Neurologic Deficit

Fig. 7-6. The investigations and treatment of neurologic deficit in sickle cell disease. (Modified from Davies SC, Wonke B. The management of hemoglobinopathies. In: Hann IM, Gibson BES, guest editors. Bailliere's Clinical Hematology. London: Bailliere Tindall, 1991;361.)

• Transcranial Doppler (TCD) measurement: TCD measurements record the highest time-averaged mean blood flow velocity in 2-mm increments in the middle cerebral artery, the distal internal carotid artery, the anterior or posterior cerebral arteries, and the basilar artery. The results are categorized as normal (velocity <170 cm/sec); conditional (170-200 cm/sec); and abnormal (>200 cm/sec). It is a noninvasive assessment of brain blood flow identifying children with SCD at high risk for stroke and "asymptomatic" brain disease. TCD can be used as a screening tool in children as young as 2 years of age and should be performed yearly. If the results are conditional (170-200 cm/sec), then the patient should have an examination every 2 months. Patients with abnormal velocities (>200 cm/sec) need to have repeat TCD to ensure that they do not progress to abnormal within 2-8 weeks. In patients with an abnormal TCD, a chronic transfusion regime reduces the risk of stroke by >90%.

Treatment

• Exchange transfusion: This limits the amount of acute sickling in poorly perfused areas of the brain. Patients usually show marked improvement in motor function. After initial exchange, a maintenance exchange transfusion program should be carried out (for about 4 years). A regular program designed to keep HbS less than 20% lowers the recurrence rate of stroke to less than 10%.

• Fetal hemoglobin stimulating agents (e.g., hydroxyurea): These may prevent further stroke.

• Nitric oxide (NO): This is a potent vasodilator. Inhaled NO in SCD patients with acute chest syndrome produces a dramatic improvement in oxygenation.

• Stem cell transplantation.

Cardiovascular system

Abnormal cardiac findings are present in most patients and are primarily a result of chronic anemia and the compensatory increased cardiac output.

1. Cardiomegaly: Found in most patients. Left ventricular hypertrophy occurs in about 50% of patients. Decreased left ventricular contractility occurs in one third of SCD patients.

2. Myocardial dysfunction: Secondary to fibrosis and hemosiderosis.

3. Heart sounds: Moderate intensity murmur, blowing in character with wide splitting of second heart sound.

4. Electrocardiogram (ECG) abnormalities: Sinus tachycardia; left ventricular hypertrophy; left axis deviation; inverted T waves; sinus arrhythmia.

5. Radiologic findings: Cardiac enlargement involving all chambers; prominent pulmonary artery segment.

6. Echocardiographic findings: Both left and right ventricular dilatation; increased stroke volume; abnormal septal motion.

7. Pulmonary hypertension and cor pulmonale: Usually occurs in older patients and may be related to previous repeated chest syndromes.

Lungs

1. Reduced PaO2.

2. Reduced PaO2 saturation.

3. Increased pulmonary shunting.

4. Acute chest syndrome (ACS): This is the most common cause of death and the second most common cause of hospitalization. Distinguishing ACS from infectious and noninfectious causes is often difficult (see Table 7-11). The incidence is about 24 events per 100 patients in young children. The incidence in other sickle cell genotypes is lower (SS > Sp0-thalassemia > SC > Sp+-thalassemia), and concomitant a-thalassemia does not appear to affect ACS rates. Fetal hemoglobin (HbF) levels are inversely proportional to the frequency of ACS, and an increase in HbF (10-15%) decreases the incidence of ACS by about 50% in all age groups. This may also explain why patients with the homozygous CAR haplotype have ACS more commonly and severely than do those with either homozygous Benin or Senegal haplotypes.

The incidence of ACS has been shown to be inversely proportional to the degree of anemia and directly proportional to the white blood cell count; increased levels of cytokines and/or white cell adhesion to the endothelium may play a role in this. ACS has a striking association with vaso-occlusive crisis (VOC). About 30% of all ACS events are preceded or accompanied by a pain crisis. About 50% of ACS events are associated with infections. Streptococcus pneumoniae is the most common causative organism in ACS in young children. Mycoplasma and Chlamydia are two common organisms that may be related to severe ACS. Parvovirus infection can also result in ACS not only by direct infection, but also by causing bone marrow necrosis with subsequent pulmonary fat embolism (PFE) syndrome. The frequency of PFE in patients with SCD is not uncommon (15%). It usually follows a VOC. Pulmonary infarction is usually due to obstruction of small or medium-sized vessels and is possibly secondary to occlusion from adhesion of sickled RBCs to endothelial cells.

