Spinal Cord Subacute Combined Degeneration

Etiology

SCD is most commonly caused by a deficiency in vitamin B12. The primary sources of vitamin B12 are dietary and include meat, eggs, and dairy products. Vitamin B12 obtained from these products is absorbed in the ileum along with the intrinsic factor produced by the parietal cells in the stomach. Alteration at the level of dietary intake, absorption, or intrinsic factor activity can cause vitamin B12 deficiency and, in turn, the neurological manifestations of SCD of the spinal cord. 

Dietary deficiency is an unlikely cause of vitamin B12 deficiency as liver stores last up to 3 years. However, in patients who are strict vegans or older individuals, particularly those in assisted facilities, dietary deficiencies have been identified as causes of vitamin B12 deficiency. Vitamin B12 deficiency can be suspected as the cause of unexplained anemia in patients with other autoimmune conditions such as vitiligo or thyroiditis. In such patients, pernicious anemia can be identified as the cause. It is an autoimmune condition where antibodies are formed against the parietal cells in the stomach, decreasing the production of the intrinsic factor(IF) and altering the absorption of vitamin B12.[3][4]

Malabsorption as a cause of vitamin B12 deficiency can be due to loss of intrinsic factor in patients post-gastrectomy or after gastric bypass surgery. 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.[5] Many diseases that affect the small intestine can lead to the malabsorption of vitamin B12. 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.[6] Ileal resection can result in a deficiency by reducing the absorptive surface area. Small intestinal bacterial overgrowth is seen in intestinal motility disorders and anatomic abnormalities (blind loop, diverticulitis). It has also been associated with fish tapeworm infestations, which compete with the host for vitamin B12 absorption.

Certain medications, such as metformin, proton pump inhibitors, and nitrous oxide, have been associated with vitamin B12 deficiency. Proton pump inhibitors reduce gastric acid production, impairing vitamin B12 dissociation from its protein-bound form in the diet. Metformin is the best-known medication causing B12 deficiency by interfering with calcium-dependent ileal absorption of B12. The effect can be reversed with calcium supplements.[7]

SCD can be caused by a functional deficit of vitamin B12 secondary to repeated use of nitrous oxide. Nitrous oxide inactivates vitamin B12 by oxidizing the cobalt in the vitamin B12 molecule. The functionally deficient vitamin B12 causes impaired methionine synthase activity, which leads to impaired myelin maintenance and axonal degeneration. 

Copper deficiency has been recognized as another important cause of SCD. The clinical presentation and underlying causes can be very similar to vitamin B12 deficiency, including gastric bypass and small bowel resection. Copper deficiency may cause similar neurological deficits in patients, including the classic SCD.[8] It also causes anemia or pancytopenia. The other reason for copper deficiency is excessive zinc intake.[9]

Epidemiology

Limited studies have evaluated the incidence of SCD of the spinal cord. Not all patients with vitamin B12 deficiency will manifest SCD of the spinal cord. A magnetic resonance imaging (MRI) study correlated the abnormal spinal cord signal found in patients with vitamin B12 deficiency and estimated an incidence of subacute combined degeneration of the spinal cord in 14.8% of them.[10] In all the patients, the spinal cord changes were reversed after appropriate treatment.

Vitamin B12 deficiency is the most prevalent cause of SCD of the spinal cord. It is more common among older individuals, particularly those residing in assisted facilities, as revealed by low serum vitamin B12 levels and high serum methylmalonic acid (MMA) levels.[11] This may be due to inadequate dietary intake of food products rich in vitamin B12 over a prolonged time.[12] Vitamin B12 deficiency is also more prevalent in developing countries where up to 40% of the population has either marginal or low vitamin B12 levels.[13]

The incidence of SCD due to copper deficiency is unknown and understandably rare. Upper gastrointestinal surgery is the most common cause of copper deficiency, followed by zinc toxicity and malabsorption.[14]

SCD due to nitrous oxide abuse is increasingly recognized. This has resulted from an exponential increase in recreational nitrous oxide (Whippits) use over the past decade. It is now the second most common recreational drug use among 16-24-year-olds in the UK.[15] About 3.4% of nitrous oxide users experience neurological symptoms consistent with SCD.[15]

