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`6. Ter-pogossian MM, Mullan NA, Hud JT. Design considera·
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`7. Kushner MJ, Alavi A, Reivich M, et al. Contralateral cerebellar
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`8. Jones SJ, Robinson GD, McIntyre E. Tandem Van de Graaff
`accelerator production of positron labeled radiopharmaceucicals
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`9. Kushner~. Rosenquist A, Alavi A, et al. Cerebral metabolism
`and patterned visual stimulation: a positron emission tomo(cid:173)
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`10. Hawkins RA., Phelps ME, Huang SC, Kuhl DE. Effect of isch(cid:173)
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`12. Shishido F, Uemura K, lnugami A, et al. Remote effects in
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`blood flow and Oll."}'gen metabolism using positron computed
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`13. Segraves M, Rosenquist AC. The distribution of the cells of
`origin of callosal projections in ca.c visual cortex: J Neumsd
`1982;2:1079-1089
`14. Heilman KM, Valenstein E, Watson RT. Neglect. In: Asbury
`AK, McKhann GM, McDonald WL, eds. Diseases of the ner(cid:173)
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`15. Kiyosawa M, Bosley TM, Kushner M, et al. Positron emission
`tomography study of the effect of eye closure 11nd optic nerve
`damage on human cerebral glucose metabolism. Am J Ophthal•
`mol 1989;108:147-152
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`tomography in a patient with progressive mulcifocal lcukoen•
`cephalopathy. Neurology 1988;38:1864-1867
`
`Enclosure:
`
`re: EP 1 957 106
`of July 11, 2014
`
`Reitstotter Kinzebach
`
`V asoactive Peptide Release
`in the .Extracerebral
`Circulation of Humans
`During Migraine Headache
`P. J. Goadsby, MD, PhD,* L Edvinsson, MD, PhD,t
`and R. Ekman, MDt
`
`The innervation of the cranial. vessels by the trigeminal
`nerve, the trigeminovascular system, has recently been
`the subject of study in view of its possible role in the
`mediation of some aspects of migraine. Since stimula(cid:173)
`tlon of the trigeminal ganglion in humans leads to facial
`pain and flushing and associated release of powerful
`neuropeptide vac;odilator substances, their local release
`into the extracerebral circulation of humans was deter(cid:173)
`mined in patients who had either common or classic
`migraine. Venous blood was sampled from both the ex(cid:173)
`ternal jugular and the cubital fossa ipsilateral to the side
`of headache. Plasma levels of neuropeptide Y, vasoac(cid:173)
`tive intestinal polypeptide, substance P, and caldtonin
`gene-related peptide were determined using sensitive
`radioimmunoassays for each peptide, and values for the
`cubital fossa and external jugular and a control popula(cid:173)
`tion were compared. A substantial elevation of the cal(cid:173)
`citonin gene-related peptide level in the external jugu(cid:173)
`lar but not the cubital fossa blood was seen in both
`classic and common migraine. The increase seen in
`cla'lSic migraine was greater than that seen with com(cid:173)
`mon migraine. The other peptides measured were unal(cid:173)
`tered. This finding may have
`importance in the
`pathophysiology of migraine.
`
`Goadsby PJ, Edvinsson L, Ekman R. Vasoaccive
`peptide release in the extra.cerebral circulation
`of humans during migraine headache.
`Ann Neurol 1990;28:183-187
`
`In spite of considerable debate concerning the patho(cid:173)
`physiology of migraine, there is general agreement,
`and indeed good clinical evidence [lJ, that the cranial
`vessels play some role in either the pathogenesis or the
`expression of the migraine syndrome. Recently, con(cid:173)
`siderable literature has characterized the innervation of
`these vessels as being with both classic and nonclassic
`
`From the "Department of Neurology, The Prince Henry and Prince
`of Wales Hospitals, and the School of Medicine, University of New
`South Wales, Sydney, Australia, and the Deparcmenrs of tinternal
`Medicine and tNeurochemistry, University of Lund, Lund, Sweden.
