Subacute combined degeneration of the spinal cord is a neurological complication of vitamin B12 (cobalamin) deficiency. A deficiency of vitamin B12 can occur as a result of nutritional deficiency, reduced absorption due to altered gastrointestinal anatomy or function, or due to the intake of certain drugs. Subacute combined degeneration is characterized by degeneration of the dorsal columns and the lateral columns of the spinal cord due to demyelination. It commonly presents with sensory deficits, paresthesia, weakness, ataxia, and gait disturbance. In severe untreated cases, it can lead to spasticity and paraplegia. It is crucial to promptly identify and treat vitamin B12 deficiency to prevent the development of this serious neurological complication.
Subacute combined degeneration is an acquired condition that is caused by vitamin B12 deficiency. The absorption of vitamin B12 is a multistep process; any abnormality in the steps of absorption can lead to a deficiency. The causes of vitamin B12 deficiency include the following:
1. Nutritional Deficiency
Cobalamin is a water-soluble vitamin. Although it can be stored in large amounts, vitamin B12 cannot be synthesized by the human body and requires supplementation from dietary sources. Therefore, vitamin B12 deficiency can develop if dietary intake is low, and body stores are depleted. Cobalamin is mainly present in food derived from animals such as meat, fish, dairy products, eggs, and fortified cereals. The richest sources of vitamin B12 are clams and animal liver, the latter of which has historically been used to treat vitamin B12 deficiency. Plant-based food does not contain cobalamin. Therefore, strict vegetarians and vegans are at risk of developing vitamin B12 deficiency. Individuals who follow strict vegan diets are especially prone to developing deficiency when there is increased demand for vitamin B12, such as during pregnancy or lactation. Breastfed infants whose mothers have B12 deficiency can also develop a deficiency unless they receive supplementation.
2. Gastric Abnormalities
3. Small Bowel Disease
Many diseases that affect the small intestine can lead to malabsorption of vitamin B12. These include inflammatory bowel disease, sprue, radiation enteritis, lymphoma, and amyloidosis. Celiac disease can lead to vitamin B12 deficiency if there is non-adherence to a gluten-free diet. Ileal resection can result in a deficiency by reducing the absorptive surface area. Small intestinal bacterial overgrowth, seen in intestinal motility disorders, anatomic abnormalities (blind loop, diverticulitis), and chronic pancreatitis increases the utilization of vitamin B12-intrinsic factor and can lead to a deficiency.
4. Pancreatic Disease
Pancreatic enzymes are required to cleave vitamin B12 from salivary proteins (haptocorrins) and transfer it to the intrinsic factor. This step is interrupted in patients with pancreatic insufficiency or chronic pancreatitis and can lead to reduced absorption of vitamin B12.
5. Drug-induced
Several medications, such as gastric acid suppressants, metformin, and nitrous oxide, can result in vitamin B12 deficiency.
6. Fish tapeworm infestation
Ingestion of raw freshwater fish can lead to infestation with Dibothriocephalus latus, which competes with the host for vitamin B12 absorption and can result in a deficiency.
7. Genetic abnormalities
Vitamin B12 deficiency can occur in neonates with genetic abnormalities such as transcobalamin deficiency and Imerslund Grasbeck syndrome.
The epidemiology of vitamin B12 deficiency is complex due to its multiple etiologies. Generally, vitamin B12 deficiency is more common in the elderly, and its prevalence increases with age. A study on the survivors of the Framingham heart study showed 5% of elderly patients aged 67 to 96 years had low vitamin B12 levels, and an additional 6% had a functional deficiency indicated by high methylmalonic acid (MMA) and homocysteine levels.[8] Similarly, surveys conducted in the US and UK found that 6% of people aged 60 and older had B12 deficiency, while an additional 20 % had borderline B12 levels.[9] Malabsorption is the leading cause of B12 deficiency in the elderly.
