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Extraoperative cortical stimulation of motor function in children
Original Articles
Extraoperative Cortical Stimulation of Motor Function in Children Shiro Chitoku, MD*¶, Hiroshi Otsubo, MD*¶, Yu Harada, MD*, Venita Jay, MD†¶, James T. Rutka, MD, PhD‡, Shelly K. Weiss, MD*, Mohamed Abdoll, MSc§, and O. Carter Snead, III, MD*¶ The purpose of the study was to investigate factors altering the amperage threshold needed to provoke functional responses in children with epilepsy. Twenty patients (4-18 years of age) who underwent epilepsy surgery at our institution from 1996-2000 after insertion of subdural grid electrodes were reviewed retrospectively. Extraoperative electrical cortical stimulation was performed with 50-Hz biphasic pulses of 0.2 ms in duration using a “distance reference” technique. Amperage thresholds of primary motor responses and afterdischarges were evaluated. The patients were grouped according to underlying pathology: eight with neuronal migration disorders (group A) and 12 with other disorders (group B). The motor cortex was defined successfully in all children because the afterdischarges threshold was higher than the motor cortical threshold. Amperage thresholds ranged from 2-20 mA (mean ⴝ 7.7) for primary motor function. An inverse relationship was found between amperage threshold and age: the younger the patient, the higher the threshold (P ⴝ 0.0005). Patients in group A required a higher amperage (2-20 mA, mean ⴝ 8.6) for motor cortical mapping than those in group B (2-14 mA, mean ⴝ 6.4). Younger children with neuronal migration disorders require a higher amperage threshold to achieve adequate motor functional mapping with careful observation of afterdischarges. © 2001 by Elsevier Science Inc. All rights reserved. Chitoku S, Otsubo H, Harada Y, Jay V, Rutka JT, Weiss SK, Abdoll M, Snead OC III. Extraoperative cortical stimulation of motor function in children. Pediatr Neurol 2001;24:344-350.
From the *Division of Neurology and Department of Paediatrics; † Department of Pathology; ‡Division of Neurosurgery and Department of Surgery; and §Department of Population Health Sciences; The Hospital for Sick Children and the University of Toronto; and the ¶ Bloorview Epilepsy Research Program; Toronto, Canada.
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Introduction Medically refractory epilepsy is seen more often in the extratemporal lobe in children, which is proximal to the functional cortex, than in the temporal lobe [1]. Functional mapping is especially important in treating children with this type of epilepsy to avoid causing permanent deficits. Subdural electrodes implanted for 3-10 days are needed to provide detailed localization of the functional cortex in relation to an adjacent epileptogenic zone [2]. The stimulation technique used for extraoperative mapping in adults often fails to elicit clinical responses in infants and younger children because the maximum amperage is usually set too low. Empirical evidence has been reported that indicates difficulty in defining the functional cortex in the developing brain in infants and younger children [3,4]. Jayakar et al. [3] developed an alternative paradigm to elicit responses from the immature cortex, but their methodology cannot be applied with the stimulators available in most other institutions. If amperage thresholds in younger children can be estimated using conventional techniques, functional mapping can be performed successfully without missing certain thresholds. It has been theorized that the failure of motor functional mapping in infants results from their immature, inherently less-excitable rolandic cortex [4]. However, the relationship between age and amperage threshold in eliciting motor function responses has not been studied previously. In addition, neuronal migration disorders (NMDs), which are frequently seen in younger children with intractable seizures, may be a factor in the inability to perform cortical functional mapping because they are often harbored in the central cortex [5,6]. The purpose of this study was to investigate the rela-
Communications should be addressed to: Dr. Chitoku; Division of Neurology and Department of Paediatrics; The Hospital for Sick Children; 555 University Ave.; Toronto, M5G IX8, Canada. Received September 15, 2000; accepted February 20, 2001.
© 2001 by Elsevier Science Inc. All rights reserved. PII S0887-8994(01)00264-8 ● 0887-8994/01/$—see front matter
Table 1.
Group/ Pt No.
Clinical data of epilepsy patients (n ⴝ 20)
Age (yr)/ Sex
A/1
6/M
A/2 A/3 A/4 A/5 A/6 A/7 A/8 B/1 B/2 B/3 B/4 B/5 B/6 B/7 B/8 B/9 B/10 B/11 B/12
6/F 9/F 12/M 13/F 13/F 16/F 18/M 4/M 7/M 9/M 10/M 11/F 11/M 13/F 15/F 15/M 15.5/F 16/F 16/F
MRI Findings
Surgical Hemisphere
Ictal Onset Zone and Active Interictal Zone Detected by IVEEG
Surgical Procedures Lobectomy and Cortical Excision
Normal
L
T, F
ATL, F, C
Normal L-cerebral atrophy L-F thick gyrus Normal R-cerebral atrophy L-F abnormal sulcus R-F thick gyrus Normal Normal Normal R-T thick gyrus Normal Normal Normal Normal Normal Normal Normal Normal
R L L L R L R L L R R R R R R R L R R
P, O, F P, F F P T, O F F T, C, P F, T T, O T, O, C P, T F, C, T, P F F, P, T F, C Mesial T C T, F
P, O, F F, P F P T, O AFL F ATL None T, O T, O lobectomy, AH ATL, P, post T F, ATL, P FL AFL, T F ATL None ATL
Region of MST Motor, sensory, posterior T Motor, premotor Premotor, sensory Motor, sensory Motor, sensory Premotor, motor Cortical resection only R-premotor Motor Motor Motor, sensory Sensory Motor Motor, premotor Sensory Sensory, premotor Motor Post T, premotor Motor, sensory Motor, sensory
Outcome* (Follow-up Months) IIB (38) III (22) II (17) IA (25) IVA (23) IB (8) IA (3) IA (7) III (5) IIB (34) IVB (19) IA (1) IIA (38) III (33) I (10) IA (29) IA (46) IA (21) II (41) III (3)
* According to Engel’s classification. Abbreviations: A ⫽ Group of neuronal migration disorders AFL ⫽ Anterior frontal lobectomy AH ⫽ Amygdalohippocampectomy ATL ⫽ Anterior temporal lobectomy B ⫽ Normal varient or gliosis group C ⫽ Central
F L O P R T
⫽ ⫽ ⫽ ⫽ ⫽ ⫽
Frontal lobe Left Occipital Parietal Right Temporal
tionships among age, pathology, and amperage threshold in provoking motor functional responses extraoperatively in children with intractable epilepsy. Materials and Methods Subjects Records of 20 patients, 4-18 years of age, who underwent epilepsy surgery after subdural grid electrode insertion at The Hospital for Sick Children in Toronto (from June 1, 1996 to April 30, 2000) were reviewed retrospectively. The patients were divided into two groups based on underlying pathology: group A, patients with NMD; and group B, patients in whom pathology was reported to be either gliosis or unremarkable (non-NMD). Two patients had undergone previous operations in the same hemisphere but not in the central cortex. Table 1 summarizes patient characteristics, results of investigations, surgical procedures, and outcomes classified according to Engel’s criteria [7].
