Longitudinally extensive optic neuritis in neuromyelitis optica spectrum disorder

Journal of the Neurological Sciences 345 (2014) 209–212

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Longitudinally extensive optic neuritis in neuromyelitis optica spectrum disorder John H. Pula a,⁎, Jorge C. Kattah b, Bonnie Keung b, Huaping Wang c, Jennifer Daily d a

Department of Neurology, NorthShore University Health System Glenview, IL 60026, USA Department of Neurology, University of Illinois College of Medicine at Peoria, USA University of Illinois College of Medicine at Peoria, USA d University of Buffalo School of Medicine and Biomedical Sciences, USA b c

a r t i c l e

i n f o

Article history: Received 17 May 2014 Received in revised form 20 July 2014 Accepted 21 July 2014 Available online 28 July 2014 Keywords: Longitudinally extensive Optic neuritis Neuromyelitis optica NMO NMO spectrum disorder Multiple sclerosis

a b s t r a c t Background: Neuomyelitis optica, sarcoid, and multiple sclerosis can all cause optic neuritis. Further means of distinguishing the causes of optic neuritis among these etiologies would be valuable for the clinician. Methods: This is a retrospective, cohort study from a single university based hospital and neuro-ophthalmology clinic. Blinded interpretation of orbit MRIs was performed on patients with acute optic neuritis from multiple sclerosis (n = 25), sarcoid (n = 5) and neuromyelitis optica spectrum disorder (n = 6). Results: A length of N40 mm anterior visual pathway enhancement distinguished neuromyelitis optica spectrum disorder from multiple sclerosis (p = 0.0376). No statistically significant differences were found for presence of pain or papillitis, however there was a trend for bilateral involvement and chiasmal involvement in neuromyelitis optica spectrum disorder compared to multiple sclerosis. Conclusions: In acute optic neuritis, enhancing anterior visual pathway lesion length N 40 mm helps differentiate neuromyelitis optica spectrum disorder from multiple sclerosis. This degree of involvement can be considered longitudinally extensive optic neuritis. Further characterization is necessary as this degree of enhancement occurs in other clinical syndromes besides neuromyelitis optica. © 2014 Elsevier B.V. All rights reserved.

1. Introduction The anterior visual pathway (AVP) is morphologically and physiologically part of the central nervous system, with a similar response to injury. Demyelinating and inflammatory processes that affect the AVP are typically disruptive of the local blood brain barrier. In optic neuritis (ON), this phenomenon manifests as contrast enhancement on magnetic resonance imaging (MRI) [1]. The purpose of this study was to evaluate for longitudinal extension of radiographic AVP enhancement among different diseases causing optic neuritis. Research rationale was based upon the fact that the neurobiology of spinal cord and anterior visual pathways possesses similar clinical and pathologic characteristics. Eugene Devic noted this in the original descriptions of his eponymous disease [2,3]. Moreover, radiographic extensive involvement differentiates transverse myelitis (TM) in neuromyelitis optica spectrum disorders (NMOSD) from other etiologies such as multiple sclerosis (MS) [4]. Our major hypothesis was that AVP enhancement would more often be longitudinally extensive in NMOSD more often than in other causes of ON such as MS or sarcoidosis. Although AVP enhancement

⁎ Corresponding author at: University of Illinois College of Medicine in Peoria, 530 NE Glen Oak Avenue, Peoria, IL 61637, USA. Tel.: +1 847 657 58001; fax: +1 309 655 2040. E-mail address: [email protected] (J.H. Pula).

http://dx.doi.org/10.1016/j.jns.2014.07.049 0022-510X/© 2014 Elsevier B.V. All rights reserved.

may involve the nerves, chiasm, or optic tracts, for simplicity we refer to this condition as longitudinally extensive optic neuritis (LEON). 2. Methods This is a retrospective cohort study. A University Institutional Review Board approved the data review of patient records and imaging by the investigators. The study setting was a single neuro-ophthalmology practice in a University hospital and clinic. A retrospective review of consecutive patients presenting with presumed inflammatory optic neuritis between 2009 and 2012 was performed. Patient selection was based on a clinical diagnosis of optic neuritis in the context of multiple sclerosis, sarcoidosis, or NMOSD. Sarcoidosis was diagnosed based on pathologic confirmation. NMOSD was defined as optic neuritis in the setting of aquaporin-4 seropositive status. Multiple sclerosis was diagnosed based on revised McDonald criteria. Inclusion criteria involved fatsuppression orbit MRI sequences confirming pathologic AVP enhancement, and neuro-ophthalmologic exam within four weeks of optic neuritis onset. Patients were excluded if they received corticosteroids or other immunosuppression for the acute optic neuritis episode prior to MRI. Thirty-six patients met study criteria. Digitized orbit MR images for these patients were coded and transferred to a review station. Fig. 1 displays representative orbit MRI image measurement technique.

