Acta Neurol Belg DOI 10.1007/s13760-015-0479-z
ORIGINAL ARTICLE
Longitudinally extensive transverse myelitis in neuromyelitis optica: a prospective study of 13 Caucasian patients and literature review Rodica Ba˘las¸ a1,3 • Smaranda Maier1 • Zoltan Bajko1 • Anca Motataianu1 Alexandra Cris¸ an1 • Adrian Ba˘las¸ a2
•
Received: 29 September 2014 / Accepted: 17 April 2015 Ó Belgian Neurological Society 2015
Abstract Neuromyelitis optica (NMO) is a homogenous disease that can be diagnosed by an association of clinical, neuroimaging and serological aspects. We analysed our 4 years NMO series with longitudinally extensive transverse myelitis (LETM) during the disease course. We included consecutive adult Caucasian patients who were diagnosed with definite NMO, or cases of NMO-IgG seropositive LETM considered as limited forms of NMO. Patients included were negative for other diseases (autoimmune, infectious, etc.). We report the Expanded Disability Status Scale (EDSS), brain and spine MRI, CSF, NMO-IgG, treatment, motor and visual outcome. Thirteen cases fulfilled the inclusion criteria, and the mean follow-up period was 3.74 ± 1.8 years. The initial motor deficit was severe with the mean value of motor functional parameter of 4.46 ± 1 and improved at discharge to 2.53 ± 1.4 (p \ 0.001). With treatment, the outcome after LETM attack was good in 10 patients, with a significant improvement of the EDSS mainly upon motor deficit, while visual function had a very slight amelioration. The CSF analysis was normal in 8 cases; spinal MRI showed evidence of LETM in all patients while brain MRI was normal in 7. NMO-IgG is a & Rodica Ba˘las¸ a [email protected] 1
First Neurological Clinic, Multiple Sclerosis Centre, Emergency County Hospital, University of Medicine and Pharmacy, Targu Mures, Romania
2
Neurosurgical Clinic, Emergency County Hospital, University of Medicine and Pharmacy, Targu Mures, Romania
3
Mures¸ County Clinical Emergency Hospital, Neurology Clinic I, Gh. Marinescu 50, 540136 Taˆrgu Mures¸ , Mures¸ County, Romania
biomarker for NMO that is of diagnostic value in cases of isolated LETM. LETM has a better outcome than ON in NMO Caucasians. Spinal MRI is essential for NMO diagnosis in the presence of LETM and the absence of multiple brain MRI lesions. Maintenance immunosuppressive therapy reduces the frequency of attacks. Keywords Neuromyelitis optica Devic disease Longitudinal extensive transverse myelitis Azathioprine
Introduction Neuromyelitis optica (NMO), also known as Devic’s disease, is an inflammatory demyelinating disease that consists of recurrent attacks of longitudinally extensive transverse myelitis (LETM) and optic neuritis (ON). Since the first description by Devic in 1894, NMO has been sometimes confounded with the optic-spinal form of multiple sclerosis (MS). In 2004, Lennon et al. [1] discovered that the syndrome was associated with a specific autoantibody (NMO-IgG) that binds to the water channel aquaporin-4. Revised diagnostic criteria were elaborated in 2006 by Wingerchuk et al. [2], which consist of the required criteria of LETM and ON and at least two of the following three supportive criteria: (1a) magnetic resonance imaging (MRI) of the brain not meeting the diagnostic criteria for MS; (b) MRI of a spinal cord lesion extending over C3 vertebral segments; (c) NMO-IgG seropositivity. From a pathological point of view, the spinal cord involvement in NMO is characterised in the acute phase by a notable axonal injury leading to diffuse swelling. In severe cases, the entire spinal cord is affected by a continuous or patchy distribution [3].
123
Acta Neurol Belg
Pathophysiologically, NMO features a predominantly T helper type 2 immune response with prominent humoral mechanisms; the important therapeutic implication is response to plasma exchange. Due to the strategic location of the demyelinating lesions and their failure to remyelinate, the clinical manifestations are very severe and sometimes lead to important sequelae [4]. The serum biomarker of NMO is NMO-IgG (also termed aquaporin-4 antibodies; AQP4-Ab), which binds selectively to the water channel protein aquaporin-4, destroying it, regardless of the stage or site of involvement. Demyelination in NMO is different than in MS and is secondary to (a) oligodendrocytes which are injured at the paranode where they are in contact with astrocytic foot processes containing AQP4; (b) demyelination which is determined by the axonal injury at the internode; c) glutamate toxicity. NMO-specific lesions (loss of AQP4) were described in the area postrema also. In the brain, this water channel is mostly situated in astrocytic foot processes at the blood–brain barrier (BBB) having an important role in the integrity and function of the BBB. In NMO, astrocytic damage can be the primary pathology [1, 3, 5, 6]. We analysed our 4-year NMO series to identify patients that were diagnosed, treated and followed in our MS centre and who had LETM at the onset or during the clinical course of the disease. In this study, we aimed to determine the characteristics of LETM in definite NMO or isolated forms of NMO (LETM plus NMO-IgG positive) in a Caucasian population in which any other known spinal cord demyelinating aetiologies had been excluded. To the best of our knowledge, no study with these inclusion criteria has been performed before.
Materials and methods This was a prospective observational study that included all consecutive single or recurrent LETM cases that either fulfilled the criteria for NMO or for limited forms of NMO. We included patients diagnosed in a 4-year interval (1 April 2010–31 March 2014) in the MS Centre from Emergency County Hospital, Targu Mures, Romania. All patients or a first-degree relative signed an inform consent; the study was approved by the local ethics committee and was carried out according to the Declaration of Helsinki. We included adult Caucasians patients who fulfilled NMO Wingerchuk et al. [2] criteria for NMO, or cases of NMO-IgG seropositive LETM considered according to Weinshenker et al. [5] as limited forms of NMO. We included consecutive patients older than 18, with a monophasic or polyphasic evolution of NMO, for whom medical information regarding clinical attacks, visual
123
evoked potentials (VEP), spinal and brain MRI, and serum NMO-IgG were available. We excluded patients who had been shown to be positive for other autoimmune connective diseases (Sjogren syndrome, systemic lupus erythematosus, anti-phospholipid antibodies, sarcoidosis, etc.), or any other infectious, neoplasia or deficiency diseases of the nervous system or patients with an attack of acute myelitis (\3 vertebral segments), patients with brain MRI meeting diagnostic criteria for MS, or patients suspected of having NMO but without LETM (cases with ON and positive for NMO-IgG, etcetera). Upon admission, for each patient we documented the demographic information (sex, age at LETM or NMO onset, history of autoimmunity), medical history, clinical course of the neurological deficit, and all recorded laboratory and imaging data (Table 1). All patients underwent a complete neurological examination with the calculation of Expanded Disability Status Scale (EDSS) both at admission and at discharge [7]. The same clinical evaluation, together with evidence of new relapses, was performed at follow-up. The detection of NMO-IgG in the serum of the patients was performed by enzyme-linked immunosorbent assay (ELISA). The interpretation was as follows: positive AQP4 Ab C6 U/mL and negative AQP-4Ab B4 U/mL; values of 5 U/mL were considered inconclusive and the detection was repeated. We documented only the negative/positive status of our patients and not the value of NMO-IgG. The majority of patients (12; 92.3 %) underwent cerebrospinal fluid (CSF) analyses. Normal values of CSF were considered: proteins 15–60 mg/dL, white blood cell counts 0–5/mm3. All patients underwent MRI of the spinal cord and of the brain using a GE Sigma 1.5 T scanner. The spinal cord was imaged in the sagittal and axial plane. The dimension, location and signal intensity of the demyelinating spinal lesion were measured and marked down. The brain MRI was performed in the axial plane with 3 mm thick slices and the number, dimension and location of demyelinating lesions were noted. Statistical analysis Differences between variables were described using standard statistics and were evaluated for significance using t tests or Wilcoxon’s rank-sum tests. Differences were considered significant if p value was \0.05.
