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Etiology-specific differences in motor function after hemispherectomy
Epilepsy Research (2013) 103, 221—230
journal homepage: www.elsevier.com/locate/epilepsyres
Etiology-specific differences in motor function after hemispherectomy Nicolien M. van der Kolk a,b,1, Kim Boshuisen b,2, Ron van Empelen c,3, Suzanne M. Koudijs b,2, Martin Staudt d,e, Peter C. van Rijen f,4, Onno van Nieuwenhuizen b,2, Kees P.J. Braun b,∗,2 a
Department of Neurology, Radboud University Nijmegen Medical Center, PO Box 9101, 6500HB Nijmegen, The Netherlands Rudolf Magnus Institute of Neuroscience, Department of Child Neurology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands c Child Development and Exercise Center, Division of Paediatrics, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands d Clinic for Neuropaediatrics and Neurorehabilitation, Epilepsy Center for Children and Adolescents, Schön-Klinik Vogtareuth, 83209 Priem am Chiemsee, Germany e Department of Paediatric Neurology and Developmental Medicine, University Children’s Hospital, Tübingen, Germany f Rudolf Magnus Institute of Neuroscience, Department of Neurosurgery, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands b
Received 19 March 2012; received in revised form 4 August 2012; accepted 19 August 2012 Available online 11 September 2012
KEYWORDS Functional hemispherectomy; Motor function; Etiology
Summary Prediction of functional motor outcome after hemispherectomy is difficult due to the heterogeneity of motor outcomes observed. We hypothesize that this might be related to differences in plasticity during the onset of the underlying epileptogenic disorder or lesion and try to identify predictors of motor outcome after hemispherectomy. Thirty-five children with different etiologies (developmental, stable acquired or progressive) underwent functional hemispherectomy and motor function assessment before hemispherectomy and 24 months after hemispherectomy. Preoperatively, children with developmental etiologies performed better in terms of distal arm strength and hand function, but not on gross motor function tests. Postoperatively, the three etiology groups performed equally poor in muscle strength and hand function, but gross motor
∗
Corresponding author. Tel.: +31 887554003; fax: +31 887555350. E-mail addresses: [email protected] (N.M. van der Kolk), [email protected] (K. Boshuisen), [email protected] (R. van Empelen), [email protected] (S.M. Koudijs), [email protected] (M. Staudt), [email protected] (P.C. van Rijen), [email protected] (O. van Nieuwenhuizen), [email protected] (K.P.J. Braun). 1 Tel.: +31 243613396; fax: +31 243541122. 2 Tel.: +31 887554003; fax: +31 887555350. 3 Tel.: +31 887554030; fax: +31 887555333. 4 Tel.: +31 88-7557977; fax: +31 302542100. 0920-1211/$ — see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.eplepsyres.2012.08.007
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N.M. van der Kolk et al. function improved in those with acquired and progressive etiologies. Loss of voluntary hand function and distal arm strength after surgery was associated with etiology, intact insular cortex and intact structural integrity of the ipsilesional corticospinal tract on presurgical MRI scans. In conclusion, postoperative motor function can be predicted more precisely based on etiology and on preoperative MRI. Children with developmental etiology more often lose distal arm strength and hand function and show less improvement in gross motor function, compared to those with acquired pathology. © 2012 Elsevier B.V. All rights reserved.
Introduction Functional hemispherectomy is a successful treatment for catastrophic childhood epilepsy caused by hemispheric or unilateral multilobar epileptogenic lesions. The spectrum of neurological deficits that occur after surgery shows a great, and thus far largely unexplained, variance among the operated children, making it difficult to predict functional outcome for individual patients. Consistent with conventional ideas about the neuroanatomy of motor pathways (Kandel et al., 2000), the obligatory ipsilateral corticospinal control of motor function after hemispherectomy is characterized by a hemiparesis in which the arm is more affected than the trunk or leg, with a distal-proximal gradient within the extremities (van Empelen et al., 2004). Nevertheless, hand function after hemispherectomy can vary from no functional use, to the preservation of some functions such as grasping or even individual finger movements (Holthausen et al., 1997; Holloway et al., 2000; Staudt, 2002; Devlin et al., 2003; de Bode et al., 2005). Although strengthening of ipsilateral corticospinal and corticoreticulospinal connections has been assumed to be a major mechanism associated with partial recovery after brain damage (Staudt, 2004a; Benecke, 1991), the heterogeneity of motor outcomes observed after hemispherectomy indicates that the quality of ipsilateral motor control varies. This may be attributed to differences in reorganizational capacity or plasticity, which is more powerful in the immature nervous system than in the adult brain (Kennard, 1936). In addition, hand function in patients with congenital hemiparesis depending on ipsilateral corticospinal pathways was inversely correlated to the timing of brain lesions or malformations acquired at different gestational ages (Staudt, 2004a). Children who undergo hemispherectomy suffer brain damage during two separate events: during the structural development of the epileptogenic disorder and during the surgery. Given the decrease in reorganizational capacity during maturation, it is likely that the first occurring event has the highest potential of influencing motor outcome. Indeed, a linear and independent correlation between age at surgery and postoperative hand function is lacking and both supportive and contradictive studies have been reported (Muller et al., 1991; Graveline, 1999; Cukiert et al., 2009). Holthausen et al. (1997) was the first to report that the type of the underlying pathology (i.e. the timing of its ontogeny) might be more important than the age at surgery. Results of the relatively few studies that address the age at ontogeny of the epileptogenic disorder in relation to motor outcome after hemispherectomy, are inconsistent (Holthausen et al., 1997; Devlin et al., 2003; de Bode
et al., 2005; Lettori, 2008). Our previous study on motor outcome in twelve children after hemispherectomy suggested a specific time course of motor recovery for different body areas. The influence of underlying pathology was not assessed (van Empelen et al., 2004). In this study we aim to assess time course of motor function recovery of specifically the upper extremity (hand) and of gross motor function in relation to the underlying etiology (as an indication for the time during which the first brain damage occurred) in a large cohort of children who underwent functional hemispherectomy.
Methods This is a retrospective consecutive cohort study of 35 children who underwent functional hemispherectomy for medically intractable hemispheric epilepsy between 1996 and 2007 in the Wilhelmina Children’s Hospital, and in whom longitudinal standardized investigations of motor function were performed. The study was approved by the medical ethical and research committee of the University Medical Center Utrecht, and written informed consent was given by all parents.
Patients Thirty-five children were elected by the Dutch Collaborative Epilepsy Surgery Program to undergo functional hemispherectomy and were included in the standardized follow-up investigations (a subset of this population has been subject to previous functional outcome studies (van Empelen et al., 2004)). The underlying pathology was ascertained mainly from Magnetic Resonance Imaging (MRI) and infrequently from pathologic examination of surgery specimens, when available. Patients were classified according to their pathology, as previously described (Devlin et al., 2003), into three etiological subgroups that also indicated the ontogeny of their epileptogenic condition: ‘developmental’ (hemimegalencephaly, cortical dysplasia or other), ‘acquired’ (stable and non-progressive brain lesions, occurring perinatally or early in postnatal life, mostly consisting of ischemic or hemorrhagic pathology) or ‘progressive’ (Rasmussen’s encephalitis or Sturge—Weber Syndrome). From the patients’ records, we collected age at surgery, age at onset of epilepsy, pre- and postoperative IQ, side of hemispherectomy, duration of epilepsy and the postoperative seizure status 2 years after hemispherectomy. All patients were postoperatively enrolled in a local rehabilitation program.
Etiology-specific differences in motor function after hemispherectomy
223
Table 1 Demographics of the study population. Demographics are shown per etiology group (number of patients and male/female ratio are displayed at the top of the column) and p-values are given for between-etiology-group-comparisons. Age at onset of the epileptic seizures, age at surgery and consequent exposure time to epileptic seizures differ significantly between the etiology groups. ns = not significant.
