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Neurologic Manifestations of Hematologic Disorders
Anemia
Iron-Deficiency Anemia
Nonspecific neurologic symptoms of tiredness, fatigue, weakness, poor concentration, irritability, faintness, dizziness, tinnitus, and headache are commonly associated with anemia. Occasionally, more concrete neurologic syndromes arise, such as the association of both idiopathic intracranial hypertension and cerebral venous sinus thrombosis with iron-deficiency anemia. The intracranial hypertension may resolve and recur with resolution and recurrence of the iron-deficiency anemia. In some patients with iron-deficiency anemia, thrombocytosis may be so high that it suggests a myeloproliferative disorder. The increased platelet mass may result in transient ischemic attacks (TIAs) or cerebral infarction. Profound anemia, particularly when associated with thrombocytopenia, may produce a retinopathy with papilledema, cotton-wool exudates, flame-shaped hemorrhages, retinal edema, and even retinal detachment. Blindness is a rare but well-recognized complication of massive hemorrhage; swelling of the optic discs is followed within a few weeks by optic atrophy.
Focal neurologic signs may arise from severe anemia in conjunction with severe cerebral atherosclerosis; symptoms may resolve completely over hours as the hemoglobin is increased. Severe anemia may also produce signs and symptoms that mimic Guillain–Barré syndrome.
Transient erythroblastopenia of childhood may present with papilledema and transient hemiparesis.
Restless legs syndrome may also be associated with various forms of iron-deficiency anemia including that related to frequent blood donation. Diminished iron and iron storage protein is found in the substantia nigra in restless legs syndrome, even in the presence of normal serum levels of iron and ferritin. It is recommended that patients with ferritin levels less than 75 µg/L, receive iron supplementation with the goal of achieving a ferritin level exceeding 100 µg/L. Restless legs syndrome may be associated with genes involved in iron metabolism and a third of the population carries genetic or systemic factors making them susceptible to the syndrome when peripheral iron is reduced. Iron deficiency and a strong family history (present in 72%) are characteristic of childhood-onset restless legs syndrome.
The US Health, Aging and Body Composition (Health ABC) study identified an association between anemia and an increased 10-year risk of dementia. The precise relationship is unclear.
Vitamin B 12 Deficiency
Vitamin B 12 (cobalamin) is a water-soluble micronutrient that serves as a coenzyme for cytosolic methionine synthase and mitochondrial methylmalonyl-CoA mutase. Cellular deficiency of cobalamin results in elevated levels of the B 12 -dependent metabolites, methylmalonic acid (MMA), and homocysteine. Serum vitamin B 12 has limited diagnostic value as a stand-alone marker; low serum levels of vitamin B 12 do not always represent deficiency, and severe functional deficiency has been identified in the presence of normal or even high levels of serum vitamin B 12 . There are no well-defined cut-offs for deficiency—likely deficiency has been defined as a value of less than 148 pmol/L and possible deficiency as a value between 148 and 258 pmol/L. Falsely normal or elevated levels of vitamin B 12 have been reported when high-titer intrinsic factor antibodies interfere with the competitive-binding luminescence assay. Falsely low levels have been associated with multiple myeloma, oral contraceptive use, folate deficiency, and pregnancy. MMA levels increase in the presence of cellular deficiency of biochemically active tissue vitamin B 12 , often preceding reduced plasma cobalamin levels, such that elevated MMAs can be found in the presence of a serum cobalamin within the reference range. Elevated total serum homocysteine is a sensitive marker of cobalamin deficiency but may also be related to familial hyperhomocysteinemia, levodopa therapy, renal insufficiency, and folate deficiency.
Among elderly individuals with low vitamin B 12 levels, 20 to 40 percent have normal homocysteine and MMA blood levels and therefore should not be considered deficient in vitamin B 12 . Holo-transcobalamin (metabolically active fraction of vitamin B 12 ) represents up to 20 percent of the total vitamin B 12 present in serum. It has been suggested that it is more accurate in assessing the biologically active fraction of vitamin B 12 in circulation than the serum B 12 itself. It is not known whether and how holo-transcobalamin levels vary in patients with inborn errors of intracellular vitamin B 12 metabolism.
