Dear Mr Eden,

I am sorry it took so long to answer your questions but we have consulted a
number of various specialists. The following answers come from Melker
Lindqvist, associate professor of neuroradiology, Department of
Neuroradiology, Karolinska Hospital, S-171 76 Stockholm.
We would appreciate very much if your company could pay
us for the costs of consulting professor Lindqvist. We have paid him 15.000
SEK for the many hours he has spent investigating these complicated matters,
which have resulted in the very valuable information below. The amount
15.000 SEK should be put inte bankaccount number 1 56 16-6, belonging to
Postgirot Bank Sweden. Please also note "The national board of health and
welfare, unit 335, project 72 11 13."

From a paper in the American Journal of Neuroradiology (AJNR) in 1995 (ref.
18) about  the Stockholm School of Neuroradiology  by the two famous Swedish
neuro-radiologists, Professor Erik Lindgren and Professor Torgny Greitz, the
following paragraph is quoted: "The Stockholm School took a stand against
the use of these (oil based) contrast media at an early stage, and they were
hardly ever used in Sweden. Considering the number of postmyelographic
arachnoiditis that are now reported, this may seem to have been a wise
decision."

Instead of oil based contrast agents gas (air or oxygen) was used in Sweden
for ventriculography and encephalography for investigation of intracranial
lesions. Gas myelography was used for investigation of the spinal cord, and
from the late 1940´s most centres in Sweden used the ionic water soluble
contrast medium methiodal sodium (Abrodil, Kontrast U) for lumbar
myelography. The same techniques were used in most centres in the other
Scandinavian countries and to some extent in Germany and France. The rest of
the world used almost exclusively the oil based contrast agent iophenylate
(Pantopaque, Myodil) for both intracranial and spinal examinations.

What were the reasons for these fundamental differences in neuroradiologic
technique ? Why did the Swedish radiologists avoid oil based contrast media?
Or, why were not gas myelography, pneumoencephalography and lumbar
myelography with water soluble contrast agent accepted as alternatives to
examinations with oil based media in the rest of the world ? The interesting
question seems to be: Could the large number of postmyelographic
arachnoiditis, that have been reported over the years, have been avoided ?

The general view of the Stockholm School of Neuroradiology on these issues
are presented in a book chapter by Lindgren (ref. 13) and in the above
mentioned paper by Lindgren and Greitz (ref. 18).


Questions 1 - 2:

1. Why did Sweden never use oil based contrast agents ?

2. If Sweden believed that there was a danger with oil based contrast agents
what research did it perform to verify this?

The risk of arachnoiditis with oil based contrast media. In the 1930´s and
1940´s the department of radiology at the Serafimer Hospital in Stockholm
was headed by the famous neuroradiologists Erik Lysholm and Erik Lindgren
working together with an equally famous neurosurgeon, professor Herbert
Olivecrona. Patients from all over the world were referred to professor
Olivecrona, and many of these patients had been examined elsewhere with oil
based contrast media. During the radiological examinations of these patients
at the Serafimer Hospital the neuroradiologists noted remaining contrast
medium in the subarachnoid space, both in the head and in the spinal canal.
The oil deposits were often fixed (did not move with change of the patients
position), and they were also associated with local thickening of the
meninges. This was interpreted as arachnoiditis caused by the contrast
medium, and in a few cases this arachnoiditis caused difficulties in the
removal of a tumor at surgery (ref. 13).

In 1928 Odin, Rundström and Lindblom published a supplement of Acta
Radiologica entitled "Iodized oils as an aid to the diagnosis of lesions of
the spinal cord and a contribution to the knowledge of adhesive
arachnoiditis" (ref. 25). These authors, working in Sweden, used their own
home-made oily media out of soya and sesame oils in addition to Lipiodol.
Their preparations made out of sesame oil had less adverse effect than
Lipiodol. They observed clinical signs of acute meningeal reaction similar
to acute meningitis. However, they did not perform a long term follow up of
their patients.

Except for this supplement (ref. 25) no scientific studies seem to have been
performed in Sweden to test the early or late adverse effects of the oil
based contrast media. Some papers on late and persisting sequelae from the
use of Myodil and Pantopaque started to appear in the international
literature in the 1940´s and 1950´s: Tarlov 1945 (ref. 29), Luce 1951 (ref.
19), Hurteau 1954 (ref. 7), Davies 1956 (ref. 4). A case of death following
Pantopaque myelography was reported by Erickson et coll. in 1953
(ref.6).

