A CROSS SECTIONAL STUDY OF EFFECT OF ANTICONVULSANT THERAPY ON

CALCIUM HOMEOSTASIS

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1 INTRODUCTION

2 REVIEW OF LITERATURE

3 AIMS & OBJECTIVES

4 MATERIALS & METHODS

5 RESULTS

6 DISCUSSION

7 CONCLUSION

8 LIMITATIONS

9 BIBLIOGRAPHY

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Glossary Abbreviations

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INTRODUCTION

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INTRODUCTION

Epilepsy is a chronic neurological disorder affecting people of all ages and ethnicities.

Clinically it may include sudden, transient abnormal manifestations such as motor, sensory,

autonomic responses and alteration in consciousness or in behavior. Seizures usually occur for a

brief duration and may cause post seizure residual effects such as an impairment in the

consciousness levels. 1

Literally, the word epilepsy is derived from the Greek root word ‘Epilambanein’. This translates

to meaning ‘to be seized’ or ‘to be overwhelmed with surprise. Mentions of epileptic disorder

can be traced back to ancient times as far as 4000 years back. Many theories had been postulated

regarding the causes and manifestation of epilepsy across various global cultures.

The manifestations of epilepsy such as the forced cry, falling to the ground, twitching, and jerky

movements have been long since thought due to caused be possession with the spirits. In some

cultures, people with epilepsy have been stigmatized, while in some others, they were thought to

be chosen or being possessed by gods. In some regions, epilepsy has even thought to be

contagious, this leading to people hesitating to touch patients of epilepsy when they have a

seizure episode. The associated stigma mostly leads to exclusion of the affected persons from

society. This has a great impact especially in the education of children and the young, further

adding on to the economic burden of the society. 2

Epilepsy has been defined by International League Against Epilepsy (ILAE; 1993) as a condition

characterized by recurrent (two or above) epileptic seizures, unprovoked by any immediate

identified cause.3 According to Cowan et al,4(2002)

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epilepsy is considered to be a heterogeneous group of neurological disorders characterized by

unprovoked, recurrent and paroxysmal seizure activity.

A study on the Indian perspectives regarding epilepsy was conducted by Santhosh N.S et

al.5(2014). They mention that the burden epileptic disorders among low-income countries is

almost twice than that among high income countries. In addition, the mortality due to epilepsy is

higher among low income countries, since untreated epilepsy is common. Untreated epilepsy in

turn, was often found to be associated with reduced awareness, or stigma related to the disease

leading to delays and inadequate seeking of health care.

Amudhan et al. 5(2015) continuing from the same study, mention that despite improvements in

education and social parameters over time, there has been not much significant change regarding

the stigma and discrimination in epilepsy patients. They mention that there is a vicious cycle

between economic burden and poor disease outcome among epilepsy patients.

As per the WHO estimates, epilepsy is easy to treat with daily medications that are relatively

less expensive. In both low and middle income countries, up to 70% of the patients can be

successfully treated. Even though epilepsy is mostly treatable, 75% of the people in developing

countries do not receive the treatment they require. This is called the treatment gap. This is due

to varying reasons such as lack of trained staff, reduced availability of medicines and traditions,

stigma etc. This contributes to overall mortality and morbidity among patients with epilepsy.6

Since epilepsy and its treatment are lifelong, it causes alterations in body’s physiology. One of

the major impact is on the bone mineral metabolism and Vitamin D levels. There is growing

evidence indicating the multi-pronged effect of epilepsy and anti-epileptic drugs on the bone

mineral density and serum levels of calcium, phosphate, alkaline phosphatase and Vitamin D3

7

levels. There are studies which show that (Pack A.M) patients on anti-epileptic drugs are more

prone for fractures and abnormal bone mineral metabolism.

Awareness on such factors is essential during the treatment of epileptic patients in order to

reduce lifelong morbidity and mortality. But despite the overwhelming evidence there still

remains a lack of consensus among the treating neurologists with respect to bone health and

Vitamin D levels of epilepsy patients. Studies have shown that only 28% of the adult

neurologists routinely evaluate the bone health among epileptic patients and among them only

57% refer patients to the specialists concerned. Only 7% of the neurologists routinely

supplement calcium and Vitamin D in patients on anti-epileptic drugs.7

Many studies recommend prophylactic supplementation of calcium and Vitamin D along with

regular monitoring of Vitamin D3 levels among epileptic patients on anti-epilpetic drugs. Yet,

the dose and standard guidelines have not been yet developed. The studies conducted so far have

been performed only in Western Countries. There is still a lack of studies assessing the bone

health of epileptic patients in developing countries such as India where the burden of epilepsy is

much higher.

Hence epilepsy as such as a major public health concern. Reducing the health complications of

epileptic patients during the course of treatment can provide an improved quality of life. Cost

effective options such as the early assessment of bone health and providing the necessary

treatment can thus reduce the complications and would be beneficial for patients suffering from

epilepsy. This study seeks to assess the same.

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AIMS & OBJECTIVES

AIMS AND OBJECTIVES:

To study the prevalence of calcium homeostasis abnormalities in patients on chronic anticonvulsant therapy.

To assess serum Vitamin D level in patients on chronic anticonvulsant therapy.

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REVIEW OF LITERATURE11

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REVIEW OF LITERATURE:

Epilepsy: Definitions/ types

As per recent International League Against Epilepsy (ILAE, 2014)8, The diagnosis of epilepsy be

considered as a disease of the brain defined by any of the following conditions

At least two unprovoked (or reflex) seizures occurring >24 h apart

One unprovoked (or reflex) seizure and a probability of further seizures similar to the

general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the

next 10 years

Diagnosis of an epilepsy syndrome.

Epilepsy is considered to be resolved for individuals who either had an age-dependent epilepsy

syndrome but are now past the applicable age or who have remained seizure-free for the last

10 years and off antiseizure medicines for at least the last 5 years. "Resolved" is not necessarily

identical to the conventional view of "remission or "cure." Different practical definitions may be

formed and used for various specific purposes. This revised definition of epilepsy brings the term

in concordance with common use. 8

This above definition implies that during an episode of seizure, a large number of neurons in

the brain are activated in an abnormal way at the same time. Various etiologies can play a role in

deciding the nature of the seizure. Some of them are, the person’s age, sleep-wake cycle, brain

trauma, genetics, intake of certain drugs etc.

There have been various attempts at classifying epilepsy over time. Initially they were classified

as grand mal and petit mal seizures but they were loose terms. Then, for more than 35 years,

generalized and focal seizures were the terms used to classify. This was based on whether seizure

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activity started on one or both sides of the brain. Partial seizures in turn was classified into

simple partial and complex partial seizures depending on the presence of consciousness or

impaired consciousness respectively during the episodes.

The revised classification for epilepsy is based on three components occurring during the

episodes namely:

1. The place of origin of seizure activity within the brain

2. Level of consciousness during the episode of seizure

3. Other key features

Depending on the place of origin of seizures, seizure is classified into:

Focal seizures: Starts in the neural network in one brain hemisphere.

Generalized seizures: Both hemispheres are involved during the onset of seizures

Unknown: The place of onset cannot be found out. But later, the point of origin may

be localized.

Based on the level of awareness the patient has, during a seizure, it may be further classified into,

Focal aware: Despite a person not being able to talk or respond during a seizure, in case

their awareness remains preserved, it is called focal aware seizure.

Focal impaired awareness: If the level of awareness is affected or impaired at any point

during an episode of seizure, it is called focal impaired awareness. This persists even if

the patient retains a vague idea of what happened.

Awareness unknown: In case, the level of awareness cannot be found out from history

taking during the seizure episode, it is called awareness unknown.

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Generalized seizures: This type of seizure episodes invariably affects the patient’s level

of consciousness to a certain extent. Hence this type does not have any specific terms to

describe seizure episodes.

Depending on the symptoms the person experiences during the seizure episodes, seizures are

further classified into:

Focal motor seizure: Some type of motor activity such as twitching, jerking or

automatisms occur during the seizure episode.

Focal non-motor seizure: Changes in sensory experiences, emotions etc. occur during the

episode.

Aura: The earliest symptoms a person may experience which herald the impending

seizure episode.

Generalized seizure on the other hand, can be classified into

Generalized motor seizure: This term corresponds to the previously used terminology

‘Generalized tonic clonic seizure’.

Generalized non-motor seizure: Absence seizures are mostly included under this

classification.

Most classification thus, are by the signs and symptoms. Additional information such as video

records, EEG, MRI scans can also be used if they are available. Genetic syndromes can also be

included in the classification.3

Global burden of epilepsy:

The prevalence of epilepsy varies across the world and affects all ethnicities, age and gender.

Despite its global occurrence it is still under explored in many parts of this world. The World

Health Organization’s project atlas is one of the major undertakings along with the International

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League Against Epilepsy to quantify the disease burden. The prevalence of epilepsy varies with

each country. High prevalence occurs among the adolescents and in the pediatric age group.2, 6, 9

Despite the data in prevalence, very less data is available regarding the incidence of epilepsy in

low and middle income countries. In general, the incidence rate is higher in developing countries

than among developed countries. The overall prevalence of epilepsy has been estimated to be

around 10 per 1000 persons. 10

According to the estimates by the World Health Organization (WHO), around 50 million

people all over the world are affected by epilepsy and it has been recognized as the most

common neurological disorder at the world level.

Four-fifths of the world’s population of epileptic individuals live in the low and middle income

countries such as India. Epilepsy was estimated to be responsible for 0.5% of the global burden

of disease. It accounts for 7,307,975 disability adjusted life years (DALYs) in 2005. More than

half of the world wide burden of epilepsy occurs in 39% of the population found in the

developing countries. These countries also have the highest levels of mortality.

Around 4 to 10 individuals per 1000 population have been estimated to have active epilepsy at

any point in time. This proportion can increase up to 7 to 14 in the case of low and middle

income countries. All over the world, 2.4 million people are being diagnosed with epilepsy each

year. This translates to 30 to 50 cases per 1000 population in the case of high income countries

and twice higher in low and middle income countries.

In addition, the WHO atlas in epilepsy states that the annual incidence of epilepsy ranges from

24-53 cases per 100,000 population among developed countries. In developing countries, there

are no prospective studies available for the incidence of epilepsy. The available data indicates a

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prevalence of 49.3 to 190 cases per 100,000 population. The causative factors such as trauma,

birth defects are higher in developing countries. But the data is difficult to interpret and compare

since there is a lack of age adjustment and epilepsy usually has a bimodal peak with age.

On the world level, the incidence rates are higher among women. In developed countries, the

incidence rates are rising among the elderly and decreasing among the children. This increase in

prevalence among elderly is due to the increase in life expectancy and the consequent rise in

prevalence of cerebrovascular diseases. The decreasing prevalence among children is due to the

availability of better obstetric and neonatal care and the control of infections.

The prevalence of individuals with active epilepsy is higher among regions such as Sub-Saharan

Africa, Central and South America. The prevalence is higher among rural than in urban areas.

