Antidepressant effect of vagal nerve stimulation in epilepsy patients: a systematic review.

BACKGROUND: Vagal nerve stimulation (VNS) is an effective palliative therapy in drug-resistant epileptic patients and is also approved as a therapy for treatment-resistant depression. Depression is a frequent comorbidity in epilepsy and it affects the quality of life of patients more than the seizure frequency itself. The aim of this systematic review is to analyze the available literature about the VNS effect on depressive symptoms in epileptic patients. MATERIAL AND METHODS: A comprehensive search of PubMed, Medline, Scopus, and Google Scholar was performed, and results were included up to January 2020. All studies concerning depressive symptom assessment in epileptic patients treated with VNS were included. RESULTS: Nine studies were included because they fulfilled inclusion criteria. Six out of nine papers reported a positive effect of VNS on depressive symptoms. Eight out of nine studies did not find any correlation between seizure reduction and depressive symptom amelioration, as induced by VNS. Clinical scales for depression, drug regimens, and age of patients were broadly different among the examined studies. CONCLUSIONS: Reviewed studies strongly suggest that VNS ameliorates depressive symptoms in drug-resistant epileptic patients and that the VNS effect on depression is uncorrelated to seizure response. However, more rigorous studies addressing this issue are encouraged.

Effect of repetitive transcranial magnetic stimulation on action myoclonus: A pilot study in patients with EPM1.

OBJECTIVE: The objective of this study was to explore the short-term effects of repetitive transcranial magnetic stimulation (rTMS) on action myoclonus. METHODS: Nine patients with Unverricht-Lundborg (EPM1) progressive myoclonus epilepsy type underwent two series of 500 stimuli at 0.3Hz through round coil twice a day for five consecutive days. Clinical and neurophysiological examinations were performed two hours before starting the first rTMS session and two hours after the end of the last rTMS session. RESULTS: Eight patients completed the protocol; one discontinued because of a transient increase in spontaneous jerks. The unified myoclonus rating scale indicated a 25% reduction in posttreatment myoclonus with action score associated with an increase in the cortical motor threshold and lengthening of the cortical silent period (CSP). The decrease in the myoclonus with action scores correlated with the prolongation of CSP. CONCLUSIONS: Repetitive transcranial magnetic stimulation can be safely used in patients with EPM1, improves action myoclonus, and partially restores deficient cortical inhibition.

The semiology of psychogenic nonepileptic seizures revisited: Can video alone predict the diagnosis? Preliminary data from a prospective feasibility study.

OBJECTIVE: To investigate if, when, and to what extent visual information contained in a video-recorded event allows experienced epileptologists to predict the diagnosis of psychogenic nonepileptic seizures (PNES) without the aid of electroencephalography (EEG). METHODS: Five neurologists actively practicing in epilepsy centers in Italy and the United States were asked to review 23 videos capturing representative events of 21 unselected consecutive patients admitted for long-term video-EEG monitoring (VEM). Four raters were blind to EEG and clinical information; one rater was not. They were requested to (1) rate the videos for quality and content; (2) choose among four diagnoses: (a) epileptic seizures (ES); (b) PNES; (c) Other nonepileptic seizures (NES; (syncope, movement disorder, migraine, etc.); (d) "Cannot Say"; and (3) explain in their own words the main reasons leading to the diagnosis of choice. RESULTS: All raters predicted the diagnosis correctly in 7 of 23 videos (all ES or PNES) (30.4%), whereas all raters failed in 5 of 23 cases (three Other NES, one PNES, one Cannot Say) (21.7%). The conditions that facilitate, and those that interfere with, a confident diagnosis were predictable. Degree of accuracy among raters was not uniform and was consistently better in three raters. Two among the four blind raters were as accurate as the rater who was not blinded. Interrater agreement was "moderate" (k = 0.52) for the overall group; "moderate" for ES (k = 0.53); "substantial" for PNES (k = 0.63); "fair" for Other NES (k = 0.21)-similar to the results obtained in a previous study evaluating the reliability of combined video-EEG. SIGNIFICANCE: In about one third of cases, a confident diagnosis of PNES/ES can be established on clinical grounds based on video data alone. Our results benefit all affected patients, particularly those with no access to video-EEG monitoring units.

