The Skull and Spine

By Jack Reynolds

T HE SKULL and the spine are often affected by the two fundamental pathologic pro-

cesses in the sickle cell hemoglobinopathies that act on bone: marrow hyperplasia, which occurs in response to severe chronic anemia, and tissue ischemia caused by vaso-occlusion. The changes produced are reflected in a variety of roentgeno- graphic features. A few of the signs are almost unique to this disease. Others are nonspecific, because similar changes may result from other disorders. Since it is the primary purpose of this presentation to emphasize the positive diagnostic value of these useful findings, a word of caution is in order so that they may be viewed in proper perspective. Some patients with severe symptom- atic sickle cell anemia fail to develop any of the stigmata described below.‘**

THE SKULL

Marrow Hyperplasia

Roentgen changes caused by compensatory marrow hyperplasia are commonly encountered and present in a variety of patterns.

Granular texture. A coarse granular or stip- pled pattern, best seen in the upper parietal region, is present in approximately 25% of patients with the homozygous disease. It may be detected in the first year of life and may precede other signs of marrow hyperplasia. It often per- sists into adult life and may be the only skull abnormality present. 3-5 The granular texture results from the growth of many small lucent foci of hyperplastic red marrow within the diploe.

This finding, although frequently seen, is of limited diagnostic value because it mimics, not only the stippled radiolucent pattern produced by

From the Department of Radiology, University of Texas Health Science Center at Dallas.

Jack Reynolds: Professor and Vice Chairman, Department of Radiology.

Address reprint requests to Jack Reynolds, MD, Profes- sor and Vice Chairman, Department of Radiology, South- western Medical School, University of Texas Health Science Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75235.

0 1987 by Grune & Stratton, Inc. 0037-I 98X/87/2203-0006SO5.00/0

other forms of osteoporosis, but a similar granu- lar texture is often encountered in the upper portion of the parietal bones in normal subjects.3

Diploic thickening. The bones of the cranial vault may become thickened in response to ery- throid hyperplasia. The increased bulk of the diploic component of the skull causes calvarial thickening and there is a concomitant thinning of the outer table. The changes in these components make it easier to distinguish the structural alter- ations produced by the chronic anemia from simple thickening of the cranial vault seen in many normal individuals. In normal subjects with unusually thick skulls, all of the component layers of the calvarium contribute to the increased thickness. Thus, a thick skull can be objectively evaluated by assessing the ratio of the combined thickness of the inner and outer tables to the diploic width. In normal subjects examined at this institution, the ratio averaged 1 .O: 1.4 and did not exceed 1.0:2.3. In sickle cell patients with calvarial thickening, the ratio ranged from 1.0:2.3 to 1 .0:7.3.3V4 Conservatively, therefore, the presence of a diploic layer > 2.5 times the combined thickness of the inner and outer tables should be taken as evidence of a diseased state (Fig 1).

Diploic thickening becomes most pronounced in the frontal and parietal regions. It does not involve the squamous portions of the temporal or occipital bones.5 Sebes and Diggs6 noted it in 22% of their sickle cell patients. Among a large group of adult patients with homozygous sickle cell disease examined at my institution, diploic thickening was found in 47%. In this same study, the frequency of this sign in a comparable group with mixed sickle cell hemoglobinopathy (SC and S-T) was only 17%.* Diploic thickening may begin early, toward the end of the first year of life. The first changes appear in the frontal bone, but before adolescence parietal thickening pre- dominates.6

The presence of simple diploic thickening lacks diagnostic specificity, since it is seen in other forms of anemia such as the thalassemias, hereditary spherocytosis, and severe iron defi- ciency anemia.’ It is also encountered in unre- lated disorders such as Dilantin (Parke-Davis,

168 &m?insrsin/b?nrgc?n~/~gy, Vol XXII, NO 3 (July), 1987: pp 168-175

THE SKULL AND SPINE

Fig 1. Typical moderate thickening of the diploe (ar- row) due to marrow hyperplasia. The ratio of the combined thickness of the inner and outer tables to the thickness of the diploic layer is approximately 1:3. (Reproduced with permission of JAMA 1977;238:248,01977, American Medi- cal Association.)

Morris Plains, NJ) toxicity,8 after surgical treat- ment of hydrocephalus,’ in congenital cyanotic heart disease with polycythemia,” and, for unex- plained reasons, in pseudohypoparathyroidism.”

