FULL-LENGTH ORIGINAL RESEARCH
Seizure semiology and EEG findings in mitochondrial diseases Justyna A. Chevallier, Gretchen K. Von Allmen, and Mary Kay Koenig Epilepsia, 55(5):707–712, 2014 doi: 10.1111/epi.12570
SUMMARY
Dr. Justyna Chevallier is a research associate with the University of Texas Medical School at Houston in the Department of Pediatrics, Division of Child & Adolescent Neurology.
Objective: Seizures constitute a frequent yet under-described manifestation of mitochondrial disorders (MDs). The aim of this study was to describe electroencephalography (EEG) findings and clinical seizure types in a population of children and adults with mitochondrial disease. Methods: Retrospective chart review of 165 records of children and adults with mitochondrial disease seen in the University of Texas Houston Mitochondrial Center between 2007 and 2012 was performed; all subjects were diagnosed with confirmed mitochondrial disease. EEG findings and clinical data, including seizure semiology and response to antiepileptic drugs (AEDs), were analyzed and categorized. Results: Sixty-six percent (109/165) of subjects had a routine EEG performed. Sixtyone percent (67/109) of EEG studies were abnormal and 85% (56/67) had epileptiform discharges. The most common EEG finding was generalized slowing (40/67, 60%). The most frequent category of epileptiform activity seen was multifocal discharges (41%), followed by focal (39%) and generalized (39%) discharges. Clinical seizures were seen in 55% of subjects and the most common types of seizures observed were complex partial (37%) and generalized tonic–clonic (GTC; 37%). The most common seizure type in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) was GTC (33%), with generalized or focal discharges seen on EEG. In Leigh syndrome GTC (11%) and complex partial (11%) seizures were the most frequent types. Of 60 subjects with clinical seizures, 28% were intractable to medical treatment. Significance: Mitochondrial disorder should be included in the list of differential diagnosis in any child that presents with encephalopathy, seizures, and a fluctuating clinical course. Given the relatively high prevalence of EEG abnormalities in patients with MD, EEG should be performed during initial evaluation in all patients with MD, not only upon clinical suspicion of epilepsy. KEY WORDS: Mitochondrial disorder, Epilepsy, Electroencephalographic findings.
Mitochondrial disorders (MDs) constitute a heterogeneous group of disorders that can affect virtually any organ and system, with a strong predilection toward the central nervous system (CNS). Among the wide spectrum of CNS manifestations, seizures constitute one of the Accepted January 21, 2014; Early View publication March 7, 2014. Department of Pediatrics, Division of Child and Adolescent Neurology, University of Texas Health Science Center, Houston, Texas,U.S.A. Address correspondence to Mary Kay Koenig, Department of Pediatrics, Division of Child and Adolescent Neurology, University of Texas Health Science Center, 6410 Fannin Street, Suite 732, Houston, TX 77030, U.S.A. E-mail: [email protected] Wiley Periodicals, Inc. © 2014 International League Against Epilepsy
most frequent, with mitochondrial dysfunction identified as both a cause of seizures and a trigger for neuronal cell death.1 Although the true prevalence of epilepsy in patients with MDs is unknown, the reported seizure frequency in children with MDs ranges from 35 to 61%,2–4 and epilepsy occurs more frequently in association with certain types of mitochondrial disease.1 In addition to participating in cellular calcium homeostasis, generation of reactive oxygen species, and oxidative phosphorylation, mitochondria are a primary source of neuronal ATP, and mitochondrial dysfunction significantly affects neuronal excitability and synaptic transmission. Mechanisms postulated in the literature as
707
