Pernicious Anemia (Vitamin B12 Deficiency)
Defining the anatomy of the patient's complaints should be the first priority. As with any medical evaluation, the patient's history can provide much information. Her complaint of recent difficulties with concentration and memory suggests an encephalopathy. The gradual onset of symmetric, distal extremity numbness and paresthesias is consistent with a subacute/chronic polyneuropathy. Gait difficulty can result from numerous areas of dysfunction (pyramidal, extrapyramidal, cerebellar, sensory, frontal lobe). She complained of neck pain shooting down the back and into the arms. This description is consistent with Lhermitte's phenomenon, which is an electric shock sensation radiating down the spine or into the limbs upon flexion of the neck; this symptom localizes to either the posterior columns of the high cervical cord or to the nucleus gracilis and cuneatus in the low-mid medulla. Therefore, a careful assessment of the history reveals evidence for an encephalopathy, polyneuropathy, and a process involving the high cervical cord/lower medulla.
The general physical exam was unremarkable. However, the neurologic exam does provide localizing signs. The "stocking-and-glove" sensory loss is consistent with a polyneuropathy. The presence of a sensory level loss to vibration and proprioception helps to identify dysfunction of either the posterior columns of the spinal cord or of the dorsal root ganglia. An abnormal Romberg test also identifies a deficit in proprioception of the lower extremities. The patient's so-called slapping gait is characteristic of a sensory ataxia. This is seen when a patient has the inability to determine the location of his feet and the progress of any ongoing movements because of a loss in proprioceptive input from the legs. The resulting gait is wide-based and slow; each foot is thrust forward and then slapped down onto the ground in an effort to increase sensory information from that foot. Increased muscle tone in the lower extremities, hyperreflexia, and bilateral Babinski signs suggest pyramidal tract dysfunction. Thus, the neurologic exam supports the presence of a polyneuropathy, and also supplies evidence for dysfunction of both the posterior columns and of the corticospinal (pyramidal) tracts of the spinal cord.
Her evaluation began with an assessment of possible causes of encephalopathy. Initial studies, including blood glucose, electrolytes, oxygen saturation, kidney and liver function, drug screen, and medication review were all unrevealing. An EEG was performed to further characterize the mild encephalopathy, and it did not show evidence of epileptiform activity. The confluent, symmetric white matter lesions seen on the CT scan and confirmed by MRI can be consistent with multiple sclerosis, HIV encephalitis, storage diseases, or other leukoencephalopathies (including vitamin B12 deficiency). However, encephalopathy and prominent proprioceptive difficulties are uncommon presenting symptoms of multiple sclerosis. HIV encephalitis is a possibility, but it would only account for the encephalopathy; furthermore, she did not have any clear risk factors for HIV transmission, and an HIV test was eventually negative. Most of the leukodystrophies (Krabbe's, metachromatic leukodystrophy, Pelizaeus-Merzbacher, Cockayne syndrome, Alexander's, and Canavan's) present in infancy or early childhood. Adrenoleukodystrophy is an X-linked disorder; female carriers can present with myelopathy but usually do not develop the other clinical features of dementia, visual loss, and adrenal insufficiency.
Involvement of both the posterior columns and of the pyramidal tracts is characteristic of subacute combined degeneration of the spinal cord, the pathological process seen in vitamin B12 deficiency. Friedreich's ataxia, a hereditary degenerative condition resulting in ataxia, can also cause this pattern of involvement. However, the onset of symptoms with Friedreich's ataxia typically occurs before the age of 20 years, and the condition is inherited in an autosomal recessive manner. Recent studies have implicated an intronic trinucleotide repeat (GAA) on chromosome 9 involving a gene encoding for frataxin.
Lhermitte's sign occurs most commonly with multiple sclerosis, but can also be seen with other lesions of the cervical cord, including tumors, cervical disc herniation, post-trauma, post-radiation myelopathy, and intrinsic lesions. Having defined a myelopathy involving the cervical cord, it was important to obtain an imaging study of the cervical spine to rule out significant spondylosis or a mass lesion. The MRI of the cervical spine did show spinal stenosis which could partially account for the hyperreflexia seen in the lower extremities, but did not show enough cord involvement to account for the degree of the patient's symptoms.
