Short Communication
A Case Report on Juvenile Neuromyelitis Optica: Early Onset, Long Remission Period, and Atypical Treatment Response Christiane Elpers1
Catharina C. Gross2
Barbara Fiedler1
1 University Children’s Hospital Muenster, General Pediatrics—
Neuropediatric Department, University of Muenster, Muenster, Germany 2 Department of Neurology, University of Muenster, Muenster, Germany
Sven G. Meuth2
Gerhard Kurlemann1
Address for correspondence Christiane Elpers, MD, University Children’s Hospital Muenster, General Pediatrics—Neuropediatric Department, University Hospital Muenster, Albert-Schweitzer-Campus 1; 48149 Muenster, Germany (e-mail: [email protected]).
Neuropediatrics 2015;46:292–295.
Abstract
Keywords
► neuromyelitis optica ► aquaporin 4 (NMO–IgG) ► rituximab
Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease of the central nervous system and preferentially targets the optic nerves and spinal cord. NMO is rare in children and clinical course of the disease is highly variable as described in studies. Here, we present a case report of a young girl presenting with a rare course of pediatric NMO with an early disease onset at the age of 12 years, a relapse free interval of 4 years, evidence of NMO immunoglobulin G (IgG) and an unusual response against immunosuppressive therapy. The aim of this report is to highlight the potentially long remission period between relapses complicating proper diagnosis despite well defined diagnostic criteria. In addition, we want to encourage the use of rituximab in pediatric NMO, although larger cohorts are warranted to establish B cell depleting therapies in juvenile NMO.
Case Report In April 2007, a 12-year-old Caucasian girl was admitted to a peripheral hospital with sudden paresis of the left arm and progressive paresis of her left leg. In addition, she complained of dizziness and neck pain. No further neurological deficits could be detected at presentation, especially no signs or symptoms of optic neuritis (ON). Cerebrospinal fluid (CSF) analysis revealed normal cell numbers, negative oligoclonal bands (OCBs), and only slightly elevated protein levels. No evidence of viral or bacterial infections could be detected. No testing of aquaporin-4 antibodies (NMO–IgG) in serum or CSF was performed. Magnetic resonance imaging (MRI) of the spinal cord demonstrated a longitudinal extensive transverse myelitis (LETM) from C2 to T2 (see ►Fig. 1A). Cerebral MRI was normal. No family history of multiple sclerosis (MS) or other demyelinating diseases of the central nervous system was reported. At initial presentation, she was treated with
received January 18, 2015 accepted after revision April 6, 2015 published online June 9, 2015
steroid pulse therapy (1,000 mg methylprednisolone) over 10 days with oral tapering over 3 months accompanied by anti-infectious therapy with a third-generation cephalosporin antibiotic (cefotaxime) and acyclovir over 10 days. Under therapy, she showed complete remission of the left-sided hemiparesis but developed a Cushing syndrome. Four years later (April 2011), for the first time, the patient was referred to our hospital because of a sudden loss of vision of the left eye. Clinical evaluation ascertained amaurosis of the left eye with a relative afferent pupillary deficit (RAPD), absent light reaction but normal fundoscopy. Visual-evoked potentials were initially not reproducible. CSF analysis showed slightly elevated protein levels but no OCBs (see ►Fig. 2A). Cerebral MRI depicted gadolinium enhancement of the left optic nerve indicating unilateral ON while further cerebral lesions are lacking in particular signal alteration in MS-related regions, in periaqueductal gray matter or around the fourth ventricle. Spinal MRI demonstrated
© 2015 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0035-1554101. ISSN 0174-304X.
Downloaded by: Rutgers University. Copyrighted material.
292
NMO in Children
Elpers et al.
