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Beta-lactam antibiotics as a possible novel therapy for managing epilepsy in autism, a case
report and review of literature
Abstract
Autism is a disorder with unknown etiology. There are only a few FDA approved medications
for treating of autism. Co-occurring of autism and epilepsy is common. Glutamate antagonists
improve some symptoms of autism. Ceftriaxone, a beta-lactam antibiotic, increases the
expression of glutamate transporter 1 which decreases extracellular glutamate level. Current
literature hypothesized that modulating astrocyte glutamate transporter expression by ceftriaxone
or cefixime might improve some symptoms of autism. This is a case report of a child with autism
and epilepsy that seizures are decreased after taking cefixime
Keywords: Autistic Disorder, cefixime, Anti-Bacterial Agents, glutamates, Membrane
Transport Proteins, Therapeutics, inflammation, epilepsy.
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Introduction
Autism is a complex disorder with the impairment of verbal communications, social relationship
problems, repetitive behaviors, and restrictive interests. Its etiology is not clearly known and
there is a debate about its mechanisms of pathogenesis. There is no cure for autism. So, novel
therapeutic interventions for treating autism are highly needed. Meanwhile, autism is highly
comorbid with epilepsy (OR=22.2; 95% CI=16.8-29.3) (Selassie, Wilson et al. 2014).
Nevertheless, treatment refractory epilepsy in autism is up to 33.9% (Sansa, Carlson et al. 2011).
in addition, surgical and agus nerve stimulator (VNS) implantation outcomes in the patients with
both autism and epilepsy are less effective than in other treatment refractory epilepsy patients
(Sansa, Carlson et al. 2011).
The beta-lactam antibiotics of cefixime and ceftriaxone are from third-generation cephalosporin.
Ceftriaxone increases GLT1/EAAT2 expression (Nizzardo, Nardini et al. 2011). Glutamate
neurotoxicity may contribute as a pathological mechanism for autism (Harada, Taki et al. 2010).
There is an abnormality of GABA to glutamate ratio (Harada, Taki et al. 2010) or imbalance of
the inhibitory to excitatory systems in the neurobiology of autism (Polleux and Lauder 2004).
Glutamate synthesis inhibition attenuates the neurotoxic activity in Rett’s syndrome (Maezawa
and Jin 2010). It is suggested that the factors which attenuate the hyperglutaminergic state in
autism may improve its symptoms (Ghanizadeh 2010). Also, improving GABAergic system is
proposed to be effective (Ghanizadeh 2010).
Glutamate is a crucial neurotransmitter in the brain. It is released from cells into extracellular
fluid and then removed by glutamate transporters. This transportation contributes the controlling
of excitatory synaptic transmissions.
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The excitatory amino acid transporter of EAAT2 (or GLT1) is one of the main glutamate
transporters in brain. About 90% of glutamate transporters in brain are EAAT2 (Yamada,
Kawahara et al. 2006). Excitatory amino acid transporters keep the extracellular glutamate level
less than the neurotoxic level and GLT-1 is the major determinant of glutamate level in
extracellular fluid. The decreased expression and function of astrocyte glutamate transporters
enhances the levels of extracellular glutamate in epilepsy and Tuberous Sclerosis Complex
(Zeng, Ouyang et al. 2007). Tuberous Sclerosis Complex is usually co-morbid with epilepsy and
autism. Astrocyte glutamate transporters are deficient in animal models of epilepsy in Tuberous
Sclerosis Complex (Zeng, Bero et al. 2010). This abnormality is also reported in human and
animal models of epilepsy. In addition, targeting astrocytic mechanisms has been introduced as a
novel treatment approach for epilepsy and TSC (Zeng, Bero et al. 2010).
Cefixime is a beta lactam antibiotic. Ceftriaxone is also a beta lactam antibiotic improves
expression of glutamate transporter (GLT-1) (Nizzardo, Nardini et al. 2011) . These transporters
play an important role in vitro and in vivo for preventing of glutamate neurotoxicity. Ceftriaxone
decreases extracellular glutamate level by the enhancement of astrocyte glutamate transporters
expression (Zeng, Bero et al. 2010). In addition, ceftriaxon toxicity is very low. A recently
published study showed that ceftriaxone is neuroprotective during the acute phase of
ischemia (Kim and Jones 2012).
Already, the antagonism of glutamate receptors has been suggested for treatment of autism.
