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Orthotopic liver transplantation is the treatment of choice for stage 3 and 4 encephalopathy, assuming the patient is a candidate. SUGGESTED READINGS Bade AS, Jones EA, Skolnick P The pathogenesis and treatment of hepatic encephalopathy: evidence for the involvement of benzodiazepine receptor ligands. Pharmacol Rev 43:27, 1991 Butterworth RF: Pathophysiology of hepatic encephalopathy:the ammonia hypothesis revisited. p. 9. In Bengtsson F, Jeppsson B, Almdal T, Vilstrup H (eds): Progress in Hepatic Encephalopathy and Metabolic Nitrogen Exchange. CRC Press, Boca Raton, FL, 1991 Cole M, Mullen KD: Hepatic coma and portal-systemic encephalopathy. p. 326. In Johnson RT, Griffin JW (eds): Current Therapy in Neurologic Disease. 4th Ed. BC Decker, St Louis, 1993

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Conn HO: Hepatic encephalopathy. p. 69. In Schiff L, Schiff ER (eds): Diseases of the Liver. Vol. 2. JB Lippincott, Philadelphia, 1993 Rothstein JD,Garland W, Puia G et al: Purification and characterization of naturally occurring benzodiazepine receptor ligands. J Neurochem 58:2102, 1992 Rothstein JD, Guidotti A Endozepines: non-benzodiazepine endogenous allosteric modulators of GABA, receptors. p. 115. In Izquierdo I, Medina J (eds): Naturally Occurring Benzodiazepines: Structure, Distribution and Function. Ellis Horword, London, 1993 Victor M, Rothstein JD: Neurologic manifestations of hepatic disease. p. 1442. In Asbury AK, McKhann GM, McDonald WI (eds): Diseases of the Nervous System. WB Saunders, Philadelphia, 1992

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196 Neurologic Complications of Sickle Cell Disease Robert J. Adams Sickle cell diseases and thalassemias are common medical conditions that predispose to a small but important list of neurologic problems. This chapter focuses on the neurologic complications most commonly encountered in these diseases, with emphasis on diagnosis and treatment. These hemoglobinopathies are genetic abnormalities involving the production of hemoglobin. Sickle cell disease (SCD) is any condition in which the production of an abnormal hemoglobin (Hb) causes in vivo distortion of the erythrocyte (sickling), which in turn causes hemolysis and intermittent vascular obstruction. Thalassemias are diseases in which one or both of the a- or P-chains are underproduced, leading to imbalanced globin chain synthesis, abnormal hemoglobin, and subsequent damage to the red blood cell or its precursor. Thalassemias are further characterized as to the degree of underproduction, with a “0”superscript indicating no production and one or two “+” symbols denoting partial production. In SCD the chains are abnormal; in thalassemia they are normal but the hemoglobin tetramer is abnormal. The genes predisposing to these conditions are found primarily but not exclusively among certain ethnic populations. People of African, Saudi Arabian, or Asian descent have a likelihood of carrying genes for SCD and a-thalassemia, and people with lineage from countries bordering the Mediterranean Sea and all parts of Asia have a predisposition to P-thalassemia. However, any of these conditions may be seen in people from any racial background. Patients with SCD or thalassemia usually are

diagnosed through newborn screening or because all the clinically significant hemoglobinopathies produce some degree of anemia that comes to attention before any neurologic symptoms develop. It is rare for a neurologic complication to lead to the diagnosis of hemoglobinopathy. Clinically the most important of these diseases are homozygous SCD (Hb SS or sickle cell anemia), sickle C (Hb SC) disease, and P-thalassemia (also called Cooley’s anemia or thalassemia major), but many abnormal hemoglobin variants have been reported. More than one genetic abnormality may coexist in the same patient (e.g., sickle-thalassemia). Patients with sickle Pothalassemia have a malignant course similar to Hb SS, but sickle P+-thalassemia shows a much milder course and is less likely to have neurologic complications. The bewildering array of molecular aberrations and abnormal hemoglobins, the complex and varying terminologies, and the coexistence of conditions make it difficult for the neurologist to be confident that some of the less common hematologic abnormalities are related to the neurologic illness at hand. The ameliorating effect of fetal hemoglobin, which may be upregulated to levels much higher than normal in the presence of SCD, may partially negate the negative effect of Hb S. It is important to emphasize that whereas many case reports and small series exist in the literature, only a few neurologic syndromes have been firmly associated with the hemoglobinopathies, most of these with homozygous Hb SS. The clinician is cautioned against assuming a causal relationship in such patients without first

