ANEMIA
Iron-Deficiency Anemia
Nonspecific neurological symptoms of tiredness, fatigability, weakness, poor concentration, irritability, faintness, dizziness, tinnitus, and headache are commonly associated with anemia. Occasionally, more concrete neurological syndromes arise, and a number of case reports have drawn attention to the association of benign intracranial hypertension and cerebral venous sinus thrombosis with iron-deficiency anemia.1,2 The benign intracranial hypertension may resolve and recur with resolution and recurrence of the iron-deficiency anemia.2 In some patients with iron-deficiency anemia, thrombocytosis may be marked and may be so high as to suggest a myeloproliferative disorder. The increased platelet mass may be accompanied by signs and symptoms of cerebrovascular insufficiency, either as transient cerebral ischemic attacks (TIAs) or as cerebral infarction or amaurosis fugax. Profound anemia, particularly if associated with thrombocytopenia, may produce a retinopathy comprising papilledema, cotton-wool exudates, flame-shaped hemorrhages, retinal edema, and even retinal detachment. Blindness is a rare but long-recognized complication of massive hemorrhage; swelling of the optic discs is followed within a few weeks by optic atrophy.
Focal neurological signs may arise from severe anemia in conjunction with severe cerebral atherosclerosis. Symptoms may resolve completely over hours as the hemoglobin is increased.3 Severe anemia may produce signs and symptoms that mimic Guillain–Barré syndrome.4
Transient erythroblastopenia of childhood has been noted to present with papilledema and transient hemiparesis.5 Restless legs syndrome may be associated with iron-deficiency anemia including frequent blood donation.6 Iron deficiency and a strong family history (present in 72%) are characteristic of childhood-onset restless legs syndrome.7

Vitamin B12 Deficiency

Vitamin B12 deficiency may result in lesions affecting the peripheral nerves, spinal cord, optic nerves, and brain. Addisonian pernicious anemia is an important cause of vitamin B12 deficiency, but the neurological complications may also result from vitamin B12 deficiency secondary to malabsorption syndromes, gastric and ileal resections, terminal ileal removal for lower urinary tract reconstruction,8 blind loops, infestation with fish tapeworm, and dietary deficiency, particularly in vegans. It is essential to realize that all the neurological complications of vitamin B12 deficiency may occur with no appreciable alteration in the peripheral blood picture. There may be no anemia, and erythropoiesis may even be normoblastic. Lindenbaum and colleagues confirmed that neuropsychiatric disorders due to vitamin B12 deficiency occur commonly in the absence of anemia or macrocytosis and suggested that measurements of serum methylmalonic acid and total homocysteine both before and after treatment are useful in the diagnosis of these disorders.9

Peripheral Neuropathy

The frequency of peripheral neuropathy as a complication of vitamin B12 deficiency is difficult to determine accurately, since the sensory symptoms of peripheral neuropathy may be identical to those of vitamin B12 myelopathy. However, the findings of muscle wasting and absent reflexes confirm the presence of neuropathy. Electrophysiological studies indicate that the neuropathy is secondary to a dying-back type of axonal degeneration, and neuropathological studies have demonstrated the loss of large myelinated fibers in distal sensory nerves as well as axonal degeneration in teased-fiber preparations.

Paresthesias and numbness appear first in the feet and legs, accompanied by loss of reflexes, superficial sensory impairment in a stocking distribution, and impairment of vibration sense. Later, there are similar sensory changes in the hands, together with wasting and weakness of the distal leg muscles.

Myelopathy

Demyelination followed by axonal degeneration seems to affect the most heavily myelinated fibers first, which may explain why lesions appear first in the posterior columns and later in the lateral columns. They tend first to appear at the mid-thoracic level. The term subacute combined degeneration is appropriate for describing this process in most cases because symptoms and signs usually progress over several weeks and months. However, progression may be rapid, resulting in severe clinical disability within a week or two; or it may be much more chronic, developing over a year or more.

Sensory symptoms appear first in the feet, accompanied by early and severe impairment of proprioception and vibration sense. The ankle reflexes are usually absent, owing to the invariable concomitant peripheral neuropathy, but the knee reflexes become exaggerated sooner or later, and subsequently the plantar responses become extensor. Severe sensory ataxic spastic paraparesis may be virtually the sole manifestation of vitamin B12 myelopathy. Bladder symptoms of urinary urgency leading to incontinence occur later. Pseudoathetosis of the fingers, hands, or toes due to severe loss of joint position sense can be a rare but prominent feature.