Mean age at onset of seizures (years (SD)) Mean age at surgery (years (SD)) Mean exposure time (years (SD)) Mean IQ Preoperative (<50/50—90) Postoperative (<50/50—90) Side of surgery (R/L) Engel classification 2-years postoperatively (I/II/III/IV)
Developmental n = 13 (6/7)
Acquired n = 13 (7/6)
Progressive n = 9 (1/8)
p-Value
0.28 (0.361)
0.7 (0.72)
3.3 (4.0)
p = 0.025
1.53 (1.22)
5.1 (3.74)
7.0 (5.05)
p = 0.004
1.25 (1,07)
4.40 (3.73)
3.65 (2.89)
p = 0.015
8/5 6/5 (2 missing)
5/8 4/8 (1 missing) 7/6 10/0/2/1
3/6 3/6
ns ns
5/2 8/0/1/0
ns ns
7/6 12/1/0/0
The demographics of the study population are displayed in Table 1. Thirteen patients had early developmental disorders [seven with hemimegalencephaly (HME), five with cortical dysplasia (CD), and one child with an interhemispheric cystic malformation, bilateral colpocephaly and delayed myelination]. Thirteen had static and acquired lesions [six with periventricular hemorrhages, six with perinatally acquired ischemic cortico-subcortical lesions, and one child with hemispheric atrophy in the context of hemiconvulsion—hemiplegia—epilepsy syndrome (acquired at two years of age)]. Nine had progressive disorders [five with Rasmussen’s encephalitis, four with progressive atrophy and calcifications due to Sturge—Weber syndrome]. None of the four patients with Sturge—Weber syndrome had clear associated gyration abnormalities and all four had signs of progressive disease prior to surgery.
Surgical strategy of functional hemispherectomy The temporal operculum was removed by ultrasonic aspiration. The temporal horn of the lateral ventricle was opened, leaving intact the middle cerebral artery (MCA) branches emerging from the distal part of the Sylvian fissure. Next, the amygdala was aspirated and mesial frontotemporal tracts were disconnected reaching subpially the choroideal point. The frontal operculum was removed, and the frontal horn of the lateral ventricle was opened. The insular cortex was removed in 27 of the 35 patients, leaving intact the MCA branches. Last, an intraventricular callosotomy was performed using the anterior cerebral artery as a landmark and the tail of the hippocampus and the fornix were subpially transected.
Motor function assessment Motor impairments and gross motor function were assessed preoperatively and 2 years postoperatively for all patients by
the same experienced pediatric physical therapist (R.E.) in the outpatient clinic of the Wilhelmina Children’s Hospital. Muscle strength of arms and legs was measured according to the criteria for manual muscle testing using the 6-point Medical Research Council (MRC) scale (0 = no palpable muscle contraction; 1 = flicker or trace of contraction; isometric movement only, 2 = active movement with gravity eliminated, 3 = active movement against gravity, 4 = active movement against gravity and (some) resistance, 5 = normal power). The strength of the flexors and abductors of the shoulder and hip were measured and averaged as proximal arm and leg strength, respectively. The strength of the dorsal and palmar flexors of the wrist and the dorsal and plantar flexors of the ankle was measured and averaged as distal arm and leg strength, respectively. The individual MRC scores at pre- and postoperative follow-ups are compared and any change is considered as a decrease or increase. To evaluate gross motor function, we used the Gross Motor Function Measure (GMFM-88), which is a standardized clinical observational instrument designed to evaluate changes in gross motor function in children with cerebral palsy (Russell, 1989). It assesses how much of an activity a child can achieve, instead of how well it is performed. Based on differences in self-initiated movement, with particular emphasis on sitting and walking, motor disability of the children was allocated into one of the five classification levels of the Gross Motor Function Classification Score (GMFCS) at each assessment (Rosenbaum, 2008). To evaluate the motor function development during follow-up, the GMFM-88 scores of each child were compared with reference data available for motor development of children with cerebral palsy (CP) with the same age and motor disability (as indicated by their GMFCS level) (Russell et al., 2002; van Empelen et al., 2005). For both pre- and postoperative assessments, scores per etiology group were depicted in a boxplot against the reference line of their age- and GMFCS-matched CP counterparts in order to visualize the developmental progress per etiology group.
224 We reviewed the records of the treating pediatric neurologist and the physical therapist to assess the pre- and postoperative ability to walk, which was confirmed during the telephone interview with the parents. Preoperative data on walking ability were available for 23 of the 35 children (12 children were aged below two years at surgery and were therefore considered too young to be able to walk). Postoperative data on the ability to walk independently were available for all children.
Pre- and postsurgical hand function, in relation to analyses of preoperative MRIs We conducted a structured telephone interview (mean time after hemispherectomy 6 years and 9 months; range 2 years and 1 month to 12 years and 8 months) during which the parents were asked whether the child was able to voluntarily grasp an object from a table and utilize his/her affected hand at the time of the interview and before surgery. Preoperative data on hand function was available in 29 children; three were too young (i.e. younger than four months) to reliably judge their ability to grasp and parents of three patients could not recollect presurgical hand function. Postoperative data on hand function were available in 34 children (one child was lost to follow-up). Of the 29 children whose pre- and postoperative data on hand function were available, preoperative MRI scans were re-examined by an experienced child neurologist (M.S.) for indicators of ipsilesional corticospinal tract (CST) damage. Disruption of the ipsilesional corticospinal projections to the paretic hand was assumed when at least one of the following features were observed: (a) destruction of the ‘‘hand knob’’ region of the precentral gyrus, (b) cystic or gliotic destruction of the subcortical white matter between the ‘‘hand knob’’ and the posterior limb of the internal capsule, (c) destruction of the internal capsule, (d) severe brainstem asymmetry (Fig. 1). Asymmetry of the
N.M. van der Kolk et al. brain stem was assessed on axial MR images depicting the mesencephalon, the pons, and the medulla oblongata, and was graded as ‘‘severe’’ when the ipsilesional brainstem on any of these axial images showed a volume reduction of more than 1/3 compared with the contralesional side. The researcher was blinded for the pre- and postoperative motor function of the patients. We correlated (presumed) preoperative integrity versus disruption of the ipsilesional crossed corticospinal projections to the paretic hand, with loss versus preservation of grasping with the paretic hand after hemispherectomy.
Data analyses Cross-sectional analyses between etiology subgroups were performed for the preoperative and two years postoperative results, using a Kruskal—Wallis test, Chi-square or a Fisher exact test. Longitudinal comparison of the course of the motor function within each etiology group was done with the Wilcoxon Signed Ranks test. Determinants of the eventual functional motor outcome measures were assessed with logistic regression analysis. All statistical analyses were calculated using SPSS software [version 18.0]. P-values < 0.05 were considered statistically significant.
Results Muscle strength Before hemispherectomy patients with developmental etiologies had a significantly better distal arm and leg strength (p = 0.041 and p = 0.036, respectively) compared to the other patients (Fig. 2). Two years after hemispherectomy, muscle strength was significantly decreased compared to presurgical values in distal (p = 0.002) and proximal (p = 0.002) arm and distal leg muscles (p = 0.013) in children with developmental
Figure 1 Regions analyzed for CorticoSpinal Tract (CST) disruption. The following four regions were analyzed for signs of disruption of the corticospinal tract: (1) destruction of the ‘‘hand knob’’ region of the precentral gyrus. In (A) the hand knob on the right hemisphere is destroyed, whereas on the left side the hand knob region is intact (arrow). (2) Cystic or gliotic destruction of the subcortical white matter between the ‘‘hand knob’’ and the posterior limb of the internal capsule. In (B) the subcortical white matter of the left hemisphere is disrupted. (3) Destruction of the internal capsule, as is shown in the right hemisphere in (C). (4) Severe brain stem asymmetry as depicted in (D).
