Clinical Review & Education

JAMA Clinical Challenge

Progressive Weakness and Memory Impairment

in a Middle-aged Man
Ersilia M. DeFilippis, MD; Alec Petersen, MD; Maria A. Yialamas, MD

Figure 1. Sagittal view of magnetic resonance imaging of the spine.

A previously healthy 61-year-old man presented to the emergency department with a

4-week history of severe weakness and difficulty ambulating independently. He had diffi- WHAT WOULD YOU DO NEXT?
culty rising from a seated position. Additional symptoms included progressive numbness
and tingling of the hands and feet. His family also reported progressive memory impair- A. Check a serum vitamin B12 level,
ment during this period. An extensive review of systems was otherwise unremarkable, ex- methylmalonic acid (MMA) level,
cept for a few months of intermittent nausea, increased abdominal bloating, and anorexia. or both
Physical examination revealed normal vital signs, normal cardiopulmonary findings, at-
rophy in the calf muscles bilaterally, 4 of 5 symmetric strength in the upper and lower ex-
B. Obtain magnetic resonance
tremity extensor muscles, and an unsteady shuffling gait. He had decreased vibration and
imaging (MRI) of the brain
proprioception in both lower extremities, with hyperreflexia and a positive Babinski reflex
on the left side. Mental status examination revealed delayed recall of 1 of 4 words.
Complete blood cell count revealed a white blood cell count of 4.7 × 103/μL; hemoglo- C. Order a rapid plasma reagin
bin level, 10.9 g/dL; hematocrit, 31.8%; and platelet count, 202 × 103/μL. Mean corpuscu- (RPR) test
lar volume was 119 fL. Results of renal function and liver function tests were normal. Be-
cause of the asymmetric hyperreflexia and concern for a spinal cord lesion, magnetic D. Perform an electromyogram
resonance imaging (MRI) of the spine was performed (Figure 1).

Diagnosis
Vitamin B12 deficiency
What to Do Next
A. Check a serum vitamin B12 level, MMA level, or both
The keys to the correct diagnosis are the combination of sensory
ataxia, progressive weakness, paresthesias, cognitive impairment,
and macrocytic anemia. MRI demonstrates prolonged T2 signal
(Figure 2) in the posterior columns of the thoracic and cervical spi-
nal cord, suggesting subacute combined degeneration, most com-
monly seen with vitamin B12 deficiency.
The differential diagnosis for distal symmetric polyneuropathy
includes tabes dorsales in the setting of syphilis, HIV-associated pe-
ripheral sensory neuropathy, toxic neuropathies, copper deficiency,
and paraproteinemia.1 Although neurosyphilis can present with cog-
nitive impairment and dorsal and lateral column symptoms, it is

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 Clinical Review & Education JAMA Clinical Challenge

