Keywords
anemia, vitamin B 12 , folic acid, sickle cell, thalassemia, spherocytosis, paroxysmal nocturnal hemoglobinuria, cold agglutinin, cryoglobulin, kernicterus, neuroacanthocytosis, leukemia, myeloma, Waldenström macroglobulinemia, paraprotein, lymphoma, lymphomatoid granulomatosis, polycythemia, thrombocytosis, myelofibrosis, hemorrhage, hemophilia, disseminated intravascular coagulation, hemolytic uremic syndrome, phospholipid antibody syndrome, hereditary thrombophilia, thrombosis
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 pseudotumor cerebri and cerebral venous sinus thrombosis with iron-deficiency anemia. The pseudotumor cerebri 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 frequent blood donation. Iron deficiency and a strong family history (present in 72%) are characteristic of childhood-onset restless legs syndrome.
Vitamin B 12 Deficiency
Caution must be exercised when interpreting serum vitamin B 12 values as 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 low levels have been associated with multiple myeloma, oral contraceptive use, folate deficiency, and pregnancy. Elevated total serum homocysteine is a sensitive marker of vitamin deficiency but may also be related to familial hyperhomocysteinemia, levodopa therapy, renal insufficiency, and folate deficiency. Methylmalonic acid levels increase in the presence of vitamin B 12 deficiency, often preceding reduced cobalamin levels. A low vitamin B 12 level alone does not automatically define a deficiency. Among elderly individuals with low vitamin B 12 levels, 20 to 40 percent have normal homocysteine and methylmalonic acid blood levels and therefore should not be considered deficient in vitamin B 12 . Holotranscobalamin may be the most sensitive measure of erythrocyte cobalamin deficiency but is rarely used in clinical practice.
Vitamin B 12 deficiency may be caused by Addisonian pernicious anemia, 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. The neurologic complications of vitamin B 12 deficiency may occur without appreciable alteration in the peripheral blood; erythropoiesis may even be normoblastic, particularly when vitamin B 12 deficiency coincides with iron-deficiency anemia. Elevated serum methylmalonic acid and total homocysteine are useful in the diagnosis of vitamin B 12 deficiency. Failure of intracellular transport of vitamin B 12 by transcobalamin 2 can lead to functional deficiency, but with normal serum vitamin B 12 ; it is suggested by the presence of elevated serum methylmalonic acid or homocysteine, with low levels of transcobalamin 2. Such patients may respond to high-dose injections of vitamin B 12 .
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.
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 multiple neurologic abnormalities.
Folate Deficiency
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 has been described in a few patients. 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. There is evidence from studies in animals that abnormal cerebrospinal fluid (CSF) circulation may result in impaired cortical development along with hydrocephalus and neural tube defects as a result of disturbed folate metabolite delivery.
Sickle Cell Disease
Most of the complications of sickle cell anemia (Hb SS) or of sickle C disease (Hb SC) relate to the formation of sickle cells, which occurs because of the insolubility of deoxygenated hemoglobin S polymers. These sickle cells adhere to various receptors on the vascular endothelium, producing aggregates and vessel occlusion. Children with sickle cell disease have reduced levels of the majority of endothelial coagulation inhibitors, further enhancing the adhesive interactions between sickle cells with 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 Hb S; the percentage of Hb S in sickle cell trait can vary from 25 to 45 percent. In circumstances of severe hypoxemia, even patients with sickle cell trait (Hb SA) 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 6th birthday, and 37 percent by their 14th 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. 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 Hb SC disease but a proliferative retinopathy is described. Recurrent transient impairment of vision due to occlusion of major retinal vessels is an unusual manifestation of Hb SS 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. Axonal sensorimotor neuropathy may also be a feature of β-thalassemia.
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.
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 and leads to the 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 was found in 10 percent of patients, including cerebral venous thrombosis, subarachnoid hemorrhage, and intracerebral hemorrhage. Eculizumab is an effective treatment.
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. 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, opisthotonus, 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 in 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 creatinine 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 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 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 commonest 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.
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.
Leukoencephalopathy and other Encephalopathies
A variety of encephalopathic complications of chemotherapy, radiotherapy, and opportunistic infection are discussed in detail in Chapter 28 , Chapter 45 .