The reported increase in prevalence may be attributed to factors such as methodological

differences, increased consanguineous marriages and other environmental factors. Data

regarding prevalence are mainly useful for postulating the probable etiologies for epilepsy. 9

With respect to Asian countries, studies indicate that the prevalence in the country of China is

3.6 per 100 population. The prevalence was 3.65 per thousand males and 2.5 per 1000 in

females. In town areas, the prevalence was 2.45 per 1000 and rural areas, it was much higher at

3.7 per 1000 population. 11The prevalence of generalized tonic-clonic seizures was 3.12%, partial

seizures was 0.57% and unclassifiable seizures was 0.23%. The incidence rates of epilepsy range

from 28.8 per 100,000 to 35.0 per 100,000 annually.12

Studies estimate that the prevalence of epilepsy in Bangladesh is around 1.5 to 2 million. It

comes to 10 to 20 cases per 1000 population and is most common in the young adult age group

between 16 to 31 years. The prevalence is found to be somewhat higher than among the

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neighboring countries.The prevalence is high among the males and generalized seizures is the

predominant type of seizure, similar to China. .13-15

The prevalence of epilepsy in Europe has decreased over time. Studies mention that the

prevalence of epilepsy which is 6.2 per 1000 population according to 2010 statistics, was

previously 7.1 per 1000 in 1994 and 7.6 in 1999. Generalized seizures is prevalent among 60%

of the population, 12% had mixed tonic, clonic seizures, 3% had simple partial seizures and less

than 5% had absence seizures. The incidence rate in epilepsy in United Kingdom is 47 per

100,000 population. 16-20

Among African countries, data collection is a major area of difficulty. A questionnaire survey

was conducted among the tropical countries. Based on the results, the average prevalence of

epilepsy was quite high at 15.83 per 1000 population. (M.DC) The prevalence had a high

variability ranging from 2.2 to 58 per thousand population. Sudan had a low prevalence rate at

0.9 per 1000 population.21 Active epilepsy had a bimodal peak at 20 to 29 years first when the

prevalence was 11.5 per 1000. The second peak was at 40 to 49 years of age with prevalence of

8.2 per 1000 population. Those with age 60 or more had the lowest prevalence of epilepsy at 3.1

per 1000 population. 13, 14, 22

Very few of the studies assessing the burden of epilepsy are conducted in Asian countries

despite the fact that epilepsy is highly prevalent in these regions. Mac et al.23 mention that the

estimates on the prevalence of epilepsy appear to be low in general and were collected mostly by

door to door surveys. These estimates are available for only 11 countries. Figures for yearly

incidence in countries such as China and India are similar to the developed nations such as

Europe and America, but are lower than Africa and Latin America. The peak during childhood

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and young adult age group is similar to the developed nations, but the secondary peak at old age

is not yet reported in Asian countries.

In view of all the above studies assessing the burden of epilepsy, there are comparatively lesser

number of studies on the distribution of epilepsy based on race and ethnicity. Theodore et

al.24(2006) studied the prevalence of epilepsy comparing the African-Americans and the

Caucasians. The age adjusted prevalence of African-Americans was higher at 8.2 per 1000

compared to the Caucasians who had an age adjusted prevalence of 5.4 per 1000 population.

According to another study by Bharucha et al.25(1998) the prevalence of active epilepsy among

South Asians was comparatively lower than among non-South Asians. According to Wright et

al.26(2000), the differences in this prevalence may be attributable to multiple factors such as the

availability of preventive health care services, infrastructure and the risk of infections.

Burden of epilepsy in India:

One of the earliest studies on the epidemiology of epilepsy in India was carried out by Sridharan

R. et al.27 (1999). The overall crude prevalence was estimated to be 5.35 per 1000 population.

The adjusted prevalence was 5.59/1000. The prevalence was lower among rural (4.94/1000) than

in urban areas (6.34/1000). Men had a higher prevalence (6.05/1000) compared to women

(5.18/1000). The younger age had higher age specific prevalence rates. More than 70% in the

rural areas with epilepsy were either not receiving treatment at all or were receiving inadequate

treatment. They mention that the projected number of annual new epilepsy cases would be

around 0.5 million. This will further add on to the treatment gap existing in rural areas.

Iyer R.S et al.28 (2011) studied the primary care management practices for epilepsy among

doctors in the state of Kerala in India. They mention that very few doctors diagnosed focal

seizures and diagnostic modalities such as electroencephalograms were overused. Continuous

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anti-epileptic drug prophylaxis was prescribed for febrile convulsions and suboptimal doses were

mostly used for management of epilepsy. Most doctors were not found to be aware of alternate

management options in case of drug resistant epilepsies. Hence they recommend that educating

the primary care physicians is essential for reducing the treatment gap in case of epilepsy in

India. Moreover, educating on anti-epileptic drugs and the need based referral system were also

found to be an area of focus. There are various studies assessing the burden of epilepsy in India.

A hospital based study was conducted by Panagariya et al.29 (2014) in North-West India. They

assessed the clinical profile and the response to drug therapy among epilepsy patients in a

tertiary care centre. The study was conducted over a period of 5 years. Among the patients with

epilepsy male: female ratio was 2:1. Around 62.83% of the patients were from the lower socio

economic status. Once initiated on treatment, most patients were seizure free after 2 years.

Pandey S. et al.30 (2014) conducted a study on epilepsy among the younger age group of 1 to 18

years. According to this study, the prevalence rate of epilepsy was 6.24 per 1000 population.

Febrile seizures and neurocysticercosis were the two most important etiologies of childhood

seizures. They mention the need for an effective community based approach in managing

epilepsy during childhood.

Banerjee T.K et al.31 (2015) mention that between 2003 and 2004 the overall prevalence of

epilepsy was 4.71 cases per thousand population in the region of Kolkata. The annual incidence

of epilepsy after adjusting for age was 38.3 per 100,000 population. They all cause standardized

mortality ratio due to epilepsy was 2.4. With respect to the quality of life and life expectancy,

epilepsy was responsible for 755 per 100,000 years of life lost (YLL) and 14.45 to 31.10 years of

life lost to disability (YLD) per 100,000 population. In both cases, males had higher values than

females. On the whole, the disability adjusted life years (DALY) lost due to epilepsy was 846.96

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in 2007-08. Males had a significantly higher value of DALY at 1183.04 compared to females

(463.81) per 100,000.

Hara. H.S et al.32 (2015) conducted a population based epidemiologic study to assess the burden

of epilepsy in Punjab. They performed a door to door survey in a rural population of more than 1

lakh individuals. According to this study, the crude period prevalence of epilepsy was 7.67, and

point prevalence was 7.44 per 1000. The crude incidence rate was 60.76 per 100,000 during in

2007. In this study, there was no significant difference in active epilepsy when compared

between genders. The prevalence of active epilepsy was found to be 14.7% and symptomatic

epilepsy was 19.2%. A majority 64.5% of epilepsy cases had an undetermined cause and 1.5%

had a dual diagnosis.

Megiddo.,I. et al.33 (2016) mention that 6 to 10 million people in India are living with active

epilepsy and among them, less than 50% receive treatment. With respect to the health and

economic consequences, public financing for anti-epileptic treatments could help avert around

800,000 to 1,000,000 Disability adjusted life years in India when compared to current situation

where the majority of expenses are out of pocket. If public financing continued for 10 years,

households save more than 80 million US dollars in the form of medical expenses. They mention

that public financing for first and second line anti-epileptic drugs along with surgery is a cost-

effective and a practical option across the Indian states.

Epilepsy can be a very important public health issue among developing countries. This was

suggested by Senanayake N and G.C Roman34(1993) in a study on the epidemiology of epilepsy

among developing countries. In such countries, the prevalence of epilepsy has been estimated to

be up to 57/1000 population. In countries such as India, lack of infrastructure, infections such as

neurocysticercosis, birth injuries, road traffic accidents etc. contribute to the high burden of the

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disease. They also mention that many such risk factors are modifiable and hence there is an

increasing need for addressing this issue among developing countries.

Common etiological causes of convulsions:

Epilepsy is heterogeneous in its etiopathogenesis. The causative factors vary between developing

and developed countries due to the varying distribution of risk factors. The etiologies can be

broadly classified into genetic and acquired.

The predominantly genetic or developmental causes are:

1. Genetic mutations/polymorphisms

2. Malformations of cortical development

3. Cavernous and arteriovenous malformations

4. Neurocutaneous syndrome.

The acquired causes include:

1. Brain tumors

2. Traumatic epilepsy

3. Parasitic brain infections

4. Bacterial/viral infections of the nervous system

5. Perinatal adverse events

6. Hippocampal sclerosis

7. Cerebral immunologic disorder

8. Stroke

9. Alzheimer’s disease

Many gene mutations are associated with epilepsy, yet they still remain a minor contribution to

the proportion of epilepsy cases. Some of the strongest indications that, the risk of epilepsy

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among monozygotic twins is 62% and 18% in dizygotic twins. (Johnson, Lopes) This

concordance is significantly much more for idiopathic and symptomatic generalized epilepsy

than it is for partial seizures. This indicates that syndrome specific genetic determinants may be

operational in determining the risk of epilepsy. 35

The mechanisms involved in the genetic association with epilepsy may include death of neurons,

alteration in neuronal excitability as well as a synergism of genetics and environmental factors.

Epilepsy occurs in certain chromosomal abnormalities as well. 36

Benign or malignant brain tumors are associated with a 30% incidence of epilepsy. The risk for

developing brain tumor associated epilepsy is higher among adults than in children. This depends

on multiple factors such as the grade of the tumor, location, hemispheric dysfunction or an

incomplete surgical removal of tumor.

Brain injury is yet another major cause of epilepsy. In a population based study conducted by

Hauser WA et al.37 (1993), it was reported that among 6% of the population with epilepsy, head

trauma was the causative factor. In general, around a fifth of the epilepsy cases are associated

with a history of previous brain injury.38The risk of developing epilepsy varies with the degree of

injury.

Infectious causes such as meningitis caused by viruses or bacteria is yet another etiology for

epilepsy. Despite the reduction in mortality rates over the years due to better access to health

care and immunizations, the persistence of neurologic sequelae after bacterial or viral meningitis

causes further morbidities. After bacterial meningitis, many children are left with neurologic

residual effects. Even after a year, a proportion of the children are left with onset of seizures

which were not associated with fever.39The 20-year risk of developing unprovoked seizures was

found to be 22% for those who had viral encephalitis as well as seizures early during the fever.

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But the risk of epilepsy for those with aseptic seizures was similar compared to the general

population.40

Another more important cause of epilepsy in endemic regions such as India and South America

is neurocysticercosis. In countries such as Peru, neurocysticercosis is responsible for around 30

to 50% of all the cases of epilepsy. In these places, nearly half of the population live at the risk of

infection with Taenia solium. Calcified cysts due to neurocysticercosis are the causative agents

for epilepsy. In addition, there can be a delay between the onset of infection and the occurrence

of seizures in patients. This in turn, depends on factors such as the pathogenicity of Taenia

solium, the genetic strains and the predisposition of the host to develop epilepsy. 41, 42

Among the elderly population, one of the most important risk factors for epilepsy is stroke. One

third of the epilepsy cases among the elderly is due to stroke. Among those who have had stroke,

around 2 to 4% develop epilepsy at some point later on in life.43, 44 The risk factors for developing

epilepsy in stroke depend on several factors such as the type of stroke, the location of the stroke

and the disability caused due to it.