`Receive<l Jan 16, 1990. Accepted for publication Feb 15, 1990.
`Address correspondence to Dr Goadsby, Department of Neurol(cid:173)
`ogy, Clinical Sciences Building, The Prince Henry Hospital, Little
`Bay, NSW 2036 Australia.
`
`Copyright© 1990 by the American Neurological Association 183
`
`

`

`neurotransmitters. These newly described substances
`may provide insights into the neural control of the
`cqmial vessels and also suggest directions for therapy
`in vascular headache.
`The transmitters found in nerves supplying the
`extracerebral vessels include the classic amine trans(cid:173)
`mitters, such as noradrenaline, serotonin, and acecyl(cid:173)
`choline, as well as many recently described neuropep(cid:173)
`tides, such as neutopeptide Y (NPY), vasoactive
`intestinal polypeptide (VIP), substance P (SP), calcito(cid:173)
`nin gene-related peptide (CGRP), peptide histidine
`isoleucine, neurokinin A (NKA) and B, and gastrin(cid:173)
`releasing peptide (for review see Edvinsson and col(cid:173)
`leagues [2}). Of these the peptides that are clearly
`vasodilators are CGRP, VIP, SP, and NKA. Impor(cid:173)
`tantly from the viewpoint of cranial nociception, SP,
`NKA, and CGRP are colocalized in neurons in the
`trigeminal system (3, 4] and are thus well placed to be
`involved in vascular headache.
`In a recent human study, stimulation of the trigemi(cid:173)
`nal ganglion (thermocoagulation for tic douloureux),
`an otherwise painful procedure done under general
`anesthesia, was linked to marked increases of both SP
`and CGRP in the external jugular vein. Furthermore
`these changes were only seen in association with facial
`flushing ipsilateral to the side of stimulation [5}. Inter(cid:173)
`estingly such changes were not seen when CGRP and
`SP levels were measured in the peripheral circulation
`(antecubital vein) [6]. Moreover, measurement of
`either SP or VIP in peripheral blood in patients with
`common or classic migraine demonstrated no changes
`in either peptide during headache [7]. In this study the
`levels of several neuropeptides were studied in mi(cid:173)
`graineurs during headache by local cranial sampling
`from the external jugular vein.
`
`Methods
`
`Patients
`Data were collected from 22 patients who presented to the
`Neurology Outpatients and Casualty Department com(cid:173)
`plaining of symptoms consistent with either common or
`classic migraine [8}. The study protocol was reviewed by an
`Institutional Ethics Committee (P. J. G.'s) and the patients
`gave informed consent following an explanation of the pro(cid:173)
`cedure. The patient was reseed supine and blood collected
`from the antecubital and external jugular veins on the same
`side. In the case of unilateral headache, sampling was per(cid:173)
`formed on the side ipsilaceral co the headache. The head(cid:173)
`aches had been present from 1 to 7 hours, with a median
`duration of 3 hours, at the time of sampling.
`
`samples were freeze-dried and dispatched to Sweden for as(cid:173)
`say. Samples were coded and all peptide determinations were
`performed blinded. The plasma was concentrated tenfold for
`assay and the result divided by 10 for presentation.
`
`Radioimmunoassays
`Plasma levels of NPY were analyzed using a sensitive radio(cid:173)
`immunoassay with a rabbit antiserum raised against synthetic
`porcine NPY (from Dr P. C. Emson, Cambridge, England)
`conjugated to bovine serum albumin with carbodiimide (9].
