Epilepsy & Behavior 33 (2014) 24–30
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Brief Communication
Reversible and irreversible cranial MRI findings associated with status epilepticus A.M. Cartagena a,b,⁎, G.B. Young b, D.H. Lee b,c, S.M. Mirsattari b,c,d,e a
Department of Neurology/Clinical Neurophysiolgy, Detroit Medical Center, Wayne State University, Detroit, Michigan, USA Department of Clinical Neurological Sciences, Western University, London, Canada Department of Medical Imaging, Western University, London, Canada d Department of Medical Biophysics, Western University, London, Canada e Department of Psychology, Western University, London, Canada b c
a r t i c l e
i n f o
Article history: Received 1 November 2013 Revised 2 February 2014 Accepted 3 February 2014 Available online 12 March 2014 Keywords: Status epilepticus MRI Epilepsy
a b s t r a c t Objective: There is limited information on neuroimaging changes in status epilepticus (SE). The objective of this study was to characterize the abnormalities associated with SE in cranial MRI of patients with SE. Methods: A retrospective review of our records from 2001 to 2010 identified 203 patients with SE. Magnetic resonance imaging (MRI) changes considered were not attributable to any neurological disorder. Results: Ten patients who met the inclusion criteria were found to have significant abnormalities. Magnetic resonance imaging findings included increased T2 signal changes in the gray and/or white matter with corresponding diffusion-weighted imaging (DWI) abnormalities (n = 9). Apparent diffusion coefficient (ADC) values were both reduced (n = 3) and increased (n = 3). Other findings included changes affecting one hemisphere, a perilesional and homologous region, hippocampal changes, and findings in the thalamus, basal ganglia, brain stem, and cerebellum. Conclusions: Magnetic resonance imaging changes were diffuse. Notably, MRI changes were found to involve the brain stem, cerebellum, basal ganglia, and thalamus. Magnetic resonance imaging changes in the latter areas have not been previously well described. In addition, MRI changes tended to evolve after 1 week; therefore, serial MRI is recommended in order to follow and highlight the MRI changes related to the neuroanatomic involvement seen in status epilepticus. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Status epilepticus (SE) is a neurological emergency with a mortality rate between 10% and 20% [1]. Despite the breadth of knowledge regarding SE, there remains limited concrete information on the neuroanatomic changes that may occur in patients with SE. Neuroimaging has become the most important tool for advancing our knowledge of these neuroanatomic changes in vivo. Radiographic descriptions of findings related to SE were not well described until the latter half of the 20th century. Aicardi et al. provided the initial description of changes seen on radiographic imaging [2] using pneumoencephalograms on children; abnormalities such as acute unilateral brain swelling and residual ventricular dilatation were described. As imaging techniques became more sophisticated, more evidence became available regarding physiologic changes related to SE. Eventually, in 1987, further reports
⁎ Corresponding author at: Department of Neurology/Clinical Neurophysiolgy, Detroit Medical Center, Wayne State University, Detroit, Michigan, US. E-mail address: [email protected] (A.M. Cartagena). 1525-5050/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2014.02.003
of changing and disappearing lesions with neuroanatomic correlation to seizure foci were published as seen on CT scan [3]. Since the advent of MRI, our descriptive knowledge has increased. It remains unclear, however, whether there is a pattern of changes that can be attributed to SE. The objective of this study was to review the abnormalities associated with SE in cerebral MRI of patients with SE at London Health Sciences Centre, a tertiary care center in South Western Ontario, Canada and to determine whether an imaging pattern was present. 2. Patients and methods 2.1. Inclusion criteria A retrospective review of our electroencephalogram (EEG) database was conducted. The patients included in the EEG database were admitted between the years 2001 and 2010. In total, 203 patients with SE were identified. Inclusion criteria were the following: (1) having seizures lasting a minimum of 30 min or recurrent seizures without
A.M. Cartagena et al. / Epilepsy & Behavior 33 (2014) 24–30
25
Table 1a Patient characteristics without prior seizure history (1–3). NORSE = new-onset refractory status epilepticus. Age (year/sex)
Seizure type
Duration (days)
Electroencephalogram (EEG) findings
Status epilepticus etiology
Relevant medical history
1
35/male
14
22/female
Unknown, NORSE
Depression, uveitis, glaucoma None
3
21/male
Generalized spike–wave, polyspike–wave, maximum frontal Maximum left temporal spike–wave, multiple independent spikes Maximum right temporal spike–wave, multiple independent spikes, burst suppression
Unknown, NORSE
2
Generalized convulsive status epilepticus, nonconvulsive status epilepticus Generalized convulsive status epilepticus
Unknown, NORSE
None
Generalized convulsive status epilepticus, nonconvulsive status epilepticus
58 21
recovery in between them for at least 30 min including nonconvulsive electrographic seizures, (2) having cerebral MRI showing signal changes after SE in sequences temporally related to seizures, and (3) having MRI changes not attributed to an underlying primary neurological disorder including the condition that precipitated the SE. Ethics approval was obtained according to our institutional standards. 2.2. Patient characteristics Ten patients (5 females; mean age = 35.0 ± 11.89 SD years) met the inclusion criteria. Seven patients had a history of epilepsy; three patients presented with SE as their first manifestation of epilepsy (Tables 1a and 1b). 2.3. MRI characteristics Postictal images were obtained from a 1.5-tesla MRI scanner with routine sequencing and maximum 5-mm slice thickness. Magnetic resonance imaging scans were performed within 12 days of SE presentation. A total of 17 cases (including 7 dummy cases) without clinical information were given to a certified neuroradiologist (DHL) for review.