708 J. A. Chevallier et al. potential causes of epileptogenesis in primary mitochondrial disease include the following: alterations in calcium homeostasis, excitotoxicity, and overproduction of free radicals.5 Syndromic mitochondrial disorders associated with epilepsy as a dominating phenotypic feature include AlpersHuttenlocher syndrome (AHS), ataxia neuropathy spectrum (ANS), Leigh syndrome, myoclonic epilepsy myopathy sensory ataxia (MEMSA), and myoclonic epilepsy with ragged red fibers (MERRF). The most common type of seizures seen in these syndromic MDs is generalized tonic–clonic (GTC).1 Mitochondrial encephalopathy lactic acidosis and stroke-like syndrome (MELAS) is associated with either complex partial or generalized seizures, frequently presenting with status epilepticus.6 Studies that systematically explore seizure semiology in pediatric patients with MD are scarce,3,4,7–9 and only a few case series were found correlating electroencephalography (EEG) findings with epileptic semiology in this population.4,7,8 In a series of 48 children with epilepsy and confirmed MD, 2 (4%) had Otahara syndrome, 10 (21%) had West syndrome, 12 (25%) had Lennox-Gastaut, 2 (4%) had Landau-Kleffner syndrome, 14 (29%) had generalized epilepsy, and 8 (17%) presented with partial seizures.9 Another study of 56 children with mitochondrial disease reported the following seizures types: neonatal refractory status epilepticus, neonatal myoclonic epilepsy, infantile spasms, refractory status epilepticus, epilepsia partialis continua, and myoclonic epilepsy. Myoclonic seizures and status epilepticus represented the most common seizure types (n = 29; 52%).8 A retrospective study of 31 children and adults with MDs showed partial seizures with focal or multifocal onset in 22 (71%). Generalized myoclonic seizures were present in five patients (16%) with classic MERRF.7 EEG findings in a group of 46 mitochondrial patients with epilepsy was described by Lee et al.4; the most frequent EEG finding was slow background activity (61%), and the most common seizure types were partial (50%) and myoclonic (48%). In individuals with MERRF, generalized epileptiform discharges or generalized photoparoxysmal responses have also been reported.10 Photoparoxysmal EEG responses have also been described in patients with MERRF, MELAS, overlapping phenotypes, and in one child with Leigh syndrome.7 The University of Texas Houston Mitochondrial Center is one of the largest mitochondrial centers in the United States, and the center collaborates with the University of Texas Comprehensive Epilepsy Program, a full-service epilepsy center with magnetoencephalography and a Level 4 Epilepsy Monitoring Unit. As such, this center is uniquely qualified to study both epilepsy and mitochondrial disease. The objective of the present study was to describe the EEG findings and seizure semiology in a cohort of 165 children and adults with MD. Epilepsia, 55(5):707–712, 2014 doi: 10.1111/epi.12570
Methods This study was a retrospective chart review of clinical records for consented children and adults with MD seen at the University of Texas Houston Mitochondrial Center between July 2007 and October 2012. All patients seen during the designated time frame with a confirmed diagnosis were evaluated.11 Data were included from routine 21-channel EEG studies recorded for 20–30 min in the awake, drowsy, or sleep states, either at the University of Texas Houston or another institution. Available EEG studies and/or their reports were reviewed by a single epileptologist with special qualification in pediatrics. Clinical information was retrieved from the subjects’ medical records.
Results Clinical records of 165 children and adults age (1–79 y/o) with confirmed MD were reviewed. One hundred nine subjects evaluated (66%) had routine 21-channel EEG performed either at the University of Texas Houston or another institution. Forty-nine subjects (45%) were female and 60 (55%) were male (Table 1). Twenty-six patients (24%) were adults (≥18 years), 24 subjects (22%) were adolescents (10–17 years), 58 subjects were children (2–9 years), and 1 (1%) subject was G 10158 T>C 12535 C>T 24459 G>A 92766 G>A nDNA mutations HIBCH LETM1 NDUFS2 POLG1 SURF1
Total subjects
Abnormal EEG
Normal EEG
7 1 2 2 1 1 1 1 1
5 (71%) 0 2 (100%) 0 1 (100%) 0 1 (100%) 0 0
2 (29%) 1 (100%) 0 2 (100%) 0 1 (100%) 0 1 (100%) 1 (100%)
1 1 1 6 1
0 0 1 (100%) 5 (83%) 0
1 (100%) 1 (100%) 0 1 (17%) 1 (100%)
Figure 1. Distribution of EEG findings among 67 subjects with abnormal EEG findings. Epilepsia ILAE
(11%) had nonconvulsive status epilepticus visualized on EEG. Three patients (33%) had GTC seizures, two (22%) with generalized discharges on the EEG, and one (11%) with focal discharges on EEG. Two patients (22%) had complex partial seizures. Of the five patients with depletion syndrome, three (60%) had no seizures but EEG showed diffuse slowing in two (40%) and generalized discharges in one (20%). One (20%) had Lennox-Gastaut syndrome and one (20%) had focal seizures with generalized discharges on EEG (Fig. 4).
