Accepted Manuscript Neuromyelitis optica spectrum disorders with antibodies to myelin oligodendrocyte glycoprotein or aquaporin-4: Clinical and paraclinical characteristics in Algerian patients
Melissa Bouzar, Smail Daoudi, Samira Hattab, Amel A. Bouzar, Kumaran Deiva, Brigitte Wildemann, Markus Reindl, Sven Jarius PII: DOI: Reference:
S0022-510X(17)33755-3 doi: 10.1016/j.jns.2017.08.3254 JNS 15532
To appear in:
Journal of the Neurological Sciences
Received date: Revised date: Accepted date:
26 June 2017 24 August 2017 28 August 2017
Please cite this article as: Melissa Bouzar, Smail Daoudi, Samira Hattab, Amel A. Bouzar, Kumaran Deiva, Brigitte Wildemann, Markus Reindl, Sven Jarius , Neuromyelitis optica spectrum disorders with antibodies to myelin oligodendrocyte glycoprotein or aquaporin-4: Clinical and paraclinical characteristics in Algerian patients. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jns(2017), doi: 10.1016/j.jns.2017.08.3254
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Neuromyelitis optica spectrum disorders with antibodies to myelin oligodendrocyte glycoprotein or aquaporin-4: clinical and paraclinical characteristics in Algerian patients Melissa Bouzar1, Smail Daoudi1, Samira Hattab1, Amel A Bouzar 1, Kumaran Deiva2,Brigitte
CR
IP
T
Wildemann3, Markus Reindl4, Sven Jarius 3
1
Centre hôspitalo-universitaire Nedir Mohamed, service de Neurologie Tizi Ouzou, Algérie
2
US
Centre de Référence National des Maladies Neuro-inflammatoires de l'Enfant. Assistance
AN
publique-hopitaux de Paris, Hôpitaux Universitaires Paris Sud, site Bicêtre Service de Neuropédiatrie, France. 3
M
Molecular Neuroimmunology Group, Department of Neurology, University Hospital Heidelberg,
ED
Germany 4
CE
PT
Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
AC
*Corresponding author:
Melissa Bouzar, MD, 9, place Saint Bruno, allée FE, 38000 Grenoble, France; telephone: 00 33 6 51 38 22 42, email: [email protected]
Keywords: Neuromyelitis optica spectrum disorders (NMOSD), antibodies,aquaporin-4 (AQP4), myelin oligodendrocyte glycoprotein (MOG), optic neuritis, myelitis, Algeria, cell-based assay 1
ACCEPTED MANUSCRIPT Keywords Neuromyelitis optica spectrum disorders (NMOSD), antibodies, aquaporin-4 (AQP4), myelin oligodendrocyte glycoprotein (MOG), optic neuritis, myelitis, Algeria, cell-based assay
Conflict of interest statement
IP
T
M.B., S.J., S.H., A.A.B. and S.D. report no conflicts of interest. The work of B.W. was supported by research grants from the DietmarHopp Foundation and from Merck Serono.The work of M.R.
CR
is supported by research grants Bridge I EDNA (FFG and Euroimmun) and “BIG-WIG MS” from
US
the Austrian Federal Ministry of Science, Research and Economy.The Neurological Research Laboratory (M.R., Medical University of Innsbruck and Tirol Kliniken) receives payments for
AN
antibody assays (AQP4 and anti-neuronal antibodies) and for MOG and AQP4 antibody
ED
M
validation experiments organized by Euroimmun (Germany).
PT
Abstract
Background: Neuromyelitis optica(NMO) is a severe autoimmune inflammatory disorder of the
CE
central nervous system. NMO and its abortive forms are referred to as NMO spectrum disorders (NMOSD). NMOSD are mostly associated with antibodies to aquaporin-4 (AQP4-IgG).
AC
However, recent studies have demonstrated antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) in a subset of patients. Data on NMOSD in North Africa are sparse. Objective: To describe the frequency of MOG-IgG and AQP4-IgG among patients with optic neuritis (ON) and/or myelitis in Algeria as well as the clinical and paraclinical features associated with these antibodies.