some degree of MRI abnormalities on final neuroimaging. Follow-up MRI was up to 8 months after initial SE. Results are summarized in Table 2. Overall initial MRI findings included increased T2 signal changes in the gray and/or white matter with corresponding diffusion-weighted abnormalities (n = 9). Apparent diffusion coefficient values were reduced in three patients and increased in three. Findings also included changes affecting one cerebral hemisphere (n = 1), significant lobar swelling (n = 2), perilesional and homologous regions (n = 1), the hippocampi (n = 8), the thalamus and basal ganglia (n = 3), and the brain stem and cerebellum (n = 3). In total, eight patients displayed extratemporal changes in the following areas: cortical, basal ganglia, thalamus, external capsule, brain stem, cerebellum, occipital lobes, and insular cortices. The population identified without a prior seizure history was young: mean age = 26.0 (SD ± 7.81) years. All three patients were eventually diagnosed with new-onset refractory status epilepticus (NORSE). In those patients with a prior seizure history, antiepileptic drug reduction and noncompliance were seen as triggers in 4 patients, while three cases of SE were of an unknown etiology. 4. Discussion
3. Results
4.1. Status epilepticus and neuronal changes
Magnetic resonance imaging findings were widespread, both reversible and irreversible, and followed no consistent pattern. Magnetic resonance imaging findings were deemed irreversible if there was notable diffuse atrophy in the same region as the acute changes on follow-up MRI or if T2 hyperintensity remained unchanged on subsequent imaging (n = 7). Atrophy was diagnosed based on expertise (DHL). Magnetic resonance imaging findings were deemed reversible if signal intensity decreased or disappeared on follow-up MRI. Three patients had reversible findings on follow-up MRI (cases 4, 6, and 7); however, all patients who had follow-up MRIs (including cases 4, 6, and 7) were left with
The pathological explanation for MRI changes following SE is mostly extrapolated from animal studies [4–6]. There is either widespread neuronal necrosis [7] or neuronal injury that can be caused by a number of mechanisms including the following: ATP deficiency due to failure of Na/K ATPase pump, lactic acidosis, release of excitatory neurotransmitters such as glutamate, release of inflammatory mediators, increased membrane ion permeability, and possible activation of caspase pathways leading to apoptosis [8,9]. The neuronal necrosis can, in addition, be selective [10]. These histological and biochemical changes then manifest into tissue injury, which has been described to occur in various
Table 1b Patient characteristics with a prior seizure history (4–10). Age (year/sex)
Seizure type
Duration (days)
EEG findings
Status epilepticus etiology
Relevant medical history
4
27/male
Generalized epilepsy
Ecstasy/alcohol abuse, asthma
44/male
Posttraumatic epilepsy (well controlled)
Periodic lateralized epileptiform discharges (right parietooccipital) –
Unknown
5
Multiple, frequent episodes of SE 7
Unknown
6
24/male
21
37/female
8
59/female
b1
Right hemispheric spikes/periodic lateralized epileptiform discharges Left temporal–parietal seizures and spikes Generalized slowing (postictal)
Unknown
7
Generalized epilepsy (cause is unknown) since the age of 9 Complex partial seizures, secondarily generalized tonic–clonic Primary generalized epilepsy
Motor vehicle accident with traumatic brain injury (age: 20) Past history of alcohol and drug abuse (hashish) Left parietal cortical dysplasia
9
41/female
Posttraumatic epilepsy
14
Right frontal polyspike–wave
10
40/female
?
b1
Slowing maximum left temporal (postictal)
93
Tapering antiepileptic drugs Sepsis
Tapering antiepileptic drugs Noncompliance
Renal failure (failed transplant), colitis, mixed connective tissue disease Epilepsy (age: 15), corpus callosotomy (age: 22) Epilepsy (age: 30), drug abuse in the past
26 Table 2 MRI findings in patients with SE. DWI = diffusion-weighted imaging, ADC = apparent diffusion coefficient, MRS = magnetic resonance spectroscopy, N = normal, INA PVWM = inappropriate periventricular white matter, MTS = mesial temporal sclerosis. Initial MRI Timing from onset (days) 1
7
DWI increased signal
ADC
Yes
N
Yes
↑
T2 hyperintensity Hippocampus
Cortex
Basal ganglia + thalamus
Brain stem + cerebellum
N
N
Basal ganglia + thalamus
Brain stem + right and left cerebellum
Right and left
Left mesial frontal, insular
N
N
Other
Timing
DWI Δ
T2 hyperintensity
Comments/other
No gadolinium enhancement, abnormal periventricular lesions
b1 week
Yes
Diffuse atrophy (worse)
4 months
No
8 weeks
No
7 months
No
Subcortical, cerebellum and brain stem, abnormal right MRS (minimal change) Subcortical, brain stem, cerebellum, WM Bilateral MTS (↑ signal and volume loss) Bilateral MTS
No gadolinium enhancement, bilateral internal capsule
3
b7
Yes
Not done
Left N right
N
N
N
Left fornix
b1 week
No
4
11
Yes
↓
Right
Right frontal, parietal, occipital
N
Right cerebellar peduncle
T2 corpus callosum
3 weeks
No
4 months
No
8 months
No
5
3
Yes
↓ Right hippocampus
Right
6
12
Yes
Not done
Right
Bilateral frontal, temporal, right parietal Right hemisphere
7
b7
Yes
↑ Left parietal, + left hippocampus
Left
8
2
No
↑ Cerebellar white matter
9
7
Yes
10
3
Yes
Atrophy, right worse ≫ left, posttraumatic encephalomalacia INA PVWM (right hemisphere)
N
N
Right thalamus
N
Left parietal
N
N
MRS abnormal right and left temporal
N
Right frontal
Left
Not done
Right and left
Left frontal, occipital, parietal N
Brain stem + right and left cerebellum N