Pathophysiology

The significant pathological changes involved in SCD of the spinal cord are multifocal, diffuse demyelination, and axonal loss, particularly in the white matter of the spinal cord. These demyelinating changes predominately affect the dorsal column, lateral corticospinal tracts, and sometimes the spinothalamic tracts. Clinical presentations include paresthesias, ataxia, sensory loss, cognitive impairment, and muscle weakness. These symptoms are collectively seen in patients with SCD of the spinal cord.[16]

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. Vitamin B12 is a cofactor for 2 essential enzymes involved in preserving myelin. Homocysteine methyltransferase converts homocysteine to methionine. Methionine is the precursor for S-adenosyl methionine, which is required to maintain the neuron sheath. Methylmalonyl-CoA mutase converts methylmalonyl-CoA to succinyl-CoA. This step is necessary for myelin synthesis. The deficiency of vitamin B12 leads to the accumulation of methylmalonic acid (MMA), methylmalonyl-CoA, and propionyl-CoA. MMA impairs the synthesis of myelin and results in the incorporation of abnormal lipids in myelin, leading to demyelinating changes that manifest as SCD of the spinal cord.[17][18]

Nitrous oxide inactivates vitamin B12 by oxidation of the cobalt ion in cobalamin and makes the vitamin B12 functionally inactive. As a consequence, the methionine synthase activity is reduced. Reduced methionine results in myelin maintenance failure and secondary axonal degeneration in SCD.[19]

Copper is a trace metal element functioning as a prosthetic group in several key metabolic enzymes such as cytochrome-C oxidase and copper-zinc superoxide dismutase. It is essential for the function and structure of various tissues, especially the bone marrow and the central nervous system. Copper deficiency may result in anemia and even pancytopenia. In the nervous system, it may cause copper deficiency myelopathy, typical for SCD.[20] Copper deficiency is also commonly caused by excessive zinc intake because the 2 divalent cations share the same absorption carrier-involved pathway in the duodenum. Excessive zinc intake will cause copper deficiency. Cases have been reported even in patients with Wilson disease who develop copper deficiency due to excessive zinc in the treatment scheme.[21]

Histopathology

Multifocal, diffuse demyelination, axonal loss, and myelopathic spongy vacuolation, particularly in the dorsal and lateral white matter tracts of the spinal cord, are the first changes observed in SCD of the spinal cord. Demyelinating changes predominately affect the dorsal column, lateral corticospinal tracts, and sometimes the spinothalamic tracts.

Microscopic examination shows initial swelling of the largest myelin sheath fibers, which progresses to the destruction of myelin. There is an accumulation of macrophages and lymphocytes on the myelin sheaths. If treatment is not administered promptly, dense gliosis of the tissue ensues.

History and Physical

In patients with suspected SCD of the spinal cord, a detailed neurological examination may show spastic paraparesis, impaired Romberg sign, loss of vibration sense, proprioception, 2-point discrimination, ataxic gait, and reduced sensation.[16][17] These changes can be linked to the demyelinating effects on the lateral corticospinal tracts and the dorsal column pathway. Signs and symptoms of peripheral neuropathies affecting predominantly the lower limbs may coexist. Subacute cognitive decline can be present; vitamin B12 is a cause of reversible dementia and one that can show good neurological outcomes with prompt treatment.[18]

Specific risk factors should be investigated while the history of Crohn or celiac disease, medication use, history of autoimmune diseases, and patient diet details are obtained. Patients should be asked about chronic intake of medications such as proton pump inhibitors and metformin. Surgeries, especially gastrointestinal surgery history, are always necessary to note. A detailed diet history should include vegetarian and vegan diets, as well as intake of supplements, especially zinc and copper. A careful history of nitrous oxide (Whippits) use must be obtained, especially in younger patients. The presence of systemic organ-specific diseases such as type I diabetes, thyroid diseases, and vitiligo may indicate an underlying cause of pernicious anemia.

