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Subacute Combined Degeneration of Spinal Cord

Combined System Disease

Subacute combined degeneration of spinal cord may develop as a consequence of deficient nutrition and is characterized by progressive demyelination of the dorsal and lateral columns of the spinal cord.


Presentation

Patients suffering from SCD present with neurological symptoms arising from progressive demyelination of the spinal cord. However, the underlying nutrient deficiency will likely cause a variety of other disturbances. These may or may not affect the patient's life quality, but they are most certainly of diagnostic value. Symptom onset is insidious and complaints aggravate slowly.

Initially, spinal cord damage may manifest in form of sensory deficits, particularly in form of symmetric paresthesias and numbness. Pall hypoesthesia is considered an important early symptom of SCD. Proprioception may be significantly disturbed and with regards to affected parts of the body, patients may lose their position sense. Reflexes are generally blunted or absent, but hyperreflexia has also been reported. The latter suggests lesions of the corticospinal tract. If the legs are affected - which is most commonly the case - gait disorders may turn into ataxia and finally into the inability to stand. Spastic paraparesis and tetraparesis or tetraplegia are symptoms of advanced SCD.

Neuropsychiatric symptoms are common. Lethargy, irritability, mood swings and confusion have been registered in SCD patients. Dementia is a rare finding.

Visual impairment, motor deficits, and spasticity may be associated with SCD but are only present in a minor share of patients.

Because the vast majority of SCD patients suffer from vitamin B12 deficiency, they also develop anemia (and consequent fatigue, weakness, palpitations, and dyspnea), glossitis, abdominal pain, and diarrhea. They may lose weight. Copper deficiency, folic acid deficiency and vitamin E deficiency may cause anemia and manifest similarly [9].

