Epilepsy & Behavior 31 (2014) 85–90
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Childhood-onset nonprogressive chronic encephalitis Philippe Rizek a, Christina Cheung a, Richard S. McLachlan a, Brent Hayman-Abello b, Donald H. Lee c, Robert R. Hammond a,d, Seyed M. Mirsattari a,c,e,f,⁎ a
Department of Clinical Neurological Sciences, Western University, London, Canada Psychology Services, London Health Sciences Centre, London, Ontario, Canada Department of Medical Imaging, Western University, London, Canada d Department of Pathology, Western University, London, Canada e Department of Medical Biophysics, Western University, London, Canada f Department of Psychology, Western University, London, Canada b c
a r t i c l e
i n f o
Article history: Received 15 July 2013 Revised 3 October 2013 Accepted 9 November 2013 Available online 22 December 2013 Keywords: Rasmussen's Chronic encephalitis Natural history Nonprogressive variant Epilepsy surgery Epilepsia partialis continua
a b s t r a c t Purpose: The purpose of this study was to describe a series of patients with pathologically proven chronic encephalitis who had a nonprogressive course during a long follow-up, suggestive of a “benign” variant of Rasmussen's encephalitis (RE). Methods: Four patients who were referred to our Comprehensive Epilepsy Program at London Health Science Centre in London, Ontario, were diagnosed with chronic encephalitis on a pathological basis after epilepsy surgery to treat their partial-onset seizures. Results: None of our four cases followed the typical course of RE despite their childhood-onset seizures between ages 2 and 12 years. One was preceded by a mild head trauma and fever at onset. None had epilepsia partialis continua (EPC). Their long-term follow-up revealed a nonprogressive form of the syndrome with respect to the neurological examination, EEG, MRI, and neuropsychological findings. Conclusion: These cases extend the spectrum of childhood-onset intractable epilepsy with chronic encephalitis to include nonprogressive variants of RE. The absence of EPC may be a prognostic indicator of a nonprogressive course. © 2013 Elsevier Inc. All rights reserved.
1. Introduction
2. Case histories
Rasmussen's encephalitis (RE) is an inflammatory neurological disease that manifests with medically intractable partial seizures and a progressive clinical course including unilateral cerebral atrophy, hemiparesis, and cognitive impairment [1]. The exact etiology of RE is unknown, although viral causes [2–4], autoantibodies [5–9], and cytotoxic T-cell mechanisms [10,11] have been proposed. Antiepileptic drugs (AEDs) are usually ineffective in treating the seizures in RE, while hemispherectomy is effective in childhood in arresting its progression. Since its first description by Rasmussen and colleagues in 1958 [2], a number of atypical features are reported that have widened the clinical spectrum of RE [12]. We present four cases of pathologically confirmed chronic encephalitis, all of which had childhood-onset intractable partial seizures with or without secondary generalization. None of them experienced significant neurological or radiological decline despite continued partial seizures.
Four patients referred to our Comprehensive Epilepsy Program were unexpectedly diagnosed with chronic encephalitis on a pathological basis after epilepsy surgery to treat their medically intractable partialonset seizures.
Abbreviations: RE, Rasmussen's encephalitis; CE, chronic encephalitis; EEG, electroencephalography; MRI, magnetic resonance imaging; EPC, epilepsia partialis continua. ⁎ Corresponding author at: B10-108, 339 Windermere Road, London, Ontario N6A 5A5, Canada. Fax: +1 519 663 3440. E-mail address: [email protected] (S.M. Mirsattari). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.11.005
2.1. Patient 1 This 38-year-old, right-handed woman began having seizures at age 12 years with multiple seizure types, which were refractory to AEDs. Her most frequent seizures consisted of facial twitching around her nose bilaterally with inability to speak while retaining awareness and comprehension, occurring up to 4–5 times per day. She also experienced motionless staring spells with retained awareness. Occasionally, she had head turning to the left with clonic jerking of the left hand and mouth with inability to speak but retained awareness followed by secondary generalization. Postictally, she was unable to move or talk for about 15 min. Preoperative EEG at age 24 years demonstrated right frontal spikes and seizures; her cranial MRI demonstrated right frontal cortical atrophy (Figs. 1A, B). Preoperative neuropsychological testing showed frontal lobe dysfunction maximal in the right hemisphere manifesting with difficulties in some executive abilities
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(planning, nonverbal reasoning), hand strength and speed (worse on the left), verbal fluency, and mildly in verbal learning. She underwent a limited right inferior frontal lobe resection at the age of 26 years that revealed pathology consistent with RE (Figs. 2A–F) [13]. Postoperatively, she had reduced fine finger movements in her left hand, and neuropsychological testing revealed a decline in nonverbal reasoning, verbal abilities, and attention. Seizure frequency and severity decreased by 50% postoperatively, but she continued to have catamenial partial seizures and rare secondarily generalized seizures despite 3 AEDs. Cranial MRI study postoperatively at age 28 (Figs. 1C, D) showed mild right frontal atrophy associated with some increase in T2-weighted signal intensities in the right frontal lobe and left cerebellum. These findings subsided in subsequent MRIs, and all imaging thereafter remained static, the most recent ones being at the ages of 33 and 38, respectively (Figs. 1E–H). Follow-up EEGs and neurological and neuropsychological examinations over 12 years remained stable. 