Vitamin B 12 deficiency may be caused by Addisonian pernicious anemia (elevated intrinsic factor and parietal cell antibodies), vitamin B 12 malabsorption syndromes (including gastric and ileal resections, terminal ileal removal for lower urinary tract reconstruction, blind loops, and infestation with fish tapeworm), and dietary deficiency, particularly in vegans. A range of medications such as metformin and proton-pump inhibitors may also transiently induce reversible cobalamin deficiency, as does nitrous oxide inhalation. Advanced-stage patients with Parkinson disease receiving continuous intraduodenal infusion of levodopa-containing intestinal gel develop peripheral neuropathies thought to arise from transient deficiency of vitamins B 6 and B 12 .
Subclinical vitamin B 12 deficiency rarely evolves into clinical deficiency and the need for its treatment has not been fully established in spite of its much higher prevalence than clinical B 12 deficiency.
The neurologic complications of vitamin B 12 deficiency may occur without appreciable alteration in the peripheral blood; erythropoiesis may even be normoblastic, notably when vitamin B 12 deficiency coincides with iron-deficiency anemia. Elevated MMA and total homocysteine are useful in establishing the diagnosis.
Functional vitamin B 12 deficiency is defined by elevated levels of the B 12 -dependent metabolites, MMA, and/or homocysteine, despite normal serum vitamin B 12 values. Failure of intracellular transport or metabolism of vitamin B 12 , for example by mutations in the transcobalamin 2 gene, can lead to cellular B 12 deficiency . Such patients may respond to high-dose injections of vitamin B 12 . Functional vitamin B 12 deficiency is common in subjects with advanced malignancy and cancer-related neuropathic pain and may respond to vitamin B 12 therapy.
Peripheral Neuropathy
Sensory symptoms of peripheral neuropathy may be identical to those of vitamin B 12 myelopathy. Somatosensory evoked potentials become abnormal before changes develop in peripheral nerves. Electrophysiologic studies indicate that the length-dependent neuropathy is secondary to a dying-back type of axonal degeneration, and neuropathologic studies have demonstrated loss of large myelinated fibers in distal sensory nerves as well as axonal degeneration in teased-fiber preparations.
Myelopathy
Demyelination followed by axonal degeneration affects the most heavily myelinated fibers first, which may explain why lesions appear primarily in the posterior columns and then later in the lateral columns. Progression may be subacute or rapid.
Suspicion that a sensory neuropathy may be related to vitamin B 12 deficiency should be raised by upper-limb onset or an associated Lhermitte phenomenon. Myelopathy is accompanied by early and severe impairment of proprioception and vibration sense, sometimes accompanied by motor signs of the neuropathy. A severe sensory ataxic spastic paraparesis may be the sole manifestation of the myelopathy. Bladder symptoms may occur later. Pseudoathetosis is rare but may be prominent. Magnetic resonance imaging (MRI) may reveal hyperintense T2 signal in the dorsal cervical cord. Similar changes may occur with copper deficiency that may also arise from malabsorption following upper gastrointestinal surgery.
Encephalopathy
Multiple foci or diffuse areas of demyelination occur with little evidence of glial cell proliferation or axonal degeneration. Symptoms include disorders of mood, mental slowing, poor memory, confusion, agitation, delusions, visual and auditory hallucinations, aggression, dysphasia, and incontinence.
Neuropsychiatric assessment in patients presenting to general physicians with vitamin B 12 or folic acid deficiency identifies organic mental change of unspecified nature in around 25 percent of patients, and affective disorders in around 20 percent of patients. The response to vitamin B 12 therapy is variable.
Optic Neuropathy
Optic neuropathy is rare and may be the presenting feature. Optic atrophy may ensue.
Disordered Eye Movements
Downbeat nystagmus, paralysis of upward gaze, and internuclear ophthalmoplegia have all been attributed to vitamin B 12 deficiency and have responded to therapy.
