Prospective longitudinal study on prognostic factors of visual recovery and structural change after a first episode of optic neuritis.

BACKGROUND AND PURPOSE: This study was undertaken to determine the role of optical coherence tomography (OCT) in predicting the final visual and structural outcome, and to evaluate the correlation between functional eye outcome and retinal changes, in patients with a first episode of optic neuritis (ON). METHODS: In this prospective study, consecutive adult patients with acute ON underwent ophthalmological evaluation at baseline and at 1 and 12 months, including OCT measurements of peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell and inner plexiform layer, and inner nuclear layer thicknesses; high- and low-contrast visual acuity; visual field assessment; and baseline brain magnetic resonance imaging. Univariate and multivariate linear regressions were used to assess predictive factors of outcome. Correlations between 12-month visual function and retinal structure were estimated by Spearman coefficients. Two groups of patients were analyzed, with or without multiple sclerosis (MS). RESULTS: Among 116 patients, 79 (68.1%) had MS, and 37 (31.9%) had ON not related to MS (including 19 idiopathic [i.e., isolated] ON, and 13 and five with myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies, respectively). We found no independent predictive factor of visual and retinal outcome. Analysis of the relationship between the visual field test (mean deviation) and pRNFL thickness demonstrated a threshold of 75.4 µm and 66.4 µm, below which the mean deviation was worse, for patients with MS (p = 0.007) and without MS (p < 0.001), respectively. CONCLUSIONS: We found that inner retinal layer measurements during the first month are not predictive of final outcome. The critical threshold of axonal integrity, below which visual function is damaged, is different between patients with and without MS.

Vascular origin in acute transient visual disturbance: A prospective study.

BACKGROUND AND PURPOSE: This study was undertaken to validate a clinical score of vascular origin in patients with acute transient visual disturbances (TVDs) without diplopia. METHODS: We conducted a prospective study in an ophthalmology emergency department and a transient ischemic attack (TIA) clinic. Patients underwent clinical evaluation including a tailored questionnaire, brain, vascular, and ophthalmologic investigations, and 3-month follow-up. TVDs were classified according to vascular or nonvascular origin by three independent experts based on all clinical, cerebrovascular, and ophthalmologic investigations, but blind to the questionnaire results. A clinical score was derived based on clinical variables independently associated with a vascular origin, and was externally validated in an independent cohort. RESULTS: An ischemic origin of TVD was found in 45% (67/149) of patients in the derivation cohort. Age and six questions were independently associated with an ischemic origin. A nine-point score (≥70 years old = 2; monocular visual loss = 2; black or white vision = 1; single episode = 1; lack of headache = 2; diffuse, constricted, altitudinal, or lateralized visual loss pattern on drawings = 1) showed good discriminative power in identifying ischemic origin (c-statistic = 0.82) and was replicated in the validation cohort (n = 130, 25% of ischemic origin, c-statistic = 0.75). With a score ≥ 4, sensitivity was 85% (95% confidence interval = 68-95) and specificity was 52% (95% confidence interval = 41-62). In both cohorts, ophthalmologic evaluation found a vascular cause in 4% and was noncontributive in 85%. After 3 months, no patients had a stroke, TIA, or retinal infarct. CONCLUSIONS: Our score may assist in predicting a vascular origin of TVD. Ophthalmologic evaluation, when not readily available, should not delay the neurovascular evaluation.

Prediction of Postoperative Risk of Raised Intracranial Pressure After Spontaneous Skull Base Cerebrospinal Fluid Leak Repair.

