Subacute Combined Degeneration of the Spinal Cord (Archive)

Etiology

Subacute combined degeneration is an acquired condition caused by vitamin B12 deficiency. Vitamin B12 absorption is a multistep process; any abnormality in the absorption steps can lead to a deficiency.

The causes of vitamin B12 deficiency include the following:

Nutritional Deficiency

Cobalamin is a water-soluble vitamin. Although cobalamin 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 animal-derived foods, 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.[3]

Individuals who follow strict vegan diets are especially prone to developing deficiency when increased demand for vitamin B12 is present, such as during pregnancy or lactation. Breastfed infants whose mothers have B12 deficiency can also develop a deficiency unless they receive supplementation.

Gastric Abnormalities

Gastric surgery/gastritis: Vitamin B12 in food exists in a protein-bound form. The entry of food into the stomach stimulates gastric acid production, which leads to the dissociation of vitamin B12 from these proteins. The release of vitamin B12 from the protein-bound form is necessary to bind with the intrinsic factor and its eventual absorption. Loss of parietal cells of the stomach due to gastric surgery or gastritis leads to a decline in the production of gastric acid and intrinsic factor, which can result in vitamin B12 deficiency.[4][5] Procedures considered high risk for vitamin B12 deficiency include partial or total gastrectomy (for gastric cancer) and bariatric surgeries such as sleeve gastrectomy and Roux-en-Y gastric bypass.[6]

Autoimmune gastritis/pernicious anemia: Autoimmune gastritis, previously known as pernicious anemia, is the most common cause of vitamin B12 deficiency. The condition occurs due to autoimmune-mediated destruction of the parietal cells, chronic inflammation, and atrophy of the mucosa of the corpus and fundus of the stomach. Normally, the intrinsic factor (produced by the parietal cells) binds to vitamin B12 and facilitates its transport to the ileum, where the vitamin can be absorbed. Therefore, the destruction of the parietal cells and subsequent intrinsic factor deficiency leads to reduced uptake of vitamin B12.

Small Bowel Disease

Many diseases that affect the small intestine can lead to the malabsorption of vitamin B12.[7] These include inflammatory bowel disease, sprue, radiation enteritis, lymphoma, and amyloidosis. Celiac disease can lead to vitamin B12 deficiency if non-adherence to a gluten-free diet is evident.[8] 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.

Pancreatic Disease

Pancreatic enzymes are required to cleave vitamin B12 from salivary proteins (haptocorrins) and transfer the vitamin 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.

Drug-Induced

Several medications, such as gastric acid suppressants, metformin, and nitrous oxide, can result in vitamin B12 deficiency.

Gastric acid suppressants: Patients prescribed histamine H2 receptor antagonists and proton pump inhibitors in high doses or for longer than 2 years are at risk of developing cobalamin deficiency. The underlying mechanism suppresses gastric acid production, preventing vitamin B12 from dissociating from its protein-bound form. This reduces the amount of vitamin B12 available for binding to intrinsic factor and reduces absorption.[9]

Metformin: Metformin, a common anti-diabetic medication, can cause B12 deficiency in approximately 10% to 30% of patients. The mechanism involves interference with calcium-dependent ileal absorption of the B12-intrinsic factor complex. The effect of metformin on B12 absorption is reversible with calcium supplementation.[10] 

Nitrous oxide: Subacute combined degeneration has been observed in patients who use nitrous oxide recreationally or are exposed to the substance as an anesthetic agent.[11] The mechanism involves nitrous oxide-induced inactivation of vitamin B12 and inhibition of methionine synthetase, disrupting methylation and deoxyribonucleic acid synthesis and leading to injury of the neuronal axons. Patients with a pre-existing B12 deficiency are particularly prone to developing acute life-threatening neurological symptoms on exposure to nitrous oxide, which may be fatal.[12]

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.

