PEDIATRICS Vol. 122 No. 5 November 2008, pp. e1039-e1047 (doi:10.1542/peds.2007-2758)
ARTICLE |
Spectrum of Pediatric Neuromyelitis Optica
a Section of Child Neurology, Department of Pediatrics, Texas Children's Hospital, Houston, Texas
b Departments of Neurology
c Molecular and Human Genetics
e Radiology, Baylor College of Medicine, Houston, Texas
d Section of Ophthalmology, Department of Head and Neck Surgery, University of Texas M. D. Anderson Cancer Center, Houston, Texas
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ABSTRACT |
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 TOP ABSTRACT PATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIXREFERENCES |
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OBJECTIVE. Our goal was to describe the spectrum of clinical phenotypes, laboratory and imaging features, and treatment in pediatric patients with neuromyelitis optica.
PATIENTS AND METHODS. The study consisted of a retrospective chart review of patients followed in a pediatric multiple sclerosis center with a diagnosis of neuromyelitis optica spectrum disorder.
RESULTS. Nine patients with neuromyelitis optica spectrum disorders were included, all of whom were female. There were 4 black children, 2 Latin American children, 2 white children, and 1 child of mixed Latin American/white heritage. Median age at initial attack was 14 years (range: 1.9–16 years). Median disease duration was 4 years (range: 0.6–9 years). Tests for neuromyelitis optica immunoglobulin G were positive for 7 patients. Eight patients had transverse myelitis and optic neuritis, and 1 patient had longitudinally extensive transverse myelitis without optic neuritis but had a positive neuromyelitis optica immunoglobulin G antibody titer. Cerebral involvement on MRI was found in all subjects, 5 of whom were symptomatic with encephalopathy, seizures, hemiparesis, aphasia, vomiting, or hiccups. Immunosuppressive therapy reduced attack frequency and progression of disability.
CONCLUSIONS. Pediatric neuromyelitis optica has a diverse clinical presentation and may be difficult to distinguish from multiple sclerosis in the early stages of the disease. The recognition of the broad spectrum of this disease to include signs and symptoms of brain involvement is aided by the availability of a serum biomarker: neuromyelitis optica immunoglobulin G. Early diagnosis and immunosuppresive treatment may help to slow the accumulation of severe disability.
Key Words: neuromyelitis optica • multiple sclerosis • central nervous system • encephalomyelitis • spinal cord
Abbreviations: NMO—neuromyelitis optica • CNS—central nervous system • MS—multiple sclerosis • ON—optic neuritis • TM—transverse myelitis • IgG—immunoglobulin G • AQP4—aquaporin 4 • LETM—longitudinally extensive transverse myelitis • SIADH— syndrome of inappropriate antidiuretic hormone secretion • FANA—fluorescent antinuclear antibody • EDSS—Expanded Disability Status Scale • FLAIR—fluid attenuated inversion recovery • IVIg—intravenous immunoglobulin • CSF—cerebrospinal fluid • WBC—white blood cell • dsDNA—double-stranded DNA
Neuromyelitis optica (NMO) is a demyelinating disease of the central nervous system (CNS) that is often difficult to distinguish from multiple sclerosis (MS). There is still debate whether NMO is a distinct disease from MS.1–4 NMO has been described as a more aggressive disease and not responsive to the immunomodulatory therapies used to treat MS.5
Diagnostic criteria for NMO were described in 1999 to include optic neuritis (ON), transverse myelitis (TM), and no symptoms or MRI findings implicating other CNS regions.6 In 2004, an antibody, serum NMO immunoglobulin G (IgG), was found to be a sensitive and specific biomarker for this disease, a discovery confirmed by several independent laboratories.7–9 This antibody is directed against aquaporin 4 (AQP4), a regulatory water channel with high levels of CNS expression.10
Based on preliminary validation studies of this biomarker, the Pediatric Multiple Sclerosis Study Group suggested the following for the diagnosis of pediatric NMO: (1) ON and TM required as major criteria; and (2) either longitudinally extensive transverse myelitis (LETM) with MRI demonstrating involvement of 
3 spinal segments or NMO IgG seropositivity.11 It is important to note that these criteria did not incorporate brain MRI findings in NMO, which were subsequently described.12
Diagnostic criteria were revised in 2006 by using likelihood ratios to develop several models, including NMO IgG as well as spinal cord and brain MRI findings.13 These models were analyzed to determine which provided the greatest sensitivity and specificity. Statistical analysis of a model identical to that proposed for pediatric NMO had a sensitivity of 100% but inadequate specificity of 79%. Additional inclusion into the variables of a brain MRI not meeting Paty criteria for MS demonstrated a sensitivity of 99% and specificity of 90%, suggesting the importance of brain imaging in trying to ensure the diagnosis.