Lamination of the diploe. In some patients with thickened diploe, fine curvilinear layers of denser bone are seen within the lucent marrow

169

(Fig 2). They lie parallel to the inner table and are likened to the laminated pattern of onion skin.5,12 Although noted in six of 17 patients by Williams et alI3 in Nigeria, it has seldom been described from other countries. With rare excep- tion, all reported cases have been in children between 2 and 7 years of age. Microscopic exam- ination of the region in six patients showed “long, continuous bony trabeculae running parallel to one another but separated . . . by hypercellular islands of marrow.“13 The mechanism by which this “onion skin” pattern is formed is uncertain, but it may be due to repeated surges of erythroid hyperplasia during childhood, resulting in epi- sodic diploic expansions.

This lamination is not unique to sickle cell disease. It has been observed in the thickened skull of children who have undergone a decom- pression procedure for hydrocephalus; as a result of the loss of intracranial volume, there is an inward growth of the inner table, resulting in thickening of the diploe within which curvilinear densities appear.‘4*‘5

“Hair-on-end” pattern. In some patients, truly massive diploic thickening occurs accompa- nied by thinning of the outer table. This may result in fine linear densities resembling spicules of bone, based on the inner table and perpendicu- lar to it. The appearance has been compared to hair standing on end or to porcupine quills. Considered a common finding in sickle cell ane- mia in the older literature, it is not frequently seen. Even in homozygotes the incidence is <5%.3~6 It has not been described in the mixed sickle cell hemoglobinopathies (Fig 3).

The hair-on-end pattern is frequently encoun-

Fig 2. A 9-month-old infant with SS disease. Note thickened diploe with laminated pattern.

JACK REYNOLDS

Fig 3. Adult with SS disease, showing massive thickening of the diploe and the “hair-on-end” pat- tern.

tered in fl thalassemia.“j In this disease, the burgeoning marrow hyperplasia usually prevents the development of the frontal sinuses, whereas they are nearly always present in the adult sickle cell patient, even when the diploe is greatly enlarged.” Rarer causes of vertical striations in thickened diploe include severe iron deficiency anemia7 and cyanotic congenital heart disease.”

Tissue Ischemia

Unlike most other bones, signs of infarction are not common in the skull and are usually found only in older patients. Perhaps the most valid manifestation of this process is generalized sclerosis of the cranial vault. This probably occurs gradually over the years and is probably due to the coalescence of many small healed bone infarcts.4*‘8

Small lucent foci resembling myeloma or nor- mal pacchionian granulations have been de- scribed, and these may represent areas of infarc- tion replaced by fibrous tissue.” A biopsy showed vascular thrombi and necrosis in such a lesion,” but others have shown similar lucent foci to represent islands of hyperplastic marrow.6 Sev- eral investigators have described rounded lucent defects surrounded by a ring of sclerotic bone, the so-called “doughnut” lesion, in sickle cell patients.18~“~2’ While these may well represent areas of infarction surrounded by a zone of bony repair, pathologic documentation has yet to be provided.6

THE SPINE

Marrow Hyperplasia

Coarse trabecular pattern. Compensatory hyperplasia of the erythroid cells within the marrow of the vertebral bodies exerts pressure on the trabeculae. As a result, finer trabeculae are destroyed and the bone becomes more radiolu- cent. The remaining thicker trabeculae, now surrounded by lucent marrow devoid of smaller trabeculae, are thrown into contrast with the background, and stand out with greater clarity. Radiographically, the texture of the vertebra becomes coarse, striated, or lacy (Fig 4).

This coarse trabecular texture, seen in both children and adults, may involve the entire spine. It was noted in approximately half of the sickle cell anemia patients,4 but others have found it more frequently.‘* Although the need for com- pensatory marrow hyperplasia is diminished in patients with mixed hemoglobinopathy, a lacy bony texture is sometimes encountered.3.4 Radio- lucent coarse-textured bone is seen in a number of other conditions, such as the other severe anemias, Gaucher’s disease, and osteomalacia.

Compression deformities. As the result of trabecular destruction from marrow hyperplasia, the centra may be weakened to the point of collapse. Changes in shape due to compression were mentioned in the earlier literature,‘.23‘25 which describes simple flattening of the centra or a concave depression of one or both end-plates. In

THE SKULL AND SPINE

Fig 4. Adult with SS disease, showing the coarse trabecular pattern produced by marrow hyperplasia in the vertebrtal bodies.

simple flattening, the rectilinear shape is pre- served, and only the height to width ratio is altered. To aid in the objective assessment of simple flattening, Diggs et al’ determined the normal adult height to width ratio of the first four lumbar centra and found it to average 1.0:1.4 in the AP view and 1.0:1.2 in the lateral. With true flattening, the measurements clearly exceed this ratio.12 Simple flattening is seen most often in the lumbar and lower thoracic regions4 This flat, broad appearance may involve a num- ber of contiguous centra, in which case the spine may resemble the appearance in Scheuermann’s disease.

