Late Cognitive and Adaptive Outcomes of Patients with Neuroblastoma-Associated Opsoclonus-Myoclonus-Ataxia-Syndrome: A Report from the Children’s Oncology Group

Abstract

Background:

Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare autoimmune disorder of the nervous system presenting with abnormal eye and limb movements, altered gait, and increased irritability. Two to four percent of children diagnosed with neuroblastoma have neuroblastoma-associated OMAS (NA-OMAS). These children typically present with non-high-risk neuroblastoma that is cured with surgery, with or without chemotherapy. Despite excellent overall survival, patients with NA-OMAS can have significant persistent neurological and developmental issues.

Objective:

This study aimed to describe long-term neurocognitive and adaptive functioning of patients with NA-OMAS treated with multi-modal therapy including intravenous immunoglobulin (IVIG) on Children’s Oncology Group (COG) protocol ANBL00P3.

Methods:

Of 53 children enrolled on ANBL00P3, 25 submitted evaluable neurocognitive data at diagnosis and at least one additional time point within 2 years and were included in the analyses. Adaptive development was assessed via the Vineland Adaptive Behavior Scale, and validated, age-appropriate measures of intellectual function were also administered.

Results:

Twenty-one of the twenty-five patients in this cohort ultimately received IVIG. Descriptive spaghetti plots suggest that this cohort demonstrated stable long-term cognitive functioning and adaptive development over time. This cohort also demonstrated decreased OMAS scores over time consistent with improved OMAS symptoms.

Conclusions:

While statistical significance is limited by small sample size and loss to follow up over 10 years, findings suggest stable long-term cognitive and adaptive functioning over time in this treated cohort.

Introduction

Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare autoimmune disorder of the nervous system that presents with abnormal eye and limb movements, altered gait, and increased irritability. The diagnosis can be made when 3 of the following 4 features are present: (1) opsoclonus, (2) ataxia or myoclonus, (3) behavior change or sleep disturbance, and (4) neuroblastoma.¹ Studies in the UK and Japan report rates between 0.18 and 0.27 cases per million with mean age of presentation between 16.5 and 18 months of age.^2,3

In children, there is a known association between neuroblastoma and OMAS, and 2–4% of children diagnosed with neuroblastoma present with OMAS.⁴ If a patient presents with OMAS, there is a 50% chance that an underlying peripheral neuroblastic tumor is identified.⁵ Patients with neuroblastoma-associated OMAS (NA-OMAS) typically present with favorable biologic features and non-high-risk neuroblastoma that is cured with surgery alone or surgery with less intensive chemotherapy and tend to have higher overall survival.^3,6–9

Despite improved survival, the majority of patients with NA-OMAS may have decreased quality of life due to persistent neurological deficits associated with OMAS, including delayed motor and coordination development, behavioral problems, poor sleep, delayed speech, and impaired cognition.⁸ Therefore, it is recommended that patients with OMAS undergo monitoring of their cognitive and physical development, even after the presenting symptoms resolve, including follow up of ataxia, language development, attention, executive function, and sleep, in addition to formal neurocognitive assessments to identify on-going educational needs.¹⁰

Given the rarity of this disease, however, the limited research on the neurocognitive functioning of patients with NA-OMAS has been largely based on retrospective studies involving small samples and case reports.^11–18 There have been no prospective trials that included serial assessment of cognitive or psychological outcomes. Motor function deficits, including ataxia, apraxia, coordination difficulties, tremor, and poor fine motor skills, have been described in two-thirds of patients followed for up to five decades after diagnosis and therapy, though these deficits typically do not severely affect daily function and activity.^1,8,10,19,20 However, cognitive and behavioral difficulties, including intellectual disability, learning disability, dyslexia, poor attention, impaired expressive language and visuospatial function, behavioral problems, and sleep disorders, do severely impact daily function and can affect the majority of patients followed long-term.^{1,6,8,10,12,19,20}