`125Iodine NPY (1 251-NPY) used as a tracer was purified by
`high-performance liquid chromatography (HPLC). The anti(cid:173)
`serum cross-reacted with peptide YY (PYY) to 33% but not
`with C-terminal fragments of NPY and PYY (NPY 13-36
`and PYY 13-36) nor with bovine pancreatic polypeptide,
`gastrin-inhibiting peptide, peptide histidine isoleucine, VIP,
`or secretin. Antiserum (200 µ,l, diluted 1 : 40,000) was in(cid:173)
`cubated first with 100 µ.l of standard (synthetic NPY; Penin(cid:173)
`sula, Belmont, CA) or with plasma samples for 24 hours and
`then with 200 µ.l (about 2500 cpm) of rhe HPLC purified
`tracer for another 24 hours. Bound and free 1251-NPY were
`separated using dextran-coated charcoal. Each sample was
`assayed in serial dilution and corrected for nonspecific bind(cid:173)
`ing. The detection limit was 11. 7 pmol/liter while the interas(cid:173)
`say variation was 6. 5%. Because of the cross-reactivity with
`PYY, each sample was also assayed for PYY-like immuno(cid:173)
`reactivicy and 33% of the values obtained were subtracted
`from the correspoJ1ding values for NPY-like immunoreac(cid:173)
`tivity [9}. However, these values were very low and from a
`practical point of view they did not interfere with the values
`for NPY-like immunoreactivity.
`Immunoreactive SP was _quantitated using a rabbit anti(cid:173)
`serum SP-2 in a final dilution of 1: 50,000 and (tyrosine8)-SP
`was used as. the tracer. The detection limit is 4 pmol/liter.
`The SP-2 antiserum does not detect any known tachykinin
`besides SP [11}.
`Immunoreactive CGRP was quantitatcd using a rabbit
`antiserum (R-8429), raised against synthetic rat CGRP con(cid:173)
`jugated co bovine serum albumin and used at a final dilution
`of 1 : 37,500. Iodinated CGRP was purified by HPLC, allow(cid:173)
`ing measurements of CGRP-like material with a minimum
`detection of 10 pmol/liter. The CGRP antiserum showed no
`cross-reaction with any of the peptides listed above [12).
`Immunoreactive VIP was determined using a rabbit anti(cid:173)
`serum (code 7852, Milab, Malmo, Sweden). The antiserum
`was used in a dilution of ·t : 40,000 and does not react with
`peptide histidine isoleucine, secretin, or glucagon. The de(cid:173)
`tection limit was 4 pmol/liter and the interassay variation was
`8.5% [13].
`
`Statistics
`Data are presented as mean :t standard error of mean
`(SEM). The levels of the peptides in migraineurs were com(cid:173)
`pared to age- and sex-matched control subjects using an un(cid:173)
`paired t test.
`
`Blood Processing
`Blood was collected into tubes prepared with both aprotinin
`(Trasylol) (5000 KIU) and heparin (500 IU), transponed on
`ice and centrifuged at 2,000 rpm for 1 5 minutes. Plasma was
`aliquoted into vials for storage at - 30°C. In batches the
`
`Results
`Twenty-two patients (6 men, 16 women) ranging in
`age from 22 co 58 years (36 ± 13 years ± SD) were
`studied. In each case neuropeptides were determined
`
`184 Annals of Neurology Vol 28 No 2 August 1990
`
`

`

`Table 1. Changes in Neuropeptides during
`Classic Migraine (with Aura) Headachea
`
`VIP
`
`CGRP
`
`SP
`
`NPY
`
`Site
`External jugular 9 ± 3b 92 ± 11c
`< 6
`40 ± 6
`Cubital fossa
`< 40
`< 6
`Control values
`
`5 ± 2
`5 ± 3
`<4
`
`146 ± 15
`140 ± 13
`< 130
`
`• All values are pmol/liter.
`bTwo pacients were outliers an<l had higher levels; see text.
`ccGRP level is significantly elevated in rhe external jugular blood of
`classic migraineurs (t3y = 6.9, p < 0.001).
`VIP = vasoactive intestinal polypeptide; CGRP = calcitonin gene(cid:173)
`relared peptide; SP = substance P; NPY = neuropeptide Y.
