SCOPE: Evaluation and management of neurological manifestations of vitamin B12 deficiency including peripheral neuropathy, subacute combined degeneration of the spinal cord, and cognitive changes. Includes diagnosis, treatment, monitoring of neurological recovery, and identification of underlying etiology (pernicious anemia, malabsorption, dietary deficiency). Excludes pure hematologic B12 deficiency without neurological involvement. For general peripheral neuropathy workup, see the Peripheral Neuropathy template.
DEFINITIONS:
- Subacute Combined Degeneration (SCD): Demyelination of posterior columns and lateral corticospinal tracts of the spinal cord due to B12 deficiency; presents with sensory ataxia, spasticity, and proprioceptive loss
- Pernicious Anemia: Autoimmune destruction of gastric parietal cells causing intrinsic factor deficiency and B12 malabsorption; most common cause of severe B12 deficiency
- Methylmalonic Acid (MMA): Metabolite elevated in B12 deficiency; more sensitive than serum B12 alone; specific for B12 (not elevated in folate deficiency)
- Homocysteine: Elevated in both B12 and folate deficiency; less specific than MMA for B12 deficiency alone
- Intrinsic Factor (IF): Glycoprotein produced by parietal cells; required for B12 absorption in terminal ileum
- Holotranscobalamin (Active B12): The biologically active fraction of circulating B12; may be more sensitive than total B12
PRIORITY KEY: STAT = Immediate | URGENT = Within hours | ROUTINE = Standard | EXT = Extended/atypical cases | - = Not applicable to this setting
Confirmed or suspected B12 deficiency with neurological symptoms; preferred parenteral route
1000 mcg :: IM :: daily x 7 days :: 1000 mcg IM daily x 7 days, then 1000 mcg IM weekly x 4 weeks, then 1000 mcg IM monthly indefinitely
Cobalt or cobalamin hypersensitivity (rare); Leber hereditary optic neuropathy (relative)
Reticulocyte count at day 5-7 (reticulocyte crisis confirms response); B12 and MMA at 1-2 months; CBC at 1-2 months; potassium during first 48 hours (hypokalemia from erythropoiesis)
STAT
STAT
ROUTINE
STAT
Hydroxocobalamin IM
IM
Alternative to cyanocobalamin; longer-acting; preferred in some countries; better for cyanide toxicity
1000 mcg :: IM :: daily x 7 days :: 1000 mcg IM daily x 7 days, then 1000 mcg IM every other day x 2 weeks, then 1000 mcg IM monthly indefinitely
Cobalt or cobalamin hypersensitivity (rare); Leber hereditary optic neuropathy (relative)
Reticulocyte count at day 5-7; B12 and MMA at 1-2 months; CBC at 1-2 months; potassium during first 48 hours (hypokalemia from erythropoiesis)
STAT
STAT
ROUTINE
STAT
Cyanocobalamin SC
SC
If IM injection contraindicated (anticoagulation, thrombocytopenia) or patient preference
1000 mcg :: SC :: daily x 7 days :: 1000 mcg SC daily x 7 days, then 1000 mcg SC weekly x 4 weeks, then 1000 mcg SC monthly indefinitely
Cobalt or cobalamin hypersensitivity (rare); Leber hereditary optic neuropathy (relative)
Reticulocyte count at day 5-7; B12 and MMA at 1-2 months; CBC at 1-2 months; potassium during first 48 hours (hypokalemia from erythropoiesis)
URGENT
URGENT
ROUTINE
URGENT
Potassium supplementation
IV/PO
Prevent hypokalemia during B12 replacement; erythropoiesis consumes potassium
20 mEq :: PO :: daily PRN :: 20-40 mEq PO daily; monitor potassium q12-24h during first 48 hours of B12 replacement; supplement if K <3.5 mEq/L
Hyperkalemia; renal failure (use cautiously)
Potassium levels q12-24h during initial treatment
URGENT
URGENT
-
URGENT
Magnesium sulfate IV
IV
Correct hypomagnesemia; magnesium required for enzymatic reactions involving B12
2 g :: IV :: once PRN :: 2 g IV over 2 hours if Mg <1.5 mg/dL; then oral magnesium oxide 400 mg PO daily
Renal failure; heart block
Magnesium levels; cardiac monitoring during IV infusion
URGENT
URGENT
-
URGENT
Folic acid
PO
Correct concurrent folate deficiency; MUST give with B12 to avoid masking B12 deficiency
1 mg :: PO :: daily :: 1 mg PO daily; NEVER give folate without B12 in suspected B12 deficiency (may worsen neurological damage)
None significant
Ensure B12 is being co-administered; reticulocyte count