Discussion Epilepsy in MD is an under-investigated subject, despite the fact that seizures constitute a very frequent manifestation of MD and are associated with poor clinical outcome.8 Epilepsia, 55(5):707–712, 2014 doi: 10.1111/epi.12570
Figure 2. Distribution of EEG discharges among 56 subjects with MD and epileptiform activity. Epilepsia ILAE
Figure 3. Distribution of seizure types among 60 patients with clinical seizures. Epilepsia ILAE
Seizures can represent the first manifestation of MD and should be considered, especially in children that present with seizures and encephalopathy, multiorgan symptomatology, or a fluctuating clinical course.12 The present study sought to better describe the types of seizures in the context of MD. In this case series, EEG abnormalities were found in 61% of subjects with MD. The most common EEG abnormality was generalized slowing (present in 60% of subjects), with isolated generalized slowing found in 7% of subjects; this concurs with the previous report of Lee et al. finding of generalized slowing in 61% of their cohort. The most frequent type of epileptiform activity seen was multifocal discharges (41%), followed by focal (39%) and generalized (39%) discharges. Clinical seizures were seen in 55% of subjects, and the most common types of seizures observed were complex
711 Seizures in Mitochondrial Diseases
Figure 4. Seizure types and EEG findings in 31 subjects with syndromic MD diagnosis. Epilepsia ILAE
partial (37%) and GTC (37%). Two previous pediatric series also reported a predominance of generalized epilepsy,3,9 whereas one adult series reported complex partial seizures with focal and multifocal epilepsy as the most prevalent type (71%).7 Myoclonic seizures were found in 22% of subjects in our study, which contrasts with findings reported by El Sabbagh et al., where myoclonic seizures constituted the predominant seizure type.8 Partial (50%) and myoclonic (48%) clinical seizures were also predominant in case series by Lee et al.4 Intractable seizures are associated with poor clinical outcomes and severe neurologic impairments.3 In the present study, 28% of subjects were not controlled with medical treatment alone. The most common seizure type in patients with MELAS was GTC (33%) with generalized or focal discharges seen on EEG; 22% of MELAS patients had complex partial seizures, which correlates with findings from previous reports.6 GTC and complex partial seizures were also the most frequent seizure types in patients with Leigh syndrome (GTC: 11%, complex partial: 11%). An obvious limitation of these findings is the very small sample size, preventing establishment of a clear relationship between specific syndromes and seizures. Larger cohorts investigating patients with mitochondrial disorders and epilepsy are crucial to develop a more clear
understanding of epilepsy and EEG abnormalities in this population. Correlation between seizure type, EEG findings, MD severity, and developmental delay needs to be investigated and established in both syndromic and nonsyndromic MD. A better understanding of the pathophysiology underlying epilepsy in the context of MD could lead to more efficacious, individualized therapeutic strategies. Of interest, we found that approximately one third of our subjects with epilepsy were intractable to treatment, which is similar to patients with epilepsy in general. Further studies could also investigate which treatments for epilepsy (AEDs, ketogenic diet, vagus nerve stimulation, and so on) are most effective for patients with MD and various seizure types and EEG findings, and whether MD syndromes or particular clinical seizure types are more likely to be associated with intractability to medications. Mitochondrial disorder should be included in the list of differential diagnosis for any child who presents with encephalopathy, seizures, and a fluctuating clinical course. Considering the relatively high prevalence of EEG abnormalities in patients with MD, EEG should be performed during initial evaluation in all patients with MD, not only upon clinical suspicion of epilepsy. Early detection is of the utmost importance to limit cognitive and developmental deterioration in these fragile patients. Epilepsia, 55(5):707–712, 2014 doi: 10.1111/epi.12570
712 J. A. Chevallier et al.
Disclosures None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. All of the authors approve of the final version of this article.
