Abstract
Background
The objective of this study was to estimate serum vitamin B12 levels and its correlation with severity of clinical presentation in patients with trigeminal neuralgia (TN).
Methods
A total of 80 participants were included and rendered into study group: 40 TN patients and control group: 40 healthy individuals. The serum vitamin B12 estimation of each participant was carried out by using serum vitamin B12 ELISA kit and pain characteristics of TN patients were recorded in details.
Results
The mean serum vitamin B12 level was noticed to be significantly lower (p = 0.042) in study group (296.87 ± 248.75 pg/mol) as compared to control group (423.5 ± 296.41 pg/mol). There was a statistically significant difference in serum vitamin B12 level between vegetarian TN patients and those who were on mixed diet (p = 0.001). The pain associated with TN predominantly reported unilaterally involving the right side (55%), female gender (55%) and mandibular division (50%). Although pain intensity showed no significant relation (p = 0.024), duration of pain reported a strong negative association with mean serum vitamin B12 levels in TN patients (p = 0.001).
Conclusions
Vitamin B12 supplements can be added to the established treatment protocol for the holistic management of TN patients particularly those who are on vegetarian diet.
Keywords: Trigeminal neuralgia, Vitamin b12 deficiency, Visual analogue scale, Vegetarian diet, Mixed diet
Graphical abstract
1. Introduction
International Association for the Study and Pain (IASP) stated Trigeminal Neuralgia (TN) as “a sudden, usually unilateral, severe, brief, stabbing, recurrent pain in the distribution of one or more branches of the fifth cranial nerve”.1 There is a reported incidence of 4–5 per 100,000 annually, and is seen more commonly in women than in men. TN is typically seen in older age group, with a peak incidence in 50–80 years.2 TN persuades events of extreme, piercing, electric current like pain in regions of the face where the nerve tributaries are supplied.1 The pain attacks (Tics) classically starts suddenly by light touch to certain areas; are usually unilateral and remain for 1–2 min. The pain can be reactivated by contacting the face, cleaning teeth, and rumination or even by talking and is typically introduced as unexpected, extreme, or electric shock like.3 After every attack, there is typically a refractive period during which stimulation of the trigger area may not induce the pain.4 Therefore, TN is considered to be a devastating disorder that grossly results in deterioration of the overall life quality of the patients.
Vitamin B12 is a water-soluble vitamin that is essential for the standard cellular function as well as growth & development and exist in traces in the diet. Vitamin B12 is generally considered to be useful in regenerative nourishment, and keeps geriatric population from turning anemic. It is well known that vitamin B12 helps in managing peripheral neuropathy with sufficient protection.5 Methylcobalamin, a type of vitamin B12 defends against neurological issues and maturing.6 As compared to other water soluble vitamins, vitamin B12 is not passed out rapidly in urine. It collects and gets stored in the liver, kidney etc. As an end result, vitamin B12 insufficiency may not be manifested till 5–6 years of food providing insufficient quantity.7 However, recent research exhibited that vitamin B12 insufficiency is far extensive than previously considered.8
Currently, knowledge regarding etiology of TN is unclear, however, age, gender, hypertension and arteriovenous shunt are considered to be its risk factors.9 Therefore, careful listening to the patient's emotional, social, functional and behavioural experiences help improve diagnosis of this poorly recognised entity.10 There is a consensus that TN is usually caused by demyelination of trigeminal sensory fibers. Although several theories have hypothesized a role of reduced serum vitamin B12 levels in painful events of TN,8 there is no certified documentation to date. The lower serum vitamin B12 might be incapable of repairing the injured myelin sheath giving rise to painful and pain free episodes.11 However, a very few studies have been documented in the literature regarding vitamin B12 levels among TN patients reporting to a dental college. Therefore, by considering the probable promising utility of vitamin B12 in the management of TN in future, the present study was aimed to evaluate serum vitamin B12 levels and its correlation with clinical presentation in patients with TN.
