15
Childhood Multiple Sclerosis (MS): Multimodal Evoked Potentials (EP) and Magnetic Resonance Imaging (MRI) Comparative Study By
v. Scaioli1, v. Rumi2, c. Cimino3 and L. Angelini2
1Department of Clinical
Neurophysiology, 2Department of Neuropediatrics, 3Department of Neuroradiology, Istituto Neurologico "C. Besta", Milano, Italy
Introductlon
We compared the diagnostic sensitivity of magnetic resonance imaging (MRI) and evoked potential (EP) studies in aseries of 19 children affected by clinically definite (16 cases) and laboratory supported (3 cases) multiple sclerosis (MS). MRI revealed abnormal areas consistent with demyelinating plaques in 18 out of 19 cases: multiple lesions in 16 and an isolated lesion in 2 cases. Abnormal areas we.re more frequently found in supratentorial regions than in other areas of the central nervous system. In all patients, the distribution, form and topography of the lesions were typical of MS and similar to those found in the adult form of the disease. Multimodal EP were abnormal in 16 out of 19 cases. Visual (VEP) and somatosensory evoked potentials (SEP) abnormalities were frequently asymptomatic and VEPs were particularly sensitive in ascertaining childhood MS. MRI was slightly more sensitive than multimodal EP in confirming the clinical diagnosis of childhood MS. However, in suspected or probable MS with normal MRI, VEPs and SEPs may contribute to the definition of clinical diagnosis because of their capacity to demonstrate asymptomatic involvement in central nervous system (CNS) regions which escape conventional MRI investigation (i. e. the optic nerve and central somatosensory pathways).
Multiple sclerosis (MS) with onset in childhood is considered as a rare clinical condition. After early reports of sporadic cases (12, 30), more detailed clinical pictures have been described only recently (3, 8, 19, 31). The presence of atypical symptoms at onset and an erratic course of the illness in childhood MS are more frequent than in adult MS, which accounts for the difficulty in establishing an accurate and early clinical diagnosis. The assistanc.e of laboratory techniques may, therefore, be helpful in diagnosing childhood MS. Evoked potential (EP) techniques and cerebrospinal fluid examination have been the most powerful tools in revealing central nervous system involvement in MS (4, 11, 22, 26, 32) given that brain CT scans contributed rather poorly to the diagnosis of MS (20). Nowadays, magnetic resonance (MRI) is considered the most sensitive imaging technique in detecting multiple focal demyelinating areas in the brain of MS patients (5, 14). Despite this, there are only a few reports on MR imaging (MRI) findings in children affected by MS (16, 18). Detailed MRI and EP data are available only for the adult form of MS (6, 9, 10, 15, 17, 28), whereas no comparative MRIIEP report is available for children affected by this disease. Using multimodal EPs and MRI techniques we studied aseries of 19 patients affected by MS with onset before the age of 15 years in order to: 1 - evaluate the relative diagnostic utility of MRI and EP; 2 - analyze the possible correlation between the type of EP abnormalities and the location of the lesions detected by MRI.
Keywords Material and methods Multiple sclerosis - Evoked potentials Magnetic resonance imaging - Neuropediatrics
Patients Sixteen children (8 male and 8 female) affected by clinically definite (CD) MS and three (1 male, 2 female) affected by laboratory-supported definite (LSD) MS according to Poser's classification (29), were included in this study.
Reeeived Getober 16,1989; aeeepted February 14,1990
Ages ranged from 8.1 to 21.7 years (mean = 14.75 ± 3.5 yrs.). Age at onset ranged from 4.2 to 15 years (mean = 10.5 ± 2.6 yrs.).
Neuropediatrics 22 (1991) 15-23 © Hippokrates Verlag Stuttgart
The clinical follow-up ranged from 2 months to 8.8 years (mean = 3.3 ± 2.1 yrs.).
Downloaded by: NYU. Copyrighted material.
Abstract
v. Scaioli et al
N europediatrics 22 (1991)
Sixteen patients had a relapsing-remitting course; the symptoms were multifocal, including pyramidal and/or cerebellar signs, optic neuritis or blurred vision, sensory impairment, cranial nerve defects and spinal cord symptoms in different combinations. Unusual symptoms, such as extrapyramidal signs (1 patient), mood disturbances (2 patients), epileptic seizures (3 patients) and facial myokimia (1 patient) characterized the onset of the disease in six patients. In one patient, the clinical course was initially characterized by sensory impairment, pyramidal and cerebellar signs and brainstem involvement which became subsequently progressive, and was characterized by paraparesis and ataxia. Two patients had a single bout suggestive for multifocal white matter involvement. Ophthalmological (visual acuity, fundoscopic and visual field) examinations as weIl as otological (pure tone audiograms and otoscopy) investigations were performed in all patients before the EP study. Cerebrospinal fluid analysis (oligoclonal bands and IgG index) were performed in all patients.
Evoked potentials 1. Visual EPs A reversing checker-board pattern subtending a full-field of 12 x 16° at the patient's eye was projected from a TV screen. Each eye was tested by acheck which subtented 60', 30' and 15' at areversal rate of 0.8 Hz; contrast 50 % (mean luminance of 70 cd/m2 ). EEG activity was recorded by means of an active electrode placed 5 cm above the inion and referred to Fz. Amid-frontal electrode served as ground. Time analysis was 500 ms; band pass filter 1-100 Hz (-12 dB/oct). PI 00 latency, N80-PI 00 interpeak time as index of temporal dispersion and N80-P100 amplitude were considered.
2. Brainstem auditory EPs A click of 100 Jlsec of rarefaction polarity and 70 dB above the patients' threshold was applied to each ear. EEG activity was recorded by means of electrodes placed above the vertex (Cz) and referred to the mastoid ipsilateral and contralateral process of the stimulated ear. Amid-frontal electrode served as ground. Time analysis was 10 msec; band-pass filter 50-3000 Hz (-12 dB/oct). Latencies of waves I, 111 and V, the interpeak time 1-111, 111-V and I-V and the amplitude ratio VII were considered. 3. Somatosensory EPs An electrical stimulus was applied to the median nerve at the wrist in order to produce moderate contraction of the thenar eminence. Active electrodes were placed at the Erb's point (for the N9 brachial plexus component), above the second and seventh cervical (for the NIl and N13 spinal cord components) and above the scalp at C3' and C4' (for the N20 cortical component). Cephalic (Fz), non-cephalic (shoulder contralateral to the stimulus) and auricular (linked ear) references were used.
Latency of N9, N13 and N20, interpeak time N9-N13, N13-N20 and N9-N20 and the amplitude ofN9 and N20-P25 were considered. A simultaneous recording of the ipsilateral and contralateral centro-parietal responses was made by means of the non-cephalic reference, in order to obtain a topodiagnostic evaluation. The far-field components P9, PlI, P14 and the N18 component were also considered. Time analysis was 100 ms; band-pass filter 5-3000 Hz (-12dBI oct) . At least two averages, free from muscle or movement artefacts (100 single responses for VEPs, 2000 for BAEPs, and 1000 for SEPs) from each test were obtained in all patients. For each type of evoked potential, 31 normal subjects, matched for sex and age represented a control group. Latencies and interpeak time were considered abnormal when they exceeded control mean values by more than 2.5 standard deviation (SD). Evoked potentials were considered abnormal when they showed decreased amplitude and uneven reproducibility of one or more components.
Magnetic resonance imaging MRI was performed using a Philips Gyroscan superconductive unit operating at a field strength of 0.5 Tesla. All patients were studied on the sagittal planes by means of the Fast Field Echo (FFE) spin Echo Technique with T1-weighted images (TR 380, TE 17) and by means of intermediate and T2-weighted images (TR 2100, TE 50,100) on the transverse or coronal planes, with MRI section thicknesses of 8, 6 and 5 mm. Intermediate and T2-weighted images are considered more sensitive in demonstrating parenchymal abnormalities.
Results Summarized clinical, electrophysiological and neuroradiological findings are reported in Table 1. Trimodal evoked potential studies showed abnormalities in at least one of the tests in 16 out of 19 patients (84.2 0/0). The relative frequency of abnormalities of each EP test was as folIows: VEPs in 13 patients (68.4 %), median SEPs in 8 patients (42 %); BAEPs in 7 patients (36.8 %). VEPs showed the highest sensitivity: in 6 cases they were the only EP procedure that resulted abnormal, whereas SEPs and BAEPs were the only abnormal EP in only 1 and 2 patients respectively. Trimodal EPs were abnormal in 5 patients. MRI supported the diagnosis of MS in 18 out of 19 patients (94.70/0). The most frequently detected abnormal areas were in the supratentorial regions ( 161 18 patients) (88.8 %). In the infratentorial regions, areas of increased signal intensity were found in 11 out of 18 patients (61 %): 5 in the brainstem, 2 in the cerebellum and 4 in both the brainstem and cerebellum. Cervical spinal cord lesions were observed in 2 pa-
Downloaded by: NYU. Copyrighted material.
16
EP and MRI Studies in Childhood MS
Neuropediatrics 22 (1991)
17
Table 1
2
Pt.
Sex
Age
Oiagnosis
Optic Visus neuritis (ON) 00 brainstem syndrome (B) sensory symptoms (S)
E.S.
M
17
C01
B,S
S.A.
M
15
C01
B
3
A.L.
F
11
C01
B
4
C.S.
M
21
C01
5
M.F.
M
16
C01
ON (00), B,S ON (OS), B,S
6
C.A.
F
15
C01
B,S
7
G.F.
M
19
C01
ON (OS)
g
C.S.
F
18
C01
ON (00), B
9
0.0.
F
14
C01
B
10
G.R.
F
8
C01
11 12
M.R. M.F.