Myelomatosis
Myelomatosis is the best-recognized expression of the plasma cell dyscrasias, which include Waldenström macroglobulinemia, monoclonal gammopathy of unknown significance (MGUS), paraproteinemias, plasmacytoma, plasma cell leukemia, primary amyloidosis, and the heavy-chain diseases. The major neurologic complications are: (1) compression of the spinal cord, cauda equina, or solitary nerve roots; (2) cranial nerve involvement; (3) intracranial myeloma; and (4) peripheral neuropathy. Pure meningeal myeloma is rare and presents with confusion, altered consciousness, and cranial nerve palsies. In 20 percent of cases, it is associated with plasma cell leukemia. Multiple myeloma with hyperviscosity may result in cerebral infarction.
Spinal Myeloma
The vertebrae are commonly infiltrated by myeloma cells, which may extend into the extradural space. Vertebral body collapse may produce neurologic deficits. Acute paraplegia sometimes occurs due to spontaneous epidural hematoma.
Extradural myeloma tumor may occur without local bone involvement, and intradural deposits may arise by spread along nerve roots via intervertebral foramina, causing radicular symptoms and signs. Spinal cord compression is sometimes caused by amyloid deposits. Infiltration of the spinal cord by myeloma cells and paraneoplastic myelopathy are rare. The lower thoracic area of the spinal cord is the most commonly affected. Patients with IgA myeloma seem to be at greater risk of spinal cord compression.
Neurologic symptoms usually develop comparatively slowly but may do so over one or two weeks. Back pain for several weeks or months commonly precedes evidence of spinal cord compression.
Cranial Myeloma
Cranial myeloma is rare. The predominant sites of occurrence are the region of the sella and cavernous sinus, the body of the sphenoid, and the apex of the petrous bones. Orbital myeloma is well recognized and may present as an orbital mass with proptosis and ophthalmoplegia. Infiltration of the optic nerve may occur with features of optic neuritis. Ophthalmoplegia results from amyloid infiltration of the extraocular muscles. Primary plasmacytomas may originate in the cranial vault or the dura. Direct infiltration of the brain by myeloma cells is exceptionally rare, as is diffuse meningeal involvement.
Symptoms and signs of elevated intracranial pressure are often the earliest indications of intracranial myeloma. Other manifestations depend on the site of the lesion. Concomitant renal failure, anemia, hypercalcemia, and hyperviscosity contribute to symptoms.
Peripheral Neuropathy
Five types of neuropathy have been described in association with myelomatosis:
- 1.
Paraneoplastic neuropathy producing demyelination and axis cylinder degeneration
- 2.
Ischemic neuropathy due to amyloid deposition in the vasa nervorum
- 3.
Amyloid infiltration of the peripheral nerves
- 4.
Infiltration of the peripheral nerves by myeloma tissue
- 5.
Drug-induced neuropathy
Neuropathy occurring in myelomatosis is heterogeneous, arising from perineural or perivascular immunoglobulin deposition, with or without amyloid infiltration. It is particularly associated with IgG and IgM myeloma. The neuropathy is a typically mild, progressive, length-dependent, symmetric, sensory-motor neuropathy, with sensory involvement being predominant. Amyloid deposition leads to a painful small fiber neuropathy. Direct infiltration by myeloma or amyloid tissue may produce an asymmetric or mononeuritic picture.
Although it is a complication of the established disease in diffuse myelomatosis, a paraneoplastic neuropathy is usually the presenting feature of a solitary, commonly sclerotic, plasmacytoma. This combination has a distinct male predominance. The neuropathy is usually sensory-motor, with the motor component predominating. Localized radiotherapy to the bone lesion effectively arrests and usually alleviates the neuropathy with good long-term survival.
The POEMS syndrome (polyneuropathy, organomegally, endocrinopathy, monoclonal gammopathy, and skin changes) is a type of plasma cell dyscrasia associated with osteosclerotic myeloma. The major criteria for the diagnosis are the presence of polyneuropathy, with a clonal plasma cell disorder, sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease (lymphoid hyperplasia with marked follicular capillary proliferation and endothelial hyperplasia, which may be restricted to a single lymph node or may be a more generalized lymphadenopathy).
