2006 The Authors Journal compilation 2006 Blackwell Munksgaard
Acta Neurol Scand 2006: 113: 72–81 DOI: 10.1111/j.1600-0404.2005.00555.x
ACTA NEUROLOGICA SCANDINAVICA
Focal cortical dysplasia: prevalence, clinical presentation and epilepsy in children and adults Bast T, Ramantani G, Seitz A, Rating D. Focal cortical dysplasia: prevalence, clinical presentation and epilepsy in children and adults. Acta Neurol Scand 2006: 113: 72–81. 2006 The Authors Journal compilation 2006 Blackwell Munksgaard. Focal cortical dysplasias (FCD) are defined as circumscribed malformations of cortical development. They result from an impairment of neuronal proliferation, migration and differentiation. In the diagnosis of focal epilepsy FCD prevalence ranges between 5% and 25%, depending on patient collective and imaging techniques. Several ÔcryptogenicÕ epilepsies may be caused by FCD but have not been diagnosed because of the lack of high-quality magnetic resonance imaging assessment.Retrospective analysis of patients who have undergone epilepsy surgery can be biased because of the fact that they represent a mere subset of potential FCD diagnoses. Epilepsy typically manifests within the first years of life, but has been documented up to the age of 60 years. Cognitive impairment commonly accompanies early onset. Epilepsy is often refractory to antiepileptic drug (AED) treatment. Clinical observations and pathophysiological findings illustrate intrinsic epileptogenicity. Upregulation of drug transporter proteins has been found in FCD tissue. There is no specific drug treatment in FCD, as any AED used in focal epilepsy could prove effective. A sequential AED therapy should be designed individually and take side effects as well as developmental progresses into consideration. Fifty to sixty-five percent of FCD patients are rendered seizure-free after surgery. Presurgical evaluation should be initiated after two unsuccessful AED trials. Both risks and potential benefits regarding seizure control and developmental impairment need to be considered on an individual basis when deciding between surgical intervention and conservative treatment. Current knowledge on epilepsy course and psychomotor development in FCD is limited in the absence of qualified long-term studies combining imaging with cognitive evaluation.
Focal cortical dysplasias (FCD) play an increasingly important part in the field of presurgical epilepsy diagnosis. High-resolution magnetic resonance imaging (MRI), improved investigation protocols, and post-processing methods, have facilitated the identification of FCD in a vast number of focal epilepsies that were previously classified as cryptogenic (1–5). Epilepsy features are well described for classical malformations caused by a disturbance of cortical migration (heterotopia, pachygyria and lissencephaly) or cortical organization (polymicrogyria). Informa72
T. Bast1, G. Ramantani1, A. Seitz2, D. Rating1 1 Department of Paediatric Neurology, University of Heidelberg, Heidelberg, Germany; 2Department of Neuroradiology, University of Heidelberg, Heidelberg, Germany
Key words: CNS malformation; focal cortical dysplasias; refractory epilepsy; magnetic resonance imaging; epilepsy surgery; outcome Thomas Bast, Department of Paediatric Neurology, University Hospital of Heidelberg, INF 150, D 69120 Heidelberg, Germany Tel.: (+49) 6221 568228 Fax: (+49) 06221 565744 e-mail:
[email protected] Accepted for publication October 11, 2005
tion regarding clinical presentation in FCD is limited, compared with other types of malformations.