The treatment for ACS is:

Intravenous (IV) antibiotics.

Hydration with alkalinization (hydration: IV plus oral fluids at one time maintenance are sufficient). Overhydration may result in pulmonary edema because patients with ACS are particularly susceptible. Pain control: nonsteroidal agents (narcotic sparing effect) and narcotics. Careful monitoring is required to reduce the risk of hypoventilation. Adrenergic bronchodilators (to improve peak expiratory flow rates). Oxygen therapy (in hypoxemic patients).

Exchange transfusions (in severe hypoxemia: PaO2 <70 mmHg in room air);

prophylactic transfusions (in recurrent ACS). Hydroxyurea (in recurrent ACS). Stem cell transplantation (in recurrent ACS).

5. Pulmonary fibrosis—chronic lung disease: Early identification of progressive lung disease using pulmonary function testing is imperative. Aggressive treatment has little benefit in end-stage lung disease and this should be avoided by prophylactic transfusions.

Kidney

1. Increased renal flow.

2. Increased glomerular filtration rate.

3. Enlargement of kidneys; distortion of collecting system on intravenous pyelogram.

4. Hyposthenuria (urine concentration defect): Hyposthenuria is the first manifestation of sickle cell-induced obliteration of the vasa recta of the renal medulla. Edema in the medullary vasculature is followed by focal scarring, interstitial fibrosis, and destruction of the countercurrent mechanism. Hyposthenuria results in a concentration capacity of more than 400-450 mOsm/kg and an obligatory urinary output as high as 2000 mL/m2/day, causing the patient to be particularly susceptible to dehydration. The increased urine output is associated with nocturia, often manifesting as enuresis. Treatment of enuresis includes imipramine (adolescents) at a starting dose 25 mg/day, increasing to a maxi mum of 100 mg/day; intranasal 1-deamino-8-D-arginine vasopressin (DDAVP) (0.01%): 10-40 |g at bedtime.

5. Hematuria: Papillary necrosis is usually the underlying anatomic defect. Treatment of papillary necrosis is aggressive IV hydration. Frank hematuria usually resolves, although bleeding can be prolonged.

6. Renal tubular acidification defect.

7. Increased urinary sodium loss (may result in hyponatremia).

8. Hyporeninemic hypoaldosteronism and impaired potassium excretion are results of renal vasodilating prostaglandin increase in patients with SCD.

9. Proteinuria: Persistent increasing proteinuria is an indication of glomerular insufficiency, perihilar focal segmental sclerosis, and renal failure. Intraglomerular hypertension with sustained elevations of pressure and flow is the prime etiology of the hemodynamic changes and subsequent proteinuria. If proteinuria persists for more than 4-8 weeks, angiotensin-converting enzyme (ACE) inhibitors (i.e., enalapril) are recommended.

10. Nephrotic syndrome: A 24-hour urine protein of more than 2 g/day, edema, hypoalbuminemia, and hyperlipidemia may indicate progressive renal insufficiency. The efficacy of steroid therapy in the management of nephrotic syndrome in SCD is not clear. Carefully monitored use of diuretics is indicated to control edema.

11. Chronic renal failure—uremia. Renal failure can be managed with peritoneal dialysis, hemodialysis, and transplantation.

Liver and biliary system

1. Chronic hepatomegaly.

2. Liver function tests: Increased serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT).

3. Cholelithiasis (incidence):

All patients with SCD should have periodic routine sonographic examinations of the gallbladder. Even if patients have asymptomatic cholelithiasis, laparoscopic cholecystectomy is recommended. Children tolerate elective cholecystectomy well with little morbidity if prepared properly for surgery. Operating during the acute phase, however, carries a significant risk of complications. Persistent Salmonella bacteremia is also an indication for elective cholecystectomy in a patient with gallstones.

4. Transfusion-related hepatitis.

5. Intrahepatic crisis: Intrahepatic sickling can result in massive hyperbilirubine-mia, elevated liver enzyme values, and a painful syndrome mimicking acute cholecystitis or viral hepatitis. Fulminant hepatic failure, massive cholestasis, hepatic encephalopathy, and shock are rare complications and require exchange transfusion.

6. Hepatic necrosis, portal fibrosis, regenerative nodules, and cirrhosis are common postmortem findings that may be a consequence of recurrent vascular obstruction and repair.

Bones

Skeletal changes in SCD are common because of expansion of the marrow cavity, bone infarcts, or both.