Infantile Vitamin B 12 Deficiency
Infantile vitamin B 12 deficiency may result from maternal vitamin B 12 deficiency causing encephalopathy, epilepsy, and microcephaly. Long-term cognitive impairment and developmental delay may ensue.
Imerslund–Graesbeck Syndrome
This is an autosomal recessive condition caused by a defect in the receptor of the vitamin B 12 –intrinsic factor complex of the ileal enterocyte and resulting in megaloblastic anemia, proteinuria, and mild multiple neurologic abnormalities.
Nitrous Oxide
Nitrous oxide, which is commonly used as a recreational drug, irreversibly binds to, oxidizes, inactivates, and depletes vitamin B 12 . Prolonged use typically presents as subacute combined degeneration of the spinal cord, but other presentations include sensorimotor peripheral neuropathy with demyelinating features in the absence of clinical or imaging evidence of myelopathy. Recovery is variable.
Folate Deficiency
In adults, the neurologic manifestations of folate deficiency include impaired cognition, dementia, depression, peripheral neuropathy, and subacute combined degeneration of the spinal cord. Cerebral folate deficiency typically presents in early infancy with seizures, delayed motor and cognitive development, cerebellar ataxia, spasticity, and visual and hearing impairment. Juvenile and adult-onset cases also occur. Peripheral neuropathy caused by folate deficiency has been described in a few cases in the absence of thiamine and vitamin B 12 deficiency and alcoholism. Subacute combined degeneration of the cord accompanying diet-induced folic acid deficiency may occur and improves after treatment with folic acid. A variety of folate transport and metabolic disorders have been described, and blocking antibodies against folate receptors have been found in the serum in 25 of 28 children with cerebral folate deficiency and in none of matched controls.
Sickle Cell Disease
The complications of sickle cell anemia (HbSS) or of sickle C disease (HbSC) arise from formation of sickle cells and from hemolysis, with free hemoglobin and other erythrocyte products scavenging nitric oxide. Sickle cells adhere to various receptors on vascular epithelium producing aggregates, activation of platelets, production of inflammatory cytokines, vasomotor dysfunction with vessel occlusion, and proliferative vasculopathy. Children with sickle cell disease have reduced levels of the majority of endothelial coagulation inhibitors, further enhancing the adhesive interactions between sickle cells and injured cell membranes and endothelial cells.
Sickling occurs when PO 2 is low. In the presence of circulatory stasis or reduced cardiac output, oxygen extraction is increased such that sickling is more likely to occur. In sickle cell trait, the severity of sickling depends on the amount of HbS; the percentage of HbS in sickle cell trait can vary from 25 to 45 percent. In circumstances of severe hypoxemia, even patients with sickle cell trait (HbSA) may develop symptoms.
One-quarter of patients with sickle cell disease have neurologic manifestations, with cerebral infarction being most common. Cerebral infarction on brain MRI in the absence of a history or physical findings of stroke occurs in 27 percent of patients before their sixth birthday, and 37 percent by their fourteenth birthday. Intracranial hemorrhage is much rarer; subarachnoid hemorrhage is the most common form and is usually aneurysmal in etiology. In children, hemorrhage tends to be primary and possibly related to vasculopathy leading to stenosis of large extracranial or intracranial vessels from fibrous proliferation of the intima. Moyamoya syndrome has been described in sickle cell disease and trait.
Less common neurologic features include cranial neuropathies, radiculopathy, ischemic mononeuropathy, radiculomyelopathy from vertebral collapse as a result of bone infarction, spinal cord infarction, hypopituitarism, ischemic optic neuropathy, TIAs, and seizures.
Hydroxyurea reduces the frequency of painful episodes by raising the level of HbF, reducing vaso-occlusive events and mortality, and is the accepted standard of care. Voxelotor, a hemoglobin oxygen-affinity modulator, inhibits hemoglobin S polymerization, increases hemoglobin oxygen affinity and reduced red cell sickling, hemolysis, and anemia, and is a promising and significant disease modifier.
