Ann. rheum. Dis. (1974), 33, 86

Vertebral changes in ochronosisAnatomical and radiological study of one case

R. LAGIER AND S. SIT'AJFrom the Department ofPathology, University of Geneva, Switzerland,and the Rheumatic Diseases Research Centre, Piestany, Czechoslovakia

This discussion of ochronotic spinal changes is basedon the post mortem examination of a 50-year-oldwoman who had been hospitalized for 3 years withschizophrenia and ochronosis. Clinical articularmanifestations of ochronosis were present but slightin the limbs, the spine was stiff, and radiography of

Accepted for publication May 17, 1973.

the vertebral column showed pathognomonic ochro-notic changes.

Material and methodsFrontal and sagittal planes of an anterior slice from thelumbar column were studied (T 11071/69); each fragmentwas x-rayed, decalcified, and embedded in celloidin(paraffin for some small pieces).

(a) Posterior aspect of slice: intervertebral discs are (b) Anterior view: bony bridges join the vertebrae giving apigmented and show penetration ofbone which may lead to bamboo aspect. Occasional islands ofpigmented cartilagevertebral ankylosing (L1-2), and to marginal bony bridges are visible on the surface, especially in spaces L3-4 andoccasionally incorporating islands ofdisc (the crater seen in L4-5L3 is an artefact) FIG. 1 Lumbar vertebral slice: L2, 3, and4 complete, Ll and 5 incomplete.

copyright. on A

pril 18, 2021 by guest. Protected by

http://ard.bmj.com

/A

nn Rheum

Dis: first published as 10.1136/ard.33.1.86 on 1 January 1974. D

ownloaded from

Vertebral changes in ochronosis 87

FIG. 2 X-ray view of the specimen from Fig. 1, showing disc calcification and marginal bony bridgeformation

Sections were studied unstained, and stained withhaematoxylin and eosin, van Gieson, or Nile blue (auseful, although non-specific stain for ochronotic pigment(Cooper and Moran, 1957; O'Brien, La Du, and Bunim,1963)). Calcium deposits in a fragment of intervertebraldisc were studied by x-ray diffraction.

Findings

I. INTERVERTEBRAL DISC LESIONSMacroscopically the discs appeared black (Figs 1(a),3(a)), but, on microscopic examination, the unstainedsections appeared ochre, whence Virchow's termochronosis. Pigmentation was greatest in the hyalinecartilage joining the vertebral body to the disc(Kleinschmidt, 1922; Putschar, 1966), and decreasedthrough the annulus fibrosus to the nucleus pulposus(Fig. 3(b)).The fundamental disc architecture was preserved.

Even when the nucleus pulposus was obliterated,with fraying of the internal border of the annulusfibrosus on the sides ofa split in the centre of the disc,there was no chondrocytic proliferation or fibro-cartilaginous remodelling as found in the 'degenera-tive chondroses' (Fig. 7(a)).

Grossly the discs were hard and brittle. At themargins, occasional sharply pointed splinters ofvarious sizes could be seen microscopically. Thesesplinters were either embedded in a fibrous reaction

(Fig. 4) or tightly packed in an osteosclerotic re-modelling (Fig. 6), especially in an intervertebralbridge, where islands of pigmented cartilage mayremain visible on the surface (Fig. lb). Segments ofdisc were sometimes separated from one another bypenetrating bone that was occasionally found to weldadjacent vertebrae (Figs l(a), 5(a)).The disc fragments were usually surrounded by

histiocytes containing phagocytosed ochronoticpigment and some haemosiderin deposits. In themarrow, the histiocytes were numerous in proximityto the fragments, but decreased rapidly at a distance(Fig. 5(b)).The classic heavy calcareous deposits predominated

in the internal zone of the annulus fibrosus (Fig. 7(b)).In corroboration of other observations (Bywaters,Dorling, and Sutor, 1970), x-ray diffraction showedthese deposits to be composed of apatite.