BACKGROUND: A relationship between idiopathic intracranial hypertension and spontaneous skull base cerebrospinal fluid (CSF) leaks has been proposed, by which CSF leak decreases intracranial pressure (ICP) and masks the symptoms and signs of elevated ICP. These patients are at risk of developing papilledema, symptoms of elevated ICP, or a recurrent CSF leak after CSF leak repair. The objective of this study was to assess whether radiographic signs of raised ICP on preoperative magnetic resonance or computed venography (MRI or CTV) are predictors of postoperative papilledema, recurrence of CSF leak, or need for CSF shunt surgery. METHODS: We performed a retrospective review of systematically collected demographics, fundus examination, and presurgical brain MRI and magnetic resonance venography/computed tomography venography (MRV/CTV) in patients seen at 1 institution between 2013 and 2019 with spontaneous skull base CSF leak repair. Patients were divided into 2 groups depending on whether they developed papilledema, recurrent CSF leak, or required CSF shunting (Group 1) or not (Group 2). RESULTS: Fifty-seven patients were included, among whom 19 were in Group 1. There was no difference in demographic characteristics or clinical features between patients in Group 1 and Group 2. Controlling for other imaging features, bilateral transverse venous sinus stenosis (TVSS) on preoperative imaging increased the odds of being in Group 1 by 4.2 times (95% confidence interval [CI], 1.04-21.2, P = 0.04), optic nerve tortuosity decreased the odds of being in Group 1 by 8.3 times (95% CI: 1.4-74.6, P = 0.02). CONCLUSION: Imaging of the intracranial venous system with MRV or CTV is warranted before repair of spontaneous CSF leak, as bilateral TVSS is an independent risk factor for postoperative papilledema, CSF leak recurrence, or need for a CSF shunting procedure.

Self-Reported Weight and Height Among Idiopathic Intracranial Hypertension Patients.

BACKGROUND: Idiopathic intracranial hypertension (IIH) mostly affects overweight and obese women. Severe obesity is associated with poorer visual outcomes in IIH, and weight gain can precipitate IIH and increase the risk of recurrence. Conversely, weight loss can decrease intracranial pressure and is an effective IIH treatment. Therefore, accurate monitoring of weight and body mass index (BMI) is important to help guide the management of IIH patients. Our goal was to compare estimated and measured BMI among patients with presumed IIH and non-IIH controls to determine whether these vital signs should be systematically measured when evaluating patients for IIH. METHODS: A retrospective chart review was performed of consecutive patients with reported and measured weight and height seen in one ophthalmology-based neuro-ophthalmology clinic for IIH between January 2, 2018 and September 10, 2018. Patients with IIH or presumed IIH were compared to non-IIH controls, matched according to age (±5 years), BMI (±5 kg/m unless ≥40 kg/m), sex, and race. Patients with confirmed IIH were asked to self-report their weight when seen in follow-up and they were weighed to compare their self-reported vs measured percent weight change. RESULTS: We included 379 subjects (140 patients; 239 controls) among whom 75 of the IIH patients were matched to non-IIH controls. Patients with presumed or definite IIH accurately estimated their height and generally underestimated their weight by a median of 1.8 kg (4 lb), resulting in a median BMI underestimate of 0.9 kg/m. There was no difference in BMI underestimation when comparing presumed or definite IIH patients to matched non-IIH controls while controlling for insurance status, smoking, diabetes, and vascular disease (P = 0.66). As BMI increased, all subjects underestimated their BMI more (by 0.9% per 10 measured BMI unit increase), when controlling for age, sex, and race (P < 0.003). Sixteen confirmed IIH patients were seen in follow-up. At initial neuro-ophthalmology consultation, these subjects underestimated their weight by a mean of 3.2%. At last follow-up they underestimated their weight by only 1.2% (P = 0.03). CONCLUSIONS: There was no evidence that IIH or presumed IIH patients had a different perception of their weight than non-IIH controls at initial neuro-ophthalmology consultation. Both patients and matched controls tended to underestimate their weight by the same amount, resulting in an overall BMI underestimation of approximately 1% per 10 measured BMI unit increase. Heavier subjects tended to underestimate their body weight and resultant BMI more, and IIH patients tended to estimate their weight more accurately at follow-up. Our results emphasize the need to systematically objectively measure the weight of presumed IIH patients seen in an ophthalmology clinic.

Do Most Patients With a Spontaneous Cerebrospinal Fluid Leak Have Idiopathic Intracranial Hypertension?

