difference between epilepsy and control group in PGC volume. Compression of PGC on surrounding brain structures was found in 3/29 patients (10.34%) in epilepsy group and in 11/63 patients (17.46%) in control group with no statistically significant difference between epilepsy and control group. All patients with epilepsy were put on antiepileptic therapy (AET). During the follow up period, 23 patients (79.31%) were seizure free, 3 patients (13.04%) had reduction in seizure frequency, whereas 3 patients had no improvement in seizure frequency. Two patients from epilepsy group and 3 patients from control group were operated with histologically confirmed diagnosis of PGC in 4, and pinealocytoma in 1 patient. CONCLUSIONS: In patients with PGC, epileptic seizures were classified as: complex partial seizures (with or without secondary generalization), GTCS and absance seizures. All patients were put on AET. During follow up period 79.31% patients were seizure free. There was no difference in PGC volume, nor in described compression of the PGC on surrounding brain structures between epilepsy and control group. Based on our findings, pathomechanism of epileptic seizures in patients with PGC cannot be attributable solely to PGC volume or described compression on surrounding brain structures based on MRI findings.

Chromosome damage and cancer risk in the workplace: the example of cytogenetic surveillance in Croatia.

The use of cytogenetic assays in the surveillance of populations occupationally exposed to genotoxic carcinogens originates from the assumption that chromosomal alterations might be causally involved in early stages of carcinogenesis. Historical cohort studies have since 1990s consistently reported an association between the level of chromosomal aberrations (CA) in peripheral lymphocytes of healthy subjects and the risk of cancer. Only in few cases, have these results been transformed into a regulatory tool for improving occupational safety. The cytogenetic surveillance program adopted for more than two decades in the Republic of Croatia is one of these few examples. Croatian workers exposed to genotoxic agents were systematically screened for CA, to identify occupational settings needing a priority intervention. Significant increases of mean CA frequency were observed in groups exposed to ionizing radiation, chemical agents, and mixed exposures when compared with a group of unexposed referents. CA data on 736 men and 584 women, monitored between 1987 and 2000, have been associated with cancer incidence. Although the small size of the cohort did not allow for reaching statistical significance, the medium tertile of the CA frequency distribution was associated with a doubling of cancer incidence rate ratio (IRR=2.40; 95% CI 0.85-6.77) when compared with the lowest tertile. For chromosome-type CA, IRR was non-significantly increased for both the medium (IRR 1.53, 95% CI 0.58-3.99) and high categories (IRR 1.69; 95% CI 0.61-4.72). Recommendations for future strategies comprise the inclusion of predictive biomarkers in surveillance programs, the definition of a regulatory framework, and their possible use for the identification of individual risk profiles.

Differences of blink-reflex abnormalities in patients suffering from idiopathic and symptomatic trigeminal neuralgia.

We investigated the brainstem blink reflex in patients suffering from idiopathic and symptomatic trigeminal neuralgia to establish possible dysfunction in the reflex cycle and determine eventual differences between the two disease types. The study included 35 patients with idiopathic disease and seven patients with symptomatic disease, their results compared with those of 50 normal controls. We stimulated the forehead afferents of the supraorbital nerve and recorded the response from both orbicularis oculi muscles. We tested latencies of bilateral late components (R2, R2'), irritative R3 component and the incidence of R3 component. The patients with idiopathic trigeminal neuralgia showed normal parameters of blink reflex, except for the greater incidence of R3 component. Patients with symptomatic trigeminal neuralgia showed prolonged latencies of R2, R2' and R3 components when stimulating the afflicted side, but no significant difference in incidence of R3 component compared with the control group. The results indicate that abnormalities of blink reflex are significantly different in the two groups of patients. The high incidence of R3 component seems to be typical of idiopathic disease, whereas the prolonged latencies of late reflex components after stimulation of the afflicted side seem to be typical for symptomatic disease. These results suggest that testing the blink reflex may prove a significant aid in distinguishing the idiopathic and symptomatic disease types.

[Etiology and treatment of epilepsy in the elderly]. / Etiologija i lijecenje epilepsije osoba starije dobi.