Etiology-specific differences in motor function after hemispherectomy
225
Figure 2 Error bar plots of preoperative and 2-year postoperative muscle strength. Preoperative distal arm and leg strength differs significantly between the three etiology groups (black brackets). Preoperative distal arm strength (top left plot) is significantly better compared to postoperative strength in patients with developmental (blue bars) and progressive etiologies (green bars). Preoperative proximal arm strength (top right plot) and distal leg strength (bottom left plot) is significantly better compared to postoperative strength in patients with developmental etiologies (blue brackets). No significant difference between pre- and postoperative strength within and between etiology groups were found for proximal leg strength (bottom right plot). Significant differences are indicated with the brackets; black for whole group comparisons, color-coded brackets correspond with the etiology groups and indicate differences between pre- and postoperative scores. *p < 0.05, **p < 0.01, ***p < 0.005. (left bars are blue, middle bars are red, and green bars are right in each plot). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
etiologies, and in distal arm muscles (p = 0.047) in patients with progressive etiologies. In patients with acquired etiologies, preoperative poor muscle strength was unaltered two years after surgery (Fig. 2). After surgery, the majority of the children (88.6%) had a poor distal arm strength (
Gross motor function Preoperatively, patients in the three etiology groups showed a similar developmental delay in gross motor
function compared to age-and GMFCS-matched CP counterparts (Fig. 3). Two years after surgery, gross motor development had significantly improved in patients with acquired (p = 0.013) and progressive etiologies (p = 0.021). Children with developmental etiologies had a significantly poorer development compared to the other two etiologies (p = 0.014). Both acquired and progressive etiologies performed at a similar level as their age- and GMFCS-matched counterparts, whereas patients with developmental etiologies still performed below their references (Fig. 3). The number of children able to walk independently before surgery (10 out of 23 children who were old enough to walk) did not differ significantly between the etiology groups (1 out of 5 developmental, 6 out of 11 acquired, and 3 out of
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N.M. van der Kolk et al.
Figure 3 GMFCS- and age-adjusted GMFM scores preoperative and 2 years postoperative. Reference values based on scores of CP children with the same age and GMFCS level were subtracted from the GMFM scores of the hemispherectomized children. If the hemispherectomized children score as well as their CP references they should obtain a score of 0, as is indicated with the reference line (gray dotted line). Preoperatively all children score below their CP reference scores, whereas 2 years after hemispherectomy a significant difference exists between the etiologies with the largest difference between the reference score and the actual score in the children with developmental etiologies.
7 progressive lesions). Two years after hemispherectomy 26 out of 35 patients (74.3%) were able to walk independently (8 with progressive disorders, 10 with acquired disorders and 8 with developmental etiologies; Table 2). None of the patients who were unable to walk postoperatively could walk prior to surgery (they were either too young to walk pre-operatively or they had never acquired the skills to walk before operation).
Pre- and postsurgical hand function, in relation to analyses of preoperative MRI’s Although preoperatively only 33% (4 out of 12) of the children with acquired lesions were able to grasp with their affected hand compared to 67—71% in the other 2 groups (6 out of 9 children with developmental lesions, 5 out of 7 children with progressive pathology), there was no significant difference between the etiology groups. Two years after hemispherectomy only 4 out of 34 patients (11.8%) were able to voluntarily grasp with their affected hand (two had hemimegalencephaly, one suffered from periventricular hemorrhage, and one had a perinatal ischemic stroke). Three of the 29 children, whose hand function was known both prior to and after surgery, were excluded for MRI analysis, because imaging was of insufficient quality, scans could not be retrieved, or pathology was bilateral. Therefore a total of 26 patients with unilateral pathology were included in the MRI analysis. Based on MRI analysis, a preoperative disruption of the ipsilesional (i.e. contralateral) corticospinal projections to the paretic hand was assumed in twelve patients, eleven with acquired lesions and one child with SWS. No changes in hand function were observed in any of these patients after surgery, including two patients (one with thalamic hemorrhagic stroke, one with perinatal ischemic stroke) who were able to voluntarily grasp before surgery and kept this
ability after hemispherectomy. From the remaining 14 patients whose corticospinal tracts were judged as presumably intact on preoperative MRI scans, nine had developmental etiology, one acquired pathology, and four children suffered from progressive disorders. Eleven of these 14 patients had voluntary hand function prior to surgery, ten lost hand function, and only one patient (hemimegencephaly) developed hand function anew in the years following surgery. Therefore, in children with preoperative hand function (n = 13), the risk of losing the ability to voluntarily grasp was 0% (0 out of 2 patients) when presurgical MRI revealed evidence of corticospinal tract disruption, and 91% (10 out of 11 patients) when no evidence for a disruption of the ipsilesional corticospinal tracts was seen on MRI.
Determinants of postoperative motor function All performed regression analyses are displayed in Table 2. Univariate regression modeling to study the possible determinants of postoperative decrease of distal arm strength, loss of hand function, and the inability to walk postoperatively, revealed that etiology (decrease distal arm strength p = 0.017), intact structural integrity of the ipsilesional corticospinal tract on presurgical MRI scans (loss of hand function p < 0.001), and intact insular cortex (loss of hand function p = 0.04) were significantly associated with postoperative loss of hand function or decrease in distal arm strength (Table 2A). All other clinical paramaters did not relate to these three motor outcome measures. Since etiology and age of surgery are, at least partially, codependent we also performed a bivariate regression analysis, which showed an independent significant effect of the time of occurrence of the epileptogenic lesion on deterioration of distal arm strength (Table 2B).
Etiology-specific differences in motor function after hemispherectomy
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Table 2 Determinants of postoperative motor outcome. (A) Depicts the univariate logistic regression analyses and (B) depicts the bivariate logistic regression analysis including etiology and age at surgery. Decrease of hand strength is defined as any decrease in MRC between postoperative (2-years after hemispherectomy) and preoperative values. No independent walking defines the patients that are unable to walk independently postoperatively. Loss of hand function postoperatively indicates the loss of the preoperative ability to voluntarily grasp. In both (A) and (B) etiology is analyzed as a 3-level categorical variable, using the developmental etiology group as a reference. Therefore the p-value’s stated after the total numbers indicate the overall significance of this variable, whereas the separate p-values for the two other etiology groups (besides the reference group) indicate whether the outcome measure is significantly different for the acquired or progressive etiologies compared to the reference group (developmental etiology). As stated in the methods, MRI analysis was performed in relation to loss of hand function only. Therefore analysis between CTS damage on preoperative MRI and decrease in distal arm strength or the postoperative inability to walk was not applicable (n.a.).. Decrease of distal arm strenth
No independent walking
Loss of hand function
Developmental (reference) Acquired Progressive Total Left Right Total Yes No Total Engel I Engel II, III, IV Total Yes No Total
12/13
5/13
5/9
4/13 (p = 0.006) 6/9 (p = 0.154) 22/35 (p = 0.017) 13/19 9/16 22/35 (p = 0.459) 17/27 5/8 22/35 (p = 0.981) 20/30 2/5 22/35 (p = 0.268) 3/12 17/20 n.a. p = 0.311 p = 0.210
3/13 (p = 0.399) 1/9 (p = 0.181) 9/35 (p = 0.370) 5/19 4/16 9/35 (p = 0.929) 7/27 2/8 (p = 0.958) 6/30 3/5 9/35 (p = 0.079) n.a. n.a. n.a. p = 0.118 p = 0.10
2/13 (p = 0.059) 5/7 (p = 0.518) 12/29 (p = 0.050) 6/16 6/13 12/29 (p = 0.638) 7/23 5/6 12/29 (p = 0.04) 10/24 2/5 12/29 (p = 0.945) 0/12 10/14 10/26 (p < 0.001)* p = 0.215 p = 0.341
Developmental (reference) Acquired Progressive Total
12/13
5/13
5/9
4/13 (p = 0.004) 6/9 (p = 0.085) 22/35 (p = 0.013) p = 0.311
3/13 (p = 0.843) 1/9 (p = 0.671) 9/35 (p = 0.857) p = 0.118
2/13 (p = 0.174) 5/7 (p = 0.222) 12/29 (p = 0.052) p = 0.215
(A) Univariate analysis Etiology (categorical)
Side of hemispherectomy Type of surgery (insulectomy)
Postoperative seizure status
CST damage on preoperative MRI Age at surgery Exposure time (B) Bivariate analysis Etiology (categorical)
Age at surgery *
Fisher’s exact test.
