Malformations of cortical development and epilepsy

<p class="article-intro">Malformations of cortical development (MCD) are clinically and etiologically heterogenous structural brain abnormalities due to aberrant development of neurons which under normal circumstances would form the cerebral cortex. MCD are increasingly recognised as a major cause of medically refractory epilepsy in children and adults.</p> <p class="article-content"><div id="keypoints"> <h2>Keypoints</h2> <ul> <li>Malformations of cortical development (MCD) occur when the normal process of cerebral cortical development including proliferation, migration, and organization is disrupted.</li> <li>Only 5&ndash;20 % of patients with epilepsy due to MCD enter seizure remission for more than one year under appropriate antiepileptic treatment.</li> <li>In drug resistant patients, epilepsy surgery remains the only realistic chance for seizure freedom.</li> </ul> </div> <h2>Classification of MCD</h2> <p>MCD are categorised based upon the step at which cortical development was probably first disturbed:¹</p> <ul> <li>MCD due to abnormal proliferation/ apoptosis</li> <li>MCD due to abnormal neuronal migration</li> <li>MCD due to abnormal late migration/ cortical organization</li> </ul> <p>The most commonly utilised classification is based on MRI features of MCD, but also considers pathophysiological background, genetics and histopathology of some MCD.¹</p> <h2>Pathophysiology, genetics and prevalence of MCD</h2> <p>Neuronal migration is a phenomenon that underlies the organisation of the mammalian brain. Cortical neurons that are born in the proliferative ventricular zone migrate to their final destination in the developing cortex, where they form a six-layered cerebral cortex.^2-4 The majority of neurons migrate from the ventricular zone towards the pial surface along the scaffold of radial glial cells. Some neurons, however, migrate towards the pial surface tangentially.⁵ Upon reaching cortical plate, the neurons arrange in &bdquo;insideout&ldquo; order: newly arrived neurons bypass the older ones and land in the marginal zone, which lays below the pial surface and basal lamina. In individuals with MCD due to abnormal neuronal proliferation/ apoptosis, there are either too few (increased apoptosis) or too many (increased proliferation) neurons. In patients with MCD due to abnormal neuronal migration, the fraction of newly born neurons is incapable of moving from the ventricular zone, where eventually the conglomerates of grey matter are formed.⁴ In MCD due to abnormal post-migrational organization, the neurons organize within cortical plate in an abberant way resulting mainly in polymicrogyria.<br /><br /> The etiology of MCD is heretogenous, they may develop as a result of intrauterine injury due to exogenous factors (hypoxia, irradiation etc.) or develop as a part of a genetic disease.<br /><br /> A significant progress has been made in understanding genetic causes and intracellular mechanisms of MCD.^{1, 6} Mutation types, their severity and affected pathways play key roles in determining the phenotype of MCD. Mictotubule transport, centrosomal positioning, nuclear transport (associated with LIS1 mutation), microtubule stabilization (associated with DCX mutation), vesicle trafficking and fusion (ARFGEF2 and FLNA), and neuroependymal integrity (MEKK4 and FLNA) in neuronal migration are important factors in the development of MCD.^7-9 Recently, mutations affecting microtubule proteins TUBA1A, TUBA8, TUBB2B and TUBB3 have been associated with abnormal neuronal migration (lissencephaly) and postmigrational development (polymicrogyria or polymicrogyria-like dysplasias).^10-14 In general, there are over 200 genetic causes known for different MCD.<br /><br /> The prevalence of MCD is unknown as most of the cases reported in the literature had seizures, which may represent a referral bias as some individuals with MCD (up to 20 % ) have no seizures.¹⁵ In patients with epilepsy, MCD is not uncommon and it comprises about 10 % of all malformations of cortical development in our own large series of about 5000 patients (personal observation, unpublished data).</p> <h2>Imaging of MCD</h2> <p>Increasing availability of advanced MR techniques enabled in vivo diagnosis of different types of MCD. However, MCD may remain undetected even with high resolution MRI and could be found only at histology after surgery; around a quarter of patients with refractory epilepsy and normal MRI may have MCD.¹⁶ MR image post-processing increases the rate of detection of some MCD (e.g., focal cortical dysplasia [FCD] and subcortical band heterotopia) by around 10&ndash;15 % .^{17, 18}<br /><br /> FCD is the most challenging of all MCD to diagnose on MRI. Correlation of MRI abnormalities with different histological types of FCD has been extensively studied. The spectrum of MRI findings is well accepted for FCD type II and includes increased cortical thickness, abnormal gyral/ sulcal patterns, blurring of the greywhite matter junction, and transmantle location of signal changes affecting both white and grey matter (Figure 1, A).^19-21 The most sensitive MRI parameters for FCD type II are grey-white matter junction blurring (present in 76 % ), white matter signal change in T2 (55 % ) and FLAIR (61 % ) sequences.