INTRODUCTION:

• The treatment of neurologic illness frequently requires chronic, long-term therapy

with medication that may cause significant interactions with nutritional status.
• Clinical impact of these drug–nutrient interactions may include altered vitamin
nutriture, increased or decreased metabolism of drugs or nutrients, and alterations in
gastrointestinal motility.
• The combined effects of these interactions place patients receiving chronic medical
therapy at risk for various degrees of malnutrition.
• A review of the scientific background of these adverse interactions, as well as
possible therapeutic interactions, follows; the intent is to allow clinicians to
optimize the medical and nutrition therapy of this patient population.
ANTIEPILEPTIC DRUGS:
• Antiepileptic drugs (AEDs) are used to achieve seizure control in patients
with epilepsy.
• Patients frequently require long-term therapy with one or more
medications.
• Due to the influence of AEDs, alterations in bone metabolism and status of
B vitamins have been documented.
• Absorption of some AEDs may be negatively impacted by co-
administration with certain vitamins and enteral nutrition products.
Bone Mineral Status:
REVIEW OF MECHANISMS/SCIENTIFIC BASIS:

• The use of AEDs has been shown to have a significant impact on bone mass and
bone mineral density (BMD) in various populations. Consequently, AED use has
been associated with an increased risk of bone fractures.
• Many theories have been suggested for alterations in BMD in epileptic patients and
have included evaluation of the role of AED-associated enzyme induction. The
enzyme-inducing AEDs include carbamazepine, phenobarbital, phenytoin,
• While the non-enzyme-inducing AEDs include clonazepam, topiramate, valproic
acid.
• Enzyme-inducing AEDs cause hepatic induction of the cytochrome P450 (CYP)
enzyme system responsible for vitamin D metabolism.
• With increased catabolism of vitamin D via the CYP, the result is decreased levels
of active vitamin D and inadequate intestinal calcium absorption, hypocalcaemia,
increased levels of parathyroid hormone, and increased bone turnover.
REPORTED CASES:
• Younger males (age 25–44 years) in this study were shown to have more than a 2.5-fold
increased prevalence of femoral bone loss.
• In a population of older women, there was a 1.6-fold increased rate of annual bone loss at the
calcaneus and the total hip when continuous users of AEDs were compared to nonusers.
• Patients on enzyme inducing AEDs had a statistically significant increased risk of both
osteopenia and osteoporosis across all age and gender groups. When compared to a medically
normal population based on World Health Organization guidelines, 40% of the patients
receiving AEDs were osteopenic compared to an expected rate of 15.3%, while 18% were
Chapter 17 / Influence of Neurological Medication on Nutritional Status 485 osteoporotic
compared to an expected rate of 0.6% in healthy individuals.
• Case reports of osteopenia and hypocalcemia further highlight the implications of alterations
in bone homeostasis in patients on AEDs.
• Other risk factors commonly associated with osteopenia in these patients such as low vitamin
D levels, small body size, and Down syndrome were not present; lifestyle factors associated
with bone loss such as tobacco use, steroid use, and immobility were also not associated with
osteopenia in this case.
• Hypocalcemia reduced seizure control in a 32-year-old mentally retarded, institutionalized
patient who began having seizures despite therapeutic drug levels. Calcium levels normalized
after 2 months of supplementation, and the patient subsequently became seizure-free. Loss of
seizure control due to hypocalcemia may be an uncommon clinical presentation that can be
successfully treated with calcium and vitamin D supplementation.
CLINICAL RELEVANCE:
• Risk of fracture is significantly higher in patients with epilepsy when compared to a
healthy population.
• In particular, the risk of hip fracture was three times higher in both men and women
>50 years of age. Whether fractures are traumatic as a result of seizure activity or
pathologic in nature is poorly defined. Due to the possible effects of AEDs on BMD,
it is suggested that AED use is an independent risk factor for bone loss and
subsequent fractures.
• The effects of AEDs may cause osteopenic/osteoporotic fracturesFew neurologists
routinely screen their patients for bone disease (18), which increases the risk for
considerable bone loss and fractures in this population prior to diagnosis.
• In patients treated with phenytoin, carbamazepine, and valproic acid,
supplementation with vitamin D has been shown to increase levels of 25(OH)-vitamin
D3 and parathyroid hormone and improve ultrasound measures of bone
mineralization.
RESEARCH NEEDS:

