J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.11.1124 on 1 November 1976. Downloaded from

Journal ofNeurology, , and Psychiatry, 1976, 39, 1124-1128

Sclerosing spinal pachymeningitis1 A complication of intrathecal administration of Depo-Medrol2 for multiple sclerosis

J. L. BERNAT3, C. H. SADOWSKY, F. M. VINCENT, R. E. NORDGREN, AND G. MARGOLIS From the Departments ofMedicine (Neurology) and Pathology, Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire, USA

SYNOPSIS Reported complications of intrathecal steroid therapy include aseptic , infectious meningitis, and arachnoiditis. We report a case of sclerosing spinal pachymeningitis com- plicating the attempted intrathecal administration of Depo-Medrol for multiple sclerosis. The lesion is characterised by concentric laminar proliferation ofneomembranes within the subdural space ofthe by guest. Protected copyright. entire and cauda equina, resulting from repeated episodes ofinjury and repair to the spinal by Depo-Medrol. There is clinical and laboratory evidence that Depo-Medrol produces meningeal irritation and that the vehicle is the necrotising fraction.

Intrathecal corticosteroids have been used to treat a What has clearly been learned from multiple trials variety of neurological disorders, notably multiple is that the use of intrathecal steroids is not without sclerosis, arachnoiditis, and herniated intervertebral risk. There have been reports of associated adhesive disc. The efficacy of intrathecal steroids in the treat- arachnoiditis (Dereux et al., 1956; Goldstein et al., ment of arachnoiditis has been demonstrated 1970; Nelson et al., 1973; Dullerud and Morland, (Feldman and Behar, 1961; Sehgal and Gardner, 1976; Nelson, 1976), (Goldstein et 1962; Savastano, 1968). Subarachnoid and epidural al., 1970; Nelson et al., 1973; Schock and Wieczorek, injections of steroids have been shown to be of value 1974), (Roberts et al., 1967), in the palliation of radicular symptoms of herniated cryptococcal meningitis and epidural abscess (Shealy, intervertebral disc (Gardner et al., 1963; Winnie et al., 1966), in addition to the transient immediate effects of 1972; Dilke et al., 1973). The efficacv of intrathecal leg paraesthesiae (Nelson et al., 1973), bladder steroids in the treatment of multiple sclerosis, how- paralysis (Van Buskirk et al., 1964; Lance, 1969), ever, remains controversial. Treatment has been and meningeal irritation (Feldman and Behar, 1961). reported to reduce spasticity (Lance, 1969), improve The infectious meningitides presumably reflect poor

gait and sphincter control (Baker, 1967), and lead to technique or an immunosuippressive steroid effect, http://jnnp.bmj.com/ a more rapid remission of symptoms (Boines, 1963). while the transient and aseptic complications are con- However, other studies have failed to document sidered to represent a chemical inflammatory res- improvement or have demonstrated only transient ponse to an irritant present in the steroid preparation. benefit (Van Buskirk et al., 1964; Goldstein et al., The following case demonstrates an additional 1970; Nelson et al., 1973). untoward complication occurring when the steroid preparation gains access to the subdural space.

' Presented at the Twenty-Eighth Annual Meeting of the American Academy of Neurology, Toronto, April 1976. CASE REPORT on September 25, 2021 2The trade name is used as the authors attribute the complication described to the vehicle ofthe injection fluid and not to methylpredniso- When first examined in 1972, this 35 year old woman lone acetate. Editor. described a 10 year history of remitting and relapsing s Address for correspondence: Dr James L. Bernat, Division of Neurology, Dartmouth-Hitchcock Medical Center, Hanover, New symptoms including transient limb paraesthesiae, Hampshire 03755. USA. gait unsteadiness, visual blurring, headaches, vertigo, (Accepted 9 July 1976.) tinnitus, urinary retention, and hand tremor. Exam- 1124 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.11.1124 on 1 November 1976. Downloaded from

