Cortical Visual Impairment Treated by Plasmapheresis in a Child With Metronidazole-Induced Encephalopathy

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Cortical Visual Impairment Treated by Plasmapheresis in a Child With Metronidazole-Induced Encephalopathy Melinda Y. Chang, MD, Mark S. Borchert, MD Downloaded from http://journals.lww.com/jneuro-ophthalmology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 05/04/2022 A 14-year-old boy with a history of Gardner syndrome, Turcot syndrome with APC mutation, fourth ventricular ependymoma status after resection and radiation at age 2 years, and hepatic focal nodular hyperplasia (FNH) and chronic liver disease was admitted for bloody diarrhea. His stool was positive for Clostridium difficile, and he was started on oral metronidazole, 30 mg/kg/day. He also had ascites and pulmonary edema, which were attributed to liver failure and treated with albumin, furosemide, and spironolactone. Other medications included calcium, ferrous sulfate, vitamin K, and potassium chloride. Nine days after admission, he had a 10–15 minute episode of altered mental status with stiffening of all 4 extremities, concerning for new-onset seizure. Neurologic examination the next day showed normal mental status, strength, sensation, reflexes, gait, and coordination. He underwent brain MRI that was unremarkable. Electroencephalography showed rare left parieto-occipital epileptiform discharges and excessive diffuse beta activity, which was considered nonspecific and could be a result of toxic or metabolic effect. He was started on levetiracetam. Three days later, he complained of vision changes that developed overnight. He was seen by ophthalmology and was noted to have light perception in each eye. His neurologic examination remained normal. Notably, his vision was recorded as 20/20 in each eye 9 months earlier. Fundus examination showed bilateral congenital hypertrophy of the retinal pigment epithelium lesions, unchanged from previous fundus photographs. The rest of the ophthalmologic examination was normal. He was diagnosed with cortical visual impairment (CVI). Repeat brain MRI showed new confluent T2/FLAIR (fluid-attenuated inversion recovery) hyperintensities with The Vision Center at the Children’s Hospital of Los Angeles (MYC, MSB), Los Angeles, California; and Roski Eye Center (MYC, MSB), Department of Ophthalmology, University of Southern California, Los Angeles, California. Supported by an unrestricted grant to the Department of Ophthalmology from Research to Prevent Blindness, New York, NY. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Address correspondence to Melinda Y. Chang, MD, The Vision Center at Children’s Hospital of Los Angeles and Roski Eye Institute, Department of Ophthalmology, 4650 Sunset Boulevard, Mailstop #88, Los Angeles, CA 90027; E-mail: [e-mail] e66 corresponding diffusion restriction involving the bilateral posterior frontal, parietal, and occipital periventricular white matter and splenium of the corpus callosum, with no corresponding enhancement (Fig. 1). The next day, the patient developed altered mental status with slurred speech and inability to ambulate. Neurologic examination demonstrated normal limb strength, sensation, and reflexes but poor postural and head control. Given the MRI findings, metronidazole-induced encephalopathy (MIE) was suspected, and the medication was stopped. Hepatic encephalopathy was also in the differential, although serum ammonia was normal, and he was started on lactulose. Posterior reversible encephalopathy syndrome was also considered but believed less likely given absence of predisposing factors such as hypertension, renal failure (serum creatinine 0.32 mg/dL), and exposure to immunosuppressive drugs such as cyclosporine. He underwent lumbar puncture and extensive laboratory workup to rule out infectious, inflammatory, and autoimmune causes of encephalopathy. These studies were consistent with known liver failure and otherwise unremarkable (See Supplemental Digital Content, Table E1, http:// links.lww.com/WNO/A383), with the exception of low thiamine and zinc, which were supplemented, and low serum copper and ceruloplasmin, which led to a concern for Wilson disease. However, genetic testing for Wilson disease was negative. Genetic testing for mitochondrial and other metabolic disorders was not performed, but serum and cerebrospinal fluid (CSF) lactate and pyruvate were normal. Over the next 5 days, his neurologic status continued to deteriorate, and he became nonverbal and unable to follow commands. He was started on plasmapheresis for presumed MIE. Neurologic symptoms improved rapidly, and the mental status normalized by the end of the 7-day course. Ophthalmologic examination revealed improved vision with ability to see large lighted toys with bright colors. Follow-up MRI demonstrated resolution of restricted diffusion and minimal residual T2 hyperintensity along the periventricular white matter and splenium (Fig. 2). The patient was discharged to rehabilitation. Ophthalmology examination 2 months after onset of vision loss demonstrated best-corrected visual acuity of 20/150 in each eye and stable fundus findings. Neurologic examination was normal. He continued levetiracetam with no