1. Dactylitis: First few years of life. Dactylitis usually is not seen in older children because as the child ages, the sites of hematopoiesis move from a peripheral location such as the fingers and toes to more central locations such as the arms, legs, ribs, and sternum. Infants with dactylitis often tolerate these episodes very well and may require only acetaminophen or nonsteroidal inflammatory agents (NSAIDs).

2. Avascular necrosis (AVN): The most common cause of AVN of the femoral head is sickle cell disease. The incidence is much higher with coexistent a-thalassemia in patients who have frequent painful crises and in those with the highest hematocrits. The pathophysiology is sludging in marrow sinusoids, marrow necrosis, healing with increased intramedullary pressure, bone resorption, and eventually collapse. About 50% of patients are asymptomatic. Symptomatic patients have significant chronic pain and limited joint mobility. The diagnosis is made radiographically and shows subepiphyseal lucency and widened joint space and flattening or fragmentation and scarring of the epiph-ysis. On MRI, avascular necrosis of femoral head can be detected before deformities are apparent on radiograph.

Treatment: Therapy for AVN is largely supportive, with bed rest, NSAIDs, and limitation of movement during the acute painful episode. Transfusion therapy does not seem to delay progression of AVN. Core decompression of the affected hip has been reported to reduce pain and stop progression of the disease. In this procedure, avascularized bone is removed to decompress the area with the potential for subsequent new bone formation. This procedure seems to be beneficial only in the early stages of AVN and before loss of the integrity of the femoral head. AVN of the hip may have its onset in childhood, so thorough musculoskeletal examination with concentration on the hips should be performed at least yearly in children with SCD. This ensures that AVN is detected early when it is in its most treatable form. Total hip replacement may be the only option for severely compromised patients; 30% of replaced hips require surgical revision within 4.5 years, and more than 60% of patients continue to have pain and limited mobility postoperatively. Avascular necrosis of the humeral head is uncommon. Patients are less symptomatic, and arthroplasty is exceedingly rare.

3. Widening of medullary cavity and cortical thinning: Hair-on-end appearance of skull on radiograph.

4. Fish-mouth vertebra sign on radiograph.

Eyes

1. Retinopathy: Sickle retinopathy is common in all forms of SCD, but particularly in those patients with hemoglobin SC disease.

Nonproliferative retinopathy: Occlusion of small blood vessels of the eye and retinal neovascularization are very common (30% as young as 5-7 years of age) and are usually not associated with defects in visual acuity.

Treatment: Hydroxyurea therapy may slow or prevent further vaso-occlu-sion. This in turn may have a favorable effect by reducing subsequent neovas-cularization.

Proliferative retinopathy: Occlusion of small blood vessels in the peripheral retina may be followed by enlargement of existing capillaries or development of new vessels. Clusters of neovascular tissue "sea fans" grow into vitreous and along the surface of the retina. Sea fans may cause vitreous hemorrhage, which results in transient or prolonged loss of vision. Small hemorrhages resorb, but repeated leaks cause formation of fibrous strands. Shrinkage of these strands can cause retinal detachment.

Treatment: Photocoagulation may be effective in retinal detachment.

With proper screening and new methods such as laser surgery most of the complications of retinopathy can be avoided. Annual ophthalmologic examina tions including inspection of the retina are indicated for children older than 5 years of age.

2. Angioid streaks: These are pigmented striae in the fundus caused by abnormalities in Baruch's membrane due to iron or calcium deposits or both. They usually produce no problems for the patient, but occasionally they can lead to neovascularization that can bleed into the macula and decrease vision.

3. Hyphema: Blood in the anterior chamber (hyphema) rarely occurs secondary to sickling in the aqueous humor, because of its low pH and PaO2. Anterior chamber paracentesis may be performed if pressure is increased.

4. Conjunctivae: Comma-shaped blood vessels, seemingly disconnected from other vasculature, can be seen in the bulbar conjunctiva of patients with SCD and variants (SS > SC > Sp-thalassemia). These produce no clinical disability. Their frequency may be related to the number of irreversibly sickled cells in the blood. This abnormality can be identified by using the +40 lens of an ophthalmoscope.

Ears

Twelve percent of patients have high-frequency sensorineural hearing loss. The pathophysiology of the auditory apparatus appears to be sickling in the cochlear vas-culature with destruction of hair cells.

