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]

  Serum B12, methylmalonic acid, Schilling test, Complete Blood Count- looking for megaloblastic anemia if there is also folic acid deficiency or macrocytic anemia. [en.wikipedia.org]

  B12 deficiency anemia due to intrinsic factor deficiency 2016 2017 2018 2019 Billable/Specific Code Applicable To Addison anemia Biermer anemia Pernicious (congenital) anemia Congenital intrinsic factor deficiency D51.0 ) vitamin B12 deficiency ( ICD [icd10data.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]

  Stomach acid R protein Intrinsic Factor Distal 80cm of ileum Pernicious anemia -Decreases absorption of B12 -Condition where antibodies are generated against parietal cells SCD pathology Edema and destruction of myelin SCD initial symptoms Paresthesia [quizlet.com]

• Pain

  الصفحة 415 - AD (2000) Cytoarchitectonic and immunohistochemical characterization of a specific pain and temperature relay, the posterior portion of the ventral medial nucleus, in the human thalamus. [books.google.com]

  Clinically the classical triad is: extensor plantars (UMN) absent knee jerks (LMN) absent ankle jerks (LMN) Pain and temperature sensation are preserved as the spinothalamic tracts are preserved. [mrcpandme.blogspot.com]

  Tactile, pain, and temperature sensations are usually spared but may be difficult to assess in older people. Some patients are irritable and mildly depressed. [msdmanuals.com]

  We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 13, 2019 [patientslikeme.com]

  Management Frontiers in Medicine Epidemics Zika Virus Ebola Virus View all topics Health Policy Epidemics Pain Management Ebola Virus Multimedia Multimedia Selected Multimedia View all multimedia Audio Clinical Practice Audio Interviews Interactive Medical [nejm.org]

• Fatigue

  We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 13, 2019 [patientslikeme.com]

  Patients present with signs of anemia (e.g., fatigue) and/or neurological manifestations such as paresthesia, spasticity, ataxia, and neuropsychiatric disorders. [amboss.com]

  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. [symptoma.com]

  He had been losing the flavor of foods and, in the last month, he presented severe fatigue and rapidly progressive cognitive impairment with memory problems, with episodes of agitation, confusion and incoherent speech. [scielo.br]

  Later consequences include dementia, seizures, irritability, fatigue, headaches, insomnia, loss of concentration, poor memory, and loss of energy. [britannica.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]

  The patient also complained of worsening lower-extremity weakness for approximately 10 days that led to multiple falls, as well as a “pins and needles” sensation in her lower extremities for approximately 1 year. [ajhp.org]

  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]

• Congestive Heart Failure

  heart failure GI manifestations of Vit B12 deficiency Beefy, red, smooth, and sore tongue Loss of papillae that is more pronounced along edges Hematologic manifestations of Vit B12 deficiency Megaloblastic anemia Pancytopenia (leukopenia, thrombocytopenia [quizlet.com]

  Our scope of specialties include interventional cardiology, congestive heart failure, pulmonary hypertension, adult congenital heart disease, electrophysiology and fetal echocardiography. [mednax.com]

• Cough

  A nasal tone to the voice and weakness of coughing are early signs of damage to these nerves. [britannica.com]

• Numbness of the Feet

  […] in her feet when she stood up or walked. [omicsonline.org]

• Suggestibility

  These observations suggest that a combination of orally administered folic acid and parenterally injected liver extract may maintain a better hematologic status than either substance alone. 5. [bloodjournal.org]

  Presence of IgM gammopathy suggests immune mediated pathogenesis. Disclosure: Dr. Balawi has nothing to disclose. Dr. Oh has nothing to disclose. Dr. Alsharabati has nothing to disclose. [neurology.org]

  Anti-intrinsic factor antibodies suggest pernicious anemia as an underlying disease of vitamin B12 deficiency and SCD. [symptoma.com]

  It has been suggested that cobalamin plays a role in the expression of tumor necrosis factor alpha (TNF-a) and epidermal growth factor (EGF), which is separate from its catalytic activity. [neuropathologyweb.org]

