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Ruling out mimics of MS:

Standard tests obtained when ruling out mimics of MS:

       ANA, ESR, Lyme titer, ACE level, CXR, B12, folate

Additional tests to be considered in atypical cases:

  • Urine/blood for biochemical studies, including levels of:
    • WBC arylsulfatase A (yellow top, Mayo Clinic Genetics Lab) (MLD) #1
    • Very long chain fatty acids (green top, Mayo Clinic Genetics Lab and Athena) (ALD and AMN) #2
    • Fasting Blood lactate, Quantitative plasma amino acid and Urine organic acid analyses (MELAS) #3
    • Hexosaminidase A (Tay Sachs)
    • Galactocerebrosidase C (Gal-C) (Krabbe)
    • Palmitoyl protein thioesterase 1 (adults), tripeptidyl peptidase 1, CLN3, and CLN5 (NCL)
    • NPC-1 (Niemann Pick)
  • Additional: buccal or rectal mucosa biopsy for electron microscopy (if NCL suspected), skin biopsy for fibroblast cultures (enzyme assays), or peripheral blood smear (vacuolated monocytes in NCL); referral to specialized clinic
  • HIV test
  • Vasculitis w/u:
    • Pathergy skin test (Behcet’s) -> Dermatology Referral
    • Skin biopsy if suspicious rash present -> Dermatology Referral
    • Rheumatology Referral
  • Lumbar puncture, Evoked potentials, EMG/NCVs (if neuropathy or myopathy suspected)
  • Brain biopsy (rarely needed): fingerprint profiles, curvilinear and rectilinear bodies by E.M. in NCL oligodendrocytes; diffuse white matter gliosis by light microscopy in NCL; helpful in systemic histiocytosis and Whipple disease, lymphoma
  • Notch3 mutations in CADASIL, ACE levels in sarcoidosis

Management of Initial Demyelinating Episode


  1. Episode should be typical of MS: optic neuropathy, ascending sensory loss, brainstem attack, hemiparesis, hemisensory loss. There should be no reasonable alternate explanation such as migraine, stroke, Lyme, LE, etc.
  2. Episode should be clearly and obviously focal within the CNS
  3. No prior episode of CNS dysfunction (if so, consider MS as diagnosis)
  4. Symptoms and signs should stabilize, or have stabilized, or improved, with or without steroid treatment


  1. MRI should be categorized as
    • Typical of MS
    • Possible demyelinating disease, or inconclusive for MS
    • Normal
  2. Typical of MS includes: (based on Barkhof 1997 and McDonald 2001)
    • –9 or more T2 hyper intense lesions
    • –1 or more Gd enhancing lesions
    • –3 or more lesions that are ovoid, fingers, or oriented perpendicular to ventricle
    • –1 or more infratentorial lesions especially of MCP
    • –1 or more spinal cord lesions, especially if ovoid, non space taking, and not opposite areas of spondylosis

Typical must satisfy 3 of these 5 criteria.

  1. Inconclusive includes:
    • Fewer than 9 lesions
    • Smaller, scattered lesions not near ventricle and not ovoid
    • Atypical large, or space taking lesions
    • Diffuse white matter hyper intensity
    • Any indication of infarction elsewhere in brain.
  2. Normal means normal
    • Should include all relevant parts of brain and spinal cord.

Spinal Fluid

  • If done. Protein less than 80 mg.%. Cells less than 50 predominantly lymphocytes.
  • OGB’s or elevated IgG index can make MRI criteria less stringent:
    • If present, only 2 of 5 criteria need be met.


  1. Steroids for significant disability. EDSS over 2, acuity less than 20/60, or AI over 2. 3 days minimum, 5 days standard.
  2. ABC drugs: one of two courses of action should be chosen:
    • A. Delay if diagnosis of MS not established:
      • Episode atypical
      • MRI criteria not met
      • Alternate explanation of deficit
    • B. Begin if data:
      • Meet criteria for MS
      • Indicate high likelihood of MS (per CHAMPS). Choice of this course of action would be based on clinical judgment, and might be chosen because of:
      • Strong family history of MS
      • Marked deficit at time of presentation
      • Marked clinical/MRI correlation (e.g. myelopathic symptoms with LhermitteÕs and cervical cord lesion by MRI)/
      • If course A is chosen, planned monitoring consisting of exam and repeat MRI every 4 months.
      • Choice of ABC drug would reflect clinician and patient preference.
      • Planned monitoring to assess treatment effectiveness including exam and periodic MRI.

