Table 2.
The clinical and paraclinical biomarkers of conversion to secondary progressive multiple sclerosis (SPMS).
| Biomarkers of conversion | Measure | Pathophysiological | Advantages | Disadvantages | Evidence | |
|---|---|---|---|---|---|---|
| to SPMS | correlate | grade | ||||
| Clinical biomarkers | EDSS | 20 steps from 0 to 10 Relevant increase: ≥1 point when score is ≤ 5.5, ≥0.5 when score is ≥6.0 |
Neuroaxonal damage, primarily spinal | Easily accessible Time efficient |
Depends on walking ability Does not reflect cognition Lacks inter- and intrarater reliability |
High |
| MSFC | Time to walk 25 feet (T25FW) and put nine pegs in and out of a box with holes (9HPT), number of correct out of 60 possible answers (PASAT) Relevant change: ≥20% in MSFC subscores |
Neuroaxonal damage, primarily cerebral | Easily accessible Evaluates measures not included in EDSS |
PASAT less sensitive to detect cognitive worsening 9HPT and PASAT demonstrate practice effect |
High | |
| SDMT | Number of correct substitutions within a 90 s interval (maximum 110) Relevant change: ≥4 points or ≥10% |
Neuroaxonal damage, primarily cortical and subcortical | Time efficient Easy to administer Change sensitive Independent of language |
Practice effect | High | |
| Visual function | Number of correctly identified letters (LCLA chart) Relevant change: ≥7 letters loss |
Neuroaxonal damage in anterior visual pathway | Time efficient | Requires a retroilluminated cabinet or a standardized room | Low | |
| Olfactory function | Number of correctly discriminated (D) and identified (I) odors DI-score of maximum 32 points Relevant change: ≥2 points |
Neuroaxonal damage in olfaction-related brain regions | Time efficient Easy to administer Easily accessible |
Multiple external confounders (smoking, hunger state, upper respiratory tract infection, corticosteroids) | Low | |
| MRI | Brain atrophy | Global and regional cortical and subcortical atrophy Relevant change: ≥0.4% per year |
Neuroaxonal damage, cerebral | Highly reproducible | Pseudoatrophy effect Dependent on confounding factors (hydration, diurnal fluctuations, lifestyle, comorbidities) Technical limitations (heterogenous acquisition protocol, scanner variability) |
Moderate |
| SELs | Number of iron rim lesions Relevant change: not known |
Chronic demyelination, leading to neuroaxonal damage |
In vivo assessment of chronic demyelination Highly reproducible |
Technical limitations | Low | |
| Spinal cord atrophy | Cervical spinal cord average CSA Relevant change: not known |
Neuroaxonal damage, spinal cord | Higher rate of change compared to brain atrophy | Anatomical (high mobility, low dimensions) and imaging (low tissue contrast) limitations High impact of lesions on measurements |
Moderate | |
| OCT | pRNFL | Thickness in μm Relevant change: >1.5 μm |
Axonal degeneration, antero- and retrograde | Non-invasive Easily accessible Highly reproducible |
Prone to confounding from optic neuritis | Moderate |
| GCIPL | Thickness in μm Relevant change: >1.0 μm |
Neuronal degeneration | Faster detection of damage, larger range of change and less prone to confounding from optic neuritis (compared to pRNFL) Higher sensitivity (compared to brain atrophy) |
Requires rigorous quality control for image quality and segmentation | Moderate | |
| Biomarkers in blood and CSF | Nf | Nf levels in serum and/or CSF Relevant change: not known |
Neuroaxonal degeneration | Blood: Quick and easy collection Easily available for repeated measurement |
CSF: invasive, low availability for repeated measurement low accessibility of Simoa | Moderate |
| GFAP | GFAP levels in serum and/or CSF Relevant change: not known |
Reactive astrogliosis | Low | |||
| sTREM2 | sTREM2 levels in serum and/or CSF Relevant change: not known |
Microglial activation | Low | |||
| CHI3L1 | CHI3L1 levels in serum and/or CSF Relevant change: not known |
Reactive astrogliosis | Low | |||
CHI3L1, chitinase 3-like 1; CSA, cross-sectional area; CSF, cerebrospinal fluid; EDSS, Expanded Disability Status Scale; GFAP, glial fibrillary acidic protein; LCLA, low-contrast letter acuity; mGCIPL, macular ganglion cell-inner plexiform layer; MRI, magnetic resonance imaging; MSFC, Multiple Sclerosis Functional Composite; Nf, neurofilament; OCT, optical coherence tomography; ON, optic neuritis; PASAT, Paced Auditory Serial Addition Test; pRNFL, peripapill ary retinal nerve fiber layer; SDMT, Symbol Digit Modalities Test; SELs, slowly expanding lesions; sTREM2, soluble triggering receptor 2; T25FW, Timed 25-Foot Walk Test; 9HPT, 9-Hole Peg Test.