Diagnosis of Subacute Combined Degeneration
Subacute combined degeneration (SCD) is diagnosed through a combination of clinical neurological findings, laboratory confirmation of vitamin B12 deficiency with functional markers, and characteristic MRI findings showing symmetric T2-hyperintensity in the dorsal and lateral columns of the spinal cord. 1, 2
Clinical Presentation
The diagnosis begins with recognizing the characteristic neurological syndrome:
- Sensory deficits: Look for impaired proprioception, vibratory sense, tactile sensation, and pain perception, typically affecting the lower extremities first 3
- Motor abnormalities: Assess for gait ataxia, muscle weakness, spasticity, and abnormal reflexes (hyperreflexia or hyporeflexia) 3
- Subjective symptoms: Patients report paresthesias and numbness in the trunk and limbs, often described as "pins and needles" or "electric shocks" 3
- Peripheral nerve involvement: Reduced peripheral nerve conduction velocity may be present 3
Critical pitfall: Neurological symptoms often appear before hematologic changes develop, so the absence of anemia does not exclude SCD. 4 Up to one-third of patients with SCD lack megaloblastic anemia at presentation. 4
Laboratory Diagnosis
Initial B12 Testing
Start with serum total vitamin B12 or active B12 (holotranscobalamin) as the first-line test—never use methylmalonic acid (MMA) as initial screening. 4
Interpretation of total serum B12:
- <180 pg/mL (<133 pmol/L): Confirmed deficiency—proceed directly to treatment 4
- 180-350 pg/mL (133-258 pmol/L): Indeterminate range—measure MMA to confirm functional deficiency 4
- >350 pg/mL (>258 pmol/L): Deficiency unlikely, but consider MMA if high clinical suspicion persists 4
Interpretation of active B12 (holotranscobalamin):
- <25 pmol/L: Confirmed deficiency 4
- 25-70 pmol/L: Indeterminate—measure MMA 4
- >70 pmol/L: Deficiency unlikely 4
Confirmatory Functional Testing
When B12 results fall in the indeterminate range or clinical suspicion remains high despite normal serum B12, measure methylmalonic acid (MMA). 4 This is crucial because standard serum B12 testing misses functional deficiency in up to 50% of cases. 4
- MMA >271 nmol/L: Confirms functional B12 deficiency with 98.4% sensitivity 4
- Homocysteine >15 μmol/L: Supports B12 deficiency but is less specific than MMA (can be elevated in folate deficiency or renal impairment) 4
Diagnostic algorithm for metabolites:
- Elevated MMA + elevated homocysteine = B12 deficiency 4
- Normal MMA + elevated homocysteine = folate deficiency or MTHFR dysfunction 4
Additional Laboratory Studies
- Complete blood count: Check for macrocytic anemia (MCV >98 fL), though this may be absent in one-third of cases 4
- Folate level: Always check concurrently, as deficiencies often coexist 4, 3
- Intrinsic factor antibodies: If pernicious anemia is suspected 4
- Gastrin level: Markedly elevated (>1000 pg/mL) in pernicious anemia 4
MRI Findings
Spinal cord MRI is essential for confirming SCD and excluding alternative diagnoses, though conventional MRI has only 52.8% sensitivity. 2
Characteristic MRI Patterns
T2-weighted images show symmetric hyperintensity in the dorsal and lateral columns of the spinal cord: 2, 5
Cervical spine (most common site, 33-62.5% of cases):
- Axial images reveal symmetric linear T2-hyperintensity in an "inverted V" pattern in the posterior columns 2, 5
- This is considered the typical sign of SCD 2
Thoracic spine (19-25% of cases):
- Axial images show bilateral paired nodular T2-hyperintensity resembling "binoculars" or "dumbbell" pattern 2, 5
Less common sites:
- Brain stem and cerebellar involvement can occur but is rare 6
- Anterior horn involvement is extremely rare 2
MRI Technical Considerations
- T2-weighted sequences are most sensitive for detecting spinal cord signal abnormalities 2, 5
- Contrast enhancement is typically absent or minimal—only 1 in 8 patients showed slight enhancement in one series 2
- Follow-up MRI after treatment shows resolution or decreased extent of lesions, confirming the diagnosis 2, 5, 7
Important caveat: Normal MRI does not exclude SCD. Nearly half of patients (47.2%) with clinically confirmed SCD show no abnormal signal intensity on conventional MRI. 2 Therefore, diagnosis relies heavily on clinical and laboratory findings.
Differential Diagnosis Considerations
Red flags that suggest alternative diagnoses on spinal cord imaging: 8
- Subpial enhancement and "trident sign" (subpial enhancement plus central canal enhancement) suggest neurosarcoidosis or, rarely, B12 deficiency itself 8
- Longitudinally extensive lesions with "cloud-like" enhancement suggest neuromyelitis optica spectrum disorder 8
- Leptomeningeal enhancement suggests sarcoidosis, granulomatous disease, or vasculitis 8
Other conditions mimicking SCD clinically: 8
- Acute transverse myelitis (infectious or inflammatory)
- Copper deficiency myelopathy
- HIV-associated myelopathy
- Nitrous oxide toxicity (causes identical clinical and MRI findings to B12 deficiency) 7
Diagnostic Algorithm Summary
Recognize the clinical syndrome: Dorsal column dysfunction (impaired proprioception/vibration) plus lateral column dysfunction (spasticity, weakness) 1, 3
Measure serum B12 or active B12 first (not MMA) 4
If B12 <180 pg/mL or active B12 <25 pmol/L: Diagnose deficiency and initiate treatment immediately 4
If B12 180-350 pg/mL or active B12 25-70 pmol/L: Order MMA; if >271 nmol/L, confirm functional deficiency 4
Obtain spinal cord MRI to look for characteristic "inverted V" (cervical) or "binoculars" (thoracic) pattern on T2-weighted images 2, 5
Check folate, complete blood count, and homocysteine concurrently 4, 3
Investigate underlying cause: Test for pernicious anemia (intrinsic factor antibodies, gastrin), malabsorption disorders, dietary insufficiency, or medication-induced deficiency (metformin, PPIs, H2 blockers, nitrous oxide exposure) 4, 7
Critical warning: Never administer folic acid before treating B12 deficiency, as it may mask anemia while allowing irreversible neurological damage to progress. 1, 3