293
tion on the left eye. Azathioprine (AZA, 2 mg/kg body weight) was started according to recommendations of NMO therapy in adult patients by NEMOS2 accompanied by oral cortisone for the first 4 weeks. Testing of thiopurine methyltransferase (TPMT)-polymorphism was negative. AZA therapy was discontinued after 2 months because of the adverse effects with neutropenia and pancreatitis and the patient was finally started with rituximab (1,000 mg at days 1 and 14, then depending on B cell counts once yearly over 3 years). The patient responded with significantly decreased CD19þ B cell counts (see ►Fig. 2B) accompanied by a stable clinical disease course (residual neurological deficits with only reduced light perception of the left eye) and no further lesions in MRI follow-up over 3 years.
Our case report adds to the literature by highlighting the variability of the clinical course of pediatric NMO3 with a long-remission period between disease-defining symptoms. A comparable course of pediatric NMO was reported by Huppke at al with a 6-year relapse-free period in a cohort of six children diagnosed with NMO.4 In addition, several case reports in adult patients with NMO revealed relapse-free intervals for several years.3 In contrast, Absoud et al5 recently
Fig. 1 (A) Representative T2-weighted sagittal image of the contiguous, hyperintense, central spinal cord lesion over more than three vertebral segments (C2–T2, left) with marginal gadolinium-enhancement (right) in T1-weighted images. (B) Follow-up magnetic resonance imaging after 4 years: the upper part presents sagittal and axial T2-weighted images of the residual longitudinal spinal cord lesion (C3–C6). Lower coronary T2-weighted, fat-saturated image shows a hyperintense left optic nerve with markedly unilateral optic atrophy in thin layer sections compared with the healthy eye.
residual LETM (see ►Fig. 1B). NMO–IgG were tested positive in serum; myelin oligodendrocyte glycoprotein (MOG) antibodies were not performed. Taken together, pediatric NMO was diagnosed based on the initial LETM at the age of 12 years in combination with typical spinal MRI findings, positive NMO–IgG, and a second relapse with ON.1 Steroid pulse therapy (1,000 mg methylprednisolone) over 7 days was administered without significant improvement of visual function. Despite a second pulse therapy (2,000 mg methylprednisolone over 7 days), which was performed according to the family’s preference, no improvement could be achieved, wherefore plasmapheresis was initiated. After eight cycles, the patient showed poor recovery with only light discrimina-
Fig. 2 (A) CSF results and testing of NMO-IgG at initial presentation with longitudinal extensive transverse myelitis (1st LP) and at time of optic neuritis (2nd LP) are shown;. (B) Course of CD19 þ and CD27 þ B cell counts is presented under treatment with rituximab (symbolized by ) within 3 years; significant depletion after first administration of rituximab and little increases is demonstrated before each further rituximab cycle. After a threshold value of 2% of CD19 þ, B cell count (and 2% of CD27 þ B cells) rituximab was reconsidered and administered if B cell count is confirmed in a second measurement within 2 weeks. Repopulation of CD19 þ B cells occurred after an interval of 10 to 12 months after each rituximab administration. Once repopulation of CD19 þ B cells was detected and confirmed, rituximab was applied within 4 weeks. CSF, cerebrospinal fluid; NMO-IgG, aquaporin-4 antibodies; LP, lumbar puncture; OCB, negative oligoclonal band. Neuropediatrics
Vol. 46
No. 4/2015
Downloaded by: Rutgers University. Copyrighted material.
Discussion
NMO in Children
Elpers et al.
