Reorganization in Congenital HemiparesisAcquired at Different Gestational Ages
Martin Staudt, MD,1,2 Christian Gerloff, MD, PhD,3 Wolfgang Grodd, MD, PhD,2 Hans Holthausen, MD,4
Gerhard Niemann, MD, PhD,1 and Ingeborg Krageloh-Mann, MD, PhD1
It is well established that the reorganizational potential of the developing human brain is superior to that of the adultbrain, but whether age-dependent differences exist already in the prenatal and perinatal period is not known. We havestudied sensorimotor reorganization in 34 patients with congenital hemiparesis (age range, 5–27 years), using transcra-nial magnetic stimulation and functional magnetic resonance imaging during simple hand movements. Underlying pa-thologies were brain malformations (first and second trimester lesions; n � 10), periventricular brain lesions (early thirdtrimester lesions; n � 12), and middle cerebral artery infarctions (late third trimester lesions; n � 12). Of this cohort,eight patients with malformations and all patients with periventricular lesions have been published previously. In allthree groups of pathologies, transcranial magnetic stimulation identified patients in whom the paretic hand was con-trolled via ipsilateral corticospinal projections from the contralesional hemisphere (n � 16). In these patients, the motordysfunction of the paretic hand correlated significantly with the timing period of the underlying brain lesion. Thisdemonstrates that the efficacy of reorganization with ipsilateral corticospinal tracts indeed decreases during pregnancy.
Ann Neurol 2004;56:854–863
Brain lesions acquired during the prenatal and perina-tal period (“congenital” lesions) cause different types ofstructural pathologies, depending mainly on the matu-rational stage of the brain at the time of the insult,with a certain but not prominent overlap between thelesion types and the timing periods:1–4 Adverse eventsoccurring during cerebral morphogenesis and neuronalmigration (ie, during the first and second trimester ofpregnancy) typically result in brain malformations,whereas insults acquired beyond this period (ie, duringthe third trimester of pregnancy) typically lead to gli-otic or cystic defects. Such defects can be further sub-divided into those affecting predominantly the periven-tricular white matter (eg, periventricular leukomalacia,or periventricular hemorrhages), which originatemainly during the “early” third trimester, and those af-fecting mostly gray matter structures (eg, basal ganglia/thalamic lesions, parasagittal “watershed” lesions, orcorticosubcortical infarctions), which originate mainlyduring the “late” third trimester of pregnancy or peri-natally. This timing difference between different typesof defective lesions is, however, not as straightforwardas the difference between malformative (first and sec-
ond trimester) and defective lesions (third trimester) ingeneral, because large-vessel infarctions also have beenobserved in preterm infants.5,6
When only one hemisphere is affected by such “con-genital” lesions, the contralesional hemisphere possessesa great compensatory potential, which can by far ex-ceed the reorganizational capabilities in the adult brainafter lesions of similar severity.7–9 In the sensorimotorsystem, the mechanisms underlying this postlesionalplasticity have been extensively studied by means oftranscranial magnetic stimulation (TMS),10–20 positronemission tomography,21–23 functional magnetic reso-nance imaging (fMRI),24,25 and both TMS andfMRI.26–33 None of these studies, however, addressedthe issue of whether reorganization after congenitalbrain damage is influenced by the “timing” of the le-sion within the prenatal and perinatal period. This wasthe scope of this study.
Patients and MethodsPatientsThis study was based on the data obtained from 34 patientswith congenital hemiparesis. Results on two subgroups of
From the 1Department of Pediatric Neurology and DevelopmentalMedicine, University Children’s Hospital; 2Section ExperimentalMR of the CNS, Department of Neuroradiology, RadiologicalClinic; 3Cortical Physiology Research Group, Hertie Institute forClinical Brain Research, University of Tubingen, Tubingen; and the4Clinic for Neuropediatrics and Neuro-Rehabilitation–EpilepsyCenter for Children and Adolescents, Vogtareuth, Germany.
Received Mar 26, 2004, and in revised form Aug 24. Accepted forpublication Aug 24, 2005.