Anemia
  • In pernicious anemia, intrinsic factor secretion is reduced and it is not uncommon to see patients who suffer from both SCD and pernicious anemia.[symptoma.com]
  • anemia due to intrinsic factor deficiency 2016 2017 2018 Billable/Specific Code Applicable To Addison anemia Biermer anemia Pernicious (congenital) anemia Congenital intrinsic factor deficiency D51.0 ) vitamin B12 deficiency ( ICD-10-CM Diagnosis Code[icd10data.com]
  • Complication Spinal cord subacute combined degeneration complications Complications of anemia and ataxia are paralyzed Usually accompanied by anemia associated with anemia, but also because of its clinical manifestations of spinal cord and lateral cord[healthfrom.com]
  • Synthetic folic acid in oral doses of 15 mg. daily induced satisfactory hematopoietic responses in 3 patients with pernicious anemia in severe relapse, but only slight hematopoietic response in a fourth patient with mild pernicious anemia but severe subacute[bloodjournal.org]
  • Hematologically, it can present as anemia (microcytic, normocytic, or macrocytic) and neutropenia. Thrombocytopenia is relatively rare.[unboundmedicine.com]
Falling
  • I can do all sorts of exercise in the water without risking a fall and it has really strengthened the muscles in my legs so now when I trip I can usually save myself rather than falling in a heap![healthunlocked.com]
  • Five days into his hospitalization, he remained a fall risk, continued to display dysmetria on the finger-to-nose test, and still complained of visual hallucinations.[em-consulte.com]
  • One primary type of generalized seizure is tonic-clonic seizures, in which an individual loses consciousness without warning, falls, and stiffens, because of muscle contractions.[britannica.com]
Ataxia
  • Lateral corticospinal tract dysfunction produces spasticity and dorsal spinocerebellar tract dysfunction causes ataxia .[en.wikipedia.org]
  • Stomach acid R protein Intrinsic Factor Distal 80cm of ileum -Decreases absorption of B12 -Condition where antibodies are generated against parietal cells Edema and destruction of myelin Paresthesia in hands and feet sensory loss gait ataxia distal weakness[quizlet.com]
  • Severe limb and trunk ataxia, worsened during blind-walking. Vibration and position-sense were disturbed on the trunk and the limbs, whereas heat and pain sensation were preserved. Lhermitte sign was present.[neuroanatomy.wisc.edu]
  • […] injury, deep sensory loss, sensory ataxia and spastic paralysis mainly accompanied by peripheral sensory disturbances.[healthfrom.com]
Paresthesia
  • Stomach acid R protein Intrinsic Factor Distal 80cm of ileum -Decreases absorption of B12 -Condition where antibodies are generated against parietal cells Edema and destruction of myelin Paresthesia in hands and feet sensory loss gait ataxia distal weakness[quizlet.com]
  • Clinically, paresthesia, sensory ataxia, and sometimes spastic paraplegia are present. The disease is the result of pernicious anemia.[medical-dictionary.thefreedictionary.com]
  • She had paresthesias that started in the feet and ascended up to the trunk. She had fallen several times with no loss of consciousness. On exam, she had reduced vibration and proprioception in the legs.[shmabstracts.com]
  • Conclusion A patient who abused nitrous oxide chronically developed ataxia, paresthesia, and urinary retention while self-medicating with cyanocobalamin.[ajhp.org]
  • Initially, spinal cord damage may manifest in form of sensory deficits, particularly in form of symmetric paresthesias and numbness. Pall hypoesthesia is considered an important early symptom of SCD.[symptoma.com]
Peripheral Neuropathy
  • Peripheral neuropathy: Vitamin deficiency can also be associated with peripheral neuropathy, so a variety of vitamin deficiency at the same time there are B12 deficiency in subacute combined degeneration at the same time combined with typical peripheral[healthfrom.com]
  • Neurologically, it can manifest as myelopathy and peripheral neuropathy simulating subacute combined degeneration. Bone marrow findings can mimic myelodysplasia resulting in occasional inappropriate referral for bone marrow transplantation.[unboundmedicine.com]
  • Clinically, vitamin E deficiency causes a sensory peripheral neuropathy, ataxia, retinitis pigmentosa, and skeletal and cardiac myopathy.[en.wikipedia.org]
  • neuropathy Diabetes mellitus Vitamin B12 deficiency Subacute combined degeneration of the spinal cord Sciatica Intermittent claudictaion of thigh Buttock claudication Fracture femur Subacute combined degeneration of the spinal cord: Causes and Types[rightdiagnosis.com]
Irritability
  • Lethargy, irritability, mood swings and confusion have been registered in SCD patients. Dementia is a rare finding. Visual impairment, motor deficits, and spasticity may be associated with SCD but are only present in a minor share of patients.[symptoma.com]
  • […] friedreich ataxia, vit E deficiency Neurologic manifestations of Vit B12 deficiency Paresthesia Peripheral neuropathy Combined systems disease (demyelination of dorsal columns and corticospinal tract) Behavioral manifestations of Vit B12 deficiency Irritability[quizlet.com]
  • Symptom Spinal cord subacute common degeneration symptoms common symptoms walking on the cotton sensory sense of depression sphincter dysfunction spastic muscle tension increased diarrhea gloves or short socks ... irritable face pale pale fingers end[healthfrom.com]
  • People have general weakness, tingling and numbness in the hands and feet, and stiff limbs and may become irritable, drowsy, and confused. Blood tests can confirm vitamin B 12 deficiency.[merckmanuals.com]
  • As the disease worsens, symptoms may include any of the following: Clumsiness , stiff or awkward movements Change in mental state , such as memory problems, irritability, apathy , confusion, or dementia Decreased vision Depression Sleepiness Unsteady[scripps.org]
Confusion
  • Lethargy, irritability, mood swings and confusion have been registered in SCD patients. Dementia is a rare finding. Visual impairment, motor deficits, and spasticity may be associated with SCD but are only present in a minor share of patients.[symptoma.com]
  • People have general weakness, tingling and numbness in the hands and feet, and stiff limbs and may become irritable, drowsy, and confused. Blood tests can confirm vitamin B 12 deficiency.[merckmanuals.com]
  • The classic clinical presentation of WE is a triad of eye abnormalities (nystagmus, oculomotor paralysis, paralysis of conjugate gaze), ataxia of stance and gait, and mental symptoms , such as withdrawal and confusion.[neuropathology-web.org]
  • As the disease worsens, symptoms may include any of the following: Clumsiness , stiff or awkward movements Change in mental state , such as memory problems, irritability, apathy , confusion, or dementia Decreased vision Depression Sleepiness Unsteady[scripps.org]
  • As the disease worsens, symptoms may include any of the following: Clumsiness , stiff or awkward movements Change in mental state, such as memory problems, irritability, apathy, confusion, or dementia Decreased vision Depression Sleepiness Unsteady gait[medlineplus.gov]

Workup

Magnetic resonance imaging and laboratory analyses of blood samples are the mainstays of SCD diagnosis. The former aims at a direct evaluation of spinal cord and brain damage. Characteristic findings are symmetric hyperintense lesions of the dorsal and lateral columns of the spinal cord; in most cases, such lesions are first recognized in the thoracic spinal cord. Similar pathological alterations may also be observed in the brain.

