University of khartoum

Faculty of Medicine

Postgraduate Medical Studies Board

RADIOLOGICAL BONE MANIFESTATION OF

SICKLE CELL ANAEMIA IN SUDANESE PATIENTS

By

MANAL MOHEMED KAMAL MOHEMED MBBS (university of Gezira )Sudan

Athesis submitted in partial fulfillment for the requirments of the degree

of clinical MD in Radiology, December , 2004

Supervisor

PROF. MUTASIM ELSEED MBBS, DMRD, MD

Khartoum Teaching Hospital

:قال تعــالى

) 4(الذي علم بالقلم ) 3(إقرأ ورُبك األآرم

)5(عّلم اإلنسان ما لم يعلم

صدق اهللا العظيم

To

My Family

And

My Teacher

ACKNOWLEDGMENT

Iam very grateful to Dr.MUTASIMELSEED, Radiologist,

Khartoum teaching hospital for his enormous help in the preperation of

this work .

I thank Dr. Bakhita Ata Alla, Consultant Paediatric and the director

of the sickle cell clinic for her help .I would like to express my

appreciation to Dr. ELGINADE AWAD, Radiologist, for his excellent

helps & pretious efforts in reading and interpretating the radiographs .

CONTENTS Page

Dedication…………………………………………..……. I Acknowledgment…………………………………….……II Abbreviations…………………………………….………III English abstract……………………….………….………..V Arabic abstract………………………….………….…….VII List of tables……………………………………….……..IX List of figures………………………………………….…..X CHAPTER ONE INTRODUCTION AND LITERATURE REVIEW ……….1 OBJECTIVE ………………………………………………..18 CHAPTER TWO MATERIALS & METHODS…………………………..……….19 CHAPTER THREE RESULTS ………………………………………………….…..22

CHAPTER FOUR DISCUSSION …………………………………………….……53 CONCLUSION …………………………………………….….. 58 RECOMMENDATIONS …………………………………….. 59 REFERENCES …………………………………………….……60 APPENDIX (Questionnaire) …………………………....… 70 Copies of radiographic films……………………………….… 71-73

ABBREVIATIONS Abbreviation meaning ACS 7 Acute chest syndrome CT Computerised Tomography 1st First HAS Heterozygous hemoglobin(sickle cell trait ) Hb Hemoglobin Hb F Fetal hemoglobin Hb S Sickle cell hemoglobin Hb SS Homozygous hemoglobin (sickle cell anaemia ) LL Lower limb MRI Magnetic Resonance Imaging _ Ve Negative +Ve . Positive RBC Red blood cell SCA Sickle cell anaemia SCD Sickle cell disease SCT Sickle cell trait T1 Longtudinal relaxation time T2 Transverse relaxation time TC99m Techntium 99m radiopharmacetical UL Upper Limb

ABSTRACT

Sickle cell anaemia (SCA) is a disease caused by production of abnormal

haemoglobin, which binds with other abnormal haemoglobin molecules within the red

blood cell to cause rigid deformation of the cell. This deformation impairs the ability

of the cell to pass through small vascular channels, sludging and congestion may

result, followed by ischaemia and infarction of the tissue.

This is a descriptive hospital-based study which was conducted in the Sickle Cell

Clinic and Khartoum Teaching Hospital in Khartoum State in Sudan.One hundred

patients with SCA were included in this study. The study was carried out in the period

from April 2003 to January 2004.

All the patients were investigated by plain radiography for the lateral skull, spine,

and limbs.

The vast majority of the patients (98%) presented once at least with acute painful

crisis. While 48 patients presented with additional presentations such as chest

infection, jaundice ..etc.

Most of the patients (62%) presented for the first time at the age range of 6-12

months.

The skeletal plain films radiography showed that the limbs were affected more (31%)

in the form of decreased bone density and mixed density and soft tissue involvement,

followed by spine affection (25%) in the form of decreased bone density (25 patients)

and vertebral end plate central depression.

The radiographic films showed that (9%) of skulls were affected in the form of

decreased bone density in 6 patients and increased bone size in 9 patients (widened

diploic space).

The radiological films of the lower limbs of 5 patients showed bone infarction while 2

films showed signs of secondary infection.

There is no direct correlation between clinical symptoms and radiological findings.

خص األطروحةمل

ض الخلية المنجلية يحدث نتيجة لتكوين خضاب دم شاذ، يتحد مع جزيئات خضاب مر

الدم تما ينتج عنه تغير في شكل كروياالدم الشاذة األخرى داخل كرويات الدم الحمراء، م

هذا التغير في شكل كرويات الدم الحمراء يحد من قدرة هذه الخاليا على المرور . الحمراء

داخل األوعية الدموية الصغيرة، ويؤدي لتكدس هذه الخاليا وانسدادهذه األوعية الدموية

.الصغيرة، وهذا بدوره يؤدي لحدوث إقفار وإحتشاء أنسجة الجسم

معتمدة على المرضى الذين يراجعون عيادة مرضى لجريت هذه الدراسة الوصفية واأ

.الخلية المنجلية وعيادات مستشفى الخرطوم األخرى

ملت الدراسة مائة شخص يعانون من مرض الخلية المنجلية خالل الفترة من أبريل ش

.م2004م وحتى شهر يناير 2003

فقاري لسينية لجانب الجمجمة، العمود ام فحص المائة مريض بواسطة األشعة الت

. واألطراف

كانوا يعانون من أزمة آالم حادة من حين آلخر، باإلضافة %) 98(عظم المرضى م

. الخ.. مثل التهاب الصدر واليرقان %) 48(لشكاوى أخرى

ألول مرة في الفئة العمرية %) 62(هرت أعراض المرض على معظم المرضى ظ

) . شهر12- 6(

م الجسم إصابة من جراء األنيميا المنجلية اشعة السينية أظهرت بأن أكثر عظور األص

واإلصابة تكون في شكل قلة عظم وتضخم في األنسجة %) 31(هي عظام األطراف

مريض 25وذلك في شكل قلة عظم %) 25(يلي هذا إصابة عظام العمود الفقاري . الرخوة

إصابة عظام الجمجمة في المرتبة الثالثة إذ ثم تأتي . وانبعاج في فقارات العمود الفقري