2.2. Patient 2 This 26-year-old, right-handed woman began having seizures at two years of age. Her perinatal history was only remarkable for urgent caesarian section because of breech presentation at birth. Her seizures manifested with a sensation of numbness in the lateral aspect of her left hand that spread proximally to involve the entire left side of her body with or without involvement of her face, each lasting several seconds. She had rare generalized tonic–clonic seizures (GTCSs) since her early teens that were occasionally preceded by left foot heaviness, odd feeling in the left side of her body, or left facial twitching for a total duration of about 5 min. Postictally, she was clumsy on her left side. Neurological examination was normal. Electroencephalography at 11 years of age revealed right frontal central originating seizure spreading to the parietal area and spikes maximal in the right posterior temporal–central–parietal area. Cranial MRI was unremarkable. Initial neuropsychological evaluation at 11 years of age showed deficits in language (naming, expressive vocabulary), memory for faces, and reduced dexterity of the left hand, consistent with dysfunction in left neocortical temporal and right frontotemporal regions. She underwent a right temporal neocortical resection and multiple subpial transections in the right perirolandic region at age 16 years, which did not improve her seizure outcome. Pathology was consistent with RE. Postoperative neurological examinations over 10 years remained normal aside from mild reduced dexterity in her left toes likely related to her surgery at age 16 years. Postoperative EEGs consistently demonstrated spikes in the right posterior head regions with maximal expression in the right posterior temporal region. Subsequent cranial MRIs only showed encephalomalacia in the right pericentral region consistent with previous surgery. Neuropsychological assessment at age 22 years revealed some possible decline in visual memory – not unexpected following a nondominant temporal lobe resection – but most other abilities were at similar levels (for her age) as presurgical performance. Other cognitive functioning including general intellectual abilities remained stable over time. 2.3. Patient 3 This 28-year-old, right-handed woman began having seizures at age 6 years, a day after she was hit in the left side of her head with a swinging rollerblade of another child that caused nausea and headaches without loss of consciousness. She experienced fever, periocular twitching on one side, and nausea followed by generalized SE the next day that lasted about an hour. She then developed about 3 seizures per month that consisted of a warm feeling in her legs followed by a “shocky” sensation in her stomach that occasionally progressed to loss
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of awareness, staring, repetitive swallowing, and inappropriate but clear words or phrases lasting 2–3 min each. Half of these seizures progressed to the elevation of her right arm, head deviation to the right, GTCSs, postictal fatigue, and occasional right upper extremity weakness. Her neurological examination at age 11 years was notable for right homonymous hemianopia. Her EEG at that time, including subdural recordings, mainly showed left occipital originating seizures but with evidence of multifocal spikes throughout the left hemisphere. Cranial MRI showed mild left hemispheric atrophy and left mesial temporal sclerosis (MTS). Neuropsychological testing at age 12 years revealed low average overall intellectual abilities and average performance in language and memory testing but problems with visual– motor organization, copying speed, and bilateral manual dexterity. She underwent left occipital corticectomy at age 13 years. Pathology was consistent with RE. Postoperatively, she continued to have left hemispheric seizures. Subsequent scalp EEG showed multifocal spikes throughout the left hemisphere with seizures arising from the left posterior temporal and the left mesial frontal areas. Her cranial MRI at age 20 years showed left occipital encephalomalacia with increased T2-weighted signals associated with thickening in the left temporal lobe, frontal operculum, insula, and cingulate gyrus. Her cranial MRI studies at ages 24, 25, and 26 years (Figs. 3A–F) and neuropsychological testing at age 26 years remained unchanged. She underwent a left mesial frontal resection at age 28 years to help further control her seizures, which were refractory to AEDs. Postoperatively, she had decreased severity of seizures, rarely becoming generalized, but continued to have daily seizures. Neurological examination, EEG, MRI, and neuropsychological testing remained unchanged. 2.4. Patient 4 This 29-year-old, right-handed man began having seizures at the age of four and a half years, two months after a recurrent flu-like illness. His most frequent seizures consisted of twitching of his eyelids on the left side without losing awareness that lasted up to 20 s, in clusters of up to 200 per day for a month and then none for several months. His second seizure type consisted of a nonspecific sensation followed by rightward head deviation associated with right facial and eyelid twitching, nonsense speech, and loss of awareness without postictal aphasia or weakness. His other seizures consisted of blank stares associated with frequent eyelid blinks bilaterally with retained awareness. His neurological examination showed slow spontaneous speech, mildly flattened right nasolabial fold, slow fine finger movements on the right, and mildly increased tone in the right upper extremity. Electroencephalography showed left inferior rolandic seizures. Neuropsychological testing at ages 5, 6, and 10 documented low average to average verbal intellectual abilities (i.e., 14th to 25th percentile), consistent with dominant (left) temporal lobe impairment. At age 14 years, neuropsychological testing revealed a decline in verbal intellectual abilities (i.e., to b1st percentile) and, at age 15 years, showed further decline in some aspects of language, attention, and processing speed in addition to the weakness in verbal ability compared to visual–spatial intellectual abilities. Cranial MRI studies between ages 8 and 15 showed progressive widening of the left sylvian fissure and atrophy of the left temporal lobe with increased T2-weighted signals. By age 16, there was no further deterioration, and most scores on neuropsychological testing remained unchanged or slightly improved. He underwent a left temporal lobectomy at age 16 years, despite left frontal and temporal seizures based on semiology. Pathology was consistent with RE. Postoperatively, his temporal lobe seizures stopped, and inferior rolandic seizures reduced in frequency to 3–4 per month. These primarily consisted of a rightward head jerking, drooling, and
Fig. 1. Patient 1, MRI head. A, B: Preoperative (age 24): (coronal T2 and axial T1 sequences) mild right frontal focal atrophy/encephalomalacia. C, D: Postoperative (age 28): (coronal FLAIR) right frontal encephalomalacia, larger with surrounding high T2 signal, likely gliosis, and left cerebellar high T2 signal. E–H: (coronal FLAIR): E, F (age 33), G, H (age 38): changes seen in the right frontal lobe and cerebellum remain unchanged.
