2.1. Clinical Case
A thirteen-year-old girl presented with several days of right-sided torticollis, gaze impairment, left-sided weakness, and changes in speech. Neurologic exam was notable for pseudobulbar affect, intranuclear ophthalmoplegia, left hemiparesis, and ataxia. Brain magnetic resonance imaging (MRI) showed a T2 hyperintense white matter lesion on left cerebellar hemisphere extending to the brainstem, with associated restricted diffusion and mild peripheral enhancement (
Figure 1a). A spine MRI showed an intramedullary T2 hyperintense lesion of the cord at T4–T5 with mild enhancement (
Figure 1b,c). Visual evoked potentials revealed reduced amplitudes bilaterally. A lumbar puncture showed 123 nucleated cells with lymphocytic predominance, normal protein and IgG index, and no oligoclonal bands. Serum NMO immunoglobulin G (IgG) was negative. The patient was initially diagnosed with clinically isolated syndrome (CIS) with brain stem and cerebellar presentation, with high risk for MS. She was treated with a five-day course of high dose steroids, followed by two doses of intravenous immunoglobulin (IVIG) and inpatient rehabilitation because of slow and poor recovery. She recovered significantly and was ambulatory at the time of discharge. Two months after initial presentation, she was readmitted with recurrence of gait instability, slurred speech, and left-sided weakness. Repeat brain MRI showed interval progression of the demyelinating process now involving the superior vermis and middle cerebellar peduncle with new patchy enhancement as well as longitudinal transverse T4–T7 T2/stir hyperintensity with cord swelling and patchy contrast enhancement. Lumbar puncture showed 13 nucleated cells, normal protein, high IgG index and six oligoclonal bands (one in serum). Aquaporin 4 antibodies (AQP4-ab) were positive and she was diagnosed with neuromyelitis optica (NMO).
2.2. Epidemiology and Pathophysiology
NMOSD are central nervous system (CNS) demyelinating conditions which primarily affect the optic nerves and spinal cord via unique pathophysiologic mechanisms and are different from the classic CNS demyelinating condition of MS. Pediatric NMOSD accounts for about 4% of total NMO cases in the United States [
1]. Disease onset occurs at about 10 years of age, which is similar to MS (13 years), but higher than ADEM (5 years). Disease onset before 11 years of age is more common in ADEM (96%) than MS (20%) and NMO (54%) [
1]. Among children younger than 11 years of age at disease onset, the female to male ratio in MS has been reported to be 1.1:1, while NMO is more common in females (1.5:1). These gender differences are further accentuated in patients ≥11 years of age, with MS and NMO being more common in females (F:M of 1.86:1 for MS, 3.25:1 for NMO) [
1]. This highlights the effect of sex hormones on the onset of these demyelinating conditions, which is supported by the fact that pregnancy affects disease severity for NMO and MS [
2,
3,
4]. NMOSD epidemiology also displays racial variation. Asian and Afro-American/Afro-European populations have a younger mean age of onset than Caucasians, and Afro-American/Afro-European populations are more likely to have a severe attack at onset than Asian and Caucasian populations [
5].
The discovery of the NMO-IgG antibody which was found to target the aquaporin-4 water channel (AQP4), did not only provide a reliable biomarker for the diagnosis of NMO, but also helped in the understanding of the disease process [
6,
7,
8]. Specifically, AQP4 loss is seen in astrocytes, and NMO has been proposed to be an immune astrocytopathy, driven mainly by antibodies against AQP4, and hence also referred to as an immune aquaporinopathy [
9,
10,
11]. It is primarily considered to be a humoral immune-driven pathologic process, whereas MS was classically considered to be a cell-mediated pathologic process. However, we now know that MS can involve both humoral and cell-mediated arms of the immune system attacking the CNS, and hence therapies targeting T cells, B cells or antibodies produced by plasma cells, can work in MS, depending on the major pathologic process involved in individual MS patients [
12]. This is in contrast to NMOSD, where B cell and antibody clearance strategies are effective, but certain MS therapies that do not target humoral immunity can exacerbate disease [
11,
13,
14,
15,
16].
NMO also involves the sensitization of Th17 cells to AQP4 peptides. These Th17 cells help the B cells that are activated by conformationally intact AQP4 proteins, thereby producing AQP4-ab [
11]. Hence, T cells do not directly cause astrocyte damage in NMO, but help potentiate the humoral response, and this immunologic process is driven outside the CNS [
17]. NMO pathogenesis likely involves both a genetic and an environmental component. From the genetic standpoint, NMOSD seems to be associated with human leukocyte antigen HLA-DRB1*03, which is also associated with other autoimmune conditions like systemic lupus erythematous (SLE) [
18]. This is in contrast to MS, which is associated with HLA-DRB1*1501, and this variant is not associated with NMOSD [
18]. Environmentally, NMO could be related to gut dysbiosis, as it has been suggested that patients with NMO have an overabundance of Clostridium perfringens in their gut [
19]. From the molecular standpoint, the ABC transporter permease of C. perfringens has a peptide sequence which shares 90% homology to a region of the AQP4 protein, which can explain cross-reactivity between these proteins [
20].