In developed countries, vitamin B12 is uncommon in children but can affect breastfeeding infants whose mothers are vegan or B12 deficient. In developing regions such as Latin America, the Indian Subcontinent, and certain parts of Africa, a higher prevalence of vitamin B12 deficiency has been observed. For example, a study conducted in Latin America concluded that approximately 40 % of children and adults have either marginal or low vitamin B12 levels.[10] A similar trend has been observed in studies conducted in India, Kenya, and Bhutanese refugees.[11][12][13] The high prevalence of Vitamin B12 deficiency in subjects from developing countries is associated with insufficient dietary intake of animal rich foods. Pernicious anemia, which is the most common cause of vitamin B12 deficiency overall, is most common in Northern Europeans, especially in those of Scandinavian descent.[14]
Few studies have estimated the proportion of patients with cobalamin deficiency with clinical or radiological findings of subacute combined degeneration. A case series conducted on cobalamin deficient patients with clinical signs of subacute combined degeneration showed magnetic resonance imaging (MRI) findings consistent with the diagnosis in 14.8 % of cases.[15]
Vitamin B12 plays a vital role in DNA synthesis and odd chain fatty acid metabolism, which are required to maintain the integrity of neuronal myelin. It acts as a cofactor for the following enzymes:
Although the neurological manifestations of vitamin B12 deficiency are caused by demyelination, the mechanism by which cobalamin deficiency leads to demyelination is not entirely clear. Earlier experimental studies conducted on animals suggest that methyl group deficiency due to dysfunction of homocysteine methyltransferase was the primary pathophysiological mechanism.[16]
Other studies point towards the abnormal accumulation of methylmalonyl-CoA, propionyl-CoA, and abnormal fatty acids as the cause for the demyelination of tracts in the spinal cord. Recent studies have shed light on another mechanism of demyelination, which involves an imbalance between the levels of tumor necrosis factor-alpha (TNF-α) and epidermal growth factor (EGF) and interleukin-6. Experiments conducted on gastrectomized rats that had developed subacute combined degeneration were observed to have high levels of TNF and low levels of EGF and IL-6. This finding has also been observed in the cerebrospinal fluid of human subjects with subacute combined degeneration.[17]
The classic histological finding is multifocal myelopathic spongy vacuolation. This occurs due to intra-myelin edema and interstitial edema of the white matter of the dorsal and lateral columns.[18] Early microscopic changes include swelling of myelin sheaths, which predominantly affects the largest fibers. This is followed by the destruction of myelin sheaths and the perivascular accumulation of foamy macrophages and lymphocytes.
Demyelinating lesions initially appear in the center of the dorsal columns of the upper thoracic cord. The lesions then spread laterally to involve lateral corticospinal tracts and cranially involving the cervical cord and medulla. As demyelination and vacuolation progress, axons begin to undergo degeneration. In the late stages of the disease, dense gliosis occurs. Electron microscopic changes include separation of myelin lamellae and formation of intra-myelin vacuoles in the dorsal and lateral columns of the spinal cord.
History taking should focus on identifying the underlying cause of B12 deficiency. For example, dietary history may help identify nutritional deficiency as the cause. An inquiry should be made about gastrointestinal symptoms, such as diarrhea, hematochezia, or steatorrhea. Steatorrhea may indicate malabsorption of vitamin B12 due to celiac disease or pancreatic insufficiency. Past history of malabsorptive disorders (inflammatory bowel disease, celiac disease, etc.) and gastrointestinal surgical procedures (ileal resection, gastrectomy, bariatric surgery) should be noted. Alcohol intake should be documented, as it can cause macrocytosis and is associated with reduced dietary intake. Patients should be inquired about chronic intake of medications such as proton pump inhibitors, histamine receptor antagonists, and metformin. Sexual history should also be noted, as human immunodeficiency virus (HIV) and neurosyphilis are important differentials for subacute combined degeneration. A family history of genetic disorders and autoimmune disorders should be elicited.
Neurological Symptoms
Neurological symptoms may be the presenting symptoms of cobalamin deficiency and may precede the onset of hematological findings. Clinical findings are symmetrical and occur due to the involvement of the dorsal columns, spinocerebellar tracts, and lateral corticospinal tracts. In addition to spinal cord involvement, patients may also have signs and symptoms of peripheral nerve involvement, visual deficits, and neuropsychiatric disease (depression and dementia).
Other Symptoms
Anemia due to underlying B12 deficiency can present with pallor, fatigue, and signs of congestive heart failure in severe cases. Glossitis may be observed as a beefy red tongue and occurs due to loss of tongue papillae. A yellow-lemon tint due to jaundice may also be observed.
The goals of evaluating a patient with subacute combined degeneration are as follows:
1. Identify hematological abnormalities of cobalamin deficiency:
A complete blood count (CBC) and blood smear help to identify hematological abnormalities due to cobalamin deficiency such as macrocytosis, anemia, and hyper segmented neutrophils. Macrocytosis, which is defined as mean corpuscular volume (MCV) of more than 100 fL, may occur without anemia. However, an MCV greater than 115 fl is considered more specific for B12 deficiency and helps differentiate it from other causes of macrocytosis. Furthermore, a normal MCV does not rule out B12 deficiency.[8] Other hematological findings include mild leucopenia or thrombocytopenia. Reticulocytopenia may be seen due to suppressed erythrocyte production. Markers of hemolysis such as indirect bilirubin, and lactate dehydrogenase may be elevated. It is important to note that subacute combined degeneration may occur in the absence of hematological abnormalities.