The bone marrow contains less than 5 percent plasma cells (in multiple myeloma, the bone marrow contains more than 10% plasma cells), but demonstrates megakaryocyte hyperplasia and clustering reminiscent of a myeloproliferative disorder (significantly, the JAK2 V617F mutation is absent). Patients with osteosclerotic myeloma usually have multiorgan involvement including skin change, lymphadenopathy, papilledema, peripheral edema, hepatomegaly, splenomegaly, and ascites. Dispenzieri has proposed new criteria for POEMS syndrome.
The neuropathy is of a symmetric sensory-motor demyelinating type, with clinical similarities to chronic inflammatory demyelinating polyneuropathy, including an elevated CSF protein. Possibly as a result of thrombocytosis, there is a 13 percent risk of stroke over 5 years.
A particularly localized form of neuropathy due to infiltration of the carpal tunnel by amyloid deposits is well recognized. Concurrent neuropathy and myositis due to sarcolemmal deposits of IgD in IgD myeloma has been described.
Neuropathy may also be a consequence of drug treatments for myeloma. Thalidomide induces a length-dependent sensory-motor neuropathy with autonomic involvement in 70 percent of patients treated for 12 months. Bortezomib and vincristine may also result in neuropathy, although there appears to be an interaction between myeloma-related factors and the patient’s genetic background in the development of treatment-induced peripheral neuropathy.
Neurologic Effects of Metabolic Complications
Neurologic complications may result from hypercalcemia, uremia, and hyperviscosity. Symptomatic hyperviscosity is much more common in Waldenström macroglobulinemia (10 to 30%) than it is in myeloma (2 to 6%). Symptoms of hyperviscosity usually appear when the normal serum viscosity of 1.4 to 1.8 centipoise (cP) reaches 4 to 5 cP, corresponding to a serum IgM level of at least 3 g/dl, an IgG level of 4 g/dl, and an IgA level of 6 g/dl.
Hypercalcemia and uremia cause increasing headaches, confusion, disorientation, somnolence, stupor, coma, uremic convulsions, and myoclonic twitching.
Neurologic Complications of Immunodeficiency
Immunodeficiency is a common feature of myelomatosis. In the CNS, this is reflected by the development of meningitis (bacterial, viral, fungal) and cerebral abscess. Pneumococcal infection is particularly implicated, as is herpes zoster virus and, more rarely, cryptococcosis and toxoplasmosis. Profound septicemia may be complicated by cerebral DIC. Progressive multifocal leukoencephalopathy may also occur.
Macroglobulinemia (Waldenström Disease)
Neurologic symptoms occur in 25 percent of patients with macroglobulinemia. An antibody-related neuropathy is found in 5 to 10 percent of cases and is associated with IgM kappa, some of which has specificity for myelin-associated glycoprotein. Other mechanisms such as lymphocytic infiltration of the peripheral nerves, amyloidosis, and a bleeding tendency have also been suggested as an explanation for the neuropathy. Patients have been reported with lymphoplasmacytic cells infiltrating meninges and nerve roots, producing progressive leg weakness from lumbar radiculopathy. Chemotherapy and irradiation of the involved nerve roots may lead to significant improvement.
Complete unilateral ophthalmoplegia has been described, as has an isolated lesion of the fourth cranial nerve.
Other neurologic complications relate to hyperviscosity and bleeding tendency. Exceptionally, Waldenström disease is complicated by primary intracerebral lymphoma, progressive multifocal leukoencephalopathy, or a humorally mediated immune myopathy from IgM-kappa antibodies directed against muscle surface protein.
Light/Heavy Chain Deposition Disease
A variety of lymphoplasmacytic processes may produce abnormal light or heavy chains such as chronic lymphocytic leukemia or lymphoma and nodal marginal cell lymphoma. These may be the result of the emergence of a mutated clone of plasma cells that occurs after the use of certain chemotherapeutic agents such as melphalan. Light/heavy chain deposition disease may occur in the absence of detectable underlying systemic neoplastic lymphoproliferative processes, even after prolonged follow-up for more than 10 years. Light chain deposition disease may be associated with a local clone of plasma cells (extramedullary plasmacytomas). They are most common in the sixth decade.