We report our pediatric NMO experience at the Center for Pediatric Multiple Sclerosis in Houston, Texas. This is one of the largest published cohorts of pediatric NMO from a single center and is, to our knowledge, the first reported series focusing on the diverse presentation in the pediatric population using the newly proposed criteria. This report highlights distinguishing characteristics for the disease to include brain MRI findings that should be considered in the diagnosis.
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PATIENTS AND METHODS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIXREFERENCES |
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A retrospective record analysis was performed for patients seen in the Texas Children's Hospital Center for Pediatric Multiple Sclerosis between 2001 and 2007. All patients were seen and evaluated by the principal author (Dr Lotze). Patient information was extracted from an institutional review board-approved database. All patients meeting current pediatric NMO diagnostic criteria were included. One patient who was NMO IgG-seropositive with recurrent LETM without ON was included because her clinical course was otherwise typical for NMO and thought to represent the broader disease spectrum. Information extracted from the database included age, ethnicity, attack history, MRI findings, laboratory values, disability, and response to treatment. NMO IgG-seropositive status was collected at the time of initial evaluation. Repeat testing was performed in 7 patients during the course of disease.
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RESULTS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIXREFERENCES |
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Demographics
Nine patients meeting inclusion criteria for NMO spectrum disorder were identified. Clinical and laboratory characteristics are summarized in Table 1. Selected case histories (patients 1, 2, and 9) are reported in the Appendix demonstrating 3 distinct presentations. All patients were female. Reported ethnicities of the children were black (4 [44%]), Latin American (2 [22%]), white (2 [22%]), and mixed Latin American/white heritage (1 [11%]). Median age at the time of the study was 16 years (range: 6–20). Median age at initial attack was 14 years (range: 1.9–16) with median disease duration of 4 years (range: 0.6–9). Mean relapse rate per year was 2.6 (range: 1–4), and median disability based on the Expanded Disability Status Scale (EDSS) score was 3 (range: 0–8).
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Optic Neuritis
ON occurred concurrently with TM in 5 patients and 12 months after an initial presentation of TM in 1 patient (patient 5). In 2 other patients (patients 3 and 8), TM followed the initial presentation of ON, with the 2 attacks separated by 3 and 18 months, respectively. ON was bilateral at onset in 5 patients (Fig 1 A and B) and bilateral sequential in 2 patients (patients 7 and 8), with attacks separated in time by 2 and 12 months, respectively. One patient had unilateral ON (patient 6). Visual impairment varied both between and within each patient. Four patients (patients 1, 4, 7, and 8) had severe vision impairment, with complete vision loss in the affected eye. In the remainder, vision recovered to at least 20/25. Patient 8 has complete vision loss in the right eye after her initial attack of ON, but the vision in her left eye recovered to 20/25.