2. Confirm B12 deficiency:
A) Serum B12 levels
Chemiluminescence assay is the most commonly used assay to measure serum B12. It has a sensitivity of 95 % and a specificity of ≤80 % in patients with symptoms of deficiency. Generally, B12 levels >300 pg/mL are considered normal. Levels between 200 and 300 pg/mL are borderline and <200 pg/ml are low and are considered deficient. However, serum B12 levels should be interpreted cautiously due to several reasons:
There are several assays to measure serum B12 levels, therefore, reference ranges vary.[19]
B) Metabolite Levels
Methylmalonic acid (MMA) and homocysteine are intermediates of cobalamin metabolism, and their elevation is used to confirm B12 deficiency. Measuring MMA and homocysteine is indicated when neurological findings of B12 deficiency are present, but serum B12 levels are either normal or borderline. The normal range for methylmalonic acid is from 70 to 270 nmol/L and for homocysteine from 5 to 15 micromol/L. Methylmalonic acid is considered a more accurate marker of deficiency than B12 levels. Methylmalonic acid is also a more specific marker of B12 deficiency compared to homocysteine. While homocysteine can be elevated in folate and B12 deficiency, methylmalonic acid is elevated only in B12 deficiency. Therefore, an elevation of both methylmalonic acid and homocysteine suggests B12 deficiency. Elevation of homocysteine with normal methylmalonic acid indicates folate deficiency. It is important to note that methylmalonic acid may be elevated in other conditions such as renal failure and methylmalonic aciduria.
C) Folate Levels
Folate deficiency can mimic the hematological picture of cobalamin deficiency. Therefore, serum folate levels should also be measured, especially in patients with alcohol use, a folate-deficient diet, and abnormal gastrointestinal anatomy or function.
3. Determine the cause of cobalamin deficiency:
Patients who are found to have B12 deficiency without an obvious cause should undergo testing for autoantibodies to detect pernicious anemia. Anti-intrinsic factor antibody measurement has low sensitivity but high specificity and can, therefore, be used to confirm the diagnosis of pernicious anemia.[21] Anti-parietal antibodies may also be present. If antibodies are absent, further testing with serum gastrin levels may be indicated when suspicion for pernicious anemia is high. The Schilling test, a test historically used to determine a patient's absorptive capacity of cobalamin, is now considered obsolete. Bone marrow examination is usually avoided as it is invasive and not specific for B12 deficiency.
4. Identify demyelinating lesions:
In the early stages of the disease, demyelination is observed in the spine MRI as bilateral paired regions of T2 hyperintensity in the dorsal columns of the cervical and upper thoracic spinal cord. This finding is often referred to as “Inverted V” or “Inverted rabbit ears” sign. In later stages, T2 hyperintensity may also be seen in the lateral columns of the spinal cord. A decreased T1-weighted signal and contrast enhancement of the same regions may also be observed. Prompt treatment can improve signal abnormalities seen on the MRI.[22]
Subacute combined degeneration is treated with vitamin B12 supplementation, which can be administered by intramuscular, deep subcutaneous, oral, or sublingual routes. The most commonly used preparations are cyanocobalamin and hydroxocobalamin. The dose of vitamin B12, route of administration, and duration of treatment depends on the presenting symptoms, the urgency of treatment, the underlying etiology, and the patient's preference.
Generally, cobalamin deficiency is treated with doses of 1000 mcg orally once daily. Patients with malabsorption require higher oral daily dosing of 1000 to 2000 mcg. Parenterally, cyanocobalamin is administered at a dose of 1000 mcg once a week for one month, followed by 1000 mcg once every month. Patients with subacute combined degeneration require more aggressive and rapid treatment to prevent irreversible neurological deficits. Such patients are best treated by parenteral therapy, at least initially, and can be transitioned to oral therapy once the deficiency is corrected. A suggested dosing regimen for patients with neurological symptoms is 1000 mcg every alternate day for two weeks, followed by once every month administration of cyanocobalamin.[19] Parenteral therapy is also preferred in patients non-compliant to oral therapy or those with altered gastrointestinal anatomy. Patients with an irreversible cause of cobalamin deficiency, such as pernicious anemia and bariatric surgery, require supplementation for life. On the other hand, patients with reversible causes of deficiency (drug-induced, dietary deficiency) are treated until the deficiency is corrected.