Subcortical cerebral infarction and venous sinus thrombosis have also been described in sickle cell trait. Measurement of IQ in children with hemoglobin SS demonstrates modest reductions, suggesting diffuse brain injury.
Cerebrovascular complications are relatively uncommon in HbSC disease, but a proliferative retinopathy is described. Recurrent transient impairment of vision due to occlusion of major retinal vessels is an unusual manifestation of HbSS disease.
Thalassemia
Chronic anemias are associated with extramedullary hematopoiesis. There have been a few reports of spinal cord compression, most commonly in the middle to lower thoracic region. Surgical decompression plus radiotherapy is curative. Treatment with corticosteroids, blood transfusions, and local radiotherapy has also been successful. Transfusion to maintain the hemoglobin level above 12.5 g/dL may resolve minor compression of the spinal cord, with near-complete resolution of the extradural hematopoietic mass. Visual failure secondary to suprasellar extramedullary hematopoiesis in β-thalassemia has been described.
Severe forms of β-thalassemia, particularly following splenectomy, can be associated with hypercoagulability, with an increased risk of cerebral venous thrombosis. There is a reported association with moyamoya syndrome. Neurophysiologic evaluation demonstrates polyneuropathy in 39 percent, myopathy in 28 percent, and both in 17 percent of patients, correlating with iron overload.
Hereditary Spherocytosis
Hereditary spherocytosis has few neurologic sequelae. It is associated with a state of chronic anemia which results in a reduced cholesterol level and therefore a reduced rate of carotid occlusion and stroke. There have been reports of moyamoya syndrome in children with hereditary spherocytosis, and of anterior ischemic optic neuropathy in adults.
Paroxysmal Nocturnal Hemoglobinuria
Paroxysmal nocturnal hemoglobinuria is a rare acquired hematopoietic stem-cell disorder arising from a range of mutations in the phosphatidylinositol glycan class A ( PIGA ) gene, resulting in a deficiency of a glycosyl phosphatidylinositol–anchored protein. It may occur de novo or in association with marrow hypoplasia, ranging from pancytopenia to aplastic anemia. It results in deficiency in the binding of several protective red cell membrane proteins and leads to hypersensitivity to complement. The disorder is characterized by intravascular hemolysis and manifested by episodes of hemoglobinuria and venous thrombosis. Hemolysis occurs throughout the day and is not paroxysmal, but hemoglobinuria is seen when the first concentrated urine is passed in the morning. The commonest manifestation is large-vessel venous thrombosis particularly in the brain and portal system. The spinal cord is not affected. An occasional patient suffers TIAs that have been attributed to the hypercoagulable state induced when excess thromboplastin is released from lysing red blood cells. Increased sensitivity of the red cells to lysis by complement stimulates platelet aggregation, leading to hypercoagulability. The hemoglobin released by hemolysis binds with circulating nitric oxide and inhibits the relaxation of smooth muscle, which results in abnormal tone of vascular smooth muscle, vasculopathy, and endothelial dysfunction. A neurologic cause of death is described in 10 percent of patients, including cerebral venous thrombosis, subarachnoid hemorrhage, and intracerebral hemorrhage. Moyamoya has been associated with paroxysmal nocturnal hemoglobinuria. The majority of patients without neurologic symptoms have brain MRI white matter abnormalities related to chronic ischemic small-vessel disease.
Eculizumab, a humanized monoclonal antibody that inhibits complement component C5, is an effective treatment, but allogeneic bone marrow transplantation is the only cure.
Cold Agglutinin Disease
Cold agglutinin disease is a form of autoimmune hemolytic anemia usually associated with IgM antibodies (rarely IgG and IgA cold-reactive autoantibodies) directed against erythrocytes with binding activity that increases as the temperature approaches 0°C. Cold-associated circulatory symptoms are very common. It is associated with a low-grade lymphoproliferative B-cell disorder in 90 percent of cases, but with a very low rate of developing overt lymphoma. Cold-induced circulatory symptoms with characteristic seasonal variations in anemia occur. The anemia is variable and usually not severe, though approximately 50 percent of patients are transfusion dependent at some time during the disease. Cold agglutinin–associated asymmetric sensory-motor neuropathy has been described as a feature of transformation to Waldenström macroglobulinemia.