Deep + subcortical white matter changes
↓
Right basal ganglia + thalamus N
N
N
Swelling left frontal, occipital encephalomalacia left frontotemporal Diffuse atrophy
Bilateral hippocampi, left N right, minimal change Slight ↓ right occipital Subcortical gray, bilateral hippocampi (MTS) Subcortical gray, splenium of the corpus callosum
Diffuse atrophy (worse) Diffuse atrophy Minimal change, left frontal lesion disappeared Minimal change Right cerebellar peduncle resolved Diffuse atrophy INA PVWM (right worse N left), diffuse atrophy
Not performed
1 1 6 1
week month months week
Same Right hemispheric swelling Same Right hemispheric swelling ↓ Right thalamic hyperintensity Right MTS + right hemiatrophy New right parietal, left parietal Left hippocampus not as bright unchanged on DWI 2 weeks Yes New right parietal deep lesion, right New right hemispheric changes occipital; old right parietal gone, DWI, ↑ T2 left temporal left parietal unchanged, new left temporal Not performed (patient died secondary to respiratory distress and intestinal ischemia)
2 weeks
Yes Yes No Yes
Yes
Not performed
Diffuse bihemispheric, cerebellum
Bilateral DWI hyperintensity, diffuse cortical thickening (left frontotemporal)
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6
Follow-up MRI
A.M. Cartagena et al. / Epilepsy & Behavior 33 (2014) 24–30
anatomic locations including the pyriform cortex, amygdala, and hippocampus [6,11–13]. The subsequent swelling of the neuropil can be seen on MRI as T2-weighted hyperintensity; T2-weighted hyperintensity has been described as appearing after several hours of SE [6,11–15]. 4.2. Status epilepticus and hippocampal changes on MRI Acute hippocampal edema and reversible, transient changes on MRI in the setting of SE have been well described [15,16] and were common in this series (80% of patients). In the group of patients without a history of seizures, 2 of 3 had hippocampal changes (increased T2 hyperintensity), and the changes were seen in both hippocampi. In the group of patients with a history of prior seizures, 6 of 7 had increased T2 hyperintensity of their hippocampi, and in 3 of those 7, the MRI changes were seen in the regions of EEG abnormalities. In follow-up MRI, 3 of the 8 patients with hippocampal changes were described as having mesial temporal sclerosis due to hippocampal atrophy and abnormal T2 signal intensity of the hippocampus(i). In the patients without hippocampal changes on MRI, increased T2 signal intensity was present in both the cerebellum and the brain stem. Overall, eight patients had extratemporal changes. Extratemporal is defined as including the cerebral cortex, basal ganglia, thalamus, external capsule, brain stem, cerebellum, occipital lobes, and insular cortices. As there is scarce literature regarding extratemporal changes, we wish to highlight the findings seen in our case series. 4.3. Status epilepticus and extratemporal changes Recently, there has been a report of transient MRI abnormalities seen in bilateral external capsules and frontotemporal and insular
27
cortices in a 39-year-old female with no prior seizure history [17]; these findings are very similar to our patient (case 2) who presented with NORSE. The MRI changes present in the external capsules of our patient (case 2) have been included (Fig. 1). Boyd et al. [18] have well described bilateral thalamic pulvinar changes in a 26-year-old male with NORSE. Thalamic changes were seen in case 6, a 24-year-old male with generalized epilepsy (cause is unknown) since the age of 9, who developed epilepsia partialis continua (EPC) of undetermined etiology affecting his right hemisphere for 48 h. His full medical history has been described elsewhere by our group [19]. His SE led to irreversible MRI changes involving his right hemisphere including his thalamus (Fig. 2). Thalamic changes were also seen in case 8, a 59-year-old female with significant medical comorbidities in addition to IGE. Her MRI was significant for changes in the right basal ganglia, right thalamus, and throughout her brain stem and both cerebellar hemispheres. Again, no alternative etiology was identified for her neuroimaging changes, and, unfortunately, no follow-up imaging was obtained as she died unexpectedly from intestinal ischemia. Magnetic resonance imaging changes in the cerebellum as a consequence of SE have been explained as a result of crossed cerebellar diaschisis in SE, with evidence of contralateral cerebellar involvement with a supratentorial epileptic focus [20]. There is also evidence for contralateral cerebellar hypometabolism during seizures [21]. In case 1, however, MRI displayed several foci of abnormalities in the white matter, and no supratentorial focus on EEG was identified to support crossed cerebellar diaschisis. The brain stem was also involved (Fig. 3). After several months of follow-up, no alternative explanation was found for the MRI changes despite exhaustive infectious, autoimmune, and neoplastic investigations. In addition, a brain biopsy of the left frontal lobe white matter was eventually undertaken, which showed only
Fig. 1. Case 2: magnetic resonance imaging (MRI) less than one week after presentation of status epilepticus (SE). (a–c) Axial fluid attenuation inversion recovery (FLAIR) images revealing increased signal (black arrows) in the hippocampi, external capsule, and insulae and, cortically, in the left mesial frontal lobe; (d) coronal FLAIR with increased signal (white arrows) in the hippocampi; (e) axial diffusion-weighted imaging (DWI) with diffusion restriction (black arrows) in the external capsule.
