Definition and Molecular Basis Definition and Molecular Basis of Diseaseof Disease

Sickle cell disease (SCD): a recessively Sickle cell disease (SCD): a recessively inherited chronic hemolytic anemiainherited chronic hemolytic anemia

Caused by a single nucleotide substitution Caused by a single nucleotide substitution in the in the ββ globin gene on chromosome 11 globin gene on chromosome 11 – Hemoglobin S : GTG Hemoglobin S : GTG GAG results in GAG results in

substitution of valine for glutamatesubstitution of valine for glutamate Mutant hemoglobin polymerizes under low Mutant hemoglobin polymerizes under low

oxygen conditions and form bundles that oxygen conditions and form bundles that distort red cells into the classic sickle distort red cells into the classic sickle shape shape

33

PathophysioloPathophysiologygy

DeoxygenationDeoxygenation

polymerization of hemoglobin polymerization of hemoglobin

sickling of red cells sickling of red cells

endothelial damage/activationendothelial damage/activation

RBC and leukocyte adhesion RBC and leukocyte adhesion to endothelium, to endothelium, vasoconstrictionvasoconstriction

vascular occlusion, organ vascular occlusion, organ ischemia and end-organ ischemia and end-organ

damagedamage

PathophysiologyPathophysiology

Severity of disease varies widely Severity of disease varies widely among individuals and disease type:among individuals and disease type:

SS disease is most severeSS disease is most severe SC and S-beta thalSC and S-beta thal00 disease portend disease portend

intermediate severityintermediate severity SA (one normal allele=trait) is SA (one normal allele=trait) is

generally asymptomaticgenerally asymptomatic

Initial Clinical PresentationInitial Clinical Presentation

Typically presents in infancy after 6 Typically presents in infancy after 6 months of age, when Hb F is waningmonths of age, when Hb F is waning

– Birth hemoglobin F: Birth hemoglobin F: αα22γγ22– Hemoglobin A: Hemoglobin A: αα22ββ22– Hemoglobin S: Hemoglobin S: αα2S22S2

Pain and anemia are hallmarks of diseasePain and anemia are hallmarks of disease

Initial Clinical PresentationInitial Clinical Presentation

Suggestive historical findings:Suggestive historical findings:

– Family history of known SCDFamily history of known SCD– Family history of sudden death in young childFamily history of sudden death in young child– Frequent painFrequent pain– Frequent chest infectionsFrequent chest infections– Failure to gain weight despite good nutritionFailure to gain weight despite good nutrition– Persistent jaundicePersistent jaundice– Classic sequelae (hand/foot syndrome, Classic sequelae (hand/foot syndrome,

priapism)priapism)

Initial Clinical PresentationInitial Clinical Presentation

Physical Exam findings are nonspecific:Physical Exam findings are nonspecific:

– scleral icterusscleral icterus– pale mucous membranespale mucous membranes– systolic murmur throughout precordiumsystolic murmur throughout precordium– splenomegalysplenomegaly

Initial Clinical PresentationInitial Clinical Presentation

Predictors of adverse outcome at presentation:Predictors of adverse outcome at presentation:

– dactylitis in infant <1y/odactylitis in infant <1y/o

– Hb<7g/dLHb<7g/dL

– leukocytosis absent infectionleukocytosis absent infection

– priapismpriapism

Laboratory Findings and Laboratory Findings and DiagnosisDiagnosis

Hemolytic anemia: low hemoglobin, Hemolytic anemia: low hemoglobin, high reticulocyte count, elevated LDH high reticulocyte count, elevated LDH and decreased haptoglobinand decreased haptoglobin

Peripheral blood smear: Peripheral blood smear:

Diagnosis: Sodium Diagnosis: Sodium metabisulfitemetabisulfite

Screening for SCD with sodium Screening for SCD with sodium metabisulfite metabisulfite – Add Na metabisulfite to bloodAdd Na metabisulfite to blood– Seal mixed sample in airtight container Seal mixed sample in airtight container

or under coverslipor under coverslip– Look for sickling under microscopeLook for sickling under microscope

Does not differentiate trait from Does not differentiate trait from diseasedisease

Diagnosis: Hemoglobin Diagnosis: Hemoglobin ElectrophoresisElectrophoresis

Sequelae: Vaso-occlusive/pain Sequelae: Vaso-occlusive/pain crisiscrisis

Occurs in 60% of SS patients when vaso-Occurs in 60% of SS patients when vaso-occlusion occlusion tissue ischemia tissue ischemia

May be triggered by infection, temperature May be triggered by infection, temperature extremes, dehydration or stress but extremes, dehydration or stress but usually w/o identifiable cause.usually w/o identifiable cause.