Brivaracetam in Unverricht-Lundborg disease (EPM1): Results from two randomized, double-blind, placebo-controlled studies.

OBJECTIVE: To evaluate efficacy, tolerability, and safety of adjunctive brivaracetam (BRV) in patients with Unverricht-Lundborg disease (EPM1). METHODS: Two prospective, multicenter, double-blind, phase III trials (N01187/NCT00357669; N01236/NCT00368251) in patients (≥16 years) with genetically ascertained EPM1, showing moderate-severe myoclonus (action myoclonus score ≥30/160), randomized (1:1:1) to twice-daily BRV (N01187: 50 or 150 mg/day; N01236: 5 or 150 mg/day), or placebo. Both studies comprised a baseline period (2 weeks), 2-week up-titration period, 12-week stable-dose maintenance period, and down-titration or entry into long-term follow-up study. Symptoms of myoclonus were assessed by Unified Myoclonus Rating Scale (UMRS). Primary efficacy end point was percent reduction from baseline in action myoclonus score (UMRS section 4) at last treatment visit. Safety assessments included treatment-emergent adverse events (TEAEs). RESULTS: N01187: 50 patients randomized, 47 completed; N01236: 56 patients randomized, 54 completed. Median (min-max) percent reduction from baseline in action myoclonus score is the following-N01187: placebo 5.6 (-81.3 to 53.8), pooled BRV group (primary efficacy analysis) 21.4 (-50.0 to 73.6), BRV 50 mg/day 26.3 (-35.8 to 69.2), BRV 150 mg/day 16.9 (-50.0 to 73.6); N01236: placebo 17.5 (-170 to 61.5), BRV 5 mg/day -4.6 (-430 to 81.8), BRV 150 mg/day (primary efficacy analysis) 12.3 (-58.3 to 96.9). Estimated differences versus placebo were not statistically significant. TEAEs were reported by 72-75% placebo-treated and 56-83% BRV-treated patients. SIGNIFICANCE: Effect of BRV on action myoclonus was not statistically significant. However, action myoclonus score showed wide intrapatient variability and may not have been the optimal tool to measure severity of myoclonus in EPM1. Both studies had very high completion rates (95.3% overall), and a high percentage of patients (88.7% overall) entered long-term follow-up; both likely to be influenced by good tolerability. These studies demonstrate the feasibility of rigorous trials in progressive myoclonic epilepsy.

Validation of a novel classification model of psychogenic nonepileptic seizures by video-EEG analysis and a machine learning approach.

The aim of this study was to validate a novel classification for the diagnosis of PNESs. Fifty-five PNES video-EEG recordings were retrospectively analyzed by four epileptologists and one psychiatrist in a blind manner and classified into four distinct groups: Hypermotor (H), Akinetic (A), Focal Motor (FM), and with Subjective Symptoms (SS). Eleven signs and symptoms, which are frequently found in PNESs, were chosen for statistical validation of our classification. An artificial neural network (ANN) analyzed PNES video recordings based on the signs and symptoms mentioned above. By comparing results produced by the ANN with classifications given by examiners, we were able to understand whether such classification was objective and generalizable. Through accordance metrics based on signs and symptoms (range: 0-100%), we found that most of the seizures belonging to class A showed a high degree of accordance (mean±SD=73%±5%); a similar pattern was found for class SS (80% slightly lower accordance was reported for class H (58%±18%)), with a minimum of 30% in some cases. Low agreement arose from the FM group. Seizures were univocally assigned to a given class in 83.6% of seizures. The ANN classified PNESs in the same way as visual examination in 86.7%. Agreement between ANN classification and visual classification reached 83.3% (SD=17.8%) accordance for class H, 100% (SD=22%) for class A, 83.3% (SD=21.2%) for class SS, and 50% (SD=19.52%) for class FM. This is the first study in which the validity of a new PNES classification was established and reached in two different ways. Video-EEG evaluation needs to be performed by an experienced clinician, but later on, it may be fed into ANN analysis, whose feedback will provide guidance for differential diagnosis. Our analysis, supported by the ML approach, showed that this model of classification could be objectively performed by video-EEG examination.

