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Immunomodulation in Pediatric-Onset Multiple Sclerosis: A Review


Authors:

Emily Prichard,1 Quratulain Shekoh,2 Rachel Cohen,3 Moshe Shalom3


Institution

1University of Colorado Colorado Springs, CO, USA

2Texas Tech University Health Science Center, TX, USA

3Tel Aviv University Sackler Faculty of Medicine, Tel Aviv, Israel

 

Conflicts of Interest: The authors report no conflicts of interest

Funding: No funding was provided in the production of this study



Abstract

This paper endeavors to cross-compare both established and poorly studied pharmacotherapies used in the treatment of pediatric-onset multiple sclerosis (POMS) and their role in optic neuritic symptom management, with emphasis placed on second-line non-steroidal therapies and therapies adjunctive to conventional steroid use given the incidence of steroid- resistance, steroid-dependency, and monotherapeutic steroids failing to achieve a desired clinical outcome. In light of the current paucity of literature describing the efficacy of extant MS treatments in preserving ocular integrity in pediatric subjects, children’s likelihood of treatment success will be inferred herein on the basis of adult outcomes measured by way of serial VEP/OCT/DFE screenings and corroborating pediatric cohort studies from which outcomes non- differential from those seen in adults can be evinced. Moreover, due attention will be lent to the incidence of childhood risk factors (e.g., retinopathies secondary to pediatric-onset diabetes mellitus) that dispose subjects to ocular toxicities associated with agents discussed herein.


Introduction

Multiple sclerosis is a disease of the central nervous system (CNS) that affects approximately 400,000 individuals in the United States and 2.1 million individuals worldwide (1). In this disease, the body’s immune system attacks and deteriorates myelin sheath that wraps the axons of nerves (2). Due to its myelination, the optic nerve’s function is often disrupted in patients with MS. Optic neuritis (ON) is inflammation of the optic nerve due to demyelination and affects the afferent visual pathway.


Previous treatments in adults have shown that steroids can lead to increased symptom severity as well as relapse, leading to the need of improvement in the treatment for ON. Those who have taken immunosuppressants before being treated for ON have shown increased resistance and dependence to steroids, with pediatric patients showing even more resistance.


Fingolimod has been shown to cause macular edema and increase ME severity in patients with MS, especially those with diabetes mellitus. Children, however, have been underrepresented or not well reported in such studies. Interferon β-1a has not shown ocular improvements but has shown to be a good prophylaxis for negative optic symptoms in adults with MS. Being that pediatric patients have been administered equivalent doses; these findings can be deemed true for them as well.


Natalizumab is a last resort drug used for adults due to its known correlation with PML; this is mainly attributed to JCV seropositivity, a factor that increases with age. Being that PML is induced with increased JCV seropositivity, children under the age of 10, who don’t contain JCV antibodies in their blood may benefit from such a drug. Studies have shown that NTZ is beneficial for the younger population but must be used with caution as this population also receives the VZV vaccine. When given concomitantly with NTZ, the VZV vaccine can cause permanent vision loss. However, like with the other drugs mentioned, more research is necessary and crucial in order to create better therapies for patients with MS.


Role of Myelin in the Nervous System

Myelin is crucial for the proper functioning of the nervous system for numerous reasons (3): Firstly, it serves as insulation layer for neurons by preventing the leakage of current from the axon, thereby increasing the distance along the axon that a given local current can flow passively (4). The presence of myelin also enables rapid conduction of action potentials (AP) along the neuronal axon (5). As a comparison between velocities, an unmyelinated nerve fiber can conduct an AP at a range of about 0.5 to 10.0 meters/second, whereas a myelinated axon can conduct an AP at up to 150 meters/second (4). This is due to the presence of nodes of Ranvier (NOR), spaced gaps in the myelin sheath in which action potentials can be propagated, a phenomenon known as saltatory conduction (4). It is on these NOR where sodium channels regulate electrical impulse conduction required to generate an AP. If the entire surface of the axon was lacking myelination, the generation of the AP would occur throughout the axon, delaying the flow of current (4). Together, the presence of myelin and NOR ensure a system of fast, smooth, and saltatory propagation of electrical signals in neurons (4). Moreover, myelination allows physical and trophic support to neurons against mechanical forces by creating a microstructural network that stiffens the white matter of the brain (3, 6). This is important for neuronal development, as studies have shown that a brain that is not completely myelinated appears softer and more vulnerable to mechanical insult, as observed in shaken baby syndrome (6).

