What are the causes, clinical presentation, diagnostic evaluation, and treatment recommendations for subacute combined degeneration of the spinal cord?

Subacute Combined Degeneration of the Spinal Cord

Overview

Subacute combined degeneration (SCD) is a neurological emergency caused by vitamin B12 deficiency that requires immediate treatment with hydroxocobalamin 1 mg intramuscularly on alternate days until no further neurological improvement occurs, followed by lifelong maintenance therapy every 2 months. 1, 2

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Etiology

SCD results from demyelination of the dorsal and lateral columns of the spinal cord due to vitamin B12 deficiency 3. The underlying causes include:

• Pernicious anemia (autoimmune destruction of intrinsic factor) 2
• Malabsorption disorders (celiac disease, Crohn's disease, ileal resection) 2
• Post-bariatric surgery (gastric bypass) 2
• Strict vegetarian/vegan diet (reduced dietary intake) 2, 3
• Nitrous oxide exposure (inactivates vitamin B12) 3
• Medications that interfere with B12 absorption 2

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Clinical Presentation

Sensory Manifestations

• Dorsal column dysfunction: Loss of proprioception and vibration sense, typically starting in the lower extremities 4
• Paresthesias: "Pins and needles" or "electric shock" sensations in the trunk and limbs 2, 4
• Loss of tactile and pain sensation 2, 4

Motor Manifestations

• Gait ataxia (sensory ataxia from proprioceptive loss) 2, 4
• Muscle weakness 2, 4
• Spasticity and abnormal reflexes (hyperreflexia or hyporeflexia) 2, 4

Critical Clinical Pearls

• Neurological symptoms often precede hematologic changes—up to one-third of patients lack megaloblastic anemia at presentation 4
• Peripheral nerve conduction studies may show reduced velocity, indicating concurrent peripheral neuropathy 2, 4

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Diagnostic Evaluation

Laboratory Testing Algorithm

Step 1: Initial Screening

• Measure serum total vitamin B12 or active B12 (holotranscobalamin) first—do NOT use methylmalonic acid (MMA) as the initial screening test 4

Step 2: Interpret B12 Results

• Serum B12 <180 pg/mL (<133 pmol/L): Confirmed deficiency → start treatment immediately 4
• Serum B12 180–350 pg/mL (133–258 pmol/L): Indeterminate → proceed to MMA measurement 4
• Serum B12 >350 pg/mL (>258 pmol/L): Deficiency unlikely, but consider MMA if clinical suspicion remains high 4

Alternative: Active B12 Thresholds

• <25 pmol/L: Confirmed deficiency 4
• 25–70 pmol/L: Indeterminate → order MMA 4
• >70 pmol/L: Deficiency unlikely 4

Step 3: Confirmatory Functional Testing

• MMA >271 nmol/L confirms functional B12 deficiency with 98.4% sensitivity 4
• Standard serum B12 misses functional deficiency in up to 50% of cases 4, 5
• Homocysteine >15 µmol/L supports B12 deficiency but is less specific (also elevated in folate deficiency or renal impairment) 4

Step 4: Concurrent Testing

• Complete blood count: May show macrocytic anemia (MCV >98 fL), though absent in ~33% of cases 4, 6
• Serum folate: Check concurrently as folate deficiency frequently coexists 2, 4
• Intrinsic factor antibodies and gastrin: Markedly elevated gastrin (>1000 pg/mL) identifies pernicious anemia 4

MRI Spinal Cord Imaging

Indications: MRI is required to confirm SCD and exclude alternative diagnoses (demyelinating diseases, copper deficiency myelopathy, HIV-associated myelopathy, spinal cord compression) 7, 4

Characteristic T2-Weighted Patterns:

• Cervical spine: Symmetric linear hyperintensity in an "inverted V" pattern within the posterior columns (most common site, 33–62% of cases) 4
• Thoracic spine: Bilateral paired nodular hyperintensity resembling "binoculars" or "dumbbell" pattern (19–25% of cases) 4
• Contrast enhancement: Typically absent; only ~12% show minimal enhancement 4

Critical Limitation: Conventional MRI sensitivity is only ~53% for SCD—a normal MRI does NOT rule out the diagnosis 4, 8. One study found MRI abnormalities in only 8 of 54 patients (14.8% sensitivity) 8.