Conversation analysis in the differentiation of psychogenic nonepileptic and epileptic seizures in pediatric and adolescent settings.

The differential diagnosis of epileptic seizures (ES) and psychogenic nonepileptic seizures (PNES) is often difficult, especially in pediatric and adolescent settings. Conversation analysis (CA) can be a worthwhile diagnostic tool in adults. The aim of this study was to assess the diagnostic value of CA in Italian children and adolescents. Ten patients (seven females and three males), diagnosed using video-EEG as having either ES or PNES, underwent a video-recorded interview by a physician from outside the center specifically trained for this purpose. An external linguistic rater then examined the video recordings and transcripts using CA. Diagnoses formulated on the basis of interactional and linguistic features of the patients' speech were compared with diagnoses made by seizure experts on the basis of all available clinical information including the video-EEG findings. Conversation analysis diagnoses corresponded to the video-EEG diagnoses in 8 out of 10 cases. In conclusion, while some conversational adaptation is necessary to enable children and adolescents to share their seizure experiences with an adult health professional, this study indicates the differential diagnostic potential of a CA approach in these young people with PNES or epilepsy. Larger samples are obviously needed to confirm these findings.

Childhood trauma and psychogenic nonepileptic seizures: A review of findings with speculations on the underlying mechanisms.

OBJECTIVE: The objective of this review was to examine the possible link between psychological trauma in a patient's medical history and the onset of psychogenic nonepileptic seizures (PNES). METHODOLOGY: An electronic search of published reports was made using the search engines PubMed-MedLine, EBSCO, PsycINFO, SFX, and Embase and the keywords "PNES", "psychogenic seizures", "sexual abuse", and "trauma". RESULTS: A correlation emerged between history of childhood trauma and the presence of PNES. Antecedent trauma was more frequent in females than in males and in patients exhibiting psychiatric disorders but was inversely correlated with cognitive impairment. CONCLUSIONS: In the presence of PNES, it is important to accurately investigate the patient's medical history in search of psychological trauma, particularly in women and in patients with psychiatric disorders.

Metaphoric language in the differential diagnosis of epilepsy and psychogenic non-epileptic seizures: Time to move forward.

Conversation analysis (CA) to identify metaphoric language (ML) has been proposed as a tool for the differential diagnosis of epileptic (ES) and psychogenic nonepileptic seizures (PNES). However, the clinical relevance of metaphoric conceptualizations is not clearly defined. The current study aims to investigate the ML utilized by individuals with ES and PNES in a pulled multi-country sample. Two blinded researchers examined the transcripts and videos of 54 interviews of individuals (n = 29, Italy; n = 11, USA; n = 14, Russia) with ES and PNES, identifying the patient-seizure relationship representative of the patient's internal experience. The diagnoses were based on video-EEG. Metaphors were classified as "Space/place", "External force", "Voluntary action", and "Other". A total of 175 metaphors were identified. No differences between individuals with ES and PNES were found in metaphoric occurrence (χ2 (1, N = 54) = 0.07; p = 0.74). No differences were identified when comparing the types of metaphors utilized by participants with ES and those with PNES. Patients with PNES and ES did not demonstrate differences in terms of occurrence and categories in ML. Therefore, researchers and clinicians should carefully consider the use of metaphor conceptualizations for diagnostic purposes.

Prevalence and clinical features of sexual dysfunction in male with epilepsy: the first southern Italy hospital-based study.

