Clinical Neurology and Neurosurgery 122 (2014) 29–33

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4-T fMRI of the motor and sensory cortices in patients with polymicrogyria and epilepsy J.G. Burneo a,∗ , R. Bartha b , J. Gati b , A. Parrent a , D.A. Steven a a b

Epilepsy Program, Schulich School of Medicine, University of Western Ontario, London, Ontario, Canada Robarts Research Institute, London, Ontario, Canada

a r t i c l e

i n f o

Article history: Received 15 August 2013 Received in revised form 17 January 2014 Accepted 18 March 2014 Available online 26 March 2014 Keywords: Epilepsy Polymicrogyria Functional MRI Reorganization

a b s t r a c t Objective: Malformations of cortical development (MCD) are an increasingly recognized cause of medically intractable epilepsy. We assessed the role of fMRI in evaluating the motor and somatosensory cortices, as well as if there is possible reorganization of these vital areas in patients with polymicrogyria. Methods: We included 2 patients with polymicrogyria and epilepsy. Somatosensory and motor cortices were assessed with a 4 T fMRI. These findings were compared with direct cortical stimulation. Results: Localization of the sensorimotor cortices was adequately identified by fMRI. These vital areas did not reorganize outside the malformation of cortical development. Conclusion: fMRI is a tool that can allow identification of these vital areas of the brain in a non-invasive manner. Practice implications: Adequate localization of the sensorimotor cortices is important for optimal patient selection, surgical strategy, and to determine the maximal extent of the resection. The clinical implications for such understanding are not limited to it; these findings should help researchers understand more of the neurobiology of MCDs and even possibly clues to the mechanisms of epileptogenesis associated with such malformations. © 2014 Elsevier B.V. All rights reserved.

1. Introduction Epilepsy is characterized by the risk of recurrent seizures that affects all ages, races, and genders without preference. Approximately 20% of patients have medically uncontrolled (intractable) epilepsy [1]. For many of these patients epilepsy surgery offers the only opportunity to become completely or nearly free of seizures. Surgical therapy for intractable epilepsy is no longer an intervention of last resort. It is now considered more frequently as it may achieve seizure-free outcomes in patients with otherwise intractable epilepsy. Localization of the epileptogenic zone and eloquent functional cortex prior to any surgery is vital for successful outcomes and preservation of neurological function. At present, the standard-of-care for mapping brain function is direct cortical stimulation, which must be performed during a craniotomy. The advent of high resolution magnetic resonance imaging (MRI) has made it possible to detect Malformations of cortical

∗ Corresponding author at: Epilepsy Program, University of Western Ontario, London Health Sciences Center, 339 Windermere Road, B10-118, London, Ontario N5A5A5, Canada. Tel.: +1 519 663 3464; fax: +1 519 663 3498. E-mail address: [email protected] (J.G. Burneo). http://dx.doi.org/10.1016/j.clineuro.2014.03.020 0303-8467/© 2014 Elsevier B.V. All rights reserved.

development (MCD) and other forms of brain dysgenesis in an increasing number of patients with intractable epilepsy that were formerly defined as cryptogenic [2]. In patients with intractable epilepsy associated with MCD in the central or rolandic regions, unpredictable localization of the primary somatosensory and motor functions may exist. This localization is essential for optimal patient selection, surgical strategy, and to determine the maximal extent of the resection. We report on two patients with polymicrogyria and epilepsy in whom we performed an innovative approach to assess the location of the somatosensory and motor cortices, with functional MRI (fMRI).

2. Methods Two patients with epilepsy and polymicrogyria were identified. They underwent standard pre-surgical evaluation with prolonged scalp video-EEG monitoring, 1.5 T MRI, neuropsychological evaluation and single photon emission computed tomography (SPECT). They also underwent placement of intracranial electrodes and further monitoring with video-EEG.

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The standard clinical 1.5 T MRI using “Epilepsy Protocol” consisted on fine-cuts T1 axial and coronal, T2 and FLAIR coronal, DWI sequences in axial, and MPGR in axial cuts. Localization of their motor and sensory areas were identified using BOLD-based fMRI at 4 T (Varian Unity INOVA, Palo Alto, CA, USA). The data were acquired using standard hybrid birdcage RF coil. Automated linear and higher order field shimming was performed using RASTAMAP [3] to minimize image distortions in the fMRI data sets. Localizer images were then acquired to plan one set of volumetric images consisting of 64 slices (2.5 mm thick, TR/TE = 10/5 ms) covering the entire brain using a T1-weighted inversion prepared (TI = 500 ms) segmented turbo FLASH sequence to produce high gray matter/white matter contrast. During fMRI acquisition, patients performed self-paced motor tasks of both hands by opposing the thumb to each finger starting at the index and ending on the fifth digit, and the feet by asking the patients to do some foot tapping. For evaluation of the somatosensory cortex, repetitive tactile stimulation was applied by a painless pneumatic pressure device that was clipped to each finger of each hand (4D neuroimaging, San Diego, CA, USA) [4]. fMRI was performed using a multi-slice EPI sequence (matrix 64 × 64) acquired with 4 mm × 4 mm × 5 mm voxels. A total of 70 image sets were collected divided into 7 task-rest cycles with ten sets in each state.fMRI data were analyzed using SPM. The results obtained by fMRI were validated by comparison to the results obtained from direct cortical stimulation. The results were not shared with the clinical team at time of surgical planning. Intra- and extra-operative cortical stimulation was performed with a constant current Grass Stimulator. Bipolar stimulation was used with subdural grid or strip electrodes, while a hand held monopolar stimulator is typically used in the operating room. The results of the direct cortical stimulation were presented in an image created by co-registration of a pre-operative high-resolution 1.5 T MRI of the brain with a post-operative CT scan done with subdural electrodes in place using the Epilepsy Viewer program from Atamai (Atamai Inc., Calgary, Alberta, Canada). This program allows co-registration fMRI, CT and anatomical MRI. Based on standard assessment (without including the fMRI data), and after discussion of the best strategies, surgical resection was performed in each patient. 3. Case 1

