Adherence to anti-seizure medications in the Swedish Prospective Regional Epilepsy Database and Biobank for Individualized Clinical Treatment (PREDICT).

The aim of this study was to describe the extent of, and risk factors for, non-adherence to anti-seizure medications (ASMs) in adult people with epilepsy (PWE) in Sweden. A cross-sectional multi-centre study was performed of PWEs in western Sweden, with data from medical records, and a questionnaire filled in by the participants including self-reports on how often ASM doses had been forgotten during the past year. Participants were categorized into adherent if they forgot at 0-1 occasion, and non-adherent if they forgot at 2-10 or >10 occasions. Demographic and clinical factors were compared by Chi2- or Fisher's test and a logistic regression model was used to find risk factors for non-adherence. In the cohort of 416 PWE aged median 43, IQR 29-62 years, 398 patients were prescribed ASM treatment at inclusion, and 39 % (n = 154) were in the non-adherent group. Significant factors in the multivariable analysis were: younger age, seizure freedom the past year, valproate treatment and experiencing side effects. The rate of self-reported non-adherence was high, illustrating a need for continuous focus on fundamental aspects of epilepsy care. The identified risk factors could enable quality improvement projects and patient education to be directed to those at risk of non-adherence.

Prevalence and nature of patient-reported antiseizure medication side effects in a Swedish regional multi-center study.

PURPOSE: Side effects is one of the major clinical problems in epilepsy care. We assessed the prevalence of ASM side effects in participants in a large regional multicenter observational study in western Sweden and aimed to identify risk factors and inventory the nature of side effects with different ASM regimes. METHODS: Cross-sectional analysis of survey answers and clinical characteristics of 406 adult participants recruited to a regional observational study between December 2020 and March 2023. Half of the participants had been seizure free for one year. Second-generation or newer ASMs were the most common. RESULTS: A total of 164 (40 %, 95 %CI: 36-45) patients reported side effects. Patients reporting side effects were younger (median 41 vs 47 years, p = 0.015), had more frequently experienced a seizure in the last year (p = 0.02), and were more often on ASM polytherapy (p < 0.01). ASM polytherapy and age were significant risk factors in regression models, but the explanatory value was low. The most common side effect was tiredness followed by cognitive symptoms. CONCLUSIONS: Our findings show that side effects are still common in epilepsy care and suggests that unnecessary polypharmacy should be avoided. Apart from number or ASMs, predicting who will experience side effects is difficult and more research on individual vulnerability is needed.

Protein profiling in plasma for biomarkers of seizure.

PURPOSE: A biochemical way to measure seizures would greatly benefit epilepsy research and clinical follow-up. Short-term biomarkers like lactate exist, and interest in biomarkers representative of longer-term seizure burden is growing. In this exploratory study, we aimed to identify markers in blood plasma that differentiate persons with recent seizures from persons with epilepsy and long-standing seizure freedom. METHODS: A proteomic analysis was performed on plasma samples of 120 persons with seizures using the Olink Neuro-exploratory panel. Participants were selected from a regional biobank study in Västra Götaland (Sweden) and categorized into two groups: recent seizure and seizure-free. The panel contained 92 proteins linked to neurological diseases and processes, and levels of these proteins were compared between the patient groups to identify potential markers of seizure activity. RESULTS: We identified significant differences in protein levels between the recent seizure and seizure-free patient groups for Cadherin-15 [(CDH15; p = 0.008)], Latent transforming growth factor beta-binding protein 3 [(LTBP3; p = 0.002)], Phosphoethanolamine/phosphocholine phosphatase 1 [(PHOSPHO1; p = 0.011)], and Progestagen associated endometrial protein [(PAEP; p = 0.0005)]. CONCLUSION: The findings in this study present CDH15, LTBP3, PHOSPHO1 and PAEP as candidate markers of seizure activity. Further confirmatory studies are needed.

Neurofilament light, glial fibrillary acidic protein, and tau in a regional epilepsy cohort: High plasma levels are rare but related to seizures.

