Hydrocephalus in Neurosarcoidosis: Clinical Course, Radiographic Accompaniments, and Experience with Shunting.

BACKGROUND: Hydrocephalus is an uncommon manifestation of neurosarcoidosis (7-14% of reported cohorts) that poses unique challenges to patient management. Despite being a recognized complication of neurosarcoidosis, very little is known about how hydrocephalus influences its clinical course, management, and prognosis. OBJECTIVES: To characterize hydrocephalus as a clinical manifestation of neurosarcoidosis, highlight which patients required cerebrospinal fluid (CSF) diversion, understand the mediating role of immunomodulatory treatments, and report outcomes in this cohort. METHODS: Patients with a diagnosis of neurosarcoidosis seen at Emory Healthcare [01/2011-8/2021] were included if hydrocephalus was one manifestation of their disease. Means and proportions were compared between shunted and non-shunted groups using the Wilcoxon rank-sum test for continuous variables and the Fisher's exact test for categorical variables. RESULTS: Twenty-two patients with neurosarcoidosis and hydrocephalus as one disease manifestation were included (22/214, 10.3%). Hydrocephalus was communicating in 13 (13/20, 65.0%) and obstructive in 6 patients (6/20, 30.0%), with features of both seen in 1 patient (1/20, 5.0%). Chronic presentations were typical (12/22, 54.5%) with altered sensorium, gait dysfunction, headache, and weakness being present in the majority of patients. There was a rostral-to-caudal gradient in ventriculomegaly, with the lateral ventricles most affected (20/20, 100%) and the fourth ventricle the least (12/20, 60%). Meningoventricular inflammation was the most common neuroinflammatory accompaniment (18/20, 90.0%), especially infratentorial leptomeningitis (16/20, 80.0%) and fourth ventriculitis (9/20, 45.0%). Thirteen patients (13/22, 59.1%) required ventriculoperitoneal shunts (VPS). Factors associated with shunt placement were younger age at neurosarcoidosis onset (p = 0.019) and hydrocephalus onset (p = 0.015), obstructive hydrocephalus (p = 0.043), and lateral ventriculitis (p = 0.043). In the 6 patients (6/13, 46.2%) with preceding extraventricular drain (EVD) placement, all failed to wean, including 5/6 patients who received high-dose steroids while the EVD was in place. Almost all (19/20, 95.0%) were treated with steroid-sparing agents, including nine (9/20, 45.0%) with tumor necrosis factor (TNF) inhibitors. Modified Rankin Scale score at last outcome was 3.04 (range 0-6). CONCLUSION: Patients with neurosarcoidosis and hydrocephalus experience unique challenges in the management of their disease, including the potential need for CSF diversion, in addition to traditional anti-inflammatory treatments. Younger patients, those with obstructive hydrocephalus, and those with lateral ventriculitis warrant particular consideration for VPS placement, but the decision to shunt likely remains a highly individualized one. The requirement for multiple lines of immunotherapy beyond steroids and moderate disability at last follow-up suggest hydrocephalus may reflect a more severe form of neurosarcoidosis.

Tofacitinib-induced Progressive Multifocal Leukoencephalopathy with Immune Reconstitution Inflammatory Syndrome.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) with subsequent immune reconstitution inflammatory syndrome (IRIS) is a rare disease associated with compromised immune systems. It has never been described in a patient taking tofacitinib. CASE PRESENTATION: A 49-year-old woman with history of systemic lupus erythematous treated with tofacitinib presented with several weeks of intermittent fevers and altered mental status. MRI revealed multifocal T2-weighted FLAIR hyperintensities in the subcortical white matter, including the subcortical U-fibers, without mass effect or contrast enhancement, compatible with PML. Tofacitinib was stopped and the patient's symptoms initially improved. However, the patient presented again less than a week after discharge with three days of left arm weakness, left facial droop, dysarthria, and one day of confusion. Repeat MRI demonstrated interval progression in T2/FLAIR hyperintensities with development of patchy gadolinium enhancement on T1-post contrasted sequences, consistent with development of IRIS in the setting of tofacitinib cessation. DISCUSSION: This is the first case describing PML-IRIS in the setting of administration and subsequent cessation of tofacitinib.

Epileptiform Abnormalities in Acute Ischemic Stroke: Impact on Clinical Management and Outcomes.

PURPOSE: Studies examining seizures (Szs) and epileptiform abnormalities (EAs) using continuous EEG in acute ischemic stroke (AIS) are limited. Therefore, we aimed to describe the prevalence of Sz and EA in AIS, its impact on anti-Sz drug management, and association with discharge outcomes. METHODS: The study included 132 patients with AIS who underwent continuous EEG monitoring >6 hours. Continuous EEG was reviewed for background, Sz and EA (lateralized periodic discharges [LPD], generalized periodic discharges, lateralized rhythmic delta activity, and sporadic epileptiform discharges). Relevant clinical, demographic, and imaging factors were abstracted to identify risk factors for Sz and EA. Outcomes included all-cause mortality, functional outcome at discharge (good outcome as modified Rankin scale of 0-2 and poor outcome as modified Rankin scale of 3-6) and changes to anti-Sz drugs (escalation or de-escalation). RESULTS: The frequency of Sz was 7.6%, and EA was 37.9%. Patients with Sz or EA were more likely to have cortical involvement (84.6% vs. 67.5% P = 0.028). Among the EAs, the presence of LPD was associated with an increased risk of Sz (25.9% in LPD vs. 2.9% without LPD, P = 0.001). Overall, 21.2% patients had anti-Sz drug changes because of continuous EEG findings, 16.7% escalation and 4.5% de-escalation. The presence of EA or Sz was not associated with in-hospital mortality or discharge functional outcomes. CONCLUSIONS: Despite the high incidence of EA, the rate of Sz in AIS is relatively lower and is associated with the presence of LPDs. These continuous EEG findings resulted in anti-Sz drug changes in one-fifth of the cohort. Epileptiform abnormality and Sz did not affect mortality or discharge functional outcomes.