Intracranial Video Electroencephalography (IVEEG) Subdural grids (Ad-Tech Medical Instrument Co., Racine, WI) were constructed for each patient based on scalp interictal and ictal electroencephalographic (EEG) results, interictal spike sources, and somatosensory-evoked fields demonstrated by magnetoencephalography (MEG) and seizure semiology. Grid size was determined on the basis of
three-dimensional (3D) magnetic resonance imaging (MRI) using 1.5-mm thin-slice T1 images (ISG Viewing Wand System; ISG Technologies, Mississauga, Ontario, Canada). The grids consisted of 55-137 platinum electrodes (mean ⫽ 112), 5 mm in diameter, embedded in silastic sheet (Ad-Tech Medical Instrument Co.). Center-to-center interelectrode distances ranged from 10-13 mm. Split-screen and time-locked video EEG was used to review the clinical behavior of seizures (BMSI 5000; Nicolet, Madison, WI). The digitized EEG data (200 samples/ second per channel) were selected by means of alarm button triggers, automatic seizure, and spike detection, and then stored for review.
Stimulation Procedure Mapping of motor, sensory, and language functions was performed in one-to-two sessions on the third or fourth day after grid implantation. This study evaluated only primary motor responses. Because the young children did not consistently cooperate on sensory and language tests, the results were not accurate enough to evaluate. Stimulations were delivered with 50-Hz biphasic pulses (pulse duration, 0.2 ms) up to 25 seconds in duration in one train. Pulses were given to electrode pairs at an initial intensity of 2 mA, increasing by 1-2 mA to a maximum of 20. We used the distance reference technique described by Lesser et al. [8], which stimulates between a target electrode in the area of interest and a reference electrode situated at the periphery of the subdural grid array. The stimulation was paused as soon as clinical responses or clinical seizures were noted. EEG was recorded simultaneously and monitored by the physician using referential montage to detect an afterdischarge.
Chitoku et al: Pediatric Motor Cortical Threshold 345
Table 2.
Results of cortical stimulation of the motor cortex (n ⴝ 20)
Group/ Pt. No
Number of Electrodes
Amperage Threshold of Face and Hand
Threshold of AD and Seizure
Epileptic Zone in Motor Cortex
4 3 9 8 11 5 9 3 6 3 7 4 12 5 9 8 5 6 9 12
14 18-20 (m ⫽ 18.7) 6-12 (m ⫽ 10) 3-6 (m ⫽ 5.1) 4-14 (m ⫽ 10) 3-4 (m ⫽ 3.3) 2-4 (m ⫽ 2.9) 3-6 (m ⫽ 5) 8-10 (m ⫽ 8.3) 10-14 (m ⫽ 12.7) 8-12 (m ⫽ 11.4) 4-10 (m ⫽ 8) 2-4 (m ⫽ 2.9) 4-5 (m ⫽ 4.4) 2-3 (m ⫽ 2.1) 2-5 (m ⫽ 4) 5-12 (m ⫽ 8.2) 2-3 (m ⫽ 2.5) 3-6 (m ⫽ 4.5) 8-10 (m ⫽ 8.3)
14 (m ⫽ 14) 18-20 (m ⫽ 19.3) 12 (m ⫽ 12) 4-8 (m ⫽ 6.8) 6-10 (m ⫽ 7.7) 4-6 (m ⫽ 4.8) 4 4-6 (m ⫽ 5.3) 8-10 (m ⫽ 9.5) 10-14 (m ⫽ 11.3) 12 (m ⫽ 12) — 6 (m ⫽ 6) — — — 10-12 (m ⫽ 11.3) — 3-12 (m ⫽ 8.2) 8-9 (m ⫽ 8.3)
⫹ ⫹ ⫺ ⫹ ⫹ ⫹ ⫺ ⫺ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫺ ⫹ ⫺ ⫹ ⫹
A/1 A/2 A/3 A/4 A/5 A/6 A/7 A/8 B/1 B/2 B/3 B/4 B/5 B/6 B/7 B/8 B/9 B/10 B/11 B/12
Abbreviations: AD ⫽ Afterdischarge M ⫽ Mean
Definition of Response
Results
A primary motor response was defined as the local movement of a contralateral part of the body in response to cortical stimulation while the patient was at rest; for example, a simple isolated movement, such as contraction of the eyelid, tongue, mouth, hand, or finger [9]. When an afterdischarge was detected, its clinical manifestation was observed carefully and stimulation was paused until the afterdischarge stopped. The amperage thresholds required for afterdischarge and seizure inducement were compared with those needed for motor cortical response.
Table 2 summarizes the results of stimulation of the motor cortex for each patient.
Surgical Resection Cortical excision and multiple subpial transection (MST) were performed over the ictal onset zone and active interictal zone on days 3-10 after implantation of the subdural grid. The grid was removed after the surgical area had been identified.
Amperage Threshold An inverse relationship was found between age and amperage threshold (P ⫽ 0.0005): younger patients required a higher threshold to provoke motor function (Fig 1). Comparison of amperage thresholds between groups A and B, based on the age distribution (Fig 2), depicted a marginally insignificant difference (P ⫽ 0.058): group A patients, especially younger ones, tended to need a higher threshold (2-20 mA; mean ⫽ 8.6) than those in group B (2-14 mA; mean ⫽ 6.4).
Pathologic Examination
Afterdischarges
All the surgical specimens collected were processed for conventional histologic and immunohistochemical analysis using either the avidinbiotin complex or peroxidase-antiperoxidase techniques.