OBJECTIVE: Higher levels of biochemical blood markers of brain injury have been described immediately after tonic-clonic seizures and in drug-resistant epilepsy, but the levels of such markers in epilepsy in general have not been well characterized. We analyzed neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and tau in a regional hospital-based epilepsy cohort and investigated what proportion of patients have levels suggesting brain injury, and whether certain epilepsy features are associated with high levels. METHODS: Biomarker levels were measured in 204 patients with an epilepsy diagnosis participating in a prospective regional biobank study, with age and sex distribution correlating closely to that of all patients seen for epilepsy in the health care region. Absolute biomarker levels were assessed between two patient groups: patients reporting seizures within the 2 months preceding inclusion and patients who did not have seizures for more than 1 year. We also assessed the proportion of patients with above-normal levels of NfL. RESULTS: NfL and GFAP, but not tau, increased with age. Twenty-seven patients had abnormally high levels of NfL. Factors associated with such levels were recent seizures (p = .010) and epileptogenic lesion on radiology (p = .001). Levels of NfL (p = .006) and GFAP (p = .032) were significantly higher in young patients (<65 years) with seizures ≤2 months before inclusion compared to those who reported no seizures for >1 year. NfL and GFAP correlated weakly with the number of days since last seizure (NfL: rs = -.228, p = .007; GFAP: rs = -.167, p = .048) in young patients. NfL also correlated weakly with seizure frequency in the last 2 months (rs = .162, p = .047). SIGNIFICANCE: Most patients with epilepsy do not have biochemical evidence of brain injury. The association with seizures merits further study; future studies should aim for longitudinal sampling and examine whether individual variations in NfL or GFAP levels could reflect seizure activity.

Methodological Approaches to Ketogenic Dietary Treatments in Glioma Patients from a Nutritional Point of View.

Ketogenic diets (KD) have received increasing interest in neuro-oncology based on their ability to inhibit glioma growth In Vitro and their established role in medically refractory seizures. This review analyses the methodological aspects of KD treatment alongside standard care for patients with gliomas from a nutritional point of view. A literature search was performed in March 2022 searching PubMed and Scopus. We identified 13 articles including 187 patients with a histological-new or recurrent-diagnosis of glioma and treated by KD during the course of the disease. Dietary treatments were categorized as the classical ketogenic diet (CKD), the Modified Atkins diet (MAD), and the medium-chain triglyceride (MCT) diet. We identified a large variation in dietary characteristics regarding restriction of carbohydrates, ketogenic ratio, and additional dietary support. This striking heterogenicity in the methodological approaches of KD treatments made it problematic to compare effects between the included studies. Therefore, a standardized definition of KD for patients with glioma and a consensus on methodological implementation is needed. It would also be desirable to further investigate to what extent KD treatment can be optimized to secure optimal nutrient status and patient satisfaction.

SARS-COV-2 a trigger of myelin oligodendrocyte glycoprotein-associated disorder.

SARS-COV-2 frequently cause neurological disorders and is sometimes associated with onset of autoimmune diseases affecting the nervous system. Over recent years, a rare but distinct diagnosis designated myelin oligodendrocyte glycoprotein-associated disorder (MOGAD) has been recognized in patients with attacks of optic neuritis, myelitis, or encephalomyelitis and increased levels of anti-MOG antibodies. The cause of MOGAD is unknown. However, there have been reports of single cases of MOGAD in patients with Covid-19 infection. We report a series of SARS-CoV-2 positive patients that developed MOGAD, but a homology search did not support a cross-reactive immune response to SARS-CoV-2 spike-protein and MOG.

Long-term outcome of 200 patients referred to a first seizure clinic.

