Epilepsy & Behavior 49 (2015) 178–183
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Brief Communication
Recurrent nonconvulsive status epilepticus in a patient with progressive left hemispheric leukoencephalopathy after a remote viral meningoencephalitis Ya-Ju Lin a,⁎, Chiening Lo b, Sho-Jen Cheng c, Chao-Liang Chou a, I-Hung Hseuh a a b c
Department of Neurology, MacKay Memorial Hospital, No. 92, Sec 2, Zhong-shan North Road, Taipei 104, Taiwan Department of Neurology, National Cheng Kung University Hospital Dou-Liou Branch, No. 345, Jhuangjing Road, Dou-Liou City, Yun-Lin County 640, Taiwan Department of Radiology, MacKay Memorial Hospital, No. 92, Sec 2, Zhong-shan North Road, Taipei 104, Taiwan
a r t i c l e
i n f o
Article history: Revised 9 May 2015 Accepted 12 May 2015 Available online 29 June 2015 Keywords: Nonconvulsive status epilepticus (NCSE) Epileptiform discharge EEG MRI Leukoencephalopathy Postencephalitic epilepsy
a b s t r a c t Nonconvulsive status epilepticus (NCSE), defined as changes in behavior and/or mental processes from baseline with continuous epileptiform discharges, remains a diagnostic and treatment challenge. Here, we present a 68-year-old female who developed 3 episodes of NCSE 10 years after a viral meningoencephalitis which gradually progressed to left hemispheric leukoencephalopathy. In this case, we hypothesize that immune-mediated mechanisms and perhaps genetic predisposition played a role in epileptogenesis, and these will be discussed. This article is part of a Special Issue entitled “Status Epilepticus”. © 2015 Elsevier Inc. All rights reserved.
1. Introduction
2. Case presentation
Nonconvulsive status epilepticus (NCSE) is a term used to denote a range of conditions in which electrographic seizure activity is prolonged and results in nonconvulsive clinical symptoms [1]. Clinically, it could be defined as changes in behavior and/or mental processes from baseline with continuous epileptiform discharges in electroencephalogram (EEG) without major motor signs [2]. As it is a very heterogeneous clinical disorder consisting of various subtypes, there are yet no universally accepted diagnostic criteria for NCSE, and it has remained a diagnostic and treatment challenge, especially in the elderly [2–4]. Considered as a form of cerebral response, NCSE is dependent largely on age, the level of cerebral development of the individual (cerebral integrity/maturity), epilepsy syndrome, and the anatomical location of the epileptic activity [1]. Based on Shorvon's review, it is suggested to be best subdivided primarily by age, because the forms of epilepsy in children are utterly different from those in adults, which is especially true in NCSE. Here, we present a 68-year-old female who developed 3 episodes of NCSE 10 years after a viral meningoencephalitis which gradually progressed to left hemispheric leukoencephalopathy.
This 68-year-old female patient had no major medical history in the past but had a fever with severe headache, drowsy consciousness, and intermittent incoherent speech in March, 2001. Her cerebrospinal fluid (CSF) study showed mild pleocytosis (white cell count: 15/cm3, all were lymphocytes), mild elevated protein (57 mg/dL), and negative cultures for viruses and bacteria. Initially, her electroencephalogram (EEG) showed diffuse slow waves, but it returned to normal in 2 weeks. The magnetic resonance imaging (MRI) of her brain showed nonspecific periventricular white matter changes; thus, viral meningoencephalitis was diagnosed. She recovered completely and remained well until November, 2010, when she became confused after an Escherichia coli urinary tract infection (UTI), with tremor-like movement and speech disturbance, which lasted for around 1 day. Cerebrospinal fluid study and brain MRI were unremarkable. Biochemistries, autoimmune profile, and CSF cultures for pathogens were all negative. Electroencephalogram showed diffuse slow waves only when she was confused, but focal sharp waves at F3C3T3 were recorded when she was clinically asymptomatic 10 days after (Fig. 1-1). The focal sharp waves were brief, lasting less than 30 s in a twelve-minute recording. No specific treatment was given this time. The second episode was on August 30, 2012 where she presented with fever, acute changes in her mental processes for a duration of 2 weeks, abnormal gazing and nystagmoid-like eye movements,
⁎ Corresponding author. Tel.: +886 225433535; fax: +886 225433642. E-mail addresses: [email protected] (Y.-J. Lin), [email protected] (C. Lo), [email protected] (S.-J. Cheng), [email protected] (C.-L. Chou), [email protected] (I.-H. Hseuh).
http://dx.doi.org/10.1016/j.yebeh.2015.05.023 1525-5050/© 2015 Elsevier Inc. All rights reserved.