Classification and definitions Focal cortical dysplasia
In 1971, Taylor et al. first described FCD in resection specimens from 10 patients with lobectomy performed due to refractory epilepsy (6). FCD arise in the initial phases of cortical development as
Epilepsy in FCD a consequence of abnormalities during neuroglial proliferation and differentiation, neuronal migration, and post-migratory cortical organization (7). Diverse FCD classification schemes were proposed, which consider features of imaging, genetics, developmental biology and pathophysiology (8–15). The wide variety of different classification systems seems to alienate clinical epileptologists. The histopathological classification systems proposed by Palmini and Lu¨ders (14) and Tassi et al. (16) are the two prime systems that are currently used. Both classification systems are grounded on a clear distinction between the two FCD subgroups: sheer architectural abnormalities of the cortex without abnormal neurones are discriminated from FCD with abnormal and dysplastic neurones (Table 1). In this study, we have decided to utilize the classification system of Palmini and Lu¨ders, except when referring to studies based on different classification systems. According to the Palmini and Lu¨ders classification, FCD is divided in type 1 (A ¼ isolated architectural abnormalities, B ¼ plus giant or immature, but not dysmorphic neurones) and type 2 (A ¼ architectural abnormalities with dysmorphic neurones but without balloon cells, B ¼ plus balloon cells) (15). In addition, mild cortical dysplasia is described as ectopically placed neurones in or adjacent to layer 1 or microscopic neuronal heterotopia outside layer 1. Microdysgenesis
The term ÔmicrodysgenesisÕ, introduced by Meencke and Janz (17), has been rather controversial thus far. Some authors have used this term
Table 1 Histopathological classification of focal cortical dysplasia Palmini and Lders (14) Mild cortical dysplasia: Ectopically placed neurones in or adjacent to layer 1 or microscopic neuronal heterotopia outside layer 1 FCD 1A: Isolated architectural abnormalities of the cortex FCD 1B: Architectural abnormalities plus giant or immature, but not dysmorphic neurones FCD 2A: Architectural abnormalities with dysmorphic neurones but without balloon cells FCD 2B: Architectural abnormalities with dysmorphic neurones and balloon cells
Tassi et al. (16) Architectural dysplasia: Abnormal cortical lamination and ectopic neurones in white matter
Cytoarchitectural dysplasia: Giant neurofilament-enriched neurones and altered cortical lamination
Taylor-type dysplasia: Giant dysmorphic neurones and balloon cells with laminar disruption
in the denotation of subtle dearangements of focal cortical architecture such as cortical laminar disorganization, single white-matter neurones as well as neurones in the molecular layer, persistent granular layer and marginal glioneuronal heterotopia (13). Malformations of cortical development
The term refers to malformations arising from various aetiologies and presenting with diverse characteristics. In the clinical practice, the classification system of Kuzniecky and Barkovich has gained wide acceptance (11). According to this classification, malformations of cortical development (MCD) fall into the following categories: (i) malformations caused by abnormal neuronal and glial proliferation (e.g. hemimegalencephaly, FCD), (ii) malformations caused by abnormal neuronal migration (e.g. heterotopia, lissencephaly) and (iii) malformations caused by abnormal cortical organization (e.g. polymicrogyria, FCD without balloon cells). Magnetic resonance imaging studies in FCD
Focal cortical dysplasia exhibits a variety of features that in MRI studies are not always all present in combination, nor pathognomonic in isolation (Fig. 1): (i) local cortical thickening (often in combination with cortical hyperintensity), (ii) blurring of the grey-matter to white-matter surface, (iii) signal changes in the underlying white matter, usually with an increased signal on T2-weighted images and occasionally with a decreased signal on T1-weighted images (11). The sensitivity of MRI studies can be best judged from the histopathological findings in patients that have undergone surgery (Table 2). The MRI sensitivity ranges between 63% and 98% in recent studies (18–24). Reports from epilepsy surgery programmes may not be used as the gold standard to evaluate MRI sensitivity because of an obvious bias: if no FCD is detected in MRI, the patient is less likely to be offered an operative therapy than in the case of a focal lesion. Thus, the varying rates of FCD detected may be attributed to the diverse quality and precision of presurgical MRI investigations. In contrast, the presurgical protocol applied may influence the ranking of intracranial EEG studies in MRI-negative cases. Up to 50% of patients with refractory cryptogenic epilepsy (i.e. no MRI lesion) undergoing surgical treatment are shown to have an FCD: Bautista et al. reported of a total of 21 patients with normal MRI who underwent resec73
Bast et al.