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Fig. 2. Representative neuropathological findings (photomicrographs taken from patient 1). A. Cerebral cortex is altered by prominent capillaries, neuronal loss, sparse perivascular lymphocytes, and diffuse as well as subpial “Chaslin's” gliosis (bracket) (hematoxylin and eosin, bar = 100 μm). B. Thin cuffs of perivascular lymphocytes (arrows) are present in the cortex and subcortical white matter (hematoxylin and eosin, bar = 50 μm). C. Subpial “Chaslin's” (bracket) and diffuse gliosis in the cerebral cortex (anti-GFAP immunohistochemistry, bar = 100 μm). D. Lymphocytes infiltrate the perivascular space and adjacent neuropil (anti-CD45 (LCA) immunohistochemistry, bar = 50 μm). E. Patchy cortical microglial nodule formation (anti-HLADR immunohistochemistry, bar = 100 μm). F. Activated cortical microglia are increased in density and ramification (anti-HLADR immunohistochemistry, bar = 50 μm).
inability to speak. His postoperative scalp EEGs consistently showed broad left frontocentral spikes. His MRI at age 18 demonstrated postoperative changes only. He has remained neurologically stable and able to return to full-time work. 3. Discussion The typical presentation of RE consists of a chronic illness causing seizures and a slowly progressive hemiparesis without febrile illness associated with a chronic inflammatory process, marked by patchy neuronal loss, gliosis, lymphocytic infiltrates, and microglial activation [2]. The European consensus statement outlined a stage-wise course of RE [11]. Stage I consists of a prodromal phase with a relatively low seizure frequency and, rarely, a mild hemiparesis that may last a median of 7.1 months (range: 0 months to 8 years). Stage II consists of an acute disease with frequent simple partial motor seizures and development of hemiparesis. Stage III consists of a residual form with permanent and stable hemiparesis. Despite varied stages of RE, the reported pathological process has been the same among all the patients [2,13]. Many cases do not follow the proposed stages of RE. Stage I may last longer [1]. One of the 13 patients in one European study had a less progressive course [14]. Similar to several other published cases of chronic encephalitis diagnosed on a pathological basis [15–20], none of our four cases followed the expected stages of RE. Late onset in adulthood and adolescence [15,16,21], temporal lobe epilepsy [18], familial epilepsy
with bilateral involvement [17], brainstem manifestations [19], onset before age 2 years with bilateral cerebellar findings [22], and epilepsy plus movement disorders with more benign outcome [20] have all been reported as variants of RE. In one of our patients (patient 3), the onset was preceded by a mild head trauma and fever. Although immunotherapy is sometimes used in chronic encephalitis with varying results, despite ongoing seizures, our patients did not have a progressive course to justify immunotherapy. Adolescent RE and adult-onset RE account for about 10% of all cases [16]. Previously reported cases with milder disease course tended to be those with adolescent or adult-onset disease [15,16,21]. Recently, Gambardella et al. [20] described 3 cases of pathologically confirmed chronic encephalitis (2 adult-onset, 1 late childhood-onset) as variants of RE with milder and nonprogressive courses. All four of our patients had onset of their seizures in childhood (ages 2–12 years; mean age of 6 years). All were retrospectively diagnosed with chronic encephalitis based on pathology from surgery, prior to which there was limited progression but none postoperatively over the next 10–15 years. Retrospectively, they fulfill many of the main diagnostic criteria for RE [11], including focal seizure, unilateral cortical deficit, unihemispheric slowing and unilateral seizure onset on EEG, and focal cortical atrophy with gray or white matter T2 signal on MRI. Typically, RE presents with partial-onset seizures. About one-third of the seizures in RE consist of GTCSs, and one-fifth consist of generalized or focal SE. Focal motor seizures may occur in 3/4 of patients with RE
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Fig. 3. A–F (patient 3, MRI head, coronal FLAIR sequence). A, B: Postoperative changes at age 24 remain stable on follow-up imaging at age 25 (C, D) and age 26 (E, F).