Results A total of 13 cases fulfilled the inclusion criteria for a period of 4 years. Their mean age at LETM onset was 31.8 years, SD ± 14.4. Sex distribution was as follows: 9
56/F
26/F
26/M
22/F
18/M
37/M
44/F
19/F
36/F
61/M
18/F
21/F
30/F
VEP P100 latency
LE 130 ms
1 BE
2 BF
3 BN
4 BK
5 BL
6 TJ
7 PI
8 MU
9 OG
10 RI
11 MN
12 RC
13 LA
Patient
1 BE
LE 160 ms with low amplitude RE 117 ms
LE 112 ms, RE 130 ms
LE 140 ms, RE P100 absent
3 BN
4 BK
0.4
7
20
5
1
4
0.3
1
7
3
4
8
0
Disease duration, y
2 BF
RE 130 ms
Onset age, y/sex
Patient
LETM
C3–D1
Cervical C1-C4 T2,FLAIR hyperintensities
C5–D3
Cervivothoracic T2, STIR hyperintensity
Spinal MRI lesion
2
NMO
NMO
&15 4
LETM
NMO
LETM
NMO
NMO
NMO
NMO
NMO
NMO
LETM
Phenotype
4
4
1
1
1
2
4
1
2
1
Total no.of attacks
6.0/4.0
4.5/3.0
6.0/3.5
4/2.5
6.5/6.0
7.5/4.0
T2 FLAIR hyperintense left pontomesencephalic lesion
2 Small demyelinating cerebral lesions
Normal
0–0
5–3
3–3
4–2
5–4
4–2
4–2
5–5
5–3
Normal
Normal
Elevated proteins and
Normal
limphocytes
None
2
6
None
CSF cell counts
NMO IgG
present
present
absent
present
MP/OCS ? Imuran
MP/OCS
MP/OCS ? Imuran
MP/Imuran
Treatment of the attack/long-term
No
Yes
Yes
No
Yes
No
No
6–4
yes
4–1
No
Yes
No
Yes
No
Severe visual disability
6–5 6–decesed
3–2
3–1
5–5
4–1
3–1
3–2
5–5
4–2
6–4
FP pyramidal at onset/at discharge/visual at onset/at discharge
CSF protein, mg/Dl
8.0/decesed
6.0./4.0
4.0/2.0
6.0/4.0
4.5/2.5
6.5/4
6.0/4.5
EDSS at onset/at discharge
1 right frontal subcortical lesion
Brain MRI
Cervical myelitis
Cervico-thoracic myelitis
Right ON followed 4 years later by Cervico-thoracic myelitis
Repeated cervical myelitis
Cervical myelitis
Cervical myelitis
Cervico-dorsal myelitis
Cervical myelitis
Cervicothoracicmyelits
Bilateral simultaneous ON ? cervicothoracic
Right ON ? cervical myelitis
Cervical myelitis
Cervicothoracic myelitis
First attack site
Table 1 Demogrpahic, laboratory, imaging and therapeutic characteristics of the patient group
Acta Neurol Belg
123
123 C3–C5 C2–C6
LE 102 ms
RE P100 absent LE 104 ms, RE 110 ms
12 RC
13 LA
Normal
T2 FLAIR hyperintense brainstem lesion
cortical demyelinating lesions of \3 mm diameter
1 Periventricular and 1 juxta-
Normal
Normal Normal
Normal
4 demyelinating periventricular T2 Hypersignals
Normal
Brain MRI
MP methylprednisolone, OCS oral corticosteroids, VEP visual evoked potentials, LE left eye, RE right eye
C6–D2
LE, RE P100 absent
ND
11 MN
C4–C6
C3–D1 C1–C4
10 RI
RE P100 absent
LE, RE P100 absent LE 110 ms with low amplitude
8 MU 9 OG
C1–D2 T2, Flair hyperintense spinal cord involvement
T2 Flair hyperintense spinal cord involvement
ND
C1–C5
LE 131 ms
C5–D2
Spinal MRI lesion
RE P100 absent
7 PI
6 TJ
RE 143 ms
5 BL
LE 120 ms
VEP P100 latency
Patient
Table 1 continued
limphocytes
Normal
Proteins elevate
lymphocites None
8
None 3
Normal
None ND
None
3
None
CSF cell counts
Elevated proteins
Normal ND
Normal
Elevated proteins
Normal
CSF protein, mg/Dl
Present
Present
present
Present
present absent
present
Absent
present
NMO IgG
MP/Imuran
MP/OCS ? Imuran
MP/OCS ? Imuran
MP/Imuran
MP/Imuran Plasmapheresis/ OCS ? Imuran
Plasmepheresis
Plasmepheresis/Imuran
MP, plasmapheresis/ Imuran
Treatment of the attack/long-term
Acta Neurol Belg
Acta Neurol Belg
patients were females (69.2 %) with a mean age of 30.12 years; the 4 males had a mean age of 33. The mean follow-up period was 3.74 ± 1.8 years. The mean disease duration was 4.64 ± 5.4 years. Only five patients had a monophasic evolution; the remaining eight patients had at least two attacks. Among the patients with monophasic evolution at the time of inclusion, two (patients 3 and 4) had the classical simultaneous ON and LETM (15.38 % of all cases). The relapsing form was found in 6 women with the mean relapse rate for the entire follow-up period of 4.6 ± 4.3 years. We included 4 cases (30.7 %) of LETM that were positive for NMO-IgG and were negative for other autoimmune diseases. Regarding the clinical evolution, 3 patients had a monophasic course at the time of inclusion and one case had repeated LETM. In this small group, the mean age at onset was 41.5 years. Although the patients did not have any clinical signs of ON, 2 had very modified VEP at least in one eye, with the absence of P100 wave as proof of a severe subclinical ON. Regarding the motor deficit at the onset of acute LETM, all patients had severe handicap; in 61.5 % of cases, this was paraparesis (6 females, 2 males) and 38.5 % had tetraparesis (4 females, 1 male). The mean value of the motor functional parameter at onset was 4.46 ± 1 and the mean value improved at discharge to 2.53 ± 1.4; this was statistically significant (p \ 0.001). The initial EDSS was 5.82 ± 1.22. The outcome after the first attack was good in 10 patients, with a significant improvement of the EDSS to 4.11 ± 2 (p = 0.01), mainly upon motor deficit, which had a remitting course after treatment, while visual function had a very slight amelioration without any statistical significance (initial visual functional parameter was 3.88 ± 1.83 vs. discharge visual parameter 3.4 ± 1.6, p value 0.9). In 6 of the 9 cases with visual involvement, the visual deficit was persistent to counting fingers or worse in one eye. Patient 7 died in the course of the first attack that consisted in a severe cervical-thoracic LEMT, which led to respiratory failure. At LETM onset, 8 patients had positive Lhermitte sign; severe bladder dysfunction was found in 7 patients (3 had incontinence and 4 had urinary retention). The CSF was normal in the majority (8) of patients. Four patients had a mild pleocytosis (\50 9 106/L), with the proportion of neutrophils being over 60 %. Spinal cord MRI pathological findings were as follows: in sagittal slice with high signal intensity on the T2 weighted cord lesion extending over 3 or more vertebral segments; in axial T2 showing extensive swelling of the spine (Fig. 1). In nine patients, intravenous gadolinium DTPA was given and the T1 weighted images showed diffuse enhancement over two-four segments of the spinal cord (Fig. 2).
