CASE-LETTER

Simultaneous Optic Neuropathy and Osmotic Demyelinating Syndrome in Hyperemesis Gravidarum

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16-year-old African American girl at the 20th week of pregnancy presented with blurry vision. She had been having nausea and vomiting requiring home intravenous ondansetron. She could tolerate only liquids and had lost 30 pounds (approximately 25% of body weight) over the course of pregnancy. On the day of admission, she woke up with painless binocular blurry vision. She denied diplopia, limb weakness, dysarthria, numbness, headaches, and confusion. She went to other hospital where brain computed tomography showed symmetric hypodensity in the pons. This finding prompted transfer to our hospital. Her medical history included 1 spontaneous abortion and hyperemesis requiring hospitalization twice during this pregnancy. Family history was negative for hypercoagulability, sickle cell disease, and multiple sclerosis. Her grandfather had stroke at an old age. She denied smoking, alcohol drinking, and use of illicit drugs. On physical examination, blood pressure was 100/68 mm Hg with heart rate of 90 beats/minute. General examination was unremarkable except mild pitting edema in both legs. She was alert and oriented. Fundoscopy showed mild superior and inferior swelling of the optic discs bilaterally, with bilateral peripapillary retinal nerve fiber layer hemorrhages. No other hemorrhage was noted either in macula or in the periphery of retina. Color vision was decreased, despite good visual acuity. Other cranial nerve examinations were normal. She had full strength and normal tone in limbs. Sensation was intact. Deep tendon reflexes were normal with downward plantar reflex bilaterally. Cerebellar function test was normal. Neck was supple. Blood test revealed normocytic anemia (9.7 g/dL), hypokalemia (2.3 mmol/L), hypomagnesemia (0.7 mg/dL), low blood urea nitrogen (BUN) (,3.0 mg/dL), hypoalbuminemia (2.5 g/dL) and normonatremia (136 mmol/L). Twenty-four hour urinary protein was 0.273 gram/day. Magnetic resonance imaging (MRI) showed T2 hyperintense signal abnormality in pons with restricted diffusion (Figure 1). Magnetic resonance angiogram and venogram were negative for vascular stenosis or occlusion. Cerebrospinal fluid analysis was normal with one white cell, normal protein (23 mg/dL) and glucose (71 mg/dL). Immunoglobulin G (IgG) index was 0.57, and myelin basic protein level was normal. Cerebrospinal fluid studies for viral, bacterial and fungal infection were negative. Under diagnosis of nutritional optic neuropathy with osmotic demyelinating syndrome (ODS), intravenous thiamine and folic acid replacement was initiated. Serum thiamine level was low (64 nmol/L; normal range, 70–180 nmol/L). Vitamin B12 level was 514 pg/mL. Obstetric evaluation revealed a fetus with pericardial and pleural effusion and possible brain malformations. Dilatation and curettage was performed after intrauterine fetal death was confirmed. Nausea and blurry vision significantly improved after the procedure. Three months after discharge, patient was free from nausea and vomiting with 6 pound weight gain. T2 hyperintense signal was decreased in size on repeated MRI. Serum thiamin level was normal at 87 nmol/L. Fundus examination 5 months after discharge showed normal fundi without edema.

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Nutritional optic neuropathy is an uncommon disease in developed countries, characterized by optic disc changes and loss of the papillomacular nerve fiber layer.1 The most commonly deficient vitamins are B1 (thiamine), B2 (rivoflavin), B3 (niacin), B12 (cobalamin), and folate. Nutritional optic neuropathy shares clinical and fundoscopic findings with Leber’s hereditary optic neuropathy and toxic optic neuropathy since their pathophysiology is all related to impaired energy metabolism in optic nerve. Abnormal energy metabolism slows down axonal transport of mitochondria, leading to eventual optic atrophy.1 Nerve fibers with less myelin, smaller axon, or high firing rates are more dependent on axonal transport and, subsequently, become more vulnerable to nutrition deficiencies. The papillomacular bundle has high concentration of parvocellular ganglion cells with higher firing rate than magnocelluar ganglion cells.2 Since axonal transport is length dependent, peripheral neuropathy is often associated with optic neuropathy from conditions such as thiamine or cobalamin deficiency. Clinical features of nutritional optic neuropathy include gradual, bilaterally decreased color vision, centrocecal scotomas, swelling of the nerve fiber layer in the arcuate bundles and eventual optic disc pallor in the papillomacular bundles. Nutritional or toxic optic neuropathies are also known to cause mild disc edema, especially in early phase as in our case, sometimes with secondary retinal bleeding.1 Our patient is thought to have optic neuropathy mainly from hyperemesis-associated malnutrition including thiamine deficiency. Low thiamine can impair energy production because its active form, thiamine pyrophosphate (TPP), participates in carbohydrate metabolism. Decreased level of TPP is linked to reduced red blood cell (RBC) transketolase activity, leading to impaired oxygen uptake and energy metabolism. Daily requirement of thiamine is higher during pregnancy because of high metabolic demand. Thiamine measurement sometimes has a limited value to define abnormal metabolism caused by thiamine deficiency. Measurements of RBC transketolase activity and TPP stimulation of RBC transketolase levels are more reliable tests. Measurement of serum pyruvate or lactate level is sometimes helpful. ODS is a rare, acquired, noninflammatory demyelinating disease characterized anatomically by the involvement of basis pontis and pathologically by focal loss of myelin sheath and spared axon.3 It can have various clinical presentations including quadriparesis, bulbar dysfunction, lock-in syndrome, confusion, seizure, cerebellar ataxia, and extrapyramidal symptoms. Some of them are attributed to extrapontine myelinolysis in internal capsule, basal ganglia, or cerebellum. The 1st reported case was patients with hyponatremia in alcoholism and malnutrition. Most cases are related to abrupt correction of hyponatremia causing sudden osmolality changes. In our case, although the patient had normal sodium level, calculated serum osmolarity was 276 osmol/kg (2½Naþ½glucose=18 þ ½BUN=2:82). Current understanding about ODS is that changes in osmolality and energy deficiency in brain cells are major pathophysiologic factors.3 Brain cells, mostly glial cells, are adapted to hypo-osmotic stress within 2 days by taking inorganic and organic osmolytes out of cells. When low serum osmolality is corrected, brain cells try to adapt themselves again by producing organic osmolytes and upregulating ion channels. These processes depend on energy supply and take more time than driving osmolytes out to extracelluar space. Poorly adjusted osmoregulatory system due to rapid osmolality changes or energy depletion causes cellular shrinkage, resulting in axonal shear stress, loss of