Response to therapy is assessed by monitoring hematological markers and improvement in symptoms. Generally, markers of hemolysis decrease in one to two days, and reticulocytosis occur within three to four days. This is followed by the improvement of anemia and the disappearance of hyper segmented neutrophils, which takes approximately two weeks. Leucopenia and thrombocytopenia take three to four weeks to resolve. Vitamin B12 levels should also be monitored at regular intervals. Monitoring is conducted more frequently in patients with subacute combined degeneration and should be continued until a complete response has been elicited. While laboratory markers show rapid improvement, clinical improvement for neurological symptoms takes at least 3 to 12 months.[23] In some cases, neurological deficits may be permanent and may not be reversible even with cobalamin supplementation. Patients should also be monitored for hypokalemia during therapy, which can occur due to the uptake of potassium by red blood cells. Failure to respond to therapy should prompt consideration of patient compliance, an initial failure to identify malabsorption, or the possibility of a different diagnosis. A failure of hematological markers to improve should also prompt the physician to exclude other causes of anemia, such as iron deficiency.
Several other conditions present with involvement of the dorsal and lateral columns and can mimic the clinical and radiologic findings of subacute combined degeneration:
In most patients, treatment halts the disease progression and results in clinical and radiological improvement of neurological deficits. However, the degree of improvement varies. While 86 % show clinical resolution after treatment, only 14 % attain complete clinical resolution. The degree of anemia and level of serum vitamin B12 does not affect the prognosis of subacute combined degeneration. However, patients with the following characteristics tend to have better short-term neurological outcomes:[24][25]
If not treated promptly, subacute combined degeneration can lead to neurological complications such as paraplegia or quadriplegia. Bowel and bladder incontinence can also occur. A failure to correct the underlying anemia may result in congestive heart failure. Patients with autoimmune gastritis are at risk of developing gastric carcinoma and carcinoid tumors, which can increase morbidity and mortality. Patients with autoimmune gastritis are also prone to developing other autoimmune conditions such as type 1 diabetes mellitus, Hashimoto thyroiditis, vitiligo, myasthenia gravis, and rheumatoid arthritis. A deficiency of cobalamin in pregnant women is associated with a higher risk of spontaneous abortions, low birth weight, fetal growth restriction, and neural tube defects. Children born to vitamin B12 deficient mothers are at higher risk of developing neurodevelopmental abnormalities.
The recommended dietary allowance of vitamin B12 for adults is 2.5 mcg per day. A higher dose of 2.6 mcg is required for pregnant women. Patients on strict vegetarian or vegan diets should be advised to take vitamin B12 supplements to prevent deficiency. This is especially important in pregnant and lactating women to prevent a deficiency in the neonate. Due to the high incidence of B12 deficiency in the elderly, patients older than 50 years should be advised to consume a diet fortified with vitamin B12. Indefinite routine supplementation is required for patients who have undergone bariatric surgery.[26]
Screening for vitamin B12 deficiency should be considered in patients receiving chronic treatment with proton pump inhibitors, H2 antagonists, and metformin. Patients with atrophic gastritis, gastrectomy, and pancreatectomy may also benefit from routine screening. Preoperative screening for cobalamin deficiency should be considered for patients requiring anesthesia with nitrous oxide.
Subacute combined degeneration is a rare but treatable complication of vitamin B12 deficiency, which is best managed by a multidisciplinary care team of internists, neurologists, gastroenterologists, and hematologists. Regular supplementation with vitamin B12 should be given to high-risk patients such as vegans and bariatric surgery patients to prevent neurological damage.
All clinicians must be aware of this condition as the presenting neurological symptoms are subtle and can be missed unless the clinician has a high index of suspicion. Patients with risk factors for cobalamin deficiency (veganism, gastrointestinal surgery, autoimmune gastritis, malabsorption, drug-induced) should be monitored for neurological symptoms of subacute combined degeneration. The presence of macrocytosis, hyper segmented neutrophils, and a mean corpuscular volume should also alert the physician to the possibility of an underlying cobalamin deficiency. [Level 2-3] In such cases, cobalamin, as well as folate levels, should be checked due to their close metabolic relationship. [Level 1]
Plasma homocysteine and methylmalonic levels can be used to support the diagnosis if serum B12 levels are borderline. Anti-intrinsic factor antibodies should be checked in patients with suspected pernicious anemia, the most common cause of cobalamin deficiency (Level 1). Treatment with cyanocobalamin must be started without delay in patients with subacute combined degeneration to reverse and prevent irreversible neurological deficits. Treatment is continued until the deficiency is corrected and may extend indefinitely in patients with irreversible causes of B12 deficiency, such as pernicious anemia. Neurological deficits of subacute combined degeneration require regular assessment and monitoring by a neurologist.
Physical and occupational therapy may be necessary to reduce spasticity and improve gait and balance control. Patients may also require consultations with gastroenterology to determine if malabsorption is the cause of the deficiency. Those patients with pernicious anemia require gastroenterology referral for upper gastrointestinal endoscopy to exclude gastrointestinal malignancy.[19]
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