Neuro-Ophthalmic Complications in Patients Treated With CTLA-4 and PD-1/PD-L1 Checkpoint Blockade.

BACKGROUND: In recent years, CTLA-4 and PD-1/PD-L1 checkpoint inhibitors have proven to be effective and have become increasingly popular treatment options for metastatic melanoma and other cancers. These agents work by enhancing autologous antitumor immune responses. Immune-related ophthalmologic complications have been reported in association with checkpoint inhibitor use but remain incompletely characterized. This study seeks to investigate and further characterize the neuro-ophthalmic and ocular complications of immune checkpoint blockade treatment. METHODS: A survey was distributed through the secure electronic data collection tool REDCap to neuro-ophthalmology specialists in the North American Neuro-Ophthalmology Society listserv. The study received human subjects approval through the University of California at Los Angeles Institutional Review Board. The survey identified patients sent for neuro-ophthalmic consultation while receiving one or more of a PD-1 inhibitor (pembrolizumab, nivolumab, or cemiplimab); PD-L1 inhibitor (atezolizumab, avelumab, or durvalumab); or the CTLA-4 inhibitor ipilimumab. Thirty-one patients from 14 institutions were identified. Patient demographics, neuro-ophthalmic diagnosis, diagnostic testing, severity, treatment, clinical response, checkpoint inhibitor drug used, and cancer diagnosis was obtained. RESULTS: The checkpoint inhibitors used in these patients included pembrolizumab (12/31), nivolumab (6/31), combined ipilimumab with nivolumab (7/31, one of whom also received pembrolizumab during their course of treatment), durvalumab (3/31), ipilimumab (2/31), and cemiplimab (1/31). Malignant melanoma (16/31) or nonsmall cell lung carcinoma (6/31) were the most common malignancies. The median time between first drug administration and the time of ophthalmological symptom onset was 14.5 weeks. Eleven patients had involvement of the optic nerve, 7 patients had inflammatory orbital or extraocular muscle involvement, 6 patients had ocular involvement from neuromuscular junction dysfunction, 4 patients had cranial nerve palsy, and 4 patients had non neuro-ophthalmic complications. Use of systemic corticosteroids with or without stopping the checkpoint inhibitor resulted in improvement of most patients with optic neuropathy, and variable improvement for the other ophthalmic conditions. CONCLUSION: This study describes the variable neuro-ophthalmic adverse events associated with use of immune checkpoint inhibitors and contributes a more thorough understanding of their clinical presentations and treatment outcomes. We expect this will increase awareness of these drug complications and guide specialists in the care of these patients.

A Case of Bilateral Endogenous Candida dubliniensis Endophthalmitis Treated with Aggressive Local and Systemic Therapy.

Candida dubliniensis is an emerging pathogen implicated in a variety of infections in immunocompromised hosts. A 79-year-old male with autoimmune pancytopenia on chronic oral steroid therapy was admitted for suspected sepsis and started on empirical antibiotics and micafungin. He developed floaters and decreased vision while on this regimen and was diagnosed with bilateral candida endophthalmitis. Blood cultures grew C. dubliniensis.Intravenous therapy was switched to voriconazole and amphotericin B. He also received aggressive intravitreal antifungal therapy consisting of 100 µg/0.1 mL voriconazole (4 OD, 3 OS) and 5 µg/0.1 mL amphotericin B (3 OD, 1 OS) over 2 weeks that resulted in local control of infection. The right eye developed a retinal detachment 1 month after initial presentation that was repaired by 25-gauge pars plana vitrectomy, scleral buckle, laser and silicone oil. At the 15-month follow-up exam, subsequent to silicone oil removal, membrane peel and cataract surgery, OD visual acuity had improved to 20/80. OS was phakic and 20/25. Aggressive intravitreal antifungal therapy combined with intravenous therapy may control endophthalmitis and avoid the risks associated with pars plana vitrectomy during acute infection.

Analysis of the Essential Oils of Five Artemisia Species and Evaluation of their Cytotoxic and Proapoptotic Effects.

