A total of 102 individuals meeting criteria for RIS were identified. Longitudinal clinical data were available on 93 subjects. Cervical spine MRI scans acquired prior to the development of the first clinical event in subjects with RIS were available in 71 of these cases. Thoracic MRI scans were acquired on 17 subjects. Some subjects with RIS were excluded from this analysis due to either the lack of a cervical spine MRI study (n = 17) or a cervical imaging study acquired after the onset of clinical symptoms (n = 5). The demographics of the excluded subjects without presymptomatic cervical spine MRI studies were not significantly different from the study cohort (data not shown). summarizes the demographic data of the study cohort.
Demographics of subjects with RIS with cervical spine MRI
The reasons for brain MRI were highly varied (). The majority of the cases underwent brain MRI for evaluation of headache. A brain MRI scan was the initial neuroimaging study acquired with the exception of 3 cases in which CT imaging of the head was performed following a traumatic event, revealing brain parenchymal anomalies prior to the acquisition of brain MRI sequences. Cervical spinal cord imaging was acquired on one patient prior to the brain MRI during the evaluation of a congenital cervical rib. Overall, the reasons for acquiring a cervical spine MRI evaluation were nonuniform, with data acquired at the discretion of the referring physician or MS specialist providing longitudinal care. Cervical spine MRI scans were acquired shortly after RIS identification (median time 0.34 years [IQR 0.0–7.8]) during the medical workup for demyelinating disease, or as a baseline measure of disease during longitudinal care.
Cervical spinal cord anomalies highly suggestive of demyelination were discovered on imaging prior to clinical progression in 25 (35%) of the 71 subjects. Gadolinium-enhancing lesions were observed in 6 cases. Of the thoracic MRI studies performed, 6 of 17 demonstrated abnormalities suggestive of demyelination (5 of the 6 cases with concomitant cervical spine lesions). Clinical progression to a diagnosis of CIS or PPMS was observed in 21 of these 25 subjects (84%) over a median time of 1.6 years (IQR 0.8–3.8). This clinical conversion time was reduced to 1 year (IQR 0.25–3.55) when evaluating the time interval from the cervical spine imaging study to the first clinical event. The most common clinical event for these subjects was localized to the spinal cord, long tract motor, or long tract sensory pathways (n = 15) followed by involvement of the brainstem (n = 4) and optic nerve (n = 2). Prior to the development of the initial neurologic event, no focal deficits were identified on the neurologic examination. Of the subjects who progressed clinically, 2 demonstrated a progressive subtype and subsequently met criteria for PPMS.
Clinical progression to an acute event was observed in 3 (brainstem [n = 2], optic nerve [n = 1]) of the 46 subjects who did not possess an abnormality within the cervical spinal cord. summarizes the clinical outcomes from subjects with RIS with cervical spine MRI data.
Summary of clinical and radiologic characteristics of subjects with RIS with MRI cervical spine data
Of the subjects with RIS with cervical spine lesions who progressed clinically, 19% were referred to our Center after the first clinical episode. Of the 3 individuals who progressed clinically but lacked involvement of the cervical spine, all subjects developed an initial event while being actively followed in our Center.
The diagnostic predictive value of an asymptomatic spinal cord lesion in subjects with RIS for development of the first clinical relapse or progression to a diagnosis of PPMS was determined with a sensitivity of 87.5% (95% CI 67.6–97.3), specificity of 91.5% (79.6–97.6), and positive predictive value of 84.0%. A substantial increase in the odds of clinical progression was observed (OR 75.3 [16.1–350.0]; p < 0.0001, 2-tailed Fisher exact test) in those subjects with RIS who possessed one or more lesions within the cervical spine ().
Predictive utility of an asymptomatic spinal cord lesion for clinical conversion to clinically isolated syndrome or primary progressive MS
Next, a multivariate regression model was used to assess the relative influences of several baseline covariates on the clinical outcome (). In the multivariate logistic regression model, a substantial increase in the odds of clinical progression was observed when abnormalities typical for MS were present within the cervical spinal cord (OR 128.0, 95% CI 13.0–1256.5, p < 0.0001), whereas the presence of a lesion within the brainstem or posterior fossa involvement was moderate (OR 9.2 [1.1–75.2], p = 0.04). The association of age with progression also appeared to be important; for every 10-year increase in age, the odds of converting clinically were reduced (OR 0.38 [0.15–0.97]; p = 0.04).
Multivariate logistic regression model evaluating the impact of significant covariates on clinical conversion to CIS or PPMS
PPMS subtypes were identified in a total of 3 cases; however, only 2 (61-year-old man and 66-year-old woman) were incorporated into the data analysis. The third case involved a 41-year-old man, initially imaged (brain scan) following a spell who subsequently developed progressive unilateral leg weakness persisting over 12 months approximately 2 years after RIS identification. A spinal cord MRI scan was acquired after the report of progressive leg weakness revealing 3 nonenhancing foci throughout the cervical spine. His case was removed from the data analysis because the cervical imaging study was acquired after the onset of a clinical symptom. In both PPMS cases, formal criteria for PPMS were met.10
When a sensitivity analysis was performed with progressive subtypes removed, no significant changes in the outcomes were observed.