Figure 1. MRI of four patients with FCD. Typical features are (i) focal cortical thickening (patient 1 and 3), (ii) blurring of the greymatter to white-matter surface (patient 1–3), (iii) signal changes in the underlying white matter, usually with an increased signal on T2-weighted images (patient 1–4). MRI acquisition: Philips Gyroscan NT, 0.5 T. Parameters: T2 DE SE transversal (slide thickness 6 mm; TR: patient 1, 3, 4: 2203, patient 2: 2385; TE: patient 1, 4: 120, patient 2, 3: 90). T2 3D TSE coronar (slide thickness 1.8 mm; TR 3000; TE 120). FLAIR coronar (slide thickness 2.5 mm; TR 5000; TE 100; TI 1900). T1 IR coronar (slide thickness 2.5 mm; TR 1492; TE 25; TI 400).
tive surgery for intractable epilepsy in Cleveland, OH between 1997 and 2000. In 1 ⁄ 9 temporal and 9 ⁄ 12 extratemporal lobe resections, histopathological findings unmasked an FCD (18). Incomplete myelination may result in negative MRI findings (25) (Fig. 2). In infants, where myelination is incomplete, MRI may fail to reveal an FCD, because of the lack of visual differentiation between white and grey matter. According to recent MRI studies, architectural abnormalities (FCD type 1) can be separated from typical FCD type 2 (Taylor-type dysplasia). Focal cortical thickening, blurring of grey–white matter junction (19) and hyperintensity of the subcortical white matter on T2-weighted sequences (19, 21, 23) indicate a balloon cell dysplasia. In FCD type 1 (architectural dysplasia), focal brain hypoplasia with shrinkage and moderate signal intensity alterations in the white-matter core are frequently observed (19). MRI-post-processing, i.e. automated detection of grey-matter malformations based on an optimized voxel-based morphometry, may help to identify FCD and gain relevance in the near future (1, 3, 5). 74
Comment: An important clinical conclusion is that a negative (routine-) MRI does not rule out the possibility of an FCD. Grey–white matter differentiation may be absent in the developing brain before the myelination process is complete. Thus an MRI should be repeated after the second year of life in the case of ÔcryptogenicÕ focal epilepsy. FCD prevalence
It is difficult to extract information regarding FCD prevalence because of varying selection criteria and investigation methods applied in reported data. In each study the diversity in investigation methods leads to certain sampling bias. Data from epilepsy surgery series
In the field of epilepsy surgery, there is a growing rate of patients who are operated on the ground of FCD. Rates of up to 25% of all operated patients are reported to have FCD (16). There is an obvious advantage in surgical studies, because the diagnosis of FCD is set according to the histopathological
Epilepsy in FCD Table 2 FCD-related sensitivity of MRI in histopathologically proven cases Author
Year
Study period
Wyllie et al. (24) Klos et al. (21) Bautista et al. (18) Colombo et al. (19) Kral et al. (22) Fauser et al. (20) Lawson et al. (23)
1998 2002 2003 2003 2003 2004 2005
1990–1996 1990–2000 1994–2000 1996–2000 1989–1999 1998–2003 1990–2001
Patient collective 31 68 55 49 53 67 30
children/adolescents with FCD children with FCD patients with FCD (24 isolated FCD) patients with FCD patients with FCD patients with FCD children with FCD
Positive MRI (%) 87 951 752 633 964 985 976
1
Forty-one of 68 patients presented FCD without and 27/68 FCD with balloon cells. Histopathology of MRI-negative cases is not reported. FCD was classified as follows: 8/68 mild cortical dysplasia, 38 type 1 and 21 type 2 FCD. Dual pathology was present in 31 of 55 patients. In patients with pure FCD MRI was positive in 75%. A FCD-negative MRI was found in 13% of 55 patients. 3 Rate of positive MRI varied among histopathological subtypes: architectural dysplasia (n ¼ 28) 75%, cytoarchitectural dysplasia (n ¼ 6) 50% and dysplasia with balloon cells (n ¼ 15) 67%. 4 An additional 11 patients were not included in the study due to lacking MRI studies or previous poor quality MRI, out of the scope of epilepsy surgery. FCD showed balloon cells in 21/28 extratemporal and 2/24 temporal lesions. 5 A voxel-based statistical MRI post-processing analysis revealed FCD in a single case, while the conventional MRI analysis was negative (histopathological diagnosis of FCD2A). 6 MRI was insufficient in four additional patients. In case of balloon cell type FCD only one MRI was negative. 2
Figure 2. Effect of myelination on MRI sensitivity. Top: Normal T2-weighted MRI of a 7-month-old child suffering from left temporal lobe epilepsy. Bottom: Same patient at 19 months of age. MRI is suspect for FCD with blurred grey– white matter surface and prolonged T2-signal. MRI acquisition: Philips Gyroscan NT, 0.5 T, T2 DE SE. TE 120. TR age adapted (Top 3000, Bottom 2674). Please note that MR scans are not depicted in identical sections.
findings. However, there is a clear disadvantage in dealing with a highly preselected patient group. Only patients with refractory epilepsy who presented with operable focal epilepsies are reported. The prevalence of FCD remains unclear in the case that epilepsy is less refractory to drug treatment or nonoperable. FCD in imaging studies
Imaging studies in epilepsy – The initial data available originate from the early 1990s, when MRI techniques had not yet reached current standards.