BACKGROUND: The association between cerebrospinal fluid (CSF) leaks at the skull base and raised intracranial pressure (ICP) has been reported since the 1960s. It has been suggested that spontaneous CSF leaks might represent a variant of idiopathic intracranial hypertension (IIH). We review the evidence regarding the association between spontaneous CSF leaks and IIH, and the role of ICP in the pathophysiology of nontraumatic skull base defects. We also discuss the management of ICP in the setting of CSF leaks and IIH. EVIDENCE ACQUISITION: References were identified by searches of PubMed from 1955 to September 2018 with the terms "idiopathic intracranial hypertension" and "cerebrospinal fluid leak." Additional references were identified using the terms "pseudotumor cerebri," "intracranial hypertension," "benign intracranial hypertension," and by hand search of relevant articles. RESULTS: A CSF leak entails the egress of CSF from the subarachnoid spaces of the skull base into the surrounding cavitary structures. Striking overlaps exist regarding demographic, clinical, and radiological characteristics between IIH patients and those with spontaneous CSF leaks, suggesting that some (if not most) of these patients have IIH. However, determining whether a patient with spontaneous CSF leak may have IIH may be difficult, as signs and symptoms of raised ICP may be obviated by the leak. The pathophysiology is unknown but might stem from progressive erosion of the thin bone of the skull base by persistent pulsatile high CSF pressure. Currently, there is no consensus regarding the management of ICP after spontaneous CSF leak repair when IIH is suspected. CONCLUSIONS: IIH is becoming more widely recognized as a cause of spontaneous CSF leaks, but the causal relationship remains poorly characterized. Systematic evaluation and follow-up of patients with spontaneous CSF leaks by neuro-ophthalmologists will help clarify the relation between IIH and spontaneous CSF leaks.

Nonmydriatic Fundus Photography in Patients with Acute Vision Loss.

Background:Acute visual loss is a common chief complaint in emergency department (ED) patients, but the scarcity of ophthalmologists in most EDs limits its evaluation.Introduction:Our objective was to evaluate whether nonmydriatic fundus photography (NMFP) in the ED helps triage patients with acute visual loss.Materials and Methods:We included 213 patients with acute visual loss evaluated in the ED with NMFP as part of the Fundus Photography versus Ophthalmoscopy Trial Outcomes in the ED studies. Demographics, referral patterns, results of NMFP, and final diagnoses were recorded.Results:A final ophthalmological diagnosis was made in 109/213 (51%) patients. NMFP allowed a definite diagnosis in 51/109 (47%) patients: 14 nonglaucomatous optic neuropathies, 10 papilledema, 13 acute retinal ischemia, 2 retinal detachments, 2 choroidal metastases, 4 maculopathies, and 6 glaucoma. In 58/109 (53%) patients, NMFP was not diagnostic even when interpreted remotely by ophthalmologists due to disorders undiagnosable with NMFP. Ophthalmology consultation was requested in 109/213 (51%) patients, 41/54 (76%) patients with abnormal NMFP versus 68/159 (43%) patients with normal NMPF (p < 0.001).Discussion:Although NMFP allowed rapid diagnosis in 51/213 (24%) patients presenting to the ED with acute visual loss, NMFP alone was not sufficient to detect all ocular diseases; ophthalmology consultation was more often requested when NMFP was abnormal.Conclusions:Our study emphasizes the limitations of teleophthalmology with NMFP in remotely detecting ocular diseases related to acute visual loss in the ED. NMFP helped triage and referral decisions and can be used to complement ophthalmology consultations in the ED.

A Puzzling Ocular Motility Disorder: Apparent Up-Gaze Fatigability in a Patient With Oculomotor Nerve Compression.

We report the case of a woman who developed right third nerve dysfunction with synkinesis and ocular neuromyotonia secondary to a compressive arterial aneurysm. Surprisingly, our examination showed a downward drift of the right eye in sustained up-gaze resulting in transient hypotropia, suggesting either fatigability of the superior rectus or contraction of the inferior rectus. We believe this ocular motility pattern is secondary to a co-contraction of the inferior rectus in up-gaze caused by synkinesis (explaining the downward drift), followed by failure of the inferior rectus to relax upon return to primary position caused by ocular neuromyotonia (explaining the hypotropia).

Fundus Photography vs. Ophthalmoscopy Outcomes in the Emergency Department (FOTO-ED) Phase III: Web-based, In-service Training of Emergency Providers.

We evaluated a web-based training aimed at improving the review of fundus photography by emergency providers. 587 patients were included, 12.6% with relevant abnormalities. Emergency providers spent 31 minutes (median) training and evaluated 359 patients. Median post-test score improvement was 6 percentage points (IQR: 2-14; p = 0.06). Pre- vs. post-training, the emergency providers reviewed 45% vs. 43% of photographs; correctly identified abnormals in 67% vs. 57% of cases; and correctly identified normals in 80% vs. 84%. The Fundus photography vs. Ophthalmoscopy Trial Outcomes in the Emergency Department studies have demonstrated that emergency providers perform substantially better with fundus photography than direct ophthalmoscopy, but our web-based, in-service training did not result in further improvements at our institution.