Afterdischarges provoked despite careful stimulation, with or without clinical seizures, were recorded in 15 patients: eight in group A and seven in group B. The amperage thresholds for afterdischarges ranged from 2-20 mA (mean ⫽ 9.3). Fourteen of 15 patients had afterdischarge thresholds equal to or higher than the thresholds for clinical responses of the motor cortex. In the one remaining patient, afterdischarges occurred at a lower amperage outside the motor cortex. The mean amperage threshold of afterdischarges was lower in group B (3-14 mA; mean ⫽ 9.2) than in group A (4-20 mA; mean ⫽ 9.5).
Statistical Analysis The relationship between amperage threshold and the patient’s age was investigated using simple linear regression analysis. Analysis of covariance was used to investigate the relationship between groups A and B in terms of the age-threshold relationship and the relationship between the epileptic and nonepileptic zone subgroups in both groups A and B. Statistical significance was defined as P ⬍ 0.05.
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Figure 1. Patient age vs amperage threshold (linear regression analysis: slope ⫽ ⫺0.784, P ⫽ 0.0005).
Amperage Threshold Difference between Epileptic and Nonepileptic Cortex We also compared amperage thresholds between patients in each group whose epileptic zone involved the motor cortex (five in group A and eight in group B) and between patients in whom it did not (three in group A and four in group B). In group A the mean threshold in the epileptic motor cortex was 10.2 mA compared with 6 mA
in the nonepileptic cortex. In group B the comparable figures were 7.6 and 4.2 mA, respectively. The amperage threshold in the epileptic motor cortex tended to be higher than in the nonepileptic in both groups, but the difference was not significant (analysis of covariance, P ⫽ 0.794).
Pathologic Findings Analysis of specimens taken from group A patients revealed the presence of cortical dysplasia in all of them. Various migration abnormalities were also noted universally, consisting of subtle morphologic change of gray matter in two patients, and disorganization of neuronal size, shape, and orientation in addition to heterotopic neurons in five. Tuberous sclerosis was diagnosed in the remaining patient in group A, which was based on the presence of balloon cells without any other physiologic profile. Tissue analysis in group B patients revealed gliosis in 10 of them. Because the remaining two patients underwent only MST, no surgical specimens were obtained.
Follow-up of Motor Function and Seizure Outcome
Figure 2. Relationship between age and amperage threshold by groups A and B. Linear regression analysis: group A (dotted line), slope ⫽ ⫺1.1, P ⫽ 0.007; group B (solid line), slope ⫽ ⫺0.52, P ⫽ 0.0378). There was a marginally insignificant difference between the two groups. Analysis of covariance: age ⫻ group interaction, P ⫽ 0.1212; intercepts, P ⫽ 0.0585.
No permanent hemiparesis was noted after MST over the epileptic central cortex in 19 patients. However, temporary facial and hand motor weakness was observed in 12 patients (group A: five; group B: seven) after MST over the motor cortex. Seizure outcomes are summarized in Table 1, illustrating that among the patients with a follow-up period longer than 12 months, significant relief
Chitoku et al: Pediatric Motor Cortical Threshold 347
Figure 3. In the top panel a subdural grid array consisting of 40 channels is placed over the left frontotemporal central region of Patient 1, group A. The bottom panel illustrates the intraoperative view taken at the end of the monitoring and immediately before cortical excision. The numbers on subdural electrodes indicate the epileptogenic zone. The anterior temporal region, outlined by a thick white line, was also identified as part of the epileptogenic zone. Letters A, B, C, and D represent the motor facial area, identified by extraoperative functional mapping. Anterior temporal lobectomy (anterior to numbers 29 and 37) was performed; MST was performed over the electrodes identified by numbers and letters.
of seizures (Engel’s class I and II) was noted in three of five patients in group A, and in six of eight in group B. Illustrative Case (Patient A-1) Patient A-1 was a 6-year-old right-handed male whose seizure disorder began at 7 months of age. The seizures became refractory to multiple antiepileptic medications at 3.5 years of age, and his speech deteriorated. Magnetic resonance imaging (MRI) depicted no abnormal findings. Single-photon emission computed tomography revealed left hemispheric hypoperfusion. Scalp-recorded EEG depicted high-amplitude interictal spikes on the bilateral frontal regions. Prolonged scalp-recorded EEG demonstrated paroxysmal generalized discharges with left frontal predominance spreading to the left central region. MEG demonstrated epileptic spike sources on the bilateral frontotemporal areas spreading above the sylvian fissure with
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left-sided predominance. A subdural grid with 59 channels was implanted over the left frontotemporoparietal area (Fig 3). IVEEG revealed that ictal epileptiform discharges began in the left frontotemporal area and spread to the frontocentral area. Cortical stimulation of 14 mA in intensity was required to provoke a right facial motor response (electrodes 7, 15, 21, and 22). The same intensity was required to provoke an afterdischarge in the motor cortex on electrodes 8, 22, and 24. Based on the IVEEG findings, an anterotemporal lobectomy was performed together with MST over the frontocentral and posterotemporal regions. Variable thickness was observed in the cortices where irregular nuclear alignment coexisted with areas of variable neuronal density in the temporal neocortex. Numerous heterotopic neurons were identified in the white matter. The pathologic diagnosis was cortical dysplasia, with poor cortical lamination, but without mesial temporal abnormality. The patient’s seizure frequency
decreased markedly, and his condition has remained stable 38 months after the operation (Engel’s class IIa). Discussion The amperage threshold of cortical stimulation must be estimated to define the functional cortex in children and to avoid excessive stimulation that might provoke seizures. The threshold needed to define the functional cortex in children has been studied extensively by electrical stimulation of chronically implanted subdural electrodes [3,4,8, 10]. Jayakar et al. [3], using the standard paradigm, found it difficult to detect the threshold in children less than 5 years of age because of a lower afterdischarge threshold. Physicians have stimulated the functional cortex within a range of 2 and 10 mA in most adult patients [11-13]; however, in pediatric trials, the functional cortex is rarely stimulated over 15 mA [8,11]. Stimulation performed under such limited amperage might be unable to detect the threshold in young children, unless a “dual-increment paradigm” requiring specialized technology is used (described by Jayakar [3]). In our pediatric series the optimal threshold was detected up to a maximum level of 20 mA, generally lower than that for afterdischarges. This study confirmed the