References 1. Finsterer JZarrouk Mahjoub S. Epilepsy in mitochondrial disorders. Seizure 2012;21:316–321. 2. Debray FG, Lambert M, Chevalier I, et al. Long-term outcome and clinical spectrum of 73 pediatric patients with mitochondrial diseases. Pediatrics 2007;119:722–723. 3. Khurana DS, Salganicoff L, Melvin JJ, et al. Epilepsy and respiratory chain defects in children with mitochondrial encephalopathies. Neuropediatrics 2008;39:8–13. 4. Lee HF, Chi CS, Tsai CR, et al. Epileptic seizures in infants and children with mitochondrial diseases. Pediatr Neurol 2011;45:169–174. 5. Cock H, Schapira AH. Mitochondrial DNA mutations and mitochondrial dysfunction in epilepsy. Epilepsia 1999;40(Suppl. 3):33–40.
Epilepsia, 55(5):707–712, 2014 doi: 10.1111/epi.12570
6. Kaufman KR, Zuber N, Rueda-Lara MA, et al. MELAS with recurrent complex partial seizures, nonconvulsive status epilepticus, psychosis, and behavioral disturbances: case analysis with literature review. Epilepsy Behav 2010;18:494–497. 7. Canafoglia L, Franceschetti S, Antozzi C, et al. Epileptic phenotypes associated with mitochondrial disorders. Neurology 2001;56:1340– 1346. 8. El Sabbagh S, Lebre AS, Bahi-Buisson N, et al. Epileptic phenotypes in children with respiratory chain disorders. Epilepsia 2010;51:1225– 1235. 9. Lee YM, Kang HC, Lee JS, et al. Mitochondrial respiratory chain defects: underlying etiology in various epileptic conditions. Epilepsia 2008;49:685–690. 10. Lorenzoni PJ, Scola RH, Kay CS, et al. MERRF: Clinical features, muscle biopsy and molecular genetics in Brazilian patients. Mitochondrion 2011;11:528–532. 11. Bernier FP, Boneh A, Dennett X, et al. Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 2002;59:1406–1411. 12. Kang HC, Kwon JW, Lee YM, et al. Nonspecific mitochondrial disease with epilepsy in children: diagnostic approaches and epileptic phenotypes. Childs Nerv Syst 2007;23:1301–1307.
Seizure semiology and EEG findings in mitochondrial diseases Justyna A. Chevallier, Gretchen K. Von Allmen, and Mary Kay Koenig Epilepsia, 55(5):707–712, 2014 doi: 10.1111/epi.12570
SUMMARY
Dr. Justyna Chevallier is a research associate with the University of Texas Medical School at Houston in the Department of Pediatrics, Division of Child & Adolescent Neurology.
Objective: Seizures constitute a frequent yet under-described manifestation of mitochondrial disorders (MDs). The aim of this study was to describe electroencephalography (EEG) findings and clinical seizure types in a population of children and adults with mitochondrial disease. Methods: Retrospective chart review of 165 records of children and adults with mitochondrial disease seen in the University of Texas Houston Mitochondrial Center between 2007 and 2012 was performed; all subjects were diagnosed with confirmed mitochondrial disease. EEG findings and clinical data, including seizure semiology and response to antiepileptic drugs (AEDs), were analyzed and categorized. Results: Sixty-six percent (109/165) of subjects had a routine EEG performed. Sixtyone percent (67/109) of EEG studies were abnormal and 85% (56/67) had epileptiform discharges. The most common EEG finding was generalized slowing (40/67, 60%). The most frequent category of epileptiform activity seen was multifocal discharges (41%), followed by focal (39%) and generalized (39%) discharges. Clinical seizures were seen in 55% of subjects and the most common types of seizures observed were complex partial (37%) and generalized tonic–clonic (GTC; 37%). The most common seizure type in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) was GTC (33%), with generalized or focal discharges seen on EEG. In Leigh syndrome GTC (11%) and complex partial (11%) seizures were the most frequent types. Of 60 subjects with clinical seizures, 28% were intractable to medical treatment. Significance: Mitochondrial disorder should be included in the list of differential diagnosis in any child that presents with encephalopathy, seizures, and a fluctuating clinical course. Given the relatively high prevalence of EEG abnormalities in patients with MD, EEG should be performed during initial evaluation in all patients with MD, not only upon clinical suspicion of epilepsy. KEY WORDS: Mitochondrial disorder, Epilepsy, Electroencephalographic findings.
