Increased ER Stress After Experimental Ischemic Optic Neuropathy and Improved RGC and Oligodendrocyte Survival After Treatment With Chemical Chaperon.

Purpose: Increased endoplasmic reticulum (ER) stress is one of the earliest subcellular changes in neuro-ophthalmic diseases. In this study, we investigated the expression of key molecules in the ER stress pathways following nonarteritic anterior ischemic optic neuropathy (AION), the most common acute optic neuropathy in adults over 50, and assessed the impact of chemical chaperon 4-phenylbutyric acid (4-PBA) in vivo. Methods: We induced AION using photochemical thrombosis in adult mice and performed histologic analyses of key molecules in the ER stress pathway in the retina and optic nerve. We also assessed the effects of daily intraperitoneal injections of 4-PBA after AION. Results: In the retina at baseline, there was low proapoptotic transcriptional regulator C/EBP homologous protein (CHOP) and high prosurvival chaperon glucose-regulated protein 78 (GRP78) expression in retinal ganglion cells (RGCs). One day after AION, there was significantly increased CHOP and reduced GRP78 expressions in the ganglion cell layer. In the optic nerve at baseline, there was little CHOP and high GRP78 expression. One day after AION, there was significantly increased CHOP and no change in GRP78 expression. Treatment immediately after AION using daily intraperitoneal injection of chemical chaperone 4-PBA for 19 days significantly rescued Brn3A+ RGCs and Olig2+ optic nerve oligodendrocytes. Conclusions: We showed for the first time that acute AION resulted in increased ER stress and differential expression of ER stress markers CHOP and GRP78 in the retina and optic nerve. Rescue of RGCs and oligodendrocytes with 4-PBA provides support for ER stress reduction as possible treatment for AION.

A simple saccadic reading test to assess ocular motor function in cerebellar ataxia.

Cerebellar ataxia is a neurological disorder due to dysfunction of the cerebellum that affects coordination of fine movement, gait, and balance. Although ataxic patients commonly exhibit abnormal eye movement and have difficulties with saccadic reading, quantification of ocular motor abilities during reading in the clinical setting is rarely done. In this study, we assess visual performance with simple reading tests that can be used in the clinical setting and performed video infrared oculography in 11 patients with hereditary or acquired cerebellar ataxia and 11 age-matched controls. We found that compared with controls, ataxic patients read significantly slower on regularly and irregularly spaced 120 single-digit number reading tasks (read aloud) (p = 0.02 for both) but not on a word reading task (read silently), although there was large variability on the word reading task. Among the 3 reading tasks, the regularly spaced number reading task had the greatest difference (44%) between ataxic patients and controls. Analysis of oculography revealed that ataxic patients had slower reading speeds on the regularly spaced number reading task because of significantly higher saccade and fixation counts, impairment of small amplitude progressive saccades as well as large amplitude, line-changing saccades, greater fixation dispersion, and irregularity of scan paths and staircase gaze patterns. Our findings show that infrared oculography remains the gold standard in assessment of ocular motor difficulties during reading in ataxic patients. In the absence of this capability in the clinical setting, a simple 120 regularly spaced single-digit saccadic number reading test, which most patients can perform in less than 2 minutes, can be a possible biomarker for ocular motor abilities necessary for reading.

Vertical diplopia and oscillopsia due to midbrain keyhole aqueduct syndrome associated with severe cough.

PURPOSE: Midline structural defects in the neural axis can give rise to neuro-ophthalmic symptoms. We report a rare case of keyhole aqueduct syndrome presenting after two years of severe cough due to gastroesophageal reflux disease. OBSERVATIONS: A 58-year-old woman with a 2-year history of daily, severe cough presented to the neuro-ophthalmology clinic with progressive diplopia and oscillopsia. Examination revealed a 1-2 Hz down-beating nystagmus in primary gaze that worsened with left, right, and down gazes. Gaze evoked nystagmus and mild paresis were also seen with up gaze. There was an incomitant left hypertropia due to skew deviation that worsened with right and up gazes and improved with down gaze. She also had a right-sided ptosis and a 3 mm anisocoria not due to cranial nerve 3 paresis or Horner's syndrome. Brain magnetic resonance imaging showed a 1.5 mm × 11.7 mm × 6 mm midline cleft in the ventral midbrain communicating with the cerebral aqueduct, consistent with keyhole aqueduct syndrome. Her nystagmus and diplopia improved with oral acetazolamide treatment, at high doses of 2500-3000 mg per day. CONCLUSIONS AND IMPORTANCE: We report the first case of midbrain keyhole aqueduct syndrome with ocular motor and other neuro-ophthalmic manifestations associated with severe cough. Although her cough was effectively treated and intracranial pressure measurement was normal, her ophthalmic symptoms continued to progress, which is common in previous cases reported. Treatment with acetazolamide led to significant improvement, supporting the use of acetazolamide in this rare condition.