OBJECTIVES: To determine what proportion of our First Seizure referrals reflected true unprovoked first seizures or epilepsy, and to assess the long-term diagnostic accuracy of our First Seizure Clinic (FSC) by quantifying the risk of subsequent seizures in our FSC cohort. METHODS: We prospectively collected data of 200 adult patients referred to the FSC between May 2014 and December 2015. We reviewed clinical notes, electroencephalography (EEG) data and performed telephone follow-up at 28-month post-diagnosis. RESULTS: Of the 200 patients referred to the FSC, 181 attended. At the initial assessment, 39 of these patients were diagnosed with epilepsy, with most of these patients (59%) found to have a history of previous seizures. Fifty patients were diagnosed with a first seizure, of which 28% were labelled as provoked seizures. Sixty nine of the patients received another diagnosis and 23 were labelled as indeterminable. At 28 months follow-up, 11 (22%) of patients who received a diagnosis of first seizure subsequently received a diagnosis of epilepsy. In the remaining groups, only 5 (5%) patients were diagnosed with epilepsy (of these three were in the indeterminable group). CONCLUSIONS: Our study shows that 50% of the patients referred to a FSC had not experienced a seizure but were given an alternative diagnosis. Secondly, our study indicates that the risk of seizure recurrence following a first seizure is quite low (22%). This is because a substantial proportion of the patients were diagnosed with epilepsy already at the first assessment. The high proportion of patients being diagnosed with epilepsy was mainly due to a history of previous seizures. Thirdly, patients who were given an alternative diagnosis at the first assessment had a low probability (5%) for seizure recurrence.

Perry syndrome: a case of atypical parkinsonism with confirmed DCTN1 mutation.

Perry syndrome is a rare neurological condition characterised clinically by depression, sleep disturbance, central hypoventilation and parkinsonism. Perry syndrome is a TAR DNA-binding protein 43 (TDP-43) proteinopathy associated with mutated dynactin-1 protein, inherited in an autosomal dominant manner. Several pathogenic mutations in exon 2 in the dynactin 1 gene have been identified; p. F521, p. G67d, p. G71R, p. G71E, p. G71A, p. T72p, p. Q74p and p. Y78C. We present the second known case Perry syndrome with confirmed DCTN1 mutation (p. Y78C) in New Zealand, who initially was thought to have a depressive illness. Perry syndrome should be considered in the differential diagnosis of young parkinsonism, especially if there is family history of sleep disorders, weight loss and/or marked depression.

Low-fat versus ketogenic diet in Parkinson's disease: A pilot randomized controlled trial.

BACKGROUND: Preliminary evidence suggests that diet manipulation may influence motor and nonmotor symptoms in PD, but conflict exists regarding the ideal fat to carbohydrate ratio. OBJECTIVES: We designed a pilot randomized, controlled trial to compare the plausibility, safety, and efficacy of a low-fat, high-carbohydrate diet versus a ketogenic diet in a hospital clinic of PD patients. METHODS: We developed a protocol to support PD patients in a diet study and randomly assigned patients to a low-fat or ketogenic diet. Primary outcomes were within- and between-group changes in MDS-UPDRS Parts 1 to 4 over 8 weeks. RESULTS: We randomized 47 patients, of which 44 commenced the diets and 38 completed the study (86% completion rate for patients commencing the diets). The ketogenic diet group maintained physiological ketosis. Both groups significantly decreased their MDS-UPDRS scores, but the ketogenic group decreased more in Part 1 (-4.58 ± 2.17 points, representing a 41% improvement in baseline Part 1 scores) compared to the low-fat group (-0.99 ± 3.63 points, representing an 11% improvement) (P < 0.001), with the largest between-group decreases observed for urinary problems, pain and other sensations, fatigue, daytime sleepiness, and cognitive impairment. There were no between-group differences in the magnitude of decrease for Parts 2 to 4. The most common adverse effects were excessive hunger in the low-fat group and intermittent exacerbation of the PD tremor and/or rigidity in the ketogenic group. CONCLUSIONS: It is plausible and safe for PD patients to maintain a low-fat or ketogenic diet for 8 weeks. Both diet groups significantly improved in motor and nonmotor symptoms; however, the ketogenic group showed greater improvements in nonmotor symptoms. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Cerebrospinal fluid markers of neuronal and glial cell damage in patients with autoimmune neurologic syndromes with and without underlying malignancies.