Adenotonsillar hypertrophy

Adenotonsillar hypertrophy giving rise to upper airway obstruction can become a problem from the age of 18 months. The marked hypertrophy is compensation for the loss of lymphoid tissue in the spleen. It occurs in at least 18% of patients. In severe cases, this can cause hypoxemia at night with consequent sickling. Early ton-sillectomy may be indicated in these patients.

Skin

Cutaneous ulcers of the legs occur over the external or internal malleoli. Leg ulcers usually do not occur in childhood. Ulceration may result from increased venous pressure in the legs caused by the expanded blood volume in the hypertrophied bone marrow. The incidence is higher in patients with low steady-state hemoglobin values or low fetal hemoglobin production.

Treatment

Rest; elevation of the leg

Protection of the ulcer by the application of a soft sponge-rubber doughnut Debridement and scrupulous hygiene

Iodosorb wound dressing to induce localized proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-6 (IL-6) Low-pressure elastic bandage and above-the-knee elastic stockings to improve venous circulation Exchange transfusion therapy if ulcers persist despite optimal care Antistaphylococcal antibiotic treatment if skin colonized with Staphylococcus aureus Oral administration of zinc sulfate (220 mg three times a day) to promote healing of leg ulcers Split-thickness skin grafts.

Genitourinary-priapism

Priapism is marked by a painful failure of detumescence of the penis. Mean age of priapism in patients with SCD is about 12 years. Priapism usually occurs at early morning hours, probably related to sleep acidosis. The normal slow blood flow pattern in the penis is similar to the blood flow in the spleen and renal medulla. Failure of detumes-cence is due to venous outflow obstruction or to prolonged smooth muscle relaxation, either singly or in combination. Postpubertal patients tend to have prolonged and recurrent episodes. With repeated episodes, the cavernosa is fibrosed and hyalinized and blood no longer flows. Treatment decisions must be made and implemented promptly within 12 hours, because the time the patient has been in the priapismic state correlates with the presence of irreversible infarction and future dysfunction.

A history should be obtained as to the precise timing of the onset and the state of recurrence. If the shaft of the penis is hard and painful in the area of the cavernosa but the glans is soft and the patient is able to urinate, there is relatively little involvement of the spongiosa. Urinary obstruction is the clinical hallmark, along with engorgement of the glans, of secondary involvement of the corpora spongiosa. An MRI scan of the penis can determine if the obstruction is confined to the corpora cavernosa (bicorporal) or if there is involvement of the spongiosa (tricorporal). Involvement of the spongiosa is indicative of cavernosa infarction.

Treatment: Hydration

Partial exchange transfusion (most effective within 24 hours from the onset)

Analgesia (i.e., morphine sulfate)

Sedation (i.e., hydroxyzine pamoate [Vistaril])

Oxygen

Sitz bath or hot compresses. Surgical procedures for acute episodes:

Corporal aspiration and irrigation (repeat, if necessary) Cavernoglans shunt Cavernosaphenous shunt.

Surgical procedures for impotence:

Insertion of penile prosthesis.

Prevention of priapism. For recurrent priapism, prophylactic exchange transfusion is very effective. In children (Tanner 1, 2, 3) and adolescents (Tanner 4, 5) who still retain penile function after a major episode of priapism, treatment with hydroxyurea might be considered. Treatment for at least 2 years might allow for healing and should not interfere with normal sexual activity.

Growth and Development

1. Birth weight is normal. However, by 2-6 years of age, the height and weight are significantly delayed. The weight is more affected than the height, and patients with sickle cell anemia and Sp0-thalassemia experience more delay in growth than patients with HbSC disease and Sp+-thalassemia. In general, by the end of adolescence, patients with sickle cell disease have caught up with controls in height but not weight. The poor weight gain is likely to represent increased caloric requirements in anemic patients with increased bone marrow activity and cardiovascular compensation. Zinc deficiency may be a cause of poor growth. In these patients, zinc supplementation (dose of 220 mg three times a day) at about 10 years of age should be administered. Growth hormone levels and growth hormone stimulation studies appear to be normal in children who have impaired growth.

2. Delayed sexual maturation: Tanner 5 is not achieved until the median ages of 17.3 and 17.6 years for girls and boys, respectively. In males, decreased fertility with abnormal sperm motility, morphology and numbers is prominent. Zinc sulfate 220 mg three times a day may be effective for sexual maturity in these patients; females are more responsive than males.

Functional Hyposplenism

1. By 6 months of age, significant splenomegaly is apparent and persists during childhood, after which the spleen undergoes progressive fibrosis (autosplenec-tomy).

