Madhura A. Tamhankar

Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis

Objective: Varicella-zoster virus (VZV) infection may trigger the inflammatory cascade that characterizes giant cell arteritis (GCA). Methods: Formalin-fixed, paraffin-embedded GCA-positive temporal artery (TA) biopsies (50 sections/TA) including adjacent skeletal muscle and normal TAs obtained postmortem from subjects >50 years of age were examined by immunohistochemistry for presence and distribution of VZV antigen and by ultrastructural examination for virions. Adjacent regions were examined by hematoxylin & eosin staining. VZV antigen–positive slides were analyzed by PCR for VZV DNA. Results: VZV antigen was found in 61/82 (74%) GCA-positive TAs compared with 1/13 (8%) normal TAs (p < 0.0001, relative risk 9.67, 95% confidence interval 1.46, 63.69). Most GCA-positive TAs contained viral antigen in skip areas. VZV antigen was present mostly in adventitia, followed by media and intima. VZV antigen was found in 12/32 (38%) skeletal muscles adjacent to VZV antigen–positive TAs. Despite formalin fixation, VZV DNA was detected in 18/45 (40%) GCA-positive VZV antigen–positive TAs, in 6/10 (60%) VZV antigen–positive skeletal muscles, and in one VZV antigen–positive normal TA. Varicella-zoster virions were found in a GCA-positive TA. In sections adjacent to those containing VZV, GCA pathology was seen in 89% of GCA-positive TAs but in none of 18 adjacent sections from normal TAs. Conclusions: Most GCA-positive TAs contained VZV in skip areas that correlated with adjacent GCA pathology, supporting the hypothesis that VZV triggers GCA immunopathology. Antiviral treatment may confer additional benefit to patients with GCA treated with corticosteroids, although the optimal antiviral regimen remains to be determined.

Isolated Third, Fourth and Sixth Cranial Nerve Palsies From Presumed Microvascular Versus Other Causes: A Prospective Study

PURPOSE To estimate the proportion of patients presenting with isolated third, fourth, or sixth cranial nerve palsy of presumed microvascular origin versus other causes. DESIGN Prospective, multicenter, observational case series. PARTICIPANTS A total of 109 patients aged 50 years or older with acute isolated ocular motor nerve palsy. TESTING Magnetic resonance imaging (MRI) of the brain. MAIN OUTCOME MEASURES Causes of acute isolated ocular motor nerve palsy (presumed microvascular or other) as determined with early MRI and clinical assessment. RESULTS Among 109 patients enrolled in the study, 22 had cranial nerve III palsy, 25 had cranial nerve IV palsy, and 62 had cranial nerve VI palsy. A cause other than presumed microvascular ischemia was identified in 18 patients (16.5%; 95% confidence interval, 10.7-24.6). The presence of 1 or more vasculopathic risk factors (diabetes, hypertension, hypercholesterolemia, coronary artery disease, myocardial infarction, stroke, and smoking) was significantly associated with a presumed microvascular cause (P = 0.003, Fisher exact test). Vasculopathic risk factors were also present in 61% of patients (11/18) with other causes. In the group of patients who had vasculopathic risk factors only, with no other significant medical condition, 10% of patients (8/80) were found to have other causes, including midbrain infarction, neoplasms, inflammation, pituitary apoplexy, and giant cell arteritis (GCA). By excluding patients with third cranial nerve palsies and those with GCA, the incidence of other causes for isolated fourth and sixth cranial nerve palsies was 4.7% (3/64). CONCLUSIONS In our series of patients with acute isolated ocular motor nerve palsies, a substantial proportion of patients had other causes, including neoplasm, GCA, and brain stem infarction. Brain MRI and laboratory workup have a role in the initial evaluation of older patients with isolated acute ocular motor nerve palsies regardless of whether vascular risk factors are present.

Analysis of Varicella-Zoster Virus in Temporal Arteries Biopsy Positive and Negative for Giant Cell Arteritis