Autoimmune neurologic syndromes can be paraneoplastic (associated with malignancies and/or onconeural antibodies), or non-paraneoplastic. Their clinical presentation is often similar. As prognosis is related to malignancy treatment, better biomarkers are needed to identify patients with malignancy. We investigated cerebrospinal fluid (CSF) markers of neuronal (neurofilament light chain, NFL and total tau protein, T-tau) and glial (glial fibrillary acidic protein) damage. CSF-NFL and T-tau were increased in both paraneoplastic and non-paraneoplastic autoimmune syndromes. Patients with manifest malignancies were older, had less epilepsy, more focal central and peripheral neurological signs and symptoms, and worse long-term outcome, than those without malignancy. CSF-NFL-levels predicted long-term outcome but were not diagnostic for malignancy, after age adjustment.

Diagnostic performance of cerebrospinal fluid total tau and phosphorylated tau in Creutzfeldt-Jakob disease: results from the Swedish Mortality Registry.

IMPORTANCE: Identifying a clinical distinction between the invariably lethal prion disease Creutzfeldt-Jakob disease (CJD) and nonprion rapidly progressive dementias is important and sometimes difficult; thus, reliable tools for diagnosis are in great demand. OBJECTIVE: To test the diagnostic performance of dementia cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phosphorylated tau (P-tau), and the T-tau to P-tau ratio for CJD by analyzing the results from a large database of routine clinical samples in combination with diagnosis information from the Swedish Mortality Registry. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study. We cross-referenced the Swedish Mortality Registry with a data set of CSF measurements of T-tau and P-tau performed in routine clinical testing at the Clinical Neurochemistry Laboratory of the Sahlgrenska University Hospital, which serves most of Sweden. The data set consisted of 9765 deceased individuals with CSF measures, including 93 with CJD, with 52 autopsy-verified samples (56%). MAIN OUTCOMES AND MEASURES: For each patient, T-tau and P-tau levels in CSF were measured and the T-tau to P-tau ratio was calculated. Biomarker levels (adjusted for age and sex) were analyzed in relation to the recorded cause of death and time of death. We specifically tested a previously defined CJD biomarker profile (T-tau >1400 ng/L and T-tau to P-tau-ratio >25). RESULTS: Patients who died of CJD had elevated CSF T-tau levels and T-tau to P-tau ratio, but not elevated CSF P-tau levels, compared with patients who died of Alzheimer disease (AD) and other dementias. The previously defined biomarker profile had a specificity of 99.0%, a sensitivity of 78.5%, and a positive likelihood ratio of 79.9. When tested against common differential diagnoses, the sensitivity, specificity, and positive likelihood ratio of this profile was 78.5%, 99.6%, and 196.6, respectively, in relation to AD and 78.5%, 99.3%, and 109.3, respectively, in relation to other dementias. In CJD individuals (n = 30) with repeated measurements, but not in those with AD (n = 242) or other dementias (n = 258), T-tau levels and T-tau to P-tau ratios increased over time. CONCLUSIONS AND RELEVANCE: In this routine clinical setting, the combination of increased T-tau levels and increased T-tau to P-tau ratios in CJD patients has a very high specificity against important differential diagnoses to CJD and may serve as a clinically useful diagnostic test.

The endogenous peptide antisecretory factor promotes tonic GABAergic signaling in CA1 stratum radiatum interneurons.

Tonic GABAergic inhibition regulates neuronal excitability and has been implicated to be involved in both neurological and psychiatric diseases. We have previously shown that the endogenous peptide antisecretory factor (AF) decreases phasic GABAergic inhibition onto pyramidal CA1 neurons. In the present study, using whole-cell patch-clamp recordings, we investigated the mechanisms behind this disinhibition of CA1 pyramidal neurons by AF. We found that application of AF to acute rat hippocampal slices resulted in a reduction of the frequency, but not of the amplitude, of spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons. Miniature inhibitory postsynaptic currents (mIPSCs), recorded in the presence of tetrodotoxin (TTX), were however not affected by AF, neither in CA1 pyramidal cells, nor in stratum radiatum interneurons. Instead, AF caused an increase of the tonic GABAA current in stratum radiatum interneurons, leaving the tonic GABAergic transmission in CA1 pyramidal cells unaffected. These results show that the endogenous peptide AF enhances tonic, but not phasic, GABAergic signaling in CA1 stratum radiatum interneurons, without affecting tonic GABAergic signaling in CA1 pyramidal neurons. We suggest that this increased tonic GABAergic signaling in GABAergic interneurons could be a mechanism for the AF-mediated disinhibition of pyramidal neurons.

