Clinical Course of Patients With Ophthalmoplegia Caused by Radiographically Detectable Brainstem Demyelination Occurring as a Clinically Isolated Demyelinating Syndrome

Demyelinating brainstem lesions often causing ophthalmoplegia may occur as the first manifestation of a clinically isolated demyelinating syndrome (CIS). CIS could be the initial attack of clinically definite multiple sclerosis (CDMS) should a second symptomatic attack occur. We report a series of patients with ophthalmoplegia occurring as CIS and assess potential factors affecting the clinical course and final outcome.A computer search was performed for patients evaluated in a university academic neurology practice to identify those with the diagnosis of diplopia. Selection was then made of patients who met the criteria for CIS, and these individuals formed the basis of this study.Ten of 327 patients presenting with diplopia fulfilled inclusion criteria. Of these, all had ophthalmoplegia in primary position of gaze or symptomatic internuclear ophthalmoplegia, and all recovered irrespective of brain MRI findings, steroid use, presence of oligoclonal bands, or progression to CDMS.The ophthalmoplegia of CIS tends to improve with time, regardless of later progression to CDMS. More analysis is needed to fully understand this unique presentation of demyelination.

Clinical Course of Patients With Ophthalmoplegia Caused by Radiographically Detectable Brainstem Demyelination Occurring as a Clinically Isolated Demyelinating Syndrome John H. Pula, MD, Kyle Brock, MD, Jorge C. Kattah, MD Background: Demyelinating brainstem lesions often causing ophthalmoplegia may occur as the first mani-festation of a clinically isolated demyelinating syndrome (CIS). CIS could be the initial attack of clinically definite multiple sclerosis (CDMS) should a second symptomatic attack occur. We report a series of patients with oph-thalmoplegia occurring as CIS and assess potential fac-tors affecting the clinical course and final outcome. Methods: A computer search was performed for patients evaluated in a university academic neurology practice to identify those with the diagnosis of diplopia. Selection was then made of patients who met the criteria for CIS, and these individuals formed the basis of this study. Results: Ten of 327 patients presenting with diplopia fulfilled inclusion criteria. Of these, all had oph-thalmoplegia in primary position of gaze or symptomatic internuclear ophthalmoplegia, and all recovered irre-spective of brain MRI findings, steroid use, presence of oligoclonal bands, or progression to CDMS. Conclusion: The ophthalmoplegia of CIS tends to improve with time, regardless of later progression to CDMS. More analysis is needed to fully understand this unique pre-sentation of demyelination. Journal of Neuro-Ophthalmology 2011;31:234-238 doi: 10.1097/WNO.0b013e31821a4851 2011 by North American Neuro-Ophthalmology Society While the spectrum of ocular motor abnormalities in multiple sclerosis (MS) has been previously reported (1-4), the course of ophthalmoplegia as a clinically isolated demyelinating syndrome (CIS) has been less well charac-terized (5-7). Knowledge regarding the evolution of oph-thalmoplegia in CIS is essential in establishing diagnostic criteria and developing prognostic and therapeutic recom-mendations. We identified a cohort of patients with isolated ophthalmoplegia from focal demyelination. While it is clear that the risk of developing clinically definite multiple sclerosis (CDMS) following CIS depends on multiple factors, especially the presence of multiple demyelinating lesions on brain MRI (8), there is little information re-garding whether the severity or course of ophthalmoplegia in CIS might be predictive of progression to CDMS. METHODS Approval from the University of Illinois Institutional Re-view Board was obtained. All cases of ophthalmoplegia presenting to our neuro-ophthalmology clinic between July 2003 and July 2007 were reviewed, and patients meeting eligibility criteria were selected (Table 1). Follow-up of selected cases continued until January 2010. All patients underwent neurologic