Occasionally, the noncompressible slightly convex intervertebral disc smoothly depresses the end-plate to create a concave deformity involving the entire articular surface of the vertebral body. This process may involve one or both end-plates of a vertebra and may occur in association with flattening of the centrum.22V24-26 Infrequently, a vertebral body undergoes eccentric collapse to produce a wedge-shaped deformity. This is most likely to occur in the thoracic spine.

Persistent anterior vertebral notching. A notch or cleft is frequently visible in the center of the ventral surface of the vertebral bodies of normal children under the age of 2 years. It is best seen in the lateral projection. The notch contains venous sinusoidal reservoirs and a pene-

171

trating artery. It is a vascular conduit, in essence, a nutrient foramen. It is absent or only faintly visible in older children.

Riggs and Rockett27 observed that this notch is abnormally large in young children with sickle cell disease. They found it to persist well into the first decade of life, most prominently between the ages of 3 and 6 years. The enlargement is probably due to enlargement of the vessels that pass through the foramen in response to the increased circulatory demands of the bulky hyperplastic marrow in the centrum. Enlarged notches have also been noted in children with other marrow-packing disorders, such as thalas- semia major, Gaucher’s disease, and metastatic neuroblastoma.28

TISSUE ISCHEMIA

Vertebral Sclerosis

Like the rest of the skeleton, the bones of the spine suffer many small infarcts. This begins early in life and is reflected clinically in recurrent episodes of back pain. The frequency of these attacks varies widely among individuals. Al- though the damaged bone may be replaced by lucent fibrous or hyaline tissue, repair is often by means of new bone laid down on the existing trabeculae. These create small foci of increased density, which, over a period of time, may coa- lesce to produce diffuse vertebral sclerosis.4,‘2.25,29 The entire spine may be involved.

Generalized increase in the density of the spine is not a frequent manifestation of sickle cell disease and because it takes years to evolve, is encountered mainly in older patients. Since it may exist in the absence of the other spinal manifestations of the disease, the changes may be mistaken for other conditions that produce diffuse spinal sclerosis, such as chronic renal failure, carcinoma of the prostate, myelofibrosis, and fluoride intoxication.

Massive collapse of centra. Acute massive collapse of vertebral bodies is not frequent in the United States.20*22*24 It is most common in the lumbar and lower thoracic regions and may involve two or three contiguous vertebrae with narrowing of the intervening disc spaces. The involvement begins with back pain, followed in a few weeks by roentgen evidence of bony rarefac- tion and then vertebral collapse. In the ensuing months, healing occurs and the involved cen-

172

trum, although densely sclerotic, may be recon- structed with only minor residual deformity.

There seems little doubt that some of these lesions are produced at least in part by osteomye- litis.” The radiologic appearance is clearly com- patible with infection, and the presence of Sal- monella organisms has been confirmed in some patients so afflicted. *’ It is probable that the process begins with massive infarction of the centrum. Then, as a result of the necrosis, local tissue resistance is altered, permitting the growth of bacteria, particularly Salmonella3’

Central cupping of the end-plate. A distinc- tive change in the shape of the vertebral end- plates occurs in many patients with homozygous sickle cell hemoglobinopathy as well as the mixed forms, producing a sign that is of proven diagnos- tic value (Fig 5).4*32 Both the upper and lower surfaces of the centrum demonstrate a concave depression, which superficially may resemble the biconcave deformity seen in osteoporosis, multi- ple myeloma, metastatic carcinoma, or occasion- ally in sickle cell disease. However, instead of a continuous curve along the entire end-plate, the cupping of sickle cell disease is confined to the middle 50% to 60% of the end-plate, and is usually located at or slightly behind the midcor- onal plane. The floor of the cup is not curved but

JACK REYNOLDS

flat, and the cortical bone at its base is slightly thickened. Since the cupping does not extend to the periphery of the end-plate, the surfaces ante- rior and posterior to the depression are flat. As a result, the deformed centrum in sickle cell dis- ease presents a more rectilinear and angular contour when compared with the curved or arcuate shape of simple collapse. The appearance has been said to resemble a bulky capital “H.” (Figs 6 and 7).

It should be emphasized that the distinctive features of this deformity are best seen in the lateral view. Indeed, perhaps due to the geometry of the projection, a centrum so involved may appear as simply biconcave on the AP view. Although both the upper and lower end-plates are usually symmetrically deformed, the changes are occasionally confined to only one surface.33 When central cupping is present, it usually involves a number of contiguous vertebral bodies and occasionally is seen throughout the spine.