Published online Nov 24, 2004, in Wiley InterScience(www.interscience.wiley.com). DOI: 10.1002/ana.10145
Address correspondence to Dr Staudt, Department of PediatricNeurology, University Children’s Hospital, Hoppe-Seyler-Str. 1,D-72076 Tubingen, Germany.E-mail: [email protected]
this large cohort have been published previously.30,31 Ex-tending our findings in patients with malformations of cor-tical development (MCDs; first- and second-trimester le-sions)31 and with periventricular (PV) lesions (early-third-trimester lesions),30 we have now studied an additionalsample of 12 patients born at term or near term with infarc-tions in the middle cerebral artery (MCA) territory (late-third-trimester lesions). Furthermore, the sample size of pa-tients with malformations was expanded by two additionalsubjects (TMS only). Demographic data and medical histo-ries of these newly studied 14 patients are given in Tables 1and 2.
Informed written consent and approval from the local eth-ics committee (Ethikkommission der Medizinischen Fakul-tat, Eberhard-Karls-Universitat Tubingen) were obtained onthe condition that, in epileptic subjects, TMS for scientificpurposes was used only when no seizure had occurred duringthe last 2 years before the examination. Several patients suf-fering from therapy-refractory seizures were examined as part
of their preoperative diagnostic workup before possible epi-lepsy surgery.
The methodologies of clinical assessment, TMS, andfMRI already have been described in detail in our previousstudies,30,31 and they will be summarized briefly in the fol-lowing text. As reported previously, we used an “adult” TMSand fMRI protocol for patients aged 16 years or older and a“pediatric” protocol for the younger children, which was alsoapplied for mentally retarded adult patients to account fortheir lower abilities to cooperate.
Clinical AssessmentParetic hand function was graded with the sequential fingeropposition task as 1 � normal performance; 2 � slow orincomplete performance; 3 � inability to perform any inde-pendent finger movement, but with a preserved grasp func-tion; and 4 � no active grasping.30,31 The presence of mirrormovements (MMs) was assessed as described in the refer-
Table 1. Clinical Data and Transcranial Magnetic Stimulation Results of the 14 Newly Studied Patients
PatientNo. Sex
Age atExamination
(yr)
Prenatal and Perinatal Data Epilepsy
GA(w)
BirthWeight
(gm)HC(cm)
ApgarScore Abnormalities
Time SinceLast
Seizure (yr)Current
AED
1 F 5 38 3,500 34 10/10 — 1 CBZ
2 F 11 39 3,310 35.5 10/10 3 mo tokolysis Ongoing VPACBZLEV
3 M 24 40 3,400 n/a “normal” — 19 CBZ
4 M 19 35 2,850 34 1/2/3 Cerclage, PROM,‘birth asphyxia’c
3 CBZ
5 F 12 40 3,150 35 9/10/10 Vacuum extraction 7 —
6 M 17 39 3,080 35 7/8/10 Preeclampsia,abnormal CTG,caesarean section
No epilepsy
7 F 15 38 3,000 32 7/9/10 PROM No epilepsy
8 M 27 40 3,600 36.5 10 — No epilepsy
9 F 25 39 3,000 35 6/10/10 Breech presentation,caesarean section
No epilepsy
10 M 11 41 3,140 34.5 9/10/10 Neonatal infection,L cephalohematoma
Ongoing LTGSTM
11 F 13 40 2,680 n/a “normal” — Ongoing OXCLTGPHT
12 F 15 38 3,180 35 10/10/10 — No epilepsy
13 M 5 39 3,450 32.5 10/10 — Ongoing PHTVPA
14 M 8 36 3,560 35 7/9/10 Vacuum extraction;neonatal seizures
Ongoing VPAOXC
aPatients not studied by EMG.bLatencies measured at maximum stimulator output.cNo further details available.
� � present; — � absent; (�) subclinical phasic EMG activity; AED � antiepileptic drugs; B � basal ganglia; (c) � contracted; CS �caesarian section; CBZ � carbamazepine; CLB � clobazam; CTG � cardiotocogram; ED � extensor digitorum muscle; F � frontal lobe;FDI � first dorsal interosseus muscle; GA � gestational age; HC � head circumference; LEV � levotiracetame; LTG � lamotrigine; MCA� middle cerebral artery; n/a � not available; OXC � oxcarbazepine; P � parietal lobe; PROM � premature rupture of membranes; (r) �relaxed; STM � sulthiame; T � temporal lobe; Th � thalamus; VPA � valproate.