Encephalopathy

The pathological changes in the brain are similar to those in the spinal cord. Multiple foci or diffuse areas of demyelination in the white matter occur with little evidence of glial cell proliferation or axonal degeneration. Changes appear most marked in the corpus callosum and in the frontal and parietal white matter. A variety of symptoms occur, consisting of disorders of mood, mental slowing, poor memory, confusion, agitation, delusions, visual and auditory hallucinations, aggression, dysphasia, and incontinence.

Shorvon and associates assessed the neuropsychiatric state of 50 patients with megaloblastosis due to vitamin B12 deficiency and that of 34 patients due to folate deficiency presenting to hematologists or general physicians.10 One third of each group had no neuropsychiatric complications. Peripheral neuropathy was the most common complication of vitamin B12 deficiency (40%). Eight patients (16%) had evidence of subacute combined degeneration of the cord, and one (2%) had optic atrophy. Organic mental change of unspecified nature occurred in 26 percent, and affective disorders in 20 percent.

Response to vitamin B12 therapy is variable. Healton and associates confirmed that all patients respond to some extent to treatment, and recovery was complete in virtually half.11 The severity score was reduced by 50 percent in 91 percent of instances. Residual long-term moderate or severe neurological disabilities were observed in 6.3 percent. The degree of neurological disability remaining after treatment was related to two factors—the nature of the neurological disability and the duration of symptoms before treatment.

Optic Neuropathy

Optic neuropathy due to vitamin B12 deficiency is rare. It is reputedly more common in men. It may precede, coincide, or follow the anemia or the myelopathy. The characteristic visual abnormality is a centrocecal scotoma, usually appearing earlier to red than to white, which may be associated with constriction of the periphery of the visual field leading to optic atrophy. With early and adequate treatment, recovery may be complete.

Disordered Eye Movements

Downbeat nystagmus,12 paralysis of upward gaze,13 and internuclear ophthalmoplegia14 have been attributed to vitamin B12 deficiency and have responded to vitamin B12 therapy.

Extrapyramidal syndrome

Kumar described the rapid onset of a typical parkinsonian syndrome over 10 days in a man found to have vitamin B12 deficiency that showed a dramatic response to parenteral vitamin B12. At 5-year follow-up there were no residual neurological signs.15

Infantile Vitamin B12 Deficiency

Infantile vitamin B12 deficiency may result from maternal vitamin B12 deficiency causing encephalopathy, epilepsy, and microcephaly.16

Imerslund-Graesbeck Syndrome

Vitamin B12 malabsorption in the ileum has been suggested to be the underlying cause of this syndrome, which consists of megaloblastic anemia, proteinuria, and multiple neurological abnormalities. A young Saudi child with spasticity, truncal ataxia, cerebral atrophy, megaloblastic anemia, and proteinuria completely recovered following vitamin B12 therapy.17

Folate Deficiency

In the study of Shorvon and colleagues previously mentioned, affective disorders (mostly depression) and organic mental change were the most common neuropsychiatric complications of folate deficiency.10 Peripheral neuropathy was seen in a few patients, but there was no instance of optic atrophy or myelopathy. Subacute combined degeneration of the cord and optic atrophy occurred only in the patients with vitamin B12 deficiency. However, diet-induced folic acid deficiency with subacute combined degeneration of the spinal cord that improved significantly after treatment with folic acid has been recorded.18

Mental and physical retardation, hypotonia, cerebral atrophy, seizures, ataxia, and athetoid movements are associated with congenital folate malabsorption; calcification of the basal ganglia has also been reported. Allen and colleagues have associated the Kearns–Sayre syndrome—progressive external ophthalmoplegia, conduction heart block, atypical pigmentary degeneration of the retina, calcification of the basal ganglia, white matter hypodensities on cranial computed tomography (CT), and “ragged red fiber” myopathy—with low cerebrospinal fluid (CSF) folate levels.19