The deformity is usually first noted in late childhood, but early, barely distinguishable changes have been described in a 9-month-old patient2’ and another 17-month-old.” However, the typical features generally evolve at the time of adolescence and are fully developed when growth ceases. Later in life, the classic squared-

Fig 5. Examples of end-plate depression in sickle cell disease, showing the typical central cuplike deformity. (A) A 1 S-year-old patient with SS disease. 18) A 21-year-old patient with SS disease. The height to width ratio is also altered.

THE SKULL AND SPINE

Fig 6. Diagram showing the diier- ences between (A) the biconcave defor-

i- _” ” ” . . . ‘.,

mity produced by simple compression of

E

: weakened bone, and (6) the centrally t’. ‘. located cuplike depression seen in sickle :. 1

..,.. . . . ,. : ..’ _.

cell disease. (Modified reproduction with permission of Williams & Wilkins, J. Reynolds, “A ra-evaluation of the ‘fish vertebra’ sign in sickle cell anemia.” I, American Journal of Roentgenology, vol

p--+-f

.. 97. pp 693-707. 0 1966 by American Roentgen Ray Society.? A

off shape may be modified if the periphery of the end-plates becomes depressed from weight bear- ing on softened bone.‘*

the nutrient artery that serve the central portion of the growth plate must course through the hyperplastic marrow.

The exact mechanism responsibIe for the localized end-plate depression in this disease is unknown. The few histologic studies performed have shown no evidence of overt infarction.34 However, a theory based on local inhibition of bone growth has been advanced.4*32 During child- hood, vertical growth of the centrum is produced by endochondral new bone formation at the junction between the bony end-plate and the cartilage of the disc. To function normally, the growth zone requires an abundant blood supply, which reaches this region through branches of the nutrient artery and through short vessels derived from the periosteal arteries that enter the periphery of the growth plate. The branches of

The long passage through a region of high metabolic demand provides an environment that is conducive to intravascular sickling of the red cells. Such a mechanism, acting over time, is capable of critically impeding circulation to the center of the growth zone, and of retarding endochondral new bone formation in this region. However, the periphery of the growth plate is served with well-oxygenated blood via short per- forating arteries from the periosteal vessels, so that bone growth progresses at a normal pace. Therefore, it is proposed that the distinctive central cupping of the end-plates is due to the effects of chronic local ischemia on bone growth (Fig 8).

Fig 7. Roentgenograms showing the differences between the simple, biconcave deformity caused by collapse and the end-plate cupping typical of sickle cell disease. (A) Patient with multiple myeloma, showing arcuate depression of the entire end-plate. (6) Patient with SS disease showing centrally located, flat-based cupping.

JACK REYNOLDS

As stated earlier, this vertebral deformity occurs in patients with mixed sickle cell hemoglo- binopathy, as well as in homozygotes. A recent study at this institution showed the sign to be present in 31 of 73 adults with SS disease (42.5%), and in 23 of 75 comparable patients with a mixed sickle cell disorder (30.6%). Per- haps the main point of these statistics is to point out that this bony stigma, commonly cited as a major diagnositc criterion in the sickle cell hemo- globinopathies, is actually present in less than half of the patients.

It has been shown that a number of other diseases may produce end-plate cupping that, although of different pathogenesis, is morpholog- ically similar to that of sickle cell disease. Iso- lated case reports have described these changes in thalassemia major,3s Gaucher’s disease,20v3627 homocystinuria:’ chronic renal disease,39 parox- ysmal nocturnal hemoglobinuria, alcoholism, histiocytosis X with healing vertebra plana, and in young women on birth control pills.4o I have encountered similar cupping in a patient with osteogenesis imperfecta. Schwartz et a13’ sug- gested that the end-plate deformity in some of these diseases evolves as the result of an initial massive collapse of the centrum perhaps due to infarction, followed by repair, with more com- plete remodeling taking place at the periphery of the end-plate because of its better blood supply, thus leaving the center of the surface depressed.

Fig 8. A schematic diagram of the blood supply of a centrum showing the two major sources that serve the region of endochondral bone growth. Note that the central portion of this region is supplied by branches of the nutrient artery while branches of the periosteal vessels enter its periphery. (Reproduced with permission of Wil- liams 61 Wilkins. J. Reynolds. “A re- evaluation of the ‘fish vertebra’ sign in sickle cell anemia.” American Journal of Roentgenology, ~0197. pp 693-707. @ 1986 by American Roentgen Ray Society.?

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THE SKULL AND SPINE 175

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