II. BONE MODIFICATIONSOsteogenic remodelling was found secondary tointervertebral disc deterioration, ultimately leadingto intervertebral welding and bony bridges (Figs1 (a), 3, 5, 6).The lamellar structure of the bone attests to the

slow activity of the remodelling; the process wasslightly more active in contact with the disc fragments,especially between the vertebral bodies (as demon-

(a) Anteroposterior diewt? (b) anid (c) Radiographs ofsections 1 cm. thick adjacent tothe cut surface of the specimen, show-ing disc calcificationsanid bonyt, bridges more c learly

copyright. on A

pril 18, 2021 by guest. Protected by

http://ard.bmj.com

/A

nn Rheum

Dis: first published as 10.1136/ard.33.1.86 on 1 January 1974. D

ownloaded from

88 Annals ofthe Rheumatic Diseases

FIG. 3 Lumbar disc L2-3

(a) Macroscopic view, showingdiscs invaded by bone, bothcentrally and by marginal bridges.Surface of celloidin-embeddedspecimen. x 1-3

(b) Unstained histological section.Pigment confined to disc, and mostpronounced in cartilaginous platebetween intervertebral body andannulusfibrosus. x 1-9

(c) Haematoxylin and eosin stainbetter demonstrates the bonybridges, on the right, in associationwith a segment of longitudinalligament. x 1V9

strated by some signs of aborted erosion, and bysome osteoid borders). Rarely, pigmented osteocyteswere seen.

Further from the discal lesions, there was moderateosteoporosis (Cerveiiansky, Sit'aj, and Urbanek,1959; Klaus, Klizek, and Vranesic, 1961; Kolar andKtizek, 1968; Louyot, Gaucher, and Montet, 1967),but no abnormal endosteal remodelling. On thewhole,the marrow was haemopoietic, and was fibrous onlyin the immediate vicinity of the deteriorated discs.Slight subperiosteal deposits of pigment were

exceptionally observed near a disc, but, with theexception of some exposed parts of the discs, theanterior surface of the vertebral column appearedto be unpigmented (Fig. 1(b)). The rare segments ofligament present in the specimen were unpigmented.

Discussion

Clinical and radiological manifestations of spinalochronosis, brought about by the slow impregnationof the discs by homogentisic acid, usually begin in

the third decade (Louyot and others, 1967; Sit'aj,1963), about 10 years before the appearance ofperipheral manifestations. Radiological and postmortem observations show that the entire spine maybe involved, but that the earliest manifestations areusually lumbar. This early predilection may berelated to the multiple and complex forces to whichthe spine is submitted. The articular manifestationsofan otherwise generalized ochronotic impregnation,thus would seem to depend on local mechanicalconditions.The discal deterioration of ochronosis differs

from that of the vertebral 'degenerative chondroses',often seen with ageing or consequent upon mechanicaldisorders. Ochronotic disc deterioration is due to abrittleness comparable to that observed in thecartilage, or fibro-cartilage, of an ochronotic di-arthrodial joint (Lagier, Boussina, Taillard,Sasfavian, Chafizadeh, and Fallet, 1971; Lichtensteinand Kaplan, 1954; Putschar, 1966).The disc fragments thus formed, provoke a

reaction in adjacent connective tissue identical to

VF

NF ko

copyright. on A

pril 18, 2021 by guest. Protected by

http://ard.bmj.com

/A

nn Rheum

Dis: first published as 10.1136/ard.33.1.86 on 1 January 1974. D

ownloaded from

Vertebral changes in ochronosis 89

Diagram: thic-k linies e=rei-te-<__w bh al ouitlinie; thin linies =-fibrous

buntdles of lonigituidinial liga-| inr7r7enit,; black ar eas - - fr agmenletts1;; ofpigmtiented disc

wC

FIG. 4 Histological detail of lumbar disc L2-3, leftborder. Fragments of deteriorated disc are imprisoned inthe connective tissue remodelling deep to the longitudinalligament and, deeper, in the newly formed intervertebralbone. x 6 5.

that induced in the synovial membrane of a hip orknee joint by the debris of articular cartilage (Steigerand Lagier, 1972). The osteosclerotic remodellingabout such disc fragments is histologically com-

parable to that of the eburnation of ochronotic*diarthrodial joints.

The pigmented deposits in some histiocytes of themarrow appear secondary to the deterioration of thecartilage, as we have also observed in the femoralhead. It is interesting to speculate that the pigmentfound in bone marrow may ultimately escape fromthe marrow, either phagocytosed or simply trdns-ported, and may thus become the source ofochronoticdepositions in non-tendinous non-cartilaginous sites,such as the walls of large arteries or of the heart.As reported in other studies (Gardner, 1965;

Nishimori, Ito, and Hakuno, 1970), no pigmentationwas seen on the anterior longitudinal ligament.

