sclerosing spinal pachymeningitis1 - bmj · steroid preparation. theideal preparation for...

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

Sclerosing spinal pachymeningitis1A 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 meningitis,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 lesionis characterised by concentric laminar proliferation ofneomembranes within the subdural space of theentire spinal cord and cauda equina, resulting from repeated episodes of injury and repair to the spinaldura mater by Depo-Medrol. There is clinical and laboratory evidence that Depo-Medrol producesmeningeal irritation and that the vehicle is the necrotising fraction.

Intrathecal corticosteroids have been used to treat avariety of neurological disorders, notably multiplesclerosis, arachnoiditis, and herniated intervertebraldisc. The efficacy of intrathecal steroids in the treat-ment of arachnoiditis has been demonstrated(Feldman and Behar, 1961; Sehgal and Gardner,1962; Savastano, 1968). Subarachnoid and epiduralinjections of steroids have been shown to be of valuein the palliation of radicular symptoms of herniatedintervertebral disc (Gardner et al., 1963; Winnie et al.,1972; Dilke et al., 1973). The efficacv of intrathecalsteroids in the treatment of multiple sclerosis, how-ever, remains controversial. Treatment has beenreported to reduce spasticity (Lance, 1969), improvegait and sphincter control (Baker, 1967), and lead toa more rapid remission of symptoms (Boines, 1963).However, other studies have failed to documentimprovement or have demonstrated only transientbenefit (Van Buskirk et al., 1964; Goldstein et al.,1970; Nelson et al., 1973).

' Presented at the Twenty-Eighth Annual Meeting of the AmericanAcademy of Neurology, Toronto, April 1976.2The trade name is used as the authors attribute the complicationdescribed to the vehicle ofthe injection fluid and not to methylpredniso-lone acetate. Editor.s Address for correspondence: Dr James L. Bernat, Division ofNeurology, Dartmouth-Hitchcock Medical Center, Hanover, NewHampshire 03755. USA.(Accepted 9 July 1976.)

What has clearly been learned from multiple trialsis that the use of intrathecal steroids is not withoutrisk. There have been reports of associated adhesivearachnoiditis (Dereux et al., 1956; Goldstein et al.,1970; Nelson et al., 1973; Dullerud and Morland,1976; Nelson, 1976), aseptic meningitis (Goldstein etal., 1970; Nelson et al., 1973; Schock and Wieczorek,1974), tuberculous meningitis (Roberts et al., 1967),cryptococcal meningitis and epidural abscess (Shealy,1966), in addition to the transient immediate effects ofleg paraesthesiae (Nelson et al., 1973), bladderparalysis (Van Buskirk et al., 1964; Lance, 1969),and meningeal irritation (Feldman and Behar, 1961).The infectious meningitides presumably reflect poortechnique or an immunosuippressive steroid effect,while the transient and aseptic complications are con-sidered to represent a chemical inflammatory res-ponse to an irritant present in the steroid preparation.The following case demonstrates an additional

untoward complication occurring when the steroidpreparation gains access to the subdural space.

CASE REPORT

When first examined in 1972, this 35 year old womandescribed a 10 year history of remitting and relapsingsymptoms including transient limb paraesthesiae,gait unsteadiness, visual blurring, headaches, vertigo,tinnitus, urinary retention, and hand tremor. Exam-

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ination revealed bilateral temporal disc pallor, righthomonymous hemianopia, bilateral internuclearophthalmoplegia, vertical nystagmus, diminishedposition and vibration sensation below the knees,truncal ataxia, diffuse hyperreflexia, a right extensorplantar response, and euphoria. Her cerebrospinalfluid (CSF) protein was 0.46 g/l with 25.9% gammaglobulin. The diagnosis of multiple sclerosis wasmade. A two weeks course ofintramuscular ACTH 40units twice daily failed to produce objective improve-ment.Over the next year she received six intrathecal

injections of Depo-Medrol 80 mg. With each injec-tion, she claimed transient benefit but no objectiveimprovement was documented.Repeat examinations in 1973 and 1974 revealed

progression of her illness to include a diminished rightcorneal reflex, flattening of the right nasolabial fold,diminished gag reflexes, spastic paraparesis, and aneurogenic bladder. A trial of percutaneous epiduraldorsal column stimulation failed to reduce herspasticity. In February 1975, she was given intrathecalDepo-Medrol 80 mg without subsequent subjectiveor objective improvement. The CSF opening pressurewas 90 mm H20; the protein content was 1.33 g/l;there were no cells and the fluid was sterile.On 8 October 1975, she suddenly developed head-

ache, right-sided weakness, and difficulty in speaking.On examination, she was alert and presented newfindings of right hemiparesis, right hemihypaesthesia,and nonfluent dysphasia. There were no signs ofmeningeal irritation. A course of ACTH was begun,then terminated when she became febrile and devel-oped oedema. Lumbar puncture was performed onthe sixth hospital day. Opening pressure and mano-metrics were unobtainable. The CSF contained34 x 106 red blood cells per litre, no leucocytes,protein content of 16 g/l and glucose of 5.0 mmol/l.The fluid was sterile. Depo-Medrol 80mg was instilledintrathecally. She suffered a sudden cardiorespiratoryarrest on the tenth hospital day.