Fig. 1 Sagittal T2 weighted MRI examination showing a hyperintense, longitudinally extensive cervical spinal cord lesion
Brain MRI was normal in 7 (53.8 %). The remaining 6 patients had a reduced number (1–4) of demyelinating T2 hypersignals involving the supratentorial white matter. The first attack was treated in most of the patients (69.2 %) with high dose of Methylprednisolone (1 g/day for 5–7 days) alone. In the remaining 4 cases, Methylprednisolone was followed by therapeutic plasma exchange (TPE) as the symptomatology did not regress under corticoids. For long-term treatment, we used Azathioprine 2.5 mg/ kg/day as a target dose (50 % of patients), oral prednisone (8.3 %) (starting with 1 mg/kg/day and then decreasing to the lowest dose of maintenance) or a combination of both (41.6 %) in patients that continued to have relapses on the monotherapy presented above.
Discussions Wingerchuk et al. [2] found that the combination of LETM with normal brain MRI and the addition of NMO-IgG seropositivity was more than 99 % sensitive for the diagnosis of NMO. Our inclusion criteria were based upon these scientific findings when we included serum NMOIgG ? cases of LETM together with confirmed NMO patients. Nevertheless, we had only 2 cases that fulfilled the traditional NMO diagnosis with a simultaneous monophasic event consisting of both ON and LETM. This low percentage of classical NMO onset was also found by other authors [6, 8, 9]. Clinical aspects of NMO can be of a monophasic disorder or a relapsing form. The relapsing form was 3 times more frequent in women than in men, while the monophasic form appeared to occur at an almost equal
123
Acta Neurol Belg
Fig. 2 Sagittal and axial T1 weighted MRI examination after contrast administration showing diffuse enhancement
percentage in both sexes. The same conclusion was described by other authors [2, 9, 10]. The prevalence of NMO with relapsing episodes is higher than the monophasic form (80 vs. 20 %), as found by Lennon et al. [1]. We also found 1.6-fold more frequent cases of recurrent NMO than monophasic ones. We had a higher percentage of monophasic NMO due to our inclusion criteria, which absorbed NMO-IgG seropositive LETM after the first attack. The majority of our cases had severe motor symptomatology at the first attack, but after remission (at discharge or after several months) the motor deficit improved. For example, 7 out of the 12 patients in the O’Riordan et al. [6] series were confined to a wheelchair. In the Oxford group 34 % of NMOpatients had developed permanent motor disability [11]. The regression of motor deficit was more important than that found by other authors. Between relapses, there was no progressive aggravation; however, on the contrary, in a few cases there was progressive improvement. The lack of progression of motor deficit between attacks is typical for NMO [1, 7, 9, 12]. The predilection of NMO for developing autoimmunity to AQP4 at the spinal cord and optic nerve is not fully understood [4]. The immunoreactive sites in the spinal cord are the astrocytic foot processes and the abluminal surface of blood vessels. Also, AQP4 is found in spinal cord grey matter. NMO lesions show a loss of AQP4 associated with myelin that is relatively preserved in some of these lesions [2]. The better outcome of spinal cord involvement in our NMO patients than that described in other series might
123
have multiple explanations: (a) we included only Caucasian patients as the population in our centre, as it is known that the outcome of demyelinating diseases in the white population is better than in non-white ones; (b) it has been shown that genetic factors may influence the clinical outcome, with Afro-Caribbean patients having a younger age at disease onset, more brain and multifocal attacks and a higher likelihood of visual disability than Caucasian patients [11]; (c) our patients had a reduced number of relapses in the first 2 years of evolution. Wingerchuk et al. [9] found a much worst prognosis in the following conditions: patients with systemic lupus or a related non-organspecific autoimmune disorder or autoantibodies, patients with increased number of relapses in the first 2 years of evolution, and increased severity of the first attack. Serum testing for NMO-IgG is the standard test for the diagnosis of NMO [13]. We found this immunological pattern to be positive in 77 % of our cases. To increase disease accuracy, Klawiter et al. [14] proposed the combination of NMO-IgG serum and CSF testing. A direct correlation was found between NMO-IgG titre and LETM severity, supporting NMO-IgG as a biomarker for NMO activity [4, 14, 15]. Myelin-Oligodendrocyte Glycoprotein Antibodies should be tested in patients with AQA4-Abnegative NMO and NMO-spectum disease. There are some reasons to include this MOG Ig ? subgroup of patients under the umbrella of NMO-spectrum disease, but other reasons that underly this clinical phenotype might represent an opticospinal type 2 MS variant [16–18]. Seropositivity for the NMO-IgG marker is strongly predictive of the risk of relapse of LETM and the final outcome, including mortality (patient 7 was positive for AQP4-Ab) [10].