Staudt et al: Congenital Hemiparesis 855
ences,30 including surface electromyogram (EMG) recordingsfrom forearm extensor muscles during repetitive opening andclosing of the other hand to search for subclinical “mirror”contractions30,31 in patients without clearly visible MM.
Transcranial Magnetic StimulationTranscranial magnetic stimulation (TMS) was performed us-ing a MagStim 200 Stimulator (Magstim; Whitland, Wales,UK) equipped with a focal 2 � 70mm figure-eight coil anda Nicolet IV D EMG unit (Nicolet Biomedical Instruments,Madison, WI) (digitization rate � 10kHz, high-pass filter �100Hz, low-pass filter � 5kHz, registration time after stim-ulus � 50 milliseconds). Motor-evoked potentials (MEPs)were recorded bilaterally, using surface EMG electrodes at-tached over the respective target muscles (M. extensor digito-rum in the “adult” protocol, M. interosseus dorsalis I in the“pediatric” protocol). This modification of the original(adult) protocol30 was performed, because the optimal elec-trode position is easier to achieve for M. interosseus dorsalis I,
and its MEPs show a better signal-to-noise ratio. This short-ens and facilitates the examination in less cooperative sub-jects. Because, in normal controls, neither muscle (at rest)shows MEPs when the ipsilateral hemisphere is stimu-lated,30,34 the findings from the two muscles are comparablefor the purpose of this study.
Both hemispheres were searched systematically for ipsilat-eral or contralateral MEPs. For each detected MEP, the fol-lowing parameters were determined separately: the optimalpoint (defined as the scalp position at which a reproduciblemuscle response was elicited with the lowest stimulation in-tensity), the motor threshold at rest (defined as the mini-mum stimulation intensity that produced at least five MEPsexceeding 50�V in 10 trials), and the latency (measuredfrom a superposition of three traces from consecutive stimu-lations over the optimal point at 110% of motor threshold atrest). When subjects were not sufficiently cooperative for aprecise assessment of motor thresholds, we measured the la-
Table 2. Clinical Data and Transcranial Magnetic Stimulation Results of the 14 Patients
aPatients not studied by EMG.bLatencies measured at maximum stimulator output.cNo further details available.
� � present; — � absent; (�) subclinical phasic EMG activity; AED � antiepileptic drugs; B � basal ganglia; (c) � contracted; CS �caesarian section; CBZ � carbamazepine; CTG � cardiotocogram; ED � extensor digitorum muscle; F � frontal lobe; FDI � first dorsalinterosseus muscle; GA � gestational age; HC � head circumference; LEV � levotiracetame; LTG � lamotrigine; MCA � middle cerebralartery; n/a � not available; OXC � oxcarbazepine; P � parietal lobe; PROM � premature rupture of membranes; (r) � relaxed; STM �sulthiame; T � temporal lobe; Th � thalamus; VPA � valproate.
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tencies at the lowest stimulation intensities at which MEPswere reliably elicited (indicated by “�” in Table 2).
TMS was generally applied with the target muscles re-laxed, as determined by acoustic monitoring of the EMGduring the examination. Complete relaxation of the paretichand was, however, impossible for Patient 7 because of se-vere spasticity (Fig 2L); furthermore, in many of the youngerpatients receiving antiepileptic medication at the time of thestudy, MEPs could be reliably elicited only using voluntaryprecontraction of the target muscles (see Table 2). The de-tailed course of the examination and the documentation ofabsent responses have been described previously.30,31
Functional Magnetic Resonance ImagingAdult patients were examined with a 1.5T Siemens VISIONsystem. Functional imaging data were acquired using awhole-brain multislice echo planar imaging (EPI) sequence35
(TE 84 milliseconds, 1-mm gap, 27 axial slices, voxel size2 � 2 � 5mm3), with an acquisition time (TA) of 4.87seconds and an interscan interval (TR) of 8 seconds, so thatthe scanning noise ceased for 3.13 seconds after each scan.The experiment was arranged in a block design, with alter-nations between four epochs of silent rest and four epochs ofactivation. Each epoch consisted of six scans, so that the totalexperiment comprised 48 scans.
