Continuing Education Activity

Subacute combined degeneration is a preventable, reversible medical condition that affects the brain, spinal cord, and peripheral nerve with devastating effects if untreated. It manifests with cognitive, motor, and sensory symptoms. This activity reviews the evaluation and management of subacute combined degeneration of the spinal cord and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

• Identify the etiology of subacute combined degeneration of the spinal cord.
• Review the evaluation of subacute combined degeneration of the spinal cord.
• Outline the management options available for subacute combined degeneration of the spinal cord.

Introduction

Subacute combined degeneration of the spinal cord is a disease affecting the lateral and posterior columns of the spinal cord, primarily due to demyelination. It can present in patients who are deficient in vitamin B12, producing hematological and neurological manifestations.[1] Vitamin B12 is an active cofactor in the synthesis of deoxyribonucleic acid (DNA) and myelin.

Subacute combined degeneration of the spinal cord can be caused by inadequate oral intake of vitamin B12, poor absorption of vitamin B12, or by the use of medications such as metformin, proton pump inhibitors, and nitrous oxide.  Unexplained anemia, coupled with neurological symptoms, should raise suspicions of subacute combined degeneration, and an evaluation investigating vitamin B12 deficiency in susceptible populations should be done.

Etiology

Subacute combined degeneration of the spinal cord 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 from 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 subacute combined degeneration 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 that are strict vegans or the elderly, particularly those in assisted facilities, dietary deficiencies have been identified as causes for vitamin B12 deficiency.

Vitamin B12 deficiency can be suspected as the cause of unexplained anemia in patients who have 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 and altering the absorption of vitamin B12.[2][3]

Malabsorption as a cause of vitamin B12 deficiency can be due to loss of intrinsic factor seen in patients post gastrectomy or after gastric bypass surgery. Malabsorption is also found after the loss of absorption surface area in the ileum in patients with surgical resection following Crohn disease. 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 as well.

Epidemiology

Limited studies have evaluated the incidence of subacute combined degeneration of the spinal cord. Not all patients with vitamin B12 deficiency will manifest subacute combined degeneration 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.[4] In all the patients, the spinal cord changes were reversed after appropriate treatment.

Vitamin B12 deficiency is the most prevalent cause of subacute combined degeneration of the spinal cord. It is more common among the elderly, particularly those residing in assisted facilities revealed by low serum vitamin B12 levels and high serum methylmalonic acid (MMA) levels.[5]This may be due to inadequate dietary intake of food products rich in vitamin B12 over a prolonged time.[6] Vitamin B12 deficiency is also more prevalent in developing countries where up to 40% of the population have either marginal or low vitamin B12 levels.[7]

Pathophysiology

 The significant pathological changes involved in subacute combined degeneration 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 and lateral corticospinal tracts, and sometimes the spinothalamic tracts. Clinical presentations include paresthesias, ataxia, sensory loss, dementia, and muscle weakness. These symptoms can collectively be seen in patients with subacute combined degeneration of the spinal cord.[8]

Vitamin B12 is utilized as a cofactor for two essential enzymes involved in the preservation of 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  produced leads to the accumulation of methylmalonyl-CoA and propionyl-CoA. A deficiency of vitamin B12 results in the accumulation of MMA, which can impair the synthesis of myelin and result in the incorporation of abnormal lipids in myelin, leading to demyelinating changes that manifest as subacute combined degeneration of the spinal cord.[9][10]

Histopathology

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

Microscopic examination shows initial swelling of the largest myelin sheaths 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 is observed.

History and Physical

In patients with suspected subacute combined degeneration of the spinal cord, a detailed neurological examination may show spastic paraparesis, impaired Romberg's sign, loss of vibration sense, proprioception, and two-point discrimination, ataxic gait, and reduced sensation.[8][9] These changes can be linked to the demyelinating effects on the lateral corticospinal tracts and the dorsal column pathway. If the spinothalamic tract is involved, sensory neuropathies of the lower limbs may also 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.[10]

Specific risk factors should be investigated while the history of Crohn's or celiac disease, medication use, history of autoimmune diseases, and details of the patient's diet is being obtained.

The hematological implications of this disease would 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 as a product of hemolysis triggered by increased red blood cell turnover, and glossitis as impairment in DNA synthesis 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 like mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration will reveal macrocytic anemia (MCV>100).[11] 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. An elevated MMA and elevated homocysteine levels would rule out a diagnosis of folate deficiency. Methylmalonic acid is considered a more accurate marker of deficiency than homocysteine levels or B12 levels.

The presentation of neurological signs alone in the absence of anemia has been noticed as well.[8] The radiological evaluation includes a complete spine MRI, which will show hyperintense lesions localized to the posterior columns of the spinal cord, which may be apparent in T2 weighted images of the cervical and thoracic spinal cord.[9] The involvement of the lateral tracts, although present clinically, rarely presents radiologically. 