Deviations from Guideline

Exceptions may occur because of:

  • Age (young or old) – for Pediatric MS patients see Partners Pediatric MS Center
  • Pregnancy or planned pregnancy
  • Severe deficit (i.e. tending toward more aggressive treatment)
  • Inconvenient travel

Partners MS Center Practice Guidelines for administration of Beta-interferons

  • CBC with diff, LFTs at baseline, 3, 6 months then q6 months thereafter
  • Yearly TSH
  • If LFTs less than 2 times normal: Repeat in 1 month.  If LFTs trending upward beyond 2 times normal: Halve medication dose and repeat labs in 1 month
  • If LFTs continue to trend upward at ½ dose: Discontinue medication and rechallenge once levels are close to normal
  • Titration option for Avonex: 2 weeks at 15 mcg then increase to 30 mcg
  • If WBC 3000-4000, recheck in one month.  If WBC<3 halve dose or discontinue for one month.  If leucopenia persists consider switch to a different medicine.

Guidelines for assessment of disease activity and therapeutic decisions for patients on disease modifying therapy (interferon/glatimer acetate)

Definition of disease activity: Patient must have been on medication for 6 months at least

  1. Attacks: any objectively documented attack, including optic neuritis, motor, cerebellar, or spinal cord attack
  2. Progression: worsening on EDSS, AI, or any change in FSS if patient is at EDSS > 6.0
  3. MRI: presence of 1 or more GD+ lesions, increase in number (volume) of T2 lesions even in the absence of clinical changes.

Treatment options if persistent disease activity

  1. Add methylprednisolone boosters for 6 months, then repeat MRI
  2. Switch to Rebif, Betaseron, or double dose Avonex, repeat MRI in 6 months
  3. Cytoxan, Novantrone, or Methotrexate
  4. No change in therapy, repeat MRI in 6 months
  1. Add methylprednisolone boosters for 6 months, then repeat MRI
  2. Cytoxan, Novantrone, or Methotrexate
  3. No change in therapy, repeat MRI in 6 months
  1. Switch to Avonex or Betaseron
  2. Add methylprednisolone boosters for 6 months, then repeat MRI
  3. Cytoxan, Novantrone, or Methotrexate
  4. No change in therapy, repeat MRI in 6 months
  1. Add methylprednisolone boosters for 6 months, then repeat MRI
  2. Cytoxan, Novantrone, or Methotrexate
  3. No change in therapy, repeat MRI in 6 months

Is there any place for obtaining anti-interferon neutralizing antibody levels?

  1. The levels need to be repeated in 2 months
  2. If patient is being considered for a switch from one interferon to another interferon formulation, antibody levels should be obtained.
  3. If patient has evidence of failure, the therapy needs to be altered anyway and is not to receive another interferon, no need to check antibody levels.

Use of cyclophosphamide in treatment failures on interferon / glatimer acetate.

  • Patients are treated with cyclophosphamide/methylprednisolone (CTX/MP) monthly for the first year, every 6 weeks in the second year and every 2 months in the third year.
  • MRI is performed prior to initiation of therapy and at yearly intervals at the time when the frequency of treatments is being tapered. If MRI shows activity the tapering schedule may be altered.
  • Patients are taken off their inject able therapy when receiving CTX/MP (? after they have reached the appropriate CTX dose). Inject able therapy is restarted 6 months prior to discontinuation of CTX/MP.
  • In some instances, the physician/patient may elect longer or shorter treatment periods. Unless there are issues of toxicity or tolerability, minimum therapy is monthly for 1 year. If treatment is for only 2 years, tapering begins in the second year (every 6 weeks for 6 months, then every 2 months for 6 months). If treatment is given beyond 3 years, tapering continues and CTX/MP given every 10 weeks (4th year) and at every 12 weeks (5th year).


  • Interferons are considered Category C and Copaxone category B
  • If disease stable:
    • discontinue Avonex/Betaseron 1-2 months before attempting pregnancy,
    • Methyl boosters and Copaxone may be continued up the time of pregnancy
  • If disease unstable (Multiple attacks, new Gd+ lesions on MRI);
    • attempt to stabilize disease with change in meds, adding methyl boosters.
    • If disease continues to be active consider chemoÉdiscuss with patient options, if male sperm banking, if female embryo freezing, adoption.

When to restart therapy:

  • If breast feeding: stop breast feeding after 6 weeks and resume therapy
  • If not breast feeding: restart therapy within 1-2 weeks as practicable


  • Recommendation: BCP OK
  • Hormone replacement: encourage hormone replacement to prevent osteoporosis

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