  Results of magnetic resonance imaging (MRI) were highly suggestive of SCD, which is typically seen in primary vitamin B 12 deficiency but has been reported in the context of chronic nitrous oxide exposure. [ajhp.org]

• Ataxia

  Lateral corticospinal tract dysfunction produces spasticity and dorsal spinocerebellar tract dysfunction causes ataxia. [ipfs.io]

  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]

  Clinically, vitamin E deficiency causes a sensory peripheral neuropathy, ataxia, retinitis pigmentosa, and skeletal and cardiac myopathy. [neuropathologyweb.org]

  Case Presentation: A 28‐year‐old nursing student with a history of bipolar disorder presented to Tucson Medical Center with symptoms of ataxia and bilateral lower‐extremity weakness of a few weeks’ duration. [shmabstracts.com]

• Paresthesia

  Stomach acid R protein Intrinsic Factor Distal 80cm of ileum Pernicious anemia -Decreases absorption of B12 -Condition where antibodies are generated against parietal cells SCD pathology Edema and destruction of myelin SCD initial symptoms Paresthesia [quizlet.com]

  Imerslund-Gräsbeck syndrome (genetic defect of cobalamin IF complex receptor), Crohn disease Subacute combined degeneration can be triggered by exposure to nitrous oxide in B12 deficient patients Clinical features Progressive sensory abnormalities, ascending paresthesias [pathologyoutlines.com]

  Clinically, paresthesia, sensory ataxia, and sometimes spastic paraplegia are present. The disease is the result of pernicious anemia. [medical-dictionary.thefreedictionary.com]

  Conclusion A patient who abused nitrous oxide chronically developed ataxia, paresthesia, and urinary retention while self-medicating with cyanocobalamin. [ajhp.org]

  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]

• Irritability

  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 B12 deficiency. [merckmanuals.com]

  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]

• Peripheral Neuropathy

  […] due to folic acid deficiency Neuropathy due to vitamin B12 deficiency Optic neuropathy due to vitamin B12 deficiency Pantothenic acid deficiency Peripheral nerve disorder due to vit B12 deficiency Peripheral neuropathy due to B12 deficiency Peripheral [icd9data.com]

  MS does not affect peripheral nerve conduction studies bc it is a disease of the Central Nervous system (not peripheral) YOU MIGHT ALSO LIKE... 57 terms Clerkship: Neuro - PreTest (Neoplasms & Metabolic) 92 terms Peripheral Neuropathies 96 terms Path1 [quizlet.com]

  Demyelinating or axonal peripheral neuropathies can occur. In the early stages of subacute combined degeneration, decreased position and vibratory sensation in the extremities is accompanied by mild to moderate weakness and hyporeflexia. [msdmanuals.com]

  An axonal peripheral neuropathy (a form of Beri-Beri disease) affecting the distal parts of the extremities is seen in 80% of patients. [neuropathologyweb.org]

  Clinically, vitamin E deficiency causes a sensory peripheral neuropathy, ataxia, retinitis pigmentosa, and skeletal and cardiac myopathy. [ipfs.io]

• Confusion

  Paranoia (megaloblastic madness), delirium, confusion, and, at times, postural hypotension may occur in advanced cases. The confusion may be difficult to differentiate from age-related dementias, such as Alzheimer disease. [msdmanuals.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 B12 deficiency. [merckmanuals.com]

  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]

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]

  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]

  Serum B12, methylmalonic acid, Schilling test, Complete Blood Count- looking for megaloblastic anemia if there is also folic acid deficiency or macrocytic anemia. [en.wikipedia.org]

  […] feet SCD progressive symptoms sensory loss gait ataxia distal weakness, especially in legs Subacute Combined Degeneration -syndrome of sensory loss -spastic paresis associated with pathological lesions in dorsal columns and lateral corticosinal tracts -macrocytic [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 of [ipfs.io]

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 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].

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

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].

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.

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.

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.

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.

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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.
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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.