and neuroophthalmologic examina-tion with documentation of eye position in primary gaze, assessment of saccadic pursuit and vergence eye movements, and qualification of prismatic correction. In all cases, data from the last recorded measurement were used as the final measurement. Eye movements were not recorded at every patient follow-up visit between first and final measurements. Patients were included only if brain MRI findings cor-related with the ocular motor disorder. At our institution, MRI was performed with a Siemens 1.5 Tesla Magnetom Vision/Plus and used a slice thickness of 5 mm with no gap, Department of Neurology and Neuro-Ophthalmology (JHP, JCK), University of Illinois College of Medicine at Peoria, Peoria, Illinois; and Saint Louis University School of Medicine (KB), St Louis, Missouri. Presented in part at the 57th Annual Meeting of the American Academy of Neurology, April 2005, Miami, FL. The authors have no conflicts of interest. Address correspondence to John H. Pula, MD, Department of Neurology and Neuro-Ophthalmology, University of Illinois College of Medicine at Peoria, 530 NE Glen Oak Avenue, Peoria, IL 61637; E-mail: [e-mail] 234 Pula et al: J Neuro-Ophthalmol 2011; 31: 234-238 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. including T1, T2, FLAIR, diffusion weighted imaging, and postcontrast sequences. Outside imaging used a 1.5-T MRI and included the same sequences. All films were reviewed by a neuroophthalmologist and neuroradiologist, both of whom had clinically relevant information prior to inter-preting the scan. All patients had a comprehensive meta-bolic panel, complete blood count and differential, sedimentation rate, and antinuclear antibody. Follow-up MRI, lumbar puncture, and treatment decisions depended on the clinical course of each patient. RESULTS Records of 327 consecutive cases presenting with diplopia to our neuro-ophthalmology clinic were reviewed. Of these, 17 (5%) met criteria for CIS. ‘‘However, 4 of these 17 patients did not have at least 10 months of follow-up, and 3 did not have a brain MRI lesion corresponding to their clinical deficit.'' Of the remaining 10 patients, the mean age at presentation was 29.8 years (range, 18-46 years; median, 31.5 years), and 7 were women. Six of 10 patients had an isolated sixth nerve palsy (Fig. 1). The range of esotropia in primary position was 2-20 prism diopters, and all worsened with abduction of the paretic eye. Three patients had a unilateral internuclear ophthalmoplegia (INO), and 1 patient had a one-and-a-half syndrome. All cases of INO had nystagmus of the abducting eye, and none had skew deviation. Mean total patient follow-up was 43.9 months (median, 28 months; range, 10-122 months). Eye movement measurements were recorded on at least 2 occasions. Range between initial and final measurements was 1-122 months. At final examination, all 10 patients were orthophoric in primary position. Table 2 summarizes the clinical features of our patient cohort. In 3 patients with sixth nerve palsy, there was a residual ophthalmoplegia ranging from 6 to 16 diopters in the di-rection of the paretic muscle over 30-98 months of follow-up. In 1 case (Case 2), the esotropia increased to 12 prism diopters in primary position and 25 prism diopters in left gaze within the first 3 weeks before improving. All 3 patients who presented with INO experienced full recovery. Case 9 presented with a one-and-a-half syndrome with impaired right gaze and an adduction deficit in the right eye. During the course of follow-up, the one-and-a-half syndrome resolved, but the patient later developed a left sixth nerve palsy. Of the 10 patients, 7 had other asymptomatic lesions on brain MRI at presentation. These MRI abnormalities in-cluded T1 hypointensities (black holes), enhancing lesions, and cerebellar hyperintensities, all occurring in presumably noneloquent areas of the parenchyma. The maximum TABLE 1. Inclusion and exclusion criteria for analysis Inclusion Criteria Exclusion Criteria Age 18-55 years Prior diagnosis of MS Initial presentation of diplopia Symptoms or signs other than diplopia or ophthalmoplegia