Mitochondrial disorders (MDs) constitute a heterogeneous group of disorders that can affect virtually any organ and system, with a strong predilection toward the central nervous system (CNS). Among the wide spectrum of CNS manifestations, seizures constitute one of the Accepted January 21, 2014; Early View publication March 7, 2014. Department of Pediatrics, Division of Child and Adolescent Neurology, University of Texas Health Science Center, Houston, Texas,U.S.A. Address correspondence to Mary Kay Koenig, Department of Pediatrics, Division of Child and Adolescent Neurology, University of Texas Health Science Center, 6410 Fannin Street, Suite 732, Houston, TX 77030, U.S.A. E-mail: [email protected] Wiley Periodicals, Inc. © 2014 International League Against Epilepsy
most frequent, with mitochondrial dysfunction identified as both a cause of seizures and a trigger for neuronal cell death.1 Although the true prevalence of epilepsy in patients with MDs is unknown, the reported seizure frequency in children with MDs ranges from 35 to 61%,2–4 and epilepsy occurs more frequently in association with certain types of mitochondrial disease.1 In addition to participating in cellular calcium homeostasis, generation of reactive oxygen species, and oxidative phosphorylation, mitochondria are a primary source of neuronal ATP, and mitochondrial dysfunction significantly affects neuronal excitability and synaptic transmission. Mechanisms postulated in the literature as
707
708 J. A. Chevallier et al. potential causes of epileptogenesis in primary mitochondrial disease include the following: alterations in calcium homeostasis, excitotoxicity, and overproduction of free radicals.5 Syndromic mitochondrial disorders associated with epilepsy as a dominating phenotypic feature include AlpersHuttenlocher syndrome (AHS), ataxia neuropathy spectrum (ANS), Leigh syndrome, myoclonic epilepsy myopathy sensory ataxia (MEMSA), and myoclonic epilepsy with ragged red fibers (MERRF). The most common type of seizures seen in these syndromic MDs is generalized tonic–clonic (GTC).1 Mitochondrial encephalopathy lactic acidosis and stroke-like syndrome (MELAS) is associated with either complex partial or generalized seizures, frequently presenting with status epilepticus.6 Studies that systematically explore seizure semiology in pediatric patients with MD are scarce,3,4,7–9 and only a few case series were found correlating electroencephalography (EEG) findings with epileptic semiology in this population.4,7,8 In a series of 48 children with epilepsy and confirmed MD, 2 (4%) had Otahara syndrome, 10 (21%) had West syndrome, 12 (25%) had Lennox-Gastaut, 2 (4%) had Landau-Kleffner syndrome, 14 (29%) had generalized epilepsy, and 8 (17%) presented with partial seizures.9 Another study of 56 children with mitochondrial disease reported the following seizures types: neonatal refractory status epilepticus, neonatal myoclonic epilepsy, infantile spasms, refractory status epilepticus, epilepsia partialis continua, and myoclonic epilepsy. Myoclonic seizures and status epilepticus represented the most common seizure types (n = 29; 52%).8 A retrospective study of 31 children and adults with MDs showed partial seizures with focal or multifocal onset in 22 (71%). Generalized myoclonic seizures were present in five patients (16%) with classic MERRF.7 EEG findings in a group of 46 mitochondrial patients with epilepsy was described by Lee et al.4; the most frequent EEG finding was slow background activity (61%), and the most common seizure types were partial (50%) and myoclonic (48%). In individuals with MERRF, generalized epileptiform discharges or generalized photoparoxysmal responses have also been reported.10 Photoparoxysmal EEG responses have also been described in patients with MERRF, MELAS, overlapping phenotypes, and in one child with Leigh syndrome.7 The University of Texas Houston Mitochondrial Center is one of the largest mitochondrial centers in the United States, and the center collaborates with the University of Texas Comprehensive Epilepsy Program, a full-service epilepsy center with magnetoencephalography and a Level 4 Epilepsy Monitoring Unit. As such, this center is uniquely qualified to study both epilepsy and mitochondrial disease. The objective of the present study was to describe the EEG findings and seizure semiology in a cohort of 165 children and adults with MD. Epilepsia, 55(5):707–712, 2014 doi: 10.1111/epi.12570
Methods This study was a retrospective chart review of clinical records for consented children and adults with MD seen at the University of Texas Houston Mitochondrial Center between July 2007 and October 2012. All patients seen during the designated time frame with a confirmed diagnosis were evaluated.11 Data were included from routine 21-channel EEG studies recorded for 20–30 min in the awake, drowsy, or sleep states, either at the University of Texas Houston or another institution. Available EEG studies and/or their reports were reviewed by a single epileptologist with special qualification in pediatrics. Clinical information was retrieved from the subjects’ medical records.