published a mean time to a next relapse of 0.76 years in a large cohort of 20 pediatric patients with NMO and associated pediatric NMO with an early recurrence of symptoms. Several case reports demonstrate the broad spectrum of pediatric NMO and thereby reveal the complications to establish proper diagnosis.3 The proportion of cases positive for NMO–IgG seems to be almost equal in children with NMO6 and adult patients suffering from NMO (78 vs. 86%, respectively) but seronegative cases of pediatric NMO are reported particularly in combination with a monophasic disease course.4,6 In NMO–IgG, negative cases testing of MOG antibodies is indicated as the presence of these antibodies or absence of both (MOG, NMO–IgG) seems to have a distinct clinical phenotype and disease course7,8 and might be helpful to distinguish children at high risk for NMO from those with other demyelinating diseases. NMO spectrum disorders (NMOSD) unifies patients with or without NMO–IgG presenting with different clinical symptoms such as ON or LETM or affecting additional parts of the brain (e.g., brain stem and hypothalamus). Furthermore, testing of NMO–IgG antibodies is urgently required even after a single clinical episode of ON or LETM for early diagnosis. Here, NMO could have been already confirmed at initial presentation (LETM) according to the recently proposed revised diagnostic criteria for NMO by Wingerchuk. This emphasizes the difficulty to diagnose NMO despite of well-defined diagnostic criteria2 which might result in delayed treatment initiation. Therefore, clinicians should be aware of the variable disease course of NMO and the possibility of a long-remission period in pediatric cases with NMO. Children with either ON or myelitis, especially LETM, that do not meet criteria for NMO, require a long-term clinical follow-up. According to the recommendation of NEMOS,2 our patient first received immunosuppressive therapy with AZA to avoid further relapses and disability progression. A good safety profile for AZA has been demonstrated in adult NMO9 and even in single studies in pediatric NMO.10 However, despite overall good tolerability, adverse effects can occur typically in terms of neutropenia and/or pancreatitis as presented in our case report. Individuals with low activity of TPMT are at higher risk for severe adverse effects,2 but here no TPMT polymorphism was found. If first-line treatment failed, early switch to rituximab or mitoxantrone and mycophenolate mofetil (MMF) is recommended to preserve remission.11 As data for use of MMF in pediatric NMO is lacking, we introduced rituximab 6 months after initial presentation. Rituximab significantly reduces relapses up to 88% in NMO11 or at least stabilizes the disease course.10,12 Safety profile of rituximab administration was shown to be acceptable in adults13 and children14 with only a minority of patients developing severe adverse effects confirming the 2014 recommendation of NEMOS for rituximab as a first-line treatment option.2 As no adverse event occurred during the past 3 years of rituximab therapy, our case contributes insights to the favorable tolerability and safety profile of rituximab in pediatric NMO. Furthermore, the patient demonstrated a good treatment response with significant depletion of CD19þ B cell counts after first administration which sustained at low levels for Neuropediatrics
Vol. 46
No. 4/2015
several months (see ►Fig. 2B). No further relapse occurred in the disease course during a follow-up period of 3 years contributing to the accepted association between sufficient B cell depletion and relapse rate.2 Compared with published data, our case showed a quite long-term depletion of CD19þ B cell counts, which were monitored monthly by flow cytometry (FACS) of peripheral blood. Thus, rituximab only had to be administered annually. In adults, CD19þ B cells seems to increase more rapidly after administration as repetition of rituximab is recommended every 6 months.15 Kim et al suggest CD27þ B cell count instead of CD19þ B cells as a more precise biomarker in NMO to predict new relapse and indication for additional rituximab therapy.15 In children, there is so far no guideline for timing of B cell monitoring under rituximab treatment. Even in adult NMO different protocols for treatment surveillance are evident. Some proposed administration every 6 to 12 months independent from B cell counts. Furthermore, measurement of CD19þ B cells is suggested every 1 to 3 months but the threshold value of redosing rituximab is not known.13 On the basis of our case report, measurement of CD19þ B cell counts by FACS might be sufficient once every 3 months. So far, pediatric NMO still requires a defined monitoring and treatment algorithm to optimize patient care.
Conclusion This case of pediatric NMO highlights the potential long-remission period between relapses in NMO which complicates proper diagnosis despite well-defined diagnostic criteria. Here, testing of NMO–IgG is strongly recommended—even after a single clinical episode of ON or LETM to allow early diagnosis. In addition, the use of rituximab should be considered as a therapeutic alternative which can be closely monitored by B cell counts if other standard interval treatment fails. However, larger trials are warranted to define specific guidelines for diagnosis and therapy in children with NMO.