2
ACCEPTED MANUSCRIPT Methods: Retrospective testing of 42 patients with optic neuritis and/or myelitis treated at the teaching hospital of TiziOuzou for MOG-IgG and AQP4-IgG, and retrospective evaluation of the patients' medical records. Results: Six of 42 (14.3%) patients were positive for AQP4-IgG and 3/42 (7.1%) were positive for MOG-IgG. No patient was positive for both AQP4-IgG and MOG-IgG. All antibody-
IP
T
positive patients were women. MOG-IgG was associated with severe episodes of ON in all
CR
MOG-IgG-positive patients. Steroid treatment was followed by complete remission in two patients. AQP4-IgG was associated with ON and/or longitudinally extensive transverse
US
myelitis (LETM), often with severe onset. While all six of the AQP4-IgG-positive patients met the 2015 IPND criteria for NMOSD, only one of the three MOG-IgG-positive patients did so.
AN
Interestingly, clinically silent extensive spinal cord or brain lesions were present in two of the three MOG-IgG-positive patients, and altered visual evoked potentials without clinical evidence
M
of ON were found in three of the six AQP4-IgG-positive patients.
ED
Conclusion: MOG-IgG and AQP4-IgG are found in a substantial subset of Algerian patients with ON and/or myelitis, are present predominantly in women, and may be associated with
PT
differences in clinical presentation and, possibly, outcome. Only a subset of MOG-IgG positive
AC
CE
patients meets the current diagnostic criteria for NMOSD.
3
ACCEPTED MANUSCRIPT Introduction Neuromyelitis optica (NMO) is a severe autoimmune inflammatory disorder of the central nervous system (CNS) that predominantly targets the optic nerves and spinal cord [1, 2]. NMO and the limited forms of the disease are referred to by the umbrella term neuromyelitis optica
T
spectrum disorders (NMOSD). The current international diagnostic criteria for NMOSD
IP
distinguish two categories: NMOSD with antibodies to aquaporin-4 (AQP4-IgG) and NMOSD
CR
without AQP4-IgG or unknown AQP4-IgG serostatus [3]. A subgroup of patients with AQP4-IgGnegative NMOSD has recently been shown to be serologically characterized by the presence of
US
antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) [4-7]. So far, only little information is available on the frequency and clinical characteristics of MOG-IgG- and AQP4-IgG-positive
AN
NMOSD in North African patients. In this study, we describe the clinical and paraclinical features
M
of a cohort of Algerian patients with ON and/or myelitis for MOG-IgG and AQP4-IgG.
ED
Patients and methods
PT
We retrospectively reviewed the medical files of 43 patients treated at the hospital of TiziOuzou, Algeria, between January 2004 and December 2015 for monophasic (m) or recurrent (r)
CE
inflammatory disease affecting the optic nerve and/or the spinal cord. Patients with infectious and systemic disorders were excluded. The female to male ratio was 1.9:1.The patients’ median
AC
age at the time of testing was 33 years (range 19-58 years); two patients (4.65%) were children with recurrent severe optic neuritis (ON). Eleven (25.6%) patients were being followed up for ON, of whom six (54.5%) had bilateral involvement of the optic nerves, 9 patients (81.8%) had a long-term follow-up (beyond two years). Twenty-two (51.3%) patients were followed up for myelitis: 14 of these patients had recurrent longitudinally extensive transverse myelitis (rLETM); two recurrent non-extensive transverse myelitis (rNETM); one rLETM and an area postrema 4
ACCEPTED MANUSCRIPT syndrome (APS), one of the core clinical syndromes of NMOSD, characterized by unexplained hiccups, nausea and vomiting; one monophasic NETM and an APS; one rNETM and a brainstem syndrome other than APS; one mLETM and mNETM associated with the presence of auto-antibodies ; and one rLETM associated with a thalamic syndrome. Nine (20.9%) patients had both ON and myelitis, either sequentially or simultaneously, seven of whom (87.5%) had
IP
T
recurrent disease. One (2.3%) patient with multiple sclerosis (MS) and AQP4-IgG-positive
CR
NMOSD in a sister was also tested for both antibodies. All patients gave their informed consent to be tested for AQP4-IgG and MOG-IgG and to participate in the study. All these patients had a
US
long-term follow-up.
In 34 patients, serum was tested for MOG-IgG by means of a fixed cell-based assay
AN
(CBA; assay-specific cut-off ≥1:10; University of Heidelberg, Germany) [8] and a live CBA (cutoff ≥1:160, Medical University Innsbruck, Austria) [4, 8] in parallel and for AQP4-IgG by means
M
of a commercial fixed CBA (Euroimmun, Lübeck, Germany, Cut-off >=1:10) [9]. HEK293 cells
ED
transfected with full-length human MOG or AQP4, respectively, were used as antigenic substrate; mock-transfected cells were used as control substrate. One patient was tested for
PT
MOG-IgG and AQP4-IgG using a CBA in France as previously described [10] and eight patients
CE
were tested for MOG-IgG and AQP4-IgG using commercial CBAs in Algeria (Euroimmun; Germany). Demographic, clinical, imaging and laboratory data were collected and analysed in a
Results
AC
stratified manner according to each patient’s antibody serostatus.