Cryoglobulinemia
Cryoglobulins are serum proteins or protein complexes that undergo reversible precipitation at low temperatures. Three main types are recognized. Type I, most commonly monoclonal IgM or IgG, is seen in association with multiple myeloma, Waldenström macroglobulinemia, and other lymphoproliferative disorders. Type II consists of mixed immunoglobulin complexes in which the monoclonal antibody has specificity for polyclonal IgG and occurs in association with lymphoproliferative diseases, autoimmune disorders, and hepatitis. Type III cryoglobulin is composed of polyclonal immunoglobulin and is found in infections and autoimmune disorders. Neurologic complications are common in types II and III, with mononeuritis multiplex, peripheral symmetric sensorimotor axonal or demyelinating polyneuropathy, and small-fiber sensory neuropathy being the most common findings. More rarely, cerebral ischemia or vasculitis may occur.
Kernicterus
Kernicterus may be produced by any hemolytic process of sufficient severity in neonates, particularly in premature infants with physiologic jaundice. It is part of the spectrum of symptoms of acute bilirubin encephalopathy. In the developed world, an underlying cause is found in most patients. Glucose-6-phosphate dehydrogenase is a major source of protection from bilirubin-induced oxidative stress, and its deficiency syndrome leads to a high incidence of kernicterus. Whenever the serum unconjugated bilirubin level exceeds 20 mg/dL during the first few weeks of life, kernicterus may occur, though there is a poor correlation between bilirubin levels and disease severity. Unconjugated bilirubin is highly lipid soluble; it enters the brain and binds to neurons resulting in neuronal loss, demyelination, and gliosis, particularly in the basal ganglia and cerebellum. The neurologic features range from decreased alertness, hypotonia, and poor feeding to retrocollis, opisthotonos, and long-term sequelae. Chronic changes may evolve over a number of years, including the development of eye movement abnormalities, hearing loss, and extrapyramidal disorders (particularly athetosis and, less commonly, chorea). Cognitive function is relatively well preserved.
Rare Neurologic Syndromes and Red Cell Abnormalities
The term neuroacanthocytosis describes a number of conditions associated with abnormal erythrocyte membrane constituents, resulting in the formation of spiculated cells.
Pantothenate kinase–associated neurodegeneration, or neurodegeneration with brain iron accumulation type I (NBIA-1), is an autosomal recessive disorder in which classic forms are associated with PANK2 mutations on chromosome 20. Patients are normal at birth but then develop acanthocytosis, dystonia, dysarthria, rigidity, occasional spasticity, cognitive impairment and dementia, pigmentary retinal degeneration, optic atrophy, and iron accumulation in the brain, particularly in the globus pallidus. MRI shows the “eye-of-the-tiger sign”—hyperintensity within the hypointense medial globus pallidus—but this sign may not be present in early cases. The classic form presents in the first decade, with progression and loss of independent ambulation within 15 years. Atypical forms develop in the second decade and progress slowly, with retained independent ambulation up to 40 years later. Intermediate forms are described. Early onset is associated with pigmentary retinopathy, whereas a later onset is associated with speech disorders and psychiatric features. Pantothenate kinase catalyzes the first committed step in the universal biosynthetic pathway leading to CoA and is located in the mitochondrial intermembrane space. Mutations in PANK2 are also found in HARP syndrome (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration).
Bassen – Kornzweig disease (neuroacanthocytosis with abetalipoproteinemia) is a recessively inherited syndrome characterized by acanthocytosis, retinitis pigmentosa, increasing cerebellar ataxia, peripheral neuropathy, steatorrhea, and complete or almost complete lack of serum β-lipoproteins, with onset during childhood. The microsomal triglyceride transfer protein ( MTTP ) gene is essential for synthesizing β-lipoproteins for the absorption and transport of fats and cholesterol. Mutations in the gene result in deficiency of fat-soluble vitamins, A, D, E, and K, though deficiency of vitamin E is the primary cause of the degeneration in spinocerebellar and dorsal columns of the spinal cord. Treatment with vitamins A and E as early as possible is helpful.
