Nese Dericioglu

Non-expert use of quantitative EEG displays for seizure identification in the adult neuro-intensive care unit.

Video-EEG monitoring is the ultimate way to diagnose non-convulsive status epilepticus (NCSE) in intensive care units (ICU). Usually EEG recordings are evaluated once a day by an electrophysiologist, which may lead to delay in diagnosis. Digital EEG trend analysis methods like amplitude integrated EEG (aEEG) and density spectral array (DSA) have been developed to facilitate recognition of seizures. In this study, we aimed to investigate the diagnostic utility of these methods by non-expert physicians and ICU nurses for NCSE identification in an adult neurological ICU. Ten patients with NCSE and ten control patients without seizures were included in the study. The raw EEG recordings of all subjects were converted to both aEEG and DSA and displayed simultaneously without conventional EEG. After training for seizure recognition with both methods, two physicians and two nurses analyzed the visual displays individually, and marked seizure timings. Their results were compared with those of a study epileptologist. Participants analyzed 615h of EEG data with 700 seizures. Overall, 63% of the seizures were recognized by all, 15.6% by three, 11.6% by two, 8.3% by one rater and only 1.5% were missed by all of them (sensitivity was 88-99%, and specificity was 89-95% when the ratings were assessed as 1-h epochs). False positive rates were 1 per 2h in the study and 1 per 6h in the control groups. Interrater agreement was high (κ=0.79-0.81). Bilateral independent seizures and ictal recordings with lower amplitude and shorter duration were more likely to be missed. There was no difference in performance between the rating of physicians and nurses. Our study demonstrates that bedside nurses, ICU fellows and residents can achieve acceptable level of accuracy for seizure identification using the digital EEG trend analysis methods following brief training. This may help earlier notification of the electrophysiologist who is not always available in ICUs.

Multidrug resistance in patients undergoing resective epilepsy surgery is not associated with C3435T polymorphism in the ABCB1 (MDR1) gene.

PURPOSE The C3435T polymorphism in the gene coding for P-glycoprotein (ABCB1) has been correlated with drug resistance in patients with epilepsy. However, replication studies have revealed conflicting results and the reason for this is not clear. We investigated the frequency of C3435T polymorphism in epileptic Turkish patients who underwent resective epilepsy surgery and compared our results with healthy controls. METHODS DNA samples were obtained from 100 healthy controls and 89 consecutive adult patients who underwent resective brain surgery due to refractory seizures at our epilepsy center. Genotypes for the C3435T polymorphism were determined by PCR and restriction analysis. RESULTS Comparison of drug-resistant patients and healthy controls revealed no significant difference in allele frequency (C vs. T; chi(2)=0.015, p=0.90) and genotype frequency (chi(2)=2.05, p=0.36). The findings in the pure hippocampal sclerosis (HS) group (n=73) were not significantly different from control subjects, either (allele frequency: chi(2)=0.29, p=0.59; genotype frequency: chi(2)=2.14, p=0.34). CONCLUSIONS Our findings failed to prove an association between C3435T polymorphism and drug resistance in a sample of Turkish patients with refractory epilepsy who underwent resective brain surgery.