Thus the decision already around 1935 by the leading Swedish
neuroradiologists not to use oil based contrast media was mainly based on
clinical observations among their own patients rather than on published or
unpublished scientific examinations. As an example of this type of clinical
observations the following  case was reported by Lindgren in a lecture in
1984. The manuscript of this lecture was published in Swedish by Nycomed,
Stockholm in 1994 (ref. 17). (The quoted part is translated by Professor
Lindqvist.)

"It may seem strange that oily based contrast media, especially Pantopaque,
were used to such a large extent (especially in America), since these
contrast media doubtless caused arachnoiditis, although the clinical
importance of these changes were and are debated. We had a nurse with some
vague symptoms and performed a pneumoencephalography on her with negative
result. She was convinced that she had an intracranial lesion, so she went
to America, where she was examined with positive contrast medium, also with
negative result. She came back to Sweden, and after two years she developed
serious symptoms. We performed a new pneumoencephalogram. No air entered the
intracranial space in a normal way. An air ventriculography was performed
and showed a dilated ventricular system, including the fourth ventricle. At
surgery extensive adhesions were found in the posterior fossa. In my opinion
it is thus clear that positive contrast media, at least in some cases, can
cause clinically significant arachnoiditis."

What other reasons, except for the risk of arachnoiditis, contributed to the
Swedish decision ?

The physical properties of the oil based media were not ideal. They did not
mix with the cerebrospinal fluid (CSF), had high viscosity and had a
tendency to be split up in droplets. For these reasons they did not fill out
narrow spaces, for instance the subarachnoid pockets surrounding the spinal
roots and the narrow parts of the intracranial subarachnoid cisterns, and
thus did not allow visualisation of fine anatomical details.

The Swedish neuroradiologists were masters of air studies and claimed that
air encephalography and ventriculography in the hands of skilled
neuroradiologists had proved capable of giving equally good results as
examinations performed with oil based media (ref. 17). Several publications
on neuroradiologic investigations with gas (air or oxygen) emanated from
"The Swedish School of Neuroradiology" at the Serafimer Hospital. Examples
of important papers are: Lysholm et coll. published
"Das Ventrikulogramm" part I -III 1931 - 1937 (ref. 20-22). Lindgren
published "On the diagnosis of tumors of the spinal canal by aid of gas
myelography" in 1939 (ref. 15), "A pneumographic study of the temporal horn
with special reference to tumors in the temporal region" in1948 ( ref. 16)
and "Some aspects on the technique of encephalography" in 1949 (ref. 14).

The neuroradiologists at the Serafimer Hospital became famous for their
clinical and scientific achievements and attracted many colleges from abroad
who came to the Serafimer Hospital for training. One of them was James Bull
from London, and he made the following statement at the Symposium
Neuroradiologicum in Rotterdam in 1949: "There is no doubt that air or
oxygen is the contrast material of choice. The degree of success one obtains
with air is an index of ones ability as a neuro-radiologist. In my view the
more often one falls back on positive contrast material, the less capable
one proves oneself as a neuroradiologist." (ref. 13).

The organisation of Swedish radiology. The first and main prerequisite for
the international success of Swedish radiology was the fact that independent
departments of radiology were created already when diagnostic radiology was
introduced in Sweden. The man who had the main responsibility for this was
Gösta Forssell, the first director of the Roentgen Institute at the
Serafimer Hospital in 1908. He managed to convince the authorities that each
hospital should have only one x-ray department, and the heads of roentgen
departments in Sweden should have the same position as other clinical heads.
(In most European countries, as well as in the US, each clinical speciality
had its own small roentgen department, usually run by a clinician.) The
Swedish organisation meant that specially trained radiologists took the full
responsibility not only for the "interpretation" of the images, but also for
the choice of technique, including the risk of complications involved. (ref.
18). For this reasons Swedish radiologists were in charge of all parts of
the diagnostic procedures, for instance lumbar puncture and the injection of
air for the air studies and all parts of the angiographic procedures.

Technical development. The independent status of the radiology department at
the Serafimer Hospital gave the radiologists the opportunity not only to
develop examination technique, but also to work together with the local
industry in developing new technical equipment for radiology. To give just
one example: Lysholm, in co-operation with the Elema Schoenander company, in
1931 constructed the "Lysholm skull table" that for many years was used for
encephalography and angiography.


Question 3:

Has Sweden found any problems with water based contrast agents ?

