Clik~~/ N~wolog~ trnd Neurosurpry, 94 ( 1992) X23-327

0 1992 Elhevier Science Publishers B.V. All rights reserved 030~.8467/92/$0.5.(M)

CLINELI 00224

Society Proceedings

Amsterdam Society of Neurologists Amsterdam. 3 October, 7 November, 12 December. 1991

and 5 February, 2 April and 7 May I992

Secretariat: Amsterdamsche Neurologenvereeniging

(Received for publication 5 October 1992)

323

1. Terminals on spinal motoneurons: origin, transmitters and

ultrastructure - J.C. Holstege, Department of Anatomy, Eras-

mus Universitv Medical School. Rotterdwn, The Nethrrkmds

Terminals in the spinal motoneuron pool originate from differ-

ent parts of the nervous system. These fiber systems are usually

referred to as the peripheral, propriospinal and supraspinal pro,jec-

tions.

I. The peripheral projections are mainly derived from muscle

spindles. They were identified after intra-axonal injections of Ia-

afferent fibers with HRP and were large terminals containing

spherical vesicles (S-type), probably using glutamate as a transmit-

ter. They are often contacted presynaptically by other terminals

(P-types), which contain GABA as inhibitory transmitter. This

arrangement is the morphological substrate of presynaptic inhibi-

tion as it is found in the simple stretch reflex.

2. The propriospinal projections to spinal motoneurons include

motor axon recurrent collaterals. These terminals are S-type and

contain acetylcholine as a transmitter. The bulk of the proprionpi-

nal projections to motoneurons originates from intemeurons lo-

cated in the same or nearby segments. giving rise to both F- and

S-type terminals. The transmitters in the F-type terminals (contain-

ing many flattened vesicles) are GABA and glycine. often coex-

isting in the same terminal. They act as inhibitory transmitters, e.g.

from Renshaw cells. The excitatory intemeuronal projections are

probably of the S-type and contain glutamate as a transmitter, hut

aspartate and acetylcholine may also be present.

3. An important supraspinal projection to spinal motoneuronx

is derived from the motor cortex, especially in primates, like chim-

panzee and man. The terminals of these projections are S-type and

may contain glutamate as a transmitter. Brain stem projections to

spinal motoneurons have also been identified, including F-, S-, and

G (granular-type terminals. The G-type terminals are derived

from the caudal raphe nuclei and contain serotonin, sometimes in

co-existence with substance P or other peptides. The F- and S-type

terminals are derived from the ventromedial lower brain stem and

from the vestibular nuclei. The F-type terminals contain GABA

and/or glycine, while the S-type terminals may contain glutamate

or aspartate. In addition, there ia a noradrenergic projection from

the locus coeruleus and a dopaminergic projection from the pos-

terior hypothalamus to spinal motoneurona.

2. End-plates in Lambert-Eaton myasthenic syndrome show

enlargement of contact between muscle and nerve - L.F.G.M. Hesselmans, F.G.I. Jennekens. J.H.J. Wokke, M. de

Visser. E.G. Klaver-Krol, M. DeBaets. F. Spaans, J. Kartman

and H. Veldman. Utrecht. Amsterdam, Muzstricht, The

Nethlrrland,r

We performed a quantitative light and electron microscopical

study of intercostal muscle biopsies of 5 patients. The main light

microscopical findings included a significant increase in the num-

ber of end-plates per muscle tibre, and a tendency for enlargement

of the end-plates. These two phenomena lead to enlargement of the

area of contact between nerve and muscle. This was interpreted as

a compensatory phenomenon. At the ultrastructural level no quan-

titative changes at the presynaptic side of the neuromuscular.iunc-

tion were observed. but we found the mean postsynaptic area and

membrane length to be significantly decreased. putatively due to

small postsynaptic regions of newly created neuromuscular junc-

tions. The secondary changes in Lambert-Eaton myasthenic syn-

drome end-plates as seen in this study are similar to those reported

in experimental blocking of acetylcholine release. and to other

disorders with a deficiency of neuromuscular transmission.