`
`Table 2. Changes in Neuropeptides during
`Common Migraine (without Aura) Headache"
`
`VIP
`
`CGRP
`
`SP
`
`NPY
`
`Site
`External jugular <6
`Cubical fossa
`<6
`< 20
`Control values
`
`86 ± 4b
`43 ± 6
`< 40
`
`6 ± 2
`4 ± 1
`<4
`
`130 ± 15
`133 ± 10
`< 130
`
`"All values are pmol/liter.
`bCGRP level is significantly elevated in the external jugular blood of
`common migraineurs (111 = 6.5, p < 0.001).
`VIP = vasoaccive intestinal polypeptide; CGRP = cakiconin gene(cid:173)
`related peJJride; SP = substance P; NPY = neuropepcide Y.
`
`from both the peripheral circulation (cubical fossa) and
`the cranial circulation (external jugular vein). In all
`patients studied whether they had classic (with aura;
`n = 10) or common migraine (without aura; n = 12),
`CGRP levels were elevated in the cranial circulation
`but not in peripheral blood. The level of CGRP in
`classic migraneurs was greater than that seen in those
`with common migraine. The levels in both groups
`were, however, much greater than those observed in
`control groups either for blood sampled from the
`cubical fossa [14J or for CGRP in a smaller group
`sampled from the external jugular vein ['.)J. The cubical
`fossa control group consisted of 31 healthy un(cid:173)
`medicated subjects aged 20 to 80 years, while the ex(cid:173)
`ternal jugular control group consisted of 12 healthy
`women aged 19 to 2 5 years. As a group there were no
`changes in SP, NPY, or VIP levels. Two patients,
`however, from the classic migraine group had promi(cid:173)
`nent symptoms of lacrimation and rhinorrhea and both
`had marked elevations in cranial VIP levels (3 7 and 36
`pmol/liter). The data for both classic and common mi(cid:173)
`graineurs for each of the peptides are presented in
`Tables l and 2, respectively.
`
`Discussion
`These data for the first time demonsrrate changes in
`neuropeptides in the cranial circulation in humans, in
`
`association with the common clinical problem of mi(cid:173)
`graine. CGRP is the most powerful of the neurovascu(cid:173)
`lar peptides; it is localized in nerves that innervate the
`cranial vessels whose cell bodies arise from the main
`sensory innervation of the anterior cranium, the tri(cid:173)
`geminal system, and its level is clearly elevated in mi(cid:173)
`graine. This increase cannot be simply due to a pooling
`effect of the cannula insertion since it is not seen in the
`other peptides measured on the same samples. Several
`lines of investigation, both anatomical and physiologi(cid:173)
`cal, suggest the importance of the crigeminal innerva(cid:173)
`tion of the cranial vessels, the trigeminuvascula.r sys(cid:173)
`tem. Anatomical studies have clearly demonstrated
`chat peptide-containing nerves from the trigeminal
`ganglion innervate both the cerebral and the ex(cid:173)
`tracercbral vessels [15]. Markers for vascular innerva(cid:173)
`tion, such as SP (4, 16, 17}, have been shown to be
`significantly reduced after trigeminal ganglionectomy.
`It has also been shown that cranial vessels have CGRP(cid:173)
`and NKA- containing nerves (2, 3]. These peptides
`are also found in the trigeminal ganglion and are pow(cid:173)
`erful vasodilators [3, 4].