M F
14 22
CD1 C01
13
G.M.
F
16
C01
14
P.K.
F
12
C01
OS
Pure tone audiograms
Evoked potentials VEPs BAEPs SEPs
8/10
8/10 norm.
+
10/10
10/10 norm.
+
1/10
9/10 norm.
+
10/10
10/10 norm.
+
10/10 10/10 norm.
norm.
+
+
+
10/10 norm. 9/10
norm.
+
B,S B,S
5/10 8/10
2/10 norm. 8/10 norm.
+ +
+
+ +
B,S
10/10
10/10 norm.
+
+
+
10/10
10/10 norm.
+
M
14
C01
S
4/10
6/10 norm.
+
16 17 18
C.L. M.B. B.S.
M F F
8 14 15
C02 LS01 LS02
B ON (00) ON (OS)
9/10 1/10 4/10
9/10 norm. 10/10 norm. 4/10 norm.
+ +
19
G.A.
M
10
LS03
B
10/10
10/10 norm.
= normal
+
10/10 norm
S.A.
(+) = abnormal (7) = not available
+
+
15
Legends~ (-)
+
9/10
B,S
Spinal cord lesions
lesions 8/10 norm.
10/10
M.RI. Brainstem (B) and cerebellar
(e)
10/10
10/10
Supratentorial lesions
+
+
multiple periventr. multiple periventr. corpus callosum internal capsule bil. multiple periventr. multiple periventr. multiple periventr. corpus callosum multiple periventr. right parietal region single multiple periventr. subcortical areas external capsule, lett thalamus small periventr. multiple periventr. right cerebral peduncle
8 (single) 8 etwo)
C (two)
B (two)
C (single) 8 (twa)
C(multiple)
C4-C5 multiple periventr. corpus callosum multiple periventr. corpus callosum multiple periventr. corpus callosum multiple periventr. corpus callosum, biparietal, right temporooccipital regions right internal capsule right cerebral peduncle
B
B (single) C (single) B (four) C (two) C (single)
8 (three)
+
+
two periventricular multiple periventr.
B (single)
C2
Downloaded by: NYU. Copyrighted material.
Case no.
V. Scaioli et al
N europediatrics 22 (1991)
Correlations between clinical data and EP and MRI jindings 1. Visual system Optic neuritis was diagnosed in 6 patients (25 %). In two cases (Nos. 5 and 7) the condition was remote (several years) and both patients regained complete visual function (visual acuity of 10/10 in both eyes). In four cases (Nos. 4, 8, 17 and 18) the symptoms were recent or in evolution and an abrupt reduction in visual function was revealed with visual acuity ranging from 1/20 to 4/10. Two patients (Nos. 11 and 15) presented a gradual, insidious reduction in vision and visual acuity ranged from 2/10 to 6/10. Of the remaining patients, none presented visual complaints and visual acuity ranged from 8/10 to 10/10. Optic neuritis was the only symptom at the onset of the disease in two patients (Nos. 17 and 18). VEPs were abnormal in 21 eyes of 13 patients. Only in four cases (6 eyes) the abnormalities correlated with a recent optic neuritis. Asymptomatic involvement of visual pathways was detected by VEPs in 8 patients (13 eyes). In the two cases with remote optic neuritis and full recovery of visual acuity, VEPs were normal in one (No. 7) and abnormal in the other (No. 5) (2 eyes). The abnormality most frequently detected was an increase in P100 latency with preserved waveform: this was observed in 14/21 eyes with check-size stimulation of 60' and in 11/21 eyes with check-size stimulation of 15' (Fig. 2). An abnormal response characterized by distorted waveform was observed in 3/21 eyes with 60' and in 9/21 eyes with 15' check-size stimulation. Only in 1 eye of 1 patient with optic neuritis were the responses extinguished for hoth 60' and 15' check-size stimulation. Increased latency of the P100 component (exceeding 3 SD of the normal mean value) only to 15' check-size stimulation (but with normal response to 60' check-size) was
os 60'
Fig. 1
Definite MS (Case 8). a) Transverse and b) coronal T2weighted images (TR1933; TE100) show several iperintense areas, consistent with demyelinating plaques involving the brainstem, the cerebellum, al1d the supratentorial white matter.
30'
15'
tients (11.1 0/0). A representative case of MRI picture in childhood MS is shown in Fig. 1; supratentorial and infratentorial multiple demyelinating plaques were found.
Fig. 2
VEPs recorded in asymptomatic left eye of Case 13. An increase of latency of P100 component (*) was observed to 60', 30' and 15' checksize, without reduction in amplitude. Visual acuity was 10/10 in both eyes.
Downloaded by: NYU. Copyrighted material.
18
Neuropediatrics 22 (1991)
EP and MRI Studies in Childhood MS
os
19
At the time of this study, it was not possible to demonstrate abnormalities in optic nerves by means of the routine MRI brain examination techniques usually employed in our Department.
60'
2. Brainstem
15".T
~~.O}lV 50ms
Fig. 3 VEPs recorded in Case 15, left eye. An increase of latency of P100 component (*), with preserved shape and amplitude, was observed to 60' and 30' check-size stimulation; to 15' check-size stimulation only a late positive component (*), markedly reduced in amplitude, was obtained. The patient referred an insidious reduction of vision and the visual acuity was 4/10 in right eye and 6/10 in left eye.
Positive correlations between BAEPs and MRI abnormalities in the brainstem were found in 6 patients. Three patients with abnormal MRI signal intensity in the brainstem had normal BAEPs, whereas only 1 patient showed BAEP abnormalities in spite of anormal MRI brainstem signal. Symptoms or signs of brainstem involvement were more frequent with combined brainstem BAEP-MRI abnormalities (14 vs 10), whereas no subclinical brainstem involvement was detected by either BAEP or MRI.
00
Comparison between the sensitivity of BAEPs and MRI showed that 2 out of 3 patients with normal BAEPs had lesions located outside the acoustic pathways: one patient had lesions in the midbrain and the other in the medulla. In the
60'
30'
RE
~~.OJJV
CZ-Ai
50ms Fig. 4 VEPs recorded in asymptomatic right eye of Case 2. A slight reduced amplitude of VEP to 60' and 30' check-size stimulation, without increased latency of P100 component (*); to 15' check-size stimulation a questionable response was obtained. Visual acuity was 8/10 in both eyes.
LE Cz-Ai
observed in one eye of a patient with contralateral abnormal responses due to unilateral optic neuritis and in both eyes of one of the two patients with remote optic neuritis. In 9 eyes of 7 patients, VEPs abnormalities were more pronounced for 15' check-size stimulation than for 60' check-size, and were characterized by extinguished responses (6 eyes) (Figs. 3 and 4) and an irregular response pattern with "w" waveform (1 eye).
----l ~.15}1V 1ms Fig. 5 BAEPs recorded in Case 8. For right (RE) and left (LE) ear stimulation, 1 and 1I wave were the only BAEPs component clearly recognizable; the subsequent BAEPs waves were quite suppressed and only a later positive component (V?) was present. Two separate M RI brainstem lesions were identified.
Downloaded by: NYU. Copyrighted material.
30'
Isolated multifocal brainstem involvement was found in two patients (Nos. 16 and 19), and brainstem involvement associated with other symptoms or signs was diagnosed in twelve other patients. Pure tone audiograms were normal in all patients. BAEPs were abnormal in 7 patients (36.8 %); all of whom had symptoms or signs suggesting brainstem involvement. The BAEP abnormalities observed were: - absence of one or more components associated with an increase in latencies in two patients (4 ears) (Nos. 8, 12) (Fig. 5); - an increase in latencies in two patients (4 ears) (Nos. 6, 14) (Fig. 6); - a reduced amplitude ofV wave (200 %) in one patient (1 ear) (No. 3); - an increase in latencies with reduced V wave amplitude in two others (4 ears) (Nos. 13 and 14) (Fig. 7).
V. Scaioli et al
N europediatrics 22 (1991)
3. Somatosensory system
Cz-Ai
Sensory disturbances during multifocal poussees were observed in five patients. At the onset of the disease, only one case (No. 11) displayed a sensory-motor syndrome suggesting spinal cord involvement. Another patient (No. 15) displayed the same symptoms together with the involvement of brain structures. SEPs were abnormal in 8 patients (420/0; 14/16 sides) but only in 4 out of 9 patients with sensory signs or symptoms. However, in 4 other cases subclinical somatosensory impairment was revealed by SEPs.
I
Cz-Ai
~.9.15}JV 1ms Fig. 6 BAEPs recorded in Case 6. For right (upper traces) and left (Iower traces) ear stimulation an increase of latency and interpeak time, with preserved shape, was observed. The patient had MRI brainstem findings consistent with inferior colliculi lesion.
RE Cz..Ai
SEP pattern abnormalities were classified in agreement with Mauguiere (24). In two patients (Nos. 3 and 13) (4 sides) the far-field P9 and PlI were clearly recognizable with normal parameters while the P14 component appeared questionable and N18 was almost suppressed. The N20 component was abolished bilaterally in one (No. 3) and unilaterally in the other patient (No. 13) in whom latency delay was observed on the other side (Fig. 8). SEP findings in these patients showed an abnormal cervico-medullary pattern suggesting significant lesions located in the cervical spinal cord or in the brainstem. In four cases (Nos. 2, 10, 14 and 19) (6 sides) the far-field P9, PlI, P14 and the N18 components were preserved, whereas the N20 component was slightly to moderately increased in latency and more clearly reduced in amplitude. Central conduction time N13-N20 was significantlyincreased in these four cases (Figs. 9 and 10). These patients had an abnormal thalamo-cortical pattern: therefore significant lesions located within the thalamo-cortical sensory pathways can be hypothesized. The last two patients (Nos. 8 and 11) (4 sides) showed a combination of the above described cervicomedullary and thalamo-cortical patterns: that means, in one
LE Cz...Ai
Fz-Cd
sh-cd I
Fig. 7 BAEPs recorded in Case 14. Bilateral abnormalities consistent with reduced amplitude of wave V, inversion of amplitude ratio IjV were observed; to right (RE) ear stimulation wave V was also increased in latency. Multiple MRI brainstem lesions were found.
