Surgical treatment for epilepsy: a retrospective Swedish multicenter study

The characteristics of patients suffering from drug resistant epilepsy, including the results of the preoperative evaluation and epilepsy surgery were retrospectively analyzed in a Swedish multicenter 10-year cohort of children and adults. Altogether 152 patients (65 children and 87 adults) treated during the period 1980–1990 in three epilepsy centers were included and followed-up 2 years after surgery. Median age at onset of seizures was 4 years for the children and 12 years for the adults. A localization related epilepsy was present in 85% of the children and in 95% of the adults. The mean number of seizure types in the children was 1.7 (range 1–4) and in the adults 1.8 (range 1–4). The median monthly seizure frequency was 52 and 15 for children and adults respectively. Resective surgery was performed in 143 cases (94 temporal, 31 extratemporal, 9 multilobar and 9 major resection procedures) and palliative procedures in 16 cases (13 callosotomies and 3 stereotactic amygdalotomies). Postoperative neurological deficits were detected in 9% of the patients after temporal lobe resections and in 15% of the patients after extratemporal and multilobar resection procedures. Two years after resective surgery 53% of the children and 49% of the adults were seizure free. Another 25% of the patients had a more than 50% reduction of seizure frequency. In the postoperative non seizure free group of patients there was a negative correlation between decrease in weighted seizure severity and decrease in seizure frequency. This finding stresses the need for including other parameters than seizure frequency when evaluating the outcome of epilepsy surgery.     

Intracranial EEG potentials estimated from MEG sources: A new approach to correlate MEG and iEEG data in epilepsy

Detection of epileptic spikes in MagnetoEncephaloGraphy (MEG) requires synchronized neuronal activity over a minimum of 4cm2. We previously validated the Maximum Entropy on the Mean (MEM) as a source localization able to recover the spatial extent of the epileptic spike generators. The purpose of this study was to evaluate quantitatively, using intracranial EEG (iEEG), the spatial extent recovered from MEG sources by estimating iEEG potentials generated by these MEG sources. We evaluated five patients with focal epilepsy who had a pre‐operative MEG acquisition and iEEG with MRI‐compatible electrodes. Individual MEG epileptic spikes were localized along the cortical surface segmented from a pre‐operative MRI, which was co‐registered with the MRI obtained with iEEG electrodes in place for identification of iEEG contacts. An iEEG forward model estimated the influence of every dipolar source of the cortical surface on each iEEG contact. This iEEG forward model was applied to MEG sources to estimate iEEG potentials that would have been generated by these sources. MEG‐estimated iEEG potentials were compared with measured iEEG potentials using four source localization methods: two variants of MEM and two standard methods equivalent to minimum norm and LORETA estimates. Our results demonstrated an excellent MEG/iEEG correspondence in the presumed focus for four out of five patients. In one patient, the deep generator identified in iEEG could not be localized in MEG. MEG‐estimated iEEG potentials is a promising method to evaluate which MEG sources could be retrieved and validated with iEEG data, providing accurate results especially when applied to MEM localizations. Hum Brain Mapp 37:1661–1683, 2016. © 2016 Wiley Periodicals, Inc .     

Two novel laboratory tests facilitating diagnosis of glycine encephalopathy (nonketotic hyperglycinemia)

Glycine encephalopathy (GE), also known as non-ketotic hyperglycinemia, is a life-threatening metabolic disease caused by inherited deficiency of the glycine cleavage system (GCS). GE is characterized by accumulation of a large amount of glycine in serum and cerebrospinal fluids. In typical cases with GE, coma, profound hypotonia, and intractable seizures develop within several days of life. Patients with atypical symptoms may have delayed or missed diagnosis because of non-specific symptoms. It is sometimes problematic to confirm the diagnosis of GE since it requires either invasive liver biopsy for measurement of GCS activity or exhaustive mutational screening of three GCS genes, GLDC, AMT, and GCSH. We herein describe two novel laboratory tests for diagnosis of GE, [1-¹³C]glycine breath test and the multiplex ligation-dependent probe amplification (MLPA) for detection of large deletions in GLDC. The [1-¹³C]glycine breath test has been developed for noninvasive enzymatic diagnosis of GE. Because the GCS generates CO₂ by degradation of glycine, the GCS activity could be evaluated in vivo by measurement of exhaled ¹³CO₂ after administration of a stable isotope, [1-¹³C]glycine. The MLPA has been developed for improvement in mutation detection rate in GE: Deletions involving multiple GDLC exons are prevalent among GE patients, but cannot be detected by the exon-sequencing analysis. Two novel diagnosis methods would facilitate diagnosis of hyperglycinemic patients as having GE.     

