Low Vitamin B 12 Syndrome in Trigeminal Neuralgia

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Introduction
Trigeminal neuralgia (tic douloureux) is a disorder of the h cranial (trigeminal) nerve that causes episodes of intense, stabbing, electric shock-like pain in the areas of the face where the branches of the nerve are distributed -lips, eyes, nose, scalp, forehead, upper jaw, and lower jaw.
e International Association for the Study of Pain (IASP) de nes trigeminal neuralgia as a sudden, usually unilateral, severe, brief, stabbing, recurrent pain in the distribution of one or more branches of the h cranial nerve [1].Typically, brief attacks of pain are triggered by talking, chewing, brushing teeth, and shaving, applying make-up or even a slight breeze.Generally, it is a clinical diagnosis, although imaging may be necessary to exclude other pathology.
e trigeminal nerve has 3 sensory divisions known as V1 (Ophthalmic) which supplies the eye, forehead and nose, V2 (Maxillary) which supplies the upper teeth, gums and lip, the cheek, lower eyelid and the side of the nose and V3 (Mandibular) supplying the lower teeth, gums and lip.Pain can involve one or more branches of the trigeminal nerve.
First line of treatment of trigeminal neuralgia is usually in the form of anticonvulsant drug, especially carbamezepine.When medication does not satisfactorily manage pain, various surgical options are available, including microvascular decompression, radiofrequency ablation and stereotactic radiosurgery, with a gamma knife.
Microvascular decompression is the only procedure that has successfully provided long term pain relief [2].Devor and Rappaport con rmed from biopsy specimens that demyelination occurred during nerve compression.It is widely believed that the sustained pulsatile of the compression demyelinates sensory axons in the nerve and nerve root.ey hypothesized that MVD provides prolonged pain relief due to remyelination a er the decompression [3].e cranial nerves, except for the rst and second, are part of the peripheral nervous system.e Schwann cells produce and maintain myelin to the peripheral nerve axons.About one quarter of the axons in the PNS are myelinated.e cause for trigeminal neuralgia is not clearly understood.Multiple theories have been proposed, and some implicate a low vitamin status with trigeminal neuralgia pain however to date there is no conclusive evidence.Vitamin B12 (cobalamin) is an important water-soluble vitamin.In contrast to other water-soluble vitamins it is not excreted quickly in the urine, but rather accumulates and is stored in the liver, kidney and other body tissues.As a result, vitamin B12 de ciency may not manifest itself until a er 5 or 6 years of a diet supplying inadequate amounts.
Cyanocobalamin has been shown to reduce spinal nerve ligation induced alloydnia and tactile allodynia in rats and therefore may have a role in humans [4].Vitamin B12 functions as a methyl donor and works with folic acid in the synthesis of DNA and red blood cells and is vitally important in maintaining the health of the insulation sheath (myelin sheath) that surrounds nerve cells.
Low vitamin B12 levels can have consequences long before anaemia is evident.e normal serum level of vitamin B12 in Australia ranges between 106 to 665 pg/ml.Researchers now propose that the current standard norms of vitamin B 12 levels are too low.Recent research indicates that B 12 de ciency is far more widespread than formerly believed.In a cross-sectional, population-based study of 1048 aged subjects, low serum total vitamin B12 (<205 pg/ml) was observed only in 6.1% and borderline vitamin B12 (205-350 pg/ml) in 32% of the subjects [8].A large study performed at Tu s University by the USDA found that 39 percent of studied group of 3,000 had low values, using a vitamin B 12 concentration of 350 pg/mL as a criterion of "low level" [9].e treatment of trigeminal neuralgia can be challenging and in the search for alternatives, vitamin B12 has been found to be a clinically useful pharmacological useful tool for patients with neuropathic pain.Large dose of vitamin B12 were used with good e ect in therapy of trigeminal neuralgia in 1953 and 1954 [10,11], but since then clinical studies supporting its use are lacking.e object of this study was to investigate whether patients with trigeminal neuralgia had lower levels of vitamin B12 compared to patients with other facial pain syndromes and whether increasing the level of vitamin B12 improve pain levels.

