Individualised prediction of drug resistance and seizure recurrence after medication withdrawal in people with juvenile myoclonic epilepsy: A systematic review and individual participant data meta-analysis.

Background: A third of people with juvenile myoclonic epilepsy (JME) are drug-resistant. Three-quarters have a seizure relapse when attempting to withdraw anti-seizure medication (ASM) after achieving seizure-freedom. It is currently impossible to predict who is likely to become drug-resistant and safely withdraw treatment. We aimed to identify predictors of drug resistance and seizure recurrence to allow for individualised prediction of treatment outcomes in people with JME. Methods: We performed an individual participant data (IPD) meta-analysis based on a systematic search in EMBASE and PubMed - last updated on March 11, 2021 - including prospective and retrospective observational studies reporting on treatment outcomes of people diagnosed with JME and available seizure outcome data after a minimum one-year follow-up. We invited authors to share standardised IPD to identify predictors of drug resistance using multivariable logistic regression. We excluded pseudo-resistant individuals. A subset who attempted to withdraw ASM was included in a multivariable proportional hazards analysis on seizure recurrence after ASM withdrawal. The study was registered at the Open Science Framework (OSF; https://osf.io/b9zjc/). Findings: Our search yielded 1641 articles; 53 were eligible, of which the authors of 24 studies agreed to collaborate by sharing IPD. Using data from 2518 people with JME, we found nine independent predictors of drug resistance: three seizure types, psychiatric comorbidities, catamenial epilepsy, epileptiform focality, ethnicity, history of CAE, family history of epilepsy, status epilepticus, and febrile seizures. Internal-external cross-validation of our multivariable model showed an area under the receiver operating characteristic curve of 0·70 (95%CI 0·68-0·72). Recurrence of seizures after ASM withdrawal (n = 368) was predicted by an earlier age at the start of withdrawal, shorter seizure-free interval and more currently used ASMs, resulting in an average internal-external cross-validation concordance-statistic of 0·70 (95%CI 0·68-0·73). Interpretation: We were able to predict and validate clinically relevant personalised treatment outcomes for people with JME. Individualised predictions are accessible as nomograms and web-based tools. Funding: MING fonds.

Do the neurologists recognize autoimmune epilepsy well enough? What is the effect of the pandemic on this matter?

INTRODUCTION: The concept of "autoimmune epilepsy" (AE) has been emphasized more frequently through the recent increase in recognition of various autoantibodies specific to neuronal proteins. AIMS: To evaluate the attitudes of neurologists in regard to AE, to review the differential diagnosis, treatment options, and to reveal the effect of COVID-19 on this matter. METHODS: A detailed questionnaire prepared for AE was sent to neurologists via social media and WhatsApp after the approval of the Ethics Committee. The responses of 245 respondents working in different settings were analyzed, and the group with 15 years or less experience in neurology was statistically compared to the group with more than 15 years of experience. RESULTS: Awareness and knowledge levels on AE seemed high in all groups, while 11% had never thought about AE during the differential diagnosis in real life. Before starting treatment, 20% thought that the autoantibody result should definitely support it, and 77.6% reported that they did not recognize AE well. Participants stated that satisfactory guidelines for diagnosis and treatment (88.2%) and widespread laboratory support (83.7%) were lacking. Neurologists with less experience and those working outside of training hospitals get more often consultation from an experienced clinician while diagnosing and conduct more detailed investigations at the diagnosis stage (p = 0.0025, p = 0.0001). CONCLUSION: This first survey study conducted in a large group of neurologists on the attitudes for the concept of AE suggested that postgraduate education, and diagnostic and treatment guidelines should be organized and antibody screening tests need to be better disseminated.

Headache in idiopathic/genetic epilepsy: Cluster analysis in a large cohort.

