Treatment of Specific Impairments in Multiple Sclerosis

The references listed below are used in this DynaMed topic primarily to support background information and for guidance where evidence summaries are not felt to be necessary. Most references are incorporated within the text along with the evidence summaries.

1. National Institute for Health and Care Excellence (NICE). Multiple sclerosis in adults: Management. NICE 2022 Jun:NG220PDF.
2. National Institute for Health and Care Excellence (NICE). Neuropathic pain - pharmacological management: The pharmacological management of neuropathic pain in adults in non-specialist settings. NICE 2014 CG173PDF, updated 2022 Sep .

• European Federation of Neurological Sciences (EFNS) rating of recommendations
  • level of evidence
    • Level A rating - established as effective, ineffective, or harmful; requires ≥ 1 convincing class I study or ≥ 2 consistent, convincing class II studies
    • Level B rating - probably effective, ineffective, or harmful; requires ≥ 1 convincing class II study or overwhelming class III evidence
    • Level C rating - possibly effective, ineffective, or harmful; requires ≥ 2 convincing class III studies
  • classification of evidence for therapeutic intervention
    • Class I - adequately powered prospective, randomized, controlled clinical trial with masked outcome assessment in representative population or adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations requiring
      • randomization concealment
      • clearly defined primary outcome(s)
      • clearly defined exclusion/inclusion criteria
      • adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
      • relevant baseline characteristics presented and substantially equivalent among treatment groups or appropriate statistical adjustment for differences
    • Class II - prospective matched-group cohort study in representative population with masked outcome assessment that meets criteria above or randomized, controlled trial in representative population that lacks 1 of above criteria
    • Class III - all other controlled trials (including well-defined natural history controls or patients serving as own controls) in representative population, where outcome assessment is independent of patient treatment
    • Class IV - evidence from uncontrolled studies, case series, case reports, or expert opinion
  • Reference - EFNS guideline on pharmacological treatment of neuropathic pain (Eur J Neurol 2010 Sep;17(9):1113)
• American Academy of Neurology (AAN) grading system for recommendations
  • levels of evidence
    • Level A
      • established as effective, ineffective, or harmful, or established as useful/predictive or not useful/predictive, for given condition in specified population
      • requires ≥ 2 consistent Class I studies, or (in exceptional cases) 1 convincing Class I study meeting all criteria with large magnitude of effect (relative rate of improved outcome > 5 with lower limit of confidence interval > 2)
    • Level B
      • probably effective, ineffective, or harmful, or probably useful/predictive or not useful/predictive, for given condition in specified population
      • requires ≥ 1 Class I study or ≥ 2 consistent Class II studies
    • Level C
      • possibly effective, ineffective, or harmful, or possibly useful/predictive or not useful/predictive, for given condition in specified population
      • requires ≥ 1 Class II study or ≥ 2 consistent Class III studies
    • Level U - data inadequate or conflicting; given current knowledge; treatment (test, predictor) is unproven
  • classifications of studies
    • Class I study
      • randomized, controlled clinical trial with masked or objective outcome assessment in a representative population
      • relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences
      • required criteria
        • a) concealed allocation
        • b) primary outcome(s) clearly defined
        • c) exclusion/inclusion criteria clearly defined
        • d) adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias
        • e) noninferiority or equivalence trial claiming to prove efficacy for 1 or both drugs also requires
          • authors explicitly state clinically meaningful difference to be excluded by defining threshold for equivalence or noninferiority
          • standard treatment used in study is substantially similar to that used in previous studies establishing efficacy of standard treatment (including mode of administration, dose, and dose adjustments for drugs)
          • inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of standard treatment
          • interpretation of results of study is based upon per-protocol analysis that takes into account dropouts or crossovers
    • Class II study
      • randomized controlled clinical trial of intervention of interest in representative population with masked or objective outcome assessment that lacks 1 criteria a-e above, or prospective matched cohort study with masked or objective outcome assessment in representative population that meets b-e above
      • relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences
    • Class III study - all other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (such as blood tests, administrative outcome data)
    • Class IV study - studies not meeting Class I, II, or III criteria including consensus or expert opinion
  • Reference - AAN guideline on complementary and alternative medicine in multiple sclerosis (AAN 2013 Dec PDF)

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