Pitfalls in the Use of Stereoacuity in the Diagnosis of Nonorganic Visual Loss.

PURPOSE: The Titmus Stereotest (Stereo Optical Co., Inc., Chicago, IL) has been used to estimate visual acuity (VA) in the evaluation of nonorganic visual loss. Previous predictions were derived from optical degradation of VA in normal subjects and may not account for the variability seen in patients with neuro-ophthalmic pathologies included in the differential diagnosis of nonorganic visual loss. The purpose of this study was to evaluate the relationship between Titmus stereoacuity and minimal VA based on a real-world testing environment. DESIGN: Cross-sectional observational study. PARTICIPANTS: All patients treated at the authors' neuro-ophthalmology service between April 25, 2014, and July 31, 2014. METHODS: All subjects underwent routine neuro-ophthalmic examination, including Titmus stereoacuity measurements. A compound Bayesian logit-lognormal model accounting for heteroscedasticity was used to determine 95% and 99% prediction intervals of the worse eye's near VA based on stereoacuity. Logarithm of the minimum angle of resolution VA and log stereoacuity were analyzed. MAIN OUTCOME MEASURES: Titmus stereoacuity and worse eye VA. RESULTS: Of 561 patients, 364 subjects 11 to 91 years of age were included. Titmus stereoacuity was associated positively with VA: 9 circles correct (40 seconds of arc) indicated VA of at least 20/40 with 95% confidence and VA of at least 20/79 with 99% confidence; 6 circles correct (80 seconds of arc) indicated VA of at least 20/62 and 20/180, respectively; and 4 circles correct (140 seconds of arc) indicated VA of at least 20/110 and 20/570, respectively. CONCLUSIONS: When fully accounting for individual variation and the full spectrum of neuro-ophthalmic diseases affecting VA, stereoacuity remains associated with VA, but previous commonly used VA estimates based on stereoacuity overestimated VA. Our results more accurately predict minimum VA from Titmus stereoacuity and should be used preferentially when evaluating patients with suspected nonorganic visual loss. We demonstrated that Titmus stereoacuity cannot definitively establish normal VA, and therefore can suggest, but not fully establish, the diagnosis of nonorganic visual loss.

The Optic Canal Size Is Associated With the Severity of Papilledema and Poor Visual Function in Idiopathic Intracranial Hypertension.

BACKGROUND: To determine whether the size of the bony optic canal is associated with the severity of papilledema and poor visual function in idiopathic intracranial hypertension (IIH). METHODS: We performed a retrospective review of definite patients with IIH with requisite brain magnetic resonance imaging allowing for optic canal measurement. Clinical characteristics and automated (Humphrey) visual field results were reviewed; papilledema was graded according to the modified Frisén scale. Cross-sectional area of the optic canals was measured independently by 2 readers and averaged for each canal. Logistic regression modeling was applied. RESULTS: Sixty-nine patients with IIH were included (mean age: 33; 91% women; 65% black). Controlling for age, sex, body mass index, race, and cerebrospinal fluid (CSF) opening pressure, each mm increase in canal size was associated with a 0.50 dB reduction in Humphrey visual field mean deviation (P = 0.006); this was likely mediated by the increased odds of Grade 4-5 papilledema or optic atrophy in patients with larger canals (odds ratio: 1.30 [95% CI: 1.10-1.55; P = 0.003] for Grade 4-5 papilledema or atrophy vs grade <4 papilledema per mm increase in canal size). CONCLUSIONS: Poor visual function and severe papilledema or optic atrophy were associated with a larger optic canal. Potential mechanisms include alteration of local CSF flow or bony remodeling at the optic canals.

Update on the Diagnosis and Treatment of Idiopathic Intracranial Hypertension.

