ing the use and interpretation of fMRI recording in the presentstudy. First, the authors used binocular visual stimulation, al-though they analyzed separately the activation in each hemi-sphere. Second, Jenkins et al considered the LOC ipsilateral tothe affected eye as the “affected LOC.” However, it is wellknown that in the LOC there is a representation of the con-tralateral visual field of both eyes.2 Given the fact that a binoc-ular stimulation was used, it is not surprising that a weaker ac-tivation was seen in both LOCs (each receiving the contralateralinformation from both eyes). In addition, regarding this func-tional organization and contrary to what the authors did, theaffected LOC should be seen as that contralateral to the affectedeye, given the fact that each temporal (larger) visual fieldprojects to the contralateral hemisphere. Finally, the fact that theLOC activation at baseline is weaker among ON patients com-pared with controls could be seen more as a consequence ofvisual dysfunction at this time than a predictor of visual func-tion at 12 months. Although visual acuity is reported and takenas a measure of visual function, visual field integrity is not takeninto account and could easily explain a weaker LOC activity inON patients, and should thus be seen as a consequence morethan a cause of visual recovery.

Unite Fonctionnelle Vision et Cognition and TREAT VisionTeam, Adolphe de Rothschild Ophthalmological Foundationand National Center for Scientific Research, Paris, France

Potential Conflicts of InterestNothing to report.

References1. Jenkins et al. Neuroplasticity predicts outcome of optic neuritis

independent of tissue damage. Ann Neurol 2010;67:99–113.

2. Larsson J, Heeger DJ. Two retinotopic visual areas in humanlateral occipital cortex. J Neurosci 2006;26:13128–13142.

DOI: 10.1002/ana.21988

ReplyThomas Jenkins, MB, ChB

We thank Dr Chokron for the points she raises regarding ourfunctional magnetic resonance imaging (fMRI) study of acuteoptic neuritis (ON),1 in which evidence for early neuroplasticreorganization in the lateral occipital complexes (LOCs) is pre-sented, and will respond to each in turn.

First, she suggests that we used binocular visual stimula-tion. In fact, we used planofilter (red/green anaglyph) spectacles,which allow dichoptic stimulation. Although not without limi-tations, this technique is well recognized.2,3 The presentationwas manipulated to provide monocular stimulation. Alternatingred/green checkerboard stimuli were presented, so that eachcolor was invisible through the corresponding monocular filter.A central fixation cross, viewed binocularly, facilitated fixationand monitoring of attention during the experiments. A pilot

study of controls showed no activation in visual areas during theperiods when the checkerboards were supposed to be invisible,implying negligible cross talk.

Second, the term affected LOC refers to the mean fMRIactivation of both left and right LOCs by monocular stimula-tion of the eye affected by ON, rather than to the ipsilateralLOC of the affected eye. The study was not designed to specif-ically stimulate the contralateral visual field, hence it was rea-sonable to average the responses between each LOC.

Third, she comments that the baseline LOC activationappears to be weaker in ON patients when compared with con-trols, although this is not reported in our paper. We described areduced LOC activation associated with affected eye stimulationat baseline, compared with the fellow eye response. We agreethat this reduction is most likely to be due to reduced afferentinput secondary to optic nerve inflammation, and suggests thathigher visual areas are not robust to disruption in visual input, apoint that has been debated in previous studies.3,4 Despite this,the baseline affected eye LOC response still predicted vision at 1year. This finding led to our proposal of clinically relevant adap-tive neuroplasticity. The association between baseline LOCfMRI response and visual recovery cannot be explained solelythrough a mechanism of severity of acute visual loss because: (1)There was no association between visual outcome and earlyfMRI response in primary visual cortex; (2) Visual outcome wasassociated with LOC activation following stimulation of the fel-low eye; and (3) In the interaction analyses (Tables 5 and 6),baseline LOC activity was generally a more robust predictor ofoutcome than baseline acuity.

Finally, we chose visual acuity as the outcome measurebecause central visual losses are more disabling to patients. Wealso collected visual field data during the study and found sig-nificant associations between early fMRI responses and recoveryusing this outcome (results not reported in the paper).

Department of Brain Repair and RehabilitationUCL Institute of Neurology, London, UK

Potential Conflicts of InterestNothing to report.

References1. Jenkins TM, Toosy AT, Ciccarelli O, et al. Neuroplasticity pre-

dicts outcome of optic neuritis independent of tissue damage.Ann Neurol 2010;67:99–113.

2. Haynes JD, Deichmann R, Rees G. Eye-specific effects of binoc-ular rivalry in the lateral geniculate nucleus. Nature 2005;438:496–499.

3. Levin N, Orlov T, Dotan S, et al. Normal and abnormal fMRIactivation patterns in the visual cortex after recovery from opticneuritis. NeuroImage 2006;33:1161–1168.

4. Korsholm K, Madsen KH, Frederiksen JL, et al. Recovery fromoptic neuritis: an ROI-based analysis of LGN and visual corticalareas. Brain 2007;130:1244-1253.