Analyses of blood samples should include a complete hemogram and measurement of serum levels of vitamin B12, copper, folic acid, and vitamin E. Values below reference ranges indicate nutrient deficiencies. However, in the case of functional nutrient deficiencies, serum concentrations of the respective nutrients will not be altered. Here, it is of utmost importance to consider the entirety of anamnestic data, findings of physical examination and diagnostic imaging as well as hematological alterations before confirming or ruling out a diagnosis [3]:

  • With regards to the hemogram, both vitamin B12 deficiency and folic acid deficiency cause megaloblastic hyperchromic anemia.
  • In contrast, copper deficiency is typically associated with microcytic hypochromic anemia.
  • Increased serum levels of methylmalonic acid or homocysteine point at vitamin B12 deficiency despite physiological serum concentrations of that cofactor.
  • Anti-intrinsic factor antibodies suggest pernicious anemia as an underlying disease of vitamin B12 deficiency and SCD.

Resolution of abnormal findings on magnetic resonance images, hemogram and blood biochemistry is a well-suited parameter to assess a patient's response to therapy. Even after finishing drug therapy, the respective exams should be carried out every three months until a complete resolution is achieved or no further improvement is expected. It may take more than a year to reach this point. Of course, remission of clinical symptoms is still the most important sign of therapeutic success.

Macrocytic Anemia
  • She had macrocytic anemia (MCV 115), and vitamin B12 levels were in the low normal range—254 pg/mL (reference for low, 239). She did have elevated homocysteine and methylmalonic acid levels.[shmabstracts.com]
  • anemia Differential Diagnosis for PROGRESSIVE SPASTIC PARAPLEGIA -degenerative disorders -demyelinating disorders -infectious disorders -inflammatory disorders -neoplastic disorders -nutritional disorders -vascular disorders -HIV, lyme, MS, neurosyphilis[quizlet.com]
  • Tests Serum B12, Malonic Acid, Methylmalonic Acid , Schilling Test , Complete Blood Count- looking for megaloblastic anemia if there is also folic acid deficiency or macrocytic anemia MRI- T2 images may reveal increased signal within the white matter[ipfs.io]
  • Laboratory blood analyses disclosed macrocytic anemia (Hemoglobin [Hb]: 6.4 g/dl; mean corpuscular volume [MCV]: 137 fl), and low serum vitamin B12 (110 pg/ml). After a blood transfusion, her Hb rose to 11 g/dl and her MCV to 112.5 fl.[omicsonline.org]

Treatment

Treatment consists in supplementation of the deficient nutrient, most commonly vitamin B12. Most physicians prefer to start by intramuscular application of 1 mg vitamin B12 per day for one or two weeks before prolonging the administration intervals to a week or month. Maintenance doses may be given.

Common protocols are:

  • 1 mg vitamin B12 per day for a week; 1 mg vitamin B12 per week for a month; 1 mg vitamin B12 per month for as long as considered necessary
  • 1 mg vitamin B12 per day for two weeks; 1 mg vitamin B12 per week for three months; 1 mg vitamin B12 per month for as long as considered necessary

Some patients may require life-long supplementation of vitamin B12. If vitamin B12 deficiency results from an underlying, curable disease, the latter should be adequately treated. In the case of pernicious anemia, high-dose supplementation is necessary to increase the absolute amount of vitamin B12 that is absorbed in the terminal ileum. This therapeutic approach is based on the fact that about 1% of orally administered vitamin B12 is absorbed as intrinsic factor-independent [10].

Copper deficiency, folic acid deficiency, and vitamin E deficiency are treated by supplementing the respective nutrient.

Patients should be queried regarding their dietary habits and need to be advised to keep a healthy, balanced diet.

Prognosis

Prognosis largely depends on disease progress at the time of diagnosis. The underlying nutrient deficiency is easily treated in most cases, but extensive damage to the central nervous system may be irreversible and result in permanent disability [3].