3. Effects of vincristine and ORG 2766 on the microtubular

system in the pond snail Lymnaeu stagnalis - Linda J. Mul-

ler, Carry M. Moorer-van Delft and Harry H.Boer. Fuculty oj’

Riolo,yv, Section Histology trncl Electron Mic,roscvpy. Frw

Uniwrsity. Amsterdam, The Netherlands

Since the early sixties vincristine (VCR). a vinca alkaloid is

being used as an anti-tumor agent. This drug exerts severe neuro-

toxic side-effects. Since VCR turned out to be a very potent drug

a new strategy was followed. i.e. co-administration of drugs that

counteract neurotoxicity. The use of these drugs requires animal

experiment research in which infomation concerning cellular

changes due to the drugs is gathered. A test system was developed

to predict vinca alkaloid neurotoxicity using identified peptidergic

neurons of the snail l,vmnuerc stirgna1i.s.

VCR reacts with the microtubular system by the formation of

pamcrystalline inclusions. Quantification ot’ these structures in

axons in the cerebral commissure appeared to be a good parameter

to describe vinca alkaloid induced neurotoxicity.

To investigate drugs rn~~dulatil~g neurotoxicity, the peptide

ORG 3766. an ACTH analogue was tested in the snail model

system. This was done because in a clinical trial evidence was

presented that ORG 2766 prevents the induction of peripheral

neuropathies when administered simultaneously with cisplatin in

ovarian cancer patients. In the model system it was found that

ORG 2766 stimulates the formation of microtubulea at concentra-

tions as low as 10M8 M by approximately Xl-.SO%. The beneficial

effect of this drug is most probably related to microtubule forma-

tion.

Magnetic resonance imaging (MRI) has allowed a detailed

description of the morphological elements involved in de- and

dysmyelinating disorders and to identify changes pertinent to a

diagnosis, specific for a disease entity or a group of disorders. For

our purpose we proposed a classification of the hereditary myelin

disorders based on the location of the enzyme defect in the cellular

organelles. This made it possible to describe the MR patterns in

lysosomal, peroxisom~, and mit~hond~al disorders. Though, ap-

patently, the group of organic and aminoacidopa~ies is a hetero-

geneous group we were able to distinguish five major MR patterns.

We loaded a database with the MR data of all patients with a

confirmed diagnosis and established of each of the structural ele-

ments the frequency of involvement in a specific disease entity.

This resulted in a frequency histogram of involvement of structural

elements per diagnostic group (Neuroradiology ( 199 I ) 33: 47%

493). New cases can now be compared with this database, com-

puterization yielding a diagnostic probability (percentage) and

confidence intervals (resulting from the number of cases per sub-

category). (Computer program developed by J.J.P. Nauta, Dept.

Theory of Medicine, Epidemiology and Biostatistics. Free Univer-

sity, Amsterdam.)

5. Photosensitivity in epileptk patients - D.G.A. Kasteleijn-

Nolst TrenitC, Heemstede, The Nethertunds

Little is known about the relationship between the occurrence

of a classical photoparoxysmal response on IPS in the EEG labora-

tory and the occurrence of spontaneous or visually induced seiz-

ures. We studied 100 photosensitive patients and 100 sex-, age-

and referral-matched controls with respect to eiec~ophysiologic~

parameters as well as to clinical and seizure history. 94 of the 100

photosensitive patients had a seizure history of mainly tonic-clonic

seirures, absence seizures. myoclonuh and cornplc~ partral WI/

ures. Visually- and/or self-induced seizures were tound in 59 of the

94 (63%) photosensitive patienk visually-induced seirures in 55

patients and self-induced sekures in 23. Moor patients (35) had

seizures when watching television, while sunlight provoked al-

tacks in 3 1. and artificial lighting in 2 I. Only h had a history ot

pattern-induced seizures such as caused by linear patterns on wall-

paper, clothing, Venetian blinds and escalator\.