Characterized by severe pain often in Characterized by severe pain often in extremities, involving the long bones, or extremities, involving the long bones, or the abdomen. May last hours to days.the abdomen. May last hours to days.

Sequelae: Vaso-occlusive/pain Sequelae: Vaso-occlusive/pain crisiscrisis

Management:Management: Hydration: 20cc/kg NS bolus, then PO/IV Hydration: 20cc/kg NS bolus, then PO/IV

hydration at 1.5 x maintenance (hydration at 1.5 x maintenance (notnot for for acute chest)acute chest)

Pain ladder: Pain ladder: Paracetamol 15mg/kg PO q4hr ADDParacetamol 15mg/kg PO q4hr ADDIbuprofen 10 mg/kg PO q6hr ADDIbuprofen 10 mg/kg PO q6hr ADDCodeine 1mg/kg PO q4hrCodeine 1mg/kg PO q4hrCHANGE Codeine to Tramadol (need dose) CHANGE Codeine to Tramadol (need dose) CHANGE Tramadol to Morphine 0.1mg/kg q4hrCHANGE Tramadol to Morphine 0.1mg/kg q4hr

Ambulation to prevent acute chestAmbulation to prevent acute chest Oxygen to maintain O2 sat > 95%Oxygen to maintain O2 sat > 95%

Sequelae: InfectionSequelae: Infection

By age 1 >> 30% of Hb SS pts are By age 1 >> 30% of Hb SS pts are asplenic, asplenic,

by age 6>>90% are asplenicby age 6>>90% are asplenic This makes children especially This makes children especially

vulnerable to infection/sepsis with vulnerable to infection/sepsis with encapsulated organisms, esp. Strep encapsulated organisms, esp. Strep pneumoniaepneumoniae

Sickle Cell patients are also more Sickle Cell patients are also more susceptible to osteomyelitis susceptible to osteomyelitis (Salmonella and Staph spp.)(Salmonella and Staph spp.)

Sequelae: Infection(cont’d)Sequelae: Infection(cont’d)

Management of fever:Management of fever: For T For T ≥38, send: Hb, malaria smear, ≥38, send: Hb, malaria smear,

CXR, UA (under 2 years or CXR, UA (under 2 years or symptoms)symptoms)

Administer Ceftriaxone 50 mg/kg QD Administer Ceftriaxone 50 mg/kg QD until clinically improving OR 3 daysuntil clinically improving OR 3 days

Change to amoxclav or ampicillin to Change to amoxclav or ampicillin to complete 14 dayscomplete 14 days

Sequelae: Acute Chest Sequelae: Acute Chest SyndromeSyndrome

Characterized by new respiratory Characterized by new respiratory distress, CXR infiltrate, distress, CXR infiltrate, hypoxia(O2<95%) and/or chest painhypoxia(O2<95%) and/or chest pain

Occurs in 40% of patients with SS Occurs in 40% of patients with SS diseasedisease

Can progress rapidly to ARDSCan progress rapidly to ARDS cause unknowncause unknown May be caused by viral or bacterial May be caused by viral or bacterial

infection, fat embolisminfection, fat embolism

Sequelae: Acute Chest Sequelae: Acute Chest SyndromeSyndrome

Management :Management :

CeftriaxoneCeftriaxone 50mg/kg IV daily, then 50mg/kg IV daily, then when pain improving ampicillin or when pain improving ampicillin or amoxclavamoxclav

If O2<94 and Hb < 6 g/dL, consider If O2<94 and Hb < 6 g/dL, consider transfusiontransfusion

Do not hydrate > 1x maintenance Do not hydrate > 1x maintenance (furosemide with transfusion)(furosemide with transfusion)

Sequelae: StrokeSequelae: Stroke

11% of SS patients have a stroke by 11% of SS patients have a stroke by age 20 with peak incidence between age 20 with peak incidence between 2 and 102 and 10

Presents as focal neurologic deficit or Presents as focal neurologic deficit or seizureseizure