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A.M. Cartagena et al. / Epilepsy & Behavior 33 (2014) 24–30
Fig. 2. Case 6: magnetic resonance imaging (MRI) during status epilepticus (a, b) and six months after SE (c, d). (a, b) Diffuse diffusion restriction and edema in the right hemisphere including the thalamus on axial diffusion-weighted imaging (DWI); diffusion restriction is also noted in the left mesial temporal and lateral temporal cortices; (c, d) axial T2 and coronal fluid attenuation inversion recovery (FLAIR) several months after onset revealing dramatic right hemispheric atrophy.
mild microvacuolation and minimally increased cellularity with no evidence of demyelination. In case 4 the cerebellar peduncle was involved and it was ipsilateral to the supratentorial cortical MRI changes and again no focality was identified on EEG. These unpredictable changes in the cerebellum associated with SE are rare. The brain stem and cerebellum may be involved in SE because of their widespread cortical connections. The extensive reciprocal networks of the brain stem and cerebellum with the cerebral cortex may be affected as a consequence of the ongoing biochemical microalterations occurring elsewhere in the cerebral cortex. In crossed cerebellar diaschisis due to SE, a possible explanation is that injury is caused by excessive neuronal transmission from prolonged excitatory synaptic activity via the corticopontine–cerebellar pathways [20] — this may also help to explain the brain stem involvement. 4.4. Time frame of MRI changes seen in SE The literature refers to T2-weighted hyperintensity appearing after only several hours of SE [6,11–15]. In this study, T2-weighted hyperintensity was seen as appearing as early as 2 days. Patients were not imaged before 2 days because of their hemodynamic instability
and barriers in transportation in the ICU setting. After initial MRI, the timing of follow-up imaging ranged from less than 1 week up to 8 months. In 3 of 4 patients who were imaged within 1 week of their initial MRI, no significant changes were noted (cases 1, 3, and 6). Patients imaged after 1 week had changes from their baseline MRI (cases 4, 7, and 9). Overall, 5 of the 8 patients with follow-up imaging had changes seen on serial MRI. 5. Conclusion This is a retrospective study with a small sample size. Despite our small sample size, our findings indicate that SE can cause a variety of unpredictable MRI findings that are liable to change and evolve on serial MRI. These MRI changes can be focal, multifocal, hemispheric, or diffuse. In addition to the well-known hippocampal changes, we describe several cases of extratemporal changes. Although no specific pattern was identified, it is worthwhile to note that in those patients with changes on MRI imaging, changes occurred after 1 week of follow-up. Greater attention to such MRI findings and more aggressive serial neuroimaging is necessary in order to adequately highlight neuroimaging changes related to SE and follow their (often)
A.M. Cartagena et al. / Epilepsy & Behavior 33 (2014) 24–30
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Fig. 3. Case 1: MRI six days after the onset of SE. (a–d) Axial T2-weighted sequencing displaying multiple areas of increased signal intensity in the brain stem and cerebellum and basal ganglia. (a) Brain stem (white arrow), (b) cerebellum (white arrow), (c) basal ganglia and thalamus (white arrow), (d) periventricular white matter (white arrow).
progressive course. By following MRI changes related to SE with serial imaging, patterns might be identified regarding the neuroanatomic circuitry involved. Conflict of interest statement None. Author contributions Dr. Cartagena drafted and wrote the manuscript. All others (Drs. G.B. Young, D.H. Lee, and S. Mirsattari) were directly involved in helping with writing and editing the manuscript and provided expert advice. This study did not receive sponsorship or funding. Dr. Cartagena reports no disclosures. Dr. Mirsattari reports no disclosures. Dr. Young reports no disclosures. Dr. Lee reports no disclosures.
References [1] DeLorenzo RJ, Pellock JM, Towne AR, Boggs JG. Epidemiology of status epilepticus. J Clin Neurophysiol 1995;12:316–25. [2] Aicardi J, Amsili J, Chevrie JJ. Acute hemiplegia in infancy and childhood. Dev Med Child Neurol 1969;11:162–73. [3] Kramer RE, Lüders H, Lesser RP, Weinstein MR, Dinner DS, Morris HH, et al. Transient focal abnormalities of neuroimaging studies during focal status epilepticus. Epilepsia 1987;28:528–32. [4] Fabene PF, Marzola P, Sbarbati A, Bentivoglio M. Magnetic resonance imaging of changes elicited by status epilepticus in the rat brain: diffusion-weighted and T2-weighted images, regional blood volume maps, and direct correlation with tissue and cell damage. Neuroimage 2003;18:375–89. [5] Roch C, Leroy C, Nehlig A, Namer IJ. Predictive value of cortical injury for the development of temporal lobe epilepsy in 21-day-old rats: an MRI approach using the lithium-pilocarpine model. Epilepsia 2002;43:1129–36. [6] Wang Y, Majors A, Najm I, Xue M, Comair Y, Modic M, et al. Postictal alteration of sodium content and apparent diffusion coefficient in epileptic rat brain induced by kainic acid. Epilepsia 1996;37:1000–6. [7] Wasterlain CG, Fujikawa DG, Penix L, Sankar R. Pathophysiological mechanisms of brain damage from status epilepticus. Epilepsia 1993;34(Suppl. 1):S37–53. [8] Lansberg MG, O'Brien MW, Norbash AM, Moseley ME, Morrell M, Albers GW. MRI abnormalities associated with partial status epilepticus. Neurology 1999;52: 1021–7.
