Reversible dementia in the setting of multiple medical comorbidities due to B12 deficiency

Abstract

Vitamin B12 deficiency is a cause of reversible dementia that must be ruled out in the evaluation of neurocognitive decline. We present a case of neurocognitive decline secondary to B12 deficiency where the workup was obscured by multiple competing diagnoses and treatment with empiric B12 supplementation reversed symptoms. Although the pretest probability was low, the morbidity from undiagnosed B12 deficiency is high, warranting a trial of B12 supplementation that resolved the patient’s symptoms.

Background

We present the case of reversible dementia thought to be due to vitamin B12 deficiency with workup obfuscated by multiple medical comorbidities. B12 deficiency is prevalent with severe sequelae that must be ruled out in cases of new neurocognitive decline. We review the test characteristics of B12 deficiency and highlight how thresholds for acceptable sensitivity change not just with pretest probability but the morbidity of the diagnosis as well.

Case presentation

A retired man in his 70s with a history of end-stage renal disease on haemodialysis, chronic obstructive pulmonary disease, peripheral artery disease, coronary artery disease, insulin-dependent diabetes and hypertension presented to his primary care office with subacutely worsening cognition and visual hallucinations. History was provided by himself and his wife. Over the 6 months prior to presentation, he had new personality changes, hallucinations and continuous cognitive decline. His wife reported he has been difficult to reason with and inattentive. He reported weekly episodes of seeing and believing that there are rats on the floor and people doing exercises in his home. His wife noted his personality seemed angrier and more labile and he did not seem to understand his wife when she spoke to him.

Four weeks prior, he was hospitalised for anaemia with dyspnoea on exertion and a haemoglobin of 75 g/L down from a baseline between 90 g/L and 110 g/L. While hospitalised, his haemoglobin decreased to 68 g/L requiring transfusion with one unit of packed red blood cells. Laboratory testing was significant for a hypoproliferative reticulocyte index, serum iron of 25 ug/dL, ferritin of 670 ng/mL, serum B12 of 247 pg/mL, homocysteine of 29.3 umol/L (reference=<15 umol/L), methylmalonic acid of 937 nmol/L (reference 0–378 nmol/L) and folate of 6.7 ng/mL (reference>=4.7 ng/mL). Workup for haemolysis was negative. Colonoscopy demonstrated a nonbleeding 4 mm polyp that was partially resected and CT of the head, chest, abdomen and pelvis with contrast were unremarkable. During his hospitalisation, he received 400 mg of intravenous iron, oral B12 and folic acid. The patient was discharged from the hospital with a haemoglobin of 80 g/L. His medications included daily pantoprazole for gastritis and did not include metformin. He had an unremarkable nonvegetarian diet. He had no symptoms or history of malabsorption.

In the doctor’s office, the patient reported fatigue and continued hallucinations. Though his fatigue was improving since his hospitalisation, he and his wife both continued to report hallucinations.

On physical exam, he appeared as an elderly man dressed in casual clothing sitting on an examination table not responding to any internal stimuli. Blood pressure was 160/75 mm Hg, heart rate was 81 beats per minute and oxygenation was at a baseline 91% in the setting of his chronic obstructive pulmonary disease. Neurologically, he was alert and oriented to self and place, but did not know the year nor President. He had 5/5 strength in shoulder and hip flexion. Sensation to light touch was intact across both extremities. His gait was unsteady with short strides. He denied hallucinations at the time of examination. His thought process was linear, but he was inattentive and difficult to direct.

Mini-Mental Status Examination was 25. His score on the Patient Health Questionnaire-2 was 0.

Investigations

A full serological workup for reversible dementia was sent (table 1). EEG did not show any seizures or epileptic activity. Carotid duplex showed bilateral mild atherosclerosis. MRI of the head showed age-appropriate volume loss, evidence of microvascular disease and no masses.

Table 1.

Serological testing

Test	Value (initial)	Value (4 week follow-up)	Reference
Paraneoplastic panel	Negative	–	Negative
Vitamin B1	123.6 nmol/L	–	66.5–200 nmol/L
Zinc	68 ug/dL	–	44–115
Copper	117 ug/dL	–	69–132 ug/dL
Lyme IgM	Negative	–	Negative
Vitamin B12	482 pg/mL	–	232–1245 pg/mL
Folate	6.7 ng/mL	–	>=4.7 ng/mL
Methylmalonic acid	460 nmol/L	580 nmol/L	0–378 nmol/L
Homocysteine	29.3 umol/L	25 ummol/L	=<15 umol/L
Haemoglobin	83 g/L	–	130–170 g/L
Antiparietal cell antibody	Negative	–	Negative
Intrinsic factor blocking antibody	Negative	–	Negative
Thyroid stimulating hormone	1.36 uLU/mL	–	0.27–4.20 uLU/mL
Treponema antibody	Negative	–	Negative
Ferritin	467 ng/mL	–	30–400 ng/mL

Differential diagnosis

To summarise, our patient was a man in his 70s—with uncontrolled hypertension, diabetes, vasculopathy with peripheral artery disease, coronary artery disease and end-stage renal disease on haemodialysis presenting with hallucinations and subacute cognitive decline. He was found to have symptomatic hypoproliferative macrocytic anaemia with a low-normal serum B12 yet an elevated serum methylmalonic acid and homocysteine.

