Subacute Combined Degeneration of the Spinal Cord Case File

Subacute Combined Degeneration of the Spinal Cord Case File

Eugene C. Toy, MD, Ericka Simpson, MD, Pedro Mancias, MD, Erin E. Furr-Stimming, MD

CASE 22

A 48-year-old man complains of “numbness and stiffness” in his arms for the past 4 months. His gait has gradually deteriorated because of unsteadiness. On examination, the patient appears older than his stated age. His hair is nearly completely gray. There is slight limitation of head movement to either side but no pain with neck extension. His tongue is red and depilated. His gait is broad based, and he is unable to walk in a straight line. He is able to stand with his feet together with his eyes open, but he nearly fell when his eyes were closed. He has normal arm coordination but is ataxic on the heel-knee-shin maneuver. Deep tendon reflexes (DTRs) are 3+ in the arms, trace at the knees, and absent at the ankles. Both plantar responses are extensor. He has a positive jaw jerk and a snout reflex. There is a stocking pattern decrease in sensation and a marked decrease in vibration and joint position sense in the toes and ankles. Cranial nerves are normal, and there are mild problems with memory and calculation. T2-weighted magnetic resonance imaging (MRI) of the brain demonstrates extensive areas of high-intensity signal in the periventricular white matter. MRI of the spine shows a hyperintense signal along the posterior column of the spinal cord.

▶ What is the most likely diagnosis?

▶ What is the next diagnostic step?

▶ What is the next step in therapy?

ANSWERS TO CASE 22:

Subacute Combined Degeneration of the Spinal Cord                        

Summary: This is a case of a 48-year-old patient with a progressive gait disorder characterized by sensory ataxia caused by impaired position sense and spasticity. His examination is significant for both peripheral and central nervous system (CNS) involvement, primarily affecting the white matter fibers of the posterior columns of the spinal columns and pyramidal tracts and large myelinated peripheral nerve affecting coordination and muscle tone.

• Most likely diagnosis: Vitamin B12 deficiency
• Next diagnostic step: Serum vitamin B12 level, and if the level is low, subsequent testing to determine the source of B12 malabsorption
• Next step in therapy: Intramuscular vitamin B12

ANALYSIS

Objectives

1. Understand the range of pathologic and clinical manifestations of vitamin B12 deficiency.
2. Know the differential diagnosis of vitamin B12 deficiency.
3. Understand the types of tests to confirm the diagnosis and etiology of vitamin B12 deficiency.
4. Be aware of the proper mode of repletion of vitamin B12.

Considerations

The pertinent features of this case include unsteadiness of gait, numbness, and stiffness. The physical examination helps to localize the pathology. There was a stocking pattern decrease in sensation, specifically involving vibration and joint position sense, which strongly suggests a neuropathy involving myelinated fibers ascending through sensory peripheral nerves to the dorsal columns of the spinal cord, at or above the lumbar level. The pathologically increased reflexes in the arms and knees along with the presence of primitive reflexes (jaw jerk, snout reflex, and Babinski) are “upper motor neuron signs” and suggest involvement of the corticospinal tract above the level of the cervical spinal cord. In this case, one would expect increased reflexes in the legs also, unless there is a coexistent neuropathy. The ataxic heel-knee-shin maneuver also points to aberrant input to the cerebellum, which travels through large fibers. The mild problems on mental status examination indicate possible cortical or subcortical dysfunction. All of these findings suggest involvement at multiple levels of the nervous system. The imaging study confirms involvement of myelinated regions in the spinal cord, specifically the dorsal columns, and in the brain. Assuming all these signs/symptoms are manifestations of a single entity, a systemic disease should be considered, such as human immunodeficiency virus 1 (HIV-1)–associated vacuolar myelopathy, Lyme disease, multiple sclerosis, neurosyphilis, or vitamin B12 deficiency. Neuropathic conditions would not be expected to give upper motor neuron signs. Additional clues on the general physical examination are the abnormal tongue and prematurely graying hair.

APPROACH TO:

Subacute Combined Degeneration of the Spinal Cord                                        

Spinal cord diseases are common, and many are treatable if discovered early. The spinal cord is a tubular structure originating from the medulla of the brain and extending through the lumbar region in the vertebral column. Ascending sensory and descending motor white matter tracts are located peripherally; posterior columns govern joint position, vibration, and pressure, lateral spinothalamic tracts carry pain and temperature, and ventral corticospinal tracts carry motor fibers.