Laboratory tests included CSF studies, which were unremarkable. A normal CSF protein made the diagnosis of an inherited dysmyelinating condition less likely. Moreover, the CSF, VER, and BAER were not supportive of a diagnosis of multiple sclerosis. A megaloblastic anemia was present which was consistent with (but not a necessary requirement of) the diagnosis of vitamin B12 deficiency. Obviously, a low serum B12 level in this clinical setting provided more supportive evidence. The abnormal Schilling test, which demonstrated a defect in absorption in cobalamin absorption that improved with addition of intrinsic factor, was diagnostic of pernicious anemia.
The patient was started on vitamin B12 intramuscular injections. She was given 1000 mcg two times per week for two weeks, and then 1000 mcg monthly thereafter. Almost immediately after the initiation of injections, she reported improvement in concentration. Within two weeks, she noted improvement in gait. Six months later, she still has mild gait difficulty, but with rehabilitation, she has become able to walk without a walker.
Vitamin B12 deficiency is one of a few nutritional diseases encountered regularly by neurologists in North America. Vitamin B12, cyanocobalamin, is abundant in meat, fish, and most animal by-products. Vegetables are generally devoid of this vitamin, but even strict vegetarians rarely develop a clinical deficiency because only 5 mcg of vitamin B12 is needed per day and an adequate amount is provided by legumes. Most cases of B12 deficiency result from difficulties in B12 absorption, not in a deficiency of dietary intake.
The onset of symptoms is usually insidious, with paresthesias in the hands and feet present in the majority of patients. The next most common complaints include weakness and unsteadiness of gait. Cerebral symptoms may occur and can include confusion, delusions, hallucinations, mental slowing, and depression. Some patients also complain of GI symptoms, such as dyspepsia, flatulence, and altered bowel habits.
On examination, most patients have signs of both spinal cord and peripheral nerve involvement, although either can be affected first in the early stage of this disorder. Loss of position or vibration sense is the most common abnormality. Motor impairment may range from only mild clumsiness to a spastic paraplegia. The effect on reflexes is quite variable, tendon reflexes in the legs can be decreased or absent (from peripheral nerve dysfunction) or increased with extensor plantar responses (from pyramidal tract dysfunction). Visual impairment can be seen; ophthalmological exam may show bilateral visual loss, optic atrophy, and centrocecal scotomata. Brainstem or cerebellar signs or even reversible coma may occur.
Hematological abnormalities, including hypersegmentation of polymorphonuclear cells and a macrocytic anemia, can be seen; however, they may be completely absent at the time of neurological presentation. Current state-of-the-art testing uses serum cobalamin levels as a screening test, and the Schilling test and serum or urine methylmalonic acid and homocysteine determinations as confirmatory tests. The cobalamin assay is complicated by the fact that most of the cobalamins present in serum are bound to several transport proteins (transcobalamins I, II, and III). Myeloproliferative and hepatic disorders may raise the concentration of transcobalamin I and III, and this may result in a falsely normal serum level. In contrast, pregnancy may give low measurements in the absence of deficiency.
A Schilling test, which would detect impaired intestinal absorption of vitamin B12, should be performed if there is enough clinical suspicion for the disease, and may reveal low vitamin B12 absorption even when the serum level is normal.
Leukoencephalopathy, evidenced by confluent white matter abnormalities on MRI, is becoming increasingly recognized as a possible presenting sign of cobalamin deficiency, even in the absence of anemia or myelopathy.
Nonspecific EEG abnormalities may be seen, and if present, normalization of findings on follow-up EEGs can provide an early objective demonstration of a beneficial response to vitamin B12 therapy. Visual and somatosensory responses are frequently abnormal, nerve conduction studies show small or absent sural nerve potentials in about 80% of patients.