UNLABELLED: Epilepsy currently affects 1.0%-1.5% of elderly population, and its prevalence and incidence rise as the number of old people increases worldwide. Antiepileptic drugs are the mainstay of treatment. Their phrarmacokinetics differ in old age and polypharmacotherapy often leads to drug interactions. Many of the affected have concomitant cardiovascular, metabolic, cerebrovascular, neurodegenerative or neoplastic diseases. Antiepileptic drugs add to the burden of medication and may produce neurotoxicity or cognitive impairment. PURPOSE: To give an overview of epidemiologic data and pharmacological management of epilepsy in the elderly. It is a common and important clinical problem. The increased awareness of this phenomenon has led to better understanding of the etiology of seizures and complexity of the pharmacokinetics in the elderly. METHOD: Data of 246 patients with epilepsy admitted to our Department during the year 2001 were retrospectively analyzed. RESULTS: Forty-three (17.4%) patients were older than 65. Thirty-two (74.4%) patients, 20 male and 12 female, had a newly diagnosed epilepsy. The etiology of seizures included cerebrovascular diseases in 22 (68.8%), trauma in 4 (12.5%), primary tumors in 3 (9.4%) and metastases in 3 patients (9.4%). The initial antiepileptic drug (AED) was phenytoin in 15 (46.9%), carbamazepine in 14 (43.8%), carbamazepine plus phenytoin in 2 (6.3%), valproic acid in 1 (3.1%), diazepam in 3 (9.4%) and oxazepam in 2 (6.3%) patients. Later, during follow-up, lamotrigine was introduced in 4 (12.5%) patients as a monotherapy and in 3 (9.4%) patients as add-on therapy. Topiramate was introduced in 1 patient as monotherapy and add-on therapy each. Gabapentin was introduced in one patient as add-on therapy. CONCLUSION: Cerebrovascular disease is the most common cause of new-onset seizures in the elderly. Pharmacological treatment is complicated by the age related changes of pharmacokinetics and pharmacodynamics and drug-drug interactions. Phenytoin and sodium valproate are the first choice agents for generalized tonic-clonic seizures, with carbamazepine preferred for partial seizures. The newer AEDs, such as gabapentin and lamotrigine, also warrant some consideration as the first-line agents because of their efficacy and favorable effect profile. The optimal management of epilepsy requires rapid investigation, accurate diagnosis, effective therapy, education and assured support.

Visual evoked potentials in patients with pineal gland cyst.

AIMS: The functional effect of the pineal gland cyst is difficult to evaluate with visual field examination. The aim of this study is to investigate the usefulness of visual evoked potentials (VEP) in patients with pineal gland cyst due to the possible compression on the visual pathway. SUBJECTS AND METHODS: Black-and-white pattern-reversal checkerboard VEP were recorded in 75 patients (50 females and 25 males, mean age 26.3 ± 15.7 and 25.6 ± 17.6 years, respectively) with pineal gland cyst detected on magnetic resonance of the brain (subject group) and 75 age and sex-matched control subjects (control group). Amplitudes and P100 latencies were collected and later grouped as: (1) normal finding; (2) prechiasmal; (3) prechiasmal and postchiasmal; and (4) postchiasmal dysfunction. RESULTS: P100 latencies differed significantly between subject (110.26 ± 13.23 ms) and control group (101.01 ± 5.36 ms) (p < 0.01). Findings of the VEP differed significantly (p < 0.01) between subject and control group, mainly due to the postchiasmal dysfunction frequency in subject group. Findings of the VEP differed significantly according to the pineal gland cyst volume (p = 0.006) with more frequent postchiasmal dysfunctions among subjects with larger cysts. Postchiasmal changes were significantly more frequent in patients with described compression of the cyst on surrounding brain structures (p = 0.016). CONCLUSIONS: Postchiasmal dysfunction on VEP can be seen in patients with pineal gland cyst, mostly with larger cysts and with compression of the cyst on surrounding brain structures. VEP serve as a useful method to determine functional impairment of the visual pathway in patients with pineal gland cyst.

Sporadic Creutzfeldt-Jakob disease in a patient with episodes of nonconvulsive status epilepticus: case report.

Creutzfeldt-Jakob disease is the most common form of human prion diseases. A 57-year-old woman was transferred to our Department from a local hospital, where she had been treated for two weeks due to consciousness disorders and convulsive epileptic attacks that progressed to refractory status epilepticus. Electroencephalography showed diffuse spike-wave complex discharges and development of nonconvulsive status epilepticus. The causes of metabolic encephalopathy and paraneoplastic syndrome were ruled out. A combination of clinical features and findings of diagnostic procedures including electroencephalography, biomarkers in the cerebrospinal fluid and magnetic resonance imaging suggested with great probability that the patient was affected with sporadic Creutzfeldt-Jakob disease.