Idiopathic intracranial hypertension (IIH) is a rare disorder occurring more frequently in obese women of childbearing age, resulting in increased intracranial pressure (ICP) from an unknown cause. Recent advances in epidemiology, imaging, and treatment have provided a better understanding of IIH in recent years, with better identification of visual risk factors and atypical forms of IIH, including fulminant IIH and spontaneous cerebrospinal fluid leaks, and a randomized clinical trial providing the rationale for the use of acetazolamide. In addition, a revised version of the modified Dandy criteria for the diagnosis of IIH was suggested in 2013, with better definition of IIH in adults and children; however, controversy regarding nomenclature has precluded its acceptance among IIH experts. Finally, questions regarding the best surgical strategy, the indications for venous sinus stenting, and the diagnostic role of the radiologic findings commonly seen in IIH have remained unanswered.

Asymmetric papilledema in idiopathic intracranial hypertension.

BACKGROUND: Very asymmetric papilledema in idiopathic intracranial hypertension (IIH) is rare, and few studies have dealt with this atypical presentation of IIH. Our aim was to describe the clinical and radiologic features of patients with IIH and very asymmetric papilledema. METHODS: We identified all adult patients from our IIH database with very asymmetric papilledema defined as a ≥2 modified Frisén grade difference between the 2 eyes. Demographic data and initial symptoms were collected, and all brain imaging studies performed at our institution were reviewed. RESULTS: Of the 559 adult patients with definite IIH, 20 (3.6%; 95% confidence interval [CI], 2.3-5.6) had very asymmetric papilledema at initial evaluation. They were older (39 vs 30 years; P < 0.001), had lower cerebrospinal opening pressure (35.5 vs 36 cm of water; P = 0.03), and were more likely to be asymptomatic compared with patients with symmetric papilledema (27% vs 3%; P < 0.001). Visual fields were worse on the side of the highest-grade papilledema (P = 0.02). The bony optic canal was smaller on the side of the lowest-grade edema in all 8 patients (100%) in whom the imaging was sufficient for reliable measurements (P = 0.008). CONCLUSIONS: IIH with very asymmetric papilledema is uncommon. Very asymmetric papilledema may result from differences in size of the bony optic canals, supporting the concept of compartmentation of the perioptic subarachnoid spaces.

Brain Imaging in Idiopathic Intracranial Hypertension.

BACKGROUND: The primary role of brain imaging in idiopathic intracranial hypertension (IIH) is to exclude other pathologies causing intracranial hypertension. However, subtle radiologic findings suggestive of IIH have emerged with modern neuroimaging. This review provides a detailed description of the imaging findings reported in IIH and discusses their possible roles in the pathophysiology and the diagnosis of IIH. EVIDENCE ACQUISITION: References were identified by searches of PubMed from 1955 to January 2015, with the terms "idiopathic intracranial hypertension," "pseudotumor cerebri," "intracranial hypertension," "benign intracranial hypertension," "magnetic resonance imaging," "magnetic resonance venography," "computed tomography (CT)," "CT venography," "imaging," and "cerebrospinal fluid (CSF) leak." Additional references were identified by hand search of relevant articles. When possible, we extracted the number of patients and control subjects from each study for each radiological finding. When at least 2 studies used the same criteria to define a radiological finding, all patients from these studies were pooled to obtain a mean sensitivity and specificity with 95% confidence interval. RESULTS: Specific neuroimaging findings may suggest long-standing IIH, including empty sella, flattening of the posterior globes, optic nerve head protrusion, distention of the optic nerve sheaths, tortuosity of the optic nerve, cerebellar tonsillar herniation, meningoceles, CSF leaks, and transverse venous sinus stenosis. CONCLUSION: Although IIH remains a diagnosis of exclusion, the most recently proposed diagnostic criteria have included neuroimaging findings to suggest IIH when major diagnostic criteria are not fulfilled. However, these findings are not diagnostic of IIH, and their presence is not required for the diagnosis of definite IIH. Their incidental discovery on brain imaging should not prompt invasive procedures, unless other signs of IIH, such as papilledema, are present.

Noninvasive Papillary Urothelial Carcinoma of the Bladder: An Institutional Experience Focusing on Tumors With Borderline Features.

