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Journal ofNeurology, Neurosurgery, and Psychiatry, 1979, 42, 392-401

Systemic lupus erythematosus clinically resemblingmultiple sclerosis and with unusual pathological andultrastructural featuresINGRID V. ALLEN, J. H. D. MILLAR, J. KIRK,AND ROSEMARY K. A. SHILLINGTON

From the Institute of Neurological Sciences, Royal Victoria Hospital, and Department of Pathology(Neuropathology), Queen's University, Belfast

SUMMARY A case of systemic lupus erythematosus is described which clinically resembledmultiple sclerosis and in which the lesions were restricted to the central nervous system. Thenecropsy findings of vascular thickening and necrosis in the spinal cord and in a posterior nerveroot explain the main clinical abnormalities. Clinical signs of the terminal peritonitis secondaryto cholecystitis were absent or minimised probably because of the steroid therapy and spinalcord necrosis. Primary demyelination was not demonstrated though electronmicroscopy revealedlattice fibrillar inclusions within a few myelin sheaths. An unusual ultrastructural feature wasthe finding of "rod-shaped tubular bodies" in large numbers in the endothelial cells of cerebralblood vessels. The incidence and morphology of these organelles are compared with those of theintracisternal tubuloreticular structures (TRS) commonly found in systemic lupus erythematosus.

The involvement of the central nervous system insystemic lupus erythematosus (SLE) was empha-sised by Osler (1900) in the series of patientswhich he reported. Neurological complicationsare recognised as an important cause of death inthis disease (Feng et al., 1973) and may developbecause of primary involvement of the nervoussystem, secondary to the disease affecting otherorgans, or because of the effects of therapy onthe nervous system. There are several referencesin the literature (Fulford et al., 1972; April andVansonnenberg, 1976) to SLE resembling multiplesclerosis. The reported presence of high levels ofviral antibodies (particularly to paramyxoviruses)and of demyelination in both diseases has led tothe supposition that there may be a commonpathogenetic factor. This view is strengthened bya report of homozygous twins one of whom hadSLE, the other multiple sclerosis (Holmes et al.,1967). The present case is reported because of itsclinical resemblance to multiple sclerosis, andbecause of the rarity of reports of central nervoussystem involvement as the only or the earliestmanifestation of SLE. The case provided anAddress for reprint requests: Dr I. V. Allen, Institute of Pathology,Royal Victoria Hospital, Grosvenor Road, Belfast, Northern Ireland.Accepted 14 November 1978

opportunity for a detailed pathological study ofthe spinal cord and for electronmicroscopy onrelatively fresh brain material as necropsy wasperformed three hours after death.

Case report

The patient, a 65 year old housewife, was ad-mitted to the Royal Victoria Hospital, Belfast, on29 July 1975 with severe chest pain. She had ahistory of ischaemic heart disease, and the painwas considered to be cardiac in origin. A few daysafter admission she complained of a marked in-crease in weakness of her legs and inability to passurine. One year previously she had been diagnosedas suffering from ischaemic heart disease and sincethen she had noticed that her legs were becomingweaker, with numbness and pain on exertion. Shealso complained of dyspnoea on exertion and ofattacks of nocturnal dyspnoea. There was nohistory of abdominal pain but she complained ofoccasional vomiting.She had suffered from intermittent diplopia for

six months 30-35 years previously. In September1972 she was admitted to hospital complaining ofweakness and numbness of the left leg. The numb-ness spread up to the level of the waist and the

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Systemic lupus erythematosus clinically resembling multiple sclerosis

arms felt heavy. These symptoms lasted for a fewweeks. In November 1972, she developed vertigoand deafness in the right ear which recovered overa period of weeks. In July 1973, she lost the visionof the left eye over a period of a few days. Thiswas thought to be caused by occlusion of thecentral retinal artery. There was no recovery ofvision.On examination there were xanthelasmas around

both eyes. The blood pressure was 120/75 mmHg,pulse rate 112 per min and the jugular venouspressure was not raised. Fine crepitations wereheard at both lung bases. The left eye was blindwith no perception of light. Its optic disc waspale. Cranial nerves were otherwise normal. Therewas no abnormality in the arms except for slightgeneralised weakness. The legs were very weak(left particularly). The left knee jerk and rightankle jerk were absent, and both plantar reflexeswere extensor. Sensation to pinprick was absentto a definite level at T4 dermatome. Some pain wasfelt in the left leg. Proprioception was absent inthe left leg but was normal in the right leg.Femoral and popliteal pulses were difficult to feelbut posterior tibial and dorsalis pedis pulses werepalpable.Radiography of the chest showed moderate left