A public health approach to clinical therapeutics in psychiatry: directions for new research

The mental health field is transforming the culture of treatment research by moving from a narrow regulatory model geared to drug approval and registration to a more inclusive public health model. Thus, whereas regulatory antidementia trials will exclude patients with psychiatric or neurologic symptoms or substance abuse and require them to be physically healthy and living with a caregiver, ie, 90% of the presenting Alzheimer population, the public health model promises to improve patient care by addressing the types of practical questions and functional outcomes typically the concern of clinicians: Does treatment enhance function? How can we keep people well once they have been made well? Why do treatments not work as well in practice as in clinical trials? Public health studies are conducted in the world of actual practice with time-pressured clinicians taking care of large numbers of patients with uncertain clinical presentations, complex comorbidities, and varying degrees of interference with ideal levels of compliance. The exclusive focus on symptoms is expanded to include outcomes related to issues of function, disability, morbidity, mortality, resource use, and quality of life. Highly controlled efficacy research is still needed to establish treatment merit, but efficacy now marks only the beginning of the process of inquiry.     

Quality of life after extratemporal epilepsy surgery: a prospective clinical study

PURPOSE: The purpose of this prospective clinical study was to assess quality of life (QOL) and impact of seizure status on QOL in patients with extratemporal epilepsy after surgery. PATIENTS AND METHODS: Twenty-three consecutive patients who had been operated due to extratemporal epilepsy were included in this study. Quality of Life Inventory in Epilepsy-10 (QOLIE-10) questionnaire was completed by all patients before 6 months and 2 years after surgery. Results obtained from short- and long-term follow-up were compared to baseline. Furthermore, patients who were seizure-free since surgery and those who had seizure were also compared in terms of outcome in QOL after surgery. RESULTS: All patients showed significantly improved QOL in both short- and long-term follow-ups compared to preoperative status regardless of seizure status (p<0.001). Seizure-free patients showed better QOL than those of patients who continued to have seizure during postoperative period. Furthermore, improved QOL was correlated with seizure status and shorter duration of epilepsy (p=0.001). CONCLUSION: Our findings showed that improved QOL is related to postoperative seizure status. However, future clinical studies including larger population of patients with extratemporal epilepsy are required to elucidate the role of other factors.     

Cost-effectiveness of surgical treatment compared to medical treatment in patients with drug-refractory epilepsy: A systematic review

Background and purpose

Approximately 30% of epilepsy patients develop a drug-refractory epilepsy, that is, seizures cannot be controlled with antiepileptic drugs. Surgery has been evaluated as an effective but costly form of treatment. The aim of this systematic review is to synthesize the available evidence on the cost-effectiveness of surgical treatment compared to medical treatment for these patients.

Method

A systematic literature search was performed in MEDLINE, Embase, PsycINFO, Cochrane Library and the National Health Service Economic Evaluation Database until September 2022. Title, abstract and full-text screening were conducted by two researchers. Original studies published in English or German analyzing the cost-effectiveness of surgical compared to medical treatment were included. Study characteristics, effectiveness measures, costs and incremental cost-effectiveness ratios (ICERs) were extracted. The quality of studies was assessed using the Drummond checklist.

Results

Fourteen studies were included. Most studies evaluated surgery as cost-effective. The ICER per patient seizure free ranged from dominant to purchasing power parity US dollars (PPP-USD) 479,275. The ICER per 1% seizure reduction ranged from PPP-USD 227 to PPP-USD 342. The ICER per year without seizures was PPP-USD 4202 and the ICER per quality-adjusted life-year ranged from dominant to PPP-USD 90,874. The studies varied greatly in their methodology and time horizon.

Conclusion

Surgical treatment is cost-effective compared to medical treatment, especially when a lifetime horizon is adopted. It is concluded that all disease-specific costs should be considered over a long period when assessing the cost-effectiveness of epilepsy treatment. From an economic perspective, efforts should be made to improve access to surgical treatment for patients with drug-refractory epilepsy.     