Ictal Scalp EEG Findings in Patients with Mesial Temporal Lobe Epilepsy

The syndrome of mesial temporal lobe epilepsy (MTLE) is a well-defined clinical entity that responds to surgical treatment in a considerable number of patients. Although it has been subjected to intensive clinical research, few investigators have published the ictal scalp EEG findings and looked for specific features that might predict postoperative outcome. This study was designed to examine ictal scalp EEG characteristics in detail, in a group of patients with pathologically confirmed hippocampal sclerosis (HS). Patients who underwent long-term video-EEG monitoring at our center during a 3-year period and were diagnosed to have MTLE and pathologically proven HS were included in this retrospective study. All ictal scalp EEGs were investigated in a common reference montage, paying attention to the localization, morphology and frequency of ictal discharges that were accepted to represent a specific phase if the findings were sustained for at least 3 seconds. Any significant change in localization, morphology or frequency of discharges was said to represent a different phase. The ictal EEG patterns in different phases were later compared among seizures of different patients. In addition, the ictal EEG characteristics of the patients in Group I (Engels classification) were compared with the ictal EEG findings in patients who were included in another group. All the patients have been followed for more than 5 years. Seventy-one ictal EEGs were investigated in 25 adult patients (11 M, 14 F). Onset patterns were lateralized in 81.7% and localized in 76% of the seizures. Thirteen different patterns of onset were detected, the most common of which was the cessation of interictal discharges (35.2%). The most common ictal pattern following the initial changes was ipsilateral temporal rhythmic theta-delta activity (85.2%) that occurred on the average 13.4 seconds after onset. Nonlocalized/lateralized seizure onset of all the seizures or bilateral independent onset was present in 75% of the patients in Groups II-III, whereas this ratio was 14.3% in the patients in Group I (p=0.031). In conclusion, ictal scalp EEG in MTLE allows correct lateralization and localization in most of the seizures. Onset patterns may vary considerably; however, a later significant pattern consisting of rhythmic ipsilateral temporal build-up develops in the majority of seizures. Some ictal EEG characteristics may be related to post-operative outcome.

Blockade of GABA synthesis only affects neural excitability under activated conditions in rat hippocampal slices

The primary goal of this study was to establish whether inhibition of GABA synthesis was sufficient to induce network hyperexcitability in a rat hippocampal slice model comparable to that seen with GABA receptor blockade. We used field and intracellular recordings from the CA1 region of rat hippocampal slices to determine the physiological effects of blocking GABA synthesis with the convulsant, 3-mercaptoproprionic acid (MPA). We measured the rate of synthesis of GABA and glutamate in slices using 2-13C-glucose as a label source and liquid chromatography-tandem mass spectrometry. There was little effect of 3.5mM MPA on evoked events under control recording conditions. Tissue excitability was enhanced following a series of stimulus trains; this effect was enhanced when GABA transport was blocked. Evoked inhibitory potentials (IPSPs) failed following repetitive stimulation and MPA. Spontaneous epileptiform activity was seen reliably with elevated extracellular potassium (5mM). GABA synthesis decreased by 49% with MPA alone and 45% with the combination of MPA and excess potassium; GABA content was not substantially altered. Our data indicate: (1) GABAergic inhibition cannot be significantly compromised by MPA without network activation; (2) GABAergic synaptic inhibition is mediated by newly synthesized GABA; (3) there is a depletable pool of GABA that can sustain GABAergic inhibition when synthesis is impaired under basal, but not activated conditions; (4) overt hyperexcitability is only seen when newly synthesized GABA levels are low.

Cell death and survival mechanisms are concomitantly active in the hippocampus of patients with mesial temporal sclerosis.

Mesial temporal lobe epilepsy (MTLE) is often characterized pathologically by severe neuronal loss in the hippocampus. In this study we investigated concomitant appearance of the pro-apoptotic and anti-apoptotic mechanisms in injured neurons in epileptic human hippocampi. Postsurgical hippocampal specimens of randomly selected 25 patients with MTLE were studied with standard immunohistochemical techniques to detect the below markers of cell death pathways: truncated Bid - tBid, mitochondrial translocation of Bax (markers of pro-apoptotic Bcl-2 protein activation) and nuclear translocation of AIF (caspase-independent pro-apoptotic pathway). For cell survival pathways, we investigated the expression of c-IAP1, c-IAP2 and Hsp70 (heat shock protein). Immunopositive cells were counted in different regions of the hippocampus. We also verified IAP (inhibitor of apoptosis) expression with Western blotting. The results were statistically compared with hippocampi from non-epileptic autopsy controls. In patient hippocampi, Bax and tBid immunoreactivity were significantly increased and Bax staining was consistent with mitochondrial translocation. AIF was not translocated to the nucleus. c-IAP1 and c-IAP2 were barely detectable in control hippocampi, whereas their expression was dramatically increased in the patients in all hippocampal subfields. Interestingly, these neurons were also positively co-labeled for tBid and translocated Bax. Hsp70 immunreactivity was significantly increased in all surviving neurons in patient hippocampi whereas degenerating neurons failed to express Hsp70. Our findings are consistent with both pro-apoptotic and anti-apoptotic mechanisms being active within the same hippocampal neurons of patients with MTLE, illustrating an ongoing struggle between cell death and survival mechanisms in neurons under stress.