Acta Neurol Belg
Spinal MRI showed evidence of longitudinally extensive spinal cord lesions in all of our patients mainly in the cervical region. This finding had a significant discriminative power and a sensitivity of 98 %, with a specificity of 83 %, among the diagnostic criteria for NMO published by Wingerchuk et al. [2]. NMO differs from MS in a variety of aspects but the relationship between NMO and systemic autoimmune diseases is under a strong scientific debate. NMO spectrum disorders represent in many cases the association of AQP-4 Ab with multiple other autoantibodies [19]. To avoid any discussion related to our patients, we excluded all cases with positive testing for any systemic autoimmune disease. Methylprednisolone in high doses (1 g/day, 3–5 days) was the primary treatment for attacks of LETM. For severe cases that were unresponsive to corticoids, plasma exchange was performed every other day up to a total of seven. Limited literature data suggest that initial treatment with intravenous glucocorticoids plus plasma exchange is associated with better outcomes compared with corticoid treatment alone [20]. Randomised controlled trials are not available in NMO as this pathology is rare in clinical practice. Treatment after the first attack of LETM is very important for prophylaxis against further attacks, especially ON, which has a very poor prognosis regarding visual outcome. Azathioprine alone or in association with oral corticoids was well tolerated. This long-term immunosuppressive treatment is recommended rather than MS immunomodulatory therapies. We had two patients (cases 11 and 12) that were treated for a few years with interferon-b 1b due to misdiagnosis; both kept presenting with attacks of both LEMT and ON. Also, patient 11 received mitoxantrone, which had a positive effect on disease evolution. In a recent publication, Fujihara and Nakashima reported a NMO case that after receiving Alemtuzumab developed insidiously progressive and intractable nausea, vomiting that led to severe weight loss, and progressive bilateral visual loss; despite enteral feeding the patient died later. The authors speculated that Alemtuzumab might have activated innate immunity to enhancing production of AQP4IgG or MOG-IgG. Other recommended immunosuppressants are mycophenolate mofetil 2 g/day and rituximab (1000 mg intravenously twice separated by 2 weeks, repeated every 6–9 months) [19, 21–23].
Conclusions NMO-IgG is a biomarker for NMO that is of diagnostic value in cases of isolated LEMT. Myelitis is frequently complete and more commonly separated from ON. Myelitis has a better outcome than ON. MRI is essential for
NMO diagnosis, especially in the presence of a long demyelinating spinal cord of more than 3 vertebral segments and the absence of multiple brain MRI lesions. Treatment of NMO exacerbations is achieved with high-dose methylprednisolone followed by plasmapheresis in more severe cases; azathioprine alone or in combination with prednisone is well tolerated. Acknowledgments This study was supported by the internal research grant of the University of Medicine and Pharmacy Taˆrgu Mures¸ , 16171/2014. Conflict of interest
The authors have nothing to declare.
Ethical standard The study was approved by the local ethics committee and was carried out according to the Declaration of Helsinki. Informed consent inform consent.
All patients or a first-degree relative signed an
References 1. Lennon VA, Wingerchuk DM, Kryzer TJ et al (2004) A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 364:2106–2112 2. Wingerchuk DM, Lennon VA, Pittock SJ et al (2006) Revised diagnostic criteria for neuromyelitis optica. Neurology 66:1485–1489 3. Roemer SF, Luchinetti C (2010) Immune effector heterogeneity in multiple sclerosis and related CNS inflammatory demyelinating disorders. In: Kilpatrick T, Ransohoff RM, Wesselingh S (ed) Inflammatory diseases of the central nervous system. Cambridge University Press, pp 47–73 4. Cree B (2008) Neuromyelitis optica: diagnosis, pathogenesis and treatment. Curr Neurol Neurosci Rep 8:427–433 5. Weinshenker B, Vukusic S, Wingerchuk D et al (2005) NMOIgG predicts relapse in patients with longitudinally extensive ‘‘idiopathic’’ transverse myelitis. Neurology 64:621–630 6. O’Riordan JI, Gallagher HL, Thompson AJ et al (1996) Clinical CSF, and MRI findings in Devic’s neuromyelitis optica. J Neurol Neurosurg Psychiatry 60:382–387 7. Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452 8. Mandler RN, Ahmed W, Dencoff JE (1998) Devic’s neuromyelitis optica: a prospective study of seven patients treated with prednisone and azathioprine. Neurology 51:1219–1220 9. Wingerchuk DM, Lennon VA, Pittock SJ et al (2007) The spectrum of neuromyelitis optica. Lancet Neurol 6:805–815 10. Matiello M, Weinshenker BG (2010) Neuromyelitis optica. In: Lucchinetti CF, Hohlfeld R (ed) Multiple sclerosis. Saunders Elsevier, pp 258–275 11. Kitley J, Leite MI, Nakashima I et al (2012) Prognostic factors and disease course in aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan. Brain 135:1834–1849 12. Kitley J, Leite MI, Kuker W et al (2013) Longitudinally extensive transverse myelitis with and without aquaporin-4 antibodies. JAMA Neurol 70:1375–1381 13. Lennon VA, Kryzer TJ, Pittock SJ et al (2005) IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 202:473–477
123
Acta Neurol Belg 14. Klawiter EC, Alvarez E, Xu J et al (2009) NMO-IgG detected in CSF in seronegative neuomyelitis optica. Neurology 72:1101–1103 15. Takahashi T, Fujiara K, Nakashima I et al (2007) Anti-aquaporin4 antibody is involved in the pathogenesis of NMO: a study on antibody titre. Brain 130:1235–1243 16. Jarius S, Paul F, Franciotta et al (2011) Cerebrospinal fluid findings in aquaporin-4 antibody-positive neuromyelitis optica: results from 211 lumbar punctures. J Neurol Sci 306:82–90 17. Kitley J, Waters P, Woodhall M et al (2014) Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies. A comparative study. JAMA Neurol 71:276–283 18. Zamvil SS, Slavin AJ (2015) Does MOG Ig-positive AQP4-seronegative opticospinal inflammatory disease justify a diagnosis of NMO spectrum disorder? Neurol Neuroimmunol Neuroinflamm 2(1):e62. doi:10.1212/NXI.0000000000000062 (eCollection 2015 Feb. Review)
123
19. Wingerchuk DM, Weinshenker B (2012) The emerging relationship between neuromyelitis optica and systemic rheumatologic autoimmune disease. Mult Scler J 18:5–10 20. Merle H, Olindo S, Jeannin S et al (2012) Treatment of optic neuritis by plasma exchange (add-on) in neuromyelitis optica. Arch Ophthalmol 130:858 21. Watanabe S, Misu T, Miyazama I et al (2007) Low-dose corticosteroids reduce relapses in neuromyelitis optica: a retrospective analysis. Mult Scler 13:968–974 22. Trebst C, Jarius S, Berthele A et al (2014) Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the neuromyelitis optica study group (NEMOS). J Neurol 261:1–16 23. Fujihara K, Nakashima I (2014) Secondary progression and innate immunity in NMO: A possible link to alemtuzumab therapy? Neurol Neuroimmunol Neuroinflamm 1(3):38. doi:10.1212/NXI. 0000000000000038
ORIGINAL ARTICLE
Longitudinally extensive transverse myelitis in neuromyelitis optica: a prospective study of 13 Caucasian patients and literature review Rodica Ba˘las¸ a1,3 • Smaranda Maier1 • Zoltan Bajko1 • Anca Motataianu1 Alexandra Cris¸ an1 • Adrian Ba˘las¸ a2
•
Received: 29 September 2014 / Accepted: 17 April 2015 Ó Belgian Neurological Society 2015
