Subacute combined degeneration (SCD) is an acquired neurologic complication of vitamin B12 (cobalamin) or, rarely, vitamin B9 (folate) deficiency. SCD is characterized by progressive demyelination of the dorsal and lateral spinal cord, resulting in peripheral neuropathy; gait ataxia; impaired proprioception, vibration, and fine touch; optic neuropathy; and cognitive impairment. 1 In addition to SCD, other neurologic manifestations of B12 deficiency include dementia, depression, visual symptoms due to optic atrophy, and behavioral changes. 2 The prevalence of SCD in the US has not been well documented, but B12 deficiency is reported at 6% in those aged < 60 years and 20% in those > 60 years .3
Causes of B12 and B9 deficiency include advanced age, low nutritional intake (eg, vegan diet), impaired absorption (eg, inflammatory bowel disease, autoimmune pernicious anemia, gastrectomy, pancreatic disease), alcohol use, tapeworm infection, medications, and high metabolic states. 2,4 Impaired B12 absorption is common in patients taking medications, such as metformin and proton pump inhibitors (PPI), due to suppression of ileal membrane transport and intrinsic factor activity. 5-7 B-vitamin deficiency can be exacerbated by states of increased cellular turnover, such as polycythemia vera, due to elevated DNA synthesis.
Patients may experience permanent neurologic damage when the diagnosis and treatment of SCD are missed or delayed. Early diagnosis of SCD can be challenging due to lack of specific hematologic markers. In addition, many other conditions such as diabetic neuropathy, malnutrition, toxic neuropathy, sarcoidosis, HIV, multiple sclerosis, polycythemia vera, and iron deficiency anemia have similar presentations and clinical findings. 8 Anemia and/or macrocytosis are not specific to B12 deficiency. 4 In addition, patients with B12 deficiency may have a normal complete blood count (CBC); those with concomitant iron deficiency may have minimal or no mean corpuscular volume (MCV) elevation. 4 In patients suspected to have B12 deficiency based on clinical presentation or laboratory findings of macrocytosis, serum methylmalonic acid (MMA) can serve as a direct measure of B12 activity, with levels > 0.75 μmol/L almost always indicating cobalamin deficiency. 9 On the other hand, plasma total homocysteine (tHcy) is a sensitive marker for B12 deficiency. The active form of B12, holotranscobalamin, has also emerged as a specific measure of B12 deficiency. 9 However, in patients with SCD, measurement of these markers may be unnecessary due to the severity of their clinical symptoms.
The diagnosis of SCD is further complicated because not all individuals who develop B12 or B9 deficiency will develop SCD. It is difficult to determine which patients will develop SCD because the minimum level of serum B12 required for normal function is unknown, and recent studies indicate that SCD may occur even at low-normal B12 and B9 levels. 2,4,10 Commonly, a serum B12 level of < 200 pg/mL is considered deficient, while a level between 200 and 300 pg/mL is considered borderline. 4 The goal level of serum B12 is > 300 pg/mL, which is considered normal. 4 While serologic findings of B-vitamin deficiency are only moderately specific, radiographic findings are highly sensitive and specific for SCD. According to Briani and colleagues, the most consistent finding in SCD on magnetic resonance imaging (MRI) is a “symmetrical, abnormally increased T2 signal intensity, commonly confined to posterior or posterior and lateral columns in the cervical and thoracic spinal cord.” 2