Antiepileptic treatment for anti-NMDA receptor encephalitis: the need for video-EEG monitoring

Anti-NMDA receptor encephalitis is a severe disorder characterised clinically by seizures, autonomic instability, and severe disturbances of memory, behaviour, and cognition. Due to the severity of symptoms, many patients are admitted to the intensive care unit. For some patients, the presence of various movement disorders and abnormal autonomic signs, as well as a history of seizures, lead to a false impression of status epilepticus, which is reported in 6% of the cases. Here, we present two young female patients, one of whom had ovarian teratoma. Both patients were referred to our neurological intensive care unit with a diagnosis of status epilepticus. However, prolonged video-EEG findings were compatible with encephalopathy. We avoided aggressive treatment with intravenous anaesthetics and both patients recovered after immunotherapy, one of whom received surgery. Physicians should be cautious in interpreting abnormal movements and autonomic signs in such patients and video-EEG monitoring is advised when status epilepticus is suspected.

Heart rate variability remains reduced and sympathetic tone elevated after temporal lobe epilepsy surgery

PURPOSE There is evidence of autonomic dysregulation in temporal lobe epilepsy. The structures removed during temporal lobectomy are important centers of central cardiovascular control; therefore surgery may conceivably alter the cardiovascular autonomic function. The effects of temporal lobectomy on autonomic cardiac control are controversial. We investigated the effects of temporal lobectomy on heart rate variability (HRV) in the early and late postoperative periods. METHODS We used 1-h ECG recordings to assess heart rate variability by spectral analysis in 24 consecutive patients who underwent temporal lobectomy due to intractable temporal lobe epilepsy. ECG recordings were performed before and twice (early and late) after surgery. The results were compared with age and sex matched controls. RESULTS When compared with controls, all the time and frequency domain indices (SDRR, RMSSD, TP, LF and HF) were significantly lower in the patient group before surgery. Findings were similar in the early and late post-operative periods except that the LF/HF ratio increased in the patient group after the late post-operative period. Within the patient group, compared to pre-operative results, normalized HF was increased in the early post-operative period; however in the late post-operative period, LF/HF ratio was increased. CONCLUSIONS These findings show that in patients with intractable temporal lobe epilepsy, HRV is decreased globally in both sympathetic and parasympathetic domains. While the total HRV remains reduced throughout the postoperative periods, the LF/HF ratio, i.e., sympathovagal balance is altered, in favor of parasympathetic side early after surgery, but towards the sympathetic side after the first postoperative month.

Creutzfeldt-jakob disease presenting as hyperparathyroidism and generalized tonic status epilepticus

Creutzfeldt-Jakob disease is the most common disorder among the very rare human transmissible subacute spongiform encephalopathies. Sporadic, familial or iatrogenic forms of the disease can be seen. The common presentations of the disease include rapidly progressive cognitive decline, behavioral changes, visual disturbances and cerebellar dysfunction. Hyperparathyroidism and toxicity of lithium and bismuth have been reported to induce similar symptoms and EEG findings, leading to a Creutzfeldt-Jakob like syndrome. We report a very rare case of Creutzfeldt-Jakob disease presenting with hyperparathyroidism and generalized tonic status epilepticus.