Diagnostic value of some less frequently considered blink reflex parameters in idiopathic trigeminal neuralgia.

AIM OF THE STUDY: We have done a study investigating the value of some less frequently considered Blink reflex parameters for establishing the diagnosis of idiopathic trigeminal neuralgia. PATIENTS: The study was done on 50 patients suffering from idiopathic trigeminal neuralgia, diagnosed according to the guidelines of the International Classification of Headache Disorders, with no other apparent illness. METHODS: We have stimulated the supraorbital nerve at the forehead (foramen n. supraorbitalis) and recorded the reflex response on both mm. orbiculares oculi. Incidence of following findings was determined: (1) occurrence of ipsilateral R3 component, (2) prolonged duration (>25 ms) of R2 when stimulating the affected side and (3) occurrence of R1 component during the stimulation of contralateral supraorbital nerve. We have compared these findings to those of 50 healthy subjects from the control group (Chi-square, p < 0.05). Sensitivity, specificity and diagnostic value for individual parameters were determined. RESULTS AND CONCLUSION: All three parameters tested proved to have a significantly higher incidence in the group of subjects. The occurrence of R3 component on the affected side showed the highest diagnostic value. SIGNIFICANCE: We believe these findings could electrophysiologically reinforce the clinically established diagnosis of idiopathic trigeminal neuralgia.

Transplacental genotoxicity of antiepileptic drugs: animal model and pilot study on mother/newborn cohort.

Antiepileptic drugs (AED) as transplacental agents are known to have adverse effects on fetal development. Genotoxicity of AEDs is still not fully understood. The aim of present study was to investigate the transplacental genotoxicity of valproate on animal model and in 21 mothers and their newborns receiving AED. In both studies, in vivo micronucleus (MN) assay was used. Pregnant dams were exposed to Na-valproate (100mg/kg) on gestational days 12-14. Dams and pups receiving Na-valproate showed a significantly increased MN frequency (5.17 ± 1.17/1000; 5.20 ± 1.48/1000) compared to the control (1.0 ± 0.58/1000; 1.67 ± 1.03/1000). In mother/newborn study a significant increase of MN frequency was detected in newborns of mothers taking AEDs (3.09 ± 0.49/10,000) compared to the referent newborns (1.56 ± 0.22/10,000). The results of this study suggest that AEDs may act as transplacental genotoxins. Launching the mother/newborn cohorts for genotoxicological monitoring may give a significant new insight in health effects of AEDs.

Emergency EEG and diagnostic yield.

The aim of the study was to determine whether an acute loss of consciousness, mental status change or related symptoms correlated with the presence of epileptiform abnormalities on urgent EEG. We analyzed 228 consecutive patients admitted to Emergency Room during the past 12 months and referred for urgent EEG evaluation. All patients had either a brief loss of consciousness or acute brain disorder, with a clinical diagnosis of epilepsy, syncope, head trauma, headache, transient ischemic attack (TIA) or vertigo. Statistical analysis was performed using Spearman's rho test for group comparison and multivariate regression analysis. The mean age of patients was 48 +/- 20 years. The frequency of referring clinical diagnoses was as follows: epilepsy 44.7% (102/228), TIA 15.8% (36/228), syncope 15.4% (35/228), headache 11% (25/228), vertigo 7.9% (18/228) and acute head trauma 5.3% (12/228). EEG indicated epileptiform abnormalities in 14.9% (34/228) and focal slowing in 9.2% (21/228) of patients. The majority of them (26%; 21/81) had a clinical diagnosis of epilepsy. There was a significant correlation between clinical diagnosis of epilepsy and epileptiform EEG (Spearman's rho = 0.13; P < 0.04). Multivariate regression analysis showed that there was no predictive value in the clinical diagnosis of epilepsy and epileptiform EEG (beta = 1.483, P = 0.16). In conclusion, epilepsy was the most common clinical diagnosis in patients referred for urgent EEG. There was a significant correlation between the diagnosis and specific EEG abnormalities, however, the diagnosis of epilepsy failed to predict epileptiform activity on EEG. Study results suggested urgent EEG to have a high yield in patients with epilepsy.