inverse relationship between amperage threshold and age: the younger children required a higher threshold to elicit a functional response. Although reported previously [3], a clinical response may only be obtained at thresholds higher than the afterdischarge threshold. In our series, one patient exhibited a lower afterdischarge threshold in the epileptic region outside the central cortex. Our technique, which used an online display of digital referential EEG recording up to 128 channels at the time of cortical stimulation, illustrates subtle rhythmic discharges of afterdischarges right to the end of stimulation. On the basis of these results, careful cortical stimulation with increments of amperage in the higher range and online digital EEG monitoring can identify the primary motor cortex in younger children without risk of seizures. Younger patients with NMD tended to have a higher amperage threshold than those with non-NMD pathology and needed stimulation higher than 10 mA to provoke a motor response. Characteristic changes in NMD, revealed by pathologic examination, consist of disorganization of the cortical layer, abnormal cell migration, and hypergenesis or hypogenesis of cortical neuronal cells. The higher amperage threshold of the motor cortex in the abnormal developing brain could result from a disorganized neuronal network in which normal functional cells are surrounded by dysplastic cells. Advanced neuroimaging techniques have succeeded in delineating the subtle lesions of NMD in younger patients with refractory epilepsy [14-16]. Furthermore, NMD has often been reported in the central region on MRI scans [17-19]. In some patients with cortical dysplasia, however, the epileptogenic area was more extensive than the visible lesion identified on MRI scans [18,20-22]. Otsubo et al. [23] reported pediatric
patients with NMD that provoked positive epileptiform discharges on EEG, indicating that the disorders were located around the central cortex. In addition, Palmini et al. [24] noted specific EEG rhythmic discharges, suggesting that NMD was intrinsically epileptogenic. These focal and intrinsic epileptiform discharges of NMD can be explained by cellular hyperexcitability, which provokes medically intractable seizures; however, abnormal neuronal function in the developing brain could be explained by damaged normal tissue secondary to NMD. NMD is believed to cause hyperexcitability, and the higher amperage threshold of the primary motor cortex in younger children with NMD also could result in disorganized neuronal structures. This study has confirmed that the early developing brain raises the amperage threshold of primary motor function. Pediatric neurosurgeons and neurologists need to take note of the inverse relationship between age and threshold. Cautious observation of afterdischarges using online digital EEG can make successful functional mapping in pediatric patients possible. Amperage threshold differences between NMD and other disorders demonstrated a tendency for the amperage threshold of patients in the NMD group to be elevated. We need to predict the higher amperage threshold in younger children with NMD that is depicted on both MRI and EEG.
This article was prepared with the assistance of Editorial Services, The Hospital for Sick Children, Toronto, Ontario, Canada.
References [1] Wyllie E, Comair YG, Kotagal P, Bulacio J, Bingaman W, Ruggieri P. Seizure outcome after epilepsy surgery in children and adolescents. Ann Neurol 1998;44:740-8. [2] Minassian BA, Otsubo H, Weiss S, Elliott I, Rutka JT, Snead OC III. MEG localization in pediatric surgery: Comparison with invasive intracranial EEG. Ann Neurol 1999;46:627-33. [3] Jayakar P, Alvarez LA, Duchowny MS, Resnick TJ. A safe and effective paradigm to functionally map the cortex in childhood. J Clin Neurophysiol 1992;9:288-93. [4] Wyllie E, Awad I. Invasive neurophysiologic techniques in the evaluation for epilepsy surgery in children. In: Lu¨ders HO, ed. Epilepsy surgery. New York: Raven Press, 1991:409-12. [5] Kuzniecky R, Andermann F, Tampieri D, Melanson D, Olievier A, Leppik I. Bilateral central macrogyria: Epilepsy, pseudobullbar palsy, and mental retardation—a recognizable neuronal migration disorder. Ann Neurol 1989;25:547-54. [6] Desbiens R, Berkovic SF, Dubeau F, et al. Life-threatening focal status epilepticus due to occult cortical dysplasia. Arch Neurol 1993;50: 695-700. [7] Engel J Jr. Outcome with respect to epileptic seizures. In Engel J Jr, ed. Surgical treatment of the epilepsies. New York: Raven Press, 1993:609-12. [8] Lesser RP, Luders H, Klem G, Dinner D, Morris H, Hahn J. Cortical afterdischarge and functional responses thresholds: Results of extraoperative testing. Epilepsia 1984:615-21. [9] Uematsu S, Lesser R, Fisher RS, et al. Motor and sensory cortex in humans: Topography studied with chronic subdural stimulation. Neurosurgery 1992;31:59-72. [10] Duchowny M, Jayakar P, Harvey AS, Levin B, Resnic TJ,
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Alvertz LA. Language cortex representation: Effects of developmental versus acquired pathology. Ann Neurol 1996;40:31-8. [11] Penfield W. Epilepsy and surgical therapy. Arch Neurol Psychiatry 1936;36:449-84. [12] Fedio P, Van Buren JM. Memory deficits during electrical stimulation of the speech cortex in conscious man. Brain Lang 1974;1: 29-42. [13] Van Buren JM, Fedio P, Frederick GC. Mechanisms and localization of speech in the parietotemporal cortex. J Neurosurg 1978; 2:233-9. [14] Barkovich AJ, Rowley HA, Andermann F. MR in partial epilepsy: Value of high-resolution volumetric techniques. Am J Neuroradiol 1995;16:339-43. [15] Barkovich AJ, Kuzuniecky RI, Ballon AW, Grant PE. Focal transmantle dysplasia: A specific malformation of cortical development. Neurology 1997;49:1148-52. [16] Bastos AC, Comeau RM, Andermann F, et al. Diagnosis of subtle focal cortical dysplastic lesions. Curvilinear reformatting from three dimensional magnetic resonance imaging. Ann Neurol 1999;46:8894. [17] Kuzniecky R, Berkovic S, Andermann F, et al. Focal myoclo-
nus and rolandic cortical dysplasia: Classification by magnetic resonance imaging. Ann Neurol 1988;23:317-25. [18] Kuzniecky R, Morawetz R, Faught E, Black L. Frontal and central lobe cortical dysplasia. Clinical, EEG, and imaging features. Dev Med Child Neurol 1995;37:159-66. [19] Palmini A, Andermann F, Olivier A, Tampieri D, Robitaille Y. Focal neuronal migration disorders and intractable partial epilepsy: A study of 30 patients. Ann Neurol 1991;30:741-9. [20] Chugani HT, Shields WD, Shewmon DA, Olson DM, Phelps ME, Peacock WJ. Infantile spasms: I. PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatment. Ann Neurol 1991;29:110-2. [21] Lee N, Radtke RA, Gray L, et al. Neuronal migration disorders. Positron emission tomography correlations. Ann Neurol 1994;35:290-7. [22] Jayakar P. Invasive EEG monitoring in children: When, where, and what? J Clin Neurophysiol 1999;16:408-18. [23] Otsubo H, Steinlin M, Hwang P, et al. Positive epileptiform discharge in children with neuronal migration disorders. Pediatr Neurol 1997;16:23-31. [24] Palmini A, Gambardella A, Andermann F, et al. Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results. Ann Neurol 1995;37:476-87.