Gas myelography was not a good technique for the diagnosis of lumbar disk
disease because the air did not give enough contrast. Oil based media had
the physical disadvantages mentioned above and were thus not ideal. The
Swedish radiologist Arnell had been experimenting with the water soluble
contrast medium methiodal sodium (Abrodil, Kontrast U) and finally reached
the conclusion that Abrodil could be used for lumbar myelography (ref.2).
However it was so irritating that it had to be combined with spinal
anaesthesia, and even so the medium was so toxic that it was not allowed to
reach the spinal cord. Thus the examination had to be restricted to the
lumbar region, but in that region it proved to give excellent visualisation
of the lumbosacral nerve roots and their sleeves. Improved technique for
lumbar myelo-graphy with Abrodil was published by Lindblom in 1946 (ref.11).
For Swedish radiologists the need for spinal anaesthesia, before the
injection of the contrast medium, was not regarded as a big problem since
they were in charge of the whole procedure. The contrast medium was excreted
via the kidneys, and no residual contrast medium could be seen in the spinal
canal after one day. In 1937 Lindblom published an investigation of
complications of myelography by Abrodil (ref. 12). The investigation was
based on 721 cases collected from several Swedish hospitals. Several cases
with complications were noted, for instance drop in blood pressure with
shock, lumbar pain, spasm in the legs and even 3 cases with "secondary
shock, and paralysis of the legs and sphincters for weeks." However, no
complications with persistent neurological symptoms were found among these
721 patients.

In spite of the limitations Abrodil had such great advantages for the
diagnosis of lumbar disk disease that it soon became the medium of choice
for lumbar myelography. For many years permanent complications to
myelography with methiodal sodium were unknown. In 1956 Munroe (ref. 24) and
in 1959 Söderberg et coll. (ref. 28) published a few cases with cauda equina
syndrome after myelography with methiodal sodium. However, their papers were
not published in the radiological literature, and for a long time their
observations remained unknown to the radiologists. In 1972 came the first
publication (ref. 3) on adhesive arachnoiditis after myelography with ionic
water soluble contrast media, and since then several papers have been
published with reports on adhesive arachnoiditis after water soluble
contrast media (ref. 1,5, 8, 9, 10, 26, 27 ). By that time the new nonionic
contrast medium metrizamide was already on its way, and methiodal sodium was
withdrawn from the market in 1974.

Since the introduction of the water soluble nonionic contrast media
metrizamide (Amipaque) and later iohexol (Omnipaque) complications of
clinical importance are practically unknown.

Swedish neuroradiologists were strongly opposed to oil based contrast media
because of their tendency to give arachnoiditis, and still they were so late
to discover the same type of complications caused by methiodal sodium
(Abrodil, Kontrast U) which was used extensively in Sweden for many years.
The explanation for this seems to be that the water soluble media, as
opposed to the oil based, disappear completely from the subarachnoid space.
If a patient was examined a second time there was thus nothing in the
pictures that indicated that the arachnoiditis like changes that had
developed since the previous examination were caused by the contrast medium.
The incidence of postmyelographic arachnoiditis was also low with methiodal
sodium as compared both to oil based media and to later introduced water
soluble ionic contrast media like Conray and Dimer-X.

Question 4:

What is Sweden´s position on epidural steroid injections? Are they
considered safe?
Conclusions from Professor Melker Lindqvist.

"The question about the safety of epidural steriod injections is difficult
for me, as a neuroradiologist, to answer. I have consulted Björn Meyerson
who is professor of neurosurgery with treatment of chronic pain as his
special interest. He in turn has discussed the problem with associate
professor Staffan Arnér, head of the pain treatment clinic at the Karolinska
Hospital. They agree that the beneficial effect of epidural steroid
injections in patients with arachnoiditis and similar chronic pain syndromes
can be questioned, and this type of treatment is not much used in Sweden.
However, except in the case of inadvertent injection into the subarachnoid
space, they do not think this treatment is harmful. In an extensive report
in 2000 on "Back and neck pain" by the Swedish Council on Technology
Assessment in Health care (SBU Report 145) the conclusions seem to be the
same."