A report from 2002 indicated that cognitive and adaptive development was significantly delayed in almost all patients (14/17 and 16/17, respectively), with older patients demonstrating more severe deficits.¹² A portion of this sample (n=13) was followed up several years later with some improvement noted in performance, particularly in cognitive functioning, with the largest gains observed in younger patients.¹¹ Notably, OMAS symptoms were persistent in this sample, with few patients able to come off therapy. Those who were able to achieve remission from their OMAS symptoms had more favorable cognitive outcomes. Given the findings from this cohort, Mitchell and colleagues followed another small sample of patients (n=14) whose OMAS was treated more intensively at first presentation.¹³ They noted that these patients, regardless of age, demonstrated improved neuropsychological outcomes, with median cognitive and adaptive scores within normal limits. A case series from India (n=6) demonstrated similar findings with near normal development attained for those patients who quickly achieved remission from their OMAS symptoms.¹⁴ An additional report of eleven patients with a mean follow-up time of 7.6 years demonstrated that a majority of patients showed mild neurologic deficits (7/11, 64%) and performed within the average range (6/11, 55%), suggesting that certain patients with NA-OMAS can achieve average neurocognitive function despite mild residual neurologic deficits, with the possibility for improvement over time.²¹

The largest study to date of patients with OMAS involved a retrospective and prospective cohort study of 81 patients from three countries, with cognitive testing data available in less than half of patients.²² Findings ultimately supported earlier work and indicated that OMAS relapses were significantly associated with decreased cognitive functioning over time. While this collection of clinical reports has certainly highlighted the benefits of early treatment for OMAS, there remain numerous unanswered questions regarding the trajectory of cognitive and adaptive outcomes in this population, and there is a significant need for prospective serial assessments of functioning in patients with OMAS.

Several studies have demonstrated that more intensive therapy improves neurocognitive outcomes in patients with OMAS.^8,13 In an effort to better assess the benefits of treatment on the acute symptoms of OMAS as well as on long-term outcomes, the first prospective, randomized clinical trial for children with NA-OMAS (ANBL00P3, ClinicalTrials.gov identifier NCT00033293) was designed and implemented in the Children’s Oncology Group (COG). This study demonstrated that intravenous immune globulin (IVIG) was a beneficial addition to prednisone and risk-adapted chemotherapy as it significantly improved OMAS response rate by one year.⁹ The study’s secondary objectives included assessment of treatment effect on long term functional and neurologic outcomes in patients with NA-OMAS. This report describes cognitive and adaptive outcomes including formal testing and neurologic examinations of patients with NA-OMAS over time.

Methods

Procedures

Pediatric patients less than 8 years of age with newly diagnosed NA-OMAS who had not received prior chemotherapy were eligible for enrollment on ANBL00P3. A detailed description of the study and primary outcomes has been previously reported.⁹ In summary, patients received risk-adapted chemotherapy according to the standard of care at the time that the study was conducted.²³ All patients, regardless of stage at diagnosis, received cyclophosphamide and steroids and were randomized to either receive (IVIG+) or not receive IVIG (no-IVIG).

Patients on the IVIG+ arm could receive IVIG for up to 12 months in the absence of disease progression or unacceptable toxicity. If a patient’s neuroblastoma did not respond, they were taken off protocol therapy. If a patient’s OMAS progressed and they were on the no-IVIG arm, they were eligible to receive IVIG. If a patient’s OMAS progressed and they were on the IVIG+ arm, they were eligible to receive corticotropin-releasing hormone (ACTH).

OMA symptoms involving stance, gait, arm/hand movement, opsoclonus, and mood/behavior were classified as mild, moderate, or severe using a scale developed by Mitchell and Pike.^6,9 Neurological symptoms were evaluated at 2 months, 6 months, and 1 year. Response was defined as the best score of the three evaluations and summated to categorize patients as having had a complete response (CR), partial response (PR), no response (NR), or progressive disease (PD). Patients who crossed over from no-IVIG to IVIG+ or who received ACTH were classified as having had NR. Responders included patients with CR or PR. Non-responders included patients with NR or PD.