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considering alternative and more common explanations for neurologic disease. There has been recent evidence that both environmental and genetic or epigenetic factors in addition to the basic gene defect play a role in the causation of stroke in this disorder, but at present this research has not led to new therapies. ACUTE MANIFESTATIONS Bacterial meningitis and stroke are the most important acute central nervous system emergencies to consider in the Hb SS patient with acute brain dysfunction. Meningitis

It is crucial to consider meningitis, for two reasons: The association of meningitis with Hb SS is less well known than that of stroke, often leading to the erroneous assumption that all brain problems in Hb SS are caused by stroke; and treatment is effective if started early. Most cases are caused by pneumococcus, and diagnosis and treatment with antibiotics and steroids should be undertaken as in any case with suspected or proven bacterial meningitis. This is primarily a problem in young children, many of whom now receive vaccine and prophylactic daily antibiotics. Chronic treatment with 250 mg of penicillin twice per day is common practice for children with Hb SS, which may complicate the interpretation of cerebrospinal fluid findings in cases of suspected meningitis. Hb SS patients are at risk of Salmonella osteomyelitis, and this agent may cause meningitis. Increased risk of Haemophilus influenme and Escherichia coli infections has also been suggested. Bacterial meningitis is associated with at least a 15% incidence of long-term neurologic sequelae including seizures, sensorineural hearing loss, focal neurologic deficits, and hydrocephalus. Release of cytokines, believed to play a causative role in inflammatory injury to brain during the infection, can be

reduced experimentally with steroids. Dexamethasone has been shown to improve outcome in childhood meningitis and should be used at a dosage of 0.15 mg/kg intravenously every 6 hours for 4 days beginning at the start of antibiotic treatment. Cerebral ischemia and hearing loss resulting from bacterial meningitis do not seem to be more common in SCD even though these patients are already at higher risk for such problems because of their hemoglobinopathy. Susceptibility to infection is caused by loss of splenic function and other abnormalities of the immune system. Adults with a history of frequent transfusions before 1985 must be considered at risk for human immunodeficiency virus infection. The initial manifestations, diagnostic tests, and management of the most important acute neurologic complications of Hb SS are shown in Table 196-1. Stroke

Stroke is the most common neurologic complication of Hb SS. The prevalence of symptomatic cerebrovascular disease may reach 10% in the United States, and as many as 15% to 20% of patients may have abnormal neuroimaging suggesting cerebrovascular disease. Unless otherwise specified, this discussion pertains only to symptomatic disease. In general, cerebral infarction tends to occur in children and intracranial hemorrhage in adults, but many exceptions are seen, and all manifestations have been reported in all age groups. Stroke may follow pain crisis, infection, and other systemic illness, but it is unclear whether such prodromes are characteristic or coincidental. Elevated blood levels of cytoadherence molecules may promote vaso-occlusion. Acute worsening of anemia was noted before 5 of 17 first-time strokes in one study, suggesting that sudden lowering of the oxygen-carrying capacity may cause ischemia in the presence of arterial stenosis. Other factors suggested to trigger symptoms include obstructive sleep apnea and

W TABLE196-1. Neurologic Complications of Homozygous Sickle Cell Disease

Syndrome

Symptoms

Neurologic Examination Findings

Diagnosis

Initial Treatment

Meningitis

Headache, lethargy, seizure, coma

Meningismus, stupor, coma

CSF abnormal; CT may

Transient weakness numbness; alteration of behavior

Normal or focal, transient deficits

CT, EEG, and CSF exam

Antibiotics; dexamethasone 0.15 mg/kg every hour for 4 days Transfusion; evaluate large vessels by angiography, TCD

Hemiparesis, hemisensory loss, abnormal speech or vision Headache, hemiparesis

Hemiparesis, aphasia, or other cortical abnormalities Hemiparesis, may have lethargy or coma