Abstract Neuromyelitis optica (NMO) is a homogenous disease that can be diagnosed by an association of clinical, neuroimaging and serological aspects. We analysed our 4 years NMO series with longitudinally extensive transverse myelitis (LETM) during the disease course. We included consecutive adult Caucasian patients who were diagnosed with definite NMO, or cases of NMO-IgG seropositive LETM considered as limited forms of NMO. Patients included were negative for other diseases (autoimmune, infectious, etc.). We report the Expanded Disability Status Scale (EDSS), brain and spine MRI, CSF, NMO-IgG, treatment, motor and visual outcome. Thirteen cases fulfilled the inclusion criteria, and the mean follow-up period was 3.74 ± 1.8 years. The initial motor deficit was severe with the mean value of motor functional parameter of 4.46 ± 1 and improved at discharge to 2.53 ± 1.4 (p \ 0.001). With treatment, the outcome after LETM attack was good in 10 patients, with a significant improvement of the EDSS mainly upon motor deficit, while visual function had a very slight amelioration. The CSF analysis was normal in 8 cases; spinal MRI showed evidence of LETM in all patients while brain MRI was normal in 7. NMO-IgG is a & Rodica Ba˘las¸ a [email protected] 1
First Neurological Clinic, Multiple Sclerosis Centre, Emergency County Hospital, University of Medicine and Pharmacy, Targu Mures, Romania
2
Neurosurgical Clinic, Emergency County Hospital, University of Medicine and Pharmacy, Targu Mures, Romania
3
Mures¸ County Clinical Emergency Hospital, Neurology Clinic I, Gh. Marinescu 50, 540136 Taˆrgu Mures¸ , Mures¸ County, Romania
biomarker for NMO that is of diagnostic value in cases of isolated LETM. LETM has a better outcome than ON in NMO Caucasians. Spinal MRI is essential for NMO diagnosis in the presence of LETM and the absence of multiple brain MRI lesions. Maintenance immunosuppressive therapy reduces the frequency of attacks. Keywords Neuromyelitis optica Devic disease Longitudinal extensive transverse myelitis Azathioprine
Introduction Neuromyelitis optica (NMO), also known as Devic’s disease, is an inflammatory demyelinating disease that consists of recurrent attacks of longitudinally extensive transverse myelitis (LETM) and optic neuritis (ON). Since the first description by Devic in 1894, NMO has been sometimes confounded with the optic-spinal form of multiple sclerosis (MS). In 2004, Lennon et al. [1] discovered that the syndrome was associated with a specific autoantibody (NMO-IgG) that binds to the water channel aquaporin-4. Revised diagnostic criteria were elaborated in 2006 by Wingerchuk et al. [2], which consist of the required criteria of LETM and ON and at least two of the following three supportive criteria: (1a) magnetic resonance imaging (MRI) of the brain not meeting the diagnostic criteria for MS; (b) MRI of a spinal cord lesion extending over C3 vertebral segments; (c) NMO-IgG seropositivity. From a pathological point of view, the spinal cord involvement in NMO is characterised in the acute phase by a notable axonal injury leading to diffuse swelling. In severe cases, the entire spinal cord is affected by a continuous or patchy distribution [3].
123
Acta Neurol Belg
Pathophysiologically, NMO features a predominantly T helper type 2 immune response with prominent humoral mechanisms; the important therapeutic implication is response to plasma exchange. Due to the strategic location of the demyelinating lesions and their failure to remyelinate, the clinical manifestations are very severe and sometimes lead to important sequelae [4]. The serum biomarker of NMO is NMO-IgG (also termed aquaporin-4 antibodies; AQP4-Ab), which binds selectively to the water channel protein aquaporin-4, destroying it, regardless of the stage or site of involvement. Demyelination in NMO is different than in MS and is secondary to (a) oligodendrocytes which are injured at the paranode where they are in contact with astrocytic foot processes containing AQP4; (b) demyelination which is determined by the axonal injury at the internode; c) glutamate toxicity. NMO-specific lesions (loss of AQP4) were described in the area postrema also. In the brain, this water channel is mostly situated in astrocytic foot processes at the blood–brain barrier (BBB) having an important role in the integrity and function of the BBB. In NMO, astrocytic damage can be the primary pathology [1, 3, 5, 6]. We analysed our 4-year NMO series to identify patients that were diagnosed, treated and followed in our MS centre and who had LETM at the onset or during the clinical course of the disease. In this study, we aimed to determine the characteristics of LETM in definite NMO or isolated forms of NMO (LETM plus NMO-IgG positive) in a Caucasian population in which any other known spinal cord demyelinating aetiologies had been excluded. To the best of our knowledge, no study with these inclusion criteria has been performed before.
Materials and methods This was a prospective observational study that included all consecutive single or recurrent LETM cases that either fulfilled the criteria for NMO or for limited forms of NMO. We included patients diagnosed in a 4-year interval (1 April 2010–31 March 2014) in the MS Centre from Emergency County Hospital, Targu Mures, Romania. All patients or a first-degree relative signed an inform consent; the study was approved by the local ethics committee and was carried out according to the Declaration of Helsinki. We included adult Caucasians patients who fulfilled NMO Wingerchuk et al. [2] criteria for NMO, or cases of NMO-IgG seropositive LETM considered according to Weinshenker et al. [5] as limited forms of NMO. We included consecutive patients older than 18, with a monophasic or polyphasic evolution of NMO, for whom medical information regarding clinical attacks, visual
123
evoked potentials (VEP), spinal and brain MRI, and serum NMO-IgG were available. We excluded patients who had been shown to be positive for other autoimmune connective diseases (Sjogren syndrome, systemic lupus erythematosus, anti-phospholipid antibodies, sarcoidosis, etc.), or any other infectious, neoplasia or deficiency diseases of the nervous system or patients with an attack of acute myelitis (\3 vertebral segments), patients with brain MRI meeting diagnostic criteria for MS, or patients suspected of having NMO but without LETM (cases with ON and positive for NMO-IgG, etcetera). Upon admission, for each patient we documented the demographic information (sex, age at LETM or NMO onset, history of autoimmunity), medical history, clinical course of the neurological deficit, and all recorded laboratory and imaging data (Table 1). All patients underwent a complete neurological examination with the calculation of Expanded Disability Status Scale (EDSS) both at admission and at discharge [7]. The same clinical evaluation, together with evidence of new relapses, was performed at follow-up. The detection of NMO-IgG in the serum of the patients was performed by enzyme-linked immunosorbent assay (ELISA). The interpretation was as follows: positive AQP4 Ab C6 U/mL and negative AQP-4Ab B4 U/mL; values of 5 U/mL were considered inconclusive and the detection was repeated. We documented only the negative/positive status of our patients and not the value of NMO-IgG. The majority of patients (12; 92.3 %) underwent cerebrospinal fluid (CSF) analyses. Normal values of CSF were considered: proteins 15–60 mg/dL, white blood cell counts 0–5/mm3. All patients underwent MRI of the spinal cord and of the brain using a GE Sigma 1.5 T scanner. The spinal cord was imaged in the sagittal and axial plane. The dimension, location and signal intensity of the demyelinating spinal lesion were measured and marked down. The brain MRI was performed in the axial plane with 3 mm thick slices and the number, dimension and location of demyelinating lesions were noted. Statistical analysis Differences between variables were described using standard statistics and were evaluated for significance using t tests or Wilcoxon’s rank-sum tests. Differences were considered significant if p value was \0.05.