BACKGROUND: In this study, the essential oil composition and cytotoxic activities of five Artemisia species were determined. METHODS: The collected plants were water-distilled separately to obtain oils which were then subjected to gas chromatography (GC) and gas chromatography/mass spectrometry GC/MS analyses to identify their compositions. Cancer cells were exposed to different concentrations of samples and cell viability was measured using AlamarBlue® assay. Apoptotic cells were analyzed by propidium iodide (PI) staining and flow cytometry. RESULTS & CONCLUSION: To study the amount of pro-apoptotic proteins and the apoptosis mechanism, Western blot method was used. Although all samples were cytotoxic at the highest concentration, the oil of A. kulbadica showed the strongest activity among other plants. Carvacrol (IC50 21.11 µg/ml) had the most cytotoxic effects among other components. Carvacrol, 1,8-cineole and 4-terpineole caused an increase in the amount of Bax protein and cleaved peroxisome proliferator-activated receptors (PPAR) and caspase proteins in DU 145 cells.

An Incidental Finding of Ecchordosis Physaliphora in a Case of Abducens Nerve Palsy: Case Report.

Ecchordosis physaliphora (EP) is a rare non-malignant mass that originates from remains of the notochord and is typically asymptomatic. A 42-year-old man presented with sudden onset of painless horizontal diplopia and his neurological exam showed sixth cranial nerve palsy. Magnetic resonance imaging (MRI) identified a non-enhanced retroclival mass (EP) with increased signal intensity on T2 and decreased signal intensity on T1-weighted sequences. He was treated with methylprednisolone, completely recovered in four weeks and has remained symptom free. Conservative management should be attempted before surgery in all cases since symptoms can resolve spontaneously and EP could be an incidental finding.

Ipilimumab-induced Adenohypophysitis and Orbital Apex Syndrome: Importance of Early Diagnosis and Management.

Ipilimumab is a novel anti-melanoma agent known to infrequently cause multi-organ autoimmunity. We report a case of pituitary hypophysitis and orbital inflammation followed by an orbital apex syndrome. A 64-year-old woman with a history of skin melanoma, receiving ipilimumab treatment, was seen for near total loss of vision in the right eye and proptosis. Headache of 3-month duration preceded the onset of diplopia followed by severe loss of vision in the right eye. Neuro-ophthalmologic examination was consistent with an orbital apex syndrome. Extensive blood work and magnetic resonance imaging of the brain and orbit suggested an inflammatory process, rather than a metastatic lesion. Accordingly, the patient received high-dose methylprednisolone followed by tapering oral prednisone. At the 6-month follow-up visit, visual acuity on the right eye had significantly improved but diplopia remained, associated with large amplitude esotropia that improved incompletely though while on prednisone. The favourable outcome supported a final diagnosis of ipilimumab-induced inflammatory orbital apex syndrome and clinically silent pituitary adenohypophysitis. The case presented herein highlights unexpected ipilimumab-associated adverse effects and proposes the possibility of and interaction between inflammatory and immune mechanisms.

The medial vestibular nuclei, a vulnerable target in thiamine deficiency.

BACKGROUND: Bilateral medial vestibular nuclei (MVN) is a common target in thiamine depletion and results in acute vestibular failure. Involvement of the MVN was present in 27 out of 38 brainstem sections reported in the largest thiamine deficiency autopsy cohort with Wernicke's encephalopathy. METHOD: Serial clinical, imaging and vestibulo-ocular reflex gain measured with the video head impulse (vHIT) in one patient with acute thiamine deficiency. RESULTS: Low horizontal VOR gain correlated with an abnormal manual head impulse and with MRI evidence of MVN in an alcohol-dependent patient with low thiamine levels. The vertical VOR gain was either normal or mildly abnormal. Thiamine replacement and normal diet restored the VOR gain and MRI signal changes to normal. CONCLUSION: This single case study provides clinical-imaging correlation for symmetric MVN compromise in thiamine deficiency, its effect on the VOR gain and the favorable response to thiamine and diet replacement when identified early.