Peripheral neuropathy is found in approximately 20 percent of cases. Light chain deposits may be seen in the endoneurium. In cases of light chain deposition disease, peripheral nerve involvement has been reported occasionally.
Paraproteinemias
Monoclonal gammopathy of unknown significance (MGUS) is characterized by low-titer (<3 g/dl) bands of IgM, IgG, or IgA. They are found in 1 percent of healthy individuals over the age of 25 years, increasing to 3 percent in those over 70 years. The majority are IgG, and less than 15 percent are IgM. The prevalence of MGUS in those with idiopathic neuropathy is 10 percent, of which IgM accounts for 50 percent of cases, especially those with demyelinating neuropathies. Immunoelectrophoresis or immunofixation may be required to detect smaller bands. Urine light chains are rare. In MGUS, the marrow contains less than 5 percent plasma cells; blood counts are normal, and lymphadenopathy, organomegaly, and skeletal lesions do not occur. Investigation may identify primary systemic amyloidosis, myeloma, macroglobulinemia, cryoglobulinemia, lymphoma, or lymphoproliferative disorder. Approximately one-third of patients with MGUS will develop myeloma, macroglobulinemia, amyloidosis, or a lymphoproliferative disorder over 20 years; this is sometimes heralded by an unusually rapid, progressive course of the neuropathy. The risk of progression of MGUS to multiple myeloma or related disorders is about 1 percent per year.
Approximately 5 percent of patients with MGUS will develop a polyneuropathy, associated in the majority with an IgM band. The median age of onset is in the sixth decade with a slowly progressive, distal, symmetric sensory-motor polyneuropathy or, less commonly, a predominantly sensory neuropathy. A presentation resembling chronic inflammatory demyelinating polyneuropathy is well recognized, although this condition differs from the typical form due to more dominant sensory symptoms, an older age at onset, and a slower, more progressive course. Neurophysiologic studies commonly demonstrate a mixed axonal and demyelinating picture. Predominant axonal degeneration is uncommon; pure demyelination is particularly associated with IgM MGUS. CSF protein levels may be markedly elevated.
Antibody to myelin-associated glycoprotein may be identified in paraproteinemic neuropathy and in as many as half of the cases of IgM MGUS. It has a particular phenotype of a distal acquired demyelinating symmetric sensory and motor neuropathy. It is slowly progressive with prominent sensory ataxia and tremor. Histologically there is widening of the myelin lamellae. A neuropathy associated with antibody to myelin-associated glycoprotein may also occur with concurrent Waldenström macroglobulinemia or B-cell lymphoma.
The clinical pattern of antisulfatide antibody neuropathy is a sensory-predominant, distal, symmetric polyneuropathy, which may be axonal or demyelinating in type. Antisulfatide antibody–associated neuropathy accounts for about 5 percent of the cases of IgM gammopathy. The clinical pattern is similar to that of the neuropathy associated with anti–myelin-associated glycoprotein, but pain and small-fiber symptoms are more common.
Other binding specificities are described, including GM1 ganglioside and disialosyl gangliosides, but the pathogenic role of these antibodies is unclear. IgG and IgA MGUS are less likely than IgM MGUS to be associated with identifiable antineuronal antibodies and are comparatively less common than IgM neuropathies, less likely to be demyelinating or sensory, and more likely to respond to plasmapheresis.
Chronic ataxic neuropathy with ophthalmoplegia, M-protein, cold agglutinins, and disialsyl antibodies (CANOMAD) is an IgM MGUS with a characteristic phenotype. Pathologically, anti-ganglioside antibodies, anti-GD1b and anti-GQ1b, produce both demyelinating and axonal features. Weakness affects oculomotor and bulbar muscles with similarities to Miller Fisher syndrome and may either be fixed or follow a relapsing-remitting course.
A condition of gait ataxia and late-onset polyneuropathy (GALOP syndrome) is also seen in the presence of serum IgM gammopathy. The features include prominent falls in patients aged 60 to 85 years with a gradually progressive, distal, symmetric sensory-predominant polyneuropathy with demyelinating features on nerve conduction studies.
