Artificial Intelligence to Detect Papilledema from Ocular Fundus Photographs.

BACKGROUND: Nonophthalmologist physicians do not confidently perform direct ophthalmoscopy. The use of artificial intelligence to detect papilledema and other optic-disk abnormalities from fundus photographs has not been well studied. METHODS: We trained, validated, and externally tested a deep-learning system to classify optic disks as being normal or having papilledema or other abnormalities from 15,846 retrospectively collected ocular fundus photographs that had been obtained with pharmacologic pupillary dilation and various digital cameras in persons from multiple ethnic populations. Of these photographs, 14,341 from 19 sites in 11 countries were used for training and validation, and 1505 photographs from 5 other sites were used for external testing. Performance at classifying the optic-disk appearance was evaluated by calculating the area under the receiver-operating-characteristic curve (AUC), sensitivity, and specificity, as compared with a reference standard of clinical diagnoses by neuro-ophthalmologists. RESULTS: The training and validation data sets from 6779 patients included 14,341 photographs: 9156 of normal disks, 2148 of disks with papilledema, and 3037 of disks with other abnormalities. The percentage classified as being normal ranged across sites from 9.8 to 100%; the percentage classified as having papilledema ranged across sites from zero to 59.5%. In the validation set, the system discriminated disks with papilledema from normal disks and disks with nonpapilledema abnormalities with an AUC of 0.99 (95% confidence interval [CI], 0.98 to 0.99) and normal from abnormal disks with an AUC of 0.99 (95% CI, 0.99 to 0.99). In the external-testing data set of 1505 photographs, the system had an AUC for the detection of papilledema of 0.96 (95% CI, 0.95 to 0.97), a sensitivity of 96.4% (95% CI, 93.9 to 98.3), and a specificity of 84.7% (95% CI, 82.3 to 87.1). CONCLUSIONS: A deep-learning system using fundus photographs with pharmacologically dilated pupils differentiated among optic disks with papilledema, normal disks, and disks with nonpapilledema abnormalities. (Funded by the Singapore National Medical Research Council and the SingHealth Duke-NUS Ophthalmology and Visual Sciences Academic Clinical Program.).

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.

Headache in Idiopathic Intracranial Hypertension: Findings From the Idiopathic Intracranial Hypertension Treatment Trial.

OBJECTIVE: To characterize the phenotype, headache-related disability, medical co-morbidities, use of symptomatic headache medications, and headache response to study interventions in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). METHODS: Patients with untreated IIH and mild vision loss enrolled in the IIHTT and randomized to acetazolamide (ACZ) and weight loss or placebo (PLB) and weight loss had prospective assessment of headache disability using the Headache Impact Test-6 (HIT-6) questionnaire. Subjects with headache at the baseline visit were assigned a headache phenotype using the International Classification for Headache Disorders version 3 beta (ICHD-3b). Medication overuse was determined using the participants' reported medication use for the preceding month and ICHD-3b thresholds for diagnosing medication overuse headache. We investigated relationships between headache disability and various other clinical characteristics at baseline and at 6 months. RESULTS: Headache was present in 139 (84%) of the 165 enrollees at baseline. The most common headache phenotypes were migraine (52%), tension-type headache (22%), probable migraine (16%), and probable tension-type headache (4%). Fifty-one (37%) participants overused symptomatic medications at baseline, most frequently simple analgesics. A similar amount of improvement in the adjusted mean (± standard error) HIT-6 score occurred in the ACZ (-9.56 ± 1.05) and PLB groups (-9.11 ± 1.14) at 6 months (group difference -0.45, 95% CI -3.50 to 2.60, P = .77). Headache disability did not correlate with any of the studies, variables of interest, which included: the lumbar puncture opening pressure at baseline or at 6 months, body mass index, the amount of weight lost, papilledema grade, perimetric mean deviation, or the use of hormonal contraception. Headache disability was significantly associated with patient-reported quality of life in the physical, mental, and visual domains. CONCLUSIONS: Headache was common, of varied character, disabling, and associated with poorer quality of life in our cohort of patients with mild visual impairment. The lack of correlation between headache disability and cerebrospinal fluid (CSF) pressure at baseline and at the end of the randomized phase of the study implies that headache in IIH may be related to factors other than intracranial hypertension, and that specific headache treatment is needed in addition to therapies directed at lowering CSF pressure.