Six (14.3%) of 42 patients were positive for AQP4-IgG, 3/42 (7.1%) were positive for MOG-IgG, and 33 of 42 (78.6%) were negative for both AQP4-IgG and MOG-IgG. None was positive for both AQP4-IgG and MOG-IgG. The MS patient with a sister diagnosed as AQP4-IgG-positive 5
ACCEPTED MANUSCRIPT NMOSD was negative both for AQP4-IgG and MOG-IgG and was excluded from further analysis. See Supplementary Table 1 for further details. The main clinical and paraclinical features of all AQP4-IgG- and MOG-IgG-positive patients are summarized in Table 1. The frequencies of AQP4-IgG and MOG-IgG are summarized in Table 2 and were 9%
T
and 18.8%, respectively, among patients with ON (without myelitis), 16.7% and 0% among
IP
patients with LETM (without ON), 0% and 0% among patients with NETM (without ON), and
CR
22.2% and 11.1% among patients with a history of both ON and myelitis.If only patients with either ON and LETM are considered, 25% and 12.5% had AQP4-IgG and MOG-IgG,
US
respectively. Three patients had an APS, none of whom were positive for AQP4-IgG or MOG-
AN
IgG.
M
Clinical and paraclinical findings in MOG-IgG-positive patients
ED
Patient 1 developed unilateral ON at the age of 32, leading to complete blindness in the affected eye. After 10 days of treatment with intravenous methylprednisolone (IVMP) (1 g/day) her visual
PT
acuity returned to normal. She then took oral corticosteroids. However, 6 weeks after the first attack and after reduction of her corticosteroid dosage, she developed severe ON in the other
CE
eye, again resulting in unilateral blindness. Once again, treatment with IVMP resulted in
AC
complete recovery. Under subsequent immunosuppressive therapy with azathioprine, no further attacks have occurred over a period of 1 year. Cerebral MRI during both attacks showed T2hyperintense, longitudinally extensive optic neuritis (LEON) without involvement of the optic chiasm and the optic tract. No cerebral lesions were found, and her spinal cord MRI findings were normal. Analysis of the cerebrospinal fluid showed
Melissa Bouzar, Smail Daoudi, Samira Hattab, Amel A. Bouzar, Kumaran Deiva, Brigitte Wildemann, Markus Reindl, Sven Jarius PII: DOI: Reference:
S0022-510X(17)33755-3 doi: 10.1016/j.jns.2017.08.3254 JNS 15532
To appear in:
Journal of the Neurological Sciences
Received date: Revised date: Accepted date:
26 June 2017 24 August 2017 28 August 2017
Please cite this article as: Melissa Bouzar, Smail Daoudi, Samira Hattab, Amel A. Bouzar, Kumaran Deiva, Brigitte Wildemann, Markus Reindl, Sven Jarius , Neuromyelitis optica spectrum disorders with antibodies to myelin oligodendrocyte glycoprotein or aquaporin-4: Clinical and paraclinical characteristics in Algerian patients. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jns(2017), doi: 10.1016/j.jns.2017.08.3254
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Neuromyelitis optica spectrum disorders with antibodies to myelin oligodendrocyte glycoprotein or aquaporin-4: clinical and paraclinical characteristics in Algerian patients Melissa Bouzar1, Smail Daoudi1, Samira Hattab1, Amel A Bouzar 1, Kumaran Deiva2,Brigitte
CR
IP
T
Wildemann3, Markus Reindl4, Sven Jarius 3
1
Centre hôspitalo-universitaire Nedir Mohamed, service de Neurologie Tizi Ouzou, Algérie
2
US
Centre de Référence National des Maladies Neuro-inflammatoires de l'Enfant. Assistance
AN
publique-hopitaux de Paris, Hôpitaux Universitaires Paris Sud, site Bicêtre Service de Neuropédiatrie, France. 3
M
Molecular Neuroimmunology Group, Department of Neurology, University Hospital Heidelberg,
ED
Germany 4
CE
PT
Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
AC
*Corresponding author:
Melissa Bouzar, MD, 9, place Saint Bruno, allée FE, 38000 Grenoble, France; telephone: 00 33 6 51 38 22 42, email: [email protected]
Keywords: Neuromyelitis optica spectrum disorders (NMOSD), antibodies,aquaporin-4 (AQP4), myelin oligodendrocyte glycoprotein (MOG), optic neuritis, myelitis, Algeria, cell-based assay 1
ACCEPTED MANUSCRIPT Keywords Neuromyelitis optica spectrum disorders (NMOSD), antibodies, aquaporin-4 (AQP4), myelin oligodendrocyte glycoprotein (MOG), optic neuritis, myelitis, Algeria, cell-based assay
Conflict of interest statement
IP
T
M.B., S.J., S.H., A.A.B. and S.D. report no conflicts of interest. The work of B.W. was supported by research grants from the DietmarHopp Foundation and from Merck Serono.The work of M.R.
