Comment

www.thelancet.com/neurology Vol 12 August 2013 733

be directly associated with epilepsy cause (eg, mesial temporal sclerosis) or severity. The study by Feldmann and colleagues5 provides evidence that P-glycoprotein upregulation might be to some extent linked to cause, since it was confi ned to an area surrounding the seizure focus in some patients. This scenario could be considered the worst of both worlds—that is, the drug would be able to enter the rest of the brain (not to mention other target organs such as the liver and skin) and therefore produce both systemic and CNS toxicity, but would be excluded from the brain region where it otherwise could produce a benefi cial eff ect.

Another possible explanation for the data presented by Feldmann and colleagues5 is that seizures themselves increase P-glycoprotein expression. This interpretation would explain why the patients with temporal lobe epilepsy who were seizure free, and who presumably had treatment resistance at sometime in their treatment course (most are on polytherapy, many with second line drugs such as clobazam and vigabatrin), had lower P-glycoprotein expression. Are these patients now seizure free because P-glycoprotein expression was able to return to normal, or did it return to normal after they were rendered seizure free? Each scenario would lead to a diff erent causal hypothesis. Hypothesis one is that the P-glycoprotein is producing treatment resistance in some patients, and the absence of P-glycoprotein upregulation has allowed treatment sensitivity in others. Another equally plausible hypothesis would be that upregulation is a marker of seizure burden rather than a cause. Notably, higher seizure frequency was associated with greater P-glycoprotein expression. In either case, reversal of the upregulation might contribute to improvement in seizure control.

Further exploration should answer some of these important questions. For example, repeated study of a single patient might help in understanding whether P-glycoprotein overexpression is static or dynamic.

Jacqueline A French NYU Comprehensive Epilepsy Center, 223 East 34th Street, New York, NY, 10016, USAJacqueline.French@nyumc.org

CorrectionsMehanna R, Jankovic J. Movement disorders in cerebrovascular disease. Lancet Neurol 2013; 12: 597–608—In this Review, the section of the fi gure showing a circuit diagram for hyperkinesias contained several errors. The thick red arrow between STN and GPe should have been a thin red arrow, the thin blue arrow between STN and GPi should have been a thin red arrow, and the thin blue arrow between GPe and GPi should have been a thick blue arrow. This section of the fi gure has been replaced with a corrected diagram (shown) in the online version as of July 15, 2013.

Healthy Parkinson’s disease Hyperkinesia

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Figure: Models of basal ganglia dysfunctionSTN=subthalamic nucleus. GPi=globus pallidus pars interna. GPe=globus pallidus pars externa. SNc=substantia nigra pars compacta. TH=thalamus. SNr=substantia nigra pars reticulata. D1=dopamine receptor D1. D2=dopamine receptor D2.

I have received grant funding from The Milken Foundation, the Epilepsy Therapy Project, NINDS, UCB, Pfi zer, Lundbeck, Eisai, Upsher-smith, Vertex, Impax, Mapp Pharmaceuticals, and Novartis. I am president of the Epilepsy Study Consortium, a non-profi t organisation that receives payments for consulting and clinical trial activities from Acorda Therapeutics, Aprecia, Avanir, Biotie, Catalyst, Concert, Cyberonics, Eisai Medical Research, Electrocore, Eli Lilly, GlaxoSmithKline, Icagen, Impax, Johnson and Johnson, LGCH, Mapp Pharmaceuticals, Marinus, Neurelis, Neurotherapeutics, Neuropace, NeuroVista Corporation, Novartis, Ono Pharma USA, Lundbeck, Pfi zer, Sepracor, Sunovion, SK Life Science, Supernus Pharmaceuticals, UCB/Schwarz Pharma, Upsher Smith, Valeant, Vertex, and Vivus.

1 Rogawski MA. The intrinsic severity hypothesis of pharmacoresistance to antiepileptic drugs. Epilepsia 2013; 54 (suppl 2): 33–40.

2 Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N Engl J Med 2011; 365: 919–26.

3 Srivastava AK, White HS. Carbamazepine, but not valproate, displays pharmacoresistance in lamotrigine-resistant amygdala kindled rats. Epilepsy Res 2013; 104: 26–34.

4 Brodie MJ, Barry SJ, Bamagous GA, Kwan P. Eff ect of dosage failed of fi rst antiepileptic drug on subsequent outcome. Epilepsia 2013; 54: 194–98.

5 Feldmann M, Asselin M-C, Liu J, et al. P-glycoprotein expression and function in patients with temporal lobe epilepsy: a case-control study. Lancet Neurol 2013; published online June 18. http://dx.doi.org/10.1016/S1474-4422(13)70109-1.

6 Haerian BS, Roslan H, Raymond AA, et al. ABCB1 C3435T polymorphism and the risk of resistance to antiepileptic drugs in epilepsy: a systematic review and meta-analysis. Seizure 2010; 19: 339–46.