Lymphoma
The nervous system is involved through direct spread from primary nodal and extranodal sites. Occasionally, primary Hodgkin disease and primary non-Hodgkin lymphoma (including microglioma, reticulum cell sarcoma, and histiocytic lymphoma) of the CNS are seen. Neurologic complications result from direct invasion and compression of the nervous system or from secondary paraneoplastic syndromes. CNS involvement occurs most commonly with lymphoblastic lymphoma, large B-cell lymphoma, diffuse undifferentiated lymphoma, and diffuse histiocytic lymphoma.
Spinal Cord and Meningeal Involvement
Spinal cord and meningeal involvement is relatively common. Extradural deposits arise as the result of direct spread from the retroperitoneal or postmediastinal spaces via the intervertebral foramina from tumor growth along nerve roots, or by direct invasion from an affected vertebral body. Intramedullary metastases of lymphoblastic lymphoma are a rare but recognized complication. The segmental arterial supply may also become compressed, resulting in ischemic myelopathy. Rarely, an acute necrotizing myelopathy appears as a remote paraneoplastic effect of a lymphoma. Subacute paraneoplastic myelopathy may occur in Hodgkin disease.
Spinal cord segments C5 to T8 are most commonly involved, although compression may occur at any level, including the cauda equina. Nerve roots may be invaded and enlarged by the lymphoma, causing pain and sensorimotor segmental syndromes.
Intracranial Involvement
Intracranial involvement usually arises from infiltration via the skull base by direct extension from involved cervical lymph nodes, or by lymphatic spread. On rare occasions, lymphoma of the skull bones spreads to form an intracranial mass. Tumor is usually found extradurally but may present as a subdural mass that sometimes invades the underlying brain, or it may be purely intracerebral. Almost all cases of lymphomatous meningitis are found in patients with diffuse non-Hodgkin lymphoma.
Meningeal lymphoma may have a protracted course with spontaneous remission. Intracranial deposits seem to be associated more often with histiocytic lymphoma, and orbital deposits more commonly with lymphocytic lymphoma. Intracranial deposits are rarely seen in lymphocytic lymphoma unless leukemia has supervened.
Paraneoplastic Syndromes and other Neurologic Complications
A range of paraneoplastic syndromes and treatment-associated complications associated with the lymphomas are discussed in Chapter 27 , Chapter 28 .
Burkitt Lymphoma
Burkitt lymphoma is an aggressive peripheral B-cell lymphoma. It is endemic in equatorial Africa where it is frequently found in children with reduced immunity to Epstein–Barr virus (EBV), often affecting the mandible. It is found internationally in a sporadic form in adolescents and young adults, but is also common in individuals infected with human immunodeficiency virus (HIV); 90 percent of the endemic form, 20 percent of sporadic cases, and 40 percent of HIV-related cases are associated with EBV infection, which causes an upregulation of c-myc , a gene controlling transcription regulation.
Burkitt lymphoma is frequently complicated by nervous system involvement, most commonly paraplegia, cranial neuropathies, and CSF pleocytosis. Tumor spreads through the bones of the face, skull, and orbit and along cranial nerves. Spinal cord compression from direct extension from the vertebral bodies or via the intervertebral foramina is well recognized, and ischemic myelopathy may result from compression of radicular arteries. Patients with facial tumors are likely to develop orbital involvement and ophthalmoplegia. Infiltration of the skull base may produce other cranial nerve palsies and an inflammatory CSF.
Primary CNS Lymphoma
Primary CNS lymphoma (PCNSL) is rare, accounting for about 2.5 percent of primary brain tumors. Recently reported incidence rates in the United States population increased from 0.02/100,000 persons in the first two decades of life, to 0.3/100,000 in patients aged 35 to 44 years, and up to 2.13/100,000 in patients 75 to 84 years old.