With kind regards

Marianne Thorén
Principal Administrative Officer
The Division of Medical Quality Development
The Department of Health and Medical Services
The National Board of Health and Welfare
S-106 30 Stockholm
SWEDEN


References

1. Ahlgren P: Long term side effects after myelography with water
soluble contrast media: Conturex, Conray meglumin 282 and Dimer-x.
Neuroradiology (1973), 206

2. Arnell T et coll.: Myelography with skiodan (Abrodil).
Acta Radiologica 12 (1931), 287

3. Autio E et coll: Adhesive arachnoiditis after lumbar myelography
with meglumine iothalamate (Conray).
Acta Radiological Diagnosis 12 (1972), 17

4. Davies FL: Effect of unabsorbed radiographic contrast media on the
central nervous system.
Lancet 2 (1956), 747

5. Dullerud R et coll.: Adhesive arachnoiditis after lumbar
radiculography with Dimer-X and Depo-Medrol.
Radiology 119 (1976), 153

6. Erickson TC et coll.: Late meningeal reaction to ethyl
idophenylundecylate used in myelography. Report of a case that terminated
fatally.
JAMA 153 (1953), 636

7. Hurteau EF et coll.: Arachnoiditis following the use of iodized oil.
The Journal of Bone and Joint Surgery 36-A (1954), 393

8. Irstam L et coll.: Water-soluble contrast media and adhesive
arachnoiditis. I. Reinvestigation of nonoperated cases.
Acta Radiologica Diagnosis 14 (1973), 497

9. Irstam L et coll.: Water-soluble contrast media and adhesive
arachnoiditis. II. Reinvestigation of operated cases.
Acta Radiologica Diagnosis 15 (1974), 1

10. Irstam L et coll.: Water-soluble contrast media and adhesive
arachnoiditis
Acta Radiologica Diagnosis 15 (1974), 356

11. Lindblom  K: Lumbar myelography with Abrodil.
Acta Radiologica 27 (1946), 1

12. Lindblom K: Complications of myelography by Abrodil.
Acta Radiologica 28 (1947), 69

13. Lindgren E: A history of neuroradiology. In: Newton, Potts, eds.
Radiology of the skull and brain. Skull. Vol 1, Book 1. St Louis: C.V.Mosby,
1971:1-25

14. Lindgren E: Some aspects on the technique of encephalography.
Acta Radiologica 31 (1949), 161

15. Lindgren E: On the diagnosis of tumors of the spinal cord by the aid
of gas myelography.
Acta Chirurgica Scandinavica 82 (1939), 303

16. Lindgren E: A pneumographic study of the temporal horn with special
reference to tumors in the temporal region.
Acta Radiologica, suppl. 69 (1948)

17. Lindgren E: En tillbakablick på neuroradiologiens tidigaste
utveckling. (In Swedish)
Nycomed, Stockholm 1994

18. Lindgren E and Greitz T: The Stockholm school of neuroradiology.
AJNR 16 (1995), 351

19. Luce JC et coll.: Pantopaque meningitis due to hypersensitivity.
Radiology 57 (1951), 878

20. Lysholm E et coll.: Das Ventrikulogramm, part 1.
Acta Radiologica, suppl. 24 (1931) 1

21. Lysholm E et coll.: Das Ventrikulogramm, part 3.
Acta Radiologica, suppl. 25 (1935) 1

22. Lysholm E et coll.: Das Ventrikulogramm, part 2.
Acta Radiologica, suppl. 26 (1937) 1

23. Mason MS et coll.: Complications of Pantopaque myelography. Case
report and review.
Journal of Neurosurgery 19 (1962), 302

24. Munro D: Lumbar and sacral compression radiculitis (herniated lumbar
disk syndrome).
The New England Journal of Medicine 254 (1956), 243

25. Odin M et coll.: Iodized oils as an aid to the diagnosis of lesions
in the spinal cord and a contribution to the knowledge of adhesive
arachnoiditis.
Acta Radiologica, suppl. VII, 1928

26. Rådberg C et coll.: Late sequelae following lumbar myelography with
water-soluble contrast media.
Acta Radiologica Diagnosis 14 (1973), 507

27. Skalpe IO: Adhesive arachnoiditis following lumbar radiculography
with water-soluble contrast agents. A clinical report with special reference
to metrizamide.
Radiology 121 (1976), 647

28. Söderberg L et coll.: Neurological complications following
myelography with water soluble contrast medium.
Acta Ortopaedica Scandinavica 28 (1959), 220

29. Tarlov IM: Pantopaque meningitis disclosed at operation.
JAMA 129 (1945), 1014

30. The Swedish Council on Technology Assessment in Health Care. SBU
Report 145, May 2000. Nachemson A ed: Back and neck pain.