6. Ha~morr~agic and ischaemic &ions in the preterm infant - L.S. de Vries, Wilhetmin~~ ~-~~~tdr~n k Hospitut, lirrechr, Thr

Nethertunds

Neuroimaging and cranial ultrasound in particular has greatly

increased the potential to understand the processes involved in

prenatal and perinatal damage.

As soon as ultrasonography was available it became clear that

particularly intraventricular haemorrhages are very common in

very low birth weight infants. As long as the brain parenchyma is

not involved and ~sth~morrhagic ventricular dilatation is treated

at an early stage the outcome may be ~rn~~ably good. Besides

haemorrhagic lesions, ischaemic lesions such as leukomalacia. can

occur. With higher resolution equipment, cystic periventricular

leukomalacia can be diagnosed. Extensive cystic leukomalacia in

the periventricular or deep white matter invariably leads to the

development of cerebral palsy during infancy. The use of cranial

ultrasound made clear which lesions will lead to severe neurologi-

cal sequelae.

7. Herpes simplex encephalitis: an exprimantal~aud clinkal study on early non-invasive diagnosis - R.H. Boerman, A.K.

Raap, B. Bloem, E.I?J. Arnoldus, M. van der Ploeg and A.C.B.

Peters, Leiden, The Nez~erl~nd~

The aim of this study has &en to develop a rapid, noninvasive

method for the early diagnosis of herpes simplex encephalitis

(HSE) and to investigate the process of spread of HSV to the

cerebrospinal fluid (CSF). A meaningful comparison of the various

diagnostic methods is best carried out in an animal model. In this

study brain stem encephalitis induced in mice after comeal inocu-

lation has been used. Spread to the CNS occurs principally through

the trigeminal nerves resulting in inflammation of trigeminal nu-

clear complex extending to the meninges. Spread along the

meningeal rami as a rn~hanis~~ of spread to the temporal lobes in

human HSE has been postulated, but was not observed in this

model. In addition, extensive spread to the nasat mucosa and the

olfactory nerves as we11 as spread through other cranial nerves

occurred. The onset and composition of CSF pleocytosis followed

the development of brain stem meningoencephalitis closely. HSV

spreads to the CSF at a rather late stage and only after productive

infection in CNS cells and extensive inflammation of the tissue has

occurred. Viral spread to the CSF is limited, even though heavily

infected cells border on the subarachnoid space. The virus appears

to be transported to the CSF by infected leukocytes.

The results of detection of HSV in CSF of infected mice by

routine and spun-spliced viral culture, dot-blot hyb~~zation,

325

immunofluorescence on CSF cells and the polymerase chain reac-

tion (PCR) are presented. These show the PCR to be superior to

all other techniques. A positive PCR did not correlate with the

interval post-inoculation but rather with the spread of HSV within

the brain tissue. Similar results were obtained on CSF from pa-

tients with HSE. The search for an early, non-invasive method for

the diagnosis of HSE has ended now that detection of viral DNA

in CSF of patients with HSE during the first week has been re-

ported.

8. Perimeseneephalic nonaneurysmal haemorrhage - Gabriel

J.E. Rinkel, Department qf Neurology, University of Utrecht,

Utrecht, The Netherlands

Patients with perimesencephalic subarachnoid haemorrhage

are characterized by accumulation of blood in the cisterns around

the midbrain and a normal four-vessel angiogram. The clinical

course and outcome of 77 patients with a perimesencephalic ha-

emorrhage were compared with those of 36 patients with an

aneu~smai pattern of haemo~hage on CT but a normal angio-

gram. All patients with a ~~mesencephalic haemorrhage had a

normal level of consciousness on admission and, apart from neck

stiffness, were neurologically unremarkable. None of these pa-

tients rebled, none suffered delayed cerebral ischaemia and only

3 patients (5%) developed signs of acute hydrocephalus. Four of

the 36 patients with an aneurysmal pattern of haemorrhage on CT

had a rebleed, which was fatal in 3. One patient had a CT-proven

episode of cerebral ischaemia, and 5 patients deteriorated from

acute hydrocephalus. After a median period of follow up of 55

months, none of the patients with a perimesencephalic haemor-

rhage had rebled, and none had died or was left disabled as a result

of the haemo~hage (0%: 95% confidence interval O-5%). Nine of

the patients with an aneurysmat pattern of haemorrhage on CT had

died or were left disabled as a result of the haemorrhage (25%;

95% confidence interval 1443%).