Management: Management: TransfusionTransfusion

Sequelae: Acute Splenic Sequelae: Acute Splenic SequestrationSequestration

Sudden enlargement of the spleen Sudden enlargement of the spleen accompanied by a >2g/dL decrease in Hb from accompanied by a >2g/dL decrease in Hb from baseline, often w/ thrombocytopeniabaseline, often w/ thrombocytopenia

Occurs in children <3y/oOccurs in children <3y/o Can cause sudden circulatory collapseCan cause sudden circulatory collapse

Management:Management: Immediate volume expansion with crystalloidImmediate volume expansion with crystalloid TransfusionTransfusion If >2 episodes If >2 episodes splenectomysplenectomy

Sequelae: Aplastic CrisisSequelae: Aplastic Crisis Caused by infection with Parvovirus B19 (fifth Caused by infection with Parvovirus B19 (fifth

disease) which invades young erythroblasts in disease) which invades young erythroblasts in bone marrowbone marrow

Often presents with fever, URI sx and drop in Often presents with fever, URI sx and drop in HbHb

RBC life expectancy in SS disease is 10-20 RBC life expectancy in SS disease is 10-20 days, thus decrease in RBC production has days, thus decrease in RBC production has profound effect.profound effect.

Bone marrow recovery typically within 7-10 Bone marrow recovery typically within 7-10 daysdays

Management:Management: Transfusion if symptomatic with Hb drop.Transfusion if symptomatic with Hb drop.

Sequelae: AnemiaSequelae: Anemia

Compensated anemia at baselineCompensated anemia at baseline Baseline Hb normally 8-9 g/dlBaseline Hb normally 8-9 g/dl Overtransfusion can predispose to Overtransfusion can predispose to

transfusion transmitted infections transfusion transmitted infections and iron overloadand iron overload

ManagementManagement Transfuse for Hb < 5g/dL or <6g/dL Transfuse for Hb < 5g/dL or <6g/dL

with cardiac decompensationwith cardiac decompensation

Indications for Simple Indications for Simple TransfusionTransfusion

Final hematocrit after transfusion <30%.Final hematocrit after transfusion <30%. Simple Transfusion for: Simple Transfusion for:

– aplastic crisesaplastic crises– splenic sequestrationsplenic sequestration– Acute chest syndromeAcute chest syndrome– Before surgeryBefore surgery– Priapism resistant to medical managementPriapism resistant to medical management– StrokeStroke– Persistent pain despite proper pain Persistent pain despite proper pain

managementmanagement

Indications for Exchange Indications for Exchange TransfusionTransfusion

For stroke, severe ACSFor stroke, severe ACS

Other SequelaeOther Sequelae

Priapism: May require surgical drainage, Priapism: May require surgical drainage, phenylephrine injection, exchange transfusionphenylephrine injection, exchange transfusion

Dactylitis (hand-foot syndrome): painful Dactylitis (hand-foot syndrome): painful swelling of hands and feet which occurs in swelling of hands and feet which occurs in infants.infants.

Avascular necrosis of the humeral/femoral Avascular necrosis of the humeral/femoral headhead

CholelithiasisCholelithiasis RetinopathyRetinopathy Chronic leg ulcers Chronic leg ulcers

Bone involvement in sickle Bone involvement in sickle cell diseasecell disease

the commonest clinical manifestationthe commonest clinical manifestation

both in the acute and as a source of both in the acute and as a source of chronic, progressive disabilitychronic, progressive disability

Acute bone problems in Acute bone problems in sickle cell diseasesickle cell disease

Vaso-occlusive crises Vaso-occlusive crises

affect virtually all patientsaffect virtually all patients

can occur in virtually any organ, it is particularly common in the can occur in virtually any organ, it is particularly common in the bone marrow, resulting in bone marrow infarction typically in the bone marrow, resulting in bone marrow infarction typically in the medullary cavity or epiphyses (Lonergan et al, 2001; Kim & Miller, medullary cavity or epiphyses (Lonergan et al, 2001; Kim & Miller, 2002). 2002).

Clinically : intense Clinically : intense painpain localized to one or more areas of localized to one or more areas of their skeleton. localized their skeleton. localized tendernesstenderness, swelling and , swelling and erythemaerythema over the site of infarction; over the site of infarction; feverfever and and leucocytosisleucocytosis are also are also common (Smith, 1996).common (Smith, 1996).