VITAMIN B12 DEFICIENCY

Vitamin B12 deficiency usually presents as paresthesias in the hands and feet and loss of vibratory sense. There is a diffuse effect on the spinal cord, primarily the posterior lateral columns, explaining the early loss of vibratory sense and joint position. Late in the course, optic atrophy and cognitive changes as well a sensory ataxia can occur. Macrocytic anemia is common.

Cyanocobalamin is a compound that is metabolized to a vitamin in the B complex commonly known as vitamin B12. Vitamin B12 is the most chemically complex of all the vitamins. The structure of B12 is based on a corrin ring with cobalt as the central metal ion. Once metabolized, cobalamin is a coenzyme in many biochemical reactions, including DNA synthesis, methionine synthesis from homocysteine, and conversion of propionyl into succinyl coenzyme A from methylmalonate. Dietary cobalamin (Cbl), obtained through animal meats, enters the stomach bound to animal proteins. Absorption requires many factors, including stomach acid, R-protein, intrinsic factor from parietal cells, and the distal 80 cm of the ileum for transport. Following ingestion, vitamin B12 is cleaved from other proteins by gastric acid and binds to intrinsic factor in the duodenum. The intrinsic factor cobalamin complex is absorbed in the ileum. However, 1% of vitamin B12 is absorbed passively in the terminal ileum, independent of intrinsic factor. Following absorption, vitamin B12 binds to transcobalamin II, which is responsible for the delivery of vitamin B12 to tissues. Interference in any of these points can lead to malabsorption of vitamin B12. In addition, there are a number of inborn errors of metabolism that can interfere with both the absorption and the action of vitamin B12.

The most common cause of vitamin B12 deficiency is malabsorption because of pernicious anemia, a condition where antibodies are generated to the parietal cells of the stomach, and the necessary proteins, including intrinsic factor, are not available; thus vitamin B12 is unable to be absorbed. There are many other causes, however, that should be considered, such as bariatric surgery, intestinal parasites, various medications, and rare genetic disorders. Decreased intake may also occur in those who eat a vegan diet or are malnourished.

Pathologically, in experimental subacute combined degeneration (SCD), there is edema and destruction of myelin. Thus, the clinical presentation of SCD is caused by dorsal column, lateral corticospinal tract, and sometimes lateral spinothalamic tract dysfunction. The initial symptoms are usually paresthesias in the hands and feet. This condition can progress to sensory loss, gait ataxia, and distal weakness, particularly in the legs. If the disease goes untreated, a spastic paraparesis can evolve. Common findings on examination are loss of vibratory and joint position sense (due to involvement of the dorsal column) and upper motor neuron signs (weakness, spasticity, hyperreflexia, and extensor plantar responses). The syndrome of sensory loss as well as spastic paraparesis associated with pathologic lesions in the dorsal columns and lateral corticospinal tracts is referred to as SCD. There are also effects on other body systems, most conspicuously hematologic with the macrocytic (megaloblastic) anemia.

DIFFERENTIAL DIAGNOSIS

The clinical manifestations of vitamin B12 deficiency are noted in Table 22–1. The differential diagnosis for progressive spastic paraplegia includes degenerative, demyelinating, infectious, inflammatory, neoplastic, nutritional, and vascular disorders, including HIV-1–associated vacuolar myelopathy, Lyme disease, multiple sclerosis, neurosyphilis, toxic neuropathy, and copper deficiency. The differential diagnosis of SCD is broad, but B12 deficiency should be considered in any patient with progressive sensory symptoms or weakness or even cognitive decline.

LABORATORY CONFIRMATION

Testing for vitamin B12 deficiency includes a direct assay of the vitamin as well as looking at the indirect effect of abnormal reactions, resulting in altered metabolite levels. The definitions of Cbl (vitamin B12) deficiency are as follows: serum Cbl level less than 150 pmol/L on two separate occasions or serum Cbl level less than 150 pmol/L and total serum homocysteine level greater than 13 μmol/L or methylmalonic acid greater than 0.4 μmol/L (in the absence of renal failure and folate and vitamin B6 deficiencies). It is important to note that many patients with neurologic manifestations may still have normal or borderline low values of cobalamin, and the hematologic manifestations may not present until later in the disease course. Therefore, in these cases where vitamin B12 deficiency is suspected, it is important to measure levels of methylmalonic acid and homocysteine, both of which should be elevated. The hematologic manifestations of vitamin B12 deficiency can be mimicked by folate deficiency, but this does not mimic the neurologic manifestations. In addition, the multiple organ systems and subsystems affected are highly variable from patient to patient. 