2.3. Clinical Presentation
As encompassed in the term “neuromyelitis optica”, the typical clinical presentation of NMOSD is that of optic neuritis (ON) and/or longitudinally extensive transverse myelitis (LETM) (defined as lesions spanning >3 complete vertebral segments), in the context of seropositivity for AQP4-IgG antibodies [
6,
21]. Clinically, NMO (previously referred to as Devic’s disease) was first described by Eugène Devic and Fernand Gault in 1894 at Congrès Français de Médecine in Lyon, France [
22]. The distinction between NMO and MS has been evolving ever since, taking into account not only the differences in clinical presentation but also in imaging and serology.
The most common presenting symptoms in the pediatric population include visual and motor impairment, seizures, and constitutional symptoms like fever and vomiting [
1]. The most common localizations for a primary presentation are to optic nerve, brainstem, and spinal cord [
1]. The area postrema can be selectively affected in NMO, and vomiting has been reported as a presenting symptom in 38% of pediatric NMO patients [
1,
23]. It should be noted that the majority of children with AQP-4 seropositive NMO have at least one episode of ON (83%) or LETM (78%) [
24].
2.4. Diagnosis
The discovery of AQP4-IgG revolutionized the diagnosis of NMOSD, providing an objective and reproducible tool for diagnosing this entity and differentiating it from MS [
6,
25]. However, NMOSD can be diagnosed in the absence of AQP4-IgG antibodies if additional criteria are met [
25]. The clinical case above highlights the importance of having NMOSD on the differential when the complete diagnostic criteria might not be met initially at presentation, as the disease can be seronegative for AQP4-IgG. Although relapsing disease is more common in the pediatric population, it should be noted that monophasic NMO tends to be seronegative for AQP4-IgG when compared to relapsing disease [
26].
The US network of pediatric MS centers report showed that 97% of pediatric NMO patients met the revised NMOSD 2015 criteria as defined by the international panel on NMO diagnosis (IPND). This was a remarkable improvement from the 2006 Wingerchuk criteria met by only 49% pediatric NMO patients [
21]. The new criteria take into account patients who are seronegative for AQP4-IgG antibody or where such testing is not available, by making clinical and imaging requirements more stringent (
Figure 2). It defines six core clinical characteristics including: ON, acute myelitis, area postrema syndrome (hiccups, nausea or vomiting), acute brainstem syndrome, acute diencephalic syndrome (or symptomatic narcolepsy), and symptomatic cerebral syndrome. In the absence of AQP4-IgG, it is still possible to diagnose NMOSD with more stringent clinical and radiologic criteria: presents with at least two different core clinical characteristics, one of which is either ON, acute myelitis with LETM, or area postrema syndrome, and must also fulfill additional MRI criteria characteristic of NMOSD.
The IPND 2015 took into account the recommendations from the Pediatric Working Group members and found the new diagnostic criteria to be compatible for pediatric patients, with a few caveats: acute myelitis associated with LETM lesion on MRI may be less specific in pediatric NMOSD, and more children present with monophasic LETM [
25]. The decrease in specificity (increase in false positivity) of LETM MRI lesions in the pediatric population is proposed to be due to the presence of LETM lesions in pediatric MS (~15%) and pediatric monophasic ADEM. Additionally, monophasic LETM in the pediatric population is usually seronegative for AQP4-IgG [
27]. This highlights the fact that LETM lesions in isolation are not as predictive of NMOSD in the pediatric population [
25,
27]. Moreover, about 45% of children who are seropositive for AQP4-IgG, experience recurrent cerebral manifestations including encephalopathy. Hence, IPND 2015 proposes that children who present with polyfocal demyelinating lesions with encephalopathy and have seropositivity for AQP4-IgG, should have a diagnosis of NMOSD over ADEM [
25].
From an imaging standpoint, MRI is the most widely used and accepted modality to aid in the diagnosis of NMOSD, and differentiates it from MS and other demyelinating conditions. Characteristic MRI findings suggestive of NMOSD include optic neuritis lesions extending greater than ½ optic nerve length, involvement of the optic chiasm, extensive intramedullary myelitis lesions involving >3 spinal segments, and diencephalic lesions [
25]. Other rare but characteristic MRI findings for NMOSD include the involvement of the area postrema in the dorsal medulla and periependymal brainstem lesions [
25]. T2 lesions involving <3 complete vertebral segments, predominantly peripheral cord lesions (>70%), are suggestive of MS over NMOSD [
25].
