Neuropsychiatric B12 Deficiency Without Anemia

Lindenbaum J et al. • N Engl J Med

Key Finding

Neuropsychiatric symptoms can occur without anemia or macrocytosis

Original title: “Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis”

Plain English Summary

Landmark study demonstrating neuropsychiatric manifestations of B12 deficiency can occur without anemia or macrocytosis, highlighting the need for early detection.

In-Depth Analysis

Background

Dr. John Lindenbaum and colleagues from Columbia University published this landmark study in the New England Journal of Medicine (PMID: 3374544), establishing that neuropsychiatric manifestations of B12 deficiency can occur without anemia.

Study Design

Design: Case series with detailed clinical evaluation Population: 141 consecutive patients with neuropsychiatric abnormalities due to cobalamin deficiency Key analysis: Presence/absence of anemia and macrocytosis at presentation

Key Findings

Hematologic findings at presentation:

Finding	Percentage
No anemia AND no macrocytosis	28%
No anemia (any MCV)	35%
No macrocytosis (any Hgb)	33%

Neuropsychiatric manifestations:

•Peripheral neuropathy: 41%
•Ataxia: 23%
•Dementia: 19%
•Psychiatric symptoms: 10%

Critical finding: Over one-quarter of patients had NO hematologic abnormalities despite significant neurological disease.

Mechanistic Insights

B12 deficiency affects:

•Myelin synthesis: Methylmalonyl-CoA accumulation disrupts fatty acid synthesis for myelin
•Methylation reactions: Impaired SAMe production affects neurotransmitter synthesis
•DNA synthesis: Less affected in neurons (non-dividing) than in bone marrow

The nervous system may be more sensitive to marginal deficiency than bone marrow.

Clinical Implications

This study changed clinical practice:

•Cannot rely on CBC to rule out B12 deficiency
•Must test B12 directly when neurological symptoms present
•Early treatment critical—neurological damage may be irreversible

Metabolic Health Perspective

For metabolic optimization, B12 levels >500 pg/mL provide neurological protection. The absence of anemia provides false reassurance. Patients on metformin or with malabsorption need monitoring regardless of blood counts.