2.1. Cognitive Functioning Outcomes in POMS
Assessment of cognitive functioning in POMS continues to advance, with ongoing improvement in assessment batteries, understanding of disease correlates, and additional focus on risk factors and protective features. Research has consistently found that approximately one third of pediatric patients with MS suffer from neurocognitive impairment. This is somewhat less than what is typically reported in the adult literature, which ranges from 50% [
21,
22,
23,
24] to close to 70% [
25,
26]. Early diagnosis of cognitive dysfunction can be extremely important in POMS, given that physical status can be well preserved. Children also appear to be more vulnerable to cognitive impairment early on in the disease process.
Areas of neurocognitive impairment in POMS often mimic those in adults, including processing speed, working memory, and visual spatial processing; however, there have been additional findings of impact on language, which is not typical in the adult cohort [
27,
28,
29,
30,
31,
32]. Poor verbal knowledge has implications in outcomes of education and general functional attainment. It may be associated with direct impact of disease process on learning and language development, as well as a secondary interference from high absenteeism from school due to medical complications and impact of other neurocognitive defects impacting learning (attention, processing speed, etc.). Nevertheless, language impairment is not always reported in patients with POMS. One recent study examining a large number of patients from several clinics in the United States reported language as the least frequent domain showing impairment in their cohort [
24].
Early longitudinal studies found evidence of cognitive decline in patients with POMS [
29,
33,
34]. An initial Italian study was startling, with findings suggesting worsening of cognitive functioning in 70% of their POMS patients over only 2 years, despite relatively stable physical and disease status [
34]. Further evaluation, extending these results to 5 years in 48 patients, showed there was some evidence of improvement in 67% of patients from year 2 to year 5 [
35]. Comparisons between baseline and 5-year follow-up assessments showed 56% of patients declined on their impairment index, 25% improved, and close to 19% remained stable. Declines were associated with male sex, younger age of onset, and lower education. The US Pediatric MS Network findings suggest a limited decline in cognitive functioning over a 1–2-year time span [
36]. Another recent study examining patients and controls over a 1-year period found that controls generally showed greater improvement than patients, and 25% (7/28) of patients showed clinically significant decline [
37]. They suggest that the lower rate of improvement may be indicative of lack of age-appropriate development. Ongoing longitudinal analysis will help to clarify the severity and frequency of cognitive decline, as well as provide insight regarding effective intervention strategies and disease-related correlates that may help in preventing or reducing the disease impact on cognitive functioning.
2.2. Psychosocial and Functional Outcomes
We assume, and to some degree know, that neurocognitive deficits and physical disability lead to functional impairment (e.g., poor academic progress and need for school accommodations, inability to participate in sports). The adult literature continues to show us that cognitive decline and disability level, together with progressive course, influence social and work-related function in adults with early-onset MS [
38,
39]. However, scientific evaluation of functional outcomes in children is limited. Functional outcomes tend to be harder to identify and quantify in children. In adults, vocational placement or employment is often used. In children, we know school is the primary functional outcome to examine, but there can be many reasons why a child fails in school other than cognitive impairment. There are some initial findings showing the effects of POMS on school functioning, such as high absenteeism, need for special education services, and being held back or dropping out of school [
27,
28,
32]. Our center has consistently shown that approximately two thirds of patients (approximately
n = 66) receive or have received a combination of therapeutic intervention (occupational, physical, or speech/language therapies) and/or require special education plans or have academic accommodations in place at their schools (personal communication). The majority require classroom accommodations (e.g., extended time on exams, reduced workload, providing extra support during longer absences), with younger patients typically requiring more therapeutic intervention (occupational, physical, speech/language therapy).
We also know that there are several additional factors to cognitive impairment, such as fatigue, depression, and poor quality of life, which can impact functional outcomes, regardless of MS progression. Measurement of mood and fatigue and understanding their impact on cognitive and daily functioning in patients with MS has been more consistent in the adult literature [
40,
41]. Recent focus has increased in the pediatric population, but further examination is necessary.
