Comment on “Global N-Acetylaspartate Declines Even in Benign Multiple Sclerosis”

Published ahead of print on April 28, 2011
doi: 10.3174/ajnr.A2528

American Journal of Neuroradiology 32:E118, June-July 2011
© 2011 American Society of Neuroradiology

F. Aboul-Eneina
aDepartment of Neurology
SMZ-Ost Donauspital
Vienna, Austria

We have read with great interest the article “Global N-Acetylaspartate Declines Even in Benign Multiple Sclerosis” by Rigotti et al.1 It is generally accepted that axonal injury is the pathologic substrate for the symptoms and disability seen in patients with multiple sclerosis (MS), a supposed inflammatory central nervous system disease of unknown origin. The visualization of certainmetabolites such as N-acetylaspartate (NAA) may represent axonal loss, axonal integrity, or axonal function.

It remains completely unclear why each patient with MS follows his or her own individual disease course and why, until now, no marker could be established that may allow a reliable prediction.2 NAA levels vary even in healthy controls and decline with age. A supposed NAA decline per year, extrapolated by a mathematic model including only 1 NAA baseline measurement, disease duration, and so forth, could never replace a long-term follow-up study (as already mentioned by the authors). However, it is still very intensely discussed whether axonal injury does really exist in all patients with MS and, if so, whether axonal injury already occurs in the very early disease stages and progresses steadily and “clinically silently,” even when patients with MS remain clinically stable. That the NAA levels of 43 patients with relapsing-remitting MS (RRMS) with very benign disease courses, very low lesion load, and, in part, very long disease duration (range, 15–35 years) are that low is astonishing and should have been discussed in detail and compared with the different data published recently.36 Did the included patients with RRMS fulfill the Barkhof criteria and were oligoclonal bands detectable?


  1. Rigotti DJ, Gonen O, Grossman RI, et al. Global N-acetylaspartate declines even in benign multiple sclerosis.AJNR Am J Neuroradiol 2011;32:204–09[Abstract/Free Full Text]
  2. Gilmore CP, Cottrell DA, Scolding NJ, et al. A window of opportunity for no treatment in early multiple sclerosis?Mult Scler 2010;16:756–59[Free Full Text]
  3. Benedetti B, Rovaris M, Rocca MA, et al. In vivo evidence for stable neuroaxonal damage in the brain of patients with benign multiple sclerosisMult Scler 2009;15:789–94[Abstract/Free Full Text]
  4. Kirov II, Patil V, Babb JS, et al. MR spectroscopy indicates diffuse multiple sclerosis activity during remissionJ Neurol Neurosurg Psychiatry 2009;80:1330–36[Abstract/Free Full Text]
  5. Aboul-Enein F, Krssák M, Höftberger R, et al. Reduced NAA levels in the NAWM of patients with MS is a feature of progression: a study with quantitative magnetic resonance spectroscopy at 3 TeslaPLoS One2010;5:e11625[CrossRef][Medline]
  6. Aboul-Enein F, Krssák M, Höftberger R, et al. Diffuse white matter damage is absent in neuromyelitis opticaAJNR Am J Neuroradiol 2010;31:76–79[Abstract/Free Full Text]



Published ahead of print on April 28, 2011
doi: 10.3174/ajnr.A2561

American Journal of Neuroradiology 32:E119, June-July 2011
© 2011 American Society of Neuroradiology

O. Gonena
aDepartment of Radiology
New York University
New York, New York

We thank Dr Aboul-Enein for his comments. As Dr Aboul-Enein pointed out, the heterogeneity of the multiple sclerosis (MS) disease course in individual patients makes it an interesting problem that is, at the same time, also very difficult to study. This is due primarily to its decades-long course, especiallybecause other MR imaging markers have so far yielded mixed results in their long-range predictions.13 Our study was, therefore, predicated on the notion that neuronal damage has long been implicated as the main cause of MS damage (see Kornek and Lassmann for a review4) and that it may occur even before a confirmed clinical diagnosis of the disease.5,6

We were surprised, therefore, that our cohort of patients with MS, all of whom fulfilled the Barkhof criteria,7 have retained “clinical silence,” (ie, little to no decline during a long [≥15 years] disease duration) but have whole-brain N-acetylaspartate (WBNAA) indistinguishable from that projected from individualswith MS of a much shorter disease duration. The choice of a clinically benign cohort came to circumvent, in part, the need for a difficult long serial study by applying instead the argument that patients with MS who are “benign” after 15–35 years have always been so. Most surprising, the expectation that theirWBNAA would also be benign (ie, analogous to that of controls) was refuted; this result indicates that global neuronal sparing is, in fact, not a feature of this phenotype.

While we agree that there is no substitute for a lengthy follow-up, the observation that the cross-sectional amount of NAA loss depends on the disease duration supports (though does not prove) the notion that the decline in this marker in the benign population is indistinguishable from cross-sectional rates of patients with MS of much shorter disease duration and is substantially lower than that in healthy contemporaries. This finding suggests that fortuitous lesion location and efficient brain plasticity may be the 2 likely mechanisms that distinguish benign from nonbenign phenotypes. The implication of this likely conjecture is that this overall decrease in healthy neurons may eventually sap compensatory ability and/or that one or a few lesions in the spine or in eloquent regions may have precipitous consequences. This outcome is increasingly likely, specifically in light of the new research, mentioned in the original letter.8


  1. Agosta F, Rovaris M, Pagani E, et al. Magnetization transfer MRI metrics predict the accumulation of disability 8 years later in patients with multiple sclerosisBrain2006;129:2620–27[Abstract/Free Full Text]
  2. Rovaris M, Agosta F, Sormani MP, et al. Conventional and magnetization transfer MRI predictors of clinical multiple sclerosis evolution: a medium-term follow-up studyBrain 2003;126:2323–32. Epub 2003 Aug 2322[Abstract/Free Full Text]
  3. Fisniku LK, Brex PA, Altmann DR, et al. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosisBrain 2008;131:808–17[Abstract/Free Full Text]
  4. Kornek B, Lassmann H. Axonal pathology in multiple sclerosis: a historical noteBrain Pathol 1999;9:651–56[Medline]
  5. Rocca MA, Mezzapesa DM, Falini A, et al. Evidence for axonal pathology and adaptive cortical reorganization in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosisNeuroimage2003;18:847–55[CrossRef][Medline]
  6. Filippi M, Rovaris M, Inglese M, et al. Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trialLancet2004;364:1489–96[CrossRef][Medline]
  7. Barkhof F, Filippi M, Miller DH, et al. Comparison of MR imaging criteria at first presentation to predict conversion to clinically definite multiple sclerosisBrain 1997;120:2059–69[Abstract/Free Full Text]
  8. Kirov I, Patil V, Babb JS, et al. MR spectroscopy indicates diffuse multiple sclerosis activity during remissionJ Neurol Neurosurg Psychiatry 2009;80:1330–36[Abstract/Free Full Text]
Comment on “Global N-Acetylaspartate Declines Even in Benign Multiple Sclerosis”