during the course of their illness [12], with epilepsia partialis continua (EPC) being a primary component [23]. None of our cases presented with EPC, while all 4 patients had evidence of multifocal hemispheric dysfunction including involving the rolandic area, making them distinct from the typical presentation in RE. Given that none of our patients presented with EPC nor did the three patients reported by Gambardella et al. [20], the absence of EPC may serve as a prognostic indicator of a nonprogressive course. Autoantibodies and cell-mediated autoimmunity against glutamate receptors have been proposed to contribute to the pathophysiological processes in RE [9]. As has been proposed in the
pathogenesis of MTS [24,25], glutamate excitotoxicity might be the main or contributing factor to the focal atrophy and progression of typical cases of RE, i.e., the disease becomes self-sustained by EPC following the initial presumed immunological insult. A larger series or multicenter prospective study is required to determine if absence of EPC implies a “benign” course. In summary, we describe four patients with childhood-onset chronic encephalitis whose long-term follow-up revealed a nonprogressive course with respect to clinical neurological status, EEG findings, and for the most part, MRI and neuropsychological findings. These cases
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extend the spectrum of childhood-onset chronic encephalitis to include nonprogressive variants, which are likely under-recognized. We propose that these cases and other aforementioned variants may serve to revise the diagnostic criteria for RE. The absence of EPC may serve as a prognostic indicator of a milder disease course. Disclosure None of the authors has any conflict of interest to disclose. References [1] Rasmussen T, Andermann F. Rasmussen’s syndrome: symptomatology of the syndrome of chronic encephalitis and seizures: 35-year experience with 51 cases. In: Luders H, editor. Epilepsy surgery. New York: Raven Press; 1991. p. 173–8. [2] Rasmussen T, Olszewski J, Lloyd-Smith D. Focal seizures due to chronic localized encephalitis. Neurology 1958;8:435–45. [3] Power C, Poland SD, Blume WT, Girvin JP, Rice GP. Cytomegalovirus and Rasmussen's encephalitis. Lancet 1990;336:1282–4. [4] McLachlan RS, Levin S, Blume WT. Treatment of Rasmussen's syndrome with ganciclovir. Neurology 1996;47:925–8. [5] Rogers SW, Andrews PI, Gahring LC, Whisenand T, Cauley K, Crain B, et al. Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis. Science 1994; 265:648–51. [6] Wiendl H, Bien CG, Bernasconi P, Fleckenstein B, Elger CE, Dichgans J, et al. GluR3 antibodies: prevalence in focal epilepsy but no specificity for Rasmussen's encephalitis. Neurology 2001;57:1511–4. [7] Mantegazza R, Bernasconi P, Baggi F, Spreafico R, Ragona F, Antozzi C, et al. Antibodies against GluR3 peptides are not specific for Rasmussen's encephalitis but are also present in epilepsy patients with severe, early onset disease and intractable seizures. J Neuroimmunol 2002;131:179–85. [8] Yang R, Puranam RS, Butler LS, Qian WH, He XP, Moyer M, et al. Autoimmunity to munc-18 in Rasmussen's encephalitis. Neuron 2002;28:375–83. [9] Takahashi Y, Mori H, Mishina M, Watanabe M, Kondo N, Shimomura J, et al. Autoantibodies and cell-mediated autoimmunity to NMDA-type GluRepsilon2 in patients with Rasmussen's encephalitis and chronic progressive epilepsia partialis continua. Epilepsia 2005;46(Suppl. 5):152–8.
[10] Bien CG, Bauer J, Deckwerth TL, Wiendl H, Deckert M, Wiestler OD, et al. Destruction of neurons by cytotoxic T cells: a new pathogenic mechanism in Rasmussen's encephalitis. Ann Neurol 2002;51:311–8. [11] Bien CG, Granata T, Antozzi C, Cross JH, Dulac O, Kurthen M, et al. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis. A European consensus statement. Brain 2005;128:454–7. [12] Hart Y. Rasmussen's encephalitis. Epileptic Disord 2004;6:133–44. [13] Aguilar MJ, Rasmussen T. Role of encephalitis in pathogenesis of epilepsy. Arch Neurol 1960;2:663–76. [14] Bien CG, Widman G, Urbach H, Sassen R, Kuczaty S, Wiestler OD, et al. The natural history of Rasmussen's encephalitis. Brain 2002;125:1751–9. [15] McLachlan RS, Girivin JP, Blume WT, Reichman H. Rasmussen's chronic encephalitis in adults. Arch Neurol 1993;50:269–74. [16] Hart Y, Andermann F, Fish DR, Dubeau F, Robitaille Y, Rasmussen T, et al. Chronic encephalitis and epilepsy in adults and adolescents: a variant of Rasmussen's syndrome? Neurology 1997;48:418–24. [17] Silver K, Andermann F, Meagher-Villemure K. Familial alternating epilepsia partialis continua with chronic encephalitis: another variant of Rasmussen syndrome? Arch Neurol 1998;55:733–6. [18] Henessy