By Kimberly Pargeon, MD
Assistant Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Pargeon reports no financial relationships relevant to this study.
Synopsis: The authors retrospectively conducted a voxel-based analysis of T1 MRI scans to compare gray matter volumes in 12 cases of sudden unexpected death in epilepsy (SUDEP) acquired at a median of 2 years before death with patients at high or low risk for SUDEP and with healthy controls, and demonstrated significant anatomical differences between the groups.
Source: Wandschneider B,et al. Structural imaging biomarkers of sudden unexpected death in epilepsy. Brain 2015;138:2907-2919.
Sudden unexpected death in epilepsy (SUDEP) is one of the most common causes of premature, non-accidental death in patients with chronic epilepsy, with an estimated incidence of sudden death in epilepsy patients being 20 times that of the general population. It is typically defined as sudden and unexpected death with no history of trauma or drowning, with or without an associated seizure, and excluding cases of status epilepticus. In cases of “definite” SUDEP, no other identifiable cause is found on post-mortem examination.1
The present study was retrospective and conducted at a tertiary care center in the UK. The authors identified 12 patients from a clinical database who died with either definite (n = 2) or probable (n = 10) SUDEP and matched those with 53 living patients with epilepsy. Patients were stratified into “high-” or “low-” risk groups using a risk factor analysis score gleaned from Hersdorffer et al.1 Increased risk was associated with nocturnal seizures, frequent (≥ 3/year) generalized tonic-clonic seizure, young age at onset, and/or long disease duration. There were 34 “high-” and 19 “low-” risk patients. All patients had to have undergone a high-resolution T1 volume scan using the same 3T MRI scanner. All groups were matched for gender, age, epilepsy syndrome, and disease duration, and those with major brain lesions were excluded. Scans of 15 healthy age- and gender-matched controls were included for comparison. Coronal T1 MRIs were analyzed using voxel-based morphometry with statistical mapping software.
The primary finding was that SUDEP cases and those at high clinical risk showed increased gray matter volume in the right anterior hippocampus and the parahippocampal gyrus relative to those at low risk and controls. Decreased gray matter volume was also seen in the bilateral posterior thalamus for SUDEP cases and on the left for high-risk patients, which for all patient groups seemed to be correlated with disease duration. Several subgroup analyses were performed, which demonstrated no effects related to presence of lesions, seizure frequency, and different sites of ictal onset, although relatively limited information was available for the latter.
Commentary
Although SUDEP remains a leading cause of death in individuals with chronic epilepsy, the pathophysiology still remains somewhat unclear. The most noteworthy finding was the increased gray matter volumes in the right hippocampus and parahippocampal gyrus in SUDEP cases and in subjects at high risk. The authors postulated that this could represent one of two anatomical changes. One possibility could be microdysgenesis within the hippocampus with dystrophic neurons and diminished gray-white matter demarcation, as seen in many cases of sudden unexpected death in childhood. Another possibility could be gliosis, which would represent a response to injury, altering neuronal activity and increasing susceptibility for SUDEP. The authors further cited a study by Bernhardt et al looking at post-surgery seizure freedom rates and using structural imaging findings for predicting outcomes.2 Although most groups demonstrated unilateral or bilateral atrophy, a subgroup that was more likely to have unsuccessful surgery showed bilateral increased volumes in the hippocampus and amygdala. Further histopathology confirmed hippocampal gliosis in almost all of these patients.
Another key finding was the right lateralization, which they attributed to characteristics of autonomic regulation. The right limbic system, specifically the right insula, plays a significant role in sympathetic outflow. Complex arrhythmias and even sudden death have been attributed to acute right-sided insular strokes, suggesting a potential mechanism in SUDEP. The secondary finding of decreased volume in the posterior thalamus across all epilepsy groups correlated with increased disease duration. The authors postulated this may be related to repeated hypoxic insults. The posterior thalamus appears to play a significant role in mediating respiratory responses, which may break down with repeated injury. Thus, the authors concluded that these combined changes may increase potential for SUDEP.
It still remains unclear whether this small subset of SUDEP cases is representative of high-risk patients for sudden death and whether findings are generalizable. For instance, there were two instances of left mesial temporal sclerosis (MTS) among the SUDEP cases, but no instances of right MTS, so this could have been a factor. For instance, a recent meta-analysis of voxel-based morphometry studies on unilateral refractory temporal lobe epilepsy found significantly decreased gray matter volumes in ipsilateral mesiotemporal structures and bilateral thalami in both refractory left and right temporal lobe epilepsy.3 Regardless, if a replicable imaging biomarker could be demonstrated, this could assist clinicians in identifying those patients at greatest risk for sudden death.
REFERENCES
- Hersdorffer DC, et al. Combined analysis of risk factors for SUDEP. Epilepsia 2011;52:1150-1159.
- Bernhardt BC, et al. Magnetic resonance imaging pattern learning in temporal lobe epilepsy: Classification and prognostics. Ann Neurol 2015;77:436-446.
- Li J, et al. A meta-analysis of voxel-based morphometry studies on unilateral refractory temporal lobe epilepsy. Epilepsy Res 2012;98:97-103.