Transient ischemia

Cerebral infarction

show cerebral edema normal; MRI or MRA with contrast may show abnormality CT shows decreased attenuation; MRI shows decreased signal CT shows intraparenchyma1 blood

Transfusion; hydration; repeat CT 3-4 days

Check for coagulopathy; treat cerebral edema as needed; angiography when stable CT shows location of Stupor, coma, neck stiffSubarachnoid or Sudden severe headache, Transfuse; close observaness; may have normal blood; MR may show intraventricular vomiting, depression of tion, nimodipine, 60 aneurysm or consciousness exam mg every 4 hours PO; hemorrhage moyamoya intraventricular shunt for acute hydrocephalus; angiography when stable Seizure Tonic-clonic movements, Postictal or normal; may History, EEG, MRI with Treat focal seizures as contrast may show ceimpairment of conhave transient focal TIAs; generalized seirebral infarct zure treatment desciousness weakness Dends on etiolonv Abbreviations: CSF, cerebrospinal fluid; CT,computed tomography; EEC, electroencephalogram;MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; TCD, transcranial Doppler; TI& transient ischemic attack. lntraparenchymal hemorrhage

~

~

Chapter 196 H Neurologic Complications of Sickle Cell Disease

transfusion after prolonged priapism. However, most strokes occur without a recognized prodrome. Cerebral Infarction Cerebral infarction typically presents with the sudden onset of symptoms of acute hemispheric dysfunction, including hemiparesis, altered speech or aphasia, and hemisensory and visual deficits without alteration of consciousness. Seizures, often partial in onset, accompany about 20% of cases. Few are preceded by recognized transient ischemic attacks, although reporting of symptoms may be incomplete because infarction is especially common in young children with SCD. The initial cranial computed tomography (CT) often shows evidence of prior undetected brain lesions. Examination usually shows some degree of hemiparesis, which typically undergoes significant improvement in days to weeks after the ictus. Although motor symptoms improve, patients may show cognitive deficits. Posterior circulation syndromes and isolated cranial palsies caused by central nervous system disease are rare and probably represent neuropathy rather than stroke. Most patients with brain infarction who are studied with cerebral angiography show typical findings: dilated vessels generally, focal areas of stenosis or occlusion in the distal internal carotid artery and proximal middle and anterior cerebral arteries, variable irregularities of more distal vessels, and recruitment of willisian, leptomeningeal, and extracranial-intracranial collateral pathways. Although sickled cells do not pass well through the microcirculation, the simplistic notion that plugging is the cause of stroke is inadequate because both the large arteries and microcirculation are involved. The most important lesions are those at the level of the circle of Willis. Although the cause is not known, the initiating event could be injury to endothelium followed by loss of the thromboresistant properties of the endothelium and either gradual formation of clot or acute blockage of vessels by thrombus. The anemia itself, which is associated with high blood flow rates, may also predispose to vessel wall damage. Once initiated, the lesions are extended over time by endothelial hyperplasia, fibroblasts, fibrin thrombi, and even thrombus, with sickle red cells incorporated into the lesion. Acute thrombus formation causing total occlusion and hemodynamic failure may be the precipitating event, or stroke may be caused by artery-artery embolus. Hemodynamic failure is suggested by pathologic studies and neuroradiologic series showing a high incidence of so-called border zone infarctions between major arterial territories and in subcortical areas. Moyamoya is present in up to 30% of patients who have been studied by angiography. The cervical carotid artery and the vertebrobasilar system show only dilation or narrowing believed to be secondary to intracranial disease. The case shown in Figure 196-1 illustrates many of the typical features. This series is from a young girl who presented with left hemiparesis. Her initial scans showed old unrecognized infarcts, both deep and cortical lesions, and bilateral border zone infarctions. Angiography showed severe bilateral distal internal carotid artery disease with moyamoya formation and evidence of circle of Willis, leptomeningeal, and extracranial-intracranial vessels providing collateral circulation. Other potential causes of cerebral infarction in Hb SS are seldom noted in the literature, but these should be considered, especially in older patients and children without typical CT or angiographic findings. Patients with SCD often have cardiomyop-