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[9] Bruehl C, Hagemann G, Witte OW. Uncoupling of blood flow and metabolism in focal epilepsy. Epilepsia 1998;39:1235–42. [10] Men S, Lee DH, Barron JR, Munoz DG. Selective neuronal necrosis associated with status epilepticus: MR findings. AJNR Am J Neuroradiol 2000;21:1837–40. [11] Righini A, Pierpaoli C, Alger JR, Di Chiro G. Brain parenchyma apparent diffusion coefficient alterations associated with experimental complex partial status epilepticus. Magn Reson Imaging 1994;12:865–71. [12] Ebisu T, Rooney WD, Graham SH, Mancuso A, Weiner MW, Maudsley AA. MR spectroscopic imaging and diffusion-weighted MRI for early detection of kainateinduced status epilepticus in the rat. Magn Reson Med 1996;36:821–8. [13] Bouilleret V, Nehlig A, Marescaux C, Namer IJ. Magnetic resonance imaging followup of progressive hippocampal changes in a mouse model of mesial temporal lobe epilepsy. Epilepsia 2000;41:642–50. [14] Nakasu Y, Nakasu S, Morikawa S, Uemura S, Inubushi T, Handa J. Diffusion-weighted MR in experimental sustained seizures elicited with kainic acid. AJNR Am J Neuroradiol 1995;16:1185–92. [15] Tien RD, Felsberg GJ. The hippocampus in status epilepticus: demonstration of signal intensity and morphologic changes with sequential fast spin-echo MR imaging. Radiology 1995;194:249–56.
[16] Kim JA, Chung JI, Yoon PH, Kim DI, Chung TS, Kim EJ, et al. Transient MR signal changes in patients with generalized tonicoclonic seizure or status epilepticus: periictal diffusion-weighted imaging. AJNR Am J Neuroradiol 2001;22:1149–60. [17] Gujjar A, Jacob PC, Al-Asmi A, Ramachandiran N, Obaidi A, Jain R. Reversible MRI changes in prolonged status epilepticus: a case report. Int J Neurosci 2011;121:341–5. [18] Boyd JG, Taylor S, Rossiter JP, Islam O, Spiller A, Brunet DG. New-onset refractory status epilepticus with restricted DWI and neuronophagia in the pulvinar. Neurology 2010;74:1003. [19] Korngut L, Young GB, Lee DH, Hayman-Abello BA, Mirsattari SM. Irreversible brain injury following status epilepticus. Epilepsy Behav 2007;11:235–40. [20] Samaniego EA, Stuckert E, Fischbein N, Wijman CA. Crossed cerebellar diaschisis in status epilepticus. Neurocrit Care 2010;12:88–90. [21] Calistri V, Caramia F, Bianco F, Fattapposta F, Pauri F, Bozzao L. Visualization of evolving status epilepticus with diffusion and perfusion MR imaging. AJNR Am J Neuroradiol 2003;24:671–3.
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Brief Communication
Reversible and irreversible cranial MRI findings associated with status epilepticus A.M. Cartagena a,b,⁎, G.B. Young b, D.H. Lee b,c, S.M. Mirsattari b,c,d,e a
Department of Neurology/Clinical Neurophysiolgy, Detroit Medical Center, Wayne State University, Detroit, Michigan, USA Department of Clinical Neurological Sciences, Western University, London, Canada Department of Medical Imaging, Western University, London, Canada d Department of Medical Biophysics, Western University, London, Canada e Department of Psychology, Western University, London, Canada b c
a r t i c l e
i n f o
Article history: Received 1 November 2013 Revised 2 February 2014 Accepted 3 February 2014 Available online 12 March 2014 Keywords: Status epilepticus MRI Epilepsy
a b s t r a c t Objective: There is limited information on neuroimaging changes in status epilepticus (SE). The objective of this study was to characterize the abnormalities associated with SE in cranial MRI of patients with SE. Methods: A retrospective review of our records from 2001 to 2010 identified 203 patients with SE. Magnetic resonance imaging (MRI) changes considered were not attributable to any neurological disorder. Results: Ten patients who met the inclusion criteria were found to have significant abnormalities. Magnetic resonance imaging findings included increased T2 signal changes in the gray and/or white matter with corresponding diffusion-weighted imaging (DWI) abnormalities (n = 9). Apparent diffusion coefficient (ADC) values were both reduced (n = 3) and increased (n = 3). Other findings included changes affecting one hemisphere, a perilesional and homologous region, hippocampal changes, and findings in the thalamus, basal ganglia, brain stem, and cerebellum. Conclusions: Magnetic resonance imaging changes were diffuse. Notably, MRI changes were found to involve the brain stem, cerebellum, basal ganglia, and thalamus. Magnetic resonance imaging changes in the latter areas have not been previously well described. In addition, MRI changes tended to evolve after 1 week; therefore, serial MRI is recommended in order to follow and highlight the MRI changes related to the neuroanatomic involvement seen in status epilepticus. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Status epilepticus (SE) is a neurological emergency with a mortality rate between 10% and 20% [1]. Despite the breadth of knowledge regarding SE, there remains limited concrete information on the neuroanatomic changes that may occur in patients with SE. Neuroimaging has become the most important tool for advancing our knowledge of these neuroanatomic changes in vivo. Radiographic descriptions of findings related to SE were not well described until the latter half of the 20th century. Aicardi et al. provided the initial description of changes seen on radiographic imaging [2] using pneumoencephalograms on children; abnormalities such as acute unilateral brain swelling and residual ventricular dilatation were described. As imaging techniques became more sophisticated, more evidence became available regarding physiologic changes related to SE. Eventually, in 1987, further reports
⁎ Corresponding author at: Department of Neurology/Clinical Neurophysiolgy, Detroit Medical Center, Wayne State University, Detroit, Michigan, US. E-mail address: [email protected] (A.M. Cartagena). 1525-5050/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2014.02.003