Although all cytologic types are observed, 90 percent belong to the high-grade category of non-Hodgkin lymphoma, the majority being clonal and of B-cell origin, as evidenced by their monoclonal expression of either kappa or lambda light-chain immunoglobulin . Less common histologic types include low-grade lymphomas, Burkitt lymphomas, and T-cell lymphomas. Non-Hodgkin PCNSL has an extremely poor prognosis. Tumor masses are usually multicentric and ill-defined. Immunocompromised individuals are at greatest risk. The incidence of these tumors is increasing, and their association with HIV only partly accounts for this rise. Primary CNS lymphoma in immunodeficient patients is often associated with EBV, which is detected frequently in the CSF.
Imaging displays discrete, often large, enhancing tumors with bilateral hemispheric involvement spreading through the corpus callosum. Despite the fact that these tumors are highly radiosensitive, the prognosis for PCNSL is worse than for other extranodal lymphomas, and late morbidity and mortality may occur from radiation necrosis. Treatment with chemotherapy and radiation usually leads to remission but with a significant recurrence rate.
Primary lymphoma of the spinal cord is exceptionally rare, as is primary lymphoma of the nerve roots, including the cauda equina.
Peripheral neuropathy of the paraneoplastic type may occur in association with PCNSL.
Intravascular Lymphoma
Intravascular lymphoma is a rarely diagnosed subtype of generalized lymphoma, usually of large B-cell origin, producing vascular occlusion of arterioles, capillaries, and venules ( Figs. 25-3 and 25-4 ). More than 25 to 50 percent of cases present with neurologic symptoms, and two-thirds develop neurologic symptoms during the course of the disease. The presentation may be diffuse or focal, and suggestive of vascular disease. Dementia, stroke-like episodes, myelopathy, cranial neuropathy, peripheral neuropathy, and brainstem syndromes predominate. The diagnosis is often difficult because of marked variability in clinical presentation and nonspecific laboratory and radiologic findings, especially when CNS symptoms are the only manifestation. Imaging demonstrates multifocal lesions in the brain suggestive of microvascular or demyelinating disease. Angiography may show a beaded appearance reminiscent of vasculitis. The CSF findings are nonspecific, and cerebral biopsy should be undertaken in suspected cases.
Lymphomatoid Granulomatosis
Lymphomatoid granulomatosis is a rare, aggressive extranodal EBV-positive B-cell lymphoproliferative disease involving predominantly the lung. The nervous system is involved in one-third of patients. It may occur in patients with Sjögren syndrome, chronic viral hepatitis, rheumatoid arthritis, renal transplantation, and HIV infection. The usual presenting symptoms are fever, weight loss, malaise, cough, dyspnea, and neurologic symptoms, which can include encephalopathy, seizures, hemiparesis, cranial neuropathy, optic neuropathy, peripheral neuropathy, and mononeuritis multiplex. Pathologically, there is a nodular polymorphous mononuclear cell infiltrate with prominent vascular infiltration and often necrosis. Varying numbers of large, often atypical, CD20-positive B-lymphocytes are present within a background containing numerous polyclonal reactive CD3-positive small T-lymphocytes and scattered admixed plasma cells. There is extensive infiltration of T-lymphocytes and histiocytes in the meninges and cerebral blood vessel walls within the brain parenchyma and along nerve roots and peripheral nerves that mimics vasculitis and can result in vascular occlusion. Morphologically, there is an overlap in higher-grade forms (grades 2 and 3) with variants of large B-cell lymphoma, and multiple lesions in a single patient may show wide variation in histologic grade. Treatment depends on grade, with grade 3 being managed as diffuse large B-cell lymphoma.
Polycythemia
A group of conditions previously thought to be distinct entities have been shown to have a common genetic etiology in exon 14 V617F mutations of the JAK2 (Janus kinase 2) gene, including essential polycythemia, essential thrombocythemia, and myelofibrosis—the classic bcr/abl -negative myeloproliferative disorders. Each disease represents a stem cell–derived clonal myeloproliferation. The presence of this JAK2 mutation may be used as a diagnostic test.
There are many causes of polycythemia, including erythropoietin-producing neoplasms and non-malignant renal cysts and inappropriately elevated erythropoiesis induced by hypoxemia such as from right-to-left cardiac or pulmonary shunts. The term idiopathic erythrocytosis has been used to describe patients with primary polycythemia who do not fulfill the criteria for polycythemia vera, including testing negative for the JAK2 exon 14 V617F mutation; however, some patients considered to have idiopathic erythrocytosis on clinical grounds have been found to have JAK2 mutations within exon 12.