In a study by Bladin CF et al.45 (2000), among all patients with stroke, 8.9% developed seizures.

Among those with hemorrhagic stroke, 10.6% developed seizures and among those with

ischemic stroke 8.6% developed seizures. Recurrent seizures were present among 2.5% of the

stroke patients. Late onset of the first seizure episode was an independent risk factor for

developing epilepsy.

Another factor strongly associated with the risk of epilepsy is chronic alcohol consumption.

According to a study by Samokhvalov AV et al.46 (2010), a strong association with a relative risk

of 2.19 is found between chronic alcohol consumption and epilepsy. Moreover, the risk of

acquiring epilepsy increased with the increase in dose of alcohol consumed. Seizures among

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alcoholics include alcohol withdrawal seizures and other seizures with mechanisms other than

withdrawal.47Many of the alcohol users with epilepsy were also found to have alcohol

dependence. Most of them experience generalized tonic-clonic seizures. 48

In developing countries like India, an important risk factor for childhood epilepsy is adverse

events occurring perinatally such as sepsis, birth asphyxia and cardiovascular insufficiency.

49Among term infants, cerebral palsy can occur in situations with or without encephalopathy.

Among those who had newborn term encephalopathy, 13% had cerebral palsy. In addition,

cognitive impairment and epilepsy were found to be common and severe among the survivors

compared to those who did not have encephalopathy during the newborn period. 50

Anticonvulsant agents:

Once a patient has been diagnosed with epilepsy and a decision has been made regarding the

starting of treatment, the choice of anticonvulsant depends on multiple factors. Some of them

include the type of seizures, the beneficial, adverse effects and the patient profile. If the drug

levels are carefully monitored and maintained at the therapeutic levels, it is possible to achieve

adequate seizure control and at the same time, minimize adverse effects. In addition, special

situations such as febrile seizures, pregnancy and status epilepticus necessitate additional

considerations as well.

Medical management of epilepsy has multiple reasons. Some types of seizures such as

generalized tonic-clonic seizures pose a significant risk of permanent brain injury or death.

Recurrent episodes of seizure is detrimental to the intellectual function. Untreated seizures

worsen with passing time and status epilepticus is associated with a 20% increased risk of

mortality. Other types of seizures such as absence seizures and partial seizures lead to temporary

decrease in the intellectual performance in addition to the risk of injury. 51

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An ideal drug for the management of epilepsy is expected to have adequate control of seizures

without affecting the mood, sleep, intellect, physical performance and arousal response. Since

epilepsy is the result of neurons firing abnormally in the brain, it is difficult to find a drug that

selectively affects neurons causing seizures while sparing the normal neurons. In some instances,

there needs a trade-off between achieving seizure control and minimizing the adverse effects of

drugs.

Classification:

According to the structural chemistry, the anti-epileptic drugs may be classified as follows:

i) Barbiturate: e.g Phenobarbitone, Primodone, Mephobarbitone.

ii) Hydantoins: Phenytoin, Fosphenytoin, Mephenytoin, Phenyl Ethyl Hydantoin.

iii) Oxazolidinediones: Paramethadone, Trimethadone.

iv) Phenacemide: Phenacemide, phenyl ethyl acetyl urea.

v) Benzodiazepines: Nitrazepam, Clonazepam.

vi) Iminostilbenes: Carbamezepine

vii) Miscellaneous: Ethoxzolamide, Sodium valproate, Sulthiame.

According to the mechanism of action, anti-epileptic drugs are classified into:

i) Modulation of ion channels in the neurons: e.g Lamotrigine, Carbamezepine,

Ethosuximide, Zonasemide.

ii) Potentiation of the inhibitory action of γ-amino Butyric Acid: Phenobarbital,

Benzodiazepines, Tiagabine, Vigabatrin.

iii) Drugs having multiple mechanisms of action: Valproic acid, Gabapentin, Topiramate.

iv) Other mechanisms of action: This includes newer drugs such as Levetiracetam.52

Mechanism of action of anticonvulsant drugs:

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The mechanism of action of anticonvulsants is not very clearly understood in its entirety. Most

of them have been postulated to act via molecular mechanisms in order to selectively affect the

epileptogenic neurons. It blocks such neurons without affecting the neighbouring normal

neurons. Three fundamental mechanisms have been recognized so far at the cellular level.

i) Modulating the voltage gated Sodium, Potassium and Calcium channels.

ii) Enhancing the Gamma Amino Butyric Acid mediated inhibitory neurotransmission.

iii) Attenuating the excitatory transmission of neurons

iv) Affecting the ionotropic glutamate receptors.

Sodium and potassium channels are responsible for excitation while Potassium and Chloride

channels are responsible for inhibition.

Phenytoin is a drug of the hydantoin class. It is one of the first line drugs for generalized tonic-

clonic and partial seizures. Phenytoin acts mainly on the voltage gated sodium channels. It

prolongs the inactivated state of the sodium channel thereby enhancing the refractory period of

the firing of neurons. It has also been postulated to block high voltage calcium channels for

reducing the release of Glutamate which an excitatory neurotransmitter. 53

Carbamazepine is one of the members of the family of tricyclic antidepressants. This has more

value in partial and generalized tonic-clonic seizures. Some of its implicated mechanisms of

action include prolonging the inactivated state of Sodium channel and inhibitory action on the

Glutamine mediated neurotransmission.

Lamotrigine is derived from Phenyltriazine which is a member of Folate antagonists. The

predominant site of action is on the sodium channels which get blocked due to the action of the

drug. Lamotrigine has both pre-synaptic and post-synaptic action. Pre-synaptically, the release of

excitatory neurotransmitter is blocked. Post-synaptically, the action is similar to other

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anticonvulsants. It reduces the excitability of neurons. Initially lamotrigine was useful as an

additional therapy. But now it is being used as a single drug as well.

Oxcarbazepine is similar to carbamazepine in chemical and therapeutic profile. On the other

hand, the bioavailability and tolerability are better than carbamazepine. The mechanism of action

is inhibition of fast voltage gated sodium channels. It has additional actions on calcium and

potassium channels.

Ethosuximide is the drug of choice in absence seizures. The chief site of action of the drug is on

the thalamo-cortical system which is responsible for absence seizures. Zonisamide blocks

sodium channels. It also decreases the voltage dependent T currents and decrease the glutamate

induced synaptic excitation. It also serves as a weak carbonic anhydrase inhibitor.

Phenobarbitone is the first anti-epilpetic drug to be introduced. But now the use has reduced due

to its cognitive and behavioral side effects. Phenobarbitone has allosteric activation of the GABA

receptor and thus prolongs the duration of opening of the chloride channels. In addition, it has

other mechanisms of action such as blocking of voltage gated calcium channels and inhibiting

the excitatory glutamate receptor. 54

Benzodiazepines are widely used throughout the world. Among benzodiazepines, the drugs

commonly used in epilepsy are clonazepam, clobazam, lorazepam and diazepam. This is one of

the important drugs used in the management of acute epileptic attacks. The site of action is on

the alpha subunit of the GABA receptor. The duration of the channel conducting is not affected

but the frequency of opening of the chloride channel is opened. 55

Vigabatrin was initially used in the management of partial seizures. It inhibits the enzyme

GABA transaminase which causes the breakdown of the inhibitory neurotransmitter GABA. This

is useful especially in patients who do not respond to the other medications. 56

28

Tiagabine is an anti-epilpetic drug which inhibits the uptake of GABA into the membranes of

the synaptosome, neurons and the glial cells. It preferably enters into the glial cells than the

neurons. In addition, it selectively acts on the GAT-1 of the GABA transporter and potentiates

the inhibitory action mediated by the neurons. 57

One of the chief anticonvulsant drugs which has multiple mechanisms of action of sodium

valproate. Valproate is a branched chain carboxylic acid with a broad spectrum of actions.

Similar to phenytoin, it has a frequency dependent prolongation of the inactivated state of

sodium channel. In addition, it weakly attenuates the calcium ion mediated T current. Also, it

increases the synthesis of GABA from glutamic acid and enhances its inhibitory action.

Gabapentin is a newer drug widely used in the treatment of partial seizures. It crosses the blood

brain barrier and has an enhancing effect on the release of GABA. Gabapentin has additional

uses in the management of diabetic neuropathy pain and migraine prophylaxis.

Felbamate acts primarily on the NMDA subtype of the glutamate receptor. It also inhibits the

glycine induced increase in the intracellular levels of calcium. It has been approved for the

treatment of partial seizures. 58

Topiramate has a complex mechanism of action. It modulates the calcium influx in neurons

through AMPA and kainate type of receptors. It also modulates the action of voltage gated

sodium channels. Similar to zonisamide, it is also a weak inhibitor of carbonic anhydrase. 59

Levetiracetam is another newly developed drug which modulates the synaptic vesicular protein

SV2A. This in turn enhances the release of inhibitory neurotransmitters. There is experimental

evidence indicating that the basic cell functions and neurotransmissions are not affected by

levetiracetam. 60

29

Impact of anticonvulsant agents on calcium homeostasis:

The association between anticonvulsant drugs and calcium deficiency was under research even

during the 1970s. Bouillion R et al. (1975) measured the serum levels of calcium, Vitamin D and

parathyroid hormone among patients on anti-epilpetic drugs. Low serum levels of calcium and

Vitamin D3 was found among those on anticonvulsant drugs relative to the control group. After

treating them with oral Vitamin D3 for three weeks, even though the serum 25-OHD increased, it

was still subnormal and neither the serum calcium levels nor secondary hyperparathyroidism was

corrected. Hence they confirmed the deficiency of calcium among patients on anticonvulsant

therapy.

The low serum calcium levels is a result of low levels of Vitamin D. In a study by Richens A and

D.J Rowe.61 (1970) on patients taking anti-epileptic drugs, 22.5% were found to have subnormal

serum calcium and 29% had raised serum alkaline phosphatase levels. This was found to be due

to accelerated clearance of Vitamin D by the hepatic enzymes.

Hence, bone health among people on anti-epilpetic drugs is impaired. They are often at risk for

conditions such as changes in bone mineral metabolism, osteoporosis and increased risk of

fractures. Even though, women are more at risk for conditions such as osteoporosis, both genders

are equally at risk for anti-epilpetic drug induced bone disease. 62

Epilepsy itself is a major risk factor on poor bone health. This is due to many factors such as

restriction of physical activity due to seizures, co-morbid conditions that have neurological

deficits and falls due to seizures. Hence the pathogenesis of bone disease on epilepsy is more

complicated and multi-factorial. 63With the increasing utilization of anti-epilpetic drugs for other

non-seizure indications, the effect of these drugs on bone health is emerging as a threat to

millions of people worldwide. 64

30

Verrotti A et al.65 (2000) investigated the effect of carbamazepine on bone metabolism. They

compared patients on carbamazepine to health controls. They found that the markers of bone

formation such as serum levels of alkaline phosphatase, osteocalcin, propeptides of Type I and

III collagen were found to be more among those on carbamazepine compared to healthy controls.