Most : no further complications. Most : no further complications.

However, when marrow infarction involves the However, when marrow infarction involves the epiphysesepiphyses, , this may give rise to this may give rise to joint effusions joint effusions that are clinically similar that are clinically similar to septic arthritis (Smith, 1996; Kim & Miller, 2002), or to septic arthritis (Smith, 1996; Kim & Miller, 2002), or where there is infarction of where there is infarction of vertebral bone marrowvertebral bone marrow, to , to collapse of the vertebrae with a typical collapse of the vertebrae with a typical ‘fish mouth‘fish mouth’ ’ appearance (Lonergan et al, 2001).appearance (Lonergan et al, 2001).

DactylitisDactylitis

<7 years, particularly1–2 years<7 years, particularly1–2 years , vaso-occlusive crises frequently , vaso-occlusive crises frequently

occur in the small bone of the hands occur in the small bone of the hands and feet (dactylitis), and feet (dactylitis),

still contain haemopoietic bone still contain haemopoietic bone marrow (Kim & Miller, 2002). marrow (Kim & Miller, 2002).

Clinically: acute, painful swelling of Clinically: acute, painful swelling of one or more of the digits. one or more of the digits.

Most resolve within 2 weeks, by Most resolve within 2 weeks, by which time new bone formation is which time new bone formation is evident Radiologically and there evident Radiologically and there may be a ‘moth eaten’ appearance may be a ‘moth eaten’ appearance of the involved digits because of of the involved digits because of cortical thinning and irregular cortical thinning and irregular attenuation of the medullary spaces attenuation of the medullary spaces (Lonergan et al, 2001); (Lonergan et al, 2001);

rarely, involvement and infarction of rarely, involvement and infarction of the epiphyses leads to premature the epiphyses leads to premature fusion and shortened fusion and shortened fingers(Babhulkar et al, 1995).fingers(Babhulkar et al, 1995).

Imaging during acute vaso-Imaging during acute vaso-occlusive crisesocclusive crises

The diagnosis of a painful crisis is The diagnosis of a painful crisis is predominantly a predominantly a clinicalclinical one. one.

Standard radiographs Standard radiographs are generally not are generally not helpful >>> usually normal during the acute helpful >>> usually normal during the acute phase phase

although over the ensuing months although over the ensuing months radiographs often show areas of ill-defined radiographs often show areas of ill-defined translucency followed by arc-like translucency followed by arc-like subchondral and intramedullary lucent areas subchondral and intramedullary lucent areas and patchy sclerosis (Lonergan et al, 2001).and patchy sclerosis (Lonergan et al, 2001).

radioisotope bone scanning radioisotope bone scanning can reliably detect areas of infarction in the can reliably detect areas of infarction in the acute phase acute phase

(Amundsen et al, 1984; Skaggs et al, 2001; Kim & Miller, 2002). (Amundsen et al, 1984; Skaggs et al, 2001; Kim & Miller, 2002).

Unfortunately, despite its sensitivity, radioisotope bone scanning Unfortunately, despite its sensitivity, radioisotope bone scanning has proved has proved unreliableunreliable in distinguishing infarction from other in distinguishing infarction from other complications such ascomplications such as

osteomyelitis (see below) (Amundsen et al, 1984; Rao et al, osteomyelitis (see below) (Amundsen et al, 1984; Rao et al, 1985; 1985; Kim & Miller, 2002), and it is therefore not useful as a routine Kim & Miller, 2002), and it is therefore not useful as a routine diagnostic investigation in sickle cell disease.diagnostic investigation in sickle cell disease.

Magnetic resonance Magnetic resonance imaging (MRIimaging (MRI

is also a very sensitive imaging technique for detecting is also a very sensitive imaging technique for detecting bone and bone marrow infarction (Mankad et al, 1988; van bone and bone marrow infarction (Mankad et al, 1988; van Zanten et al, 1989; Mankad et al, 1990; Bonnerot et al, Zanten et al, 1989; Mankad et al, 1990; Bonnerot et al, 1994; Deely & Schweitzer, 1997; Frush et al, 1999).1994; Deely & Schweitzer, 1997; Frush et al, 1999).

