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Abstracts voordrachten KNF-dagen 20 April 2006

120% supramaximal stimulation suffices for CMAP recordings

Ellen M. Maathuis, Gerhard H. Visser, Joleen H. Blok
Dept. of Clinical Neurophysiology, Erasmus MC Rotterdam, The Netherlands

Introduction: Recordings of the maximum CMAP require sufficiently strong stimuli. To achieve this in clinical
practice, the lowest stimulus intensity (SI) that produces a maximal CMAP on visual inspection is usually
increased by a varying amount (between 20 and 50% of the determined SI) for final recordings.4-6 The aim of this
study was to determine how large this surplus SI should be. The use of a supramaximal SI is motivated by the
probabilistic response of axons to applied stimuli1-3 over an “activation range” of SI values (range over which the
firing probability increases from 0 to 100%). Starting from the SI at which the maximum CMAP can first be
obtained (SImax), SI should therefore be increased by an amount identical to the activation range of a MU to be
certain of maximal CMAPs on every subsequent stimulus. For that reason, we aimed to determine the width of
this activation range as percentage of SImax.
Methods: We used stimulated single fiber EMG (SFEMG) of the first dorsal interosseus muscle in 5 healthy
subjects. The ulnar nerve was stimulated percutaneously at the wrist. When visual inspection indicated that a
stable single fiber potential was obtained, the number of times the MU was activated in response to 50 stimuli of
constant SI was determined for a range of SI. This number was expressed as percentage of the 50 applied stimuli
to obtain the firing probability of the MU. If another potential could be obtained by slight manipulation of the
needle or by adjusting SI beyond the range of the first, stimulus-reponse curves were recorded for this second
fiber. After two or three MU curves were obtained, the needle was shifted to a significantly different position
within the muscle and the procedure was repeated. Each recording of a MU curve was followed by a registration
of the so-called scan of the muscle (CMAP vs. SI), to determine the lowest SI at which the maximum CMAP
could be recorded (SImax). The widths of the activation ranges of the recorded MUs and SImax were determined
using curve-fitting procedures implemented in Matlab. Finally, for each MU activation curve the supramaximal
percentage (SMP) value was determined by dividing its range width into SImax.
Results: Between 4 and 7 different MU activation curves were obtained per subject (total 27). These curvewere
mostly obtained for low to intermediate SIs (SIs that generated CMAPs of 0-35% of the maximum CMAP). The
corresponding SMP values ranged between 2.0% and 9.0%; their mean value was 4.5%. There was no
statistically significant correlation between SMP and SI (Spearman correlation; p=0.43).
Discussion & Conclusions: An important result of this study is that we have been able to isolate the
contributions of single fibers in stimulated single fiber EMG of a distal muscle even at higher stimulus
intensities. As far as we know, this possibility has not been reported previously. Because our results showed no
systematic bias towards larger or smaller SMP with increasing SI, we consider them sufficiently representative
for the highest threshold MUs. Adding 10% to SImax suffices to obtain maximal CMAPs consistently in healthy
subjects. Because accurate determination of SImax may be difficult and because results in patients may be
different, we recommend use of an additional safety margin of 10%. We conclude that stimulation at 120%
(1.2×SImax) suffices to obtain maximal CMAPs.
References :
1. Bergmans J (1970). The physiology of single human nerve fibres. Vander.
2. Brown WF, Milner Brown HS (1973). J Neurol Neurosurg Psychiatry. 1976 Mar;39(3):249-57.
3. Hales JP, Lin CS, Bostock H. J Physiol. 2004 Sep 15;559(Pt 3):953-64.
4. Kimura J. Electrodiagnosis in diseases of nerve and muscle. New York: Oxford University Press, 2001.
5. Meulstee J. Stimulatietechniek. In: Van Dijk J.G. (Ed.) EMG voor de algemeen neuroloog.
6. Oh SJ. Clinical Electromyography.Baltimore: Williams & Wilkins, 1993. Motor Evoked Potentials as a biological outcome measure in Multiple Sclerosis?
NF Kalkers, RLM Strijers, MMS Jasperse, V Neacsu, F Barkhof, CH Polman, CJ Stam
Vumc, Amsterdam, the Netherlands.