The aim of the study was to evaluate the prevalence and the etiology of sexual dysfunctions (SD) in a group of epileptic outpatients. Sixty Italian men (30 patients and 30 controls), living in Sicily, were enrolled in the study. Our diagnostic investigation included physical and neurological examination, EEG, MRI and Hamilton Depression and Anxiety Scales administration. A "semi-structured" questionnaire and the short form of the Sex relation Evaluation Schedule Assessment Monitoring were administered to the whole sample to evaluate their sexual well-being. There was no correlation between SD and type of epilepsy, EEG abnormalities and different antiepileptic drugs, while a weak correlation was observed between seizure frequency and the main SD. Forty-seven percent of the patients were affected by mild to moderate depression and 73.3% were anxious. Moreover, those patients who had uncontrolled seizures presented alteration in their social and affective area. Our findings showed a low prevalence of SD in epileptic male outpatients, especially concerning hyposexuality, and an important role of the seizure frequency in the multifactorial aetiology of sexual impairment in epilepsy. However, larger and multicenter studies are needed to better define the effects of epilepsy per se and the individual treatments on sexual function.

A retrospective multicentric study on the effectiveness of intravenous brivaracetam in seizure clusters: Data from the Italian experience.

OBJECTIVE: Nearly half of people with epilepsy (PWE) are expected to develop seizure clusters (SC), with the subsequent risk of hospitalization. The aim of the present study was to evaluate the use, effectiveness and safety of intravenous (IV) brivaracetam (BRV) in the treatment of SC. METHODS: Retrospective multicentric study of patients with SC (≥ 2 seizures/24 h) who received IV BRV. Data collection occurred from January 2019 to April 2022 in 25 Italian neurology units. Primary efficacy outcome was seizure freedom up to 24 h from BRV administration. We also evaluated the risk of evolution into Status Epilepticus (SE) at 6, 12 and 24 h after treatment initiation. A Cox regression model was used to identify outcome predictors. RESULTS: 97 patients were included (mean age 62 years), 74 (76%) of whom had a history of epilepsy (with drug resistant seizures in 49% of cases). BRV was administered as first line treatment in 16% of the episodes, while it was used as first or second drug after benzodiazepines failure in 49% and 35% of episodes, respectively. On the one hand, 58% patients were seizure free at 24 h after BRV administration and no other rescue medications were used in 75 out of 97 cases (77%) On the other hand, SC evolved into SE in 17% of cases. A higher probability of seizure relapse and/or evolution into SE was observed in patients without a prior history of epilepsy (HR 2.0; 95% CI 1.03 - 4.1) and in case of BRV administration as second/third line drug (HR 3.2; 95% CI 1.1 - 9.7). No severe treatment emergent adverse events were observed. SIGNIFICANCE: In our cohort, IV BRV resulted to be well tolerated for the treatment of SC and it could be considered as a treatment option, particularly in case of in-hospital onset. However, the underlying etiology seems to be the main outcome predictor.

Conversation analysis in the differential diagnosis of Italian patients with epileptic or psychogenic non-epileptic seizures: a blind prospective study.

The differential diagnosis of epileptic seizures (ES) and psychogenic non-epileptic seizures (PNES) is often difficult. The diagnostic gold standard is video-EEG, but this procedure is limited because of its high cost and is not always available. Research groups from Germany and Britain have used conversation analysis (CA) of patients' descriptions of their seizures as a means of differentiating the type of seizure. The aim of this study was to verify the value of their considerations in relation to the Italian language. Ten subjects (five with ES and five with PNES) diagnosed by means of the video-EEG recording of one seizure were studied under blind conditions by a linguist. The patients with ES described their seizures in as much detail as possible and tried to reconstruct the experience as fully as they can, making an effort to describe their subjective symptoms, quantify the duration of the phases preceding and following the seizure, and use the image of an external entity overcoming them. On the contrary, the patients with PNES repeated their extraneousness to the events that occur, refused to reply, expressed amnesia, reconstructed the happening by referring to descriptions provided by witnesses, and often describe their seizures using the image of an internal entity of which they were victims. The linguist correctly identified nine cases out of ten using CA.

Carbamazepine-induced non-epileptic myoclonus and tic-like movements.