IMPORTANCE Giant cell arteritis (GCA) is the most common systemic vasculitis in elderly individuals. Diagnosis is confirmed by temporal artery (TA) biopsy, although biopsy results are often negative. Despite the use of corticosteroids, disease may progress. Identification of causal agents will improve outcomes. Biopsy-positive GCA is associated with TA infection by varicella-zoster virus (VZV). OBJECTIVE To analyze VZV infection in TAs of patients with clinically suspected GCA whose TAs were histopathologically negative and in normal TAs removed post mortem from age-matched individuals. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study for VZV antigen was performed from January 2013 to March 2015 using archived, deidentified, formalin-fixed, paraffin-embedded GCA-negative, GCA-positive, and normal TAs (50 sections/TA) collected during the past 30 years. Regions adjacent to those containing VZV were examined by hematoxylin-eosin staining. Immunohistochemistry identified inflammatory cells and cell types around nerve bundles containing VZV. A combination of 17 tertiary referral centers and private practices worldwide contributed archived TAs from individuals older than 50 years. MAIN OUTCOMES AND MEASURES Presence and distribution of VZV antigen in TAs and histopathological changes in sections adjacent to those containing VZV were confirmed by 2 independent readers. RESULTS Varicella-zoster virus antigen was found in 45 of 70 GCA-negative TAs (64%), compared with 11 of 49 normal TAs (22%) (relative risk [RR] = 2.86; 95% CI, 1.75-5.31; P < .001). Extension of our earlier study revealed VZV antigen in 68 of 93 GCA-positive TAs (73%), compared with 11 of 49 normal TAs (22%) (RR = 3.26; 95% CI, 2.03-5.98; P < .001). Compared with normal TAs, VZV antigen was more likely to be present in the adventitia of both GCA-negative TAs (RR = 2.43; 95% CI, 1.82-3.41; P < .001) and GCA-positive TAs (RR = 2.03; 95% CI, 1.52-2.86; P < .001). Varicella-zoster virus antigen was frequently found in perineurial cells expressing claudin-1 around nerve bundles. Of 45 GCA-negative participants whose TAs contained VZV antigen, 1 had histopathological features characteristic of GCA, and 16 (36%) showed adventitial inflammation adjacent to viral antigen; no inflammation was seen in normal TAs. CONCLUSIONS AND RELEVANCE In patients with clinically suspected GCA, prevalence of VZV in their TAs is similar independent of whether biopsy results are negative or positive pathologically. Antiviral treatment may confer additional benefit to patients with biopsy-negative GCA treated with corticosteroids, although the optimal antiviral regimen remains to be determined.

Management of acute cranial nerve 3, 4 and 6 palsies: role of neuroimaging.

Purpose of review This article will discuss the management of isolated, acute cranial nerve 3,4 and 6 palsies with special focus on the role of neuroimaging in older adults based on recently published data. Recent findings Acute cranial nerve palsies affecting the third, fourth or sixth cranial nerves in isolation or in combination with other neurological signs and symptoms can be due to a variety of causes such as ischemia, inflammation, infection and compression of the ocular motor nerves. Although neuroimaging is generally recommended in all individuals presenting with ocular motor nerve palsies that occur in association with other neurological signs and symptoms, the indications for neuroimaging in older individuals (age > 50 years) who present with acute isolated ocular motor nerve palsies are less clear and controversial. Past and recent studies have attempted to address this question. A recent prospective study found that overall 16.5% of adult patients presenting with acute ocular motor mononeuropathy had structural lesions on MRI scan and 4.6% with fourth and sixth nerve palsies and no risk factors were found to have positive MRI scans. Summary On the basis of recently published data, we recommend contrast-enhanced MRI for all patients presenting with acute, isolated ocular motor mononeuropathies irrespective of age. Studies have clearly shown a small but significant prevalence of important findings in this group of patients thus favoring neuroimaging at the time of diagnosis.

The role of orbital ultrasonography in distinguishing papilledema from pseudopapilledema

PurposeTo determine the sensitivity and specificity of orbital ultrasonography in distinguishing papilledema from pseudopapilledema in adult patients.MethodsThe records of all adult patients referred to the neuro-ophthalmology service who underwent orbital ultrasonography for the evaluation of suspected papilledema were reviewed. The details of history, ophthalmologic examination, and results of ancillary testing including orbital ultrasonography, MRI, and lumbar puncture were recorded. Results of orbital ultrasonography were correlated with the final diagnosis of papilledema or pseudopapilledema on the basis of the clinical impression of the neuro-ophthalmologist. Ultrasound was considered positive when the optic nerve sheath diameter was ≥3.3 mm along with a positive 30° test.ResultsThe sensitivity of orbital ultrasonography for detection of papilledema was 90% (CI: 80.2–99.3%) and the specificity in detecting pseudopapilledema was 79% (CI: 67.7–90.7%).ConclusionsOrbital ultrasonography is a rapid and noninvasive test that is highly sensitive, but less specific in differentiating papilledema from pseudopapilledema in adult patients, and can be useful in guiding further management of patients in whom the diagnosis is initially uncertain.

Acute visual loss after ipilimumab treatment for metastatic melanoma

BackgroundIpilimumab, a humanized CLTA-4 antibody is a standard therapy in the treatment of advanced melanoma. While ipilimumab provides an overall survival benefit to patients, it can be associated with immune related adverse events (IrAEs).Case presentationHere we describe a patient treated with ipilimumab who experienced known IrAEs, including hypophysitis, as well as a profound vision loss due to optic neuritis. There are rare reports of optic neuritis occurring as an adverse event associated with ipilimumab treatment. Furthermore, the patient experienced multiple complications from high dose steroids used to manage his IrAEs.ConclusionsThis case highlights the need for recognition of atypical immune mediated processes associated with newer checkpoint inhibitor therapies including ipilimumab.