The CNS consists of the brain, spinal cord and the optic nerve (2). In the CNS, glial cells, specifically Oligodendrocytes form myelin (7). Glial cells are non-neuronal cells found in the CNS that provide metabolic and physical support to surrounding neurons (7). The composition of myelin is made up of a high ratio of lipid to protein, with a predominance of cerebrosides being glycosphingolipids (GSLs) with a single sugar attached to ceramides (waxy lipid molecules) (5). The two major GSLs of the myelin include galactosylceramide (GalC) and its sulfated form, galactosylceramide I(3)-sulfate (SGC) (8). In addition to cerebrosides, myelin also consists of varying ratios of cholesterol, ethanolamine-containing plasmalogens, and lecithin (5). Moreover, myelin proteolipid protein (PLP) also known as Folch-Lees protein consists of fatty acids that are ester-linked to hydroxy amino acids (5). Although found in much lesser quantities, DM-20 is a protein that also makes up the structure of myelin (). Understanding the composition of myelin is crucial to understanding the mechanism of myelin-specific antigens that become selected during the progression of MS (9).


Pathophysiology

Although there are several factors that lead to the progression of MS, the exact triggering points are still not fully understood (Loma). The general consensus about the pathology of MS encompasses a combination of immune-mediated and neurodegenerative processes (11, 12, 13).

In immune-mediated processes, the body’s immune system crosses the blood brain barrier (BBB) into the CNS and mistakenly targets its own tissues, including the myelin sheaths (11). This is primarily due to the dysregulation of the adaptive immune system, specifically involving T-cells and B-cells (14, 15). T cells are responsible for the recognition and killing of foreign substances (16). In MS, CD8+ T, a type of killer T-cells becomes activated and causes an imbalance in production of pro-inflammatory cytokines like IL-17 and lymphotoxin (11, 17). Cytokines are cell signaling proteins that help regulate an immune response, including a pro- inflammatory or anti-inflammatory (18). The overproduction of cytokines like interferon gamma (INF-y), and tumor necrosis factor (TNF-α) not only cause inflammation but signal additional immune cells like microglia towards the destruction of myelin sheath (19,20). In addition, B- cells are noted to play a role in the progression of MS (15). B-cells are mainly responsible for the production of antibodies (21). Antibodies are protein molecules that bind and neutralize foreign substances, inhibiting their entry into the host cell (22). In MS, B-cells produce antibodies that bind to myelin proteins and signal other immune cells, including T-cells for target (23). The combined activation of these immune cells begin the wave of destruction initiating demyelination of neuronal cells (14, 15).


Another factor that contributes to the progression of MS is the ongoing neurodegeneration (24, 25). Neurodegeneration is the loss of neurons and their function. In the process of demyelination caused by immune-mediated processes, not only are the myelin sheaths affected, disruption to the axonal transport and damage of nerve fibers are also noted (26, 27). This is because without the myelin sheaths, neurons become more vulnerable and prone to degeneration which in turn leads to their loss of function (28). Cytokines like TNF released by the immune cells directly impact neurons via oxidative stress (29). Oxidative stress occurs when there is a high ratio of reactive oxygen species (ROS) to antioxidants (29). ROS are the natural byproducts of cellular mechanisms and become harmful when present in excessive amounts due to their ability to damage lipids, proteins, and cellular DNA, ultimately causing cell death (30). Progressive damage to the nerves that control sight and eye movement can accumulate to such an extent as to be sight-threatening (41).


Ophthalmic Involvement in MS: Visual Pathway Structure and Function

Among its many symptoms, MS has a predilection towards affecting the anterior-visual pathway (31). The anterior-visual pathway consists of structures that come before a stimulus reaches the lateral geniculate nucleus (LGN). These structures include the retina, optic nerve, optic chiasm, and optic tract (32). The optic nerve is composed of approximately 1.2 million axons of adult retinal ganglion cells (33). Ganglion cells are projection neurons of the retina that are liable for sending retinal input to the post-synaptic targets in the brain (34). The axons of these cells merge at the optic disk, an area on the posterior eye that lacks photoreceptors, and thus acts as a blind spot in the visual field (33). Unlike most of the other cranial nerves, the optic nerve is considered to be part of the CNS, as it originates from the diencephalon (35). Because the optic nerve is a part of the CNS, it is myelinated by oligodendrocytes and ensheathed in three meningeal layers (33).


The optic nerve can be divided into four parts: intraocular, intraorbital, intracanalicular, and intracranial (36). In notable disorders such as MS, damage to the optic nerve can occur along any of the four segments, a feature that is crucial when evaluating clinical features (36). Additionally, axonal loss targets inflammation, demyelination, and axonal degeneration of all structures in the anterior-visual pathway along with LGN, optic radiations (OR), and both the primary and associated visual cortex regions (37, 38). Visual disturbances due to MS can occur in the afferent and efferent visual pathways, affecting an individual's ability to see and affecting eye movement and coordination, respectively (39).


Afferent and Efferent Visual Pathways

The afferent visual pathway comprises structures related to the sensory part of the vision and is responsible for receiving, relaying, and processing retinal input (40). Optic neuritis (ON), an inflammatory condition of the optic nerve, results from inflammatory demyelination of the optic nerve. ON is considered one of the most common and earliest signs of MS, affectingapproximately 15-20% of individuals with MS (54). Due to the high degree of association between ON and MS, patients suffering from ON with no prior history of a demyelinating event are commonly evaluated for MS.