`Physiological studies have shown that activation of
`the trigeminal ganglion in humans [ 18), in the monkey
`(19J, and in the cat (20} results in increases in extra(cid:173)
`cerebral blood flow. In the cat the response is due to
`both antidromic activation of trigeminal nerves (20%)
`and orthodromic activation of the faciaVgreater super(cid:173)
`ficial petrosal nerve dilator system (80%). The latter
`response acts through the sphenopalacine and otic gan(cid:173)
`glia [21} and is mediated by the dilator transmitter VIP
`[22]. Moreover, activation of the trigeminal system is
`capable of altering regional cerebral blood flow at least
`in part through a facial/greater superficial petrosal
`nerve outflow [23], a system that can alter cerebral
`blood flow independent of cerebral glucose utilization
`[24}. Moskowitz and colleagues suggested a possible
`functional role, at least for the trigeminal arm of this
`innervation, by demonstrating that pial arteriolar re(cid:173)
`sponses to hypertension are attenruated by trigemi(cid:173)
`nalectomy and that increases in cerebral blood flow,
`measured with radiolabeled microspheres, are also re(cid:173)
`duced after trigcminal ganglionectomy but not by tri(cid:173)
`geminal nerve root section [26}. It was also shown that
`trigeminal activation either in the cat or in humans can
`lead to release of both CGRP and SP into the cranial
`circulation [5] but not into the peripheral circulation,
`at least not in detectable levels (6}. The specific eleva(cid:173)
`tion of only CGRP in these migraineurs during head(cid:173)
`ache may reflect highly localized activity in cranial
`vascular afferent pathways, although the finding of
`elevated levels of VIP in a subgroup of the migraineurs
`with aura (classic migraine) suggests that isolated tri(cid:173)
`geminal activation may not be the full exrenc of the
`pathophysiology of this condition.
`In the clinical setting it is clear that in one-third of
`
`Brief Communication: Goadsby et al: Peptides m Headache · 185
`
`

`

`patients the source of the headache is peripheral [l],
`with a concurrent marked asymmetry of facial temper(cid:173)
`ature [27l These observations imply that at least in
`part there is an important peripheral mechanism that,
`given the normality of the extracerebral vessels of mi(cid:173)
`graineurs [28], may be neural in origin. The added
`observations that ice-cream headache and ice-pick
`pains are lateralized to the usual side of a migraineur's
`headache [29, 30} and that implantation of an elec(cid:173)
`trode in the periaqueductal gray matter can itself pro(cid:173)
`duce a headache identical in quality to migraine [31)
`suggest that central mechanisms must be of importance
`in migraine. Whatever the primary site of pathology,
`the pivotal role of the trigeminovascular connections
`has been suggested for some years [32, 33]. The data
`presented here provide the first clear evidence in hu(cid:173)
`mans that these mechanisms are activated in migraine.
`· In summary, it has been shown that there is a
`marked and cranially exclusive increase in craniovascu(cid:173)
`lar levels of the powerful dilator peptide CGRP <luring
`the headache phase of migraine. This substance is also
`clearly present in trigeminal neurons, and these neu(cid:173)
`rons are ideally placed to have a pivotal role in mi(cid:173)
`graine. These data provide a link between the basic
`anatomical and physiological observations of the tri- ·
`geminovascular system and migraine. This study also
`indicates a possible direction for therapeutic interven(cid:173)
`tion as well as advancing the understanding of the fun(cid:173)
`damental pathophysiological events in migraine.
`
`This study was supported by the National Health and Medical Re(cid:173)
`search Councils of Australia and Sweden (014X-05958) and by
`grants from Warren and Cheryl Anderson, The J. A- Perini Family
`Trust, the Basser Trust, and the Australian Brain Foundation.
`
`The authors thank the patients whose generous cooperation made
`this study possible. The authors also thank Prof. J. W. Lance for his
`comments and Dr B. You! for help with initial part of the study.
`
`Presented in preliminary form at the IVth International Headache
`Congress, Sydney, Australia, October 14-18, 1989.
`
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`186 Annals of Neurology Vol 28 No 2 August 1990
`
`

`

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`
`Relapse_ of Inf ant Botulism
`
`Tracy A. Glauser, MD, Henry C. Maguire, MD,
`and John T. Sladky, MD
`
`We report on 3 infants who had relapse of infant botu(cid:173)
`lism after apparent resolution of clinical symptoms. This
`group represented 5% of the infants with confirmed in(cid:173)
`fant botulism who were treated at our institution since
`1976. The exact cause for these relapses was unclear, but
`three potential mechanisms are examined. There were
`no historical, clinical, or electrophysiological predictors
`of relapse. Although at the time of writing recovery
`from relapse appeared complete, dose follow-up of pa(cid:173)
`tients recovering from a bout of infant botulism is neces(cid:173)
`sary.