Li et al. applied MRI in a total of 341 patients with refractory focal epilepsy (26). In 12% of patients, an MCD was established. However, there is no clear statement to the rate of FCD. In a similar study, Cakirer et al. reported an MCD rate of 15% in 73 patients with refractory focal epilepsy; 4% were classified as FCD (27). Chan et al. (2) investigated 42 epilepsy surgery candidates with refractory neocortical partial epilepsy by means of high-resolution MRI. In 10 of 42 cases, a FCD was uncovered; five of these patients were under 5 years of age and one of 10 had a hemimegalencephaly. MRI findings in the remaining 32 patients were not reported and the criteria according to which an FCD was ruled out remain unclear. Imaging studies in MCD – Several MRI studies in MCD report FCD rates that are related to certain inclusion criteria. In 1995, Raymond et al. reported seven cases with FCD out of a total of 100 MCD patients (28). In 1999, Leventer et al. investigated 109 patients with a variety of malformations (12). Of these patients 21% were uncovered to have FCD. Comment: The drawback of studies that are based solely on imaging techniques is that FCD cannot be eliminated as a diagnosis through negative MRI findings. Patients with refractory epilepsy, for which surgical intervention is not considered, are seldom investigated by means of high-resolution MRI and post-processing techniques. In uncomplicated cases, neuroimaging studies are frequently not performed. FCD prevalence is underestimated because epilepsies are classified as cryptogenic in these poorly investigated cases.
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Bast et al. FCD in clinical studies
Although frequently quoted in the context of FCD studies, Guerrini et al. (29) and Dravet et al. (30) reported only generally about clinical presentation of MCD. These implemental studies were based on imaging and operative outcome. It is important to realize that a relatively low ratio of FCD was present among all cases, consisting in 6 of 90 and 3 of 50 patients, respectively. None of the great prospective studies thus far, regarding aetiology and clinical course of focal epilepsy (31, 32) have specifically addressed the issue of FCD, although these studies have been frequently cited. In a prospective study, Stephen et al. found that 12% of 550 adolescents and adults with focal epilepsy had a MCD (32). It is not possible to draw conclusions from this data regarding FCD frequency. The group of MCD included 36 different forms of malformations and the exact rate of FCD among these is not reported. The study took place between 1984 and 1997, when the quality of MRI was rather poor. A total of 189 of 550 epilepsies were classified as cryptogenic, and it is probable that a higher number of FCD cases could have been diagnosed from this group. In a similar study, Semah et al. prospectively investigated 2200 adult patients (>16 years of age) between 1990 and 1997 (31). Sixty-two per cent of epilepsy syndromes were classified as focal and 81 cases harboured MCD, while an additional 38 cases presented dual pathology (MCD and hippocampal sclerosis). The FCD rate among the investigated patients was unaccounted for in this study. A recent study of Fujiwara and Shigematsu (33) analysed aetiological factors of symptomatic epilepsy in childhood. The prevalence of MCD reached 13% in 199 patients, of which FCD was again not differentiated as a subgroup. Erikkson and Koivikko (34) investigated the prevalence of childhood epilepsy in a Finish region. MCD was identified in 23% of the children with generalized or focal epilepsy in this study. It is not evident what kind of cerebral imaging was applied, and if all patients underwent imaging for evaluation. Histopathological studies
The epidemiological–neuropathological studies of Meencke and Veith provide some data on the frequency of cortical malformations (35), even though the term FCD was not used. Histopathological studies revealed so-called microdysgenesis in 6% and typical malformations in 1.5% of unaffected controls. Among epilepsy patients, 76
higher rates of microdysgenesis (37.7%) and typical malformations (14%) were observed. Comment: The true prevalence of FCD in epilepsy patients remains unclear, most estimates are necessarily biased by selection and reporting. Studies solely based on imaging harbour numerous drawbacks, including false-negative MRI and a wide variability in the imaging techniques applied. Furthermore, the high-quality MRI imaging techniques according to the standards of epilepsy surgery are not applied to each and every patient with localization-related epilepsy. FCD as the cause of focal epilepsy can be roughly estimated at 5–10% in developed countries. However, the prevalence of FCD in focal epilepsy may in fact be lower than 5%, when referring to epilepsy patients on a global basis. In less-developed countries, infectious diseases such as neurocysticercosis may play a more prominent role in epilepsy aetiology (36). Characteristics of epilepsy syndrome and clinical course