• Newer AED regimens should be evaluated to determine their role in development

of bone disease. The impact of calcium and vitamin supplementation on rates of
bone loss should also be evaluated prospectively to identify specific
supplementation guidelines for implementation in this at-risk population.
B-Vitamin Status:
REVIEW OF MECHANISMS/SCIENTIFIC BASIS:
• Folate (FA) and vitamin B12 are important cofactors needed for the remethylation of
homocysteine to methionine
• Vitamin B6 is necessary for the metabolism of homocysteine to cystathionine (25). An inverse
relationship between plasma homocysteine and folate levels exists in patients on AED
therapy; folate levels are decreased in patients on AEDs
• The low folate levels seen in individuals receiving AEDs are attributable to several different
mechanisms: alteration in intestinal pH causing impaired intestinal absorption; inhibition of
intestinal conjugases to hydrolyze the polyglutamates of dietary folate into an absorbable
form; interference with transport of folate into tissues; and depletion of folate due to its role
as a cofactor in phenytoin metabolism.
• Deficiencies of the B vitamins may result in hyperhomocysteinemia with a subsequent
increase in cardiovascular risk in individuals treated with AEDs. The mechanism for vitamin
B6 or vitamin B12 alterations in AED therapy is unclear. Pregnant women on chronic AED
therapy may also be at risk for impaired B-vitamin status associated with AED.
• The increased risk of congenital malformations is attributed to the teratogenic
effects of AED, and women with epilepsy have double the risk of having a child
with a congenital malformation when compared to women not receiving AED.

REPORTED CASES:

• FA deficiency was found in 8–18% of patients. Deficient patients were on long-

term therapy (>5 years) and required multiple AED for seizure control.
• Levels of vitamin B12 were within normal limits while methionine levels were low,
suggesting that FA deficiency was responsible for the induction of elevated
homocysteine levels. Supplementation with FA resulted in normalized
homocysteine levels.
• In comparisons of epileptic patients on AED to epileptic patients not on AED with a
group of age- and sex-matched healthy controls, 64% of epileptic patients on AED
had hyperhomocysteinemia versus 20% of epileptics not on AED.
• In epileptic patients treated with phenytoin, significantly lower FA levels were
found compared to non-AED patients.
CLINICAL RELEVANCE:

• It appears that individuals on long-term therapy, particularly with enzyme inducing

drugs, may be at risk for FA deficiency and possibly alterations in vitamin B6 and
B12 levels. A consistent inverse relationship between folate status and Plasma total
homocysteine levels suggests that intervention may be possible. Mortality risk from
cardiovascular event in epileptic patients is significant, as high as three times
compared to other populations.
• Supplementation with folic acid, vitamin B6, and riboflavin was shown to
normalize Plasma total homocysteine levels and to increase FA and vitamin B6
status. Hyperhomocysteinemia may also increase risk of fetal malformations or
delay fetal growth.
RESEARCH NEEDS:
• The clinical impact of elevated homocysteine levels in epileptic patients, as
well as the outcomes of interventions to modify hyperhomocysteinemia, should
be evaluated prospectively. With regard to pregnancy complications, research is
needed to determine all the mechanisms of NTD in women receiving AED
therapy.
CLINICAL RECOMMENDATIONS:

• Individuals on long-term AED therapy should be screened for

hyperhomocysteinemia and FA deficiency.
• Individuals on carbamazepine with elevated homocysteine levels should also be
screened for vitamin B12 deficiency and supplemented accordingly. FA
supplementation should be considered in all women of childbearing age on AED.