Perampanel as an Add-On Therapy in Patients with Refractory Status Epilepticus and Postanoxic Encephalopathy: A Real-Life Single-Center Retrospective Cohort Study.

BACKGROUND: Data on the efficacy of perampanel in refractory status epilepticus (RSE) and postanoxic encephalopathy (PAE) are limited; its use in such conditions is currently off-label. METHODS: We conducted a retrospective cohort study of consecutive adult patients with RSE, including PAE, exhibiting electroencephalographic patterns indicative of status epilepticus who were treated at our center (January 2018 to December 2022) with assessment of clinical and electroencephalographic outcomes. RESULTS: Thirty-six patients were included in the study, of whom 29 had nonanoxic RSE and 7 had PAE. Within the nonanoxic RSE subgroup, 45% (13 of 29; 95% confidence interval [CI] 27-63%) of study participants were responders, 34% (10 of 29; 95% CI 17-52%) were partial responders, and 21% (6 of 29; 95% CI 6-35%) were nonresponders. In the PAE subgroup (n = 7), no patients fully responded to perampanel; 43% (3 of 7; 95% CI 6-80%) were partial responders, and 57% (4 of 7; 95% CI 20-95%) were nonresponders. Responder and nonresponder study participants exhibited overlapping baseline characteristics. No significant differences in duration of hospitalization were observed between responders and nonresponders in both subgroups. Responders in the RSE subgroup had a median discharge modified Rankin Scale score of 3 (interquartile range 3-4), and nonresponders had a median discharge modified Rankin Scale score of 5 (interquartile range 5-6). CONCLUSIONS: Despite limitations from the retrospective design and the small population size, this study suggests that perampanel use in nonanoxic RSE appears to yield promising results at moderate doses, including a tendency toward a better functional outcome at discharge, without significant adverse effects. However, in patients with PAE, the drug seems to show suboptimal performance. Perampanel appears to have promising efficacy as an add-on therapy in nonanoxic RSE. However, in patients with PAE, its efficacy seems to be lower. Further studies are warranted to confirm these observations.

Predictors of seizure detection and EEG clinical impact in an italian tertiary emergency department.

BACKGROUND AND OBJECTIVES: Epileptic seizures pose challenges in emergency departments (ED), affecting up to 10% of admitted patients. This study aimed to assess emergency electroencephalogram (EmEEG) utilization, identifying factors predicting seizure detection and its influence on clinical decisions. METHODS: A retrospective review of 1135 EmEEGs on 1017 patients at a tertiary teaching hospital between June 2022 and June 2023 was conducted. Data included demographics, medical history, EmEEG indications, neuroimaging findings, and clinical outcomes. Statistical analyses utilized Fisher's exact tests and logistic regression models. RESULTS: EmEEG detected status epilepticus-related seizures in 5.40% of cases, seizures without status epilepticus in 3.05%, and status epilepticus without discrete seizures in 3.74%. Epileptiform abnormalities were noted in 22.12% of EmEEGs. EmEEG influenced initial diagnoses (21.24%), antiseizure medication changes (20.85%), and discharge decisions (39.04%). Predictors for seizures/status epilepticus included previous neurosurgery, seizures in the ED, and cognitive/behavioral impairment (p < 0.001). EmEEG significantly altered initial diagnoses based on witnessed seizures, involuntary movements, epileptiform abnormalities, and 1-2 Hz generalized periodic discharges (p < 0.001). Changes in antiseizure medications correlated with seizure occurrence, neuroimaging results, epileptiform abnormalities, and EEG background slowing (p < 0.001). Factors influencing discharge decisions included previous neurosurgery, consciousness impairment, acute neuroimaging pathology, EEG focal slowing, and EEG background slowing (p < 0.001). DISCUSSION: The study clarifies EmEEG's role in modifying initial diagnoses, treatment approaches, and discharge decisions. The study provides insights into the nuanced impact of EmEEG in different clinical scenarios, offering valuable guidance for clinicians in selecting patients for EmEEG, particularly in conditions of limited EEG availability.