The preoperative clinical data gathered from presurgical work-up in patients with refractory epilepsy are often sparsely reported. Bearing in mind that only refractory epilepsy patients undergo surgery, the following characteristics can be summarized (16, 18, 20–22, 37–40). Epilepsy due to FCD commonly begins in the first few years of life and may occur shortly after birth. The histopathological type without balloon cells (type 2A) is related to a very early onset compared with FCD with balloon cells (type 2B) (23). Single cases presented with epilepsy onset after the fourth decade in life in late adulthood. Fauser et al. reported a patient with late epilepsy onset at the age of 60 (20). The data collected from epilepsy surgery, predominantly in adult series, point to a history of febrile seizures in 5.5% (22) to 25% (16) of patients; 10% (37) to 30% (41) of patients have suffered a status epilepticus (18, 42, 43). Epilepsia partialis continua can often be associated with FCD localization in the pre- and post-central cortical region (37, 44, 45). Bautista et al. reported the following epilepsy risk factors in the personal history of 55 patients operated for FCD (18): positive family history of epilepsy in 18%, febrile seizures in 16%, status epilepticus in 11%, trauma in 16%, CNS infection in 11% and perinatal complications in 4%. Therefore, one should consider the possibility of an FCD, even in the presence of other obvious factors of epileptogenesis. In FCD patients, who have been operated on in early childhood, drawbacks in psychomotor
Epilepsy in FCD development were observed in up to 70–80% (37–39). In a study conducted by Lawson et al. (23), mild to severe mental retardation was present in 15 of 30 children. Only patients with FCD type 2A showed severe retardation (n ¼ 5); 14.5% (18) to 31% (16) of operated patients were found to have pathologic neurological examinations. Patients who underwent epilepsy surgery in adulthood showed cognitive deficits or a previously delayed development in 22% (18) to 50% (40) of cases. ÔCatastrophicÕ epilepsy with stagnation in development was reported in 31% of children with FCD by Klos et al. This stagnation was clearly associated with the underlying epilepsy syndrome (21). Lortie et al. studied a group of 28 children with FCD and epilepsy onset in the first year of life (46). Over the course of the study, 27 of 28 patients presented developmental problems and neuropsychological shortcomings. It is presumed that the size of lesion (40), the localization (especially in the case of temporal localization) (47) and even the histopathological subtype (23) play a major role in the manifestation and grade of developmental delay. Chassoux et al. reported on 28 FCD patients, including 14 children who underwent epilepsy surgery (37). In these patients, an early epilepsy onset correlated with a posterior localized or multilobar lesion. Psychiatric features were strongly associated with early epilepsy onset and posterior localization. The authors further concluded that a mental retardation was related to early onset, whereas a normal development or minor developmental delay was associated with more circumscribed lesions. Comment: Focal epilepsy caused by FCD commonly appears in early childhood and often encompasses febrile seizures and status epilepticus. Early onset epilepsy is commonly associated with major cognitive or neuropsychological shortcomings. Patients operated in childhood are more frequently affected in comparison with adults. A possible theoretical explanation is that a severe course of epilepsy leads to earlier surgical intervention. In addition, inadequately investigated or reported factors could very likely be responsible for developmental shortcomings such as (i) localization and extent of the FCD (often poorly defined by MRI), (ii) epilepsy impact, including epileptic encephalopathy, and (iii) side-effects of polytherapy with antiepileptic drugs (AEDs), which is most always inevitable. Dual pathology
The term Ôdual pathologyÕ describes the coincidence of extrahippocampal temporal lesions and
