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Intractable Epilepsy, Hemispheric Malformation, and Generalized Electroencephalography Abnormalities
Author's Accepted Manuscript
Intractable Epilepsy, Hemispheric Malformation and Generalized EEG Abnormalities Leeda Ahmadi M.B.B.S, Elaine Wirrell
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S1071-9091(14)00024-2 http://dx.doi.org/10.1016/j.spen.2014.04.005 YSPEN471
To appear in: Semin Pediatr Neurol
Cite this article as: Leeda Ahmadi M.B.B.S, Elaine Wirrell, Intractable Epilepsy, Hemispheric Malformation and Generalized EEG Abnormalities, Semin Pediatr Neurol , http://dx.doi.org/10.1016/j.spen.2014.04.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Intractable Epilepsy, Hemispheric Malformation and Generalized EEG Abnormalities Authors 1. Leeda Ahmadi, M.B.B.S 2. Elaine Wirrell, Professor, Divisions of Child and Adolescent Neurology and Epilepsy, Mayo Clinic, Rochester MN Author contributions LA and EW both were involved in the clinical management of the patient. LA wrote the draft of the manuscript and both LA and EW contributed to the editing of the manuscript. EW provided the figures. Funding The authors received no financial support for the research, authorship, and/or publication of this article. Ethical Approval No ethical approval was required for this article.
CASE REPORT An 8 year old right hand dominant boy with medically intractable epilepsy, global developmental delay and left hemiparesis presented to our center for possible surgical evaluation for his seizure disorder. He was the product of a healthy pregnancy, delivered by repeat cesarean section at term and received some bag‐mask oxygen at birth. He had no history of febrile seizures, significant head injury or brain infection. Seizure onset was at age 3 when he presented with a seizure characterized by jaw clenching, repeated emesis with eye deviation to the left, which lasted for 2‐3 minutes and was followed by postictal limpness. He underwent EEG and MRI, and was commenced on valproate. He remained seizure‐free for 11 months, but again presented with a cluster of seizures consisting of unresponsiveness with repetitive opening and closing of the right hand and mouth, lack of movement on the left side and eye deviation to the left. Each seizure lasted approximately 2‐3 minutes and he had ten events over a two hour period, finally resolving after a dose of rectal diazepam. He continued to have isolated seizures of similar semiology, occurring 2‐3 times per week. Additionally, he developed a second semiology consisting of briefly nodding his head backwards, with occasional falls that would occur 6‐12 times per day. Valproate was further increased, followed by addition of chlorazepate without benefit. Levetiracetam was then added which resulted in seizure freedom for eight months. Seizures of similar semiology recurred for a brief period during an intercurrent illness but then resolved again for twelve months with higher doses of levetiracetam. At eight years of age, seizures again recurred but were unresponsive to higher doses of valproate or levetiracetam. Placement of a vagal nerve stimulator did not afford any benefit, at which point he was referred to our center. His seizures were of two semiologies. With the first, his head would drop forword, both eyes would twitch and deviate to the left. Additionally he may have shaking of both legs, maximally on the left. These seizures would last 5‐10 seconds and were occurring 50‐150 times per
day. His second semiology was similar, but progressed to generalized clonic activity, and occurred approximately daily. He had sustained numerous injuries as a result of these seizures, including a recent fracture of his left upper extremity. He had global developmental delay and had plateaued, although not regressed in development, since recurrence of his seizures. He attended a special education class full time in Grade 2. He could recognize approximately 14 letters, knew some letter sounds and could rote count. His examination was significant for a left hemiparesis which was longstanding as suggested by a smaller left hand and foot and shorter left leg. He was able to ambulate independently and while his left hand was weaker, he did have some independent finger movement. No neurocutaneous lesions were noted on Woods lamp exam. The remainder of his exam was unremarkable. His MRI demonstrated an extensive right hemispheric malformation of cortical development most prominent within the right frontal and occipital lobes (Figure 1). His interictal EEG showed multifocal and generalized spike wave, maximal over the right centrotemporal region, and in sleep these discharges were nearly continuous (Figure 2). Multiple seizures were recorded which often began with right centrotemporal region theta activity but rapidly became generalized (Figure 3). He underwent right functional hemispherectomy just before his ninth birthday and has remained seizure‐free during the intervening two years from surgery. His development markedly improved to the point he is now able to read sentences and perform single digit addition. His focus and attention are markedly improved. Regarding motor function, he is able to ambulate independently although he has minimal movement of his left wrist, hand or fingers.