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Transverse Myelitis
All patients had symptoms consistent with TM during their disease course. One patient (patient 7) had a segmental spinal cord lesion involving C2 at initial presentation. She then had an attack of LETM (C1–C6) 4 years later. The remainder of patients had spinal cord involvement greater than 3 spinal segments at onset. LETM on MRI most frequently involved the cervico-thoracic spinal cord (Fig 1C). In 7 patients who had spinal cord imaging performed at the time of acute attacks of TM, enhancement of lesions was found after administration of gadolinium. One patient (patient 9) had recurrent episodes of LETM but did not have clinical, neurophysiologic, or imaging evidence of ON. However, here serum NMO IgG level was positive, and her clinical response to plasmapheresis supported an antibody-mediated disease. In addition, her clinical phenotype was similar to other patients, including a more severe disease course with several attacks per year and significant disability. This patient and 2 others (patients 1 and 4) had atrophy of the spinal cord at segments of previous attacks as measured by progressive decrease in caliber of the cord on serial imaging (Fig 2 A and B).
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Brain Involvement
Three patients had symptoms attributed to brain disease. Seizures occurred with the first clinical attacks in 2 patients (patients 4 and 7). Both patients developed epilepsy and required treatment with anticonvulsants. Serial imaging of patient 7 demonstrated atrophy and increased fluid attenuated inversion recovery (FLAIR) signal in the left mesial temporal lobe. Patient 2 developed aphasia as part of her third attack with a lesion in the left temporal lobe. Her initial attack was characterized by syndrome of inappropriate antidiuretic hormone secretion (SIADH) attributed to disease involvement of the hypothalamus on brain imaging (Fig 3A). Patient 7 had aphasia as part of her initial presentation with a thalamic lesion on MRI.
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All patients in our cohort had abnormalities on brain MRI from disease onset (Fig 3). Distribution of the lesions demonstrated on brain MRI is summarized in Table 2 and Fig 4. Nonspecific changes (nonovoid, nonenhancing, nonperiventricular deep white matter lesions or too few to satisfy the Barkof criteria for MS) were found in 8 patients at initial presentation. Atypical lesions (large confluent cerebral or diencephalon lesions) were seen in 1 patient on the initial MRI. With serial imaging during the course of follow-up, 2 patients met Barkof criteria for separation in space on MRI.
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Eight patients had periventricular lesions, including the temporal horns of the lateral ventricles, the third and fourth ventricles, and the periaqueductal region. Four patients had lesions involving the corpus callosum, 4 had hypothalamic lesions, and 2 had parahippocampal lesions. Juxtacortical and central white matter lesions were found in 5 patients. Three patient (patients 2, 4, and 7) developed generalized atrophy on serial images as measured by increase in size of the lateral ventricles and sulcal spaces (Fig 2 C and D). All of these patients had a higher lesion load in the central white matter compared with other patients in the cohort.
NMO Serology
NMO IgG was evaluated through the clinical Neuroimmunology Laboratory at Mayo Clinic by using indirect immunofluorescence assay on a substrate of mouse CNS and kidney tissues.7 Seven patients had NMO IgG seropositivity. Patient 2's NMO IgG seroconverted from positive to negative status during chronic treatment with daily mycophenolate mofetil plus monthly pulse intravenous immunoglobulin and methylprednisolone. Patient 5 was initially seronegative after a course of plasmapheresis, but converted to seropositive during a second attack. Her NMO IgG later returned negative results during treatment with rituximab. Patient 8 seroconverted to a negative NMO IgG during treatment with rituximab. Four months later she returned positive results again.
Menstrual Irregularities
Three patients (patients 2, 3, and 5) had irregular menstrual cycles before their initial attack. Their cycles became regular while receiving immunosuppressive treatment. Catamenial exacerbation of disease occurred in 1 patient, and initiating oral contraceptives corresponded with decreased attacks. One patient (patient 7) had an uncomplicated pregnancy and delivered a healthy term infant. She had no clinical relapses during the pregnancy but 1 month after delivery had an attack of ON and TM.