Y.-J. Lin et al. / Epilepsy & Behavior 49 (2015) 178–183
aphasia, and right hemiparesis after several episodes of myoclonic jerks. Brain MRI done 4 days after the onset revealed white matter changes and a small high signal intensity lesion with restricted diffusion at the left frontal cortex in the diffusion-weighted imaging (DWI) (Figs. 2B, C). Continuous EEG showed periodic lateralized epileptiform discharges (PLEDs) involving the left hemisphere with occasional generalization (Fig. 1-2). Initially, valproate was given but was ineffective, so levetiracetam up to 3000 mg/day was administered instead, which showed optimal effect, and she gradually recovered to her usual state within 2 months. Her EEG and MRI signal changes also resolved in the follow-up study. The third episode was on November 8, 2013, after an influenza vaccination and a UTI. This time, she presented with profound right hemiplegia, global aphasia, persistent drowsy consciousness, intermittent abnormal gazing to the right side, and mild focal twitching at the right shoulder. Brain MRI done on the 4th day showed no significant changes in comparison to the one done 11 months earlier in the OPD. Electroencephalogram exhibited lateralized slow waves over the left hemisphere with left frontocentral sharp waves (Fig. 1-3). Technetium-99m ECD brain perfusion scan with single photon emission computed tomography (SPECT) showed hyperperfusion of her left frontal, parietal, and temporal lobes when her consciousness was impaired (Fig. 4). Since her neurologic deficits persisted, EEG and MRI were repeated 2 months later: EEG showed left lateralized slow waves (Fig. 1-4), and MRI revealed extensive left leukoencephalopathy with hyperintensity signal in the fluid-attenuated inversion recovery (FLAIR) images (Figs. 2A′, B′ C′, lower left) and scattered high signal intensity of the left temporal and parietal lobes in the DWI (Figs. 2A, B, C, lower left). Her MR angiography (MRA) showed bead-like appearance with less vessel branching of the left middle cerebral artery (MCA) (Fig. 3). Immunemediated vasculitis was highly suspected at this stage. Thus, autoimmune profile, including lupus anticoagulant, anticardiolipin, antineutrophil cytoplasmic antibody (ANCA), antimicrosomal, antithyroglobulin, N-methyl-D-aspartate receptor antibody (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor 1 (AMPA 1), AMPA 2, gamma-aminobutyric acid (GABA), antileucine-rich glioma inactivated-1 (LGI1), and contactin-associated protein-like 2 (CASPR2), was checked, but all laboratory findings were negative. Corticosteroid, zonisamide, and clonazepam were added for seizure control in addition to levetiracetam. But she showed only modest responses. At a later stage, only levetiracetam 4000 mg/day, zonisamide 100 mg/day, and clonazepam 2 mg/day were used while steroids were gradually tapered within 3 months. She remains aphasic but could walk with a walking stick 1 year later. Follow-up brain MRI in February, 2015 still showed some scattered restricted diffusion lesions seen bifrontally and an atrophic left hemisphere. 3. Discussion 3.1. Clinical manifestations and her EEG Based on the definition of NCSE, this patient could well fit into this category: there were simultaneous EEG changes with good correlation to the cognitive disturbances, no major convulsive motor manifestations, and a good response from the patient to the antiepileptic drug (AED) treatment [2–6]. Complex partial status epilepticus (CPSE) of frontal origin was highly suggested which are the most common form of extra-temporal seizures and often drug-refractory [5,6]. Cockerell et al. had reported that recurrence of CPSE within regular intervals was common, even during effective AED treatments [5]. Usually, there were no unifying causes for recurrence and no cognitive decline or neurologic deterioration during the recurrence, but our patient was the exception. Her serial EEG recordings in each episode showed the process of her epileptogenesis, which was confined to the left frontal–temporal lobes. In the first episode, her first EEG showed diffuse slow waves, with
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epileptiform discharges located at the left frontocentral area detected later in the follow-up EEG (Fig. 1-1). In the second and third episodes, PLEDs, lateralized slow waves, and bursts of sharp waves were recorded (Figs. 1-2, 1-3). All these activities resolved when her impaired mental processes and focal deficits recovered to her usual state, which were compatible with working criteria for NCSE suggested by Beniczky et al. [7]. 