Confirmatory effects of the anatomic and physiologic consequences of B12 deficiency involve nerve conduction studies and MRI. Findings in these cases include modest expansion of the cervical and thoracic spinal cord and increased signal intensity on T2-weighted images, primarily in the dorsal columns and lateral pyramidal tracts.

TREATMENT

Treatment of vitamin B12 deficiency involves administering the vitamin in a fashion to bypass the pathologic steps in the transport process. This usually involves intramuscular administration of the vitamin, first to build up stores and then on a monthly basis—specifically, 1000 μg/d for 1 week, then 1000 μg/wk for 1 month. After this, 1000 μg/mo is given until the cause of deficiency is corrected, or for life in the case of pernicious anemia. This is effective for all forms of deficiency. There are also methods of oral administration that are sometimes effective since 1% of vitamin B12 is absorbed passively in the terminal ileum without interaction with intrinsic factor. Treatment can reverse or stop most, if not all, of the sequelae of vitamin B12 deficiency.

CASE CORRELATION

• See also Case 24 (Multiple Sclerosis)

COMPREHENSION QUESTIONS

22.1 Vitamin B12 repletion by which of the following routes will be effective in virtually all causes of B12 deficiency?

A. Concentrated oral vitamin B12

B. Nasal vitamin B12 administration

C. A diet high in red meats

D. Intramuscular B12 administration

22.2 Which feature of the clinical picture might make you most suspicious of vitamin B12 deficiency as a cause for a patient with spastic paresis and sensory loss?

A. Severe signs and symptoms developing over 1 day

B. Loss of pain and temperature sensation in excess of vibration and joint position sense

C. Severe weakness with spasticity and loss of all sensory modalities in the legs with a neurogenic bladder

D. Anemia with an increased mean corpuscular volume (MCV) and hypersegmented polymorphonuclear cells

22.3 Which feature of vitamin B12 deficiency is not mimicked in at least some cases of typical multiple sclerosis?

A. Loss of vibration and joint position sensation in the feet

B. Positive Babinski signs

C. Slowed nerve conduction velocities

D. Increased signal on T2 imaging in the spinal cord

ANSWERS

22.1 D. Intramuscular administration is nearly always effective. The other forms require some aspect of the body’s B12 absorption system.

22.2 D. Megaloblastic anemia is the characteristic finding in vitamin B12 deficiency. The clinical picture usually develops over months, not days. Usually, all limbs are involved to some extent, and severe involvement of the legs and not arms makes one consider an anatomic lesion in the spinal cord. In addition, vibration and joint position sense are usually involved much more than pain and temperature.

22.3 C. Multiple sclerosis is by and large a disorder of the CNS and does not affect peripheral nerve conduction studies.

    CLINICAL PEARLS    

▶ Vitamin B12 deficiency typically affects peripheral nerves, as well as the dorsal columns and lateral corticospinal tracts, giving a syndrome of spasticity with ataxia as a result of loss of joint position sense. There are many more neurologic signs, however, that can variably be seen. ▶ Copper deficiency can present with signs and symptoms identical to vitamin B12 deficiency. Acquired copper deficiency is associated with intestinal disease such as celiac disease, gastric bypass surgery, excessive zinc supplementation, and liver disease such as Wilson disease. Symptoms can improve or stabilize with copper repletion and correction of cause. ▶ Nerve conduction studies can show both demyelinating and denervation features in vitamin B12 deficiency. ▶ The most common cause of vitamin B12 deficiency is pernicious anemia. ▶ Intramuscular administration of vitamin B12 is the most effective way of treating this condition and can reverse or stop the neurologic features. ▶ Vitamin B12 deficiency is associated with a macrocytic anemia.

REFERENCES

Andrès E, Loukili NH, Noel E, et al. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ. 2004;171(3):251-259. 

Goodman BP. Metabolic and toxic causes of myelopathy. Continuum (Minneap Minn). 2015; 21(1 Spinal Cord Disorders):84-99. 

Reynolds E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 2006;5(11):949-960. 

Scalabrino G. Cobalamin (vitamin B[12]) in subacute combined degeneration and beyond: traditional interpretations and novel theories. Exp Neurol. 2005;192:463-479. 

Ulrich A, Müller D, Linnebank M, Tarnutzer AA. Pitfalls in the diagnostic evaluation of subacute combined degeneration. BMJ Case Rep. 2015;2015.

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