We have investigated the proteolytic cleavage of the cellular (PrPC) and pathological (PrPSc) isoforms of the human prion protein (PrP) in normal and prion-affected brains and in tonsils and platelets from neurologically intact individuals. The various PrP species were resolved after deglycosylation according to their electrophoretic mobility, immunoreactivity, Sarkosyl solubility, and, as a novel approach, resistance to endogenous proteases. First, our data show that PrPC proteolysis in brain originates amino-truncated peptides of 21 to 22 and 18 (C1) kd that are similar in different regions and are not modified by the PrP codon 129 genotype, a polymorphism that affects the expression of prion disorders. Second, this proteolytic cleavage of PrPC in brain is blocked by inhibitors of metalloproteases. Third, differences in PrPC proteolysis, and probably in Asn glycosylation and glycosylphosphatidylinositol anchor composition, exist between neural and non-neural tissues. Fourth, protease-resistant PrPSc cores in sporadic Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker F198S disease brains all have an intact C1 cleavage site (Met111-His112), which precludes disruption of a domain associated with toxicity and fibrillogenesis. Fifth, the profile of endogenous proteolytic PrPSc peptides is characteristic of each disorder studied, thus permitting the molecular classification of these prion diseases without the use of proteinase K and even a recognition of PrPSc heterogeneity within type 2 CJD patients having different codon 129 genotype and neuropathological phenotype. This does not exclude the role of additional factors in phenotypic expression; in particular, differences in glycosylation that may be especially relevant in the new variant CJD. Proteolytic processing of PrP may play an important role in the neurotropism and phenotypic expression of prion diseases, but it does not appear to participate in disease susceptibility.

SUMMARYObjective: Small temporal pole encephalocele (STPE) can be the pathologic substrate of epilepsy in a subgroup of patients with noninformative magnetic resonance imaging (MRI). Herein, we analyzed the clinical, neurophysiologic, and radiologic features of the epilepsy found in 22 patients with STPE, and the frequency of STPE in patients with refractory focal epilepsy (RFE). Methods: We performed an observational study of all patients with STPE identified at our epilepsy unit from January 2007 to December 2014. Cases were detected through a systematic search of our database of RFE patients evaluated for surgery, and a prospective collection of patients identified at the outpatient clinic. The RFE database was also employed to analyze the frequency of STPE among the different clinical subgroups. Results: We identified 22 patients with STPE (11 women), including 12 (4.0%) of 303 patients from the RFE database, and 10 from the outpatient clinic. The median age was 51.5 years (range 29-75) and the median age at seizure onset was 38.5 years (range 15-73). Typically, 12 (80%) of 15 patients with left STPE reported seizures with impairment of language. Among the RFE cases, STPE were found in 9.6% of patients with temporal lobe epilepsy (TLE), and in 0.5% of those with extra-TLE (p = 0.0001). STPEs were more frequent in TLE patients with an initial MRI study reported as normal (23.3%) than in those with MRI-visible lesions (1.4%; p = 0.0002). Stereo-electroencephalography was performed in four patients, confirming the localization of the epileptogenic zone at the temporal pole with late participation of the hippocampus. Long-term seizure control was achieved in four of five operated patients. Significance: STPE can be a hidden cause of TLE in a subgroup of patients with an initial report of "normal" MRI. Early identification of this lesion may help to select patients for presurgical evaluation and tailored resection.

The COVID-19 pandemic represents an unprecedented international crisis with significant health, economic, and social consequences. This scenario has forced the medical community to face new practical and ethical challenges that require rapid responses. Early data show a variety of neurological manifestations in a significant proportion of patients with SARS-CoV-2 infection, 1,2 although there is little documentation of the effects on people with epilepsy. 2,3 In this study, we assess the impact of the COVID-19 pandemic in a particularly vulnerable population: individuals with genetic developmental and epileptic encephalopathies (DEEs) and their caregivers. Although children appear to present milder COVID-19 manifestations, 4 patients with DEEs present an increased susceptibility to certain triggers related to viral infections and respiratory comorbidities, are at risk of missing medical follow-up and emergency assistance due to health care resource allocation focus on COVID-19 patients, and are exposed to broader sociopsychological impact related to lockdown. Therefore, this study evaluates the impact of the pandemic on patients with genetic DEEs and their caregivers in Spain, one of the current hotspots of the pandemic.This study was a cross-sectional survey open between April 7 and April 11, 2020, 23-27 days after national lockdown was established in Spain. Participants were caregivers of DEE patients with proven or suspected genetic origin, recruited through patient advocacy groups, using internet-based sources. They were asked to fill out a structured questionnaire. Informed written consent was obtained from each caregiver. This methodology, previously used for Dravet syndrome and other neurodevelopmental diseases, 5 permits collecting larger samples for rare conditions. Statistical analysis was performed with R v3.6.2.A total of 277 responses from caregivers were collected, covering several different conditions. The most frequent genetic diagnoses were as follows: SCN1A, CDKL5, STXBP1, KCNQ2, PCDH19, and SYNGAP1 (see Table 1). DEEs of suspected genetic origin with negative genetic findings were reported by 36.8%. Mean age was 12.4 years; 58.1% were female. Fifteen patients (5.5%) were reported to present typical LETTER

Amyloid beta protein deposition in cortical and leptomeningeal vessels, causing the most common type of cerebral amyloid angiopathy, is found in sporadic and familial Alzheimer's disease (AD) and is the principal feature in the hereditary cerebral hemorrhage with amyloidosis, Dutch type. The presence of the Apolipopriotein E (APOE)-epsilon4 allele has been implicated as a risk factor for AD and the development of cerebral amyloid angiopathy in AD. We report clinical, pathological and biochemical studies on two APOE-epsilon4 homozygous subjects, who had senile dementia and whose main neuropathological feature was a severe and diffuse amyloid angiopathy associated with perivascular tau neurofibrillary pathology. Amyloid beta protein and ApoE immunoreactivity were observed in leptomeningeal vessels as well as in medium-sized and small vessels and capillaries in the parenchyma of the neocortex, hippocampus, thalamus, cerebellum, midbrain, pons, and medulla. The predominant peptide form of amyloid beta protein was that terminating at residue Val40, as determined by immunohistochemistry, amino acid sequence and mass spectrometry analysis. A crown of tau-immunopositive cell processes was consistently present around blood vessels. DNA sequence analysis of the Amyloid Precursor Protein gene and Presenilin-1 (PS-1) gene revealed no mutations. In these APOE-epsilon4 homozygous patients, the pathological process differed from that typically seen in AD in that they showed a heavy burden of perivascular tau-immunopositive cell processes associated with severe amyloid beta protein angiopathy, neurofibrillary tangles, some cortical Lewy bodies and an absence of neuritic plaques. These cases emphasize the concept that tau deposits may be pathogenetically related to amyloid beta protein deposition.