Symptomatic lesion visible on MRI Risk factors for ischemia Ophthalmoplegia on examination Follow-up of at least 10 months History of trauma, tumor, sarcoid, myasthenia gravis, aneurysm, migraine, hematoma, or infection FIG. 1. Patient 2. T2 axial (A) and T2 coronal (B) MRIs demonstrate lesion (arrows) in the right pontomedullary tegmentum resulting in an ipsilateral sixth nerve palsy. Pula et al: J Neuro-Ophthalmol 2011; 31: 234-238 235 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 2. Clinical features and follow-up data for patients presenting with ophthalmoplegia as a CIS with a corresponding MRI lesion Patient Number (Age at Presentation/ Sex) Initial Eye Motility Measurement Time Between Initial and Final Measurements (Months) Final Eye Motility Measurement Symptomatic Lesion Location on Initial Brain MRI Asymptomatic T2 Lesions on Initial Brain MRI Total Follow-up Time (Months) Lumbar Puncture Steroids (1 g of IVMP 3 5 d) After Initial Attack Follow-up Course 1 (31/M) 20D E PP; 35D E gaze R 16 Ortho all R pons Yes 16 No Yes No IM or new clinical attacks 2 (22/M) 4D E PP; 6D E gaze R 30 Ortho PP; 6D E gaze R R pons Yes 30 Yes (.5 OCB) Yes Symptomatic INO after 7 months with new cervical cord and brain MRI lesions; started natalizumab 3 (33/F) 20D E PP; 35D E gaze L 55 Ortho PP; 16D E gaze L L pons Yes 67 No Yes Started interferon beta-1b; no new MRI lesions or symptoms 4 (32/M) R INO 19 Ortho all; no INO R periaqueductal Yes 18 Yes (no OCB) Yes No IM or new clinical attacks 5 (38/F) R INO 122 Ortho all; no INO R cerebral peduncle No 122 No No New enhancing lesions on 9-month brain MRI, glatiramer started at that time 6 (37/F) 16D E PP; 30D E gaze R 23 Ortho all R pons Yes 30 No Yes Developed optic neuritis within follow-up period 7 (22/F) 4D E PP; 8D E gaze R 25 Ortho all R pons No 26 No No Optic neuritis after 18 months + new brain MRI lesions 8 (19/F) L INO 1 Ortho all; no INO L midbrain No 18 Yes (no OCB) No No IM or new clinical attacks 9 (46/F) R one-and-a-half syndrome 98 Ortho PP; 8D E gaze L R pons Yes 102 Yes (no OCB) Yes No clinical attacks; new MRI lesions at 72 months; started glatiramer 10 (18/F) 2D E PP; 10D E gaze L 2 Ortho all L pons Yes 10 No Yes Optic neuritis after 9 months; entered into clinical trial at that time d, days; E, esotropia; F, female; gaze L, in left gaze; gaze R, in right gaze; IM, immunomodulatory therapy; IVMP, intravenous methylprednisolone; M, male; OCB, oligoclonal bands; ortho all, orthophoric in all directions of gaze; ortho PP, orthophoric in the primary position of gaze. 236 Pula et al: J Neuro-Ophthalmol 2011; 31: 234-238 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. number of asymptomatic white matter lesions was 24. There was no relationship between the clinical presentations either to the size of the symptomatic lesion or to lesion proximity to the ocular motor cranial nerve nucleus. During the study period, 4 patients developed a second clinical attack diagnostic of CDMS. Case 2 developed a symptomatic INO, and Cases 6, 7, and 10 developed optic neuritis. Three patients who received steroids and 1 of 3 who did not receive steroids developed CDMS. All 3 pa-tients with a residual ophthalmoplegia had received steroids during their initial attack. Cases 1, 5, and 9 developed new white matter lesions on brain MRI without progressing to CDMS. Of the 4 patients who developed CDMS, 3 (Cases 2, 6, and 10) had asymptomatic white matter lesions on brain MRI at pre-sentation. Case 7 initially had no asymptomatic brain MRI lesions; however, over 24 months, Case 7 developed 6 new brain MRI lesions and a second clinical attack. Four patients underwent spinal tap. One patient who had oligoclonal bands (OCB) developed CDMS. Three patients with no OCB have not developed MS (range of follow-up: 18-102 months). Regarding 3 patients with CIS who would otherwise have met inclusion criteria, except they lacked a corresponding symptomatic brainstem MRI lesion, 2 had other asymp-tomatic brain MRI lesions consistent with demyelination. These 2 patients have progressed to CDMS, while the 1 patient with a normal brain MRI did not. The