of changing and disappearing lesions with neuroanatomic correlation to seizure foci were published as seen on CT scan [3]. Since the advent of MRI, our descriptive knowledge has increased. It remains unclear, however, whether there is a pattern of changes that can be attributed to SE. The objective of this study was to review the abnormalities associated with SE in cerebral MRI of patients with SE at London Health Sciences Centre, a tertiary care center in South Western Ontario, Canada and to determine whether an imaging pattern was present. 2. Patients and methods 2.1. Inclusion criteria A retrospective review of our electroencephalogram (EEG) database was conducted. The patients included in the EEG database were admitted between the years 2001 and 2010. In total, 203 patients with SE were identified. Inclusion criteria were the following: (1) having seizures lasting a minimum of 30 min or recurrent seizures without
A.M. Cartagena et al. / Epilepsy & Behavior 33 (2014) 24–30
25
Table 1a Patient characteristics without prior seizure history (1–3). NORSE = new-onset refractory status epilepticus. Age (year/sex)
Seizure type
Duration (days)
Electroencephalogram (EEG) findings
Status epilepticus etiology
Relevant medical history
1
35/male
14
22/female
Unknown, NORSE
Depression, uveitis, glaucoma None
3
21/male
Generalized spike–wave, polyspike–wave, maximum frontal Maximum left temporal spike–wave, multiple independent spikes Maximum right temporal spike–wave, multiple independent spikes, burst suppression
Unknown, NORSE
2
Generalized convulsive status epilepticus, nonconvulsive status epilepticus Generalized convulsive status epilepticus
Unknown, NORSE
None
Generalized convulsive status epilepticus, nonconvulsive status epilepticus
58 21
recovery in between them for at least 30 min including nonconvulsive electrographic seizures, (2) having cerebral MRI showing signal changes after SE in sequences temporally related to seizures, and (3) having MRI changes not attributed to an underlying primary neurological disorder including the condition that precipitated the SE. Ethics approval was obtained according to our institutional standards. 2.2. Patient characteristics Ten patients (5 females; mean age = 35.0 ± 11.89 SD years) met the inclusion criteria. Seven patients had a history of epilepsy; three patients presented with SE as their first manifestation of epilepsy (Tables 1a and 1b). 2.3. MRI characteristics Postictal images were obtained from a 1.5-tesla MRI scanner with routine sequencing and maximum 5-mm slice thickness. Magnetic resonance imaging scans were performed within 12 days of SE presentation. A total of 17 cases (including 7 dummy cases) without clinical information were given to a certified neuroradiologist (DHL) for review.
some degree of MRI abnormalities on final neuroimaging. Follow-up MRI was up to 8 months after initial SE. Results are summarized in Table 2. Overall initial MRI findings included increased T2 signal changes in the gray and/or white matter with corresponding diffusion-weighted abnormalities (n = 9). Apparent diffusion coefficient values were reduced in three patients and increased in three. Findings also included changes affecting one cerebral hemisphere (n = 1), significant lobar swelling (n = 2), perilesional and homologous regions (n = 1), the hippocampi (n = 8), the thalamus and basal ganglia (n = 3), and the brain stem and cerebellum (n = 3). In total, eight patients displayed extratemporal changes in the following areas: cortical, basal ganglia, thalamus, external capsule, brain stem, cerebellum, occipital lobes, and insular cortices. The population identified without a prior seizure history was young: mean age = 26.0 (SD ± 7.81) years. All three patients were eventually diagnosed with new-onset refractory status epilepticus (NORSE). In those patients with a prior seizure history, antiepileptic drug reduction and noncompliance were seen as triggers in 4 patients, while three cases of SE were of an unknown etiology. 4. Discussion
3. Results
4.1. Status epilepticus and neuronal changes
Magnetic resonance imaging findings were widespread, both reversible and irreversible, and followed no consistent pattern. Magnetic resonance imaging findings were deemed irreversible if there was notable diffuse atrophy in the same region as the acute changes on follow-up MRI or if T2 hyperintensity remained unchanged on subsequent imaging (n = 7). Atrophy was diagnosed based on expertise (DHL). Magnetic resonance imaging findings were deemed reversible if signal intensity decreased or disappeared on follow-up MRI. Three patients had reversible findings on follow-up MRI (cases 4, 6, and 7); however, all patients who had follow-up MRIs (including cases 4, 6, and 7) were left with
The pathological explanation for MRI changes following SE is mostly extrapolated from animal studies [4–6]. There is either widespread neuronal necrosis [7] or neuronal injury that can be caused by a number of mechanisms including the following: ATP deficiency due to failure of Na/K ATPase pump, lactic acidosis, release of excitatory neurotransmitters such as glutamate, release of inflammatory mediators, increased membrane ion permeability, and possible activation of caspase pathways leading to apoptosis [8,9]. The neuronal necrosis can, in addition, be selective [10]. These histological and biochemical changes then manifest into tissue injury, which has been described to occur in various
Table 1b Patient characteristics with a prior seizure history (4–10). Age (year/sex)
Seizure type
Duration (days)
EEG findings
Status epilepticus etiology
Relevant medical history
4
27/male
Generalized epilepsy
Ecstasy/alcohol abuse, asthma
44/male
Posttraumatic epilepsy (well controlled)
Periodic lateralized epileptiform discharges (right parietooccipital) –
Unknown
5
Multiple, frequent episodes of SE 7
Unknown
6
24/male
21
37/female
8
59/female
b1
Right hemispheric spikes/periodic lateralized epileptiform discharges Left temporal–parietal seizures and spikes Generalized slowing (postictal)
Unknown
7
Generalized epilepsy (cause is unknown) since the age of 9 Complex partial seizures, secondarily generalized tonic–clonic Primary generalized epilepsy
Motor vehicle accident with traumatic brain injury (age: 20) Past history of alcohol and drug abuse (hashish) Left parietal cortical dysplasia
9
41/female
Posttraumatic epilepsy
14
Right frontal polyspike–wave
10
40/female
?