Disclosure Christiane Elpers has received honoraria for lecturing and travel expenses for attending meetings from Bayer, Biogen Idec, and Sanofi-Aventis. Catharina C. Gross is funded by the German Research Foundation (single grant GR3946/2–1). She received speaker honoraria for lecturing and travel expenses for attending meetings from Bayer Health Care, Genzyme, and Novartis Pharma GmbH. Barbara Fiedler has received honoraria for lecturing and travel expenses for attending meetings from UCB and Desitin. Sven G. Meuth has received honoraria for lecturing and travel expenses for attending meetings and has received financial research support from Bayer, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, MSD, Novartis, Novo Nordisk, Sanofi-Aventis, and Teva. Gerhard Kurlemann has received honoraria for attending scientific advisory board from UCB, Eisai and Viropharma and for lecturing from Desitin, Eisai, Viropharma, UCB and Dibropharma.
Downloaded by: Rutgers University. Copyrighted material.
294
NMO in Children
9 Costanzi C, Matiello M, Lucchinetti CF, et al. Azathioprine: tolera-
1 Wingerchuk DM. Diagnosis and treatment of neuromyelitis optica. 2
3 4
5
6
7
8
Neurologist 2007;13(1):2–11 Trebst C, Jarius S, Berthele A, et al; Neuromyelitis Optica Study Group (NEMOS). Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol 2014;261(1):1–16 Bomprezzi R, Postevka E, Campagnolo D, Vollmer TL. A review of cases of neuromyelitis optica. Neurologist 2011;17(2):98–104 Huppke P, Blüthner M, Bauer O, et al. Neuromyelitis optica and NMO-IgG in European pediatric patients. Neurology 2010;75(19): 1740–1744 Absoud M, Lim MJ, Appleton R, et al. Paediatric neuromyelitis optica: clinical, MRI of the brain and prognostic features. J Neurol Neurosurg Psychiatry 2015;86(4):470–472 Banwell B, Tenembaum S, Lennon VA, et al. Neuromyelitis opticaIgG in childhood inflammatory demyelinating CNS disorders. Neurology 2008;70(5):344–352 Sato DK, Callegaro D, Lana-Peixoto MA, et al. Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology 2014;82(6):474–481 Rostasy K, Reindl M. Role of autoantibodies in acquired inflammatory demyelinating diseases of the central nervous system in children. Neuropediatrics 2013;44(6):297–301
295
10
11
12
13
14
15
bility, efficacy, and predictors of benefit in neuromyelitis optica. Neurology 2011;77(7):659–666 Tenembaum SN. Treatment of multiple sclerosis and neuromyelitis optica in children and adolescents. Clin Neurol Neurosurg 2013;115(Suppl 1):S21–S29 Mealy MA, Wingerchuk DM, Palace J, Greenberg BM, Levy M. Comparison of relapse and treatment failure rates among patients with neuromyelitis optica: multicenter study of treatment efficacy. JAMA Neurol 2014;71(3):324–330 Beres SJ, Graves J, Waubant E. Rituximab use in pediatric central demyelinating disease. Pediatr Neurol 2014;51(1): 114–118 Pellkofer HL, Krumbholz M, Berthele A, et al. Long-term follow-up of patients with neuromyelitis optica after repeated therapy with rituximab. Neurology 2011;76(15):1310–1315 Dale RC, Brilot F, Duffy LV, et al. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology 2014;83(2):142–150 Kim SH, Kim W, Li XF, Jung IJ, Kim HJ. Repeated treatment with rituximab based on the assessment of peripheral circulating memory B cells in patients with relapsing neuromyelitis optica over 2 years. Arch Neurol 2011;68(11): 1412–1420
Neuropediatrics
Vol. 46
No. 4/2015
Downloaded by: Rutgers University. Copyrighted material.
References
Elpers et al.