Sh-Ci'
AI-Cv6 1
AI-Er
third case, a clear correlation was not possible because of technicallimitations (movement artifacts at MRI). A poor correlation between the number and size of abnormal signal areas at MRI and the severity and type of BAEP alteration was found (6 patients); however, the type of BAEP abnormality showed a good correspondence with the 10cation of the lesions within the brainstem: all of the 6 patients had lesions in the lower pons.
Fig.8 Case 13. SEPs to median nerve stimulation; cephalic (Fz) and noncephalic reference (shoulder) for cortical leads (contralateral -Cc'- and ipsilateral -Ci' - centroparietal regions) and linked ear (AI) for Erb's point (Erb) and spinal cord (Cv6). On right and left side pg and PlI far-field are present; P14 and later component are absent. The spinal cord N 13 component appear suppressed.
Downloaded by: NYU. Copyrighted material.
20
EP and MRIStudies in Childhood MS
Neuropediatrics 22 (1991)
21
13) with abolished N13 and N20 components had no detectable lesion in either the brainstem or the cervical spinal cord. FZ-CC'Ir=_-~--
N11 N13
I
,
~
AI-Cv6.1.~~ _ _'"C'!~~....c:...--,..-:"'--e,..;;>ooo~"",,-,,~-~ 1
AI-Erb!1 ~
_16.pV 7.ms
Fig. 9 Case 8. Same recording condition as in Fig. 8. SEPs to right median nerve stimulation: the far-field P9, PlI, and P14 and the N18 component are normal. The N20 component was increased in latency.
Sh-Cc
sh-ci
Sh·C~
I
sh-ci
Ir
_ls.}Jv '] ms
Fig. 10 Case 14. SEP to right median nerve stimulation are normal (upper traces). To left side stimulation the far-field P9, PlI, P14 and the N18 component were normal: the N20 cortical component was markedly reduced in amplitude and slightly increased in latency (Iower traces).
side the P 14 and the N 18 were substantially abolished and in the other side only the N20 component was abnormal. MRI findings fit poorly with the types of SEP abnormalities. Only one (No. 11) of the four patients with a cervico-medullary pattern had a single MRI lesion in the cervical spinal cord; one (No. 3) had no MRI lesions in the brainstem or cervical spinal cord and the other two showed lesions in the brainstem. It is worth noting that the two patients (Nos. 8 and
In addition, three other patients with normal SEPs had MRI lesions in the subcorlical parietal region (2 cases) or in the internal capsule (1 case).
Discussion In the last years, EP and MRI were extensively investigated in MS and their diagnostic superiority, in comparison with other laboratory techniques, is weIl established. RecenUy, in several papers, MRI and EP were compared in adult MS and the relative diagnostic values, the sensitivity and the specificity of these techniques has been evaluated. Only a few data are available for pediatric patients affected by MS in which the utility of EP and MRI has to be clarified. The rarity of MS in childhood and the frequency of an atypical clinical presentation (i. e. epileptic seizures, acute psychosis, extrapyramidal involvement or facial myokymia), as observed in abaut one third of our patients, emphasized the relative usefulness of MRI and EP techniques in the ascertainment of this disorder. The comparison of EP and MRI results indicate that these techniques had a high diagnostic yield, and that MRI is the more sensitive diagnostic tool in ascertaining of MS. In fact a high frequency of multifocal brain involvement was revealed in the present study as has also been reported in adult MS series (16~ 27). However, it must be kept in mind that 16 out of 19 patients had a clinical diagnosis of Definite Multiple Sclerosis. In the adult population, MRI has been reported to be more sensitive than EP in Suspected or Probable MS (14), while in Definite MS high diagnostic sensitivity has been reported for both EP studies and MRI techniques (6, 17); only by Giesser (15) a higher sensitivity for EP than for MRI has been reported. Although no specific pattern for MS was identified, the topography~ form and distribution of the MRI findings were similar to those described in numerous studies performed in adults, and were typical of MS. In agreement with previous studies MRI revealed abnormalities in supratentorial brain structures more frequently than in other brain regions (84.2 % vs 63.1 %) and with a higher incidence than that of VEPs and SEPs (47.4 %). In the brainstem, clinical signs and symptoms were encountered more frequently (73.7 %) than MRI-detected lesions (47.4 %) or BAEPs (36.8 %). For MRI-detected lesions in the brainstem and cerebellum, positive correlations with clinical, electrophysiological and imaging techniques were found. No asymptomatic lesion was demonstrated by either BAEP or MRI, particularly in the brainstem. In effect BAEPs are considered to be less sensitive than other EP procedures and laborato-
Downloaded by: NYU. Copyrighted material.
1
Of the six patients with a thalamo-corlical pattern' one (No. 2) had bilaterallesions in the internal capsule but unilateral SEP abnormalities; one (No. 14) had a left internal capsule lesion but a right SEP thalamo-corlical pattern; two (Nos. 10 and 19) showed only periventricular lesions and one (No. 11) had no lesions either in the brainstem or in the supratentorial brain areas. Only in the sixth patient (No. 8) was a left thalamo-cortical pattern associated with a left thalamic MRI lesion.
Neuropediatrics 22 (1991)
ry tests in adult MS, independently of the clinical category (6, 34); the results of our study in childhood confirms these data while indicating that BAEPs may be useful in confirming equivocal clinical brainstem symptoms. VEPs and SEPs frequently detected asymptomatic involvement of the CNS in brain regions which elude conventional MRI investigations, i. e. optic nerves and part of the central somatosensory pathways. In fact, VEP and SEP abnormalities were frequently present in patients without clinical disturbances, and SEPs showed no positive correlations with MRI. In addition, it must be remembered that the cervical spinal cord was the CNS region in which MRI detected abnormal areas less frequently. VEPs are probably the most sensitive EP procedure for detecting subclinical abnormalities in MS with onset in childhood. This assumption has been recently confirmed in comparative studies between MRI of the optic nerve and VEPs in MS patients with optic neuritis (ON) and with isolated ON (25). Although technical reasons may be responsible for the non-correspondance between MRI and VEP, other factors might contribute to the discrepancies observed. The extent of the involvement of the optic nerve may be small and small size lesions, although significant enough to produce clinical or electrophysiological signs, may be undetectable to MRI (25). As a matter of fact, a high incidence of extinguished or suppressed responses was observed with small check-size stimulation, suggesting a selective involvement of fibers originating from the central region of the retina (33). Moreover, it has been suggested that several pathophysiological mechanisms may be responsible for electrophysiological abnormalities in MS (1, 2). The different types of VEP abnormalities observed in the majority of asymptomatic nerves in our patients employing different checksize stimulations support this view. The use of non-cephalic references in SEP recording proved to be highly sensitive in providing detailed information about the topography of the lesions along the somatosensory pathways. Distinct, separate neural generators for spinal N13 and far-field P14, as weIl as for N18 and N20 have been suggested by studies performed in normals (7) and confirmed by studies in patients with weIl-Iocalized lesions (21, 24, 35). Furthermore, the topodiagnostic localizing power of SEPs for lesions along the ascending somatosensory pathways has allowed the identification of some definite pathophysiological patterns of SEP abnormalities (13). In most of the papers dealing with MRI and SEPs in MS, recordings were made using only the cephalic reference and so comparison with MRI was not feasible. Only recently the usefulness of SEP recordings by means of noncephalic reference has been emphasized in MS (13), but no comparative study with MRI has been performed. The poor correlation between SEPs and MRI found in the present series may be due to the clinical stage of the disease, with the cumulative effect of undetectable MRI lesions along the somatosensory pathways leading to SEP abnormalities. Therefore, it may be deduced that the highly variable course of MS and the longitudinal axial extension of afferent sensory fibers make it difficult and unnecessary to find a satisfactory anatomo-pathophysiological correlation. In conclusion, although MS with onset in childhood is a rare clinical condition, it should be considered not
V. Scaioli et al
only in young patients with disseminated multifocal acute symptoms, but also in those with isolated focal brain syndromes. MRI and EP are useful both in confirming equivocal signs and, particularly, in revealing asymptomatic multifocal CNS involvement. MRI and EP appear not only to give reciprocal confirmation of a clinical diagnosis of MS, but also, as the present report indicates, to provide information concerning the spatial and temporal distribution of demyelinating plaques in the brain.
References 1
Blumhardt, L. B.: Visual Field Defects and Pathological Alteration in To-
8
pography: Factors Complicating the Estimation of Visual Evoked Response "Delay" in Multiple Sclerosis. In: Evoked Potentials. Cracco, R. Q., Bodis-Wollner, 1. (Eds.), New York, Alan R. Liss (1986) 354-365 Bodis-Wollner, I., M. Ono.fij: System diseases and visual evoked potentials diagnosis in neurology: changes due to synaptic malfunction. Ann. NY Acad. Sei. 388 (1982) 327-348 Bye, A. M. E., B. Kendall,]. Wilson: Multiple sclerosis in childhood: a new look. Dev. Med. Child Neurol. 27 (1985) 215-222 Chiappa, H. K.,]. L. Harrison, E. B. Brooks, R. R. Young: Brainstem auditory evoked responses in 200 patients with multiple sclerosis. Ann. Neurol. 7 (1980) 135-143 Crisp, D. T,]. E. Kleiner, G.]. DeFillip,]. 1. Greenstein, T H. Liu, D. Sommers: Clinical correlation with magnetic resonance imaging in multiple sclerosis. Neurology 35 (Suppl. 1) (1985) 137 Cutler,]. R., M.]. Aminoff, M. Brant-Zawadski: Evaluation of patients with multiple sclerosis by evoked potentials and magnetic resonance imaging: a comparative study. Ann. Neurol. 20 (1986) 645-648 Desmedt,]. E., G. Cheron: Central somatosensory conduction in man; neural generators and interpeak latencies of the far-field components recorded from neck and right or left scalp or earlobes. Electroencephalogr. Clin. Neurophysiol. 50 (1980) 382 Duquette, P., T]. Murray,]. Pleines, G. C. Ebers, D. Sadovnick, P.