Hence they concluded that carbamazepine results in increase bone mineral metabolism.

Erbayat Altay et al.66 in 2000, investigated the effect of Anti-epileptic drugs on Bone mineral

metabolism. They enrolled children with idiopathic epilepsy on Anti-epileptic drugs for more

than a year. The bone mineral density of children on Valproate and Carbamazepine did not differ

significantly from the control group. But the serum calcium levels were subnormal and alkaline

phosphatase levels were higher in children taking anti-epileptic drugs. Thus they concluded that

even though the Anti-epileptic drugs did not significantly affect the bone mineral metabolism,

routine monitoring of the risk of Vitamin D and calcium deficiency and supplementing the same

were important.

Sato Y et al.67 (2001) studied the effect of valproic acid an enzyme inhibitor on the bone mineral

metabolism. They compared the bone mineral densities among those on valproate monotherapy,

phenytoin and healthy controls. On analysis, 14% among those on valproate and 13% on

phenytoin had reduced bone mineral density compared to healthy controls. Among those on

valproate, 23% had reduced T-scores less than 2.5 which signified osteoporosis and 37% had

osteopenia. Serum levels of calcium were significantly higher among those on valproate

compared to the phenytoin and control groups. Serum levels of bone Gla protein which is a

marker for bone formation and pyrolidine cross linked carboxy-terminal telopeptide of Type I

collagen was significantly higher among both valproate and phenytoin groups compared to the

31

controls. Thus they concluded that long term therapy with valproate leads to reduced bone

mineral density despite valproate being an enzyme inhibitor.

Farhat D et al.68 (2002) mention that long term anti-epileptic drug usage causes multiple

abnormalities in calcium and bone metabolism. They evaluated those on anti-convulsant therapy

for at least 6 months and measured the serum levels of Vitamin D and bone mineral density. On

analysis, they found that the bone mineral density was significantly affected due to anti-epileptic

drugs. Duration of seizures and multiple drugs were some of the factors associated with a

decrease in bone mineral density. Hence they recommended regular monitoring of bone health

among those with epilepsy.

El-Haji Fuleihan G. et al.69 (2008) studied the predictors of bone mineral density among

ambulatory patients on anticonvulsants. They found that hypovitaminosis D was prevalent

among patients on anti-epilpetic drugs. Adults but not children had reduced bone mineral

density. Reduced bone mineral density was significantly associated with increased duration of

treatment. Both enzyme inducers as well as non-inducers resulted in reduced bone mineral

density. Enzyme inducers caused a severe reduction in bone mineral density at the spine and hip.

Hence they recommended identifying those at risk and regular monitoring of bone mineral

density.

Nakken KO et al.70 (2010) studied the pathology of bone loss due to anticonvulsants. They

mentioned that there is increasing evidence of the biochemical abnormalities which result from a

disturbed bone mineral metabolism, reduced bone mineral density and a two-fold to six-fold

times increased risk of fractures among those on anti-epileptic drugs when compared with the

general population. Among the anti-epileptic drugs, enzyme inducers such as phenytoin,

32

phenobarbitone and carbamazepine along with the enzyme inhibitor valproate significantly

affects bone mineral metabolism.

Even though the effects on bone health may not be apparent initially, reduced bone mineral

density occurs even during 1 to 5 years after the onset of therapy. The authors recommend that

clinicians promote bone protective behavior among those on anticonvulsants. The measures

include exposure to sunlight, weight training exercises and avoiding other factor which deplete

bone health such as smoking and alcohol. Dietary calcium and Vitamin D supplementation has to

be ensured. Regular monitoring of bone mineral density has been recommended as well.

Osteoporotic treatment should be initiated among those with pre-existing bone loss.

Meier C.et al. 71(2011) mention the mechanisms responsible for the reduced bone mineral

density due to anti-epileptic drugs. Anti-epilpetic drugs induce cytochrome p450 enzymes which

metabolize Vitamin D. This results in the accelerated conversion of Vitamin D to its inactive

metabolites. This in turn, causes reduced calcium absorption and subsequent secondary

hyperparathyroidism. They recommend prophylactic administration of Vitamin D and calcium to

all patients on anti-epileptic drugs. For patients who are on long term therapy on anticonvulsants,

bone mineral density measurement has been recommended. Among adults who are at increased

risk of fractures, bisphosphonates have been recommended.

Phabphal et al.72 (2013) sought to determine the association between the polymorphism of Bsml

gene for Vitamin D receptor and 25-hydroxy Vitamin D, bone mineral density and serum

calcium levels among those with epilepsy. Based on the findings, those with Bsml polymorphism

of the Vitamin D receptor gene had a significantly lower bone mineral density of the lumbar

spine and femoral neck compared to those with the wild type Vitamin D receptor gene. The

33

serum levels of 25-hydroxy Vitamin D levels were also significantly higher than those with the

wild type gene for the Vitamin D receptor. However, serum Parathyroid hormone levels were not

significantly correlated with the Bsml polymorphisms. Hence this might be an alternate

explanation why some patients may be more prone to anticonvulsant induced reduction of serum

Vitamin D3 levels.

Nicholas AM et al.73 (2013) studied the effects of anti-epilpetic drugs on the risk of fractures.

They followed up people on anti-epilpetic drugs and conducted a cohort study of 15 years

duration. On analysis they found that there were 7356 fractures among 63259 participants. In

women, the hazard ratio for fracture was 1.22 (95% C.I: 1.12 – 1.34) and 1.49 for hip fractures.

(95% CI: 1.15-1.94). In men, the hazard ratio for the same were 1.09 and 1.53 respectively. For

every 10000 women who were put on liver enzyme inducing anti-epilpetic drugs, 48 more

fractures would results which will include 10 more hip fractures. In the case of men, there would

be 4 more hip fractures. Hence they conclude that in addition to the effects on bone mineral

density, anti-epilpetic drugs increase the risk of fractures. Hence they recommend further

research to develop more strategies to manage bone health among those on anti-epileptic drugs.

Salimipour H et al.74 (2013) studied the effects of newer anti-epilpetic drugs on bone mineral

metabolism. They included the patients on anti-epileptic drugs and classified them into groups

based on the newer drugs vs. the older drugs and, enzyme inducing vs. non-inducing and

monotherapy vs. polytherapy. They measured bone mineral density among the patients and

compared them based on the above groups. They concluded that, regardless of the types of anti-

epilpetic drugs, enzyme inducer or non-inducer, patients on anticonvulsants showed a significant

reduction in bone mineral density. Patients on enzyme inducers should a significant reduction in

femoral neck bone density compared to those on non-enzyme inducers. Patients on

34

carbamazepine showed a reduced bone mineral density in the lumbar and femoral neck regions.

Patients on valproate and polytherapy had bone mineral density comparable to healthy controls.

Hence they mention that patients even on newer anti-epileptic drugs are at an increased risk of

reduced bone mineral density. They recommend regular preventive care and prophylaxis for

maintaining optimum bone health.

Razazizan N et al.75 (2015) studied the serum levels of calcium, Vitamin D and alkaline

phosphatase among children with epilepsy and compared them to healthy controls. Ambulatory

children who were on anticonvulsant drugs for at least 6 months were included and their serum

levels were measured. In contrast to other studies showing low Vitamin D levels among those

with epilepsy, the study participants had normal Vitamin D3 levels similar to healthy controls.

Only the alkaline phosphatase levels were elevated among those who were on anticonvulsant

drugs.

The effect of anti-epileptic drugs on bone health can be affected by confounding factors such as

dietary calcium. In order to study the patterns of dietary calcium intake among patients with

epilepsy, a study was conducted by Menon B et al.76 (2010) in Andhra Pradesh, India. According

to the results of this study, the dietary calcium intake of children and adolescents was far below

the recommended RDA of 400 mg/day by the Indian Council of Medical Research. This low

dietary was compounded by the presence of increased phytates and reduced proteins in the diet,

which may limit the intestinal absorption of Calcium. In addition, only 42% of the patients

consumed milk and milk products which are the chief sources of Calcium. Hence they

recommended calcium supplementation and fortification along with educational interventions in

order to improve the bone health among people with epilepsy.

35

Pettifor et al.77(2004) identified that infants and children living in tropics and subtropical regions

are at an increased risk of Vitamin D deficiency. The reasons for this are the deficiency of

Vitamin D and its metabolites in breast milk, inadequate sunlight exposure due to local customs

and traditions and low dietary calcium intake which is characteristic of cereal based diets. The

same applies to children of immigrants living in temperate countries, while those in equatorial

regions are spared due to adequate sunlight exposure.

In a study by Sonmez F.M et al.78 (2015), newly diagnosed epilepsy patients were included.

Their serum Vitamin D3 levels were compared to healthy controls. Even though there was no

significant difference in the levels of Calcium, phosphorus and alkaline phosphatase levels

between the two groups, the patients with epilepsy had significantly lower Vitamin D3 levels

compared to the controls. This difference held true even after making adjustments for seasonal

variations.

A systematic review of the literature on bone health among children with epilepsy was carried

out by Vestergaard P et al.79 (2015). According to the findings, monotherapy with carbamezipine

or valproate was associated with reduced bone mineral density. But therapy with phenytoin,

phenobarbital or levetiracetam did not find any significant association with bone mineral density.

Polytherapy was found to be associated with a greater decline in bone mineral density. The

effects of anti-epileptic drugs on bone health was further accentuated in the presence of low

Vitamin D levels. Hence the authors recommend routine supplementation of Vitamin D and

calcium among those on anti-epileptic drugs.

Aksoy D et al.80 (2016) studied the effect of Oxcarbazepine and Levetiracetam monotherapy

among patients with epilepsy. They concluded that on longitudinal follow-up, the Vitamin D3,

ionized calcium and serum calcium levels declined significantly than the control group. This in

36

turn led to bone loss, abnormal mineralization and fractures. Hence based on the findings, they

suggest regular assessment of Vitamin D3, calcium and ionized calcium levels among those with

epilepsy.

Arora et al.81(2016) mention that increased clearance of Vitamin D due to enzyme inducing anti-

epilpetic drugs may not be the sole reason for the reduced bone mineral density seen among

patients on anti-convulsant drugs. Reduced levels of Vitamin D is not consistently found among

all the patients, and increased bone metabolism may occur even in the absence of Vitamin D

deficiency. Reduced calcium absorption from the gut can occur due to reduced levels of

biologically active form of Vitamin D. This results in hypocalcemia and secondary

hypersecretion of Parathyroid hormone occurs. Hyperparathyroidism in turn, causes increased

bone resorption and thus reduced bone mineral density and increased risk of fractures. Other

proposed mechanisms include the direct effect of anticonvulsants on bone cells, resistance to the

action of parathyroid hormone, inhibiting the secretion of calcitonin and impaired absorption of

calcium. 82

Dura-Trave et al.83 (2017) investigated the Vitamin D levels in children with epilepsy taking

Valproate and Levetiracetam monotherapy. The serum levels of Calcium and 25- OHD were

significantly lower in the children with epilepsy compared to healthy controls. Hence they

recommended that Vitamin D status of children on anti-epileptic drugs such as Valproate should

be closely monitored, and providing Vitamin D supplements should be considered on a regular

basis.