Introduction: Several outcome measures for measuring disability and progression are used in Multiple
Sclerosis (MS) trials. Clinical outcome measures include the Expanded Disability Status Scale (EDSS)
and the MS Functional Composite (MSFC), the latter comprising tests for cognitive function, hand-
function (9 hole peg test; 9-HPT) and leg function (timed walk test; TWT). Biological outcome
measures include Magnetic Resonance Imaging (MRI) techniques. However, none of these appear to
be ‘gold standards’ for measuring in vivo pathology and disability. Therefore, Motor Evoked Potentials
(MEP) were proposed, providing data on the function of the central motor pathways. MEP could
therefore serve as an objective marker of neurological dysfunction. We studied whether MEP can serve
as a sensitive and reliable measure for evaluating neurological dysfunction in MS, by relating MEP to
clinical and MRI measures.
Methods: Fifty-two patients with MS were included. We performed transcranial magnetic stimulation
of the motor cortex on each patient to determine the conduction time to both arms (m. adductor quinti)
and both legs (m. tibialis anterior). We recorded F-wave responses and used these to calculate the
Central Conduction Time (CCT). We calculated Z-scores for each CCT (ZCCT) based on reference
values matched for height. All patients underwent an MRI scan, of which T1 and T2 brain lesion
volumes, brain volume and spinal cord volume were derived. The MSFC and EDSS were performed in
all patients. For statistical analysis, Spearman rank correlation coefficients were calculated and linear
regression analysis was performed with the MSFC and EDSS as dependent measure.
Results: We found a significant correlation between TWT and ZCCT of both legs (r=0.43 and
r=0.45;p<0.01). Patients with absent CCT’s to one or both legs performed significantly worse on the
TWT than patients with present CCT’s (p<0.001).We found no significant correlations between
ZCCT’s of the individual arms and their corresponding 9-hole peg test. T1 lesion volume correlated
with ZCCT of the right arm (r=0.31;p<0.05), left arm (r=0.29;p<0.05) and left leg (r=0.30;p<005), as
T2 lesion volume and brain volume correlated with ZCCT of the right arm only (r=0.30;p<0.p<0.05
and r=-0.47 and p<0.05 respectively). The EDSS showed correlations with ZCCT of the right arm
(r=0.41;p<0.01), left arm (r=0.36;p<0.05), left leg (r=0.51;p<001) and right leg (r=0.46;p<0.01). Linear
regression analysis revealed that the MSFC was explained by both T1 lesion volume and ZCCT left
arm (adjusted R2=0.56), and that EDSS was explained by both ZCCT right arm and T2 lesion volume
(adjusted R2=0.52).
Conclusion: In this study we found a relation between MEP, brain and spinal cord MRI measures, and
both the EDSS and the MSFC. Moreover, a model for explaining disability in MS revealed that MEP
provides an added value above MRI measures, suggesting that MEP can serve as a biological outcome
measure in MS.
Can hyperventilation cause syncope?
R.D.Thijs1, J.G. van den Aardweg 2, J.J. van Lieshout 3, R.H.A.M. Reijntjes1, J.Gert van Dijk1
1Department of Neurology and Clinical Neurophysiology, Leiden University Medical Centre, Leiden,
the Netherlands
2 Department of Pulmonology, Medical Centre Alkmaar, Alkmaar, the Netherlands
3 Department of Internal Medicine, Academic Medical Centre, Amsterdam, the Netherlands.

Background: Contrary to common belief, it is not clear whether hyperventilation can cause syncope.
Hyperventilation has been observed to precede tilt-induced vasovagal syncope, but it is unknown
whether it contributes to or counteracts syncope.
Methods: 11 Healthy subjects were studied in three conditions: normal ventilation (NV), hypocapnic
hyperventilation (HHV) and isocapnic hyperventilation (IHV). The target end-tidal CO2 tension of the
HHV condition was set at 2.0-2.5%. For each condition measurements were first taken for 15 min. in a
supine and then 15 min. in a tilted position. Heart rate (HR), finger blood pressure, and cerebral blood
flow velocity of middle cerebral artery (CBFV) were measured continuously. ANOVA testing for
repeated measures was used with a Bonferroni-Holmes correction for multiple comparisons.
Results: No subject experienced a syncopal episode. HHV caused a significant increase of the supine
HR (95% CI 7 -16 bpm) and mild changes of the supine mean arterial pressure (MAP) (95% CI -1 mm
Hg - +6 mm Hg) compared to NV. However, a significant increase of the supine MAP was observed in
the last 10 minutes of HHV compared to the first five minutes of HHV (95% CI 2 mm Hg – 12 mm
Hg). Also compared to NV, IHV caused a significant increase of the supine MAP (95% CI 1-13 mm
Hg) without substantial changes of the supine HR. During head-up tilt, no significant changes of HR
were found during HV or IHV. However, the MAP in the tilted position was compared to NV
significantly increased during HV (95% CI 3 - 11 mm Hg) and even more markedly increased during
IHV (95% CI 11 – 20 mm Hg).
Conclusion: In healthy subjects prolonged HHV did not provoke syncope. The finding of a higher
blood pressure in the tilted position suggests that prolonged HHV in fact protects against syncope in
healthy subjects.
This increase of MAP is best explained through increased action of the respiratory pump: this not only
increases ventilation, but also increases venous return through a more negative inspiratory pressure,
which in turn affects the arterial circulation.
Utility and feasibility of the H-reflex in spastic children treated with intrathecal baclofen: a
placebo-controlled study