CONNECTIONS—Web Site Update Provided by Steven M. Leber, M.D., Ph.D. and Kenneth J. Mack, M.D., Ph.D. Personal digital assistants (PDAs) are becoming commonly used in neurology. Many neurology and pediatric texts are being converted to PDA format, and some of these volumes are available as shareware. Although it is inconvenient to read a full text on a PDA, it is helpful to have databases available, such as for pediatric drug dosing. In addition, programs are currently available to electronically write prescriptions from a PDA, download patient data, calculate body surface area, and much more. Potentially useful sites include: PDAMD (www.pdamd.com); Healthy Palm Pilot (www.healthypalmpilot.com); Peripheral Brain (pbrain.hypermart.net); Handango (www.handango.com); Palm Gear (www.palmgear.com); Jim’s Palm Pages (www.jimthompson.net/pilot/); Handheldmed.com (www.handheldmed.com); CollectiveMed.com (www.collectivemed.com/pda/); @Hand Med Texts (www.athandmedical.com); and Evidence Based Medicine (www3.mtco.com/glwoods/Default.htm).
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Extraoperative Cortical Stimulation of Motor Function in Children Shiro Chitoku, MD*¶, Hiroshi Otsubo, MD*¶, Yu Harada, MD*, Venita Jay, MD†¶, James T. Rutka, MD, PhD‡, Shelly K. Weiss, MD*, Mohamed Abdoll, MSc§, and O. Carter Snead, III, MD*¶ The purpose of the study was to investigate factors altering the amperage threshold needed to provoke functional responses in children with epilepsy. Twenty patients (4-18 years of age) who underwent epilepsy surgery at our institution from 1996-2000 after insertion of subdural grid electrodes were reviewed retrospectively. Extraoperative electrical cortical stimulation was performed with 50-Hz biphasic pulses of 0.2 ms in duration using a “distance reference” technique. Amperage thresholds of primary motor responses and afterdischarges were evaluated. The patients were grouped according to underlying pathology: eight with neuronal migration disorders (group A) and 12 with other disorders (group B). The motor cortex was defined successfully in all children because the afterdischarges threshold was higher than the motor cortical threshold. Amperage thresholds ranged from 2-20 mA (mean ⴝ 7.7) for primary motor function. An inverse relationship was found between amperage threshold and age: the younger the patient, the higher the threshold (P ⴝ 0.0005). Patients in group A required a higher amperage (2-20 mA, mean ⴝ 8.6) for motor cortical mapping than those in group B (2-14 mA, mean ⴝ 6.4). Younger children with neuronal migration disorders require a higher amperage threshold to achieve adequate motor functional mapping with careful observation of afterdischarges. © 2001 by Elsevier Science Inc. All rights reserved. Chitoku S, Otsubo H, Harada Y, Jay V, Rutka JT, Weiss SK, Abdoll M, Snead OC III. Extraoperative cortical stimulation of motor function in children. Pediatr Neurol 2001;24:344-350.
From the *Division of Neurology and Department of Paediatrics; † Department of Pathology; ‡Division of Neurosurgery and Department of Surgery; and §Department of Population Health Sciences; The Hospital for Sick Children and the University of Toronto; and the ¶ Bloorview Epilepsy Research Program; Toronto, Canada.
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Introduction Medically refractory epilepsy is seen more often in the extratemporal lobe in children, which is proximal to the functional cortex, than in the temporal lobe [1]. Functional mapping is especially important in treating children with this type of epilepsy to avoid causing permanent deficits. Subdural electrodes implanted for 3-10 days are needed to provide detailed localization of the functional cortex in relation to an adjacent epileptogenic zone [2]. The stimulation technique used for extraoperative mapping in adults often fails to elicit clinical responses in infants and younger children because the maximum amperage is usually set too low. Empirical evidence has been reported that indicates difficulty in defining the functional cortex in the developing brain in infants and younger children [3,4]. Jayakar et al. [3] developed an alternative paradigm to elicit responses from the immature cortex, but their methodology cannot be applied with the stimulators available in most other institutions. If amperage thresholds in younger children can be estimated using conventional techniques, functional mapping can be performed successfully without missing certain thresholds. It has been theorized that the failure of motor functional mapping in infants results from their immature, inherently less-excitable rolandic cortex [4]. However, the relationship between age and amperage threshold in eliciting motor function responses has not been studied previously. In addition, neuronal migration disorders (NMDs), which are frequently seen in younger children with intractable seizures, may be a factor in the inability to perform cortical functional mapping because they are often harbored in the central cortex [5,6]. The purpose of this study was to investigate the rela-
Communications should be addressed to: Dr. Chitoku; Division of Neurology and Department of Paediatrics; The Hospital for Sick Children; 555 University Ave.; Toronto, M5G IX8, Canada. Received September 15, 2000; accepted February 20, 2001.
© 2001 by Elsevier Science Inc. All rights reserved. PII S0887-8994(01)00264-8 ● 0887-8994/01/$—see front matter
Table 1.
Group/ Pt No.