MJ, Koutroumanidis MD, Dean AF, Jarosz J, Elwes MD, Binnie CD, et al. Chronic encephalitis and temporal lobe epilepsy: a variant of Rasmussen's syndrome? Neurology 2001;56:678–81. [19] Quesada CM, Urbach H, Eiger CE, Bien CG. Rasmussen encephalitis with ipsilateral brain stem involvement in an adult patient. J Neurol Neurosurg Psychiatry 2007;78: 200–1. [20] Gambardella A, Andermann F, Shorvon S, Le Piane E, Aguglia U. Limited chronic focal encephalitis: another variant of Rasmussen syndrome? Neurology 2008;70: 374–7. [21] Vadlamudi L, Galton CJ, Jeavons SJ, Tannenberg AE, Boyle RS. Rasmussen's syndrome in a 54 year old female: more support for an adult variant. J Clin Neurosci 2000;7: 154–6. [22] Yacubian EM, Marie SK, Valerio RM, Jorge CL, Yamaga L, Buchpiguel CA. Neuroimaging findings in Rasmussen's syndrome. J Neuroimaging 1997;7:16–22. [23] Hart YM. Medical treatment of Rasmussen's syndrome (chronic encephalitis and epilepsy): effect of high dose steroids or Ig in 19 pts. Neurology 1994;44: 1030–6. [24] Liu Z, Mikati M, Holmes GL. Mesial temporal sclerosis: pathogenesis and significance. Pediatr Neurol 1995;12:5–16. [25] Sharma AK, Reams RY, Jordan WH, Miller MA, Thacker HL, Snyder PW. Mesial temporal lobe epilepsy: pathogenesis, induced rodent models and lesions. Toxicol Pathol 2007;35:984–99.
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Childhood-onset nonprogressive chronic encephalitis Philippe Rizek a, Christina Cheung a, Richard S. McLachlan a, Brent Hayman-Abello b, Donald H. Lee c, Robert R. Hammond a,d, Seyed M. Mirsattari a,c,e,f,⁎ a
Department of Clinical Neurological Sciences, Western University, London, Canada Psychology Services, London Health Sciences Centre, London, Ontario, Canada Department of Medical Imaging, Western University, London, Canada d Department of Pathology, Western University, London, Canada e Department of Medical Biophysics, Western University, London, Canada f Department of Psychology, Western University, London, Canada b c
a r t i c l e
i n f o
Article history: Received 15 July 2013 Revised 3 October 2013 Accepted 9 November 2013 Available online 22 December 2013 Keywords: Rasmussen's Chronic encephalitis Natural history Nonprogressive variant Epilepsy surgery Epilepsia partialis continua
a b s t r a c t Purpose: The purpose of this study was to describe a series of patients with pathologically proven chronic encephalitis who had a nonprogressive course during a long follow-up, suggestive of a “benign” variant of Rasmussen's encephalitis (RE). Methods: Four patients who were referred to our Comprehensive Epilepsy Program at London Health Science Centre in London, Ontario, were diagnosed with chronic encephalitis on a pathological basis after epilepsy surgery to treat their partial-onset seizures. Results: None of our four cases followed the typical course of RE despite their childhood-onset seizures between ages 2 and 12 years. One was preceded by a mild head trauma and fever at onset. None had epilepsia partialis continua (EPC). Their long-term follow-up revealed a nonprogressive form of the syndrome with respect to the neurological examination, EEG, MRI, and neuropsychological findings. Conclusion: These cases extend the spectrum of childhood-onset intractable epilepsy with chronic encephalitis to include nonprogressive variants of RE. The absence of EPC may be a prognostic indicator of a nonprogressive course. © 2013 Elsevier Inc. All rights reserved.
1. Introduction
2. Case histories
Rasmussen's encephalitis (RE) is an inflammatory neurological disease that manifests with medically intractable partial seizures and a progressive clinical course including unilateral cerebral atrophy, hemiparesis, and cognitive impairment [1]. The exact etiology of RE is unknown, although viral causes [2–4], autoantibodies [5–9], and cytotoxic T-cell mechanisms [10,11] have been proposed. Antiepileptic drugs (AEDs) are usually ineffective in treating the seizures in RE, while hemispherectomy is effective in childhood in arresting its progression. Since its first description by Rasmussen and colleagues in 1958 [2], a number of atypical features are reported that have widened the clinical spectrum of RE [12]. We present four cases of pathologically confirmed chronic encephalitis, all of which had childhood-onset intractable partial seizures with or without secondary generalization. None of them experienced significant neurological or radiological decline despite continued partial seizures.
Four patients referred to our Comprehensive Epilepsy Program were unexpectedly diagnosed with chronic encephalitis on a pathological basis after epilepsy surgery to treat their medically intractable partialonset seizures.