Among a broad differential reversible dementia, vitamin B12 deficiency stood out given his elevated homocysteine and methylmalonic acid in the setting of symptomatic hypoproliferative macrocytic anaemia. A serum B12 of 247 pg/mL typically indicates measuring homocysteine and methylmalonic acid to diagnose B12 deficiency, but elevated homocysteine and methylmalonic acid could be alternatively explained by end-stage renal disease.¹ Neurodegenerative causes such as vascular dementia, Alzheimer’s dementia and Parkinson’s disease were also on the differential.

Treatment

While further workup including functional fluorodeoxyglucose-positron emission tomography (FDG-PET) was pursued to further work up neurodegenerative causes, vitamin B12 supplementation was continued via injections once weekly for 4 weeks followed by once monthly.

Outcome and follow-up

On follow-up 1 month later, his mini-mental status increased from 25 to 29, his hallucinations stopped, and his wife reported improved mood and cognition. Haemoglobin increased from 82 g/L to 113 g/L. Methylmalonic acid and homocysteine remained elevated in the setting of end-stage renal disease at 580 nmol/L and 25 umol/L respectively.

Discussion

Vitamin B12 deficiency can cause symptoms ranging from mild fatigue to profound neuropsychiatric defects. Vitamin B12 is necessary for the conversion of methylmalonic acid to succinyl CoA and homocysteine to methionine. The American Academy of Family Physicians recommends screening first with complete blood cell counts and a serum B12 level. Serum B12 levels less than 150 pg/mL are diagnostic for B12 deficiency.² Testing for methylmalonic acid is indicated for low-normal levels less than 350 pg/mL.³

The sensitivity of serum B12 <200 pg/mL for elevation of methylmalonic acid is 65%–95% for proven clinical deficiency and 50% for detecting elevated levels of methylmalonic acid, and 50%–60% specific for clinical response to supplementation and 80% specific for detecting elevated levels of methylmalonic acid.⁴ Serum B12 levels <350 pg/mL are 90% sensitive and 25% specific for elevated levels of methylmalonic acid. Serum methylmalonic acid >400 nmol/L is 98% sensitive for clinical deficiency and poorly specific for clinical response when in the range for 300–1000 nmol/L in addition to being elevated in renal failure. Serum homocysteine >21 umol/L were 96% sensitive for a clinical deficiency but are not specific because folate deficiency and renal insufficiency also elevated homocysteine.⁴ Similar case reports have pointed to the clinical significance of false negatives in serum B12 levels and even methylmalonic acid and homocysteine.^{5 6} Randomised trial data suggest that B12 supplementation reduces progression from mild cognitive impairment to Alzheimer’s dementia.⁷

In this case, ruling out the pivotal diagnosis of reversible dementia from B12 deficiency motivates high sensitivity testing and a high index of clinical suspicion in the interpretation of these tests. Chronic pantoprazole use could have been a predisposing factor in this patient. On initial evaluation, serum B12 was <350 pg/mL meriting follow-up testing with homocysteine and methylmalonic acid. In cases where testing methylmalonic acid or homocysteine is unavailable or expensive, trialling B12 supplementation for serum B12 <350 pg/mL may be merited as both a diagnostic and therapeutic intervention. While a normal level of homocysteine and methylmalonic could rule out the diagnosis, elevated levels could be explained by either his end-stage renal disease or B12 deficiency. There are several well justified alternative diagnoses other than B12 deficiency because microvascular changes are seen on MRI, the patient’s gait hints towards Parkinson’s disease, the elevated homocysteine and methylmalonic acid can be explained by end-stage renal disease. Despite this, reversible causes of dementia had not been ruled out. The patient’s cognitive decline, hallucinations and symptomatic anaemia improved with aggressive B12 repletion, underscoring the importance having a high index of suspicion and a low threshold of treatment for reversible causes of neurocognitive decline.

Learning points.

• Serum B12 levels between 200 and 350 pg/mL indicate further testing with methylmalonic acid and homocysteine.

• Methylmalonic acid and homocysteine are elevated in end-stage renal disease and B12 deficiency.

• Proton pump inhibitors are a risk factor for vitamin B12 deficiency.

• Reversible causes of dementia must be completely ruled out in the evaluation of new neurocognitive decline.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).