Method
As part of patient's routine clinical assessment for the management of trigeminal neuralgia, serum vitamin B12 levels were performed on all patients referred to their treating neurologist.A questionnaire was designed to facilitate details of patient facial pain condition, history, level of pain and if they were taking vitamin B12, folic acid supplements, amount and type used.Participation was on a voluntary basis.Pain patients and their partners were encouraged to have their serum vitamin B12 and folic acid measured in laboratory test.
Recently, holocobalamin assays have become available [12], due to the uncertain clinical signi cance of the total vitamin B12 level, but these were not widely available when this study was commenced.Patients found to be taking vitamin B12 supplementation were excluded from the study.
is was an observation study performed as part of the patient's conventional medical treatment.It was reviewed by the Sydney South West Area Heath Service Ethics Review Board and granted exemption from a full review.e study was conducted adhering to the Declaration of Helsinki.

Results
A total of 76 patients took part in this study.ere were 53 females aged between 37-78 years and 23 males aged between 18 -82 years.e average age for the group was 63.3 years.57 patients had trigeminal neuralgia, the 19 patients with other facial pain included 3 with trigeminal dea erentation pain, 8 with trigeminal neuropathic pain, 2 with short lasting, unilateral neuralgiform headache attacks with conjuntival injection and tearing (SUNCT) syndrome, 2 with glossopharyngeal neuralgia, 1 with geniculate neuralgia and 1 with post-herpetic neuralgia.e average age in the trigeminal neuralgia group was 62.2 years compared to 63.8 in the control group (p>0.05).e male: female ratio was also similar.
Based on the laboratory reference ranges, (106-675 pg/ml), none of our patient group were found to have laboratory vitamin B12 de ciency, as serum vitamin B12 levels ranged from 106 pg/ml to 695 pg/ml [13,14].Of signi cance however was that 23% patients with trigeminal neuralgia had serum vitamin B12 levels of less than 205 pg/mL, compared to only 12% of controls (p<0.05),when using the criterion based on the USDA recommendation in 2000 that vitamin B12 de ciency be regarding as a serum total vitamin B12 of less than 205 pg/mL.

Discussion
is study indicates that patients with trigeminal neuralgia have a low vitamin B12 syndrome, as 23% of patients with trigeminal neuralgia, compared to only 12% of patients with other causes of facial pain had serum vitamin B12 levels less than 200 pg/ml.ese results are markedly abnormal when compared to a cross-sectional, populationbased study of 1048 aged subjects in which low serum total vitamin B12 (<205 pg/ml) was observed in only 6.1% population controls [8].
ere is no known toxicity from taking additional vitamin B12.Methylcobalamin may even be protective against neurotoxicity by enhancing brain cell methylation, as it has been shown that methylcobalamin protected against glutamate-aspartate and nitroprusside-induced neurotoxicity in rat cortical neurons [5].
One problem encountered was the di erent measurement units from di erent laboratories.Most used picomol (pmo/mL), while others used picogram (pg/mL) and microgram (µg/mL).Reports in Australian are in pmol/L while literature worldwide uses pg/ml.Conversion was made for the purpose of comparisons [15].Molecular weight of B12 = 1355.38daltons.
To convert pmol/L to pg/ml-no.pmol x 0.7378 = pg/ml To convert pg/ml to pmol/L-no.pg/ml x 1.35 = pmol/L It is possible that low vitamin B12 levels fail to sustain the demand of repair to the myelin from a nerve that is continuously being traumatised.
is may be one of the explanations why trigeminal neuralgia pain is intermittent.When vitamin B12 levels are reasonable, myelin sheaths repair quickly, but when vitamin B12 levels are low, the repair rate is slower, as one Schwann cell can only myelinate 0.2-1.8mm of cytoplasmic membrane along the length of one axon [16].Low vitamin B12 or B12 de ciency most o en results from food -cobalamin malabsorption due to gastric dysfunction and may be exacerbated by the use of acid-lowering agents such as H2 blockers, antacids and proton pump inhibitors.Absorption of vitamin B12 depends on the stomach to produce high concentration of hydrochloric acid and enough intrinsic factor.