من المرضى قد تأثرت عظام الجمجمة بسبب %) 9(أظهرت أفالم األشعة السينية أن في

.المرض ونتج عن ذلك تباعد بين الغالف الداخلي والخارجي لعظام الجمجمة

ألشعة السينية لألطراف السفلى ألربعة من المرضى أظهر وجود احتشاء عظام كما ا

. ظام الثنين من المرضىعأظهرت عالمات التهاب ثانوي بال

توجد عالقة مباشرة في جميع الحاالت بين األعراض السريرية للمرضى وبين ال

.لتغيرات في العظام نتيجة للمرض والتي تظهرها األشعة السينيةا

List of Tables

Page

Table 1: Sex distribution in the study group 28

Table 2 : Tribes distribution in the study group 30

Table 3 : Age (years) distribution in the study group 32

Table 4 : Parents relationship in the study group 34

Table 5 : Age of first presentation of the disease 36

Table 6 : Family history of sickle cell anaemia 38

Table 7 : Haemoglobin percent of patients in the study group 40

Table 8: Distribution of bone involvement in the study group 42

Table 9:Distribution of soft tissue involvement in the study

group 44

Table 10: Correlation of presenting symptoms with skeletal

radiological findings 46

Table 11: : Relationship between skeletal radiological findings

and duration of the disease 48

Table 12: Correlation of initial skeletal radiographic findings

with onset of clinical manifestations 50

Table 13:The Site of bone affected in different age group 52

List Of Figures

Page

Fig . 1 : Sex distribution in the study group 29

Fig . 2 : Tribes distribution in the study group 31

Fig . 3: Age (years ) distribution in the study group 33

Fig .4: Parents relationship in the study group 35

Fig .5 : Age of first presentation of the disease 37

Fig . 6 : Family history of sickle cell anaemia 39

Fig . 7: Haemoglobin percent of patients in the study group 41

Fig . 8 : Distribution of bone affected in the study group 43

Fig . 9: : Distribution of soft tissue involvement in the study

group 45

Fig. 10 : Correlation of presenting symptoms with radiological

findings 47

Fig . 11 : Relationship between skeletal radiological findings

and duration of the disease 49

Fig . 12 : Correlation of initial radiographic findings with onset

of clinical manifestations 51

INTRODUCTION AND

LITERATURE REVIEW

Introduction:

The most important structural abnormality of the haemoglobin (Hb)

chain is sickle cell haemoglobin (Hbs). Hbs results from a single-base

mutation of adenine to thymine which produces a substitution of valine

for glutamic acid at the sixth codon of the B-globin chain. In the

homozygous state (sickle cell anaemia) both genes are abnormal (Hbss),

where as in the heterozygous state (sickle cell trait, HAS) only one

chromosome carries the gene. As the synthesis of HbF is normal, the

disease usually does not manifest itself until the HbF decreases to adult

levels at about 6 months of age (1).

The first published account of SCA was by Herrick in 1910 (2), who

described the clinical and haematological manifestations of the disease in

a 20 years – old dental student from Grenada. Later, Paling et al (3)

determined that a point mutation in the gene coding the β chain of the

haemoglobin molecule resulted in a single amino acid substitution (valine

for glutamic acid) in the B chain, which when presents on both

chromosomes in a patient, resulted in sickle cell haemoglobin or HbS.(3)

This single amino acid substitution leads to a complex array of

abnormal haemoglobin chain interactions , RBC cell membrane

permeability changes, endothelial adhesion, vascular occlusion, and

increased haemolysis (4).

Sickle cell disease (SCD) refers to a group of genetic disorders

characterized by the production of Hbs. The spectrum of clinical disease

includes sickle cell anaemia, haemoglobin SC disease sickle beta-

thalassemic and sickle O- thalassemic disease, with manifestations that

range from mild, discomfort making symptoms and arthralgia to life- and

limb threatening complications (5,6).

SCA occurs mainly in Africans but is also found in India, the middle

East and Southern Europe (1). In the United States sickle disorders are

encountered most frequently in African Americans.

Thus sickle cell trait and sickle cell disease occur in both African –

Americans and Caucasians (7).

Pathophysiology of S.C.A

The HbS B chain, with valine at the sixth position, has an unusual

propensity to bind with other HbS chain (contained in other

haemoglobin molecules within the (RBC) when deoxygenated. The basic

structural unit that results is a twisted, ropelike structure composed

primarily of two complete haemoglobin molecule strands, with binding

between the B chains. This process is referred to as polymerization. The

result is a strand of relatively rigid, polymerized haemoglobin molecules.

On to this basic polymer, other haemoglobin molecules may also

polymerize, leading to large polymer strands. These rigid strands

distorted the RBC into a variety of elongated shapes and decreased its

deformability (8). This sets the stage for vascular obstruction and

haemolysis.

Vascular occlusion is the hallmark of S.C.A and is the basis for

systemic, clinical manifestations. Polymerization causes the RBCs to

assume bizarre shapes, become less deformable , and predisposes them to

early destruction in the spleen and liver. Due to altered membrane

characteristics and less deformability sickled cells become trapped in the

vasculature causing occlusive symptoms, subsequent ischaemia and

acidosis.

A cascade that creates a vicious cycle causing more sickling (9).

Early destruction of sickled red cells causes a chronic haemolytic

anaemia with elevated reticulocytes count.

Clinical and radiological features:

Acute, painful vaso-occlusive crises are the most common, and

earliest, clinical manifestations of SCA. Half of all patients with SCA

experience a painful crisis by 4-9 years of age. The pain is usually

described as bone pain, although crises may involve virtually any organ.