Clinical data of epilepsy patients (n ⴝ 20)
Age (yr)/ Sex
A/1
6/M
A/2 A/3 A/4 A/5 A/6 A/7 A/8 B/1 B/2 B/3 B/4 B/5 B/6 B/7 B/8 B/9 B/10 B/11 B/12
6/F 9/F 12/M 13/F 13/F 16/F 18/M 4/M 7/M 9/M 10/M 11/F 11/M 13/F 15/F 15/M 15.5/F 16/F 16/F
MRI Findings
Surgical Hemisphere
Ictal Onset Zone and Active Interictal Zone Detected by IVEEG
Surgical Procedures Lobectomy and Cortical Excision
Normal
L
T, F
ATL, F, C
Normal L-cerebral atrophy L-F thick gyrus Normal R-cerebral atrophy L-F abnormal sulcus R-F thick gyrus Normal Normal Normal R-T thick gyrus Normal Normal Normal Normal Normal Normal Normal Normal
R L L L R L R L L R R R R R R R L R R
P, O, F P, F F P T, O F F T, C, P F, T T, O T, O, C P, T F, C, T, P F F, P, T F, C Mesial T C T, F
P, O, F F, P F P T, O AFL F ATL None T, O T, O lobectomy, AH ATL, P, post T F, ATL, P FL AFL, T F ATL None ATL
Region of MST Motor, sensory, posterior T Motor, premotor Premotor, sensory Motor, sensory Motor, sensory Premotor, motor Cortical resection only R-premotor Motor Motor Motor, sensory Sensory Motor Motor, premotor Sensory Sensory, premotor Motor Post T, premotor Motor, sensory Motor, sensory
Outcome* (Follow-up Months) IIB (38) III (22) II (17) IA (25) IVA (23) IB (8) IA (3) IA (7) III (5) IIB (34) IVB (19) IA (1) IIA (38) III (33) I (10) IA (29) IA (46) IA (21) II (41) III (3)
* According to Engel’s classification. Abbreviations: A ⫽ Group of neuronal migration disorders AFL ⫽ Anterior frontal lobectomy AH ⫽ Amygdalohippocampectomy ATL ⫽ Anterior temporal lobectomy B ⫽ Normal varient or gliosis group C ⫽ Central
F L O P R T
⫽ ⫽ ⫽ ⫽ ⫽ ⫽
Frontal lobe Left Occipital Parietal Right Temporal
tionships among age, pathology, and amperage threshold in provoking motor functional responses extraoperatively in children with intractable epilepsy. Materials and Methods Subjects Records of 20 patients, 4-18 years of age, who underwent epilepsy surgery after subdural grid electrode insertion at The Hospital for Sick Children in Toronto (from June 1, 1996 to April 30, 2000) were reviewed retrospectively. The patients were divided into two groups based on underlying pathology: group A, patients with NMD; and group B, patients in whom pathology was reported to be either gliosis or unremarkable (non-NMD). Two patients had undergone previous operations in the same hemisphere but not in the central cortex. Table 1 summarizes patient characteristics, results of investigations, surgical procedures, and outcomes classified according to Engel’s criteria [7].
Intracranial Video Electroencephalography (IVEEG) Subdural grids (Ad-Tech Medical Instrument Co., Racine, WI) were constructed for each patient based on scalp interictal and ictal electroencephalographic (EEG) results, interictal spike sources, and somatosensory-evoked fields demonstrated by magnetoencephalography (MEG) and seizure semiology. Grid size was determined on the basis of
three-dimensional (3D) magnetic resonance imaging (MRI) using 1.5-mm thin-slice T1 images (ISG Viewing Wand System; ISG Technologies, Mississauga, Ontario, Canada). The grids consisted of 55-137 platinum electrodes (mean ⫽ 112), 5 mm in diameter, embedded in silastic sheet (Ad-Tech Medical Instrument Co.). Center-to-center interelectrode distances ranged from 10-13 mm. Split-screen and time-locked video EEG was used to review the clinical behavior of seizures (BMSI 5000; Nicolet, Madison, WI). The digitized EEG data (200 samples/ second per channel) were selected by means of alarm button triggers, automatic seizure, and spike detection, and then stored for review.
Stimulation Procedure Mapping of motor, sensory, and language functions was performed in one-to-two sessions on the third or fourth day after grid implantation. This study evaluated only primary motor responses. Because the young children did not consistently cooperate on sensory and language tests, the results were not accurate enough to evaluate. Stimulations were delivered with 50-Hz biphasic pulses (pulse duration, 0.2 ms) up to 25 seconds in duration in one train. Pulses were given to electrode pairs at an initial intensity of 2 mA, increasing by 1-2 mA to a maximum of 20. We used the distance reference technique described by Lesser et al. [8], which stimulates between a target electrode in the area of interest and a reference electrode situated at the periphery of the subdural grid array. The stimulation was paused as soon as clinical responses or clinical seizures were noted. EEG was recorded simultaneously and monitored by the physician using referential montage to detect an afterdischarge.
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Table 2.
Results of cortical stimulation of the motor cortex (n ⴝ 20)
Group/ Pt. No
Number of Electrodes
Amperage Threshold of Face and Hand
Threshold of AD and Seizure
Epileptic Zone in Motor Cortex
4 3 9 8 11 5 9 3 6 3 7 4 12 5 9 8 5 6 9 12
14 18-20 (m ⫽ 18.7) 6-12 (m ⫽ 10) 3-6 (m ⫽ 5.1) 4-14 (m ⫽ 10) 3-4 (m ⫽ 3.3) 2-4 (m ⫽ 2.9) 3-6 (m ⫽ 5) 8-10 (m ⫽ 8.3) 10-14 (m ⫽ 12.7) 8-12 (m ⫽ 11.4) 4-10 (m ⫽ 8) 2-4 (m ⫽ 2.9) 4-5 (m ⫽ 4.4) 2-3 (m ⫽ 2.1) 2-5 (m ⫽ 4) 5-12 (m ⫽ 8.2) 2-3 (m ⫽ 2.5) 3-6 (m ⫽ 4.5) 8-10 (m ⫽ 8.3)
14 (m ⫽ 14) 18-20 (m ⫽ 19.3) 12 (m ⫽ 12) 4-8 (m ⫽ 6.8) 6-10 (m ⫽ 7.7) 4-6 (m ⫽ 4.8) 4 4-6 (m ⫽ 5.3) 8-10 (m ⫽ 9.5) 10-14 (m ⫽ 11.3) 12 (m ⫽ 12) — 6 (m ⫽ 6) — — — 10-12 (m ⫽ 11.3) — 3-12 (m ⫽ 8.2) 8-9 (m ⫽ 8.3)
⫹ ⫹ ⫺ ⫹ ⫹ ⫹ ⫺ ⫺ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫺ ⫹ ⫺ ⫹ ⫹
A/1 A/2 A/3 A/4 A/5 A/6 A/7 A/8 B/1 B/2 B/3 B/4 B/5 B/6 B/7 B/8 B/9 B/10 B/11 B/12
Abbreviations: AD ⫽ Afterdischarge M ⫽ Mean
Definition of Response
Results
A primary motor response was defined as the local movement of a contralateral part of the body in response to cortical stimulation while the patient was at rest; for example, a simple isolated movement, such as contraction of the eyelid, tongue, mouth, hand, or finger [9]. When an afterdischarge was detected, its clinical manifestation was observed carefully and stimulation was paused until the afterdischarge stopped. The amperage thresholds required for afterdischarge and seizure inducement were compared with those needed for motor cortical response.