Discussion In our selected etiology cohorts, patients with developmental etiologies had better hand function and distal arm strength prior to surgery than those with other pathologies. After hemispherectomy, however, there was no difference in hand function or arm strength between the groups. Inherently, patients with developmental etiologies more often lost hand function and muscle strength following hemispherectomy. Interestingly, although muscle strength after surgery did not differ between the etiology groups, gross motor development improved two years postoperatively in patients with perinatally acquired or progressive lesions, whereas developmental delay persisted in children with
developmental lesions. This could be explained by the bilateral character of the underlying pathology in patients with developmental etiologies, which also disturbs the structural and functional integrity of the remaining ‘‘healthy’’ hemisphere. Indeed, both structural (Jahan, 1997; Salamon et al., 2006) and functional contralateral abnormalities have been reported previously in hemimegalencephaly (Soufflet et al., 2004; Salamon et al., 2006), the pathology that constitutes more than half of our developmental etiology group. It has previously been shown that higher motor scores after hemispherectomy were correlated with higher scores on language and cognitive developmental tests (Jonas, 2004). Moreover, language and speech delay in otherwise healthy children often coincides with fine and gross motor problems
228 (Muursepp et al., 2009). Therefore, a delay in gross motor function is considered to be part of an overall developmental delay or maturational lag and probably reflects the diffuse pathology that also affects the presumed healthy hemisphere. Although the surgical treatment of epilepsy clearly had a positive effect on gross motor function, at least in patients with acquired and progressive etiologies, the exposure time to epileptic seizures preoperatively did not influence postoperative hand function or the ability to walk. Possibly, not the total duration of the exposure to seizures, but rather the existence of an epileptic encephalopathy, that is interrupted by hemispherectomy, influences gross motor development. Altogether, this clear postoperative improvement in gross motor function in children with acquired and progressive pathologies should be weighted carefully against the theoretical risk of increased hand motor deficits, in the prediction of postsurgical motor recovery and in the pre-operative counseling of parents. Contrary to the gross motor function the prognosis of hand function after hemispherectomy appears to be poor. The deterioration of arm strength and hand function in patients with developmental etiologies after hemispherectomy suggests that the dysgenic cortex is not necessarily devoid of function. This has also been previously shown by functional imaging studies in patients with cortical malformations (Preul et al., 1997; Marusic et al., 2002; Burneo et al., 2004; Staudt, 2004b; Vitali et al., 2008) and several studies on the innervation pathways of the affected hand in patients with malformations of cortical development reported both ipsilateral (Maegaki et al., 1995; Macdonell et al., 1999; Vandermeeren et al., 2002; Staudt, 2002) and contralateral innervation of the hand (Preul et al., 1997; Nezu et al., 1999; Vandermeeren et al., 2002; Staudt, 2004b). Obviously both the extent and location of the hemispheric dysgenesis or damage will influence the remaining activity of the affected motor tracts. In addition, the timeframe during which the pathology evolves may also contribute to the degree of functional deficits; acute vascular pathology will leave no time for compensatory strategies and may therefore result in loss of function, whereas slowly evolving cortical malformations may allow the motor system to compensate resulting in preservation of function. The maintenance of ipsilateral corticospinal projections during ontogeny is determined by the amount of activity in the damaged hemisphere (Staudt, 2004a; Eyre, 2007). This activity-dependent competition results in atrophy of either one of the tracts, and starts around the time when the first corticospinal projections reach the spinal cord in the 24th week of gestation (Eyre, 2007). When damage to the motor cortices occurs (far) after this competition takes place, the ipsilateral motor control of distal muscles is limited. The exact timeline for this competition remains to be elucidated but it is suggested that it mainly takes place in the final trimester of pregnancy (Eyre, 2007). Imaginably, patients with developmental etiologies and a preserved crossed corticospinal tract are at risk of losing function after surgery. In our cohort of patients with developmental etiologies the majority probably still had contralateral motor control, because hand function decreased after surgery. In bivariate analysis, etiology was significantly associated with postoperative decrease of strength and function, independent of age at surgery. However, a minor effect of age at surgery on
N.M. van der Kolk et al. motor outcome cannot be fully excluded due to the limited number of patients per etiology group in this study. A systematic evaluation of the corticospinal tracts on preoperative MRI’s can provide a relatively good estimate of the extent and location of the damage to the corticospinal tracts, which in turn correlates well with the postoperative outcome. In addition to the visual analysis of structural MRI as performed in this study, further information about the integrity of crossed corticospinal pathways and the presence of ipsilateral corticospinal pathways can be obtained from MR diffusion tensor tractography and transcranial magnetic stimulation. Indeed, there are first reports of their usefulness in the prediction of motor outcome after hemispherectomy (Shimizu et al., 2000; Staudt, 2004a; Eyre, 2007; Koudijs et al., 2010). In our opinion, these techniques should nowadays be used in patients prior to possible hemispherectomy, in order to optimally characterize their individual corticospinal motor systems, and to gain experience in the usefulness of these diagnostic tools for the prediction of postoperative motor outcome.
Limitations This study has two important limitations. First, the data on both the pre- and postoperative hand function (i.e. the ability to grasp) was gathered retrospectively by telephone interview, which can lead to recall bias. Second, the observed differences between the three etiology groups are subject to selection bias due to different weighing of arguments in the decision making toward hemispherectomy. Many patients with developmental lesions had early-onset catastrophic epilepsies, and an early operation was often considered the only option, even if a higher risk of postoperative motor deterioration had to be accepted. Similarly, in patients with progressive lesions, a deterioration of motor functions could be predicted during the natural course of their disease anyhow; therefore, their higher risk of motor deterioration by the operation itself could be accepted more readily. This situation is different in the patients with acquired lesions: their lesions are static, so that a stable motor function in the natural course must be assumed (as opposed to the patients with progressive lesions), and their epilepsies often do not start as early as in the patients with developmental lesions. Therefore, hemispherectomy in this subgroup is often only considered in patients with already severe hemiparesis, who have ‘‘nothing to lose’’ in terms of motor function. In this scenario, it is tempting to speculate that in the future, when hopefully a better prediction of a preservation of hand function post hemispherectomy becomes available, this surgical treatment will be offered to more patients with acquired pathologies and relatively good motor function.
Conclusions Many parents and patients move forward with hemispherectomy knowing that there may be an increase in motor deficits in exchange for the possible benefits of seizure relief. However, to what extent motor function deteriorates is difficult to predict, leaving parents uncertain about their child’s
Etiology-specific differences in motor function after hemispherectomy future. Our results show that the amount of motor function that is lost differs per etiology group and, more importantly, that certain etiology groups, despite a decrease in hand function and strength, improve in gross motor function development. The loss of muscle strength and hand function can be more precisely predicted by analyzing the integrity of crossed corticospinal pathways on presurgical MRI scans.