Enrolled patients were eligible to complete serial psychological assessments if able to participate. Assessments were requested at diagnosis, 2 months, 6 months, and then yearly up to 10 years following diagnosis. The assessment battery included measures of cognitive, adaptive, emotional/behavioral, and fine motor functioning, with some variation in measures based on patient age at assessment. This report will focus exclusively on cognitive and adaptive functioning. Adaptive functioning was assessed via the Vineland Scales of Adaptive Behavior.²⁴ This is a semi-structured interview completed with parents that includes assessments of communication, daily living skills and socialization, which combine to yield an Adaptive Behavior Composite. The measure is appropriate for children from birth to 18 years and thus was used for all patients at all time points. Cognitive functioning was assessed via one of three psychologist-administered measures based on patient age: Bayley Scales of Infant and Toddler Development, 2^nd edition (BSID-II)²⁵, Wechsler Preschool and Primary Scales of Intelligence, Revised (WPPSI-R)²⁶, and Wechsler Intelligence Scale for Children, 3^rd edition (WISC-III)²⁷ though a few patients were assessed via WISC-IV and WISC-V. All three measures produce an overall indicator of global cognitive development (BSID-II – Mental Development, WPPSI-R/WISC-III – full-scale IQ). Consistent with prior research, the three indicators were collapsed into one category of cognitive functioning for analytic purposes.²⁸ For both adaptive and cognitive functioning, scores yield a standardized normative mean of 100, with a standard deviation of 15, and scores below 85 are considered clinically below expectations.

Statistical analysis

Given the small sample size and the limited number of observations available per patient, the decision was made to analyze all patients in one group, rather than attempting to determine differences in neurocognitive function by treatment arm. Additionally, due to the high frequency of encounters that only included cognitive or adaptive measures and not both, these measures were considered separately for all analyses. Thus, analyses were conducted for the whole cohort together, rather than by intent-to-treat, and analysis was not conducted to assess for treatment effect.

Given the unbalanced nature of the available data (unequal measurement time points, various numbers of measurements per individual, and missing data), a descriptive analysis is the best approach. However, to incorporate all the available quantitative data as comprehensively as possible, several linear mixed effects models including various covariance structures (compound symmetry, autoregressive, unstructured) and random intercepts were fit. A repeated measures model with exponential covariance pattern was selected since it allows for the correlation between two possibly unequally spaced measurement intervals to decrease as the distance between measurements increases and yielded the smallest Akaike information criterion (AIC). No model is perfectly suited for these data given its nature, so interpretations should be made with the understanding that some of the model assumptions may not hold.

Results

Participants

Fifty-three children were enrolled on ANBL00P3 across 39 COG institutions. Of these, 35 participants (66%) completed at least one psychological assessment that assessed cognitive and/or adaptive outcomes. Due to a combination of factors (e.g., scheduling, patient medical status, patient behavioral status, presence/absence of a psychologist at the site, non-English speaking), no patient completed assessments at all timepoints. Of these 35 participants, five were excluded because test data were not available at diagnosis, and one was excluded due to invalid scores related to language translation issues. Of the remaining 29, four were excluded due to lack of additional adaptive data in the first two years. Of note, two years was chosen to balance the intent to show long-term outcomes with the decreased availability of data over time.

The remaining 25 patients provided adaptive data at diagnosis and at least one subsequent time point in the first two years of follow up. Of those 25 patients, ten were not included in the cognitive analysis because of lack of additional cognitive data in the first two years. The remaining 15 patients provided both cognitive and adaptive data at diagnosis and at least one subsequent time point during the first two years of follow up. Please see Supplemental Figure S1 for a CONSORT diagram.

Clinical & Treatment Characteristics

Median age at diagnosis of patients in this analysis was 18.6 months (range 2.9 to 48.5 months). 56% of the cohort was female and 44% were male. The majority (56%) of patients had International Neuroblastoma Staging System (INSS) Stage 1 disease; 28% had INSS Stage 2B disease (Table 1). The baseline characteristics of patients with neurocognitive data was similar overall compared to those of patients without neurocognitive data. Of patients with neurocognitive data (n=25), two patients had mild OMAS, 18 patients had moderate OMAS, four had severe OMAS, and one was not classified due to lack of complete grading data available at diagnosis. Of patients without neurocognitive data (n=28), three had mild OMAS, 19 had moderate OMAS, four had severe OMAS, and two were not classified due to lack of complete grading data available at diagnosis.

Table 1.