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athy, and cardiogenic embolus may be underdiagnosed. The danger is to assume that the stroke is caused by HB SS and fail to consider entities such as endocarditis, drug abuse coagulopathy, antiphospholipid antibodies, arterial dissection, paradoxical embolus, or venous disease. Diagnosis is made from the clinical picture and either CT or magnetic resonance imaging (MRI) evidence of infarction. These techniques allow the acute distinction between hemorrhage and infarction and provide evidence as to the vascular territories involved. Diagnostic testing addresses three questions: What is the cause of the patient’s symptoms? If a stroke is the cause, are the symptoms caused by cerebral infarction or hemorrhage? What is the likelihood of recurrence? Management depends on prompt recognition of the cause of symptoms. The presenting symptoms and signs of four manifestations of cerebrovascular disease are described in Table 196-1, along with the results of diagnostic tests and initial management strategies. A patient presenting with a history of a transient focal neurologic deficit, especially hemiparesis, should be assumed to have had a transient ischemic attack or (less likely) a seizure with postictal weakness. Although cerebral ischemia (transient loss of brain blood flow) is the most likely, initial consideration should also be given to diseases other than stroke. If meningitis is suspected, treatment should be initiated with antibiotics at once and a CT scan performed, followed by a lumbar puncture. The CT scan in the acute evaluation of a patient with neurologic symptoms is the best initial diagnostic test because it can be performed rapidly and requires little cooperation. It is not necessary to use intravenous contrast to rule out most emergency conditions, but diagnostic sensitivity is enhanced by its use for other conditions. Brain tumors may present with transient symptoms but more typically are associated with subacute or chronic symptoms. The CT also helps to distinguish these conditions. Focal seizures should prompt evaluation for stroke risk. The electroencephalogram may help to localize the brain lesion, but imaging of the brain and assessment of the large vessels are necessary to evaluate cerebrovascular risk fully The cause of generalid seizures, especially in adults, may be obvious from the history, and an extensive workup may not be appropriate. Cranial CT or MRI should be done in all patients with suspected stroke to eliminate other lesions and to identify hemorrhages. Cerebral angiography is clearly useful when the diagnosis of cerebrovascular disease is doubtful and chronic transfusion is being considered. This situation arises in young children with extremity symptoms that might represent stroke or painful crisis. In such cases the angiogram is used to decide on transfusion. Angiography is safe in Hb SS if the patient is prepared with hydration and reduction of Hb S to a low level, arbitrarily 30% or less. Transfusion is initiated if the angiogram shows extensive large vessel disease and is withheld in the absence of impressive disease. Whether magnetic resonance angiography or transcranial Doppler can substitute for angiography depends on local experience with these noninvasive techniques. Transcranial Doppler can identify children at risk for stroke before symptoms develop, and a randomized controlled clinical trial showed 90% risk reduction with prophylactic transfusion. If the CT is normal or shows new or old cerebral infarction, the standard treatment of children is hydration with transfusion. Acute treatment of a proven or suspected cerebral infarction consists of immediate partial or complete exchange transfusion and intravenous hydration with isotonic fluids. Although

Neurology in General Medicine W

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Hematology

B

A

C

D

FIG. 196-1. Series from a 12-year-old girl with sickle cell disease who presented with left hemiparesis. She had been under observation because a transcranial Doppler performed 9 months earlier had shown high velocities in the right internal carotid artery consistent with narrowing and an abnormally low left middle cerebral artery velocity, suggesting severe stenosis or occlusion. (A) Axial T2-weighted magnetic resonance imaging (MRI) showing deep and cortical high signal lesions consistent with infarction. The deep border zone lesions (arrows) are particularly characteristic of sickle cell disease. Also typical is the presence of old hyposymptomatic lesions on MRI performed when these patients develop symptoms. (B) Axial proton density MRI showing decreased signal in the right middle cerebral artery distribution and bilateral high-signal areas in the centrum semiovale. (C) Lateral projection of a conventional angiogram during a left common carotid injection. A distal internal carotid artery occlusion and moyamoya (open arrow) are seen. The most distal patent segment of the internal carotid artery (single black arrow) is narrowed in the typical location just beyond the ophthalmic artery. This angiogram also demonstrates enlargement of the posterior communicator on the right with anterograde flow posteriorly. Typically the posterior cerebral artery, which is rarely involved in the sickle cell vasculopathy, will supply collateral flow to the anterior circulation through pericallosal collaterals or leptomeningeal collaterals (not shown) to the middle cerebral artery territory. Also depicted in this case are transdural collaterals from the external carotid circulation (double mows). (0) Anteroposterior projection of the right common carotid artery injection showing distal internal carotid narrowing and apparent occlusion of the anterior cerebral artery (open arrow). Note that the middle cerebral branches are enlarged, another typical feature of sickle cell disease apparent on both angiography and MRl/magnetic resonance angiography, and there is evidence of leptomeningeal collateral flow from the middle to the anterior circulation on this side (solid arrow).