They are presumed to be caused by microvascular occlusion with

subsequent tissue Ischemia. In young children, vaso-occlusive crises

most commonly manifest as dactylitis, a painful swelling of the hands,

fingers, feet, and toes.

Other problems, in SCA include osteomyelitis, osteonecrosis,

splenic infarct, splenic sequestration, acute chest syndrome, stroke,

papillary necrosis, and renal insufficiency (10).

The lung:

The lung is a common site of involvement in SCA. Injuries range

from processes such as pneumonia and acute chest syndrome (ACS), to

chronic entities, such as pulmonary fibrosis. Pulmonary complications

constitute the second leading cause of hospitalization (after acute painful

crisis) and are now the leading cause of death for patients with SCA (11).

Pneumonia is much more common in children with SCA than in the

unaffected paediatric population. It is estimated that children with SCA

are 100 times more susceptible to develop pneumonia than other

children, and they have a 30% recurrence rate (12).Impaired immune status

a result of functional asplenia and other abnormalities in the immune

process, render the patients with SCA more prone to infection, which

most frequently manifests as pneumonia (4,13).

Preventing this frequent recurrent, and sometimes life threatening

complication is the goal of daily oral penicillin prophylaxis, begun by

age 3 months and continued to at least 5 years of age (4,14).

The cause of acute chest syndrome ACS is not fully understood, and

there have been many causative agents identified, including infection and

fat emboli, frequently, the underlying cause is not discovered in

individual patients (4). ACS may progress to respiratory distress syndrome

and death.

The severity of the clinical symptoms distinguishes ACS from the

clinically milder pneumonia. Because ACS may be caused by

pneumonia, the two entities may constitute a continuum.

ACS is the second leading cause of hospitalization in patients with

SCA, after painful crises. It accounts for 25% of deaths in patients with

SCA and is currently the single leading cause of death in SCA. Children

are more prone than adults to develop ACS (50% of all children will

experience at least one episode of ACS), but adults have a higher

mortality rate (4.3%) than do children (1.8% ). (11) A CS is also a

common postoperative complication in patients who have undergone

general anaethesia and may be seen in up to 10% of these patients (15).

The radiographic finding necessary for the diagnosis of ACS is

single or multiple areas of pulmonary consolidation. However, 30-60%

of patients have no initial radiographic abnormality, often because they

are admitted for another reason (usually for pain crisis), and subsequently

develop ACS (16,17,18). Abnormal chest radiographs show middle and

lower lobe airspace disease, more commonly than upper lobe disease.

Pleural effusions are frequent and do not help to differentiate infectious

from non infectious causes of ACS. One study noted that non infectious

consolidations in children tended to clean much more rapidly than

infectious consolidations (16).

Repeated episodes of pulmonary insults such as ACS and

pneumonia may lead to chronic pulmonary disease, which may

ultimately prove fatal, in the patient with SCA . Chronic pulmonary

disease occurs in approximately 4% of patients (19).

At radiography a fine reticular pattern representing generalized

fibrosis is seen in the lungs (19). At CT, typical findings include septal

thickening, dilated secondary pulmonary lolules, traction bronchiectasis,

and architectural distortion.

Despite CT abnormalities, pulmonary function testing may be

normal in patient with chronic lung disease (20).

The skeletal system:

The skeletal system of patients with SCA is remarkable for its long

preservation, and frequent expansion, of red (cellular ) marrow. In

healthy individuals, red marrow converts to yellow (Fatty) marrow during

childhood,with the transition beginning in the distal regions of the

appendicular skeleton and moving to the more proximal regions. This

process begins soon after birth, and by the second decade of life, red

marrow residue persist in the pelvis, sternum , ribs and vertebrae(21).

The epiphyses are fat- containing throughout life. In patients with

SCA, most of their marrow space tends to be preserved as red marrow

sometimes even in their epiphysis.Expansion of the medullary space due

to increased haemopoietic demands from the anaemia may be especially

evident in the skull, where a hair- on - end appearance may result from

diploic space widening . Persistence of red marrow may make detection

of marrow abnormality such as infarction and infection difficult (21) Sebs

and Diggs (22) reported that among 194 patients ( aged 4 months to 55

years) with sickle cell disease, skull radiographs of 10 (5%) revealed

vertical striations, termed hair -on- end appearance. This appearance was

not seen before the age of 5 years. (23)

The classical hair-on-end sign was recognized only when thin

spicules were observed. There was no correlation between the

prominence of this finding and the clinical courses of the disease, nor was

there a consistency or relationship connecting onset, progression, and

severity of the anaemia.

It is debatable whether the hair-on-end (22) sign may be reversed

following treatment of anaemia . Moseley (24) reported that resolution of

the hair-on-end appearance following treatment begins with development

of a new compact outer table of the skull. Some radial spicules may

remain even after the new outer table is formed, but eventually the

spicules disappear and the size of the diploic space, while still wider than

normal, is decreased. However, Sebes and Diggs (22) subsequently

reported that the hair-on-end sign persisted without regression in all

patients observed from 2½ months to 22 years. His group failed to

confirm the reversibility of the hair-on-end changes as previously

reported by Moseley.

Skeletal complications of SCA include infarction and

osteomyelitis. Both of these problems are assumed to be caused by the

congested, cellular marrow found throughout much of the skeletal system

of patients with SCA. This cellular marrow impedes blood flow, which

enhances stasis, regional hypoxia, and sickling. Infarction may

result(25,26).