heart enlargement, no evidence of dissectinganeurysm of aorta, and considerable elevation ofthe right diaphragm. An ECG on 26 August 1975was normal; on 1 September it showed ischaemicchanges in inferolateral leads. There was abnor-mality of serum enzymes. A myelogram wasnormal. The CSF contained 15 lymphocytes/,ul,protein 0.6 g/l, WR negative; Lange curve 0000000,LE cells were seen in blood on six occasions; ANFwas positive; ESR 100 mm/hr, and bone marrowwas hyperplastic in keeping with the level of steroidtherapy (see below). The WR was negative; VDRLnegative; RPCFT negative; and FTA/ABSnegative.A diagnosis of systemic lupus erythematosus

was made with the brunt of the lesions affectingthe central nervous system as in previously re-ported cases (Fulford et al., 1972). The chest paincorresponded to the sensory level and was con-sidered to be neuritic. With steroid treatment therewas a slight improvement in power in the legs and,strikingly, the vision in the left upper quadrantof the left eye returned and she could read 6/36despite the fact that the left eye had been totallyblind for two years. The ESR also fell to normallimits. However, she complained of recurrentsevere chest pain and, apart from chest infectionand the sensory level, no adequate explanationwas found. Towards the end of January 1976 the

character of the pain changed. She now com-plained of generalised colicky abdominal painwithout nausea or vomiting and without epigastrictenderness. This pain lasted three days. She diedon 27 February 1976. For two days before herdeath she complained of severe central chest painwhich radiated down the left arm.

NECROPSY: MATERIAL AND METHODSNecropsy was carried out three hours after death.Blocks for histology were fixed in 10% bufferedformalin. Paraffin sections were cut at 7 ,um,frozen sections at 15 ,um. Fixed sections of brain,optic nerves, and spinal cord were stained usingthe following techniques: haematoxylin and eosin(H and E), Spielmeyer/fat, Woelcke, Weigert'selastic tissue stain. Sections of kidney were stainedby H and E and Martius' scarlet/blue for fibrin.Blocks for electronmicroscopy (grey and whitematter from right and left frontal and temporallobes) were trimmed to 1-2 mm cubes and im-mediately fixed in cold 2.5% glutaraldehyde in0.1 M s-collidine buffer. After post-fixation inosmium tetroxide the blocks were dehydrated andembedded in Epon 812. Areas for viewing in theelectronmicroscope were selected after examina-tion by light microscopy of toluidine blue-stainedsemithin (1 um) sections. Ultrathin sections weredouble stained with uranyl acetate and lead citrate,and examined in an AEI EM801 electronmicro-scope. Blocks from the choroid plexus initiallyfixed and stored in buffered formalin were washed,transferred to buffered glutaraldehyde, and pro-cessed for electronmicroscopy by identical methods.

NECROPSY FINDINGSThe body was that of an obese woman (weight57 kg, height 1580 mm).Cardiovascular system There was no macroscopicabnormality of the heart (weight 280 g). Coronaryatheroma was slight, and histologically there wasno evidence of infarction or ischaemic fibrosis.There was slight atheroma of the abdominal aortabut there was no occlusion of major arteries, andhistological sections of the carotid and vertebralarteries did not show any abnormality.Respiratory system There was a mild terminalbronchopneumonia but no other abnormality.Gastrointestinal system The peritoneal cavityshowed acute peritonitis; the fibrinous exudatewas most marked over the omentum and loops ofsmall intestine. The cause of the peritonitis wasperforation of the gall bladder which containedmixed infective stones, and was acutely andchronically inflamed. The liver (1300 g) histo-logically showed extensive focal necrosis and

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Ingrid V. Allen, J. H. D. Millar, J. Kirk, and Rosemary K. A. Shillington

contained as a coincidental finding a 90 mmdiameter simple fibrous-walled cyst. There was noabnormality of oesophagus, stomach, intestine,or pancreas.Genitro-urinary system Each kidney weighed120 g and both had the same appearance. Thecortical surface was slightly scarred and ratherpale. There was no cortical or medullary atrophy,and the pelvis was not inflamed. Histologically,small scars were present in the cortex: in these,glomeruli were hyalinised and there was associ-ated lymphocytic infiltration. Medium sizedarteries showed slight musculo-elastic hyperplasiaand some afferent arterioles were hyalinised. Withspecialised staining there was no evidence ofglomerular basement membrane thickening, wireloop formation, or fibrin deposition. The bladderwas chronically inflamed.Haemopoietic and lymphoreticular system Thespleen (140 g) did not show "onion skin" fibrosisand the pulp was histologically normal. Lymphnodes and bone marrow were also histologicallynormal.Endocrine system The pituitary gland did notshow hyalinisation of basophil cells. Adrenal,thyroid, parathyroid glands and ovaries werenormal.Bone Sections from rib and vertebral columnwere examined. The bone trabeculae were normal.The bone marrow was active and contained normalcellular precursors.Central nervous system The brain did not showany macroscopic abnormality but, histologically,in many sections from the deep white matter ofthe hemispheres and in the basal ganglia smallblood vessels showed lymphocytic cuffing (Fig. 1)and perivascular deposition of lipochrome. Corporaamylacea were prominent around the lateralventricles. There was no demyelination.The spinal cord showed softening, shrinkage,