The American Journal of the Medical Sciences



Volume 347, Number 1, January 2014

Case-Letter

FIGURE 1. Brain magnetic resonance imaging on admission reveals bilateral, asymmetric, high signal intensity in the basis pontis on the diffusion-weighted image (A) with low signal intensity at the same area on the apparent diffusion coefficient image (B). The same area has high signal intensity on fluid attenuated inversion recovery image (C). Three months later, fluid attenuated inversion recovery image shows subtle lesion with mildly increased signal intensity (D).

blood-brain barrier, inflammation and then demyelination.3 In our case, decreased energy source as a result of malnutrition is postulated to be a major contributor to ODS and optic neuropathy. It is notable that serum potassium was low at 2.3 mEq/L. Potassium is also an important factor for the regulation of cellular osmolality. Hypokalemia is known to decrease the activity of Na-K-ATPase rendering brain cells less responsive to increasing osmolality.3,4 Hypokalemia with or without hyponatremia has been observed in other cases of ODS.5 Undetectably low BUN is another interesting finding in our case. An animal experiment using uremic rats showed that high concentration of BUN enhances the production of myoinositol, one of intracellular organic osmolytes. Therefore, BUN is thought to protect brain from osmotic stress.5 Our case did not have any symptoms or signs suggesting ODS. However, brain MRI shows nearly symmetric bat wing–shaped lesion in the pons with bright signal on T2-weighed and dark signal on T1-weighted sequences. It spares corticospinal tracts, tegmentum and ventrolateral portion of the pons. These radiologic findings are typical for ODS.3,6 One postmortem analysis found 15 cases of asymptomatic ODS out of more than 3000 autopsies and 6 of 15 cases had active lesion.7 Therefore, asymptomatic ODS with active lesion is rare but possible even without related electrolyte abnormalities. In addition, hyperemesis gravidarum without other accompanied diseases is one of the uncommon conditions associated with ODS.3 We made a diagnosis of ODS based on radiology findings in context Ó 2013 Lippincott Williams & Wilkins

of hyperemesis gravidarum. Decreased signal intensity on the apparent diffusion constant indicates that her ODS was in acute process, despite the absence of symptoms.4 We think that the ocular symptom from nutritional optic neuropathy brought immediate medical attention before ODS became symptomatic in this case. In summary, we report a case of nutritional optic neuropathy and asymptomatic ODS in a young patient with malnutrition because of hyperemesis gravidarum. Ocular symptoms in the setting of poor nutrition can be a warning sign of other devastating neurological complications that warrant thorough investigation.

Dong In Sinn, MD David Bachman, MD Wuwei Feng, MD, MS Department of Neurology, Medical University of South Carolina, Charleston, South Carolina The authors have no financial or other conflicts of interest to disclose. REFERENCES 1. Sadun AA, Guran S, Patel V. Hereditary, nutritional, and toxic optic atrophies. In: Yanoff M, Duker JS, editors. Ophthalmology. 3rd ed. Edinburgh: Mosby; 2008. p. 976–9.

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2. Purvin VA. Optic neuropathies for the neurologist. Semin Neurol 2000; 20:97–110. 3. King JD, Rosner MH. Osmotic demyelination syndrome. Am J Med Sci 2010;339:561–7. 4. Lohr J. Osmotic demyelination syndrome following correction of hyponatremia: association with hypokalemia. Am J Med 1994;96: 408–13.

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5. Soupart A, Silver S, Schrooeder B, et al. Rapid (24-hour) reaccumulation of brain organic osmolytes (particularly myo-inositol) in azotemic rats after correction of chronic hyponatremia. J Am Soc Nephrol 2002;13:1433–41. 6. Hurley RA, Filley CM, Taber KH. Central pontine myelinolysis: a metabolic disorder of myelin. J Neuropsychiatry Clin Neurosci 2011;23:369–74. 7. Newell KL, Kleinschmidt-DeMasters BK. Central pontine myelinolysis at autopsy: a twelve year retrospective analysis. J Neurol Sci 1996:142:134–9.

Volume 347, Number 1, January 2014

Simultaneous optic neuropathy and osmotic demyelinating syndrome in hyperemesis gravidarum.

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