Bone infarction is estimated to be at least 50 times more common

than osteomyelitis in SCA, at least in children (27) , infarction typically

occurs in the meduallary cavity and the epiphysis, and it has been

described in essentially every marrow- containing bone. Bone marrow

infarction is thought to be the underlying cause of most pain crisis in

SCA, and may result in fat embolic and ACS. Ischaemia rapidly causes

pain, even before infarction is manifested; therefore, radiographs obtained

early during pain crisis often appear normal. Patients with SCA are also

prone to silent infarction and the discovery of osteonecrosis may be an

incidental finding. (3)

Infarction manifests overtime (which often takes months), first with

an ill- defined zone of radiolucency, which subsequently develops arclike

subchondral and inframedullary lucent areas, with patchy lucent and

sclerotic areas. A peripheral rim of sclerosis is often seen, especially with

medullary bone infarcts. At CT, an infarct initially manifests as disruption

of the normal trabecular architecture and may be difficult to detect. As

infarction progresses, it appears, as circular areas of decreased

attenuation.

MR imaging is likely the most sensitive radiological form of

investigation, as it may show abnormality as soon as a few days, after the

ischaemic insult. Infarction appears as an area of high signal intensity on

T2- weighted and inversion recovery image. (28) Abnormal periosteal

signal intensity soft-tissue changes may also be seen at MR imaging,

making differentiation between infarction and osteomyelitis difficult. (29)

Overtime, these areas will become low signal intensity on all MR images

(regardless of pulse sequence) as fibrosis and sclerosis replace the

infarcted region.

Osteonecrosis affects patients with all genotypes of SCD, but occurs

most often in those with SCA and alpha Thalassemia (2,35). Osteonecrosis

usually affects the articulating surfaces and heads of long bones. The over

all prevalence of Osteonecrosis of the femoral head in SCD patients older

than 5 years of age is about 10%. The prevalence of Osteonecrosis of the

humeral head is approximately 5%. (30)

Patients typically present with complaints of pain or limitation of

motion in the shoulder, hip, or other joints. Some patients describe

worsening of their symptoms with movement of the joint (e.g. walking,

climbing stairs). Pain also, may worsen without movement. Intermittent

or persistent groin or buttock pain also, although less common. (31)

In the early stages, radiographs appears normal(32). After several

months, however, radiographs may show areas of increased density

mixed with areas of increased Lucency(33). Progression of radiographic

findings include femoral head molding, segmental collapse, joint space

narrowing and complete joint degeneration(34). Dactylitis, or hand-foot

syndrome, is the term used to describe painful, swollen hands and feet

accompanied by fever it is most often seen in children younger than 4

years and is very uncommon after 7 years of age. Dactylitis is often the

first clinical manifestation of SCA. At histopathological evaluation, there

is extensive infarction of the marrow, medullay trabeculae, and the inner

layer of cortical bone as well as subperiosteal new bone formation and

periosteal elevation.(35)

At radiography, the hands and feet initially appear normal. Within

10 days of the onset of symptoms, periostitis with subperiosteal new bone

is typically evident.

There is also cortical thinning, irregular attenuation of the medullary

spaces, and an overall moth-eaten appearance of the involved bones of

the hands and feet .(36)

Osteomyelitis is a serious complication of SCA. It is most common

in the diaphyseal region of bone in this patient population and most often

found in the femur, tibia and humerus (37). Patients with SCA and

osteomyelitis present with pain, fever erythema and an elevated white

blood count. The most commonly encountered organism is salmonella,

followed by staphylococcus aureus. Among non- SCA patients,

staphylococcus aureus is the most common cause of osteomyelitis (13,25,38).

Osteomyelitis, although much less common than infarction, may be

difficult to discriminate from infarction, even with clinical, laboratory,

and radiological information. Both may manifest with pain, fever,

swelling, erythema, and a mildly elevated white blood cell count.

Imaging is often reguested to help determine the likelihood of

osteomyelitis (39,37).

Radiographic findings of periostitis and osteopenia are nonspecific

and may be seen with both infarction and infection.

These signs may progress to sclerosis.

CT may depict subperiosteal abcess and fluid collections once

thought to be diagnostic of osteomyelitis, although these finding may be

seen with infarction as well (29,37). MR Imaging is the preferred modality

for evaluating marrow. Osteomyelitis demonstrates abnormally elevated

signal intensity in the marrow on T2- weighted and invertion recovery

images the edges of this abnormal signal intensity area are typically ill

defined. The most sensitive and specific pulse sequence is T1 weighted,

performed with fat saturation after administration of gadolinium- based

contrast material. In cases of osteomyelitis, the areas of abnormal

enhancement are almost always infected. Unfortunately, marrow

infarction may have a very similar appearance at MR imaging, with areas

of abnormal high signal intensity on T2 weight and inversion recovery

images and regional enhancement. Thus, the differentiation of infection

from marrow infarction at MR imaging may not be possible.(29,40)

Soft-tissue abnormalities such as oedema and abnormal

enhancement of periosteum, muscle, deep fascia, and subcutaneous fat

were once thought to indicate osteomyelitis; unfortunately, the same

soft-tissue abnormalities may also be seen with infarction.(29,40)

Studies of scintigraphic evaluation with various combinations of

technetium -99m methylene diphosphonate, gallium- 67, and Tc-99m

sulfur colloid have failed to produce definitive results. In conclusion,

imaging alone does not yet allow reliable and accurate differentiation of

osteomyelitis from infarction.(25.29.40)

Radiological changes of the spine are mainly due to :

Bone marrow hyperplasia in two thirds of patients with Hb SS disease,

the vertebrae become biconcave as the intervertebral discs

compress the vertebral plates and the weakened medulla.

Massive infarction of the vertebral bodies is rare. Commonly

infarction, propably due to venous thromboembolism, results in

loss of vascular supply to the central part of the vertebral plate, this

has a single vein and artery, whilst the periphery of the plate

receives multiple vessels. Infarction weakens the central part of the

plate, producing a stepped depression, the floor of depression forms

a flat sclerotic margin during the course of healing . (41) This

appearance which iscalled the ( lincoln log ) or H – shaped vertebra

deformity is found in 10% of patients, and it is almost

pathognomonic of SCA . (19)

The brain

Stroke, atrophy, and cognitive impairment are major consequences

of SCA. Approximately 25% of all patients with SCA will have a

neurological complication over their life time, 11% of these

complications will occur by age 20 years.(42,43) Many children will

experience silent infarction (defined as absence of clinical symptoms with

MR imaging findings of infarct).