Acknowledgement This work was supported by the Epilepsy Fund of the Netherlands [NEF 08-10 to K.B. and K.P.J.B.].
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journal homepage: www.elsevier.com/locate/epilepsyres
Etiology-specific differences in motor function after hemispherectomy Nicolien M. van der Kolk a,b,1, Kim Boshuisen b,2, Ron van Empelen c,3, Suzanne M. Koudijs b,2, Martin Staudt d,e, Peter C. van Rijen f,4, Onno van Nieuwenhuizen b,2, Kees P.J. Braun b,∗,2 a
Department of Neurology, Radboud University Nijmegen Medical Center, PO Box 9101, 6500HB Nijmegen, The Netherlands Rudolf Magnus Institute of Neuroscience, Department of Child Neurology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands c Child Development and Exercise Center, Division of Paediatrics, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands d Clinic for Neuropaediatrics and Neurorehabilitation, Epilepsy Center for Children and Adolescents, Schön-Klinik Vogtareuth, 83209 Priem am Chiemsee, Germany e Department of Paediatric Neurology and Developmental Medicine, University Children’s Hospital, Tübingen, Germany f Rudolf Magnus Institute of Neuroscience, Department of Neurosurgery, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands b
Received 19 March 2012; received in revised form 4 August 2012; accepted 19 August 2012 Available online 11 September 2012
KEYWORDS Functional hemispherectomy; Motor function; Etiology
Summary Prediction of functional motor outcome after hemispherectomy is difficult due to the heterogeneity of motor outcomes observed. We hypothesize that this might be related to differences in plasticity during the onset of the underlying epileptogenic disorder or lesion and try to identify predictors of motor outcome after hemispherectomy. Thirty-five children with different etiologies (developmental, stable acquired or progressive) underwent functional hemispherectomy and motor function assessment before hemispherectomy and 24 months after hemispherectomy. Preoperatively, children with developmental etiologies performed better in terms of distal arm strength and hand function, but not on gross motor function tests. Postoperatively, the three etiology groups performed equally poor in muscle strength and hand function, but gross motor
∗
Corresponding author. Tel.: +31 887554003; fax: +31 887555350. E-mail addresses: [email protected] (N.M. van der Kolk), [email protected] (K. Boshuisen), [email protected] (R. van Empelen), [email protected] (S.M. Koudijs), [email protected] (M. Staudt), [email protected] (P.C. van Rijen), [email protected] (O. van Nieuwenhuizen), [email protected] (K.P.J. Braun). 1 Tel.: +31 243613396; fax: +31 243541122. 2 Tel.: +31 887554003; fax: +31 887555350. 3 Tel.: +31 887554030; fax: +31 887555333. 4 Tel.: +31 88-7557977; fax: +31 302542100. 0920-1211/$ — see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.eplepsyres.2012.08.007
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N.M. van der Kolk et al. function improved in those with acquired and progressive etiologies. Loss of voluntary hand function and distal arm strength after surgery was associated with etiology, intact insular cortex and intact structural integrity of the ipsilesional corticospinal tract on presurgical MRI scans. In conclusion, postoperative motor function can be predicted more precisely based on etiology and on preoperative MRI. Children with developmental etiology more often lose distal arm strength and hand function and show less improvement in gross motor function, compared to those with acquired pathology. © 2012 Elsevier B.V. All rights reserved.
Introduction Functional hemispherectomy is a successful treatment for catastrophic childhood epilepsy caused by hemispheric or unilateral multilobar epileptogenic lesions. The spectrum of neurological deficits that occur after surgery shows a great, and thus far largely unexplained, variance among the operated children, making it difficult to predict functional outcome for individual patients. Consistent with conventional ideas about the neuroanatomy of motor pathways (Kandel et al., 2000), the obligatory ipsilateral corticospinal control of motor function after hemispherectomy is characterized by a hemiparesis in which the arm is more affected than the trunk or leg, with a distal-proximal gradient within the extremities (van Empelen et al., 2004). Nevertheless, hand function after hemispherectomy can vary from no functional use, to the preservation of some functions such as grasping or even individual finger movements (Holthausen et al., 1997; Holloway et al., 2000; Staudt, 2002; Devlin et al., 2003; de Bode et al., 2005). Although strengthening of ipsilateral corticospinal and corticoreticulospinal connections has been assumed to be a major mechanism associated with partial recovery after brain damage (Staudt, 2004a; Benecke, 1991), the heterogeneity of motor outcomes observed after hemispherectomy indicates that the quality of ipsilateral motor control varies. This may be attributed to differences in reorganizational capacity or plasticity, which is more powerful in the immature nervous system than in the adult brain (Kennard, 1936). In addition, hand function in patients with congenital hemiparesis depending on ipsilateral corticospinal pathways was inversely correlated to the timing of brain lesions or malformations acquired at different gestational ages (Staudt, 2004a). Children who undergo hemispherectomy suffer brain damage during two separate events: during the structural development of the epileptogenic disorder and during the surgery. Given the decrease in reorganizational capacity during maturation, it is likely that the first occurring event has the highest potential of influencing motor outcome. Indeed, a linear and independent correlation between age at surgery and postoperative hand function is lacking and both supportive and contradictive studies have been reported (Muller et al., 1991; Graveline, 1999; Cukiert et al., 2009). Holthausen et al. (1997) was the first to report that the type of the underlying pathology (i.e. the timing of its ontogeny) might be more important than the age at surgery. Results of the relatively few studies that address the age at ontogeny of the epileptogenic disorder in relation to motor outcome after hemispherectomy, are inconsistent (Holthausen et al., 1997; Devlin et al., 2003; de Bode
et al., 2005; Lettori, 2008). Our previous study on motor outcome in twelve children after hemispherectomy suggested a specific time course of motor recovery for different body areas. The influence of underlying pathology was not assessed (van Empelen et al., 2004). In this study we aim to assess time course of motor function recovery of specifically the upper extremity (hand) and of gross motor function in relation to the underlying etiology (as an indication for the time during which the first brain damage occurred) in a large cohort of children who underwent functional hemispherectomy.
Methods This is a retrospective consecutive cohort study of 35 children who underwent functional hemispherectomy for medically intractable hemispheric epilepsy between 1996 and 2007 in the Wilhelmina Children’s Hospital, and in whom longitudinal standardized investigations of motor function were performed. The study was approved by the medical ethical and research committee of the University Medical Center Utrecht, and written informed consent was given by all parents.
Patients Thirty-five children were elected by the Dutch Collaborative Epilepsy Surgery Program to undergo functional hemispherectomy and were included in the standardized follow-up investigations (a subset of this population has been subject to previous functional outcome studies (van Empelen et al., 2004)). The underlying pathology was ascertained mainly from Magnetic Resonance Imaging (MRI) and infrequently from pathologic examination of surgery specimens, when available. Patients were classified according to their pathology, as previously described (Devlin et al., 2003), into three etiological subgroups that also indicated the ontogeny of their epileptogenic condition: ‘developmental’ (hemimegalencephaly, cortical dysplasia or other), ‘acquired’ (stable and non-progressive brain lesions, occurring perinatally or early in postnatal life, mostly consisting of ischemic or hemorrhagic pathology) or ‘progressive’ (Rasmussen’s encephalitis or Sturge—Weber Syndrome). From the patients’ records, we collected age at surgery, age at onset of epilepsy, pre- and postoperative IQ, side of hemispherectomy, duration of epilepsy and the postoperative seizure status 2 years after hemispherectomy. All patients were postoperatively enrolled in a local rehabilitation program.
Etiology-specific differences in motor function after hemispherectomy
223
Table 1 Demographics of the study population. Demographics are shown per etiology group (number of patients and male/female ratio are displayed at the top of the column) and p-values are given for between-etiology-group-comparisons. Age at onset of the epileptic seizures, age at surgery and consequent exposure time to epileptic seizures differ significantly between the etiology groups. ns = not significant.