Chorea-acanthocytosis is an autosomal recessive disorder linked to the VPS13A gene on chromosome 9 which encodes chorein. The neurologic features commence between 25 and 45 years with behavioral change and obsessive-compulsive disorder, followed later by the development of progressive choreiform movements of the limbs, face, mouth, lips, and throat—lip and tongue biting is characteristic. Myopathy and neuropathy may occur. In addition, motor or vocal tics, dystonia, parkinsonism, progressive supranuclear palsy, and apraxia of eyelid opening have been described. Serum creatine kinase levels are elevated; serum lipoproteins are normal.
McLeod neuroacanthosis is an X-linked syndrome with absent expression of Kx erythrocyte antigens, weak expression of Kell glycoprotein antigens, and increased serum creatine kinase levels. A range of other features may include hemolytic anemia, myopathy, limb chorea, facial tics, lip and tongue biting, neuropathy, dystonia, seizures, psychiatric changes, cognitive impairment, and dilated cardiomyopathy.
Huntington disease-like syndrome (HDL2) is an autosomal dominant disorder found almost exclusively in people of African ancestry. It is characterized by a trinucleotide repeat in the junctophilin-3 gene. Acanthocytosis is a variable feature. There is striatal and cortical atrophy, as well as intranuclear protein aggregates. HDL2 is clinically and radiologically indistinguishable from Huntington disease, with typical juvenile and late-onset forms.
A progressive spinocerebellar syndrome and sideroblastic anemia occur together in an X-linked recessive mutation in the ABCB7 gene that encodes the ATP-binding cassette subfamily B member 7, mitochondrial. It is a mitochondrial disorder caused by a mutation in the nuclear genome. Cerebellar ataxia and dysarthria develop by 1 year of age, with accompanying long-tract signs. The neurologic signs tend to be stable until the fifth decade, when slow progression may occur. Neuropathy and myopathy have been described in association with sideroblastic anemia.
Triosephosphate isomerase deficiency is a rare autosomal recessive metabolic disorder characterized by chronic hemolytic anemia, progressive neurologic dysfunction, and an increased susceptibility to infection. The neurologic features consist of a dystonic-dyskinetic syndrome with gross intention tremor and amyotrophy and hypotonia of the trunk and limbs, sometimes with corticospinal signs. There is electromyographic evidence of denervation with normal nerve conduction velocities, suggestive of anterior horn cell impairment. It has been suggested that low triosephosphate isomerase activity leads to a metabolic block in the glycolytic pathway and hence to an impairment of the cellular energy supply.
Proliferative Disorders
Leukemia
Involvement of the central nervous system (CNS) is primarily due to infiltration with leukemic cells, but may occur as the result of hemorrhage, infection, drug- and radiation-induced neurotoxicity, electrolyte disturbance, and impairment of cerebral circulation from leukostasis.
Meningeal Leukemia
The most common presenting symptoms are headaches, nausea, and vomiting, sometimes associated with lethargy and irritability, neck stiffness, drowsiness, coma, and convulsions. Diffuse meningeal infiltration impairs the circulation of CSF and can result in communicating hydrocephalus. Papilledema is the most common sign. The leukemic deposits may compress or infiltrate the cranial nerves or spinal nerve roots and spread between the nerve fibers.
The diagnosis of meningeal leukemia is confirmed on CSF examination in approximately 90 percent of cases. Flow cytometric analysis of CSF has the highest diagnostic yield. The CSF pressure is usually elevated and reduced glucose concentration may be found. In 10 percent of cases the CSF is normal and repeated CSF examinations may be required.
Acute myelomonocytic leukemia accompanied by pericentric inversion of chromosome 16 is a unique subtype associated with a high incidence of CNS involvement in the form of leptomeningeal deposits and granulocytic sarcoma (chloroma).