9. Treatment of spasmodic torticollis - J.W.M. Brans, J.D.

Speelman and B.W. Ongerboer de Visser, Amsterdam, The

Netherlands

We report our experience with botulinum toxinum (BTX), ap-

plicated by hollow EMG needles during EMG monito~ng, in 30

patients with spasmodic torticollis (ST). There were I27 ~eatment

sessions with a mean interval of 3.6 months between sessions and

a mean dose of 170 mouse-units per session. The results were

assessed on an objective scale (Tsui, 1986) and on a self-assess-

ment scale. In 90 of the 127 sessions (7 1%) and in 22 of the 30

patients (73%) a positive effect was observed. Pain relief was

evident in I4 of I8 patients (78%). Side-effects, mainly consisting

of dysphagia (9%), local pain (4%) or weakness of the cervical

muscles (2%), were mild and transient.

10. Clinical neurophysiolo~~al investigations in patients with he~facial spasms and blephar~p~m - J.L.A. Eekhof, L.J.

Bour, J.D. Speelman, PP. Devriese and B.W. Ongerboer de

Visser, Amsterdam, The Netherlands

Lateral spreading phenomena in patients with hemifacial

spasms are obtained by simultaneous recording from the orbicu-

laris oculi and mentalis muscles and stimulation of the zygomatic

or mandibular facial nerve branches. We found activity in one of

the indirectly stimulated muscles in all investigated patients.

In patients with blepharospasm and hemifa~ial spasms, abnor-

mal recovery curves of the RZ-response from the blink-reflex are

found. We made recovery curves of 23 patients with hemifacial

spasms and 21 patients with blepharospasm. The mean of the

individual curves for both patient groups differed from the control

group. The difference was most evident in the group with ble-

pharospasm. Hyperexcitability of brainstem interneurons is prob-

ably responsible for the abnormal curves, although in hemifacial

spasm hyperexcitability of the facial motoneurons may also play

a role.

11. Videofluoroscopic follow-up of post-polio patients with late

progressive dysphagia - B. Ivanyi, S.S.K.S. Phoa and M. de

Visser, Anisterdfzm, The Neth~rla~d.~

We have undertaken a prospective study with repeat video-

fluoroscopy in 8 of 43 patients with post-polio syndrome (PPS),

aged 35-52 years (mean 45), complaining of late or progressive

dysphagia. The mean interval between acute paralytic poliomyeli-

tis (APP) and onset of new or progressive swallowing difficulties

was 2’7 years (range 2345). Two patients reported the existence

of mild dysphagia at the time of maximal recovery after APP with

deterioration after years of stability. One patient recovered

completely but dysphagia reappeared later. The ~maining 5 pa-

tients did not recall overt butbar involvenlent during APP

On initial ~~ideofluoroscopy, 6 patients showed slight or moder-

ate signs of oropharyngeal dysfunction, whereas this examination

was normal in 2.

Seven patients who reported worsening of their swallowing

difficulties were seen for videofluoroscopic follow-up after 12-36

months (mean 18). Slight progression was observed in only 1 patient. We conclude that PPS patients complaining of late or

progressive dysphagia do not show a significant deterioration of

oropharyngeal function on a I-3-year follow-up.