Mean age at onset of seizures (years (SD)) Mean age at surgery (years (SD)) Mean exposure time (years (SD)) Mean IQ Preoperative (<50/50—90) Postoperative (<50/50—90) Side of surgery (R/L) Engel classification 2-years postoperatively (I/II/III/IV)
Developmental n = 13 (6/7)
Acquired n = 13 (7/6)
Progressive n = 9 (1/8)
p-Value
0.28 (0.361)
0.7 (0.72)
3.3 (4.0)
p = 0.025
1.53 (1.22)
5.1 (3.74)
7.0 (5.05)
p = 0.004
1.25 (1,07)
4.40 (3.73)
3.65 (2.89)
p = 0.015
8/5 6/5 (2 missing)
5/8 4/8 (1 missing) 7/6 10/0/2/1
3/6 3/6
ns ns
5/2 8/0/1/0
ns ns
7/6 12/1/0/0
The demographics of the study population are displayed in Table 1. Thirteen patients had early developmental disorders [seven with hemimegalencephaly (HME), five with cortical dysplasia (CD), and one child with an interhemispheric cystic malformation, bilateral colpocephaly and delayed myelination]. Thirteen had static and acquired lesions [six with periventricular hemorrhages, six with perinatally acquired ischemic cortico-subcortical lesions, and one child with hemispheric atrophy in the context of hemiconvulsion—hemiplegia—epilepsy syndrome (acquired at two years of age)]. Nine had progressive disorders [five with Rasmussen’s encephalitis, four with progressive atrophy and calcifications due to Sturge—Weber syndrome]. None of the four patients with Sturge—Weber syndrome had clear associated gyration abnormalities and all four had signs of progressive disease prior to surgery.
Surgical strategy of functional hemispherectomy The temporal operculum was removed by ultrasonic aspiration. The temporal horn of the lateral ventricle was opened, leaving intact the middle cerebral artery (MCA) branches emerging from the distal part of the Sylvian fissure. Next, the amygdala was aspirated and mesial frontotemporal tracts were disconnected reaching subpially the choroideal point. The frontal operculum was removed, and the frontal horn of the lateral ventricle was opened. The insular cortex was removed in 27 of the 35 patients, leaving intact the MCA branches. Last, an intraventricular callosotomy was performed using the anterior cerebral artery as a landmark and the tail of the hippocampus and the fornix were subpially transected.
Motor function assessment Motor impairments and gross motor function were assessed preoperatively and 2 years postoperatively for all patients by
the same experienced pediatric physical therapist (R.E.) in the outpatient clinic of the Wilhelmina Children’s Hospital. Muscle strength of arms and legs was measured according to the criteria for manual muscle testing using the 6-point Medical Research Council (MRC) scale (0 = no palpable muscle contraction; 1 = flicker or trace of contraction; isometric movement only, 2 = active movement with gravity eliminated, 3 = active movement against gravity, 4 = active movement against gravity and (some) resistance, 5 = normal power). The strength of the flexors and abductors of the shoulder and hip were measured and averaged as proximal arm and leg strength, respectively. The strength of the dorsal and palmar flexors of the wrist and the dorsal and plantar flexors of the ankle was measured and averaged as distal arm and leg strength, respectively. The individual MRC scores at pre- and postoperative follow-ups are compared and any change is considered as a decrease or increase. To evaluate gross motor function, we used the Gross Motor Function Measure (GMFM-88), which is a standardized clinical observational instrument designed to evaluate changes in gross motor function in children with cerebral palsy (Russell, 1989). It assesses how much of an activity a child can achieve, instead of how well it is performed. Based on differences in self-initiated movement, with particular emphasis on sitting and walking, motor disability of the children was allocated into one of the five classification levels of the Gross Motor Function Classification Score (GMFCS) at each assessment (Rosenbaum, 2008). To evaluate the motor function development during follow-up, the GMFM-88 scores of each child were compared with reference data available for motor development of children with cerebral palsy (CP) with the same age and motor disability (as indicated by their GMFCS level) (Russell et al., 2002; van Empelen et al., 2005). For both pre- and postoperative assessments, scores per etiology group were depicted in a boxplot against the reference line of their age- and GMFCS-matched CP counterparts in order to visualize the developmental progress per etiology group.
224 We reviewed the records of the treating pediatric neurologist and the physical therapist to assess the pre- and postoperative ability to walk, which was confirmed during the telephone interview with the parents. Preoperative data on walking ability were available for 23 of the 35 children (12 children were aged below two years at surgery and were therefore considered too young to be able to walk). Postoperative data on the ability to walk independently were available for all children.
Pre- and postsurgical hand function, in relation to analyses of preoperative MRIs We conducted a structured telephone interview (mean time after hemispherectomy 6 years and 9 months; range 2 years and 1 month to 12 years and 8 months) during which the parents were asked whether the child was able to voluntarily grasp an object from a table and utilize his/her affected hand at the time of the interview and before surgery. Preoperative data on hand function was available in 29 children; three were too young (i.e. younger than four months) to reliably judge their ability to grasp and parents of three patients could not recollect presurgical hand function. Postoperative data on hand function were available in 34 children (one child was lost to follow-up). Of the 29 children whose pre- and postoperative data on hand function were available, preoperative MRI scans were re-examined by an experienced child neurologist (M.S.) for indicators of ipsilesional corticospinal tract (CST) damage. Disruption of the ipsilesional corticospinal projections to the paretic hand was assumed when at least one of the following features were observed: (a) destruction of the ‘‘hand knob’’ region of the precentral gyrus, (b) cystic or gliotic destruction of the subcortical white matter between the ‘‘hand knob’’ and the posterior limb of the internal capsule, (c) destruction of the internal capsule, (d) severe brainstem asymmetry (Fig. 1). Asymmetry of the
N.M. van der Kolk et al. brain stem was assessed on axial MR images depicting the mesencephalon, the pons, and the medulla oblongata, and was graded as ‘‘severe’’ when the ipsilesional brainstem on any of these axial images showed a volume reduction of more than 1/3 compared with the contralesional side. The researcher was blinded for the pre- and postoperative motor function of the patients. We correlated (presumed) preoperative integrity versus disruption of the ipsilesional crossed corticospinal projections to the paretic hand, with loss versus preservation of grasping with the paretic hand after hemispherectomy.
Data analyses Cross-sectional analyses between etiology subgroups were performed for the preoperative and two years postoperative results, using a Kruskal—Wallis test, Chi-square or a Fisher exact test. Longitudinal comparison of the course of the motor function within each etiology group was done with the Wilcoxon Signed Ranks test. Determinants of the eventual functional motor outcome measures were assessed with logistic regression analysis. All statistical analyses were calculated using SPSS software [version 18.0]. P-values < 0.05 were considered statistically significant.
Results Muscle strength Before hemispherectomy patients with developmental etiologies had a significantly better distal arm and leg strength (p = 0.041 and p = 0.036, respectively) compared to the other patients (Fig. 2). Two years after hemispherectomy, muscle strength was significantly decreased compared to presurgical values in distal (p = 0.002) and proximal (p = 0.002) arm and distal leg muscles (p = 0.013) in children with developmental
Figure 1 Regions analyzed for CorticoSpinal Tract (CST) disruption. The following four regions were analyzed for signs of disruption of the corticospinal tract: (1) destruction of the ‘‘hand knob’’ region of the precentral gyrus. In (A) the hand knob on the right hemisphere is destroyed, whereas on the left side the hand knob region is intact (arrow). (2) Cystic or gliotic destruction of the subcortical white matter between the ‘‘hand knob’’ and the posterior limb of the internal capsule. In (B) the subcortical white matter of the left hemisphere is disrupted. (3) Destruction of the internal capsule, as is shown in the right hemisphere in (C). (4) Severe brain stem asymmetry as depicted in (D).