Cerebral vasculitis and multi-focal neurological deficits due to allopurinol-induced hypersensitivity syndrome.

Drug-induced hypersensitivity syndrome (DIHS) is a multi-system syndrome resulting from an idiosyncratic reaction to medication. While it commonly results in multi-organ involvement, particularly the liver, there are few reports of DIHS causing cerebral vasculitis and neurological deficits. We report the case of a 63-year old woman with DIHS secondary to allopurinol leading to multiple neurological deficits with magnetic resonance imaging findings consistent with a cerebral vasculitis.

Altered spontaneous synaptic inhibition in an animal model of cerebral heterotopias.

We have investigated spontaneous synaptic transmission in hippocampal nodular heterotopias in rats exposed to methylazoxymethanol (MAM) in utero. Pregnant Wistar rats were injected with MAM at E16. Acute hippocampal slices were prepared from the rat pups P14 to P40. Whole-cell voltage-clamp recordings were made from visually identified neurons using IR-DIC video microscopy. Synaptic events were recorded from either heterotopic neurons in the CA1 region or "slice-matched" normotopic CA1 pyramidal neurons. Both the spontaneous inhibitory (sIPSC) and excitatory synaptic transmission (sEPSC) to the same neurons were recorded. We found a profound reduction in the frequency of sIPSCs in the heterotopic neurons vs. normotopic neurons. No significant differences in the frequency of sEPSCs were found. We also found a profound reduction in the frequency of spontaneous IPSCs in normotopic neurons following application of the GABA reuptake blocker, NO-711, even in the presence of a GABA(B) receptor antagonist (CGP 55845). Preferentially blocking extrasynaptic GABA(A) receptors caused an increased frequency of sIPSCs in the heterotopic neurons. Our data suggest that there is a predominant change in inhibitory synaptic transmission, as measured by changes in sIPSCs, with no change in excitatory synaptic transmission to heterotopic neurons in hippocampus of rats exposed to MAM in utero. We suggest that this change is caused by an increase in the extracellular concentration of GABA but is not mediated via activation of presynaptic GABA(B) receptors. Rather, we propose that the increased extracellular GABA concentration in the heterotopias dampens the activity in inhibitory neurons via activation of extrasynaptic GABA(A) receptors.

Lamotrigine increases the number of BrdU-labeled cells in the rat hippocampus.

Antidepressant medication and electroconvulsive therapy stabilize mood symptoms and increase hippocampal neurogenesis. We examined whether lamotrigine, suggested to give rise to mood-stabilizing and antidepressant effects in addition to its antiepileptic properties, also increases the number of newborn cells in rat hippocampus. Rats (on day P21) received lamotrigine, valproate, or saline intraperitoneally once daily for 7 days. All animals received four intraperitoneal injections of bromodeoxyuridine (BrdU) on day P28 and were sacrificed the next day. Quantification of BrdU-labeled cells in the granule cell layer of the dentate gyrus showed an increased number of newborn cells in rats receiving lamotrigine (42.6 ± 3.5 cells/slice) compared with valproate (31.6 ± 2.8) and controls (32.2 ± 3.1; P<0.05). The increased number of BrdU-labeled cells suggests increased neurogenesis, possibly explaining the mood-stabilizing and antidepressant effects of lamotrigine.

Choreathetosis due to abuse of levothyroxine.

Choreathetosis due to thyrotoxicosis is a rare movement disorder of acute onset. Here we present the first report of choreathetosis secondary to abuse of levothyroxine. A 35-year-old woman with autoimmune thyroiditis tripled her daily levothyroxine intake and lost 20 kg of weight during the following 6 months. She soon developed incapacitating choreathetosis. When levothyroxine was reduced to her usual dosage, all symptoms vanished in 7 days. The prompt effect of dose correction points towards a direct influence of levothyroxine on the basal ganglia; alternatively, the effects of levothyroxine might have been indirect and, possibly, autoimmune-mediated. Abuse of levothyroxine and related thyroid-tropic substances should be included into the differential diagnosis of acute choreathetosis.