combined sensory and motor deficit that manifests as peripheral neu-

Figure 2. Sagittal (panel A) and axial (panel B) views of magnetic resonance
imaging of the spine demonstrate prolonged T2 signal (arrowheads) in the
posterior columns of the thoracic and cervical spinal cord.
unlikely in this patient, given the degree of macrocytosis. MRI of the
brain would not be the best next step, because the patient’s bilateral
length-dependent proprioceptive sensory deficits with hyperre-
flexia and a positive Babinski sign suggest a spinal cord lesion. An elec-
tromyogram could be considered to evaluate muscle weakness, but
it would be important to check a serum B12 level before performing
this more invasive procedure.
Discussion
B12, a water-soluble vitamin, serves as a cofactor in biochemical re-
actions for nucleotide synthesis and DNA methylation.2 In B12 defi-
ciency, frequent mitoses required for normal hematopoiesis are pref-
erentially affected, resulting in megaloblastic anemia. Vitamin B12
deficiency results in demyelination of the spinal cord’s dorsal col-
umn (carrying afferent proprioception) and lateral column. The lon-
gest nerve fibers are most impaired, causing a length-dependent
ropathy and paresthesias. Associated neuropsychiatric symptoms
include irritability, personality changes, dementia, and psychosis.2
Since B12 cannot be synthesized by the human body, it must
be consumed and absorbed. Most animal products in the human
diet contain protein-bound vitamin B12, which binds to intrin-
sic factor in the stomach. The B 12 –intrinsic factor complex is
absorbed in the terminal ileum, and B12 is then bound to transco-
balamin II. Causes of B12 deficiency include poor intake, gastrec-
tomy, pernicious anemia, disorders of the terminal ileum, and trans-
cobalamin II deficiency.2
Diagnosis of B12 deficiency is made with serum levels as well as a
peripheral blood smear. B12 is an essential cofactor in the conversion
of MMA to succinyl-CoA within the mitochondria, resulting in the
buildup of MMA. Therefore, an elevated serum MMA level is a sensi-
tive marker of B12 deficiency.2 B12 is also a key cofactor in homocyste-
ine metabolism; elevated homocysteine serum levels can be seen in
early cobalamin and folate deficiency. Low folate levels should also be
repleted; otherwise, symptoms of neuropathy may persist.
When a dietary cause is not suspected and there is no known ana-
tomical predisposition (eg, gastrectomy), B12 deficiency attribut-
able to antibodies to intrinsic factor is the most likely diagnosis.3
Peak age at onset is 60 years. Antibodies to intrinsic factor are highly
specific and present in 70% of patients, while antibodies to parietal
cells are less specific but present in 90% of patients with pernicious
anemia.4 Patients with pernicious anemia may need endoscopic
evaluation, because the condition is associated with an increased
incidence of gastric adenocarcinoma and carcinoid tumors.5
Patient Outcome
Serum B12 level was below the level of detection (<30 pg/mL [22.13
pmol/L]). Homocysteine level was elevated (28.55 [reference
range, 0.68-1.62] mg/L [211.2 {5.0-12.0} μmol/L]) and MMA level
was 22 μmol/L (reference range, <0.40 nmol/mL), consistent with
B12 deficiency.
Esophagogastroduodenoscopy revealed a lack of gastric folds,
consistent with atrophic gastritis. Parietal cell antibody IgG level was
positive, confirming the diagnosis of pernicious anemia. The pa-
tient was treated with intramuscular vitamin B12 (1000 mg daily) for
5 days, followed by weekly injections to complete an 8-g load. This
was followed by monthly 1000-mg injections. The patient’s ane-
mia, memory impairment, and neurologic abnormalities resolved
within 2 months of treatment.

ARTICLE INFORMATION
Author Affiliations: Department of Medicine,
Brigham and Women’s Hospital, Boston,
Massachusetts.
Corresponding Author: Maria A. Yialamas, MD,
Department of Medicine, Brigham and Women’s
Hospital, 75 Francis St, Boston, MA 02115
(myialamas@bwh.harvard.edu).
Section Editor: Mary McGrae McDermott, MD,
Senior Editor.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
none were reported.
Additional Contributions: We thank the patient for
providing permission to share his information.
Submissions: We encourage authors to submit
papers for consideration as a JAMA Clinical
Challenge. Please contact Dr McDermott at
mdm608@northwestern.edu.
REFERENCES
1. Callaghan BC, Price RS, Feldman EL. Distal
symmetric polyneuropathy: a review. JAMA. 2015;
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2. Langan RC, Goodbred AJ. Vitamin B12 deficiency:
recognition and management. Am Fam Physician.
2017;96(6):384-389.
3. Green R, Datta Mitra A. Megaloblastic anemias:
nutritional and other causes. Med Clin North Am.
2017;101(2):297-317. doi:10.1016/j.mcna.2016.09.013
4. Green R. Vitamin B12 deficiency from the
perspective of a practicing hematologist. Blood.
2017;129(19):2603-2611. doi:10.1182/blood-2016
-10-569186
5. Murphy G, Dawsey SM, Engels EA, et al. Cancer
risk after pernicious anemia in the US elderly
population. Clin Gastroenterol Hepatol. 2015;13(13):
2282-2289. doi:10.1016/j.cgh.2015.05.040

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