Sickle Cell Disease

Most if not all of the clinicopathological complications of sickle cell anemia (Hb SS) or of sickle C disease (Hb SC) relate to the formation of sickle cells; these cells form because of the insolubility of deoxygenated hemoglobin S polymers, and they produce vascular occlusion by adhering to various receptors on the vascular endothelium, producing aggregates and thrombotic vessel occlusion. The neurological complications also result from a point mutation that causes vasculopathy of both large and small vessels.20 In circumstances of severe hypoxemia, even patients with sickle cell trait (Hb SA) may develop vaso-occlusive disease. Factors exacerbating the sickling phenomenon include hypoxia, dehydration, acidosis, and infection. Children with sickle cell disease have a reduced level of the majority of endothelial coagulation inhibitors, which further enhances the adhesive interactions between sickle cells with injured cell membranes and endothelial cells.21

As sickling occurs in the venous circulation, central venous Po2, not arterial Po2, is the critical factor. There is a trace of sickling in homozygous disease even when hemoglobin is 100 percent saturated with oxygen, whereas at 65 and 50 percent oxygen saturation there is 75 and 100 percent sickling, respectively. In heterozygous disease with 40 percent hemoglobin S (Hb S), sickling starts at 40 percent saturation. The critical Po2 is 30 mmHg for sickle cell disease and 20 to 30 mmHg for sickle cell trait. In the presence of circulatory stasis or reduced cardiac output, oxygen extraction may be so high that venous Po2 is reduced to dangerously low values despite normal arterial oxygen tension. In sickle cell trait, the severity of sickling depends on the actual amount of Hb S rather than the proportions of hemoglobin A (Hb A) and Hb S. The percentage of Hb S in sickle cell trait can vary from 25 to 45 percent. In vitro studies suggest that in carriers who have a high concentration of Hb S, the risk of sickling is not much less than in patients with sickle cell disease.22

The incidence of neurological manifestations in patients with sickle cell disease approximates 25 percent, with cerebral infarction and hemiparesis being most common. Cerebral infarction tends to occur in young children, and transfusion greatly reduces the risk of a first stroke in affected children who have abnormal high-velocity flow on transcranial Doppler ultrasonography.23 Intracranial hemorrhage is much rarer; it tends to occur more often in adults and is more commonly subarachnoid. In adults, the subarachnoid hemorrhage is usually associated with ruptured aneurysms, which frequently are multiple and commonly involve the posterior circulation. In children, it tends to be primary and possibly related to fibrotic endarteritis and fragmentation of the internal elastic lamina of the larger proximal intracranial arteries.24 Stenosis of large extracranial or intracranial vessels may occur secondary to a vasculopathy and fibrous proliferation of the intima.

Other neurological manifestations of sickle cell disease include aphasia, cranial neuropathies,25 radiculopathy, ischemic mononeuropathy,26 radiculomyelopathy from vertebral crushing as a result of successive bone infarction, paraplegia, spinal cord infarction, hypopituitarism, ischemic optic neuropathy, optic atrophy, transient ischemic attacks, and seizures. Prengler and colleagues suggested that vasculopathy and focal hypoperfusion might be relevant to the seizures associated with sickle cell disease.27 Spinal cord infarction is rare, and there has been only one autopsy report of this complication.28 Subcortical cerebral infarction has also been described in sickle cell trait,29,30 as has cerebral venous sinus thrombosis.31

In contrast to homozygous sickle cell disease, cerebrovascular complications are relatively uncommon in Hb SC disease. The association of proliferative retinopathy with Hb SC disease is well known. Fabian and Peters found a significant increase in retinopathy, stupor, coma, and seizures in patients with Hb SC disease compared with matched control subjects.32 Recurrent transient impairment of vision due to occlusion of major retinal vessels is an unusual manifestation of Hb SS disease.