Table 2 summarizes the results of stimulation of the motor cortex for each patient.
Surgical Resection Cortical excision and multiple subpial transection (MST) were performed over the ictal onset zone and active interictal zone on days 3-10 after implantation of the subdural grid. The grid was removed after the surgical area had been identified.
Amperage Threshold An inverse relationship was found between age and amperage threshold (P ⫽ 0.0005): younger patients required a higher threshold to provoke motor function (Fig 1). Comparison of amperage thresholds between groups A and B, based on the age distribution (Fig 2), depicted a marginally insignificant difference (P ⫽ 0.058): group A patients, especially younger ones, tended to need a higher threshold (2-20 mA; mean ⫽ 8.6) than those in group B (2-14 mA; mean ⫽ 6.4).
Pathologic Examination
Afterdischarges
All the surgical specimens collected were processed for conventional histologic and immunohistochemical analysis using either the avidinbiotin complex or peroxidase-antiperoxidase techniques.
Afterdischarges provoked despite careful stimulation, with or without clinical seizures, were recorded in 15 patients: eight in group A and seven in group B. The amperage thresholds for afterdischarges ranged from 2-20 mA (mean ⫽ 9.3). Fourteen of 15 patients had afterdischarge thresholds equal to or higher than the thresholds for clinical responses of the motor cortex. In the one remaining patient, afterdischarges occurred at a lower amperage outside the motor cortex. The mean amperage threshold of afterdischarges was lower in group B (3-14 mA; mean ⫽ 9.2) than in group A (4-20 mA; mean ⫽ 9.5).
Statistical Analysis The relationship between amperage threshold and the patient’s age was investigated using simple linear regression analysis. Analysis of covariance was used to investigate the relationship between groups A and B in terms of the age-threshold relationship and the relationship between the epileptic and nonepileptic zone subgroups in both groups A and B. Statistical significance was defined as P ⬍ 0.05.
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Figure 1. Patient age vs amperage threshold (linear regression analysis: slope ⫽ ⫺0.784, P ⫽ 0.0005).
Amperage Threshold Difference between Epileptic and Nonepileptic Cortex We also compared amperage thresholds between patients in each group whose epileptic zone involved the motor cortex (five in group A and eight in group B) and between patients in whom it did not (three in group A and four in group B). In group A the mean threshold in the epileptic motor cortex was 10.2 mA compared with 6 mA
in the nonepileptic cortex. In group B the comparable figures were 7.6 and 4.2 mA, respectively. The amperage threshold in the epileptic motor cortex tended to be higher than in the nonepileptic in both groups, but the difference was not significant (analysis of covariance, P ⫽ 0.794).
Pathologic Findings Analysis of specimens taken from group A patients revealed the presence of cortical dysplasia in all of them. Various migration abnormalities were also noted universally, consisting of subtle morphologic change of gray matter in two patients, and disorganization of neuronal size, shape, and orientation in addition to heterotopic neurons in five. Tuberous sclerosis was diagnosed in the remaining patient in group A, which was based on the presence of balloon cells without any other physiologic profile. Tissue analysis in group B patients revealed gliosis in 10 of them. Because the remaining two patients underwent only MST, no surgical specimens were obtained.
Follow-up of Motor Function and Seizure Outcome
Figure 2. Relationship between age and amperage threshold by groups A and B. Linear regression analysis: group A (dotted line), slope ⫽ ⫺1.1, P ⫽ 0.007; group B (solid line), slope ⫽ ⫺0.52, P ⫽ 0.0378). There was a marginally insignificant difference between the two groups. Analysis of covariance: age ⫻ group interaction, P ⫽ 0.1212; intercepts, P ⫽ 0.0585.
No permanent hemiparesis was noted after MST over the epileptic central cortex in 19 patients. However, temporary facial and hand motor weakness was observed in 12 patients (group A: five; group B: seven) after MST over the motor cortex. Seizure outcomes are summarized in Table 1, illustrating that among the patients with a follow-up period longer than 12 months, significant relief
Chitoku et al: Pediatric Motor Cortical Threshold 347
Figure 3. In the top panel a subdural grid array consisting of 40 channels is placed over the left frontotemporal central region of Patient 1, group A. The bottom panel illustrates the intraoperative view taken at the end of the monitoring and immediately before cortical excision. The numbers on subdural electrodes indicate the epileptogenic zone. The anterior temporal region, outlined by a thick white line, was also identified as part of the epileptogenic zone. Letters A, B, C, and D represent the motor facial area, identified by extraoperative functional mapping. Anterior temporal lobectomy (anterior to numbers 29 and 37) was performed; MST was performed over the electrodes identified by numbers and letters.