Implications in treatment:

One of the earliest studies was an interventional study carried out by Jekovec-Vrhovsek M et

al.84 in 2000. They aimed at studying the effect of Calcium and Vitamin D supplementation on

37

bone mineral density among children with cerebral palsy who were on long term anti-epileptic

drugs. It was found that bone mineral density significantly improved among children who were

supplemented with Vitamin D and calcium compared to the group without any supplements.

Drezner MK et al. 85(2004) studied the management of bone disease due to anticonvulsant drugs.

They recommend prophylactic Vitamin D supplementation in a dose of upto 2000 IU/day for all

patients on anticonvulsants even from the initiation of treatment. Regular intake of calcium at

doses of 600 to 1200 grams per day need to be ensured as well. If the patient has osteopenia or

osteoporosis, supplementation with Vitamin D at a dose of 2000 to 4000 IU per day is needed.

Osteomalacia on the other hand, requires higher doses of Vitamin D up to 5000 to 15,000 IU per

day. If the patient’s response to Vitamin D supplementation is inadequate, bisphosphonates may

be given. But routine use of bisphosphonates are not recommended for those on long term

treatment with anti-epilpetic drugs.

Valsamis et al.64 (2006) conducted a study and recommended certain guidelines regarding

surveillance of bone health among children with epilepsy and measures for maintaining the

same. According to the results of this study, they do not recommend routine screening of bone

mineral density among children before the achievement of peak bone mass. However, they

suggest routine supplementation of Calcium along with Vitamin D among children regularly.

Bisphosphonates on the other hand, have been recommended only for adults and not for children,

considering the risks and benefits.

Furthermore they have mentioned that low calcium and Vitamin D deficiency are potentially

treatable factors and hence they should not be neglected. Inactivity which is common among

epileptic patients is another significant contributor leading to bone loss which should be

38

minimized. Despite the growing evidence regarding the effect of anticonvulsant drugs on bone

health, the authors mention that there was a lack of awareness among the treating physicians.

They also add that there are no definite guidelines so far regarding the screening and

management of Vitamin D deficiency and osteopenia among those with epilepsy.

Other conflicting evidences arise as well. In a study by Espinosa P.S et al.86 (2011), the

association between anti-epilpetic drugs on the bone fracture occurrence among anti-epilpetics

was observed and the effect of supplementation of calcium and Vitamin D were studied. They

included participants on anti-epilpetic drugs who were taking additional calcium and Vitamin D

supplements. They observed that 11.7% among those on calcium and Vitamin D supplements

experienced fractures compared to 9.9% among those who were not on supplements. The

difference was not statistically significant. Among the anti-epilpetic drugs, phenytoin was

associated with an increased risk of fractures. Hence they mention that among the study

population, calcium and Vitamin D supplementation had no effect on the risk of fractures.

Lazzari A et al.87 (2013) conducted the anti-epileptic drug and osteoporosis prevention trial for

the prevention of bone loss and fractures among those with epilepsy. It was a 2 year, prospective,

double blinded randomized controlled trial. They supplemented all those on anti-epileptic drugs

with calcium and Vitamin D. The study group received risendronate in addition to calcium and

Vitamin D. The primary end point was bone mineral density. Risk of fractures was the secondary

end point. At the end of the study period, supplementation of calcium and Vitamin D resulted in

significant raise in bone mineral density among more than 69% participants in both study and

control groups. Participants on risendronate in addition, had increased bone mineral density at

the lumbar region. Further, addition of risendronate prevented the incidence of new vertebral

fractures among the study group compared to the controls.

39

Liang Y.W et al. (2017), reported that the bone metabolism disorders caused in children on

Valproate for epilepsy can be prevented by supplementing with Vitamin D and calcium. 88

40

MATERIALS & METHODS

41

Study site: This study was conducted in the Department of Pediatrics, southern railway

headquarters hospital , Perambur

Study population:The children below 12 years on either single or multiple anticonvulsant

medication was considered as study population

Study design: The current study was a descriptive cross sectional study.

Sample size:

The sample size was calculated assuming the expected portion of people on AED developing

hypocalcemia as 16.5% (The mid value of the range reported by Richens A et al29). As per the

previous hospital records, the expected number of patients on long term AED therapy attending

our department was about 200.The other parameters used for sample size calculation were 5%

precision and 95% confidence level.

The following formula was used for sample size calculation.

n '= N Z2 P(1−P)d2 ( N−1 )+Z2 P(1−P)

Where n’= Sample size with finite population correction,

N = Population Size :200

42

Z = Z statistic for a level of confidence: 1.96

P = Expected proportion: 0.165

d = Precision: 0.05

After substituting the above-mentioned values, the total required sample size would be 104. To

account for non-participation rate of 5% per month 6 subjects will be additionally sampled in to

the study. Hence the total sample size required at the time of recruitment is 110.

Sampling method: All the eligible subjects were recruited into the study consecutively by

convenient sampling till the sample size is reached.

Study duration: The data collection for the study was done between May 2017 to April 2018

for a period of 1 year.

Inclusion Criteria:

Patients (0 to 12 years) who were on the following single or multiple anticonvulsants

commonly used in our hospital.

Patient taking the following drugs for more than 6 months

Sodium valproate.

Phenobarbitone.

Phenytoin.

43

Carbamazepine.

Levitriacetam

clobazam

Any patient with seizure disorder was considered irrespective of whether seizure is

primary or secondary.

Exclusion criteria:

Patients with kidney disease

Patients with liver disease

Malabsorption syndromes

The above-mentioned conditions may per se cause disturbances in calcium homeostasis

and hence will be excluded from the study.

Patients on any other drug that may interfere with calcium homeostasis.

Non compliance with anti-convulsant therapy.

Ethical considerations: Study was subjected to approval by institutional human ethics

committee. Informed written consent was obtained from all the study participants and only those

participants willing to sign the informed consent was included in the study. The risks and

benefits involved in the study and voluntary nature of participation were explained to the

participants before obtaining consent. Confidentiality of the study participants was maintained.

Data collection tools: All the relevant parameters were documented in a structured study

proforma.

44

Methodology:

After obtaining informed consent, Detailed history regarding epilepsy treatment

(number of anticonvulsants and its duration ,compliance,seizure control) will be obtained

from all children enrolled in the study.Complete physical examination will be carried out

on all patients. Under strict aseptic precautions 5 ml of blood collected and to laboratory

immediately for evaluation.Calcium measured by arsenazo III method, Phosphorus measured by

molybate UV method,serum alkaline phosphatase by IFSS method, vitamin D and Parathyroid

hormone by CLIA method. Calcium level will be corrected in cases with hypoalbuminemia.

Renal and liver function tests will be done to rule out other causes of hypovitaminosis D. Results

will be analysed by using statiscal method.

STATISTICAL METHODS:

Calcium level, vitamin D level, parathyroid hormone level were considered as primary outcome

variable.

Duration (in months), total drugs, seizure controlwere considered as Primary explanatory

variable

Descriptive analysis: Descriptive analysis was carried out by mean and standard deviation for

quantitative variables, frequency and proportion for categorical variables. Data was also

represented using appropriate diagrams like bar diagram, pie diagram.

45

Normality test for quantitative variables

A shapiro- wilk’s test (p>0.05) and a visual inspection of their histograms, normal Q-Q plots and

box plots showed that the calcium level, total drugs and duration (in months), serum calcium

were non-normally distributed.

The comparison total drugs and serum calcium was assessed by comparing the median values.

Kruskal Wallis test was used to assess statistical significance. Data was also represented using

appropriate diagrams like comparative boxplots.

The association between duration, total drugs, seizure control and calcium level, was assessed by

cross tabulation and comparison of percentages. Chi square test was used to test statistical

significance. Data was also represented using appropriate diagrams like clustered bar diagram.

P value < 0.05 was considered statistically significant. IBM SPSS version 22 was used for

statistical analysis.1

46

OBSERVATIONS AND RESULTS

47

RESULTS:

A total of 105 subjects were included in the final analysis.

Table 1: Descriptive analysis of age (in years) in study population (N=105)

Parameter Mean ± SD Median Min Max95% C.I

Lower UpperAge (in years) 4.93 ± 2.15 5.00 1.00 9.00 4.52 5.35

The mean age was 4.93 in the study population. Ranged between 1 year to 9 years(95% CI4.52to

5.35). (Table 1)

Table 2: Descriptive analysis of gender in study population (N=105)

Gender Frequency PercentagesMale 56 53.30%Female 49 46.70%

Among the study population male participants were 56 (53.30%) remaining 49 (46.70%) were

female. (Table 2 & Figure 1)

48

Figure 1: Pie chart of gender in the study population (N=105)

53.30%46.70% Male

Female

Table 3: Descriptive analysis of diagnosis in study population (N=105)

Diagnosis Frequency Percent

Idiopathic 32 30.50%

complex partial seizure 32 30.50%

Absence seizures 11 10.50%

Myoclonic seizure 12 11.40%

Post meningitis sequlae 5 4.80%

Inborn error of metabolism 4 3.80%

Infantile hemiplegia 3 2.90%

Tuberous sclerosis 2 1.90%

Sturge weber syndrome 2 1.90%

Rasmussen encephalitis 2 1.90%

The majority of the 30.50% people had idiopathic and complex partial seizure for each. The

proportion of absence seizures, myoclonic seizure, post meningitis sequlae was 10.50%, 11.40%

and 4.80% respectively. (Table 3 & Figure 2)

49

Figure 2: Bar chart of diagnosis in the study population (N=105)

0.00%

5.00%

10.00%

15.00%

20.00%

25.00%

30.00%

35.00%30.50% 30.50%

10.50% 11.40%

4.80% 3.80% 2.90% 1.90% 1.90% 1.90%

Diagnosis

Perc

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ge

Table 4: Descriptive analysis of drugs in study population (N=105)

Drugs Frequency PercentSodium valproate 54 51.40%Carbamazepine 33 31.40%Levitriacetam 22 21.00%Phenytoin 21 20.00%Phenobarbitone 18 17.10%Clobazam 11 10.50%

Among the study population, 54 (51.40%) participants were taken sodium valproate, 33

(31.40%) participants were taken carbamazepine, 22 (21%) participants were taken

levitriacetam, 21 (20%) participants were taken phenytoin, 18 (17.10%) participants were taken

Phenobarbitone and 11 (10.50%) participants were taken clobazam. (Table 4 & Figure 3)

Figure 3: Bar chart of drugs in study population (N=105)

50

Sodium valproate Carbamazepine Levitriacetam Phenytoin Phenobarbitone Clobazam0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%51.40%