Results A total of 13 cases fulfilled the inclusion criteria for a period of 4 years. Their mean age at LETM onset was 31.8 years, SD ± 14.4. Sex distribution was as follows: 9
56/F
26/F
26/M
22/F
18/M
37/M
44/F
19/F
36/F
61/M
18/F
21/F
30/F
VEP P100 latency
LE 130 ms
1 BE
2 BF
3 BN
4 BK
5 BL
6 TJ
7 PI
8 MU
9 OG
10 RI
11 MN
12 RC
13 LA
Patient
1 BE
LE 160 ms with low amplitude RE 117 ms
LE 112 ms, RE 130 ms
LE 140 ms, RE P100 absent
3 BN
4 BK
0.4
7
20
5
1
4
0.3
1
7
3
4
8
0
Disease duration, y
2 BF
RE 130 ms
Onset age, y/sex
Patient
LETM
C3–D1
Cervical C1-C4 T2,FLAIR hyperintensities
C5–D3
Cervivothoracic T2, STIR hyperintensity
Spinal MRI lesion
2
NMO
NMO
&15 4
LETM
NMO
LETM
NMO
NMO
NMO
NMO
NMO
NMO
LETM
Phenotype
4
4
1
1
1
2
4
1
2
1
Total no.of attacks
6.0/4.0
4.5/3.0
6.0/3.5
4/2.5
6.5/6.0
7.5/4.0
T2 FLAIR hyperintense left pontomesencephalic lesion
2 Small demyelinating cerebral lesions
Normal
0–0
5–3
3–3
4–2
5–4
4–2
4–2
5–5
5–3
Normal
Normal
Elevated proteins and
Normal
limphocytes
None
2
6
None
CSF cell counts
NMO IgG
present
present
absent
present
MP/OCS ? Imuran
MP/OCS
MP/OCS ? Imuran
MP/Imuran
Treatment of the attack/long-term
No
Yes
Yes
No
Yes
No
No
6–4
yes
4–1
No
Yes
No
Yes
No
Severe visual disability
6–5 6–decesed
3–2
3–1
5–5
4–1
3–1
3–2
5–5
4–2
6–4
FP pyramidal at onset/at discharge/visual at onset/at discharge
CSF protein, mg/Dl
8.0/decesed
6.0./4.0
4.0/2.0
6.0/4.0
4.5/2.5
6.5/4
6.0/4.5
EDSS at onset/at discharge
1 right frontal subcortical lesion
Brain MRI
Cervical myelitis
Cervico-thoracic myelitis
Right ON followed 4 years later by Cervico-thoracic myelitis
Repeated cervical myelitis
Cervical myelitis
Cervical myelitis
Cervico-dorsal myelitis
Cervical myelitis
Cervicothoracicmyelits
Bilateral simultaneous ON ? cervicothoracic
Right ON ? cervical myelitis
Cervical myelitis
Cervicothoracic myelitis
First attack site
Table 1 Demogrpahic, laboratory, imaging and therapeutic characteristics of the patient group
Acta Neurol Belg
123
123 C3–C5 C2–C6
LE 102 ms
RE P100 absent LE 104 ms, RE 110 ms
12 RC
13 LA
Normal
T2 FLAIR hyperintense brainstem lesion
cortical demyelinating lesions of \3 mm diameter
1 Periventricular and 1 juxta-
Normal
Normal Normal
Normal
4 demyelinating periventricular T2 Hypersignals
Normal
Brain MRI
MP methylprednisolone, OCS oral corticosteroids, VEP visual evoked potentials, LE left eye, RE right eye
C6–D2
LE, RE P100 absent
ND
11 MN
C4–C6
C3–D1 C1–C4
10 RI
RE P100 absent
LE, RE P100 absent LE 110 ms with low amplitude
8 MU 9 OG
C1–D2 T2, Flair hyperintense spinal cord involvement
T2 Flair hyperintense spinal cord involvement
ND
C1–C5
LE 131 ms
C5–D2
Spinal MRI lesion
RE P100 absent
7 PI
6 TJ
RE 143 ms
5 BL
LE 120 ms
VEP P100 latency
Patient
Table 1 continued
limphocytes
Normal
Proteins elevate
lymphocites None
8
None 3
Normal
None ND
None
3
None
CSF cell counts
Elevated proteins
Normal ND
Normal
Elevated proteins
Normal
CSF protein, mg/Dl
Present
Present
present
Present
present absent
present
Absent
present
NMO IgG
MP/Imuran
MP/OCS ? Imuran
MP/OCS ? Imuran
MP/Imuran
MP/Imuran Plasmapheresis/ OCS ? Imuran
Plasmepheresis
Plasmepheresis/Imuran
MP, plasmapheresis/ Imuran
Treatment of the attack/long-term
Acta Neurol Belg
Acta Neurol Belg
patients were females (69.2 %) with a mean age of 30.12 years; the 4 males had a mean age of 33. The mean follow-up period was 3.74 ± 1.8 years. The mean disease duration was 4.64 ± 5.4 years. Only five patients had a monophasic evolution; the remaining eight patients had at least two attacks. Among the patients with monophasic evolution at the time of inclusion, two (patients 3 and 4) had the classical simultaneous ON and LETM (15.38 % of all cases). The relapsing form was found in 6 women with the mean relapse rate for the entire follow-up period of 4.6 ± 4.3 years. We included 4 cases (30.7 %) of LETM that were positive for NMO-IgG and were negative for other autoimmune diseases. Regarding the clinical evolution, 3 patients had a monophasic course at the time of inclusion and one case had repeated LETM. In this small group, the mean age at onset was 41.5 years. Although the patients did not have any clinical signs of ON, 2 had very modified VEP at least in one eye, with the absence of P100 wave as proof of a severe subclinical ON. Regarding the motor deficit at the onset of acute LETM, all patients had severe handicap; in 61.5 % of cases, this was paraparesis (6 females, 2 males) and 38.5 % had tetraparesis (4 females, 1 male). The mean value of the motor functional parameter at onset was 4.46 ± 1 and the mean value improved at discharge to 2.53 ± 1.4; this was statistically significant (p \ 0.001). The initial EDSS was 5.82 ± 1.22. The outcome after the first attack was good in 10 patients, with a significant improvement of the EDSS to 4.11 ± 2 (p = 0.01), mainly upon motor deficit, which had a remitting course after treatment, while visual function had a very slight amelioration without any statistical significance (initial visual functional parameter was 3.88 ± 1.83 vs. discharge visual parameter 3.4 ± 1.6, p value 0.9). In 6 of the 9 cases with visual involvement, the visual deficit was persistent to counting fingers or worse in one eye. Patient 7 died in the course of the first attack that consisted in a severe cervical-thoracic LEMT, which led to respiratory failure. At LETM onset, 8 patients had positive Lhermitte sign; severe bladder dysfunction was found in 7 patients (3 had incontinence and 4 had urinary retention). The CSF was normal in the majority (8) of patients. Four patients had a mild pleocytosis (\50 9 106/L), with the proportion of neutrophils being over 60 %. Spinal cord MRI pathological findings were as follows: in sagittal slice with high signal intensity on the T2 weighted cord lesion extending over 3 or more vertebral segments; in axial T2 showing extensive swelling of the spine (Fig. 1). In nine patients, intravenous gadolinium DTPA was given and the T1 weighted images showed diffuse enhancement over two-four segments of the spinal cord (Fig. 2).