oph-thalmoplegia in all 3 of these patients improved over time. DISCUSSION Relapsing-remitting MS involves both inflammatory and neurodegenerative processes. While the underlying patho-physiology probably involves both genetic and environ-mental factors, specific triggers for the onset and clinical course of the disease are unknown. Although CIS often represents early MS (9), this is not always the case. Late MS is associated with progressive atrophy and axonal loss, with fewer relapses and remissions than the predominant in-flammatory attacks of early MS (10). For this reason, data specifically regarding the course of CIS ophthalmoplegia may help determine if there are clinical findings or test results that could distinguish it from ophthalmoplegia due to MS. MS plaques with the brainstem causing diplopia may involve the nuclear or fascicular portion of ocular motor cranial nerves or the medial longitudinal fasciculus. The most common deficit in our series was sixth nerve palsy followed by INO and one-and-a-half syndrome. Our series did not include patients with a third or fourth nerve palsy, which is uncommon in MS (11,12), or a skew deviation, which often occurs with INO. The ophthalmoplegia improved in all our patients, and at last examination, they were all orthophoric in primary position. Three patients continued to have a residual phoria after 30-98 months of follow-up. This high rate of im-provement correlates with other reports of CIS (13) and suggests that ophthalmoplegia, which worsens over time, should be reevaluated for causes other than demyelination. Our results also indicate that initial treatment for diplopia should be prismatic correction, and surgical correction, if considered, should not be performed until repeat exami-nations show that eye position is stable. Steroids given at onset of ophthalmoplegia (Table 2) did not appear to alter the clinical outcome. The 3 patients not given steroids were orthophoric at their last evaluation. All 3 patients with residual phoria in lateral gaze received steroids initially. Because follow-up testing intervals were variable, it is unclear if steroids decrease symptom duration (14). The American Academy of Neurology has a practice parameter regarding the use of steroids to treat ON (15). While no such protocol exists for brainstem demyelination, it is our practice to discuss treatment options with our patients and reach a shared conclusion. To be included in our series, all patients had lesions on MRI correlating to their clinical deficit. In patients who met inclusion criteria except for not having a visible MRI lesion, INO was the most common presentation. In other series, MRI lesion detection rate for INO varies from 45% to 100% (16). It will be notable, as more case series are reported, to determine if there is a correlation between the size and location of the demyelinating lesion on MRI and the degree of ophthalmoplegia. In this underpowered series, we were unable to find a correlation with size of the lesion on MRI to the clinical syndrome or the degree of ophthalmoplegia. Although a few lesions appeared to involve the abducens nucleus, no gaze palsy was observed. We and others note that T2 and proton density sequences provide the best views of the brainstem (17). A limitation of our study was that only 1.5-T MRI was used. The use of 3-T MRI would likely have increased the number of patients in our cohort, as symptomatic lesions unseen with 1.5-T MRI may have been visible with a stronger magnet. Other limitations include retrospective analysis, lack of uniformity in follow-up and measurement interval, and variation in treatment with steroids and im-munomodulatory agents. Initiating treatment after a first demyelinating event may delay the onset of CDMS (9). However, there continues to be a debate regarding the appropriate time to start MS therapies (18). We discuss this controversy with our patients and engage them in the decision-making process. Some start immunomodulation after an initial demyelinating event, while others elect to be monitored clinically or for MRI changes. Analysis of more patients with CIS