3.2. Transient vs permanent abnormal MRI changes Brain MRI is an important diagnostic tool to differentiate NCSE from other acute brain insults, such as acute ischemic stroke. Diffusionweighted imaging and FLAIR images are most useful in detecting early seizure-caused neuronal damage and its severity [7,8]. Usually, the NCSE-related MRI abnormalities were transient and reversible but can be irreversible and lead to cell death and local brain atrophy if left untreated or inadequately treated [9,10]. The serial MRI changes of this patient were compatible with previous reports [8,10], including restricted diffusion in DWI and hyperintensity signal in FLAIR imaging, except decreased vascularity in MRA. In her first MRI, there were no significant changes. In the 2nd episode, restricted diffusion in DWI was found in the left frontal area (Figs. 2B, C, upper middle) with concomitant PLEDs on EEG (Fig. 12). In her 3rd episode, although the initial MRI done on the 4th day of onset did not exhibit any new abnormality, brain SPECT on the following day showed asymmetrically increased perfusion in the left temporal, frontal, and parietal lobes (Fig. 4), suggesting ictal activity. Her prolonged seizures with persistent consciousness disturbance apparently were associated with or led to severe cortical neuron necrosis with mixed cytotoxic edema (restricted diffusion in DWI, Figs. 2A, B, lower left) and vasogenic edema (extensive hyperintensity located at the left hemisphere in FLAIR, Figs. 2A′, B′ lower left). In contrast to prior reports which showed increased vascularity in MRA due to NCSE [7,8], her MRA showed bead-like appearance in the left distal M1 (Fig. 3, curved arrow) and occlusion of the left MCA branches (Fig. 3, arrow) during her last episode of NCSE. Immunemediated obliterans vasculitis and/or prolonged seizures might have induced hypoxia and hypoperfusion of the left hemisphere [10]. Her most recent brain MRI (February, 2015) (Figs. 2 and 3, lower right), 14 months after the 3rd episode, showed that the left leukoencephalopathy had become less prominent but revealed a more atrophic left hemisphere, with partial recanalization of her left MCA branches, suggesting possible permanent neuronal damages. 3.3. Possible pathogenesis and epileptogenesis According to the definition of NCSE [1], the pathogenesis and epileptogenesis are believed to be strongly associated with aging processes, functional degradation, and genetic predisposing factors [1–4]. Evidence has shown that the number of patients with NCSE without preexisting epilepsy is increasing with age, making up more than 70% of patients aged over 60 [2], particularly those with a specific focal epileptic activity (localization-related syndrome) [2]. Preexisting epilepsy syndrome is a strong risk factor, as well as comorbidities such as old stroke, trauma, dementia, and acute medical/neurological problems, especially systemic infection. History of central nervous system infection (either encephalitis or meningitis) is strongly associated with subsequent development of recurrent, unprovoked seizures, known as postencephalitic epilepsy (PEE) with the highest risk occurring during the first 5 years [12,13]. In a recent study of PEE in adult patients by Singh et al. [13], PEE developed in 29.9% of patients with various clinical seizure patterns, most of which were focal (80%). The presence of acute inhospital seizures and abnormal brain MRI were the strongest predictors, which were not shown in our patient. In the report of Trinka et al. [14], the majority (72%) of PEE was complex partial seizure with or without
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Fig. 1-1
Fig. 1-2
Fig. 1-3
Fig. 1-4
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Fig. 2. Serial MRI changes from 2010 to 2015: small high signal intensity with restricted diffusion found in the left frontal lobe (B, C, arrow) on Sep 3, 2012 but disappeared later; extensive leukoencephalopathy with some restricted diffusion over the left temporoparietal area (A, A′, B, and B′, double arrow) on Jan 15, 2014 and, eventually, tissue loss and atrophy of the left hemisphere (A, A′, arrow head). Surprisingly, there was still some different scattered restricted diffusion lesions (B and C, dashed arrow) found in the follow-up images.
generalized epilepsy. The temporal lobe was the most vulnerable region affected in PEE, usually associated with mesial temporal sclerosis and/or focal atrophy [13–16]. The time from acute insult to the onset of refractory postencephalitic seizures was associated with the anatomic localization, lesion size, and the age at encephalitis [15,16]. Generally, PEE developed with a shorter latent period in patients with extratemporal/ multifocal or generalized epilepsy (median: 0.1 year in the Montreal patient series) and longer period in patients with nonherpes simplex
encephalitis (median: 3.8 years in the Yale series) [14,16]. It seemed to be relatively resistant to the medical treatment in patients with extratemporal or neocortical foci and in the elderly [17]. But quite a favorable outcome was observed in a recent large series from Mayo Clinic for adult patients [13]. As for this patient, it is speculated that her remote viral meningoencephalitis 10 years ago might have led to focal neuronal damage and later was transformed into a potential epileptogenic focus over the left frontal and temporal region. Her
Fig. 1. Series of EEG. 1: EEG on Nov 19, 2010 showed episodic sharp waves with phase reversed at F3C3T3 even without clinical symptoms; 2: EEG on Sep 10, 2012 showed PLEDs about 1 Hz over the left hemisphere; 3: EEG on Nov 18, 2013 showed sharp waves over F3C3 and left lateralized slow waves; and 4: EEG on Jan 03, 2014 showed lateralized slow waves over the left hemisphere.
