Patient Harm Due to Diagnostic Error of Neuro-Ophthalmologic Conditions

PURPOSE: To prospectively examine diagnostic error of neuro-ophthalmic conditions and resultant harm at multiple sites. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: A total of 496 consecutive adult new patients seen at 3 university-based neuro-ophthalmology clinics in the United States in 2019 to 2020. METHODS: Collected data regarding demographics, prior care, referral diagnosis, final diagnosis, diagnostic testing, treatment, patient disposition, and impact of the neuro-ophthalmologic encounter. For misdiagnosed patients, we identified the cause of error using the Diagnosis Error Evaluation and Research (DEER) taxonomy tool and whether the patient experienced harm due to the misdiagnosis. MAIN OUTCOME MEASURES: The primary outcome was whether patients who were misdiagnosed before neuro-ophthalmology referral experienced harm as a result of the misdiagnosis. Secondary outcomes included appropriateness of referrals, misdiagnosis rate, interventions undergone before referral, and the primary type of diagnostic error. RESULTS: Referral diagnosis was incorrect in 49% of cases. A total of 26% of misdiagnosed patients experienced harm, which could have been prevented by earlier referral to neuro-ophthalmology in 97%. Patients experienced inappropriate laboratory testing, diagnostic imaging, or treatment before referral in 23%, with higher rates for patients misdiagnosed before referral (34% of patients vs. 13% with a correct referral diagnosis, P < 0.0001). Seventy-six percent of inappropriate referrals were misdiagnosed, compared with 45% of appropriate referrals (P < 0.0001). The most common reasons for referral were optic neuritis or optic neuropathy (21%), papilledema (18%), diplopia or cranial nerve palsies (16%), and unspecified vision loss (11%). The most common sources of diagnostic error were the physical examination (36%), generation of a complete differential diagnosis (24%), history taking (24%), and use or interpretation of diagnostic testing (13%). In 489 of 496 patients (99%), neuro-ophthalmology consultation (NOC) affected patient care. In 2% of cases, neuro-ophthalmology directly saved the patient's life or vision; in an additional 10%, harmful treatment was avoided or appropriate urgent referral was provided; and in an additional 48%, neuro-ophthalmology provided a diagnosis and direction to the patient's care. CONCLUSIONS: Misdiagnosis of neuro-ophthalmic conditions, mismanagement before referral, and preventable harm are common. Early appropriate referral to neuro-ophthalmology may prevent patient harm

A phase Ib/IIa clinical trial of dantrolene sodium in patients with Wolfram syndrome

BACKGROUNDWolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial.METHODSBased on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions.RESULTSDantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and isoprostane, were elevated in subjects.CONCLUSIONThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT02829268FUNDINGNIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs

Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to rapid and severe bilateral vision loss. Idebenone has been shown to be effective in stabilizing and restoring vision in patients treated within 1 year of onset of vision loss. The open -label, international, multicenter, natural history -controlled LEROS study (ClinicalTrials.gov NCT02774005) assesses the efficacy and safety of idebenone treatment (900 mg/day) in patients with LHON up to 5 years after symptom onset (N = 199) and over a treatment period of 24 months, compared to an external natural history control cohort (N = 372), matched by time since symptom onset. LEROS meets its primary endpoint and confirms the long-term efficacy of idebenone in the subacute/dynamic and chronic phases;the treatment effect varies depending on disease phase and the causative mtDNA mutation. The findings of the LEROS study will help guide the clinical management of patients with LHON

Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to rapid and severe bilateral vision loss. Idebenone has been shown to be effective in stabilizing and restoring vision in patients treated within 1 year of onset of vision loss. The open-label, international, multicenter, natural history-controlled LEROS study (ClinicalTrials.gov NCT02774005) assesses the efficacy and safety of idebenone treatment (900 mg/day) in patients with LHON up to 5 years after symptom onset (N = 199) and over a treatment period of 24 months, compared to an external natural history control cohort (N = 372), matched by time since symptom onset. LEROS meets its primary endpoint and confirms the long-term efficacy of idebenone in the subacute/dynamic and chronic phases; the treatment effect varies depending on disease phase and the causative mtDNA mutation. The findings of the LEROS study will help guide the clinical management of patients with LHON

Functional Connectivity in Patients with Clinically Isolated Optic Neuritis

Optic neuritis (ON) is common in MS, and visual dysfunction is a major cause of disability in MS patients. Conventional magnetic resonance imaging (MRI) techniques show only a loose correlation between MRI lesion burden and disability in MS, and do not capture physiologic response by the brain to injury. Resting state functional MRI (rs-fMRI) is a novel method of assessing functional connections in the brain by exploring correlations in blood oxygen level dependent (BOLD) fluctuations throughout the brain, and represents a promising technique for exploring changes in brain functional connections.EXAMfmr

Paradoxical Worsening of Myasthenic Ptosis after Ice Test

To report two patients with confirmed myasthenia gravis demonstrating paradoxical worsening of ptosis with initial IceTest

Horner's Syndrome and Cavernous Sinus Involvement in Giant Cell Arteritis

To report an unusual case of giant cell arteritis presenting with left cavernous sinus syndrome

Does It Apply To The Eye? Secondary Prevention of Stroke After Transient Monocular Visual Loss

Amaurosis fugax (from the Greek, "amaurosis," meaning dark, and the Latin, "fugax," meaning fleeting) refers to a transient loss of vision in one or both eyes. Varied use of common terminology may cause some confusion when reading the literature.curriculum_fellow; VBneurodisocularischemia; VBtransientvisuallos

Walsh & Hoyt: Headache Attributable to Disorders of the Eyes

Ocular disease may cause headaches and may be overlooked by the primary care physician and general neurologist. It is important to be aware of these ocular conditions, both to provide accurate and effective management, and to spare the patient unnecessary testing and treatments. Since eye pain is ultimately mediated by the trigeminal nerve, many primary and secondary headache disorders may present with localized eye pain. The history may provide important clues to an ocular etiology. Conjunctival injection, pupillary abnormalities, and corneal edema are common symptoms in eye-related headaches, but are not always present. Visual loss and diplopia associated with head and/or eye pain should suggest an ocular etiology. A complete ophthalmic examination should be performed, with careful inspection of the eyelids, conjunctiva and orbits, biomicroscopic examination of the anterior segment, and measurement of intraocular pressure. Many primary headache syndromes, particularly the trigeminal autonomic cephalgias, may present with pain localized around the eye; in such cases, excluding an ocular etiology allows proper diagnosis and management

Walsh & Hoyt: Tension-Type Headache

Tension-type headache (TTH) is the most common form of primary headache, with a lifetime prevalence ranging from 3078%. However, it remains the least studied of the primary headache syndromes, despite the fact that TTH may have the highest socioeconomic impact. Further, migraine headache is often misdiagnosed as TTH. In one study, 37% of patients originally diagnosed with TTH were later found to have migraine. The situation is complicated by the fact that migraine and TTH may coexist in the same patient. Indeed, the symptoms of each headache type may overlap. Muscle tension is often considered a unique feature of TTH, while migraine is commonly felt not to be associated with muscle tension or neck pain. Recent studies have suggested that neither of these assumptions may be correct. One study demonstrated that of 144 patients meeting IHS criteria for migraine, 75% described neck pain associated with the attacks. The second edition of the IHS criteria divides TTH into episodic and chronic forms. Episodic TTH is further subdivided into frequent and infrequent forms