9
Weldon, S. Warren, D. W. Paty, A. Upton, W. Hader, R. Nelson, A. Auty, B. Neufeld, C. Meltzer: Multiple sclerosis in childhood: clinical profile in 125 patients. J. Pediatr. 111 (1987) 359-363 Eisen, A., K. Odusote, D. Li, W. Robertson, S. Purvis, K. Eisen, D. Paty:
2
3 4
5
6
7
Comparison of magnetic resonance imaging with somatosensory testing in MS suspected. Muscle Nerve 10 (1987) 385-390 10 Farlow, M. R., O. N. Markand, M. K. Edwards,]. C. Stevens, 0.]. Kolar: Multiple sclerosis: magnetic resonance imaging, evoked responses, and spinal fluid electrophoresis. Neurology 36 (1986) 828-831 11 Fischer, C., F. Mauguiere, V. Ibanez,]. Couljon: Potentieis evoques visueIs, auditifs precoces et somesthesiques dans la sclerose en plaques (917 cas). Rev. Neurol. 5 (1986) 517-523 12 Gaerlinger, M. H.: Contribution al'etude de la sclerose en plaques infantile. L'Echo Med. Nord (1909) 13-37 13 Garcia-Larrea, L., F. Mauguiere: Latency and amplitude abnormalities of the scalp far-field P14 to median nerve stimulation in multiple sclerosis. A SEP study of 122 patients recorded with non-cephalic reference montage. Electroencephalogr. Clin. Neurophysiol. 71 (1988) 180-186 14
Gebarsky, S. S., T O. Gabrielse, S. Gilman,]. E. Knake,]. T Latack, A. M. Aisen: The initial diagnosis of multiple sclerosis: clinical impact of
15
Giesser, B. S., D. Kurtzberg, H. G. Vaughan,]. C. Arezzo, M. L. Aisen, C. R. Smith, N. G. LaRocca, L. C. Scheinberg: Trimodal evoked potential
magnetic resonance imaging. Ann. Neurol. 17 (1985) 469-474
compared with magnetic resonance imaging in the diagnosis of multiple sclerosis. Arch. Neurol. 44 (1987) 281-284 16 Golden, G. S., R. C. Woody: The role of nuclear magnetic resonance imaging in the diagnosis of MS in childhood. Neurology 37 (1987) 689-683 17 Guerit,]. M., A. Monje Argiles: The sensitivity of multimodal evoked potentials in multiple sclerosis. A comparison with magnetic resonance imaging and cerebrospinal fluid analysis. Electroencephalogr. Clin. Neurophysiol. 70 (1988) 230-238 18 Haas, G., G. Schorth,]. Krageloh-Man, M. Buchwald-Saal: Magnetic resonance imaging of the brain of children with multiple sclerosis. Dev. Med. Child Neurol. 29 (1987) 586-591 19
Izquierdo, G., O. Lyon-Caen, R. Marteau, Martinez-Parra, F. Lermitte, P. Castaigne,].]. Hauw: Early onset multiple sclerosis. Clinical study in 12 pathologically proven cases. Acta Neurol. Scand. 73 (1986) 493-497
Downloaded by: NYU. Copyrighted material.
22
EP and MRI Studies in Childhood MS
N europediatrics 22 (1991)
L., W. R. Kinkel, 1. Polachini, R. P. Kinkel: Correlations ofnuclear magnetic resonance imaging, computerized tomography, and clinical profiles in multiple sclerosis. Neurology 36 (1986) 27-34 21 Matthews, W. B., M. Esiri: Multiple sclerosis plaque related to abnormal somatosensory evoked potentials. J. Neurol. Neurosurg. Psychiatry 42 (1979) 940-942 22 Matthews, W. B.,]. R. B. Wattam-Bell, E. Pountney: Evoked potentials in the diagnosis of multiple sclerosis: a follow-up study. J. Neurol. Neurosurg. Psychiatry 45 (1982) 303-307 23 Mauguiere, F.: Short-latency somatosensory evoked potentials to upper limb stimulation in lesions of brainstem, thalamus and cortex. Electroencephalogr. Clin. Neurophysiol. (Suppl.) 39 (1987) 302-309 24 Mauguiere, F., V. Ibanez: The dissociation of early SEP component in lesions of the cervico-medullary junction: a cue for routine interpretation of abnormal cervical responses to median nerve stimulation. Electroencephalogr. Clin. Neurophysiol. 62 (1985) 406-420 25 Miller, D. H., M. R. Newton,]. C. Van der Poel, E. P. G. H. Du Boulay, A. M. Halliday, B. E. Kendal, G. ]ohnson, D. G. MacManus, 1. F. Moseley, W. 1. McDonald: Magnetic resonance imaging of the optic nerve in optic neuritis. Neurology 38 (1988) 175-179 26 Milner, B. A., D. Regan,]. R. Heron: Differential diagnosis of multiple sclerosis by visual evoked potential recording. Brain 97 (1974) 755-772 27 Ormerod,]. E. C., D. H. Miller, W.1. McDonald, E. P. G. H. DuBoulay, P. Rudge, B. E. Kendal, 1. F. Moseley, G. ]ohnson, P. S. Tofts, A. M. Halliday, A. M. Bronstein, F. Scaravilli, A. E. Harding, D. Barnes, K.]. Zilkha: The role of NMR imaging in the assessment of multiple sclerosis and isolated neurologicallesions. A quantitative study. Brain 110 (1987) 1579-1616 28 Paty, D. W.,].]. F. Oger, L. F. Kastrukoff, S. A. Hashimoto,]. P. Hooge, A. A. Eisen, K. A. Eisen, S.]. Purves, M. D. Low, V. Brandeis, W. D. Robertson, D. K. B. Li: MRI in the diagnosis of multiple sclerosis: a prospective study with comparison of clinical evaluation, evoked potentials, oligoclonal banding and CT. Neurology 38 (1988) 180-185 29 Poser, C. M., D. W. Paty, L. Scheinberg, W.1. McDonald, F. A. Davis, G. C. Ebers, K. P. ]ohnson, W. A. Sibley, D. H. Silberberg, W. W. Tourtellotte: New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann. Neurol. 13 (1983) 227-231 30 Rimbaud, L., Riser, Geraud: De la sclerose en plaques chez l'enfant. Rev. Neurol. 5 (1938) 477-481 31 Sheremata, W., S. B. Brown, R. R. Curless, H. G. Dunn: Childhood multiple sclerosis: areport of 12 cases. Ann. Neurol. 10 (1981) 304 32 SmalI, D. G., W. B. Matthews, M. Small: The cervical somatosensory evoked potential (SEP) in the diagnosis of multiple sclerosis. J. Neurol. Sci35 (1978)211-224 33 Tartaglione, A., A. Oneto, F. Bandini, L. Spadavecchia, E. Gandolfo, E. Favale: Electrophysiological detection of "silent" plaques in the optic pathways. Acta Neurol. Scand. 76 (1987) 246-250 34 Tramo, M.]., M.]. Scheck, B. C. P. Lee, S. Rapoport: Evoked potentials and MRI in the diagnosis of multiple sclerosis. Neurology 35 (Suppl. 1) (1985) 105 35 Urasaki, E., S. Vada, C. Kadoya, H. Matsusaki, A. Yokota, S. Matsuoka: Absence of spinal N13-P13 and normal scalp far-field P14 in a patient with syringomyelia. Electroencephalogr. Clin. Neurophysiol. 71 (1988) 400-404
23
20 ]acobs,
Dr. V. Scaioli Dept. of Clinical Neurophysiology Istituto Neurologico "C. Besta" Via Celoria No. 11 1-20133 Milano, Italy
100 und mehr knifflige Impffragen Downloaded by: NYU. Copyrighted material.
Von U. QUAST, Marburg/Lahn 3., erweiterte Auflage von »Hundert knifflige Impffragen« 1991, 232 Seiten, 4 Abbildungen, 8 Tabellen, 12 x 19 cm, kartoniert DM 29,ISBN 3-777J-0994-X
Das Studium dieser wesentlich erweiterten praxisnahen, fundierten Übersicht wird für viele Fragestellungen eine korrekte Antwort geben und daher dem Arzt auch die für Impfungen so notwendige Aufklärungsarbeit ermöglichen.
Ich bestelle aus dem Hippokrates Verlag Stuttgart durch die Buchhandlung: ........ Expl. QUAST, 100 und mehr knifflige Impffragen, DM 29,ISBN 3-7773-0994-X
Unterschrift
.
Näm'e'('iiiö'girChst'St~'iiip'eÜ"""'"''''''''''''''''''''''''
Straße Ort
..·····..·······..······ ··· · ·..·..·..· ····
.