A Case Report on Juvenile Neuromyelitis Optica: Early Onset, Long Remission Period, and Atypical Treatment Response Christiane Elpers1
Catharina C. Gross2
Barbara Fiedler1
1 University Children’s Hospital Muenster, General Pediatrics—
Neuropediatric Department, University of Muenster, Muenster, Germany 2 Department of Neurology, University of Muenster, Muenster, Germany
Sven G. Meuth2
Gerhard Kurlemann1
Address for correspondence Christiane Elpers, MD, University Children’s Hospital Muenster, General Pediatrics—Neuropediatric Department, University Hospital Muenster, Albert-Schweitzer-Campus 1; 48149 Muenster, Germany (e-mail: [email protected]).
Neuropediatrics 2015;46:292–295.
Abstract
Keywords
► neuromyelitis optica ► aquaporin 4 (NMO–IgG) ► rituximab
Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease of the central nervous system and preferentially targets the optic nerves and spinal cord. NMO is rare in children and clinical course of the disease is highly variable as described in studies. Here, we present a case report of a young girl presenting with a rare course of pediatric NMO with an early disease onset at the age of 12 years, a relapse free interval of 4 years, evidence of NMO immunoglobulin G (IgG) and an unusual response against immunosuppressive therapy. The aim of this report is to highlight the potentially long remission period between relapses complicating proper diagnosis despite well defined diagnostic criteria. In addition, we want to encourage the use of rituximab in pediatric NMO, although larger cohorts are warranted to establish B cell depleting therapies in juvenile NMO.
Case Report In April 2007, a 12-year-old Caucasian girl was admitted to a peripheral hospital with sudden paresis of the left arm and progressive paresis of her left leg. In addition, she complained of dizziness and neck pain. No further neurological deficits could be detected at presentation, especially no signs or symptoms of optic neuritis (ON). Cerebrospinal fluid (CSF) analysis revealed normal cell numbers, negative oligoclonal bands (OCBs), and only slightly elevated protein levels. No evidence of viral or bacterial infections could be detected. No testing of aquaporin-4 antibodies (NMO–IgG) in serum or CSF was performed. Magnetic resonance imaging (MRI) of the spinal cord demonstrated a longitudinal extensive transverse myelitis (LETM) from C2 to T2 (see ►Fig. 1A). Cerebral MRI was normal. No family history of multiple sclerosis (MS) or other demyelinating diseases of the central nervous system was reported. At initial presentation, she was treated with
received January 18, 2015 accepted after revision April 6, 2015 published online June 9, 2015
steroid pulse therapy (1,000 mg methylprednisolone) over 10 days with oral tapering over 3 months accompanied by anti-infectious therapy with a third-generation cephalosporin antibiotic (cefotaxime) and acyclovir over 10 days. Under therapy, she showed complete remission of the left-sided hemiparesis but developed a Cushing syndrome. Four years later (April 2011), for the first time, the patient was referred to our hospital because of a sudden loss of vision of the left eye. Clinical evaluation ascertained amaurosis of the left eye with a relative afferent pupillary deficit (RAPD), absent light reaction but normal fundoscopy. Visual-evoked potentials were initially not reproducible. CSF analysis showed slightly elevated protein levels but no OCBs (see ►Fig. 2A). Cerebral MRI depicted gadolinium enhancement of the left optic nerve indicating unilateral ON while further cerebral lesions are lacking in particular signal alteration in MS-related regions, in periaqueductal gray matter or around the fourth ventricle. Spinal MRI demonstrated
© 2015 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0035-1554101. ISSN 0174-304X.
Downloaded by: Rutgers University. Copyrighted material.
292
NMO in Children
Elpers et al.