Ammon’s horn sclerosis (48). According to this definition, the majority of associated lesions are MCD: Salanova et al. investigated 37 patients operated for dual pathology. Heterotopia (n ¼ 18) and cortical dysplasia (n ¼ 9) were the most common findings (49). In contrast, over one-third of cases of FCD are associated with a hippocampal sclerosis: 36% (19/52) (16), 38% (21/55) (18), 43% (29/68) (20). Patients with dual pathology showed a tendency for earlier epilepsy onset and longer epilepsy duration compared with patients presenting with plain FCD. Epilepsy surgery was performed later in life in patients with dual pathology. Milder forms of FCD (mild cortical dysplasia, FCD type 1) showed a higher rate of temporal localization and were more frequently associated with hippocampal sclerosis in the series of Fauser et al. (20). In presurgical evaluation, the presence of dual pathology must be taken into consideration because of the common association between FCD and hippocampal sclerosis. Tassi et al. (16) described patients that on the ground of MRI investigation were thought to have FCD and postoperatively after histopathological evaluation presented hippocampal sclerosis. Others that were diagnosed with plain hippocampal sclerosis per MRI showed a dual pathology in the histopathological examination performed postoperatively (16). Fauser et al. examined 29 patients with dual pathology. MRI findings were false negative with regard to FCD in one patient and for hippocampal sclerosis in eight cases (20). Several authors use the term Ôdual pathologyÕ in addition to the classical definition to describe FCD in combination with other lesions, like low-grade gliomas (18, 22) or even infarction and remote injury (18). In the case of an apparent neoplastic lesions the possibility of an associated FCD should be considered.
Treatment and prognosis in FCD Surgical treatment in FCD
In epilepsy caused by FCD, surgical resection is an important treatment modality. The postoperative rate of FCD patients rendered seizure-free varies from about 50% (4, 16, 21, 24, 39) to approximately 65% (18, 20, 23) in major patient collectives. However, a publication bias involving an under-representation of less successful surgical cases and series cannot be ruled out. The highest rate of seizure-free patients following epilepsy surgery for FCD was 72% in a large single study including 53 patients (22). Various 77
Bast et al. histopathological subtypes were shown to have a diverse postoperative prognosis: the proportion of patients rendered seizure-free as a result of surgical treatment was significantly lower in FCD type 2 (especially type 2a) compared with milder forms of FCD (mild cortical dysplasia/FCD type 1) (20). This view was also supported by other investigations that related a higher epileptogenicity to areas with histopathological characteristics for FCD type 2a, compared with areas with FCD type 1 (50). In the series of Fauser et al. (20) the higher rate of seizure freedom in patients with FCD type 1 may be attributed to a higher rate of temporal localization compared with FCD type 2. The rate of seizure-free outcome in the group with temporal resection is actually comparable with amygdalohippocampectomy in plain hippocampal sclerosis. Hippocampal sclerosis may have presented the prime epileptogenic factor in this collective. Medical treatment in FCD
Numerous clinical observations support the notion that epilepsy due to FCD is commonly refractory to drug treatment. However, there is no clear statement regarding the exact rate of drug resistance. The data derived from epilepsy surgery does not match this purpose, as pharmacoresistance is a prerequisite to surgical treatment. It is a common mistake to cite studies that fail to discern between MCD and FCD when estimating rates of pharmacoresistance. The results reported by Guerrini et al. (29) are often quoted to support the view that the prognosis in FCD epilepsy is not necessarily unfavourable regarding antiepileptic treatment. It is remarkable that only six of 90 MCD patients were diagnosed with FCD. Of these six patients, four were resistant to drug treatment and one underwent surgical resection. Accordingly, in the frequently cited study of Dravet et al. (30) only three of 50 patients with epilepsy and malformations presented FCD. Data from patients with perisylvian polymicrogyria (n ¼ 11) and FCD (n ¼ 3) were combined in order to investigate the outcome under conservative treatment. In this case, it remains unclear whether the FCD patients were among those with refractory epilepsy. Data from 550 adolescents and adults with localization-related epilepsy were analysed in a large prospective study on epilepsy prognosis conducted by Stephen et al. (32). Twelve per cent of cases presented an MCD, of these 54% of patients were seizure-free for over a year by the last examination. The variation to cryptogenic epilepsy (58% seizure-free) was not significant. However, 78