Transient ocular motor nerve palsies associated with presumed cranial nerve schwannomas.

BACKGROUND: Cranial nerve schwannomas are radiologically characterized by nodular cranial nerve enhancement on magnetic resonance imaging (MRI). Schwannomas typically present with gradually progressive symptoms, but isolated reports have suggested that schwannomas may cause fluctuating symptoms as well. METHODS: This is a report of ten cases of presumed cranial nerve schwannoma that presented with transient or recurring ocular motor nerve deficits. RESULTS: Schwannomas of the third, fourth, and fifth nerves resulted in fluctuating deficits of all 3 ocular motor nerves. Persistent nodular cranial nerve enhancement was present on sequential MRI studies. Several episodes of transient oculomotor (III) deficts were associated with headaches, mimicking ophthalmoplegic migraine. CONCLUSIONS: Cranial nerve schwannomas may result in relapsing and remitting cranial nerve symptoms.

Impairment of habituation of the auditory brain stem response in migrainous vertigo.

OBJECTIVES: We evaluated the auditory brain stem response (ABR) in migrainous vertigo (MV). METHODS: Four subjects who met clinical criteria for definite MV and 4 subjects with non-vertiginous migraine (NVM) underwent ABR testing while asymptomatic and within 16 hours of a symptomatic episode. Four control subjects were also tested. A set of 4 consecutive 750-click series was administered at 50-, 60-, and 70-dB intensities. We compared the groups in terms of habituation of the amplitude of wave IV-V (habituation of IV-V) from the first through fourth series for each set. RESULTS: The habituation of IV-V amplitude to 50-dB stimuli was significantly less (p = 0.047) in the symptomatic MV group (5.08% +/- 22.32%) than in the symptomatic NVM group (-21.44% +/- 13.50%) or the control group (-26.06% +/- 9.76%). The habituation of IV-V amplitude to 70-dB stimuli in the MV group was significantly less (p = 0.031) during symptomatic testing (-3.43% +/- 8.89%) than during asymptomatic testing (-21.23% +/- 6.41%). CONCLUSIONS: The habituation of IV-V amplitude is reduced during MV attacks. This finding suggests impaired brain stem inhibition at the level of the inferior colliculus, which shares serotonergic connections with the dorsal raphe nucleus, an area hyperactive in migraine.

Nonvestibulocochlear cranial nerve schwannomas.

OPINION STATEMENT: Nonvestibulocochlear cranial nerve schwannomas traditionally have been managed by surgical excision. Although debulking surgery is still considered the first treatment option for larger tumors, stereotactic radiosurgery is now preferred for smaller tumors because of its high tumor control rate and low treatment-related morbidity. Furthermore, an initial period of radiologic and clinical observation following the diagnosis should be strongly considered for smaller tumors because some may not grow or may grow at a slow rate. Medical management of tumor-associated symptoms (when present) should not be ignored. Most importantly, the time has come to embark on the first randomized controlled trials comparing clinical and radiologic observation, surgery, and radiosurgery in the management of cranial nerve schwannomas.

Interferon-beta treatment in multiple sclerosis attenuates inflammatory gene expression through inducible activity of the phosphatase SHP-1.

Interferon-beta is a current treatment for multiple sclerosis (MS). Interferon-beta is thought to exert its therapeutic effects on MS by down-modulating the immune response by multiple potential pathways. Here, we document that treatment of MS patients with interferon beta-1a (Rebif) results in a significant increase in the levels and function of the protein tyrosine phosphatase SHP-1 in PBMCs. SHP-1 is a crucial negative regulator of cytokine signaling, inflammatory gene expression, and CNS demyelination as evidenced in mice deficient in SHP-1. In order to examine the functional significance of SHP-1 induction in MS PBMCs, we analyzed the activity of proinflammatory signaling molecules STAT1, STAT6, and NF-kappaB, which are known SHP-1 targets. Interferon-beta treatment in vivo resulted in decreased NF-kappaB and STAT6 activation and increased STAT1 activation. Further analysis in vitro showed that cultured PBMCs of MS patients and normal subjects had a significant SHP-1 induction following interferon-beta treatment that correlated with decreased NF-kappaB and STAT6 activation. Most importantly, experimental depletion of SHP-1 in cultured PBMCs abolished the anti-inflammatory effects of interferon-beta treatment, indicating that SHP-1 is a predominant mediator of interferon-beta activity. In conclusion, interferon-beta treatment upregulates SHP-1 expression resulting in decreased transcription factor activation and inflammatory gene expression important in MS pathogenesis.