OBJECTIVE: The link between headache and epilepsy is more prominent in patients with idiopathic/genetic epilepsy (I/GE). We aimed to investigate the prevalence of headache and to cluster patients with regard to their headache and epilepsy features. METHODS: Patients aged 6-40 years, with a definite diagnosis of I/GE, were consecutively enrolled. The patients were interviewed using standardized epilepsy and headache questionnaires, and their headache characteristics were investigated by experts in headache. Demographic and clinical variables were analyzed, and patients were clustered according to their epilepsy and headache characteristics using an unsupervised K-means algorithm. RESULTS: Among 809 patients, 508 (62.8%) reported having any type of headache; 87.4% had interictal headache, and 41.2% had migraine. Cluster analysis revealed two distinct groups for both adults and children/adolescents. In adults, subjects having a family history of headache, ≥5 headache attacks, duration of headache ≥ 24 months, headaches lasting ≥1 h, and visual analog scale scores > 5 were grouped in one cluster, and subjects with juvenile myoclonic epilepsy (JME), myoclonic seizures, and generalized tonic-clonic seizures (GTCS) were clustered in this group (Cluster 1). Self-limited epilepsy with centrotemporal spikes and epilepsy with GTCS alone were clustered in Cluster 2 with the opposite characteristics. For children/adolescents, the same features as in adult Cluster 1 were clustered in a separate group, except for the presence of JME syndrome and GTCS alone as a seizure type. Focal seizures were clustered in another group with the opposite characteristics. In the entire group, the model revealed an additional cluster, including patients with the syndrome of GTCS alone (50.51%), with ≥5 attacks, headache lasting >4 h, and throbbing headache; 65.66% of patients had a family history of headache in this third cluster (n = 99). SIGNIFICANCE: Patients with I/GE can be clustered into distinct groups according to headache features along with seizures. Our findings may help in management and planning for future studies.

Reevaluation of the Critically Ill Patients With Nonconvulsive Status Epilepticus by Using Salzburg Consensus Criteria.

OBJECTIVE: We aimed to assess the usefulness of the Salzburg Consensus Criteria (SCC) for determining the prognosis of critically ill patients with nonconvulsive status epilepticus (NCSE). METHODS: We retrospectively reviewed consecutive patients with unconsciousness followed up in the intensive care unit (ICU). Three clinical neurophysiologists, one of them blinded to clinical and laboratory data, reevaluated all EEG data independently and determined NCSE according to SCC. The incidence of NCSE and ictal EEG patterns and their relationship to clinical, laboratory, neuroradiological, and prognostic findings were assessed. RESULTS: A total of 107 consecutive patients with mean age 68.2 ± 15.3 years (57 females) were enrolled in the study. Primary neuronal injury was detected in 59 patients (55.7%). Thirty-three patients (30.8%) were diagnosed as NCSE. While authors decided to treat 33 patients (30.8%), 32 patients (29.9%) had been treated in real-life evaluation. Clinical and EEG improvement were detected in 12 patients (11.3%) in real-life treatment group showing correlation with lack of intubation and ICU stay related to postsurgical event. Rate of mortality (45.8%) was high showing association with systemic-metabolic etiology, severity of coma and presence of "plus" modifiers in the EEG. CONCLUSION AND SIGNIFICANCE: Our findings suggest that SCC is highly compatible with clinical practice in the decision for treatment of patients with NCSE. The presence of "plus" modifiers in the EEG was found to be associated with mortality in these patients and was a significant marker for the high mortality rate.

Delta Brush Pattern Is Not Unique to NMDAR Encephalitis: Evaluation of Two Independent Long-Term EEG Cohorts.

PURPOSE: Although its specificity has not previously been investigated in other cohorts, delta brush pattern (DBP) is increasingly reported in the EEGs of patients with anti- N-methyl-d-aspartate receptor (NMDAR) encephalitis. METHODS: We aimed to investigate the DBP in the EEGs of 2 cohorts; patients with change in consciousness for various causes monitored in the intensive care unit (ICU) (n = 106) and patients with mesial temporal lobe epilepsy (MTLE) with or without antineuronal antibodies (n = 76). RESULTS: These patients were investigated for the presence of DBP, defined as an EEG pattern characterized by delta activity at 1 to 3 Hz with superimposed bursts of rhythmic 12- to 30-Hz activity. Two investigators blindfolded for the clinical and immunological data independently analyzed the EEGs for recognition of this pattern. An EEG picture compatible with DBP was observed in 4 patients; only 1 of them (1.3%) belonged to the MTLE group. She did not bear any of the investigated autoantibodies and was seizure-free after epilepsy surgery. In the ICU group, there were 3 additional patients showing DBP with various diagnoses such as hypoxic encephalopathy, brain tumor, stroke, and metabolic derangements. All of them had died in 1-month period. CONCLUSIONS: Our results underlined that DBP is not unique to NMDAR encephalitis; it may very rarely occur in MTLE with good prognosis after surgery and second, in ICU patients who have high mortality rate. Therefore, the presence of this pattern should alert the clinician for NMDAR encephalitis but other possible etiologies should not be ignored.

Electroencephalographic Patterns Recorded by Continuous EEG Monitoring in Patients with Change of Consciousness in the Neurological Intensive Care Unit.