ON is specifically associated with the afferent visual pathways (39). Some of the most common symptoms to occur in ON are unilateral vision disturbances, color vision deficits, and pain of movement of the eyeball (54). Impacts to visual acuity in patients with ON is said to range from mild to severe, and can be categorized as generalized or focal defects. With generalized defects, there is a decrease in light sensitivity in both the peripheral and central vision. In focal defects, central vision is compromised, with centrocecal scotoma being the most common defect.


Another characteristic of ON is relative afferent pupillary defect (APD), in which the pupils react differently to light stimuli, indicative of unilateral optic nerve damage. In a clinical setting, patients suffering from ON due to MS are evaluated via a swinging flashlight test (54). In this test, each eye is stimulated using a bright light in an alternating pattern. Unequal constriction of the two pupils, with the affected eye having reduced constriction, is indicative of an APD.


Additionally, it is well established that patients with MS may experience dyschromatopsia and contrast sensitivity, with or without the presence of ON (38). Color perception is granted via cone photoreceptor cells in the retina, which are sensitive to red, blue, and green lights (37). These cells are able to detect incoming light spectra and transmit the visual stimuli to bipolar cells, which further transmit the signal to retinal ganglion cells to be sent to the brain (37). According to previous studies, it has been noted that red-green visual impairment is the most common patient reported defect in MS patients (38).


The efferent visual pathway is responsible for the oculomotor aspect of vision, which assists in the control of eye movements and enables object clarity and capturing of visual information (40). It is estimated that around 40-70% of patients with MS suffer from disturbances in eye movement (43).


Some common symptoms of ocular motility caused by MS include acquired pendular nystagmus (APN), saccadic intrusion/oscillations, and internuclear ophthalmoplegia (INO) (41). In APN, the eye moves involuntarily back and forth in a wave-like fashion causing difficulty in gaze holding and clarity of the object (43). Moreover, saccadic oscillations are rapid involuntary eye movements that disrupt smooth pursuit eye movements or visual fixations (44). Lastly, INO causes trouble in binocular coordination and results in a slower movement of the adducting eye during horizontal motions (41). INO, is caused by a lesion in the medial longitudinal fasciculus MLF located in the brainstem (45). MLF is a densely myelinated nerve bundle that is in charge for extraocular muscle movements (46).

The findings of such ocular movement discrepancies suggest the critical role clinicalexamination contributes in diagnosing and evaluating the prognosis of MS (44).

 

Pharmacologic Management of Pediatric-onset Multiple Sclerosis: Foreword on the Incidence of Steroidal Treatment Failure and Associated Visual Outcomes

Existing data, while largely confined to adult patients, highlight a trend of exceptionally poor prognoses in patients whose symptoms and relapse frequency are managed with conventional steroids (e.g. IV methylprednisolone, PO corticosteroids, etc.) (47). A 1-month observational study was conducted to gauge the likelihood of therapeutic failure in steroid- treated adult MS patients. Per the North American Research Committee on Multiple Sclerosis (NARCOMS), worsened symptom severity was measured as occurring in patients administered IV methylprednisolone and PO corticosteroids at a rate of 32% and 34% respectively; when juxtaposed with similar outcomes reported in untreated patients (which occur at a rate of 39%), this finding is significant (47). In addition, 30% of IV methylprednisolone recipients and 38% of PO corticosteroid recipients reported unchanged or increased relapse frequency post-treatment (47). The 76% rate at which analogous outcomes are measured in untreated patients suggests a need for a shift in pharmacotherapeutic treatment protocol (47).


A 2020 study attempting to identify predictive features of steroid-resistance in adults with neuromyelitis optica spectrum disorder (NMOSD) (an autoimmune disorder that exhibits characteristics typical of MS save for its selectively targeting the optic nerve, spinal cord, and brainstem) found that a history of previous immunosuppressant use, higher levels of CSF protein, and active lesions in the brainstem were prevalent in steroid-resistant patients (48). An observed incidence of steroid-resistance, defined therein as post-treatment ON and transverse myelitis attacks, in 55 of 197 (27.9%) study participants led researchers to surmise that patients presenting with the described risk factors may warrant more aggressive intervention, such as monotherapeutic plasma exchange (PE) or combination therapy consisting of IVMP and biologics (e.g., PE, intravenous immune globulin (IVIG), etc.) so as to circumvent risk of steroid-dependence (48, 49, 50).


Among other generalized side effects that are associated with prolonged steroid use such as insomnia, irritability, and growth retardation, pediatric patients are at an increased risk for developing steroid-resistance and dependency, especially those demonstrating the above risk factors (49, 50, 51). Additionally, pediatric-onset multiple sclerosis (POMS) is associated with a greater frequency and severity of relapse, and an increased propensity for the development of profound cognitive deficits and irreversible disability (52). In light of the stark consequences of suboptimal treatment, recent literature has sought to reassess the default treatment paradigm and delineate the pros and cons of aggressive treatment utilizing historically last-resort immunomodulatory agents.