Etiology

The most common cause of SCD is vitamin B12 deficiency. This vitamin serves as a cofactor for enzymes that affect myelin synthesis, which is why the corresponding nutrient deficiency leads to progressive demyelination and SCD. Vitamin B12 deficiency, in turn, may be caused by malabsorption due to intrinsic factor-related pathologies. In pernicious anemia, intrinsic factor secretion is reduced and it is not uncommon to see patients who suffer from both SCD and pernicious anemia. Malabsorption may also result from gastrointestinal disorders like celiac disease, Crohn disease or tropical sprue. Functional vitamin B12 deficiency may also lead to SCD but constitutes a diagnostic challenge since serum vitamin B12 levels are not altered in affected individuals [3]. Moreover, vegetarians, vegans and people who underwent gastric surgery have increased risks of vitamin B12 deficiency [4].

Further causes of SCD are a copper deficiency, folic acid deficiency and vitamin E deficiency [1]. Patients who receive enteral nutrition, who underwent gastric surgery or supplement large amounts of zinc are predisposed for copper deficiency. Dietary deficiency, pregnancy, and lactation are commonly associated with folic acid deficiency.

Of note, a plethora of legal and illicit drugs, either prescribed to treat comorbidities or used recreationally, may provoke the nutrient deficiencies described above.

Besides nutrient deficiencies, the following conditions have been related with SCD [1]:

  • Exposure to nitrous oxide
  • Exposure to chlorpyrifos
  • Chikungunya
  • Human immunodeficiency virus infection / AIDS

Epidemiology

SCD is considered an uncommon disease and the lifetime risk of developing this demyelinating disease has been estimated to be about 1 in 10,000. These values are in accordance with those reported for pernicious anemia.

Minors and young adults are rarely affected; incidence rates increase when considering people in their fifth decade of life and peak in the elderly. However, this information should be interpreted with care: In most cases, years may pass from disease onset until first clinical symptoms occur. SCD prevalence among young people may indeed be similar to other age groups, but the diagnosis of the disease may not be easy during early stages [5].

Sex distribution
Age distribution

Pathophysiology

Vitamin B12, sometimes also referred to as cobalamin, serves as a cofactor for methylmalonyl coenzyme A mutase and methionine synthase.

The former catalyzes the conversion of methylmalonyl coenzyme A to succinyl coenzyme A. Accumulation of methylmalonyl coenzyme A due to reduced enzymatic activity inhibits myelin synthesis and a variety of other metabolic processes [6]. Therefore, vitamin B12 deficiency is associated with progressive demyelination and SCD.

As its name implies, methionine synthase is required for the synthesis of methionine, an essential amino acid. This enzyme transfers a methyl group from 5-methyltetrahydrofolate to homocysteine, a reaction that yields tetrahydrofolate and methionine. Thus, vitamin B12 deficiency leads to accumulation of homocysteine and inadequate synthesis of tetrahydrofolate and methionine. Homocysteine induces endothelial dysfunction [7]; tetrahydrofolate plays an important role in DNA synthesis. Insufficient synthesis of tetrahydrofolate limits cell proliferation and cells with a rapid turnover - hematopoietic stem cells for instance - will primarily be affected [8]. Cells are unable to progress from the G2 stage into the mitosis stage, continue to grow but don't divide. This is what leads to megaloblastic anemia.

Of note, dietary folic acid is converted into 5-methyltetrahydrofolate and therefore, folic acid deficiency provokes symptoms very similar to those of vitamin B12 deficiency. Supplementation of folic acid may even cure vitamin B12 deficiency-induced anemia, but will rarely improve neurologic pathologies except for those rare cases of SCD due to folic acid deficiency.

Prevention

Most people are able to prevent nutrient deficiencies by keeping a healthy, balanced diet. Vegetarians and vegans have particularly high risks of consuming little amounts of vitamin B12 and should consider the possibility of supplementing their diet.

Patients who suffer from nutrient deficiencies due to malabsorption or other, non-curable diseases should undergo regular blood testing.

Summary

Subacute combined degeneration of spinal cord (SCD) is a demyelinating disease triggered by deficiencies of certain nutrients. The vast majority of cases are associated with vitamin B12 deficiency. However, lack of copper, folic acid and vitamin E have been related with very similar clinical pictures [1]. These nutrients are required for myelin synthesis and for a variety of other metabolic processes. Thus, patients may present with complex clinical pictures of neurologic, psychiatric, gastrointestinal and hematological disorders.