INTRODUCTION: Our aim was to examine the frequency of various electrographic patterns including periodic discharges (PD), repetitive spike waves (RSW), rhythmic delta activities (RDA), nonconvulsive seizures (NCS) and nonconvulsive status epilepticus (NCSE) in continuous EEG monitoring (cEEG) of the critically ill patients with change of consciousness and the presence of specific clinical and laboratory findings associated with these important patterns in this study. METHODS: Patients with changes of consciousness in the neurological intensive care unit (NICU) were consecutively monitored with cEEG during 2 years. Their clinical, electrophysiological, radiological and laboratory findings were evaluated retrospectively. RESULTS: This sample consisted of 57 (25 men) patients with a mean age of 68.2 years. Mean duration of cEEG monitoring was 2532.6 minutes. The most common electrographic patterns were PD (33%) and NCS-NCSE (26.3%). The presence of NCS-NCSE was significantly associated with PD (57.9%, p<0.001). PD and NCS-NCSE were the mostly seen in patients with acute stroke and hypoxic encephalopathy. Duration of monitoring was significantly longer in the group with PD and NCS-NCSE (p:0.004, p:0.014). Detection of any electrographic pattern in EEG before monitoring was associated with the presence of any pattern in cEEG (59.3%, p<0.0001). Convulsive or nonconvulsive seizure during monitoring was common in patients with electrographic patterns (p<0.0001). 66.7% of NCS-NCSE was seen within the first 12 hours and 26.7% was seen within the 12-24 hours of the monitoring. CONCLUSION: Detection of any electrographic pattern in EEG before monitoring was associated with the presence of any important pattern in cEEG monitoring. This association suggest that at least 24 hours-monitoring of these patients could be useful for the diagnosis of clinical and/or electrographic seizures.

Are There Any Specific EEG Findings in Autoimmune Epilepsies?

This study evaluated the EEG findings of patients whose seizures were associated with a possible autoimmune etiology. Our aim was to find clues to distinguish patients with antineuronal antibodies (Ab) through EEG studies. We reviewed our database and identified antineuronal Ab positive epilepsy patients with or without autoimmune encephalitis. These patients had Abs to N-methyl-d-aspartate receptor (NMDAR) (n = 5), glycine receptor (GLY-R) (n = 5), contactin-associated protein-like 2 (CASPR-2) (n = 4), uncharacterized voltage-gated potassium channel complex (VGKC) antigens (n = 2), glutamic acid decarboxylase (GAD) (n = 2), Hu (n = 1), and amphiphysin (n = 1). The control group consisted of 21 seronegative epilepsy or encephalopathy patients with similar clinical features. EEG findings were compared between the groups in a blindfolded design. We did not find any significant difference in EEG findings between antineuronal Ab positive epilepsy patients and seronegative control group. It was remarkable that four seropositive but none of the seronegative patients presented with nonconvulsive status epilepticus (NCSE) or focal motor status epilepticus. Continuous theta and delta rhythms were observed in 5 (71%) seropositive patients with autoimmune encephalitis and 2 (25%) seronegative patients. Eight (40 %) seropositive patients showed a frontal intermittent rhythmic delta activity (FIRDA) pattern as opposed to 5 (24%) seronegative patients. Two patients with NMDAR Ab positivity showed rhythmic delta waves superimposed with beta frequency activity resembling "delta brush" pattern. EEG seems as a limited diagnostic tool in differentiating epilepsy and/or encephalopathy patients with a possible autoimmune etiology from those without. However, antineuronal Abs associated with encephalitis should be considered in the etiology of status epilepticus forms. A possible autoimmune etiology for seizures may be considered in the presence of continuous slow waves, FIRDA, and delta brush pattern in the EEG.

Vascular Ischemia as a Cause of Transient Global Amnesia: A Patient Series.

INTRODUCTION: Epileptic, migrainous, and vascular pathologies may cause transient global amnesia (TGA); however, the mechanism of causation remains unclear. We investigated possible vascular causes of TGA. METHODS: We retrospectively evaluated the clinical and radiologic studies of 13 patients with TGA. On admission, patients underwent diffusion-weighted imaging (DWI) and intra- and extracranial magnetic resonance angiography (MRA); vascular risk factor profiles for diabetes, hypertension, and hyperlipidemia; electroencephalography; and neuropsychological tests. Seven patients underwent control DWIs 24 h after symptom onset. RESULTS: One patient had two punctiform acute infarcts in the left hippocampus, and one had a left pontine paramedian acute infarct. In the second patient, control DWI showed additional left hippocampal and right frontal acute infarcts. None of the patients had electroencephalographic evidence of epileptic activity. All patients except for one had at least one vascular risk factor. The second patient was shown to have paroxsysmal atrial fibrillation during follow-up. CONCLUSION: Minor posterior circulation ischemic stroke appears to cause TGA in some patients. Evaluations such as DWI and vascular risk factor assessment may be helpful in making the diagnosis.