Adult hypertropia: a guide to diagnostic evaluation based on review of 300 patients

PurposeTo highlight the key clinical features of various aetiologies of adult hypertropia and to discuss the diagnostic approach towards evaluation of vertical double vision.MethodsThis is a retrospective cross-sectional study. A total of 300 consecutive patients with vertical diplopia were evaluated by a single neuro-ophthalmologist and strabismologist in a tertiary care setting from 2005–2008. The medical records of all patients with vertical diplopia coded with one of the following diagnoses; hypertropia, diplopia, thyroid eye disease, fourth nerve palsy, ocular myasthenia, congenital strabismus, and third nerve palsy were reviewed. The main outcome measures were determination of aetiologies of hypertropia.ResultsFourth nerve palsy and thyroid eye disease were the most common causes of vertical diplopia in our series and comprised more than 50% of patients. The other causes of vertical diplopia were ocular surgery, orbital fracture, neurosurgery, childhood strabismus, skew deviation, third nerve palsy, myasthenia gravis, and decompensated hyperphorias. Ocular motility deficits were seen in 33% of the cohort of whom thyroid eye disease comprised the largest group. Orbital ultrasonography was sensitive in detecting thyroid orbitopathy.ConclusionIn the majority of patients, the aetiologies of hypertropias can be ascertained by history and careful ophthalmic examination alone. Fourth nerve palsy and thyroid eye disease were the most common causes of vertical diplopia in this series.

Alexia without agraphia following biopsy of a left thalamic tumor

Alexia without agraphia is a rare disconnection syndrome characterized by the loss of reading ability with retention of writing and verbal comprehension. We report a patient who developed alexia without agraphia after undergoing a biopsy for a malignant glioma involving the left thalamus. A 15-year-old right-handed male presented with 3 days of severe headache, and vomiting, and 1 month of blurry vision in his right visual field. Magnetic resonance imaging of the brain disclosed a large exophytic mass originating in the left thalamus, with mass effect and hydrocephalus. The patient underwent biopsy of the left thalamic mass via a transcallosal approach. Postoperatively, the patient complained of inability to read or identify letters. Examination revealed alexia without agraphia. The syndrome of alexia without agraphia can be rarely caused after surgery. A transcallosal procedure through the splenium of the corpus callosum may disrupt the visual association fibers traveling from the right occipital cortex to the left angular gyrus. In our case the syndrome occurred because of a preexisting right homonymous hemianopia resulting from a left thalamic tumor.

Success of prisms in the management of diplopia due to fourth nerve palsy.

Background: To analyze the success of prism use in alleviating diplopia in patients with fourth nerve palsy and to provide recommendations for prism prescription. Methods: In this retrospective cohort study, the medical records of 83 patients who were prescribed prisms for symptomatic diplopia due to fourth nerve palsy were analyzed. Data on the nature and duration of diplopia, motility and alignment findings, and amount and type of prism prescribed were recorded. The success of prescribed prismatic correction was assessed by the patients self-reporting of satisfaction with prism use and follow-up records. The main outcome measure was the satisfaction rate associated with the use of prisms (satisfaction score 1 or 2) in patients with fourth nerve palsy. Results: There were 69 patients with congenital fourth nerve palsy and 14 patients with acquired fourth nerve palsy who received prisms. The mean primary position (±SD) deviation in this group was 7.8 (±4.6) prism diopters (PD). The mean prism prescription was 6 (±2.9) PD. Overall, 92% of patients were satisfied with the use of prisms. During the length of follow-up, which ranged from 2 months to more than 6 years (median: 18 months), 86% of the cohort continued using prisms while 14% of patients underwent strabismus surgery. Among 15 patients who had primary position deviation greater than 15 PD, 80% of the patients reported satisfaction with prisms, and in the 11 patients who received 10 PD or more of prismatic correction, 82% were satisfied. Conclusion: Prisms are an effective modality for the management of patients with symptomatic diplopia due to fourth nerve palsy. Even in patients with larger deviations including those who were prescribed greater than 10 PD of correction, the success rate of prisms in alleviating diplopia was high. Prisms should be considered as initial therapy in symptomatic patients with fourth nerve palsy.

Effectiveness of prisms in the management of diplopia in patients due to diverse etiologies

PURPOSE To study the effectiveness of prisms in the management of diplopia from different etiologies and over a broad range of ocular misalignment. METHODS In this retrospective cohort study, resolution of diplopia in 94 patients who were prescribed prisms was studied. RESULTS Among 94 patients, 88% reported complete or partial resolution of double vision (95% confidence interval: 84.1% to 95.6%) with highest improvement noted in the divergence insufficiency and skew deviation group (100%) compared to 64% improvement noted in patients with convergence insufficiency. More than 85% of patients who were prescribed greater than 10 diopters of prism and those with oblique prism prescriptions also reported resolution of diplopia. Eighty-nine percent of the cohort continued with prism use and 11% opted for strabismus surgery. CONCLUSION In this study, prisms were effective in alleviation of diplopia over a broad range and for different etiologies of double vision.