Pediatric patients were examined with a 1.5T SiemensSONATA system. Functional images also were acquired us-ing EPI (TR, 6 seconds; TA, 2.4 seconds; TE, 37 millisec-onds; voxel size, 3 � 3 � 5mm3). The epochs of activationand of rest were shorter (epoch length, 30 seconds � 5scans), with a total scan time of 8 minutes � 80 scans, dur-ing which eight epochs of rest alternated with eight epochsof hand movement.
Subjects were asked to repetitively open and close the pa-retic hand with a frequency of approximately 1Hz during theactivation task; during the rest period, they were asked tosimply lie still. In adult subjects, the commands “nowmove!” and “now pause!” were given in the 3.13-secondbreaks in between actual scanning at the beginning of therespective epochs; in the children, the commands were givenin the 3.6-second breaks before each scan; that is, every 6
seconds. Task performance was controlled visually by the ex-aminer.
Postprocessing and statistical analysis of the functional im-ages were performed using SPM99 (Statistical ParametricMapping; Wellcome Department of Cognitive Neurology,University College London, London, UK), with an activa-tion threshold of p � 0.05 at voxel level, corrected for mul-tiple comparisons, and an additional cluster threshold of fivevoxels. Because large brain defects like the ones in this studycan severely hamper the automated coregistration algorithmsof SPM99, we avoided this procedure by displaying all acti-vations immediately on the (functional) EPI images of eachindividual patient (see Fig 2).
Diffusion Tensor ImagingDiffusion tensor imaging (DTI) data were acquired from allpatients with MCA infarctions except for Patient 14 (lack ofcooperation), using the SONATA system (EPI, 46 axialslices, TR 170 milliseconds, TE 90 milliseconds, 128 � 128matrix, diffusion weighting b � 1,000 sec/mm2, voxel size1.5 � 1.5 � 3 mm3). Ten identical acquisitions for six di-rections and an unweighted image (b � 0 sec/mm2) wereobtained, with a total scan time of 7.02 minutes.
Images were processed using an in-house modification ofthe Diffusion Tensor Imaging Toolbox for SPM99 (http://www.poldracklab.org/sp/spm_dti.html). To compensate forhead movements and scanner-intrinsic spatial drifts, we re-aligned the 10 diffusion images for each direction (SPM99),and only the averaged image for each direction was used todetermine the diffusion tensor for each voxel. For visualiza-tion, color maps were calculated coding the directions of thelargest eigenvectors by color (red, left to right; green, anteriorto posterior; blue, head to feet) and fractional anisotropy bybrightness.
ResultsNeurological ExaminationThe hand motor dysfunction scores for each patient aregiven in Table 2. Four subjects did not possess any use-ful hand motor control (score 4). Of these, Patients 10,
Fig 1. Structural magnetic resonance imaging (axial inversion recovery [Patient 1] and axial reconstructions from T1-weightedthree-dimensional data sets [all others]) from all newly studied patients. Note the preservation of the central sulcus (white arrows)in Patient 1 with a large frontal pachygyria (arrowheads), and in Patient 2 with a parietal focal cortical dysplasia (arrowheads).
Staudt et al: Congenital Hemiparesis 857
13, and 14 were able to perform some voluntary fingermovements, however, without their being able to pickup an object from the table. Patient 12 was completelyunable to move the fingers of the paretic hand directly(thus, MM in the nonparetic hand could not be as-sessed; see Table 2); her only way to produce minimal
finger movements in the paretic hand was to performforceful, high-amplitude contractions with her nonpa-retic hand, which led to some MM in the paretic hand.