of seizures (Engel’s class I and II) was noted in three of five patients in group A, and in six of eight in group B. Illustrative Case (Patient A-1) Patient A-1 was a 6-year-old right-handed male whose seizure disorder began at 7 months of age. The seizures became refractory to multiple antiepileptic medications at 3.5 years of age, and his speech deteriorated. Magnetic resonance imaging (MRI) depicted no abnormal findings. Single-photon emission computed tomography revealed left hemispheric hypoperfusion. Scalp-recorded EEG depicted high-amplitude interictal spikes on the bilateral frontal regions. Prolonged scalp-recorded EEG demonstrated paroxysmal generalized discharges with left frontal predominance spreading to the left central region. MEG demonstrated epileptic spike sources on the bilateral frontotemporal areas spreading above the sylvian fissure with
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left-sided predominance. A subdural grid with 59 channels was implanted over the left frontotemporoparietal area (Fig 3). IVEEG revealed that ictal epileptiform discharges began in the left frontotemporal area and spread to the frontocentral area. Cortical stimulation of 14 mA in intensity was required to provoke a right facial motor response (electrodes 7, 15, 21, and 22). The same intensity was required to provoke an afterdischarge in the motor cortex on electrodes 8, 22, and 24. Based on the IVEEG findings, an anterotemporal lobectomy was performed together with MST over the frontocentral and posterotemporal regions. Variable thickness was observed in the cortices where irregular nuclear alignment coexisted with areas of variable neuronal density in the temporal neocortex. Numerous heterotopic neurons were identified in the white matter. The pathologic diagnosis was cortical dysplasia, with poor cortical lamination, but without mesial temporal abnormality. The patient’s seizure frequency
decreased markedly, and his condition has remained stable 38 months after the operation (Engel’s class IIa). Discussion The amperage threshold of cortical stimulation must be estimated to define the functional cortex in children and to avoid excessive stimulation that might provoke seizures. The threshold needed to define the functional cortex in children has been studied extensively by electrical stimulation of chronically implanted subdural electrodes [3,4,8, 10]. Jayakar et al. [3], using the standard paradigm, found it difficult to detect the threshold in children less than 5 years of age because of a lower afterdischarge threshold. Physicians have stimulated the functional cortex within a range of 2 and 10 mA in most adult patients [11-13]; however, in pediatric trials, the functional cortex is rarely stimulated over 15 mA [8,11]. Stimulation performed under such limited amperage might be unable to detect the threshold in young children, unless a “dual-increment paradigm” requiring specialized technology is used (described by Jayakar [3]). In our pediatric series the optimal threshold was detected up to a maximum level of 20 mA, generally lower than that for afterdischarges. This study confirmed the inverse relationship between amperage threshold and age: the younger children required a higher threshold to elicit a functional response. Although reported previously [3], a clinical response may only be obtained at thresholds higher than the afterdischarge threshold. In our series, one patient exhibited a lower afterdischarge threshold in the epileptic region outside the central cortex. Our technique, which used an online display of digital referential EEG recording up to 128 channels at the time of cortical stimulation, illustrates subtle rhythmic discharges of afterdischarges right to the end of stimulation. On the basis of these results, careful cortical stimulation with increments of amperage in the higher range and online digital EEG monitoring can identify the primary motor cortex in younger children without risk of seizures. Younger patients with NMD tended to have a higher amperage threshold than those with non-NMD pathology and needed stimulation higher than 10 mA to provoke a motor response. Characteristic changes in NMD, revealed by pathologic examination, consist of disorganization of the cortical layer, abnormal cell migration, and hypergenesis or hypogenesis of cortical neuronal cells. The higher amperage threshold of the motor cortex in the abnormal developing brain could result from a disorganized neuronal network in which normal functional cells are surrounded by dysplastic cells. Advanced neuroimaging techniques have succeeded in delineating the subtle lesions of NMD in younger patients with refractory epilepsy [14-16]. Furthermore, NMD has often been reported in the central region on MRI scans [17-19]. In some patients with cortical dysplasia, however, the epileptogenic area was more extensive than the visible lesion identified on MRI scans [18,20-22]. Otsubo et al. [23] reported pediatric
patients with NMD that provoked positive epileptiform discharges on EEG, indicating that the disorders were located around the central cortex. In addition, Palmini et al. [24] noted specific EEG rhythmic discharges, suggesting that NMD was intrinsically epileptogenic. These focal and intrinsic epileptiform discharges of NMD can be explained by cellular hyperexcitability, which provokes medically intractable seizures; however, abnormal neuronal function in the developing brain could be explained by damaged normal tissue secondary to NMD. NMD is believed to cause hyperexcitability, and the higher amperage threshold of the primary motor cortex in younger children with NMD also could result in disorganized neuronal structures. This study has confirmed that the early developing brain raises the amperage threshold of primary motor function. Pediatric neurosurgeons and neurologists need to take note of the inverse relationship between age and threshold. Cautious observation of afterdischarges using online digital EEG can make successful functional mapping in pediatric patients possible. Amperage threshold differences between NMD and other disorders demonstrated a tendency for the amperage threshold of patients in the NMD group to be elevated. We need to predict the higher amperage threshold in younger children with NMD that is depicted on both MRI and EEG.
This article was prepared with the assistance of Editorial Services, The Hospital for Sick Children, Toronto, Ontario, Canada.
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nus and rolandic cortical dysplasia: Classification by magnetic resonance imaging. Ann Neurol 1988;23:317-25. [18] Kuzniecky R, Morawetz R, Faught E, Black L. Frontal and central lobe cortical dysplasia. Clinical, EEG, and imaging features. Dev Med Child Neurol 1995;37:159-66. [19] Palmini A, Andermann F, Olivier A, Tampieri D, Robitaille Y. Focal neuronal migration disorders and intractable partial epilepsy: A study of 30 patients. Ann Neurol 1991;30:741-9. [20] Chugani HT, Shields WD, Shewmon DA, Olson DM, Phelps ME, Peacock WJ. Infantile spasms: I. PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatment. Ann Neurol 1991;29:110-2. [21] Lee N, Radtke RA, Gray L, et al. Neuronal migration disorders. Positron emission tomography correlations. Ann Neurol 1994;35:290-7. [22] Jayakar P. Invasive EEG monitoring in children: When, where, and what? J Clin Neurophysiol 1999;16:408-18. [23] Otsubo H, Steinlin M, Hwang P, et al. Positive epileptiform discharge in children with neuronal migration disorders. Pediatr Neurol 1997;16:23-31. [24] Palmini A, Gambardella A, Andermann F, et al. Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results. Ann Neurol 1995;37:476-87.
CONNECTIONS—Web Site Update Provided by Steven M. Leber, M.D., Ph.D. and Kenneth J. Mack, M.D., Ph.D. Personal digital assistants (PDAs) are becoming commonly used in neurology. Many neurology and pediatric texts are being converted to PDA format, and some of these volumes are available as shareware. Although it is inconvenient to read a full text on a PDA, it is helpful to have databases available, such as for pediatric drug dosing. In addition, programs are currently available to electronically write prescriptions from a PDA, download patient data, calculate body surface area, and much more. Potentially useful sites include: PDAMD (www.pdamd.com); Healthy Palm Pilot (www.healthypalmpilot.com); Peripheral Brain (pbrain.hypermart.net); Handango (www.handango.com); Palm Gear (www.palmgear.com); Jim’s Palm Pages (www.jimthompson.net/pilot/); Handheldmed.com (www.handheldmed.com); CollectiveMed.com (www.collectivemed.com/pda/); @Hand Med Texts (www.athandmedical.com); and Evidence Based Medicine (www3.mtco.com/glwoods/Default.htm).
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