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Show ORIGINAL CONTRIBUTION Ocular Motor and Imaging Abnormalities of Midbrain Dysfunction in Osmotic Demyelination Syndrome Kristen M. Hawthorne, MD, Christopher J. Compton, MS, Michael S. Vaphiades, DO, Glenn H. Roberson, MD, and Lanning B. Kline, MD Abstract: After rapid correction of severe hypona-tremia, a 36- year- old man developed osmotic demye-lination syndrome ( ODS), manifested neurologically by impaired cognition, extremity weakness, bilateral third cranial nerve palsies, and gaze- evoked upbeat and rotary nystagmus. Brain MRI showed restricted diffusion in the rostral midbrain and temporal and parietal lobes but not in the pons. Over several weeks, all neurologic and imaging deficits resolved. This is the first report to document ocular motor abnormal-ities associated with midbrain dysfunction in ODS. ( J Neuro- Ophthalmol 2009; 29: 296- 299) O smotic demyelination syndrome ( ODS) describes a spectrum of neurologic symptoms resulting from central nervous system demyelination precipitated by rapid correction of hyponatremia. ODS was first described in 1959 by Adams et al ( 1) and labeled central pontine myelinolysis ( CPM) after a symmetric demyelinating lesion of the central pons was noted post mortem in alcoholics and malnourished individuals. In 1962, another subset of patients with ODS was described as having autopsy findings of demyelinating lesions in the external and internal capsules and anterior commissure, so- called extrapontine myelinolysis ( EPM) ( 2). Subsequent reports ( 3,4) have documented that EPM can occur in the cerebellum, cerebrum, thalamus, subthalamic nucleus, hypothalamus, hippocampus, corpus callosum, mamillary, medial, and lateral geniculate bodies. A few reports have even documented midbrain involvement ( 4- 6). Most reports document EPM and CPM together, but on occasion EPM may develop without CPM. The ocular motor findings of ODS have been sparsely and vaguely described ( 2,5,7,8). This report documents ocular motor and neuroimaging findings in a patient with ODS characterized by midbrain involvement and sparing of the pons. CASE REPORT A 36- year- old man enrolled in a 3- week survival training program held outdoors during the summer. On the 5th day of intensive physical activity, he reported feeling ill despite frequent hydration. On arrival to the emergency department, the patient was unresponsive, had a grand mal seizure, and was found to be in pulmonary edema. Mechanical ventilation was started, and the patient was found to have a serum sodium level of 114 mmol/ L ( normal: 135- 145 mmol/ L). He was actively rehydrated with a rapid correction of electrolytes. On the 2nd hospital day, the patient developed a fever to 102F, was noted to have pulmonary consolidation on chest x- ray, and was given broad- spectrum antibiotics. The serum sodium level at that time was 119 mmol/ L. On the 3rd day of hospitalization, he became afebrile and was extubated. Although his pulmonary status improved, he remained neurologically impaired. He had bilateral upper and lower extremity weakness, slurred speech, and slow mentation. His serum sodium level was now 142 mmol/ L, and brain MRI revealed areas of restricted diffusion in the rostral midbrain, as well as the medial temporal, parietal, and subfrontal cortex bilaterally ( Fig. 1). These findings were confirmed on T2 and FLAIR sequences ( Fig. 2). There were no signal abnormalities in the pons ( Fig. 3). By the 12th hospital day, the patient was alert although his speech and mentation remained slow. Neuro-ophthalmologic examination demonstrated a visual acuity of 20/ 30 in the right eye and 20/ 20 in the left eye. Color vision was normal, and visual fields were intact to confrontation. Pupils were equal in size and briskly reactive to light without relative afferent pupillary defect. There was bilateral ptosis and a prominent exotropia. Eye movements showed reduced supraduction, infraduction, and adduction of both eyes ( Fig. 4). In upgaze the patient developed Departments of Ophthalmology ( KMH, CJC, MSV, LBK) and Radiology ( GHR), University of Alabama School ofMedicine, Birmingham, Alabama. This work was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, NY. Address correspondence to Lanning B. Kline, MD, Suite 601, 700 South 18th Street, Birmingham, AL 35233; E- mail: lkline@ uabmc. edu 296 J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 upbeat nystagmus with a rotary component. Results of anterior and posterior ocular segment examinations were unremarkable. Over the next 17 days, there was complete resolution of ptosis and ocular motor abnormalities. One month after hospitalization, the patient was noted to have only occasional square- wave jerks in primary gaze. His overall clinical condition continued to improve and with intensive physical therapy he was able to walk without assistance. Cognition and speech returned to normal. Results of brain MRI on the 32nd day after hospitalization were normal. DISCUSSION We have described a patient with ODS whose case is unusual in manifesting the clinical and imaging abnormal-ities of midbrain rather than pontine dysfunction. Although pontine and extrapontine clinical and imaging manifestations are widely documented in ODS, ocular motor abnormalities have been poorly described. Zegers de Beyl et al ( 7) reported ocular bobbing, limited abduction of the left eye, and impaired caloric testing for horizontal eye movements in a patient with CPM. Other descriptions in patients with both CPM and EPM include ‘‘ pupillary abnormalities'' ( 5), ‘‘ pupillary and oculomotor abnormal-ities'' ( 2), and ‘‘ abnormalities of saccades without palsy'' ( 8). We believe our patient manifested partial bilateral third cranial nerve palsies due to