and discolouration of the T4, 5, and 6 segments.Histologically an area of necrosis was identifiedextending from T4 to T6 segment (Fig. 2). Thislesion involved the posterior columns pre-dominantly, but also involved the medial aspectof the lateral columns (left more than right). Thelateral corticospinal tracts were necrotic but thespinocerebellar tracts were preserved. Thenecrosis was old: numerous lipid-containing macro-phages were present in the substance of the spinalcord and around small blood vessels. Occasionallymphocytes were seen but there was no acuteinflammatory reaction. Many of the neurones ofthe posterior horn and of the nucleus dorsalison each side had been destroyed though some cellspersisted as pale homogeneous "ghosts" (Fig. 3).

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Fig. 1 Lymphocytic infiltration of perivascular spaceof cerebral blood vessel. H and E X 100.

The interomediolateral cell column was notsignificantly damaged. Numerous corpora amylaceawere seen in sections adjacent to the necroticsegments. The main spinal arteries in sectionsfrom T4, 5, 6 segments were not thickened orobliterated but small blood vessels showed hyalinethickening and slight lymphocytic cuffing (Fig. 4).A posterior root in a section of the necrotic cordwas partially necrotic (Fig. 5): this lesion wasalso old. The meninges in the region of the necroticsegments showed slight lymphocytic infiltrationbut there was no generalised meningitis. Therewas no abnormality of dorsal root ganglia orevidence of primary demyelination.

Light microscopy of 1 ,um epoxy sections fromthe cerebrum disclosed a generally normal appear-ance with the single exception that in some blocksfrom the cortical grey matter some small bloodvessels were thickened. Similarly, in the choroidplexus the only detectable abnormality was a mildthickening of some vessels. Electronmicroscopyshowed that in both cerebrum (Fig. 6) and choroidplexus (Fig. 7) this thickening was caused by anaccumulation of heterogeneous dense material inthe Virchow-Robin space. The bulk of thismaterial was collagen (Fig. 6) but variable amountsof amorphous, granular, or membranous materialwere also present. The basement membranes ap-peared normal and dense "organised" deposits,fibrin, fibrillar bodies, or C type virus particleswere not seen in relation to any component of thevessel walls.

Intracisternal tubuloreticular structures (TRS)were not seen in endothelial cells despite a carefulsearch of both cerebrum and choroid. However,

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Fig. 2 Necrotic lesion in thortdicspinal cord segment. Woelcke,original magnification X 10.

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Fig. 3 Necrotic lesion in spinal cord containslipophages anid necrotic neurones. H and E X100.

these cells were notable for their content of smallmembrane-bound, variably dense, microtubule-containing bodies, the so-called "rod-shapedtubular bodies" of Weibel and Palade (1964)(Figs. 7b, 8). These were more numerous andprominent in the present case than in the controlIswhich consisted of both necropsy (for example,multiple sclerosis, Huntington's chorea, and non-neurological cases) and biopsy (dementia, suspectedviral encephalitis, etc.) human material. Theendothelial cells appeared otherwise normal.Pathological appearances in the white matter werefew, the majority of axons and sheaths beingapparently normal or only altered by artefact. No

clearly identifiable naked axons were seen but afew bizarre sheaths were found (Fig. 9) whichdiffered distinctly from those seen in the controlmaterial. Such sheaths were characterised bythe presence within dilatations, of ordered fila-mentous lattice aggregates. The dilatations alsocontained heterogeneous dense aggregates andsome membranous bodies. Throughout the whitematter occasional macrophage-like cells were seen,characterised by their abundant cytoplasm andnumerous pleomorphic lysosomes.Eyes and optic nerve The eyeballs were histo-logically normal but the left optic nerve was thin,and showed gliosis and nerve fibre loss (Fig. 10).Some of the small blood vessels in the nerve sheathwere thickened. The right optic nerve was normal.Peripheral nerve In the sections examined therewas no abnormality.Striated muscle Sections from the upper limbswere normal but sections from the right and leftquadriceps showed severe neurogenic atrophy.