The hematological implications of this disease indicate that most patients will present with symptoms of fatigue, pallor, and generalized malaise, which could be correlated to the underlying megaloblastic anemia. Physical examination findings of note include pallor and jaundice, which are products of hemolysis triggered by increased red blood cell turnover, and glossitis, which is an impairment in DNA synthesis that affects the rapidly dividing cells.

Evaluation

The initial evaluation of a patient with subacute neurological symptoms and anemia should include a complete blood count, peripheral smear, and serum vitamin B12 and folate levels. Specific indices, especially mean corpuscular volume (MCV), will reveal a macrocytic anemia (MCV >100 fL).[22] Macrocytosis may occur without anemia. However, an MCV >115 fL is considered more specific for B12 deficiency and helps differentiate it from other causes of macrocytosis.[23] Hypersegmented neutrophils and macro-ovalocytes are present in the peripheral smear. A typical differential for megaloblastic anemia is folate deficiency; however, neurological findings are rare in folate deficiency. While homocysteine can be elevated in folate and B12 deficiency, methylmalonic acid(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. An elevated MMA and elevated homocysteine levels would rule out a diagnosis of folate deficiency. Methylmalonic acid(MMA) is considered a more accurate marker of deficiency than homocysteine or B12 levels. Nitrous oxide use must be seriously considered if the vitamin B12 level is normal, yet the MMA is high.[19] If the vitamin B12 and MMA levels are normal and the patient presents with signs and symptoms of SCD, it is important to check the serum levels of copper, ceruloplasmin, and zinc to rule out copper deficiency myelopathy.[8]

Neurological signs alone in the absence of anemia have been noted.[16] The radiological evaluation includes a complete spine MRI, which will show hyperintense lesions localized to the posterior columns of the spinal cord. These lesions may be apparent in T2-weighted cervical and thoracic spinal cord images.[17] The involvement of the lateral tracts, although present clinically, rarely presents radiologically. 

Investigations should cover possible dietary deficiencies and gastrointestinal causes such as Crohn or celiac disease. An evaluation that includes anti-intrinsic factor antibodies is warranted in patients with a history of autoimmune disease.[24] An MRI of the cervical or upper thoracic spine can be very valuable for patients who present with a clinical syndrome of myelopathy ie upper motor neuron pattern of weakness and/or sensory impairment of both lower extremities. The MRI typically shows bilateral symmetric T2 hyperintensity in the dorsal columns. It is often referred to as the "Inverted V"  sign. Prompt treatment results in rapid resolution of the abnormal MRI findings.[23]

Treatment / Management

The treatment for SCD of the spinal cord is the supplementation of vitamin B12 either in oral or parenteral form. The underlying cause of vitamin B12 deficiency determines the specific route and duration of therapy. Patients with Crohn disease and celiac disease should be monitored for signs and symptoms, and declining levels of vitamin B12 levels. In patients with chronic conditions that can deplete vitamin B12 levels, such as celiac disease, pernicious anemia, and Crohn disease post-resection, indefinite supplementation of vitamin B12 is warranted.[25] 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.[15]

Oral administration is indicated in conditions where dietary deficiency of vitamin B12 is identified as the cause. Parenteral administration is the route preferred in symptomatic anemia or severe neurological dysfunction, including SCD. Patients with SCD 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 other day for 2 weeks, followed by monthly administration of cyanocobalamin.[25] The symptoms and MRI findings in SCD usually improve dramatically within days to a couple of weeks with parenteral vitamin B12 on an every-other-day treatment scheme. Upon the resolution of symptoms, the oral route of administration may be used. Parenteral administration is also indicated if malabsorption is determined to be the cause, such as celiac disease or pernicious anemia. However, sufficient evidence exists to support oral administration even in these conditions if the dose is high enough to generate a favorable response. Recent studies have shown that oral treatment with vitamin B12 is as good as the intramuscular route of administration in bringing the vitamin B12 level up in the serum.[26]

Differential Diagnosis

The differential diagnosis of SCD of the spinal cord includes the following:

Copper Deficiency: A copper deficiency is an important differential when approaching the neurological presentation that is classically present in SCD of the spinal cord.[27] Copper deficiency can be seen in patients who have undergone bariatric surgery, those who have undergone excessive treatment of Wilson disease with chelators, and patients who have a history of excessive zinc intake either in supplemental form or ingestion of denture cream. Copper deficiency can also be caused by excessive zinc intake. Therefore, checking serum copper and zinc is essential in any patient with clinical SCD but normal vitamin B12 and MMA levels.

