Intracranial Hemorrhage Caused by Vitamin K Deficiency Beyond Neonatal Period

Vitamin K deficiency bleeding (VKDB) can manifest as intracranial hemorrhage (ICH) and is still prevalent in poor resource countries. Infants aged one to twelve months with the diagnosis of ICH from 1st July 2011 to 30th June 2016 were included. There were 16 cases of ICH attributed to vitamin K deficiency. Clinical presentations were anemia16 (100%), bulged fontanel 13(81.3%), seizures 10(62.5%), vomiting 8(50%) and fever 9(56.3%). Mean INR at admission was 8.575±7.267 and 1.868±0.838 after three doses of vitamin K administration. Sites of intracranial bleed were parenchymal 5(31.3%), subdural 4(25%), extradural 2(12.5%), ventricular 2(12.5%). In 3(18.8%) of cases bleeding was more extensive involving more than one site. Mortality was 4(25%) and 3(18.8%) had abnormal neurological findings at discharge. There is an urgent need for national policy for vitamin K prophylaxis at birth.


Introduction
D efi ciency of vitamin K predisposes to bleeding and it can be divided into early, classical, or late vitamin K defi ciency bleeding (VKDB) according to their onset, early (<24 h), classical (days 1-7) and late (>1 week <6 months), and by etiology into idiopathic and secondary.In secondary VKDB, in addition to breast feeding, other predisposing factors are apparent, such as poor intake or absorption of vitamin K 1 .
Late onset VKDB occurs after 7 th day of life at neonatal period and is most commonly associated with intracranial bleeding, serious neurological sequelae and death 2,3 .Other common bleeding sites are gastrointestinal and umbilical.Late onset VKDB can be incidental fi nding in 6.6% cases without signs of any bleeding 3 .Administration of Vitamin K (1mg, IM) at birth can prevent these severe complications especially hemorrhage in the central nervous system 4 .
The median (interquartile range) burden of late VKDB is 35 (10.5 to 80) per 100 000 live births in infants who do not receive prophylaxis at birth; the burden is much higher in low-and middleincome countries as compared with high-income countries 80 (72 to 80) vs 8.8 (5.8 to 17.8) per 100 000 live births 5 .A study from south western Uganda has shown high prevalence of vitamin K defi ciency in mothers and newborns 6 .
Evidences show use of parenteral vitamin K prophylaxis can signifi cantly reduce the risk of VKDB when compared with no prophylaxis 5 .Multiple oral doses are also used but parenteral vitamin K is preferred 7 .Authors regard the eff ectiveness oral route inconclusive because most of the studies used biochemical indicators which lack correlation and scientifi c evidence 8 .In view of high burden of VKDB additional dose of vitamin K is suggested for all infants 2,9 .In breast fed infants, infants with liver disease, antibiotic uses and diarrhoea there is defi nitive role of additional doses 10 .In many developing countries vitamin K prophylaxis is not routinely administered 11 .There is limited information about spectrum of VKDB and lack of uniform policy regarding vitamin K prophylaxis from the developing countries.

Material and Methods
A retrospective study was conducted in the Manipal Teaching Hospital, Pokhara, Nepal from the data retrieved from the hospital records maintained in the medical records department.All infants in the age group 1 to12 months with the discharge diagnosis of ICH during the period of 1st July 2011 to 30th June 2016 were eligible.Other causes of ICH including trauma, vascular malformations, other bleeding disorders (haemophilia, liver disease, thrombocytopenia, DIC) were excluded.Patient details including age, sex, presenting complains, physical signs, laboratory parameters haemoglobin levels coagulation profi le, international normalized ratio (INR) at admission and at 72 hours were also retrieved.CT scan reports were collected to note site of intracranial bleed.Final outcome, discharge with or without neurological defi cient, left against medical advice (LAMA) or death were recorded.Infants had received 5 mg daily doses of vitamin K for minimum of 5 days or till INR was normalized.Supportive treatment was given for features of raised intracranial pressure and seizures were treated with phenobarbitone, phenytoin and benzodiazepines.Data analysis was done using SAS University Edition and Microsoft Excel 2008.Continuous data was presented as mean and S.D. and categorical data expressed as frequency, percentage and 95% confi dence interval.

Discussion
VKDB especially classic form can be prevented by prophylaxis at birth.Intracranial haemorrhage due to VKDB causes signifi cant mortality and morbidity 3,9,10 .Neurological defi cits including developmental delay, epilepsy, blindness, strabismus, spastic paresis, growth retardation and hydrocephaly have been described in surviving infants 10 .
Mean age of presentation was 2.36± 1.97 months and ICH was more common in males (62.5%) compared to females (37.5%).Most of the infants 13 (81.25%)had not received prophylaxis at birth.Altered sensorium and pallor were universal presentation.Low haemoglobin concentration with mean haemoglobin concentration of 5.78± 1.5 gm/dl was correlated with clinical fi nding and one feature suspicious of ICH.Coma is most common symptom and Demiroren et al reported coma in 74% of patients.Bulged fontanel in infants was reliable sign and present in 81.25% of ICH.Earlier studies described bulged fontanel in 60-70% of infants with ICH 10,13,14 .
Seizures were present in 62.5% of patient in this study slightly higher than earlier studies by 58% Demiroren et al and 49% by Özdemir et al 10,13 .Half of the infants had vomiting earlier studies noted vomiting in 45% patients 10,13 .Nine (56.3%) children were febrile on admission.Fever is common symptom even in the absence of sepsis and Yilmaz et al had also described 40% patients with ICH febrile 12 .
In a bleeding infant a prolonged PT together with a normal fi brinogen level and platelet count is almost diagnostic of VKDB; rapid correction of the PT and/ or cessation of bleeding after VK administration are confi rmative 1 .There was prompt response to parenteral vitamin K and INR declined from baseline 8.57±7.2 to 1.86±8 after 48 hours.Parenchymal bleed was most common followed by subdural, multiple intracranial sites, extradural, ventricular in the present study.Earlier studies also mentioned parenchymal as most common ICH site 1,10,12 .However, another study described subdural as commonest bleed site 13 .Mortality was noted in 25% in patients with in ICH due to VKDB in this study.Demiroren et al and Yilmaz et al described mortality of 32 % and 32 % respectively 10,12 .In another study from Bastent university hospital mortality was higher 50%, however, in their cohort 58.33% had undergone surgery 13 .A One third of patients (37.5%) were discharged without frank neurological defi cit while 18.8% patients had neurological defi cient including hemiparesis, monoparesis, and cranial nerve palsy.Outcome of 18.8 % patient was unknown as they were discharged against medical advice.Finding from current study highlights urgent necessity for steps in prevention of VKDB.

Conclusion
Intracranial hemorrhage due to VKDB causes signifi cant mortality and morbidity.Diagnosis of ICH can be easily established with clinical features, neuroimaging with the supplementation of laboratory fi ndings.Parenchymal bleed is the most common bleeding site.We recommend large prospective multicenter study to know disease burden in Nepal.There is an urgent need for a national policy for vitamin K prophylaxis at birth.

Fig. 1 :
Fig. 1: Image Ia -Parenchymal bleed in left temporo-parietal region with subdural and subarachnoid extension and midline shift.Image Ib Parenchymal bleed in right frontal regional with perifocal edema and subarachnoid and subdural extension.

Table 1 :
Clinical presentations seen in the series.

Table 2 :
Laboratory fi nding of patients with Intracranial bleed.