12. Genetic heterogenei~ of hereditary motor and sensory neuropathy type I - J.E. H~gendijk, E.A.M. Janssen,

A.A.W.M. Gabreels-Festen, F.J.M. Gabreels, F. Baas, M. de

Visser and P.A. Bolhuis, Amsterdam, Nijmqen, The Nerher-

lands

We developed a test for easy and accurate detection of the

duplication in chromosome 17pl 1.2 in patients with hereditary

motor and sensory neuropathy type I (HMSN I). Application of

this test to IO sporadic patients in whom a diagnosis of HMSN I

had been made on clinical and electrophysjoiogical grounds, and

to their asymptomatic parents showed that the duplication was

present in 9 of the patients and in none of the parents. These

326

findings clearly demonstrate that these patients represent de novo mutations, thus refuting the general belief that isolated cases are autosomal recessive. However, a negative test result does not ex- clude the diagnosis HMSN because of the possibility of other modes of inheritance and other autosomal dominant mutations. The duplication was found in 7 out of 9 HMSN 1 families with male-to-male transmission. In one family, a mutation on chromo- some 17 was excluded by linkage analysis. In the other family, the lad score with one of the duplication probes was >3, indicating ailelic heterogeneity within the chromosome 17p11.2 locus.

13. Effects of cyclic AhZP and its analogues on human glioma cells - C.H. Langeveld, Department of Neurology, Free Uni-

versity, Amsterdam, The Netherlands

The second messenger adenosine 3’S’-monaphosphate (CAMP) is considered to play an important role in cell growth and differentiation. The effects of CAMP and its analogues are medi- ated by the CAMP dependent protein kinase. There is an increasing interest in the use of signal transduction pathways (such as the CAMP pathway) as targets for anticancer drugs. Recently, 8- chioro-CAMP (SClcAMP) was shown to he a more potent inhibitor of human glioma cell growth than other CAMP analogues. The mechanism by which 8ClcAMP exerts this effect is not clear.

The effects of 8-chloro-adenosine @ClA), one of the metabo- lites of 8ClcAMP, on human glioma cells are comparable to the effects of 8ClcAMP. HPLC analysis of culture medium containing 8ClcAMP revealed that part of the 8ClcAMP is converted into 8ClA. When adenosine deaminase (ADA) was added, 8ClA was inactivated and no longer detectable. HPLC analysis also showed that 8ClcAMP itself was not degraded by adenosine deaminase. However, in the presence of ADA the growth inhibitory effect of both 8ClcAMP and 8ClA was abolished. These results demon- strate that 8ClcAMP exerts its growth inviting effect mainly through its active metabolite 8ClA.

It is not known by what mechanism 8ClA inhibits glioma cell proliferation. It is unlikely that 8ClA inhibits glioma cell growth through adenosine A1 - or AZ-receptor activation.

14. Magnetic resonance spectroscopy: new possibilhdes of neu- rochemical d@~osIs - M.S. van der Knaap, Department of

Child Neurology, Free University Hospital, Amsterdam, The

Netherlands

Magnetic resonance spectroscopy (MRS) addresses in vivo me~~Iism. The most important nuclei for MRS are proton {‘H) and phosphorus (3’P). The 31P spectrum gives information about the concentration of high-energy phosphate compounds, the intracellular pH, and the metabolism of membrane phospholipids. The ‘H spectrum gives information about neuronal density and integrity, the concentration of lactate and a number of amino acids and neurotransmitters. Important areas of application are brain maturation, hypoxic-ischemic brain damage, metabolic disorders, dementia, tumors, epilepsy and multiple sclerosis. The first 3 sub- jects are discussed.

MRS of brain maturation shows changes retated to membrane deposition (especially myelination). neuronai maturation and al- terations in energy reserve.

In hypoxic-ischemic brain damage spectroscopic changes can be observed immediately following the incident and appear to be of prognostic value. Depletion of high-energy phosphates carries a poor prognosis.

In metabolic disorders MRS shows changes related to the struc- tural brain damage (loss of myelin membranes and loss of neurons: aspecific abno~~ities) and to the metabolic abnorm~ity (abnor- mal compounds or abnormally elevated compounds: specific ab- norm~ities).

15. Genetic aspects of facioscapulohumeral muscular dys&o-

phy - G.W. Padberg, O.F. Brouwer, C. Wljmenga, A.M. Gruter, L.A. Sandkuyl and R.R. Frants, Leiden, The Nether-

lands

Based on multipoint linkage analysis and the analysis of re- combinants we found the most likely position of the facioscapulo- humeral muscular dystrophy (FSHD) gene on chromosome 4 rela- tive to the presently known markers in the region 4q35: centromere - D4S171 - Fll - D4S187 - D4S163 - D4S139 - FSI-ID - telomere.