recurrence of seizures. The most recent ophthalmology follow-up 9 months after onset of vision loss demonstrated near-complete recovery, Chang and Borchert: J Neuro-Ophthalmol 2021; 41: e66-e68 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Axial brain MRI immediately after onset of vision loss, demonstrating hyperintensity of the splenium of the corpus callosum and posterior periventricular white matter on fluid-attenuated inversion recovery (FLAIR) sequence (A), with corresponding diffusion restriction on diffusion-weighted imaging (DWI, B). Areas of restricted diffusion are hypointense on apparent diffusion coefficient (ADC) imaging (C). with visual acuity of 20/40 in the right eye and 20/30 in the left eye. Metronidazole-induced encephalopathy is a rare condition, and most cases have been reported in adults (1). To the best of our knowledge, less than 10 reports of pediatric MIE exist in the literature (1,2). The most common symptoms are cerebellar dysfunction, altered mental status, and seizures (1,3). Vision loss is uncommon in MIE, occurring in only 2% of patients in one literature review (3). Optic neuropathy or, more rarely, CVI, may result in vision loss (4). Other neuro-ophthalmic manifestations of MIE include oculomotor disturbances and nystagmus (1). Neuroimaging is critical in the diagnosis of MIE. Over 90% of patients show T2/FLAIR hyperintense, bilateral, symmetric lesions of the dentate nuclei (1). Other frequently affected structures include the splenium of the corpus callosum, brainstem, and less commonly cerebral white matter. These lesions may demonstrate diffusion restriction. The differential for encephalopathy with similar MRI appearance includes Wernicke encephalopathy, bromide toxicity, and certain metabolic or mitochondrial disorders such as maple syrup urine disease (1,3). The neurologic deficits and brain lesions in MIE are at least partially reversible in approximately 90% of cases (1). Total dose of metronidazole does not affect prognosis, but late diagnosis and longer time to drug withdrawal may be associated with worse recovery (3). Hepatic failure and renal failure are associated with MIE because metronidazole is metabolized by the liver and excreted through urine (1). It is unclear whether these comorbidities worsen prognosis (1). Our patient had biopsyproven FNH and liver failure. Although FNH is typically asymptomatic in adults, it is more likely to cause complications in children (5). The only accepted treatment for MIE is cessation of metronidazole (1,3). Other proposed therapies include FIG. 2. Axial brain MRI after initiation of plasmapheresis shows reduction in hyperintensity of the splenium of the corpus callosum and posterior periventricular white matter on fluid-attenuated inversion recovery (FLAIR) sequence (A), with resolution of diffusion restriction on diffusion-weighted imaging (DWI, B). Chang and Borchert: J Neuro-Ophthalmol 2021; 41: e66-e68 e67 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence diazepam, thiamine, N-acetylcysteine, and coenzyme Q10 (1,2). Coenzyme Q10 was used in the single previous report of CVI secondary to MIE in a pediatric patient (2). In that case, CSF and MR spectroscopy demonstrated elevated lactate, and the authors theorized that metronidazole induced mitochondrial dysfunction. Because of rapid neurological decline and no improvement 5 days after metronidazole cessation, our patient was treated with plasmapheresis, with the goal of removing any residual metronidazole. However, an immune reaction to metronidazole may have also been treated by plasma exchange. Because the mechanism of metronidazole toxicity in MIE is not known (although effects on GABA transmission, mitochondrial function, and free radical formation have been postulated) (1), the means by which plasmapheresis may treat MIE is unclear. To the best of our knowledge, only one previous report of plasmapheresis for the treatment of MIE has been published (6). In this case, a 36-year-old man with MIE in the setting of alcoholic cirrhosis had persistent neurologic dysfunction 3 weeks after discontinuing metronidazole, so plasma exchange and hemodiafiltration were initiated. The patient unfortunately succumbed to the disease. Our case demonstrates that MIE can occur in the pediatric population with CVI as a primary manifestation. Neurologic deficits, including vision loss, were ultimately reversible with drug cessation and plasmapheresis. Given previous reports of poorer prognosis with delayed withdrawal of metronidazole, MIE should be considered early in the differential of children on this medication who present with acute vision loss, seizures, altered mental status, and/or e68 cerebellar dysfunction, particularly in the setting of liver or kidney failure. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: M. Y. Chang and M. S. Borchert; b. Acquisition of data: M. Y. Chang and M. S. Borchert; c. Analysis and interpretation of data: M. Y. Chang and M. S. Borchert. Category 2: a. Drafting the manuscript: M. Y. Chang and M. S. Borchert; b. Revising it for intellectual content: M. Y. Chang and M. S. Borchert. Category 3: a. Final approval of the completed manuscript: M. Y. Chang and M. S. 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