DISCUSSION
Malformations of cortical development are one of the most common pathologies reported in surgical series of pediatric epilepsy and frequently result in medically intractable epilepsy (1). They may be generalized and diffuse (ie agyria‐pachygyria band spectrum), hemispheric (hemimegalencephaly), multifocal (periventricular nodular heterotopia) or focal (pachygyria, schizencephaly or focal cortical dysplasia). Frequently, the extent of involvement predicts seizure type, severity and co‐existing neurologic disability. Severe epileptic encephalopathy and profound, early‐onset, developmental delay is characteristic with diffuse lesions, whereas more focal lesions may present with medically intractable epilepsy in otherwise well children and adults. MRI advances have been instrumental in improved detection of focal cortical dysplasias, with reported findings of increased cortical thickness, blurring of the cortical‐white matter junction, increased T2 signal, transmantle sign or localized brain atrophy. However, detection in young children prior to age 2‐3 years can be challenging due to immature myelination (2). Focal cortical dysplasias are classified into three major types with Types I and II referring to isolated focal cortical dysplasia, and Type III referring to dysplasia associated with other epileptogenic lesions, such as hippocampal sclerosis or tumors (3). The impact of intractable epilepsy in children is significant and extends well beyond uncontrolled seizures to include intellectual disability, psychiatric and behavioral problems and seizure‐ related injury and death. This young boy had an epileptic encephalopathy with electrical status epilepticus in sleep (ESES), which had led to plateauing of development. As a result of his frequent falls, he had sustained numerous injuries. The likelihood of seizure freedom in children with focal epilepsy is highly dependent on underlying etiology and number of prior AEDs which have failed for lack of efficacy. In our population‐ based study of outcome in focal epilepsy, 70.1% of children with unknown cause had favorable outcome with their first AED, compared to only 39.8% of those with a structural cause (p<0.0001) (4). In those in
whom one AED had failed, 28.6% with unknown cause, versus only 10.2% with a structural cause achieved a favorable outcome (p=0.04). Amongst structural causes, malformations of cortical development, mesial temporal sclerosis, tumors and vascular malformations had much lower rates of response to AEDs than remote brain insults. Surgery is a viable option for children with medically intractable epilepsy. In children with focal epilepsy and cortical dysplasia, it should be strongly considered after failure of 1‐2 AEDs, given the low likelihood of response to further AEDs (4). Early surgery will allow quicker control of seizures, and minimize associated comorbidities, thus improving long term outcome. Our patient had multifocal and generalized epileptiform activity on EEG. Such an EEG pattern may be seen in children with early onset brain lesions, and should not dissuade from surgical intervention (5). Our patient also had ESES, which was further impairing his developmental progress. In children with unilateral brain lesions, seizure freedom, as well as resolution of ESES, has been shown following epilepsy surgery (6). Hemispherectomy or hemispheric disconnection surgery should be considered for children with large hemispheric lesions and intractable epilepsy, including cortical dysplasias, Sturge‐Weber syndrome, large porencephalic cysts, etc. Various studies have documented good outcomes following functional hemispherectomy, with resolution or marked improvement of seizures and improved behavior (7‐9). Hemiparesis typically remains unchanged. REFERENCES 1. Kuzniecky RI, Barkovich AJ. Malformations of cortical development and epilepsy. Brain Dev 2001;23:2‐ 11. 2. Colombo N, Salamon N, Raybaud C, Ozkara C, Barkovich AJ. Imaging of malformations of cortical development. Epileptic Disord 2009;11:194‐205.
