We developed a clinical severity scale () in order to characterize clinical progression and to index potential biomarkers to disease severity. Clinical signs and symptoms in nine major domains (scored 0–5: ambulation, cognition, eye movement, fine motor, hearing, memory, seizures, speech, swallowing,) and eight minor domains (scored 0–2: auditory brainstem response, behavior, gelastic cataplexy, hyperreflexia, incontinence, narcolepsy, psychiatric, respiratory problems) were evaluated.
We initially used this scale to characterize 18 NPC patients enrolled in an NIH observational study. Patient demographics for these patients are shown in . Age at initial NIH evaluation ranged from age 4 years to age 51 years with a mean and median age of 12.9 and 8.5 years, respectively. The male to female ratio was 11:7. The most common presenting symptom in this cohort was splenomegaly (15/18, 83%) with a mean age at presentation of 3.4 years. Four patients (22%) presented with neonatal jaundice; however, in three of these cases, splenomegaly was noted by 3 months of age. Two patients (13 and 18) were noted to have learning difficulties by age 8 and 18 years, respectively. The initial symptom in the single adult onset case (patient 15) was hearing loss. Of note, hearing loss was a prominent clinical issue in the three oldest patients. A significant delay in diagnosis of NPC was observed for the majority of patients. Excluding the one patient who had an older affected sibling (patient 2), of the 16 cases initially presenting with jaundice or splenomegaly, the diagnostic delay ranged from 3 months to 19 years with a mean and median of 4.3 and 1.8 years respectively. The diagnostic delays for patients 13, 15, and 18 were, respectively, 13, 9 and 19 years.
When we scored these current patients using our severity scale, as one would expect for a progressive disorder, severity scores increased with age. However, the increase in the severity score as a function of age was non-linear (). In contrast, severity scores increase in a linear manner (r2=0.64, p<0.0001) when plotted against the time interval between the age at initial presentation and our first evaluation. The slope of the linear regression line suggests a mean rate of progression of 1.4 ± 0.3 points per year after appearance of the presenting symptom (). Because the neurological onset is insidious and often difficult to accurately determine retrospectively, for we defined the onset of the presenting symptom () as time zero. Four of the patients had total scores less than or equal to five. These signs and symptoms give an indication of the earliest clinical neurological manifestations of this disorder. Eye movement, hearing, speech, and ABR abnormalities were noted in three of the four patients. The eye movement abnormality was only apparent to the parents in one of the cases. Hearing deficits were confined to high frequency hearing loss, and did not cause functional impairment. One of these low scoring patients had mild deficits in cognition and memory. In this cohort, seven patients were being treated off-label with miglustat at the time of their initial evaluation. No obvious clustering was apparent (), and the mean rate of progression (1.4 ± 0.3) was not significantly altered when patients on miglustat were excluded from the analysis.
Figure 1 NPC clinical progression. A) Clinical severity scores for the current cohort as a function of age. B) The change in the clinical severity score between onset of symptoms and the first NIH evaluation. Patients on off-label miglustat use are indicated by (more ...)
This clinical progression scale was also applied to a chart review of 19 NPC patients. Age at initial evaluation ranged from age 2 years to age 38 years with a mean and median age of 14.7 and 14.0 years, respectively. The male:female ratio was 12:7. Severity scores versus age for individual patients are depicted in . The initial score for these patients corresponds to the initial NIH evaluation. The majority of these patients were manifesting neurological symptoms by the time they were referred to the NIH. Interestingly, once symptoms appear, the rate of progression appears to be independent of age of onset (p=0.44, r2=0.04) and remarkably similar across patients (). The progression slope for individual patients ranged from 0.8 to 5.1 with a mean slope of 1.9 ± 0.2 points per year. Excluding the single patient with very rapid progression (greater than 3 standard deviations above the mean) yields a mean progression slope of 1.7 ± 0.1 points per year.
shows the proportion of the total score that each domain contributes for both the current and historical cohort. Data from the historical cohort were divided into early (0–5 years after onset) and late (≥6 years after onset). The contribution of each domain to the total score is similar in both cohorts and no major difference was observed comparing early and late scores. We next analyzed the average severity scores from both cohorts to determine the degree of correlation between the total score and the individual domains. Although there was a statistically significant relationship between age and the total score (p=0.006), the correlation coefficient was not as high (r2=0.44) as seen with other variables. In addition, age correlated relatively poorly (r2<0.6) with the individual domains. Significant correlations were observed between the total score and all major domains except hearing. The strongest correlations (r2>0.8) with the total score were with swallowing (0.90), ambulation (0.83), memory (0.83), and cognition (0.82). Between individual components, strong correlations (r2>0.8) were only observed between ambulation and both fine motor (0.85) and swallowing (0.83). Inter-rater reliability was analyzed by determination of Cronbach’s α and Cohen’s κ. For three independent raters, Cronbach’s α was 0.845 (95% CI=0.735–0.897), 0.844 (95% CI=0.729–0.893), and 0.850 (95% CI=0.760–0.892), and the global Cronbach’s α, calculated by combining all the measures from the three raters, was 0.846 (95% CI=0.798–0.877). It is generally accepted that Cronbach’s α values over 0.70 indicate acceptable sensitivity and validity of a scale. Using the total score measured by each rater, the weighted Cohen’s κ coefficient showed a significant agreement between raters (κ=0.888, 95% CI=0.802–0.975, p<0.0001).
To model the variation of the total score per individual over time as a function of age, we combined data from both cohorts () and tested different linear mixed models using Likelihood Ratio Test (LRT). A random intercept, random shape model with no within-individual correlation best fit the data with the population progression curve described by the following equation: Ŝ=−10.7+1.87(age). The standard error of the slope is ± 0.18, and the 95% confidence interval for the slope is 1.52 to 2.23. For a given subject, future scores can be predicted by the following equation: Ŝt0+x =Ŝt0 + 1.87x; where Ŝt0 is the initial score and Ŝt0+x is the predicted future score after x years.
Figure 2 Statistical modeling. To model phenotypic progression in NPC, data from all patients was combined. Patients ranged in age from 2 to 51 years (mean=18.6, SD=11.5), number of visits ranged from 1 to 8 (mean=3.4, SD=2.1), and the total scores ranged from (more ...)