Chapter 196

randomized study of the effects of this therapy on outcome have not been performed, the therapy seems reasonable on theoretical grounds and has become common practice. The optimal transfusion method and target parameters have not been established. In theory, reduction of the Hb S level would be expected to improve blood viscosity and might improve cerebral blood flow in the region of an acute infarct. On this basis rapid rather than slow reduction is preferable because the therapeutic window for the brain is limited to a few hours after the onset of ischemia. Simple transfusions are slower than exchange methods and risk increasing the hernatocrit to levels that markedly increase blood viscosity, further impairing flow. On the other hand, the rate of exchange should not be so rapid as to risk cardiovascular instability, which could decrease brain perfusion. Given these considerations, partial exchange is recommended with the goal of reducing the Hb S to less than 30% as rapidly as can be safely accomplished. Therapeutic limits are 10 to 11 g/dL Hb and 30% to 33% hematocrit, being careful not to raise the hematocrit higher than 33% to 35% because doing so could impair cerebral blood flow via elevated viscosity. Cautious hydration with colloid or normal saline and vigilance for seizures and increased intracranial pressure from cerebral edema are appropriate measures and may best be accomplished acutely in an intensive care setting. The efficacy of transfusion has not been tested in the acute setting, but it seems to be a reasonable approach that might improve outcome by reducing blood viscosity. There is more support, although no randomized data, for the use of chronic transfusion on a long-term basis to prevent recurrent stroke, which occurs in most cases not treated with transfusion. For children with ischemic stroke the recommendation is for indefinite regular transfusions at least up to 18 or 20 years of age, frequent enough to maintain the level of Hb S to less than 30% of total hemoglobin. While on chronic transfusion patients may report transient episodes of worsening numbness or weakness, but recurrent infarction is rare. The risk of stroke recurrence is not uniform and probably depends on the condition of the arterial system when symptoms first appear. A recent multicenter retrospective study of 137 children with stroke and SCD suggested that patients who have an initial stroke associated or just after a significant medical event such as acute chest syndrome may have a lower long-term risk of recurrence. The rationale is that the risk of stroke in these cases is temporarily elevated because of some medical factor. However, the study did not correlate recurrence risk with arterial status by imaging or ultrasound. Another report suggests that children with stroke and moyamoya on imaging are at high risk of recurrence despite what is considered adequate chronic transfusion. Most patients who develop cerebrovascular symptoms and have been studied have abnormal large arteries when studied with arteriography. It is reasonable to assume that risk is in part dependent on the degree of arterial stenosis, adequacy of collaterals, and number of vessels occluded. Other factors such as platelet or leukocyte count or viscosity probably modify risk. In patients with transient symptoms and no clear CT or MRI evidence of infarction, arteriography can identify patients with significant arterial stenoses. It is invasive and expensive but clearly demonstrates the status of the large arteries. Stroke has been reported as a complication of cerebral arteriography, but hydration and reduction of Hb to less than 30% have reduced the risk significantly. The risks of transfusion probably outweigh the benefits in patients with normal large arteries and should not be used indefinitely in such cases.