Autoimmune Disease
Six patients had serologic evidence of other autoimmune antibodies or disease. Patient 1 had positive antiphospholipid antibody titers including IgG anticardiolipin and positive lupus anticoagulant. Patients 4 and 6 were found to have a positive SSA antibody (Sjogren's syndrome A/anti-Ro antibody); however, they did not meet diagnostic criteria for Sjogren disease. Patient 4 developed biopsy-proven autoimmune hepatitis early in her disease course. Six patients had fluorescent antinuclear antibody (FANA) titers of >1:320.
Family History
Six patients had a family history for autoimmune diseases. One parent had rheumatoid arthritis and antiphospholipid antibody syndrome. In another family, 1 parent had adult-onset Still's disease. In a third family, a parent had hypothyroidism. First cousins in 2 families had juvenile-onset diabetes mellitus. One patient had a paternal second cousin with MS. This cousin's history included ON, but by report he did not fulfill NMO criteria and was seronegative for NMO IgG.
Disease Course
All patients had a relapsing-remitting course. Median time to second attack was 7 months (range: 3–18 months), the median number of total attacks was 7 (range: 2–11), and the median EDSS was 3 (range 0–8).
Therapy
All patients received treatment for acute attacks with high-dose intravenous methylprednisolone (30 mg/kg per dose). Four patients were also treated with intravenous gammaglobulin and plasmapheresis for acute attacks (patients 1, 2, 5, and 9). Patient 2 was treated with a 6-month course of pulse cyclophosphamide after her third attack.
Median chronic treatment duration was 3.7 years (range: 1–9 years). Six patients were treated with steroids in combination with mycophenolate mofetil (patients 1–6) as part of their regimen. Five patients were treated with rituximab (patients 1, 5, 7, 8, and 9). Patient 9 was additionally treated with azathioprine, glatiramer acetate, and monthly plasmapheresis. Patient 2 was treated with monthly intravenous immunoglobulin (IVIg). On current therapeutic regimens, mean attack rate for the group is 0.5 per year.
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DISCUSSION |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIXREFERENCES |
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The definition of NMO has been changing over the past decade. It is now recognized that a significant percentage of the adult patients with NMO have cerebral involvement, and the identification of the NMO IgG biomarker has broadened the disease spectrum. There is increased awareness of pediatric demyelinating disease, including NMO. These changes coupled with the increased effectiveness of therapeutics, have emphasized the need to consider NMO in the differential diagnosis of inflammatory demyelinating diseases.
Although this reported cohort is too small to draw any conclusions concerning the demographics of pediatric NMO, some observations correlate with risk factors identified in other populations. All patients were female, similar to adult NMO populations that reported a female/male bias of 9:1.5 Similar to observations in pediatric MS,14 >75% of the cohort had Latin American or African ancestry. This may indicate that Northern European ancestry is less of a determinant in pediatric-onset demyelinating disease than in the adult-onset disease. In this cohort, children with Latin American ethnicity had a higher EDSS (>4.0) compared with non-Latin Americans (Fisher's exact test: 
2 = 5.62, P = .047). There was no significant correlation between age of onset (greater or <10 years) with EDSS (P = .16).
In NMO, the lesions in the spinal cord are more longitudinally extensive than MS. We observed that the lesions exhibited a rim-enhancement on post contrast T1-weighted images in contrast to MS lesions, which exhibit a more uniform enhancement. We observed a trend that more longitudinally extensive spinal cord lesions were associated with a greater disability as measured by EDSS (lineal regression: P = .054).
There was variable involvement of the optic pathways. Some patients had extensive involvement of the optic nerve, extending along the length of the nerve whereas other patients had minimal involvement limited to the optic chiasm, and 1 patient had no detectable optic pathway involvement. Additional clinical studies including optical coherence tomography and multifocal visual evoked potentials should be considered to better determine the spectrum of optic pathway involvement.15,16
Previously, brain involvement was considered to be an exclusion criterion for NMO.6 However, recent series have reported up to 60% with MRI changes in the brain.12,17–19 All patients in this study had nonspecific or atypical lesions on initial brain MRI. Two patients had additional evolution of MRI changes during their disease course to eventually satisfy Barkof criteria. The remaining patients continued to show nonspecific or atypical changes.