Genetic Abnormalities

Vitamin B12 deficiency can occur in neonates with genetic abnormalities such as transcobalamin deficiency and Imerslund-Grasbeck syndrome.[13]

Epidemiology

The epidemiology of vitamin B12 deficiency is complex due to its multiple etiologies. Generally, vitamin B12 deficiency is more common in older adults, and prevalence increases with age. Results from a study conducted on the survivors of the Framingham heart study showed that 5% of older patients (who were aged 67 to 96) had low vitamin B12 levels, and an additional 6% had a functional deficiency indicated by high methylmalonic acid and homocysteine levels.[14] Similarly, surveys conducted in the United States and the United Kingdom found that 6% of people aged 60 and older had B12 deficiency, while 20% had borderline B12 levels.[15] Malabsorption is the leading cause of B12 deficiency in older populations.

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, study results conducted in Latin America concluded that approximately 40% of children and adults have either marginal or low vitamin B12 levels.[16] A similar trend has been observed in studies conducted in India, Kenya, and Bhutanese refugees.[17][18][19] 

The high prevalence of vitamin B12 deficiency in subjects from developing countries is associated with insufficient dietary intake of animal-rich foods. Pernicious anemia, the most common cause of vitamin B12 deficiency overall, is most common in Northern Europeans, especially in those of Scandinavian descent.[20] Few studies have estimated the proportion of patients with cobalamin deficiency with clinical or radiological findings of subacute combined degeneration. A case series on cobalamin-deficient patients with clinical signs showed magnetic resonance imaging findings consistent with the diagnosis in 14.8% of cases.[21]

Pathophysiology

Vitamin B12 plays a vital role in deoxyribonucleic acid (DNA) synthesis and odd-chain fatty acid metabolism, which are required to maintain the integrity of neuronal myelin.

The vitamin is a cofactor for the following enzymes:

• Homocysteine methyltransferase: This enzyme carries out the conversion of homocysteine to methionine. Methionine is a precursor for S-adenosyl methionine, a methyl donor required to maintain the integrity of the neuron sheath. A deficiency of vitamin B12 disrupts this reaction, which leads to reduced formation of S- adenosyl methionine. This impairs the methylation of myelin basic protein and lipids and damages the myelin sheath. Homocysteine methyltransferase also catalyzes the conversion of 5-methyl-tetrahydrofolate to tetrahydrofolate, which acts as a one-carbon donor for DNA synthesis. A deficiency of vitamin B12 causes folate to be trapped in its methylated form of 5-methyl-tetrahydrofolate.
• Methylmalonyl-coenzyme A mutase: This enzyme converts methylmalonyl-coenzyme A (CoA) to succinyl-CoA, which is required for myelin synthesis. Interruption of this step leads to the accumulation of methylmalonyl-CoA and propionyl-CoA, which disrupts normal myelin synthesis and accumulates abnormal fatty acids.

Although the neurological manifestations of vitamin B12 deficiency are caused by demyelination, the mechanism of cobalamin deficiency leading to demyelination is unclear. Earlier experimental studies on animals suggest that methyl group deficiency due to the dysfunction of homocysteine methyltransferase was the primary pathophysiological mechanism.[22] 

Other results of studies point toward the abnormal accumulation of methylmalonyl-CoA, propionyl-CoA, and abnormal fatty acids as the cause of the demyelination of tracts in the spinal cord. Recent studies have shed light on another mechanism of demyelination: an imbalance between the tumor necrosis factor-alpha (TNF-α) levels, epidermal growth factor (EGF), and interleukin-6. Experiments conducted on gastrectomized rats that had developed subacute combined degeneration showed 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.[23]

Histopathology

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.[24] Early microscopic changes include swelling of myelin sheaths, predominantly affecting 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 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 the separation of myelin lamellae and the formation of intra-myelin vacuoles in the dorsal and lateral columns of the spinal cord.

History and Physical

History and Physical Examination

History intake 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.

A 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 alcohol can cause macrocytosis and is associated with reduced dietary intake. Patients should be asked 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 and neurosyphilis are significant 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).