However, regulating glutamate transporter expression and activity has this advantage that it
minimizes the pathological impact from a glutamate overload while keeping the glutamate
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physiological role. Of course, it is not clear whether the transporter of extracellular glutamate
level is decreased.
Case presentation
The patient is a 9 year old boy with autism spectrum disorder according to Diagnostic and
Statistical Manual of Mental Disorders (DSM-IV). He suffers from generalized tonic clonic
epilepsy from age 4 years. He has taken different medications such as phenobarbital, sodium
valporate, and carbamazepine with sufficient dosages and durations. However, epilepsy has
never been controlled favorably. According to his parents’ report, the patient took cefixime
200mg/day to control diarrhea about 2 years ago. The seizure episodes were dramatically
decreased 3 days after starting the medication while the there was no change in anti-epileptic
medication regime. The seizure episodes were controlled for about 5 months. Then, the number
of seizure episodes increased. His highly educated parents administered cefixime 200mg/day to
control seizure again. They reported that seizure attacks were controlled markedly after taking
cefixime for three days. The patient was not febrile while the medication trials were
administered. Both parents reported that they repeated this trial for several times to control the
seizure episodes in the recent years. The epilepsy was controlled in all of the trials after taking
cefixime for 3 to 5 days. Then, they discontinued cefixime after 7 days. They reported that there
is a marked decreased in seizure attacks number and aggressive behaviors.
Physical examination did not show any other remarkable finding such as fever, headache, and
photophobia. Brain MRI did not any abnormal finding. No remarkable finding was found in
laboratory examination.
This is a case report. His parents provided their consent for publication of this report.
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Discussion
Neuroinflammation is proposed to have a contribution in neurobiology both autism and epilepsy
(Ghanizadeh 2011, Ghanizadeh 2011, Ghanizadeh 2012, Ghanizadeh 2012). Recently, antiinflammatory and immunosuppressive drugs showed some promising therapeutic effects for
autism (Asadabadi, Mohammadi et al. 2012) and epilepsy. For example, some antibiotics as
doxycycline or minocycline or tetracycline protect against seizures in experimental seizure
models in rats and mice (Wang, Englot et al. 2012). However, Clavulanic acid, which inhibits
bacterial b –lactamases did not affect convulsions in acute seizure tests in mice (Gasior, Socala et
al. 2012).
In several trials, cefixime was administered without any co-administered medication. Therefore,
no drug interaction was an explanation for this association. A few days seizure control cannot be
attributed to short course of cefixime but the patient experiences several consequent episodes of
seizure before administering cefixime. After administering cefixime, the several episodes of
seizure were stopped. Whenever, cefixime was not administered the episode of seizure happened
again.
Seizures induce brain inflammation and interleukin (IL)-1β damaging Blood brain barrier
(Librizzi, Noe et al. 2012). Some antibiotics such as minocycline may decrease the epileptic
seizure through anti-inflammatory effects (Beheshti Nasr, Moghimi et al. 2013). this effect can
be a possible explanation for the effect of cefixime on epilepsy.
In view of the limited number of treatment approaches for autism, the proposed role of glutamate
in pathophysiology of autism (Polleux and Lauder 2004), the promising efficacy of the
antagonism of glutamate receptors for treatment of autism (Erickson, Posey et al. 2007), the
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excitatory amino acid transporters role for keeping extracellular glutamate level less than the
neurotoxic levels , the increase of expression of glutamate transporter (GLT-1) by ceftriaxone
(Nizzardo, Nardini et al. 2011), according to the evidence, it seems to be reasonable to
hypothesize that modulating astrocyte glutamate transporter expression by ceftriaxone or
cefixime might be even at least partially effective treating approach for autism and epilepsy. Of
course, overexpression in vesicular glutamate transporter levels in Drosophila causes excess
glutamate release in which leads to excitotoxicity. So, the targeting of glutamate transporters
should be highly specific and intelligent. The level of glutamate is increased in autism and it is
propsed as a target for treating autism. Therefore, targeting glutamate by the antibiotic might be
effective for treating both autism and seizure. Well controlled clinical trials are recommended to
examine the effect of beta lactam antibiotics on the animal models of autism plus epilepsy. It
needs to be reminded that at least Cefepime, a fourth-generation cephalosporin antibiotic, is
associated with sezuire in some reports (Thabet, Al Maghrabi et al. 2009). Of course, further
studies should use more objective measures such as EEG monitoring and blood drug
concentration assessment. So, this report should be considered as a preliminary report.
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