Man With Weakness, Dyspnea, and Ataxia

F

or 3 months, a 66-year-old retired man has had increasingweakness of the lower legs with stiffness,tingling, and numbness; worsening ataxia; anergia; andexertional dyspnea of insidious onset. He has lost 8 lb,and his appetite is poor. He denies fever, cough, chest orabdominal pain, paroxysmal nocturnal dyspnea, orthopnea,ankle swelling, bleeding disorders, hematemesis,melena, headache, vision problems, sciatica, joint pain,bladder or bowel dysfunction, and GI symptoms. He hasnocturia attributable to benign prostatic hypertrophy.

History.

The patient has essential hypertension,which is well controlled with lisinopril, 20 mg/d. Thereis no history of tobacco use or alcohol abuse. He hashad no surgery or transfusions.

Examination.

This well-nourished man is afebrile.Heart rate is 92 beats per minute and regular; respirationrate, 22 breaths per minute. Blood pressure is142/72 mm Hg. He has generalized pallor and palemucosa. Hydration status is good. He has mild scleralicterus but no oral erythema or candidiasis. There is nopalpable adenopathy or thyroidomegaly. The jugularvein pulse is normal; peripheral pulses are easily felt.Apex beat is within normal limits. Both heart soundsare distinctly audible, with a grade 3 pansystolic musicalmurmur throughout the pericardial area. Head andspine examination are normal; carotids are easily palpablewith no bruits.The patient is alert and oriented and responds appropriately.Cranial nerves are intact. Fundi show arterioscleroticchanges. The patient has stiffness of bothlegs with wasting and grade 3 power. Reactions to touchand pinprick are normal. Vibratory and joint sensationsare grossly impaired. Deep tendon reflexes are normalin the upper limbs but exacerbated in the lower limbs,with a positive Babinski sign. There are no meningealor cerebral signs. Lungs are clear. Abdomen is soft andbenign, with no organomegaly or tenderness.

Laboratory studies.

Hemoglobin, 7.8 g/dL; hematocrit,28%. White blood cell count, 3500/μL, with70% polymorphonuclear leukocytes, 24% lymphocytes,3% eosinophils, and 3% monocytes. Platelet count,92,000/μL; erythrocyte sedimentation rate, 70 mm/h.Mean corpuscular volume, 112 fL. A peripheral bloodsmear shows macro-ovalocytosis, anisocytosis, andpoikilocytosis; the percentage of reticulocytes is 2%.Urinalysis results are normal. Three stool testsare negative for occult blood. Serum sodium level,140 mEq/L; potassium, 4 mEq/L; chloride, 98 mEq/L.Blood bicarbonate, 24 mEq/L. Blood glucose, 110 mg/dL;blood urea nitrogen, 21 mg/dL; serum creatinine,1 mg/dL; lactate dehydrogenase, 486 IU/L. Total bilirubin,3 mg/dL; conjugated, 1 mg/dL, unconjugated, 2 mg/dL.Serum protein, 6.2 g/dL; serum albumin, 4.2 g/dL;globulin, 2 g/dL. Liver enzyme levels are normal.The peripheral blood smear is shown here.

Based on the clinical findings and the peripheralsmear, what is the likely diagnosis?

A.

Tabes dorsalis

B.

Iron deficiency anemia

C.

Subacute combined degeneration

D.

Multiple sclerosis

E.

Diabetic peripheral neuropathy

OVERVIEW

Pernicious anemia (PA) is the most common causeof vitamin B

₁₂

(cobalamin) deficiency in the westernhemisphere. In patients with PA, the production of autoantibodiesleads to destruction of gastric parietalcells. This results in deficient levels of intrinsic factor, asubstance that binds ingested B

₁₂

and ensures its absorptionin the terminal ileum. Decreased B

₁₂

absorptionresults in megaloblastic anemia. Long-term B

₁₂

deficiencycan cause reversible degenerative changes inthe CNS, a condition known as subacute combineddegeneration. The changes are seen predominantly inthe posterior columns and corticospinaltracts.PA most commonly occurs inpersons older than 60 years andof northern European descent. Itoccurs equally in men and women.It is often associated with otherautoimmune disorders, includingAddison disease, Graves disease,Hashimoto thyroiditis, hypoparathyroidism,and vitiligo.Other causes of vitamin B

₁₂

deficiency include inadequate dietaryintake (seen primarily in vegans),history of gastrectomy, useof histamine

₂

blockers and protonpump inhibitors, fish tapeworm (

Diphyllobothriumlatum

) infection, severepancreatic insufficiency, severeCrohn disease, celiac disease, blindloop syndrome, and short-bowelsyndrome.