Results Clinical records of 165 children and adults age (1–79 y/o) with confirmed MD were reviewed. One hundred nine subjects evaluated (66%) had routine 21-channel EEG performed either at the University of Texas Houston or another institution. Forty-nine subjects (45%) were female and 60 (55%) were male (Table 1). Twenty-six patients (24%) were adults (≥18 years), 24 subjects (22%) were adolescents (10–17 years), 58 subjects were children (2–9 years), and 1 (1%) subject was G 10158 T>C 12535 C>T 24459 G>A 92766 G>A nDNA mutations HIBCH LETM1 NDUFS2 POLG1 SURF1
Total subjects
Abnormal EEG
Normal EEG
7 1 2 2 1 1 1 1 1
5 (71%) 0 2 (100%) 0 1 (100%) 0 1 (100%) 0 0
2 (29%) 1 (100%) 0 2 (100%) 0 1 (100%) 0 1 (100%) 1 (100%)
1 1 1 6 1
0 0 1 (100%) 5 (83%) 0
1 (100%) 1 (100%) 0 1 (17%) 1 (100%)
Figure 1. Distribution of EEG findings among 67 subjects with abnormal EEG findings. Epilepsia ILAE
(11%) had nonconvulsive status epilepticus visualized on EEG. Three patients (33%) had GTC seizures, two (22%) with generalized discharges on the EEG, and one (11%) with focal discharges on EEG. Two patients (22%) had complex partial seizures. Of the five patients with depletion syndrome, three (60%) had no seizures but EEG showed diffuse slowing in two (40%) and generalized discharges in one (20%). One (20%) had Lennox-Gastaut syndrome and one (20%) had focal seizures with generalized discharges on EEG (Fig. 4).
Discussion Epilepsy in MD is an under-investigated subject, despite the fact that seizures constitute a very frequent manifestation of MD and are associated with poor clinical outcome.8 Epilepsia, 55(5):707–712, 2014 doi: 10.1111/epi.12570
Figure 2. Distribution of EEG discharges among 56 subjects with MD and epileptiform activity. Epilepsia ILAE
Figure 3. Distribution of seizure types among 60 patients with clinical seizures. Epilepsia ILAE
Seizures can represent the first manifestation of MD and should be considered, especially in children that present with seizures and encephalopathy, multiorgan symptomatology, or a fluctuating clinical course.12 The present study sought to better describe the types of seizures in the context of MD. In this case series, EEG abnormalities were found in 61% of subjects with MD. The most common EEG abnormality was generalized slowing (present in 60% of subjects), with isolated generalized slowing found in 7% of subjects; this concurs with the previous report of Lee et al. finding of generalized slowing in 61% of their cohort. The most frequent type of epileptiform activity seen was multifocal discharges (41%), followed by focal (39%) and generalized (39%) discharges. Clinical seizures were seen in 55% of subjects, and the most common types of seizures observed were complex
711 Seizures in Mitochondrial Diseases
Figure 4. Seizure types and EEG findings in 31 subjects with syndromic MD diagnosis. Epilepsia ILAE
partial (37%) and GTC (37%). Two previous pediatric series also reported a predominance of generalized epilepsy,3,9 whereas one adult series reported complex partial seizures with focal and multifocal epilepsy as the most prevalent type (71%).7 Myoclonic seizures were found in 22% of subjects in our study, which contrasts with findings reported by El Sabbagh et al., where myoclonic seizures constituted the predominant seizure type.8 Partial (50%) and myoclonic (48%) clinical seizures were also predominant in case series by Lee et al.4 Intractable seizures are associated with poor clinical outcomes and severe neurologic impairments.3 In the present study, 28% of subjects were not controlled with medical treatment alone. The most common seizure type in patients with MELAS was GTC (33%) with generalized or focal discharges seen on EEG; 22% of MELAS patients had complex partial seizures, which correlates with findings from previous reports.6 GTC and complex partial seizures were also the most frequent seizure types in patients with Leigh syndrome (GTC: 11%, complex partial: 11%). An obvious limitation of these findings is the very small sample size, preventing establishment of a clear relationship between specific syndromes and seizures. Larger cohorts investigating patients with mitochondrial disorders and epilepsy are crucial to develop a more clear