Silent infarction is twice as common as clinical infarction and may

occur in up to 22% of children by 12 years of age. Other less common

problems, include intraparenchymal and subarachnoid haemorrhage and

aneurism. Infarction in patients with SCA is usually ischaemic.(44)

Embolic and thrombotic strokes are unusual (45,44). Infarcts, both silent

and clinical, are best detected with MR imaging.

The spleen:

The spleen possesses a slow tortuous microcirculation that renders it

quite susceptible to congestion, sludging and polymerization. The

culmination of this process is splenic infarction, which progresses

overtime to functional autosplenectomy. The infarcted spleen is replaced

by fibrosis, with calcium and haemosiderin deposition. At 6 months of

age, 14% of patients with SCA are asplenic, at 2 years 58% are asplenic

and by 5 years of age 94% are asplenic. This has important consequences

for infection susceptibility.(4) Overtime, with infarction, the spleen

becomes small, dense and calcified. This calcification may be visible at

radiography and CT. It may also take up Tc-99m methylene

diphosphonate. The infarcted fibrotic, spleen has low signal intensity.

Acute splenic sequestration crisis is a well recognized complication of

SCA . It is defined as a fall in haemoglobin concentration of at least 2

g/dl, an increased reticulocyte count, and an enlarging spleen(46). It

occurs almost commonly in children younger than 2 years of age and is

unusual in adults with SCA due to autosplenectomy. It is estimated that

patients with SCA have a 30% probability of having an acute spleinc

sequestration event by 5years of age with a potential mortality

approaching 15% per event (46) Splenic sequestration is caused by the

accumulation of RBCs within the spleen. Clinical findings include

sudden weakness, pallor of the lips and mucous membrane, tachycardia ,

trachpnea, and abdominal fullness. In severe sequestration crisis, the

spleen can become so large that it fills the abdomen and pelvis.(47)

The kidney

The kidney in SCA has increased renal plasma flow and increased

glomerualr filtration rate.(48) By adolescence, the glomerular filtration rate

is normal, and by age 40 . It is reduced .The glomerulosclerosis may lead

to proteinuria, nephritic syndrome (in approximately 45% of patients),

and sometimes renal failure ( in 4% - 18% of patients).(49,50)

Miscellanaeous disease manifestations, complications from SCA

have been reported in nearly every tissue of the human body.

The liver is frequently involved. Histological evaluation shows

sinusoidal diltation, perisinusoidal fibrosis, ischaemic necrosis, and

cirrhosis, presumed due to infarction.(51,52) Hepatitis is also frequent .

Pigmented gallstones are evident in up to 50% of adults and 20% of

children with SCA.(52,53)

Extramedullary haematopoiesis is occasionally found in SCA

(although it is much more common in sickle cell variants such as HbS -

thal and non sickle cell anaemias such as hereditary spherocytosis). Sites

of extramedullary haematopoiesis include the thorax , liver, spleen, skin

and adrenal glands . These areas appear as focal masses and may be

confirmed with Tc-99m sulfur colloid imaging.(54)

Patients with SCA may experience acute retinal artery occlusion

with sudden loss of vision in one eye, this typically resolves in several

days, although some long – term visual impairment may result .(55)

Skull infarctions with subperiosteal haematomas have also been

implicated in a traumatic causes of epidural haematomas.(56)

Priapism (painful, persistent penile erection) is an unfortunately

common complication for male patients with SCA. By the age of 20

years , 89% of male patients will have experienced at least one

episode.(57) Repeated priapism may result in penile fibrosis and

impotence.

Investigations:

Both SCA and sickle cell trait (SCT) can be diagnosed before birth

with samples of amniotic fluid or placental tissue. It is not enough to

depend on obvious ethnicity or a childs surname for screening. People

cannot be sure of their ancestors genetic history.

The SCT could have been carried for generations without surfacing.

The most common screening test is haemoglobin electrophoresis.(58)

A normal finding is 97 percent to 100 percent HB A. A person with SCT

has 60 percent Hb A and 40 percent HbS. A person with SCA may have

86 percent to 98 percent HbS and 5 percent to 15 percent HbF. Other

blood abnormalities with SCA include elevated white blood counts

(12. . . 15000) and low haematocrits (20 percent to 30 percent) (58).

OBJECTIVES

• To study radiological findings on plain films of skull, spine,

and limbs of patients with sickle cell anaemia.

• To detect the pattern of bone changes among Sudanese cases

including changes of bone density, cortical, medullary, and

soft tissue involvement.

• To show the frequency of bone affection and correlation

with the duration and severity of clinical picture in different

age groups.

MATERIALS AND METHODS

Patients:

A total of 100 Sudanese patients were included in this study.

All patients were tested with and diagnosed by Hb electrophoresis

as having sickle cell anaemia.

- The patients were from Khartoum and other different urban

and rural parts of Sudan.

- Both sexes were included.

- The age range of patients is 5/12 – 35 years.

- Patients with other systemic disorders which can affect the

bone were excluded.

- Patients were seen every Tuesday from 8-10am.

The study was explained to all patients and to children’s mothers and

oral consents were taken. Then the patients were interviewed via a

questionnaire the questionnaire included the symptomatology, the clinical

findings as well as the radiological findings. X-rays were taken from all

patients as follows:

- X- ray lateral skull.

- X- ray lateral spine.

X- ray limb and pelvis anteroposterior.

Tecnique and radiographic positioning :-

Lateral skull : A 24 x 30 cm detailed screen cassette and table bucky

were used .The patient was prone with head in true lateral position the

affected site in contact with the film .The head was adjusted so that the

median sagital plane was parallel and the inter orbital line was at right

angle to the film . Centering point is to temporal region mid way between

the glabella and the external occipital protuberance .With the central ray

vertical to the film exposed on arrested respiration with optimum kilo

voltage mili ampere seconds that enables details of interest to be clearly

visible with focal film distance of40 inches or 102 centimeter .

