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Axonal damage accumulates in the progressive phase of multiple sclerosis: three year follow up study
  1. A Petzold1,
  2. M J Eikelenboom2,
  3. G Keir1,
  4. D Grant1,
  5. R H C Lazeron2,
  6. C H Polman2,
  7. B M J Uitdehaag2,
  8. E J Thompson1,
  9. G Giovannoni1
  1. 1Institute of Neurology, Department of Neuroinflammation, London, UK
  2. 2Department of Neurology, VU Medical Center, Amsterdam, the Netherlands
  1. Correspondence to:
 A Petzold
 Institute of Neurology, Department of Neuroinflammation, Queen Square, London WC1N 3BG, UK;


Background: Neurofilament phosphoforms (Nf) are principal components of the axoskeleton released during axonal injury. Cerebrospinal fluid (CSF) levels of Nf phosphoforms might be useful surrogate markers for disability in multiple sclerosis (MS), aid in distinguishing clinical subtypes, and provide valuable prognostic information.

Method: Thirty four patients with MS were included in a three year follow up study along with 318 controls with other non-inflammatory neurological diseases. CSF levels of two Nf heavy chain (NfH) phosphoforms (NfHSMI35, NfHSMI34) were quantified at baseline and three year follow up using new ELISA techniques. Levels of NfH phosphoforms, the degree of phosphorylation (NfHSMI34:NfHSMI35 ratio), and changes in NfH levels between baseline and follow up (ΔNfH) were related to the clinical phenotype (RR or SP/PP), to three clinical scales (Kurtzke’s EDSS, ambulation index (AI), and nine hole peg test (9HPT)), and to progression of disability.

Results: A significantly higher proportion (59%) of patients with SP/PPMS experienced an increase in NfHSMI35 levels between baseline and follow up compared with those with RRMS (14%, p<0.05). CSF NfHSMI34 levels at baseline were higher in patients with SP/PP (11 pg/ml) compared with RR (7 pg/ml, p<0.05) and NfHSMI35 levels were higher at follow up in SP/PP (129 pg/ml) compared with levels below assay sensitivity in RR (p<0.05). NfHSMI35 correlated with the EDSS (rs = 0.54, p<0.01), the AI (rs = 0.42, p<0.05), and the 9HPT (rs = 0.59, p<0.01) at follow up.

Conclusion: The increase in NfH during the progressive phase of the disease together with the correlation of NfHSMI35 with all clinical scales at follow up suggests that cumulative axonal loss is responsible for sustained disability and that high NfHSMI35 levels are a poor prognostic sign.

  • 9HPT, nine hole PEG test
  • AI, ambulation index
  • BSP, brain specific proteins
  • CSF, cerebrospinal fluid
  • CTRL, control
  • EDSS, Expanded Disability Status Scale
  • ELISA, enzyme linked immunosorbent assay
  • IEF, isoelectric focusing
  • MS, multiple sclerosis
  • Nf, neurofilament
  • NfH, neurofilament heavy chain
  • NfHSMI34, NfH detected with SMI34 antibody
  • NfHSMI35, NfH detected with SMI35 antibody
  • NfL, neurofilament light chain
  • OND, other neurological diseases
  • PP, primary progressive
  • RR, relapsing remitting
  • SP, secondary progressive
  • neurofilament phosphoforms
  • multiple sclerosis
  • prognosis
  • disease subtype
  • disability
  • axonal injury

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  • This study was devised as part of a study into biomarkers for neurodegeneration supported by the Multiple Sclerosis Society of Great Britain and Northern Ireland (AP, GG), the BR Kirk Fund of the Institute of Neurology (AP, ET), and the Multiple Sclerosis Society of the Netherlands (JE).

  • Competing interests: none declared

  • During the review process of this paper a separate study on the cerebrospinal neurofilament phosphoforms (NfHSMI34 and NfHSMI35) was published by Lim ET, Grant D, Pashenkov M, et al. Cerebrospinal fluid levels of brain specific proteins in optic neuritis. Mult Scler 2004;:–5.

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