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J.H. Pula et al. / Journal of the Neurological Sciences 345 (2014) 209–212

Fig. 1. Measurement technique of enhancement measurement for post-gadolinium orbit MRI. Fat saturation post-gadolinium orbit MRI sequences showing representative measurements for both MS (A) and NMOSD (B).

Blinded to etiology or clinical characteristics, one author (BK) determined 1) length of contiguous radiographic AVP enhancement, 2) presence or absence of bilateral optic nerve involvement, and 3) presence or absence of chiasmal involvement. Based on clinical records, 1) presence or absence of pain, and 2) presence or absence of papillitis were also recorded. 40 mm total AVP enhancement and 50 mm total AVP enhancement were chosen as lengths considered longitudinally extensive. The main outcome measure was the presence of longitudinal extension in NMOSD versus MS and sarcoid. Parts of this manuscript were presented at platform session S37 as: Longitudinally Extensive Optic Neuritis Distinguishes Neuromyelitis Optica from Multiple Sclerosis, at the 2013 American Academy of Neurology annual meeting in San Diego, California. There was no industry sponsorship or outside funding for this study. 3. Statistical analysis Fisher's exact tests were used for categorical variable comparisons due to empty cells and smaller cell counts. For continuous variables, Wilcoxon two-sample test was conducted because of the small sample size. Statistical analyses were performed using SAS 9.3 (SAS Institute Inc., Cary, NC). Two-tailed p values were calculated for all tests and p b 0.05 was considered statistically significant.

than 40 mm as compared to MS. No statistically significant differences were found in other categories; however there was a trend for bilateral involvement (4% in MS, 33% in NMOSD) and chiasmal involvement (8% in MS, 33% in NMOSD). Table 1 details patient data and p values. Lengths of AVP enhancement for NMOSD, MS, and sarcoid are depicted in the boxplot in Fig. 2. MS AVP mean involvement was 22.67 mm (range 4.39–42.0, sd 10.27). NMO AVP mean was 37.68 mm (range 22.6–54.0, sd 11.60). Sarcoid AVP mean was 27.05 mm (range 9.98–48.84, sd 17.49). The mean AVP difference did not reach statistical significance among the three groups.

5. Discussion Although some reviews have described NMOSD optic neuritis as more extensive than MS [5], only rare reports have included radiographic Table 1 Pairwise comparisons for the three groups: NMOSD, MS, and sarcoid.

N40 mm

4. Results

N50 mm

Patients with NMOSD, sarcoid, and MS were compared for the following outcome variables: N 40 mm AVP enhancement length, N50 mm AVP enhancement length, bilateral optic nerve involvement, chiasm involvement, pain, and papillitis. The only statistically significant difference among any group was N 40 mm AVP enhancement length in NMOSD versus MS (p = 0.0376), with the NMOSD group more likely to have a length of radiographic AVP enhancement greater

Bilateral Chiasm Pain Papillitis

Y N Y N Y N Y N Y N Y N

NMO

MS

Sarcoid

NMOSD vs MS

NMOSD vs sarcoid

MS vs sarcoid

n

n

n

p

p

p

3 (50) 3 (50) 1 (16.7) 5 (83.3) 2 (33.3) 4 (66.7) 2 (33.3) 4 (66.7) 4 (66.7) 2 (33.3) 2 (33.3) 4 (66.7)

2(8) 23(92) 0(0) 25(100) 1(4) 24(96) 2(8) 23(96) 19(76) 6(24) 10(40) 15(60)

2(40) 3(60) 0(0) 5(100) 1(20) 4(80) 0(0) 5(100) 4(80) 1(20) 3(60) 2(40)

0.0376

1.0

0.119

0.194

1.0

N/A

0.088

1.0

0.310

0.160

0.454

1.0

0.634

1.0

1.0

1.0

0.567

0.628

J.H. Pula et al. / Journal of the Neurological Sciences 345 (2014) 209–212

Fig. 2. Boxplot analysis representing distribution of total anterior visual pathway enhancement in multiple sclerosis, NMOSD, and sarcoid. Overall, enhancement length was greater in NMOSD as compared to MS. Mean enhancement length in each group is represented by (+). As expected, pain was present in the majority of patients with optic neuritis. Neither pain nor papillitis differentiated the etiology. The only radiographical statistically significant difference in the groups was longitudinally extensive involvement greater than 40 mm distinguishing neuromyelitis optica spectrum disorder from multiple sclerosis.

