Various Neurological Symptoms with Vitamin B12 Deficiency and Posttreatment Evaluation.

BACKGROUND: Vitamin B12 deficiency occurs primarily as a result of insufficient dietary intake in children in developing countries. Vitamin B12 deficiency produces a cluster of neurological symptoms in children. AIM: The aim of this study was to describe the vitamin B12 status of patients who were admitted with neurological symptoms and to evaluate the clinical response to vitamin B12 treatment.
MATERIALS AND METHODS: This study was conducted on children who had vitamin B12 deficiency presented with neurological findings from January 2014 to October 2016. Patients with serum vitamin B12 levels lower than 300 pg/mL received intramuscular or oral vitamin B12 treatment.
RESULTS: Three hundred and fifty-one patients presenting with neurologic symptoms and who had low serum vitamin B12 deficiency were analyzed. Our study population was composed mainly of adolescent age. The most common symptom with respect to age was headache. In infant patients, most common symptoms were seizure and developmental delay.
CONCLUSION: Early diagnosis and vitamin B12 treatment are advocated to avoid long-term injury. Our study shows that patients with serum vitamin B12 levels lower than 300 pg/mL showed clinical improvement of neurological symptoms after receiving vitamin B12 treatment. Copyright:

INTRODUCTION

Vitamin B12 deficiency is a widespread public health problem in developing countries. Inadequate dietary intake is the primarily cause of vitamin B12 deficiency in children. Vitamin B12 is naturally found in animal products, so deficiency is common in the case of poor intake of these foods in low-income countries.[1]

Vitamin B12 deficiency causes a wide range of hematological and neurological symptoms. In children, it often presents with nonspecific manifestations, such as developmental delay, movement disorders, weakness, headache, and paresthesia. The common sign of vitamin B12 deficiency is megaloblastic anemia; however, neurological symptoms can occur without hematological abnormalities.[234]

There is no consensus on treatment of patients with vitamin B12 deficiency with neurological manifestations. In this study, we aimed to describe the vitamin B12 status of patients presented with neurological symptoms and to evaluate the clinical response to vitamin B12 treatment.

MATERIALS AND METHODS

This retrospective study was conducted on children with neurological findings. The demographic data, clinical presentation, dietary histories, laboratory findings, neuroimaging and electroencephalography results, and clinical outcome of patients were collected from the medical records and reviewed. Written informed consent from the guardians on the behalf of participants involved in this study was obtained. The approval of local ethics committee was obtained (Protocol no.: 272-2.11.2016).

Patients aged 0–18 years were included in the study if they had low serum vitamin B12 levels. Those who were diagnosed with chronic neurological disorders such as epilepsy, neurometabolic disease, and iron-deficiency anemia or folate deficiency were excluded from the study. Patients who used any other drugs and who were diagnosed with primary headache according to the third edition of the International Classification of Headache Disorders criteria were also excluded, although they had low serum vitamin B12 levels.[5]

Patients whose serum vitamin B12 levels were below 300 pg/mL were considered to be vitamin B12 deficient. Severity of vitamin B12 deficiency was classified as absolute (<200 pg/mL) and borderline (200–300 pg/mL).[67] Hemoglobin (Hb) and mean corpuscular volume (MCV) levels were analyzed according to the age-adjusted normal ranges.[8]

Once a deficiency was identified, intramuscular (IM) or oral vitamin B12 treatment was started accordingly. Vitamin B12 treatment was given through injection if the patient was not able to take orally. In IM treatment regime, infant patients received vitamin B12 treatment 100 mcg daily for a week, then 100 mcg every other day for a week, followed by 100 mcg twice a week. After this regimen, they received 100 mcg monthly for 3 months. The patients older than 2 years received vitamin B12 treatment 1000 mcg daily for a week, followed by 1000 mcg every other day for a week, and then 1000 mcg twice a week. After this regimen, they were given 1000 mcg monthly for 3 months. In oral treatment regime, patients received vitamin B12 treatment 1000 mcg daily for 3 months.[9] Clinical examinations and serum vitamin B12 levels were reassessed at a 3- to 6-month follow-up visit.

Statistical analysis was performed using Statistical analysis was performed using Statistical Package for the Social Sciences software program, version 21.0. (IBM Corporation, New York, United States). Frequencies and percentages were calculated. Patients’ age and serum vitamin B12 levels were also described using mean ± standard deviation. The chi-square test and Fisher exact test were used for comparison between independent groups of categorical data. For all statistical tests, values of P < 0.05 (two-tailed) were considered statistically significant.