Notably, she had neither undergone myelographynor intrathecal injections of any medication exceptDepo-Medrol. At no time were there clinical orlaboratory findings indicative of meningitis.

PATHOLOGY

Three major central nervous system pathologicalprocesses were present at postmortem: multiplesclerosis, intracerebral haemorrhage, and sclerosingspinal pachymeningitis.

Typical demyelinative plaques of all ages and stagesofactivity were present throughout the periventricularwhite matter, centrum semiovale, midbrain, pons,medulla, and spinal cord. The older lesions demon-

strated sharply bordered foci of demyelination withaxonal sparing, loss of oligodendroglia, and astro-cytic hyperplasia. More active lesions exhibitedphagocytosis of degenerating myelin by foamymacrophages and early perivascular lymphocyticcuffing.A 5 x 5 x 5 cm recent haematoma occupied the

white matter of the left cerebral hemisphere, lateraland superior to the basal ganglia, without sub-arachnoid or ventricular extension. The brainparenchyma surrounding it was oedematous andyellowish. There was no apparent relationshipbetween the borders of the haemorrhage and thedemyelinative plaques.The entire spinal cord and cauda equina were

encased by a firm, brownish, dense new tissue obliter-ating and enlarging the subdural space, and adheringthe thickened dura mater to the arachnoid mater(Fig. 1). There was no evidence of secondary vascularcompromise of the cord or nerve roots. The new sub-dural tissue changes ranged from early and active toold and established. The most recent lesion was alinear zone of coagulative necrosis in the posteriordura mater and epidural tissues in the region of thecauda equina, probably the tract of a necrotisinginjection mass. Fresh haemorrhage, early fibroblasticand endothelial proliferation, and macrophagereaction bordered this lesion in the subdural space.The prominent process was that of organisinggranulation tissue and scar formation reflecting thevarious stages ofrepair ofa necrotising, haemorrhagiclesion. A layered pattern of reaction was seen indica-tive of repeated episodes of injury and repair, with theolder inner laminae overlain by newer laminae(Fig. 2). These neomembranes were generally closelyapposed and adherent to both inner dural and outerarachnoid membranes. The subarachnoid space wasinvolved in a similar but less severe manner, with bothold and recent changes.

DISCUSSION

A sclerosing spinal pachymeningitis resulted fromthe unintentional repeated subdural injections ofDepo-Medrol. That a necrotising agent present inDepo-Medrol was responsible for the pachymening-itis is suggested by the presence ofcoagulative necrosissurrounding the most recent needle tract, and the con-centric subdural laminar proliferation resulting fromrepeated episodes of injury and repair to the innerdura mater. That the Depo-Medrol was injected intothe subdural space is suggested by the zero openingpressure and the CSF protein of 16 g/l of the finallumbar puncture. We presume the formation of a'second sac' (Rogoff et al., 1974) early in her course,either by an unintentional subdural Depo-Medrol

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Sclerosing spinal pachymeningitis

injection or by back leakage of CSF through thearachnoid perforation. Several subsequent injectionswere placed into this sac accounting for the severaldistinct subdural neomembranes present at post-mortem examination. That a myelogram was neverperformed on this patient is pertinent because of theknown propensity of myelographic dyes to incitemeningeal inflammation (J0rgensen et al., 1975).Depo-Medrol is a suspension of methylpredniso-

lone acetate in a solution of polyethylene glycol (anonionic detergent) and myristyl-gamma-picoliniumchloride (a long chain fatty acid) so designed toproduce a mycel. The mycel acts to decrease thesolubility of the steroid in aqueous media and thusinhibits its diffusion across cell membranes (Fishmanand Christy, 1965). That Depo-Medrol regularlyproduces meningeal inflammation when injectedintrathecally has been documented clinically (Feld-man and Behar, 1961) and experimentally (Sehgal etal., 1963). Immediate reactions including back andleg pain (Feldman and Behar, 1961) and leg paraes-thesiae (Nelson et al., 1973) are common. There is adose-related CSF pleocytosis, primarily poly-morphonuclear, that exceeds 200 x106 cells/l at 24hours with traditional 80 mg doses and usuallyresolves within a week. There is a similar dose-relatedrise of CSF protein (Sehgal et al., 1963).