Causes of Low Vitamin B12
Naturally found vitamin B12 is dissociated from proteins in the stomach via the action of acid and the enzyme pepsin.
e forms of vitamin B12 released by this process are methylcobalamin and adenosylcobalamin.All forms of vitamin B12 bind to proteins called haptocorrins or R proteins, which are secreted by the salivary glands and the gastric mucosa.is binding occurs in the stomach.Pancreatic proteases partially degrade the B12-haptocorrin complexes in the small intestine where the vitamin B12 that is released then binds to intrinsic factor (IF). Intrinsic factor is a glycoprotein which is secreted by gastric parietal cells.e B12-intrinsic factor complex is absorbed from the terminal ileum into the ileal enterocytes via a process that rst requires the complex to bind to a receptor called cubilin.Within the enterocytes, vitamin B12 is released from the B12-IF complex and then binds to another protein called transcobalamin II which delivers it to the portal circulation.e portal circulation transports vitamin B12 to the liver which takes up about 50% of the vitamin; the remainder are transported to the other tissues of the body via the systemic circulation.
Vitamin B12 in the circulation is bound to the plasma proteins transcobalamin I (TCI), transcobalamin II (TCII) and transcobalamin III (TCIII).Approximately 80% of plasma B12 is bound to TCI.TCII is the principal B12 binding protein for the delivery of B12 to cells, vitamin B12 a speci c receptors for TCII. is B12 binding protein (TCII) is identical to the one that delivers vitamin B12 from the enterocytes to the portal circulation.b) Immune System -Intrinsic factor in the stomach.e most common cause of vitamin B12 de ciency is the stomach being unable to produce enough intrinsic factor.is is frequently caused by an immune system problem where antibodies attack the stomach lining and damage the cells that produce intrinsic factor.c) Bacterial overgrowth and infestation with tapeworms or other intestinal parasites that can compete for dietary vitamin B12 in the small bowel.d) Antibiotics: e use of antibiotics may alter the intestinal micro ora and may decrease the possible contribution of vitamin B12 by certain inhabitants of the micro ora (e.g.Lactobacillus species) to the body's requirement for the vitamin e) Lack of calcium in the food can also reduce the uptake and so can heavy metals.f) Megadoses of vitamin C and/or copper can cause vitamin B12 de ciency Transport [18] Once absorbed, vitamin B12 binds to transcobalamin II it is transported throughout the body.
Congenital transport-protein de ciencies, including transcobalamin II de ciency, are another rare cause of vitamin B12 de ciency.It has also been suggested that in the presence of heavy metals the cobalt atom is oxidized from CO2+ to CO3+ (denaturation) at the same time as the heavy metal is reduced.e properties of the cobalamin are hypothetically changed and vitamin B12 has lost its biological properties.

Conclusion
Fortunately, oral supplementation with vitamin B12 is safe, e cient and inexpensive.Most multi-vitamin pills contain 100-200 microgram of the cyanocobalamin form of B12. is must be converted to methylcobalamin before it can be used by the body.e actual absorption of B12 is also a problem with supplements.Swallowing 500 micrograms of cyanocobalamin can result in absorption of as little as 1.8 microgram so most multivitamins do not provide an adequate daily intake.e best approach is to dissolve a sublingual tablet of methylcobalamin (1000 micrograms) under the tongue every day.at will be su cient to maintain adequate body stores.Some physicians still maintain that monthly injections of vitamin B12 is required to maintain adequate levels in the elderly and in patients with a diagnosed de ciency.ere is however, no scienti c evidence supporting the notion that injections are more e ective than sublingual supplementation [19].e serum vitamin B12 results indicate that subjects in this study have a low vitamin B12 syndrome (<205 pg/mL) rather than clinical de ciency.Holocobalamin assays have become available to assess this better, but these were not widely available when this study was performed.A further study to assess the e cacy of vitamin B12 supplementation in the treatment of trigeminal neuralgia pain is planned.