Fig. 1 Sagittal T2 weighted MRI examination showing a hyperintense, longitudinally extensive cervical spinal cord lesion
Brain MRI was normal in 7 (53.8 %). The remaining 6 patients had a reduced number (1–4) of demyelinating T2 hypersignals involving the supratentorial white matter. The first attack was treated in most of the patients (69.2 %) with high dose of Methylprednisolone (1 g/day for 5–7 days) alone. In the remaining 4 cases, Methylprednisolone was followed by therapeutic plasma exchange (TPE) as the symptomatology did not regress under corticoids. For long-term treatment, we used Azathioprine 2.5 mg/ kg/day as a target dose (50 % of patients), oral prednisone (8.3 %) (starting with 1 mg/kg/day and then decreasing to the lowest dose of maintenance) or a combination of both (41.6 %) in patients that continued to have relapses on the monotherapy presented above.
Discussions Wingerchuk et al. [2] found that the combination of LETM with normal brain MRI and the addition of NMO-IgG seropositivity was more than 99 % sensitive for the diagnosis of NMO. Our inclusion criteria were based upon these scientific findings when we included serum NMOIgG ? cases of LETM together with confirmed NMO patients. Nevertheless, we had only 2 cases that fulfilled the traditional NMO diagnosis with a simultaneous monophasic event consisting of both ON and LETM. This low percentage of classical NMO onset was also found by other authors [6, 8, 9]. Clinical aspects of NMO can be of a monophasic disorder or a relapsing form. The relapsing form was 3 times more frequent in women than in men, while the monophasic form appeared to occur at an almost equal
123
Acta Neurol Belg
Fig. 2 Sagittal and axial T1 weighted MRI examination after contrast administration showing diffuse enhancement
percentage in both sexes. The same conclusion was described by other authors [2, 9, 10]. The prevalence of NMO with relapsing episodes is higher than the monophasic form (80 vs. 20 %), as found by Lennon et al. [1]. We also found 1.6-fold more frequent cases of recurrent NMO than monophasic ones. We had a higher percentage of monophasic NMO due to our inclusion criteria, which absorbed NMO-IgG seropositive LETM after the first attack. The majority of our cases had severe motor symptomatology at the first attack, but after remission (at discharge or after several months) the motor deficit improved. For example, 7 out of the 12 patients in the O’Riordan et al. [6] series were confined to a wheelchair. In the Oxford group 34 % of NMOpatients had developed permanent motor disability [11]. The regression of motor deficit was more important than that found by other authors. Between relapses, there was no progressive aggravation; however, on the contrary, in a few cases there was progressive improvement. The lack of progression of motor deficit between attacks is typical for NMO [1, 7, 9, 12]. The predilection of NMO for developing autoimmunity to AQP4 at the spinal cord and optic nerve is not fully understood [4]. The immunoreactive sites in the spinal cord are the astrocytic foot processes and the abluminal surface of blood vessels. Also, AQP4 is found in spinal cord grey matter. NMO lesions show a loss of AQP4 associated with myelin that is relatively preserved in some of these lesions [2]. The better outcome of spinal cord involvement in our NMO patients than that described in other series might
123
have multiple explanations: (a) we included only Caucasian patients as the population in our centre, as it is known that the outcome of demyelinating diseases in the white population is better than in non-white ones; (b) it has been shown that genetic factors may influence the clinical outcome, with Afro-Caribbean patients having a younger age at disease onset, more brain and multifocal attacks and a higher likelihood of visual disability than Caucasian patients [11]; (c) our patients had a reduced number of relapses in the first 2 years of evolution. Wingerchuk et al. [9] found a much worst prognosis in the following conditions: patients with systemic lupus or a related non-organspecific autoimmune disorder or autoantibodies, patients with increased number of relapses in the first 2 years of evolution, and increased severity of the first attack. Serum testing for NMO-IgG is the standard test for the diagnosis of NMO [13]. We found this immunological pattern to be positive in 77 % of our cases. To increase disease accuracy, Klawiter et al. [14] proposed the combination of NMO-IgG serum and CSF testing. A direct correlation was found between NMO-IgG titre and LETM severity, supporting NMO-IgG as a biomarker for NMO activity [4, 14, 15]. Myelin-Oligodendrocyte Glycoprotein Antibodies should be tested in patients with AQA4-Abnegative NMO and NMO-spectum disease. There are some reasons to include this MOG Ig ? subgroup of patients under the umbrella of NMO-spectrum disease, but other reasons that underly this clinical phenotype might represent an opticospinal type 2 MS variant [16–18]. Seropositivity for the NMO-IgG marker is strongly predictive of the risk of relapse of LETM and the final outcome, including mortality (patient 7 was positive for AQP4-Ab) [10].