Patient demographics (n=53; 25 with evaluable neurocognitive data and 28 without)¹

		Patients with evaluable neurocognitive data (n=25)	Patients without evaluable neurocognitive data (n=28)
Variable	Value	Count (%)	Count (%)
Age at Diagnosis	<18 months	12 (48.0%)	13 (46.4%)
	≥18 months	13 (52.0%)	15 (53.6%)
	Median	18.6	18.8
	Mean (SD)	20.8 (9.2)	20.7 (6.9)
Ethnicity	Hispanic or Latino	3 (12.0%)	9 (33.3%)
	Not Hispanic or Latino	22 (88.0%)	18 (66.7%)
	Unknown	0	1
Race	Asian	1 (4.2%)	0 (0.0%)
	Black or African American	6 (25.0%)	5 (20.8%)
	White	17 (70.8%)	19 (79.2%)
	Unknown	1	4
Sex	Female	14 (56.0%)	19 (67.9%)
	Male	11 (44.0%)	9 (32.1%)
Histology	Favorable	17 (73.9%)	17 (63.0%)
	Unfavorable	6 (26.1%)	10 (37.0%)
	Unknown	2	1
INSS Stage	Stage 1	14 (56.0%)	18 (64.3%)
	Stage 2A	2 (8.0%)	1 (3.6%)
	Stage 2B	7 (28.0%)	5 (17.9%)
	Stage 3	2 (8.0%)	3 (10.7%)
	Stage 4	0 (0.0%)	1 (3.6%)
Tumor MYCN Status	Amplified	1 (4.2%)	1 (3.8%)
	Not amplified	23 (95.8%)	25 (96.2%)
	Unknown	1	2
Tumor Cell Ploidy	Diploid	7 (29.2%)	6 (24.0%)
	Hyperdiploid	17 (70.8%)	19 (76.0%)
	Unknown	1	3
COG Neuroblastoma Risk Group	High	1 (4.0%)	1 (3.7%)
	Intermediate	3 (12.0%)	4 (14.8%)
	Low	21 (84.0%)	22 (81.5%)
	Unknown	0	1

¹International Neuroblastoma Staging System (INSS)

Children’s Oncology Group (COG)

Briefly, 16 of 25 (64%) patients were treated with cyclophosphamide, steroids, and IVIG upfront (IVIG+), with 9 (36%) treated with cyclophosphamide and steroids only (no-IVIG). Three patients on the IVIG+ arm were OMAS non-responders, two of whom crossed over to ACTH and 1 who had stable OMAS. Six patients on the no-IVIG arm were non-responders, five of whom ultimately received IVIG and one who had stable disease. Of the five patients who went on to receive IVIG, one additionally received ACTH. Ultimately, 21 of 25 patients (84%) received IVIG.

Adaptive functioning (Vineland)

Descriptive statistics were used to assess average adaptive functioning at each time point (Table 2). The interval of ages of patients with evaluable adaptive functioning data is 2.9–48.5 months at diagnosis. At baseline, the group mean was in the Low Average range overall (mean=86); however, 48% of participants demonstrated adaptive functioning scores in the clinically significant impairment range (score below 85). Mean scores generally remained in the Low Average range over time, with a notable proportion of patients demonstrating clinically significant deficits in adaptive functioning at each time point (Table 3).

Table 2.

Long term adaptive functioning (n=25)

	Adaptive Functioning						Age at Neurocognitive Assessment (Months)
	N	Min	Max	Median	Mean	SD	Mean	Median
Diagnosis	25	65	115	86	86	13	21.3	19.2
2 Months	13	57	108	90	86	16	24.2	23.3
6 Months	20	65	113	91	90	13	26.9	28.2
1 Year	17	35	118	84	80	21	35.7	32.9
2 years	12	64	115	83	87	15	48.2	49.5
3 years	9	76	114	93	95	14	59.4	55.0
4 years	6	78	118	103	99	18	74.1	72.0
5 years	6	70	111	94	94	15	90.1	88.9
6 years	5	60	112	87	87	22	99.6	101.0
7 years	2	80	111	96	96	22	114.9	114.9
8 years	2	76	105	91	91	21	132.6	132.6
9 years	0
10 years	1	71	71	71	71	-	147.0	147.0

Table 3.