CONTEXT.­: Noninvasive papillary urothelial carcinomas (PUCs) comprise most urinary bladder tumors. Distinction between low-grade (LG-PUC) and high-grade (HG-PUC) PUCs is pivotal for determining prognosis and subsequent treatment. OBJECTIVE.­: To investigate the histologic characteristics of tumors with borderline features between LG-PUC and HG-PUC, focusing on the risk of recurrence and progression. DESIGN.­: We reviewed the clinicopathologic parameters of noninvasive PUC. Tumors with borderline features were subcategorized as follows: tumors that look like LG-PUC but have occasional pleomorphic nuclei (1-BORD-NUP) or elevated mitotic count (2-BORD-MIT), and tumors with side-by-side distinct LG-PUC and less than 50% HG-PUC (3-BORD-MIXED). Recurrence-free, total progression-free, and specific invasion-free survival curves were derived from the Kaplan-Meier method, and Cox regression analysis was performed. RESULTS.­: A total of 138 patients with noninvasive PUC were included, with the following distribution: LG-PUC (n = 52; 38%), HG-PUC (n = 34; 25%), BORD-NUP (n = 21; 15%), BORD-MIT (n = 14; 10%), and BORD-MIXED (n = 17; 12%). Median (interquartile range) follow-up was 44.2 months (29.9-73.1 months). Invasion-free survival was different between the 5 groups (P = .004), and pairwise comparison showed that HG-PUC had a worse prognosis compared with LG-PUC (P ≤ .001). On univariate Cox analysis, HG-PUC and BORD-NUP were 10.5 times (95% CI, 2.3-48.3; P = .003) and 5.9 times (95% CI, 1.1-31.9; P = .04) more likely to invade, respectively, when compared to LG-PUC. CONCLUSIONS.­: Our findings confirm a continuous spectrum of histologic changes in PUC. Approximately a third of noninvasive PUCs show borderline features between LG-PUC and HG-PUC. Compared with LG-PUC, BORD-NUP and HG-PUC were more likely to invade on follow-up. BORD-MIXED tumors did not statistically behave differently from LG-PUC.

Genetic Profiling of African American Patients With Prostatic Adenocarcinoma Metastatic to the Lymph Nodes: A Pilot Study.

CONTEXT.­: Genetic profiling data of prostatic adenocarcinoma are derived from predominantly White patients. In African Americans, prostatic adenocarcinoma has a poorer prognosis, raising the possibility of distinct genetic alterations. OBJECTIVE.­: To investigate the genomic alterations of prostatic adenocarcinoma metastatic to regional lymph nodes in African American patients, with an emphasis on SPOP mutation. DESIGN.­: We retrospectively reviewed African American patients with pN1 prostatic adenocarcinoma managed with radical prostatectomy and lymph node dissection. Comprehensive molecular profiling was performed, and androgen receptor signaling scores were calculated. RESULTS.­: Nineteen patients were included. The most frequent genetic alteration was SPOP mutations (5 of 17; 29.4% [95% CI: 10.3-56.0]). While most alterations were associated with a high androgen receptor signaling score, mutant SPOP was exclusively associated with a low median and interquartile range (IQR) androgen receptor signaling score (0.788 [IQR 0.765-0.791] versus 0.835 [IQR 0.828-0.842], P = .003). In mutant SPOP, mRNA expression of SPOP inhibitor G3BP1 and SPOP substrates showed a significantly decreased expression of AR (33.40 [IQR 28.45-36.30] versus 59.53 [IQR 53.10-72.83], P = .01), TRIM24 (3.95 [IQR 3.28-5.03] versus 9.80 [IQR 7.39-11.70], P = .008), and NCOA3 (15.19 [IQR 10.59-15.93] versus 21.88 [IQR 18.41-28.33], P = .046). CONCLUSIONS.­: African American patients with metastatic prostate adenocarcinoma might have a higher prevalence of mutant SPOP (30%), compared to ∼10% in unselected cohorts with lower expressions of SPOP substrates. In our study, in patients with mutant SPOP, the mutation was associated with decreased SPOP substrate expression and androgen receptor signaling, raising concern for suboptimal efficacy of androgen deprivation therapy in this subset of patients.

Functional characterization of a novel c.614-622del rhodopsin mutation in a French pedigree with retinitis pigmentosa.