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Fig. 3. Serial changes of MRA: bead-like appearance of left distal M1 found (curved arrow) with subsequent left MCA branch occlusion (arrow), partially recovered on the last follow-up image done on Feb 17, 2015.
subsequent episodes of NCSE were triggered by UTI and vaccinationrelated immune-mediated process, which might be suggestive of an immune-mediated vasculitis leading to hypoxia and further
neuronal damage which could and which could explain the possibility of short-term relapse. Although, in her immune surveys, no known antibodies that could cause NCSE were found, we might
Fig. 4. Tc 99 EDC Brain SPECT on Nov 13, 2013 showed hyperperfusion over the left hemisphere, esp. the left temporal and parietal areas, indicating active metabolic status such as seizure activity.
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hypothesize that such antibody is yet to be discovered. Furthermore, we may also hypothesize that immune-related genetic predisposition might play a role in such circumstances since not every patient who experienced meningoencephalitis with no obvious comorbidities develops NCSE. 3.4. Treatment and prognosis of NCSE The prognosis of NCSE is, in general, more favorable than generalized convulsive status epilepticus; however, the underlying disease is often decisive. For example, patients with preexisting epilepsy syndromes usually have good response to treatments, while the presence of acute symptomatic etiology with advanced age and impaired consciousness is often associated with poor outcome [2,11,18,19]. In this patient, no treatment was given during or after her first episode; there was good response to levetiracetam for the 2nd one; but only modest responses were seen later despite zonisamide, clonazepam, and steroids being administered in addition to levetiracetam, which that she had been taking. It is questionable whether giving any AEDs during the first episode could have prevented her from subsequent NCSEs, given the fact that the diagnosis was not well established at that time and levetiracetam was not successful in preventing her 3rd episode. However, early diagnosis, rapid termination of seizure activities, and good control of the triggered factors would be fundamental in having favorable outcomes. 4. Conclusion In conclusion, we were able to document the process of epileptogenesis and the subsequent leukoencephalopathy developing in association with serial NCSEs demonstrated by simultaneous EEG and image studies. Urinary track infection and vaccination were the only trigger factors identified. We may presume that immune related responses and a genetic predisposition might play a role in the development of her NCSE. Further investigations and evidence are needed to support our assumption. Conflicts of interest The authors state they have no conflict of interest.
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References [1] Shorvon S. What is nonconvulsive status epilepticus, and what are its subtypes? Epilepsia 2007;48(Suppl. 8):35–8. [2] Meierkord H, Holtkamp M. Non-convulsive status epilepticus in adults: clinical forms and treatment. Lancet Neurol 2007;6:329–39. [3] Holtkamp M, Meierkord H. Nonconvulsive status epilepticus: a diagnostic and therapeutic challenge in the intensive care setting. Ther Adv Neurol Disord 2011;4: 169–81. [4] Shavit L, Grenader T, Galperin I. Nonconvulsive status epilepticus in elderly: a possible diagnostic pitfall. Eur J Int Med 2012;23:701–4. [5] Cockerell OC, Walker MC, Sander JW, Shorvon SD. Complex partial status epilepticus: a recurrent problem. J Neurol Neurosurg Psychiatry 1994;57:835–7. [6] Williamson PD, Spencer DD, Spencer SS, Novelly RA, Mattson RH. Complex partial status epilepticus: a depth-electrode study. Ann Neurol 1985;18:647–54. [7] Beniczky S, Hirsch LJ, Kaplan PW, Pressler R, Bauer G, Aurlien H, et al. Unified EEG terminology and criteria for nonconvulsive status epilepticus. Epilepsia 2013; 54(Suppl. 6):28–9. [8] Cole AJ. Status epilepticus and periictal imaging. Epilepsia 2004;45(Suppl. 