Abbreviations: RE, Rasmussen's encephalitis; CE, chronic encephalitis; EEG, electroencephalography; MRI, magnetic resonance imaging; EPC, epilepsia partialis continua. ⁎ Corresponding author at: B10-108, 339 Windermere Road, London, Ontario N6A 5A5, Canada. Fax: +1 519 663 3440. E-mail address: [email protected] (S.M. Mirsattari). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.11.005
2.1. Patient 1 This 38-year-old, right-handed woman began having seizures at age 12 years with multiple seizure types, which were refractory to AEDs. Her most frequent seizures consisted of facial twitching around her nose bilaterally with inability to speak while retaining awareness and comprehension, occurring up to 4–5 times per day. She also experienced motionless staring spells with retained awareness. Occasionally, she had head turning to the left with clonic jerking of the left hand and mouth with inability to speak but retained awareness followed by secondary generalization. Postictally, she was unable to move or talk for about 15 min. Preoperative EEG at age 24 years demonstrated right frontal spikes and seizures; her cranial MRI demonstrated right frontal cortical atrophy (Figs. 1A, B). Preoperative neuropsychological testing showed frontal lobe dysfunction maximal in the right hemisphere manifesting with difficulties in some executive abilities
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(planning, nonverbal reasoning), hand strength and speed (worse on the left), verbal fluency, and mildly in verbal learning. She underwent a limited right inferior frontal lobe resection at the age of 26 years that revealed pathology consistent with RE (Figs. 2A–F) [13]. Postoperatively, she had reduced fine finger movements in her left hand, and neuropsychological testing revealed a decline in nonverbal reasoning, verbal abilities, and attention. Seizure frequency and severity decreased by 50% postoperatively, but she continued to have catamenial partial seizures and rare secondarily generalized seizures despite 3 AEDs. Cranial MRI study postoperatively at age 28 (Figs. 1C, D) showed mild right frontal atrophy associated with some increase in T2-weighted signal intensities in the right frontal lobe and left cerebellum. These findings subsided in subsequent MRIs, and all imaging thereafter remained static, the most recent ones being at the ages of 33 and 38, respectively (Figs. 1E–H). Follow-up EEGs and neurological and neuropsychological examinations over 12 years remained stable. 2.2. Patient 2 This 26-year-old, right-handed woman began having seizures at two years of age. Her perinatal history was only remarkable for urgent caesarian section because of breech presentation at birth. Her seizures manifested with a sensation of numbness in the lateral aspect of her left hand that spread proximally to involve the entire left side of her body with or without involvement of her face, each lasting several seconds. She had rare generalized tonic–clonic seizures (GTCSs) since her early teens that were occasionally preceded by left foot heaviness, odd feeling in the left side of her body, or left facial twitching for a total duration of about 5 min. Postictally, she was clumsy on her left side. Neurological examination was normal. Electroencephalography at 11 years of age revealed right frontal central originating seizure spreading to the parietal area and spikes maximal in the right posterior temporal–central–parietal area. Cranial MRI was unremarkable. Initial neuropsychological evaluation at 11 years of age showed deficits in language (naming, expressive vocabulary), memory for faces, and reduced dexterity of the left hand, consistent with dysfunction in left neocortical temporal and right frontotemporal regions. She underwent a right temporal neocortical resection and multiple subpial transections in the right perirolandic region at age 16 years, which did not improve her seizure outcome. Pathology was consistent with RE. Postoperative neurological examinations over 10 years remained normal aside from mild reduced dexterity in her left toes likely related to her surgery at age 16 years. Postoperative EEGs consistently demonstrated spikes in the right posterior head regions with maximal expression in the right posterior temporal region. Subsequent cranial MRIs only showed encephalomalacia in the right pericentral region consistent with previous surgery. Neuropsychological assessment at age 22 years revealed some possible decline in visual memory – not unexpected following a nondominant temporal lobe resection – but most other abilities were at similar levels (for her age) as presurgical performance. Other cognitive functioning including general intellectual abilities remained stable over time. 2.3. Patient 3 This 28-year-old, right-handed woman began having seizures at age 6 years, a day after she was hit in the left side of her head with a swinging rollerblade of another child that caused nausea and headaches without loss of consciousness. She experienced fever, periocular twitching on one side, and nausea followed by generalized SE the next day that lasted about an hour. She then developed about 3 seizures per month that consisted of a warm feeling in her legs followed by a “shocky” sensation in her stomach that occasionally progressed to loss
