Bace1 Deletion in the Adult Reverses Epileptiform Activity and Sleep-wake Disturbances in AD Mice.

Alzheimer's disease (AD) increases the risk for seizures and sleep disorders. We show here that germline deletion of ß-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) in neurons, but not in astrocytes, increased epileptiform activity. However, Bace1 deletion at adult ages did not alter the normal EEG waveform, indicating less concern for BACE1 inhibition in patients. Moreover, we showed that deletion of Bace1 in the adult was able to reverse epileptiform activity in 5xFAD mice. Intriguingly, treating 5xFAD and APPNL-G-F/NL-G-F (APP KI) mice of either sex with one BACE1 inhibitor Lanabecestat (AZD3293) dramatically increased epileptiform spiking, likely resulting from an off-target effect. We also monitored sleep-wake pathologies in these mice and showed increased wakefulness, decreased non-rapid eye movement sleep, and rapid eye movement sleep in both 5xFAD and APP KI mice; BACE1 inhibition in the adult 5xFAD mice reversed plaque load and sleep disturbances, but this was not seen in APP KI mice. Further studies with and without BACE1 inhibitor treatment showed different levels of plaque-associated microgliosis and activated microglial proteins in 5xFAD mice compared with APP KI mice. Together, BACE1 inhibition should be developed to avoid off-target effect for achieving benefits in reducing epileptic activity and sleep disturbance in Alzheimer's patients.SIGNIFICANCE STATEMENT BACE1 is widely recognized as a therapeutic target for treating Alzheimer's disease patients. However, BACE1 inhibitors failed in clinical trials because of inability to show cognitive improvement in patients. Here we show that BACE1 inhibition actually reduces sleep disturbances and epileptic seizures; both are seen in AD patients. We further showed that one of clinically tested BACE1 inhibitors does have off-target effects, and development of safer BACE1 inhibitors will be beneficial to AD patients. Results from this study will provide useful guidance for additional drug development.

Anticoagulation for the treatment of septic cerebral venous sinus thrombosis in the setting of pediatric sinogenic and otogenic intracranial infections.

OBJECTIVE: Septic cerebral venous sinus thrombosis (CVST) is a recognized complication of pediatric sinogenic and otogenic intracranial infections. The optimal treatment paradigm remains controversial. Proponents of anticoagulation highlight its role in preventing thrombus propagation and promoting recanalization, while others cite the risk of hemorrhagic complications, especially after a neurosurgical procedure for an epidural abscess or subdural empyema. Here, the authors investigated the diagnosis, management, and outcomes of pediatric patients with sinogenic or otogenic intracranial infections and a septic CVST. METHODS: All patients 21 years of age or younger, who presented with an intracranial infection in the setting of sinusitis or otitis media and who underwent neurosurgical treatment at Connecticut Children's, Rady Children's Hospital-San Diego, or Ann and Robert H. Lurie Children's Hospital of Chicago from March 2015 to March 2023, were retrospectively reviewed. Demographic, clinical, and radiological data were systematically collated. RESULTS: Ninety-six patients were treated for sinusitis-related and/or otitis media-related intracranial infections during the study period, 15 (15.6%) of whom were diagnosed with a CVST. Of the 60 patients who presented prior to the COVID-19 pandemic, 6 (10.0%) were diagnosed with a septic CVST, whereas of the 36 who presented during the COVID-19 pandemic, 9 (25.0%) had a septic CVST (p = 0.050). The superior sagittal sinus was involved in 12 (80.0%) patients and the transverse and/or sigmoid sinuses in 4 (26.7%). Only 1 (6.7%) patient had a fully occlusive thrombus. Of the 15 patients with a septic CVST, 11 (73.3%) were initiated on anticoagulation at a median interval of 4 (IQR 3-5) days from the most recent neurosurgical procedure. Five (45.5%) patients who underwent anticoagulation demonstrated complete recanalization on follow-up imaging, and 4 (36.4%) had partial recanalization. Three (75.0%) patients who did not undergo anticoagulation demonstrated complete recanalization, and 1 (25.0%) had partial recanalization. None of the patients treated with anticoagulation experienced hemorrhagic complications. CONCLUSIONS: Septic CVST is frequently identified among pediatric patients undergoing neurosurgical intervention for sinogenic and/or otogenic intracranial infections and may have become more prevalent during the COVID-19 pandemic. Anticoagulation can be used safely in the acute postoperative period if administered cautiously, in a monitored setting, and with interval cross-sectional imaging. However, some patients exhibit excellent outcomes without anticoagulation, and further studies are needed to identify those who may benefit the most from anticoagulation.

