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Original Investigation |

Progressive Brain Atrophy in Super-refractory Status Epilepticus ONLINE FIRST

Sara Hocker, MD1; Elanagan Nagarajan, MD1; Alejandro A. Rabinstein, MD1; Dennis Hanson, MA2; Jeffrey W. Britton, MD1
[+] Author Affiliations
1Department of Neurology, Mayo Clinic, Rochester, Minnesota
2Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
JAMA Neurol. Published online August 15, 2016. doi:10.1001/jamaneurol.2016.1572
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Importance  Prolonged seizures in super-refractory status epilepticus (SRSE) have been shown to cause neuronal death and reorganization, and visual inspection in individual case studies has demonstrated progressive cortical and subcortical atrophy. At present, magnetic resonance imaging (MRI) studies that evaluate brain atrophy in SRSE are lacking.

Objectives  To document and quantify the development of atrophy over time in SRSE.

Design, Setting, and Participants  This retrospective medical record review included all patients with SRSE who were admitted to a tertiary referral campus of the Mayo Clinic Hospital with SRSE from January 1, 2001, to December 31, 2013. Patients with (1) an initial MRI scan performed within 2 weeks of SRSE onset, (2) a second MRI scan within 6 months of SRSE resolution, and (3) a minimum duration of 1 week between MRI scans were included. The ventricular brain ratio (VBR) was measured on T2-weighted fluid-attenuated inversion recovery (FLAIR) images at disease onset and during follow-up. Measurements were performed on axial FLAIR images with section thickness of less than 5 mm. The plane immediately superior to the caudate head was chosen for analysis. The hypothesis that atrophy develops during SRSE despite seizure control (electroencephalogram background suppression with anesthetic drugs) was tested. Data were analyzed from June 1 to December 31, 2015.

Main Outcomes and Measures  Change in VBR (ΔVBR) as a percentage of the starting measure.

Results  Nineteen patients met the inclusion criteria; these included 10 men (53%) and 9 women (47%) with a median age of 41 (interquartile range [IQR], 25-68) years. Anesthetic agents were required for a median of 13 (IQR, 5-37) days. Initial MRI was performed a median of 2 (IQR, 1-7.5) days from the onset of SRSE, and the second MRI was performed a median of 11 (IQR, 5-15.5) days from the resolution of SRSE, with a median of 40 (IQR, 15-65) days between MRI scans. Median ΔVBR was 23.3% (IQR, 10.5%-70.3%). A significant correlation between the duration of anesthetic agent use and ΔVBR was found (Spearman r = 0.54; P = .02).

Conclusions and Relevance  Atrophy developed in all patients with SRSE who underwent serial imaging, despite administration of agents for seizure control. The degree of atrophy appears to be related to the duration of SRSE.

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Figure 1.
Example Object Map

Axial fluid-attenuated inversion recovery magnetic resonance imaging scan demonstrates an object map from which ventricular and brain areas are calculated. The plane is just superior to the caudate head.

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Figure 2.
Association of Duration of Anesthetic Agent Use and Change in Vetricular Brain Ratio (ΔVBR)

The diagonal line represents the linear correlation of the duration of anesthetic agent use and the development of brain atrophy. Data points represent the 19 individual patients. See the Methods section for an explanation of how ΔVBR is calculated.

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Figure 3.
Magnetic Resonance Imaging (MRI) Scans in Patient 1

The MRI plane selected is immediately superior to the caudate head. A woman in her 20s presented with super-refratory status epilepticus (SRSE) due to autoimmune encephalitis. A, The initial MRI scan was obtained 6 days after the onset of SRSE. B, The follow-up MRI scan was obtained 128 days later, after treatment with anesthetic agents for 76 days. The follow-up scan shows diffuse atrophy with widened sulci and increased ventricular caliber. The change in vertricular brain ratio (ΔVBR) in this patient was 66.2%. See the Methods section for an explanation of how ΔVBR is calculated.