3. Blumcke I, Thom M, Aronica E, Armstrong DD, Vinters HV, Palmini A, et al. The clnicopathological spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 2011;52:158‐74. 4. Wirrell E, Wong‐Kisiel L, Nickels K. Seizure outcome after AED failure in pediatric focal epilepsy: Impact of underlying etiology . Epilepsy Behav 2014, in press. 5. Wyllie E, Lachhwani DK, Gupta A, Chirla A, Cosmo G, Worley S, et al. Successful surgery for epilepsy due to early brain lesions despite generalized EEG findings. Neurology 2007;69:389‐97. 6. Loddenkemper T, Cosmo G, Kotagal P, Haut J, Klaas P, Gupta A, et al. Epilepsy surgery in children with electrical statu epilepticus in sleep. Neurosurgery 2009;64:328‐37. 7. Moosa AN, Jehi L, Marashly A, Cosmo G, Lachhwani D, Wyllie E, et al. Long‐term functional outcomes and their predictors after hemispherectomy in 115 children. Epilepsia 2013;54:1771‐9. 8. Devlin AM, Cross JH, Harkness W, Chong WK, Harding B, Vargha‐Khadem F, Neville BG. Clinical outcomes of hemispherectomy for epilepsy in childhood and adolescence. Brain 2003;126(Pt 3):556‐66. 9. Terra‐Bustamante VC, Inuzuka LM, Fernandes RM, Escorsi‐Rosset S, Wichert‐Ana L, Alexandre V Jr, et al. Outcome of hemispheric surgeries for refractory epilepsy in pediatric patients. Childs Nerv Syst 2007;23:321‐6.
Figure 1: MRI (Figure 1a – Axial T2, Figure 1b – Coronal MPRAGE) demonstrates an extensive right hemispheric malformation of cortical development most prominent within the right frontal and occipital lobes
p EEG demonsstrating electtrical status epilepticus in ssleep (ESES) p pattern with Fiigure 2: Sleep discharges of h highest amplitude in the riight hemispheere
Fiigure 3: Seizu ure beginning in right centrrotemporal reegion. Duringg this event, the child had eeye deeviation to th he left and losss of tone
Intractable Epilepsy, Hemispheric Malformation and Generalized EEG Abnormalities Leeda Ahmadi M.B.B.S, Elaine Wirrell
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S1071-9091(14)00024-2 http://dx.doi.org/10.1016/j.spen.2014.04.005 YSPEN471
To appear in: Semin Pediatr Neurol
Cite this article as: Leeda Ahmadi M.B.B.S, Elaine Wirrell, Intractable Epilepsy, Hemispheric Malformation and Generalized EEG Abnormalities, Semin Pediatr Neurol , http://dx.doi.org/10.1016/j.spen.2014.04.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Intractable Epilepsy, Hemispheric Malformation and Generalized EEG Abnormalities Authors 1. Leeda Ahmadi, M.B.B.S 2. Elaine Wirrell, Professor, Divisions of Child and Adolescent Neurology and Epilepsy, Mayo Clinic, Rochester MN Author contributions LA and EW both were involved in the clinical management of the patient. LA wrote the draft of the manuscript and both LA and EW contributed to the editing of the manuscript. EW provided the figures. Funding The authors received no financial support for the research, authorship, and/or publication of this article. Ethical Approval No ethical approval was required for this article.