The role of patient companions in long-term video-EEG monitoring

In developing countries it is difficult to have full-time dedicated nurses in Epilepsy Monitoring Units (EMU). Our one-bed EMU is within the Neurology Service and is adequately staffed during daytime working hours only. So we created a new model where the patients companion was asked to press a nurse call button, allowing the examination of the patient by the nurse. In this study we aimed to understand how patient companions behaved and which factors influenced their behaviour. Patients were allowed to choose a single companion who were educated by the specialist monitoring nurse according to a protocol. Only the first recorded seizures of the patients were included in the study. The seizures were reviewed from the video-cassette recordings and the behaviour of the companions was scored according to the results of the following three questions: (1) when was the seizure noticed?; (2) was the nurse call button pushed?; and (3) did the companion prevent the recording of the seizure by the camera? The companions were grouped according to the following criteria; age, sex, level of education, type of relationship. The scores were compared for each criterion separately. The behaviours of the 50 companions (34F, 16M; age: 25-72) were studied. When statistically compared for age, sex and level of education, there were no significant differences between different groups. However, the mean score of the 47 companions who were immediate family members (3.72) was greater than those three who were not (1.66) In one-bed EMUs, patient companions who are family members can help nurses in the early detection of seizures.

LGI1 related limbic encephalitis and response to immunosuppressive therapy

Limbic encephalitis (LE) is characterized by a subacute onset of episodic memory impairment, disorientation, agitation, seizures and histological evidence of mesial temporal lobe inflammation. It is usually considered to have a paraneoplastic origin and is associated with specific autoantibodies in various cancers [1]. The non-paraneoplastic form has similar clinical and neuroradiological presentation. In these cases antibodies usually target voltage-gated potassium channels (VGKC) or glutamic acid decarboxylase and are, therefore, accepted as immunotherapyresponsive syndromes. Potassium channel antibodies were reported in two patients with reversible LE for the first time in 2001 [2]. Very recently, however, Dalmau et al. showed that the autoantigen associated with LE previously attributed to VGKC is, in fact, leucine-rich, glioma inactivated 1 (LGI1), a neuronal secreted protein [3]. Since this is a relatively rare condition, there have been very few publications on the clinical findings, treatment and follow-up results in this group of patients [3–6] and the optimum treatment regimen is still unknown. In this case report we present a young male patient who did not respond to plasma exchange therapy, but improved rapidly and significantly after IV pulse steroid infusion. A 31-year-old man was admitted for confusional state that had started 1 month ago. He had fever, vomiting and headache at the onset. His past medical history was unremarkable. Physical and neurologic examinations were normal apart from confusion and short-term memory deficits. Cranial MRI revealed hyperintense signals in bilateral hippocampi and the amygdaloid nuclei with little contrast enhancement (Fig. 1). At the onset of his complaints he was admitted to another hospital where he was diagnosed with herpes encephalitis and was given acyclovir without any benefit. In our clinic, blood studies including complete blood count, liver and renal function tests, tumor markers and paraneoplastic antibody analysis (anti-Hu, -Yo, -Ri, -Ma, -CV2) were all normal. Serum electrolyte analysis revealed mild hyponatremia (132 mEq/L). Cerebrospinal fluid (CSF) protein and glucose levels were normal. Analysis of CSF cytology showed increased mononuclear cells. Herpes PCR was negative. Thorax– abdomen CT scans, scrotal-pelvic ultrasonography and whole body fluorodeoxyglucose-positron emission tomography were negative for malignancy. He had two temporal lobe seizures during his follow up. Electroencephalography revealed bilateral generalized mild slow wave paroxysms, without epileptiform discharges. The patient was put on oxcarbazepine (OXC), and did not have any further seizures. In order to investigate the presence of nonparaneoplastic LE, serum and CSF samples were sent to Dr. J. Dalmau’s laboratory where antibodies for NMDA receptors and VGKC antibodies were studied. Meanwhile, the patient had six exchanges of 1.5 plasma volumes on alternate days. We could not give intravenous immunoglobulin (IVIg) because his IgA levels were very low. No clinical response was obtained in the first week after treatment with plasmapheresis and the patient was discharged from hospital. One month later we were informed that he had antibodies against LGI1. The patient was hospitalized again for IV pulse steroid treatment. At that time, his orientation in time and space had partially improved; however, he still had severe memory deficits. He had difficulty in remembering some recent events. After the B. Kaymakamzade T. Kansu E. Tan N. Dericioglu (&) Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey e-mail: noroloji2011@gmail.com