Association of CSF and PET markers of neurodegeneration with electroclinical progression in Lafora disease.

Purpose: To evaluate the electro-clinical features in association with laboratory and instrumental correlates of neurodegeneration to detect the progression of Lafora disease (LD). Methods: We investigated the electro-clinical longitudinal data and CSF Aß42, p-tau181 and t-tauAg, amyloid, and 18F-FDG PET of five unrelated LD families. Results: Three progressive electro-clinical stages were identified. The early phase was characterized by rare, generalized tonic-clonic and focal visual seizures, followed by the occurrence of myoclonus after a period ranging from 2 to 12 months. The intermediate stage, usually occurring 2 years after the onset of epilepsy, is characterized by a worsening of epilepsy and myoclonus associated with progressive dementia and cerebellar signs. Finally, the late stage, evolving after a mean period of 7 ± 1.41 years from the onset of the disease, was characterized by gait ataxia resulting in bedriddenness, severe dementia, daily/pluri-daily myoclonus, drug-resistant epilepsy, clusters of seizures or status epilepticus, and medical complications. Amyloid (CSF Aß42, amyloid PET) and neurodegenerative (CSF p-tau181 and t-tauAg, FDG-PET) biomarkers indicate a pattern of cognitive impairment of the non-Alzheimer's disease type. A total of 80% of the LD patients showed more severe hypometabolism in the second FDG-PET scan compared to the first scan performed in a lower phase; the lateral temporal lobe and the thalamus hypometabolism were associated with the presence of intermediate or late phase. Conclusions: Three electroclinical and 18F-FDG PET evolutive stages are useful biomarkers for the progression of LD and could help to evaluate the efficacy of new disease-modifying treatments. The combination of traditional CSF biomarkers improves the diagnostic accuracy of cognitive decline in LD patients, indicating a cognitive impairment of the non-Alzheimer's disease type.

Electro-clinical features and management of the late stage of Lafora disease.

Purpose: The aim of this study was to elucidate the electro-clinical features and management of the late stage of Lafora disease (LD). Methods: We investigated the electro-clinical data and medical complications of three LD patients with mutations in EPM2A and two in NHLRC1 genes during the LD late stage. Results: The late stage emerged after a mean period of 7 ± 1.41 years from the onset of the disease. All patients developed gait ataxia becoming bedbound with severe dementia. Pluri-monthly and drug-resistant myoclonic seizures, and myoclonic absence and tonic-clonic seizures were associated with daily/pluri-daily myoclonus, while the EEG/polygraphic findings showed diffusely slow activity with epileptiform abnormalities, often correlated with myoclonic jerks. Seizure emergencies with motor cluster/status epilepticus and medical complications dominated the clinical picture. In particular, video-EEG/polygraphic recordings disclosed status epilepticus with prominent motor symptoms of different subtypes refractory to IV new anti-seizure medications and responsive in 75% of cases to IV phenytoin. The main complications were dysphagia, aspiration pneumonia, acute respiratory failure, sepsis, immobility, and spasticity with bedsores. A coordinated and multidisciplinary management of the three patients with EPM2A mutations has demonstrated a reduction in seizure emergencies, medical complications and days of hospitalization, and a prolongation of the years of disease compared to the two patients with NHLRC1 mutations. Conclusion: Status epilepticus with prominent motor symptoms of different subtypes, often responsive to IV phenytoin, and multiple medical complications characterize the LD late stage. An effective management requires a multidisciplinary medical and nursing team, coordinated by an epileptologist with the aim of reducing seizure emergencies and medical complications.

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.

The effect of quarantine due to Covid-19 pandemic on seizure frequency in 102 adult people with epilepsy from Apulia and Basilicata regions, Southern Italy.

OBJECTIVE: following the COVID-19 pandemic, a quarantine was imposed to all of regions Italy by 9th March until 3rd May 2020. We investigated the effect of COVID-19 infection and quarantine on seizure frequency in adult people with epilepsy (PwE) of Apulia and Basilicata regions, Southern Italy. METHODS: This is an observational, retrospective study based on prospective data collection of 102 successive PWE. The frequency of seizures was evaluated during pre-quarantine (January- February), quarantine (March-April), and post-quarantine period (May-June), while PwE were divided into A) cases responding to treatment with ≤ 1 seizure per year; B) cases responding to treatment with 2-5 seizure per year; C) cases with drug-resistant epilepsy with ≤ 4 seizures per month; D) cases with drug-resistant epilepsy with 5-10 seizures per month. PwE underwent several self-report questionnaires regarding therapeutic compliance, mood, stress and sleep during quarantine period. RESULTS: Approximately 50 % of PwE showed seizure frequency changes (22.55 % an increase and 27.45 % a reduction) during quarantine. Seizure frequency significantly (p < 0.05) increased in PwE responding to treatment with ≤ 1 seizure per year, while significantly (p < 0.05) reduced in PwE with drug-resistant epilepsy with 5-10 seizures per month. The data was not influenced by therapeutic adherence, sleep and depression. The analysis of anxiety showed a moderate level of anxiety in PwE responding to treatment with < 1 seizure per year, while moderate stress was perceived by all PwE. Seizure frequency changes were related to quarantine, but not to COVID-19 infection. In fact, unlike other regions of Italy, particularly Northern Italy, Apulia and Basilicata regions were less affected by COVID-19 infection, and almost all PwE recognized the quarantine as a stressful event. Emotional distress and anxiety due to social isolation, but also the relative reduction of triggers for epileptic seizures were the most important factors for changes in seizure frequency. CONCLUSIONS: Our study adds to the growing concern that the indirect effects of COVID-19 pandemic will far outstrip the direct consequences of the infection.