understanding of epilepsy and EEG abnormalities in this population. Correlation between seizure type, EEG findings, MD severity, and developmental delay needs to be investigated and established in both syndromic and nonsyndromic MD. A better understanding of the pathophysiology underlying epilepsy in the context of MD could lead to more efficacious, individualized therapeutic strategies. Of interest, we found that approximately one third of our subjects with epilepsy were intractable to treatment, which is similar to patients with epilepsy in general. Further studies could also investigate which treatments for epilepsy (AEDs, ketogenic diet, vagus nerve stimulation, and so on) are most effective for patients with MD and various seizure types and EEG findings, and whether MD syndromes or particular clinical seizure types are more likely to be associated with intractability to medications. Mitochondrial disorder should be included in the list of differential diagnosis for any child who presents with encephalopathy, seizures, and a fluctuating clinical course. Considering the relatively high prevalence of EEG abnormalities in patients with MD, EEG should be performed during initial evaluation in all patients with MD, not only upon clinical suspicion of epilepsy. Early detection is of the utmost importance to limit cognitive and developmental deterioration in these fragile patients. Epilepsia, 55(5):707–712, 2014 doi: 10.1111/epi.12570
712 J. A. Chevallier et al.
Disclosures None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. All of the authors approve of the final version of this article.
References 1. Finsterer JZarrouk Mahjoub S. Epilepsy in mitochondrial disorders. Seizure 2012;21:316–321. 2. Debray FG, Lambert M, Chevalier I, et al. Long-term outcome and clinical spectrum of 73 pediatric patients with mitochondrial diseases. Pediatrics 2007;119:722–723. 3. Khurana DS, Salganicoff L, Melvin JJ, et al. Epilepsy and respiratory chain defects in children with mitochondrial encephalopathies. Neuropediatrics 2008;39:8–13. 4. Lee HF, Chi CS, Tsai CR, et al. Epileptic seizures in infants and children with mitochondrial diseases. Pediatr Neurol 2011;45:169–174. 5. Cock H, Schapira AH. Mitochondrial DNA mutations and mitochondrial dysfunction in epilepsy. Epilepsia 1999;40(Suppl. 3):33–40.
Epilepsia, 55(5):707–712, 2014 doi: 10.1111/epi.12570
6. Kaufman KR, Zuber N, Rueda-Lara MA, et al. MELAS with recurrent complex partial seizures, nonconvulsive status epilepticus, psychosis, and behavioral disturbances: case analysis with literature review. Epilepsy Behav 2010;18:494–497. 7. Canafoglia L, Franceschetti S, Antozzi C, et al. Epileptic phenotypes associated with mitochondrial disorders. Neurology 2001;56:1340– 1346. 8. El Sabbagh S, Lebre AS, Bahi-Buisson N, et al. Epileptic phenotypes in children with respiratory chain disorders. Epilepsia 2010;51:1225– 1235. 9. Lee YM, Kang HC, Lee JS, et al. Mitochondrial respiratory chain defects: underlying etiology in various epileptic conditions. Epilepsia 2008;49:685–690. 10. Lorenzoni PJ, Scola RH, Kay CS, et al. MERRF: Clinical features, muscle biopsy and molecular genetics in Brazilian patients. Mitochondrion 2011;11:528–532. 11. Bernier FP, Boneh A, Dennett X, et al. Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 2002;59:1406–1411. 12. Kang HC, Kwon JW, Lee YM, et al. Nonspecific mitochondrial disease with epilepsy in children: diagnostic approaches and epileptic phenotypes. Childs Nerv Syst 2007;23:1301–1307.