Discussion

There are numerous reports of neurologicalsymptoms in systemic lupus erythematosus andinvolvement of the central nervous system occursin about 25% of cases (Fulford et al., 1972). Inmost cases, however, the neurological signs are setagainst the background of the systemic disease,and their interpretation is, therefore, relativelyeasy. Neurological presentation of the disease isuncommon and is usually followed by progressionto the systemic form of the disease. In thepresent case the presentation of the diseasewas entirely neurological and, while the duration

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of the disease was at least three years, there was no

evidence at necropsy of involvement of systemsother than the central nervous system. A furtherunusual feature of the case was the predominanceof the spinal cord involvement. There are relativelyfew detailed descriptions of the pathology of thespinal cord in systemic lupus erythematosus.Vascular changes similar to those seen in the brainhave been described in spinal cord blood vessels

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Fig. 7 Deposition of heterogeneous electron densematerial below the endothelial basement membrane ofan arteriole in the choroid plexus, originalmagnification X 18 270; inset higher magnificationshowing structure of tubular body in endothelialcell, original magnification X50 000.

with myelomalacia in several reports (Piper, 1953;Scheinberg, 1956; de Morsier, 1962; Penn andRowan, 1968). Few descriptions of the spinal nerveroots are available although De Morsier (1962)describes demyelination of dorsal and ventral roots,and Bailey et al. (1956) describe necrosis of dorsalroot ganglia. In the present case the persistentchest pain was thought initially to be caused byischaemic heart disease, and it was three yearsafter the initial presentation that a diagnosis ofneuritic pain was made. The finding of necrosis ina posterior nerve root related to the necroticthoracic segment of the spinal cord probably atleast partially explains the chest pain. We havenot found such a lesion previously reported in theliterature on SLE.There have been many references in the litera-

ture to similarities between multiple sclerosis andSLE, both in clinical presentation (Fulford et al.,1972) and in immunopathology (Holmes et al.,1967), and some workers have described demye-lination as opposed to ischaemic necrosis (Apriland Vansonnenberg, 1976). In the present case theclinical presentation strongly resembled multiplesclerosis, but the pathological features of thatdisease were not observed. April and Vansonnen-berg (1976) describe demyelination, but they ob-

Fig. 8 Numerous dense "tubularbodies" in endothelial cell ofcerebral arteriole. Note thelongitudinally (large arrow)and transversely (small arrow)

* : , , sectioned internal tubules.Original magnification X23 000.

Fig. 9 Latticed fibrillar inclusions(arrows) and heterogeneous debrisin degenerate cerebral myelinsheath, original magnificationX5500; higher magnification of

....... the inclusions which are cut indifferent planes, reveals typical

J? Hirano body-like latticed filamentsubstructure. Both originalmagnification X30 000.

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Fig. 10 Comparison of right(a, c) and left (b, d) optic nerves,

the latter showing shrinkage andgliosis (a) and (b) H and E;(c) and (d) Woelcke, originalmagnification in all X 12.

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served only "a few intact neural fibres." Rare-faction in oither areas which stained for myelinwas attributed to considerable dilatation andvacuolation of nerve fibres. Their description,therefore, differs significantly from that of classicalchronic multiple sclerosis in which nerve fibrepreservation is relatively good.

Lattice fibrillar inclusions of the kind found ina few degenerating myelin sheaths in the presentcase have previously been seen within the oligoden-droglial (Cavanagh et al., 1971) and Schwanncell (Spencer and Thomas, 1974; Hirano andDembitzer, 1976; Hirano, 1978) adaxonal cyto-plasmic compartments in pathologically altered

animal tissue. However, in Hirano's studies, whichwere concerned with mutant Syrian hamsters withhindleg paralysis, similar though smaller inclusionswere also found, though much less commonly, incontrol animals. In these situations their fine struc-ture was indistinguishable from that of the classicHirano bodies initially described in Sommer'ssector of the hippocampus in Guamian amyotrophiclateral sclerosis-Parkinsonism-dementia complex(Hirano et al., 1968). Similar though often smallerinclusions have also been seen in other circum-stances-for example, in cerebellar tumours(Gessaga and Anzil, 1975), in normal and kuru-infected cerebellum (Field and Raine, 1968), in

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muscle disease (Neville, 1973), and within neuronalnuclei in both normal and pathological CNS(Feldman and Peters, 1972; Cragg, 1976).