The failure of both IVMP and CS in treating demyelinating ON has been described in clinical research. In one such study evaluating the utility of PO prednisone, IVMP, and CS in resolving ON in adult MS patients, all drugs used concurrently and in monotherapeutic capacities were shown to produce no meaningful or lasting improvements in final visual acuity (53). Additionally, worsened ON attack severity and frequency was reported by a subset of subjectsreceiving prednisone and CS; as such, their use as monotherapies in selectively treating ON was categorically discouraged (47, 53). IVMP, while conferring greater short-term advantages than CS insofar as improving visual acuity, was likewise deemed as producing outcomes that were similar to those observed in both the placebo and monotherapeutic CS and PO prednisone groups two years into treatment (53). It has been observed that steroidal treatment can culminate in temporary remittance of optic nerve deterioration, only for it to recur upon discontinuation of therapy, but this observation also serves to reinforce recent findings suggesting that steroid therapy fails to fully ameliorate MS accompanying ON (54).


Moreover, several studies, while few and far between, describe incidents in which central serous chorioretinopathy (CSC) developed following corticosteroid initiation in adult patients (55, 56). While CSC has been observed to occur primarily in adults aged ≥25 (57), spontaneous, isolated incidents of idiopathic CSC in children have been described in a smattering of case reports (58, 59). Steroid use culminating in childhood CSC is yet to be established, but linkage between the two can, at the very least, be speculated in light of the largely unknown pathophysiology of CSC. Clinicians should be aware of the potential relationship between corticosteroids and CSC; and hypothesized risk factors (such as family history of CSC, hypertension, and endocrinal derangement) should be taken into consideration before prescribing a steroid regimen to any patient (55, 57).

On a final note, use of corticosteroids in treating cuprizone-induced demyelination in animal models, while alleviating inflammatory features of MS, has been observed to inhibit the remyelinating processes, the implications of which may be clinically relevant concerning the use of monotherapeutic CS in treating MS (47, 60). Further research is needed to fully elucidate the costs and benefits of steroid use in the management of MS, and special consideration should be taken before prescribing steroids to any patient, especially pediatric patients.

 

Fingolimod

It has been shown that macular edema (ME), retinal vein occlusions (RVOs), retinal hemorrhaging, uveitis, and other ophthalmic complications may be associated with fingolimod use in MS management (55, 61, 62, 63). However, the development of such complications has been shown to be heavily dose-dependent and contingent on pre-existing damage to retinal vasculature (55, 61, 62, 63). In the 2007 FREEDOMS pharmacovigilance study involving an adult MS cohort, ME onset was a serious adverse event that excluded 7 study participants, with 1 subject reportedly experiencing persistent diminished visual acuity following cessation of therapy out of 429 (1.6%) that received a dose of 1.25 mg (55, 61, 62). It is possible that the total number of participants who had contracted fingolimod-associated macular edema (FAME) were underrepresented in the FREEDOMS study, as ophthalmological monitoring was chiefly conducted by way of dilated fundus examination (DFE), whereas the more sensitive optical coherence tomography (OCT) screening was administered only at the experiment onset and 24 months into study (63, 64). Moreover, FREEDOMS researchers failed to assess participants’prior ophthalmic history and excluded participants receiving the 0.5mg dose from OCT screenings, despite additional data supporting the notion that ME can occur at that dose (61).


TRANSFORMS is another frequently cited study reporting an incidence of FAME in its adult MS participants. Unlike the FREEDOMS study, TRANSFORMS implemented quarter- yearly OCT/DFE screenings regardless of the dose rendered and observed a modestly diminished rate of FAME among those treated with the 0.5mg dose (2 subjects (0.5%) out of 429 on 0.5mg versus 4 (1%) out of 420 on 1.25mg) (61, 63). An apparent commonality between both the FREEDOMS and TRANSFORMS studies was the measured onset of FAME during treatment course, with a majority of cases occurring 3-4 months into trial.


Knowing that fingolimod-attributable malignancies are heavily dose-dependent, it should be considered that dosing in pediatric patients is variable and largely contingent on patient weight. As of 2018, the official stance of the U.S. Food and Drug Administration (FDA) dictates 0.5 mg QD, the recommended adult dose, for children weighing >40 kg and 0.25 mg QD for children weighing <40 kg. <40 kg children may be tapered up to 0.5 mg QD if fingolimod blood levels are suboptimal 1-month into treatment) (65). These guidelines are applicable to children deemed as displaying no known contraindications to the drug. However, as is true of all drugs involved in MS treatment, a complete dialogue surrounding pediatric susceptibility to adverse ocular treatment outcomes observed in adults has not been cultivated as pharmacokinetic differences in treated children are poorly understood and current treatment guidelines are based in studies involving subjects that are otherwise non-differential in their health status.