31.40%

21.00% 20.00%17.10%

10.50%

Drugs

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Table 5: Descriptive analysis of Duration(in months) in study population (N=105)

Parameter Mean ± SD Median Min Max 95% C.ILower Upper

Duration(in months) 23.22 ± 11.88 22.00 8.00 72.00 20.92 25.52

The mean duration was 23.22 ± 11.88 months in the study population. Ranged between 8 to 72

months.(95% CI 20.92 to 25.52). (Table 5)

Table 6: Descriptive analysis of PTHin study population (N=105)

Parameter Mean ± SD Median Min Max 95% C.ILower Upper

PTH 27.73 ± 9.84 25.80 14.60 65.80 25.82 29.63

The mean PTH was 27.73 ± 9.84in the study population. Ranged between 14.60 to 65.80(95% CI

25.82 to 29.63). (Table 6)

51

Table 7: Descriptive analysis of parathormone level in study population (N=105)

Parathormone level Frequency PercentagesNormal (up to 28.99) 46 43.80%Elevated PTH (29 and above) 59 56.20%

Among the study population, 46 (43.80%) participants had normal parathormone level and 59

(56.20%) participants had elevated parathormone. (Table 7 & Figure 4)

Figure 4: Bar chartof parathormone level in study population (N=105)

Normal (up to 28.99) Elevated PTH (29 and above)0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

43.80%

56.20%

Parathormone level

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Table 8: Descriptive analysis of albumin in study population (N=105)

Parameter Mean ± SD Median Min Max 95% C.ILower Upper

Albumin 3.93 ± 0.29 3.90 3.40 4.80 3.87 3.99

The mean albumin was 3.93 ± 0.29 in the study population. Ranged between 3.40 g/dl to 4.80

g/dl.(95% CI 3.87 to 3.99). (Table 8)

Table 9: Descriptive analysis of serum Vitamin-D in study population (N=105)

52

Parameter Mean ± SD Median Min Max 95% C.ILower Upper

Serum vitamin D 27.91 ± 11.09 25.60 8.5 54.20 25.76 30.05

The mean serum vitamin D was 27.91 ± 11.09 in the study population. Ranged between 8.5 to

54.20(95% CI 25.76 to 30.05). (Table 9)

Table 10: Descriptive analysis of vitamin d level in study population (N=105)

Vitamin D level Frequency PercentagesHypo vitamin D 25 23.8%Normal vitamin D 80 76.2%

Among the study population, 25 (23.8%) participants had hypo vitamin D and 80 (76.2%)

participants had normal vitamin D level. (Table 10 & Figure 5)

Figure 5: Bar chart of vitamin D level in the study population (N=105)

Hypo vitamin D Normal vitamin D0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

90.00%

23.80%

76.20%

VitaminD level

Perc

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53

Table 11: Descriptive analysis of serum calcium in study population (N=105)

Parameter Mean ± SD Median Min Max 95% C.ILower Upper

Serum calcium 9.28 ± 0.89 9.50 7.8 10.80 9.10 9.45

The mean serum calcium was 9.28 ± 0.89 in the study population. Ranged between 7.8 to

10.80(95% CI 9.10 to 9.45). (Table 11)

Table 12: Descriptive analysis of calcium level in study population (N=105)

Calcium Level Frequency PercentagesHypocalcaemia 34 32.4%Normal calcium level 71 67.6%

Among the study population, 34 (32.48%) participants had hypocalcaemia and 71 (67.6%)

participants had normal calcium level. (Table 12 & Figure 6)

Figure 6: Bar chart of calcium level in the study population (N=105)

Hypocalcaemia Normal calcium level0.00%

10.00%20.00%30.00%40.00%50.00%60.00%70.00%80.00%

32.40%

67.60%

Calcium level

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Table 13: Descriptive analysis of Serum phosphorus in study population (N=105)

Parameter Mean ± SD Median Min Max 95% C.ILower Upper

Serum phosphorus 3.62 ± 0.86 3.80 2.00 5.10 3.45 3.78

54

The mean serum phosphorus was 3.62 ± 0.86 in the study population. Ranged between 2 to

5.10(95% CI 3.45 to 3.78). (Table 13)

Table 14: Descriptive analysis of phosphorus level in study population (N=105)

Phosphorus level Frequency PercentagesHypo phosphorus 32 30.5%Normal phosphorus 73 69.5%

Among the study population, 32 (30.5%) participants had hypo phosphorus and 73 (69.5%)

participants had normal phosphorus level. (Table 14 & Figure 7)

Figure 7: Pie chart of phosphorus level in study population (N=105)

30.50%

69.50%

Hypo phosphorusNormal phosphorus

Table 15: Descriptive analysis of Serum alkaline phosphatase in study population (N=105)

Parameter Mean ± SD Median Min Max 95% C.ILower Upper

Serum alkaline phosphatase 203.57 ± 124.6 152.00 96.00 454.00 183.30 223.84

The mean serum alkaline phosphatase was 203.57 ± 124.6in the study population. Ranged

between 96 to 454(95% CI 183.30 to 223.84). (Table 15)

55

Table 16: Descriptive analysis of alkaline phosphorus level in study population (N=105)

Alkaline phosphatase Frequency PercentagesNormal 80 76.2%Elevated ALP 25 23.8%

Among the study population, 80 (76.2%) participants had normal alkaline phosphatase and 25

(23.8%) participants had elevated ALP. (Table 16 & Figure 8)

Figure 8: Pie chart of alkaline phosphorus level in study population (N=105)

76.20%

23.80%

NormalElevated ALP

Table 17: Descriptive analysis of seizure control in study population (N=105)

Seizure control Frequency PercentagesYes 84 80.00%No 21 20.00%

Among the study population, 84 (80%) participants had seizure control. (Table 17 & Figure 9)

56

Figure 9: Pie chart of seizure control in study population (N=105)

80.00%

20.00%

YesNo

Table 18: Descriptive analysis of totaldrugs in study population (N=105)

Totaldrugs Frequency PercentagesSingle drug 68 64.80%Double drugs 22 21.00%Three or more drugs 15 14.30%

Among the study population, 68 (64.80%) participants were taken single drug, 22 (21%)

participants were taken double drugs and 15 (14.30%) participants were taken three or more

drugs. (Table 18 & Figure 10)

57

Figure 10: Bar chart of totaldrugs in study population (N=105)

Single drug Double drugs Three or more drugs0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00% 64.80%

21.00%14.30%

Total drugs

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ge

Table 19: Comparison of calcium level with durationinmonths(N=105)

DurationinmonthsCalcium level

Chi square P-value Hypocalcaemia Normal calcium

levelLess than 12 months

(N=19) 6 (31.6%) 13 (68.4%)0.007 0.93412 months and above

(N=86) 28 (32.6%) 58 (67.4%)

Out of 19 people with <12 months’ duration, 6 (31.6%) participants had hypocalcaemia and 13

(68.4%) participants had normal calcium level. Out of 86 people with 12 months above duration,

28 (32.6%) participants had hypocalcaemia and 58 (67.4%) participants had normal calcium

level. The difference in the proportion of calcium level between duration in months was

statistically not significant (P value 0.934). (Table 19 & Figure 11)

58

Figure 11: Clustered bar chart of comparison of calcium level with duration in months(N=105)

Less than 12 months 12 months and above 0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

31.60% 32.60%

68.40% 67.40%

Hypocalcaemia Normal calcium level

Calcium level

Perc

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Table 20: Comparison of calcium level with total drugs (N=105)

Total drugsCalcium Level

Chi square  P-value Hypocalcaemia Normal calcium level

Single drug 11 (16.2%) 57 (83.8%)23.37 <0.001Double drugs 13 (59.1%) 9 (40.9%)

Three or more drugs 10 (66.7%) 5 (33.3%)

In hypocalcaemia group,11 (16.2%) participants were taken single drug, 13 (59.1%) participants

were taken double drugs and 10 (66.7%) participants were taken three or more drugs. In normal

calcium level group,57 (83.8%) participants were taken single drug, 9 (40.9%) participants were

taken double drugs and 5 (33.3%) participants were taken three or more drugs. The difference in

the proportion of calcium level between total drugs was statistically significant (P value <0.001).

(Table 20)

Figure 12: Clustered bar chart of comparison of calcium level with total drugs (N=105)

59

Single drug Double drugs Three or more drugs0.00%

10.00%20.00%30.00%40.00%50.00%60.00%70.00%80.00%90.00%

16.20%

59.10%66.70%

83.80%

40.90%33.30%

Hypocalcaemia Normal calcium level

Total drugs

Perc

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Table 21: Comparison of median serum calcium between total drugs

Total drugsSerum calciumMedian (IQR)

Kruskal Wallis test (P value)

Single drug 9.65 (9.40, 10.10)

<0.001Double drugs 8.40 (8.10, 9.45)

Three or more drugs 8.10 (7.90, 9.20)

Among the people with single drug, the median serum calcium was 9.65 (IQR 9.40, 10.10). It

was 9.65 (IQR 9.40, 10.10) and 8.10 (IQR 7.90, 9.20) among people with double drugs and three

or more drugs. The difference in the serum calcium across total drugs was statistically significant

(P Value <0.001). (Table 21 & Figure 13)

Figure 13: Comparative boxplots of Comparison of median serum calcium between total drugs

60

Table 22: Comparison of calcium level with seizure control (N=105)

Seizure controlCalcium level Chi square P-value

Hypocalcaemia Normal calcium levelYes (N=84) 20 (23.8%) 64 (76.2%)

14.09 <0.001No (N=21) 14 (66.7%) 7 (33.3%)

Out of 84 people with seizure control, 20 (23.8%) participants had hypocalcaemia and 64

(76.2%) participants had normal calcium level. The difference in the proportion of calcium level

between seizure control was statistically significant (P value <0.001). (Table 22)

Figure 14: Clustered bar chart of comparison of calcium level with seizure control (N=105)

61

Yes No 0.00%

10.00%20.00%30.00%40.00%50.00%60.00%70.00%80.00%90.00%

23.80%

66.70%76.20%

33.30%

Hypocalcaemia Normal calcium level

Seizure control

Perc

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62

DISCUSSION

63

DISCUSSION:

A total of 105 participants were included in the study. Non-parametric tests were used since the

data was not normally distributed. The age of the participants ranged from 1 year to 9 years. The

median age was 5 years. The study participants had a higher proportion of males compared to

females in this study. 53.3% were males and 46.7% were females. But according to the WHO

report, females have a higher incidence of epilepsy compared to males. 9Among the Asian

countries the results were similar to this study. The prevalence was 3.65 per thousand males

compared to 2.5 per 1000 females. 12Similarly in Sridharan et al 27 (1999)males (6.05/1000) had a

higher prevalence compared to females. (5.18/1000). Bannerjee T.K et al.31 (2015) also reported

similar results.