b1
Slowing maximum left temporal (postictal)
93
Tapering antiepileptic drugs Sepsis
Tapering antiepileptic drugs Noncompliance
Renal failure (failed transplant), colitis, mixed connective tissue disease Epilepsy (age: 15), corpus callosotomy (age: 22) Epilepsy (age: 30), drug abuse in the past
26 Table 2 MRI findings in patients with SE. DWI = diffusion-weighted imaging, ADC = apparent diffusion coefficient, MRS = magnetic resonance spectroscopy, N = normal, INA PVWM = inappropriate periventricular white matter, MTS = mesial temporal sclerosis. Initial MRI Timing from onset (days) 1
7
DWI increased signal
ADC
Yes
N
Yes
↑
T2 hyperintensity Hippocampus
Cortex
Basal ganglia + thalamus
Brain stem + cerebellum
N
N
Basal ganglia + thalamus
Brain stem + right and left cerebellum
Right and left
Left mesial frontal, insular
N
N
Other
Timing
DWI Δ
T2 hyperintensity
Comments/other
No gadolinium enhancement, abnormal periventricular lesions
b1 week
Yes
Diffuse atrophy (worse)
4 months
No
8 weeks
No
7 months
No
Subcortical, cerebellum and brain stem, abnormal right MRS (minimal change) Subcortical, brain stem, cerebellum, WM Bilateral MTS (↑ signal and volume loss) Bilateral MTS
No gadolinium enhancement, bilateral internal capsule
3
b7
Yes
Not done
Left N right
N
N
N
Left fornix
b1 week
No
4
11
Yes
↓
Right
Right frontal, parietal, occipital
N
Right cerebellar peduncle
T2 corpus callosum
3 weeks
No
4 months
No
8 months
No
5
3
Yes
↓ Right hippocampus
Right
6
12
Yes
Not done
Right
Bilateral frontal, temporal, right parietal Right hemisphere
7
b7
Yes
↑ Left parietal, + left hippocampus
Left
8
2
No
↑ Cerebellar white matter
9
7
Yes
10
3
Yes
Atrophy, right worse ≫ left, posttraumatic encephalomalacia INA PVWM (right hemisphere)
N
N
Right thalamus
N
Left parietal
N
N
MRS abnormal right and left temporal
N
Right frontal
Left
Not done
Right and left
Left frontal, occipital, parietal N
Brain stem + right and left cerebellum N
Deep + subcortical white matter changes
↓
Right basal ganglia + thalamus N
N
N
Swelling left frontal, occipital encephalomalacia left frontotemporal Diffuse atrophy
Bilateral hippocampi, left N right, minimal change Slight ↓ right occipital Subcortical gray, bilateral hippocampi (MTS) Subcortical gray, splenium of the corpus callosum
Diffuse atrophy (worse) Diffuse atrophy Minimal change, left frontal lesion disappeared Minimal change Right cerebellar peduncle resolved Diffuse atrophy INA PVWM (right worse N left), diffuse atrophy
Not performed
1 1 6 1
week month months week
Same Right hemispheric swelling Same Right hemispheric swelling ↓ Right thalamic hyperintensity Right MTS + right hemiatrophy New right parietal, left parietal Left hippocampus not as bright unchanged on DWI 2 weeks Yes New right parietal deep lesion, right New right hemispheric changes occipital; old right parietal gone, DWI, ↑ T2 left temporal left parietal unchanged, new left temporal Not performed (patient died secondary to respiratory distress and intestinal ischemia)
2 weeks
Yes Yes No Yes
Yes
Not performed
Diffuse bihemispheric, cerebellum
Bilateral DWI hyperintensity, diffuse cortical thickening (left frontotemporal)
A.M. Cartagena et al. / Epilepsy & Behavior 33 (2014) 24–30
2
6
Follow-up MRI
A.M. Cartagena et al. / Epilepsy & Behavior 33 (2014) 24–30
anatomic locations including the pyriform cortex, amygdala, and hippocampus [6,11–13]. The subsequent swelling of the neuropil can be seen on MRI as T2-weighted hyperintensity; T2-weighted hyperintensity has been described as appearing after several hours of SE [6,11–15]. 4.2. Status epilepticus and hippocampal changes on MRI Acute hippocampal edema and reversible, transient changes on MRI in the setting of SE have been well described [15,16] and were common in this series (80% of patients). In the group of patients without a history of seizures, 2 of 3 had hippocampal changes (increased T2 hyperintensity), and the changes were seen in both hippocampi. In the group of patients with a history of prior seizures, 6 of 7 had increased T2 hyperintensity of their hippocampi, and in 3 of those 7, the MRI changes were seen in the regions of EEG abnormalities. In follow-up MRI, 3 of the 8 patients with hippocampal changes were described as having mesial temporal sclerosis due to hippocampal atrophy and abnormal T2 signal intensity of the hippocampus(i). In the patients without hippocampal changes on MRI, increased T2 signal intensity was present in both the cerebellum and the brain stem. Overall, eight patients had extratemporal changes. Extratemporal is defined as including the cerebral cortex, basal ganglia, thalamus, external capsule, brain stem, cerebellum, occipital lobes, and insular cortices. As there is scarce literature regarding extratemporal changes, we wish to highlight the findings seen in our case series. 4.3. Status epilepticus and extratemporal changes Recently, there has been a report of transient MRI abnormalities seen in bilateral external capsules and frontotemporal and insular
27
