Results
See Figure 2 for study selection ( Page et al., 2021 ). The authors identified 964 records after duplicate removal. The authors reviewed 187 full texts after title and abstract screening and retained 17 articles for data extraction and critical appraisal.

Study design characteristics are summarized in Table S1 . Only two studies prospectively followed participants from symptom presentation to diagnosis ( Beer, Rösler & Hess, 1995 ; Ravnborg et al., 1992 ) and most used retrospective, case-control designs. No study followed participants with relapsing MS (RMS) to onset of secondary-progressive MS (SPMS); however, four studies cross-sectionally compared RMS to primary-progressive MS (PPMS) or SPMS ( Facchetti et al., 1997 ; Leocani et al., 2006 ; Schmierer et al., 2002 ; Tataroglu et al., 2003 ). One study followed persons with active vs inactive RMS ( Caramia et al., 2004 ). A total of 10 studies tested for subclinical lesions in participants without clinical motor findings ( Beer, Rösler & Hess, 1995 ; Cruz-Martínez et al., 2000 ; Hess et al., 1987 ; Jung et al., 2006 ; Kale et al., 2009 ; Kandler et al., 1991 ; Magistris et al., 1999 ; Mayr et al., 1991 ; Ravnborg et al., 1992 ; Tataroglu et al., 2003 ). Two studies included comparison groups with diseases other than MS ( Beer, Rösler & Hess, 1995 ; Magistris et al., 1999 ).

MS participant characteristics are detailed in Table 3 , while control group characteristics are summarized in Table S2 . Across all studies, there were 1408 MS participants (median n = 79, range = 44–162) and 690 control participants (median n = 34, range = 10–155). Few studies matched MS and comparison groups for age or sex. Most studies used the Poser criteria to diagnose MS ( Poser et al., 1983 ), whereas no study employed the 2017 McDonald criteria ( Thompson et al., 2018 ). Average disease or symptom duration ranged from 1–10 years (median 4.6 years). Median disability score, measured using the Expanded Disability Status Scale (EDSS) ( Kurtzke, 1983 ) was 2.5 (range 1.5–6).

Notes:

Age and disease duration are reported in years. Continuous data are expressed as median (range) or mean ± standard deviation. DMT, disease modifying therapy; EDSS, Expanded Disability Status Scale; MS, multiple sclerosis; NR, not reported; PPMS, primary progressive multiple sclerosis; PrMS, progressive MS; SPMS, secondary progressive MS.

Table 4 and Figure 3 summarize diagnostic accuracy findings of all TMS techniques studied. Table S3 highlights TMS methods and Table S4 provides an in-depth summary of TMS findings. Every study reported the sensitivity of the TMS techniques employed. Specificity and DOR could be gleaned from only eight studies ( Beer, Rösler & Hess, 1995 ; Cruz-Martínez et al., 2000 ; Hess et al., 1987 ; Magistris et al., 1999 ; Mayr et al., 1991 ; Ravnborg et al., 1992 ; Schmierer et al., 2000 ; Tataroglu et al., 2003 ). Only central motor conduction time (CMCT) and MEP size (amplitude or area) were investigated by at least half of the studies reviewed. Therefore, only these techniques are discussed in detail below.

Notes:

EDSS, Expanded Disability Status Scale; MRI, magnetic resonance imaging; NR, not reported; PPMS, primary progressive multiple sclerosis; RMS, relapsing multiple sclerosis; SPMS, secondary progressive multiple sclerosis; TN, true negative; TP, true positive. *, 95% CI of diagnostic odds ratio (DOR) crossed zero, suggesting no change in odds of MS. 1 -- , DOR < 1 indicated decreased odds of MS.

CMCT. Diagnostic accuracy findings for CMCT are summarized in Table 4 and Figure 3 . CMCT was the most frequently studied TMS technique, in 16 studies ( Beer, Rösler & Hess, 1995 ; Caramia et al., 2004 ; Cruz-Martínez et al., 2000 ; Facchetti et al., 1997 ; Hess et al., 1987 ; Jung et al., 2006 ; Kale et al., 2009 ; Kale, Agaoglu & Tanik, 2010 ; Kandler et al., 1991 ; Leocani et al., 2006 ; Magistris et al., 1999 ; Mayr et al., 1991 ; Ravnborg et al., 1992 ; Schmierer et al., 2002 , 2000 ; Tataroglu et al., 2003 ). For RMS, sensitivity was greatest when upper and lower limbs were combined (median 76%, range 68–83%). Lower extremity CMCT was most specific for RMS (median 100%, range 100–100%), and was associated with the greatest odds of diagnosis (median DOR 39.17, range 22.15–135.00).

CMCT had poor sensitivity for subclinical lesions (median 19%, range 6–59%), but was up to 96% specific. CMCT tended to be more sensitive for both PPMS (median 72%, range 37–92%) and SPMS (median 96%, range 93–100%) than RMS (median 50%, range 30–63%) in head-to-head comparisons. In participants with RMS, CMCT had negligible sensitivity for detecting the onset of new disease activity ( Caramia et al., 2004 ), but normalization of CMCT was 75% sensitive for the recovery from active to inactive disease ( Cruz-Martínez et al., 2000 ).