Intravenous brivaracetam in status epilepticus: A multicentric retrospective study in Italy.

PURPOSE: to evaluate the use, effectiveness, and adverse events of intravenous brivaracetam (BRV) in status epilepticus (SE). METHODS: a retrospective multicentric study involving 24 Italian neurology units was performed from March 2018 to June 2020. A shared case report form was used across participating centres to limit biases of retrospective data collection. Diagnosis and classification of SE followed the 2015 ILAE proposal. We considered a trial with BRV a success when it was the last administered drug prior the clinical and/or EEG resolution of seizures, and the SE did not recur during hospital observation. In addition, we considered cases with early response, defined as SE resolved within 6 h after BRV administration. RESULTS: 56 patients were included (mean age 62 years; 57 % male). A previous diagnosis of epilepsy was present in 21 (38 %). Regarding SE etiology classification 46 % were acute symptomatic, 18 % remote and 16 % progressive symptomatic. SE episodes with prominent motor features were the majority (80 %). BRV was administered as first drug after benzodiazepine failure in 21 % episodes, while it was used as the second or the third (or more) drug in the 38 % and 38 % of episodes respectively. The median loading dose was 100 mg (range 50-300 mg). BRV was effective in 32 cases (57 %). An early response was documented in 22 patients (39 % of the whole sample). The use of the BRV within 6 h from SE onset was independently associated to an early SE resolution (OR 32; 95 % CI 3.39-202; p = 0.002). No severe treatment emergent adverse events were observed. CONCLUSION: BRV proved to be useful and safe for the treatment of SE. Time to seizures resolution appears shorter when it is administered in the early phases of SE.

The presenting symptoms of Lafora Disease: An electroclinical and genetic study in five Apulian (Southern Italy) families.

PURPOSE: To elucidate the presenting symptoms of Lafora Disease (LD) to differentiate it from Juvenile Myoclonic Epilepsy (JME). METHODS: We collected and evaluated the early electroclinical data of 5 unrelated Apulian (Southern Italy) LD families, 30 LD patients selected from the literature, and 30 Apulian JME patients. RESULTS: The Apulian LD patients presented with generalised tonic-clonic and focal visual seizures, followed by myoclonic seizures and action-postural myoclonus. In these patients, EEG background slowing and occipital epileptiform abnormalities were significantly more evident than in the other groups. Genetic analysis revealed the presence of mutations in the EPM2A gene in 4 families, and in the NHLRC1 gene in the remaining family. In detail, we identified 2 different point mutations in EPM2A and only 1 in NHLRC1, and expanded the molecular spectrum of the EPM2A gene mutations reporting for the first time a patient carrier of the c.243_246del genetic variant. In the previously reported LD cases, generalised tonic-clonic and focal visual seizures and myoclonus were the most frequent symptoms, as confirmed by the first EEGs showing occipital or diffuse epileptiform abnormalities with photosensitivity in the background activity slowing. In the Apulian JME patients, myoclonus appeared earlier, usually at awakening, with diffuse epileptiform abnormalities during sleep and photosensitivity in the normal background activity. The diagnosis of JME was established much earlier than the LD one. During evolution, unlike JME patients, LD patients showed a significant resistance to drugs. CONCLUSIONS: Tonic-clonic and focal visual seizures followed by myoclonic seizures and action-postural myoclonus together with EEG background slowing with diffuse and occipital epileptiform abnormalities suggest a diagnosis of LD. An early molecular confirmation allows a better diagnosis, counselling and management of affected patients and their families, and it may be useful to improve the patients' quality of life using, when possible, emerging personalized treatments that may slow the evolution of the disease.

First-aid management of tonic-clonic seizures among healthcare personnel: A survey by the Apulian section of the Italian League Against Epilepsy.

