375
Experimental Study of
Arachnoiditis from lohexol,
an Investigational Nonionic
Aqueous Contrast Medium
Victor M . Haughton 1
Khang -Ch eng Ho2
Brian T . Lipm an 3
Myelography was performed in 16 monkeys using either metrizamide o r iohe xol , a
new no nionic aqueous contrast medium . Eight of the animals received almost five
times the recommended clinical dose of contrast medium per unit of body weight; the
other eight received the equivalent of a high clinical dose. The severity of resultant
arac hn o iditi s 12 weeks later was evaluated by repeat mye lography and by histologic
study of the arachnoid. No animals had severe arachnoiditis. Two of the four animals
exa mi ned with the higher dose of metrizamide had moderate arachnoiditis and one
had mild arachnoiditis; with the lower dose o f metrizam ide, two of four animals had
mild arachn oiditis. No significant evidence of arachnoiditis was seen in any of the eight
an imal s examined with io hexol.
For mye lograph y, aqu eous contrast medi a suc h as metrizamid e have sig nific ant advantag es over gases and o ily substances [1 - 3]. They demonstrate th e
subarac hnoid space more faithfull y and leave it ph ysiolog ica lly thro ugh th e
arachnoid membrane [4]. Furthermore, metri zamid e exceeds all previo usly used
aqu eou s mye lograph ic contrast medi a in pati ent tolerance and low incidence of
comp licatio ns [ 2]. Postm yelographi c arac hno iditis, although not detected after
c lin ical myelograph y [ 1], has bee n re po rte d after ex perim e ntal mye log raphy if
suffi c iently hi gh conce ntrati ons of co ntrast medi um we re used [5, 6]. Th e major
d isadvantages of metrizamide are cost , side effec ts suc h as nausea and vo miting ,
and risk of se izures . lohexo l, a new no ni oni c aqueo us materi al, has been
deve loped for mye log raph y. We co mpared io hexol and metrizam ide w ith respect
to th e likelihood of postm ye log raphi c arach noid iti s. To determ ine if iohexo l was
potenti ally safer th an metriz amid e, both contrast media were used in larger
co ncentrati ons per unit of body we ig ht th an shou ld be used c li nicall y.
Materials and Methods
Received October 5, 1981, accepted after revision March 29. 1982.
' Department of Rad iology, Medica l College of
Wiscon sin. 9200 W. Wisconsin Ave., Milwaukee,
WI 53226. Add ress reprin t requests to V. M.
Haughton.
' Department of Pathology, Medical Coll ege of
Wisonsin, Milwa ukee , WI 53226.
3 Allen Bradley Medical Science Laboratory,
Medical Co llege of Wisconsin, Milwaukee, WI
53226.
AJNR 3:375-3 77, July/ August 1982
0195-6108 / 82 / 0304-0375 $00.00
© Am erican Roentg en Ray Society
We have previously used monkeys for expe ri mental myelography [5 - 1 0]. For the pre se nt
st udy, 16 bo nn et monkeys (5 - 7 kg ) were d ivided into fou r g roups after th ey had co mpl eted
a 4 0 day q uarantin e and a series of mycobac te ria l and in testina l parasit e testin g . Th e typ es
and amo unt s of co ntrast media used for myelograp hy in the four g roups are shown in tab le
1. Gro ups 1 and 2 rece ived, per unit of body we ight, almost five tim es th e reco mm end ed
c lini ca l dose of th e co ntrast med ium . Groups 3 and 4 rece ived rough ly the equiva len t of a
hi gh c lini ca l dose.
Th e anim als were fasted ove rni ght p ri o r to th e myelogram, but were given fluid s ad lib .
Phencyc ladi ne hydroch lo ri de (2 mg / kg) and atropine (0 .1 2 mg) were g iven intramu scu larly
for sedation before the p roced ure. Th e anim als ' lower backs were shaved and d isinfec ted .
The an imals we re then placed prone on a til tin g myelographic tab le, th e head end of whi ch
was til ted 15° above ho rizontal. Lumbar pun cture wa s performed with a 2 2 gauge disposable sp in al need le at th e L3 - L4 interspace . A 1.2 ml quant it y of c e reb rospina l flui d was
wit hdrawn and then th e co ntrast med ium was injected under flu o roscop ic monitoring .
Rad iograph s were obtained at 1 and 5 min after th e in trat heca l inj ecti on of co ntrast
HAUGHTON ET AL.
376
AJNR: 3,
Ju~ / Augu~
1982
TABLE 1: Arachnoiditis from Experimental Myelography with lohexol or Metrizamide
Group: Anima l N o.
1 (I ohexol 3 .6 ml , 370 mg I/ ml):
290
..... .......
299
300
30 1
2 (M etrizam ide 3.6 ml , 37 0 mg
11m!) :
287
... .. ...
288
289
291
3 (I ohexol 1.2 ml , 300 mg I/ ml) :
334
335
336
33 7
4 (Metrizamide 1 .2 ml , 300 mg
I/ ml) :
340
343
.... . .... . .
344
3 46
Weighl
(kg)
Myelog raphi c
Evid ence of
Arac hn oiditi s
Hi stolog ic
Arachnoidit is
Score ·
10.5
6.9
5.9
6.2
No
No
No
No
7 .2
8.7
8 .3
7.1
Block, L5-L6
No
Partial block
No
17
9
19
4
4 .2
4 .1
3.8
3 .5
No
No
No
No
3
6
6
4
3.7
3.3
3.2
3.5
No
No
No
No
9
5
10
8
8
5
0
0
. Severity of arachnoiditis based on scores in previous stud ies: 0 - 8, no arachnoiditis; 9-16, mild arachnoiditis: 17-24 moderate
arac hn oiditis: and 25-36. seve re arachnoid itis.
med ium . Th e anim als were placed in a sitting position in primate
res traint c hairs 15 min after injec ti on. Th e animals we re returned to
th eir cages 16 hr later.