Lifetime prognosis of juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is among the most common types of genetic epilepsies, displaying a good prognosis when treated with appropriate drugs, but with a well-known tendency to relapse after withdrawal. The majority of patients with JME have continuing seizures after a follow-up of two decades. However, 17% are able to discontinue medication and remain seizure-free thereafter. Clinicians should remember that there is a small but still considerable subgroup of JME patients whose seizures are difficult to treat before informing patients with newly-diagnosed JME about their "benign" prognosis. This resistant course is not fully explained, though there are many suggested factors. The dominating myoclonic seizures disappear or diminish in severity in the fourth decade of life. Despite the favorable seizure outcome in most of the cases, 3/4 of patients with JME have at least one major unfavorable social outcome. The possible subsyndromes of JME, its genetic background, and its pathophysiological and neuroimaging correlates should be further investigated.

Prevalence and characteristics of visual aura in idiopathic generalized epilepsy.

Some patients with idiopathic/genetic generalized epilepsy (IGE) experience visual aura, which can confuse the diagnosis. We sought to determine the frequency and characteristics of visual auras in IGE patients. Among the 176 IGE patients, 4 men and 7 women reported visual auras (mean age - 24 years). Syndromic diagnoses were juvenile myoclonic epilepsy in four, eyelid myoclonia with absences (EMA) in three, juvenile absence epilepsy in three, and other in one. Visual auras consisted of flashing lights, macropsia, illusional movements, and blindness. Eyelid myoclonia with absences was significantly more common in the group with visual aura (3 of 11 patients vs. 8 of 165 IGE patients; P=0.02). Furthermore, photosensitivity was found significantly more common in IGE patients with visual aura (90% vs 46% of the total IGE patients) (P=0.004). In conclusion, the visual auras do not exclude a diagnosis of IGE. The presence of visual aura in the EMA syndrome is also remarkable.

Does semiology tell us the origin of seizures consisting mainly of an alteration in consciousness?

PURPOSE: Studies on seizures only with an alteration of consciousness were limited mainly to generalized epilepsy. This seizure type has been described rarely in focal epilepsy. We aimed to analyze the semiologic features of this seizure type in focal and generalized epilepsies in a blinded design. METHODS: A total of 338 seizure videos in 100 patients were included exclusively by semiologic criteria. Two investigators evaluated the seizure semiology (aura, seizure duration, blinking, mild motor phenomena including automatisms, and so on) from the videos. Primarily the ictal electroencephalography (EEGs) studies and all laboratory findings were evaluated for the localization of the epileptogenic zone and delineating the syndromes, in the second step. KEY FINDINGS: Of the focal epilepsy patients (n = 57), the epileptogenic zone could be localized to the temporal (n = 20), frontal (n = 9), and parietooccipital (n = 3) regions. The most common etiology of the generalized epilepsy patients (n = 43) was presumably genetic (n = 33). The presence of aura (none in generalized epilepsy vs. 35% in focal epilepsy; p = 0.0008), lack of blinking (19.3% in focal vs 65.1% in generalized epilepsy; p = 0.01), and longer seizure duration (generalized 14.3 ± 17.7 s vs focal 54.9 ± 40.1 s; p < 0.0001) are significantly associated with focal epilepsy, whereas high seizure frequency (p = 0.002), family history of epilepsy (p = 0.016), and responsiveness to therapy (p = 0.004) point to generalized epilepsy with logistic regression analysis. SIGNIFICANCE: Seizures consisting mainly of an alteration in consciousness may originate from any brain lobe in focal epilepsies and also occur in generalized epilepsies. Several semiologic and clinical features that help to differentiate between focal and generalized epilepsy should be considered in the syndrome diagnosis.

Magnetic resonance spectroscopy findings in photosensitive idiopathic generalized epilepsy.