This said, fingolimod use in patients with diabetes mellitus (DM) is shown to potentially cause RVOs and associated retinopathies in addition to ME, though its incidence in children has, at present, not been investigated (44). The prevailing conjecture regarding the pathophysiology belying FAME is that damage to retinal vasculature already compromised by diabetes is synergized by fingolimod’s increasing vascular permeability in the retinal capillary bed (55, 61). Suffice it to say, this known contraindication warrants further pediatric neuro-ophthalmic research to rule out the ocular risks fingolimod use presents to diabetic children. At the same time, DM-acquired retinal damage does not discriminate between children or adults, with recent research pointing to a relationship between duration of DM and accumulated ocular abnormalities (66).


Several long-term studies attempting to infer lifelong ocular development in children displaying DM-associated abnormalities in retinal vasculature evince a high rate of transition into diabetic retinopathy occurring as early as late adolescence and early adulthood, with poor DM management presumably increasing the rate of retinal deterioration and therefore not excluding young pediatric patients from this disease configuration (67, 68). Theoretically, retinal deterioration in subjects diagnosed with DM in early childhood will have been allowed to progress to an extent that it disposes older pediatric subjects to an increased risk of FAME.


One research limitation characterizing both the FREEDOMS and TRANSFORM studies is that they expressly exclude diabetic subjects on the basis of an earlier study witnessing FAME in subjects with DM. Fingolimod, representing a superior alternative to traditionalimmunosuppressants such as cyclosporine and mycophenolate mofetil (MMF) in kidney transplantation, underwent Phase II clinical trials in 2006 (69). Study participants were stratified into three cohorts: full-dose cyclosporine (FDC)/fingolimod 2.5 mg recipients, reduced-dose cyclosporine (RDC)/fingolimod 5 mg recipients, and mycophenolate mofetil (MMF)/FDC recipients. Over the course of the trial, its sole 2 diabetic participants were confirmed to have contracted ME. Moreover, the study described generalized adverse ophthalmic outcomes as occurring in 18.4% of participants rendered fingolimod 2.5 mg/FDC and 16.6% rendered fingolimod 5 mg/RDC. In the MMF/FDC cohort, this was measured as occurring at a comparatively smaller rate of 13.3% (69). All affected participants were of mixed ophthalmic histories; thus, this finding remains pertinent insofar as weighing fingolimod’s potential ocular toxicity (69).


Adverse ophthalmic outcomes in fingolimod-treated diabetic children can be inferred based on the results of adult patients; and, if nothing else, pediatric neurologists should be astute to the necessity of performing precautionary ophthalmic examinations in this population prior to initiating fingolimod treatment in managing POMS (particularly in cases wherein comorbid DM has been poorly managed) (68). Pre-existing diabetes mellitus and disease acting on the visual pathway should not dictate treatment course, however, patients presenting with such conditions should be made aware of the increased risk of ophthalmic complications associated with fingolimod use (63). Moreover, drug-induced ME during treatment should not be assumed in the absence of a formal ophthalmic evaluation (63). It should be advised that, to date, there are no formal case reports describing ocular outcomes in FAME patients who elect to continue fingolimod treatment–much less those involving pediatric subjects (63).

Literature recognizing FAME as a treatment outcome in children is nonexistent, but in the 2018 PARADIGMS pharmacovigilance study comprised of 107 POMS subjects treated with fingolimod, one case culminated in ME and another culminated in uveitis (70). Being a smaller cohort, the rate of FAME and like complications in participants (1.9%) is proportional to incidence rates described in the aforementioned adult studies.


ME resolution or potential factors predisposing the affected study participants to drug- induced ophthalmic complications were not disclosed in the PARADIGMS study, but cases involving adult subjects have, by and by large, been observed to resolve with discontinuation of therapy (63). It is possible that children displaying poor visual outcomes were underrepresented in the study given the fact that many ocular disease states present asymptomatically. This is also true given given the study’s undisclosed ophthalmic examination methodology and frequency, its failure to take inventory of its participants’ ophthalmic histories, and the established trend of poor visual outcomes occurring months after fingolimod initiation in adults (70).


Interferon β-1a

Interferon β-1a (IFN-B1A), while recognized as being more efficacious than steroid- based therapy (53), is inarguably superseded in efficacy by second-line immunomodulating treatment in deferring and preventing relapsing episodes of MS. While true, it continues to beone of several first-line immunomodulating agents utilized in the management of MS– particularly in children. The Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) estimated adult participants’ (of which 50% presented with ON) 3- year prognosis for conversion to clinically-definite multiple sclerosis (CDMS) as being 35% – a substantially reduced likelihood compared to that estimated in its placebo group (50%) (53). This and like findings yielded by contemporaneous post-marketing analyses proved central in reshaping the optic neuritic-MS treatment paradigm which, prior to the 90s, was steroid-based.