CR
is supported by research grants Bridge I EDNA (FFG and Euroimmun) and “BIG-WIG MS” from
US
the Austrian Federal Ministry of Science, Research and Economy.The Neurological Research Laboratory (M.R., Medical University of Innsbruck and Tirol Kliniken) receives payments for
AN
antibody assays (AQP4 and anti-neuronal antibodies) and for MOG and AQP4 antibody
ED
M
validation experiments organized by Euroimmun (Germany).
PT
Abstract
Background: Neuromyelitis optica(NMO) is a severe autoimmune inflammatory disorder of the
CE
central nervous system. NMO and its abortive forms are referred to as NMO spectrum disorders (NMOSD). NMOSD are mostly associated with antibodies to aquaporin-4 (AQP4-IgG).
AC
However, recent studies have demonstrated antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) in a subset of patients. Data on NMOSD in North Africa are sparse. Objective: To describe the frequency of MOG-IgG and AQP4-IgG among patients with optic neuritis (ON) and/or myelitis in Algeria as well as the clinical and paraclinical features associated with these antibodies.
2
ACCEPTED MANUSCRIPT Methods: Retrospective testing of 42 patients with optic neuritis and/or myelitis treated at the teaching hospital of TiziOuzou for MOG-IgG and AQP4-IgG, and retrospective evaluation of the patients' medical records. Results: Six of 42 (14.3%) patients were positive for AQP4-IgG and 3/42 (7.1%) were positive for MOG-IgG. No patient was positive for both AQP4-IgG and MOG-IgG. All antibody-
IP
T
positive patients were women. MOG-IgG was associated with severe episodes of ON in all
CR
MOG-IgG-positive patients. Steroid treatment was followed by complete remission in two patients. AQP4-IgG was associated with ON and/or longitudinally extensive transverse
US
myelitis (LETM), often with severe onset. While all six of the AQP4-IgG-positive patients met the 2015 IPND criteria for NMOSD, only one of the three MOG-IgG-positive patients did so.
AN
Interestingly, clinically silent extensive spinal cord or brain lesions were present in two of the three MOG-IgG-positive patients, and altered visual evoked potentials without clinical evidence
M
of ON were found in three of the six AQP4-IgG-positive patients.
ED
Conclusion: MOG-IgG and AQP4-IgG are found in a substantial subset of Algerian patients with ON and/or myelitis, are present predominantly in women, and may be associated with
PT
differences in clinical presentation and, possibly, outcome. Only a subset of MOG-IgG positive
AC
CE
patients meets the current diagnostic criteria for NMOSD.
3
ACCEPTED MANUSCRIPT Introduction Neuromyelitis optica (NMO) is a severe autoimmune inflammatory disorder of the central nervous system (CNS) that predominantly targets the optic nerves and spinal cord [1, 2]. NMO and the limited forms of the disease are referred to by the umbrella term neuromyelitis optica
T
spectrum disorders (NMOSD). The current international diagnostic criteria for NMOSD
IP
distinguish two categories: NMOSD with antibodies to aquaporin-4 (AQP4-IgG) and NMOSD
CR
without AQP4-IgG or unknown AQP4-IgG serostatus [3]. A subgroup of patients with AQP4-IgGnegative NMOSD has recently been shown to be serologically characterized by the presence of
US
antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) [4-7]. So far, only little information is available on the frequency and clinical characteristics of MOG-IgG- and AQP4-IgG-positive
AN
NMOSD in North African patients. In this study, we describe the clinical and paraclinical features
M
of a cohort of Algerian patients with ON and/or myelitis for MOG-IgG and AQP4-IgG.