²² The regional reduction of the white matter volume in patients with FCD type II (16 % ) could be also observed, although this abnormality has been mainly noted only in FCD type I.²² In contrast to FCD type II, MRI diagnostics of FCD type I has been highly challenging. Histological-imaging correlative analysis showed that FCD type I subjects presented with MRI abnormalities in 52&ndash;83 % of cases.^{19, 21, 22} The high proportion of MRIpositive FCD type I cases could reflect the adjustment of current MRI protocols for detecting MCD. The most typical MRI findings in FCD type I were white matter signal change in FLAIR (55 % ) and T2 (53 % ) followed by regional reduction of white matter volume (32 % ) (Figure 1, B).²² FCD type I patients do not usually reveal increased cortical thickness and/or transmantle signs which appear to be almost pathognomic for FCD type II.^{21, 22}</p> <p><img src="/custom/img/files/files_datafiles_data_Zeitungen_2017_Jatros_Neuro_1701_Weblinks_s27_fig1.jpg" alt="" width="1417" height="687" /></p> <h2>Coexistence of MCD with other brain lesions</h2> <p>MCD may coexist with midbrain-hindbrain malformations and hippocampal abnormalities, which may influence the clinical features and seizure presentation of patients with MCD. In a study on 220 patients with MCD, over 30 % of patients had different types of hippocampal abnormalities, hippocampal sclerosis and hippocampal malrotation among them.²³ Patients with MCD and hippocampal abnormalities had higher rate of cognitive impairment, delayed developmental milestones and neurological deficits compared to those without hippocampal abnormalities. In the same population of patients, 17 % had infratentorial malformations along with MCD with earlier seizure onset and large, bilateral supratentorial malformations compared to those without midbrain- hindbrain anomalies.²⁴</p> <h2>Epileptogenicity and epilepsy surgery</h2> <p>About 8&ndash;12 % of patients with refractory epilepsy and up to 40 % of children with pharmacoresistant seizures and mental retardation harbour MCD.</p> <h2>25&ndash;28</h2> <p>The subgroup of MCD due to abnormal neuronal proliferation and apoptosis (e.g. focal cortical dysplasia, hemimegalencephaly, tuberous sclerosis) carries the highest risk for drug resistant epilepsy and therefore, is the most frequently encountered group of MCD in epilepsy surgery centres. MCD due to abnormal cortical migration (e.g. heterotopia, lissencephaly) have a lesser degree of epileptogenicity, but they are inappropriate surgical candidates most often due to widespread lesions involving functionally essential areas. MCD due to abnormal cortical organization (polymicrogyria with or without schizencephaly) are probably the least epileptogenic MCD.<br /><br /> Most cases (approximately 80 % ) of MCD are refractory to medical treatment. ^25&ndash;28 Therefore, the management of epilepsy due to MCD present a significant clinical issue. In drug resistant patients, epilepsy surgery remains the only realistic chance for seizure freedom. Up to 70&ndash;80 % of patients with MCD, especially FCD, may be rendered seizure free over a 2-year follow-up period following respective surgery. ^25&ndash;28</p> <h2>Functional integration of MCD</h2> <p>Functional reorganization of cerebral cortex occurs in subjects with MCD. In some MCD, functional imaging studies demonstrate activation in malformed cortices, suggesting their functional integrity. This raises concerns about post-surgical deficits in patients with MCD and medically refractory epilepsy.<br /> Functional MRI (fMRI) studies demonstrated functional integrity of some MCD or the &ldquo;shift&rdquo; of cortical function in other patients.^29&ndash;36 fMRI studies in subcortical band heterotopia showed that heterotopic grey matter may become activated along with overlying cortex during the motor and visual tasks.^{29, 33} Whether this co-activation of the band heterotopia is essential for normal function in these patients is unknown. Activation of periventricular heterotopic nodules by complex cognitive paradigms has been demonstrated in some cases; simple motor tasks, however, did not show any involvement of the heterotopic nodules.³⁰ There are few correlative studies on cortical function and histological features which demonstrated that the phenotype, epileptogenicity and functional behaviour of MCD are largely determined by their cellular and histochemical properties. This has been shown mainly in studies related to FCD.³⁷ Absence of language or motor functions in perirolandic and Broca&rsquo;s areas which exhibited histological evidence of FCD with balloon cells (type IIb) and preservation of motor functions when balloon cells were absent (types Ia,b, IIa) was found in a study which correlated direct electrical stimulation of cortex and histology in FCD.³⁷ The absence of function in FCD type IIb may be due to immature properties of balloon cells, dysmorphic and cytomegalic neurons as well as severe disruption of neuronal circuits.</p></p> <p class="article-footer"> <a class="literatur" data-toggle="collapse" href="#collapseLiteratur" aria-expanded="false" aria-controls="collapseLiteratur" >Literatur</a> <div class="collapse" id="collapseLiteratur"> <p><strong>1</strong> Barkovich AJ et al: Brain 2012; 135: 1348-69 <strong>2</strong> Ram&oacute;n y Cajal S: Textura del sistema nervioso del hombre y vertebrados. Vol. 2. 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