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of awareness, staring, repetitive swallowing, and inappropriate but clear words or phrases lasting 2–3 min each. Half of these seizures progressed to the elevation of her right arm, head deviation to the right, GTCSs, postictal fatigue, and occasional right upper extremity weakness. Her neurological examination at age 11 years was notable for right homonymous hemianopia. Her EEG at that time, including subdural recordings, mainly showed left occipital originating seizures but with evidence of multifocal spikes throughout the left hemisphere. Cranial MRI showed mild left hemispheric atrophy and left mesial temporal sclerosis (MTS). Neuropsychological testing at age 12 years revealed low average overall intellectual abilities and average performance in language and memory testing but problems with visual– motor organization, copying speed, and bilateral manual dexterity. She underwent left occipital corticectomy at age 13 years. Pathology was consistent with RE. Postoperatively, she continued to have left hemispheric seizures. Subsequent scalp EEG showed multifocal spikes throughout the left hemisphere with seizures arising from the left posterior temporal and the left mesial frontal areas. Her cranial MRI at age 20 years showed left occipital encephalomalacia with increased T2-weighted signals associated with thickening in the left temporal lobe, frontal operculum, insula, and cingulate gyrus. Her cranial MRI studies at ages 24, 25, and 26 years (Figs. 3A–F) and neuropsychological testing at age 26 years remained unchanged. She underwent a left mesial frontal resection at age 28 years to help further control her seizures, which were refractory to AEDs. Postoperatively, she had decreased severity of seizures, rarely becoming generalized, but continued to have daily seizures. Neurological examination, EEG, MRI, and neuropsychological testing remained unchanged. 2.4. Patient 4 This 29-year-old, right-handed man began having seizures at the age of four and a half years, two months after a recurrent flu-like illness. His most frequent seizures consisted of twitching of his eyelids on the left side without losing awareness that lasted up to 20 s, in clusters of up to 200 per day for a month and then none for several months. His second seizure type consisted of a nonspecific sensation followed by rightward head deviation associated with right facial and eyelid twitching, nonsense speech, and loss of awareness without postictal aphasia or weakness. His other seizures consisted of blank stares associated with frequent eyelid blinks bilaterally with retained awareness. His neurological examination showed slow spontaneous speech, mildly flattened right nasolabial fold, slow fine finger movements on the right, and mildly increased tone in the right upper extremity. Electroencephalography showed left inferior rolandic seizures. Neuropsychological testing at ages 5, 6, and 10 documented low average to average verbal intellectual abilities (i.e., 14th to 25th percentile), consistent with dominant (left) temporal lobe impairment. At age 14 years, neuropsychological testing revealed a decline in verbal intellectual abilities (i.e., to b1st percentile) and, at age 15 years, showed further decline in some aspects of language, attention, and processing speed in addition to the weakness in verbal ability compared to visual–spatial intellectual abilities. Cranial MRI studies between ages 8 and 15 showed progressive widening of the left sylvian fissure and atrophy of the left temporal lobe with increased T2-weighted signals. By age 16, there was no further deterioration, and most scores on neuropsychological testing remained unchanged or slightly improved. He underwent a left temporal lobectomy at age 16 years, despite left frontal and temporal seizures based on semiology. Pathology was consistent with RE. Postoperatively, his temporal lobe seizures stopped, and inferior rolandic seizures reduced in frequency to 3–4 per month. These primarily consisted of a rightward head jerking, drooling, and
Fig. 1. Patient 1, MRI head. A, B: Preoperative (age 24): (coronal T2 and axial T1 sequences) mild right frontal focal atrophy/encephalomalacia. C, D: Postoperative (age 28): (coronal FLAIR) right frontal encephalomalacia, larger with surrounding high T2 signal, likely gliosis, and left cerebellar high T2 signal. E–H: (coronal FLAIR): E, F (age 33), G, H (age 38): changes seen in the right frontal lobe and cerebellum remain unchanged.
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Fig. 2. Representative neuropathological findings (photomicrographs taken from patient 1). A. Cerebral cortex is altered by prominent capillaries, neuronal loss, sparse perivascular lymphocytes, and diffuse as well as subpial “Chaslin's” gliosis (bracket) (hematoxylin and eosin, bar = 100 μm). B. Thin cuffs of perivascular lymphocytes (arrows) are present in the cortex and subcortical white matter (hematoxylin and eosin, bar = 50 μm). C. Subpial “Chaslin's” (bracket) and diffuse gliosis in the cerebral cortex (anti-GFAP immunohistochemistry, bar = 100 μm). D. Lymphocytes infiltrate the perivascular space and adjacent neuropil (anti-CD45 (LCA) immunohistochemistry, bar = 50 μm). E. Patchy cortical microglial nodule formation (anti-HLADR immunohistochemistry, bar = 100 μm). F. Activated cortical microglia are increased in density and ramification (anti-HLADR immunohistochemistry, bar = 50 μm).