This phenomenon (ie, MM in the paretic handduring voluntary movements of the nonparetic hand)was also observed in Patients 11, 13, and 14. In con-
Fig 2. Synopsis of functional magnetic resonance imaging and transcranial magnetic stimulation findings in two patients. In Patient7 (left column), both transcranial magnetic stimulation and diffusion tensor imaging indicated preserved crossed corticospinal projec-tions in a small “bridge” of intact white matter in the affected hemisphere (white arrows in A, B); in Patient 11, in whom thelesion had abolished the corticospinal projections from the affected hemisphere, transcranial magnetic stimulation detected ipsilateralfast-conducting projections from the intact hemisphere. Functional magnetic resonance imaging showed bilateral activation in bothsubjects. In Patient 7, the “hand knob” area of the central sulcus was activated in affected hemisphere, whereas in the contrale-sional hemisphere, activation was located in the precentral sulcus (premotor cortex). In Patient 11, activation was observed in the“hand knobs” of both hemispheres and, in addition, in the precentral sulcus of the contralesional hemisphere. Note that most pa-tients with middle cerebral artery infarctions and ipsilateral corticospinal pathways showed severe hand motor impairments, so thata functional magnetic resonance imaging assessment of active hand function was not possible. Hence, Patient 11 is not typical forthis subgroup of patients. (B, D) Axial diffusion tensor imaging at the level of the maximum extent of the lesion. (F, H, I, J)Functional magnetic resonance imaging activation during paretic hand movement (SPM99, p � 0.05 corrected) at the level of the“hand knob,” superimposed on axial (F, H) and coronal (I, J) reconstructions from the averaged (functional) echo planar imaging.On these, a white “figure-eight coil” symbol indicates the hemisphere from which MEPs in the paretic hand (P) could be elicited.These motor-evoked potential curves are shown in K to N for both the nonparetic hand (K, M) and the paretic hand (L, N). Cor-responding anatomical images are shown in A, C, E, and G. Red arrows mark the position of the central sulcus.
858 Annals of Neurology Vol 56 No 6 December 2004
trast, during voluntary movements of the paretichand, MM in the nonparetic hand (or subclinicalphasic EMG activity) were present in all patients withMCA infarctions (see Table 2).
Assessment of Corticospinal Pathways by TranscranialMagnetic Stimulation and Diffusion-Tensor ImagingThe results of the TMS examination (latencies, motorthresholds) are given in Table 2, and MEP curves fromtwo representative (Patients 7 and 11) are displayed inFigure 2K to N. The experimental protocol was suc-cessfully completed in all subjects except for Patient 5.This 12-year-old girl complained of nausea during theexamination, so the investigation had to be stopped be-fore the motor threshold and the latency for the con-tralateral projection from the contralesional hemisphereto the nonparetic hand could be determined.
TMS of the affected hemisphere elicited MEPs inthe paretic hand in 8 of 12 patients with MCA infarc-tions (Patients 3–10). In all these eight patients, DTIconfirmed highly anisotropic, craniocaudal fiber bun-dles in anatomical positions compatible with the corti-cospinal tract (see Fig 2B), even in patients with ratherextended brain lesions (eg, Patients 5 and 7). NoMEPs could be elicited by TMS of the affected hemi-sphere in Patients 11 to 14, even when maximumstimulation intensities were applied.
TMS of the contralesional hemisphere elicited nor-mal MEPs in the contralateral nonparetic hand in allsubjects. Additional short-latency MEPs in the ipsilat-eral paretic hand were detected in the four patientswithout MEPs elicitable by TMS of the affected hemi-spheres (Patients 11–14). These ipsilateral projectionsshowed almost identical latencies as the contralateralones (�1-millisecond difference) but required higherstimulation intensities in most cases. No difference wasobserved for the optimal scalp positions from wherethese responses in the paretic and the nonparetic handwere elicited (�1cm).
A different type of ipsilateral response was detected intwo patients (Patients 3 and 9) with a preserved con-tralateral projection from the affected hemisphere. Thesmall MEPs elicited in the paretic hand by TMS of thecontralesional hemisphere in these two patients differedsignificantly in latency from the contralateral projectionsto the nonparetic hand (�8.7 milliseconds in Patient 3,�4.4 milliseconds in Patient 9; see Table 2). These re-sponses therefore were not interpreted as indicating(monosynaptic) corticospinal projections.10,20
Functional Magnetic Resonance ImagingThe fMRI experiments (paretic hand movement) weresuccessfully completed in all patients with MCA infarc-tions except for Patient 5 (artifacts as a result of severehead movements) and Patients 10, 12, 13, and 14,
who were unable to move their paretic hands to a suf-ficient degree.
All patients with preserved contralateral corticospinalpathways showed activation of the central sensorimotorareas in the affected hemisphere, which always includedthe “hand knob” area of the central sulcus (see Fig 2F).Except for mesial frontal activation (in Patients 3, 6, 8,and 9), no activation was detected anywhere else in theaffected hemispheres. Only two patients (Patients 4and 7) showed additional, minor activation in theircontralesional hemispheres. The premotor cortex(Brodmann area [BA] 6) was activated in both patients(see Fig 2F); Patient 4 showed additional activation inthe upper and lower parietal cortex (BA 7, 40) as wellas in the opercular region.