Abnormal periosteal signal intensity and soft tissue Abnormal periosteal signal intensity and soft tissue changes are frequently seen in the first few days of a changes are frequently seen in the first few days of a vasoocclusivecrisis;vasoocclusivecrisis;

however, as with scintigraphy, these changes are often however, as with scintigraphy, these changes are often difficultdifficult to distinguish from those seen in osteomyelitis to distinguish from those seen in osteomyelitis

OsteomyelitisOsteomyelitis

The increased susceptibility ??The increased susceptibility ??• HyposplenismHyposplenism• impaired complement activityimpaired complement activity• presence of infarcted or necrotic presence of infarcted or necrotic

bonebone

Diagnosis of osteomyelitis in Diagnosis of osteomyelitis in sickle cell diseasesickle cell disease

pain, swelling and tenderness over the affected area.pain, swelling and tenderness over the affected area. The most common sites are the femur, tibia or humerus (Stark et The most common sites are the femur, tibia or humerus (Stark et

al, 1991). al, 1991). Most patients also have fever and elevated inflammatory markers Most patients also have fever and elevated inflammatory markers

(Chambers et al, 2000; Skaggs et al, 2001) but the fever may be (Chambers et al, 2000; Skaggs et al, 2001) but the fever may be modestmodest

(Bennett, 1992). (Bennett, 1992).

These signs and symptoms are similar to those found in vaso-These signs and symptoms are similar to those found in vaso-occlusive crises, making the distinction between a painful crisis occlusive crises, making the distinction between a painful crisis and osteomyelitis extremely difficult on clinical groundsand osteomyelitis extremely difficult on clinical grounds

indeed osteomyelitis may not be suspected until the signs and indeed osteomyelitis may not be suspected until the signs and symptoms of a typical painful crisis have failed to resolve after 1–2 symptoms of a typical painful crisis have failed to resolve after 1–2 weeks of standard therapy (Jean-Baptiste & De Ceulaer, 2000).weeks of standard therapy (Jean-Baptiste & De Ceulaer, 2000).

Blood cultures are often sterile when taken at this stage, Blood cultures are often sterile when taken at this stage,

as it is common practice to treat patients with vaso-occlusive crises as it is common practice to treat patients with vaso-occlusive crises with broad-spectrum antibiotics upon admission, especially if they are with broad-spectrum antibiotics upon admission, especially if they are febrile. febrile.

However, in some cases, osteomyelitis presents late, as a more However, in some cases, osteomyelitis presents late, as a more indolent process often withindolent process often with

abscess formation, in which case there is usually little diagnostic difficulty abscess formation, in which case there is usually little diagnostic difficulty (Barrett-Connor, 1971; Dirschl, 1994).(Barrett-Connor, 1971; Dirschl, 1994).

On plain radiographs, the changes seen at the early stages of On plain radiographs, the changes seen at the early stages of osteomyelitis, namely periostitis and osteopenia, are nonspecific osteomyelitis, namely periostitis and osteopenia, are nonspecific and also seen in vaso-occlusion and therefore of limited value and also seen in vaso-occlusion and therefore of limited value (Lonergan et al, 2001).(Lonergan et al, 2001).

Lucent areas are not seen until much later in the natural history Lucent areas are not seen until much later in the natural history of the infection (Fig 1).of the infection (Fig 1).

Ultrasonography shows the extraosseous pathology in acute Ultrasonography shows the extraosseous pathology in acute osteomyelitis and may show periosteal elevation (William et al, osteomyelitis and may show periosteal elevation (William et al, 2000).2000).

It has also the advantage of being rapid, non-invasive and fairly It has also the advantage of being rapid, non-invasive and fairly simple to target to the area(s) of maximum pain (Sidhu & Rich, simple to target to the area(s) of maximum pain (Sidhu & Rich, 19991999

radioisotope bone scanningradioisotope bone scanning MRIMRI

despite the progress made in the despite the progress made in the development and use of imaging development and use of imaging techniques, a definitive diagnosis of techniques, a definitive diagnosis of osteomyelitis in sickle cell disease still osteomyelitis in sickle cell disease still relies more upon clinical assessment relies more upon clinical assessment together with positive cultures from blood together with positive cultures from blood or bone obtained by aspiration or biopsy, or bone obtained by aspiration or biopsy, than upon any single imaging modality.than upon any single imaging modality.