Sclerosing spinal pachymeningitis 1125 ination revealed bilateral temporal disc pallor, right strated sharply bordered foci of demyelination with homonymous hemianopia, bilateral internuclear axonal sparing, loss of oligodendroglia, and astro- ophthalmoplegia, vertical nystagmus, diminished cytic hyperplasia. More active lesions exhibited position and vibration sensation below the knees, phagocytosis of degenerating myelin by foamy truncal ataxia, diffuse hyperreflexia, a right extensor macrophages and early perivascular lymphocytic plantar response, and euphoria. Her cerebrospinal cuffing. fluid (CSF) protein was 0.46 g/l with 25.9 % gamma A 5 x 5 x 5 cm recent haematoma occupied the globulin. The diagnosis of multiple sclerosis was white matter of the left cerebral hemisphere, lateral made. A two weeks course ofintramuscular ACTH 40 and superior to the basal ganglia, without sub- units twice daily failed to produce objective improve- arachnoid or ventricular extension. The brain ment. parenchyma surrounding it was oedematous and Over the next year she received six intrathecal yellowish. There was no apparent relationship injections of Depo-Medrol 80 mg. With each injec- between the borders of the haemorrhage and the tion, she claimed transient benefit but no objective demyelinative plaques. improvement was documented. The entire spinal cord and cauda equina were Repeat examinations in 1973 and 1974 revealed encased by a firm, brownish, dense new tissue obliter- progression of her illness to include a diminished right ating and enlarging the subdural space, and adhering corneal reflex, flattening of the right nasolabial fold, the thickened dura mater to the arachnoid mater diminished gag reflexes, spastic paraparesis, and a (Fig. 1). There was no evidence of secondary vascular neurogenic bladder. A trial of percutaneous epidural compromise of the cord or nerve roots. The new sub- dorsal column stimulation failed to reduce her dural tissue changes ranged from early and active to by guest. Protected copyright. spasticity. In February 1975, she was given intrathecal old and established. The most recent lesion was a Depo-Medrol 80 mg without subsequent subjective linear zone of coagulative necrosis in the posterior or objective improvement. The CSF opening pressure dura mater and epidural tissues in the region of the was 90 mm H20; the protein content was 1.33 g/l; cauda equina, probably the tract of a necrotising there were no cells and the fluid was sterile. injection mass. Fresh haemorrhage, early fibroblastic On 8 October 1975, she suddenly developed head- and endothelial proliferation, and macrophage ache, right-sided weakness, and difficulty in speaking. reaction bordered this lesion in the subdural space. On examination, she was alert and presented new The prominent process was that of organising findings of right hemiparesis, right hemihypaesthesia, granulation tissue and formation reflecting the and nonfluent dysphasia. There were no signs of various stages ofrepair ofa necrotising, haemorrhagic meningeal irritation. A course of ACTH was begun, lesion. A layered pattern of reaction was seen indica- then terminated when she became febrile and devel- tive ofrepeated episodes ofinjury and repair, with the oped oedema. was performed on older inner laminae overlain by newer laminae the sixth hospital day. Opening pressure and mano- (Fig. 2). These neomembranes were generally closely metrics were unobtainable. The CSF contained apposed and adherent to both inner dural and outer 34 x 106 red blood cells per litre, no leucocytes, arachnoid membranes. The subarachnoid space was protein content of 16 g/l and glucose of 5.0 mmol/l. involved in a similar but less severe manner, with both The fluid was sterile. Depo-Medrol 80 mg was instilled old and recent changes. intrathecally. She suffered a sudden cardiorespiratory arrest on the tenth hospital day. DISCUSSION Notably, she had neither undergone http://jnnp.bmj.com/ nor intrathecal injections of any medication except A sclerosing spinal pachymeningitis resulted from Depo-Medrol. At no time were there clinical or the unintentional repeated subdural injections of laboratory findings indicative of meningitis. Depo-Medrol. That a necrotising agent present in Depo-Medrol was responsible for the pachymening- PATHOLOGY itis is suggested by the presence ofcoagulative necrosis surrounding the most recent needle tract, and the con- Three major central nervous system pathological centric subdural laminar proliferation resulting from processes were present at postmortem: multiple repeated episodes of injury and repair to the inner on September 25, 2021 sclerosis, intracerebral haemorrhage, and sclerosing dura mater. That the Depo-Medrol was injected into spinal pachymeningitis. the subdural space is suggested by the zero opening Typical demyelinative plaques ofall ages and stages pressure and the CSF protein of 16 g/l of the final ofactivity were present throughout theperiventricular lumbar puncture. We presume the formation of a white matter, centrum semiovale, midbrain, pons, 'second sac' (Rogoff et al., 1974) early in her course, medulla, and spinal cord. The older lesions demon- either by an unintentional subdural Depo-Medrol J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.11.1124 on 1 November 1976. Downloaded from