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Prolonged transfusion is associated with cumulative hazards from iron overload, chelation therapy, and antibody formation. Iron accumulation can be attenuated by using chronic partial exchange rather than direct transfusion and treatment with chelation. Various surgical procedures to bypass the stenosis or occlusion associated with moyamoya disease have been tried and may be suitable for patients with SCD who have significant iron overload or problems with alloimmunization that make prolonged transfusion difficult or hazardous. Enthusiasm is much lower for sustained transfusion in adults, and no consensus exists on the best means of secondary prevention in such patients. There is little experience with antiplatelet agents, but I recommend their use in adults who are not treated with transfusion. In theory, anticoagulants might be useful but could make the recognized problem of intracranial hemorrhage more ldcely in patients with extensive vascular disease and fragile moyamoya vessels. Silent or hyposymptomatic brain infarction has been detected in 10% to 20% of patients with SCD studied with MRI. These lesions may cause cognitive impairment, and recent evidence suggests that their presence indicates increased risk for clinical stroke (about 1%per year or about twice baseline) but more likely new or extensive silent infarcts (7%/year). Without other evidence of significant risk, their presence on imaging alone is not considered an indication of chronic transfusion by most workers in this area, although a clinical trial is being planned to address this issue.

lntracranlalHemorrhage Intracranial hemorrhage usually presents with ominous symptoms and signs such as sudden, severe headache, vomiting, and alteration of consciousness with or without focal findings. The cranial CT is important not only in the diagnosis of intracranial bleeding but in the determination of blood location: subarachnoid, intraparenchymal, or intraventricular. Convulsions and coma suggest massive subarachnoid or intraventricular bleeding. Parenchymal bleeding usually is subcortical and presents with depressed alertness or stupor and focal findings. Arteriographic and pathologic investigation of patients with SCD and intracranial hemorrhage identify several potential mechanisms including rupture of berry aneurysms or (less commonly) arteriovenous malformations, rupture of intraparenchymal or periventricular moyamoya-like small arteries, and no evident large artery disease (except for dilation), suggesting small vessel rupture as the presumed source. Aneurysms appear to be more common in Hb SS than in the general population, become manifest at a younger age, and may more often be multiple. Why aneurysms form is unclear, but hemodynamic stress caused by elevated flow rates has been suggested. Deleterious effects on small vessels similar to what is seen in moyamoya disease probably account for intraparenchyma1 bleeding. Bleeding risk appears to be higher in patients who have experienced previous cerebral infarction, and it may not be reduced by the use of chronic transfusion. If the CT scan shows hemorrhage, the patient should be transfused and hydrated in preparation for cerebral angiography. The clinical condition may necessitate urgent and intensive care to treat elevated intracranial pressure or acute hydrocephalus, to manage seizures, or to treat vasospasm. Patients with subarachnoid and intraventricular hemorrhage should receive nimodipine. Primarily intraventricular hemorrhage, often with third ventricular clot, is not uncommon in HB SS and is caused by parenchymal

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Seizures are more common in Hb SS because they occur in 15% to 30% of Hb SS patients with stroke, and stroke is prevalent in Hb SS. Two important points concerning seizures and Hb SS should be considered Focal seizures in children may be the only symptom of unrecognized vascular disease; a workup for large vessel disease should be considered with an eye toward transfusion to prevent stroke if significant disease and cerebral infarction is present; and in some settings patients with Hb SS receive demerol for pain management; generalized seizures may be provoked by its metabolite normeperidine and by toxic dosages of other narcotic analgesics. Apart from these considerations the diagnostic and treatment approach to seizures is the same as in any other patient. Comparative Risks

FIG. 196-2. Noncontrast cranial CT taken shortly after this 7-year-old boy with sickle cell disease presented with severe headache, vomiting, and coma. Note the blood in the third (arrow) and lateral ventricles and early increase in ventricular size. The patient expired before reaching a neurosurgical center, where emergency ventriculostomy may have been life saving. Because his scan showed little parenchymal hemorrhage, he is presumed to have died from acute ventricular obstruction. This patient had transcranial Doppler evidence of vasculopathy 2 years before his death. The presumed source of bleeding is rupture of moyamoya vessels.

