History
Clinical course
The neurologic features are attributable to pathology in the peripheral and optic nerves, posterior and lateral columns of the spinal cord (subacute combined degeneration), and in the brain. Interestingly, hematologic and neurologic manifestations are occasionally dissociated. [14, 15] An inverse correlation in the severity of both manifestations has been suggested. In patients with neuropsychiatric abnormalities, 28% lack anemia or macrocytosis.
Clinical manifestations due to vitamin B-12 deficiency are unrelated to etiology. In a prospective comparative study between antiparietal cell antibody positive and negative patients, no significant difference was shown in clinical, electrodiagnostic, and radiological features. [16]
Although the clinical features of vitamin B-12 deficiency may consist of a classic triad of weakness, sore tongue, and paresthesias, these are not usually the chief symptoms.
Onset is subacute or gradual, although more acute courses have been described, in particular after N 2 O exposure. In 1986, Schilling described 2 patients with unrecognized vitamin B-12 deficiency who developed paresthesias and poor manual dexterity 1-3 months after brief N 2 O exposure. [17] In 1995, Kinsella and Green described a 70-year-old man with paresthesias and hand clumsiness after 2 exposures to N 2 O over 3 months. [18]
Onset is often with a sensation of cold, numbness, or tightness in the tips of the toes and then in the fingertips, rarely with lancinating pains. Simultaneous involvement of arms and legs is uncommon, and onset in the arms is even rarer.
Paresthesias are ascending and occasionally involve the trunk, leading to a sensation of constriction in the abdomen and chest.
Untreated patients may develop limb weakness and ataxia.
In 1991, Healton et al performed detailed neurologic evaluations of 143 patients with vitamin B-12 deficiency; 74% presented with neurologic symptoms. [19]
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Isolated numbness or paresthesias were present in 33%.
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Gait abnormalities occurred in 12%.
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Psychiatric or cognitive symptoms were noted in 3%.
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Visual symptoms were reported in 0.5%. Symptoms include subacute progressive decrease in visual acuity, usually caused by bilateral optic neuropathy and rarely pseudotumor cerebri or optic neuritis.
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Rare autonomic features include orthostasis, sexual dysfunction, and bowel and bladder incontinence.
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Other symptoms include lightheadedness and impaired taste and smell.
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Asymptomatic neurologic manifestations can be detected using somatosensory evoked potentials (SSEP); see below.
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Nonneurologic symptoms, some of which may also reflect autonomic nervous system involvement, were present in 26%.
Constitutional symptoms, including anorexia and weight loss occurred in 50%. Low-grade fever that resolves with treatment occurred in 33% of cases. Other symptoms include fatigue and malaise.
Cardiovascular symptoms include syncope, dyspnea, orthopnea, palpitations, and angina.
Gastrointestinal symptoms include heartburn, flatulence, constipation, diarrhea, sore tongue, and early satiety.
In a prospective study of 57 patients with vitamin B-12 deficiency neurological syndrome, common presenting syndromes included myeloneuropathy (25), myelopathy (14), myeloneuroencephalopathy (13), myeloencephalopathy (4), and behavioral (1). [126]
Physical
Most patients exhibit signs of peripheral nervous system (PNS) or spinal cord involvement, but the extent of PNS involvement remains unclear, in part because both neuropathy and myelopathy can cause impaired vibration sense, ataxia, and paresthesias. Either can be affected first in the early stages. Objective sensory abnormalities usually result from posterior column involvement and less often from PNS disease.
In 1919, Woltmann found features of PNS disease in 4.9% of patients with PA, including distal hyporeflexia or areflexia; 80% of these also had evidence of cord involvement. [20]
In 1991, Healton summarized his experience with a large group of patients as follows: [19]
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Isolated neuropathy was reported in 25% of patients.
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Myelopathy occurred in 12% of cases.
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A combination of neuropathy and myelopathy was noted in 41%.
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Neuropsychiatric manifestations, such as recent memory loss with reduced attention span and otherwise normal cognition, depression, hypomania, paranoid psychosis with auditory or visual hallucinations (megaloblastic madness), violent behavior, personality changes, blunted affect, and emotional liability, were reported in 8% of patients.
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Ocular findings included a cecocentral scotoma and occurred in 0.5% of cases. Others have described optic atrophy, nystagmus, small reactive pupils, and chiasmatic lesion causing bitemporal hemianopia.
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Normal findings were noted on neurologic examination in 14% of patients despite paresthetic symptoms.
Early in the course, poor joint position and vibration sense predominate. Typically, the legs are affected before the arms. Rarely are all limbs affected simultaneously. A Romberg sign is commonly found. The gait may be wide based.
On presentation, 50% of patients have absent ankle reflexes with relative hyperreflexia at the knees. Plantars are initially flexor and later extensor. A Hoffman sign may be found.
As the disease progresses, ascending loss of pinprick, light touch, and temperature sensation occurs. Later, depending on the predominance of posterior column versus cortical spinal tract involvement, ataxia or spastic paraplegia predominates. Then, PNS involvement causes distal limb atrophy.
Cognitive testing may reveal mild impairment or frank dementia.