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Figure 4.
Fluid-Attenuated Inversion Recovery (FLAIR) Magnetic Resonance Imaging (MRI) Scans in Patient 2

The MRI planes (left, midbrain; middle, third ventricle; and right, caudate head) were selected to best demonstrate development of atrophy. The images were taken from a man in his 20s with super-refratory status epilepticus. A, The initial MRI scans were obtained on admission. B, The follow-up MRI scans were obtained 102 days later, when the cause of seizures remained cryptogenic despite an exhaustive evaluation. The change in ventricular brain ratio (ΔVBR) in this patient was 124%. The follow-up scans show diffuse atrophy with widened sulci and increased ventricular caliber. Increased FLAIR signal hyperintensity was also noted involving the corticospinal tracts. See the Methods section for an explanation of how ΔVBR is calculated.

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Confounding factors
Posted on August 15, 2016
Lecio F Pinto
Hospital das Clinicas, University of Sao Paulo - Sao Paulo - Brazil
Conflict of Interest: Lecio F Pinto received grants from UCB Biopharma for consultation and speaker.
I read with interest the article of Hocker et al. about progressive brain atrophy in super refractory status epilepticus. It's very difficult to analise these patients because there's a lot of heterogeneity and this is a concern for the findings of the present study. The role of etiology of status in the atrophy observed is difficult to split from the damage of continuous epileptic activity. Using control patients with some of these etiologies but without seizures would be interesting to analise the isolated effect of status on brain atrophy. Also some drugs used in this setting are well recognized to cause brain atrophy, including valproate and corticosteroids. I would be curious about how frequent were used in this series published by Hocker et al.
These aspects could be looked in future studies of brain atrophy in status epilepticus, and would add more data to the interesting findings of the paper.
Brain atrophy in status epilepticus. Etiology and drugs matters?
Posted on August 16, 2016
Lecio F Pinto
Hospital das Clinicas, University of Sao Paulo - Sao Paulo - Brazil
Conflict of Interest: Dr Lecio F Pinto received grants from UCB Pharma for consulting and speaker.
I read with interest the article of Hocker et al1 in JAMA Neurology on progressive brain atrophy in super refractory status epilepticus. It's very difficult to analyze status epilepticus because there's a lot of heterogeneity2.

The role of etiologic factor of status in the development brain atrophy would be very difficult to distinct from the damage of continuous epileptic activity. Using control patients with some of these etiologies but without seizures would be an interesting way to distinguish theses factors and demonstrated how important is the isolated effect of status epilepticus on brain atrophy. 

Also, the absence of case-wise data pointed in the Editorial3 is relevant and some factors not show may be a concern for the findings of the paper. Drugs used as part of the treatment in this setting are well recognized to cause brain atrophy, including valproate4, ketamine5 and corticosteroids6. I would be curious about how frequent these medications were used in this series. 

Although these points doesn’t overwhelm the importance of the findings of Hocker et al, future studies of brain atrophy in status epilepticus that address the role of etiology and other drugs used would be very useful.

1. Hocker S, Nagarajan E, Rabinstein AA, Hanson D, Britton JW. Progressive Brain Atrophy in Super-refractory Status Epilepticus. JAMA Neurol. Published online August 15, 2016. doi:10.1001/jamaneurol.2016.1572.

2. Rossetti, AO and Lowenstein DH. Management of refractory status epilepticus in adults: still more questions than answers
The Lancet Neurology. 2011;10(10):922-930.

3. Cole AJ. Status Epilepticus and Brain Atrophy: Shrinkage Is a Growing Problem.JAMA Neurol. Published online August 15, 2016. doi:10.1001/jamaneurol.2016.2639.

4. Guerrini R, Belmonte A, Canapicchi R, Casalini C, Perucca E. Reversible pseudoatrophy of the brain and mental deterioration associated with valproate treatment. Epilepsia. 1998;39(1):27-32.

5. Wang C, Zheng D, Xu J, Lam W, Yew DT. Brain damages in ketamine addicts as revealed by magnetic resonance imaging. Front Neuroanat. 2013;17(7):23

6. Spiegel W, McGeady SJ, Mansmann HC. Cerebral cortical atrophy and central nervous system (CNS) symptoms in a steroid-treated child with asthma. J Allergy Clin Immunol. 1992;89:918-919.
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