PURPOSE: To identify and functionally characterize the mutation responsible for autosomal dominant retinitis pigmentosa (adRP) in a large, six-generation French family. METHODS: Twenty individuals from this family participated in the genetic investigation. Six affected and 14 unaffected individuals from three-generations were available for linkage analysis using microsatellite markers flanking the rhodopsin (RHO) gene. A two-point logarithm of odds (LOD) score calculation was undertaken using GENEMARKER and MLINK software. Sanger sequencing of RHO was performed. Cellular localization of the mutant protein was performed by transforming SK-N-SH cells with pEGFP-N1-Rho, pEGFP-N1-Rho(P23H), and pEGFP-N1-Rho(c.614-622del). RESULTS: The proband had nyctalopia, visual field constriction, peripheral bone spicule pigmentation of the fundus, central acuity (6/24 RE; 6/12 LE) at 55 years of age. Linkage analysis of this family suggested RHO as a possible candidate since the flanking marker D3S1292 yielded a LOD score of 2.43 at θ=0. Cloning of an exon 3 PCR product and direct sequencing of single clones identified a novel deletion in the third exon of RHO, c.614-622del (p.Y206-F208del). The deleted mutant protein localized to the endoplasmic reticulum and formed inclusion bodies. CONCLUSIONS: This novel deletion in exon 3 of the RHO gene, c.614-622del results in a classical form of adRP in a multi-generation French family. Protein expression analyses confirmed that the deletion led to protein misfolding and suggest this is a class II mutation, similar to P23H, the most common class II mutation seen in North America.

Risk Stratification of Prostatic Adenocarcinoma Metastatic to the Lymph Nodes.

CONTEXT.­: The pathologic nodal staging of prostatic adenocarcinoma is binary for regional lymph nodes. Stages pN0 and pN1 indicate the absence or presence of regional nodal metastasis, respectively, whereas patients with metastasis to nonregional lymph nodes are staged as pM1a. OBJECTIVE.­: To determine the risk of recurrence of pN1 prostatic adenocarcinoma patients based on the extent of nodal tumor burden. DESIGN.­: We retrospectively reviewed pN1 patients with prostatic adenocarcinoma managed with radical prostatectomy seen between 2011 and 2019. Kaplan-Meier and Cox regression analyses were performed to compare disease-free survival. RESULTS.­: Ninety-six patients were included (median [interquartile range] age, 62 years [57-67 years]; 70 of 96 [73%] White). On univariate analysis, age >65 years (P = .008), ≥2 positive regional lymph nodes (P < .001), and a maximum size of the tumor deposit ≥2 mm (P = .004) were significantly associated with an unfavorable outcome. Controlling for age, stage, metastatic deposit size, margin status, and the presence of extranodal extension, patients with ≥2 positive regional lymph nodes were 3.03 times more likely (95% confidence interval, 1.39-6.60; P = .005) to have an unfavorable outcome. Patients with pN1M1a stage showed a disease-free survival similar to that of pN1M0 patients, after controlling for the number of positive regional lymph nodes (P = .36). CONCLUSIONS.­: Overall, pN1 patients with ≥2 positive regional lymph nodes are 3 times more likely to have an unfavorable outcome. The results suggest a benefit in further stratifying patients with metastatic prostatic adenocarcinoma to the lymph nodes into prognostically significant risk categories that could help the treating clinicians tailor subsequent patient follow-up and therapy.

Delayed diagnosis of cranial neuropathies from perineural spread of skin cancer.

Perineural spread (PNS) to cranial nerves (CNs) by cutaneous malignancies is difficult to diagnose given the indolent course and often late or absent findings on brain imaging. A 68-year-old white man with multiple cranial neuropathies secondary to PNS by squamous cell carcinoma had negative high-quality neuroimaging for 5.25 years. He first developed left facial numbness, followed 39 months later by a left CN VI palsy. Subsequent examinations over 2 years showed involvement of left seventh, right trigeminal V1-V3, and right sixth, and bilateral third nerve palsies. Repeat high-quality brain magnetic resonance imaging (MRIs) during this time showed no identifiable CNs abnormality. Full body positron emission tomography imaging and cerebrospinal fluid studies were normal. 5.25 years after initial sensory symptom onset, MRI showed new enhancement along the right mandibular branch of the trigeminal nerve with foramen ovale widening. Autopsy showed squamous cell carcinoma within both CNs sixth. A long interval to diagnosis of PNS is associated with high morbidity, emphasizing the need for earlier methods of detection when clinical suspicion is high.