Patient 11, with reorganized ipsilateral corticospinalpathways, showed activation in the “hand knob” areaof the contralesional (ipsilateral) hemisphere (corre-sponding to her “reorganized” ipsilateral primary mo-tor representation of the paretic hand) and additionalactivation in the central region of the affected hemi-sphere, near the border of the cystic lesion (see Fig2H).
Table 3 summarizes the TMS, DTI, and fMRI re-sults for all 14 patients.
DiscussionIn this and previous studies,30,31 we have assessed sen-sorimotor reorganization in congenital hemiparesis in atotal of 34 patients with three different types of struc-tural brain pathologies, reflecting different periods of
Table 3. Summary of TMS, DTI, and fMRI Findings
Patient No. TMSa DTIb fMRIc
1 c n/a n/a2 c n/a n/a3 c � R(c), MF4 c � R(c), PM(i), PA(i), OP(i)5 c � n/a6 c � R(c), MF7 c � R(c), PM(i)8 c � R(c), MF9 c � R(c), MF10 c � n/a11 i � R(c), R(i)12 i � n/a13 i � n/a14 i n/a n/a
aTMS c/i � detection of contralateral/ipsilateral corticospinal pro-jections to the paretic hand.bDTI �/� � compatible/not compatible with preserved corticospi-nal pathways from the affected hemisphere.cfMRI activation observed in R � rolandic, MF � mesial frontal,PM � premotor, PA � parietal, OP � opercular cortex, with (c)/(i) indicating the hemisphere contralateral/ipsilateral to the paretichand performing the task; n/a � not available.
TMS � transcranial magnetic stimulation; DTI � diffusion tensorimaging; fMRI � functional magnetic resonance imaging.
Staudt et al: Congenital Hemiparesis 859
brain maturation at the time of the insult (MCDs �first and second trimester of pregnancy; PV lesions �early third trimester of pregnancy; MCA infarctions �late third trimester of pregnancy).
In each of the three patient groups, TMS identifiedpatients with preserved crossed corticospinal pathwaysfrom the affected hemisphere, as well as patients withreorganized ipsilateral projections from the contrale-sional hemisphere to the paretic hand. Only two pa-tients showed both types of corticospinal projections(Patients 5 and 6 in the study on PV lesions30).
The hand motor scores associated with these threetypes of corticospinal reorganization are displayed inFigure 3. Statistical analysis (Spearman rank-order;one-tailed) showed a significant correlation betweenthe timing of the lesion (first and second vs early thirdvs late third trimester) and the hand motor dysfunctionscores (r � 0.34; p � 0.05). Hence, the earlier a “con-genital” lesion is acquired during the prenatal and peri-natal period, the better is the prognosis regarding handmotor abilities in general.
This result does, however, not necessarily reflect acorrelation between the timing of the lesion and thereorganizational potential at the time of the insult, be-cause the data are severely contaminated by the struc-tural properties of the lesion, especially because patientswith the “latest” lesions (MCA infarctions) also tend tohave the most extended brain defects. For this reason,
we have calculated a second analysis, which includedonly those patients in whom the paretic hand was con-trolled by the contralesional hemisphere via ipsilateralcorticospinal projections (solid circles in Fig 3). Inthese patients, hand function should largely depend onthe contralesional hemisphere, so that the size and to-pography of the lesion are far less relevant. This secondanalysis also showed a significant correlation betweenthe timing period and hand motor dysfunction (r �0.67; p � 0.01) and, thus, between the gestational ageat the time of the insult and the efficacy of reorgani-zation with ipsilateral corticospinal tracts.