M.A. Hovinga, V.H.J.M. van Kranen-Mastenbroekb, E.P.M. van Raaka, G.H.J.J. Spincemaillec, E.L.M. Hardyd,
J.S.H. Vlesa, on behalf of the Dutch Study Group on Child Spasticity†
aDepartment of Neurology, bDepartment of Clinical Neurophysiology, cDepartment of Neurosurgery,
dDepartment of Clinical Pharmacy and Toxicology; University Hospital Maastricht, the Netherlands

Evaluate feasibility and utility of the soleus H-reflex in identifying spinal cord neuronal
response to intrathecal baclofen (ITB) in children with severe spastic cerebral palsy.
Methods: During a randomized, double-blind, placebo-controlled dose-escalation test treatment, the
H/M ratio (maximum H amplitude/maximum M amplitude) was bilaterally recorded at baseline and 2-3
hours after intrathecal bolus administration of placebo and increasing doses of baclofen. A positive
clinical response was achieved as both an improvement in the individual treatment goal(s) and a one-
point reduction on the Ashworth Scale were observed.
Results: Eight girls and six boys, aged between 9 and 16 years (mean 13.43±2.47), were included. The
soleus H-reflex was feasible in 13 of the 14 children. The effective ITB dose was 12.5 µg in one child,
25 µg in eight and 50 µg in five children. After administration of the effective ITB dose, the H/M ratio
significantly decreased (left legs: 0.67±0.47 to 0.15±0.18, P=0.005; right legs: 0.55±0.32 to 0.14±0.19,
P=0.002). In relative terms, H/M ratios after ITB on the left and right legs measured on average 25%
and 33% of the respective baseline values. The H/M ratio after placebo was similar to baseline for both
legs (left legs: 0.67±0.47 at baseline and 0.85±0.90 after placebo; right legs: 0.55±0.32 at baseline and
0.58±0.46 after placebo). In relative terms, H/M ratios after placebo on the left and right legs measured
on average 121% and 109% of the respective baseline values.
Conclusions: This is the first randomized, double-blind, placebo-controlled dose-escalation study in
spastic children demonstrating the soleus H-reflex to be a feasible and objective measure to quantify
spinal cord neuronal response to ITB bolus administration.
Significance: We suggest introducing the soleus H-reflex as the electrophysiological gold standard for
the evaluation of spinal cord responsiveness to ITB in spastic children.
† The participants of the Dutch Study Group on Child Spasticity are: J.G. Becher, R.J. Vermeulen, VU Medisch Centrum, Amsterdam;
O.F. Brouwer, C.G.B. Maathuis, Universitair Medisch Centrum Groningen, Groningen; C.E. Catsman-Berrevoets, Erasmus MC,
Rotterdam; J. Gerritsen, Isala Klinieken, Zwolle; M.J.P.M. Geerts, Revalidatiecentrum Leijpark, Tilburg; P.H. Jongerius, Sint
Maartenskliniek, Nijmegen; O. van Nieuwenhuizen, Universitair Medisch Centrum Utrecht, Utrecht; J.J. Rotteveel, Universitair Medisch
Centrum St Radboud, Nijmegen; L.A.W.M. Speth, Hoensbroeck Revalidatiecentrum, locatie Franciscusoord, Valkenburg; H. Stroink,
Sint Elisabeth Ziekenhuis, Tilburg; J.S.H. Vles, Academisch Ziekenhuis Maastricht, Maastricht; E.G. van der Ziel, Revalidatiecentrum
Het Roessingh, Enschede.

Correspondence address of the main author
Marjanke A. Hoving, MD
Department of Neurology
University Hospital Maastricht
P. Debyelaan 25, Postbus 5800
6202 AZ Maastricht, The Netherlands
Telephone: +31433875058
Fax: +31433877055
M. Zijlmans, G.J.M. Huiskamp, M. Hersevoort, J.H. Seppenwoolde, F.S.S. Leijten, A.C. van Huffelen
Rudolf Magnus Institute, University Medical Center Utrecht, Utrecht, The Netherlands