Brain lesions in our cohort frequently involved the diencephalon, an area of high AQP4 expression along with the ependymal cells around the ventricles and the astrocytic endfeet that form the blood-brain barrier in capillaries and pia of the brain, optic nerves, and spinal cord.10 One patient had large tumefactive lesions that were nonenhancing, extended up to but not involving the subcortical U fibers, and had finger-like projections that seemed to follow glial tracts. The occurrence of these large lesions in pediatric NMO is important to recognize, because such patients might present with a clinical and radiographic phenotype suggestive of acute disseminated encephalomyelitis. However, in contrast to acute disseminated encephalomyelitis, they are at greater risk for progressive disability without immunosuppressive therapy.
Three patients had generalized cerebral atrophy by MRI. This suggests underlying background disease progression in the brain, as has been described for MS. It is unknown how much brain atrophy will accumulate in NMO, and these patients should be monitored for signs of cognitive impairment with neuropsychological evaluation.
Aphasia is an unusual presentation of demyelinating diseases20,21and has not been previously reported in any patient with NMO. Patient 7 initially presented with expressive aphasia, which was attributed to a large lesion in the thalamus. Patient 2 had an expressive aphasia secondary to tumefactive left hemisphere white matter lesions. White matter lesions may produce aphasia through diaschisis, a disruption of the white matter pathways between anatomically related language centers producing deficits indistinguishable from cortical lesions.22 This is consistent with the magnetic resonance imaging in our patient.
Four patients demonstrated an abnormal T2 signal in the diencephalon with hypothalamic involvement, supporting previous descriptions that this area is commonly affected in NMO.10 This may account for endocrine changes encountered in 1 of our patients. Case histories of adult NMO have described endocrinopathies related to hypothalamic involvement.17,23 In our series, 1 patient had symptomatic hyponatremia and with SIADH. Dysfunction of the hypothalamic-pituitary axis should be investigated in NMO because endocrinopathies may complicate the presentation.
NMO IgG titer analysis has been proposed to be a biomarker capable of distinguishing between NMO and MS or other autoimmune CNS diseases.7 It is important to note that although this antibody test is highly specific, it is not as sensitive resulting in false-negatives. Therefore, a negative NMO IgG test does not exclude the diagnosis. This is demonstrated by patient 1 who had classic clinically defined NMO but never had detectable NMO IgG antibody levels. Treatments such as plasmapheresis or rituximab may affect NMO IgG results, indicating the importance of repeat testing in patients with a clinical course consistent with this disease.
One patient in our cohort did not meet currently criteria for NMO because she did not have detectable optic pathway involvement. However, the aggressiveness of her disease course, NMO IgG seropositivity, and response to immunosuppressants suggests that recurrent LETM may be part of the NMO disease spectrum and therapy should be modified accordingly.
The relationship between NMO and other autoimmune diseases has been described.6,24,25 This cosegregation is hypothesized to relate to a similar humoral pathogenesis. NMO may occur in the setting of a clinically evident systemic autoimmune disorder. In our cohort, 6 patients had other autoimmune serologic markers, and 5 patients had a positive family history for autoimmune disease, including 1 family with a history of MS. A recent report of a large cohort of patients with NMO found 4 of 71 had a family history of MS, although there was no reported family history of NMO.6 Whereas the lifetime risk for MS in first-degree family members is estimated to be 22% to 55%,26,27 the risk for developing NMO is unknown.
At our center, the current therapeutic approach for pediatric NMO is intravenous methylprednisolone (30 mg/kg per day up to 1 g/d for 5 days) for initial treatment of acute exacerbations. Patients failing to respond within 7 days of treatment are treated with plasmapheresis. If symptoms still persist, IVIg 2 g/kg divided over 2 to 5 days is started. Daily oral prednisone and azathioprine or mycophenolate mofetil are used for chronic therapy. Patients with additional disease progression are changed to rituximab. Rituximab has been shown to be effective in adult NMO28 and needs additional study in the pediatric populations. The small size of the cohort in this retrospective observational study, as well as the nonstandardized treatments used, limits the ability to assess efficacy of any particular treatment regimen.
