Neurological Manifestations in Vitamin B12 Deficient Children: A Prospective Observational Study

Background and aim: Neurological manifestations in vitamin B12 deficient children in common. The present study determined neurological manifestations in vitamin B12 deficient children in a tertiary care centre in Rajasthan. Methods: This hospital based observational analytical study was conducted in Department of Pediatrics, Dr. S. N. Medical College, Jodhpur after approval of Institutional Ethics Committee (IEC). The study population included Vitamin B12 deficient (<250 picogram/dl) children during September 2019 to August 2020. All children aged 6 months to 5 years admitted in pediatric ward with anaemia (Hb< 11 gm/dl according to WHO Criteria) were screened for serum vitamin B12 levels out of which children having serum vitamin B12 level <250Pg/dl were included in the study. Results : More than half (63.8%) of the children aged between 6 months and 15 months. Male to female ratio was 1.58:1. 78.7% were rural and 60% were from lower socioeconomic class. 85% of the children’ family had vegetarian dietary habits. The most common clinical feature was hyperpigmentation of knuckles and skin (85% each) followed by depigmented and sparse hair (70%), and chubby face (42.5%). 65% of the children were found to have neurological manifestations. The most common neurological manifestation was developmental delay (60%) followed by hypotonia (38.7%), exaggerated reflexes (31.2%), and abnormal movements (20%). Conclusion: There is an urgent demand for early evaluation of the children so prevent further prevent developmental growth of the children.


Introduction
Vitamin B12 deficiency is a condition that is readily amenable to treatment, but its protean manifestations make diagnosis difficult in certain circumstances. Early recognition is essential to reversing the haematological and neurologic dysfunction characteristic of this disorder by means of vitamin supplementation. 1 Varied neurological manifestations of vitamin B12 deficiency have been known for over 150 years.
Although infants who are deficient in vitamin B12 due to maternal and infant vegetarianism may also be deficient in other nutrients derived from animal-source foods, such as iron and zinc, it is unlikely that the developmental problems associated with vitamin B12 deficiency could be explained by iron or zinc deficiency.
There are at least two possible mechanisms linking vitamin B12 deficiency and abnormal behavior and development: 1) threats to early brain development, possibly through demyelination; and 2) inflammation, possibly simulating an autoimmune process that blocks intrinsic factor for cobalamin absorption, similar to pernicious anemia, an autoimmune disease that blocks intrinsic factor.
Nutrient deficiencies can interfere with early brain development and function, often by restricting the myelination, dendritic arborisation, and synaptic connectivity that occur early in life. 2 The tissue levels of neurotransmitters (e.g., serotonin, dopamine, norepinephrine and acetylcholine) may be altered, resulting in neuroanatomical, neurochemical, or neurometabolic changes. The functional consequences of these alterations vary, depending on the specific nutritional deficiency and the timing of the deficiency relative to the developing neurological processes.
The present study evaluated the neurological manifestations in vitamin B12 deficient children.

Material and methods
This hospital based observational analytical study was conducted in Department of Pediatrics, Dr. S. N. Medical College, Jodhpur after approval of Institutional Ethics Committee (IEC). The study population included Vitamin B12 deficient (<250 picogram/dl) children aged between 6 months and 5 years during September 2019 to August 2020.
All children aged 6 months to 5 years admitted in pediatric ward with anaemia (Hb< 11 gm/dl according to WHO Criteria) were screened for serum vitamin B12 levels out of which children having serum vitamin B12 level <250Pg/dl (as per lower limit defined by Institute of Medicine Standing Committee, USA) were included in the study.
Children with an Acute encephalopathy syndrome as per standard epidemiologic case definition, stroke, demyelinating illness, known patient of epilepsy, pre-existing development delay, congenital CNS malformations, any known malignancy, other primary CNS disorders (both acquired and hereditary), children on vitamin B12 supplements (therapeutic or prophylactic) for at least 7 days in last one month, and/or refusal for participation in the study by parents/guardian, were excluded.

Methodology
All children aged between 6 months and 5 years admitted in a pre-decided Paediatric unit were screened for Hb levels by Complete Blood Counts (CBC). Total 1552 children were hospitalised during this study period out of which 853 children (54.37%) were between the age group of 6 months to 5 years. 361 children diagnosed out of these 853 had anaemia as per WHO criteria (Hb <11 gm/dl). In all these 361 children serum vitamin B12 levels were performed.
For this two ml of serum was collected to estimate serum vitamin B12 levels. Vitamin B12 levels were performed by a competitive chemiluminescent immunoassay. 80 patients out of these 361 had serum vitamin B12 level < 250 pg/dl (as per lower limit defined by Institute of Medicine Standing Committee, USA) and were enrolled after applying exclusion criteria. A detailed history regarding name, age, sex, address, contact number, chief complaints with duration were recorded. Complete birth history, feeding history, dietary history along with antenatal history were recorded. The socioeconomic status of the patients was established based on the Modified Kuppuswamy scale. Complete examination including general and systemic examination and anthropometry was performed. All the data were then entered into a predesigned proforma for this study. Developmental assessment of these children was performed using Denver II Development Screening Test. Laboratory investigation included complete hemogram, peripheral blood smear and serum vitamin B12 levels.
Data were presented as frequency and percentages. Table 1 shows general characteristics of the study participants. Median age at presentation was 11 months. More than half (63.8%) of the children aged between 6 months and 15 months. Male to female ratio was 1.58:1. 78.7% were rural and 60% were from lower socioeconomic class. 85% of the children' family had vegetarian dietary habits.

Weight for age
Approximately 59% children' weight for age <-3 SD while only one child had weight for age >-1 SD (Table 2).

Clinical features
The most common clinical feature was hyperpigmentation of knuckles and skin (85% each) followed by depigmented and sparse hair (70%), and chubby face (42.5%) ( Table 3). Neurological manifestation In our study, 65% of the children were found to have neurological manifestations (Figure 1)

Figure 1: Absence or presence of Neurologic manifestations on presentation
Type of neurological manifestations The most common neurological manifestation was developmental delay (60%) followed by hypotonia (38.7%), exaggerated reflexes (31.2%), and abnormal movements (20%) ( Table 4).  In our study, apart from pallor (seen in 100% patients), the most common clinical findings were hyper-pigmented skin (85%), pigmentation of distal extremities (85%), sparse and de-pigmented hair (70%) and angular chelosis/glossitis (21.8%). These findings were more common in those with severe deficiency compared to those with mild to moderate deficiency. Previous studies have reported these clinical features in a varying percentage of patients. Goraya et al 6 reported skin hyperpigmentation and sparse and depigmented hair in all 27 patients (100%). Jain et al reported knuckle hyperpigmentation in 5 (35%) cases out of 14 patients. 5

Conclusion
Neurological manifestations are indeed the most common and important clinical presentation of vitamin B12 deficiency syndrome. There is an urgent need to focus on evaluation of vitamin B12 as a routine test in early childhood.