Proportion of patients with clinically significant deficits (n=25 for adaptive function; n=15 for cognitive functioning)

	Cognitive Functioning		Adaptive Functioning
	N	N (%) Below 85	N	N (%) Below 85
Diagnosis	15	8 (53)	25	12 (48)
2 Months	4	4 (100)	13	5 (38)
6 Months	5	3 (60)	20	7 (35)
1 Year	10	6 (60)	17	9 (53)
2 years	5	5 (100)	12	7 (58)
3 years	3	2 (67)	9	3 (33)
4 years	6	0 (0)	6	2 (33)
5 years	3	2 (67)	6	1 (17)
6 years	3	1 (33)	5	2 (40)
7 years	2	1 (50)	2	1 (50)
8 years	0		2	1 (50)
9 years	2	2 (100)	0
10 years	0		1	1 (100)

To further examine longitudinal trends in adaptive functioning, data from the first two years were analyzed. Specifically, the cohort showed stable Vineland scores over time, shown as both mean scores over two years (Figure 1A) and mean change from baseline at two years (Figure 1B). In testing whether the Vineland test scores changed over time (slope=0) for all patients with scores at baseline and at least one other prior to or at two years (n=25), there was insufficient evidence to conclude that the rate of change over two years was significantly different than zero (p=0.68, 95% CI for slope parameter (−6.23, 4.11), estimated slope parameter −1.06). This fitted line is only possible for raw score data and is displayed as a dotted line only for the mean scores over two years (Figure 1A) rather than the mean change from baseline.

Figure 1A.

Mean Vineland scores over 2 years. The number of patients included at each time point is shown at the bottom along the x-axis. The dotted line is the fitted line for scores over time. P-value, 95% confidence interval (CI) for the slope parameter, and estimated slope parameter have been added in a separate table at the bottom.

Figure 1B.

Individual change in Vineland scores from baseline over 2 years. Each line depicts an individual patient’s change from baseline over 2 years (n=25). The number of patients included at each time point is shown at the bottom along the x-axis. The dark line is the mean change for the cohort at each time point smoothed by LOESS with smoothing parameter auto-selected at 1. A shadowed band has been included to represent the 95% CI.

Cognitive functioning (combined score from multiple assessments per age group)

Descriptive statistics were calculated to assess average cognitive functioning at each time point (Table 4). The interval of ages of patients with evaluable cognitive functioning data is 10.8–48.5 months at diagnosis. At baseline, the mean cognitive functioning score was in the Low Average range (mean=81). Scores remained in the Low Average or lower range over time, with a substantial proportion of participants demonstrating clinically significant impairments at each time point (Table 3).

Table 4:

Long term cognitive functioning (n=15)

	Cognitive Functioning						Age at Neurocognitive Assessment
	N	Min	Max	Median	Mean	SD	Mean	Median
Diagnosis	15	50	109	78	81	18	21.0	17.3
2 Months	4	74	82	80	79	4	32.8	27.0
6 Months	5	50	102	84	80	22	23.8	25.5
1 Year	10	65	102	82	82	12	37.4	34.7
2 years	5	67	82	72	75	7	49.4	49.5
3 years	3	74	85	80	80	6	71.4	70.1
4 years	6	85	101	91	92	6	74.5	72.5
5 years	3	84	98	84	89	8	86.9	85.8
6 years	3	83	103	92	93	10	98.2	96.7
7 years	2	78	105	92	92	19	110.0	110.0
8 years	0
9 years	2	57	66	62	62	6	132.8	132.8
10 years	0

To further examine longitudinal trends in cognitive functioning, data from the first two years were analyzed. Overall, the cohort showed stable cognitive scores over time, shown as both mean scores over two years (Figure 2A) and mean change from baseline at two years (Figure 2B). In testing whether cognitive test scores changed over time (slope=0) for all patients with scores at baseline and at least one other score within two years (n=15), there was insufficient evidence to conclude that the rate of change over two years was significantly different than zero (p=0.63, 95% CI for slope parameter (−8.37, 5.15), estimated slope parameter −1.61). This fitted line is only possible for raw score data and is displayed as a dotted line only for the mean scores over two years (Figure 2A) rather than the mean change from baseline.

Figure 2A.

Mean cognitive scores over 2 years. The number of patients included at each time point is shown at the bottom along the x-axis. The dotted line is the fitted line for scores over time. P-value, 95% CI for the slope parameter, and estimated slope paramter have been added in a separate table at the bottom.

Figure 2B.