293
tion on the left eye. Azathioprine (AZA, 2 mg/kg body weight) was started according to recommendations of NMO therapy in adult patients by NEMOS2 accompanied by oral cortisone for the first 4 weeks. Testing of thiopurine methyltransferase (TPMT)-polymorphism was negative. AZA therapy was discontinued after 2 months because of the adverse effects with neutropenia and pancreatitis and the patient was finally started with rituximab (1,000 mg at days 1 and 14, then depending on B cell counts once yearly over 3 years). The patient responded with significantly decreased CD19þ B cell counts (see ►Fig. 2B) accompanied by a stable clinical disease course (residual neurological deficits with only reduced light perception of the left eye) and no further lesions in MRI follow-up over 3 years.
Our case report adds to the literature by highlighting the variability of the clinical course of pediatric NMO3 with a long-remission period between disease-defining symptoms. A comparable course of pediatric NMO was reported by Huppke at al with a 6-year relapse-free period in a cohort of six children diagnosed with NMO.4 In addition, several case reports in adult patients with NMO revealed relapse-free intervals for several years.3 In contrast, Absoud et al5 recently
Fig. 1 (A) Representative T2-weighted sagittal image of the contiguous, hyperintense, central spinal cord lesion over more than three vertebral segments (C2–T2, left) with marginal gadolinium-enhancement (right) in T1-weighted images. (B) Follow-up magnetic resonance imaging after 4 years: the upper part presents sagittal and axial T2-weighted images of the residual longitudinal spinal cord lesion (C3–C6). Lower coronary T2-weighted, fat-saturated image shows a hyperintense left optic nerve with markedly unilateral optic atrophy in thin layer sections compared with the healthy eye.
residual LETM (see ►Fig. 1B). NMO–IgG were tested positive in serum; myelin oligodendrocyte glycoprotein (MOG) antibodies were not performed. Taken together, pediatric NMO was diagnosed based on the initial LETM at the age of 12 years in combination with typical spinal MRI findings, positive NMO–IgG, and a second relapse with ON.1 Steroid pulse therapy (1,000 mg methylprednisolone) over 7 days was administered without significant improvement of visual function. Despite a second pulse therapy (2,000 mg methylprednisolone over 7 days), which was performed according to the family’s preference, no improvement could be achieved, wherefore plasmapheresis was initiated. After eight cycles, the patient showed poor recovery with only light discrimina-
Fig. 2 (A) CSF results and testing of NMO-IgG at initial presentation with longitudinal extensive transverse myelitis (1st LP) and at time of optic neuritis (2nd LP) are shown;. (B) Course of CD19 þ and CD27 þ B cell counts is presented under treatment with rituximab (symbolized by ) within 3 years; significant depletion after first administration of rituximab and little increases is demonstrated before each further rituximab cycle. After a threshold value of 2% of CD19 þ, B cell count (and 2% of CD27 þ B cells) rituximab was reconsidered and administered if B cell count is confirmed in a second measurement within 2 weeks. Repopulation of CD19 þ B cells occurred after an interval of 10 to 12 months after each rituximab administration. Once repopulation of CD19 þ B cells was detected and confirmed, rituximab was applied within 4 weeks. CSF, cerebrospinal fluid; NMO-IgG, aquaporin-4 antibodies; LP, lumbar puncture; OCB, negative oligoclonal band. Neuropediatrics
Vol. 46
No. 4/2015
Downloaded by: Rutgers University. Copyrighted material.
Discussion
NMO in Children
Elpers et al.