One could still argue that this correlation emerges asa result of differences in the “nonprimary” motor con-tributions from the ipsilesional hemisphere, so that thepoorer outcome in patients with MCA infarctions nev-ertheless could be explained by their more extended le-sions even in the subgroup with ipsilateral corticospinalpathways. This hypothesis can, however, be rejected bythe further clinical course of Patient 7 from the studyon MCDs31. This boy, who suffered from pharmacore-fractory seizures as a result of a complex left-hemispheric malformation, and in whom TMS haddemonstrated such ipsilateral corticospinal projectionsfrom the contralesional right hemisphere, underwentleft functional hemispherectomy without any persistentdeterioration in motor functions. Thus, this patientdemonstrated that satisfactory hand function (score 2)is indeed possible with purely ipsilateral control with-out any contributions from the affected hemisphere.Therefore, the poorer hand function of many patientswith MCA infarctions and ipsilateral corticospinalpathways (score 4) cannot simply be explained by alack of “nonprimary” motor contributions from the af-fected hemisphere as a result of the extended brain le-sions in this group. Rather, this finding indicates thatin these patients with late-third-trimester lesions andpoor outcome, the reorganizational potential of thecontralesional hemisphere already had been reduced atthe time of the insult.
In the sample of subjects with preserved crossed cor-ticospinal pathways from the affected hemispheres(open circles in Fig 3), we also observed a functionaldifference between patients with MCA infarctions andpatients from the two other groups (MCDs and PVlesions). All MCD and PV patients with this findingshowed good hand function or only moderate impair-ment (scores 1 and 2; MCD, four of four patients; PV,six of six patients), whereas several patients with MCAinfarctions were severely impaired (scores 3 and 4;MCA, four of eight patients). This discrepancy couldalso be related to the lower efficacy of reorganizationwith ipsilateral corticospinal tracts in patients withMCA infarctions. Because of this lower efficacy, shift-ing the primary motor representation of the paretichand to the contralesional hemisphere might not have
Fig 3. Comparison of hand motor dysfunction scores amongpatients with congenital lesions acquired during the three ma-jor timing periods (malformations of cortical development[MCD] � first and second trimester of pregnancy; periven-tricular [PV] lesions � early third trimester of pregnancy;middle cerebral artery [MCA] infarctions � late third trimes-ter of pregnancy). (open circles) Patients with preservedcrossed corticospinal projections from the affected hemispheres;(solid circles) patients with reorganized ipsilateral projectionsfrom the contralesional hemispheres; (half-solid circles) pa-tients with both preserved contralateral and reorganized ipsi-lateral corticospinal projections to the paretic hand (5 and 6from the PV group30).
860 Annals of Neurology Vol 56 No 6 December 2004
been a better alternative for these patients, in contrastwith patients with MCDs and PV lesions, in whomreorganization with ipsilateral corticospinal tracts couldalways “offer” a satisfactory hand function (scores 2and 3).
This interpretation of corticospinal tract develop-ment and reorganization is in line with embryologicalstudies demonstrating that each motor cortex initiallydevelops bilateral corticospinal projections to bothsides of the body, and that in healthy individuals, theipsilateral corticospinal pathways are gradually with-drawn in the course of further development.12 In thisphase, there is evidence for a certain competition be-tween ipsilateral and contralateral tracts, and neuronalactivity seems to be an important factor in determiningwhich projections are maintained and which are with-drawn. When this scenario is applied to the patientsfrom our series, this would mean that after lesions ac-quired during the first, second, or early-third trimesterof pregnancy (ie, MCDs and PV lesions), neuronal ac-tivity in the ipsilateral corticospinal projections fromthe contralesional hemisphere is still strong enough toinduce withdrawal of possibly unlesioned, crossed cor-ticospinal projections from the affected hemisphere. Incontrast, when lesions occur during the late third tri-mester, the neuronal activity in the ipsilateral cortico-spinal projections from the contralesional hemispherealready might be reduced at the time of the insult, sothe remaining crossed corticospinal projections fromthe affected hemisphere are maintained even in patientswith quite severe lesions. Most of the patients whonevertheless develop ipsilateral corticospinal projectionscan apparently no longer benefit from this type of re-organization and achieve no useful hand motor control(MCA Patients 12 through 14).
