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A CROSS SECTIONAL STUDY OF EFFECT OF ANTICONVULSANT THERAPY IN
CALCIUM HOMEOSTASIS
S. No Table of Content Page No
1 INTRODUCTION
2 REVIEW OF LITERATURE
3 AIMS & OBJECTIVES
4 MATERIALS & METHODS
5 RESULTS
6 DISCUSSION
7 CONSULATION
8 LIMITATIONS
9 BIBLIOGRAPHY
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List of Tables
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List of Figure
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Glossary Abbreviations
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INTRODUCTION
5
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 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)
6
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.
8
9
AIMS & OBJECTIVES
AIMS AND OBJECTIVES:
To study the prevalence of calcium homeostasis abnormalities in patients on chronic anticonvulsant therapy.
10
To access serum Vitamin D level in patients on chronic anticonvulsant therapy.
11
REVIEW OF LITERATURE
12
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
13
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.
14
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
15
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
16
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
17
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
18
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
19
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 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. The 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
20
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
21
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
22
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 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.
23
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
24
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
25
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:
26
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 neighboring 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 barbiturate 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
27
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 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. Zonasimide 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 zonesemide, 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
Impact of anticonvulsant agents on calcium homeostasis:
29
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
parathormone 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 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 conclude 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 conclude 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 recommend 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 recommend 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
mention 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-epilpetic 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-epilpetic 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, sothern railway 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% 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.
Sodium valproate.
Phenobarbitone.
Phenytoin.
Carbamazepine.
43
Patients taking the above-mentioned drugs for more than 6 months.
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 t 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: (need to elaborate ..all the procedures done after recruitment)….clinicla
evaluation/ quantity of blood drawn..transportation..laboratory methods to estimate
calcium paramters etc..
After obtaining informed consent and making the parents and patients well aware of the study
and the need for it, blood investigations for calcium, phosphorus, alkaline phosphatase, vitamin
D, parathormone, RFT and LFT will be drawn.
Statistical Methods:
STATISTICAL METHODS:
Calcium level, vitamin d level, parathormone level were considered as primary outcome
variable.
Duration (in months), total drugs, seizure control were 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.
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.
45
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: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% CI4.52
to 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)
Figure 1: Pie chart of gender in the study population (N=105)
53.30%46.70% Male
Female
48
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)
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
enta
ge
49
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)
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
Perc
enta
ge
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
50
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 PTH in 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 ± 9.84 in the study population. Ranged between 14.60 to 65.80 (95%
CI 25.82 to 29.63). (Table 6)
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 chart of 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
Perc
enta
ge
Table 8: Descriptive analysis of albumin in study population (N=105)
51
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)
Parameter Mean ± SD Median Min Max 95% C.ILower Upper
Serum vitamin D2 27.91 ± 11.09 25.60 8.5 54.20 25.76 30.05
The mean serum vitamin d2 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)
52
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
enta
ge
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)
53
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
Perc
enta
ge
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
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)
54
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 ± 124.6 in the study population. Ranged
between 96 to 454 (95% CI 183.30 to 223.84). (Table 15)
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)
55
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)
Figure 9: Pie chart of seizure control in study population (N=105)
80.00%
20.00%
YesNo
Table 18: Descriptive analysis of total drugs in study population (N=105)
Total drugs Frequency PercentagesSingle drug 68 64.80%Double drugs 22 21.00%
56
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)
Figure 10: Bar chart of total drugs 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
Perc
enta
ge
Table 19: Comparison of calcium level with duration in months (N=105)
Duration in months Calcium 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)
57
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
enta
ge
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)
58
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
enta
ge
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
59
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)
60
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
enta
ge
61
DISCUSSION
62
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. 9 Among 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. 12 Similarly 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
63
much lesser compared to the current study. 0.57% only had partial seizures and seizures could
not be classified in 0.23%. 12 But 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 Parathormone was measured. The mean level was 27.73 and median was
25.8. The level of parathormone ranged from 25.82 to 29.63 among the study population. The cut
off of 29 was used to classify participants As having low levels and elevated levels of
parathormone. According to this cut off, 56.2% were found to have elevated levels of
parathormone.
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.
64
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-epilpetics.
Table 25: Serum calcium and anticonvulsant therapy
65
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.
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).
66
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.
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-
67
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
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.
68
When the serum parathormone 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
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:
69
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.
70
71
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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.
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.
79
63. Valsamis HA, Arora SK, Labban B, McFarlane SI. Anti-epilpetic drugs and bone
metabolism. Nutr Metab (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.
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.
80
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.
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 Psychopharmacol Neurosci. 2016;14(1):74-8.
81
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.
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
82
supplementation of calcium and vitamin D]. Zhongguo Dang Dai Er Ke Za Zhi. 2017;19(9):962-
4.
83
84
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58. 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):229-33.59. Zona C, Ciotti MT, Avoli M. Topiramate attenuates voltage-gated sodium currents in rat cerebellar granule cells. Neurosci Lett. 1997;231(3):123-6.60. Chong DJ, Lerman AM. Practice Update: Review of Anticonvulsant Therapy. Curr Neurol Neurosci Rep. 2016;16(4):39.61. Richens A, Rowe DJ. Disturbance of calcium metabolism by anticonvulsant drugs. Br Med J. 1970;4(5727):73-6.62. Pack AM. Treatment of epilepsy to optimize bone health. Curr Treat Options Neurol. 2011;13(4):346-54.63. Petty SJ, O'Brien TJ, Wark JD. Anti-epileptic medication and bone health. Osteoporos Int. 2007;18(2):129-42.64. Valsamis HA, Arora SK, Labban B, McFarlane SI. Anti-epilpetic drugs and bone metabolism. Nutr Metab (Lond). 2006;3:36.65. Verrotti A, Coppola G, Parisi P, Mohn A, Chiarelli F. Bone and calcium metabolism and anti-epilpetic drugs. Clin Neurol Neurosurg. 2010;112(1):1-10.66. 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):933-9.67. 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.
88
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):548-51.87. 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.
89