A 52-year-old right-handed physician noticed numbness and paresthesia in his hands after bicycle riding. Three weeks later, he noted similar sensations in his feet and mild unsteadiness of his gait. These symptoms persisted for 5 weeks before he brought them to the attention of his physician. He was previously healthy and was taking no medications. Neurologic examination showed mild intrinsic hand muscle weakness bilaterally. Reflexes were brisk in the arms and legs, but plantar responses were flexor. Vibration and proprioception were reduced in the hands and feet. Findings on Romberg's test were negative and his gait was normal. Further neurologic examination with nerve conduction studies showed no evidence of neuropathy.

A complete blood count showed a hemoglobin of 14.1 g/dl (normal range, 13.5-17.5 g/dl) but an elevated mean corpuscular volume of 113 fl (normal range, 80-100 fl). Serum vitamin B₁₂ level was low, less than 100 pg/ml (normal range, 200-750 pg/ml), and serum folate level was high, 17.6 ng/ml (normal range, 2.8-14.0 ng/ml). The Schilling test results were consistent with pernicious anemia. Part I, without intrinsic factor, showed decreased excretion of B₁₂; part II, with intrinsic factor, showed normal results.

MR imaging of the cervical spine (Fig. 1A,1B,1C,1D) showed increased signal intensity on T2-weighted images in the posterior columns from the C1-C6 levels, with slight enhancement after IV administration of gadolinium. No significant expansion of the cord was seen. MR imaging of the brain showed a few nonspecific foci of abnormal signal intensity on T2-weighted images in the deep white matter of the right frontal and left parietal lobes.

The patient was started on B₁₂ injections: 100 μg intramuscularly dialy for the first week, then 1000 μg intramuscularly monthly. After 3 months, his symptoms resolved and his sensory examination normalized. Follow-up cervical spine MR imaging (Fig. 1A,1B,1C,1D) 3 months after initiation of B₁₂ therapy showed marked interval resolution of the areas of abnormal signal intensity in the spinal cord. Follow-up brain MR imaging was unchanged.

We excluded clinically other causes that might have been considered before the laboratory and imaging workup. The patient had no risk factors for HIV or exposure to Lyme disease. Therefore, a cerebrospinal fluid analysis was not performed. The patient's age and lack of previous neurologic symptoms made multiple sclerosis an unlikely cause, and the subacute course of the illness was not consistent with acute disseminated encephalomyelitis.

Vitamin B₁₂ is contained in essentially all meat and dairy products. After B₁₂ is ingested, it is bound to intrinsic factor that is secreted by gastric parietal cells. The B₁₂ intrinsic factor complex binds to the mucosa of the terminal ileum, where B₁₂ is then absorbed. In the United States, B₁₂ deficiency is rarely caused by an inadequate intake, which is most often seen in strict vegetarians. More commonly, B₁₂ deficiency is the result of malabsorption syndromes such as bacterial overgrowth of the small bowel, pernicious anemia, regional enteritis, tropical sprue, or surgical procedures such as gastric fundus or ileal resection [1]. Pernicious anemia is the most common cause of B₁₂ malabsorption in the United States. It is an immune-mediated process resulting in destruction of the gastric parietal cells. This destruction leads to achlorohydria, atrophic gastritis, and decreased availability of intrinsic factor. Patients with pernicious anemia present clinically at a mean age of 60 years and often have other associated autoimmune disorders such as Graves' disease [1].

The clinical presentation of subacute combined degeneration is caused by dorsal column, lateral corticospinal tract, and sometimes lateral spinothalamic tract dysfunction. The initial symptoms are usually paresthesia in the hands and feet. This condition may progress to sensory loss, gait ataxia, and distal weakness, particularly in the legs. If the disease goes untreated, an ataxic paraplegia may evolve [2]. Specific findings on examination are loss of vibratory and joint position sense, weakness, spasticity, hyperreflexia, and extensor plantar responses. The differential diagnosis for progressive spastic paraplegia includes degenerative, demyelinating, infectious, inflammatory, neoplastic, nutritional, and vascular disorders. Some disorders with prominent vibratory and proprioceptive loss include Friedreich's ataxia, sensory neuropathies and neuronopathies, tabes dorsalis, and vitamin E deficiency. The differential diagnosis of subacute combined degeneration is broad, but B₁₂ deficiency should be considered in any patient with progressive sensory symptoms or weakness.