cortices in a 39-year-old female with no prior seizure history [17]; these findings are very similar to our patient (case 2) who presented with NORSE. The MRI changes present in the external capsules of our patient (case 2) have been included (Fig. 1). Boyd et al. [18] have well described bilateral thalamic pulvinar changes in a 26-year-old male with NORSE. Thalamic changes were seen in case 6, a 24-year-old male with generalized epilepsy (cause is unknown) since the age of 9, who developed epilepsia partialis continua (EPC) of undetermined etiology affecting his right hemisphere for 48 h. His full medical history has been described elsewhere by our group [19]. His SE led to irreversible MRI changes involving his right hemisphere including his thalamus (Fig. 2). Thalamic changes were also seen in case 8, a 59-year-old female with significant medical comorbidities in addition to IGE. Her MRI was significant for changes in the right basal ganglia, right thalamus, and throughout her brain stem and both cerebellar hemispheres. Again, no alternative etiology was identified for her neuroimaging changes, and, unfortunately, no follow-up imaging was obtained as she died unexpectedly from intestinal ischemia. Magnetic resonance imaging changes in the cerebellum as a consequence of SE have been explained as a result of crossed cerebellar diaschisis in SE, with evidence of contralateral cerebellar involvement with a supratentorial epileptic focus [20]. There is also evidence for contralateral cerebellar hypometabolism during seizures [21]. In case 1, however, MRI displayed several foci of abnormalities in the white matter, and no supratentorial focus on EEG was identified to support crossed cerebellar diaschisis. The brain stem was also involved (Fig. 3). After several months of follow-up, no alternative explanation was found for the MRI changes despite exhaustive infectious, autoimmune, and neoplastic investigations. In addition, a brain biopsy of the left frontal lobe white matter was eventually undertaken, which showed only
Fig. 1. Case 2: magnetic resonance imaging (MRI) less than one week after presentation of status epilepticus (SE). (a–c) Axial fluid attenuation inversion recovery (FLAIR) images revealing increased signal (black arrows) in the hippocampi, external capsule, and insulae and, cortically, in the left mesial frontal lobe; (d) coronal FLAIR with increased signal (white arrows) in the hippocampi; (e) axial diffusion-weighted imaging (DWI) with diffusion restriction (black arrows) in the external capsule.
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Fig. 2. Case 6: magnetic resonance imaging (MRI) during status epilepticus (a, b) and six months after SE (c, d). (a, b) Diffuse diffusion restriction and edema in the right hemisphere including the thalamus on axial diffusion-weighted imaging (DWI); diffusion restriction is also noted in the left mesial temporal and lateral temporal cortices; (c, d) axial T2 and coronal fluid attenuation inversion recovery (FLAIR) several months after onset revealing dramatic right hemispheric atrophy.
mild microvacuolation and minimally increased cellularity with no evidence of demyelination. In case 4 the cerebellar peduncle was involved and it was ipsilateral to the supratentorial cortical MRI changes and again no focality was identified on EEG. These unpredictable changes in the cerebellum associated with SE are rare. The brain stem and cerebellum may be involved in SE because of their widespread cortical connections. The extensive reciprocal networks of the brain stem and cerebellum with the cerebral cortex may be affected as a consequence of the ongoing biochemical microalterations occurring elsewhere in the cerebral cortex. In crossed cerebellar diaschisis due to SE, a possible explanation is that injury is caused by excessive neuronal transmission from prolonged excitatory synaptic activity via the corticopontine–cerebellar pathways [20] — this may also help to explain the brain stem involvement. 4.4. Time frame of MRI changes seen in SE The literature refers to T2-weighted hyperintensity appearing after only several hours of SE [6,11–15]. In this study, T2-weighted hyperintensity was seen as appearing as early as 2 days. Patients were not imaged before 2 days because of their hemodynamic instability
and barriers in transportation in the ICU setting. After initial MRI, the timing of follow-up imaging ranged from less than 1 week up to 8 months. In 3 of 4 patients who were imaged within 1 week of their initial MRI, no significant changes were noted (cases 1, 3, and 6). Patients imaged after 1 week had changes from their baseline MRI (cases 4, 7, and 9). Overall, 5 of the 8 patients with follow-up imaging had changes seen on serial MRI. 5. Conclusion This is a retrospective study with a small sample size. Despite our small sample size, our findings indicate that SE can cause a variety of unpredictable MRI findings that are liable to change and evolve on serial MRI. These MRI changes can be focal, multifocal, hemispheric, or diffuse. In addition to the well-known hippocampal changes, we describe several cases of extratemporal changes. Although no specific pattern was identified, it is worthwhile to note that in those patients with changes on MRI imaging, changes occurred after 1 week of follow-up. Greater attention to such MRI findings and more aggressive serial neuroimaging is necessary in order to adequately highlight neuroimaging changes related to SE and follow their (often)
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Fig. 3. Case 1: MRI six days after the onset of SE. (a–d) Axial T2-weighted sequencing displaying multiple areas of increased signal intensity in the brain stem and cerebellum and basal ganglia. (a) Brain stem (white arrow), (b) cerebellum (white arrow), (c) basal ganglia and thalamus (white arrow), (d) periventricular white matter (white arrow).
progressive course. By following MRI changes related to SE with serial imaging, patterns might be identified regarding the neuroanatomic circuitry involved. Conflict of interest statement None. Author contributions Dr. Cartagena drafted and wrote the manuscript. All others (Drs. G.B. Young, D.H. Lee, and S. Mirsattari) were directly involved in helping with writing and editing the manuscript and provided expert advice. This study did not receive sponsorship or funding. Dr. Cartagena reports no disclosures. Dr. Mirsattari reports no disclosures. Dr. Young reports no disclosures. Dr. Lee reports no disclosures.
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