Individual change in cognitive scores from baseline over 2 years. Each line depicts an individual patient’s change from baseline over 2 years (n=15). The number of patients included at each time point is shown at the bottom along the x-axis. The dark line is the mean change for the cohort at each time point smoothed by LOESS with smoothing parameter auto-selected at 0.5. A shadowed band has been included to represent the 95% CI

OMAS scores

The cohort showed improvement in OMAS scores over time with a consistent downward trend (median score at diagnosis: 9, median score at 1 year: 3, median score at 2 years: 1.5, with maximum possible score of 15), which supports prior literature showing that patients receiving intensive therapy have improved long term outcomes with regard to OMAS symptoms and OMAS response, as quantified by OMAS grade (Supplemental Figure S2).

Discussion

The current study examined functional outcomes, including both adaptive and cognitive functioning, in patients with NA-OMAS treated on the prospective randomized clinical trial ANBL00P3. The primary strength of this study is the prospective, longitudinal design.

The neurologic sequela of OMAS are significant and often life-long, and impact a majority of patients with OMAS.^6,8,29 Historically, favorable outcomes have been reported in less than half of patients in long-term follow up and problems include intellectual disabilities, learning disabilities such as dyslexia, and deficits in attention, productive language, visual and spatial orientation, and behavioral regulation.^6,10–13 Patients with more severe initial symptoms and younger age at diagnosis are at increased risk for chronic relapsing and remitting disease and poor long-term outcomes, including residual motor problems (60%), speech problems (66%), learning disability (51%), behavioral problems (46%), and abnormal intellectual function (66%).³⁰ Studies have shown that patients can have incomplete and impaired fine motor recovery, with ataxia, apraxia, coordination deficits, and tremor, spanning up to decades after diagnosis in 20–60% of patients.¹⁰ These symptoms do not typically affect function severely, in contrast with cognitive and behavioral deficits, which typically cause more dysfunction.

This study suggests that with treatment, patients show stable, non-deteriorating neurocognitive function in the long-term. This is consistent with other publications that have reported that patients treated with more intensive therapy tend to have improved long-term neurologic outcomes.^6,13,31 Additionally, more intensive therapy has been correlated with improvements in behavior and learning.^6,13,31 The longitudinal analysis results show that a change in the patients’ cognitive and adaptive functioning was detected over time. However, it should be noted that this analysis has limited power.

Limitations of this study include small sample size and missing data at longer follow up time points. Reasons for missing data included loss to follow up as well as lack of available trained staff to perform testing and possibly lack of insurance coverage for testing. Limited available data was most notable in the assessment of late cognitive function. This impacts the interpretation of the mean cognitive score in this cohort, as patients who did not return for follow up or were unable to complete cognitive testing could be performing at either a higher or lower level. This in turn could affect the true mean cognitive score of the group. Given that OMAS scores for the entire cohort were consistently improved in patients with long term follow up, it is possible that families were more likely to discontinue follow up in the context of improved function. Nonetheless, it is difficult to compare these results with other studies that have shown a relationship between intensive treatment and improved cognitive outcomes with intellectual functioning in the average range (>90).^11,13 Lastly, some contemporary therapies (i.e. rituximab) were not commonly used for the treatment of OMAS at the time this study was designed and opened for enrollment.

Conclusion

Rare diseases are challenging to study and even more challenging to investigate prospectively and longitudinally in the setting of limited sample size. In this cohort, patients demonstrated stable long-term cognitive and adaptive functioning over time. This study provides additional understanding of long-term neurocognitive functioning of patients with NA-OMAS through prospective serial assessments, and thus is an important addition to the existing OMAS literature.

Abbreviation

NA-OMAS

Neuroblastoma-associated opsoclonus-myoclonus-ataxia-syndrome

COG

Children’s Oncology Group

OMS

Opsoclonus-myoclonus syndrome

IVIG

Intravenous immunoglobulin

ACTH

Corticotropin releasing hormone

CR

Complete response

PR

Partial response

NR

No response

PD

Progressive disease

BSID-II

Bayley Scales of Infant and Toddler Development

WPPSI-R

Wechsler Preschool and Primary Scales of Intelligence

WISC-III

Wechsler Intelligence Scale for Children

AIC

Akaike information criterion

INSS

International Neuroblastoma Staging System

SD

Standard deviation