Localized Leukemic Deposits
Leukemic deposits may involve any part of the CNS ( Figs. 25-1 and 25-2 ). The symptoms and signs are therefore numerous, varied, and depend on the extent and site of infiltration. Blindness may occur from infiltration of the optic nerve head or chiasm, and visual impairment from retinal infiltration. Bilateral serous macular detachment with visual blurring may be the presenting symptom of acute lymphoblastic leukemia. Mental nerve involvement that produces sensory impairment of the lower lip and painless traumatic ulceration of the buccal mucosa along with “numb chin syndrome” has been reported.
Hypothalamic and pituitary dysfunction is well recognized and may be associated with hydrocephalus.
Clinically significant spinal cord involvement is unusual in leukemia; it is encountered most commonly with acute myeloid leukemia. Spinal cord syndromes arise from compression by extradural deposits; direct infiltration of the spinal cord and nerve roots; vascular occlusion by thrombus, leukemic cells, or some combination of these; or hemorrhage. Exceptionally, an acute paraneoplastic necrotizing myelopathy occurs, often with retinal changes.
Peripheral neuropathy caused directly by leukemia is rare.
Chloromas (Granulocytic Sarcoma or Extramedullary Myeloblastoma)
Chloromas are solid tumors of nonlymphatic leukemia that are more common in children than adults. Granulocytic sarcoma develops in approximately 2.5 percent of cases of acute myeloid leukemia, and it may occur in myelofibrosis or myelodysplastic syndromes as part of transformation to acute leukemia. The majority of chloromas have a distinctive green color that fades on exposure to light. Most occur subperiosteally, usually in the cranial and facial bones, especially the paranasal sinuses, mastoid air cells, or orbits; they are usually attached to the dura mater and rarely invade cerebral tissue. Chloromas are radiosensitive.
Intracranial Hemorrhage and Thrombosis
The overall incidence of intracranial hemorrhage (ICH) is around 3 percent among adult patients with hematologic malignancies. The incidence is greatest in patients with acute myeloid leukemia. Patients with intracranial lymphoma are more prone to ICH than those with acute leukemia. Chemotherapy-related endothelial injury and reduction of coagulation factors may each play a role in the pathogenesis.
Thrombocytopenia is a frequent feature of ICH and may in some cases be the result of disseminated intravascular coagulation (DIC) or leukemic infiltration of the bone marrow. Platelet production may also be impaired as a result of the myelotoxic effects of chemotherapy. Bleeding in the CNS is usually multifocal and may be confluent. DIC is a prominent feature of promyelocytic leukemia but, in other forms of leukemia, DIC is particularly marked in those with high peripheral white cell counts. It appears soon after the beginning of chemotherapy, presumably because tissue thromboplastins are released from destroyed leukocytes.
Both acute and chronic subdural hematoma may occur. Cisternal, cervical, or lumbar puncture in a thrombocytopenic patient with acute leukemia may cause a spinal subdural hematoma with resulting compression of the spinal cord or cauda equina. Cranial irradiation causes intracranial vessel narrowing and thrombotic occlusion in later life. Weakening of the vessel wall can also result in arterial dilatation and tortuosity. The sequelae of these changes are vascular malformation, aneurysmal dilatation, and arterial thrombosis.
Cellular Hyperviscosity
Marked elevation of the white cell count may produce a significant increase in whole-blood viscosity. The signs and symptoms include headache, somnolence, and impairment of consciousness. All types of leukemia may produce this syndrome, but neurologic symptoms may occur more readily in myelogenous leukemias at lower leukocyte counts, reflecting the larger cell size.
Treatment with leukapheresis may abolish the symptoms. Blood transfusions may be hazardous because they may further elevate viscosity.
Infections
In all leukemias, but particularly in the lymphoblastic leukemia of childhood, viruses (especially mumps, measles, and varicella) are the most common infective organisms of the CNS. Bacterial and fungal infections, especially aspergillosis, also occur. The increased incidence of involvement of the CNS with rare organisms or organisms that are normally nonpathogenic is contributed to by the widespread use of corticosteroids, chemotherapy, and broad-spectrum antibiotics.
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