Tauroursodeoxycholic Acid Protects Retinal Function and Structure in rd1 Mice.

We explored the potential protective effects of tauroursodeoxycholic acid (TUDCA) on cone photoreceptor survival in a model of rapid retinal degeneration, the ß-Pde6 (rd1) (rd1) mouse model. We injected two strains of rd1 mice (B6.C3-Pde6b (rd1) Hps4(le)/J and C57BL/6J-Pde6b (rd1-2)/J mice) daily from postnatal day (P) 6 to P21 with TUDCA or vehicle. At P21, retinal function was evaluated with light-adapted electroretinography (ERG) and retinal structure was observed with plastic or frozen sections. TUDCA treatment partially preserved function and structure in B6.C3-Pde6b (rd1) Hps4(le)/J mice but only partially preserved structure in C57BL/6J-Pde6b (rd1-2)/J mice. Our results suggest a possible intervention for patients undergoing rapid retinal degeneration.

Exercise and Cyclic Light Preconditioning Protect Against Light-Induced Retinal Degeneration and Evoke Similar Gene Expression Patterns.

To compare patterns of gene expression following preconditioning cyclic light rearing versus preconditioning aerobic exercise. BALB/C mice were preconditioned either by rearing in 800 lx 12:12 h cyclic light for 8 days or by running on treadmills for 9 days, exposed to toxic levels of light to cause light-induced retinal degeneration (LIRD), then sacrificed and retinal tissue harvested. Subsets of mice were maintained for an additional 2 weeks and for assessment of retinal function by electroretinogram (ERG). Both preconditioning protocols partially but significantly preserved retinal function and morphology and induced similar leukemia inhibitory factor (LIF) gene expression pattern. The data demonstrate that exercise preconditioning and cyclic light preconditioning protect photoreceptors against LIRD and evoke a similar pattern of retinal LIF gene expression. It may be that similar stress response pathways mediate the protection provided by the two preconditioning modalities.

Neuroprotective Effects of Voluntary Exercise in an Inherited Retinal Degeneration Mouse Model.

PURPOSE: Our previous investigations showed that involuntary treadmill exercise is neuroprotective in a light-induced retinal degeneration mouse model, and it may act through activation of tropomyosin-related kinase B (TrkB) receptors. This study investigated whether voluntary running wheel exercise can be neuroprotective in an inheritable model of the retinal degenerative disease retinitis pigmentosa (RP), rd10 mice. METHODS: Breeding pairs of rd10 and C57BL/6J mice were given free-spinning (active) or locked (inactive) running wheels. Pups were weaned into separate cages with their parents' respective wheel types, and visual function was tested with ERG and a virtual optokinetic system at 4, 5, and 6 weeks of age. Offspring were killed at 6 weeks of age and retinal cross-sections were prepared for photoreceptor nuclei counting. Additionally, separate cohorts of active and inactive rd10 pups were injected daily for 14 days after eye opening with a selective TrkB receptor antagonist (ANA-12) or vehicle solution and assessed as described above. RESULTS: Mice in the rd10 active group exhibited significant preservation of visual acuity, cone nuclei, and total photoreceptor nuclei number. Injection with ANA-12 precluded the preservation of visual acuity and photoreceptor nuclei number in rd10 mice. CONCLUSIONS: Voluntary running partially protected against the retinal degeneration and vision loss that otherwise occurs in the rd10 mouse model of RP. This protection was prevented by injection of ANA-12, suggesting that TrkB activation mediates exercise's preservation of the retina. Exercise may serve as an effective, clinically translational intervention against retinal degeneration.

Aerobic exercise protects retinal function and structure from light-induced retinal degeneration.

Aerobic exercise is a common intervention for rehabilitation of motor, and more recently, cognitive function (Intlekofer and Cotman, 2013; Wood et al., 2012). While the underlying mechanisms are complex, BDNF may mediate much of the beneficial effects of exercise to these neurons (Ploughman et al., 2007; Griffin et al., 2011; Real et al., 2013). We studied the effects of aerobic exercise on retinal neurons undergoing degeneration. We exercised wild-type BALB/c mice on a treadmill (10 m/min for 1 h) for 5 d/week or placed control mice on static treadmills. After 2 weeks of exercise, mice were exposed to either toxic bright light (10,000 lux) for 4 h to induce photoreceptor degeneration or maintenance dim light (25 lux). Bright light caused 75% loss of both retinal function and photoreceptor numbers. However, exercised mice exposed to bright light had 2 times greater retinal function and photoreceptor nuclei than inactive mice exposed to bright light. In addition, exercise increased retinal BDNF protein levels by 20% compared with inactive mice. Systemic injections of a BDNF tropomyosin-receptor-kinase (TrkB) receptor antagonist reduced retinal function and photoreceptor nuclei counts in exercised mice to inactive levels, effectively blocking the protective effects seen with aerobic exercise. The data suggest that aerobic exercise is neuroprotective for retinal degeneration and that this effect is mediated by BDNF signaling.