2. Functional reduction of splenic activity precedes autosplenectomy in early life. This is the consequence of altered intrasplenic circulation caused by intrasplenic sickling. It can be temporarily reversed by transfusion of normal red cells. Children with functional hyposplenia are 300-600 times more likely to develop overwhelming pneumococcal and Haemophilus influenzae sepsis and meningitis than are normal children; other organisms involved are gramnegative enteric organisms and Salmonella. The period of greatest risk of death from severe infection occurs during the first 5 years of life.

3. Functional hyposplenism may be demonstrated by the following:

a. Presence of Howell-Jolly bodies on blood smear b. 99mTc-gelatin sulfur colloid spleen scan: no uptake of the radioactive colloid by enlarged spleen c. Twenty percent (range 12-40%) pitted red cells on interference phase-contrast microscopy (Nomarski optics).

Hemostatic Changes

Almost all of the components of hemostasis are altered, resulting in a hypercoagula-ble state:

• Increased platelet activation and secretion: Increased sickle red blood cell (SRBC) adhesion to endothelium

• Increased von Willebrand factor (vWF): Abnormal adherence of SRBCs to endothelium

• Increased activated factor VII (factor VIIa) and factor X (factor Xa): Increased thrombin formation

• Increased factor VIII and fibrinogen

• Decreased protein C and protein S: Increased risk of thrombosis.

Hemostatic changes may explain some of the clinical manifestations of SCD. It is still difficult to prove that these changes are indeed involved in the pathophysiology of vaso-occlusive crisis in SCD.

Therapeutic Approaches to Altering Sickle Red Blood Cell/Endothelial Cell Interaction

• Hydroxyurea: May result in reduction of adhesive receptors on SRBCs

• Nitric oxide: Inhibits platelet activation, aggregation, and secretion; inhibits SRBC adhesion to the endothelium; reduces HbS polymerization

• Arginine: When given orally increases levels of exhaled and plasma nitric oxide (transient effect)

• Anticoagulants: (1) Minidose heparin (SC): reduces in-hospital stay; (2) low-intensity coumadin: reduces thrombin generation; and (3) low-molecular-weight heparin (LMWH): has specific activity against factors VIIa and Xa

• Antiplatelet agents: (1) Acetylsalicylic acid (ASA): no significant effect on pain crises; and (2) ASA plus dipyridamole: modest benefit.

Diagnosis

1. In utero: Sickle cell disease can be diagnosed accurately in utero by restriction endonuclease analysis of DNA prepared from fetal fibroblasts (obtained by amniocentesis). Chorionic villus biopsy offers an alternative to amniocentesis. With the advent of PCR amplification of specific DNA sequences, sufficient DNA can be obtained from a very small number of fetal cells, thereby eliminating the necessity of culturing fetal fibroblasts from amniotic fluid. These techniques should be employed before 10 weeks' gestation.

2. During newborn period: The diagnosis of sickle cell disease can be established by electrophoresis using:

a. High-performance liquid chromatography (most commonly used)

b. Citrate agar with a pH of 6.2, a system that provides distinct separation of hemoglobins S, A, and F

c. Acid and alkaline electrophoresis d. PCR amplification of DNA.

These tests can be performed on cord blood or on a dried blood specimen blotted on filter paper.

3. In older children: Table 7-12 lists the diagnosis and differential diagnosis of various sickle cell syndromes.

Prognosis

The survival time is unpredictable and is related in part to the severity of the disease and its complications (with active management, 85% survive to 20 years of age).

Causes of Death

1. Infection (peak incidence between 1 and 3 years of age)

a. Sepsis b. Meningitis

Infection is the most common cause of death and is due to splenic dysfunction. The risk of acquiring sepsis or meningitis is greater than 15% in children younger than 5 years, with a mortality rate of 30%.

2. Organ failure a. Heart b. Liver c. Kidney.

3. Thrombosis of vessels supplying vital organs a. Lungs: most common cause in adults b. Brain: most common cause in adolescents.

Ameliorating Factors

1. Persistent production of HbF into adolescence and adulthood a. A level of more than 10% HbF offers protection against stroke and avascular necrosis.

b. A level of more than 20% HbF offers protection from episodic manifestations such as painful crises or pulmonary complications.

2. Co-inheritance of a-thalassemia, which reduces the levels of hemolysis (higher hemoglobin and lower reticulocyte count)

3. Environmental factors (i.e., socioeconomic status).

Table 7-12. Differential Diagnosis in Sickle Cell Syndromes

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