EEG Correlates in the 3 Variants of Primary Progressive Aphasia.

BACKGROUND AND OBJECTIVES: The 3 clinical presentations of primary progressive aphasia (PPA) reflect heterogenous neuropathology, which is difficult to be recognized in vivo. Resting-state (RS) EEG is promising for the investigation of brain electrical substrates in neurodegenerative conditions. In this study, we aim to explore EEG cortical sources in the characterization of the 3 variants of PPA. METHODS: This is a cross-sectional, single-center, memory center-based cohort study. Patients with PPA and healthy controls were consecutively recruited at the Neurology Unit, IRCCS San Raffaele Scientific Institute (Milan, Italy). Each participant underwent an RS 19-channel EEG. Using standardized low-resolution brain electromagnetic tomography, EEG current source densities were estimated at voxel level and compared among study groups. Using an RS functional MRI-driven model of source reconstruction, linear lagged connectivity (LLC) values within language and extra-language brain networks were obtained and analyzed among groups. RESULTS: Eighteen patients with logopenic PPA variant (lvPPA; mean age = 72.7 ± 6.6; % female = 52.4), 21 patients with nonfluent/agrammatic PPA variant (nfvPPA; mean age = 71.7 ± 8.1; % female = 66.6), and 9 patients with semantic PPA variant (svPPA; mean age = 65.0 ± 6.9; % female = 44.4) were enrolled in the study, together with 21 matched healthy controls (mean age = 69.2 ± 6.5; % female = 57.1). Patients with lvPPA showed a higher delta density than healthy controls (p < 0.01) and patients with nfvPPA (p < 0.05) and svPPA (p < 0.05). Patients with lvPPA also displayed a greater theta density over the left posterior hemisphere (p < 0.01) and lower alpha2 values (p < 0.05) over the left frontotemporal regions than controls. Patients with nfvPPA showed a diffuse greater theta density than controls (p < 0.05). LLC was altered in all patients relative to controls (p < 0.05); the alteration was greater at slow frequency bands and within language networks than extra-language networks. Patients with lvPPA also showed greater LLC values at theta band than patients with nfvPPA (p < 0.05). DISCUSSION: EEG findings in patients with PPA suggest that lvPPA-related pathology is associated with a characteristic disruption of the cortical electrical activity, which might help in the differential diagnosis from svPPA and nfvPPA. EEG connectivity was disrupted in all PPA variants, with distinct findings in disease-specific PPA groups. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that EEG analysis can distinguish PPA due to probable Alzheimer disease from PPA due to probable FTD from normal aging.

Expanding the spectrum of neonatal-onset AIFM1-associated disorders.

OBJECTIVES: Pathogenic variants in AIFM1 have been associated with a wide spectrum of disorders, spanning from CMT4X to mitochondrial encephalopathy. Here we present a novel phenotype and review the existing literature on AIFM1-related disorders. METHODS: We performed EEG recordings, brain MRI and MR Spectroscopy, metabolic screening, echocardiogram, clinical exome sequencing (CES) and family study. Effects of the variant were established on cultured fibroblasts from skin punch biopsy. RESULTS: The patient presented with drug-resistant, electro-clinical, multifocal seizures 6 h after birth. Brain MRI revealed prominent brain swelling of both hemispheres and widespread signal alteration in large part of the cortex and of the thalami, with sparing of the basal nuclei. CES analysis revealed the likely pathogenic variant c.5T>C; p.(Phe2Ser) in the AIFM1 gene. The affected amino acid residue is located in the mitochondrial targeting sequence. Functional studies on cultured fibroblast showed a clear reduction in AIFM1 protein amount and defective activities of respiratory chain complexes I, III and IV. No evidence of protein mislocalization or accumulation of precursor protein was observed. Riboflavin, Coenzyme Q10 and thiamine supplementation was therefore given. At 6 months of age, the patient exhibited microcephaly but did not experience any further deterioration. He is still fed orally and there is no evidence of muscle weakness or atrophy. INTERPRETATION: This is the first AIFM1 case associated with neonatal seizures and diffuse white matter involvement with relative sparing of basal ganglia, in the absence of clinical signs suggestive of myopathy or motor neuron disease.