Nonneurologic manifestations include the following:
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General - Lemon-yellow waxy pallor, premature whitening of hair, flabby bulky frame, mild icterus, and blotchy skin pigmentation in dark-skinned patients
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Cardiovascular - Tachycardia, congestive heart failure
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Gastrointestinal - Beefy, red, smooth, and sore tongue with loss of papillae that is more pronounced along edges
Abnormal vitamin B-12 metabolism occurs in infants born to vitamin B-12–deficient mothers or those with hereditary diseases, including the Imerslünd-Grasbeck syndrome (cublin mutation resulting in decreased cobalamin transport from the intestinal lumen), transcobalamin II deficiency, and intracellular cobalamin abnormalities (classified as Cbl A though G with neurologic features in Cbl C and Cbl D, see below). Symptoms become prominent after exhaustion of vitamin B-12 stores acquired in utero. Infants present with developmental delay, failure to thrive, lethargy, poor feeding, mental retardation, seizures, listlessness, irritability, ataxia, hyporeflexia, hypotonia, pathologic reflexes, coma, tremor, and myoclonus. The latter may worsen transiently upon initiation of treatment.
Causes
Inadequate vitamin B-12 absorption is the major pathomechanism and may result from several factors.
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Intrinsic factor deficiency
PA accounts for 75% of cases of vitamin B-12 deficiency. It is an autoimmune attack on gastric IF. Antibodies are present in 70% of patients. They may block the formation of the cobalamin-IF complex or block its binding with cublin. Other antibodies are directed at parietal cell hydrogen-potassium adenosine triphosphatase (ATPase).
Juvenile PA results from inability to secrete IF. Secretion of hydrogen ions and the gastric mucosa are normal. Transmittance is autosomal recessive inheritance of abnormal GIF on chromosome arm 11q13.
Destruction of gastric mucosa can occur from gastrectomy or Helicobacter pylori infection. A Turkish study found endoscopic evidence of H pylori infection in more than 50% of vitamin B-12–deficient patients. Antibiotics alone eradicated H pylori in 31 patients, with resolution of vitamin B-12 deficiency.
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Deficient vitamin B-12 intake: Intake may be inadequate because of strict vegetarianism (rare), breastfeeding of infants by vegan mothers, alcoholism, or following dietary fads.
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Disorders of terminal ileum: Tropical sprue, celiac disease, enteritis, exudative enteropathy, intestinal resection, Whipple disease, ileal tuberculosis, and cublin gene mutation on chromosome arm 10p12.1 in the region designated MGA 1, which affects binding of the cobalamin-IF complex to intestinal mucosa (Imerslünd-Grasbeck syndrome), are disorders that affect the terminal ileum.
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Competition for cobalamin: Competition for cobalamin may occur in blind loop syndrome or with fish tapeworm (Diphyllobothrium latum).
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Abnormalities related to protein digestion related to achlorhydria: Abnormalities include atrophic gastritis, pancreatic deficiency, proton pump inhibitor use, and Zollinger-Ellison syndrome, in which the acidic pH of the distal small intestine does not allow the cobalamin-IF complex to bind with cublin.
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Medications: Medications include colchicine, neomycin, and p -aminosalicylic acid.
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Transport protein abnormality: Abnormalities include transcobalamin II deficiency (autosomal recessive inheritance of an abnormal TCN2 gene on chromosome arm 22q11.2-qter resulting in failure to absorb and transport cobalamin) and deficiency of R-binder cobalamin enzyme.
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Disorders of intracellular cobalamin metabolism: These disorders result in methylmalonic aciduria and homocystinuria in infants.
Isolated methylmalonic aciduria
Cbl A is due to deficiency of mitochondrial cobalamin reductase resulting in deficiency of adenosylcobalamin.
Cbl B is due to deficiency of adenosylcobalamin transferase resulting in deficiency of adenosylcobalamin.
Methylmalonic aciduria and homocystinuria
Cbl C is a combined deficiency of methylmalonyl CoA mutase and homocysteine:methyltetrahydrofolate methyltransferase. Patients have prominent neurologic features and megaloblastic anemia.
Cbl D is a deficiency of cobalamin reductase. Patients have prominent neurologic features.
Cbl F is a defect in lysosomal release of cobalamin.
Isolated homocystinuria
Cbl E is due to a defect in methionine synthase reductase located on chromosome arm 5p15.3-p15.2.
Cbl G is due to a defect in methyltetrahydrofolate homocysteine methyltransferase located on chromosome arm 1q43.
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Increased vitamin B-12 requirement: Requirement is increased in hyperthyroidism and alpha thalassemia.
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Other causes
In AIDS, vitamin B-12 deficiency is not infrequent. Although the exact etiology remains obscure, it is likely a multimodal process involving poor nutrition, chronic diarrhea, ileal dysfunction, and exudative enteropathy. Low vitamin B-12 levels may be more common in late than in early HIV disease.
N 2 O exposure can occur iatrogenically (ie, anesthesia) or through abuse ("whippets").
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Vitamin B-12–associated neurological diseases. Cobalamin and folate metabolism. TS = thymidylate synthase, DHFR = dihydrofolate reductase, SHMT = serine methyl-transferase.
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Vitamin B-12–associated neurological diseases. Cobalamin deficiency leads to reduced adenosylcobalamin, which is required for production of succinyl-CoA. D-methylmalonyl-CoA is converted to methylmalonic acid.
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Vitamin B-12–associated neurological diseases. Pernicious anemia. Characteristic lemon-yellow pallor with raw beef tongue lacking filiform papillae. Photo from Forbes and Jackson with permission.
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Vitamin B-12–associated neurological diseases. Fluid attenuated inversion recovery (Flair) MRI sequence in a patient with cobalamin deficiency and neuropsychiatric manifestations. Discrete areas of hyperintensities are present in the corona radiata.