There is experimental evidence that intrathecallyinjected nonionic detergent produces adhesive arach-noiditis (Hurst, 1955) and that propylene glycol, acongener of polyethylene glycol, is necrotising toaxons, myelin, and connective tissue in concentrationsas low as 10% (Margolis et al., 1953). It is thus pos-sible that the glycol is the fraction in Depo-Medrolwhich produces the meningeal inflammation, thesubsequent repair of which leads to sclerosingarachnoiditis or pachymeningitis.The subdural space reacts to repeated injury by

laminar proliferation, whereby sheets of fibroblastsfrom the inner loose areolar layer of the dura materare stimulated to proliferate longitudinally along theinner surface, producing concentric subdural fibrouslaminae (Wilson, 1940). There is a predictabletemporal pattern to the layering of the laminae, withthe oldest layer innermost and the active layers nearertheir site of production, the areolar layer of the duramater. This sequence of events is analogous to thehealing process of spinal subdural haematomata andmay also be seen in syphilitic and tuberculous sub-dural infections (Munro and Merritt, 1936; Wilson,1940). Laminar proliferation appears to be thecharacteristic response of the subdural space toinjury.The subdural space is especially sensitive to injected

irritants. The second sac produced by an injectionmass may remain localised or extend longitudinally

within the subdural space (Rogoff et al., 1974). Asthere is neithei CSF dilutional effect nor circulationof fluid in the second sac, injected substances mayirritate the dura mater in a concentrated fashion. Theencasement of the entire cord and cauda equina bysclerosing pachymeningitis in this case is consistentwith the presumption that the repeated injections ofDepo-Mediol produced a second sac which dissectedfrom the lumbar subdural space to the foramenmagnum. Thus the suggestion by Nelson et al. (1973)that repeated intrathecal doses of Depo-Medrol mayproduce setious meningeal scarring is pathologicallyverified by this case.The natural history of sclerosing spinal pachy-

meningitis is unclear. Wilson (1940) stated that thecases resulting from subdural infections progress toinvest the cord and nerve roots tightly, producingradicular symptomatology and central cord infarc-tion. In the present case, there was no clinical evidenceof radicular involvement, and any symptoms of cordinvolvement would be difficult to distinguish fromthose resulting from the demyelinative plaques.Pathologically, there was no suggestion of cord ornerve root infarction, or of malacia secondary toobstructed CSF outflow.The major complications of intrathecal steroid

therapy include chemical and infectious meningitidesand their sequelae. These complications are primarilybased upon the route ofsteroid administration and theparticular steroid preparation used, not upon thesystemic effects of the medication.Only the chemical complications may be avoided

by the removal of the necrotising agent from thesteroid preparation. The ideal preparation for intra-thecal injection should neither contain preservativessuch as alcohols or phenol, known to produce post-injection seizures (Ildirim et al., 1970), nor solubilityaltering vehicles such as glycols, known to producemeningeal inflammation (Margolis et al., 1953). Adegree of meningeal inflammation, however, isinevitable as even intrathecally injected non-preservative-containing sterile water or isotonicsaline produces brisk CSF pleocytosis (Bedford,1948).Both the infectious and chemical complications

may be obviated only by the discontinuation of theintrathecal route of steroid administration. Theindications for the use of intrathecal steroids havecome under increasing scrutiny primarily because thestudies of their efficacy have been poorly controlled,because the rationale for their use is dubious (Fish-man and Christy, 1965), and because their dangers arebecoming better appreciated. Physicians contemplat-ing the use of intrathecal steroids must considercarefully the possible advantages of this route with itsdocumented complications,

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The authors thank Dr Dewey Nelson for his helpfulreview of the manuscript.

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Bedford, T. H. B. (1948). The effect of injected solutions onthe cell content of the cerebrospinal fluid. British JournalofPharmacology, 3, 80-83.

Boines, G. J. (1963). Predictable remissions in multiplesclerosis. Delaware Medical Journal, 35, 200-202.

Dereux, J., Vandenhaute, A., and Deheck, M. (1956).Arachnoidite apparue au cours d'un traitement par lesinjections sous-arachnoidiennes d'hydrocortisone.Revue Neurologique, 94, 301-304.

Dilke, T. F. W., Bury, H. C. W., and Grahame, R. (1973).Extradural corticosteroid injection in management oflumbar nerve root compression. British MedicalJournal,2, 635-637.

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Fishman, R. A., and Christy, N. P. (1965). Fate of adrenalcortical steroids following intrathecal injection. Neuro-logy (Minneap.), 15, 1-6.

Gardner, W. J., Goebert, H. W., Jr, and Sehgal, A. D.(1963). Intraspinal corticosteroids in the treatment ofsciatica. Transactions of the American NeurologicalAssociation, 86, 275-276.

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