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CONCLUSIONS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIXREFERENCES |
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We document one of the largest, to our knowledge, pediatric cohorts of patients with NMO to date and highlights significant clinical points for pediatric patients with an NMO spectrum disorder. It is important for pediatricians to recognize that (1) the current definitions of NMO are expanding, and it is important to consider the diagnosis in the setting of classic disease with negative antibody titers or atypical disease with positive antibody titers, (2) NMO should be considered in the differential diagnosis of children with a central demyelinating event, and involvement of the brain no longer excludes this as a diagnostic possibility, (3) hypothalamic-pituitary axis function should be evaluated in pediatric patients with NMO, and (4) immunomodulatory therapies effective in MS may be of limited benefit; therefore, treatment with immunosuppressive agents may better preserve cognitive, visual, and ambulatory function in the pediatric population.
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APPENDIX |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIXREFERENCES |
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Patient 1: Classic Clinically Defined NMO and Negative Serum NMO Antibody Titer
Initial Presentation
A 23-month-old black girl developed quadriparesis, vision loss, vomiting, and irritability 1 week after receiving an influenza vaccination. MRI demonstrated diffuse increased T2 signal in both optic nerves (Fig 1 A and B) and longitudinally extensive T2 bright signal abnormality throughout the cervicothoracic spinal cord with patchy enhancement after contrast (Fig 1C). MRI of the brain and orbits showed a few small foci of increased T2 signal abnormality in the left frontal region (data not shown), and her cerebrospinal fluid (CSF) demonstrated pleocytosis with 19 white blood cells (WBCs) (40% polymorphonuclear neutrophils), elevated protein at 62 mg/dL (normal: 15–45 mg/dL), normal IgG index, and no oligoclonal bands. She was found to have multiple positive antiphospholipid antibodies including anticardiolipin IgG, and a positive lupus anticoagulant test. Her mother was evaluated for chronic arthritic symptoms and was found to also be positive for antiphospholipid antibodies. The patient was initially treated with high-dose intravenous methylprednisolone (30 mg/kg per dose) and had improvement of her vision as well as significant recovery of her arm and leg strength.
Disease Course
Optic neuritis recurred 4 months after the initial attack, for which she again received high-dose intravenous methylprednisolone followed by oral steroids with some improvement of vision. Three months later, while attempting to wean her off the oral steroids, she experienced a third relapse with recurrence of the LETM and gait failure.
Current Therapy and Clinical Status
After this third attack, she was started on monthly IVIg (1 gm/kg per dose) and daily mycophenolate mofetil and continued on daily oral steroids. Two additional relapses included bilateral optic neuritis and transverse myelitis 18 and 21 months later, respectively. At the most recent follow-up 4 years after disease onset, she was ambulatory with the assistance of a walker and has profound vision impairment and urinary incontinence. Bilateral optic atrophy is present by physical examination and on MRI. Her spinal cord has shown progressive atrophy (Fig 2 A and B). However, there remains minimal brain involvement by MRI, and she has exhibited no signs of cognitive impairment.
Patient 2: Nonclassic Clinical Presentation of NMO With Tumefactive CNS Lesions and a Positive NMO Antibody Titer
Initial Presentation
A 15-year-old right-handed white girl initially presented with a 3-week history of fatigue, nausea, blurry vision, and paresthesias in her legs and hands. A sensory level was present at T4, and she had normal mental status and no focal motor deficits. Neuroophthalmologic examination revealed slight thinning of the nerve fiber layer in the superior aspect of the left eye by optical coherence tomography. MRI of the optic nerves demonstrated increased T2 signal in the region of the optic chiasm (data not shown). MRI of the spine demonstrated increased T2 signal at C1–C2 and a second longitudinally extensive lesion at C4–C6. MRI of the brain demonstrated increased T2 signal intensity in the hypothalamus and the periventricular regions (Fig 3A) with minimal gadolinium enhancement. CSF studies showed 1 WBC with slight elevation of protein at 57 mg/dL (normal: 15–45 mg/dL), normal IgG index, and no oligoclonal bands. Hyponatremia with serum sodium as low as 111 mmol/L was found on serum chemistries. Further investigation was consistent with SIADH. She was treated initially with intravenous methylprednisolone for 5 days followed by a 6-week oral steroid taper with resolution of her SIADH and paresthesias.