inability to speak. His postoperative scalp EEGs consistently showed broad left frontocentral spikes. His MRI at age 18 demonstrated postoperative changes only. He has remained neurologically stable and able to return to full-time work. 3. Discussion The typical presentation of RE consists of a chronic illness causing seizures and a slowly progressive hemiparesis without febrile illness associated with a chronic inflammatory process, marked by patchy neuronal loss, gliosis, lymphocytic infiltrates, and microglial activation [2]. The European consensus statement outlined a stage-wise course of RE [11]. Stage I consists of a prodromal phase with a relatively low seizure frequency and, rarely, a mild hemiparesis that may last a median of 7.1 months (range: 0 months to 8 years). Stage II consists of an acute disease with frequent simple partial motor seizures and development of hemiparesis. Stage III consists of a residual form with permanent and stable hemiparesis. Despite varied stages of RE, the reported pathological process has been the same among all the patients [2,13]. Many cases do not follow the proposed stages of RE. Stage I may last longer [1]. One of the 13 patients in one European study had a less progressive course [14]. Similar to several other published cases of chronic encephalitis diagnosed on a pathological basis [15–20], none of our four cases followed the expected stages of RE. Late onset in adulthood and adolescence [15,16,21], temporal lobe epilepsy [18], familial epilepsy
with bilateral involvement [17], brainstem manifestations [19], onset before age 2 years with bilateral cerebellar findings [22], and epilepsy plus movement disorders with more benign outcome [20] have all been reported as variants of RE. In one of our patients (patient 3), the onset was preceded by a mild head trauma and fever. Although immunotherapy is sometimes used in chronic encephalitis with varying results, despite ongoing seizures, our patients did not have a progressive course to justify immunotherapy. Adolescent RE and adult-onset RE account for about 10% of all cases [16]. Previously reported cases with milder disease course tended to be those with adolescent or adult-onset disease [15,16,21]. Recently, Gambardella et al. [20] described 3 cases of pathologically confirmed chronic encephalitis (2 adult-onset, 1 late childhood-onset) as variants of RE with milder and nonprogressive courses. All four of our patients had onset of their seizures in childhood (ages 2–12 years; mean age of 6 years). All were retrospectively diagnosed with chronic encephalitis based on pathology from surgery, prior to which there was limited progression but none postoperatively over the next 10–15 years. Retrospectively, they fulfill many of the main diagnostic criteria for RE [11], including focal seizure, unilateral cortical deficit, unihemispheric slowing and unilateral seizure onset on EEG, and focal cortical atrophy with gray or white matter T2 signal on MRI. Typically, RE presents with partial-onset seizures. About one-third of the seizures in RE consist of GTCSs, and one-fifth consist of generalized or focal SE. Focal motor seizures may occur in 3/4 of patients with RE
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Fig. 3. A–F (patient 3, MRI head, coronal FLAIR sequence). A, B: Postoperative changes at age 24 remain stable on follow-up imaging at age 25 (C, D) and age 26 (E, F).
during the course of their illness [12], with epilepsia partialis continua (EPC) being a primary component [23]. None of our cases presented with EPC, while all 4 patients had evidence of multifocal hemispheric dysfunction including involving the rolandic area, making them distinct from the typical presentation in RE. Given that none of our patients presented with EPC nor did the three patients reported by Gambardella et al. [20], the absence of EPC may serve as a prognostic indicator of a nonprogressive course. Autoantibodies and cell-mediated autoimmunity against glutamate receptors have been proposed to contribute to the pathophysiological processes in RE [9]. As has been proposed in the
pathogenesis of MTS [24,25], glutamate excitotoxicity might be the main or contributing factor to the focal atrophy and progression of typical cases of RE, i.e., the disease becomes self-sustained by EPC following the initial presumed immunological insult. A larger series or multicenter prospective study is required to determine if absence of EPC implies a “benign” course. In summary, we describe four patients with childhood-onset chronic encephalitis whose long-term follow-up revealed a nonprogressive course with respect to clinical neurological status, EEG findings, and for the most part, MRI and neuropsychological findings. These cases
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extend the spectrum of childhood-onset chronic encephalitis to include nonprogressive variants, which are likely under-recognized. We propose that these cases and other aforementioned variants may serve to revise the diagnostic criteria for RE. The absence of EPC may serve as a prognostic indicator of a milder disease course. Disclosure None of the authors has any conflict of interest to disclose. References [1] Rasmussen T, Andermann F. Rasmussen’s syndrome: symptomatology of the syndrome of chronic encephalitis and seizures: 35-year experience with 51 cases. In: Luders H, editor. Epilepsy surgery. New York: Raven Press; 1991. p. 173–8. [2] Rasmussen T, Olszewski J, Lloyd-Smith D. Focal seizures due to chronic localized encephalitis. Neurology 1958;8:435–45. [3] Power C, Poland SD, Blume WT, Girvin JP, Rice GP. Cytomegalovirus and Rasmussen's encephalitis. Lancet 1990;336:1282–4. [4] McLachlan RS, Levin S, Blume WT. Treatment of Rasmussen's syndrome with ganciclovir. Neurology 1996;47:925–8. [5] Rogers SW, Andrews PI, Gahring LC, Whisenand T, Cauley K, Crain B, et al. Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis. Science 1994; 265:648–51. [6] Wiendl H, Bien CG, Bernasconi P, Fleckenstein B, Elger CE, Dichgans J, et al. GluR3 antibodies: prevalence in focal epilepsy but no specificity for Rasmussen's encephalitis. Neurology 2001;57:1511–4. [7] Mantegazza R, Bernasconi P, Baggi F, Spreafico R, Ragona F, Antozzi C, et al. Antibodies against GluR3 peptides are not specific for Rasmussen's encephalitis but are also present in epilepsy patients with severe, early onset disease and intractable seizures. J Neuroimmunol 2002;131:179–85. [8] Yang R, Puranam RS, Butler LS, Qian WH, He XP, Moyer M, et al. Autoimmunity to munc-18 in Rasmussen's encephalitis. Neuron 2002;28:375–83. [9] Takahashi Y, Mori H, Mishina M, Watanabe M, Kondo N, Shimomura J, et al. Autoantibodies and cell-mediated autoimmunity to NMDA-type GluRepsilon2 in patients with Rasmussen's encephalitis and chronic progressive epilepsia partialis continua. Epilepsia 2005;46(Suppl. 5):152–8.
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