Lateral thoracic spine : The 35 x 43 cm detail screen cassette plus table

bucky were used .The patient was in true lateral decubitus on the x – ray

couch with the arm raised above the head and flexed hips and knees with

the thoacic spine parallel to couch .Cp .is 5 cm anterior to the spinous

process of the sixth thoracic vertebra with central beam vertical to the

film exposed during quiet respiration using an exposure time of 4 sec .

and a low MA . setting and optimum KV. And FFD of 102 cm .

Anteroposterior view Hand : The used equipments were 18 x24 cm detail

screen cassette or non screen film . The patient was seated alongside the

table with palmer aspect of hand on the film Cp is head of the 3rd

metacarpal with vertical central ray of FFD 102 cm or 40 inches and

optimum KV . MAS .

Anteroposterior view Foot : The 24 x 30 cm detail screen cassette or non

screen film was used . The patient was seated on x – ray table with

flexed knees the affected sole was placed on the film centering the

vertical beam on dorsum of the foot to the cuboid – navicular region with

optimum KV . MAS . at FFD . of 102 cm

Hip joint and upper femur anteroposterior view :

Equipments used were 24 x 30 cm detail or fast screen

cassette , table bucky , stationary grid or grided cassette .The patient was

supine with affected hip in the center of x – ray couch centering with

vertical beam to the hip joint at a point 2 and half cm distal along the

perpendicular bisection of the line from the anterior superior iliac spine

to the upper border of the symphysis pubic . Exposed on arrested

respiration with optimum expsure factors and FFD . 102 cm .

All the exposed film were manually proccessed with chemical materials .

All the x-rays taken were diagnosed by radiologists.

Data analysis:

The data were entered into the computer, simple tabulation done,

descriptive analysis was done by percentage.

RESULTS

- A total of 100 Sudanese patients known as having sickle

cell disease were included in this study.

- The sickle cell disease was diagnosed on the basis of

haemoglobin electrophoresis test.

- All the 100 patients were investigated by using plain

radiography of the lateral skull, spine and anteroposterior

limbs.

- Fifty-five patients were males (55%) and forty five

patients were females (45%) (Table 1) (Figure 1).

- Most of the patients were descended from Misseria tribe

(21%). From Fallata and Housa tribe (19%), and from

Sulihab tribe (10%) while the other 50% descended from

other different tribes (Table 2) (Figure 2).

- Most of the patients were children (90%) of less than 15

years old (Table 3) (Figure 3).

- The study showed that 72% of the parents were relatives

while 28% of parents reported no relationship (Table 4)

(Figure 4).

- The vast majority of patients (98%) presented with acute

painful crises while 48 patients presented with other

complains such as chest infection, jaundice etc in addition

to the pain.

- Twenty seven (27%) patients presented early before 6

months of age. Sixity two (62%) patients presented for the

1st time at the age range 6-12 months, while only eleven

patients presented at the age of more than one year (Table

5) (Figure 5).

- Although it is difficult to trace family history according to

culture in the study group

- Sixty seven percent (67%) of patients reported positive

family history of S.C.D. while 33% of patients reported no

family history of S.C.D. (Table 6) (Figure 6).

- Haemoglobin Hb% level was generally variable in the

study group

- Sixty four patients (64%) presented with haemoglobin

level which was less than 50%. While only one patient

presented with haemoglobin of more than 59% (Table 7)

(Figure 7).

- Skeletal plain films radiography of 65 patients showed the

frequency of bone affection as follows:- The limbs and

pelvis were affected more (31%) followed by spine (25%)

then the skull (9%) (Table 8) (Figure 8).

- The radiographic films of the lateral skull showed that nine

patients were affected in the form of:- Decreased bone

density in six patients, increased bone size (diploic space)

in nine patients, no change in the cortical thickness,

medullary trabeculation, soft tissue involvement,

secondary infection, periosteal reaction or infarction.

- The lateral spine films of 25 patients were affected. The

bone density decreased in all the 25 patients (rarefaction).

The bone size decreased in 23 patients (vertebral end plate

central depression). The cortices and medullary trabeculae

of vertebral column are preserved, no periosteal reaction,

para spinal soft tissue masses, infarction or secondary

infection.

- The radiographic films of the limbs and pelvis showed the

following features:- 31 patients have bone changes in the

form of decreased bone density (rarefaction) in 22 patients

and mixed density or rarefaction with sclerosis in 8

patients. & no changes in one patient .

- The size of the bone decreased (collapsed femoral head) in

the LL of 5 patients, bone cortical thickness decreased in

the LL of 3 patients.

- Medullary trabeculation changes were seen in one upper

limb film and 5 LL films.

- There were periosteal reactions in 2 upper limbs films and

8 LL films. The upper limbs showed that 11 patients were

affected and the films of LL showed that the soft tissue

was affected in 13 patients (Table 9) ( Figure 9).

- Bone infarction was seen in the films of the LL of 4

patients and secondary infection in the films of LL of 2

patients.

- The correlation of clinical symptoms with radiological

findings was found to be as follows:- out of 65 patients

who had positive skeletal radiological findings, 59 of them

presented with clinical symptoms.

- Out of the 35 patients who had no radiological findings, 30

of them had clinical symptoms (Table 10) ( Figure 10).

- In the group of patients with the disease duration of 0-10

years the number of patients with +ve skeletal findings are

41 patients (54.66%) while the number of patients with -ve

skeletal findings are 34 (45.3%).

- In the group of patients with the disease duration of > 10

years 24 patients (96%) had +ve skeletal findings while

only one patient (4%) had –ve skeletal finding (Table 11)

( Figure 11).