CLINICAL MANIFESTATIONS

Clinical manifestations usuallydevelop insidiously and progressas stores of vitamin B

₁₂

are depleted.Patients with PA may be asymptomaticor present with a varietyof hematologic, GI, and/or neuropsychiatricmanifestations. Commonfindings are anorexia with orwithout weight loss, a painful or"burning" tongue (glossitis), andconstipation or diarrhea. Symptomsassociated with anemia--includingfatigue, light-headedness, exertionaldyspnea, or chest pain--may bepresent.Typical early neurologic symptoms include paresthesiasand numbness in the extremities. As the diseaseprogresses, patients may complain of weakness, spasticity,and ataxia; these conditions result from demyelinationof the dorsal and lateral columns of the spinal cord. Depression,dementia, memory problems, irritability or,rarely, frank psychosis may occur.Physical examination reveals pallor with lemon-tinticterus. Premature graying of the hair may be evident.Examination of the oral cavity reveals a smooth, beefyred tongue. A palpable spleen occurs in up to 20% of patients.In the early stages, peripheral vibratory and position sensations are diminished; this is accompanied bymild to moderate weakness and absent reflexes. As thedisease progresses, vibration and position sensationsare more severely affected; spasticity, Babinski sign, andataxia emerge.

DIAGNOSIS

Macrocytic anemia (mean corpuscular volumegreater than 100 fL) is present. The peripheral bloodsmear reveals oval macrocytes, anisocytosis, poikilocytosis,and hypersegmented neutrophils (more than 5% ofneutrophils with 5 or more lobes or 1% with 6 or morelobes). Mild leukopenia and thrombocytopenia may beevident. Elevated serum bilirubin and lactate dehydrogenaselevels--a result of ineffective erythropoiesis--are common.A vitamin B

₁₂

level of less than 100 pg/mL is clinicallysignificant (normal range, 200 to 900 pg/mL). Serummethylmalonic acid and homocysteine levels areelevated. Parietal cell antibodies are found in 80% to 90%of patients, but this finding is nonspecific. In contrast,antibodies to intrinsic factor are highly specific but notvery sensitive. The Schilling test is cumbersome, but itmay be useful to confirm the diagnosis of PA, especiallyin ambiguous cases or in partially treated patients.

TREATMENT

Lifelong vitamin B

₁₂

replacement, either parenteralor oral, is the mainstay of treatment for PA. The typicalregimen involves the administration of 1000 μg IM dailyfor 1 to 2 weeks, followed by 1000 μg monthly. Oral replacementwith 1000 to 2000 μg/d is also acceptable.

PROGNOSIS

Response to treatment is rapid. Patients feel betterwithin days. Reticulocytosis begins within 4 to 5 days,and the hematocrit usually returns to normal within2 months. Patients rarely require transfusions to correctPA.Patients who receive early diagnosis and treatmenthave a normal life span. Delayed treatment can lead topermanent neurologic sequelae. Patients with PA have a2- to 3-fold increased risk of gastric carcinoma andshould be followed closely.

References:

FOR MORE INFORMATION:

• Lee GR. Pernicious anemia and other causes of vitamin B₁₂ (cobalamin)deficiency. In: Lee GR, ed. Wintrobe’s Clinical Hematology. 10th ed. Baltimore:Williams & Wilkins; 1999:941-964.
• Snow CF. Laboratory diagnosis of vitamin B₁₂ and folate deficiency. Arch InternMed. 1999;159:1289-1298.
• Toh GH, van Driel IR, Gleeson PA. Pernicious anemia. N Engl J Med. 1997;337:1441-1448.