RESULTS

A total number of 351 patients with vitamin B12 deficiency enrolled in the study. Table 1 shows the participants’ demographic data. Serum vitamin B12 levels ranged from 22 to 299.6 pg/mL. Their mean serum vitamin B12 level was 215.9 ± 55.9 and absolute vitamin B12 deficiency was found in 38% patients. The mean Hb level of the patients was 12 ± 0.6g/dL and their mean MCV was 85 ± 6.2 fL. No patient had a macrocytic anemia. Table 2 shows the distribution of clinical symptoms in patients with vitamin B12 deficiency according to vitamin B12 levels.

Table 1

Demographic characteristics and clinical features in patients with vitamin B12 deficiency

Gender, n (%)
Female	229 (65)
Male	122 (35)
Age (mean)	11.8 years
Clinical symptoms, n (%)
Headache	227 (65)
Seizure	41 (12)
Dizziness	31 (9)
Syncope	13 (4)
Paresthesia	11 (3)
Developmental delay	9 (2)
Fatigue	10 (2)
Tremor	3 (1)
Forgetfulness	1 (1)
Myoclonus	5 (1)

Table 2

Clinical symptoms in patients with vitamin B12 deficiency according to vitamin B12 levels

Vitamin B12 deficiency	Absolute vitamin B12 deficiency (<200 pg/mL)	Borderline vitamin B12 deficiency (200–300 pg/mL)
Clinical symptoms, n (%)
Headache	79 (35)	148 (65)
Seizure	19 (46)	22 (54)
Dizziness	8 (26)	23 (74)
Syncope	9 (69)	4 (31)
Paresthesia	4 (36)	7 (64)
Developmental delay	5 (55)	4 (45)
Fatigue	5 (50)	5 (50)
Tremor	2 (67)	1 (33)
Forgetfulness	0	1 (100)
Myoclonus	3 (60)	2 (40)

Our patients and their mothers generally consumed inadequate animal-derived protein products due to unhealthy dietary habits and their low socioeconomic status. Fifteen infants were exclusively breastfed. Their mothers were referred to internal medicine physicians for testing vitamin B12 levels. The parents were informed about the importance of consuming animal-derived protein products and an adequate intake was recommended.

Cranial magnetic resonance imaging (MRI) was obtained in 251 patients, and it was normal in 238 patients. Nondiagnostic abnormalities (mega cisterna magna and nonspecific gliotic lesion) were detected in 12 patients and delayed myelination in one patient with developmental delay. EEG was obtained in 55 patients, and it was normal in all of them.

Serum vitamin B12 levels of all patients were found within normal ranges at follow-up visit. Their mean serum vitamin B12 level was 499.5 ± 160.7 pg/mL. Two hundred seventy-seven patients received oral therapy and 74 patients received IM therapy. A total of 307 patients (87%) showed clinical improvement to the administration of oral or IM doses of vitamin B12. No statistically significant differences in clinical improvement were observed between the two treatment groups (P > 0.05) [Table 3].

Table 3

Outcome assessment at follow-up visit between the two treatment groups

Clinical improvement with therapy	Yes	No	P value
Oral treatment, n (%)	240 (87)	37 (13)	0.434
IM treatment, n (%)	67 (90)	7 (10

One hundred and ninety-eight patients (87%) showed a reduction in the frequency and severity of the headaches. Paresthesia resolved in nine patients (82%). No seizure recurrence was observed in 36 patients (88%). Eight patients (89%) with developmental delay made developmental progress and reached age-appropriate milestones. A reduction of the tremor’s severity was observed in one patient (33%). Twenty-eight patients (90%) had no more complaint of dizziness. Eleven patients (85%) did not experience another episode of syncope. Follow-up showed resolution from fatigue, forgetfulness, and myoclonus in all cases.

Forty-one of them were infants under the age of 2 years. Table 4 shows the infant participants’ demographic data. A total of 40 (97%) infant patients’ symptoms were resolved. Only one patient with development delay failed to gain motor milestones. After vitamin B12 treatment, the patient who was presented with developmental delay and delayed myelination had normal MRI findings.

Table 4

Demographic characteristics and clinical features in infant patients with vitamin B12 deficiency

Gender, n (%)
Female	20 (49)
Male	21 (51)
Age (mean)	9 months
Clinical symptoms, n (%)
Seizure	25 (61)
Developmental delay	9 (22)
Myoclonus	5 (12)
Headache	1 (3)
Tremor	1 (2)

DISCUSSION

Vitamin B12 has an important role in deoxyribonucleic acid (DNA) synthesis that is necessary for the maintenance of neurological functions. Herein, we presented the clinical data and treatment outcomes of children with vitamin B12 deficiency.