4):72–7. [9] Huang YC, Weng HH, Tsai YT, Huang YC, Hsiao MC, Wu CY, et al. Periictal magnetic resonance imaging in status epilepticus. Epilepsy Res 2009;86:72–81. [10] Bauer G, Gotwald T, Dobesberger J, Embacher N, Felber S, Bauer R, et al. Transient and permanent magnetic resonance imaging abnormalities after complex partial status epilepticus. Epilepsy Behav 2006;8:666–71. [11] Milligan TA, Zamani A, Bromfield E. Frequency and patterns of MRI abnormalities due to status epilepticus. Seizure 2009;18:104–8. [12] Annegers JF, Hauser WA, Beghi E, Nicolosi A, Kurland LT. The risk of unprovoked seizures after encephalitis and meningitis. Neurology 1988;38:1407–10. [13] Singh TD, Fugate JE, Hocker SE, Rabinstein AA. Postencephalitic epilepsy: clinical characteristics and predictors. Epilepsia 2015;56:133–8. [14] Trinka E, Dubeau F, Andermann F, Bastos A, Hui A, Li LM, et al. Clinical findings, imaging characteristics and outcome in catastrophic post-encephalitic epilepsy. Epileptic Disord 2000;2:153–62. [15] Sellner J, Trinka E. Seizures and epilepsy in herpes simplex virus encephalitis: current concepts and future directions of pathogenesis and management. J Neurol 2012;259:2019–30. [16] Marks DA, Kim J, Spencer DD, Spencer SS. Characteristics of intractable seizures following meningitis and encephalitis. Neurology 1992;42:1513–8. [17] Trinka E, Dubeau F, Andermann F, Hui A, Bastos A, Li LM, et al. Successful epilepsy surgery in catastrophic postencephalitic epilepsy. Neurology 2000;54:2170–3. [18] Haffey S, McKernan A, Pang K. Non-convulsive status epilepticus: a profile of patients diagnosed within a tertiary referral centre. J Neurol Neurosurg Psychiatry 2004;75:1043–4. [19] Kang BS, Jhang Y, Kim YS, Moon J, Shin JW, Moon HJ, et al. Etiology and prognosis of non-convulsive status epilepticus. J Clin Neurosci 2014;21:1915–9.
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Brief Communication
Recurrent nonconvulsive status epilepticus in a patient with progressive left hemispheric leukoencephalopathy after a remote viral meningoencephalitis Ya-Ju Lin a,⁎, Chiening Lo b, Sho-Jen Cheng c, Chao-Liang Chou a, I-Hung Hseuh a a b c
Department of Neurology, MacKay Memorial Hospital, No. 92, Sec 2, Zhong-shan North Road, Taipei 104, Taiwan Department of Neurology, National Cheng Kung University Hospital Dou-Liou Branch, No. 345, Jhuangjing Road, Dou-Liou City, Yun-Lin County 640, Taiwan Department of Radiology, MacKay Memorial Hospital, No. 92, Sec 2, Zhong-shan North Road, Taipei 104, Taiwan
a r t i c l e
i n f o
Article history: Revised 9 May 2015 Accepted 12 May 2015 Available online 29 June 2015 Keywords: Nonconvulsive status epilepticus (NCSE) Epileptiform discharge EEG MRI Leukoencephalopathy Postencephalitic epilepsy
a b s t r a c t Nonconvulsive status epilepticus (NCSE), defined as changes in behavior and/or mental processes from baseline with continuous epileptiform discharges, remains a diagnostic and treatment challenge. Here, we present a 68-year-old female who developed 3 episodes of NCSE 10 years after a viral meningoencephalitis which gradually progressed to left hemispheric leukoencephalopathy. In this case, we hypothesize that immune-mediated mechanisms and perhaps genetic predisposition played a role in epileptogenesis, and these will be discussed. This article is part of a Special Issue entitled “Status Epilepticus”. © 2015 Elsevier Inc. All rights reserved.
1. Introduction
2. Case presentation
Nonconvulsive status epilepticus (NCSE) is a term used to denote a range of conditions in which electrographic seizure activity is prolonged and results in nonconvulsive clinical symptoms [1]. Clinically, it could be defined as changes in behavior and/or mental processes from baseline with continuous epileptiform discharges in electroencephalogram (EEG) without major motor signs [2]. As it is a very heterogeneous clinical disorder consisting of various subtypes, there are yet no universally accepted diagnostic criteria for NCSE, and it has remained a diagnostic and treatment challenge, especially in the elderly [2–4]. Considered as a form of cerebral response, NCSE is dependent largely on age, the level of cerebral development of the individual (cerebral integrity/maturity), epilepsy syndrome, and the anatomical location of the epileptic activity [1]. Based on Shorvon's review, it is suggested to be best subdivided primarily by age, because the forms of epilepsy in children are utterly different from those in adults, which is especially true in NCSE. Here, we present a 68-year-old female who developed 3 episodes of NCSE 10 years after a viral meningoencephalitis which gradually progressed to left hemispheric leukoencephalopathy.