Quality of life (QoL) assessment can help to determine the impact of cognitive impairment and disease burden on daily functioning. Literature examining the assessment of QoL in POMS is limited, with only a few studies to date discussing the topic. Their findings suggest significant reductions in health-related QoL (HRQOL) scores despite short disease duration and generally fair physical ability [
42]. Others have examined QoL as a tertiary measure and have found evidence of poorer quality of life [
43] but provide only a limited assessment of the correlation between QoL and cognitive impairment. One study examining young adults with pediatric-onset MS found, not surprisingly, that physical health-related QoL was related to EDSS, while depression was related to the Mental index of health related quality of life (HRQOL), but overall, there was not a significant reduction in HRQOL compared to controls [
44]. Fatigue and depression have also been shown to impact QoL in POMS [
45].
Studies exploring rates of fatigue in children with MS reported it as occurring in 20–75% of patients [
43,
46,
47,
48,
49]. A small number of studies have examined the association between fatigue and cognitive functioning. One smaller study (
n = 26) found that POMS is associated with fatigue and emotional difficulties, which were related to executive dysfunction [
50]. Goretti and colleagues [
33] found that fatigue was associated with elevated self-reported depression symptoms. Rater differences were evident, with self-reported cognitive fatigue associated with impaired problem solving, while parent-reported cognitive fatigue was associated with impaired verbal learning, cognitive flexibility, and comprehension. By contrast, several authors have found minimal evidence for a relationship between subjective fatigue (either self- or parent-reported) and objective cognitive functioning [
51,
52,
53].
Depression is another common comorbidity in patients with MS that has been minimally evaluated in pediatric-onset MS. Fatigue and depressive symptoms often tend to overlap. In our group, we found that a quarter of pediatric patients with demyelinating disorder (e.g., acute disseminated encephalomyelitis (ADEM), MS) had elevated parent-reported symptoms of depression and self-reported fatigue, and there was a higher rate of fatigue than depression in child self-report [
48]. Other studies have shown similar findings [
43,
54]. MacAllister et al. [
28] found that depression was present in half of the cases, while Goretti and colleagues found that 17% of patients based on self-report and 30% based on clinical interview were classified as having an affective disorder [
55]. An Italian group found more drastic rates of significant fatigue reported, with nearly 75% of children with MS reporting fatigue, while only a small percentage (6%) reported depression. Within this sample, over half reported that MS had negative effects on their everyday life and school [
32]. Another study examining comorbid psychiatric diagnoses and cognitive functioning in POMS found that those with a psychiatric diagnosis had a higher rate of cognitive impairment [
56]. Interestingly, cognitive functioning was found to predict the presence of clinical problems (e.g., anxiety, somatization) on self- and parent-reported behavioral assessments (behavior assessment system for children—second edition (BASC-2); [
51]).
Increased focus on evaluation and treatment of fatigue and depression in children with demyelinating disorders is essential. We have learned from the adult literature how prevalent comorbid psychiatric disorders and fatigue are in patients with MS, and how symptoms associated to fatigue and psychiatric conditions can significantly impact disease and functional outcomes [
57,
58,
59]. There is extensive literature reviewing the detrimental effects of depression on academic, social, and vocational functioning. We continue to need to increase evaluation of fatigue and symptoms of psychiatric disorder (depression, anxiety, personality change) in addition to physical outcomes and symptoms, even in young children. Moreover, analysis of the effectiveness of interventions such as psychotherapy methods (e.g., cognitive behavioral intervention), behavioral activation, group supportive counseling, educational groups, and pharmacological intervention is direly needed in this population.
Social functioning in children with POMS has also been an interesting area of recent research. With a general population increase in the rate of social functioning disorders in children (e.g., social communication disorder, autism spectrum disorder), it is interesting to look at this area of functioning in patients with POMS and how disease may impact social skill development. Charvet and colleagues (2014) examined social cognition, defined as the cognitive processes governing social situations, such as theory of mind, in a small group of patients with POMS. They found that patients with POMS performed worse on measures of theory of mind compared to controls, suggesting poorer ability to process social information [
60]. Findings were associated with cognitive dysfunction and disease characteristics (number of relapses and disease duration). Additional evaluation of the direct impact of disease on social functioning, as well as the indirect effect (missing time from school/social events, cognitive impairment, academic difficulties, inability to participate in certain group activities, etc.) will be interesting.