Investigations should cover possible dietary deficiencies and gastrointestinal causes such as Crohn's or celiac disease. 

In patients with a history of autoimmune disease, an evaluation that includes anti intrinsic factor antibodies is warranted.[12]

Treatment / Management

The treatment for subacute combined degeneration of the spinal cord is the supplementation of vitamin B12 either in oral or parenteral form. The specific route and duration of therapy are determined by the underlying cause of vitamin B12 deficiency. Patients with Crohn's 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's disease post-resection, indefinite supplementation of vitamin B12 is warranted.[13]

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. Upon the resolution of symptoms, the oral route of administration may be used. Parenteral administration is also indicated in 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.

Differential Diagnosis

An important differential when approaching the neurological presentation that is classically present in subacute combined degeneration of the spinal cord is a copper deficiency.[14] Copper deficiency can be seen in patients who have undergone bariatric surgery, those who have undergone excessive treatment of Wilson's disease with chelators, and patients who have a history of excessive zinc intake either in supplemental form or ingestion of denture cream.

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 subacute combined degeneration 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.

Methotrexate-induced myelopathy and vitamin E deficiency can mimic subacute combined degeneration. Neurological symptoms are similar to subacute combined degeneration 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 differentials for disease localized to the spinal cord are diverse. The most common non-traumatic causes include transverse myelitis, multiple sclerosis, tabes dorsalis, epidural tumors, cervical spondylosis myelopathy. Neurological symptoms are similar to subacute combined degeneration of the spinal cord, but imaging with an MRI should be sufficient to rule out these differential diagnoses.

Transverse myelitis is segmental, and inflammation usually affects one or two segments of the spinal cords and is not exclusively in the dorsal columns. Patients may present with symptoms such a tight band or girdle like sensation around the trunk. A gadolinium-enhanced spine MRI would confirm the diagnosis by revealing enhancement involving one 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 subacute combined degeneration of the spinal cord.

Tabes dorsalis is a manifestation of tertiary syphilis. As 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 with the limbs and a positive history of syphilis. This differential 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. 

Epidural tumors and cervical spondylosis myelopathy can be effectively ruled out by a spine MRI and the absence of classic findings found in subacute combined degeneration of the spinal cord.

Prognosis

Neurological outcomes have been favorable in patients with subacute combined degeneration, 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.

In most patients who have been treated with vitamin B12 supplementation, hematological improvement is rapid with the resolution of hemolysis.

Complications

Subacute combined degeneration of the spinal cord may produce residual permanent neurological deficits in patients.

Vitamin B12 deficiency due to pernicious anemia is also 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.

Consultations

Consultations are required from neurologists, dieticians, surgeons, and pharmacists.

Deterrence and Patient Education

Subacute combined degeneration of the spinal cord is a preventable and treatable disease. Prophylactic vitamin B12 administration is not routinely recommended and is only indicated in specific instances. Individuals who adhere to a strict vegan diet may deplete their vitamin B12 stores in 2-3 years due to inadequate dietary intake and hence require routine oral supplementation. This is especially important in the pre-conceptional counseling of women who are strictly vegan as the developing fetus requires vitamin B12 as well. 

Vitamin B12 supplementation is recommended post gastric or bariatric surgery due to the absence of intrinsic factor, which is physiologically produced by the parietal cells of the stomach. It is also recommended post resection of ileum due to loss of absorptive surface for vitamin B12. In patients undergoing surgeries where nitrous oxide is used as an inhalational anesthetic, monitoring of complete blood count and prompt intervention is appropriate as nitrous oxide can cause inactivation of methylcobalamin.

Enhancing Healthcare Team Outcomes

Subacute combined degeneration of the spinal cord presents in patients with risk factors for vitamin B12 deficiency. Since this is a progressive and reversible condition and the therapeutic regimens that have been explored so far are useful, it is crucial to evaluate patients who are at risk regularly. The early identification, evaluation, and treatment of this condition are imperative.

Primary care providers play an essential role in evaluating patients and identifying abnormal neurological signs and symptoms in patients with Crohn's disease, celiac disease, those that adhere to a strict vegan diet and patients post gastric or bariatric surgeries. Since symptoms present in a subacute manner, paying close attention to the history and examination can provide an early diagnosis of the disease.

Early identification and initiation of vitamin B12 supplementation in these patients have been found to improve neurological outcomes. Alerting neurologists to the concerns of the primary care provider can be beneficial in determining the optimum course of management. An interprofessional team composed of pharmacists, nurses, and other health care providers contributes to the shared decisions that can help achieve the best possible outcomes.