Treatment of osteomyelitis Treatment of osteomyelitis in sickle cell diseasein sickle cell disease

The choice of antibiotics is generally dictated by the The choice of antibiotics is generally dictated by the microorganism detected. microorganism detected.

Our first line treatment for confirmed or suspected osteomyelitis is Our first line treatment for confirmed or suspected osteomyelitis is a third line cephalosporin such as ceftriaxone, in order to make a third line cephalosporin such as ceftriaxone, in order to make sure Salmonellasure Salmonella

infections are covered.infections are covered. Ciprofloxacin is a useful alternative for older children with Ciprofloxacin is a useful alternative for older children with

Salmonella osteomyelitis, having the advantage of excellent oral Salmonella osteomyelitis, having the advantage of excellent oral bioavailability.bioavailability.

In adults, other species such as Staphylococcus, should also be In adults, other species such as Staphylococcus, should also be covered bycovered by

empirical antibiotic therapy (Sadat-Ali, 1998). empirical antibiotic therapy (Sadat-Ali, 1998).

Treatment of confirmed cases should continue for at least 6 weeks.Treatment of confirmed cases should continue for at least 6 weeks. When there is radiological evidence of accumulation of fluid at the When there is radiological evidence of accumulation of fluid at the

site of infection, drainage is recommended (Sadat-Ali, 1998). site of infection, drainage is recommended (Sadat-Ali, 1998).

Septic arthritisSeptic arthritis

Generally caused by the same organisms Generally caused by the same organisms as osteomyelitis (Ebong, 1987). as osteomyelitis (Ebong, 1987).

It rarely develops in isolationIt rarely develops in isolation Early diagnosis to prevent irreversible jointEarly diagnosis to prevent irreversible joint

damage is essential but usually not damage is essential but usually not problematic because of theproblematic because of the

ease with which diagnostic synovial fluid can ease with which diagnostic synovial fluid can be obtained.be obtained.

Other acute bone problems Other acute bone problems in sickle cell diseasein sickle cell disease

acute chest syndrome, acute chest syndrome, stress fractures (Bahebeck et al, 2002), stress fractures (Bahebeck et al, 2002), vertebral collapse vertebral collapse (Emodi & Okoye, 2001)(Emodi & Okoye, 2001) orbital compression syndrome orbital compression syndrome because of orbital bone because of orbital bone

infarction, which may present with infarction, which may present with acute periorbital acute periorbital swelling (Ganesh et al, 2001; Naran & swelling (Ganesh et al, 2001; Naran & Fontana, 2001). Fontana, 2001).

Dental problems. Dental problems. • dental caries (Laurence et al, 2002), dental caries (Laurence et al, 2002), • pulpal necrosis (O’Rourke & Hawley, 1998; Demirbas et al, pulpal necrosis (O’Rourke & Hawley, 1998; Demirbas et al,

2004; Kavadia-2004; Kavadia-

Tsatala et al, 2004) Tsatala et al, 2004) • Mandibular osteomyelitis Mandibular osteomyelitis (Adekeye & Cornah, 1985; Olaitan (Adekeye & Cornah, 1985; Olaitan

et al, 1997).et al, 1997).

Chronic bone problems in Chronic bone problems in sickle cell diseasesickle cell disease

Avascular necrosisAvascular necrosis

vaso-occlusion results in the infarction of the articular surfaces vaso-occlusion results in the infarction of the articular surfaces and heads of the long bones.and heads of the long bones.

The true prevalence >difficult to judgeThe true prevalence >difficult to judge

by using MRI, Ware et al (1991) found osteonecrosis in the by using MRI, Ware et al (1991) found osteonecrosis in the epiphyses of almost 41% of adults with sickle cell disease. epiphyses of almost 41% of adults with sickle cell disease.

Adekile et al (2001), also using MRI, found a slightly lower Adekile et al (2001), also using MRI, found a slightly lower prevalence in children (27%). prevalence in children (27%).

These studies both showed a much higher frequency of These studies both showed a much higher frequency of osteonecrosis than previously reported in studies based on osteonecrosis than previously reported in studies based on plain X-rays.plain X-rays.

The pathophysiology of osteonecrosis in sickle The pathophysiology of osteonecrosis in sickle cell diseasecell disease

seems to differ from osteonecrosis because of other seems to differ from osteonecrosis because of other aetiologies.aetiologies.