1126 J. L. Bernat, C. H. Sadowsky, F. M. Vincent, R. E. Nordgren, and G. Margolis

FIG. I Transverse section of the lumbar cord and revealing the dense sutbdural neomembranes and the thickened dura mater. by guest. Protected copyright.

:t .'.:.". .A.. .*. i., .:... !Z .: .,-:- A ..:

*-,.~ :.. *

~~~~~~~~~~~~~- E.. *.. :..

:g ...... :;a ;:

X... A~ ~ ~ A FIG. 2 Photomicrographic transverse section of the lumbar ..... V :SSi:...... * E

......

......

X.- :,5 :" ..... on September 25, 2021

... .. ' A.' *::::,:.*: { E n S it;t~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.11.1124 on 1 November 1976. Downloaded from

Sclerosing spinalpachymeningitis 1127 injection or by back leakage of CSF through the within the subdural space (Rogoff et al., 1974). As arachnoid perforation. Several subsequent injections there is neithei CSF dilutional effect nor circulation were placed into this sac accounting for the several of fluid in the second sac, injected substances may distinct subdural neomembranes present at post- irritate the dura mater in a concentrated fashion. The mortem examination. That a myelogram was never encasement of the entire cord and cauda equina by performed on this patient is pertinent because of the sclerosing pachymeningitis in this case is consistent known propensity of myelographic dyes to incite with the presumption that the repeated injections of meningeal (J0rgensen et al., 1975). Depo-Mediol produced a second sac which dissected Depo-Medrol is a suspension of methylpredniso- from the lumbar subdural space to the foramen lone acetate in a solution of polyethylene glycol (a magnum. Thus the suggestion by Nelson et al. (1973) nonionic detergent) and myristyl-gamma-picolinium that repeated intrathecal doses of Depo-Medrol may chloride (a long chain fatty acid) so designed to produce setious meningeal scarring is pathologically produce a mycel. The mycel acts to decrease the verified by this case. solubility of the steroid in aqueous media and thus The natural history of sclerosing spinal pachy- inhibits its diffusion across cell membranes (Fishman meningitis is unclear. Wilson (1940) stated that the and Christy, 1965). That Depo-Medrol regularly cases resulting from subdural infections progress to produces meningeal inflammation when injected invest the cord and nerve roots tightly, producing intrathecally has been documented clinically (Feld- radicular symptomatology and central cord infarc- man and Behar, 1961) and experimentally (Sehgal et tion. In the present case, there was no clinical evidence al., 1963). Immediate reactions including back and of radicular involvement, and any symptoms of cord leg pain (Feldman and Behar, 1961) and leg paraes- involvement would be difficult to distinguish from by guest. Protected copyright. thesiae (Nelson et al., 1973) are common. There is a those resulting from the demyelinative plaques. dose-related CSF pleocytosis, primarily poly- Pathologically, there was no suggestion of cord or morphonuclear, that exceeds 200 x106 cells/l at 24 nerve root infarction, or of malacia secondary to hours with traditional 80 mg doses and usually obstructed CSF outflow. resolves within a week. There is a similar dose-related The major complications of intrathecal steroid rise of CSF protein (Sehgal et al., 1963). therapy include chemical and infectious meningitides There is experimental evidence that intrathecally and their sequelae. These complications are primarily injected nonionic detergent produces adhesive arach- based upon the route ofsteroid administration and the noiditis (Hurst, 1955) and that propylene glycol, a particular steroid preparation used, not upon the congener of polyethylene glycol, is necrotising to systemic effects of the