Stereotactic radiosurgery in two cases of presumed fourth cranial nerve schwannoma.

A 47-year-old woman and a 45-year-old man with gradually progressive fourth cranial nerve palsy underwent stereotactic radiosurgery for presumed fourth cranial nerve schwannomas with the gamma knife at a marginal tumor dose of 14 and 13 Gy, respectively. In one patient, the ocular misalignment disappeared; in the other patient, it stabilized. MRI showed shrinkage of the tumors. These patients represent the second and third reported cases of presumed fourth cranial nerve schwannoma treated with radiosurgery and the first cases with substantial follow-up information.

SHP-1 deficiency and increased inflammatory gene expression in PBMCs of multiple sclerosis patients.

Recent studies in mice have demonstrated that the protein tyrosine phosphatase SHP-1 is a crucial negative regulator of cytokine signaling, inflammatory gene expression, and demyelination in central nervous system. The present study investigates a possible similar role for SHP-1 in the human disease multiple sclerosis (MS). The levels of SHP-1 protein and mRNA in PBMCs of MS patients were significantly lower compared to normal subjects. Moreover, promoter II transcripts, expressed from one of two known promoters, were selectively deficient in MS patients. To examine functional consequences of the lower SHP-1 in PBMCs of MS patients, we measured the intracellular levels of phosphorylated STAT6 (pSTAT6). As expected, MS patients had significantly higher levels of pSTAT6. Accordingly, siRNA to SHP-1 effectively increased the levels of pSTAT6 in PBMCs of controls to levels equal to MS patients. Additionally, transduction of PBMCs with a lentiviral vector expressing SHP-1 lowered pSTAT6 levels. Finally, multiple STAT6-responsive inflammatory genes were increased in PBMCs of MS patients relative to PBMCs of normal subjects. Thus, PBMCs of MS patients display a stable deficiency of SHP-1 expression, heightened STAT6 phosphorylation, and an enhanced state of activation relevant to the mechanisms of inflammatory demyelination.

IgG4-related ophthalmic disease.

IgG4-related disease is a fibro-inflammatory condition with tendency to form tumors with inflammatory infiltrate with IgG4 rich plasma cells and elevation of IgG4 level in serum, which may affect virtually every organ and tissue in the organism. IgG4-related ophthalmic disease may present as dacryoadenitis, myositis, other orbital tissues, hypophysitis or pachymeningitis causing cranial neuropathies. The diagnosis of IgG4-related disease is based on a typical clinical scenario, supportive laboratory data, expected radiological characteristics and distinct histopathological and immunohistochemical features. Corticosteroid followed by the use of long-term immunosuppressive therapy is the most commonly attempted treatment.

CSF pressure, papilledema grade, and response to acetazolamide in the Idiopathic Intracranial Hypertension Treatment Trial.

Previous reports suggest an association between the degree of optic nerve head edema and CSF pressure (CSFp) in idiopathic intracranial hypertension (IIH). We hypothesized that CSFp would be associated with Frisén papilledema grade (FPG) and other clinical features, and that FPG would modify the CSFp response to acetazolamide in participants in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). In the IIHTT, eligible patients underwent lumbar puncture (LP) prior to enrollment and were randomly assigned to one of two treatment groups: acetazolamide plus supervised diet or placebo plus supervised diet. Trial eligibility required baseline CSFp ≥250 mm H2O or ≥200 mm H2O with compelling clinical or imaging IIH findings. Associations between CSFp and FPG and other clinical features were examined at baseline. The effect of acetazolamide on 6-month change in CSFp was examined in those with low FPG (grades I-III) and those with high FPG (grades IV-V) at baseline. All 165 enrolled subjects had a baseline LP and 85 had an LP at 6 months. There was an association between CSFp and FPG at baseline: CSFp was more elevated in subjects with high FPG (378 ± 90 mm H2O, n = 50) than in subjects with low FPG (331 ± 77, n = 115, p = 0.002). At 6 months, acetazolamide had a similar effect on CSFp in subjects with high FPG (-79.9 mm H2O) and in subjects with low FPG (-50.9 mm H2O, p = 0.50). We found a modest association between CSFp and FPG. Acetazolamide had a beneficial effect on CSFp regardless of baseline FPG.