Red-Flag Imaging Findings Suggesting Alternative Diagnoses:

• "Trident sign" (subpial plus central canal enhancement): Neurosarcoidosis 4
• Longitudinally extensive lesions with "cloud-like" enhancement: Neuromyelitis optica spectrum disorder 4
• Leptomeningeal enhancement: Sarcoidosis, granulomatous disease, or vasculitis 4

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Treatment Recommendations

Acute Treatment Protocol for Neurological Involvement

Initial Phase:

• Hydroxocobalamin 1 mg intramuscularly on alternate days until no further neurological improvement occurs 1, 2
• Hydroxocobalamin is preferred over cyanocobalamin due to better retention in the body and safety in renal dysfunction 2

Maintenance Phase:

• Hydroxocobalamin 1 mg intramuscularly every 2 months for life 1, 2

Treatment Protocol for Patients WITHOUT Neurological Involvement

• Hydroxocobalamin 1 mg intramuscularly three times a week for 2 weeks 1
• Followed by maintenance treatment of 1 mg intramuscularly every 2–3 months lifelong 1

Critical Treatment Warning

NEVER administer folic acid before or without treating vitamin B12 deficiency—folic acid may mask the underlying B12 deficiency by correcting anemia while allowing irreversible neurological damage to progress 1, 2, 4

Monitoring During Treatment

Clinical Monitoring:

• Assess proprioception, vibration sense, gait ataxia, muscle weakness, reflexes, and paresthesias 2
• Monitor peripheral nerve conduction velocity 2

Laboratory Monitoring:

• Target homocysteine <10 μmol/L for optimal outcomes 2
• Monitor every 3 months until stabilization, then annually 2
• Repeat MMA and homocysteine to confirm biochemical response 2, 6

MRI Follow-Up:

• Spinal cord MRI abnormalities typically resolve within 3 months of treatment 3
• Complete resolution of cord signal abnormalities was observed in all treated patients in one case series 3

Addressing Underlying Etiology

Determine and treat the root cause of B12 deficiency 2:

• Pernicious anemia: Lifelong parenteral B12 therapy required 2
• Malabsorption disorders: Treat underlying condition; may require lifelong parenteral therapy 2
• Post-bariatric surgery: Lifelong supplementation mandatory 2
• Dietary insufficiency: Dietary counseling and supplementation 2

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Common Pitfalls and Caveats

Diagnostic Pitfalls

• Relying solely on serum B12 levels: Up to 50% of functional B12 deficiencies are missed without MMA testing 4, 5
• Assuming normal MRI excludes SCD: MRI sensitivity is only 14.8–53%; diagnosis is clinical and biochemical 4, 8
• Overlooking SCD in patients without anemia: One-third of patients lack megaloblastic anemia at presentation 4

Treatment Pitfalls

• Inadequate B12 replacement dosing: Monthly injections are insufficient for neurological involvement; alternate-day dosing is required until maximal improvement 9
• Administering folic acid first: This can precipitate or worsen SCD by masking B12 deficiency 1, 2, 4
• Failing to identify underlying cause: Without addressing the root cause (e.g., pernicious anemia), deficiency will recur 2

Prognostic Considerations

• Early detection and treatment are critical: SCD is reversible when detected and treated early 3
• Inverse correlation between B12 levels and clinical severity: Lower initial B12 levels predict worse clinical severity 8
• Neurological recovery may be incomplete if treatment is delayed: Prompt aggressive replacement maximizes recovery potential 9