JNNP: Spinal cord injury and gray matter atrophy independently predict the clinical deterioration of well-defined multiple sclerosis, a 5-year, multicenter study

Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative central nervous system (CNS) disease with heterogeneous evolution and clinical/radiographic features
.
Although the pathological feature of multiple sclerosis is the accumulation of local demyelinating lesions, neurodegeneration of the brain and spinal cord can also occur
.
Given the expanding treatment options for multiple sclerosis, more accurate identification of patients with poor clinical outcomes will help optimize patient management
.
Due to its sensitivity
to focal lesions (i.
e.
, demyelination) and atrophy (i.
e.
, neurodegeneration).
Longitudinal studies have shown that in patients with clinically isolated syndrome, the presence of T2 hyperintense lesions of the brain and spinal cord is associated
with long-term transformation into clinically clear MS and accumulation of disability.
In definitive multiple sclerosis, T2-weighted and T1-weighted MRI brain abnormalities were associated
with more severe disability at medium- and long-term follow-up.
Conversely, only a few studies have found that spinal cord injury predicts long-term disability
.

Brain atrophy is well known as multiple sclerosis
.
Gray matter (GM) loss is present at all stages, but is more severe in a progressive form that helps explain clinical disability
.
Available data suggest that whole-brain or GM volume loss is more predictive of subsequent disability accumulation
than other MRI measures such as lesion or white matter (WM) volume loss.
Importantly, this applies not only to whole-brain or GM volume assays such as deep GM or associated cortical regions/networks
.
Loss of spinal cord tissue, particularly in the cervical segment, occurs at a high rate in multiple sclerosis and is associated with
concurrent clinical disability.
Although there was a significant relationship between spinal cord tissue loss and short-term cumulative disability, this relationship disappeared after a longer clinical follow-up (more than 10 years), suggesting that spinal cord tissue loss may be critical for
clinical deterioration in the first few years of the disease.

Only a few MRI studies combined brain and spinal cord injuries to identify factors associated with MS exacerbations, providing inconclusive results, mainly because only a subset of variables (i.
e.
, injury or atrophy)
were analyzed.
In fact, over time, the exacerbation of clinical disability is associated
with focal lesions of the brain and cervical spinal cord and the loss of brain and spinal cord tissue.
From this perspective, a multiparameter assessment of focal demyelinating lesions and irreversible tissue loss may clarify the relative contribution
of different pathological processes to the progression of disability.
To address this, 5-year follow-up clinical data were prospectively collected from a multicenter cohort of patients diagnosed with multiple sclerosis who had previously participated in an MRI study characterized by cervical myeloid atrophy
at different stages of the disease.
The primary objective of this study was to assess the independent role
of brain and cervical cord injury in predicting interim clinical outcomes in this cohort.
This article was published in the Journal of Neurology, Neurosurgery & Psychiatry
.

367 patients with MS (326 relapsed, 41 with progressive seizures) and 179 healthy controls underwent 3.
0T brain and cervical medulla T2-weighted and three-dimensional T1-weighted MRI at
baseline.
Extended Disability Status Scale (EDSS) scores
were obtained at baseline and after a median follow-up of 5.
1 years (IQR = 4.
8–5.
2).
At follow-up, patients were classified as clinically stable/deteriorated
based on changes in EDSS.
Generalized linear mixed models identified predictors
of clinical deterioration, progression to secondary progressive (SP)MS, and EDSS=3.
0, 4.
0, and 6.
0 over 5 years.
Calculate brain T2 high-signal and T1 low-signal lesion volume (LV)
using the semi-automated methods included in Jim V.
7.
0 (Xinapse Systems, Colchester, UK).
Normal brain (NBV), cortical GM (NcGMV), deep GM (NDGMV), and WM volume (NWMV)
were calculated on lesions-filled 3D T1-weighted images using FSL SIENAX and FIRST.

At follow-up, 120/367 (33%) patients with MS had deteriorating clinical condition; 36/256 (14%) patients with relapse in remission evolved to SPMS
.
The baseline predictors of EDSS deterioration were progressive versus recurrent MS (standardized β(β) = 0.
97), higher EDSS (β=0.
41), higher number of spinal cord injuries (β=0.
41), lower normal cortical volume (β=−0.
15), and spinal cord area (β=−0.
28).

The older age (β=0.
86), the higher the EDSS value (β=1.
40), and the higher the number of spinal cord injuries (α=0.
87), independently predicted the SPMS conversion rate (C index = 0.
91).

The predictors of EDSS=3.
0 after 5 years were higher baseline EDSS (β=1.
49), higher number of spinal cord injuries (β=1.
02), and lower normal cortical volume (β=−0.
56) (C index = 0.
88).

Baseline age (β=0.
30), higher EDSS (β=2.
03), higher number of spinal cord injuries (β=0.
66), lower spinal cord area (β=−0.
41) predicted EDSS=4.
0 (C index = 0.
92).

Finally, higher baseline EDSS (β=1.
87) and number of spinal cord injuries (β=0.
54) predicted EDSS=6.
0 (C-index=0.
91).

Independent predictors of clinical disability in multivariate analyses

A combination of clinical, brain, and cervical MRI variables was found to predict clinically relevant neuroprognosis
at follow-up.
Notably, higher EDSS and higher numbers of spinal cord injuries independently predicted all neurological outcomes (i.
e.
, EDSS deterioration, SPMS evolution, EDSS milestones).

Multiparametric measurements of brain and spinal cord injury (injury and tissue loss) independently predicted 5-year disability deterioration
throughout the MS cohort and recurrent MS.
In addition, cortical volume loss correlated with EDSS=3.
0, and subspinal area was one of the determinants of
EDSS=4.
0.
Clinical deterioration was assessed by a 3-month confirmed change in EDSS scores, one of
the most widely used disability scales.
The evolution of SPMS was selected as a clinically relevant outcome
.
Finally, EDSS=3.
0, 4.
0, and 6.
0 indicate critical disability points of
disease exacerbation.
At 5 years of follow-up, 33% of patients had worsening disability and 14% of recurrent MS evolved into SPMS
.
It is worth noting that 30% of relapsed MS and 70% of progressive MS have clinical deterioration: these rates are consistent with previous studies and reflect the identification
of progressive versus recurrent MS as independent predictors of clinical exacerbations in multivariate analyses.
The importance of baseline EDSS scores for subsequent clinical outcomes is consistent
with several previous reports.

Overall, spinal cord injury and cortical volume reduction contributed to a lesser extent in predicting the 5-year clinical prognosis
of patients with multiple sclerosis.