In pediatric NMOSD, CSF collected during an acute ON episode can be bland, while during a myelitis episode CSF may be more indicative of active inflammation [
28]. During the remission phase of NMOSD, CSF can be less inflamed than during attack onset or relapse [
29]. In an acute attack of NMO, CSF typically displays significant pleocytosis with >100 nucleated cells, with a predominance of neutrophils or lymphocytes [
1,
28]. This is in contrast to MS, where pleocytosis is rarely seen and is predominantly lymphocytic if present [
1]. Oligoclonal bands (OCBs) which are classically seen in MS, are present in ~31% of pediatric NMOSD patients (versus ~68% pediatric MS patients) [
1,
30]. The decreased frequency of CSF restricted OCBs in NMOSD has been thought to be due to the absence of intrathecal IgG synthesis in NMO [
31]. This is also supported by the fact that IgG index is elevated in only ~30% of pediatric NMO patients vs. 63% of MS [
1]. The elevation of CSF protein is higher in NMOSD than MS, correlating with the fact that NMO is a disease process beginning at the astrocyte foot processes, thereby leading to a leaky blood–brain barrier (BBB) [
31]. NMO specific CSF AQP4-IgG testing can be done in suspected NMOSD cases, especially in those who are seronegative for AQP4-IgG [
28]. However, it is rare to have AQP4-IgG in CSF and not serum [
32,
33].
Interestingly, the term opticospinal MS originated in Japan and has been used to describe a specific pattern of MS, which is more prevalent in Asian countries [
25,
34]. It was an important milestone because it described a distinct form of MS which primarily affected the optic nerve and spinal cord. It is controversial whether opticospinal MS is one of the NMO spectrum disorders which includes AQP-4 IgG and MOG seropositivity, or if it is a separate entity, especially in patients who are seronegative for both AQP-4 and MOG antibodies. The IPND 2015 guidelines concluded that opticospinal MS should be considered an NMO spectrum disorder [
25].
Generally speaking, diagnostic features suggestive of MS over NMOSD include a progressive overall clinical course, presence of partial transverse myelitis not associated with LETM MRI lesions, and presence of typical MS MRI findings [
25].
2.5. Treatment and Prognosis
As a standard of clinical measure, the Extended Disability Scoring System (EDSS) has been used to monitor changes in the overall functioning of patients with MS and NMOSD [
35]. Over a period of two years after onset in the pediatric population, the number of attacks and EDSS scores were higher in patients with NMO when compared to MS [
1].
With regards to treatment, it is crucial to distinguish NMOSD from MS early on in the disease process, since certain therapies for MS like β-interferon [
13], fingolimod [
15], natalizumab [
16], alemtuzumab [
14], can aggravate NMO and even increase AQP-4 IgG titers [
13,
36].
If untreated, acute exacerbations of NMOSD are more severe than MS exacerbations and the recovery is minimal [
1,
37]. Hence, it is important to treat acute exacerbations and start suppressive therapy that should be continued during disease remission. Every NMOSD attack leads to cumulative neurological damage and disability [
37,
38]. In the pediatric population, 93–95% have relapsing disease [
1,
24]. Since acute events are primarily inflammatory in nature, the goal is to suppress this inflammatory attack, which can be achieved with steroids. Plasma exchange (PLEX) is also used in NMO as a standalone therapy or in conjunction with steroids. There is good evidence in the adult population that PLEX in conjunction with IV methylprednisolone (IVMP) is better than steroids alone [
39,
40].
With regards to suppressive immunotherapy, the most commonly used agents are Rituximab, azathioprine, and mycophenolate mofetil (MMF) [
41,
42,
43,
44]. Rituximab or MMF are preferred over azathioprine [
1]. Benefits of using Rituximab are a faster onset of action [
41] and the fact that its tolerability and dosing have been verified in the pediatric population [
42]. If the diagnosis of NMOSD vs. MS is unclear, it would be appropriate to use NMOSD suitable immunotherapy because of the risk of NMOSD exacerbation with certain MS therapies [
11].
Recently, targeting of the complement system arm of the humoral immunity has been shown to be beneficial in the adult population by repurposing of the terminal complement inhibitor eculizumab in NMOSD [
45]. This is a promising avenue with regards to management of NMOSD, but currently, the use of this in the pediatric population is limited given the lack of data and its cost.
Pediatric NMOSD patients can have a longer time to disability compared to adult-onset NMOSD with most pediatric patients surviving into adulthood [
46]. Mortality rates for adult NMOSD range between 9 and 32% worldwide over 55.2 to 75 months from diagnosis [
5,
47,
48]. This is driven by lesions involving the brainstem [
49]. With the advent of suppressive immunotherapy, disease morbidity and mortality should decline. Since NMOSD is rarely secondarily progressive, maintaining attack-free intervals with immune therapies is highly beneficial from a neurological stability standpoint [
11,
37]. In the future, the hope is to have personalized therapies for NMO. There is ongoing work in this direction, as demonstrated by the use of FCGR3A polymorphisms in predicting response to Rituximab as well as the development of therapies directly targeting AQP-4 IgG binding to AQP-4 [
50,
51,
52].