2. Material and methods
The present cross-sectional study was carried out in department of oral medicine and radiology, Sharad Pawar dental college and hospital in association with central research laboratory, Jawaharlal Nehru medical college from November 2018 to March 2020. An Institutional Ethics Committee approval was obtained from Datta Meghe institute of medical sciences (deemed to be university), Sawangi (Meghe) Wardha, India (DMIMS (DU)/IEC/2018/19/7497, dated 28/09/2018) prior to start the study. The subjects who were willing to participate in the study were recruited by convenient sampling method from patients reported to outpatient department of oral medicine and radiology. A total of 80 subjects in the age range of 20–80 years were divided in two groups as: (a) study group: 40 subjects who were primarily diagnosed as TN (including newly diagnosed cases and those who were under medication for TN) on the ground of IHS diagnostic criteria (IHS, 2004)12 and (b) control group: 40 healthy individuals without any signs & symptoms pertaining to orofacial pain and known systemic diseases or any major illness were included as controls. Participants with history of any active psychological or mental diseases were excluded. All the participants were recruited from the rural set up and were explained about the purpose of the study. An informed consent was obtained from patients and the study was performed in accordance with the Declaration of Helsinki. The detailed case history was recorded and thorough clinical examination of each participant was performed. Pain intensity was measured by visual analogue scale (VAS) in a rating of 0–10; and graded as mild (score 0–3), moderate (score 4–6) and severe (score 7–10). For serum vitamin B12 estimation, 5 ml blood sample of each participant was collected under all aseptic precautions and serum was separated from blood after labeling and then samples were stored at −20° Celsius. The estimation of serum vitamin B12 was carried out by using serum vitamin B12 ELISA kit (Calbiotech) and all the procedures were followed as given in the literature provided with the kit.
All the records were tabulated under particular groups and obtained data were analyzed by using SPSS software (SPSS 24.0 version software for Windows). The one-way ANOVA, student's T-test and chi-square test, wherever appropriate, were used to calculate the p-value. The level of statistical significance was kept at p < 0.05.
3. Results
3.1. Demographic details of subjects
A total of 80 participants were included in the present study. The mean age was found to be 48.70 ± 12.81 years and 49.72 ± 15.18 years in the study and control groups respectively. Amongst study group participants, greater proportion was of females (55%) while males (57.5%) were prevalent in control group (Table 1).
Table 1.
Demographic details and clinical profile of subjects.
| Particulars | Trigeminal neuralgia patients(n = 40) | Control subjects(n = 40) | P-value | |
|---|---|---|---|---|
| Age (years) | Mean +SD | 48.70 ± 12.81 | 49.72 ± 15.18 | 0.49 |
| Range | 30–76 | 20–57 | ||
| Sex | Male | 18 (45%) | 23 (57.5%) | 0.26 |
| Female | 22 (55%) | 17 (42.5%) | ||
| Diet | Veg | 23 (57.5%) | 22 (55%) | 0.001 |
| Mixed | 17 (42.5%) | 18 (45%) | ||
| Co-existing Condition | Diabetes Mellitus | 2 (5%) | – | 0.64 |
| Hypertension | 5 (12.5%) | – | ||
| Any other | 1 (2.5%) | – | ||
| Absent | 32 (80%) | – | ||
| Side involved | Right | 22 (55%) | – | 0.43 |
| Left | 18 (45%) | – | ||
| Nerve Involved | Mandibular (V3) | 20 (50%) | – | 0.479 |
| Maxillary (V2) | 15 (37.5%) | – | ||
| Opthalmic (V1) | 1 (2.5%) | – | ||
| Maxillary + Mandibular (V2+V3) | 3 (7.5%) | – | ||
| Maxillary + Opthalmic (V2+V1) | 1 (2.5%) | – | ||
| TN medications | <1 yr | 6 (15%) | – | 0.0001 |
| 1–2 yr | 4 (10%) | – | ||
| ˃2 yr | 14 (35%) | – | ||
| Total | 24 (60%) | |||
| No Medications | 16 (40%) | – | ||
3.2. Clinical profile of patients with trigeminal neuralgia
Out of forty, 5 (12.5%) TN patients were suffering from hypertension and were on anti-hypertensive medications and 2 (5%) TN patients had diabetes mellitus. Twenty two (55%) TN patients shown involvement of right side while left side was affected in 18 (45%) patients. The mandibular division (n = 20, 50%) was found to be predominantly affected followed by maxillary division (n = 15, 37.5%) and ophthalmic division (n = 1, 2.5%). Intriguingly, in 3 (7.5%) patients both ophthalmic & maxillary divisions were involved whereas only 1 (2.5%) patient shown involvement of maxillary & mandibular divisions (Table 1).