fMRI during paretic hand movement in the pa-tients with preserved crossed corticospinal pathwayscorroborated the preserved primary motor representa-tion of the paretic hand in the affected hemisphere byshowing strong activation in the contralateral centralsensorimotor region (affected hemisphere) in all thesepatients with MCA infarctions (Patients 3–10). Be-cause this activation always included the “hand knob”area of the precentral gyrus and the central sulcus, nosigns for intrahemispheric reorganization were de-tected. In the patients with ipsilateral corticospinalpathways, fMRI consistently showed activation in theipsilateral “hand knob” area, indicating that bothhands indeed shared a concordant cortical representa-tion in the contralesional hemisphere. Interestingly,many of these patients showed additional activationin the central region of the affected hemisphere, withno MEPs elicitable by TMS of these areas. This wasthe case in Patients 3 and 4 with MCDs,31 Patients7 through 12 with PV lesions,30 Patient 11 from thesample of MCA infarctions, and a patient reported by
Vandermeeren and colleagues33 with unilateral schi-zencephaly. The bilateral fMRI activation patterns inthese patients illustrate the need for a complementaryTMS examination, because, with fMRI alone, theipsilateral primary motor representation of the paretichand in the contralesional hemisphere cannot bedetected. The functional relevance of the “nonpri-mary” motor activation in the affected hemisphere inthese patients is still unclear and requires furtherstudy.
A novel observation was made concerning MM incongenital hemiparesis. In previous publications,MMs have been interpreted as an indicator for thepresence of ipsilateral corticospinal tracts,11,18,30 with-out differentiating between MMs in the paretic or thenonparetic hand. This interpretation must be refinedwith respect to the observations of this study. Patients5, 8, 9, and 10, all showing MM in the nonparetichand during voluntary movements of the paretichand, did not have such fast-conducting pathwaysfrom the contralesional hemisphere to the paretichand but possessed preserved contralateral corticospi-nal projections (see Table 2). Mirror activity in thenonparetic hand therefore is obviously not specific forreorganization with ipsilateral corticospinal tracts butmight represent a nonspecific motor “overflow” phe-nomenon in patients with significant motor impair-ment. MMs in the paretic hand while moving thenonparetic hand voluntarily, however, were observedonly in patients with ipsilateral corticospinal projec-tions to the paretic hand (MCA Patients 11–14; PVPatients 7–12,30 and MCD Patients 3– 831). Appar-ently, the structural abnormality of the contralesionalhemisphere of such patients (ie, the presence of ipsi-lateral corticospinal projections to the paretic hand) isalso reflected in an abnormal functionality of thishemisphere (ie, its inability to control the contralat-eral, nonparetic hand independently from the ipsilat-eral paretic hand). Thus, only MMs in the paretichand seem to be a clinical sign for the presence ofipsilateral, fast-conducting corticospinal pathwaysoriginating in the contralesional hemisphere.
This is also in accordance with observations in adultstroke patients (who apparently never develop fast-conducting ipsilateral tracts), showing that the inci-dence of associated movements in the paretic hand didnot differ from that in healthy controls, whereas MMsin the nonparetic hand could also be quite impressivein this patient group.36 A detailed review of experi-mental animal data and neurophysiological studies inhumans concerning corticospinal tract reorganizationand MM in congenital hemiparesis has been publishedelsewhere.30
Staudt et al: Congenital Hemiparesis 861
ConclusionOn the basis of this experience with 34 patients, wepropose the following “rules” of sensorimotor reorgani-zation in congenital hemiparesis. They are also com-patible with all patient data given in previous reportson sensorimotor reorganization in congenital hemipa-resis.9–20,25–29,32,33 First, when a lesion abolishes thenormal contralateral corticospinal control over the pa-retic hand, the contralesional hemisphere develops (ormaintains) fast-conducting ipsilateral corticospinalpathways to the paretic hand. Second, reorganizationwith ipsilateral corticospinal tracts can mediate a usefulhand function (score 2–3); normal hand function (ornear-to-normal � score 1), however, seems possibleonly with preserved crossed corticospinal projectionsfrom the contralateral hemisphere. Third, the efficacyof sensorimotor reorganization with ipsilateral cortico-spinal tracts decreases significantly toward the end ofpregnancy; patients with late-third-trimester lesions of-ten no longer achieve any useful hand function despitethe availability of such ipsilateral corticospinal tracts.Finally, MMs in the paretic hand (during voluntarymovements of the nonparetic hand) indicate the pres-ence of ipsilateral corticospinal projections; MMs inthe nonparetic hand are not specific for this type ofcorticospinal reorganization.
This study was supported by the Deutsche Forschungsgemeinschaft(SFB 550-C4, M.S.) and the Eberhard-Karls-University Tubingen(Fortune 584-0 and 865-0, M.S.).
We thank F. Hosl, A. Hopfner, H. Mast, M. Erb, and B. Kardatzkifor technical assistance.
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