Still, later contending studies purport a poorer relationship between IFN-B1A and reduction in Extended Disability Status Scale (EDSS) status than that which was initially believed, which is corroborated by additional revisionary studies. A large-scale longitudinal observational study incorporating the role of socioeconomic status (SES) in rate of disability progression observed no meaningful association between duration of IFB-B1A treatment and reprieve in disease course (71). It should be noted that while shorter baseline disease duration was seen in the treated cohort, EDSS outcomes were deemed near-identical between the treated and untreated cohorts, observing scores of 2.1 in the treated cohort and 2.0 in its two untreated cohorts (71).


This said, outstanding design flaws endemic to the study are acknowledged, which include but are not limited to an inability to properly distinguish between efficacy in commercially available product formulations, a failure to assess the role of neutralizing antibodies and other biological factors in treatment outcomes, and the possibility that IFN-B1A was beneficial in contexts not measured by the study. Unmeasured confounding factors were also taken into account, but assumed therein as being negligible in skewing data accrued. It is further acknowledged that shorter-term studies attempting to gauge the impact of IFN-B1A as an early- onset intervention and/or duration of use in upending disease progression have reported comparatively positive outcomes.

Nonetheless, the notion of its viability as a treatment option in children is generally supported, albeit by a limited amount of studies. Some discussion should be lent to the safety profile of IFN-B1A in treating childhood MS: a multinational 2013 study purports IFN-B1A efficacy outcomes in patients aged <12 and in patients aged 12-<18 treated with standard adult doses to be similar to outcomes measured in adult MS patients (72). Mean observation time was 1.13 years. Of its 307 participants, 97 patients presented with monofocality. Of note, 76 (24.8%) out of its 307 participants were omitted on the basis of intolerance to drug [36/76], continued incidence of relapse [31/76], and MRI-detected formation of malignancies sans relapse [9/76]. 18 serious adverse health events classified as either drug-attributed or of unknown causality were recorded as occurring in 12 participants [2/52 subjects aged <12 and 10/255 aged 12-<18].


The study concluded that the incidence of adverse health events in both cohorts treated with adult doses (IFN-B1A 44 and 22 mg, TIW) were consistent with that historically measured in adult MS patients. No meaningful differences in prognosis or incidence of side effects between cohorts were observed, nor could unanticipated side effects be gleaned from the study. Where researchers urged caution in interpreting the study’s findings due to its lacking a control group and its failure to measure the impact of patient comorbidities and conjunctive therapies ontreatment outcomes, they surmised that IFN-B1A shows utility in reducing incidence of POMS relapses (72). Interestingly, the study observed disease regression as occurring earlier in patients who had discontinued IFN-B1A and transitioned to alternative undisclosed immunomodulating agents (avg. 10.0 mo.) versus those that continued to receive IFN-B1A post-study (avg. 26.4 months).

As this paper endeavors to expand neuropediatricians’ awareness of the various ocular manifestations of drugs employed in managing POMS, special attention should be lent to IFN- B1A’s apparent inertness in the context of being a vision-saving agent. The consistency in which visual evoked potential (VEP) scores denoting unimproved eyesight have been measured in adults treated with low-dose IFN-B1A should be stressed given the still-extant tendency to administer equivalent doses to pediatric subjects in spite of the fact that they have been shown to respond more favorably to adult doses. This level of prescriptive caution is not unwarranted–as of the authorship of this paper, the FDA has yet to establish a definition proper on what constitutes optimal dosing in pediatric patients (73).

Of the few studies using VEP tests as a means of evaluating vision quality over the course of treatment, insubstantial IFN-B1A treatment impact on eyesight is a recurring theme: a 2003 study following adult MS subjects’ visual acuity after 1 and 2 years of treatment found no marked improvements in the visual acuity of IFN-B1A-treated subjects exhibiting disease-related delayed P100 latency (74). An additional 2004 study utilizing serial VEP screenings at 3, 6, 9, and 12 months following initiation of IFN-B1A 6 mil. IU in twice-weekly intervals similarly asserted that IFN-B1A exerted no influence on disease-related deficits in P100 amplitude and latency, observing poorer mid-treatment values in a portion of treated adults (75). Per both studies, IFN-B1A’s value in imparting visual pathway improvements–at least in low-dose-treated adults–can be assumed to be negligible in lieu of more substantive research. It is reasonable to extend this assumption to children, which are, as a rule, administered equivalent doses despite recent research highlighting their responding more favorably to adult doses.

This said, where the extent of IFN-B1A’s utility insofar as remediating MS-associated ophthalmic complications that have been allowed to progress appears to be limited, it is touted to be efficacious when utilized as a method of prophylaxis at symptom onset. Optic neuritic vision disturbances, which include color desaturation, diminished clarity, and pain accompanying eye movement, are profound and sudden enough to prompt patients to seek immediate medical attention, which presents a distinct treatment opportunity in stopping the disease course (54). Favorable treatment outlook, as is true of all agents utilized in MS symptom management, is contingent on the immediate initiation of IFN-B1A and swift diagnosis of ON.