Disease Course
Four months after initial presentation, she developed nausea and Lhermitte sign (a sudden transient electric-like shock extending down the spine triggered by flexing the head forward). MRI of the spine demonstrated reenhancement of the lesion at C6. She received treatment with intravenous methylprednisolone for 5 days followed by a 3-month oral steroid taper. She remained asymptomatic until 6 months after completing her steroid taper. At that time she started to experience abdominal paresthesias and leg weakness. Her MRI of the spine demonstrated a longitudinally extensive lesion in the thoracic spine (T5–T10). She was treated with intravenous methylprednisolone and started on subcutaneous interferon β-1a for a diagnosis of probable MS.
Four months later she developed severe headaches, disorientation, and right face and arm weakness. An MRI of the brain demonstrated a large right temporoparietal lesion with little enhancement (Fig 3B). Her clinical status improved after intravenous steroid treatment, except for continued frequent headaches. Three months later, her headaches became more severe and she developed an expressive aphasia. Her MRI demonstrated a large left temporal lesion despite immunomodulatory therapy (Fig 3C). Because her monotherapy treatment failed, immunosuppressive therapy was added and included monthly intravenous methylprednisolone 1000 mg and intravenous cyclophosphamide 500 mg/m72. Cyclophosphamide dosing was titrated to achieve a WBC level of 1500 to 2000. She had another attack 3 months after starting this regimen, with symptoms of blurred vision, back pain, and confusion. MRI of the brain demonstrated multiple large minimally enhancing lesions (data not shown). Five months later, she again developed an expressive aphasia with a new large lesion in the left hemisphere (Fig 3 D and E). Each of these events was treated with intravenous methylprednisolone with good response (Fig 3F).
Repeat studies including antiphospholipid antibodies, ANA, Sjogren's syndrome A/anti-Ro antibody (SSA), Sjogren's syndrome B/anti-La antibody (SSB), double-stranded DNA (dsDNA), cytoplasmic anti-neutrophil cytoplasmic antibodies (cANCA), perinuclear anti-neutrophil cytoplasmic antibodies (pANCA), rapid plasma reagin (RPR), and lupus anticoagulant were negative. Testing for NMO IgG became available and was sent during a later (December 2005) exacerbation with tumefactive lesions and found to be positive (titer = 1:3840 [normal: <1:120]). Her diagnosis was switched from probable MS to NMO with cerebral involvement, interferon was discontinued, and therapy was retargeted to a humoral disease process including monthly intravenous methylprednisolone 1000 mg, monthly IVIg (1 gm/kg per dose), and twice-daily mycophenolate mofetil 1000 mg.
Current Therapy and Clinical Status
After switching to the NMO-directed treatment plan, she had not had any additional relapses for 2 years except for 1 episode of a severe headache. At her most recent follow-up 4 years after disease onset, she had mild fatigue and her MRI showed mild cerebral atrophy. Her EDSS score was 0, her vision was 20/20, and she was attending college with a straight-A average. Her serum NMO IgG was repeated during this period of disease remission, and she has had decreasing titers and eventually seroconverted to negative.