Seizure recurrence after planned discontinuation of antiepileptic drugs in seizure-free patients after epilepsy surgery: a review of current clinical experience

PURPOSE: Although epilepsy surgery, especially temporal lobe epilepsy surgery, is well established to control seizures in patients remaining on antiepileptic drug (AED) treatment, less information is available about how many seizure-free surgical patients will relapse after discontinuation of AEDs under medical supervision. METHODS: A literature review yielded six retrospective clinical observations. RESULTS: After planned discontinuation of AEDs in patients rendered seizure free after epilepsy surgery, most often various forms of temporal lobe surgery, the mean percentage recurrence rate in adults in four studies was 33.8%[95% confidence interval (CI), 32.4-35.2%], with maximum follow-up ranging from 1 to 5 years. Seizure recurrence increased during the follow-up of 1 to 3 years and occurred within 3 years of AED discontinuation. In one study of children with temporal lobe epilepsy, the recurrence rate was 20%. More than 90% of adult patients with seizure recurrence regained seizure control with reinstitution of previous AED therapy. Seizure recurrence was unaffected by the duration of postoperative AED treatment; as a consequence, delaying discontinuation beyond 1 to 2 years of complete postoperative seizure control seems to have no added benefit. The occurrence of rare seizures or auras after surgery did not eliminate the possibility of eventual successful AED discontinuation. CONCLUSIONS: AED discontinuation is associated with a seizure recurrence in one in three patients rendered seizure free by epilepsy surgery. These results will be useful in counseling patients about discontinuing AED treatment after successful epilepsy surgery.     

Autosomal dominant nocturnal frontal lobe epilepsy and mild memory impairment associated with CHRNB2 mutation I312M in the neuronal nicotinic acetylcholine receptor

Certain paroxysmal nocturnal behaviors have been established as features of nocturnal frontal lobe epilepsy (NFLE). Despite insight into its genetics, the majority of patients with NFLE are not linked to a known mutation and clinical diagnosis remains a challenge. We describe a family presenting with stereotyped nocturnal arousals from non-rapid eye movement sleep, bilateral hand posturing, and pelvic thrusting in the mother, but subtle motor activity in the daughter, and minimal or no epileptiform EEG discharges. Despite normal IQ, there were moderate and severe verbal memory deficits in the mother and daughter, respectively. Genetic testing revealed the CHRNB2 mutation I312M in transmembrane region 3 (M3) of the neuronal nicotinic acetylcholine receptor. Phenotypic similarities in unrelated families suggest the determining role of this mutation in NFLE, whereas different inter- and intrafamilial cognitive profiles point to other factors. The absence of clear motor features of NFLE in the daughter emphasizes the shortcomings of current clinical criteria and the potential for genetic testing to further guide clinical diagnostic criteria.     

Compartmentalization of antigen specific cytokine responses to the central nervous system in CNS borreliosis: secretion of IFN-γ predominates over IL-4 secretion in response to outer surface proteins of Lyme disease Borrelia spirochetes

The neurological manifestations of Lyme disease have been proposed to be partly due to cytokine-mediated immunopathological mechanisms. In this study, the number of Borrelia-specific cells secreting interferon-γ and interleukin-4 was determined in blood and cerebrospinal fluid from patients with CNS borreliosis (n=23), other neurological diseases (n=20), and in blood from healthy controls (n=10), utilizing an ELISPOT-assay. Elevated specific secretion of IFN-γ was found in CNS borreliosis, most pronounced in cerebrospinal fluid, whereas secretion of IL-4 was strikingly low. This may indicate that symptoms are due to side effects of the immune response, since IFN-γ secretion in the absence of corresponding levels of IL-4 may be associated with tissue destruction.     

Diagnosing photosensitive epilepsy: Fancy new versus old fashioned techniques in patients with different epileptic syndromes

Purpose: To demonstrate the clinical importance of using a high quality photic stimulator for recording EEGs to diagnose photosensitivity. Methods: We performed EEG examinations on 2 adult and 2 paediatric patients with a history of visually induced seizures; routinely we used a Grass PS 40 photic stimulator (rectangular Xenon lamp giving flashes of 10 μs duration, 0.7 J, 1-30 Hz, width 7 cm, length 12 cm). We repeated the IPS with a Grass PS 33 plus stimulator (round Xenon lamp giving flashes of 10 μs duration, 1 J, 1-60 Hz, diameter 14 cm). Results: Patients were affected by both benign and catastrophic epilepsies. They complained about episodes of dizziness (case 1), dizziness accompanied by a sensation in the arms and fear (case 2), absences (case 3), and myoclonic jerks (case 4). These symptoms occurred when working with neon lights, computers or ironing striped clothes (case 1), while driving (case 2), whenever there was sunlight (case 3 and 4). Only IPS performed with the Grass PS 33 plus stimulator evoked PPRs accompanied by their typical complaints. In all cases, the revised diagnosis led to changes in their treatment and the disappearance or diminishment of their complaints and PPR range. Conclusion: A PPR can occur in various types of epilepsy, can have a different meaning, and requires a different therapeutic intervention. Only an appropriate photic stimulator with diffuse white light and a flash intensity level of 1 J/flash, can reliably demonstrate whether a patient is photosensitive, or equally important exclude it.     