Table 23: Comparison of proportion of epileptics by gender:

Study Males Females

Current study 53.3% 46.7%

WHO report9 ↓ ↑

Asian countries 12 3.65/1000 2.5/1000

Sridharan et al27 (2000) 6.05/1000 5.18/1000

An almost equal proportion of participants in this study had either idiopathic or complex partial

seizures. 30.5% had idiopathic and 30.5% roughly had complex partial seizures. One-tenth’s had

absence seizures. Myoclonic seizures were present in 11.4% of the study participants. Rest of the

participants had other less common types of seizures. Studies in Asian countries found the

prevalence of generalized tonic clonic seizures as 3.12%. The prevalence of partial seizures was

64

much lesser compared to the current study. 0.57% only had partial seizures and seizures could

not be classified in 0.23%. 12But the prevalence estimates among Europe had closer results to this

study. 3% had simple partial seizures while 5% had absence seizures. This was half the estimate

compared to the current study which estimated absence seizures to be 10%.

With regards to seizure control, 20% of the participants had inadequate seizure control. In drug

therapy, 64.8% of the participants were taking a single drug for seizure control, 21% were taking

two drugs and the remaining 14.30% were on three or more anticonvulsants for seizure control.

More than one half of the study population were taking sodium valproate for seizure control. One

third (31.40%) were taking carbamazepine. One-fifths were taking levetiracetam and another one

fifth took phenytoin. One-tenth took clobazam and 17.10% took phenobarbitone.

On an average, the mean duration of drug intake among the study population was 27.73 months.

The median duration was similarly 23.22 months. The duration of taking anticonvulsants ranged

from 8 months to 72 months.

The serum level of Parathyroid hormone was measured. The mean level was 27.73 and median

was 25.8. The level of parathyroid hormone ranged from 25.82 to 29.63 among the study

population. The cutoff of 29 was used to classify participants As having low levels and elevated

levels of parathyroid hormone. According to this cut off, 56.2% were found to have elevated

levels of parathyroid hormone.

The mean level of serum albumin in the study population was 3.93g/dl with a similar median of

3.9g/dl. Serum albumin values ranged from 3.40g/dl to 4.80g/dl.

65

The mean serum levels of Vitamin D in the study population was 27.91 with a slightly lesser

median of 25.60. The serum Vitamin D levels ranged from 8.5 to 54.20. When Vitamin D levels

were classified into normal and hypovitaminosis levels, 23.8% of the study participants were

found to be deficient or insufficient in Vitamin D. The results are similar to the studies by

Bouillion R. et al. (1975), El-Haji Fuleihan G.et al (2008)and Dura-Trave et al (2017)Razazizan

N et al (2015) reported that serum Vitamin D levels were normal among those on

anticonvulsants similar to healthy controls.

Table 24: Hypovitaminosis of Vitamin D and anticonvulsant medications.

Sl.no Study Result

1 Current study 23.8% hypovitaminosis Vitamin D

2 Bouillion R et al (1975) Low levels

3 El-Haji Fuleihan G.et al (2008) Low levels

4 Dura-Trave et al (2017) Low levels

5 Razazizan N et al (2015) Normal levels

The mean serum calcium levels among the study population was 9.28mg/l, and the median was

slightly higher at 9.5mg/l. The serum calcium levels ranged from 7.8 to 10.8 mg/l. When calcium

levels was classified into normal and low calcium levels, 32.4% were classified as having low

serum calcium levels. This estimate is higher than the 22.5% reported by Richens A and

D.J.Rowe et al (1970). Erbayat Altay et al (2000), Arora et al (2016) and Dura-Trave et al (2017)

also reported a subnormal serum calcium levels among those on anti-epileptics.

66

Table 25: Serum calcium and anticonvulsant therapy

Sl.no Study Hypocalcemia & prevalence

1 Current study 32.4%

2 Richens A and D.J.Rowe et al (1970). 22.5%

3 Erbayat Altay et al (2000) Hypocalcemia present

4 Arora et al (2016) Hypocalcemia present

5 Dura-Trave et al (2017) Hypocalcemia present

Similarly, Aksoy D et al (2016) reported that there was a longitudinal decline on serum

calcium and Vitamin D3 levels during the intake of anticonvulsants. In

contrast, Sonmez F.M et al (2015) mentioned that only serum Vitamin D was

lower along those on anticonvulsant drugs. Serum calcium, phosphorus and

alkaline phosphatase were not elevated compared to Controls.

The mean levels of serum phosphorus was 3.62 among the study participants. The median was

3.8 and ranged from 2 among the lowest participant to 5.10 among the participants with the

highest level. When serum phosphate was classified into hypophosphatemia and normal levels,

30.5% had hypophosphatemia.

When serum alkaline phosphatase was measured, the median was lower than the mean being

152IU/l and 203.57IU/l respectively. The maximum level of alkaline phosphatase was 454 IU/l.

When the serum levels were classified as normal and high, 23.8% of the study participants had

elevated levels of alkaline phosphatase. Richens A and D.J.Rowe et al (1970) reported a slightly

higher estimate of 29% of elevated alkaline phosphatase among those on anti-epilpetic drugs.

67

Verroti A et al (2000) reported that alkaline phosphatase was elevated among those on

carbamazepine compared to healthy controls. Similar results were also reported by Erbayat Altay

et al (2000) and Razazizan et al (2015).

Table 26: Alkaline phosphatase and anticonvulsant medications

Sl.no Study Results

1 Current study 23.8% ↑ levels

2 Richens A and D.J.Rowe et al (1970) 29% ↑ levels

3 Verroti A et al (200 ↑ levels

4 Erbayat Altay et al (2000 ↑ levels

5 Razazizan et al (2015 ↑ levels

When the serum calcium levels were compared to the duration of anticonvulsant therapy, the

results were not statistically significant. There was no significant different in the prevalence of

hypocalcemia among the study population who were on anticonvulsants for less than a year

compared to those taking anticonvulsants for a year or more.

When the serum calcium levels were compared with the drug intake, the results were statistically

significant. The proportion of hypocalcemic patients increased with increasing number of drugs

taken for epilepsy. Only 16.2% had hypocalcemia when they took only a single drug compared

to 59.1% among those taking two drugs and 66.7% for those on three or more drugs.

68

When the serum calcium levels were compared as such using median value among the three

groups of drug intake, there was a progressive decline in the median serum calcium levels with

increasing number of drugs taken. This is similar to the study by Farhat D et al (2002) and

Vestergaard P (2015) where the authors mention that the duration of seizures and number of anti-

epilpetic drugs was associated with a greater decline in serum calcium levels. The median value

of serum calcium was 9.65 g/l for single drug users compared to 8.4 g/dl for those on two drugs

and 8.10g/dl for those on three or more drugs. The p value was statistically significant.

When serum calcium levels were compared to achieving seizure control, those with normal

levels of serum calcium had better control of their seizures. Around 76.2% of the study

participants with normal serum calcium had achieved seizure control, while 66.7% of those with

hypocalcemia did not achieve seizure control. The difference in proportions was statistically

significant. Hence this indicates that serum calcium might have a potential role in control of

seizures as well.

CONCLUSION:

This study indicates that among young children epilepsy is more common among males than

females similar to other studies conducted in Asia. Among the young children, around one-fifths

had inadequate seizure control. Mostly two-third of participants had been taking a single drug for

seizure control. The rest were on two or more drugs. Since multiple drug intake is significantly

associated with a greater decline in serum calcium levels, this has potential implications. Since

the treatment for epilepsy is lifelong this has a greater effect among those who are diagnosed as a

69

young child. Growth of bones and bone mineral density maybe affected by anticonvulsant

medications.

Most participants were on enzyme inducing anti-epilpetic drugs such as sodium valproate,

carbamazepine and phenytoin. Since enzyme clearing drugs are associated with a greater hepatic

clearance of Vitamin D, this could result in subsequent deficiency of serum calcium. Hence this

group constitutes a high risk group which needs a closer monitoring.

When the serum parathyroid hormone levels were measured, more than half had elevated levels

of PTH. This indicates the presence of secondary hyperparathyroidism due to Vitamin D

deficiency. A little less than half of the study participants had either Vitamin D deficiency or

insufficiency. This is in accordance with the proposed mechanisms such as accelerated hepatic

clearance of Vitamin D due to anti-epilpetic drugs. In a country such as India where additional

factors such as reduced sunlight exposure, this could result in increased risk of Vitamin D

deficiency.

Around a third of the participants had hypophosphatemia and a little less than one-fourth had

elevated serum alkaline phosphatase levels. The above findings indicate an increased bone

turnover among those taking anticonvulsants. But these findings of hypocalcemia did not have

any association with the duration of anti-epilpetic drug intake. This indicates mechanisms other

than anticonvulsant drug intake may be associated with Vitamin D and calcium deficiency. This

also indicates the need to screen and identify the newly diagnosed epileptics for Vitamin D and

calcium deficiency.

On the other hand, intake of multiple anticonvulsant drugs is associated with a greater decline of

serum calcium levels. Also, more importantly, low serum calcium levels were found to be

70

associated with poor seizure control. This indicates the significant role of calcium and the

possible reverse causative mechanisms in the relation between seizures and serum calcium

levels.

Hence this indicates the need to identify and prophylactically manage Vitamin D and calcium

levels among the young children who are started on anticonvulsant medications.

RECOMMENDATIONS:

This study indicates that young children with epilepsy are at an increased risk of calcium

deficiency. Hence routine screening for calcium and Vitamin D deficiency may be performed at

the time of diagnosis and regularly during management. Furthermore, this study maybe expanded

further to perform interventional studies for developing guidelines for routine screening along

with dosages for calcium and Vitamin D supplementation. Awareness needs to be created among

pediatricians and treating neurologists regarding the risk of Vitamin D and calcium deficiency

among those on anti-epilpetic drugs. This would have additional benefits of resultant better

seizure control as well.

LIMITATIONS:

This study was a single Center study conducted in a tertiary care setting. Further studies may be

conducted in a population based primary care setting in multiple Centers for improving the

generalizability of the study results. Further, this was a cross sectional study. Cohort studies may

be conducted further for monitoring the serum calcium levels during the course of therapy.

71

72

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56. Brodie MJ. Tiagabine pharmacology in profile. Epilepsia. 1995;36 Suppl 6:S7-s9.

57. Taylor LA, McQuade RD, Tice MAB. Felbamate, a novel anti-epilpetic drug, reverses N-

methyl-D-aspartate/glycine-stimulated increases in intracellular Ca2+ concentration. European

Journal of Pharmacology: Molecular Pharmacology. 1995;289(2):229-33.

58. Zona C, Ciotti MT, Avoli M. Topiramate attenuates voltage-gated sodium currents in rat

cerebellar granule cells. Neurosci Lett. 1997;231(3):123-6.

59. Chong DJ, Lerman AM. Practice Update: Review of Anticonvulsant Therapy. Curr

Neurol Neurosci Rep. 2016;16(4):39.

80

60. Richens A, Rowe DJ. Disturbance of calcium metabolism by anticonvulsant drugs. Br

Med J. 1970;4(5727):73-6.

61. Pack AM. Treatment of epilepsy to optimize bone health. Curr Treat Options Neurol.

2011;13(4):346-54.