An increased incidence of thrombotic and hemorrhagic complications is a well-recognized phenomenon in polycythemia, in part arising from accelerated atherosclerosis. There is growing evidence that the increased risk of thrombosis is not caused by erythrocytosis or thrombosis but by interactions amongst white cells, red cells, platelets, and endothelium. The high incidence of thrombosis is attributed to an increased blood viscosity, reduced perfusion, vascular engorgement, atheromatous degeneration of vessel walls, and possibly to chronic DIC. Patients with polycythemia whose hematocrit is below 45 percent have a significantly lower rate of cardiovascular death and major thrombosis than those with a hematocrit of 45 to 50 percent. Approximately 15 percent of patients with polycythemia die of cerebral thrombosis, 87 percent of them after repeated episodes. Thromboembolism often continues to be a major clinical problem even after hematologic control has been achieved. Hemorrhage may be related to imperfect clot retraction, abnormal thromboplastin generation, and abnormalities of platelet count and function. CNS hemorrhage may be cerebral, epidural, subdural, or subarachnoid.
The clinical course of polycythemia vera is often complicated by the transition to myeloid metaplasia with myelofibrosis or acute myeloid leukemia.
Nonspecific symptoms of fullness in the head, vertigo, tinnitus, and lack of concentration are common. More specific signs such as hemiparesis, hemianesthesia, hemianopia, and aphasia depend on the site of infarction or hemorrhage. Brainstem vascular syndromes occur, as do bulbar and pseudobulbar palsy, convulsions, and coma. Amaurosis fugax, blindness, scotomas, and cerebral or brainstem transient ischemic attacks are features as well. More rarely, signs and symptoms of a progressive cerebral lesion arise because of a subdural hematoma, an expanding intracerebral blood clot, or cerebral infarction accompanied by edema. Distention and congestion of the retinal veins, central retinal venous or arterial occlusion, and papilledema may be present. Pseudotumor cerebri has been reported. Aseptic cavernous sinus thrombosis associated with internal carotid artery occlusion may occur; treatment with repeated phlebotomies and heparin may result in resolution of proptosis, pain, periorbital edema, lacrimation, venous congestion, ptosis, and ophthalmoplegia, and may restore sight. The one-and-a-half syndrome may occur and has been ascribed to brainstem ischemia.
Transient spinal cord ischemia may be the presenting feature of polycythemia vera, but spinal cord infarction is an exceptionally rare complication. Spinal cord compression due to spontaneous subdural hematoma and extramedullary hematopoiesis in the proliferative phase of polycythemia is uncommon.
Chorea, dystonia, and hyperkinetic movement disorders are also uncommon complications of polycythemia. Chorea may be of sudden onset and tends to occur in women older than 50 years. It may resolve before any significant reduction of the red cell count, but more often it resolves with correction of the polycythemia. The chorea is generalized, with predominant involvement of the face, mouth, tongue, and arms. It is not apparently related to the rare finding of a small infarct in the caudate nucleus.
Although paresthesias are not uncommon symptoms in the extremities, peripheral neuropathy due to polycythemia was previously thought to be rare. However, a prospective clinical and electrophysiologic study of 28 patients with polycythemia identified 46 percent with clinical features of neuropathy and 71 percent with neurophysiologic evidence of sensory axonal polyneuropathy, probably arising from endoneurial ischemia. Oculomotor nerve paresis as a presenting sign of acute myeloblastic leukemia complicating polycythemia has been reported.
Mutations in the SLC30A10 gene, which is highly expressed in the liver and brain and encodes a protein belonging to a large family of membrane transporters, may result in polycythemia with parkinsonism and dystonia.