Sporadic vascular dementia as clinical presentation of a new missense mutation within exon 7 of NOTCH3 gene

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disease characterized by ischemic stroke with early onset, migraine, seizures, and vascular dementia. CADASIL is associated with mutations within NOCT3 gene, mainly clustered in exons 3 and 4. We report a case of CADASIL presenting progressive subcortical dementia in the sixth decade. Neither family history, nor acute ischemic events were present. MRI findings were typical for CADASIL. NOTCH3 analysis disclosed a new missense mutation within exon 7, leading to the substitution of cysteine 366 with a tryptophan (Cys366Trp). Our finding suggests CADASIL diagnosis must be considered in patients with vascular dementia also in absence of stroke-like events and of family history.     

Zif268 and Fos-like immunoreactivity in tetanus toxin-induced epilepsy: reciprocal changes in the epileptic focus and the surround

Altered gene expression for a number of molecules has been suggested as one of the underlying mechanisms of epileptogenesis. Changes in expression of the immediate early genes, zif268 and c-fos, were investigated in chronic focal epilepsy induced by tetanus toxin (TT, 20–35 ng) injected in the rat motor cortex. Most rats injected with TT and perfused on postoperative day 5, 7 or 14 had recurrent focal seizures after a latent period of 4–13 days, and showed enhanced Zif268 immunoreactivity in a cluster of neurons at the injection site, as well as reduced Zif268 immunoreactivity in a distinct cortical zone around this cluster. C-fos or Fos-related immunoreactivity was decreased over widespread areas of frontoparietal and piriform cortex in epileptic rats, except for a focus at the injection site which, in most cases, showed increases in Fos-like immunoreactivity. Some epileptic rats showed increased Zif268 immunoreactivity in neurons of the ipsilateral ventral lateral and central lateral thalamic nuclei and increased Zif268 and Fos-like immunoreactivity in the pontine nuclei. Rats perfused before onset of seizures, showed no overt changes other than a slight decrease in Zif268 and Fos-like immunoreactivity at the injection site. The reciprocal changes in Zif268 immunoreactive neurons in the epileptic focus and the immediate surround parallel changes in gene expression for a number of molecules important in epileptogenesis and suggest a state of functional disconnection of the epileptic focus from other cortical areas that may contribute to the development and maintenance of focal epilepsy.     

Calcium signaling dysfunction in schizophrenia: a unifying approach

The present paper demonstrates a remarkable pervasiveness of underlying Ca²⁺ signaling motifs among the available biochemical findings in schizophrenic patients and among the major molecular hypotheses of this disease. In addition, the paper reviews the findings suggesting that Ca²⁺ is capable of inducing structural and cognitive deficits seen in schizophrenia. The evidence of the ability of antipsychotic drugs to affect Ca²⁺ signaling is also presented. Based on these data, it is proposed that altered Ca²⁺ signaling may constitute the central unifying molecular pathology in schizophrenia. According to this hypothesis schizophrenia can result from alterations in multiple proteins and other molecules as long as these alterations lead to abnormalities in certain key aspects of intracellular Ca²⁺ signaling cascades.     

A bag cell neuron-specific antigen localizes to a subset of dense core vesicles in Aplysia california

The bag cell neurons of Aplysia govern egg-laying through the release of a number of bioactive peptides which are processed from a common precursor. Immunoelectron microscopic studies suggest that sorting at the trans-Golgi segregates peptides from the amino terminal and carboxy terminal of the precursor into distinct classes of dense-cored vesicles (DCVs). Here we identify a novel bag cell-specific antigen (4F6 antigen) using monoclonal antibodies (MAbs). Immunoprecipitations and Western blots demonstrate that the MAb4F6 specifically recognizes a protein of 80 kDa and does not react with the egg-laying hormone precursor, processing intermediates or final products. The 4F6 antigen is localized in a subset of DCVs which also contain peptides derived from the amino terminus of the precursor. These results further demonstrate the complexity of vesicular sorting in the bag cells and also identify a novel tissue specific antigen localized to DCVs.