Phantom limb pain, traumatic neuroma, or nerve sheath tumor? Illustrative case.

BACKGROUND: Phantom limb pain and traumatic neuromas are not commonly seen in neurosurgical practice. These conditions can present with similar symptoms; however, management of traumatic neuroma is often surgical, whereas phantom limb pain is treated with conservative measures. OBSERVATIONS: A 77-year-old female patient with a long-standing history of an above-the-knee amputation experienced severe pain in her right posterior buttocks area for several years' duration, attributed to phantom limb pain, which radiated down the stump of her leg and was treated with a variety of conservative measures. A recent exacerbation of her pain led to a prolonged hospitalization with magnetic resonance imaging of her leg stump, revealing a mass in the sciatic notch, at a relative distance from the stump. The anatomical location of the mass on the sciatic nerve in the notch led to a presumed radiological diagnosis of nerve sheath tumor, for which she underwent excision. At surgery, a neuroma of the proximal portion of the transected sciatic nerve that had retracted from the amputated stump to the notch was diagnosed. LESSONS: Traumatic neuromas of transected major nerves after limb amputation should be considered in the differential diagnosis of phantom limb pain.

Changes in the epidemiology of pediatric sinogenic and otogenic intracranial infections during the COVID-19 pandemic: a single-institution study.

OBJECTIVE: Focal intracranial infections (epidural abscesses, subdural empyemas, and intraparenchymal abscesses) are uncommon complications of sinusitis and otitis media but can be associated with significant morbidity. Treatment typically requires neurosurgical and otolaryngological interventions in combination with antibiotic treatment. Historically, children have presented to the authors' pediatric referral center with sinusitis- or otitis media-related intracranial infections in low numbers. However, since the onset of the COVID-19 pandemic, the incidence of intracranial pyogenic complications has increased at this center. The objective of this study was to compare the epidemiology, severity, microbial causes, and management of pediatric sinusitis- and otitis-related intracranial infections in the periods before and during the COVID-19 pandemic. METHODS: All patients 21 years of age or younger who presented with an intracranial infection in the setting of sinusitis or otitis media and who underwent neurosurgical treatment at Connecticut Children's from January 2012 to December 2022 were retrospectively reviewed. Demographic, clinical, laboratory, and radiological data were systematically collated, and variables before and during COVID-19 were compared statistically. RESULTS: Overall, 18 patients were treated for sinusitis-related (n = 16) or otitis media-related (n = 2) intracranial infections during the study period. Ten patients (56%) presented from January 2012 to February 2020, none from March 2020 to June 2021, and 8 (44%) from July 2021 to December 2022. There were no significant demographic differences between the pre-COVID-19 and COVID-19 cohorts. The 10 patients in the pre-COVID-19 cohort underwent a total of 15 neurosurgical and 10 otolaryngological procedures, while the 8 patients in the COVID-19 cohort underwent a total of 12 neurosurgical and 10 otolaryngological procedures. Surgically obtained wound cultures yielded a variety of organisms; Streptococcus constellatus/S. anginosus/S. intermedius were more prevalent in the COVID-19 cohort (87.5% vs 0%, p < 0.001) as was Parvimonas micra (62.5% vs 0%, p = 0.007). CONCLUSIONS: At an institutional level, there has been an approximately threefold increase in cases of sinusitis- and otitis media-related intracranial infections during the COVID-19 pandemic. Multicenter studies are needed to confirm this observation and to investigate whether the mechanisms of infection are related directly to SARS-CoV-2, changes in the respiratory flora, or delayed care. The next steps will include expansion of this study to other pediatric centers throughout the United States and Canada.