Cerebellar Hemangioblastoma
Cerebellar hemangioblastoma may be associated with polycythemia, and 34 percent of these patients have von Hippell–Lindau disease, which is caused by mutations in the VHL gene. The VHL protein is involved in the inhibition of hypoxia inducible factor 1 α, which accumulates, causing the production of vascular endothelial growth factor, platelet derived growth factor B, erythropoietin, and transforming growth factor α. VHL is subdivided according to clinical manifestations, which largely correlate with the types of mutations present. Type 1 mostly have hemangioblastoma, and renal carcinoma and pheochromocytoma are rare. Patients with type 2 A are at risk of both hemangioblastoma and pheochromocytoma, but not renal carcinoma. Those with type 2B are at risk of all three tumors, with a higher risk of clear-cell renal carcinoma; persons with type 2C are only at risk of pheochromocytoma. Type 3 disease has a risk of Chuvash polycythemia.
The symptoms of cerebellar hemangioblastoma are those of increased intracranial pressure and “dizziness,” with either truncal and gait ataxia or hemiataxia with accompanying nystagmus. Neck stiffness and rarely cerebellar “fits” may occur. On examination, the symmetric or lateralized cerebellar ataxia is associated with papilledema, hemiparesis, bilateral pyramidal signs, or any combination of deficits from cranial nerve V, VI, VII, or VIII involvement. Recurrence many years after surgical treatment is typical of hemangioblastoma.
Pseudopolycythemia
Pseudopolycythemia is a condition in which an increased hematocrit is associated with normal red cell mass; plasma volume may be reduced in the absence of apparent fluid loss, related to aberrations in catecholamine metabolism. It is associated with hypertension, obesity, and stress, especially in middle-aged men who are smokers. In this condition, as in polycythemia, there is an increased risk of thromboembolism because the increased packed cell volume is associated with an increase in whole blood viscosity and reduced cerebral blood flow, predisposing to vascular occlusive episodes. In patients with a packed cell volume exceeding 54 percent, regular venipuncture with withdrawal of 100 to 250 ml blood is recommended to reduce the packed cell volume to around 46 percent.
Essential Thrombocythemia
Essential thrombocythemia is a clonal stem cell disorder, and the JAK2 V617F mutation has been identified in approximately 50 percent of patients. Mutations in MPL (thrombopoietic receptor) have been reported in approximately 4 percent of patients, and mutations in TET2 have been observed in a variety of myeloid malignancies, including JAK2 V617F–positive and –negative essential thrombocythemia.
Essential thrombocythemia is characterized more frequently by thrombotic than hemorrhagic complications. The condition is diagnosed on the basis of a persistently elevated platelet count without evidence of trauma, inflammation, hemorrhage, hyposplenism, or any other condition known to be associated with thrombocytosis.
Amaurosis fugax, transient hemiparesis or hemianesthesia, recurrent vertigo, and confusion are the characteristic symptoms. Most patients have circulating platelet aggregates or spontaneous platelet aggregation, and reduced platelet survival. Considerable clinical improvement can be achieved with antiplatelet drugs and, where appropriate, by reduction of platelet count. Evolution to myelofibrosis occurs in 3 to 10 percent of patients in the first decade after diagnosis, and in 6 to 30 percent in the second decade. Progression to acute myeloid leukemia occurs in 1 to 2.5 percent in the first decade after diagnosis, 5 to 8 percent in the second decade, and continues to increase subsequently, though this may be a consequence of treatment rather than due to the underlying disorder.
Myelofibrosis
Myelofibrosis is an uncommon myeloproliferative disorder arising predominantly in patients older than 50 years and characterized by replacement of the bone marrow by fibrous tissue associated with extramedullary hematopoiesis and marked hepatosplenomegaly. Patients are anemic, may be slightly jaundiced, and have a leukoerythroblastic blood picture. Neurologic complications are rare. A number of reports describe meningeal hematopoietic masses. Spinal cord compression from extramedullary hematopoiesis due to myelofibrosis is recognized but uncommon.
The JAK2 V617F mutation is found in about half of cases. Other mutations in the JAK2 and MPL genes have been identified, also resulting in exaggerated JAK2 signaling.
Eosinophilic Syndromes
Eosinophilia is defined as an increase in peripheral blood eosinophil count to greater than 450 cells/µl, with accompanying eosinophilic infiltration of muscle, nerve, or CSF. Eosinophilia may be observed in a wide range of conditions ( Table 25-1 ).
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