CASE REPORT An 8 year old right hand dominant boy with medically intractable epilepsy, global developmental delay and left hemiparesis presented to our center for possible surgical evaluation for his seizure disorder. He was the product of a healthy pregnancy, delivered by repeat cesarean section at term and received some bag‐mask oxygen at birth. He had no history of febrile seizures, significant head injury or brain infection. Seizure onset was at age 3 when he presented with a seizure characterized by jaw clenching, repeated emesis with eye deviation to the left, which lasted for 2‐3 minutes and was followed by postictal limpness. He underwent EEG and MRI, and was commenced on valproate. He remained seizure‐free for 11 months, but again presented with a cluster of seizures consisting of unresponsiveness with repetitive opening and closing of the right hand and mouth, lack of movement on the left side and eye deviation to the left. Each seizure lasted approximately 2‐3 minutes and he had ten events over a two hour period, finally resolving after a dose of rectal diazepam. He continued to have isolated seizures of similar semiology, occurring 2‐3 times per week. Additionally, he developed a second semiology consisting of briefly nodding his head backwards, with occasional falls that would occur 6‐12 times per day. Valproate was further increased, followed by addition of chlorazepate without benefit. Levetiracetam was then added which resulted in seizure freedom for eight months. Seizures of similar semiology recurred for a brief period during an intercurrent illness but then resolved again for twelve months with higher doses of levetiracetam. At eight years of age, seizures again recurred but were unresponsive to higher doses of valproate or levetiracetam. Placement of a vagal nerve stimulator did not afford any benefit, at which point he was referred to our center. His seizures were of two semiologies. With the first, his head would drop forword, both eyes would twitch and deviate to the left. Additionally he may have shaking of both legs, maximally on the left. These seizures would last 5‐10 seconds and were occurring 50‐150 times per
day. His second semiology was similar, but progressed to generalized clonic activity, and occurred approximately daily. He had sustained numerous injuries as a result of these seizures, including a recent fracture of his left upper extremity. He had global developmental delay and had plateaued, although not regressed in development, since recurrence of his seizures. He attended a special education class full time in Grade 2. He could recognize approximately 14 letters, knew some letter sounds and could rote count. His examination was significant for a left hemiparesis which was longstanding as suggested by a smaller left hand and foot and shorter left leg. He was able to ambulate independently and while his left hand was weaker, he did have some independent finger movement. No neurocutaneous lesions were noted on Woods lamp exam. The remainder of his exam was unremarkable. His MRI demonstrated an extensive right hemispheric malformation of cortical development most prominent within the right frontal and occipital lobes (Figure 1). His interictal EEG showed multifocal and generalized spike wave, maximal over the right centrotemporal region, and in sleep these discharges were nearly continuous (Figure 2). Multiple seizures were recorded which often began with right centrotemporal region theta activity but rapidly became generalized (Figure 3). He underwent right functional hemispherectomy just before his ninth birthday and has remained seizure‐free during the intervening two years from surgery. His development markedly improved to the point he is now able to read sentences and perform single digit addition. His focus and attention are markedly improved. Regarding motor function, he is able to ambulate independently although he has minimal movement of his left wrist, hand or fingers.
DISCUSSION
Malformations of cortical development are one of the most common pathologies reported in surgical series of pediatric epilepsy and frequently result in medically intractable epilepsy (1). They may be generalized and diffuse (ie agyria‐pachygyria band spectrum), hemispheric (hemimegalencephaly), multifocal (periventricular nodular heterotopia) or focal (pachygyria, schizencephaly or focal cortical dysplasia). Frequently, the extent of involvement predicts seizure type, severity and co‐existing neurologic disability. Severe epileptic encephalopathy and profound, early‐onset, developmental delay is characteristic with diffuse lesions, whereas more focal lesions may present with medically intractable epilepsy in otherwise well children and adults. MRI advances have been instrumental in improved detection of focal cortical dysplasias, with reported findings of increased cortical thickness, blurring of the cortical‐white