presenting as ophthalmoplegia will hopefully clarify features predictive of the clinical course. For example, in optic neuritis, the presence of a macular star or peripapillary hemorrhages argues against future demyelination. Brainstem lesions in Pula et al: J Neuro-Ophthalmol 2011; 31: 234-238 237 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. general are associated with increased conversion from CIS to CDMS and with greater disability (19). More cases should be studied to determine if the specific features of oph-thalmoplegia in CIS differentiate progression to CDMS or higher disability. In our series, diplopia caused by CIS with a correlating lesion on MRI improved over time, inde-pendent of conversion to CDMS. REFERENCES 1. Eggenberger E. Neuro-ophthalmology of multiple sclerosis. Curr Opin Ophthalmol. 1996;7:19-29. 2. Pula JH, Reder AT. Multiple sclerosis. Part I: neuro-ophthalmic manifestations. Curr Opin Ophthalmol. 2009;20:467-475. 3. Tho¨mke F, Lensch E, Ringel K, Hopf HC. Isolated cranial nerve palsies in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1997;63:682-685. 4. Frohman E, Frohman TC, Zee DS, McColl R, Galetta S. The neuro-ophthalmology of multiple sclerosis. Lancet Neurol. 2005;4:111-121. 5. Barr D, Kupersmith MJ, Turbin R, Bose S, Roth R. Isolated sixth nerve palsy: an uncommon presenting sign of multiple sclerosis. J Neurol. 2000;247:701-704. 6. Moster ML, Savino PJ, Sergott RC, Bosley TM, Schatz NJ. Isolated sixth-nerve palsies in younger adults. Arch Ophthalmol. 1984;102:1328-1330. 7. Sastre-Garriga J, Tintore´ M, Nos C, Tur C, Rı´o J, Te´llez N, Castillo´ J, Horga A, Perkal H, Comabella M, Rovira A, Montalban X. Clinical features of CIS of the brainstem/ cerebellum of the kind seen in MS. J Neurol. 2010;257: 742-746. 8. Optic Neuritis Study Group. Multiple sclerosis risk after optic neuritis: final optic neuritis treatment trial follow-up. Arch Neurol. 2008;65:727-732. 9. Frohman EM, Havrdova E, Lublin F, Barkhof F, Achiron A, Sharief MK, Stuve O, Racke MK, Steinman L, Weiner H, Olek M, Zivadinov R, Corboy J, Raine C, Cutter G, Richert J, Filippi M. Most patients with multiple sclerosis or clinically isolated demyelinating syndrome should be treated at the time of diagnosis. Arch Neurol. 2006;63:614-619. 10. Cook S. Handbook of Multiple Sclerosis, 4th edition. New York, NY: Taylor and Francis Group Publishers, 2006. 11. Newman NJ, Lessell S. Isolated pupil-sparing third-nerve palsy as the presenting sign of multiple sclerosis. Arch Neurol. 1990;47:817-818. 12. Jacobson DM, Moster ML, Eggenberger ER, Galetta SL, Liu GT. Isolated trochlear nerve palsy in patients with multiple sclerosis. Neurology. 1999;53:877-879. 13. Optic Neuritis Study Group. Visual function 15 years after optic neuritis. Ophthalmology. 2008;115:1079-1082. 14. Beck RW, Gal RL. Treatment of acute optic neuritis. Arch Ophthalmol. 2008;126:994-995. 15. Kaufman DI, Trobe JD, Eggenberger ER, Whitaker JN. Practice parameter: the role of corticosteroids in the management of acute monosymptomatic optic neuritis. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;54: 2039-2044. 16. Frohman EM, Zhang H, Kramer PD, Fleckenstein J, Hawker K, Racke MK, Frohman TC. MRI characteristics of the MLF in MS patients with chronic internuclear ophthalmoparesis. Neurology. 2001;57:762-768. 17. Miller D, Barkhof F, Montalban X, Thompson A, Filippi M. Clinically isolated syndromes suggestive of multiple sclerosis, part 2: non-conventional MRI, recovery, processes, and management. Lancet Neurol. 2005;4: 341-348. 18. Pittock S, Weinshenker B, Noseworthy J, Lucchinetti C, Keegan M, Wingerchuck D, Carter J, Shuster E, Rodriguez M. Not every patient with multiple sclerosis should be treated at time of diagnosis. Arch Neurol. 2006;63: 611-614. 19. Tintore M, Rovira A, Arrambide G, Mitjana R, Rı´o J, Auger C, Nos C, Edo MC, Castillo´ J, Horga A, Perez-Miralles F, Huerga E, Comabella M, Sastre-Garriga J, Montalban X. Brainstem lesions in clinically isolated syndromes. Neurology. 2010; 75:1933-1938. 238 Pula et al: J Neuro-Ophthalmol 2011; 31: 234-238 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.