The main differential diagnostic considerations of the combined sensory and motor features are cervical spondylosis (see Chaps. 10 and 42), multiple sclerosis of the cervical cord (see Chap. 35), non-B12-deficient combined system disease caused by low levels of serum copper (see Chap. 42), and rarities such as the female carrier state of adrenoleukodystrophy (see Chap. 36). The myelopathy associated with copper deficiency affects the posterior and lateral columns subacutely in a manner identical to that of subacute combined degeneration but unassociated with any form of B12 deficiency or related enzyme derangement. Somewhat to our surprise, the copper disorder has been as frequent as the classic type caused by B12 deficiency in our clinics. One remarkable circumstance, with which we have had experience, is the creation of severe SCD including paralysis in a B12-deficient patient whose myelopathic symptoms were misattributed to cervical spondylosis and who had an operation in which nitrous oxide was used as anesthesia.
The chief obstacle to early diagnosis of SCD is the lack of parallelism that may exist between the hematologic and neurologic signs, particularly in patients who have taken dietary or medicinal folate. Anemia may also at times be absent, sometimes for many months, even in patients who have not taken folate. For example, in a retrospective study of 141 patients with neuropsychiatric abnormalities caused by cobalamin deficiency, there were 19 patients in whom both the hematocrit and mean red blood cell volume were normal (Lindenbaum et al); in these patients, subtle morphologic abnormalities such as hypersegmented polymorphonuclear leukocytes and megaloblastosis in bone marrow smears were almost always found if carefully sought.
Serum cobalamin should be measured whenever the diagnosis of vitamin B12 deficiency is in question. Microbiologic assay (using Euglena gracilis) is the most accurate measurement, but the method is time-consuming and cumbersome and has been replaced by a commercial radioisotope dilution assay (the inexpensive chemiluminescence assay is an alternative but slightly less dependable). With the radioassay, a serum B12 level below 100 pg/mL is usually associated with neurologic symptoms and signs of vitamin B12 deficiency. A level below 200 pg/mL that is unassociated with symptoms calls for further investigation of cobalamin deficiency. However, even serum levels of 200 to 300 pg/mL may still be associated (in 5 to 10 percent of cases) with cobalamin deficiency. High serum concentrations of cobalamin metabolites, methylmalonic acid (normal range, 73 to 271 nmol/L), and homocysteine (normal range 5.4 to 16.2 mmol/L) are additional reliable indicators of an intracellular cobalamin deficiency and can be used to corroborate the diagnosis in cases of low-mid-range B12 levels (Allen et al; Lindenbaum et al). It must be emphasized that the serum cobalamin level is not a measure of total-body cobalamin. In a patient who stops absorbing ingested cobalamin, the serum levels may remain in the normal range for months or years despite decreasing tissue reserves. In patients who have received vitamin B12 parenterally, the 2-stage Schilling test is a more reliable indicator of cobalamin deficiency because it uncovers a defect in absorption of the vitamin; however, the Schilling test has been largely supplanted for routine diagnosis by the measurement of antibodies to intrinsic factor and parietal cells.