D·ät~iii··
(Preisänderung vorbehalten)
Hippokrates Verlag Stuttgart Postfach 10 2263
7000 Stuttgart 10
283
Childhood Multiple Sclerosis (MS): Multimodal Evoked Potentials (EP) and Magnetic Resonance Imaging (MRI) Comparative Study By
v. Scaioli1, v. Rumi2, c. Cimino3 and L. Angelini2
1Department of Clinical
Neurophysiology, 2Department of Neuropediatrics, 3Department of Neuroradiology, Istituto Neurologico "C. Besta", Milano, Italy
Introductlon
We compared the diagnostic sensitivity of magnetic resonance imaging (MRI) and evoked potential (EP) studies in aseries of 19 children affected by clinically definite (16 cases) and laboratory supported (3 cases) multiple sclerosis (MS). MRI revealed abnormal areas consistent with demyelinating plaques in 18 out of 19 cases: multiple lesions in 16 and an isolated lesion in 2 cases. Abnormal areas we.re more frequently found in supratentorial regions than in other areas of the central nervous system. In all patients, the distribution, form and topography of the lesions were typical of MS and similar to those found in the adult form of the disease. Multimodal EP were abnormal in 16 out of 19 cases. Visual (VEP) and somatosensory evoked potentials (SEP) abnormalities were frequently asymptomatic and VEPs were particularly sensitive in ascertaining childhood MS. MRI was slightly more sensitive than multimodal EP in confirming the clinical diagnosis of childhood MS. However, in suspected or probable MS with normal MRI, VEPs and SEPs may contribute to the definition of clinical diagnosis because of their capacity to demonstrate asymptomatic involvement in central nervous system (CNS) regions which escape conventional MRI investigation (i. e. the optic nerve and central somatosensory pathways).
Multiple sclerosis (MS) with onset in childhood is considered as a rare clinical condition. After early reports of sporadic cases (12, 30), more detailed clinical pictures have been described only recently (3, 8, 19, 31). The presence of atypical symptoms at onset and an erratic course of the illness in childhood MS are more frequent than in adult MS, which accounts for the difficulty in establishing an accurate and early clinical diagnosis. The assistanc.e of laboratory techniques may, therefore, be helpful in diagnosing childhood MS. Evoked potential (EP) techniques and cerebrospinal fluid examination have been the most powerful tools in revealing central nervous system involvement in MS (4, 11, 22, 26, 32) given that brain CT scans contributed rather poorly to the diagnosis of MS (20). Nowadays, magnetic resonance (MRI) is considered the most sensitive imaging technique in detecting multiple focal demyelinating areas in the brain of MS patients (5, 14). Despite this, there are only a few reports on MR imaging (MRI) findings in children affected by MS (16, 18). Detailed MRI and EP data are available only for the adult form of MS (6, 9, 10, 15, 17, 28), whereas no comparative MRIIEP report is available for children affected by this disease. Using multimodal EPs and MRI techniques we studied aseries of 19 patients affected by MS with onset before the age of 15 years in order to: 1 - evaluate the relative diagnostic utility of MRI and EP; 2 - analyze the possible correlation between the type of EP abnormalities and the location of the lesions detected by MRI.
Keywords Material and methods Multiple sclerosis - Evoked potentials Magnetic resonance imaging - Neuropediatrics
Patients Sixteen children (8 male and 8 female) affected by clinically definite (CD) MS and three (1 male, 2 female) affected by laboratory-supported definite (LSD) MS according to Poser's classification (29), were included in this study.
Reeeived Getober 16,1989; aeeepted February 14,1990
Ages ranged from 8.1 to 21.7 years (mean = 14.75 ± 3.5 yrs.). Age at onset ranged from 4.2 to 15 years (mean = 10.5 ± 2.6 yrs.).
Neuropediatrics 22 (1991) 15-23 © Hippokrates Verlag Stuttgart
The clinical follow-up ranged from 2 months to 8.8 years (mean = 3.3 ± 2.1 yrs.).
Downloaded by: NYU. Copyrighted material.
Abstract
v. Scaioli et al
N europediatrics 22 (1991)
Sixteen patients had a relapsing-remitting course; the symptoms were multifocal, including pyramidal and/or cerebellar signs, optic neuritis or blurred vision, sensory impairment, cranial nerve defects and spinal cord symptoms in different combinations. Unusual symptoms, such as extrapyramidal signs (1 patient), mood disturbances (2 patients), epileptic seizures (3 patients) and facial myokimia (1 patient) characterized the onset of the disease in six patients. In one patient, the clinical course was initially characterized by sensory impairment, pyramidal and cerebellar signs and brainstem involvement which became subsequently progressive, and was characterized by paraparesis and ataxia. Two patients had a single bout suggestive for multifocal white matter involvement. Ophthalmological (visual acuity, fundoscopic and visual field) examinations as weIl as otological (pure tone audiograms and otoscopy) investigations were performed in all patients before the EP study. Cerebrospinal fluid analysis (oligoclonal bands and IgG index) were performed in all patients.
Evoked potentials 1. Visual EPs A reversing checker-board pattern subtending a full-field of 12 x 16° at the patient's eye was projected from a TV screen. Each eye was tested by acheck which subtented 60', 30' and 15' at areversal rate of 0.8 Hz; contrast 50 % (mean luminance of 70 cd/m2 ). EEG activity was recorded by means of an active electrode placed 5 cm above the inion and referred to Fz. Amid-frontal electrode served as ground. Time analysis was 500 ms; band pass filter 1-100 Hz (-12 dB/oct). PI 00 latency, N80-PI 00 interpeak time as index of temporal dispersion and N80-P100 amplitude were considered.
2. Brainstem auditory EPs A click of 100 Jlsec of rarefaction polarity and 70 dB above the patients' threshold was applied to each ear. EEG activity was recorded by means of electrodes placed above the vertex (Cz) and referred to the mastoid ipsilateral and contralateral process of the stimulated ear. Amid-frontal electrode served as ground. Time analysis was 10 msec; band-pass filter 50-3000 Hz (-12 dB/oct). Latencies of waves I, 111 and V, the interpeak time 1-111, 111-V and I-V and the amplitude ratio VII were considered. 3. Somatosensory EPs An electrical stimulus was applied to the median nerve at the wrist in order to produce moderate contraction of the thenar eminence. Active electrodes were placed at the Erb's point (for the N9 brachial plexus component), above the second and seventh cervical (for the NIl and N13 spinal cord components) and above the scalp at C3' and C4' (for the N20 cortical component). Cephalic (Fz), non-cephalic (shoulder contralateral to the stimulus) and auricular (linked ear) references were used.
Latency of N9, N13 and N20, interpeak time N9-N13, N13-N20 and N9-N20 and the amplitude ofN9 and N20-P25 were considered. A simultaneous recording of the ipsilateral and contralateral centro-parietal responses was made by means of the non-cephalic reference, in order to obtain a topodiagnostic evaluation. The far-field components P9, PlI, P14 and the N18 component were also considered. Time analysis was 100 ms; band-pass filter 5-3000 Hz (-12dBI oct) . At least two averages, free from muscle or movement artefacts (100 single responses for VEPs, 2000 for BAEPs, and 1000 for SEPs) from each test were obtained in all patients. For each type of evoked potential, 31 normal subjects, matched for sex and age represented a control group. Latencies and interpeak time were considered abnormal when they exceeded control mean values by more than 2.5 standard deviation (SD). Evoked potentials were considered abnormal when they showed decreased amplitude and uneven reproducibility of one or more components.
Magnetic resonance imaging MRI was performed using a Philips Gyroscan superconductive unit operating at a field strength of 0.5 Tesla. All patients were studied on the sagittal planes by means of the Fast Field Echo (FFE) spin Echo Technique with T1-weighted images (TR 380, TE 17) and by means of intermediate and T2-weighted images (TR 2100, TE 50,100) on the transverse or coronal planes, with MRI section thicknesses of 8, 6 and 5 mm. Intermediate and T2-weighted images are considered more sensitive in demonstrating parenchymal abnormalities.
Results Summarized clinical, electrophysiological and neuroradiological findings are reported in Table 1. Trimodal evoked potential studies showed abnormalities in at least one of the tests in 16 out of 19 patients (84.2 0/0). The relative frequency of abnormalities of each EP test was as folIows: VEPs in 13 patients (68.4 %), median SEPs in 8 patients (42 %); BAEPs in 7 patients (36.8 %). VEPs showed the highest sensitivity: in 6 cases they were the only EP procedure that resulted abnormal, whereas SEPs and BAEPs were the only abnormal EP in only 1 and 2 patients respectively. Trimodal EPs were abnormal in 5 patients. MRI supported the diagnosis of MS in 18 out of 19 patients (94.70/0). The most frequently detected abnormal areas were in the supratentorial regions ( 161 18 patients) (88.8 %). In the infratentorial regions, areas of increased signal intensity were found in 11 out of 18 patients (61 %): 5 in the brainstem, 2 in the cerebellum and 4 in both the brainstem and cerebellum. Cervical spinal cord lesions were observed in 2 pa-
Downloaded by: NYU. Copyrighted material.
16
EP and MRI Studies in Childhood MS
Neuropediatrics 22 (1991)
17
Table 1
2
Pt.
Sex
Age
Oiagnosis
Optic Visus neuritis (ON) 00 brainstem syndrome (B) sensory symptoms (S)
E.S.
M
17
C01
B,S
S.A.
M
15
C01
B
3
A.L.
F
11
C01
B
4
C.S.
M
21
C01
5
M.F.
M
16
C01
ON (00), B,S ON (OS), B,S
6
C.A.
F
15
C01
B,S
7
G.F.
M
19
C01
ON (OS)
g
C.S.
F
18
C01
ON (00), B
9
0.0.
F
14
C01
B
10
G.R.
F
8
C01
11 12
M.R. M.F.