MEP size. Diagnostic accuracy findings for MEPs are summarized in Table 4 and Figure 3 . MEP size (amplitude or area) was the second-most frequently studied TMS technique, in nine studies ( Cruz-Martínez et al., 2000 ; Hess et al., 1987 ; Kale et al., 2009 ; Kale, Agaoglu & Tanik, 2010 ; Kandler et al., 1991 ; Mayr et al., 1991 ; Ravnborg et al., 1992 ; Schmierer et al., 2000 ; Tataroglu et al., 2003 ). Like CMCT, combined findings from upper and lower extremities yielded the highest sensitivity for RMS (median 58%, range 50–66%). When examined separately, the upper and lower extremities were most specific for RMS (median 100%, range 100–100%), compared to combined upper and lower extremities (median 90%, range 86–94%). However, DOR was greatest for combined upper and lower extremities (median 16.78, range 6.00–27.55). MEP size was poorly sensitive for subclinical lesions (median 29%, range 15–67%) and was not examined in relation to PPMS or SPMS, nor in active vs inactive RMS.

Associations between TMS and disease-related outcomes. Table 4 summarizes associations between TMS techniques and disease-related outcomes. Both CMCT and MEP were correlated with cerebellar function ( Cruz-Martínez et al., 2000 ; Hess et al., 1987 ; Leocani et al., 2006 ; Tataroglu et al., 2003 ). CMCT and MEP size were associated with pyramidal function in some studies ( Cruz-Martínez et al., 2000 ; Hess et al., 1987 ; Jung et al., 2006 ; Kandler et al., 1991 ; Leocani et al., 2006 ; Magistris et al., 1999 ; Mayr et al., 1991 ), but not others ( Facchetti et al., 1997 ; Mayr et al., 1991 ; Ravnborg et al., 1992 ). TMS outcomes were not related to other functional systems ( i.e ., brainstem, sensory, visual, cerebral, bowel-bladder) ( Hess et al., 1987 ; Tataroglu et al., 2003 ). EDSS was significantly associated with both CMCT and MEP size ( Cruz-Martínez et al., 2000 ; Facchetti et al., 1997 ; Kale et al., 2009 ; Kale, Agaoglu & Tanik, 2010 ; Leocani et al., 2006 ; Pisa et al., 2020 ; Schmierer et al., 2002 ). Lastly, CMCT and MEP size were modestly associated with corpus callosum atrophy, total lesion burden, and corticospinal tract lesions some studies ( Cruz-Martínez et al., 2000 ; Kale, Agaoglu & Tanik, 2010 ; Ravnborg et al., 1992 ), but not others ( Facchetti et al., 1997 ; Schmierer et al., 2000 ).

See Table 5 for a condensed summary of overall risk of bias findings and Table S5 for more detailed results. Only two studies had low risk of bias ( Beer, Rösler & Hess, 1995 ; Ravnborg et al., 1992 ), whereas the remainder had either unclear or high risk of bias. The principal source of bias was participant selection, resulting in high risk of bias in 12 studies ( Facchetti et al., 1997 ; Hess et al., 1987 ; Jung et al., 2006 ; Kale et al., 2009 ; Kale, Agaoglu & Tanik, 2010 ; Kandler et al., 1991 ; Leocani et al., 2006 ; Mayr et al., 1991 ; Pisa et al., 2020 ; Schmierer et al., 2002 , 2000 ; Tataroglu et al., 2003 ), 10 of which did not avoid a case-control design ( Facchetti et al., 1997 ; Hess et al., 1987 ; Jung et al., 2006 ; Kale et al., 2009 ; Kale, Agaoglu & Tanik, 2010 ; Kandler et al., 1991 ; Mayr et al., 1991 ; Pisa et al., 2020 ; Schmierer et al., 2000 ; Tataroglu et al., 2003 ).

Note:

H, high; L, low; U, unclear. See ref: ( Whiting et al., 2011 ).

See Table 6 for a condensed summary of biomarker assessment findings and Table S6 for more detailed results. No study demonstrated sufficient validity for TMS biomarker use ( Bielekova & Martin, 2004 ). Specifically, no study supported TMS use in epidemiologic research. Nearly all studies both failed to provide raw or participant-level data, and failed to either establish or adequately report sensitivity and/or specificity ( Beer, Rösler & Hess, 1995 ; Caramia et al., 2004 ; Cruz-Martínez et al., 2000 ; Facchetti et al., 1997 ; Hess et al., 1987 ; Jung et al., 2006 ; Kale et al., 2009 ; Kale, Agaoglu & Tanik, 2010 ; Kandler et al., 1991 ; Leocani et al., 2006 ; Magistris et al., 1999 ; Mayr et al., 1991 ; Pisa et al., 2020 ; Ravnborg et al., 1992 ; Schmierer et al., 2002 , 2000 ; Tataroglu et al., 2003 ). Twelve studies did not address the reliability of TMS techniques ( Beer, Rösler & Hess, 1995 ; Cruz-Martínez et al., 2000 ; Facchetti et al., 1997 ; Jung et al., 2006 ; Kale et al., 2009 ; Kale, Agaoglu & Tanik, 2010 ; Kandler et al., 1991 ; Mayr et al., 1991 ; Pisa et al., 2020 ; Ravnborg et al., 1992 ; Schmierer et al., 2000 ; Tataroglu et al., 2003 ). However, despite the above shortcomings, nearly all studies justified disease process-specific biological rationale for TMS to investigate MS, namely the ability to characterize demyelination and/or axonal damage.

Note:

H, high; L, low; N, no; U, uncertain. See ref: ( Bielekova & Martin, 2004 ).