Dietary vitamin B12 is released from food products by acid peptidases in the stomach; the released vitamin B12 binds to intrinsic factor (IF), a protein secreted by gastric parietal cells. The B12-IF complex is transported to the ileum, where it is absorbed into the circulation via specific receptors present on ileal mucosal cells. The vitamin B12 then binds to transcobalamins for transport to tissues. About 90% of the total body vitamin B12 (1-10 mg) is stored in the liver. Thus, even with a severe impairment in vitamin B12 absorption, an average of five years is needed to deplete the body store.
Two biochemical reactions depend on vitamin B12. The first is a folate-dependent reaction in which the methyl group of methyltetrahydrofolate is transferred to homocysteine to form methionine. This reaction depends on the enzyme methionine synthase, which has cobalamin as a cofactor. Reduced cofactor activity from vitamin B12 eventually leads to impaired DNA synthesis.The other cobalamin-dependent process, conversion of methylmalonyl coA to succinyl coA, is of unclear significance in the nervous system complications of vitamin B12 deficiency.
The pathological process has been described by the term subacute combined degeneration of the spinal cord. Microscopically, spongy changes and foci of myelin and axon destruction are seen in the white matter of the spinal cord. The most severely affected areas include the posterior and lateral columns of the cervical and upper thoracic spinal cord. In the peripheral nervous system, axonal degeneration, without significant demyelination, is seen. In some cases, involvement of the optic nerve and cerebral white matter can be seen.
One hypothesis for how vitamin B12 deficiency could result in white matter degeneration involves the role of vitamin B12 in methylation reactions. Myelin sheaths in both central white matter and peripheral nerves are composed of compact arrays of proteolipids. Altered or deficient methylation reactions because of vitamin B12 deficiency may result in the formation of fatty acids of altered sizes. These fatty acids may not be able to adopt a normal compact array within the myelin sheath. The resulting spongy form of myelin may be structurally weak and susceptible to degradation.
Most cases of vitamin B12 deficiency probably result from pernicious anemia, with defective intrinsic factor production by gastric parietal cells. The presence of circulating antibodies to parietal cells in many of these patients suggests an underlying autoimmune disorder. Gastrectomy is another cause of intrinsic factor deficiency, although it seldom causes symptomatic deficiency in isolation. Various disorders of the small intestine, such as surgical resection of the terminal ileum and blind loop syndrome, may result in malabsorption of vitamin B12. Rare cases of dietary insufficiency can be seen in strict vegetarians without evidence of malabsorption.
High-risk groups for the deficiency syndrome include the elderly, patients taking ulcer medications over long periods, patients with acquired immunodeficiency syndrome, vegetarians, patients who have undergone stomach resection or small bowel resection, or both, and patients with dementia.
Interestingly, after heavy abuse of nitrous oxide, patients can develop a clinical syndrome identical to that of vitamin B12 deficiency. Subjects improve when nitrous oxide is stopped. The mechanism appears to be an interference with the vitamin B12-dependent conversion of homocysteine to methionine. Serum vitamin B12 and the Schilling test are almost always normal. Subjects who are already deficient in vitamin B12 seem to be more susceptible to the neurologic effects of prolonged nitrous oxide exposure.
With proper treatment, at least partial improvement can be expected in most instances. Most of the improvement occurs during the first six months of therapy. Remission of symptoms correlates inversely with the time lapse between onset of symptoms and initiation of therapy. Thus, early diagnosis and treatment is vital.
A typical regimen consists of intramuscular injections of 1,000 mcg twice weekly for two weeks, followed by monthly injections of 1,000 mcg. For patients whose Schilling test demonstrates malabsorption of vitamin B12, monthly 1,000 mcg injections should be continued on a lifelong basis. There is no evidence that overdosing can speed neurologic recovery; adverse reaction to high doses of vitamin B12 is unknown. The need for B12 injections is questionable for patients with achlorhydria and for those with a marginal or low serum B12 level but no signs or symptoms of deficiency.
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