Patients with copper deficiency present with dorsal column involvement manifesting as loss of vibration sense, proprioception, spastic paraparesis, and neuropathies. Neurological symptoms are similar to SCD of the spinal cord, and the diagnosis is established if there is no response to vitamin B12 supplementation alone. These deficiencies may coexist in patients who have undergone bariatric surgery. Copper deficiency can be documented with low levels of copper and ceruloplasmin.[28]

Methotrexate-Induced Myelopathy and Vitamin E Deficiency: These conditions can mimic SCD. Neurological symptoms are similar to SCD of the spinal cord, and the diagnosis is based on a history of methotrexate use or with serum measurements of vitamin E, B12, MMA, and homocysteine levels.

Other Conditions: Other differentials for disease localized to the spinal cord are diverse. The most common nontraumatic causes include transverse myelitis, multiple sclerosis, tabes dorsalis, epidural tumors, and cervical spondylosis myelopathy. Neurological symptoms are similar to SCD of the spinal cord, but imaging with an MRI should be sufficient to rule out these differential diagnoses.

• Transverse myelitis is segmental, involves inflammation usually affecting 1 or 2 segments of the spinal cord, and is not exclusively in the dorsal columns. Patients may present with symptoms such as a tight band or girdle-like sensation around the trunk. A gadolinium-enhanced MRI of the spine would confirm the diagnosis by revealing enhancement involving 1 or more cord segments that are not limited to the dorsal or lateral columns of the cord.                       
• Multiple sclerosis generally presents with asymmetric involvement of the spinal cord and can involve numerous areas. Multiple sclerosis is further characterized by neurological symptoms that are distributed over time. Patients also show many other general neurological symptoms, including bowel and bladder involvement and cerebellar involvement. These symptoms are not typical of SCD of the spinal cord.[29]                                                                     
• Tabes dorsalis is a manifestation of tertiary syphilis. Given this disease also affects the dorsal columns of the spinal cord, it can be included in the differential diagnosis. However, tabes dorsalis is characterized by sensory ataxia and lancinating pain along the limbs and a positive history of syphilis. This diagnosis can be ruled out from a thorough history and examination. If deemed necessary, laboratory tests for syphilis can be included as a part of the workup. The other myelopathy of infectious etiology is human immunodeficiency virus (HIV) vacuolar myelopathy.                                                                                         
• HIV-positive patients with low CD4 counts share the histology, MRI findings, and symptoms of SCD. 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.[30]                                                                                                 
• Epidural tumors and cervical spondylosis myelopathy can be effectively ruled out by a spine MRI and the absence of classic findings found in SCD of the spinal cord.

Prognosis

Neurological outcomes have been favorable in patients with SCD, who are identified early and treated promptly. However, residual long-term moderate to severe neurological deficits have been noted in some, particularly those that discontinue treatment. While 86% of patients show clinical resolution after treatment, only 14% attain complete clinical resolution. In most patients treated with vitamin B12 supplementation, hematological improvement is rapid with the resolution of hemolysis. The degree of anemia and level of serum vitamin B12 do not affect the prognosis of SCD. However, patients with certain characteristics tend to have better short-term neurological outcomes.[31][32]

The characteristics linked to improved neurological outcomes include the following:

• Age younger than 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

SCD of the spinal cord may produce residual permanent neurological deficits in patients, including paraparesis, lower extremity weakness, and sensory ataxia, while vitamin B12 deficiency due to pernicious anemia is associated with an increased incidence of gastric cancer secondary to atrophic gastritis. Screening in such populations is recommended. In rare instances, untreated vitamin B12 deficiency can lead to severe anemia and high-output cardiac failure.