published a mean time to a next relapse of 0.76 years in a large cohort of 20 pediatric patients with NMO and associated pediatric NMO with an early recurrence of symptoms. Several case reports demonstrate the broad spectrum of pediatric NMO and thereby reveal the complications to establish proper diagnosis.3 The proportion of cases positive for NMO–IgG seems to be almost equal in children with NMO6 and adult patients suffering from NMO (78 vs. 86%, respectively) but seronegative cases of pediatric NMO are reported particularly in combination with a monophasic disease course.4,6 In NMO–IgG, negative cases testing of MOG antibodies is indicated as the presence of these antibodies or absence of both (MOG, NMO–IgG) seems to have a distinct clinical phenotype and disease course7,8 and might be helpful to distinguish children at high risk for NMO from those with other demyelinating diseases. NMO spectrum disorders (NMOSD) unifies patients with or without NMO–IgG presenting with different clinical symptoms such as ON or LETM or affecting additional parts of the brain (e.g., brain stem and hypothalamus). Furthermore, testing of NMO–IgG antibodies is urgently required even after a single clinical episode of ON or LETM for early diagnosis. Here, NMO could have been already confirmed at initial presentation (LETM) according to the recently proposed revised diagnostic criteria for NMO by Wingerchuk. This emphasizes the difficulty to diagnose NMO despite of well-defined diagnostic criteria2 which might result in delayed treatment initiation. Therefore, clinicians should be aware of the variable disease course of NMO and the possibility of a long-remission period in pediatric cases with NMO. Children with either ON or myelitis, especially LETM, that do not meet criteria for NMO, require a long-term clinical follow-up. According to the recommendation of NEMOS,2 our patient first received immunosuppressive therapy with AZA to avoid further relapses and disability progression. A good safety profile for AZA has been demonstrated in adult NMO9 and even in single studies in pediatric NMO.10 However, despite overall good tolerability, adverse effects can occur typically in terms of neutropenia and/or pancreatitis as presented in our case report. Individuals with low activity of TPMT are at higher risk for severe adverse effects,2 but here no TPMT polymorphism was found. If first-line treatment failed, early switch to rituximab or mitoxantrone and mycophenolate mofetil (MMF) is recommended to preserve remission.11 As data for use of MMF in pediatric NMO is lacking, we introduced rituximab 6 months after initial presentation. Rituximab significantly reduces relapses up to 88% in NMO11 or at least stabilizes the disease course.10,12 Safety profile of rituximab administration was shown to be acceptable in adults13 and children14 with only a minority of patients developing severe adverse effects confirming the 2014 recommendation of NEMOS for rituximab as a first-line treatment option.2 As no adverse event occurred during the past 3 years of rituximab therapy, our case contributes insights to the favorable tolerability and safety profile of rituximab in pediatric NMO. Furthermore, the patient demonstrated a good treatment response with significant depletion of CD19þ B cell counts after first administration which sustained at low levels for Neuropediatrics
Vol. 46
No. 4/2015
several months (see ►Fig. 2B). No further relapse occurred in the disease course during a follow-up period of 3 years contributing to the accepted association between sufficient B cell depletion and relapse rate.2 Compared with published data, our case showed a quite long-term depletion of CD19þ B cell counts, which were monitored monthly by flow cytometry (FACS) of peripheral blood. Thus, rituximab only had to be administered annually. In adults, CD19þ B cells seems to increase more rapidly after administration as repetition of rituximab is recommended every 6 months.15 Kim et al suggest CD27þ B cell count instead of CD19þ B cells as a more precise biomarker in NMO to predict new relapse and indication for additional rituximab therapy.15 In children, there is so far no guideline for timing of B cell monitoring under rituximab treatment. Even in adult NMO different protocols for treatment surveillance are evident. Some proposed administration every 6 to 12 months independent from B cell counts. Furthermore, measurement of CD19þ B cells is suggested every 1 to 3 months but the threshold value of redosing rituximab is not known.13 On the basis of our case report, measurement of CD19þ B cell counts by FACS might be sufficient once every 3 months. So far, pediatric NMO still requires a defined monitoring and treatment algorithm to optimize patient care.
Conclusion This case of pediatric NMO highlights the potential long-remission period between relapses in NMO which complicates proper diagnosis despite well-defined diagnostic criteria. Here, testing of NMO–IgG is strongly recommended—even after a single clinical episode of ON or LETM to allow early diagnosis. In addition, the use of rituximab should be considered as a therapeutic alternative which can be closely monitored by B cell counts if other standard interval treatment fails. However, larger trials are warranted to define specific guidelines for diagnosis and therapy in children with NMO.