This 68-year-old female patient had no major medical history in the past but had a fever with severe headache, drowsy consciousness, and intermittent incoherent speech in March, 2001. Her cerebrospinal fluid (CSF) study showed mild pleocytosis (white cell count: 15/cm3, all were lymphocytes), mild elevated protein (57 mg/dL), and negative cultures for viruses and bacteria. Initially, her electroencephalogram (EEG) showed diffuse slow waves, but it returned to normal in 2 weeks. The magnetic resonance imaging (MRI) of her brain showed nonspecific periventricular white matter changes; thus, viral meningoencephalitis was diagnosed. She recovered completely and remained well until November, 2010, when she became confused after an Escherichia coli urinary tract infection (UTI), with tremor-like movement and speech disturbance, which lasted for around 1 day. Cerebrospinal fluid study and brain MRI were unremarkable. Biochemistries, autoimmune profile, and CSF cultures for pathogens were all negative. Electroencephalogram showed diffuse slow waves only when she was confused, but focal sharp waves at F3C3T3 were recorded when she was clinically asymptomatic 10 days after (Fig. 1-1). The focal sharp waves were brief, lasting less than 30 s in a twelve-minute recording. No specific treatment was given this time. The second episode was on August 30, 2012 where she presented with fever, acute changes in her mental processes for a duration of 2 weeks, abnormal gazing and nystagmoid-like eye movements,
⁎ Corresponding author. Tel.: +886 225433535; fax: +886 225433642. E-mail addresses: [email protected] (Y.-J. Lin), [email protected] (C. Lo), [email protected] (S.-J. Cheng), [email protected] (C.-L. Chou), [email protected] (I.-H. Hseuh).
http://dx.doi.org/10.1016/j.yebeh.2015.05.023 1525-5050/© 2015 Elsevier Inc. All rights reserved.
Y.-J. Lin et al. / Epilepsy & Behavior 49 (2015) 178–183
aphasia, and right hemiparesis after several episodes of myoclonic jerks. Brain MRI done 4 days after the onset revealed white matter changes and a small high signal intensity lesion with restricted diffusion at the left frontal cortex in the diffusion-weighted imaging (DWI) (Figs. 2B, C). Continuous EEG showed periodic lateralized epileptiform discharges (PLEDs) involving the left hemisphere with occasional generalization (Fig. 1-2). Initially, valproate was given but was ineffective, so levetiracetam up to 3000 mg/day was administered instead, which showed optimal effect, and she gradually recovered to her usual state within 2 months. Her EEG and MRI signal changes also resolved in the follow-up study. The third episode was on November 8, 2013, after an influenza vaccination and a UTI. This time, she presented with profound right hemiplegia, global aphasia, persistent drowsy consciousness, intermittent abnormal gazing to the right side, and mild focal twitching at the right shoulder. Brain MRI done on the 4th day showed no significant changes in comparison to the one done 11 months earlier in the OPD. Electroencephalogram exhibited lateralized slow waves over the left hemisphere with left frontocentral sharp waves (Fig. 1-3). Technetium-99m ECD brain perfusion scan with single photon emission computed tomography (SPECT) showed hyperperfusion of her left frontal, parietal, and temporal lobes when her consciousness was impaired (Fig. 4). Since her neurologic deficits persisted, EEG and MRI were repeated 2 months later: EEG showed left lateralized slow waves (Fig. 1-4), and MRI revealed extensive left leukoencephalopathy with hyperintensity signal in the fluid-attenuated inversion recovery (FLAIR) images (Figs. 2A′, B′ C′, lower left) and scattered high signal intensity of the left temporal and parietal lobes in the DWI (Figs. 2A, B, C, lower left). Her MR angiography (MRA) showed bead-like appearance with less vessel branching of the left middle cerebral artery (MCA) (Fig. 3). Immunemediated vasculitis was highly suspected at this stage. Thus, autoimmune profile, including lupus anticoagulant, anticardiolipin, antineutrophil cytoplasmic antibody (ANCA), antimicrosomal, antithyroglobulin, N-methyl-D-aspartate receptor antibody (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor 1 (AMPA 1), AMPA 2, gamma-aminobutyric acid (GABA), antileucine-rich glioma inactivated-1 (LGI1), and contactin-associated protein-like 2 (CASPR2), was checked, but all laboratory findings were negative. Corticosteroid, zonisamide, and clonazepam were added for seizure control in addition to levetiracetam. But she showed only modest responses. At a later stage, only levetiracetam 4000 mg/day, zonisamide 100 mg/day, and clonazepam 2 mg/day were used while steroids were gradually tapered within 3 months. She remains aphasic but could walk with a walking stick 1 year later. Follow-up brain MRI in February, 2015 still showed some scattered restricted diffusion lesions seen bifrontally and an atrophic left hemisphere. 3. Discussion 3.1. Clinical manifestations and her EEG Based on the definition of NCSE, this patient could well fit into this category: there were simultaneous EEG changes with good correlation to the cognitive disturbances, no major convulsive motor manifestations, and a good response from the patient to the antiepileptic drug (AED) treatment [2–6]. Complex partial status epilepticus (CPSE) of frontal origin was highly suggested which are the most common form of extra-temporal seizures and often drug-refractory [5,6]. Cockerell et al. had reported that recurrence of CPSE within regular intervals was common, even during effective AED treatments [5]. Usually, there were no unifying causes for recurrence and no cognitive decline or neurologic deterioration during the recurrence, but our patient was the exception. Her serial EEG recordings in each episode showed the process of her epileptogenesis, which was confined to the left frontal–temporal lobes. In the first episode, her first EEG showed diffuse slow waves, with