hemorrhage in the deep subcortical areas with extension into the ventricular system. Such patients can undergo rapid deterioration after admission to hospital because of sudden blockage of the ventricular system (Fig. 196-2). Emergency ventriculostomy may be life saving and is associated with a good outcome if there has been little parenchymal involvement in the hemorrhage. Epidural hematoma may also be seen in the absence of major head trauma, presumably related to skull infarction and secondary bleeding. The angiogram is important to determine the cause of the bleeding. Aneurysms should be repaired after preparation of the patient with reduction of Hb S. An intracranial bleed associated with extensive large vessel intracranial occlusive disease should be followed by chronic transfusion, at least in younger patients. No data exist on the efficacy of chronic transfusion after aneurysm surgery, but continued transfusion indefinitely seems reasonable given the theories of aneurysm development in these patients. Important alternative diagnoses to consider in cases of atypical hemorrhage, infarct, or brain injury are drug abuse-related strokes and child abuse. Drug intoxication may mimic stroke symptoms in young children.

Despite an anemia that is more severe than that of Hb SS, little evidence shows that patients with P-thalassemia develop vascular disease or have higher risk of stroke. Intracranial hemorrhage with multiple blood transfusions has been reported, but this may have been caused by coagulopathy. A syndrome of hypertension, convulsions, and cerebral hemorrhage was reported in patients with thalassemia receiving blood transfusions but may have been a simple manifestation of malignant hypertension. Patients with Hb SC have a less severe anemia than those with Hb SS and a less severe clinical course generally, including little if any increased risk of neurologic disease. They do get more retinopathy, however, presumably through a higher blood viscosity because they are less anemic. Other Acute Manifestations

Other acute neurologic manifestations include sudden sensorineural hearing loss and vestibular dysfunction. These are usually caused by peripheral disease, but brainstem involvement is possible, and MRI should be considered. Only a few cases of myelopathy from spinal cord infarction or compression from extramedullary hematopoiesis have been reported. The differential diagnosis should first entertain more common causes such as transverse myelitis, demyelinating disease, or mass lesions (before Hb SS) when the spinal cord is involved. Central retinal artery occlusions have been reported. Visual disturbances may be part of a cerebrovascular syndrome or primarily retinal vascular, retinal (proliferative sickle retinopathy), or ocular from other sicklerelated cases. Despite case reports, few data suggest that patients with sickle cell trait (Hb SA) are at higher risk for neurologic disease. Consequences of Transfusion

It is important to mention that patients with hemoglobinopathy treated with chronic transfusion are at higher risk of both acute and chronic consequences of this treatment. A partial list includes immediate transfusion reactions, delayed hemolytic transfusion reactions, hypertension and seizures after transfusion, iron overload with hepatic and cardiac hemosiderosis, chelation side effects including vision and hearing problems, and infection with hepatitis B and C, human immunodeficiency virus, and possibly other agents.

Chapter 196 W

Alternatives to Transfusion

Hydroxyurea is effective in reducing pain crises, and one uncontrolled small study suggests that it may be an alternative to chronic transfusion for secondary stroke prevention after transfusion has been used for several years. It has not been tested in primary stroke prevention. Bone marrow transplantation has been used in a small number of cases and appears to arrest cerebrovascular disease, but there is no evidence that it reverses established arterial lesions. Primary Stroke Prevention

Since 1997 a strategy for primary stroke prevention has been advocated by National Heart Lung and Blood Institute based on the Stroke Prevention in Sickle Cell Anemia Trial (STOP study). In this trial 130 children with high-risk transcranial Doppler studies but no history of stroke were randomized to either standard care (episodic transfusion if elected by clinician for acute illness) or regular transfusion intended to lower Hb S to less than 30% of total hemoglobin. At the point where the standard care arm had experienced 11 strokes compared with 1 in the transfused group, the trial was halted. The untreated risk was 10% per year, compared with less than 1% per year on transfusion. The trial confirmed in a separate prospective population the ability of transcranial Doppler to detect high risk (using 200 cmhecond time-averaged maximal mean in the middle cerebral or internal carotid arteries or higher as the treatment threshold) and established a major reduction in stroke events with transfusion. However, it is not clear how long transfusion must be maintained, and a new study is being performed examining the outcome with randomized withdrawal and transcranial Doppler surveillance after 30 or more months of transfusion. There are almost no data on use of other modalities for primary or, except as noted earlier, secondary prevention. The role of antiplatelet agents and anticoagulation has not been established in this disorder.