The diagnosis of B₁₂ deficiency is made by a low serum B₁₂ level, or if the B₁₂ level is borderline, elevated levels of the metabolites homocysteine and methylmalonic acid. The hematologic changes, most notably megaloblastic anemia, are not reliable markers for B₁₂ deficiency. More than one quarter of patients with neurologic syndromes will have a normal complete blood count [3]. Pernicious anemia can be confirmed by positive findings on the Schilling test or by the presence of anti—intrinsic factor antibodies (60% sensitive), which are more specific than antiparietal cell antibodies (90% sensitive) [4]. Patients with pernicious anemia have a twofold increased risk for gastric polyps and cancer, and additional examination may be required [1].

Treatment of B₁₂ deficiency is monthly B₁₂ intramuscular injections for life. The degree of resolution of the clinical symptoms in subacute combined degeneration is inversely proportional to their duration and severity. This relationship underscores the importance of early diagnosis [2].

Pathologic studies of the spinal cord show multifocal demyelinated and vacuolated lesions in the posterior, lateral, and sometimes anterior columns. Demyelination begins as scattered plaques in the dorsal columns and progresses to the lateral columns. Wallerian degeneration of these tracts may be present. Lesions typically occur in the thoracic and cervical spinal cord but may even affect the medulla [4]. Exactly why demyelination occurs and why specific tracts are more affected than others is uncertain. One theory is that B₁₂ deficiency interferes with all methylation reactions, including those needed for myelin phospholipids. This interference leads to the production of unstable myelin [5].

Few reported cases of MR imaging of subacute combined degeneration exist [6]. Findings in these cases include modest expansion of the cervical and thoracic spinal cord and increased signal intensity on T2-weighted images, primarily in the dorsal columns [6]. In one patient, enhancement after the administration of gadolinium was similar to that of our patient [6]. Although these findings are consistent with those of subacute combined degeneration, they are nonspecific. MR imaging is useful in distinguishing the different causes of intramedullary myelopathy [7].

The differential diagnosis of an intramedullary lesion is broad and includes demyelinating disorders (multiple sclerosis), infectious causes (HIV vacuolar myelopathy and herpes viruses), inflammatory processes (sarcoidosis), ischemia, and neoplasms (astrocytomas and ependymomas) [7]. However, some features distinguish subacute combined degeneration from these other entities. In subacute combined degeneration, the abnormal signal intensity is particularly prominent in the dorsal columns. This location is suggestive of demyelinating disease. In subacute combined degeneration, this signal is usually contiguous in length over several vertebral bodies. However, in demyelinating lesions having other causes, lesions often do not exceed two vertebral bodies in length and are frequently multiple.

Other inflammatory processes and neoplasms are associated with more extensive cord expansion and enhancement. The minimal enhancement seen in this condition reflects breakdown of the blood—brain barrier. This breakdown may be caused by perivascular demyelination and inflammation [5]. Vacuolar myelopathy seen in AIDS patients may appear similar to subacute combined degeneration both in pathology and on MR imaging, but the two can usually be differentiated by the patient's history [5]. However, the resolution of the clinical symptoms and radiologic findings after B₁₂ therapy confirms the diagnosis of subacute combined degeneration.

MR imaging of the brain in B₁₂ deficiency shows confluent areas of abnormal signal intensity on T2-weighted images in the cerebral white matter, with resolution of these changes often in months after initiation of B₁₂ therapy [8]. In vacuolar myelopathy, the brain MR findings are frequently mild, often irreversible, and may be caused by small-vessel ischemia.

It is important to distinguish B₁₂ deficiency from other causes of myelopathy. Subacute combined degeneration is curable, but early detection is necessary for full clinical recovery. Although not specific for subacute combined degeneration, the MR findings have distinguishing features. MR imaging may be a useful addition to the clinical assessment in monitoring the efficacy of treatment.

Address correspondence to L. A. Loevner.