Treatment of multiple sclerosis.

Multiple sclerosis is an autoimmune inflammatory demyelinating disease of the central nervous system, characterized by multifocal inflammatory destruction of myelin, axonal damage and loss of oligodendrocytes. The disease is carried through two stages: inflammatory and degenerative. The most common form of disease in approximately 85% of the cases is RRMS (relapsing-remitting form). The treatment of MS is devided into: treatment of the acute phase of illness, prevention of new relapses and disease progression, and symptomatic treatment. Most of the changes in treatment of multiple sclerosis and most of the news in recent years concerning new drugs are used in the treatment of progression of the disease and prevention of disease relapses. Some of these drugs are registrated in most Europian countries and USA, and others are in various stages of research.

Is the role of estrogens and estrogen receptors in epilepsy still underestimated?

The etiology of epilepsy still represents an open subject of discussions and research. Contrary to the majority of diseases for which drugs are developed following the origin of disease, epilepsy is treated symptomatically because it is perceived to have diverse causes. Recent results of oncological, neurological, developmental and biochemical studies suggest that the reproductive dysfunction in men and women, as a side effect related with antiepileptic therapy, points to the single origin of this disease. It seems that contrary to the present definition of estrogen as a compound affecting seizure susceptibility, based on causal chains: of increased estrogen levels (alcohol intake) and seizure, fact that all antiepileptic drugs are aromatase inhibitors or have estrogen binding properties, described cases of seizures in epileptic patients taking quinine as preventive therapy against malaria, impact of photic activation and sleep on estrogen level, it can be assumed that estrogen plays the leading role in the mutual origin of different types of epilepsy.

Prospective surveillance of Croatian pregnant women on lamotrigine monotherapy--aspects of pre-pregnancy counseling and drug monitoring.

We prospectively surveyed 23 pregnant women with epilepsy on lamotrigine monotherapy and reported outcome of their pregnancies, including one fetal intrauterine death, one spontaneous abortion and two preterm deliveries. There were no congenital malformations in their offspring. Women with pregnancy planning and folic acid intake delivered babies with higher values of birth weight and birth length. There was large inter-patient variation during drug monitoring and in the need of dose adjustment. Individual approach to every woman and monotherapy with minimal effective lamotrigine dose with frequent drug monitoring enhances the possibility for successful pregnancy. The management of women with epilepsy should begin with pre-pregnancy counseling. Planned pregnancy enables periconceptional folic acid supplementation. Despite the small number of cases, these data indicate that la motrigine treatment during pregnancy might be relatively safe. Larger prospective studies are needed to obtain adequate power for statistical analysis including long-term cohort studies.

Blink reflex in the prediction of outcome of idiopathic peripheral partial facioparesis: follow-up study.

AIM: To determine the value of the blink reflex as a predictor of outcome of idiopathic peripheral partial facial paresis. METHOD: The study included 30 patients suffering from acute idiopathic peripheral facioparesis and 30 age- and sex-matched healthy controls. Patients with symptomatic disease were excluded on the basis of neuroradiologic and laboratory findings. We stimulated the supraorbital foramen and recorded the evoked response from both orbiculares oculi muscles. We measured the ipsilateral early phasic component (R1) and bilateral late tonic component (ipsilateral R2 and contralateral R2) immediately, and a week and 6 months after the first test. RESULTS: In the acute phase of idiopathic peripheral partial facioparesis, the blink reflex showed slightly prolonged latencies and greatly reduced amplitudes of both R1 and R2 and the normal latencies and amplitudes of R2. All subjects showed clinical symptoms and typical electromyographic (EMG) changes, whereas 24 had blink reflex abnormalities. One week after the onset, all patients were still symptomatic and showed EMG changes, but blink reflex abnormalities remained in only 11 patients. Six months after the onset, 21 patients became asymptomatic and showed no EMG changes, 7 had no clinical symptoms but showed chronic neurogenic EMG changes, whereas 2 showed both clinical symptoms and EMG changes. Blink reflex abnormalities were observed in 6 patients. The amplitudes of R1 immediately and one week after the onset were the best predictors of residual motor deficit. CONCLUSION: Blink reflex is a useful tool for follow-up and recovery prognosis in patients with partial idiopathic facioparesis, especially in the early recovery phase.