Detailed studies of Hirano bodies have shownthat they are almost invariably confined to thehippocampus, and that they occur in normalhuman brain from the age of 10 years onwards andincreasingly with age, being present in all brainsover the age of 80 years (Ogata et al., 1972;Schochet and McCormick, 1972). They are foundto be increased in various pathological situations,most noticeably in Alzheimer's disease (Schochetand McCormick, 1972; Gibson and Tomlinson,1977).The rarity of the inclusions resembling Hirano

bodies in the present case and the absence of lightmicroscopic evidence of demyelination make itseem unlikely that they indicate a significantgeneralised oligodendroglial defect such as wasproposed by Hirano (1978) to account for thedemyelination in mutant Syrian hamster. SinceHirano bodies within the sheaths of axons havenot, to our knowledge, been reported previouslyfrom normal human CNS we conclude that theyare abnormal, but rare, nonspecific byproductsresulting from secondary degenerative changes inthe oligodendroglia. Our conclusion, both fromreviewing the literature and from our observationsin the present case, is that there is little firmevidence of primary demyelination in SLE. Theobserved myelin abnormalities can be explained aspart of the ischaemic necrosis or as secondaryto Wallerian degeneration.

Several other points of clinical interest emergefrom this case. The beneficial effect of steroidtherapy on the vision of the left eye was verystriking: despite the fact that the patient had beentotally blind in this eye for two years, she re-covered vision in the left upper field quadrant.The explanation of this recovery is difficult, butone can only assume that oedema was a factor inthe blindness. The severe gall bladder disease andperitonitis were probably aggravated by thesteroid therapy, while the paucity of abdominalclinical signs at the time of death (particularlyrigidity) was presumably the result of the spinalcord lesion.

Electron microscopy of the apparentlyminimally affected cerebrum in this case is inkeeping with other studies of SLE which havepointed to the primarily vascular nature of thelesions in this disease. Failure to find the fre-quently reported (Norton, 1969; Bariety et al.,1973; Helder and Feltkamp-Vroom, 1976) butnonspecific tubuloreticular structures in the endo-plasmic reticulum or nuclear envelope of endo-

thelial cells in the cerebrum and choroid plexuswas not unexpected considering the relatively mildinvolvement of these tissues in this case. Norton(1969), for example, has pointed out that whilethey may be found frequently in affected tissuethey may be infrequent or absent in uninvolvedtissue from the same individual. The finding in thepresent case of large numbers of rod-shapedtubular bodies in endothelial cells, particularly inthe cerebrum, has not previously been reported inSLE but may be of significance in several respects.These are normally occurring but poorly under-stood specific organelles of endothelial cells(Ghadially, 1975), originally described by Weibeland Palade (1964). They have since been shownto arise directly from the cisterns of the Golgiapparatus (Sengel and Stoebner, 1970), and thereis evidence that they may discharge their contentsinto the blood plasma after fusion with the endo-thelial plasma membrane (Ohsugi and Hirano,1977). Their function is not yet fully elucidated,but they may secrete factors which enhance bloodcoagulation (Burri and Weibel, 1968), or affectblood pressure (Bertini and Santolaya, 1970). Whilethere is disagreement as to how common they arein normal adult human CNS (Herlinger et al..1974; Hirano, 1976), it is clear that in certainconditions, most notably in tumours (Kawamuraet al., 1974), they are present in increased num-bers, size, and variety of form. Dense compactforms of tubular bodies are only rarely seen ininvolved tissue in SLE. For example, Norton(1970) found numerous tubular reticular structuresbut no tubular bodies in vessels from musclebiopsy samples in cases of SLE and dermatomyo-sitis. However, in scleroderma the converse wastrue, and Norton attributed this to differences inthe form of the microvascular injury in theseconditions. He suggested that, whereas in SLE anddermatomyositis this injury was acute and episodic,in scleroderma it was more chronic and sustained.The finding of the tubular bodies in the present

case raises the question of a possible relationshipbetween variants of such bodies and the tubulo-reticular structures reported commonly in SLE.Thus, while the tubular bodies found in our casewere mainly of the dense, compact variety notlikely to be confused with tubuloreticular in-clusions, there is a striking similarity betweenmany of the published micrographs illustratingthe latter (Norton, 1969; Hass and Yunis, 1970;Bariety et al., 1973; Helder and Feltkamp-Vroom,1976), and those illustrating the vacuolar forms oftubular bodies (Kawamura et al., 1974; Ohsugiand Hirano, 1977). This apparent overlap callsinto question the validity of much of the published

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data on the incidence of tubuloreticular structuresin SLE for, despite claims to the contrary(Kawamura et al., 1974), the two types of inclusioncannot reliably be distinguished in pathologicalmaterial by objective morphological criteria.

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