`
`Glauser TA, Maguire HC, Sladky JT.
`Relapse of infant botulism.
`Ann Neutol 1990;28:187-189
`
`Infant botulism, a presynaptic blockade of neuromus(cid:173)
`cular transmission caused by a toxin elaborated by
`
`From the Division of Child Neurology, The Children's Hospital of
`Philadelphia, and The Department of Neurology, The Hospital of
`The University of Pennsylvania, Philadelphia, PA.
`Received Dec 1, 1989, and in revised form Feb 28, 1990. Accepted
`for publication Feb 28, 1990.
`Address correspondence to Dr Sladky, Division of Child Neurol(cid:173)
`ogy, Children's Hospital of Philadelphia, 34th and Civic Center
`Blvd., Philadelphia, PA 19104.
`
`Clostridium botulinum [l, 2}, is classically a monophasic
`illness_ We report on 3 infants who suffered clinical
`relapse after initial full recovery.
`
`Methods and Subjects
`Between January 1, 1976, and January 1, 1989, 63 infants
`with confirmed infant botulism were treated at The Chil(cid:173)
`dren's Hospital of Philadelphia. Each infant presented with
`the characteristic complaints of constipation followed by hy(cid:173)
`potonia, bulbar signs, and weakness. The median age at hos(cid:173)
`pitalization was 13.5 weeks (range, 2 to 33 weeks).
`Elecrrophysiologi<.:al testing was performed on every in(cid:173)
`fant. Each infant showed an incremental response in their
`compound motor action potential to high rates of repetitive
`stimulation. Definitive rnnfirmation was achieved by toxin
`identification in stool, using srandard methods [3}. All 63
`infants were infected with C. botulin11m type B. The median
`length of hospitalization was 4 weeks (range, 1 to 26 weeks).
`
`Results
`Three infants (5%) were noted to have a recurrence of
`the characteristic signs and symptoms of infant botu(cid:173)
`lism after hospital discharge and a clinically normal
`interval at home. All three were full-term appropriate
`for gestational age infants of 25- to 30-year-old women
`who had uncomplicated pregnancies, labors, and de(cid:173)
`liveries. Each infant was exclusively breastfed at home
`(in suburban Philadelphia), except for occasional use of
`honey.
`At initial presentation all 3 infants had been con(cid:173)
`stipated between 7 and 9 days and all had a 1-day
`history of poor feeding, weak cry, and floppiness. The
`neurological examination at admission in each revealed
`a poor gag, poor suck, hypotonia, and proximal weak(cid:173)
`ness. A summary of the first hospital course is shown
`in Table 1.
`.
`Following a clinically normal interval at home rang(cid:173)
`ing from 6 co 13 days, each child developed constipa(cid:173)
`tion (2 to 6 days) and then poor feeding, hypotonia,
`and weakness (1 to 4 days) and was readmitted. None
`had been re-exposed to honey. A swnmary of the sec(cid:173)
`ond hospital course is shown in Table 1. The results of
`electrophysiological testing for both admissions are
`shown in Table 2. Following discharge from the sec(cid:173)
`ond hospitalization, all 3 infants were growing and de(cid:173)
`veloping normally.
`
`Discussion
`Since infant botulism was first described in 197 6, there
`have been over 600 cases reported ( 4}. The disease is
`endemic in California, Utah, and the southeastern area
`of Pennsylvania (5, 6]. Additional risk factors for de(cid:173)
`veloping the illness appear to be breast-feeding and
`possibly consumption of honey [ 4}. In affected infants,
`ingested spores of C. botulinum germinate and release
`a toxin that inhibits the presynaptic release of acetyl(cid:173)
`choline at all postganglionic parasympathetic nerve ter-
`
`Copyright © 1990 by the American Neurological Association 187
`
`