Objective: Recording EEG during fMRI-scanning is technically feasible and safe. Software exists for
removing MR-induced EEG-artifacts. Results from the literature have shown that correlating epileptic
EEG-transients to fMRI(BOLD)-signal yields additional information about the generators of epileptic
activity. We have recorded simultaneous EEG-fMRI in patients with intractable focal epilepsy, who
have been considered for epilepsy surgery but were rejected on basis of lacking evidence regarding
Methods: We recorded fMRI-EPI-sequence (TR=2.5 sec) with simultaneous EEG using a 31-
electrode-cap in ten patients. EEG-artifacts were removed and interictal discharges were identified by
two experienced observers and an interobserver agreement analysis was performed. The consensus
epileptiform discharges were used for event-related analysis of the BOLD-response.
Results: Interobserver agreement was high in six and reasonable in two patients. Significant BOLD
(de)activation was seen in five patients. Generalized discharges yielded results in concordance with
recent reports in literature. At least one patient showed a focal BOLD-response that would justify
reconsidering epilepsy surgery. In one patient with unequivocal temporal lobe discharges no
(de)activation was found, possibly due to susceptibility-artifacts.
EEG-fMRI can clarify localization problems in selected cases. Unequivocal discharges are needed for
reliable fMRI analysis. For temporal lobe epilepsy other fMRI-sequences could be considered.

Inhibition of cortical laser evoked potentials by transcutaneous electrical nerve stimulation

Brandsma D1, van Swol CF2, Jonker G3, Boezeman EH1, van Dongen EP3, Nijhuis HJ3.
1 Department of Clinical Neurophysiology, 2 Department of Biomedical Engineering, 3 Department of
Anesthesiology and Intensive Care, St Antonius Hospital, Nieuwegein, The Netherlands.

Myelinated Aδ and unmyelinated C fibers are the primary nociceptive afferents of the
skin. Melzack and Wall (1965) have suggested an inhibition of nociceptive processing within the spinal
dorsal horn and/or thalamus by simultaneous activation of tactile afferents mediating touch (gate-
control theory). Based on this concept, patients with chronic pain are being invasively treated by
electrical stimulation of tactile Aβ afferents within peripheral/cranial nerves or the dorsal
columns/roots of the spinal cord. Furthermore, transcutaneous electrical nerve stimulation (TENS) is
being widely used as an afferent stimulation technique for pain alleviation. Although these
neuromodulatory methods have been applied for decades, their clinical application and indication are
controversial because the supposed antinociceptive effect in humans has not been objectively proven so
far. A major reason for the limited progress on the knowledge on nociception was the lack of a
quantifiable method to selectively activate Aδ and C-fibers with no or low concurrent activation of
other sensory modalities. Infrared laser stimulation of the skin has been shown to selectively activate
Aδ and C fibres, being followed by a late evoked potential at the vertex (Laser Evoked Potential (LEP),
which consists of a N2 and P2 component in a time window between 175 and 500 ms), mainly due to
Aδ stimulation and an ultralate evoked potential (>800 ms) caused by C fiber stimulation. Late LEPs
are considered to be closely related to the perception of pain and a strong relationship between the
amplitude of the LEP and subjective pain rating has been found. Therefore, determining late LEP
characteristics may be an objective way to evaluate the effects of invasive (e.g. spinal cord stimulation)
and non-invasive (TENS) pain alleviation methods.
Aim and methods: In order to determine the effect of TENS on the LEP features we performed a pilot
study in a series of thirteen healthy subjects. Cutaneous heat stimuli (0.5-3 W, 50 ms, spotsize 5 mm2)
were delivered by a 980 nm diode laser to the blackened dorsum of the right hand (C6 dermatome). To
record baseline LEPs, 10 single stimulus pulses were presented in a random order and averaged off
line. A 110 Hz twin dual channel TENS unit (Rehan Electronics Ltd, Weckford, Ireland) was then
applied for electrical stimulation of the dorsal side of the lateral forearm. The intensity of TENS was
increased until the subject felt a strong but comfortable sensation. Next, LEPs were recorded following
varying periods of TENS (1 and 10 min) and 10 min after TENS was switched off. After each laser
stimulus, subjects were instructed to report the intensity of perceived pain on a visual analogue scale
(VAS: 0-10).
Results A significant decrease in the area under the curve (AUC175 - 500 ms) was found in subjects treated
with TENS during 10 min (mean decrease 26%; 95% CI: 1.2-50.4), but not after 1 min (29%; 95% CI:
-1.8-59.8). The AUC reduction remained significant 10 min after TENS was switched off (28%; 95%
CI:3.0-52.9). The median VAS decreased 1 point (–2.5 to 3) after 1 min TENS, 2 points (range –2 to 3)
following 10 min TENS and 1 point after TENS was switched off during 10 min (range –0.5-2).
Conclusions: Our data suggest that a VAS decrease after TENS is associated by a reduction of the
AUC of the late LEP.


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