Repeat myelography and euthanasia were performed 12 weeks
later. Th e dural sac and its contents were removed, fixed in formalin ,
sec ti oned, and stained in routine manner [10]. Secti ons at L5 , L6 ,
and L7 were exam ined for evidence of arachnoid fibrosis, inflammatory cell inflammation, nerve root sheath narro wi ng , and hemorrhage. Nine region s were each scored on a scale of 0-4 for
arac hnoiditis. Th ese nine regions inc luded th e subarachnoid space,
th e arachno id membrane, and th e subd ural space at L5, L6, and
L7 . Th e reg ions were scored 0 for no evidence of fibrosis , 1 for
questionable evid ence, 2 for mild fibrosis , 3 for moderate fibrosis,
and 4 for severe fibrosis. Th e scorin g was performed by th e neuropath olog ist (K . C. H.) wit hout knowledge of the treatment protoco l
or th e mye log raphic results. Th e max imal possible score was 36.
On th e basis of co ntrol and treated animals in previous stud ies, 08 we re conside red norm al scores, 9-16 mi ld arachnoiditis , 17-24
moderate arac hnoiditis, and 25-36 severe arac hn oiditi s.
Results
All myelog rams were techn icall y satisfactory with respect
to subarachno id placement of the con trast medium and
excell ent opacification of the subarachnoid space and root
sheaths. In gro ups 3 and 4, iohexol or metrizamide effectively demonstrated the subarach noid space from abo ut L2
to L6 . In groups 1 and 2 anim als, th e entire lumbar space
and mu ch of the thoracic subarac hnoid space were opacified by the larger volu me of co ntrast medium . In group 1
anim als given the larger dose of iohexol, nei th er the second
myelogram nor the postmortem examination of the arachnoid revealed signifi can t evidence of arachnoid scarring or
inflammation (table 1). In some anatom ic sections, slight
thickening or fib ros is was noted in the arachnoid, the sub-
dural space, or the nerve root sheath. In one anim al, slight
narrowing of a root sheath secondary to fibrosis was noted,
and , in another animal, there was some epidural hemorrhag e
attributable to the myelogram just before sacrifi ce . No inflammatory ce ll inflamm ation was seen. The scores for
arachnoiditis rang ing from 0 to 8 (table 1) are indi stingu ishab le from normal or control anim als in previou s stud ies [510].
In two group 2 animals given th e larger dose of metrizamide, the myelogram 12 weeks after the test myelogram
revealed a complete or partia l block of th e subarachnoid
space due to arachnoid scarring (table 1). Histologic examination of the arac hnoid in the four animals showed slight
to moderate fibrosis in the arachnoid, subdural space, or
nerve roots. Some of th e root sheaths appeared significantly
narrowed . Slight inflammatory ce ll inflamm ation with lymphocytes and po lymorphonuclear cell s was noted in some
anim als. Epidural hemorrhage secondary to th e recent myelog ra m was also noted in one animal. With moderate arac hnoiditis in two animals and mild arachnoiditi s in one, the
scores in this group were 4-19 . The chance that the scores
in groups 1 and 2 differed fortuitously was slightly greater
than 10% (t = 24, Wi lcoxan rank sum test).
The second mye lograms in group 3 an imals showed no
chang es of ara chnoiditis . Histologic study revealed few
ab normaliti es. A few fibroti c changes were detected in this
group but no nerve root sheath narrowing or inflammatory
cell inflammation. The arac hnoiditis scores were 3 -6 (average of 5). These scores do not suggest arac hnoiditis.
In group 4 anim als, no important differences were observed between th e first and the second myelograms . Som e
fibrotic changes were detected in the subarachnoid or subdural spaces or root sheaths. In some secti ons, the arachnoid or the dura appeared thickened an d infiltrated with
AJNR:3. July / August 1982
ARACHNOIDITIS FROM IOHEXOL
lymphocytes and polymorphonuclear cells. Some nerve root
sheaths were narrowed slightly because of fibrosis . The
scores were 5-10 (average , 8). These scores signified mild
arachnoid itis in two animals. The differences between
scores in Groups 1 , 3, and 4 were not statistically significant
(Wilcoxan rank sum tests).
Discussion
Results from experimental myelography on primates have
correlated very well with clinical observations. In monkeys,
iocarmate produced arachnoiditis [5 - 8] as it did in clinical
practice [1 , 6, 9, 10], whi le metrizamide did not un less used
in excessive amounts [6 , 9, 10].
In th is study, metrizam ide produced arachnoiditis as in
previous studies of experimental metrizamide mye lography.
The concentrations of metrizamide used both in groups 2
and 4 exceeded prudent clinical practice. As in previous
studies, the severity of arachnoid itis increased as larger
concentrations of metrizamide were used .
In the present studies, iohexo l, even in very large concentrations, did not produce arachnoiditis. Although th e number
of subjects was small, these experimental studies suggest
that iohexo l used in concentrations under 300 mg Il ml
should not produce arachno iditis in c linical myelography .
Minimizing the intrathecal concentrations of aqueous c ontrast media, promoting hydration of patients, and se lecting
patients without block of the lumbar execretory roots for
contrast media probably decrease the risk of postmyelographic arachnoiditis [11 -1 5]. With equally good selection
of patients and performance of myelography , iohexol should
have at least the same margin of safety as metrizamide with
regard to postmyelographic arachnoid itis.
The radiographic properties of iohexol are comparable to
metrizamide. Excell ent demonstration of the subarachnoid
space was obtained rout inely. The elim ination of the contrast
medium does not take place w ith noticeably greater rapidity
than metrizamide .
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