Etiology-specific differences in motor function after hemispherectomy
225
Figure 2 Error bar plots of preoperative and 2-year postoperative muscle strength. Preoperative distal arm and leg strength differs significantly between the three etiology groups (black brackets). Preoperative distal arm strength (top left plot) is significantly better compared to postoperative strength in patients with developmental (blue bars) and progressive etiologies (green bars). Preoperative proximal arm strength (top right plot) and distal leg strength (bottom left plot) is significantly better compared to postoperative strength in patients with developmental etiologies (blue brackets). No significant difference between pre- and postoperative strength within and between etiology groups were found for proximal leg strength (bottom right plot). Significant differences are indicated with the brackets; black for whole group comparisons, color-coded brackets correspond with the etiology groups and indicate differences between pre- and postoperative scores. *p < 0.05, **p < 0.01, ***p < 0.005. (left bars are blue, middle bars are red, and green bars are right in each plot). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
etiologies, and in distal arm muscles (p = 0.047) in patients with progressive etiologies. In patients with acquired etiologies, preoperative poor muscle strength was unaltered two years after surgery (Fig. 2). After surgery, the majority of the children (88.6%) had a poor distal arm strength (
Gross motor function Preoperatively, patients in the three etiology groups showed a similar developmental delay in gross motor
function compared to age-and GMFCS-matched CP counterparts (Fig. 3). Two years after surgery, gross motor development had significantly improved in patients with acquired (p = 0.013) and progressive etiologies (p = 0.021). Children with developmental etiologies had a significantly poorer development compared to the other two etiologies (p = 0.014). Both acquired and progressive etiologies performed at a similar level as their age- and GMFCS-matched counterparts, whereas patients with developmental etiologies still performed below their references (Fig. 3). The number of children able to walk independently before surgery (10 out of 23 children who were old enough to walk) did not differ significantly between the etiology groups (1 out of 5 developmental, 6 out of 11 acquired, and 3 out of
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Figure 3 GMFCS- and age-adjusted GMFM scores preoperative and 2 years postoperative. Reference values based on scores of CP children with the same age and GMFCS level were subtracted from the GMFM scores of the hemispherectomized children. If the hemispherectomized children score as well as their CP references they should obtain a score of 0, as is indicated with the reference line (gray dotted line). Preoperatively all children score below their CP reference scores, whereas 2 years after hemispherectomy a significant difference exists between the etiologies with the largest difference between the reference score and the actual score in the children with developmental etiologies.
7 progressive lesions). Two years after hemispherectomy 26 out of 35 patients (74.3%) were able to walk independently (8 with progressive disorders, 10 with acquired disorders and 8 with developmental etiologies; Table 2). None of the patients who were unable to walk postoperatively could walk prior to surgery (they were either too young to walk pre-operatively or they had never acquired the skills to walk before operation).
Pre- and postsurgical hand function, in relation to analyses of preoperative MRI’s Although preoperatively only 33% (4 out of 12) of the children with acquired lesions were able to grasp with their affected hand compared to 67—71% in the other 2 groups (6 out of 9 children with developmental lesions, 5 out of 7 children with progressive pathology), there was no significant difference between the etiology groups. Two years after hemispherectomy only 4 out of 34 patients (11.8%) were able to voluntarily grasp with their affected hand (two had hemimegalencephaly, one suffered from periventricular hemorrhage, and one had a perinatal ischemic stroke). Three of the 29 children, whose hand function was known both prior to and after surgery, were excluded for MRI analysis, because imaging was of insufficient quality, scans could not be retrieved, or pathology was bilateral. Therefore a total of 26 patients with unilateral pathology were included in the MRI analysis. Based on MRI analysis, a preoperative disruption of the ipsilesional (i.e. contralateral) corticospinal projections to the paretic hand was assumed in twelve patients, eleven with acquired lesions and one child with SWS. No changes in hand function were observed in any of these patients after surgery, including two patients (one with thalamic hemorrhagic stroke, one with perinatal ischemic stroke) who were able to voluntarily grasp before surgery and kept this
ability after hemispherectomy. From the remaining 14 patients whose corticospinal tracts were judged as presumably intact on preoperative MRI scans, nine had developmental etiology, one acquired pathology, and four children suffered from progressive disorders. Eleven of these 14 patients had voluntary hand function prior to surgery, ten lost hand function, and only one patient (hemimegencephaly) developed hand function anew in the years following surgery. Therefore, in children with preoperative hand function (n = 13), the risk of losing the ability to voluntarily grasp was 0% (0 out of 2 patients) when presurgical MRI revealed evidence of corticospinal tract disruption, and 91% (10 out of 11 patients) when no evidence for a disruption of the ipsilesional corticospinal tracts was seen on MRI.
Determinants of postoperative motor function All performed regression analyses are displayed in Table 2. Univariate regression modeling to study the possible determinants of postoperative decrease of distal arm strength, loss of hand function, and the inability to walk postoperatively, revealed that etiology (decrease distal arm strength p = 0.017), intact structural integrity of the ipsilesional corticospinal tract on presurgical MRI scans (loss of hand function p < 0.001), and intact insular cortex (loss of hand function p = 0.04) were significantly associated with postoperative loss of hand function or decrease in distal arm strength (Table 2A). All other clinical paramaters did not relate to these three motor outcome measures. Since etiology and age of surgery are, at least partially, codependent we also performed a bivariate regression analysis, which showed an independent significant effect of the time of occurrence of the epileptogenic lesion on deterioration of distal arm strength (Table 2B).
Etiology-specific differences in motor function after hemispherectomy
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Table 2 Determinants of postoperative motor outcome. (A) Depicts the univariate logistic regression analyses and (B) depicts the bivariate logistic regression analysis including etiology and age at surgery. Decrease of hand strength is defined as any decrease in MRC between postoperative (2-years after hemispherectomy) and preoperative values. No independent walking defines the patients that are unable to walk independently postoperatively. Loss of hand function postoperatively indicates the loss of the preoperative ability to voluntarily grasp. In both (A) and (B) etiology is analyzed as a 3-level categorical variable, using the developmental etiology group as a reference. Therefore the p-value’s stated after the total numbers indicate the overall significance of this variable, whereas the separate p-values for the two other etiology groups (besides the reference group) indicate whether the outcome measure is significantly different for the acquired or progressive etiologies compared to the reference group (developmental etiology). As stated in the methods, MRI analysis was performed in relation to loss of hand function only. Therefore analysis between CTS damage on preoperative MRI and decrease in distal arm strength or the postoperative inability to walk was not applicable (n.a.).. Decrease of distal arm strenth
No independent walking
Loss of hand function
Developmental (reference) Acquired Progressive Total Left Right Total Yes No Total Engel I Engel II, III, IV Total Yes No Total
12/13
5/13
5/9
4/13 (p = 0.006) 6/9 (p = 0.154) 22/35 (p = 0.017) 13/19 9/16 22/35 (p = 0.459) 17/27 5/8 22/35 (p = 0.981) 20/30 2/5 22/35 (p = 0.268) 3/12 17/20 n.a. p = 0.311 p = 0.210
3/13 (p = 0.399) 1/9 (p = 0.181) 9/35 (p = 0.370) 5/19 4/16 9/35 (p = 0.929) 7/27 2/8 (p = 0.958) 6/30 3/5 9/35 (p = 0.079) n.a. n.a. n.a. p = 0.118 p = 0.10
2/13 (p = 0.059) 5/7 (p = 0.518) 12/29 (p = 0.050) 6/16 6/13 12/29 (p = 0.638) 7/23 5/6 12/29 (p = 0.04) 10/24 2/5 12/29 (p = 0.945) 0/12 10/14 10/26 (p < 0.001)* p = 0.215 p = 0.341
Developmental (reference) Acquired Progressive Total
12/13
5/13
5/9
4/13 (p = 0.004) 6/9 (p = 0.085) 22/35 (p = 0.013) p = 0.311
3/13 (p = 0.843) 1/9 (p = 0.671) 9/35 (p = 0.857) p = 0.118
2/13 (p = 0.174) 5/7 (p = 0.222) 12/29 (p = 0.052) p = 0.215
(A) Univariate analysis Etiology (categorical)
Side of hemispherectomy Type of surgery (insulectomy)
Postoperative seizure status
CST damage on preoperative MRI Age at surgery Exposure time (B) Bivariate analysis Etiology (categorical)
Age at surgery *
Fisher’s exact test.