Role of Therapeutic Plasma Exchange in Treatment of Tumefactive Multiple Sclerosis-Associated Low CD4 and CD8 Levels.

We report a 35-year-old healthy male who developed central nervous system inflammatory demyelinating disease consistent with tumefactive multiple sclerosis. About 2 weeks after onset of symptoms and prior to initiation of therapy, the patient had lymphopenia and low CD4 and CD8 levels. His lymphocyte count was 400 cells/µl (850-3,900 cells/µl), CD4 was 193 cells/µl (490-1,740 cells/µl) and CD8 was 103 cells/µl (180-1,170 cells/µl). He was treated with intravenous methylprednisolone followed by therapeutic plasma exchange, the levels of CD4 and CD8 normalized, and ultimately, he recovered completely.

Very mild stroke patients benefit from intravenous tissue plasminogen activator without increase of intracranial hemorrhage.

BACKGROUND: Intravenous recombinant tissue plasminogen activator (IV rt-PA) is an effective medication currently used to treat acute ischemic stroke within three hours of symptom onset in patients with an identifiable clinical deficit measured using the National Institute of Health Stroke Scale (NIHSS). METHODS: We compared the outcomes of 27 identified patients with an NIHSS of 6 or less who received IV rt-PA for acute ischemic stroke treatment within three hours of symptom onset in our center with 24 historic controls from the nationally available National Institute of Neurological Disorders and Stroke (NINDS) study database. RESULTS: The mean initial NIHSS was not significantly different in patients and control groups (mean +/- SD: 4.52 +/- 1.25 and 4.71 +/- 1.4) (P = 0.45). The mean modified Rankin score (mRS) at the time of discharge in patients and control group were 0.78 +/- 1.19 and 1.75 +/- 1.75, respectively. The mRS at discharge demonstrated a statistically significant (P < 0.03) improved clinical outcome for IV rt-PA treated group. The rate of intracranial hemorrhage (ICH) in the IV rt-PA group and control group was not significantly different (P = 1, odds ratio: 0.88, CI: 0.05-14.09). CONCLUSION: This retrospective study demonstrates that administering intravenous rt-PA to patients with a very mild stroke (NIHSS of 6 or less) can lead to improved clinical outcome when compared to patients with similar NIHSS who have not received similar treatment.

Does mild deficit for patients with stroke justify the use of intravenous tissue plasminogen activator?

Intravenous (IV) tissue plasminogen activator (t-PA) is an effective medication currently used to treat acute ischemic stroke within 3 hours of symptom onset in patients with an identifiable clinical deficit measured using the National Institutes of Health Stroke Scale (NIHSS). Some reports suggest that patients with milder acute ischemic stroke may improve spontaneously and may not benefit additionally from IV thrombolysis. The objective of this retrospective study was to assess the outcomes of patients at our stroke center who received IV t-PA treatment for acute ischemic stroke, within 3 hours of symptom onset, outside the setting of a clinical trial and had a NIHSS score of less than or equal to 10 compared with historic control subjects. There were 52 patients who received IV t-PA for acute ischemic stroke. Of those, 31 (male 44% [n = 14]) had a NIHSS score of 10 or less (mean NIHSS score 6 +/- 2). The mean age was 61 +/- 14 years, the mean NIHSS score was 6 +/- 2, and the mean modified Rankin scale (mRS) score was 1.4 +/- 1.5. We identified 98 patients (male 74% [n = 73]) in the National Institute of Neurological Disorders and Stroke IV recombinant t-PA study placebo group. The mean age was 65 +/- 13 years, the mean NIHSS score was 7 +/- 2, and the mean mRS score was 2.5 +/- 1.7. Assuming equal variances, the mRS score at discharge, for the IV t-PA-treated group, demonstrated a better clinical outcome that was statistically significant (P < .009). This retrospective study demonstrates that administering IV t-PA to patients with a mild stroke, measuring 10 or less by the NIHSS, can lead to improved clinical outcome when compared with patients with similar NIHSS score who have not received similar treatment.