M F
14 22
CD1 C01
13
G.M.
F
16
C01
14
P.K.
F
12
C01
OS
Pure tone audiograms
Evoked potentials VEPs BAEPs SEPs
8/10
8/10 norm.
+
10/10
10/10 norm.
+
1/10
9/10 norm.
+
10/10
10/10 norm.
+
10/10 10/10 norm.
norm.
+
+
+
10/10 norm. 9/10
norm.
+
B,S B,S
5/10 8/10
2/10 norm. 8/10 norm.
+ +
+
+ +
B,S
10/10
10/10 norm.
+
+
+
10/10
10/10 norm.
+
M
14
C01
S
4/10
6/10 norm.
+
16 17 18
C.L. M.B. B.S.
M F F
8 14 15
C02 LS01 LS02
B ON (00) ON (OS)
9/10 1/10 4/10
9/10 norm. 10/10 norm. 4/10 norm.
+ +
19
G.A.
M
10
LS03
B
10/10
10/10 norm.
= normal
+
10/10 norm
S.A.
(+) = abnormal (7) = not available
+
+
15
Legends~ (-)
+
9/10
B,S
Spinal cord lesions
lesions 8/10 norm.
10/10
M.RI. Brainstem (B) and cerebellar
(e)
10/10
10/10
Supratentorial lesions
+
+
multiple periventr. multiple periventr. corpus callosum internal capsule bil. multiple periventr. multiple periventr. multiple periventr. corpus callosum multiple periventr. right parietal region single multiple periventr. subcortical areas external capsule, lett thalamus small periventr. multiple periventr. right cerebral peduncle
8 (single) 8 etwo)
C (two)
B (two)
C (single) 8 (twa)
C(multiple)
C4-C5 multiple periventr. corpus callosum multiple periventr. corpus callosum multiple periventr. corpus callosum multiple periventr. corpus callosum, biparietal, right temporooccipital regions right internal capsule right cerebral peduncle
B
B (single) C (single) B (four) C (two) C (single)
8 (three)
+
+
two periventricular multiple periventr.
B (single)
C2
Downloaded by: NYU. Copyrighted material.
Case no.
V. Scaioli et al
N europediatrics 22 (1991)
Correlations between clinical data and EP and MRI jindings 1. Visual system Optic neuritis was diagnosed in 6 patients (25 %). In two cases (Nos. 5 and 7) the condition was remote (several years) and both patients regained complete visual function (visual acuity of 10/10 in both eyes). In four cases (Nos. 4, 8, 17 and 18) the symptoms were recent or in evolution and an abrupt reduction in visual function was revealed with visual acuity ranging from 1/20 to 4/10. Two patients (Nos. 11 and 15) presented a gradual, insidious reduction in vision and visual acuity ranged from 2/10 to 6/10. Of the remaining patients, none presented visual complaints and visual acuity ranged from 8/10 to 10/10. Optic neuritis was the only symptom at the onset of the disease in two patients (Nos. 17 and 18). VEPs were abnormal in 21 eyes of 13 patients. Only in four cases (6 eyes) the abnormalities correlated with a recent optic neuritis. Asymptomatic involvement of visual pathways was detected by VEPs in 8 patients (13 eyes). In the two cases with remote optic neuritis and full recovery of visual acuity, VEPs were normal in one (No. 7) and abnormal in the other (No. 5) (2 eyes). The abnormality most frequently detected was an increase in P100 latency with preserved waveform: this was observed in 14/21 eyes with check-size stimulation of 60' and in 11/21 eyes with check-size stimulation of 15' (Fig. 2). An abnormal response characterized by distorted waveform was observed in 3/21 eyes with 60' and in 9/21 eyes with 15' check-size stimulation. Only in 1 eye of 1 patient with optic neuritis were the responses extinguished for hoth 60' and 15' check-size stimulation. Increased latency of the P100 component (exceeding 3 SD of the normal mean value) only to 15' check-size stimulation (but with normal response to 60' check-size) was
os 60'
Fig. 1
Definite MS (Case 8). a) Transverse and b) coronal T2weighted images (TR1933; TE100) show several iperintense areas, consistent with demyelinating plaques involving the brainstem, the cerebellum, al1d the supratentorial white matter.
30'
15'
tients (11.1 0/0). A representative case of MRI picture in childhood MS is shown in Fig. 1; supratentorial and infratentorial multiple demyelinating plaques were found.
Fig. 2
VEPs recorded in asymptomatic left eye of Case 13. An increase of latency of P100 component (*) was observed to 60', 30' and 15' checksize, without reduction in amplitude. Visual acuity was 10/10 in both eyes.
Downloaded by: NYU. Copyrighted material.
18
Neuropediatrics 22 (1991)
EP and MRI Studies in Childhood MS
os
19
At the time of this study, it was not possible to demonstrate abnormalities in optic nerves by means of the routine MRI brain examination techniques usually employed in our Department.
60'
2. Brainstem
15".T
~~.O}lV 50ms
Fig. 3 VEPs recorded in Case 15, left eye. An increase of latency of P100 component (*), with preserved shape and amplitude, was observed to 60' and 30' check-size stimulation; to 15' check-size stimulation only a late positive component (*), markedly reduced in amplitude, was obtained. The patient referred an insidious reduction of vision and the visual acuity was 4/10 in right eye and 6/10 in left eye.
Positive correlations between BAEPs and MRI abnormalities in the brainstem were found in 6 patients. Three patients with abnormal MRI signal intensity in the brainstem had normal BAEPs, whereas only 1 patient showed BAEP abnormalities in spite of anormal MRI brainstem signal. Symptoms or signs of brainstem involvement were more frequent with combined brainstem BAEP-MRI abnormalities (14 vs 10), whereas no subclinical brainstem involvement was detected by either BAEP or MRI.
00
Comparison between the sensitivity of BAEPs and MRI showed that 2 out of 3 patients with normal BAEPs had lesions located outside the acoustic pathways: one patient had lesions in the midbrain and the other in the medulla. In the
60'
30'
RE
~~.OJJV
CZ-Ai
50ms Fig. 4 VEPs recorded in asymptomatic right eye of Case 2. A slight reduced amplitude of VEP to 60' and 30' check-size stimulation, without increased latency of P100 component (*); to 15' check-size stimulation a questionable response was obtained. Visual acuity was 8/10 in both eyes.
LE Cz-Ai
observed in one eye of a patient with contralateral abnormal responses due to unilateral optic neuritis and in both eyes of one of the two patients with remote optic neuritis. In 9 eyes of 7 patients, VEPs abnormalities were more pronounced for 15' check-size stimulation than for 60' check-size, and were characterized by extinguished responses (6 eyes) (Figs. 3 and 4) and an irregular response pattern with "w" waveform (1 eye).
----l ~.15}1V 1ms Fig. 5 BAEPs recorded in Case 8. For right (RE) and left (LE) ear stimulation, 1 and 1I wave were the only BAEPs component clearly recognizable; the subsequent BAEPs waves were quite suppressed and only a later positive component (V?) was present. Two separate M RI brainstem lesions were identified.
Downloaded by: NYU. Copyrighted material.
30'
Isolated multifocal brainstem involvement was found in two patients (Nos. 16 and 19), and brainstem involvement associated with other symptoms or signs was diagnosed in twelve other patients. Pure tone audiograms were normal in all patients. BAEPs were abnormal in 7 patients (36.8 %); all of whom had symptoms or signs suggesting brainstem involvement. The BAEP abnormalities observed were: - absence of one or more components associated with an increase in latencies in two patients (4 ears) (Nos. 8, 12) (Fig. 5); - an increase in latencies in two patients (4 ears) (Nos. 6, 14) (Fig. 6); - a reduced amplitude ofV wave (200 %) in one patient (1 ear) (No. 3); - an increase in latencies with reduced V wave amplitude in two others (4 ears) (Nos. 13 and 14) (Fig. 7).
V. Scaioli et al
N europediatrics 22 (1991)
3. Somatosensory system
Cz-Ai
Sensory disturbances during multifocal poussees were observed in five patients. At the onset of the disease, only one case (No. 11) displayed a sensory-motor syndrome suggesting spinal cord involvement. Another patient (No. 15) displayed the same symptoms together with the involvement of brain structures. SEPs were abnormal in 8 patients (420/0; 14/16 sides) but only in 4 out of 9 patients with sensory signs or symptoms. However, in 4 other cases subclinical somatosensory impairment was revealed by SEPs.
I
Cz-Ai
~.9.15}JV 1ms Fig. 6 BAEPs recorded in Case 6. For right (upper traces) and left (Iower traces) ear stimulation an increase of latency and interpeak time, with preserved shape, was observed. The patient had MRI brainstem findings consistent with inferior colliculi lesion.
RE Cz..Ai
SEP pattern abnormalities were classified in agreement with Mauguiere (24). In two patients (Nos. 3 and 13) (4 sides) the far-field P9 and PlI were clearly recognizable with normal parameters while the P14 component appeared questionable and N18 was almost suppressed. The N20 component was abolished bilaterally in one (No. 3) and unilaterally in the other patient (No. 13) in whom latency delay was observed on the other side (Fig. 8). SEP findings in these patients showed an abnormal cervico-medullary pattern suggesting significant lesions located in the cervical spinal cord or in the brainstem. In four cases (Nos. 2, 10, 14 and 19) (6 sides) the far-field P9, PlI, P14 and the N18 components were preserved, whereas the N20 component was slightly to moderately increased in latency and more clearly reduced in amplitude. Central conduction time N13-N20 was significantlyincreased in these four cases (Figs. 9 and 10). These patients had an abnormal thalamo-cortical pattern: therefore significant lesions located within the thalamo-cortical sensory pathways can be hypothesized. The last two patients (Nos. 8 and 11) (4 sides) showed a combination of the above described cervicomedullary and thalamo-cortical patterns: that means, in one
LE Cz...Ai
Fz-Cd
sh-cd I
Fig. 7 BAEPs recorded in Case 14. Bilateral abnormalities consistent with reduced amplitude of wave V, inversion of amplitude ratio IjV were observed; to right (RE) ear stimulation wave V was also increased in latency. Multiple MRI brainstem lesions were found.