Interstitial 6q deletion in a patient presenting with drug-resistant epilepsy and Prader-Willi like phenotype: An electroclinical description with literature review.

PURPOSE: Interstitial 6q deletions are associated with rare genetic syndromes characterized by different signs, including developmental delay, dysmorphisms, and Prader-Willi (PWS)-like features. Drug-resistant epilepsy, a relatively rare finding in this condition, is often a challenge in terms of therapeutic approach. Our aim is to present a new case of interstitial 6q deletion and to conduct a systematic review of the literature with an emphasis on the neurophysiological and clinical traits of afflicted individuals. METHODS: We report a patient with an interstitial 6q deletion. Standard electroencephalograms (EEG), video-EEG with polygraphy and MRI features are discussed. We also conducted a literature review of previously described cases. RESULTS: We describe a relatively small interstitial 6q deletion (2 Mb circa), detected by CGH-Array, not encompassing the previously described 6q22 critical region for epilepsy occurrence. The patient, a 12-year-old girl, presented with multiple absence-like episodes and startle-induced epileptic spasms since the age of 11, with partial polytherapy control. Treatment with lamotrigine induced the resolution of startle-induced phenomena. From the literature review, we identified 28 patients with overlapping deletions, often larger than our patient's mutation. Seventeen patients presented with PWS-like features. Epilepsy was reported in 4 patients, and 8 patients presented abnormal EEG findings. In our patient, the deletion included genes MCHR2, SIM1, ASCC3, and GRIK2, but, interestingly, it did not encompass the 6q22 critical region for epilepsy occurrence. The involvement of GRIK2 in the deletion may play a role. CONCLUSION: Literature data are limited, and specific EEG or epileptological phenotypes cannot yet be identified. Epilepsy, although uncommon in the syndrome, deserves a specific diagnostic workup. We speculate on the existence of an additional locus in the 6q16.1-q21 region, different from the already hypothesized q22, promoting the development of epilepsy in affected patients.

Cognitive, EEG, and MRI features of COVID-19 survivors: a 10-month study.

BACKGROUND AND OBJECTIVES: To explore cognitive, EEG, and MRI features in COVID-19 survivors up to 10 months after hospital discharge. METHODS: Adult patients with a recent diagnosis of COVID-19 and reporting subsequent cognitive complaints underwent neuropsychological assessment and 19-channel-EEG within 2 months (baseline, N = 49) and 10 months (follow-up, N = 33) after hospital discharge. A brain MRI was obtained for 36 patients at baseline. Matched healthy controls were included. Using eLORETA, EEG regional current densities and linear lagged connectivity values were estimated. Total brain and white matter hyperintensities (WMH) volumes were measured. Clinical and instrumental data were evaluated between patients and controls at baseline, and within patient whole group and with/without dysgeusia/hyposmia subgroups over time. Correlations among findings at each timepoint were computed. RESULTS: At baseline, 53% and 28% of patients showed cognitive and psychopathological disturbances, respectively, with executive dysfunctions correlating with acute-phase respiratory distress. Compared to healthy controls, patients also showed higher regional current density and connectivity at delta band, correlating with executive performances, and greater WMH load, correlating with verbal memory deficits. A reduction of cognitive impairment and delta band EEG connectivity were observed over time, while psychopathological symptoms persisted. Patients with acute dysgeusia/hyposmia showed lower improvement at memory tests than those without. Lower EEG delta band at baseline predicted worse cognitive functioning at follow-up. DISCUSSION: COVID-19 patients showed interrelated cognitive, EEG, and MRI abnormalities 2 months after hospital discharge. Cognitive and EEG findings improved at 10 months. Dysgeusia and hyposmia during acute COVID-19 were related with increased vulnerability in memory functions over time.