Disclosure Christiane Elpers has received honoraria for lecturing and travel expenses for attending meetings from Bayer, Biogen Idec, and Sanofi-Aventis. Catharina C. Gross is funded by the German Research Foundation (single grant GR3946/2–1). She received speaker honoraria for lecturing and travel expenses for attending meetings from Bayer Health Care, Genzyme, and Novartis Pharma GmbH. Barbara Fiedler has received honoraria for lecturing and travel expenses for attending meetings from UCB and Desitin. Sven G. Meuth has received honoraria for lecturing and travel expenses for attending meetings and has received financial research support from Bayer, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, MSD, Novartis, Novo Nordisk, Sanofi-Aventis, and Teva. Gerhard Kurlemann has received honoraria for attending scientific advisory board from UCB, Eisai and Viropharma and for lecturing from Desitin, Eisai, Viropharma, UCB and Dibropharma.
Downloaded by: Rutgers University. Copyrighted material.
294
NMO in Children
9 Costanzi C, Matiello M, Lucchinetti CF, et al. Azathioprine: tolera-
1 Wingerchuk DM. Diagnosis and treatment of neuromyelitis optica. 2
3 4
5
6
7
8
Neurologist 2007;13(1):2–11 Trebst C, Jarius S, Berthele A, et al; Neuromyelitis Optica Study Group (NEMOS). Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol 2014;261(1):1–16 Bomprezzi R, Postevka E, Campagnolo D, Vollmer TL. A review of cases of neuromyelitis optica. Neurologist 2011;17(2):98–104 Huppke P, Blüthner M, Bauer O, et al. Neuromyelitis optica and NMO-IgG in European pediatric patients. Neurology 2010;75(19): 1740–1744 Absoud M, Lim MJ, Appleton R, et al. Paediatric neuromyelitis optica: clinical, MRI of the brain and prognostic features. J Neurol Neurosurg Psychiatry 2015;86(4):470–472 Banwell B, Tenembaum S, Lennon VA, et al. Neuromyelitis opticaIgG in childhood inflammatory demyelinating CNS disorders. Neurology 2008;70(5):344–352 Sato DK, Callegaro D, Lana-Peixoto MA, et al. Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology 2014;82(6):474–481 Rostasy K, Reindl M. Role of autoantibodies in acquired inflammatory demyelinating diseases of the central nervous system in children. Neuropediatrics 2013;44(6):297–301
295
10
11
12
13
14
15
bility, efficacy, and predictors of benefit in neuromyelitis optica. Neurology 2011;77(7):659–666 Tenembaum SN. Treatment of multiple sclerosis and neuromyelitis optica in children and adolescents. Clin Neurol Neurosurg 2013;115(Suppl 1):S21–S29 Mealy MA, Wingerchuk DM, Palace J, Greenberg BM, Levy M. Comparison of relapse and treatment failure rates among patients with neuromyelitis optica: multicenter study of treatment efficacy. JAMA Neurol 2014;71(3):324–330 Beres SJ, Graves J, Waubant E. Rituximab use in pediatric central demyelinating disease. Pediatr Neurol 2014;51(1): 114–118 Pellkofer HL, Krumbholz M, Berthele A, et al. Long-term follow-up of patients with neuromyelitis optica after repeated therapy with rituximab. Neurology 2011;76(15):1310–1315 Dale RC, Brilot F, Duffy LV, et al. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology 2014;83(2):142–150 Kim SH, Kim W, Li XF, Jung IJ, Kim HJ. Repeated treatment with rituximab based on the assessment of peripheral circulating memory B cells in patients with relapsing neuromyelitis optica over 2 years. Arch Neurol 2011;68(11): 1412–1420
Neuropediatrics
Vol. 46
No. 4/2015
Downloaded by: Rutgers University. Copyrighted material.
References
Elpers et al.