With regards to neurological symptoms, sensory deficits predominate. The legs are more frequently involved than the arms. Initially, patients experience paresthesias and numbness, loss of vibration and position senses. The latter may provoke gait disturbances and ataxia before sensory alterations are consciously perceived. SCD follows a progressive course and may lead to spastic paralysis. It may take several years until such severe symptoms occur [2].

Furthermore, patients may claim lethargy, irritability, mood swings and confusion. Visual impairment may result from optic nerve damage.

As soon as the underlying nutrient deficiency is identified, causative treatment can be initialized. Most SCD patients respond well to dietary supplementation. However, extensive spinal cord damage may not be reversible and residual neurological deficits will remain in a significant share of cases. Concomitant symptoms like anemia, glossitis, abdominal pain and diarrhea rapidly remit under adequate therapy.

Patient Information

Subacute combined degeneration of the spinal cord (SCD) is a progressive, neurological disorder.

Causes

The direct cause of SCD is the progressive demyelination of the spinal cord, i.e., nerves passing through the spinal cord lose their myelin sheath. This myelin sheath serves as a layer of insulation and is essential for saltatory conduction.

In SCD patients, myelin synthesis is disturbed because nutrients required for distinct metabolic steps are lacking. Most SCD patients have a vitamin B12 deficiency, but the lack of copper, folic acid or vitamin E may also cause this disease.

Symptoms

Symptom onset is insidious. Most patients initially perceive tingling sensations or numbness in their limbs, most often in their legs. They may lose vibration and position sense and these complications lead to gait disorders and ataxia. Late stage SCD may manifest in form of partial or complete paralysis of legs and possibly arms.

Neuropsychiatric symptoms like lethargy, irritability, mood swings and confusion are also common.

Some patients claim visual impairment.

Diagnosis

Spinal cord and possibly brain damage are diagnosed by means of magnetic resonance imaging. Additionally, laboratory analyses of blood samples will be performed to determine the underlying nutrient deficiency. Measurement of serum levels of vitamin B12, copper, folic acid or vitamin E is important when deciding for an optimum therapeutic approach.

Further diagnostic measures may become necessary to define the cause of a determined nutrient deficiency.

Treatment

SCD treatment consists of supplementation of the nutrient whose shortage is interfering with nerve function. Thus, most SCD patients will receive vitamin B12 - initially in form of daily intramuscular injections, later in form of oral medication. Some patients may require dietary supplementation for life.

Maintenance of a healthy, balanced diet is of great importance to prevent diseases like SCD and to avoid relapses.

References

Article

  1. Garg RK, Malhotra HS, Kumar N. Approach to a case of myeloneuropathy. Ann Indian Acad Neurol. 2016; 19(2):183-187.
  2. Okada A, Koike H, Nakamura T, Watanabe H, Sobue G. Slowly progressive folate-deficiency myelopathy: report of a case. J Neurol Sci. 2014; 336(1-2):273-275.
  3. Turner MR, Talbot K. Functional vitamin B12 deficiency. Pract Neurol. 2009; 9(1):37-41.
  4. Pawlak R. Is vitamin B12 deficiency a risk factor for cardiovascular disease in vegetarians? Am J Prev Med. 2015; 48(6):e11-26.
  5. Wolansky LJ, Goldstein G, Gozo A, Lee HJ, Sills I, Chatkupt S. Subacute combined degeneration of the spinal cord: MRI detection of preferential involvement of the posterior columns in a child. Pediatr Radiol. 1995; 25(2):140-141.
  6. Scalabrino G, Veber D, Tredici G. Relationships between cobalamin, epidermal growth factor, and normal prions in the myelin maintenance of central nervous system. Int J Biochem Cell Biol. 2014; 55:232-241.
  7. Lai WK, Kan MY. Homocysteine-Induced Endothelial Dysfunction. Ann Nutr Metab. 2015; 67(1):1-12.
  8. Kannan R, Ng MJ. Cutaneous lesions and vitamin B12 deficiency: an often-forgotten link. Can Fam Physician. 2008; 54(4):529-532.
  9. Andrès E, Federici L, Serraj K, Kaltenbach G. Update of nutrient-deficiency anemia in elderly patients. Eur J Intern Med. 2008; 19(7):488-493.
  10. Andres E, Serraj K. Optimal management of pernicious anemia. J Blood Med. 2012; 3:97-103.

Symptoms

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