Refractory anti-NMDAR encephalitis successfully treated with bortezomib and associated movements disorders controlled with tramadol: a case report with literature review.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a potentially fatal autoimmune disease, characterized by autoantibody-mediated neurotransmission impairment in multiple brain locations. The course of this condition often comprises altered mental status, autonomic dysfunctions, refractory seizures and hyperkinetic movement disorders. Available disease-modifying therapies include corticosteroids, i.v. immunoglobulins, plasma exchange, rituximab and cyclophosphamide. In a subgroup of patients not responding to B-cell depletion, bortezomib, a proteasome inhibitor, has shown promising evidence of efficacy. The time course of recovery from acute phase may be very slow (weeks/months), and only few data are available in literature about the concurrent management of encephalitis-associated movement disorders. We report a case of severe anti-NMDAR encephalitis in a 29-year-old woman, not responsive to first- and second-line treatments, with persistent involuntary motor manifestations. Starting three months after symptom onset, four cycles of bortezomib have been administered; subsequently we observed a progressive improvement of neurological status. Meanwhile, motor manifestations were controlled after the administration of tramadol, a non-competitive NMDA receptor antagonist.

Treatment Challenges of a Primary Vertebral Artery Aneurysm Causing Recurrent Ischemic Strokes.

Background. Extracranial vertebral artery aneurysms are a rare cause of embolic stroke; surgical and endovascular therapy options are debated and long-term complication may occur. Case Report. A 53-year-old man affected by neurofibromatosis type 1 (NF1) came to our attention for recurrent vertebrobasilar embolic strokes, caused by a primary giant, partially thrombosed, fusiform aneurysm of the left extracranial vertebral artery. The aneurysm was treated by endovascular approach through deposition of Guglielmi Detachable Coils in the proximal segment of the left vertebral artery. Six years later the patient presented stroke recurrence. Cerebral angiography and Color Doppler Ultrasound well characterized the unique hemodynamic condition developed over the years responsible for the new embolic event: the aneurysm had been revascularized from its distal portion by reverse blood flow coming from the patent vertebrobasilar axis. A biphasic Doppler signal in the left vertebral artery revealed a peculiar behavior of the blood flow, alternately directed to the aneurysm and backwards to the basilar artery. Surgical ligation of the distal left vertebral artery and excision of the aneurysm were thus performed. Conclusion. This is the first described case of NF1-associated extracranial vertebral artery aneurysm presenting with recurrent embolic stroke. Complete exclusion of the aneurysm from the blood circulation is advisable to achieve full resolution of the embolic source.

The Blue Coma: The Role of Methylene Blue in Unexplained Coma After Cardiac Surgery.

OBJECTIVES: Methylene blue commonly is used as a dye or an antidote, but also can be used off label as a vasopressor. Serotonin toxicity is a potentially lethal and often misdiagnosed condition that can result from drug interaction. Mild serotonin toxicity previously was reported in settings in which methylene blue was used as a dye. The authors report 3 cases of life-threatening serotonin toxicity in patients undergoing chronic selective serotonin reuptake inhibitor (SSRI) therapy who also underwent cardiac surgery and received methylene blue to treat vasoplegic syndrome. DESIGN: An observational study. SETTING: A cardiothoracic intensive care unit (ICU) in a teaching hospital. PARTICIPANTS: Three patients who received methylene blue after cardiac surgery, later discovered to be undergoing chronic SSRI therapy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All 3 patients received high doses of fentanyl during general anesthesia. They all developed vasoplegic syndrome and consequently were given methylene blue in the ICU. All 3 patients developed serotonin toxicity, including coma, after this administration and diagnostic tests were negative for acute intracranial pathology. Coma lasted between 1 and 5 days. Two patients were discharged from the ICU shortly after awakening, whereas the third patient experienced a complicated postoperative course for concomitant refractory low-cardiac-output syndrome. CONCLUSIONS: Patients undergoing chronic SSRI therapy should not be administered methylene blue to treat vasoplegic syndrome.

Quantitative EEG and LORETA: valuable tools in discerning FTD from AD?