62. Petty SJ, O'Brien TJ, Wark JD. Anti-epileptic medication and bone health. Osteoporos

Int. 2007;18(2):129-42.

63. Valsamis HA, Arora SK, Labban B, McFarlane SI. Anti-epilpetic drugs and bone

metabolism. NutrMetab (Lond). 2006;3:36.

64. Verrotti A, Coppola G, Parisi P, Mohn A, Chiarelli F. Bone and calcium metabolism and

anti-epilpetic drugs. Clin Neurol Neurosurg. 2010;112(1):1-10.

65. Erbayat Altay E, Serdaroglu A, Tumer L, Gucuyener K, Hasanoglu A. Evaluation of

bone mineral metabolism in children receiving carbamazepine and valproic acid. J Pediatr

Endocrinol Metab. 2000;13(7):933-9.

66. Sato Y, Kondo I, Ishida S, Motooka H, Takayama K, Tomita Y, et al. Decreased bone

mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology.

2001;57(3):445-9.

67. Farhat G, Yamout B, Mikati MA, Demirjian S, Sawaya R, El-Hajj Fuleihan G. Effect of

anti-epilpetic drugs on bone density in ambulatory patients. Neurology. 2002;58(9):1348-53.

68. El-Hajj Fuleihan G, Dib L, Yamout B, Sawaya R, Mikati MA. Predictors of bone density

in ambulatory patients on anti-epilpetic drugs. Bone. 2008;43(1):149-55.

81

69. Nakken KO, Heuser K, Alfstad K, Tauboll E. [How do anti-epilpetic drugs work?].

Tidsskr Nor Laegeforen. 2014;134(1):42-6.

70. Meier C, Kraenzlin ME. Anti-epilpetics and bone health. Ther Adv Musculoskelet Dis.

2011;3(5):235-43.

71. Phabphal K, Geater A, Limapichart K, Sathirapanya P, Setthawatcharawanich S,

Witeerungrot N, et al. The association between BsmI polymorphism and bone mineral density in

young patients with epilepsy who are taking phenytoin. Epilepsia. 2013;54(2):249-55.

72. Nicholas JM, Ridsdale L, Richardson MP, Grieve AP, Gulliford MC. Fracture risk with

use of liver enzyme inducing anti-epilpetic drugs in people with active epilepsy: cohort study

using the general practice research database. Seizure. 2013;22(1):37-42.

73. Salimipour H, Kazerooni S, Seyedabadi M, Nabipour I, Nemati R, Iranpour D, et al.

Anti-epilpetic treatment is associated with bone loss: difference in drug type and region of

interest. J Nucl Med Technol. 2013;41(3):208-11.

74. Razazizan N, Mirmoeini M, Daeichin S, Ghadiri K. Comparison of 25-hydroxy vitamin

D, calcium and alkaline phosphatase levels in epileptic and non-epileptic children. Acta Neurol

Taiwan. 2013;22(3):112-6.

75. Menon B, Harinarayan CV, Raj MN, Vemuri S, Himabindu G, Afsana TK. Prevalence of

low dietary calcium intake in patients with epilepsy: a study from South India. Neurol India.

2010;58(2):209-12.

76. Pettifor JM. Nutritional rickets: deficiency of vitamin D, calcium, or both? Am J Clin

Nutr. 2004;80(6 Suppl):1725s-9s.

82

77. Sonmez FM, Donmez A, Namuslu M, Canbal M, Orun E. Vitamin D Deficiency in

Children With Newly Diagnosed Idiopathic Epilepsy. J Child Neurol. 2015;30(11):1428-32.

78. Vestergaard P. Effects of anti-epilpetic drugs on bone health and growth potential in

children with epilepsy. Paediatr Drugs. 2015;17(2):141-50.

79. Aksoy D, Guveli BT, Ak PD, Sari H, Atakli D, Arpaci B. Effects of Oxcarbazepine and

Levetiracetam on Calcium, Ionized Calcium, and 25-OH Vitamin-D3 Levels in Patients with

Epilepsy. Clin PsychopharmacolNeurosci. 2016;14(1):74-8.

80. Arora E, Singh H, Gupta YK. Impact of anti-epilpetic drugs on bone health: Need for

monitoring, treatment, and prevention strategies. Journal of Family Medicine and Primary Care.

2016;5(2):248-53.

81. Fitzpatrick LA. Pathophysiology of bone loss in patients receiving anticonvulsant

therapy. Epilepsy Behav. 2004;5 Suppl 2:S3-15.

82. Dura-Trave T, Gallinas-Victoriano F, Malumbres-Chacon M, Moreno-Gonzalez P,

Aguilera-Albesa S, Yoldi-Petri ME. Vitamin D deficiency in children with epilepsy taking

valproate and levetiracetam as monotherapy. Epilepsy Res. 2018;139:80-4.

83. Jekovec‐Vrhovsěk M, Kocijancic A, Preželj J. Effect of vitamin D and calcium on bone

mineral density in children with CP and epilepsy in full‐time care. Developmental Medicine &

Child Neurology. 2007;42(6):403-5.

84. Drezner MK. Treatment of anticonvulsant drug-induced bone disease. Epilepsy Behav.

2004;5 Suppl 2:S41-7.

83

85. Espinosa PS, Perez DL, Abner E, Ryan M. Association of anti-epilpetic drugs, vitamin D,

and calcium supplementation with bone fracture occurrence in epilepsy patients. Clin Neurol

Neurosurg. 2011;113(7):548-51.

86. Lazzari AA, Dussault PM, Thakore-James M, Gagnon D, Baker E, Davis SA, et al.

Prevention of bone loss and vertebral fractures in patients with chronic epilepsy--anti-epilpetic

drug and osteoporosis prevention trial. Epilepsia. 2013;54(11):1997-2004.

87. Liang YW, Feng Q, Zhang YL, Wang WJ. [Bone metabolism disorders caused by

sodium valproate therapy in children with epilepsy and the prevention of the disorders by

supplementation of calcium and vitamin D]. Zhongguo Dang Dai ErKe Za Zhi. 2017;19(9):962-

4.

84

85

86

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67. Sato Y, Kondo I, Ishida S, Motooka H, Takayama K, Tomita Y, et al. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology. 2001;57(3):445-9.68. Farhat G, Yamout B, Mikati MA, Demirjian S, Sawaya R, El-Hajj Fuleihan G. Effect of anti-epilpetic drugs on bone density in ambulatory patients. Neurology. 2002;58(9):1348-53.69. El-Hajj Fuleihan G, Dib L, Yamout B, Sawaya R, Mikati MA. Predictors of bone density in ambulatory patients on anti-epilpetic drugs. Bone. 2008;43(1):149-55.70. Nakken KO, Heuser K, Alfstad K, Tauboll E. [How do anti-epilpetic drugs work?]. Tidsskr Nor Laegeforen. 2014;134(1):42-6.71. Meier C, Kraenzlin ME. Anti-epilpetics and bone health. Ther Adv Musculoskelet Dis. 2011;3(5):235-43.72. Phabphal K, Geater A, Limapichart K, Sathirapanya P, Setthawatcharawanich S, Witeerungrot N, et al. The association between BsmI polymorphism and bone mineral density in young patients with epilepsy who are taking phenytoin. Epilepsia. 2013;54(2):249-55.73. Nicholas JM, Ridsdale L, Richardson MP, Grieve AP, Gulliford MC. Fracture risk with use of liver enzyme inducing anti-epilpetic drugs in people with active epilepsy: cohort study using the general practice research database. Seizure. 2013;22(1):37-42.74. Salimipour H, Kazerooni S, Seyedabadi M, Nabipour I, Nemati R, Iranpour D, et al. Anti-epilpetic treatment is associated with bone loss: difference in drug type and region of interest. J Nucl Med Technol. 2013;41(3):208-11.75. Razazizan N, Mirmoeini M, Daeichin S, Ghadiri K. Comparison of 25-hydroxy vitamin D, calcium and alkaline phosphatase levels in epileptic and non-epileptic children. Acta Neurol Taiwan. 2013;22(3):112-6.76. Menon B, Harinarayan CV, Raj MN, Vemuri S, Himabindu G, Afsana TK. Prevalence of low dietary calcium intake in patients with epilepsy: a study from South India. Neurol India. 2010;58(2):209-12.77. Pettifor JM. Nutritional rickets: deficiency of vitamin D, calcium, or both? Am J Clin Nutr. 2004;80(6 Suppl):1725s-9s.78. Sonmez FM, Donmez A, Namuslu M, Canbal M, Orun E. Vitamin D Deficiency in Children With Newly Diagnosed Idiopathic Epilepsy. J Child Neurol. 2015;30(11):1428-32.79. Vestergaard P. Effects of anti-epilpetic drugs on bone health and growth potential in children with epilepsy. Paediatr Drugs. 2015;17(2):141-50.80. Aksoy D, Guveli BT, Ak PD, Sari H, Atakli D, Arpaci B. Effects of Oxcarbazepine and Levetiracetam on Calcium, Ionized Calcium, and 25-OH Vitamin-D3 Levels in Patients with Epilepsy. Clin Psychopharmacol Neurosci. 2016;14(1):74-8.81. Arora E, Singh H, Gupta YK. Impact of anti-epilpetic drugs on bone health: Need for monitoring, treatment, and prevention strategies. Journal of Family Medicine and Primary Care. 2016;5(2):248-53.82. Fitzpatrick LA. Pathophysiology of bone loss in patients receiving anticonvulsant therapy. Epilepsy Behav. 2004;5 Suppl 2:S3-15.83. Dura-Trave T, Gallinas-Victoriano F, Malumbres-Chacon M, Moreno-Gonzalez P, Aguilera-Albesa S, Yoldi-Petri ME. Vitamin D deficiency in children with epilepsy taking valproate and levetiracetam as monotherapy. Epilepsy Res. 2018;139:80-4.84. Jekovec Vrhovsěk M, Kocijancic A, Preželj J. Effect of vitamin D and calcium on bone mineral‐ density in children with CP and epilepsy in full time care. Developmental Medicine & Child Neurology.‐ 2007;42(6):403-5.85. Drezner MK. Treatment of anticonvulsant drug-induced bone disease. Epilepsy Behav. 2004;5 Suppl 2:S41-7.86. Espinosa PS, Perez DL, Abner E, Ryan M. Association of anti-epilpetic drugs, vitamin D, and calcium supplementation with bone fracture occurrence in epilepsy patients. Clin Neurol Neurosurg. 2011;113(7):548-51.

90

87. Lazzari AA, Dussault PM, Thakore-James M, Gagnon D, Baker E, Davis SA, et al. Prevention of bone loss and vertebral fractures in patients with chronic epilepsy--anti-epilpetic drug and osteoporosis prevention trial. Epilepsia. 2013;54(11):1997-2004.88. Liang YW, Feng Q, Zhang YL, Wang WJ. [Bone metabolism disorders caused by sodium valproate therapy in children with epilepsy and the prevention of the disorders by supplementation of calcium and vitamin D]. Zhongguo Dang Dai Er Ke Za Zhi. 2017;19(9):962-4.

91