Radiotherapy is commonly employed to treat cancers of the head and neck and is increasingly used to treat other central nervous system (CNS) disorders. Exceeding the radiation tolerance of normal CNS tissues can result in sequelae contributing to patient morbidity and mortality. Animal studies and clinical experience suggest that neuroinflammation plays a role in the etiology of these effects; however, detailed characterization of this response has been lacking. Therefore, a dose–time investigation of the neuroinflammatory response after single-dose cranial irradiation was performed using C57BL/6 mice. Consistent with previous reports, cranial irradiation resulted in multiphasic inflammatory changes exemplified by increased transcript levels of inflammatory cytokines, along with glial and endothelial cell activation. Cranial irradiation also resulted in acute infiltration of neutrophils and a delayed increase in T cells, MHC II-positive cells, and CD11c-positive cells seen first at 1 month with doses ≥15 Gy. CD11c-positive cells were found almost exclusively in white matter and expressed MHC II, suggesting a “mature” dendritic cell phenotype that remained elevated out to 1 year postirradiation. Our results indicate that cranial irradiation leads to persistent neuroinflammatory changes in the C57BL/6 mouse brain that includes unique immunomodulatory cell populations.

Objective: To describe the effects of the anti-tumor necrosis factor neutralizing antibody, infliximab, and the antiproliferative immunosuppressant, mycophenolate mofetil, in refractory neurosarcoidosis. Methods:We treated patients with biopsy-proven sarcoidosis and CNS involvement, who had failed treatment with steroids, with infliximab (5 mg/kg on weeks 0, 2, and 6, and then every 6 -8 weeks thereafter). Six out of seven patients were co-treated with mycophenolate mofetil (1,000 mg PO BID). Patients underwent a review of symptoms and complete neurologic examination every 3 months and MRI scanning before and after 3-4 infusions of infliximab.Results: All patients reported significant symptomatic improvement by the fourth infusion of infliximab, including relief of headache and neuropathic pain, reversal of motor, sensory, or coordination deficits, and control of seizure activity. Furthermore, infliximab therapy was universally associated with a decrease in lesion size or suppression of gadolinium enhancement as documented by MRI. A positive treatment response was attained irrespective of location or distribution of CNS involvement by sarcoidosis (dural/leptomeningeal based vs intraparenchymal; cord vs brain; single lesion vs multifocal). There were no serious adverse effects in a follow-up period spanning 6 -18 months. Conclusions:Combination treatment with mycophenolate mofetil and infliximab is a promising therapeutic approach for neurosarcoidosis. Neurology GLOSSARYA ϭ azathioprine; AA ϭ African American; Cy ϭ cyclophosphamide; E ϭ etanercept; EDSS ϭ Expanded Disability Status Scale; MMF ϭ mycophenolate mofetil; MMSE ϭ Mini-Mental State Examination; N ϭ neurologic; O ϭ ophthalmologic; P ϭ pulmonary; Pq ϭ Plaquenil; R ϭ rheumatologic; Si ϭ sinuses; S ϭ steroids; TNF ϭ tumor necrosis factor; VPS ϭ ventriculoperitoneal shunt; W ϭ white.CNS infiltration occurs in approximately 5% of patients with sarcoidosis; it is associated with a less favorable course and accounts for a disproportionate amount of disability.1 Neurosarcoidosis is often difficult to manage. In one of the larger clinical series, over 70% of patients relapsed or progressed despite treatment with corticosteroids and oral immunosuppressant agents.2 Since neurosarcoidosis tends to flare in the midst of prednisone tapers, those afflicted are often subject to the complications of chronic corticosteroid usage. Hence, there is a clear need for novel therapeutic strategies in this disorder.It has been speculated that tumor necrosis factor (TNF)␣ neutralizing agents might be effective in sarcoidosis based on animal studies demonstrating a critical role of TNF␣ in granulomatous inflammation and an association between TNF␣ expression in alveolar macrophages and active pulmonary sarcoidosis. 3,4 Infliximab is a chimeric monoclonal humanmurine IgG antibody directed against TNF␣ approved for the treatment of rheumatoid

Brain metastasis (BM), the most common adult brain tumor, develops in 20% to 40% of patients with late‐stage cancer and traditionally are associated with a poor prognosis. The management of patients with BM has become increasingly complex because of new and emerging systemic therapies and advancements in radiation oncology and neurosurgery. Current therapies include stereotactic radiosurgery, whole‐brain radiation therapy, surgical resection, laser‐interstitial thermal therapy, systemic cytotoxic chemotherapy, targeted agents, and immune‐checkpoint inhibitors. Determining the optimal treatment for a specific patient has become increasingly individualized, emphasizing the need for multidisciplinary discussions of patients with BM. Recognizing and addressing the sequelae of BMs and their treatment while maintaining quality of life and neurocognition is especially important because survival for patients with BMs has improved. The authors present current and emerging treatment options for patients with BM and suggest approaches for managing sequelae and disease recurrence.

Acute neuroinflammation reduces adult hippocampal neurogenesis but the role of chronic neuroinflammation, which may be more representative of ongoing processes in CNS disorders, remains relatively unknown. Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that has been shown to acutely impair neurogenesis. To further investigate the relationship between sustained IL-1β expression and adult neurogenesis, a mouse model with an IL-1β excisionally activated transgene, IL-1βXAT, was utilized. Upon exposure to Cre recombinase, IL-1β overexpression in this model results in chronic neuroinflammation, which persists up to 12 months and causes glial activation, cellular recruitment, and deficits in learning and memory. We hypothesized that adult neurogenesis would be reduced by sustained hippocampal IL-1β overexpression and rescued by voluntary running, which has been shown to enhance neurogenesis. Hippocampal inflammation in the IL-1βXAT model severely impaired doublecortin (DCX) positive cells at 1 month and 3 months after IL-1β induction. Furthermore, BrdU labeling demonstrated a shift in cell lineage from neuronal to astroglial in the context of sustained hippocampal IL-1β overexpression. Deletion of the IL-1 receptor prevented the decrease in DCX+ cells. Voluntary running did not attenuate the effects of IL-1β expression demonstrated by DCX staining. These results suggest that chronic neuroinflammation severely impairs adult hippocampal neurogenesis and voluntary running is not beneficial as a therapy to rescue these effects.