300 mg :: PO :: qHS :: Start 300 mg qHS; titrate by 300 mg every 1-3 days to TID dosing; target 900-1800 mg/day divided TID; max 3600 mg/day; adjust for renal function (CrCl 30-59: max 1400 mg/day; CrCl 15-29: max 700 mg/day; CrCl <15: max 300 mg/day)
Severe renal impairment (dose adjust required); respiratory depression with opioids
Sedation, dizziness, peripheral edema; taper to discontinue (do not stop abruptly)
-
ROUTINE
ROUTINE
-
Pregabalin
PO
Neuropathic pain (first-line alternative)
75 mg :: PO :: BID :: Start 75 mg BID; may increase to 150 mg BID after 1 week; max 300 mg BID (600 mg/day); adjust for renal function (CrCl <60: reduce dose); Schedule V controlled substance
Severe renal impairment (dose adjust required); history of substance abuse (relative)
Sedation, weight gain, peripheral edema; dizziness; taper to discontinue
-
ROUTINE
ROUTINE
-
Duloxetine
PO
Neuropathic pain (first-line); especially effective for painful neuropathy with comorbid depression
30 mg :: PO :: daily :: Start 30 mg daily x 1 week; increase to 60 mg daily; max 120 mg/day
Localized neuropathic pain refractory to standard topical therapy
8% patch :: TOP :: q3 months :: Applied by healthcare provider for 30-60 minutes; may repeat every 3 months; pretreat area with topical lidocaine
Open wounds; capsaicin allergy
BP during application; pain during and after application; must be applied in clinical setting
-
-
ROUTINE
-
High-dose oral B12 (if parenteral not tolerated)
PO
B12 replacement when injections refused or contraindicated; compliance concerns
1000 mcg :: PO :: daily :: 1000-2000 mcg PO daily; ~1% absorbed passively independent of intrinsic factor; may be adequate for mild deficiency; monitor closely
None significant
B12 and MMA levels at 2-3 months to confirm adequate absorption; if MMA remains elevated, switch to parenteral
-
-
ROUTINE
-
Methylcobalamin SL
SL
Alternative oral B12 formulation; may have improved bioavailability
1000 mcg :: SL :: daily :: 1000-5000 mcg sublingual daily; dissolve under tongue; efficacy data limited compared to IM
None significant
B12 and MMA levels at 2-3 months; switch to parenteral if inadequate response
-
-
ROUTINE
-
Combination Therapy Note: For refractory neuropathic pain, combining agents from different classes (e.g., gabapentinoid + SNRI, or gabapentinoid + TCA) is often more effective than maximizing monotherapy. Avoid combining TCAs with SNRIs (serotonin syndrome risk). Neuropathic pain from B12 deficiency often improves or resolves with adequate B12 replacement alone; allow 3-6 months of treatment before concluding pain is refractory.
B12 injections are lifelong if pernicious anemia is the cause; stopping injections will cause neuropathy to recur and worsen
-
ROUTINE
ROUTINE
-
Neurological symptoms may take 3-12 months to improve after starting B12 replacement; improvement depends on duration and severity of deficiency before treatment
-
ROUTINE
ROUTINE
-
Return immediately if worsening weakness, difficulty walking, or new bladder/bowel dysfunction develops (may indicate progressive myelopathy requiring urgent evaluation)
ROUTINE
ROUTINE
ROUTINE
-
If self-administering B12 injections, use proper IM technique and rotate injection sites (outer thigh or deltoid); attend injection training with nursing
-
ROUTINE
ROUTINE
-
Do not take folate supplements without B12 as folate alone may mask B12 deficiency while neurological damage continues to progress
ROUTINE
ROUTINE
ROUTINE
-
Inspect feet daily for cuts, blisters, or wounds using a mirror for soles; impaired sensation increases injury risk
-
ROUTINE
ROUTINE
-
Use night lights, handrails, and remove throw rugs to prevent falls from impaired balance and proprioception
-
ROUTINE
ROUTINE
-
Test bath water temperature with elbow before entering as impaired sensation increases burn risk
-
ROUTINE
ROUTINE
-
Neuropathic pain medications take 2-4 weeks to reach full effect; do not stop gabapentin or pregabalin abruptly
-
ROUTINE
ROUTINE
-
Report new numbness, tingling, or weakness to your neurologist as this may indicate inadequate treatment or alternative diagnosis
-
ROUTINE
ROUTINE
-
If vegan or vegetarian, lifelong B12 supplementation is required as plant-based diets contain no natural B12