medication. axons, myelin, and connective tissue in concentrations Only the chemical complications may be avoided as low as 10% (Margolis et al., 1953). It is thus pos- by the removal of the necrotising agent from the sible that the glycol is the fraction in Depo-Medrol steroid preparation. The ideal preparation for intra- which produces the meningeal inflammation, the thecal injection should neither contain preservatives subsequent repair of which leads to sclerosing such as alcohols or phenol, known to produce post- arachnoiditis or pachymeningitis. injection seizures (Ildirim et al., 1970), nor solubility The subdural space reacts to repeated injury by altering vehicles such as glycols, known to produce laminar proliferation, whereby sheets of fibroblasts meningeal inflammation (Margolis et al., 1953). A from the inner loose areolar layer of the dura mater degree of meningeal inflammation, however, is are stimulated to proliferate longitudinally along the inevitable as even intrathecally injected non- inner surface, producing concentric subdural fibrous preservative-containing sterile water or isotonic http://jnnp.bmj.com/ laminae (Wilson, 1940). There is a predictable saline produces brisk CSF pleocytosis (Bedford, temporal pattern to the layering of the laminae, with 1948). the oldest layer innermost and the active layers nearer Both the infectious and chemical complications their site of production, the areolar layer of the dura may be obviated only by the discontinuation of the mater. This sequence of events is analogous to the intrathecal route of steroid administration. The healing process of spinal subdural haematomata and indications for the use of intrathecal steroids have may also be seen in syphilitic and tuberculous sub- come under increasing scrutiny primarily because the dural infections (Munro and Merritt, 1936; Wilson, studies of their efficacy have been poorly controlled, on September 25, 2021 1940). Laminar proliferation appears to be the because the rationale for their use is dubious (Fish- characteristic response of the subdural space to man and Christy, 1965), and because their dangers are injury. becoming better appreciated. Physicians contemplat- The subdural space is especially sensitive to injected ing the use of intrathecal steroids must consider irritants. The second sac produced by an injection carefully the possible advantages of this route with its mass may remain localised or extend longitudinally documented complications, J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.11.1124 on 1 November 1976. Downloaded from

1128 J. L. Bernat, C. H. Sadowsky, F. M. Vincent, R. E. Nordgren, and G. Margolis

The authors thank Dr Dewey Nelson for his helpful Lance, J. W. (1969). Intrathecal Depo-Medrol for spas- review of the manuscript. ticity. Medical Journal ofAustralia, 2, 1030. Margolis, G., Hall, H. E., and Nowill, W. K. (1953). An investigation of Efocaine, a long-acting local anesthetic REFERENCES agent. I. Animal studies. Archives of Surgery, 67, Baker, A. G. (1967). Intrathecal methylprednisolone for 715-730. multiple sclerosis. Evaluation by a standard neurological Munro, D., and Merritt, H. H. (1936). Surgical pathology rating. Annals ofAllergy, 25, 665-672. of subdural hematoma. Based on a study of one hun- Bedford, T. H. B. (1948). The effect of injected solutions on dred and five cases. Archives of Neurology and Psy- the cell content of the cerebrospinal fluid. British Journal chiatry (Chic.), 35, 64-78. ofPharmacology, 3, 80-83. Nelson, D. (1976). Arachnoiditis from intrathecally given Boines, G. J. (1963). Predictable remissions in multiple corticosteroids in the treatment of multiple sclerosis. sclerosis. Delaware Medical Journal, 35, 200-202. Archives ofNeurology (Chic.), 33, 373. Dereux, J., Vandenhaute, A., and Deheck, M. (1956). Nelson, D. A., Vates, T. S., Jr, and Thomas, R. B. Jr. Arachnoidite apparue au cours d'un traitement par les (1973). Complications from intrathecal steroid therapy injections sous-arachnoidiennes d'hydrocortisone. in patients with multiple sclerosis. Acta Neurologica Revue Neurologique, 94, 301-304. Scandinavica, 49, 176-188. Dilke, T. F. W., Bury, H. C. W., and Grahame, R. (1973). Roberts, M., Sheppard, G. L., and McCormick, R. C. Extradural corticosteroid injection in management of (1967). Tuberculous meningitis after intrathecally lumbar nerve root compression. British MedicalJournal, administered methylprednisolone acetate. Journal ofthe American Medical Association, 200, 894-896. 2, 635-637. by guest. Protected copyright. Dullerud, R., and Morland, T. J. (1976). Adhesive arach- Rogoff, E. E., Deck, M. D. F., and D'Angio, G. (1974). noiditis after lumbar radiculography with Dimer-X and The second sac. A complicating factor in regimens based Depo-Medrol. Radiology, 119, 153-155. on intrathecal medications. American Journal of Roentgenology and Radium Therapy and Nuclear Feldman, S., and Behar, A. J. (1961). Effect of intrathecal Medicine, 120, 568-572. hydrocortisone on advanced adhesive arachnoiditis and cerebrospinal fluid pleocytosis. An experimental study. Savastano, A. A. (1968). Intrathecal steroid administration Neurology (Minneap.), 11, 251-256. in postoperative arachnoiditis. Rhode Island Medical Journal, 51, 337-338. Fishman, R. A., and Christy, N. P. (1965). Fate of adrenal cortical steroids following intrathecal injection. Neuro- Schock, G., and Wieczorek, V. (1974). Meningitis nach logy (Minneap.), 15, 1-6. intrathekaler applikation von kortikosteroiden. Psy- chiatrie, Neurologie, und Medizinische Psychologie Gardner, W. J., Goebert, H. W., Jr, and Sehgal, A. D. (Leipzig), 26, 477-479. (1963). Intraspinal corticosteroids in the treatment of sciatica. Transactions of the American Neurological Sehgal, A. D., and Gardner, W. J. (1962). Pantopaque Association, 86, 275-276. 'arachnoiditis'. Cleveland Clinic Quarterly, 29, 177-188. Goldstein, N. P., McKenzie, B. F., McGuckin, W. F., and Sehgal, A. D., Tweed, D. C., Gardner, W. J., and Foote, Mattox, V. R. (1970). Experimental intrathecal admini- M. K. (1963). Laboratory studies after intrathecal stration of methylprednisolone acetate in multiple steroids. Archives ofNeurology (Chic.), 9, 64-68. sclerosis. Transactions of the American Neurological Shealy, C. N. (1966). Dangers of spinal injections without Association, 95, 243-244. proper diagnosis. Journal of the American Medical Hurst, E. W. (1955). Adhesive arachnoiditis and vascular Association, 197, 1104-1106. blockage caused by detergents and other chemical Van Buskirk, C., Poffenbarger, A. L., Capriles, L. F., and irritants. Journal of Pathology and Bacteriology, 70, Idea, B. V. (1964). Treatment of multiple sclerosis with http://jnnp.bmj.com/ 167-178. intrathecal steroids. Neurology (Minneap.), 14, 595-597. Ildirim, I., Furcolow, M. L., and Vandiviere, H. M. (1970). Wilson, S. A. K. (1940). Pachymeningitis spinalis hyper- A possible explanation of posttreatment convulsions trophica. In Neurology, vol. 1, pp. 9-11. Edited by A. N. associated with intrathecal corticosteroids. Neurology Bruce. Williams and Wilkins: Baltimore. (Minneap.), 20, 622-625. Winnie, A. P., Hartman, J. T., Meyers, H. L., Jr, Rama- J0rgensen, J., Hansen, P. H., Steenskov, V., and Ovesen, murphy, S., and Barangan, V. (1972). Intradural and N. (1975). A clinical and radiological study of chronic extradural corticosteroids for sciatica. Anesthesia and lower spinal arachnoiditis. Neuroradiology, 9, 139-144. Analgesia, 51, 990-1003. on September 25, 2021