When MRI is used to quantify lesions in AVN of the When MRI is used to quantify lesions in AVN of the femoralfemoral

head, the lesions seen in sickle cell disease are head, the lesions seen in sickle cell disease are larger than thoselarger than those

seen in osteonecrosis because of other aetiologies seen in osteonecrosis because of other aetiologies (Malizos(Malizos

et al, 2001). et al, 2001).

The most common sitesThe most common sites femoral heads >> head of the humerus, knee and femoral heads >> head of the humerus, knee and

small joints of the hands and feet (Jean-Baptiste & small joints of the hands and feet (Jean-Baptiste & De Ceulaer, 2000; Lonergan et al, 2001).De Ceulaer, 2000; Lonergan et al, 2001).

It is common to have multiple joints affected: It is common to have multiple joints affected: >50% of patients with an affected hip have >50% of patients with an affected hip have

bilateral disease and bilateral disease and 74% of those with an affected shoulder will also 74% of those with an affected shoulder will also

have AVN of the femoral head (Milner et al, 1991; have AVN of the femoral head (Milner et al, 1991; Milner et al, 1993).Milner et al, 1993).

Symptoms :painful, limited motion of the affected joint, Symptoms :painful, limited motion of the affected joint, occasionally with pain at rest.occasionally with pain at rest.

Advanced disease plain radiographs, (Lonergan et al, 2001)Advanced disease plain radiographs, (Lonergan et al, 2001)• mottled attenuation of the epiphysis,mottled attenuation of the epiphysis,• subchondral lucent areassubchondral lucent areas• flattening/collapse of the articular surfacesflattening/collapse of the articular surfaces• narrowing of the joint spacenarrowing of the joint space• articular sclerosisarticular sclerosis• osteophyte formationosteophyte formation

Untreated, 87% of affected femoral heads willUntreated, 87% of affected femoral heads will

collapse within 5 years of diagnosis (Hernigou et al, 2003).collapse within 5 years of diagnosis (Hernigou et al, 2003).

treatment options treatment options difficult to assess as no controlled trials comparing difficult to assess as no controlled trials comparing

the different approaches are published. the different approaches are published. One of the most effective methods of preventing One of the most effective methods of preventing

progression of joint damage is bed rest, in order to progression of joint damage is bed rest, in order to avoid weight bearing (Hernigou et al, 2003), avoid weight bearing (Hernigou et al, 2003), however, this has such drastic implications for however, this has such drastic implications for patients’ lives that it is usually an unacceptable patients’ lives that it is usually an unacceptable option. option.

In addition, the long-term symptomatic treatment is In addition, the long-term symptomatic treatment is ineffective and the majority of joints require surgery ineffective and the majority of joints require surgery for pain relief and functional improvement. for pain relief and functional improvement.

Early disease Early disease may improve with coring and osteotomy may improve with coring and osteotomy (Styles & Vichinsky, 1996); however, failure rates in some (Styles & Vichinsky, 1996); however, failure rates in some studies are as high as 50% at 5 years (Bishop et al, 1988; studies are as high as 50% at 5 years (Bishop et al, 1988; Clarke et al, 1989; Milner et al, 1991) and a randomizedClarke et al, 1989; Milner et al, 1991) and a randomized

controlled trial is currently in progress to determine whether controlled trial is currently in progress to determine whether decompression coring procedures can prevent progression decompression coring procedures can prevent progression ofof

AVN (Claster & Vichinsky, 2003).AVN (Claster & Vichinsky, 2003). Late disease Late disease requires joint replacement. Such patients requires joint replacement. Such patients

must be cared for in specializedmust be cared for in specialized

centres with expertise in sickle cell disease as they have a centres with expertise in sickle cell disease as they have a very high incidence of perioperative complications very high incidence of perioperative complications (compared with general orthopaedic patients), including (compared with general orthopaedic patients), including excessive blood loss, acute chest syndrome, infection and excessive blood loss, acute chest syndrome, infection and failure of prostheses (Vichinsky et al, 1999).failure of prostheses (Vichinsky et al, 1999).