ED
Patients and methods
PT
We retrospectively reviewed the medical files of 43 patients treated at the hospital of TiziOuzou, Algeria, between January 2004 and December 2015 for monophasic (m) or recurrent (r)
CE
inflammatory disease affecting the optic nerve and/or the spinal cord. Patients with infectious and systemic disorders were excluded. The female to male ratio was 1.9:1.The patients’ median
AC
age at the time of testing was 33 years (range 19-58 years); two patients (4.65%) were children with recurrent severe optic neuritis (ON). Eleven (25.6%) patients were being followed up for ON, of whom six (54.5%) had bilateral involvement of the optic nerves, 9 patients (81.8%) had a long-term follow-up (beyond two years). Twenty-two (51.3%) patients were followed up for myelitis: 14 of these patients had recurrent longitudinally extensive transverse myelitis (rLETM); two recurrent non-extensive transverse myelitis (rNETM); one rLETM and an area postrema 4
ACCEPTED MANUSCRIPT syndrome (APS), one of the core clinical syndromes of NMOSD, characterized by unexplained hiccups, nausea and vomiting; one monophasic NETM and an APS; one rNETM and a brainstem syndrome other than APS; one mLETM and mNETM associated with the presence of auto-antibodies ; and one rLETM associated with a thalamic syndrome. Nine (20.9%) patients had both ON and myelitis, either sequentially or simultaneously, seven of whom (87.5%) had
IP
T
recurrent disease. One (2.3%) patient with multiple sclerosis (MS) and AQP4-IgG-positive
CR
NMOSD in a sister was also tested for both antibodies. All patients gave their informed consent to be tested for AQP4-IgG and MOG-IgG and to participate in the study. All these patients had a
US
long-term follow-up.
In 34 patients, serum was tested for MOG-IgG by means of a fixed cell-based assay
AN
(CBA; assay-specific cut-off ≥1:10; University of Heidelberg, Germany) [8] and a live CBA (cutoff ≥1:160, Medical University Innsbruck, Austria) [4, 8] in parallel and for AQP4-IgG by means
M
of a commercial fixed CBA (Euroimmun, Lübeck, Germany, Cut-off >=1:10) [9]. HEK293 cells
ED
transfected with full-length human MOG or AQP4, respectively, were used as antigenic substrate; mock-transfected cells were used as control substrate. One patient was tested for
PT
MOG-IgG and AQP4-IgG using a CBA in France as previously described [10] and eight patients
CE
were tested for MOG-IgG and AQP4-IgG using commercial CBAs in Algeria (Euroimmun; Germany). Demographic, clinical, imaging and laboratory data were collected and analysed in a
Results
AC
stratified manner according to each patient’s antibody serostatus.
Six (14.3%) of 42 patients were positive for AQP4-IgG, 3/42 (7.1%) were positive for MOG-IgG, and 33 of 42 (78.6%) were negative for both AQP4-IgG and MOG-IgG. None was positive for both AQP4-IgG and MOG-IgG. The MS patient with a sister diagnosed as AQP4-IgG-positive 5
ACCEPTED MANUSCRIPT NMOSD was negative both for AQP4-IgG and MOG-IgG and was excluded from further analysis. See Supplementary Table 1 for further details. The main clinical and paraclinical features of all AQP4-IgG- and MOG-IgG-positive patients are summarized in Table 1. The frequencies of AQP4-IgG and MOG-IgG are summarized in Table 2 and were 9%
T
and 18.8%, respectively, among patients with ON (without myelitis), 16.7% and 0% among
IP
patients with LETM (without ON), 0% and 0% among patients with NETM (without ON), and
CR
22.2% and 11.1% among patients with a history of both ON and myelitis.If only patients with either ON and LETM are considered, 25% and 12.5% had AQP4-IgG and MOG-IgG,
US
respectively. Three patients had an APS, none of whom were positive for AQP4-IgG or MOG-
AN
IgG.
M
Clinical and paraclinical findings in MOG-IgG-positive patients
ED
Patient 1 developed unilateral ON at the age of 32, leading to complete blindness in the affected eye. After 10 days of treatment with intravenous methylprednisolone (IVMP) (1 g/day) her visual
PT
acuity returned to normal. She then took oral corticosteroids. However, 6 weeks after the first attack and after reduction of her corticosteroid dosage, she developed severe ON in the other
CE
eye, again resulting in unilateral blindness. Once again, treatment with IVMP resulted in
AC
complete recovery. Under subsequent immunosuppressive therapy with azathioprine, no further attacks have occurred over a period of 1 year. Cerebral MRI during both attacks showed T2hyperintense, longitudinally extensive optic neuritis (LEON) without involvement of the optic chiasm and the optic tract. No cerebral lesions were found, and her spinal cord MRI findings were normal. Analysis of the cerebrospinal fluid showed