Amongst forty TN patients, about half (n = 19, 47.5%) reported moderate pain; whereas 15 (37.5%) had severe pain and remaining 6 (15%) patients complained of mild pain. When compared amongst newly diagnosed and old TN patients, it was noticed that majority of the old patients had moderate pain (n = 15, 62.5%), followed by severe pain (n = 9, 37.5%). However, newly diagnosed patients mainly had mild and severe pain with equal distribution (6 patients each) and only 4 (25%) patients had moderate pain. The chi square test applied demonstrated statistically significant difference (p = 0.003) for pain intensity amongst new and old TN patients. In regard to the characteristics of pain, sharp shooting pain (n = 15, 37.5%) was most commonly noticed, followed by lancinating pain (n = 13, 32.5%). The electric shock like pain and tingling type was observed in 6 (15%) patients each. A total of 24 (60%) TN patients were undergoing medicinal treatment including 15 (40%) patients on carbamazepine, 8 (20%) were taking combination of carbamazepine and pregabalin and only 1 (3%) patient was on oxcarbamazepine. However, 16 (40%) patients were not on any medications as they were newly diagnosed at the time of recruitment in the present study. In regard to TN treatment duration, about one third of the patients underwent medications for more than 2 years and 4 (10%) & 6 (15%) patients were on medicinal therapy for 1–2 years and less than a year respectively.
3.2.1. Serum vitamin B12 levels in study and control group
The mean serum vitamin B12 level was noticed to be significantly lower (p = 0.042) in study group (296.87 ± 248.75 pg/mol) as compared to control group (423.5 ± 296.41 pg/mol) (Table 2). However, a statistically non-significant difference (p = 0.33) was observed between mean serum vitamin B12 levels of old (328.54 ± 281.85 pg/mol) and new TN patients (249.37 ± 187.25 pg/mol). In relation to the pain intensity amongst TN patients, the mean serum vitamin B12 levels was found to be lowest in patients with mild pain (199.16 ± 140.30 pg/mol) than those with moderate (364.21 ± 283.21 pg/mol) and severe pain (222.91 ± 57.55 pg/mol). However, one-way ANOVA applied to the data obtained revealed a statistically non-significant correlation (p = 0.24) (Table 3).
Table 2.
Comparison of serum vitamin B12 level in trigeminal neuralgia patients and control subjects.
| Particulars | No (%) | Mean + SD (pg/mol) | Mean std. error | p-Value |
|---|---|---|---|---|
| Trigeminal neuralgia patients | 40(100%) | 296.87 + 248.75 | 39.33 | 0.042 |
| Control subjects | 40(100%) | 423.50 + 296.41 | 46.86 |
Table 3.
Correlation of serum vitamin B12 levels with clinical presentation in trigeminal neuralgia patients.
| Particulars | No (%) | Vitamin B12 (pg/mol)(Mean + SD) | p-value | |
|---|---|---|---|---|
| Type of diet | Veg | 23 (57.5%) | 188.47 ± 89.21 | 0.001 |
| Mixed | 17 (42.5%) | 443.52 ± 316.45 | ||
| Pain intensity | Mild | 6 (15%) | 199.16 + 140.30 | 0.24 |
| Moderate | 19 (47.5%) | 364.21 + 283.21 | ||
| Severe | 15 (37.5%) | 222.91 ± 57.55 | ||
| Pain duration | <1 year | 6 (25%) | 345 ± 264.00 | 0.001 |
| 1–2 years | 12 (50%) | 244.58 ± 185.83 | ||
| 2–3 years | 4 (16.66%) | 160 ± 101.48 | ||
| ˃3 years | 2 (8.33%) | 402 ± 101.38 | ||
| TN medication | Yes | 24 (60%) | 328.54 + 281.85 | 0.33 |
| No | 16 (40%) | 249.37 + 187.25 | ||
In the present study, the correlation of duration of pain with serum vitamin B12 level in 40 TN subjects exhibited a lowest serum vitamin B12 level (160 ± 101.48 pg/mol) in patients with a history of pain duration of 2–3 years and highest in those with a history of pain duration of more than 3 years (402 ± 101.38 pg/mol). The detailed analysis reported statistically significant differences among patients with different duration of pain and serum vitamin B12 levels (p˂ 0.001). The evaluation of serum vitamin B12 levels in TN participants according to type diet demonstrated lower serum vitamin B12 levels in vegetarian patients (188.47 ± 89.21 pg/mol) than those who were on mixed diet (443.52 ± 316.45 pg/mol) with a statistically significant difference (p = 0.001) (Table 3).