Drawing a clinical distinction between frontotemporal dementia (FTD) and Alzheimer's disease (AD) is tricky, particularly at the early stages of disease. This study evaluates the possibility in differentiating 39 FTD, 39 AD, and 39 controls (CTR) by means of power spectral analysis and standardized low resolution brain electromagnetic tomography (sLORETA) within delta, theta, alpha 1 and 2, beta 1, 2, and 3 frequency bands. Both analyses revealed in AD patients, relative to CTR, higher expression of diffuse delta/theta and lower central/posterior fast frequency (from alpha1 to beta2) bands. FTD patients showed diffuse increased theta power compared with CTR and lower delta relative to AD patients. Compared with FTD, AD patients showed diffuse higher theta power at spectral analysis and, at sLORETA, decreased alpha2 and beta1 values in central/temporal regions. Spectral analysis and sLORETA provided complementary information that might help characterizing different patterns of electroencephalogram (EEG) oscillatory activity in AD and FTD. Nevertheless, this differentiation was possible only at the group level because single patients could not be discerned with sufficient accuracy.

High incidence of severe cyclosporine neurotoxicity in children affected by haemoglobinopaties undergoing myeloablative haematopoietic stem cell transplantation: early diagnosis and prompt intervention ameliorates neurological outcome.

BACKGROUND: Neurotoxicity is a recognized complication of cyclosporine A (CSA) treatment. The incidence of severe CSA-related neurological complications following hematopoietic stem cell transplantation (HSCT) is 4-11%. METHODS: We describe 6 cases of CSA related neurotoxicity out of 67 matched related HSCT performed in paediatric Middle East patients affected by haemoglobinopaties (5 beta thalassemia major, 1 sickle cell disease-SCD). Conditioning regimen consisted of iv busulphan, cyclophosphamide and graft-versus-host-disease (GvHD) prophylaxis with CSA, methylprednisolone, methotrexate and ATG. RESULTS: All 6 patients presented prodromes such as arterial hypertension, headache, visual disturbances and vomiting, one to two days before overt CSA neurotoxicity. CSA neurotoxicity consisted of generalized seizures, signs of endocranial hypertension and visual disturbances at a median day of onset of 11 days after HSCT (range +1 to +40). Brain magnetic resonance imaging (MRI) performed in all subjects showed reversible leukoencephalopathy predominantly in the posterior regions of the brain (PRES) in 5/6 patients. EEG performed in 5/6 patients was always abnormal. Neurotoxicity was not explainable by high CSA blood levels, as all patients had CSA in the therapeutic range with a median of 178 ng/ml (range 69-250). CSA was promptly stopped and switched to tacrolimus with disappearance of clinical and radiological findings. All patients are symptoms-free at a median follow up of 882 days (range 60-1065). CONCLUSIONS: Our experience suggests that paediatric patients with haemoglobinopaties have a high incidence of CSA related neurological events with no correlation between serum CSA levels and neurotoxicity. Prognosis is good following CSA removal. Specific prodromes such as arterial hypertension, headache or visual disturbances occurring in the early post-transplant period should be carefully evaluated with electrophysiological and MRI-based imaging in order to intervene promptly and avoid irreversible sequels.

Autoantibodies against oxidatively modified lipoproteins and progression of carotid restenosis after carotid endarterectomy.

BACKGROUND: The purpose of this study was to determine whether LDL oxidation could play an important pathogenic role in early restenosis after carotid endarterectomy. An immunologic and biochemical study was performed on a group of patients who underwent carotid endarterectomy, and the degree of intima-media thickness was measured 6 months after surgery. SUMMARY OF REPORT: Fifty-two consecutive patients were included in the study. The presence of antibodies against oxidized LDL in the serum at the time of surgery was evaluated and compared with echo Doppler flow imaging 6 months after the operation. A statistically significant correlation was found between the arterial wall thickness at the site of surgery and the absolute value of IgG antibodies against oxidized LDL (P<0.012) and IgM immunocomplexes (P<0.043). CONCLUSIONS: The presence of antibodies against oxidized LDL at the time of surgery seems to predict a greater intima-media wall hyperplasia at 6 months after surgery, usually recognized as early restenosis.