Fig. 1. (A) Axial view of a MRI T1-weighted image revealing the presence of bilateral perysilvian polymicrogyria as well as the absence of a septum pellucidum. (B) Three-dimensional view of a co-registered presurgical MRI and post-surgical CT (after placement of subdural electrodes) [Atamai, London, Ontario] of the same patient. In red is shown the activation of the right motor cortex, while patient was taping her fingers of the right hand. (C) Same image as in (B), but showing

Our first patient was a 24-year-old right-handed female with a history of seizures since the age of 9. Her initial seizures were generalized tonic-clonic with post-ictal Todd’s paresis. She subsequently began having multiple types of daily simple and complex partial seizures, including nocturnal generalized seizures with left Todd’s paresis, occasionally preceded by an aura of numbness of the tongue and an unusual taste. Family history was remarkable for a maternal grandmother with epilepsy of unknown etiology. Prior evaluations included prolonged video-EEG monitoring revealing generalized spikes, maximum over the right temporal and central regions (T4 and C4), and seizures of central origin spreading into the right temporal region. A 1.5 T MRI scan during the same period showed bilateral closed-lip schizencephaly with polymicrogyria and absence of the septum pellucidum and corpus callosum (Fig. 1A). Subsequent subdural electrode monitoring revealed seizure onset over the right neocortical temporal area, with extension into the mesial region. For that reason the patient

activation of the Somatosensory cortex in green. This area is posterior to the motor cortex (seen in the previous figure in red). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

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underwent right anterior temporal resection, which decreased the frequency and severity of her complex partial seizures.fMRI results revealed that the somatosensory and motor cortices remained within the expected areas of the brain despite the presence of such a large area of polymicrogyria bilaterally (Fig. 1B and C). 4. Case 2 Our second patient is a 25-year-old right-handed male with a history of seizures since the age of 8. He was seizure-free on antiepileptic drugs until age 12, when he began to have two types of stereotyped seizures. The first one involved an aura of tingling and numbness of the right upper extremity and ipsilateral side of the face lasting about 2 min, followed by dystonic posturing of the right upper limb with elevation of the right upper extremity, with occasional loss of awareness. Post-ictally he was confused with occasional right-sided hemiparesis and dysarthria. The frequency of this type of seizure was 3 times per week. The second type of events was generalized tonic-clonic seizures, every two weeks. The patient had an episode of viral encephalitis at the age of 8, and his seizures started a year later. Family history is remarkable for a maternal grandmother with epilepsy as a child. The patient was tried on a number of anti-epileptic medications, and he experienced significant side-effects including balance problems, blurred vision, poor short-term memory, as well as poor verbal memory. Video-EEG and ictal SPECT (Fig. 3) indicated seizure onset to be in the left frontal parietal region. A 1.5 T MRI showed a schizencephalic cleft on the left hemisphere with polymicrogyria in the left central parietal region (Fig. 2A). Subdural recordings captured seizures that emanated from the inferior bank of the schizencephalic cleft, as well as a posterior to it. Cortical mapping demonstrated motor function along the anterior part of the cleft, but no evidence of motor function posterior to the cleft and in the anterior parietal lobe. Somatosensory cortex was found to be located over the posterior wall of the cleft. These findings were concordant with data obtained from the 4 T fMRI (Fig. 2B and C). The patient underwent a left parietal corticectomy and has been free of generalized tonic-clonic and complex partial seizures for the past three years, although he continues to have daily auras of tingling and numbness of his right hand and forearm and remains on three antiepileptic medications. 5. Discussion Cortical dysplasia and other malformations of cortical development (MCD) were first associated with epilepsy was in 1971 [5]. Since then, MCDs have been increasingly recognized as important causes of epilepsy [6–8]. The terms dysplasia and MCD are used to describe neural tissue that has failed to develop perfectly during embryonic or fetal life, as a result of a wide variety of genetic and environmental factors. The cerebral cortex has three stages of development: neuronal and glial proliferation, neuronal migration, and finally cortical organization [9]. Problems can occur in any of these stages, causing a specific malformation depending on the stage of development. The most frequent types of MCD associated with epilepsy are cortical dysplasias, polymicrogyria, and schizencephaly. Polymicrogyria is characterized by the presence of many small microgyria separated by shallow sulci, a slightly thick cortex, neuronal heterotopias and often enlarged ventricles. It is probably associated with the Fig. 2. (A) Three-dimensional view of a co-registered presurgical MRI with postsurgical CT (after placement of subdural electrodes) [Atamai, London, Ontario]. Results from fMRI activation of the motor cortex are shown in red. The activation of the motor cortex is seen within the cleft. (B) Same patient, with fMRI results of the activation of the Somatosensory cortex in green. There is overlap of some areas of the motor and the somatosensory cortex. Parts of the somatosensory cortex are

