What are the causes of bilateral subacute combined degeneration (SSCD)?

Causes of Bilateral Subacute Combined Degeneration (SSCD)

Primary Etiology: Vitamin B12 Deficiency

Bilateral subacute combined degeneration is fundamentally caused by vitamin B12 deficiency, which leads to extensive demyelination in the central nervous system—most prominently affecting the dorsal and lateral columns of the spinal cord bilaterally. 1

The bilateral nature of SSCD is inherent to the disease process itself, as vitamin B12 deficiency causes symmetric demyelination throughout the spinal cord white matter. 2 The term "bilateral" is somewhat redundant when discussing SSCD, as the condition characteristically affects both sides of the spinal cord simultaneously due to the systemic nature of cobalamin deficiency. 1

Specific Causes Leading to SSCD

Malabsorption Disorders

• Pernicious anemia is the classic cause, resulting from autoimmune destruction of gastric parietal cells leading to intrinsic factor deficiency and subsequent B12 malabsorption. 3 This represents the most common etiology in clinical practice.

• Autoimmune gastritis can progress to severe B12 malabsorption and may present with the triad of SSCD, pernicious anemia, and gastric neuroendocrine tumors due to chronic hypergastrinemia. 3

• Post-surgical states including gastrectomy or ileal resection impair B12 absorption, as the terminal ileum is the primary absorption site requiring intrinsic factor and calcium. 4

Dietary Deficiency

• Strict vegetarian or vegan diets that exclude all animal products (meat, dairy, eggs) provide no dietary B12 source, as the vitamin is absent from plant-based foods. 4 This can manifest even in breastfed infants of vegetarian mothers who themselves may be asymptomatic. 4

Nitrous Oxide Exposure

• Nitrous oxide inhalation inactivates the biologically active form of vitamin B12, causing functional deficiency even when serum B12 levels are normal. 5, 2 This occurs through:
  • Recreational abuse: Cases report SSCD after approximately 3,000g of N2O inhalation within 5 days plus daily use for 3 weeks prior. 5
  • Surgical anesthesia exposure: Even therapeutic nitrous oxide during surgery can precipitate SSCD in susceptible individuals. 2

Medication-Induced

• Chronic medication use can impair B12 absorption or metabolism, including:
  • Methotrexate and pyrimethamine (invalidate B12 diagnostic assays and may affect metabolism) 4
  • Colchicine and para-aminosalicylic acid (produce malabsorption when used >2 weeks) 4
  • Heavy alcohol intake for >2 weeks impairs B12 absorption 4

Rare Causes

• Abnormal B12 binding proteins can cause SSCD despite high serum B12 levels, as the vitamin remains biologically unavailable. 6 This represents a unique syndrome where red blood cell B12 is low despite elevated serum levels, and plasma inhibits normal cobalamin uptake by leukocytes.

• Folic acid masking: Indiscriminate folic acid administration (>0.1 mg daily) can produce hematologic remission while allowing neurologic progression to irreversible SSCD. 4 This is a critical pitfall where anemia improves but spinal cord degeneration continues unchecked.

Critical Clinical Pitfall

The most dangerous scenario occurs when B12 deficiency progresses untreated for >3 months, producing permanent degenerative lesions of the spinal cord. 4 Additionally, SSCD can present with normal serum B12 levels in cases of nitrous oxide exposure or abnormal binding proteins, making diagnosis challenging. 6, 5 In these situations, elevated methylmalonic acid, homocysteine, and presence of intrinsic factor antibodies despite normal B12 levels should raise suspicion. 6, 5

The bilateral symmetric involvement is pathognomonic on MRI, showing T2-weighted hyperintensity in dorsal and lateral columns bilaterally. 3, 2 This imaging pattern combined with the clinical triad of spastic paresis, vibratory sense loss, and proprioceptive deficits establishes the diagnosis. 5