It is important to remember that patients with sickle cell disease may develop neurological disorders unrelated to their hemoglobinopathy and so should be investigated to exclude unrelated but treatable conditions. This is illustrated by the patient of Caprioli and colleagues who developed acute monocular visual loss with no retinal or vitreous abnormalities but who had a large aneurysm of the anterior communicating artery compressing the optic nerve.33

Thalassemia

Chronic anemias such as thalassemia are associated with extramedullary hematopoiesis, usually in the liver, spleen, or lymph nodes. There have been a few reports of extramedullary hematopoiesis in thalassemia producing spinal cord compression and paraparesis, the hematopoietic tissue presumably arising from embryonal rests in the extradural areolar tissue of mesodermal origin. Most commonly the lesion is situated in the middle to lower thoracic region of the spinal canal, and surgical decompression plus radiotherapy is curative. Treatment with corticosteroids or repeated blood transfusions together with local radiotherapy to the tumor without surgical decompression has also been successful.34 Transfusion alone to maintain the hemoglobin level above 12.5 g/dl has been reported to relieve the signs of spinal cord compression, with near-complete resolution of the extradural hematopoietic mass.35 Visual failure secondary to suprasellar extramedullary hematopoiesis in β-thalassemia has been described.36 In one study, 20 percent of β-thalassemic patients were found to have clinical and electrophysiological findings of a predominantly motor sensorimotor neuropathy.37 Severe forms of β-thalassemia are associated with an increased risk of cerebral thrombosis as well as portal and deep vein thrombosis and pulmonary embolism.38

Hereditary Spherocytosis

There has been an isolated report of two patients with hereditary spherocytosis associated with a mild spastic paraparesis for which no cause was found.39 Although it may have been an entirely fortuitous association, the authors deliberated about a possible common mechanism for the neurological and red blood cell abnormalities. This association has not been described since.

Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria is a rare acquired hematopoietic stem-cell disorder characterized by deficiency of glycosyl phosphatidylinositol (GPI)–anchored protein. This results in deficiency in the binding of several protective red cell membrane proteins and leads to hypersensitivity to complement and hemolysis. It may occur de novo or in association with marrow hypoplasia. It is characterized by intravascular hemolysis and manifested by episodes of hemoglobinuria and venous thrombosis. Increased intravascular destruction of red cells occurs at night, which results in hemoglobinuria seen when the first urine is passed in the morning. One of the commonest complications of this disorder is large-vessel thrombosis, and its occurrence in the brain and portal system accounts for the death of 50 percent of patients. The thrombotic tendency is thought to arise from deficiency in GPI-linked proteins in platelets. Although thrombosis has been reported in most organs, it has not been detected in the vessels of the spinal cord; most of the neurological complications of paroxysmal nocturnal hemoglobinuria relate to thrombosis of intracranial vessels. Cerebral arterial and venous thrombosis occurs, resulting in hemorrhagic infarction.40 During the crises of paroxysmal nocturnal hemoglobinuria, 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 hypercoagulability. In the study of Hillmen and associates, a neurological cause of death was found in 10 percent of patients, including cerebral venous thrombosis, subarachnoid hemorrhage, and intracerebral hemorrhage.41

Cold Agglutinin Disease

Cold agglutinin disease is 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. Characteristically, the disease presents as anemia and a cold-induced rash. A case is reported of a man with purpura, anemia, cold agglutinins, and a sensory and autonomic polyneuropathy that resolved on treatment with corticosteroids and plasma exchange.42

Cryoglobulinemia

Cryoglobulins are serum proteins or protein complexes that undergo reversible precipitation at low temperatures. Three main types of cryoglobulin are recognized. Type I consists of monoclonal proteins seen in association with multiple myeloma, Waldenström's macroglobulinemia, and other lymphoproliferative disorders. Type II consists of mixed immunoglobulin complexes in which the monoclonal antibody has specificity for polyclonal IgG, and is described 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. Neurological complications are not unusual, with peripheral symmetric sensorimotor axonal or demyelinating polyneuropathy being the most common finding. More rarely, acute mononeuritis or cerebral ischemia or vasculitis may occur.

Kernicterus

With the virtual elimination of hemolytic disease of the newborn, kernicterus is now uncommon in developed countries. It may be produced by any hemolytic process of sufficient severity in neonates and in premature infants by “physiological jaundice.” Whenever the serum unconjugated bilirubin level exceeds 20 mg/dl during the first few weeks of life, kernicterus may occur. Unconjugated bilirubin is highly lipid soluble; it enters the brain and binds to neurons, resulting in neuronal necrosis particularly in the basal ganglia and cerebellum. The neurological features include opisthotonos, convulsions, rigidity, involuntary movements, athetosis, deafness, nystagmus, and psychotic behavior.