analysis. Khanna et al. compared six NMO and 11 MS patients with optic neuritis and found no differences in presence, degree, extent, or type of signal change between the two groups [6]. Lesion lengths in this study were based on fraction of nerve involvement rather than total length, and LEON was not evaluated. Lim et al. reported a series of 7 NMO and 2 MS patients with optic neuritis, and found no difference in severity of swelling and enhancement between the two groups [7], but no details regarding measurement methodology or results were presented. Storoni et al. measured the extent of optic pathway involvement in optic neuritis using a novel method in which the AVP was divided into 10 segments [8]. Patients with NMOSD averaged an involvement of 4.4 segments, compared to 2.2 segments in MS. Optic tract and chiasm involvement were more common in NMO for both the Khanna and Lim studies, but lesions in these locations are not specific for NMO, and also occur in MS and sarcoid [9,10]. To our knowledge, our study is the first to compare the length of optic nerve enhancement among different causes of optic neuritis in a particular attempt to describe longitudinally extensive involvement. Three patients were excluded from analysis due to not meeting etiologic inclusion criteria. Although all three fulfilled both clinical and radiographic inclusion specifications, they did not have sarcoid, MS, or NMOSD. These three patients had AVP enhancement lengths of 30.4 mm, 102.9 mm, and 103.0 mm. The two patients with AVP involvement N100 mm had bilateral nerve and chiasm involvement, and were clinically similar to NMO, however they were seronegative for the aquaporin-4 water channel antibody. Because neither had a history of transverse myelitis, they did not meet the diagnostic criteria for NMO. Although the diagnosis of NMO itself does not require aquaporin-4 water channel, the criteria for NMOSD does require seropositivity for the NMO antibody [11]. For this study, we used the definition of optic neuritis with a positive NMO antibody to define NMOSD [12]. None of the three patients above had MS based on lack of typical brain MRI lesions. Two had an otherwise normal brain MRI and one had only a medullary lesion (clinically manifesting with intractable vomiting). The latter has been shown to be particularly prevalent in NMO [13]. Based on this fourth subgroup of patients, it is apparent that LEON, though seemingly helpful in distinguishing MS, is not specific to NMOSD. In the future, other antibodies besides aquaporin-4 will likely be uncovered, as was myelin oligodendrocyte glycoprotein [14], and this will account for seronegative patients otherwise clinically

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similar to NMO. Based on our series, we suspect LETM will also help distinguish these presentations from MS. One limitation to our analysis is that not all patients with a clinical diagnosis of MS were checked for NMO seropositivity. This may have led to a selection bias, as some patients with NMOSD have abnormal brain MRIs suggestive of MS [15]. However, in our study all patients with LEON either had NMO antibodies or did not have a brain MRI consistent with MS. There is no specific criteria defining longitudinally extensive optic neuritis. In TM, a longitudinally extensive lesion spans three or more vertebral lengths [16]. The lack of an equivalent anatomic marker may explain why no correlate exists in ON. Steroni et al.'s study provided the first objective definition of longitudinal extension, citing involvement of 4 or greater of the 10 AVP segments as highly suggestive of NMO. Also, Steroni's group found that 11/12 NMOSD AVP lesions were contiguous, which was a similar observation in our cohort. These findings are consistent with ours in that longitudinal extension may be a feature of NMOSD ON, similar to (and probably causal upon) chiasm and bilateral involvement. There is no consensus regarding which ON patients should undergo serologic NMO antibody testing [17]. Our findings provide an additional element which, when present, favors serum antibody testing. Additionally, although radiographic confirmation is not required to diagnose optic neuritis, orbital MRI sequences can add important information. In multiple sclerosis, the extent of enhancement in ON was found not to be predictive of recovery, but did correlate to initial visual deficits [18]. Our results support including orbital MRI (in addition to brain MRI) for the workup of ON. 6. Conclusion In acute optic neuritis, enhancing anterior visual pathway lesion length N 40 mm helps differentiate NMOSD from MS. This degree of involvement can be considered longitudinally extensive optic neuritis. Further characterization is necessary as LEON occurs in other clinical syndromes besides NMOSD. Author contributions John H Pula: Approved and implemented the study hypothesis. Study design. Examined patients. Drafting and revising of manuscript. Approved final manuscript. Jorge C Kattah: Hypothesis formulation and study design. Examined patients. Drafting and revising of manuscript. Approved final manuscript. Jennifer Daily: Reviewed records. Reported clinical data. Approved final manuscript. Bonnie Keung: Performed radiographic analysis. Approved final manuscript. Huaping Wang: Performed statistical analysis. Approved final manuscript. Study funding None. Conflict of interest The authors report no disclosures relevant to the manuscript. The authors alone are responsible for this manuscript. The authors have no conflicts of interest to report. There was no sponsorship or funding for this project. Acknowledgments The authors thank Mrs. Lynn Bannon and Mrs. Connie Johnson for their assistance in the preparation of this manuscript.

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