179
epileptiform discharges located at the left frontocentral area detected later in the follow-up EEG (Fig. 1-1). In the second and third episodes, PLEDs, lateralized slow waves, and bursts of sharp waves were recorded (Figs. 1-2, 1-3). All these activities resolved when her impaired mental processes and focal deficits recovered to her usual state, which were compatible with working criteria for NCSE suggested by Beniczky et al. [7]. 3.2. Transient vs permanent abnormal MRI changes Brain MRI is an important diagnostic tool to differentiate NCSE from other acute brain insults, such as acute ischemic stroke. Diffusionweighted imaging and FLAIR images are most useful in detecting early seizure-caused neuronal damage and its severity [7,8]. Usually, the NCSE-related MRI abnormalities were transient and reversible but can be irreversible and lead to cell death and local brain atrophy if left untreated or inadequately treated [9,10]. The serial MRI changes of this patient were compatible with previous reports [8,10], including restricted diffusion in DWI and hyperintensity signal in FLAIR imaging, except decreased vascularity in MRA. In her first MRI, there were no significant changes. In the 2nd episode, restricted diffusion in DWI was found in the left frontal area (Figs. 2B, C, upper middle) with concomitant PLEDs on EEG (Fig. 12). In her 3rd episode, although the initial MRI done on the 4th day of onset did not exhibit any new abnormality, brain SPECT on the following day showed asymmetrically increased perfusion in the left temporal, frontal, and parietal lobes (Fig. 4), suggesting ictal activity. Her prolonged seizures with persistent consciousness disturbance apparently were associated with or led to severe cortical neuron necrosis with mixed cytotoxic edema (restricted diffusion in DWI, Figs. 2A, B, lower left) and vasogenic edema (extensive hyperintensity located at the left hemisphere in FLAIR, Figs. 2A′, B′ lower left). In contrast to prior reports which showed increased vascularity in MRA due to NCSE [7,8], her MRA showed bead-like appearance in the left distal M1 (Fig. 3, curved arrow) and occlusion of the left MCA branches (Fig. 3, arrow) during her last episode of NCSE. Immunemediated obliterans vasculitis and/or prolonged seizures might have induced hypoxia and hypoperfusion of the left hemisphere [10]. Her most recent brain MRI (February, 2015) (Figs. 2 and 3, lower right), 14 months after the 3rd episode, showed that the left leukoencephalopathy had become less prominent but revealed a more atrophic left hemisphere, with partial recanalization of her left MCA branches, suggesting possible permanent neuronal damages. 3.3. Possible pathogenesis and epileptogenesis According to the definition of NCSE [1], the pathogenesis and epileptogenesis are believed to be strongly associated with aging processes, functional degradation, and genetic predisposing factors [1–4]. Evidence has shown that the number of patients with NCSE without preexisting epilepsy is increasing with age, making up more than 70% of patients aged over 60 [2], particularly those with a specific focal epileptic activity (localization-related syndrome) [2]. Preexisting epilepsy syndrome is a strong risk factor, as well as comorbidities such as old stroke, trauma, dementia, and acute medical/neurological problems, especially systemic infection. History of central nervous system infection (either encephalitis or meningitis) is strongly associated with subsequent development of recurrent, unprovoked seizures, known as postencephalitic epilepsy (PEE) with the highest risk occurring during the first 5 years [12,13]. In a recent study of PEE in adult patients by Singh et al. [13], PEE developed in 29.9% of patients with various clinical seizure patterns, most of which were focal (80%). The presence of acute inhospital seizures and abnormal brain MRI were the strongest predictors, which were not shown in our patient. In the report of Trinka et al. [14], the majority (72%) of PEE was complex partial seizure with or without
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Fig. 1-1
Fig. 1-2
Fig. 1-3
Fig. 1-4
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Fig. 2. Serial MRI changes from 2010 to 2015: small high signal intensity with restricted diffusion found in the left frontal lobe (B, C, arrow) on Sep 3, 2012 but disappeared later; extensive leukoencephalopathy with some restricted diffusion over the left temporoparietal area (A, A′, B, and B′, double arrow) on Jan 15, 2014 and, eventually, tissue loss and atrophy of the left hemisphere (A, A′, arrow head). Surprisingly, there was still some different scattered restricted diffusion lesions (B and C, dashed arrow) found in the follow-up images.