4. Discussion
The present study evaluated the serum vitamin B12 levels and its correlation with the clinical presentation in TN patients and observed a significantly lower serum vitamin B12 levels in TN patients as compared to healthy individuals (p = 0.042). However, non-significant differences were noted among newly diagnosed TN patients and old patients who were on medications (p = 0.33). The pain associated with TN predominantly occurs unilaterally, afflicts more often in the right side, female gender, mandibular and/or maxillary trigeminal branches,13 the same trends are confirmed in our study.
On a practical note, TN is a clinical diagnosis but imaging and routine investigations plays an important role. However, in rural set up like this, the patients usually do not visit the health care professionals because of reasons mainly poor socioeconomic conditions and fear.14,15 Thus, many a times routine estimation of serum vitamin B12 levels was not considered important and the treatment get delayed in those with lower levels. However, the intense, unbearable pain in TN forces patients to visit hospitals.
The present study reported the mean age of TN patients of 48.70 ± 12.81 years which is consistent with the past literature demonstrating higher prevalence of TN in elderly population.16,17 However, Resnick et al.18 and Monson and Rothman et al.19 acknowledged that TN typically occurs in middle age but it can also affect the young adults as well as the children. The present study observed that TN was prevalent in females. This is in agreement with reports Jainkittivong et al.16 In contrast to this, Rai et al. noticed a greater number of male TN patients in their study.17 The present study reported that 5 (12.5%) TN patients had hypertension and were on anti-hypertensive medications. Teruel et al. explored prevalence of hypertension in TN subjects but found no significant association between TN and hypertension.20 Since both TN and hypertension are seen in the elder population, presence of hypertension in TN subjects might be a co-existing condition and not a risk factor.20 In the present study, 2 (5%) TN patients were suffering from diabetes mellitus. The patients with diabetes mellitus may experience diabetic neuropathy and therefore this population might be vulnerable to TN.9,21
In the present study, 55% patients showed right side involvement which is in agreement with the previous studies demonstrating that right side is more commonly affected in TN.16,17 The mandibular division of trigeminal nerve was noticed to be most commonly affected (50%) in the present study. Similar results were reported by Jainkittivong et al.16 However, Rai et al. observed involvement of maxillary and mandibular divisions in 24 (40%) and 21 (35%) TN patients respectively.17 As noted in previous studies, the TN patients in the present study were distributed over a wide variety according to the characteristics of pain with sharp shooting pain (37.5%) as highly prevalent pain characteristics. Jainkittivong et al.16 reported 77.6% patients with sharp pain while Rappaport and Devor22 described the TN pain as shooting, electric shock like and cutting. Bagheri et al.21 described TN pain as lancinating and electric like bouts whereas Chole et al.23 in their systematic review suggested the TN pain as electric shock-like and stabbing.