seen within the cleft as well. (C) Same patient, this time showing fMRI results for motor and Somatosensory activation. It also shows the results from mapping of the motor (blue circles) and somatosensory (yellow squares) cortices. The area delineate by the red octagon is the epileptogenic region. Notice the overlap of both the somatosensory and the motor cortex.

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Fig. 3. Ictal (left-hand side) SPECT of case 2, showing the area of hyperperfusion and the contralateral cerebellar activation. On the right-hand side one can appreciate the interictal study.

occurrence of intrauterine cytomegalovirus infection, which may cause an initial diffuse or patchy astrogliosis/hypomyelination in the white matter and often diffuse or multifocal periventricular calcifications, even though other etiologies have been hypothesized [10,11].fMRI is an attractive, non-invasive method to investigate brain function because it allows functional imaging of the entire brain with good temporal and anatomic detail. Deoxyhaemoglobin acts as an endogenous paramagnetic contrast agent; changes in the local oxygenation leads to alterations in the T2*-weighted MR signal. Neuronal activation within the cerebral cortex leads to a large increase in blood flow without an increase of similar magnitude in oxygen extraction, which in turns causes a decrease in the capillary and venous deoxyhaemoglobin concentration, producing an increase in the T2*-weighted MR signal (blood oxygenation leveldependent contrast). fMRI allows localization of an event-related relative increase of oxy-hemoglobin linked to neuronal activation. Due to this capability, fMRI is useful as a non-invasive imaging tool for the assessment of the topographic organization of the somatosensory and motor cortices [12–14]. The technique has been used in previous studies in the identification of brain reorganization following strokes [15], in those studies fMRI was able to reveal markedly increased cerebral activity in the regions surrounding the issue, in the sensorimotor areas, and in the association cortices. Hence, fMRI allows for the study of brain reorganization in patients with congenital lesions and epilepsy. Non-invasive mapping of somatosensory and motor cortices in these patients may improve surgical selection and treatment. Experiments in animals and observations in humans indicate that the cerebral cortex has the capability to adapt to injury through a range of different mechanisms including changes at a cellular level, functional reorganization of intact cortical areas, and the unmasking or formation of new pathways [16,17]. Evidence of brain reorganization has been observed in patients who have suffered strokes [15], limb amputations [12], and brain injury early in life [17]. It has also been seen in patients who underwent hemispherectomy for intractable seizures [13,18]. MCD can be considered a special form of acquired injury. With the use of fMRI we tried to identify functional reorganization that may occur as a result of an MCD (namely, polymicrogyria and schizencephaly). If reorganization of cortical function can occur in early or perinatal injuries, then these early insults should be expected to demonstrate true changes

in expected localization, even more likely than other later acquired injury. Despite the presence of some preliminary work published in the literature [19], it is not known yet whether all types of MCD may demonstrate true cortical reorganization. In our 2 cases, fMRI provided unequivocal evidence of no reorganization, this finding alone provides valuable new information about plasticity in brain development, particularly when it is affected by polymicrogyria. The mechanisms underlying these findings are poorly understood, but the presence of activation in the polymicrogyric tissue indicates that these cells work as viable neurons, something that can be probably confirmed with other neuroimaging techniques, like magnetic resonance spectroscopy, where one can assess the metabolic profile of the neuronal tissue in that area. Clinically, the implications of having functional tissue in epileptic polymicrogyric cortex make things more difficult for the team planning a surgical resection of the epileptogenic area, as this may cause a neurological deficit, if located in a “vital” area of the cortex. Finally, the clinical implications for such understanding are not limited to aiding the planning and execution of epilepsy surgery; these findings should help researchers understand more of the neurobiology of MCDs and even possibly clues to the mechanisms of epileptogenesis associated with such malformations.

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4-T fMRI of the motor and sensory cortices in patients with polymicrogyria and epilepsy.

Malformations of cortical development (MCD) are an increasingly recognized cause of medically intractable epilepsy. We assessed the role of fMRI in ev...
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