- (Table 12) ( Figure 12) Shows the correlation of initial

radiographic findings with onset of clinical manfestations.

- Ninety five patients presented at the age of < 2 years. 61 of

them presented with skeletal radiographic findings. Five

patients presented at the age > 2 years four out of the

patients showed +ve skeletal radiographic findings.

- There is remarcable preservation of skeletal system as

- (Table 13) Shows the frequency of bones affected in

relation to age group and sex group.

- The spine was affected more in the age group ranging

between 11-15 years with almost equal male to female

ratio.

- The skull was affected more in those patients who are

more than 10 years old, while the upper and lower limbs

were affected at an early age group (0-5 years) and the sex

group ratio was found to be equal.

Table (1) : Sex distribution in the study group

Female 45

Male 55

Fig. 1 : Sex

45

55

FemaleMale

Table (2) : Tribes distribution in the study group

Misseria 21

Fallata 19

Sulihab 10

Other tribes 50

21 19

10

50

0

10

20

30

40

50

Misseria Fallata Sulihab Other tribes

Fig. 2 : Tribes

Table (3) : Age (years) distribution in the study group

0-5 6-10 11-15 >15

39 30 21 10

39

30

21

10

05

10152025303540

0-5 6--10 11--15 >15

Fig. 3 : Age (years)

Table (4) : Parents relationship in the study group

Relative 72

Not relative 28

Fig. 4 : Parents relationship

72

28

Relative Not relative

Table (5) : Age of first presentation of the disease

0 - <6/12 6/12 – 1 yrs > 1 yrs

27 62 11

27

62

11

0

10

20

30

40

50

60

70

Perc

enta

ge

0 - <6/12 6 - 1 yr >1 yr

Fig. 5 : Age of first presentation

Table (6) : Family history of sickle cell anaemia

Positive family history of S.C.A 67

No family history of S.C.A 33

Fig. 6 : Family history

67

33 Positive familyhistory of S.C.ANo family history ofS.C.A

Table (7) : Haemoglobin percent of patients in the study group

<30% 30-39% 40-49% 50-59% >59%

0 7 57 35 1

07

57

35

10

102030405060

<30% 30-39% 40-49% 50-59% >59%

Fig. 7 : Haemoglobin percent

Table (8) : Distribution of bone involvement in the study group

Skull Spine Limbs & pelvis Total

Bone affected 9 25 31 65

Normal cases - - - 35

Fig. 8 : Bone affected

9

25

31

35 SkullSpineLimbs & pelvisNormal cases

Table (9) : Distribution of soft tissue involvement in the study group

X-ray skull

(lateral)

X-ray spine

(lateral)

X-ray limbs

& pelvis

Total

Soft tissue

involvement

0 0 24

Normal soft

tissue

9 25 7

65

Normal cases - - - 35

Fig. 9 : Soft tissue involvement

24

35

41

Bone + softtissueinvolvementNormal cases

Normal softtissue + boneinvolvement

Table (10) : Correlation of presenting symptoms with skeletal

radiological findings

Symptoms

Radiological

findings

With symptoms Without

symptoms

+ve rad. 65 59 6

-ve rad. 35 30 5

Total 89 11

59

6

30

5

0102030405060

+ve rad. 65 -ve rad. 35

Fig. 10 : Correlation of clinical symptoms with radiological findings

With symptomsWithout symptoms

Table (11) : Relationship between skeletal radiological findings and

duration of the disease

Radiological

Duration findings

+ve Rad. -ve Rad.

0-5 45 25 20

6-10 30 16 14

11-15 15 15 -

>15 10 9 1

Total 100 65 35

Table (12) : Correlation of initial skeletal radiographic findings with

onset of clinical manifestations

Radiological

First findings

presentation

+ve Rad. -ve Rad.

<1yr 81 52 29

1-2 14 9 5

3-4 4 3 1

5-6 - - -

>6 1 1 -

Total 100 65 35

52

29

9 5 3 1 0 0 1 00

20

40

60

<1yr 1--2 3--4 5--6 >6

Fig. 12 : Correlation of initial radiographic with onset of clinical manifestations

+ve Rad.-ve Rad.

Table (13) : The Site of bone affected in different age group

Age

Site affect

0-5 6-10 11-15 >15 M F

Spine 25 1 2 15 7 13 12

Skull 9 - 2 4 3 7 2

Upper limb 13 10 2 1 - 6 7

Lower limbe18 11 3 2 2 10 8

Total 65 22 9 22 12 36 29

DISCUSSION

A total of 100 Sudanese patients diagnosed as having SCA were

studied.

Twenty seven patients presented for the 1st time before the age of

6 months, sixty two patients presented for the 1st time at the age range of

6-12 months, while 11 patients presented for the 1st time at the age of > 1

year.

Most of the patients (62%) were at the age range of 6-12 months.

This finding is consistent with the fact that the disease does not manifest

it self until the Hbf decreases to adult levels at about 6-12 of age (1).

Fifty five patients were males (55%), while 45 patients were

females (45%).

There is slight preponderance of males in the study group. This is

consistent with the results of a study conducted in Sudan, in which they

found that male to female ratio was 1.4:1(59).

Twenty one percent of patients in this study group were from

Misseria tribe in other studies done in Sudan the percentage of patients

from the Misseria tribe was found to be (25.5%), (32.9%) and (50%)

respectively(59,60,61,62).

Nineteen percent of the study group was from the Fallata and

Houssa tribes, while another study done in Sudan in 1997, concluded that

(12%) of the study group was found to be from the Fallata and Houssa

tribes. The Fallata and Houssa tribes were originally from Nigeria.

Most of the patients included in the study group were children

(90%).This may be explained by the fact that medical services are

deficient and some times not available. Most of the patients with SCA do

not have enough medical care and so they die early. Causes of early death

in patients with SCA in Sudan need to be studied.

Most of the parents of our patients (72%) are relatives. The finding

is consistent with the finding of a previous study carried out in Sudan, (59)

where high percentage of consangous marriages were observed among

the families of the children with SCA in the study group (63.4%).