this information is not sufficient to reach safe conclusions on FCD response to treatment, as the group was comprised of 36 different forms of malformations. Furthermore, the authors argue that the group of cryptogenic epilepsies probably encompassed uncovered malformations, as the two groups were similar in many aspects (positive family history 25% vs 25%, febrile seizures 11% vs 12%, seizure-free rates 54% vs 58%). In a prospective study conducted by Semah et al. in 2200 adult epilepsy patients, the group of patients with MCD (n ¼ 81) were found to have a low seizure-free rate (24%), with dual pathology presenting the worst outcome of all underlying pathologies (31). The significance of this study regarding prognosis in FCD is limited because of the fact that FCD was not differentiated from other malformations. It is therefore impossible to base a clear statement to the rate of refractory epilepsy in FCD on the study data commonly cited. A single comprehensive study exists for early childhood (46). Lortie et al. investigated 28 children with epilepsy onset on the ground of an FCD in the first 2 years of life. Eleven patients suffered from infantile spasms and all of them responded to either vigabatrin or ACTH treatment. However, only one of 28 patients remained free of focal seizures in the long run; 15 of 28 children underwent epilepsy surgery. According to the authors, early onset epilepsy in FCD is characterized by infantile spasms responsive to treatment and focal seizures that are resistant to AEDs. The clinical course in FCD epilepsy is often denoted by a temporary cessation of seizure activity. A seizure-free period of no less than 2 years was reported by Chassoux et al. in nine of 28 patients who later underwent surgical treatment (37). Specific pharmacotherapy in FCD
Currently there is no specific medical treatment for FCD. Research on animal models and the examination of resected human tissue point to a possible involvement of GABAergic neurones on epileptogenesis. According to specialist views (personal communication, evidence level 4) valproate and benzodiazepines constitute the most promising treatment option. No systematic evidence is provided representing the newer AEDs. The observed morphology and molecular genetics of tuberous sclerosis is similar to that of several forms of FCD (51). Vigabatrin has proven efficient in tuberous sclerosis and infantile spasms (52). Theoretically, the use and application of vigabatrin may present
Epilepsy in FCD one possibility to treat epilepsy in FCD. At the moment there is no clinical evidence supporting this view. Reasons for failing response to medical treatment
The frequently encountered resistance to treatment is mainly attributed to the following two factors: Intrinsic epileptogenicity: It is presumed, that the affected tissue in FCD is itself highly epileptogenic, which is a distinct characteristic when compared with non-dysplastic lesions. The intrinsic epileptogenicity in human FCD is principally favoured by clinical evidence. This clinical evidence includes: correlation of outcome and completeness of resection (24, 40), findings of invasive recordings (40, 50, 53), MEG source analysis (53–55) and PET/ SPECT (56, 57). Furthermore, in vitro investigations in human tissue of dysplastic neurones demonstrate an upregulation of glutamate receptors (58), as well as a decreased expression of GABA receptors (59, 60). Multi-drug-transporter: An activation of diverse multi-drug-transporter proteins in glial cells and dysplastic neurones can be shown in the case of FCD. Multi-drug-resistance protein 1 (MDR1) is effective in vitro in regards to phenytoin (61). MDR1 was proven to be elevated in FCD tissue in a number of studies (62–65). Furthermore, multidrug-resistance associated protein 1 (62, 65) and the major vault protein (66) may act as upregulated drug-transporters in FCD. Comment: Despite the scarcity of information on the success rate of pharmacotherapy in FCD, it is evident that the epilepsy caused by FCD is characterized by poor response to treatment. According to current opinion, each and every AED used in focal epilepsy could prove effective in FCD. Antiepileptic drug treatment should be conducted bearing in mind individual factors such as side-effects and developmental progress. Presurgical evaluation should be initiated after the second unsuccessful AED trial. Important considerations regarding epilepsy surgery compared with further conservative treatment should include the risk of seizure persistence and developmental impairment. Conclusion
The current knowledge on natural history regarding epilepsy and development in FCD patients is limited. This knowledge shortfall is due to the lack of long-term studies that combine high diagnostic quality neuroimaging studies, with developmental assessment and neuropsychological evaluation.
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