Clinical features associated with lesions other than pituitary adenoma in patients with an optic chiasmal syndrome.

PURPOSE: Pituitary adenomas are the most common cause of an optic chiasmal syndrome, and treatment of these lesions is considerably different from the treatment of most of the other lesions in this region. Although the diagnosis of a pituitary adenoma is usually inferred from the results of neuroimaging, lesions other than pituitary adenomas can have an appearance that suggests an adenoma. The objective of our study was to determine whether there are clinical findings that suggest a lesion producing a chiasmal syndrome is something other than a pituitary adenoma. DESIGN: Retrospective, case-controlled, analysis of medical record data. METHODS: The records of the Neuro-Ophthalmology Unit of the Wilmer Eye Institute were searched for patients with a chiasmal syndrome who had been evaluated before treatment and for whom pathologic or laboratory confirmation of the etiology was available. Presenting clinical features of these patients were recorded, and analyses with both a single variable and multiple variables were performed to determine whether there were any features that could identify with a high degree of probability the etiology of the lesion producing the syndrome. RESULTS: The search revealed 149 patients who met the inclusion criteria, including 90 patients with pituitary adenomas and 59 patients with other lesions. Variables that were highly suggestive of an etiology other than pituitary adenoma included symptomatic visual loss, younger age, unilateral optic disk pallor, a relative afferent pupillary defect, and an absolute or a complete visual field defect or one was greater inferiorly than superiorly. CONCLUSION: Although no single clinical feature can be used to determine the specific nature of a lesion that produces an optic chiasmal syndrome, certain features are highly suggestive of an etiology other than pituitary adenoma. When these features are present, the likelihood that a suprasellar lesion is a pituitary adenoma is much lower, regardless of the appearance on neuroimaging.

A randomized, placebo-controlled, crossover clinical trial of super blue-green algae in patients with essential blepharospasm or Meige syndrome.

PURPOSE: To evaluate the effectiveness of super blue-green algae (SBGA) supplements on the severity of essential blepharospasm treated with botulinum toxin A injections. DESIGN: Double-masked, placebo-controlled, two-period, crossover randomized trial. PATIENTS AND METHODS: The study was carried out in patients with essential blepharospasm or Meige syndrome undergoing routine treatment with botulinum toxin A injections. INTERVENTION: Patients were randomly assigned to either SBGA capsules or placebo. After 6 months of treatment, patients underwent a 6-month washout period with no treatment, then were administered the alternate treatment for an additional 6 months, thus serving as their own controls. MAIN OUTCOME MEASURES: Video documentation of blink rate and involuntary facial movements, time between botulinum toxin A injections, and patients' subjective assessment of the impact of blepharospasm on functioning were obtained at the beginning and end of the first and second (crossover) treatment periods. RESULTS: A total of 24 patients (10 men, 14 women; aged 42 to 83 years) completed both treatment periods. Mean within-patient difference in blink rate between SBGA and placebo periods was -2.1 blinks per 2 minutes (95% confidence interval [CI]: -20.8-+31.9), not statistically different from zero (P =.83). Mean within-patient difference in time between injections between SBGA and placebo periods was 4.6 days (95% CI: -13.3-+22.5), not statistically different from zero (P =.62). The lack of statistical significance may have been because of small sample size. There were no significant differences in severity of involuntary movement between SBGA and placebo treatment periods. However, patients were more likely to report limitation in function during the period they took SBGA than during the period they took placebo (odds ratio, 0.2; P =.03). CONCLUSION: Overall, we found no evidence of a beneficial effect of SBGA as an adjunct to botulinum toxin A injections; however, a few patients, all younger than 60 years, did appear to benefit from SBGA.