Osteopenia and Osteopenia and osteoporosisosteoporosis

overall reduction in bone mineral density, overall reduction in bone mineral density, attributed to marrow hyperplasia attributed to marrow hyperplasia (Brinker et al, (Brinker et al, 1998; Soliman et al, 1998; VanderJagt 1998; Soliman et al, 1998; VanderJagt et al, 2002; et al, 2002; Nelson et al, 2003). Nelson et al, 2003).

In particular, vertebral osteoporosis is common in In particular, vertebral osteoporosis is common in patients with sickle cell disease (Brinker et al, patients with sickle cell disease (Brinker et al, 19981998). ).

Impaired GrowthImpaired Growth Marrow hyperplasia (Claster & Vichinsky, 2003).Marrow hyperplasia (Claster & Vichinsky, 2003).

can cause ischaemia of the central portion of the vertebral can cause ischaemia of the central portion of the vertebral growth plate, leading to disturbance of vertebral growth and growth plate, leading to disturbance of vertebral growth and resulting in the characteristic ‘H’ shaped vertebrae because of resulting in the characteristic ‘H’ shaped vertebrae because of squared-off depression of the vertebral end plates (Reynolds,squared-off depression of the vertebral end plates (Reynolds,

). In addition to marrow hyperplasia, local anoxic events may ). In addition to marrow hyperplasia, local anoxic events may lead to premature closure of epiphyses and impaired or even lead to premature closure of epiphyses and impaired or even asymmetrical growth of the long bones of the limbs (Collett-asymmetrical growth of the long bones of the limbs (Collett-Solberg et al, 2002). Solberg et al, 2002).

Several studies have shown that children with sickle cell Several studies have shown that children with sickle cell disease have lower levels of vitamins A, B6 and D than their disease have lower levels of vitamins A, B6 and D than their ethnically matched peersethnically matched peers

Preventive Care:Preventive Care:

Daily Penicillin VK 125mg BID from Daily Penicillin VK 125mg BID from time of diagnosis (ideally<3mos) time of diagnosis (ideally<3mos) through 5 years of age (increase through 5 years of age (increase dose to 250mg BID at age 3yrs.)dose to 250mg BID at age 3yrs.)

May use erythromycin in penicillin May use erythromycin in penicillin allergic patientsallergic patients

Folic Acid 1mg daily started by 1y/oFolic Acid 1mg daily started by 1y/o Pneumococcal Vaccine (if available) Pneumococcal Vaccine (if available) All standard vaccinesAll standard vaccines

Preventive Care:Preventive Care:Stroke Prevention Trial in SCD (STOP):Stroke Prevention Trial in SCD (STOP): A two year trial of children 2-16y/o screened with transcranial A two year trial of children 2-16y/o screened with transcranial

Doppler ultrasonography and found to be high risk (flow Doppler ultrasonography and found to be high risk (flow velocity>200cm/sec)velocity>200cm/sec)

The children then randomly assigned to receive either The children then randomly assigned to receive either standard care or prophylactic transfusions to keep their HbS standard care or prophylactic transfusions to keep their HbS concentrations<30%concentrations<30%

In the group that received prophylactic transfusions, 2% had In the group that received prophylactic transfusions, 2% had strokes, compared with 16% in the control group.strokes, compared with 16% in the control group.

Therefore, current recommendations are to screen all Therefore, current recommendations are to screen all children >2y/o with transcranial doppler ultrasound and offer children >2y/o with transcranial doppler ultrasound and offer prophylactic transfusion to children with a flow prophylactic transfusion to children with a flow velocity>200cm/sec (high risk of stroke)velocity>200cm/sec (high risk of stroke)

Adams RJ, et al. Prevention of a first stroke by transfusions in children with Adams RJ, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. NEJM 1998;339:5-11ultrasonography. NEJM 1998;339:5-11

Definitive Treatment:Definitive Treatment: Hydroxyurea therapy Hydroxyurea therapy

• Indicated for children >5y/o who have severe complications of SCD

• Effective because increases HbF, decreases leukocytes, platelets and reticulocytes

• CBC must be monitored regularly when on therapy for leukopenia

Definitive Treatment: Definitive Treatment: Bone Marrow TransplantBone Marrow Transplant

Definitive cure for SCDDefinitive cure for SCD Only 14% of SCD patients have a Only 14% of SCD patients have a

human-leukocyte antigen matched human-leukocyte antigen matched donordonor

Associated with a peri-transplant Associated with a peri-transplant morbidity of ~10%morbidity of ~10%