April, 2010 551

DOI: 10.1002/ana.21992

Have We Finally Identified an AutoimmuneDemyelinating Disease?Andreas Steck, MD1 and Norman Latov, MD2

We read with great interest the article by Bennet et al1 and theaccompanying editorial by Rodriguez2 on neuromyelitis optica(NMO). As pointed out by Rodriguez, the discovery by DrVanda Lennon3 of antibodies to the water channel moleculeaquaporin-4 (AQP-4) in the serum of patients with NMO rep-resents a milestone in deciphering the pathogenesis of this con-dition. This observation, now coupled with the successful adop-tive transfer of the disease to animals by NMO antibodiesagainst AQP-4,4 puts NMO in the category of a true autoim-mune disease, or as Rodriguez puts it, “Have we finally identi-fied an autoimmune demyelinating disease?”

Concerning the statement made by Bennet et al1 that thisis the first confirmed antigenic target in human demyelinatingdiseases, we would like to point out that myelin-associated gly-coprotein (MAG) has been known to be target of autoantibodiesin patients with a demyelinating neuropathy, as independentlyreported by us in the early 1980s.5,6 In this neuropathy, anti-bodies have been shown to be deposited on the myelin sheath ofaffected nerves,7 and lesions can be reproduced by passive trans-fer of anti-MAG antibodies.8 It should also be mentioned thatMAG is an integral membrane protein of myelin, whereasAQP-4 is expressed on astrocytes but not on oligodendrocytes.The neuropathogenic mechanisms of NMO are different fromthose of multiple sclerosis (MS), with prominent edema, inflam-mation, and influx of granulocytes in a clear vasocentric pattern.In this respect, we feel that NMO should be considered as anautoimmune astrocytopathy, with demyelination as a conse-quence of autoimmunity targeting AQP-4 on astrocytes,9 and assuch it does not represent a neurological autoimmunity directedat a myelin antigen. It is interesting to see how classification ofneurological diseases depends on an exact understanding of theirmolecular pathogenesis. It should not escape our attention thatMS may have to be reclassified or subdivided, after we identifythe exact pathophysiology.

1Department of Neurology, University Hospital, Basel,Switzerland and 2Department of Neurology, Weill CornellMedical College, New York, NY

Potential Conflicts of InterestNothing to report.

References1. Bennett JL, Lam C, Kalluri SR, et al. Intrathecal pathogenic anti-

aquaporin-4 antibodies in early neuromyelitis optica. Ann Neurol2009;66:617–629.

2. Rodriguez M. Have we finally identified an autoimmune demy-elinating disease? Ann Neurol 2009;66:572–573.

3. Lennon VA, Kryzer TJ, Pittock SJ, et al. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel.J Exp Med 2005;202:473–477.

4. Bradl M, Misu T, Takahashi T, et al. Neuromyelitis optica: patho-genicity of patient immunoglobulin in vivo. Ann Neurol 2009;66:630–643.

5. Braun PE, Frail DE, Latov N. Myelin-associated glycoprotein isthe antigen for a monoclonal IgM in polyneuropathy. J Neuro-chem 1982;39:1261–1265.

6. Steck AJ, Murray N, Meier C, et al. Demyelinating neuropathyand monoclonal IgM antibody to myelin-associated glycoprotein.Neurology 1983;33:19–23.

7. Stalder AK, Erne B, Reimann R, et al. Immunoglobulin M depo-sition in cutaneous nerves of anti-myelin-associated glycoproteinpolyneuropathy patients correlates with axonal degeneration.J Neuropathol Exp Neurol 2009;68:148–158.

8. Tatum AH. Experimental paraprotein neuropathy, demyelinationby passive transfer of human IgM anti-myelin-associated glycop-rotein. Ann Neurol 1993;33:502–506.

9. Hinson SR, McKeon A, Lennon VA. Neurological autoimmunitytargeting aquaporin-4. Neuroscience (2009), DOI:10.1016/j.neuroscience.2009.08.032.

DOI: 10.1002/ana.21990

ReplyJeffrey L. Bennett, MD, PhD,1,2 Gregory P. Owens, PhD,1

Don Gilden, MD,1,3 Jack P. Antel, MD,4

and Bernard Hemmer, MD5

Drs Steck and Latov remind us that peripheral nerve demyeli-

nation has been reproduced in animals that are administered ei-

ther patient serum containing anti–myelin-associated glycopro-

tein (anti-MAG) autoantibodies1 or purified anti-MAG

immunoglobulin M paraprotein.2 Our statement was intended

to highlight the state-of-the-art experiments verifying

aquaporin-4 as the first definitive autoantigen target in central

nervous system demyelinating disease.3 The ellipsis was uninten-

tional. Given cross-reactivity between anti-MAG antibodies, and

sulfated 3-glucuronyl lactosaminyl paragloboside and sulfated

3-glucoronyl paragloboside,4,5 it would be interesting to inves-

tigate whether antibody binding to protein or glycolipid targets

is critical for the chronic peripheral nerve pathology observed

with anti-MAG paraproteinemia.

We think, however, that it is premature to classify neuro-

myelitis optica (NMO) as an autoimmune astrocytopathy, given

our imperfect understanding of the molecular pathogenesis of

disease. Although the astrocyte may be the primary target of the

antibody response, myelinolysis is a hallmark of pathology and

may be the ultimate cause of neurologic dysfunction. Recent

pathologic studies in multiple sclerosis (MS) have highlighted

oligodendrocyte6,7 and astrocyte8,9 pathology before immune

cell infiltration. These intriguing observations suggest that MS

and NMO may be still be related, and that glial cytopathies may

be critical to initiating what we currently classify as central ner-

vous system autoimmune demyelination.

ANNALS of Neurology

552 Volume 67, No. 4