Tumor necrosis factor receptor 2 activation elicits sex-specific effects on cortical myelin proteins and functional recovery in a model of multiple sclerosis.

Multiple sclerosis (MS), a demyelinating autoimmune disease of the central nervous system (CNS), predominately affects females compared to males. Tumor necrosis factor (TNF), a pro-inflammatory cytokine, signaling through TNF receptor 1 contributes to inflammatory disease pathogenesis. In contrast, TNF receptor 2 signaling is neuroprotective. Current anti-TNF MS therapies are shown to be detrimental to patients due to pleiotropic effects on both pro- and anti-inflammatory functions. Using a non-pertussis toxin (nPTX) experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice, we systemically administered a TNFR2 agonist (p53-sc-mTNFR2) to investigate behavioral and pathophysiological changes in both female and male mice. Our data shows that TNFR2 activation alleviates motor and sensory symptoms in females. However, in males, the agonist only alleviates sensory symptoms and not motor. nPTX EAE induction in TNFR2 global knockout mice caused exacerbated motor symptoms in females along with an earlier day of onset, but not in males. Our data demonstrates that TNFR2 agonist efficacy is sex-specific for alleviation of motor symptoms, however, it effectively reduces mechanical hypersensitivity in both females and males. Altogether, these data support the therapeutic promise TNFR2 agonism holds as an MS therapeutic and, more broadly, to treat central neuropathic pain.

Orbital magnetic resonance imaging of giant cell arteritis with ocular manifestations: a systematic review and individual participant data meta-analysis.

OBJECTIVES: We conducted a systematic review and individual participant data meta-analysis of publications reporting the ophthalmologic presentation, clinical exam, and orbital MRI findings in patients with giant cell arteritis and ocular manifestations. METHODS: PubMed and Cochrane databases were searched up to January 16, 2022. Publications reporting patient-level data on patients with ophthalmologic symptoms, imaged with orbital MRI, and diagnosed with biopsy-proven giant cell arteritis were included. Demographics, clinical symptoms, exam, lab, imaging, and outcomes data were extracted. The methodological quality and completeness of reporting of case reports were assessed. RESULTS: Thirty-two studies were included comprising 51 patients (females = 24; median age, 76 years). Vision loss (78%) and headache (45%) were commonly reported visual and cranial symptoms. Ophthalmologic presentation was unilateral (41%) or bilateral (59%). Fundus examination most commonly showed disc edema (64%) and pallor (49%). Average visual acuity was very poor (2.28 logMAR ± 2.18). Diagnoses included anterior (61%) and posterior (16%) ischemic optic neuropathy, central retinal artery occlusion (8%), and orbital infarction syndrome (2%). On MRI, enhancement of the optic nerve sheath (53%), intraconal fat (25%), and optic nerve/chiasm (14%) was most prevalent. Among patients with monocular visual symptoms, 38% showed pathologic enhancement in the asymptomatic orbit. Six of seven cases reported imaging resolution after treatment on follow-up MRIs. CONCLUSIONS: Vision loss, pallid disc edema, and optic nerve sheath enhancement are the most common clinical, fundoscopic, and imaging findings reported in patients diagnosed with giant cell arteritis with ocular manifestations, respectively. MRI may detect subclinical inflammation and ischemia in the asymptomatic eye and may be an adjunct diagnostic tool. CLINICAL RELEVANCE STATEMENT: Brain and orbital MRIs may have diagnostic and prognostic roles in patients with suspected giant cell arteritis who present with ophthalmic symptoms.

Diplopia and Ptosis: An Unusual Case of Prostate Cancer Metastasis to the Sphenoid Bone Treated With Palliative Radiotherapy.

We report a case of a 72-year-old male who presented to the hospital with a chief complaint of diplopia in the setting of a recent onset of urinary incontinence and right-sided back pain. He was subsequently diagnosed with prostate cancer, notably metastasizing to the right sphenoid bone, causing impingement of the oculomotor nerve. Our case is unique in that the patient's initial presentation of prostate cancer was oculomotor nerve palsy with subsequent histologic analysis of the primary tumor showing both small cell neuroendocrine carcinoma along with adenocarcinoma. Also, the initial routine stroke protocol MRI and computed tomography angiography (CTA) missed the lesion, while gadolinium-enhanced targeted MRI revealed lesions in both the spine and the orbit. This case emphasizes the need for enhanced contrast as well as focused imaging in patients presenting with diplopia with a negative initial workup for stroke. Ptosis can be a sign of metastasis from other cancers and it is important to have a broad differential including metastatic disease in patients' presenting with similar symptoms and negative initial workup who may otherwise be at risk of cancer.

Synaptic alterations and immune response are sexually dimorphic in a non-pertussis toxin model of experimental autoimmune encephalomyelitis.

Multiple sclerosis is an autoimmune disorder of the central nervous system (CNS) characterized by locomotor impairments, cognitive deficits, affective disorders, and chronic pain. Females are predominately affected by MS compared to males and develop motor symptoms earlier. However, key symptoms affect all patients regardless of sex. Previous studies have shown that demyelination and axonal damage play key roles in symptom development, but it is unclear why sex differences exist in MS onset, and effective symptom treatment is still lacking. We here used a non-pertussis toxin (nPTX) experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice, to explore chronic symptoms and sex differences in CNS autoimmunity. We observed that, like in humans, female mice developed motor disease earlier than males. Further, changes in pre- and post-synaptic protein expression levels were observed in a sexually dimorphic manner with an overall shift towards excitatory signaling. Our data suggest that this shift towards excitatory signaling is achieved through different mechanisms in males and females. Altogether, our study helps to better understand sex-specific disease mechanisms to ultimately develop better diagnostic and treatment tools.