Application of these results so far suggests that autosomal dominant facioscapulohumeral spina muscular atrophy is not a separate clinical entity. Families diagnosed as such turned out to have FSHD, linked to the chromosome 4q markers.

We found a retinal vascubpathy and a high-tone sensorineural deafness in 50% of the FSHD patients. As these extramuscular findings can be observed in the majority of the FSHD families, it is likely that they are pleiotropic effects of the FSHD gene.

Another result of the linkage studies was the recognition of a severe, infantile form of FSHD with pseudoh~~~phy of the calf muscles. These cases testify that the reported clinical manifesta- tions of infantiie FSHD, i.e. deafness and r~inupa~y, are part of the large clinical spectrum of FSHD.

16. Functional anatomy of the bippocampal region in relation to learning and memory processes - M.P. Witter, Depamnent

of Anatomy und Embryology, Free University, Amstenkw,

The Netherlands

In a series of anatomical experiments in the rat, cat and monkey, we have shown that the hippocampal formation is uniqu- ely situated at the “end-node” of numerous parallel multisensory cotticocortical pathways that. before entering the hippccampal formation, convert in the superficial layers of the adjacent entorhi- nal cortex. These layers supply the hippocampal formation with its major cortical input. Outputs of the hippocampal formation to the deep layers of the entorhinal cortex reach a variety of cortical areas, presumably reciprocating most of the polysynaptic input pathways to the hippocampal formation.

A recent detailed study in the rat on the relations between the origin and distribution of the entorhinal-hippocampal projections and the spatial distributions of the intrinsic connections of the

327

mg/m’) or placebo. Vibration perception threshold (VPT) was

examined by Vibrameter type III (Somedic). Before treatment, the

average sum-score of symptoms was 0.1 (n = 18) and deteriorated

to 2.1 (n = 12) at 1 month, 2.9 (n = 13) at 14, followed by im-

provement to 2.3 (n = 16) at 4-l 2, and 1.5 (n = 4) at 12-24 months

after the last cycle. VPT was 0.5 urn (n = 18) before treatment, 4.6

(n = 12) at 1 month, 9.4 (n = 13) at l-4, 6.7 (n = 16) at 4-12, and

2.2 urn (n = 4) at 12-24 months after the last cycle. 13 patients had

multiple observations in the period following 1 month after treat-

ment including at least one measurement after 4 months. The VPT

deteriorated in 11 patients between 1 and 4 months after treatment

and remained the same in the other 2 patients. High-dose Org 2766

prevented acute neuropathy at 1 month after cisplatin treatment;

however, these patients also deteriorated at l-4 months after dis-

continuation of treatment. The beneticial effect of Org 2766 seems

to be based on enhancing repair mechanisms rather than on pre-

venting neuropathy. Therefore, late cisplatin-induced neuropathy

might be avoided by continuation of Org 2766 administration after

cessation of cisplatin.

hippocampal formation has lead to two conclusions. (i) The hip-

pocampal intrinsic network is organized in a way to select between

different output channels that transmit hippocampally processed

information to various targets. (ii) Subfields of the hippocampal

formation contribute differently to hippocampal functioning. The

selective distribution of subcortical inputs to the hippocampal for-

mation may contribute to this proposed functional differentiation.

17. Prevention and course of cisplatin neuropathy - C.J. Vecht,

A. Hovestadt, H.B.C. Verbiest and M.E.L. van der Burg, Rot-

terdam, The Netherlands

Org 2766, an ACTH analogue, has been found to prevent

cisplatin neuropathy (N. Engl. J. Med. (1990) 322: 89-94). For the

design of appropriate further studies, accurate information on the

course of the disease after treatment is necessary, but not available.

A group of 18 patients who participated in the aforementioned

study has been subsequently followed on the development of neu-

ropathic signs and symptoms after discontinuation of treatment

with cisplatin (6 cycles of 75 mg/m*) and Org 2766 (0.1 or 1.0