On a final note, there is a widely observed association between interferon-alpha (IFN-a) and the development of various retinopathies in patients treated for viral hepatitis. While the development of ocular complications is not widely observed among IFN-B1A recipients, its incidence is described in literature. In the previously discussed PARADIGMS pharmacovigilance study endeavoring to establish safety and efficacy profiles in fingolimod and IFN-B1A-treated pediatric subjects, 1 out of 108 (0.9%) IFN-B1A recipients contracted uveitis (70). Its being one of the largest studies evaluating IFN-B1A use in children to date, this findingremains pertinent insofar as weighing ophthalmic risk in childhood treatment. As is true of fingolimod, its use is contraindicated in subjects displaying risk factors such as DM and other morbidities known to culminate in compromised retinal vasculature. Such caution should be extended to pediatric subjects considering the poorly understood pharmacokinetic activity in children receiving immunomodulating treatment, especially those displaying the aforementioned risk factors (55).


Natalizumab

Owing to its classification as a last-resort treatment in the management of aggressive relapsing remitting multiple sclerosis (RRMS), literature regarding natalizumab (NTZ) use in POMS cases, particularly as they relate to improvements in diminished visual acuity accompanying MS, is scant. The FDA currently discourages NTZ use in pediatric patients due to its association with the development of progressive multifocal leukoencephalopathy (PML) in treated adult subjects; moreover, MS disease course and susceptibility to PML in pediatric populations are poorly understood. Assuming differences in disease activity in prepubertal populations, clinicians err on the side of caution in initiating NTZ treatment in pediatric subjects, especially in children aged <10, an observed lack of drug-attributable adverse health events witnessed in existing studies involving NTZ-treated children aged <10 notwithstanding (76-82).

The probability of NTZ-induced PML has been observed to be heavily contingent on JCV (John Cunningham virus) positivity, duration of use exceeding 2 years, and history of prior immunosuppressant treatment. However, there are studies that suggest age-dependency as being a factor in JCV seroprevalence, consistently observing a marked lack of pre-treatment anti-JCV antibodies in the majority of subjects aged <10 years (80, 83, 84, 85, 86). The prevailing observation appears to be that pediatric populations aged 0-10 broadly present JCV-negative. Given the primacy of JCV-positivity in PML susceptibility, these figures highlight the prospect of reasonably safe childhood treatment with historically last-resort immunomodulating agents. Additional studies involving larger cohorts that resolutely affirm broad JCV negativity in prepubertal populations could bring forth new treatments for this age group; and both a negligible risk of drug-induced PML and the need for reevaluation of natalizumab’s indication as a last-resort treatment can be inferred.


It is already established that risk of exposure to the JCV maximizes with age (87); it should be noted, however, that a 2014 larger-scale German study observed anti-JCV antibody seropositivity in adolescent populations to be comparable to that of adult populations (88). Of the 256 serum samples analyzed therein, seropositivity rates were measured as being 46% in the <10 y.o. cohort (n = 45), 55% in the 10-13 y.o. cohort (n = 104), and 47% in the 14-17 y.o. cohort (n = 103) (88).


Recent epidemiological literature disputing these findings describe a cumulative average anti-JCV antibody seropositivity rate of 20.2% between its four cohorts aged <21 (n = 721) (85). A static trend in seropositivity is observed in these cohorts lasting into early adulthood. This precedes a steep upward trend in cohorts aged >21 in which measurements were taken that are more consistent with population seropositivity measured in the German study. Additionally, the study noted that the proportion of subjects measured as being seropositive continued to climb steeply with age, concordant with the prevailing notion that age is a factor in JCV exposure. While these findings are worth noting, this study is not without research limitations: it is stated that the study took place out of the Children’s Hospital in Denver and that the results it yielded may have merely been reflective of the holistic population health of the Denver area. Moreover, its pediatric serum samples were collected from an acute care population. Even though measures were taken to ensure that serum samples collected were yielded by subjects non-differential in health status, these factors are assumed herein as skewing data compiled.


Similar experimental design flaws are acknowledged in the German study: patient demographics were largely unknown, seropositivity as a consequence of region could not be ruled out, and there is the possibility that more severe cases were vastly overrepresented owing to the study’s having been conducted out of a referral center. However, both the German and Denver studies ultimately surmised that JCV-acquisition occurs primarily between early childhood and preadolescence, with its acquisition speculated as being a possible consequence of socioeconomic background, patient locale, and lifestyle-related factors.

The experimental design flaws plaguing the German study and a lack of corroboratory literature does not negate the clinical significance of the finding of enhanced anti-JCV antibody seropositivity in children and adolescents and further studies affirming this phenomenon may preclude these age brackets from immunomodulating treatment as an early intervention. That said, while the statistics produced by the German study are worth noting, contending studies observing the safe use of NTZ in this age group happen to be comparatively abundant: NTZ- treated adolescents displaying no drug-attributable adverse health events is a prevailing observation in the majority of existing pediatric studies, their supposed resilience against PML speculated as possibly owing to a lack of accumulated age-related immune abnormalities (76, 77, 79, 80, 81, 86, 95).