• Dorsal column involvement leads to impaired tactile discrimination, proprioception, and vibration sense. The earliest symptoms of dorsal column involvement are paresthesia, observed in the form of tingling, burning, and sensory loss of the distal extremities. The upper or lower limbs are involved first, or all 4 limbs are affected simultaneously. In addition, Lhermitte sign may be present. Loss of proprioception usually presents as difficulty maintaining balance without visual cues (eg, in the dark or with closed eyes).
• Lateral corticospinal tract dysfunction causes muscle weakness, hyperreflexia, and spasticity. Stiffness is often the initial symptom of lateral cord involvement. Diffuse hyperreflexia can occur, although ankle reflexes are usually absent. Other signs of upper motor neuron damage, such as ankle clonus and Babinski signs, may be present. Spasticity can progress to paraplegia or quadriplegia if the condition remains untreated. Sphincter involvement in advanced cases can lead to bowel and bladder incontinence.
• Spinocerebellar tract degeneration causes gait abnormalities, including sensory ataxia, which manifests as a positive Romberg sign.

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 the loss of tongue papillae. A yellow-lemon tint due to jaundice may also be observed.

Evaluation

The goals of evaluating a patient with subacute combined degeneration are as follows:

Identify Hematological Abnormalities

A complete blood count and blood smear help to identify hematological abnormalities from cobalamin deficiency (such as macrocytosis, anemia, and hypersegmented neutrophils). Macrocytosis, 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 the condition from other causes of macrocytosis. Furthermore, a normal MCV does not rule out B12 deficiency.[14] 

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. Subacute combined degeneration may occur without hematological abnormalities.

Confirm B12 Deficiency

Serum B12 levels

Chemiluminescence assay is the most commonly used assay to measure serum B12. The assay has a sensitivity of 95% and a specificity of ≤80% in patients with deficiency symptoms. 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:

Several assays measure serum B12 levels. Therefore, reference ranges vary.

• Serum B12 levels are not reliable markers for physiological stores. Most B12 measurement assays only measure the protein-bound form of B12, which is unavailable to tissues. A deficiency is possible with borderline or normal serum B12 levels and requires measurement of metabolite levels. A meta-analysis showed that one-third of patients with subacute combined degeneration have normal or high serum B12 levels.
• The test has low sensitivity in patients with autoimmune gastritis as anti-intrinsic factor antibodies interfere with chemiluminescence B12 assays.
• Some patients have falsely low serum B12 levels, although not deficient; this can occur due to multiple myeloma, human immunodeficiency virus, pregnancy, or the use of oral contraceptives.[25][26]

Metabolite levels

Methylmalonic acidemia (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 MMA is 70 to 270 nmol/L, and for homocysteine, from 5 to 15 mcmol/L.

MMA is considered a more accurate marker of deficiency than B12 levels. MMA is also a more specific marker of B12 deficiency than homocysteine. While homocysteine can be elevated in folate and B12 deficiency, MMA is elevated only in B12 deficiency. Therefore, an elevation of both MMA and homocysteine suggests B12 deficiency. Elevation of homocysteine with normal MMA indicates folate deficiency. MMA may be elevated in conditions such as renal failure and methylmalonic aciduria.

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.

Determine the Cause of Cobalamin Deficiency

Patients with 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.[27] Anti-parietal antibodies may also be present. If antibodies are absent, further testing with serum gastrin levels may be indicated when suspicion of pernicious anemia is high. The Schilling test, historically used to determine a patient's absorptive capacity of cobalamin, is now considered obsolete. Bone marrow examination is usually avoided due to the invasive and non-specific characteristics when diagnosing B12 deficiency. 

