Insufficient absorption of vitamin B12 deficiency from the gastrointestinal tract can result in a subacute degeneration of the spinal cord, optic nerves, cerebral white matter, and peripheral nerves. Although the neurologic manifestations of vitamin B12 deficiency are frequently associated with a macrocytic anemia (pernicious anemia), the latter is not always present. Neurological symptoms develop in approximately 80 percent of patients between the ages of 25 and 75 years afflicted with pernicious anemia.
They rarely as a result of secondary vitamin B12 deficiency complicating fish tapeworm (Diphyllobothrium latum) infestation, sprue, vegetarianism, or gastrointestinal surgery. (This subject is also dealt with in the discussion of Megaloblastic Anemia.)
Symptoms and signs of spinal cord involvement (combined system disease) constitute the most common neurologic manifestations, and their modte of onset and progression is remarkably uniform. Symmetrical progressive paresthesias of the feet or hands in the form of numbness, tingling, burning, tightness and stiffness, and a feeling of generalized weakness constitute the most frequent initial symptoms. Vague asthenia and lameness progress to a measurable weakness and stiffness of the legs and an unsteadiness of gait that tends to be worse in the dark. The lower limbs may give, way unexpectedly. The hands may be stiff and clumsy. When untreated, the illness progresses slowly and relentlessly.
Spasticity, ataxia, and paraplegia ensue, often followed by bowel and bladder dysfunction. In the early stages of the disease, examination of the patient often reveals few objective changes, but eventually signs of disturbed peripheral nerve and posterior and lateral column function become readily apparent. Diminution or loss of position and vibrator}.’ sense involves the legs, the hands, and. occasionally, the trunk, and tends to be pronounced. Pain, temperature, and tactile sensation sometiir.es are blunted over the distal parts of the legs in a pattern suggestive of peripheral nerve involvement. The motor examination reveals weak and. later, spastic legs and extensor plantar responses. The activity of the deep tendon reflexes is variable and appears to depend upon the severity of the illness.
The knee jerks are often hyperactive and the ankle jerks absent. In advanced cases, all stretch reflexes may be diminished or absent, but may return when vitamin therapy has been promptly instituted. Psychologic symptoms range from apathy, irritability, and suspiciousness to confusion and dementia, and at times are the presenting neurologic abnormality. On rare occasions, failing vision due to symmetrical centrocecal scotomata may be the presenting neurologic symptom of vitamin BV1 deficiency.
Pathology of Vitamin B12 Deficiency.
The lesions associated with subacute combined degeneration involve in sequence the posterior columns, the lateral columns, and the cerebral white matter. The earliest visible change consists of swelling of individual myelinated nerve fibers in small foci. These lesions subsequently coalesce into large, irregular, spongy, honeycomb-like zones of demyelination. Fibers with the largest diameter are predominantly affected. Axis cylinders tend to be spared. Myelin destruction frequently begins in the cervical and upper thoracic segments of the cord, spreading axially to involve other segments. The cerebral white matter is affected last. The large fibers of the peripheral nerves may show minimal loss of myelin.
Diagnosis of Vitamin B12 Deficiency.
A number of diseases other than vitamin BI2 deficiency affect the posterior and lateral columns of the spinal cord, the most important being multiple sclerosis, tumors, cervical spondylosis, syphilitic meningomyelitis, and familial spastic paraplegia. These entities can usually be differentiated from one another clinically, but ancillary examinations such as myelography and special tests involving the cerebrospinal fluid may be necessary to establish a correct diagnosis. In B12 deficiency of the nervous system, the cerebrospinal fluid is usually normal. The electroencephalogram is often abnormal.
The serum vitamin Br content correlates well with the severity of the neurologic impairment and is invariably low in untreated cases. The “Schilling test” using radioactive cyanocobalamin is always positive, and gastric achlorhydria can be demonstrated in almost every instance. Blood and bone marrow examinations are of limited value, particularly when the patient has been treated with folic acid, which corrects the anemia but not the neurologic manifestations. The urinary excretion of methylmalonic acid, an intermediary metabolite in the conversion of propionic acid to succinic acid, is a sensitive indicator of vitamin B, deficiency, but its relation to the lesions m the nervous system is as yet unknown.
The pathogenesis of the neurologic manifestations of vitamin B12 deficiency is unknown, although it probably differs from the biochemical lesion affecting the hematopoietic system, since the neurologic manifestations are independent of the anemia and may appear when folic acid corrects the anemia. The specific biochemical role of vitamin B12 in the nervous system has not yet been elucidated. It is an essential cofactor for at least two enzyme systems which exist in mammalian tissue, including brain: (1) methylmalonyl-CoA isomerase, which converts methylmalonyl-CoA to succinyl-CoA, a step in the utilization of propionic acid, and (2) methyl- folate-H, methyltransferase, which is responsible for the synthesis of methionine from homocysteine. In experimentally induced vitamin B12 deficiency, the activity of both of these enzyme systems is reduced in brain. These enzymes may be essential to the maintenance of the myelin sheath. An experiment/ approach/i to £fie pathogenesis of neurologic manifestations of vitamin B12 deficiency in animals has been hampered by the absence of white-matter lesions in deficient animals.
Treatment of Vitamin B12 Deficiency.
Prompt initiation of therapy is of the utmost importance, because the early neurologic manifestations can be rapidly and completely reversed. The greatest degree of improvement is achieved in patients treated within three months of onset of symptoms, although variable degrees of amelioration can be attained after longer untreated periods (six to twelve months). In the first two weeks, daily intramuscular injections of 50 meg. of cyanocobalamin, or an equivalent amount of liver USP, should be administered. During the next two months, 100 meg. of cyanocobalamin should be injected twice a week.
For the remainder of his life, the patient should receive a minimum of 100 meg. intramuscularly every month to prevent a relapse that might be caused by metabolic stress such as systemic illness or surgery. The administration of oral vitamin preparations containing folic acid must be avoided for patients with pernicious anemia since folic acid may actually precipitate neurologic complications.