Acta Neurol Belg
Spinal MRI showed evidence of longitudinally extensive spinal cord lesions in all of our patients mainly in the cervical region. This finding had a significant discriminative power and a sensitivity of 98 %, with a specificity of 83 %, among the diagnostic criteria for NMO published by Wingerchuk et al. [2]. NMO differs from MS in a variety of aspects but the relationship between NMO and systemic autoimmune diseases is under a strong scientific debate. NMO spectrum disorders represent in many cases the association of AQP-4 Ab with multiple other autoantibodies [19]. To avoid any discussion related to our patients, we excluded all cases with positive testing for any systemic autoimmune disease. Methylprednisolone in high doses (1 g/day, 3–5 days) was the primary treatment for attacks of LETM. For severe cases that were unresponsive to corticoids, plasma exchange was performed every other day up to a total of seven. Limited literature data suggest that initial treatment with intravenous glucocorticoids plus plasma exchange is associated with better outcomes compared with corticoid treatment alone [20]. Randomised controlled trials are not available in NMO as this pathology is rare in clinical practice. Treatment after the first attack of LETM is very important for prophylaxis against further attacks, especially ON, which has a very poor prognosis regarding visual outcome. Azathioprine alone or in association with oral corticoids was well tolerated. This long-term immunosuppressive treatment is recommended rather than MS immunomodulatory therapies. We had two patients (cases 11 and 12) that were treated for a few years with interferon-b 1b due to misdiagnosis; both kept presenting with attacks of both LEMT and ON. Also, patient 11 received mitoxantrone, which had a positive effect on disease evolution. In a recent publication, Fujihara and Nakashima reported a NMO case that after receiving Alemtuzumab developed insidiously progressive and intractable nausea, vomiting that led to severe weight loss, and progressive bilateral visual loss; despite enteral feeding the patient died later. The authors speculated that Alemtuzumab might have activated innate immunity to enhancing production of AQP4IgG or MOG-IgG. Other recommended immunosuppressants are mycophenolate mofetil 2 g/day and rituximab (1000 mg intravenously twice separated by 2 weeks, repeated every 6–9 months) [19, 21–23].
Conclusions NMO-IgG is a biomarker for NMO that is of diagnostic value in cases of isolated LEMT. Myelitis is frequently complete and more commonly separated from ON. Myelitis has a better outcome than ON. MRI is essential for
NMO diagnosis, especially in the presence of a long demyelinating spinal cord of more than 3 vertebral segments and the absence of multiple brain MRI lesions. Treatment of NMO exacerbations is achieved with high-dose methylprednisolone followed by plasmapheresis in more severe cases; azathioprine alone or in combination with prednisone is well tolerated. Acknowledgments This study was supported by the internal research grant of the University of Medicine and Pharmacy Taˆrgu Mures¸ , 16171/2014. Conflict of interest
The authors have nothing to declare.
Ethical standard The study was approved by the local ethics committee and was carried out according to the Declaration of Helsinki. Informed consent inform consent.
All patients or a first-degree relative signed an
References 1. Lennon VA, Wingerchuk DM, Kryzer TJ et al (2004) A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 364:2106–2112 2. Wingerchuk DM, Lennon VA, Pittock SJ et al (2006) Revised diagnostic criteria for neuromyelitis optica. Neurology 66:1485–1489 3. Roemer SF, Luchinetti C (2010) Immune effector heterogeneity in multiple sclerosis and related CNS inflammatory demyelinating disorders. In: Kilpatrick T, Ransohoff RM, Wesselingh S (ed) Inflammatory diseases of the central nervous system. Cambridge University Press, pp 47–73 4. Cree B (2008) Neuromyelitis optica: diagnosis, pathogenesis and treatment. Curr Neurol Neurosci Rep 8:427–433 5. Weinshenker B, Vukusic S, Wingerchuk D et al (2005) NMOIgG predicts relapse in patients with longitudinally extensive ‘‘idiopathic’’ transverse myelitis. Neurology 64:621–630 6. O’Riordan JI, Gallagher HL, Thompson AJ et al (1996) Clinical CSF, and MRI findings in Devic’s neuromyelitis optica. J Neurol Neurosurg Psychiatry 60:382–387 7. Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452 8. Mandler RN, Ahmed W, Dencoff JE (1998) Devic’s neuromyelitis optica: a prospective study of seven patients treated with prednisone and azathioprine. Neurology 51:1219–1220 9. Wingerchuk DM, Lennon VA, Pittock SJ et al (2007) The spectrum of neuromyelitis optica. Lancet Neurol 6:805–815 10. Matiello M, Weinshenker BG (2010) Neuromyelitis optica. In: Lucchinetti CF, Hohlfeld R (ed) Multiple sclerosis. Saunders Elsevier, pp 258–275 11. Kitley J, Leite MI, Nakashima I et al (2012) Prognostic factors and disease course in aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan. Brain 135:1834–1849 12. Kitley J, Leite MI, Kuker W et al (2013) Longitudinally extensive transverse myelitis with and without aquaporin-4 antibodies. JAMA Neurol 70:1375–1381 13. Lennon VA, Kryzer TJ, Pittock SJ et al (2005) IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 202:473–477
123
Acta Neurol Belg 14. Klawiter EC, Alvarez E, Xu J et al (2009) NMO-IgG detected in CSF in seronegative neuomyelitis optica. Neurology 72:1101–1103 15. Takahashi T, Fujiara K, Nakashima I et al (2007) Anti-aquaporin4 antibody is involved in the pathogenesis of NMO: a study on antibody titre. Brain 130:1235–1243 16. Jarius S, Paul F, Franciotta et al (2011) Cerebrospinal fluid findings in aquaporin-4 antibody-positive neuromyelitis optica: results from 211 lumbar punctures. J Neurol Sci 306:82–90 17. Kitley J, Waters P, Woodhall M et al (2014) Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies. A comparative study. JAMA Neurol 71:276–283 18. Zamvil SS, Slavin AJ (2015) Does MOG Ig-positive AQP4-seronegative opticospinal inflammatory disease justify a diagnosis of NMO spectrum disorder? Neurol Neuroimmunol Neuroinflamm 2(1):e62. doi:10.1212/NXI.0000000000000062 (eCollection 2015 Feb. Review)
123
19. Wingerchuk DM, Weinshenker B (2012) The emerging relationship between neuromyelitis optica and systemic rheumatologic autoimmune disease. Mult Scler J 18:5–10 20. Merle H, Olindo S, Jeannin S et al (2012) Treatment of optic neuritis by plasma exchange (add-on) in neuromyelitis optica. Arch Ophthalmol 130:858 21. Watanabe S, Misu T, Miyazama I et al (2007) Low-dose corticosteroids reduce relapses in neuromyelitis optica: a retrospective analysis. Mult Scler 13:968–974 22. Trebst C, Jarius S, Berthele A et al (2014) Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the neuromyelitis optica study group (NEMOS). J Neurol 261:1–16 23. Fujihara K, Nakashima I (2014) Secondary progression and innate immunity in NMO: A possible link to alemtuzumab therapy? Neurol Neuroimmunol Neuroinflamm 1(3):38. doi:10.1212/NXI. 0000000000000038