demyelinating lesions within the midbrain. In all likelihood, the fascicular portion of the third cranial nerve was affected. Pupil- sparing third cranial nerve palsies have been well documented with involvement of the fascicular portion of the nerve ( 9- 12). Gaze- evoked upbeat nystagmus with a rotary component may have been due to concurrent involvement of the rostral interstitial nuclei of the medial longitudinal fasciculus ( riMLF) bilaterally. FIG. 1. A. Axial diffusion MRI demonstrates areas of increased signal bilaterally in the medial temporal lobes, subfrontal cortex, and rostral midbrain. B. Apparent diffusion coefficient map demonstrates hypointense signal in corresponding areas, consistent with restricted diffusion. FIG. 2. A. Axial FLAIR MRI reveals areas of hyperintense signal that correspond to those seen on diffusion imaging ( Fig. 1). B. Coronal FLAIR MRI demonstrates bilateral rostral midbrain hyperintense signals ( arrows). 297 Osmotic Demyelination Syndrome J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 An understanding of the pathogenesis of ODS requires review of the physiologic changes occurring in acute and chronic hyponatremia. In the acute setting, when serum sodium decreases, water flows across the blood-brain barrier into relatively hypertonic brain cells, resulting in brain swelling. To counter this, a compensatory hydro-static pressure mechanism forces interstitial fluid rich in inorganic ions such as sodium and potassium into the cerebrospinal fluid and ultimately back into the serum. Over the next 24- 48 hours, brain cells pump out organic osmoles such as taurine and glutamine ( 2,13). At this point, brain cells have lost both inorganic ions and organic osmoles to reach an isotonic state and maintain cellular volume. With correction of hyponatremia, there is a rapid increase of inorganic ions in serum, which now becomes relatively hypertonic to brain cells. This phenomenon leads to a shift of water out of cells with subsequent cell shrinkage. To prevent this, cellular tonicity must increase, requiring a reaccumulation of inorganic ions and organic osmoles. Damage occurs because the rate of these 2 protective mechanisms is slower than the rise in serum tonicity. Cell shrinkage precipitates cell death, particularly of oligodendrocytes, leading to demyelination. This osmotic stress probably triggers apoptosis, leading to further cell loss ( 2,13,14). The classic finding in CPM is a hyperintense ‘‘ trident- shaped'' central pontine abnormality seen on T2 and FLAIR imaging ( 15,16), but this finding typically lags behind the clinical manifestations of ODS ( 17,18). With conventional MRI pulse sequences, myelinolytic lesions may not be detected within the first 2 weeks of onset. Indeed, imaging later in the clinical course has been advocated to confirm the diagnosis ( 18,19). Diffusion- weighted imaging ( DWI) and FLAIR sequences have demonstrated additional sites of involve-ment in EPM ( 20,21), including the cerebellum, cerebral cortex, thalamus, and external capsule. To our knowledge, however, there are no other reported cases of midbrain involvement detected with neuroimaging in the absence of pontine involvement. DWI has allowed earlier detection of brain lesions, probably because this technique is highly sensitive to the motion of intraparenchymal water, which is altered in ODS ( 17,18). DWI abnormalities have been detected early in the course of ODS without corresponding signal abnormalities on T1, T2, or FLAIR images ( 18). These changes may persist for 3 weeks ( 17). FIG. 3. Diffusion- weighted imaging at the level of the pons shows no areas of restricted diffusion. FIG. 4. On the 12th hospital day, the patient displays bilateral ptosis and exotropia in primary gaze position ( A). On right ( B) and left ( C) gaze, there is impaired adduction. In upgaze ( D) and downgaze ( E), gaze is limited. 298 q 2009 North American Neuro- Ophthalmology Society J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 Hawthorne et al The precise mechanism of these early signs of restricted diffusion in ODS remains to be clarified ( 17,18,21,23), It may be that in the hypernatremic state, water shifts from the extracellular to the intracellular space. The decrease in free water in the extracellular space, combined with the trapping of water in cells, may lead to restricted diffusion. Although restricted diffusion generally represents cytotoxic edema, evidently in ODS it does not, as many patients, including ours, make full neurologic recovery. Treatment of ODS is aimed at prevention. Despite numerous published recommendations regarding correc-tion of hyponatremia, there are no universally accepted guidelines ( 2). Standard practice is that hyponatremia be corrected slowly. Even after cessation of treatment, serum sodium levels can continue to rise for up to 2 days. With this in mind, it is recommended that sodium correction be ceased once neurologic symptoms have abated or the serum sodium level has increased by 10% ( 24). Advances in fluid replacement guidelines and neuro-imaging techniques have led to improved prognosis of patients with ODS. In general, approximately one third of patients progress to complete recovery, one third are left with mild neurologic deficits, and one third are left with severe neurologic impairment ( 25). Therefore, early di-agnosis and proper treatment are critical in obtaining a good outcome in patients with ODS. REFERENCES 1. Adams RD, Victor M, Mancall EL. Central pontine myelinolysis: a hitherto undescribed disease occurring in alcoholic and malnour-ished patients. AMA Arch Neurol Psychiatry 1959; 81: 154- 72. 2. Martin RJ. Central pontine and extrapontine myelinolysis: the osmotic demyelination syndromes. 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