Nitrous oxide avoidance: inform anesthesia team of B12 deficiency before any surgical procedures as N2O irreversibly oxidizes B12 and precipitates acute neurological deterioration
Stable neurological examination; able to ambulate safely (with assistance if needed); reliable follow-up arranged; B12 injection initiated or prescription provided; caregiver available for injection administration or self-injection training completed; no severe hypokalemia or electrolyte abnormality
Admit to floor
Acute or subacute myelopathy (gait ataxia, spasticity, weakness); inability to ambulate safely; severe pancytopenia requiring monitoring; need for frequent electrolyte monitoring during initial B12 replacement; concurrent acute illness complicating management; falls requiring inpatient rehabilitation assessment
Admit to ICU
Severe symptomatic anemia requiring transfusion with hemodynamic instability; high-output cardiac failure from severe anemia; severe hypokalemia with cardiac monitoring need during B12 replacement; respiratory compromise from severe weakness
Transfer to higher level
Neurology consultation not available; EMG/NCS not available for diagnostic workup; MRI not available for myelopathy evaluation; hematology evaluation required but not available locally
v1.1 (January 30, 2026)
- Eliminated all cross-references ("Same as cyanocobalamin") in Section 3A; hydroxocobalamin IM and cyanocobalamin SC rows now self-contained with full contraindications and monitoring
- Standardized structured dosing format across all treatment sections (3A, 3B, 3C) to [dose] :: [route] :: [frequency] :: [full_instructions]
- Added ICU column to Section 4B (Patient Instructions) and Section 4C (Lifestyle & Prevention) for consistent 4-venue coverage
- Cleaned gabapentin contraindications: moved renal dose adjustments to dosing field, added respiratory depression warning with opioids
- Added taper instructions to pregabalin and venlafaxine monitoring
- Corrected nortriptyline monitoring to be self-contained (removed comparative reference to amitriptyline)
- Improved magnesium sulfate dosing: added threshold and oral maintenance step-down
- Added nitrous oxide avoidance to ICU setting (Section 4C) for pre-surgical safety communication
v1.0 (January 30, 2026)
- Initial template creation
- Comprehensive laboratory workup including B12, MMA, homocysteine, IF antibodies, anti-parietal cell antibodies, and etiology-directed testing
- MRI spine for subacute combined degeneration with characteristic imaging findings
- EMG/NCS for peripheral neuropathy characterization
- B12 replacement protocols: cyanocobalamin IM, hydroxocobalamin IM, SC route, high-dose oral, sublingual
- Neuropathic pain management with gabapentinoids, SNRIs, TCAs, and topical agents
- Pernicious anemia workup including intrinsic factor antibodies, anti-parietal cell antibodies, gastrin
- Celiac disease screening with tTG-IgA and total IgA
- Comprehensive differential diagnosis including copper deficiency, MS, cervical myelopathy, nitrous oxide toxicity
- Monitoring parameters for treatment response (reticulocyte crisis, B12/MMA normalization, neurological recovery)
- Gastric surveillance recommendations for pernicious anemia
- Patient education on lifelong supplementation, nitrous oxide avoidance, and fall prevention
Begins 1-3 months; maximum improvement by 6-12 months
Paresthesias often first to improve; numbness may persist
Peripheral neuropathy (motor)
Begins 1-3 months; maximum improvement by 6-12 months
Distal weakness recovers before proximal
Proprioceptive loss / sensory ataxia
Begins 3-6 months; may take 12+ months
Incomplete recovery common if treatment delayed
Myelopathy (SCD)
Variable; begins 3-6 months
Spasticity and posterior column signs may be permanent if treatment >6 months delayed
Cognitive impairment
Begins 1-3 months; may take 12+ months
Dementia component may be partially irreversible
Optic neuropathy
Variable; may improve within weeks
Rare; bilateral vision loss
Hematologic (anemia)
Reticulocyte crisis day 5-7; Hgb normalizes 6-8 weeks
First sign of treatment response
Key principle: Earlier treatment initiation correlates with better neurological outcomes. Neurological symptoms present for >6 months before treatment have significantly lower chance of full recovery.