Sh-Ci'
AI-Cv6 1
AI-Er
third case, a clear correlation was not possible because of technicallimitations (movement artifacts at MRI). A poor correlation between the number and size of abnormal signal areas at MRI and the severity and type of BAEP alteration was found (6 patients); however, the type of BAEP abnormality showed a good correspondence with the 10cation of the lesions within the brainstem: all of the 6 patients had lesions in the lower pons.
Fig.8 Case 13. SEPs to median nerve stimulation; cephalic (Fz) and noncephalic reference (shoulder) for cortical leads (contralateral -Cc'- and ipsilateral -Ci' - centroparietal regions) and linked ear (AI) for Erb's point (Erb) and spinal cord (Cv6). On right and left side pg and PlI far-field are present; P14 and later component are absent. The spinal cord N 13 component appear suppressed.
Downloaded by: NYU. Copyrighted material.
20
EP and MRIStudies in Childhood MS
Neuropediatrics 22 (1991)
21
13) with abolished N13 and N20 components had no detectable lesion in either the brainstem or the cervical spinal cord. FZ-CC'Ir=_-~--
N11 N13
I
,
~
AI-Cv6.1.~~ _ _'"C'!~~....c:...--,..-:"'--e,..;;>ooo~"",,-,,~-~ 1
AI-Erb!1 ~
_16.pV 7.ms
Fig. 9 Case 8. Same recording condition as in Fig. 8. SEPs to right median nerve stimulation: the far-field P9, PlI, and P14 and the N18 component are normal. The N20 component was increased in latency.
Sh-Cc
sh-ci
Sh·C~
I
sh-ci
Ir
_ls.}Jv '] ms
Fig. 10 Case 14. SEP to right median nerve stimulation are normal (upper traces). To left side stimulation the far-field P9, PlI, P14 and the N18 component were normal: the N20 cortical component was markedly reduced in amplitude and slightly increased in latency (Iower traces).
side the P 14 and the N 18 were substantially abolished and in the other side only the N20 component was abnormal. MRI findings fit poorly with the types of SEP abnormalities. Only one (No. 11) of the four patients with a cervico-medullary pattern had a single MRI lesion in the cervical spinal cord; one (No. 3) had no MRI lesions in the brainstem or cervical spinal cord and the other two showed lesions in the brainstem. It is worth noting that the two patients (Nos. 8 and
In addition, three other patients with normal SEPs had MRI lesions in the subcorlical parietal region (2 cases) or in the internal capsule (1 case).
Discussion In the last years, EP and MRI were extensively investigated in MS and their diagnostic superiority, in comparison with other laboratory techniques, is weIl established. RecenUy, in several papers, MRI and EP were compared in adult MS and the relative diagnostic values, the sensitivity and the specificity of these techniques has been evaluated. Only a few data are available for pediatric patients affected by MS in which the utility of EP and MRI has to be clarified. The rarity of MS in childhood and the frequency of an atypical clinical presentation (i. e. epileptic seizures, acute psychosis, extrapyramidal involvement or facial myokymia), as observed in abaut one third of our patients, emphasized the relative usefulness of MRI and EP techniques in the ascertainment of this disorder. The comparison of EP and MRI results indicate that these techniques had a high diagnostic yield, and that MRI is the more sensitive diagnostic tool in ascertaining of MS. In fact a high frequency of multifocal brain involvement was revealed in the present study as has also been reported in adult MS series (16~ 27). However, it must be kept in mind that 16 out of 19 patients had a clinical diagnosis of Definite Multiple Sclerosis. In the adult population, MRI has been reported to be more sensitive than EP in Suspected or Probable MS (14), while in Definite MS high diagnostic sensitivity has been reported for both EP studies and MRI techniques (6, 17); only by Giesser (15) a higher sensitivity for EP than for MRI has been reported. Although no specific pattern for MS was identified, the topography~ form and distribution of the MRI findings were similar to those described in numerous studies performed in adults, and were typical of MS. In agreement with previous studies MRI revealed abnormalities in supratentorial brain structures more frequently than in other brain regions (84.2 % vs 63.1 %) and with a higher incidence than that of VEPs and SEPs (47.4 %). In the brainstem, clinical signs and symptoms were encountered more frequently (73.7 %) than MRI-detected lesions (47.4 %) or BAEPs (36.8 %). For MRI-detected lesions in the brainstem and cerebellum, positive correlations with clinical, electrophysiological and imaging techniques were found. No asymptomatic lesion was demonstrated by either BAEP or MRI, particularly in the brainstem. In effect BAEPs are considered to be less sensitive than other EP procedures and laborato-
Downloaded by: NYU. Copyrighted material.
1
Of the six patients with a thalamo-corlical pattern' one (No. 2) had bilaterallesions in the internal capsule but unilateral SEP abnormalities; one (No. 14) had a left internal capsule lesion but a right SEP thalamo-corlical pattern; two (Nos. 10 and 19) showed only periventricular lesions and one (No. 11) had no lesions either in the brainstem or in the supratentorial brain areas. Only in the sixth patient (No. 8) was a left thalamo-cortical pattern associated with a left thalamic MRI lesion.
Neuropediatrics 22 (1991)
ry tests in adult MS, independently of the clinical category (6, 34); the results of our study in childhood confirms these data while indicating that BAEPs may be useful in confirming equivocal clinical brainstem symptoms. VEPs and SEPs frequently detected asymptomatic involvement of the CNS in brain regions which elude conventional MRI investigations, i. e. optic nerves and part of the central somatosensory pathways. In fact, VEP and SEP abnormalities were frequently present in patients without clinical disturbances, and SEPs showed no positive correlations with MRI. In addition, it must be remembered that the cervical spinal cord was the CNS region in which MRI detected abnormal areas less frequently. VEPs are probably the most sensitive EP procedure for detecting subclinical abnormalities in MS with onset in childhood. This assumption has been recently confirmed in comparative studies between MRI of the optic nerve and VEPs in MS patients with optic neuritis (ON) and with isolated ON (25). Although technical reasons may be responsible for the non-correspondance between MRI and VEP, other factors might contribute to the discrepancies observed. The extent of the involvement of the optic nerve may be small and small size lesions, although significant enough to produce clinical or electrophysiological signs, may be undetectable to MRI (25). As a matter of fact, a high incidence of extinguished or suppressed responses was observed with small check-size stimulation, suggesting a selective involvement of fibers originating from the central region of the retina (33). Moreover, it has been suggested that several pathophysiological mechanisms may be responsible for electrophysiological abnormalities in MS (1, 2). The different types of VEP abnormalities observed in the majority of asymptomatic nerves in our patients employing different checksize stimulations support this view. The use of non-cephalic references in SEP recording proved to be highly sensitive in providing detailed information about the topography of the lesions along the somatosensory pathways. Distinct, separate neural generators for spinal N13 and far-field P14, as weIl as for N18 and N20 have been suggested by studies performed in normals (7) and confirmed by studies in patients with weIl-Iocalized lesions (21, 24, 35). Furthermore, the topodiagnostic localizing power of SEPs for lesions along the ascending somatosensory pathways has allowed the identification of some definite pathophysiological patterns of SEP abnormalities (13). In most of the papers dealing with MRI and SEPs in MS, recordings were made using only the cephalic reference and so comparison with MRI was not feasible. Only recently the usefulness of SEP recordings by means of noncephalic reference has been emphasized in MS (13), but no comparative study with MRI has been performed. The poor correlation between SEPs and MRI found in the present series may be due to the clinical stage of the disease, with the cumulative effect of undetectable MRI lesions along the somatosensory pathways leading to SEP abnormalities. Therefore, it may be deduced that the highly variable course of MS and the longitudinal axial extension of afferent sensory fibers make it difficult and unnecessary to find a satisfactory anatomo-pathophysiological correlation. In conclusion, although MS with onset in childhood is a rare clinical condition, it should be considered not
V. Scaioli et al
only in young patients with disseminated multifocal acute symptoms, but also in those with isolated focal brain syndromes. MRI and EP are useful both in confirming equivocal signs and, particularly, in revealing asymptomatic multifocal CNS involvement. MRI and EP appear not only to give reciprocal confirmation of a clinical diagnosis of MS, but also, as the present report indicates, to provide information concerning the spatial and temporal distribution of demyelinating plaques in the brain.
References 1
Blumhardt, L. B.: Visual Field Defects and Pathological Alteration in To-
8
pography: Factors Complicating the Estimation of Visual Evoked Response "Delay" in Multiple Sclerosis. In: Evoked Potentials. Cracco, R. Q., Bodis-Wollner, 1. (Eds.), New York, Alan R. Liss (1986) 354-365 Bodis-Wollner, I., M. Ono.fij: System diseases and visual evoked potentials diagnosis in neurology: changes due to synaptic malfunction. Ann. NY Acad. Sei. 388 (1982) 327-348 Bye, A. M. E., B. Kendall,]. Wilson: Multiple sclerosis in childhood: a new look. Dev. Med. Child Neurol. 27 (1985) 215-222 Chiappa, H. K.,]. L. Harrison, E. B. Brooks, R. R. Young: Brainstem auditory evoked responses in 200 patients with multiple sclerosis. Ann. Neurol. 7 (1980) 135-143 Crisp, D. T,]. E. Kleiner, G.]. DeFillip,]. 1. Greenstein, T H. Liu, D. Sommers: Clinical correlation with magnetic resonance imaging in multiple sclerosis. Neurology 35 (Suppl. 1) (1985) 137 Cutler,]. R., M.]. Aminoff, M. Brant-Zawadski: Evaluation of patients with multiple sclerosis by evoked potentials and magnetic resonance imaging: a comparative study. Ann. Neurol. 20 (1986) 645-648 Desmedt,]. E., G. Cheron: Central somatosensory conduction in man; neural generators and interpeak latencies of the far-field components recorded from neck and right or left scalp or earlobes. Electroencephalogr. Clin. Neurophysiol. 50 (1980) 382 Duquette, P., T]. Murray,]. Pleines, G. C. Ebers, D. Sadovnick, P.