matter junction, increased T2 signal, transmantle sign or localized brain atrophy. However, detection in young children prior to age 2‐3 years can be challenging due to immature myelination (2). Focal cortical dysplasias are classified into three major types with Types I and II referring to isolated focal cortical dysplasia, and Type III referring to dysplasia associated with other epileptogenic lesions, such as hippocampal sclerosis or tumors (3). The impact of intractable epilepsy in children is significant and extends well beyond uncontrolled seizures to include intellectual disability, psychiatric and behavioral problems and seizure‐ related injury and death. This young boy had an epileptic encephalopathy with electrical status epilepticus in sleep (ESES), which had led to plateauing of development. As a result of his frequent falls, he had sustained numerous injuries. The likelihood of seizure freedom in children with focal epilepsy is highly dependent on underlying etiology and number of prior AEDs which have failed for lack of efficacy. In our population‐ based study of outcome in focal epilepsy, 70.1% of children with unknown cause had favorable outcome with their first AED, compared to only 39.8% of those with a structural cause (p<0.0001) (4). In those in
whom one AED had failed, 28.6% with unknown cause, versus only 10.2% with a structural cause achieved a favorable outcome (p=0.04). Amongst structural causes, malformations of cortical development, mesial temporal sclerosis, tumors and vascular malformations had much lower rates of response to AEDs than remote brain insults. Surgery is a viable option for children with medically intractable epilepsy. In children with focal epilepsy and cortical dysplasia, it should be strongly considered after failure of 1‐2 AEDs, given the low likelihood of response to further AEDs (4). Early surgery will allow quicker control of seizures, and minimize associated comorbidities, thus improving long term outcome. Our patient had multifocal and generalized epileptiform activity on EEG. Such an EEG pattern may be seen in children with early onset brain lesions, and should not dissuade from surgical intervention (5). Our patient also had ESES, which was further impairing his developmental progress. In children with unilateral brain lesions, seizure freedom, as well as resolution of ESES, has been shown following epilepsy surgery (6). Hemispherectomy or hemispheric disconnection surgery should be considered for children with large hemispheric lesions and intractable epilepsy, including cortical dysplasias, Sturge‐Weber syndrome, large porencephalic cysts, etc. Various studies have documented good outcomes following functional hemispherectomy, with resolution or marked improvement of seizures and improved behavior (7‐9). Hemiparesis typically remains unchanged. REFERENCES 1. Kuzniecky RI, Barkovich AJ. Malformations of cortical development and epilepsy. Brain Dev 2001;23:2‐ 11. 2. Colombo N, Salamon N, Raybaud C, Ozkara C, Barkovich AJ. Imaging of malformations of cortical development. Epileptic Disord 2009;11:194‐205.
3. Blumcke I, Thom M, Aronica E, Armstrong DD, Vinters HV, Palmini A, et al. The clnicopathological spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 2011;52:158‐74. 4. Wirrell E, Wong‐Kisiel L, Nickels K. Seizure outcome after AED failure in pediatric focal epilepsy: Impact of underlying etiology . Epilepsy Behav 2014, in press. 5. Wyllie E, Lachhwani DK, Gupta A, Chirla A, Cosmo G, Worley S, et al. Successful surgery for epilepsy due to early brain lesions despite generalized EEG findings. Neurology 2007;69:389‐97. 6. Loddenkemper T, Cosmo G, Kotagal P, Haut J, Klaas P, Gupta A, et al. Epilepsy surgery in children with electrical statu epilepticus in sleep. Neurosurgery 2009;64:328‐37. 7. Moosa AN, Jehi L, Marashly A, Cosmo G, Lachhwani D, Wyllie E, et al. Long‐term functional outcomes and their predictors after hemispherectomy in 115 children. Epilepsia 2013;54:1771‐9. 8. Devlin AM, Cross JH, Harkness W, Chong WK, Harding B, Vargha‐Khadem F, Neville BG. Clinical outcomes of hemispherectomy for epilepsy in childhood and adolescence. Brain 2003;126(Pt 3):556‐66. 9. Terra‐Bustamante VC, Inuzuka LM, Fernandes RM, Escorsi‐Rosset S, Wichert‐Ana L, Alexandre V Jr, et al. Outcome of hemispheric surgeries for refractory epilepsy in pediatric patients. Childs Nerv Syst 2007;23:321‐6.
Figure 1: MRI (Figure 1a – Axial T2, Figure 1b – Coronal MPRAGE) demonstrates an extensive right hemispheric malformation of cortical development most prominent within the right frontal and occipital lobes
p EEG demonsstrating electtrical status epilepticus in ssleep (ESES) p pattern with Fiigure 2: Sleep discharges of h highest amplitude in the riight hemispheere
Fiigure 3: Seizu ure beginning in right centrrotemporal reegion. Duringg this event, the child had eeye deeviation to th he left and losss of tone