However, this ligament may be pigmented (Lichten-stein and Kaplan, 1954) as well as other vertebralligaments (Kleinschmidt, 1922). Inconstant im-pregnation of ligaments in ochronotic hips and kneeshas also been observed.

Polydiscal deterioration, accompanied by boneremodelling, explains the clinical manifestationsobserved in vertebral ochronosis: slow onset, discretepain, spinal stiffening, loss of physiological curves,and decrease in height (O'Brien and others, 1963).It also explains the occasional discal rupturesprovoking a radicular syndrome, which may requiresurgery (McCollum and Odom, 1965). Disc rupturesare much more frequent in males than females.

RADIOLOGYIn ochronosis, a series of non-specific bone lesionsbrings about a complete remodelling of the vertebralcolumn. When such lesions are associated withcalcifications of the discs, the radiological picture ishighly suggestive and practically pathognomonic ofvertebral ochronosis, whereas changes in the peri-pheral joints alone are non-specific (Fig. 2).

(A) Calcium deposits, similar to those in theannulus fibrosus, have also been found in the pubicsymphysis (Sit'aj, 1963), in the helix of the externalear (Mueller, Sorensen, Strandjord, and Kappas,1965; Pomeranz, Friedman, and Tunick, 1941;Thompson, 1957), and in costal cartilage (Cooperand Moran, 1957). They have not been observed indiarthrodial articulations. Since this disc calcificationis composed of apatite, and appears to be secondaryin origin, it may be considered to be dystrophiccalcification. Nevertheless, it must be distinguishedfrom other dystrophic disc calcifications which aremore common, but topographically more limited,generally to the centre of the discs. Nor should suchdeposits be confused with the deposits chondro-calcinosis, which are smaller, more peripheral, andcrystallographically different, although chondro-calcinosis may be seen in ochronotic patients.The dystrophic calcification of ochronosis, which

extensively involves multiple discs, forms radiologicalimages which, alone, evoke the diagnosis. For thisreason, ochronosis was considered to be frequent inancient Egypt (Simon and Zorab, 1961; Wells andMaxwell, 1962); however, the calcifications oftenseen in the published radiographs of mummies,appear more homogeneous and are not associatedwith narrowing of interspaces, nor with adjacentbone remodelling. It is presumed that such calci-fications are an artefact of the embalming process(Gray, 1967). This aspect of paleopathology isdiscussed elsewhere (Gardner and Griffin, 1971).

(B) Vertebral dislocation and narrowing ofinterspaces may occur at different levels due tomultiple disc deterioration. The splits in the centre of

copyright. on A

pril 18, 2021 by guest. Protected by

http://ard.bmj.com

/A

nn Rheum

Dis: first published as 10.1136/ard.33.1.86 on 1 January 1974. D

ownloaded from

90 Annals ofthe Rheumatic Diseases

fpt

.4.

-. i4. A

N

(a) Islands ofpigmentedcartilage isolated byectopic bony trabeculae.x 16

(b) Detail of island ofpigmented cartilage sur-rounded by bony trabe-culae. Only histiocytesdirectly in contact withcartilage have storedpigment. At a distance,no pigment is seen in themarrow. x 80

FIG. 5 Microscopic sections through ankylosed intervertebral disc Ll to 2, unstained

the discs explain the vacuum phenomenon image, theobservation of which, at several levels, stronglysuggests the diagnosis of ochronosis. This pheno-menon seems constant and occurs relatively early incourse of the disease (Kostka, Sit'aj, and Niepel,1965).(C) Ossification of the discs explains occasional

radiological obliteration of the vertebral interspacesand formation of marginal intervertebral bridges.DIFFERENTIAL DIAGNOSIS AND TERMINOLOGYRadiography of the vertebral column may permitthe diagnosis of ochronosis, corroborated by thefinding ofalcaptonuria, often previously unsuspected.An analysis of the differential diagnoses is thus lessimportant in practice than in theory.When the vertebrae are not welded, deterioration

of the discs provokes a condensation remodelling

of the vertebral surfaces with small lipping marginalosteophytes (Ott, 1956). This intervertebral arthroticremodelling may be distinguished from that of'degenerative chondrosis' by the overall x-ray image,and above all, by histological differences. Thisprocess should not be considered a 'degenerativerheumatism', at least, if the usual meaning of theterm is to be preserved.