generalized epilepsy. The temporal lobe was the most vulnerable region affected in PEE, usually associated with mesial temporal sclerosis and/or focal atrophy [13–16]. The time from acute insult to the onset of refractory postencephalitic seizures was associated with the anatomic localization, lesion size, and the age at encephalitis [15,16]. Generally, PEE developed with a shorter latent period in patients with extratemporal/ multifocal or generalized epilepsy (median: 0.1 year in the Montreal patient series) and longer period in patients with nonherpes simplex
encephalitis (median: 3.8 years in the Yale series) [14,16]. It seemed to be relatively resistant to the medical treatment in patients with extratemporal or neocortical foci and in the elderly [17]. But quite a favorable outcome was observed in a recent large series from Mayo Clinic for adult patients [13]. As for this patient, it is speculated that her remote viral meningoencephalitis 10 years ago might have led to focal neuronal damage and later was transformed into a potential epileptogenic focus over the left frontal and temporal region. Her
Fig. 1. Series of EEG. 1: EEG on Nov 19, 2010 showed episodic sharp waves with phase reversed at F3C3T3 even without clinical symptoms; 2: EEG on Sep 10, 2012 showed PLEDs about 1 Hz over the left hemisphere; 3: EEG on Nov 18, 2013 showed sharp waves over F3C3 and left lateralized slow waves; and 4: EEG on Jan 03, 2014 showed lateralized slow waves over the left hemisphere.
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Fig. 3. Serial changes of MRA: bead-like appearance of left distal M1 found (curved arrow) with subsequent left MCA branch occlusion (arrow), partially recovered on the last follow-up image done on Feb 17, 2015.
subsequent episodes of NCSE were triggered by UTI and vaccinationrelated immune-mediated process, which might be suggestive of an immune-mediated vasculitis leading to hypoxia and further
neuronal damage which could and which could explain the possibility of short-term relapse. Although, in her immune surveys, no known antibodies that could cause NCSE were found, we might
Fig. 4. Tc 99 EDC Brain SPECT on Nov 13, 2013 showed hyperperfusion over the left hemisphere, esp. the left temporal and parietal areas, indicating active metabolic status such as seizure activity.
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hypothesize that such antibody is yet to be discovered. Furthermore, we may also hypothesize that immune-related genetic predisposition might play a role in such circumstances since not every patient who experienced meningoencephalitis with no obvious comorbidities develops NCSE. 3.4. Treatment and prognosis of NCSE The prognosis of NCSE is, in general, more favorable than generalized convulsive status epilepticus; however, the underlying disease is often decisive. For example, patients with preexisting epilepsy syndromes usually have good response to treatments, while the presence of acute symptomatic etiology with advanced age and impaired consciousness is often associated with poor outcome [2,11,18,19]. In this patient, no treatment was given during or after her first episode; there was good response to levetiracetam for the 2nd one; but only modest responses were seen later despite zonisamide, clonazepam, and steroids being administered in addition to levetiracetam, which that she had been taking. It is questionable whether giving any AEDs during the first episode could have prevented her from subsequent NCSEs, given the fact that the diagnosis was not well established at that time and levetiracetam was not successful in preventing her 3rd episode. However, early diagnosis, rapid termination of seizure activities, and good control of the triggered factors would be fundamental in having favorable outcomes. 4. Conclusion In conclusion, we were able to document the process of epileptogenesis and the subsequent leukoencephalopathy developing in association with serial NCSEs demonstrated by simultaneous EEG and image studies. Urinary track infection and vaccination were the only trigger factors identified. We may presume that immune related responses and a genetic predisposition might play a role in the development of her NCSE. Further investigations and evidence are needed to support our assumption. Conflicts of interest The authors state they have no conflict of interest.
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