CHRONIC MANIFESTATIONS Frequent and bothersome headaches are reported in more than 30% of patients. The headache pattern may suggest migraine but more commonly resembles tension-type headache. Unless it is part of a well-established migraine pattern, severe headache with vomiting should prompt an urgent CT scan because of the increased risk of intracranial hemorrhage. No evidence shows that chronic headache is more common in patients destined to have stroke. Treatment is approached as with any similar-aged patient using episodic and prophylactic therapy as appropriate. Children with Hb SS appear to have a small but significant baseline cognitive deficit when compared with sibling controls without the disease. This deficit becomes evident by early childhood and occurs outside the recognized cerebrovascular syndromes. The cause is unclear, but recent evidence indicates that this problem begins early in life and probably is underappreciated. A child with severe learning problems should be worked up for stroke with a CT or MRI. In the presence of extensive vessel and

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parenchymal disease and clear focal deficits, transfusion should be considered. In most cases cerebral infarction is not found, however. Clinicians should be alert to the likelihood that children and adults with HB SS and perhaps other hemoglobinopathies may have special educational or training needs and should ensure that neuropsychological testing is conducted to assist in educational and vocational planning, even in the absence of major clinical manifestations of brain disease. A few cases of peripheral neuropathy with Hb SS have been reported including mental neuropathy related to mandible infarctions.

SUGGESTED READINGS Adams RJ: Neurological complications. p. 599. In Embury SH, Hebbel RP, Narla M, Steinberg MH (eds):Sickle Cell Disease: Scientific Principles and Clinical Practice. Raven Press, New York, 1994 Adams RJ, Brambilla DJ, McKie VC et ak Transfusion prevents first stroke in children with sickle cell disease: the “STOP” study. N Engl J Med 3395-11, 1998 Adams RJ, McKie V, Nichols FT et ak The use of transcranial ultrasonography to predict stroke in sickle cell disease. N Engl J Med 326:605, 1992 Adams RJ, Nichols FT Sickle cell anemia, sickle cell trail and thalassemia. p. 503. In Vinken PJ, Bruyn GW, Klawans HL (eds): Handbook of Clinical Neurology. Vascular Diseases 111.Vol. 11. Elsevier, Amsterdam, 1989 Frempong K O Stroke in sickle cell disease: demographic, clinical and therapeutic considerations. Semin Hematol 28:213, 1991 Hess DC, Adams RJ, Nichols: Sickle cell anemia and other hemoglobinopathies. Semin Neurol 11:314, 1991 Miller ST, Wright E, Abboud M et ak Impact of chronic transfusion on incidence of pain and acute chest syndrome during the Stroke Prevention Trial (STOP) in sickle-cell anemia. J Pediatr 139:785-789, 2001 Nichols FT, Jones AM, Adams RJ: Stroke Prevention in Sickle Cell Disease

(STOP) study guidelines for transcranial Doppler testing. J Neuroimaging 113354362, 2001 Olopoinia L, Frederick W, Greaves W et a 1 Pneumococcal sepsis and meningitis in adults with sickle cell disease. South Med J 83:1002, 1990

Pavlakis S G Neurologic complications of sickle cell disease. Adv Pediatr 36247, 1989

Pegelow CH, Macklin EA, Moser FG et al: Longitudinal changes in brain magnetic resonance imaging findings in children with sickle cell disease. Blood 993014-3018, 2002 Powars ER, Wilson B, Imbus C et al: The natural history of stroke in sickle cell disease. Am J Med 65461, 1978 Prengler M, Pavlakis SG, Prohovnik I, Adams R Sickle cell disease: the neurological complications. Ann Neurol 5 1:543-552, 2002 Rothman SM, Fulling KH, Nelson JS et al: Sickle cell anemia and central nervous system infarction: a neuropathological study. Ann Neurol 20684, 1986

Scothorn DJ, Price C, Schwartz D et ak Risk of recurrent stroke in children with sickle cell disease receiving blood transfusion therapy for at least five years after initial stroke. J Pediatr 140348-354, 2002 Serjeant G R The nervous system. p. 292. In Sickle Cell Disease. 2nd Ed. Oxford University Press, New York, 1992