in contrast, a patient without improvement after 22 days will have

a low fMRI response and maintain a low VA. Did the authors

adjust their analysis, not only to the baseline evaluation, but also

to the pattern of VA improvement from nadir to baseline?

Potential Conflicts of Interest

Nothing to report.

Department of Neurology, A. de Rothschild Foundation, ParisFrance

References

1. Jenkins TM, Toosy AT, Ciccarelli O, et al. Neuroplasticity predictsoutcome of optic neuritis independent of tissue damage. AnnNeurol 2010;67:99–113.

2. Beck RW, Cleary PA, Backlund JC, et al. The course of visualrecovery after optic neuritis. Experience of the Optic NeuritisTreatment Trial. Ophthalmology 1994;101:1771–1778.

DOI: 10.1002/ana.22028

ReplyThomas Jenkins, MD, Ahmed T. Toosy, PhD,Olga Ciccarelli, PhD, Katherine A. Miszkiel, FRCR,Claudia A. Wheeler-Kingshott, PhD, Andrew P. Henderson,FRACP, Constantinos Kallis, PhD, Laura Mancini, PhD,Gordon T. Plant, MD, David H. Miller, MD,and Alan J. Thompson, MD

We thank the authors for their interest in our study.1 They arguethat worse vision (visual acuity [VA]) at baseline will generate lowerfunctional magnetic resonance imaging (fMRI) responses (presum-ably in the lateral occipital complexes [LOCs]), and will predictpoor vision at 1 year. This implies that the LOC fMRI response isconsequent to reduced afferent stimulus resulting from optic nervetissue damage and is unrelated to adaptive neuroplasticity. This isan interesting point that is discussed in the article. Dissecting coli-nearities between visual fMRI responses and visual acuities can bechallenging. However, the relationship between the LOC responsesand final vision cannot be entirely due to the above explanation.First, it would be mediated through V1 (primary visual areas), butthis showed only a weak association with final VA (p ¼ 0.067),whereas the association with affected eye LOC fMRI was morestrongly significant (p ¼ 0.007) (Table 4). Second, we discoveredan association between fellow eye LOC fMRI and final vision (ofthe affected eye). This is difficult to account for by postulatingonly a direct relationship between reduced VA at baseline and theaffected eye LOC fMRI response. Third, in the interaction analyses(Tables 5 and 6), baseline LOC activity was generally a more ro-bust predictor of outcome than VA at the time of assessment.Finally, the relationship between final vision and affected eye LOCfMRI response remained weakly significant (p ¼ 0.079) whenadjusted for baseline VA. Conversely, the association between base-line vision and final vision became nonsignificant (p ¼ 0.131)when adjusting for affected eye LOC fMRI response. This impliesa less critical role for baseline vision relative to the LOC fMRIresponse in predicting final vision (Table 5).

Although baseline assessment occurred at a median of 22

days, half our patients were visually impaired (median, þ0.41;

range, �0.06 to þ1.7), and 92% showed optic nerve gadolin-

ium enhancement, implying that our cohort was still in the

acute phase of their condition.

We did not feel it would be instructive to adjust for the

‘‘pattern VA improvement from nadir to baseline.’’ VA data at

presentation to hospital are available, but do not necessarily

indicate nadir VA. Also, fMRI responses change during recov-

ery, hence fMRI at ‘‘baseline’’ probably does not represent brain

dynamics at nadir VA. Acquiring fMRI at nadir vision would

have been preferable but not possible in this study.

Potential Conflicts of Interest

Nothing to report.

Department of Brain Repair and Rehabilitation, UniversityCollege London Institute of Neurology, London, UK

Reference

1. Jenkins TM, Toosy AT, Ciccarelli O, et al. Neuroplasticity predictsoutcome of optic neuritis independent of tissue damage. AnnNeurol 2010;67:99–113.

DOI: 10.1002/ana.22030

Does Exercise Correct Dysregulation ofNeurosteroid Levels Induced by Epilepsy?Ricardo Mario Arida, PhD,1 Fulvio Alexandre Scorza, PhD,2

Michelle Toscano-Silva, MSc,1 andEsper Abrao Cavalheiro, MD, PhD2

We read with interest the elegant article entitled ‘‘Endogenous

Neurosteroid Synthesis Modulates Seizure Frequency’’ by Lawrence

and collaborators, which has appeared in Annals of Neurology.1 We

applaud the authors for pursuing this topic, but we are also inter-

ested in addressing some goals for this research. The group’s

experiments explored the role of endogenous neurosteroids on seiz-

ures in epileptic animals and reinforced the hypothesis that neuro-

steroids may represent a novel therapeutic target in epileptic disor-

ders. Lawrence and colleagues also demonstrated that inhibition of

neurosteroid synthesis can cause seizure exacerbation, likely due to

reduced neurosteroid levels in the brain. In epileptic animals, the

sensitivity of synaptic gamma-aminobutyric acid (GABA)A recep-

tors was diminished, and higher concentrations of neurosteroids

were necessary to enhance synaptic currents. In accordance with

this reasoning, we postulate that exercise might regulate neuroste-

roids in epilepsy. Studies analyzing the effect of a physical exercise

program in people with epilepsy have shown decreased frequency

of seizures during the exercise period.2 From an experimental

point of view, positive effects of exercise in rats with epilepsy have

been demonstrated by our research group over the past 3 deca-

des. For instance, physical exercise inhibited development of

amygdala kindling, attenuated the frequency of seizures, and

modified synaptic plasticity in the pilocarpine model of epilepsy,

and reduced CA1 hyper-responsiveness and promoted positive

plastic changes in the hippocampus of rats with epilepsy.3 By this

reasoning, exercise represents a physiological challenge that

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