9
Weldon, S. Warren, D. W. Paty, A. Upton, W. Hader, R. Nelson, A. Auty, B. Neufeld, C. Meltzer: Multiple sclerosis in childhood: clinical profile in 125 patients. J. Pediatr. 111 (1987) 359-363 Eisen, A., K. Odusote, D. Li, W. Robertson, S. Purvis, K. Eisen, D. Paty:
2
3 4
5
6
7
Comparison of magnetic resonance imaging with somatosensory testing in MS suspected. Muscle Nerve 10 (1987) 385-390 10 Farlow, M. R., O. N. Markand, M. K. Edwards,]. C. Stevens, 0.]. Kolar: Multiple sclerosis: magnetic resonance imaging, evoked responses, and spinal fluid electrophoresis. Neurology 36 (1986) 828-831 11 Fischer, C., F. Mauguiere, V. Ibanez,]. Couljon: Potentieis evoques visueIs, auditifs precoces et somesthesiques dans la sclerose en plaques (917 cas). Rev. Neurol. 5 (1986) 517-523 12 Gaerlinger, M. H.: Contribution al'etude de la sclerose en plaques infantile. L'Echo Med. Nord (1909) 13-37 13 Garcia-Larrea, L., F. Mauguiere: Latency and amplitude abnormalities of the scalp far-field P14 to median nerve stimulation in multiple sclerosis. A SEP study of 122 patients recorded with non-cephalic reference montage. Electroencephalogr. Clin. Neurophysiol. 71 (1988) 180-186 14
Gebarsky, S. S., T O. Gabrielse, S. Gilman,]. E. Knake,]. T Latack, A. M. Aisen: The initial diagnosis of multiple sclerosis: clinical impact of
15
Giesser, B. S., D. Kurtzberg, H. G. Vaughan,]. C. Arezzo, M. L. Aisen, C. R. Smith, N. G. LaRocca, L. C. Scheinberg: Trimodal evoked potential
magnetic resonance imaging. Ann. Neurol. 17 (1985) 469-474
compared with magnetic resonance imaging in the diagnosis of multiple sclerosis. Arch. Neurol. 44 (1987) 281-284 16 Golden, G. S., R. C. Woody: The role of nuclear magnetic resonance imaging in the diagnosis of MS in childhood. Neurology 37 (1987) 689-683 17 Guerit,]. M., A. Monje Argiles: The sensitivity of multimodal evoked potentials in multiple sclerosis. A comparison with magnetic resonance imaging and cerebrospinal fluid analysis. Electroencephalogr. Clin. Neurophysiol. 70 (1988) 230-238 18 Haas, G., G. Schorth,]. Krageloh-Man, M. Buchwald-Saal: Magnetic resonance imaging of the brain of children with multiple sclerosis. Dev. Med. Child Neurol. 29 (1987) 586-591 19
Izquierdo, G., O. Lyon-Caen, R. Marteau, Martinez-Parra, F. Lermitte, P. Castaigne,].]. Hauw: Early onset multiple sclerosis. Clinical study in 12 pathologically proven cases. Acta Neurol. Scand. 73 (1986) 493-497
Downloaded by: NYU. Copyrighted material.
22
EP and MRI Studies in Childhood MS
N europediatrics 22 (1991)
L., W. R. Kinkel, 1. Polachini, R. P. Kinkel: Correlations ofnuclear magnetic resonance imaging, computerized tomography, and clinical profiles in multiple sclerosis. Neurology 36 (1986) 27-34 21 Matthews, W. B., M. Esiri: Multiple sclerosis plaque related to abnormal somatosensory evoked potentials. J. Neurol. Neurosurg. Psychiatry 42 (1979) 940-942 22 Matthews, W. B.,]. R. B. Wattam-Bell, E. Pountney: Evoked potentials in the diagnosis of multiple sclerosis: a follow-up study. J. Neurol. Neurosurg. Psychiatry 45 (1982) 303-307 23 Mauguiere, F.: Short-latency somatosensory evoked potentials to upper limb stimulation in lesions of brainstem, thalamus and cortex. Electroencephalogr. Clin. Neurophysiol. (Suppl.) 39 (1987) 302-309 24 Mauguiere, F., V. Ibanez: The dissociation of early SEP component in lesions of the cervico-medullary junction: a cue for routine interpretation of abnormal cervical responses to median nerve stimulation. Electroencephalogr. Clin. Neurophysiol. 62 (1985) 406-420 25 Miller, D. H., M. R. Newton,]. C. Van der Poel, E. P. G. H. Du Boulay, A. M. Halliday, B. E. Kendal, G. ]ohnson, D. G. MacManus, 1. F. Moseley, W. 1. McDonald: Magnetic resonance imaging of the optic nerve in optic neuritis. Neurology 38 (1988) 175-179 26 Milner, B. A., D. Regan,]. R. Heron: Differential diagnosis of multiple sclerosis by visual evoked potential recording. Brain 97 (1974) 755-772 27 Ormerod,]. E. C., D. H. Miller, W.1. McDonald, E. P. G. H. DuBoulay, P. Rudge, B. E. Kendal, 1. F. Moseley, G. ]ohnson, P. S. Tofts, A. M. Halliday, A. M. Bronstein, F. Scaravilli, A. E. Harding, D. Barnes, K.]. Zilkha: The role of NMR imaging in the assessment of multiple sclerosis and isolated neurologicallesions. A quantitative study. Brain 110 (1987) 1579-1616 28 Paty, D. W.,].]. F. Oger, L. F. Kastrukoff, S. A. Hashimoto,]. P. Hooge, A. A. Eisen, K. A. Eisen, S.]. Purves, M. D. Low, V. Brandeis, W. D. Robertson, D. K. B. Li: MRI in the diagnosis of multiple sclerosis: a prospective study with comparison of clinical evaluation, evoked potentials, oligoclonal banding and CT. Neurology 38 (1988) 180-185 29 Poser, C. M., D. W. Paty, L. Scheinberg, W.1. McDonald, F. A. Davis, G. C. Ebers, K. P. ]ohnson, W. A. Sibley, D. H. Silberberg, W. W. Tourtellotte: New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann. Neurol. 13 (1983) 227-231 30 Rimbaud, L., Riser, Geraud: De la sclerose en plaques chez l'enfant. Rev. Neurol. 5 (1938) 477-481 31 Sheremata, W., S. B. Brown, R. R. Curless, H. G. Dunn: Childhood multiple sclerosis: areport of 12 cases. Ann. Neurol. 10 (1981) 304 32 SmalI, D. G., W. B. Matthews, M. Small: The cervical somatosensory evoked potential (SEP) in the diagnosis of multiple sclerosis. J. Neurol. Sci35 (1978)211-224 33 Tartaglione, A., A. Oneto, F. Bandini, L. Spadavecchia, E. Gandolfo, E. Favale: Electrophysiological detection of "silent" plaques in the optic pathways. Acta Neurol. Scand. 76 (1987) 246-250 34 Tramo, M.]., M.]. Scheck, B. C. P. Lee, S. Rapoport: Evoked potentials and MRI in the diagnosis of multiple sclerosis. Neurology 35 (Suppl. 1) (1985) 105 35 Urasaki, E., S. Vada, C. Kadoya, H. Matsusaki, A. Yokota, S. Matsuoka: Absence of spinal N13-P13 and normal scalp far-field P14 in a patient with syringomyelia. Electroencephalogr. Clin. Neurophysiol. 71 (1988) 400-404
23
20 ]acobs,
Dr. V. Scaioli Dept. of Clinical Neurophysiology Istituto Neurologico "C. Besta" Via Celoria No. 11 1-20133 Milano, Italy
100 und mehr knifflige Impffragen Downloaded by: NYU. Copyrighted material.
Von U. QUAST, Marburg/Lahn 3., erweiterte Auflage von »Hundert knifflige Impffragen« 1991, 232 Seiten, 4 Abbildungen, 8 Tabellen, 12 x 19 cm, kartoniert DM 29,ISBN 3-777J-0994-X
Das Studium dieser wesentlich erweiterten praxisnahen, fundierten Übersicht wird für viele Fragestellungen eine korrekte Antwort geben und daher dem Arzt auch die für Impfungen so notwendige Aufklärungsarbeit ermöglichen.
Ich bestelle aus dem Hippokrates Verlag Stuttgart durch die Buchhandlung: ........ Expl. QUAST, 100 und mehr knifflige Impffragen, DM 29,ISBN 3-7773-0994-X
Unterschrift
.
Näm'e'('iiiö'girChst'St~'iiip'eÜ"""'"''''''''''''''''''''''''
Straße Ort
..·····..·······..······ ··· · ·..·..·..· ····
.
D·ät~iii··
(Preisänderung vorbehalten)
Hippokrates Verlag Stuttgart Postfach 10 2263
7000 Stuttgart 10
283