The commonest presenting clinical manifestation was found to be

acute painful crises (98%). Forty eight percent of patients presented with

other clinical manifestations such as chest infection 40% , hepatomegaly

3% , C.V.A 3% and cholelithesis 2%,in addition to the acute painful

crises. The patients usually use the term bone pain to describe acute

painful crises. A study (10) conducted by Yaster M. et al, concluded that

acute painful vaso-occlusive crises are the most common, and earliest,

clinical manifestations of SCA. These studies also concluded that half of

all patients with SCA experience a painful crises by 4-9 years of age,

which is lower (50%) if compared with our findings (i.e. 98%). This high

percentage in our study may be explained partly by the fact that most of

our patients are poor and malnourished and so more prone to have

anaemia, infection and dehydration, which are well known factors that

precipitate acute painful crises.

The results showed that out of the 65 patients who had positive

skeletal radiological findings, only 59 of them presented with clinical

symptoms. This means that, there is no direct correlation between the

clinical symptoms and the radiological findings. This can be explained by

the fact that some patients develop bone infarction with no symptoms,

which is known as “silent infarction”.(63)

Out of the 35 patients who had no radiological findings, 30 of them

had clinical symptoms. The radiological findings were excluded by plain

radiological films which are less sensitive than MR and so this number

may include some false negatives. MR imaging is likely the most

sensitive radiological modality of investigation, as it may show

abnormality as soon as a few days, after ischaemic insult(28).

From this study it is noted that the skeletal involvement was more

in the limbs (31%) followed by the spine (25%), then the skull (9%) .

Upper and lower limbs were affected in (31%) of cases in the form

of generalized rarefaction and soft tissue involvement only in 24% with

little cortical and medullary changes and periosteal reaction. As which is

known as foot and hand syndrome or dactylitis.

The age group mainly involved is of < 5 years old (21%) and rarely

after 10 years old (3% ) .

This is consistent with another study in which the age group

affected was< 4 years and uncommon after 7 years old(35).

The lateral spine films of 23 patients (23%) out of 25 affected

spine showed decrease in the bone size in the form of vertebral end plate

central depression affecting mostly the age group of 11-15 years. This

percentage is almost double the percentage obtained in another study (19)

where they found vertebral end plate central depression in approximately

(10%) of patients. This appearance is essentially pathognomonic for SCA

and has been called the Lincoln log or H-shaped vertebra deformity.

Nine percent of lateral skull radiographs showed widening of

diploic space (hair on end appearance). Bone rarefaction was found in six

patients. No cortical or medullary changes detected, no evidence of soft

tissue involvement, secondary infection or infarction.The age group

affected was > 5 years old which is consistent with another study(22)

where (5%) of cases of the same age group were detected .

Combined bone involvement was found in 7 patients.In all of them

the spine was involved plus another bone such as limb or skull.

The age of six of them was 11 years and above. Only one of them

was below 11 years old (1.5 years old), where the spine was involved

plus secondary osteomyelitis of the left tibia.

Five patients in our study group showed osteonecrosis and signs of

femoral head collapse .In another study they found that approximately

half of all patients with SCA will develop epiphyseal osteonecrosis by the

age of 35 years (64). This low percentage of osteonecrosis in our study

may be explained partly by the form of investigation used in our study

(plain radiography) which will not show all the radiological finding as

MRI, and may be explained partly by the fact that most of the patients in

our study group (90%) are children and have not yet reached the age of

35 years.

CONCLUSION

In this study plain radiography showed that in S.C.A. The bones of the

limbs and pelvis are the most affected bones in the body.

• Plain radiography cannot show some bone changes due to

infarction and infection in patients with S.C.A especially

early on the disease course.

• The study concluded that, there is no direct relationship

between clinical symptoms and radiological findings.

• Patients with S.C.A in Sudan lack proper registration,

medical services and follow up.

• Radiographic bone findings in Sudanese patients are not

different from radiological findings in other ethnic group,

RECOMMENDATIONS

• Doctors in charge of S.C.A patients should be aware of the

importance of early detection of bone changes due to

infarctions and infection of bones, so as to avoid serious

complications later on.

• Plain radiography alone is not enough to detect bone changes

in S.C.A. Other more sensitive tools of investigations such

like MR should be used as well, especially early on.

• Patients with S.C.A in Sudan are in need of better medical

services than what is available now. They need sickle cell

clinics for children and adults, which provide specialized

medical services, such like health education to decrease

consangious marriges good investigations, management,

rehabilitation and follow up.

• The medical services should be provided free for poor

patients with S.C.A.

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Radiological Bone Manifestations in Sudanese Patients of Sickle Cell Anaemia

Name : …………………………………………….. Serial No. ( ) Age (years): a) 0-5 b) 6-10 c) 11-15 d) >15 Sex : a) Male b) Female Residence: …………………………………… Tribe: ………………….. Address or Tel. No.: …………………

Presenting Symptoms:-

i) Skeletal pain ii) Crises iii) Others:

• Pneumonia

• Jaundice

• Anaemia d) Abdominal symptom:

• Hepatosplenomegally

• Gall bladder calculi 1st presentation of the disease at: ………………………………….. Consanguinity: a) Yes b) No Family history : a) Yes b) No Hb% : ………….. Radiological findings:

Lateral skull

Lateral spine

Limbs Features changes

Yes No Yes No Yes No

Density (+, – , mix)

Site

Size (+, – , normal)

Cortical thickness (+, –)

Medullary trabeculation (+, –)

Periosteal reaction (+, –)

Soft tissue involvement (+, –)

Infarct (+, –)

Secondary infection (+, –)

Lateral Skull showing hair –on– end appearance

lateral dorsal spine showing H-shaped vertebrae

Hand foot syndrome (dactylities)

Osteonecrosis femoral head

Osteomylities tibia