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 called the "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.[28]

Treatment / Management

Subacute combined degeneration is treated with vitamin B12 supplementation, 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 depend on the presenting symptoms, the urgency of treatment, the underlying etiology, and the patient's preference.[29] Generally, cobalamin deficiency is treated with 1000 mcg orally daily. Patients with malabsorption require a higher daily dose of 1000 to 2000 mcg. Parenterally, cyanocobalamin is administered at 1000 mcg weekly for 1 month, followed by 1000 mcg monthly.

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 when the deficiency is corrected. A suggested dosing regimen for patients with neurological symptoms is 1000 mcg every alternate day for 2 weeks, followed by monthly administration of cyanocobalamin.[25] 

Parenteral therapy is also preferred in patients who are noncompliant with 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 1 to 2 days, and reticulocytosis occurs within 3 to 4 days. This is followed by the improvement of anemia and the disappearance of hyper-segmented neutrophils, which takes approximately 2 weeks. Leucopenia and thrombocytopenia take 3 to 4 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.[30] 

Neurological deficits may sometimes be permanent and irreversible 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 treatment 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 clinician to exclude other causes of anemia, such as iron deficiency.

Differential Diagnosis

Several conditions also present with involvement of the dorsal and lateral columns and can mimic the clinical and radiologic findings of subacute combined degeneration:

Metabolic Deficiency or Toxicity

Copper and vitamin E deficiency can present with T2 hyperintensity of dorsal columns and mimic the neurological deficits of subacute combined degeneration.[31] Copper deficiency mainly occurs in patients with a history of gastrointestinal surgery, zinc overload, parenteral nutrition, malabsorption, or malnutrition. Low levels of copper, ceruloplasmin, and myelodysplastic syndrome differentiate this condition from subacute combined degeneration. Vitamin E deficiency and methotrexate-induced myelopathy may also look identical.

Demyelinating Myelopathy

Transverse myelitis can cause spinal cord demyelination, but demyelination does not preferentially involve dorsal columns and is limited to 1 or 2 spinal segments. Multiple sclerosis is another cause of demyelinating lesions, although the spinal cord involvement is asymmetric and affects fewer segments.[32] Multiple sclerosis mainly affects younger patients and may be associated with other signs and symptoms (scanning speech, intention tremor, nystagmus).

Infectious Myelopathy

Vacuolar myelopathy can occur in patients who are human immunodeficiency virus (HIV)-positive with low CD4 counts and shares the histology, MRI findings, and symptoms of subacute combined degeneration. The myelopathy presents similarly with symmetrical involvement of the posterolateral columns. A history of HIV, low CD4 counts, opportunistic infections, acquired immunodeficiency syndrome-defining illness, and malignancy help establish a diagnosis.[33] Tabes dorsalis, a form of late neurosyphilis that damages the dorsal columns, can also present with sensory ataxia and bladder involvement. Differentiating features include dorsal root involvement, lancinating pain, and the presence of Argyll Robertson pupils.

Friedreich Ataxia

An autosomal recessive disorder is seen in adolescents that affects the dorsal and spinocerebellar tracts and can present with impaired proprioception, vibration, and depressed tendon reflexes.[34] Other associated features include cervical cord atrophy, hypertrophic cardiomyopathy, hammertoes, nystagmus, and pes cavus.

Leukoencephalopathy With Brainstem and Spinal Cord Involvement and Lactate Elevation

This autosomal recessive condition, seen chiefly in adolescents and children, symmetrically involves the posterolateral columns. Unlike subacute combined degeneration, this condition affects the entire spinal cord and can extend to the medulla. Other disorders include inflammatory conditions such as sarcoidosis, ischemic lesions, and malignancies.[28]

Prognosis

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 certain characteristics tend to have better short-term neurological outcomes.[35][36] 

These include the following:

• Age < 50 years
• Short disease course
• Absence of sensory deficits
• Absence of Romberg sign
• Absence of Babinski signs
• Involvement of ≤7 spinal segments on MRI
• Presence of spinal cord edema
• Contrast enhancement of the spine
• Absence of spinal cord atrophy

Complications

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, increasing 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 cobalamin deficiency 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.