IgG4-related inflammatory pseudotumor of the central nervous system responsive to mycophenolate mofetil.

Orbital apex and skull base masses often present with neuro-ophthalmic signs and symptoms. Though the localization of these syndromes and visualization of the responsible lesion on imaging is typically straightforward, definitive diagnosis usually relies on biopsy. Immunohistochemistry is important for categorization and treatment planning. IgG4-related disease is emerging as a pathologically defined inflammatory process that can occur in multiple organ systems. We present two patients with extensive inflammatory mass lesions of the central nervous system with immunohistochemistry positive for IgG4 and negative for ALK-1 as examples of meningeal based IgG4-related inflammatory pseudotumors. In both patients, there was treatment response to mycophenolate mofetil.

Quantitative differences in the immunomodulatory effects of Rebif and Avonex in IFN-ß 1a treated multiple sclerosis patients.

Interferon-ß (IFN-ß) is a current effective treatment for multiple sclerosis (MS) and exerts its therapeutic effects by down-modulating the systemic immune response and cytokine signaling. In clinical practice there are several formulations of interferon including a low dose of IFN-ß 1a formulation of 30 µg IM once weekly (Avonex) and a high dose formulation of 44 µg SC three times weekly (Rebif). Recent studies suggest that Rebif is more efficacious compared to Avonex in preventing relapses and decreasing MRI activity in relapsing remitting MS (RRMS) patients. This study examines whether there are quantitative gene expression changes in interferon-treated RRMS patients that can explain the difference in efficacy and side effects between Rebif and Avonex. Herein, RRMS patients were treated for three months with IFN-ß 1a and the levels of plasma cytokines and gene expression in peripheral blood mononuclear cells were examined. Thirty-two normal subjects were compared to thirty-two RRMS patients, of which ten were treated with Rebif and ten with Avonex. Rebif and Avonex both significantly and equally suppressed plasma TNF-α and IL-6 levels. Rebif suppressed IL-13 significantly more than Avonex. Rebif also significantly suppressed the levels of the chemokines CCL17 and RANTES, the protease ADAM8, and COX-2 at a higher degree compared to Avonex. The STAT1-inducible genes IP-10 and caspase 1 were significantly increased with Rebif compared to Avonex. In conclusion, the higher dosed, more frequently administered IFN-ß 1a Rebif when compared to IFN-ß 1a Avonex has more potent immunomodulatory effects. These quantitative results might relate to efficacy and side-effect profile of the two IFN-ß 1a formulations and provide prospective practical clinical tools to monitor treatment and adjust dosage.

Late onset optic neuropathy in methylmalonic and propionic acidemia.

PURPOSE: To describe 3 cases of late-onset bilateral optic neuropathy with visual dysfunction in patients with organic acidemia. DESIGN: Retrospective case series. METHODS: A total of 3 subjects, a 16-year-old male with methylmalonic acidemia (MMA), a 21-year-old male with MMA, and a 20-year-old female with propionic acidemia (PA), are included in this series. Comparison of the patients' clinical course, ophthalmologic exam, and testing are discussed. The outcome measures include visual acuity (VA), fundus appearance, visual fields, brain imaging, and genetic testing. RESULTS: All 3 subjects had late-onset severe bilateral VA loss with bilateral optic nerve pallor, central or cecocentral scotomas on visual field testing, and negative diagnostic workups for other causes of bilateral optic neuropathy. CONCLUSIONS: Patients with organic acidemia may develop late-onset bilateral optic neuropathy with visual dysfunction despite lifelong propiogenic amino acid restriction and dietary supplementation.

Ophthalmoplegia, proptosis, and lid retraction caused by cranial nerve hypertrophy in chronic inflammatory demyelinating polyradiculoneuropathy.

A 53-year-old woman with long-standing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) developed progressive proptosis, lid retraction, and ophthalmoplegia. MRI showed enlarged, enhancing cranial nerves that initially gave rise to diagnostic confusion with Graves disease or orbitocavernous mass lesions. This report further documents that CIDP may cause hypertrophy of ocular motor and trigeminal nerves with imaging features that suggest alternative causes.