Carbamazepine-induced abnormal movements have been reported in children and adult patients, and both non-epileptic myoclonus and tic-like movements have been reported in the same patient. Although a pathogenetic mechanism underlying carbamazepine-induced epileptic negative myoclonus has been proposed, a causative role of carbamazepine for positive myoclonus has not been fully identified. Here, we describe the video-documented case of an adult patient with non-epileptic myoclonus and tic-like movements persisting for 21 years, which appeared after he started carbamazepine treatment at 10 years of age. [Published with videosequences].

A pilot open-label trial of zonisamide in Unverricht-Lundborg disease.

Action myoclonus frequently remains the primary cause of disability in Unverricht-Lundborg disease (EPM1) patients. Pharmacological treatment of myoclonus in these patients continues to be challenging; indeed conventional AEDs may be poorly effective in monotherapy or even in combination. We carried out a pilot, open-label trial of add-on zonisamide (ZNS) in patients with EPM1. Twelve EPM1 patients with epilepsy and action myoclonus were included in the study. Oral ZNS was gradually titrated until the target dose of 6 mg/Kg/day. Unified Myoclonus Rating Scale was obtained in each subject before and after ZNS add-on. A significant reduction of myoclonus severity was reached after ZNS introduction. ZNS was generally well tolerated and only two patients withdrew due to mild adverse effects. Our trial suggests that ZNS may be a valuable therapeutic option in EPM1 patients.

Clinical and neurophysiologic features of progressive myoclonus epilepsy without renal failure caused by SCARB2 mutations.

PURPOSE: Mutations of the SCARB2 gene cause action myoclonus renal failure syndrome (AMRF), a rare condition that combines progressive myoclonus epilepsy (PME) with severe renal dysfunction. We describe the clinical and neurophysiologic features of PME associated with SCARB2 mutations without renal impairment. METHODS: Clinical and neurophysiologic investigations, including wakefulness and sleep electroencephalography (EEG), polygraphic recording (with jerk-locked back-averaging and analysis of the EEG-EMG (electromyography) relationship by coherence spectra and phase calculation), multimodal evoked potentials, and electromyography were performed on five Italian patients with SCARB2 mutations. KEY FINDINGS: The main clinical features were adolescent-young adulthood onset, progressive action myoclonus, ataxia, absence of cognitive deterioration and, in most cases, epilepsy. The severity of the epilepsy could vary from uncontrolled seizures and status epilepticus in patients with adolescent onset to absent or rare seizures in patients with adult onset. Relevant neurophysiologic findings were a pronounced photosensitivity and massive action myoclonus associated with rhythmic myoclonic jerks at a frequency of 12-20 Hz, clinically resembling a postural tremor. The cortical origin of rhythmic myoclonus was demonstrated mainly by coherence and phase analysis of EEG-EMG signals indicating a significant EEG-EMG coupling and a direct corticospinal transfer. SIGNIFICANCE: Our patients with SCARB2 mutations showed the clinical and neurophysiologic phenotype of PME, in which epilepsy could be extremely severe, extending the spectrum reported in the typical AMRF syndrome. Patients with PME of unknown origin of adolescent or young adult onset, with these neurophysiologic features, should be tested for SCARB2 mutations, even in the absence of renal impairment.

Psychodynamic interpretation of linguistic findings in patients with epileptic and psychogenic non-epileptic seizures: the role of metaphors.

This work points out the main differences in the semantic expressions used by patients with psychogenic non-epileptic seizures (PNES) and epileptic seizures (ES). In reference to the body as a phenomenological entity, in ES the concept of the body-object prevails while in PNES the body, with all its life attributes, predominates. In description of seizures and in similitudes and metaphors used, ES patients focus on the description of the attack, trying to close the "gap" with a big effort, while patients with PNES concentrate on the context and on the presence of bystanders. Patients with PNES are unable to describe their own attack, since this it is not at the core of their distress, but rather the manifestation of something else, which is hiding the extreme anguish associated with experiences of the past that cannot be revealed (expressed). In the case of ES, instead, the ability to talk and the willingness to elaborate on the emotions become useful tools for facing the disease, an entity perhaps unsurmountable but at least manageable, to the benefit of everyone. In general, we can say that the experience of a disease (real or symbolic) deserves constant attention because it gives us the opportunity not only to probe the depth of the emotional experiences but also the psychic structure of the individual in front of us. A cure would not be a cure without considering such fundamental elements. It would become a sterile exercise of prescribing medications without paying attention to the person, which is the best way of preserving dignity in a state of illness.