In the present study, the mean serum vitamin B12 level was found to be significantly lower in study group as compared to control group (p = 0.001). Jacobs et al. (2003) stated that vitamin B12 is required for the integrity of nerve tissue and low vitamin B12 may not be able to repair myelin sheath as and when the demand emerges leading to tics. This is due to the fact that, one Schwann cell can myelinate only 0.2–1.8 mm of cytoplasmic membrane.11 Methylcobalamin improves velocity of nerve conduction and promotes regeneration of injured nerve, thereby recovering the neuromuscular functions. It prevents the spontaneous discharges in pain due to neuropathy. Further vitamin B12 helps in managing peripheral neuropathy with sufficient protection. Singla et al. also noticed decrease in intensity of pain in facial neuralgia after administering vitamin B12 to these patients.24
In the present study, the correlation of pain intensity with serum vitamin B12 levels showed statistically non-significant difference (p = 0.0027). This might be due to the fact that there was uneven distribution of TN patients having among mild, moderate and severe pain. However, results of the present study revealed a statistically significant correlation (p = 0.001) between duration of pain and mean serum vitamin B12 levels of TN patients. This shows that the duration of pain increases as the serum vitamin B12 level decreases. The possibility of reduced vitamin B12 intake from diet due to onset of pain attacks while eating in most TN patients cannot be ignored as this may further lead to reduction in serum vitamin B12 levels and ultimately can increase progress of the disease. When vitamin B12 levels are reasonable, myelin sheaths get repaired quickly, but it is possible that declination in vitamin B12 levels might not maintain the demand of repair of the traumatized myelin sheath and consequently repair rate gets delayed.24 However, although the duration of pain was for more than 3 years, there was relatively higher serum B12 levels in only two patients of this study. This might be because these patients were on mixed diet. Therefore, we believe that there is a need of future prospective studies with larger sample size to evaluate the correlation of serum vitamin B12 levels and duration of pain in TN patients.
The present study reported non-significant difference for serum vitamin B12 levels between old TN patients who were on medications and newly diagnosed patients without medications. This suggests that there was hardly any effect of TN medications on the serum vitamin B12 levels. However, there can be other confounding factors like age, type of diet and the duration of this painful condition. The present study observed a statistically significant correlation between serum vitamin B12 levels of vegetarians and those on mixed diet (p = 0.001). These findings reinforce that the vegetarians are at a greater risk of vitamin B12 deficiency.17 Moreover TN patients in the present study were mostly in fifth decade of their life and it was suggested that geriatric population mostly suffer from malabsorption of vitamin B12.25 Therefore, we strongly believe that TN patients should be advised vitamin B12 supplements in one or the other form along with routine established treatment protocol so that painful episodes of TN can be minimized.
One main contribution of this cross-sectional study is that it extends previous research and helps to fill the gap in knowledge regarding lower serum vitamin B12 levels and its correlation with pain characteristics in TN patients. Few limitations of the study include small population studied with a homogenous demographic distribution due to the local patient population. The findings of the present study should be interpreted with caution, as the results obtained might not be generalizable to other parts of the world due to diverse patient characteristics. Therefore, to further authenticate the findings of the present study, future multicentric studies with longer duration with multiple time point analysis of parameters are warranted to have better insight.
5. Conclusions
The present study demonstrates significantly lower serum vitamin B12 levels in TN patients as compared to healthy individuals. The noteworthy finding in our study was that irrespective of the use of TN medications, serum vitamin B12 level was relatively lower in vegetarians than those who were on mixed diet. Moreover, the duration of pain and serum vitamin B12 levels in TN patients showed a strong negative association. As vitamin B12 is primarily required for the integrity of nerve tissue and being water soluble, it can be recommended that vitamin B12 supplements in one or the other form can be added to the established management protocol in every TN patient; particularly those who are on vegetarian diet. This might prove to be the holistic approach and ultimately can aid in improving the overall quality of life of patients. We also recommend future multi-centric cohort studies on large number of patients to explore the status of serum vitamin B12 levels in TN patients.
Source of funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
None.
Acknowledgement
Nil.
Contributor Information
Pooja Dhole, Email: poojadhole93@gmail.com.
Vidya Lohe, Email: vidyalohekadu@gmail.com.
Rahul Bhowate, Email: dr_bhowate@yahoo.com.
Shailesh M. Gondivkar, Email: shailesh_gondivkar@yahoo.com.
Ravindra Kadu, Email: dr_kadu@rediffmail.com.
Swapnil C. Mohod, Email: dr.swapnilmohod@gmail.com.
Ravikant V. Sune, Email: ravisune@ymail.com.
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