Studies investigating the pathophysiology of epileptic photosensitivity indicate variable involvement of particular brain regions. Our aim was to identify metabolic differences between photosensitive idiopathic generalized epilepsy (IGE) patients and nonphotosensitive IGE patients and normal healthy subjects by using Magnetic Resonance Spectroscopy (MRS). Fourteen patients diagnosed with photosensitive IGE were investigated. The control groups consisted of 14 age- and sex-matched healthy volunteers and 14 IGE patients without photosensitivity. MRS measurements of N-acetylaspartate (NAA), choline-containing compounds (Cho), creatine (Cr) were performed in the frontal and occipital cortex and the thalamus bilaterally using a stimulated echo acquisition mode (STEAM) technique with a voxel size of 20 x 20 x 20 mm. The values of the patients with IGE were compared with those of the normal controls and within subgroups according to the clinical variables by appropriate statistical tests. Photosensitive IGE patients showed significantly decreased concentrations of NAA in the right frontal lobe and left thalamus, decreased NAA/Cr ratio in left thalamus and significantly increased concentrations of Cho/Cr ratio in the right frontal lobe and NAA/Cr in the left occipital lobe when compared to normal controls. Furthermore, left occipital NAA concentration increased and left thalamus NAA/Cr ratios were decreased from the IGE patients without photosensitivity but without reaching statistical significance. Our results support previous MR studies suggesting an asymmetrical neuronal dysfunction in favor of the dominant occipital cortex and thalamus in photosensitive IGE patients.

The evaluation of interictal focal EEG findings in adult patients with absence seizures.

PURPOSE: To investigate the focal interictal EEG abnormalities in adult patients with absence seizures (ASs) and to identify their clinical, EEG and semiological correlates. METHODS: Fifty patients older than 18 years, diagnosed as having IGE with AS documented with ictal recordings. Interictal focal sharp or spike-waves and strictly focal paroxysmal slow activity were considered as focal EEG features. The patients having focal EEG features were classified as "Group I", whereas the remaining of them was classified as "Group II". RESULTS: We observed focal findings in 34% of the patients, mainly in frontotemporal (41%), and frontal (29%) regions. There were no significant differences with respect to the clinical parameters such as sex, epilepsy duration, positive family history and the age of the onset between the groups. Psychiatric co-morbidities were significantly higher in Group I when compared to Group II (P=0.00). Accompanying automatisms were higher in Group I, whereas eye deviation during absences was higher in Group II. In Group I, the asymmetry of the ictal discharges was more frequently observed. Focal EEG features were more frequently seen in juvenile absence epilepsy syndrome, without reaching a significance level. CONCLUSION: The focal findings in adult absence epilepsy patients could have some unknown etio-pathogenetic and prognostic implications. We emphasize the cautious interpretation of isolated interictal focal EEG abnormalities to prevent a wrong diagnosis of focal epilepsy in patients who may indeed suffer from generalized epilepsy.

MR spectroscopy findings in Lafora disease.

PURPOSE: Our aim was to investigate the [(1)H] MR spectroscopy (MRS) findings of Lafora Disease (LD), which is a disabling form of progressive myoclonic epilepsy. METHODS: Twelve patients diagnosed with LD and 12 control subjects underwent MRS studies with single-voxels of 8 cc obtained in the frontal lobe, pons, and cerebellum. The metabolites and NAA/Cr, NAA/Cho, Cho/Cr, mI/Cr ratios were calculated. Subgroup analysis was also done between 5 patients with EPM2B and 6 patients with EPM2A mutations. Two investigators scored neurological symptom severity. RESULTS: We found a statistically significant difference of NAA/Cho ratio in LD patients compared with normal controls in cerebellum (P= 0.04). In addition, both myoclonus and ataxia scores showed significant correlation with NAA/Cho ratios in the pons (P= 0.03, P= 0.04) and in the cerebellum (P= 0.04, P= 0.01), respectively. CONCLUSION: We conclude that the cerebellum is the mostly affected structure in LD and there are significant correlations of MRS findings with some clinical parameters. The differences in the group may be related to different genetic mutations besides disease duration and other clinical variables. MRS studies could provide insights about the severity of the involvement of LD.

Reduced axon number in juvenile myoclonic epilepsy demonstrated by motor unit number estimation analysis.

Some conventional and quantitative EMG studies have already demonstrated a subclinical lower motor neuron involvement in juvenile myoclonic epilepsy (JME). Our aim was to investigate this subclinical involvement by using motor unit number estimation (MUNE) analysis with modified McComas' technique. We enrolled 75 consecutive JME patients and 26 normal controls. All subjects underwent motor and sensory nerve conduction studies, concentric needle EMG and MUNE analysis of the M. abductor pollicis brevis (APB) and M. tibialis anterior (TA). The clinical and EEG findings were evaluated to correlate with MUNE values. MUNE values of the APB (54+/-25) and TA (35+/-17) muscles were significantly lower in the JME group (p<0.001) when compared to the normal controls (109+/-24 and 80+/-26 for APB and TA muscles, respectively). Our findings show that anterior hom cells were subclinically affected in some JME patients, suggesting a shared background for both JME phenotype and grey matter disorganization in spinal cord.