Ketogenic diet does not disturb neurogenesis in the dentate gyrus in rats.

The ketogenic diet, a high-fat diet, is a therapeutic alternative in the treatment of refractory epilepsy, especially in children. However, there are concerns that a high-fat diet may influence the normal development of the central nervous system and cognition. In this study we investigated the influence of ketogenic diet on adult neurogenesis in the dentate gyrus. Rats were provided with either a high-fat diet (80% fat) or a standard rat diet (5% fat) ad libitum for 4 weeks. In both female and male rats, the amounts of bromodeoxyuridine immunoreactive cells in the dentate gyrus were the same in the different groups. Our results suggest that the ketogenic diet does not disturb the neurogenesis in the rat dentate gyrus.

Excellent outcome after prolonged status epilepticus due to non-paraneoplastic limbic encephalitis.

Limbic encephalitis (LE) is frequently associated with malignancy. Non-paraneoplastic LE is less common and in this form, voltage-gated potassium channel (VGKC) antibodies are usually found. However in 2007 the spectrum was further extended by a report on four patients with presumed non-paraneoplastic LE in whom neither VGKC-antibodies nor other antibodies could be found (Samarasekera et al. 2007). Despite immunmodulatory treatment all these patients had severe neurological residual symptoms. Here we describe a further patient in whom extensive diagnostic procedures suggested non-paraneoplastic antibody-negative limbic encephalitis. Although this woman had prolonged status epilepticus during seven weeks, her outcome was excellent.

Long term follow-up of the first 70 operated adults in the Goteborg Epilepsy Surgery Series with respect to seizures, psychosocial outcome and use of antiepileptic drugs.

OBJECTIVE: To compare long term (10 years) seizure outcome, psychosocial outcome and use of antiepileptic drugs (AED) with the 2 year follow-up in adults after resective epilepsy surgery. METHODS: All adults (n = 70) who underwent resective epilepsy surgery from 1987 to 1995 in the Göteborg Epilepsy Surgery Series were included. Fifty-four had undergone temporal lobe resections and 16 extratemporal resections (12 frontal). A cross-sectional follow-up in the form of a semistructured interview was performed in late 2003. RESULTS: Mean follow-up was 12.4 years (range 8.6-16.2). Of the 70 patients (51% males), five (7%) were dead (three as a result of non-epilepsy related causes). Of the 65 patients interviewed, 38 (58%) were seizure-free at the long term follow-up: 65% of the patients with temporal lobe resections and 36% of the patients with extratemporal resections. Of the 35 patients who were seizure-free at the 2 year follow-up, 3 (9%) had seizures at the long term follow-up. Of the 30 patients who had seizures at the 2 year follow-up, 6 (20%) were seizure-free at the long term follow-up. Of all 65 patients, 45 (69%) had the same seizure status as the 2 year follow-up. Sixteen (25%) had an improved seizure status and 4 (6%) had a worsened status. Of the seizure-free patients, 11 (29%) had ceased taking AED, 28 (74%) were working and 25 (66%) had a driving license. CONCLUSIONS: Adult patients who are seizure-free 2 years after resective epilepsy surgery are most likely to still be seizure-free 10 years later. Most are working and have obtained a driving license.

Tonic GABA(A) receptor-mediated currents in human brain.

GABA(A) receptors can mediate both phasic (synaptic) and tonic (extrasynaptic) forms of inhibition. It has been proposed that tonic inhibition plays a critical part in controlling neuronal and network excitability. Although tonic GABA(A) receptor-mediated currents have been well characterized in rodents, their existence in human tissue has yet to be demonstrated. Here we show that tonic currents can be recorded from human tissue obtained from patients undergoing temporal lobectomies. Tonic GABA(A) receptor-mediated currents were present in pyramidal cells and interneurons in layer V-VI of temporal neocortex and granule cells in the dentate gyrus. These tonic currents have cell type-specific pharmacologies, opening up the possibility of targeted therapeutics.