Moreover, literature suggests that the implementation of strict treatment conditions, close monitoring, shorter duration of NTZ use, annual MRI imaging, patient education, periodic mid- treatment anti-JCV antibody serum testing, extended-interval dosing in subjects deemed at-risk for PML, treatment discontinuation at onset of severe adverse health events, and follow-up care ensuring patient adherence to regimen can serve to more effectively mitigate PML risk and optimize clinical outcomes (89, 90, 91). Additional risk-mitigation strategies for NTZ-induced PML–such as a lateral transition to other high-efficacy immunomodulating agents purported to have a diminished PML risk (e.g., ocrelizumab)–are not unsuccessful or unheard of but warrant further research (92).

On a more cautionary note–regarding the concurrent use NTZ and other standard agents used in treating MS, official EMA guidelines, at present, advise against anti-JCV antibody testing in ruling out NTZ appropriateness following initiation of PE and IVIG therapy (within 2 weeks and 6 months respectively) due to consequent post-treatment serum clearance (89). Optimal dosing and duration of use in children has not been established, but patients treated at or

 

tapered up to the standard adult dose (300 mg IV every 4 weeks) boasts a success rate in preventing relapse long-term with minimal post-treatment follow-up (79, 93).

Having established this agent’s propensity for safe use in children, NTZ appears to be a strong treatment candidate in the context of preserving ocular integrity during MS symptom management. Cases of drug-attributable vision loss describe its incidence as primarily being a signature of PML onset. Although PML is life-threatening, it appears to be a clinically circumventable phenomenon that pediatric patients do not appear to be heavily disposed towards developing. This said, a smattering of case studies involving NTZ-treated middle-aged varicella zoster virus (VZV) vaccine recipients describe irrecoverable diminished visual acuity of unknown causality following inoculation (55, 94, 95). Moreover, post-marketing analyses describe a known incidence of varicella zoster infection adjacent to NTZ treatment culminating in death via encephalitis and meningitis (89). While older adults represent the overwhelming majority of VZV vaccine recipients, immunodeficient children also qualify for the immunization. Given that NTZ/VZV vaccine-induced permanent vision loss in susceptible pediatric populations is under-investigated, clinicians should be astute to the ocular toxicity of this therapeutic combination when immunizing children demonstrating immune-related risk factors.


Two previously mentioned studies measuring P100 outcomes in adult subjects treated with IFN-B1A agreed on the diagnostic potential of VEP in the express context of deducing treatment influence on visual performance (74, 75). As VEP scores are an important marker in gauging the extent of pharmacotherapeutic action on the visual pathway, the findings of a 2011 study measuring multiple evoked potential (EP) nervous system dimensions in NTZ-treated patients are suggestive of natalizumab’s supremacy in preserving ocular integrity in high-risk patients (96). This is the only study in which EP screenings have been utilized in measuring therapeutic outcomes in NTZ-treated patients to date.

A total of 44 adult MS participants were examined 1-year prior to NTZ initiation, at study onset, and 1-year post-NTZ initiation. Prior to initiating NTZ, 81% of participants evidenced an unchanged or diminishing VEP sum score. In treated adults, NTZ was shown to markedly improve visual acuity on the order of 33% (versus 67% showing no improvement) after a 6-12 treatment duration. Considering VEP outcomes measured in adults treated with alternative immunomodulating agents, this statistic is unexampled. Such remarkable outcomes can be anticipated in NTZ-treated pediatric populations which, as has been discussed herein, appear resilient against drug-induced PML and associated severe adverse health events.


Conclusion

As has been established, literature definitively measuring treatment outcomes in adult populations is lacking–much less those expressly tailored to ophthalmic outcomes. It follows that there is an even greater paucity of literature expounding on childhood ophthalmic outcomes. A lack of proper studies into the ocular manifestations of high-efficacy immunomodulating treatment in childhood MS accounts for this paper’s mention of case series and literature describing outcomes in adult treatment of varying degrees of rarity (e.g., CSC, FAME, and

 

NTZ/VZV-induced blindness). Outcomes discussed herein are not widely known outside of the field of ophthalmology and are, if nothing else, worth drawing multidisciplinary attention to. Disease activity and pharmacokinetics belying high efficacy immunomodulating treatment in children are already poorly understood, demanding further research into the likelihood of treatment ocular outcomes similar to those seen in adults occurring in this population. This paper proposes that poor ocular outcomes described in adult studies should be weighted–their purported rarity notwithstanding–in determining the risks drugs discussed herein present to children; moreover, the scarcity of literature in both detecting and implementing preventative measures against negative ophthalmic outcomes discussed herein should be amended via further research.


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Immunomodulation in Pediatric-Onset Multiple Sclerosis— A Review
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