In the presence of marginal spurs or intervertebralbridges, the distinction should be made betweenthose of ochronosis and those of spondylosis or ofankylosing vertebral hyperostosis (Forestier andLagier, 1971). In ochronosis, the bony overgrowthsare thinner, and there is no thoracic preference.The radiographical presence of several diffuselycalcified discs is virtually diagnostic. In addition,even though spondylotic osteophytes may be present,in ochronosis, an intervertebral osteoarthrotic

copyright. on A

pril 18, 2021 by guest. Protected by

http://ard.bmj.com

/A

nn Rheum

Dis: first published as 10.1136/ard.33.1.86 on 1 January 1974. D

ownloaded from

Vertebral changes in ochronosis 91

(a) Cuti surface. . 4

X,.̂..wDS - i w ~~~~~~~~~~~~....e!

(h) Haeniatoxylin aid eosini stained (c) Radiograph of slice Isection. . 5 c'm?7. thick-. 2-3

FIG. 6 Aspects ofthe anterior border of marginal ankylosis in L2-3 (left lateral sagittal plane). The bone bridges thepigmented disc and incorporates an isolated fragment of disc

A' Ie& ='i^*t *'vfi,z'...<..> ;';remodelling or welding can also be found. For these- reas~~~~~ons,the term spondylosis is not applicable in

ochronotic spinal disease, as it does not encompassthe entire anatomical picture.The intervertebral bridges create a 'bamboo spine'

image, resembling ankylosing spondylitis; thisdiagnosis should be considered, especially whehix-raychanges in the hip, knee, and shoulder, are com-parable to those of a chronic inflammatory rheu-matism, and the more so if the pubic symphysis orsacro-iliac joints are narrowed or welded, and if theintervertebral articular facets show interspacenarrow-ing possibly associated with erosions, or even with

+4§5rA%t5; bony ankylosis (Uebermuth, 1928; Pomeranz and______________________________________________ others, 1941; Ott, 1956; Brocher, 1966). The sacro-

iliac joint is usually not eroded or welded inochronosis, Again, disc calcifications strongly suggestochronosis. and homogentisic aciduria is a constantfinding inthis disease. We thus think that the term'ochronotic ankylosing spondylitis' should beabandoned.A purely descriptive term, such as 'ochronotic

FIG. 7 DetailofintervertebraldiscL4-5 spondylopathy' would seem preferable to avoid

(above) Unstained section. Central fissure of a pigmented confusion in terminology.disc with frayed border explaining radiological image of Summarythe vacuum phenomenon. x 5

(below) X-ray ofa thin slice (1 mm). Calcium deposits are A radiological and pathological study of a case ofseen around thefissure. Not enlarged ochronotic spondylopathy is presented.

copyright. on A

pril 18, 2021 by guest. Protected by

http://ard.bmj.com

/A

nn Rheum

Dis: first published as 10.1136/ard.33.1.86 on 1 January 1974. D

ownloaded from

92 Annals ofthe Rheumatic Diseases

The principal observation was pigment impregna- be confused with vertebral osteoarthrosis, spondylo-tion ofthe intervertebral discs, resulting in brittleness, sis, ankylosing vertebral hyperostosis, or (especially)calcification, and an osteogenic reaction which may ankylosing spondylitis.give rise to intervertebral bridges and/or welding of We thank Mrs Ketty Sapounova who prepared thethe vertebral bodies. histological sections. This study was supported in part byThe radiological picture of ochronotic spondylo- a grant from the Commission F6d6rale des Maladies

pathy is practically pathognomonic, and should not Rhumatismales, Bern, Switzerland.

References

BROCHER, J. E. W. (1966) 'Die Wirbelsitulenleiden und ihre Differentialdiagnose". Thieme, StuttgartBYWATERS, E. G. L., DORLING, J., AND SUTOR, J. (1970) Ann. rheum. Dis., 29,563 (Ochronotic densification)&ERVENANSK-, J., SIT'AJ, S., AND URBANEK, T. (1959) J. Bone Jt Surg., 41A, 1169 (Alkaptonuria and ochronosis)COOPER, J. A., AND MORAN, T. J. (1957) A.M.A. Arch. Path., 64, 46 (Studies on ochronosis. I. Report of a case with

death from ochronotic nephrosis)FORESTIER, J., AND LAGIER, R. (1971) Clin. Orthop., 74, 65 (Ankylosing hyperostosis of the spine)GARDNER, D. L. (1965) 'Pathology of the Connective Tissue Diseases'. Arnold, LondonGARDNER, W. A., JR., AND GRIFFIN, C. N. (1971) J. Sth Carolina med. Ass., 67, 269 (A paleopathologic exercise. The