Patient 9: Multiphasic LETM Without ON and With a Positive NMO Antibody Titer
Initial Presentation
A 15-year-old Latin American girl presented with gait failure and urinary retention. MRI demonstrated a longitudinally extensive lesion in the medulla and extending through the cervicothoracic cord (data not shown). Her brain MRI demonstrated a few areas of increased T2 signal change involving the centrum semiovale bilaterally. CSF studies noted pleocytosis with 31 WBCs, elevated protein of 78 mg/dL (normal: 15–45 mg/dL), normal IgG index, and no oligoclonal bands. She was initially treated with high-dose intravenous methylprednisolone followed by plasmapheresis. She had some clinical improvement, but her physical impairments did not return to baseline, and she initially required a cane for ambulation.
Disease Course
After initial improvement, her symptoms recurred 4 weeks later. She received intravenous methylprednisolone for this exacerbation. After a third relapse 2 months later, her clinical picture of multiple small lesions in the brain, transverse myelitis, and no optic nerve involvement placed her initially in the clinical category of MS spectrum disease, and she was started on intramuscular interferon β-1a for maintenance therapy. Repeat CSF studies continued to show pleocytosis with 37 WBCs and no oligoclonal bands.
This patient developed a more severe clinical course with relapses every 1 to 2 months despite starting interferon therapy. After 2 months, she developed leukocytopenia, and interferon was changed to glatiramer acetate with recovery of her WBC count. She continued to have recurrent attacks every other month with symptoms that included gait failure, sensory deficits, arm weakness, dysphagia, and a central Horner syndrome on the right with associated diplopia. Ophthalmologic evaluation, including visual evoked potentials and MRI, did not find evidence for optic neuritis. She was started on monthly plasmapheresis as an adjunct therapy. Over the next 6 months, exacerbation of her disease was noted to consistently occur 1 week before beginning her menstrual cycle. She was started on an oral contraceptive to help ameliorate these symptoms. She subsequently had only 1 attack over the following 12 months. Antiphospholipid antibodies, ANA, SSA, SSB, dsDNA, cANCA, pANCA, RPR, and lupus anticoagulant were negative. During this period of time, she tested positive for serum NMO IgG. Because she had a better clinical response to humoral targeted immunosuppressant therapy rather than immunomodulatory therapy, azathioprine was added at that time for a working diagnosis of NMO.
Current Therapy and Clinical Status
At her most recent follow-up 4.5 years after disease onset, she had significant weakness in her legs and arms (0/5 in the legs and 4/5 in the arms, bilaterally symmetric). She could only walk a short distance with maximal assistance and used a wheelchair routinely for ambulatory assistance. Serial imaging by MRI demonstrated progressive atrophy of the spinal cord. Brain imaging demonstrated punctate 2- to 3-mm enhancing lesions in the juxtacortical regions of both hemispheres and in the corpus callosum (data not shown). There remained no evidence for optic pathway involvement by MRI or physical examination. She was treated with azathioprine, monthly plasmapheresis, and glatiramer acetate (continued because of patient's perceived benefit), and her attack rate has slowed from every 1 to 2 months to 1 to 2 episodes per year. She was recently started on a trial of rituximab wit the hope of further reducing her relapse rate.
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ACKNOWLEDGMENTS |
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We thank Liz Barnes, RN, for assistance with database management.
Drs Lotze and Northrop contributed equally to this work.
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FOOTNOTES |
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Accepted Jul 15, 2008.
Address correspondence to Timothy E. Lotze, MD, Texas Children's Hospital, Section of Child Neurology, Department of Pediatrics, 6621 Fannin CC 1250, Houston, TX 77030. E-mail: tlotze{at}bcm.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject There have been no descriptive studies of pediatric NMO using current diagnostic criteria. Recent identification of NMO IgG antibody suggests an expanded spectrum of disease, including patients with brain involvement and presentations similar to those of acute disseminated encephalomyelitis or MS.
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| What This Study Adds To our knowledge, this is the first descriptive study of pediatric NMO spectrum disorders that incorporated the current diagnostic criteria. We describe clinical, laboratory, imaging features, disability, and treatment responses. Potential risk factors for aggressive disease are identified.
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIXREFERENCES |
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