BackgroundPD-1 and CTLA-4 inhibitors are associated with several adverse events including a spectrum of immune-related adverse effects (irAEs). Neurologic irAEs are uncommon occurrences with varied presentations. We describe two separate cases of ipilimumab associated meningoencephalomyelitis and demyelinating polyneuropathy with unusual presentations.Case presentationTwo melanoma patients were treated with ipilimumab in the adjuvant setting. The first patient developed a meningoencephalitis following 3 doses of ipilimumab. MRI imaging of the brain confirmed leptomeningeal enhancement although cerebrospinal fluid (CSF) analyses were negative for malignant cells consistent with meningoencephalomyelitis. Although she initially improved following treatment with steroids and intravenous immunoglobulin, she subsequently relapsed. She was successfully treated with infliximab and made a complete neurological recovery. A second patient developed progressive lower extremity weakness following two doses of ipilimumab. MRI imaging of the spine confirmed diffuse nerve root enhancement consistent with acute inflammatory demyelinating polyneuropathy (AIDP). He was treated with high dose steroids with resolution of neurological symptoms. Both patients remain disease free.ConclusionsNeurological irAEs are uncommon adverse events in the context of CTLA-4 and/or PD-1 inhibitor therapy. Care must be taken to distinguish these from leptomeningeal disease. Early recognition of neurological irAEs is critical for the initiation of specific anti-inflammatory agents to prevent and potentially reverse neurological sequelae.

Image-guided microcatheter induction of PCA occlusion in rabbits can consistently produce time-dependent infarction of cortical and subcortical structures that is reliably detected by diffusion-weighted MRI, and thus may be a useful model for therapeutic studies in acute ischemic stroke.

Introduction: The rabbit small clot embolic model for large vessel occlusion (LVO) is well established, yet remains with limitations. Blind introduction of autologous thrombus often fails to occlude the target vessel, and when successful, the precise timing of occlusion and revascularization are difficult to control. Studies of cellular biology and neuroimaging of acute reversible cerebral ischemia (i.e., penumbral tissue) would benefit from a rabbit model in which LVO can be reliably induced and easily confirmed, where the time of occlusion and revascularization can be precisely controlled. Hypothesis: We hypothesized that microcatheterization of the posterior cerebral artery (PCA) in New Zealand white rabbits (NZWRs) would result in LVO, with time of revascularization controlled by microcatheter removal. We hypothesized that transient LVO would produce ischemia in subcortical structures supplied by the PCA (e.g., hippocampus), sparing the cortex, with longer duration LVO leading to irreversible cortical ischemia. Methods: Transfemoral 1.5F microcatheterization of the PCA was performed in anesthetized NZWRs using fluoroscopic guidance. LVO was maintained for 30 minutes (n=2), 60 minutes (n=2), 180 minutes (n=2) and 210 minutes (n=1), followed by microcatheter removal and reperfusion. Neuroimaging was obtained 3 hours later with MRI (3T DWI, FLAIR, gradient and perfusion sequences) and CT (64 slice noncontrast and perfusion imaging). Post-mortem histologic analysis of infarct was assessed using triphenyltetrazolium choloride (TTC) stain. Matched DWI and TTC sections were analyzed using ImageJ software. Results: Percent infarct of matched DWI and TTC sections was strongly correlated (r2 = 0.86). Transient LVO of 30-60 minutes resulted in infarction of the ipsilateral hippocampus and thalamus, sparing the cortex, while more prolonged LVO (180-210 minutes) led to cortical infarction as well. Conclusions: Image-guided microcatheter induction of LVO in NZW rabbits can reliably produce time-dependent infarction of cortical and subcortical structures, and thus may be a useful model for the study of penumbral cortical tissue.

Background: The relationship between maternal risk factors (MRFs) (particularly pre-gravid obesity, diabetes, and hypertension) and congenital heart disease (CHD) to placental and fetal brain outcomes is poorly understood. Here, we tested the hypothesis that MRF and CHD would be associated with reduced intrinsic placental and fetal brain function using a novel non-invasive technique. Methods: Pregnant participants with and without MRF and fetal CHD were prospectively recruited and underwent feto-placental MRI. Using intrinsic properties of blood oxygen level dependent imaging (BOLD) we quantified spatiotemporal variance of placenta and fetal brain. MRFs and CHD were correlated with functional characteristics of the placenta and fetal brain. Results: Co- morbid MRF (hypertension, diabetes, and obesity) reduced spatiotemporal functional variance of placenta and fetal brain (p < 0.05). CHD predicted reduced fetal brain temporal variance compared to controls (p<0.05). Interaction of MRF and CHD status was associated with reduced intrinsic pBOLD temporal variance (p=0.047). There were no significant interactions of MRFs and CHD status on either temporal or spatial variance of intrinsic brain BOLD. Conclusion: MRF and CHD reduced functional characteristic of placenta and brain in fetuses. MRF modification and management during pregnancy may have the potential to not only provide additional risk stratification but may also improve neurodevelopmental outcomes.