Charleston museum mummy)GRAY, P. H. K. (1967) Med. Radiogr. Photogr., 43, 34 (Radiography of ancient Egyptian mummies)KLAus, E., KAEK, V., AND VRANE'SIC, Z. (1961) Fortschr. Roentgenstr., 95, 242 (Die Ochronose der Wirbelsiaule

im Rontgenbild)KLENSCHMDT, W. (1922) Frankfurt. Z. Path., 28, 73 (Ueber einen Fall von 'endogener Ochronose bei Alkaptonurie')KoLAkA, J., AND KkfiEK, V. (1968) Fortschr. Roentgenstr., 109, 204 (Roentgenologische Merkmalederalkaptonurischen

Ochronose)KOSYKA, D., SIT AJ, S., AND NIEPEL, G. (1965) Forstchr. Roentgenstr., 102, 62 (Die Priivalenz des Vakuum-Phanomens

und seine pathognomonische Bedeutung bei der ochronotischen Diskopathie)LAGIER, R., BoussINA, I., TAILLARD, W., SASFAVIAN, A., CHAFZADEH, M., AND FALLET, G. H. (1971) Schweiz. med.

Wschr., 101, 1585 (Etude anatomo-radiologique d'une arthropathie ochronotique du genou)LICHTENSEIN, L., AND KAPLAN, L. (1954) Amer. J. Path., 30, 99 (Hereditary ochronosis. Pathological changes

observed in two necropsied cases)LOUYOT, P., GAUCHER, A., AND MONTET, Y. (1967) 'Le rachis ochronotique', VI European Congress on Rheuma-

tology, ed. Instituto Portugues de Reumatologia, pp. 540-546. LisbonMCCOLLUM, D. E., AND ODOM, G. L. (1965) J. Bone Jt Surg., 47A, 1389 (Alkaptonuria, ochronosis, and low-back

pain. A case report)MUELLER, M. N., SORENSEN, L. B., STRANDJORD, N., AND KAPPAS, A. (1965) Med. Clin. N. Amer., 49, 101 (Alkapto-

nuria and ochronotic arthropathy)NISmIMoR01, I., ITO, J., AND HAKUNO, T. (1970) Acta path. jap., 20, 505 (An autopsy case of alkaptonuria with

ochronosis)O'BRIN, W. M., LA Du, B. N., AND BUNIM, J. J. (1963) Am. J. Med., 34, 813 (Biochemical, pathologic, and

clinical aspects of alcaptonuria, ochronosis, and ochronotic arthropathy (Review of world literature 1584-1962)Orr, V. R. (1956) Z. Rheumaforsch, 15, 65 (Rontgenologische Beobachtungen bei Ochronosis)POMERANZ, M. M., FRIEDMAN, L. J., AND TUNICK, I. S. (1941) Radiology, 37, 295 (Roentgen findings in alkaptonuric

ochronosis)PUTsCHAR, W. G. J. (1966) New Engl. J. Med., 274, 459 (Presentation of a case)SIMON, G., AND ZORAB, P. A. (1961) Brit. J. Radiol., 34, 384 (The radiographic changes in alkaptonuric arthritis:

a report on three cases (one an Egyptian mummy)Srr'AJ, S. (1963) Rhumatologie, 15, 93 (L'arthropathie ochronotique. Alcaptonurie et ochronose)STEIGER, U., AND LAGIER, R. (1972) Ann. rheum. Dis., 31, 369 (Combined anatomical and radiological study of the

hip-joint in alcaptonuric arthropathy)THOMPSON, M. M., JR. (1957) Amer. J. Roentgenol., 78,46 (Ochronosis)UEBERMUTH, H. (1928, Virchows Arch. path. Anat., 270, 276 (Zur Kenntnis der Gelenkveranderungen bei endogener-

Ochronose (Chondrosis dissecans ochronotica)WELLS, C., AND MAXWELL, B. M. (1962) Brit. J. Radiol., 35, 679 (Alkaptonuria in an Egyptian mummy)

copyright. on A

pril 18, 2021 by guest. Protected by

http://ard.bmj.com

/A

nn Rheum

Dis: first published as 10.1136/ard.33.1.86 on 1 January 1974. D

ownloaded from