Progressive Myoclonus Epilepsies: Diagnostic Yield With Next-Generation Sequencing in Previously Unsolved Cases.

BACKGROUND AND OBJECTIVES: To assess the current diagnostic yield of genetic testing for the progressive myoclonus epilepsies (PMEs) of an Italian series described in 2014 where Unverricht-Lundborg and Lafora diseases accounted for ∼50% of the cohort. METHODS: Of 47/165 unrelated patients with PME of indeterminate genetic origin, 38 underwent new molecular evaluations. Various next-generation sequencing (NGS) techniques were applied including gene panel analysis (n = 7) and/or whole-exome sequencing (WES) (WES singleton n = 29, WES trio n = 7, and WES sibling n = 4). In 1 family, homozygosity mapping was followed by targeted NGS. Clinically, the patients were grouped in 4 phenotypic categories: "Unverricht-Lundborg disease-like PME," "late-onset PME," "PME plus developmental delay," and "PME plus dementia." RESULTS: Sixteen of 38 (42%) unrelated patients reached a positive diagnosis, increasing the overall proportion of solved families in the total series from 72% to 82%. Likely pathogenic variants were identified in NEU1 (2 families), CERS1 (1 family), and in 13 nonfamilial patients in KCNC1 (3), DHDDS (3), SACS, CACNA2D2, STUB1, AFG3L2, CLN6, NAXE, and CHD2. Across the different phenotypic categories, the diagnostic rate was similar, and the same gene could be found in different phenotypic categories. DISCUSSION: The application of NGS technology to unsolved patients with PME has revealed a collection of very rare genetic causes. Pathogenic variants were detected in both established PME genes and in genes not previously associated with PME, but with progressive ataxia or with developmental encephalopathies. With a diagnostic yield >80%, PME is one of the best genetically defined epilepsy syndromes.

Italian cohort of Lafora disease: Clinical features, disease evolution, and genotype-phenotype correlations.

BACKGROUND: Lafora disease (LD) is characterized by progressive myoclonus, refractory epilepsy, and cognitive deterioration. This complex neurodegenerative condition is caused by pathogenic variants in EPM2A/EPM2B genes, encoding two essential glycogen metabolism enzymes known as laforin and malin. Long-term follow-up data are lacking. We describe the clinical features and genetic findings of a cohort of 26 Italian patients with a long clinical follow-up. METHODS: Patients with EPM2A/EPM2B pathogenic variants were identified by direct gene sequencing or gene panels with targeted re-sequencing. Disease progression, motor functions, and mental performance were assessed by a simplified disability scale. Spontaneous/action myoclonus severity was scored by the Magaudda Scale. RESULTS: Age range was 12.2-46.2 years (mean:25.53 ± 9.14). Age at disease onset ranged from 10 to 22 years (mean:14.04 ± 2.62). The mean follow-up period was 11.48 ± 7.8 years. Twelve out of the 26 (46%) patients preserved walking ability and 13 (50%) maintained speech. A slower disease progression with preserved ambulation and speech after ≥4 years of follow-up was observed in 1 (11%) out of the 9 (35%) EPM2A patients and in 6 (35%) out of the 17 (65%) EPM2B patients. Follow-up was >10 years in 7 (41.2%) EPM2B individuals, including two harbouring the homozygous p.(D146N) pathogenic variant. CONCLUSIONS: This study supports an overall worse disease outcome with severe deterioration of ambulation and speech in patients carrying EPM2A mutations. However, the delayed onset of disabling symptoms observed in the EPM2B subjects harbouring the p.(D146N) pathogenic variant suggests that the underlying causative variant may still influence LD severity.