Nutritional vitamin B12 deficiency is common in southwest of Turkey where a Mediterranean-style diet is commonly used. The diet is rich in vegetables, fruits, legumes, nuts, and olive oil, with a limited consumption of meat.[10] All of our patients and their mothers were nonvegetarian; however, low vitamin B12 levels were associated with dietary habits. Exclusively, breastfed infants of mother who take inadequate dietary intake of animal foods may have very limited reserves of vitamin B12. Therefore, infants can develop vitamin B12 deficiency within months of birth.[1112]

The common hematologic sign of vitamin B12 deficiency is a megaloblastic anemia; however, patients may present with normal Hb level and a normal MCV.[34] Our study was conducted on children with neurological findings. No patients had a macrocytic anemia. These results support the hematological and neurological manifestations of vitamin B12 deficiency that can be dissociated.

Vitamin B12 deficiency produces a wide variety of neurological symptoms in children.[13] Goraya et al.[14] reported nine patients with infantile tremor syndrome associated with low serum vitamin B12 levels. Calik et al.[15] found that the serum vitamin B12 level in the children with tension-type headache was significantly lower than that in the control group. Our study population was mainly composed of adolescent age. The most common symptom with respect to age was headache. In infant patients, most common symptoms were seizure and developmental delay. Majority of patients with headache and dizziness had borderline vitamin B12 deficiency. So, clinicians should be aware of borderline vitamin B12 deficiency in patients with headache and dizziness.

Vitamin B12 has a significant role in the formation and maintenance of the myelin sheath of both the central and peripheral nervous systems.[1617] MRI findings include thinning of the corpus callosum, brain atrophy, and delayed myelination.[1819] In a study by Ekici et al.,[19] the most commonly found MRI findings were thinning of the corpus callosum and brain atrophy. In our study, one patient with developmental delay had delayed myelination on cranial MRI. After vitamin B12 treatment, the patient who was presented with developmental delay and delayed myelination had normal MRI findings.

The clinical symptoms are the most important factor in assessing vitamin B12 deficiency. There is no gold standard test to define deficiency. Absolute vitamin B12 deficiency was defined as a serum level less than 200 pg/mL and borderline vitamin B12 deficiency was defined as a serum level between 200 and 300 pg/mL.[67] In patients with clinical symptoms of vitamin B12 deficiency and low levels of serum vitamin B12, further confirmatory testing is not generally needed before treatment is initiated.[720] In our study, 87% of the patients with vitamin B12 deficiency showed marked clinical improvement of neurological symptoms after receiving vitamin B12 treatment. It is possible that the low B12 levels may be a coincidental finding; however, the patients clinically responded to vitamin B12 and did not require additional medical treatment, which seemed to support our diagnosis.

Vitamin B12 therapy can be administered orally or by injection. IM injections of vitamin B12 100–1000 mcg daily for 5 days, followed by 100 mcg to 1000mg weekly for 4 weeks, and a maintenance therapy of 100–1000 mcg every 1–3 months is a recommended treatment regimen for vitamin B12 deficiency.[920]

Several studies reported that a daily oral dose of 1000 mcg of vitamin B12 is sufficient to maintain a normal vitamin B12 status and that the oral administration of vitamin B12 is an effective alternative to its IM administration.[2122] In our study, follow-up vitamin B12 levels of all patients were found within normal ranges. No patients switched from IM to oral therapy and no patients required a switch back to IM therapy as a result of therapeutic failure. Our study showed that oral administration of vitamin B12 is as effective as parenteral administration in children.

Although most patients respond well to vitamin B12 treatment, residual neurological abnormalities can persist. It is commonly accepted that deficiencies in the early stages yield better results, as structural and irreversible changes in the brain may occur if left untreated.[1423]

Main limitation of this study was its retrospective design. We did not routinely perform methylmalonic acid and homocysteine measurements at our institution. Serum vitamin B12 level measurement is the main way of investigation of vitamin B12 deficiency, whereas an increase in serum levels of methylmalonic acid and homocysteine also indicates the diagnosis.[24] Further prospective, randomized controlled trials are needed to evaluate the neurological symptoms in children with vitamin B12 deficiency and the clinical response to vitamin B12 treatment.

The neurological symptoms of vitamin B12 deficiency can occur without anemia, so early diagnosis and treatment is important to prevent irreversible damage. It is also important to treat vitamin B12 deficiency in pregnant and breastfeeding women because of the importance of vitamin B12 in the brain development. Patients with serum vitamin B12 levels lower than 300 pg/mL should be treated. Physicians should be alert to identify neurological signs or symptoms of vitamin B12 deficiency, especially in high-risk populations, even in the absence of hematological symptoms or signs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.