Discussion In our selected etiology cohorts, patients with developmental etiologies had better hand function and distal arm strength prior to surgery than those with other pathologies. After hemispherectomy, however, there was no difference in hand function or arm strength between the groups. Inherently, patients with developmental etiologies more often lost hand function and muscle strength following hemispherectomy. Interestingly, although muscle strength after surgery did not differ between the etiology groups, gross motor development improved two years postoperatively in patients with perinatally acquired or progressive lesions, whereas developmental delay persisted in children with
developmental lesions. This could be explained by the bilateral character of the underlying pathology in patients with developmental etiologies, which also disturbs the structural and functional integrity of the remaining ‘‘healthy’’ hemisphere. Indeed, both structural (Jahan, 1997; Salamon et al., 2006) and functional contralateral abnormalities have been reported previously in hemimegalencephaly (Soufflet et al., 2004; Salamon et al., 2006), the pathology that constitutes more than half of our developmental etiology group. It has previously been shown that higher motor scores after hemispherectomy were correlated with higher scores on language and cognitive developmental tests (Jonas, 2004). Moreover, language and speech delay in otherwise healthy children often coincides with fine and gross motor problems
228 (Muursepp et al., 2009). Therefore, a delay in gross motor function is considered to be part of an overall developmental delay or maturational lag and probably reflects the diffuse pathology that also affects the presumed healthy hemisphere. Although the surgical treatment of epilepsy clearly had a positive effect on gross motor function, at least in patients with acquired and progressive etiologies, the exposure time to epileptic seizures preoperatively did not influence postoperative hand function or the ability to walk. Possibly, not the total duration of the exposure to seizures, but rather the existence of an epileptic encephalopathy, that is interrupted by hemispherectomy, influences gross motor development. Altogether, this clear postoperative improvement in gross motor function in children with acquired and progressive pathologies should be weighted carefully against the theoretical risk of increased hand motor deficits, in the prediction of postsurgical motor recovery and in the pre-operative counseling of parents. Contrary to the gross motor function the prognosis of hand function after hemispherectomy appears to be poor. The deterioration of arm strength and hand function in patients with developmental etiologies after hemispherectomy suggests that the dysgenic cortex is not necessarily devoid of function. This has also been previously shown by functional imaging studies in patients with cortical malformations (Preul et al., 1997; Marusic et al., 2002; Burneo et al., 2004; Staudt, 2004b; Vitali et al., 2008) and several studies on the innervation pathways of the affected hand in patients with malformations of cortical development reported both ipsilateral (Maegaki et al., 1995; Macdonell et al., 1999; Vandermeeren et al., 2002; Staudt, 2002) and contralateral innervation of the hand (Preul et al., 1997; Nezu et al., 1999; Vandermeeren et al., 2002; Staudt, 2004b). Obviously both the extent and location of the hemispheric dysgenesis or damage will influence the remaining activity of the affected motor tracts. In addition, the timeframe during which the pathology evolves may also contribute to the degree of functional deficits; acute vascular pathology will leave no time for compensatory strategies and may therefore result in loss of function, whereas slowly evolving cortical malformations may allow the motor system to compensate resulting in preservation of function. The maintenance of ipsilateral corticospinal projections during ontogeny is determined by the amount of activity in the damaged hemisphere (Staudt, 2004a; Eyre, 2007). This activity-dependent competition results in atrophy of either one of the tracts, and starts around the time when the first corticospinal projections reach the spinal cord in the 24th week of gestation (Eyre, 2007). When damage to the motor cortices occurs (far) after this competition takes place, the ipsilateral motor control of distal muscles is limited. The exact timeline for this competition remains to be elucidated but it is suggested that it mainly takes place in the final trimester of pregnancy (Eyre, 2007). Imaginably, patients with developmental etiologies and a preserved crossed corticospinal tract are at risk of losing function after surgery. In our cohort of patients with developmental etiologies the majority probably still had contralateral motor control, because hand function decreased after surgery. In bivariate analysis, etiology was significantly associated with postoperative decrease of strength and function, independent of age at surgery. However, a minor effect of age at surgery on
N.M. van der Kolk et al. motor outcome cannot be fully excluded due to the limited number of patients per etiology group in this study. A systematic evaluation of the corticospinal tracts on preoperative MRI’s can provide a relatively good estimate of the extent and location of the damage to the corticospinal tracts, which in turn correlates well with the postoperative outcome. In addition to the visual analysis of structural MRI as performed in this study, further information about the integrity of crossed corticospinal pathways and the presence of ipsilateral corticospinal pathways can be obtained from MR diffusion tensor tractography and transcranial magnetic stimulation. Indeed, there are first reports of their usefulness in the prediction of motor outcome after hemispherectomy (Shimizu et al., 2000; Staudt, 2004a; Eyre, 2007; Koudijs et al., 2010). In our opinion, these techniques should nowadays be used in patients prior to possible hemispherectomy, in order to optimally characterize their individual corticospinal motor systems, and to gain experience in the usefulness of these diagnostic tools for the prediction of postoperative motor outcome.
Limitations This study has two important limitations. First, the data on both the pre- and postoperative hand function (i.e. the ability to grasp) was gathered retrospectively by telephone interview, which can lead to recall bias. Second, the observed differences between the three etiology groups are subject to selection bias due to different weighing of arguments in the decision making toward hemispherectomy. Many patients with developmental lesions had early-onset catastrophic epilepsies, and an early operation was often considered the only option, even if a higher risk of postoperative motor deterioration had to be accepted. Similarly, in patients with progressive lesions, a deterioration of motor functions could be predicted during the natural course of their disease anyhow; therefore, their higher risk of motor deterioration by the operation itself could be accepted more readily. This situation is different in the patients with acquired lesions: their lesions are static, so that a stable motor function in the natural course must be assumed (as opposed to the patients with progressive lesions), and their epilepsies often do not start as early as in the patients with developmental lesions. Therefore, hemispherectomy in this subgroup is often only considered in patients with already severe hemiparesis, who have ‘‘nothing to lose’’ in terms of motor function. In this scenario, it is tempting to speculate that in the future, when hopefully a better prediction of a preservation of hand function post hemispherectomy becomes available, this surgical treatment will be offered to more patients with acquired pathologies and relatively good motor function.
Conclusions Many parents and patients move forward with hemispherectomy knowing that there may be an increase in motor deficits in exchange for the possible benefits of seizure relief. However, to what extent motor function deteriorates is difficult to predict, leaving parents uncertain about their child’s
Etiology-specific differences in motor function after hemispherectomy future. Our results show that the amount of motor function that is lost differs per etiology group and, more importantly, that certain etiology groups, despite a decrease in hand function and strength, improve in gross motor function development. The loss of muscle strength and hand function can be more precisely predicted by analyzing the integrity of crossed corticospinal pathways on presurgical MRI scans.
Acknowledgement This work was supported by the Epilepsy Fund of the Netherlands [NEF 08-10 to K.B. and K.P.J.B.].
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