INTRODUCTION: To evaluate the knowledge of healthcare workers about first-aid measures to be performed during and after a tonic-clonic seizure. METHODS: One hundred and fifty-four healthcare workers (86 physicians) working at 8 tertiary hospitals in the Apulia region, Italy, responded to a questionnaire comprising of 28 questions based on available Italian and international recommendations about what to do during a tonic-clonic seizure. RESULTS: One hundred and fifty-four healthcare workers completed and returned surveys with a response rate of 96.25%. There were 55 nurses (35.7%), 86 physicians (55.8%), and 13 healthcare workers with different roles (Electroencephalograph technicians, psychologists, social workers). Among physicians, there were 7 cardiologists, 3 surgeons, 12 infectious-disease specialists, 11 internal medicine specialists, 2 psychiatrists, 2 gynecologists, 27 specialists working in the emergency department, and 22 physicians with different specializations. Nearly 90% of the respondents identified head protection as important first aid, while 100% responded to not keep the legs elevated. To avoid tongue bite, both physicians and other healthcare workers would put something in the mouth (54.0%), like a Guedel cannula (71.0%) fingers (29.5%). Grabbing arms and legs, trying to stop the seizure, would be potentially performed by 11.6% of our sample. Physicians would administer a benzodiazepine during the seizure (65.7%) and during the postictal phase (29.2%), even if the patient is known to have epilepsy (23.7%), and in this case, 11.3% of respondents would administer the usual antiepileptic medications. More than half of respondents would call the emergency telephone number, because of necessary hospitalization in case of tonic-clonic seizure, even if it is experienced by a patient known to have epilepsy. CONCLUSION: Our survey suggests the need for epilepsy educational programs on first-aid management of seizures among healthcare workers.

The epilepsy phenotype in adult patients with intellectual disability and pathogenic copy number variants.

PURPOSE: To characterize the electroclinical features of epilepsy associated with intellectual disability and pathogenic copy number variations (CNVs) METHODS: we prospectively investigated 61 adult patients with epilepsy and intellectual disability or other neurodevelopmental disorders. We performed high resolution SNP-Array analysis in order to detect clinical relevant chromosomal microdeletions and microduplications. An ordinal logistic regression model was fitted with 34 demographic, clinical and EEG-related variables in order to identify the epilepsy phenotype of patients with pathogenic CNVs. RESULTS: chromosome microarray analysis identify non-polymorphic CNVs in 33 patients analyzed: 11 had an established pathogenic microdeletion/microduplication, 22 were carriers of CNVs of unknown clinical significance. Univariate analysis revealed a significant association between pathogenic CNVs and 3 electroclinical variables considered, specifically atypical absence seizures (p<0.05), tonic seizures (p<0.05), epileptic spasms (p<0.01). CONCLUSIONS: high resolution SNP-Array analysis should be evaluated in adult patients with intellectual disability and epilepsy with peculiar electroclinical features, specifically atypical absence seizures, tonic seizures, and epileptic spasms, resembling a Lennox-Gastaut syndrome without a clear structural lesion.

Intravenous lacosamide in seizure emergencies: Observations from a hospitalized in-patient adult population.

PURPOSE: to evaluate the efficacy and safety of intravenous (IV) lacosamide (LCM) in the treatment of seizure clusters (SC) and status epilepticus (SE) in hospitalized adult patients. METHODS: we prospectively analyzed treatment response, seizure outcome, and adverse effects of IV LCM in 38 patients with seizure emergencies (15 with SC, 23 with SE) during a hospital stay. The loading dose of IV LCM was 200-400mg and the maintenance dose was 200-400mg daily. Response to IV LCM was evaluated within 20min, 4h and 24h of LCM infusion. RESULTS: an acute anti-seizure effect after IV LCM was especially evident when it was first used - (SC) or second line (established SE) treatment. In particular, 87% of SC patients (13/15) and 80% of established SE (8/10) demonstrated response to LCM treatment, while no patients with super-refractory SE (0/8) responded to IV LCM according to our criteria. The loading of IV LCM was well tolerated, with mild adverse effects (2/38 temporary dizziness). In most patients, during and after administration of the loading dose of IV LCM a temporary (30min-1h) sedation was observed. No ECG and laboratory values-changes were documented in any of the patients. CONCLUSIONS: LCM is an effective and well-tolerated treatment when used to treat SC in hospitalized adult patients. As add-on therapy, it may be useful to stop seizure activity in patients with focal SE not responding to first/second-line intravenous AEDs.

Epileptic seizures, movement disorders, and breathing disturbances in Rett syndrome: diagnostic relevance of video-polygraphy.

Epileptic seizures, movement disorders and breathing disturbances may be observed in Rett syndrome, and correct diagnosis is mandatory for the management. We evaluated the usefulness of video-polygraphy in the differential diagnosis between epileptic and non-epileptic paroxysmal events in eight patients with Rett syndrome. Based on video analysis, myoclonic seizures were usually misdiagnosed as movement disorders and stereotypies; the events identified by parents as generalized tonic-clonic seizures included episodes of motor activity and breathing abnormality. Myoclonic seizures aggravated by inappropriate treatment were evident in four patients; hyperventilation and apnea during wakefulness were present in all patients, while central sleep apneas were present in one patient; sinus tachycardia and cardiac arrhythmias emerged in six patients; cortical myoclonus was disclosed in five patients. In Rett syndrome, video-polygraphy is essential in characterizing the clinical features of paroxysmal events, determining autonomic dysfunctions, documenting myoclonic motor phenomena, and evaluating the responses to the treatment of epilepsy.