The Treatment of Autism With Low-Dose Phenytoin
The Treatment of Autism With Low-Dose Phenytoin
ASDs are characterized by social deficits and communication difficulties, and stereotyped or repetitive behaviors and interests. The social deficits have been noted in autism as a failure to understand the intentions and mental states of others. The treatment of ASD has remained difficult. The only psychotropic interventions with research data strong enough to obtain a rating of 'established evidence' have been within the antipsychotic class and are for the treatment of the behavioral manifestations of ASDs.
In this case report I have described the clinical presentation of a patient with ASD who benefited clinically with increased social functioning from treatment with low-dose phenytoin. The initial sublingual test dose provided a more rapid onset of therapeutic effect compared with the variable absorption often associated with oral phenytoin, although the speed of response was consistent with other pharmaceuticals agents. The medication was well tolerated and resulted in improvements in multiple domains including the core social deficits associated with ASD. Perhaps the most significant social change was my patient's ability to establish and maintain eye contact during conversation. This provided an enhanced and more comfortable social engagement and a sense of real-time feedback on the outcome of conversation that previously had not occurred. His ability to sustain eye contact and interpret non-verbal communication may have contributed to a reduction in social anxiety and the improvement in quality of life reported by my patient and his family.
This clinical case report provides potential evidence that a low dose of a widely used anti-epileptic medication, phenytoin, may be capable of modifying the core social cognitive deficits associated with ASDs. These clinical improvements were reflected and maintained for over seven months in the AQ and DASS.
My previous clinical observations in similar patients led to use of sub-therapeutic doses of an anti-epileptic medication to improve social cognition. This discovery was unexpected and I am unaware of prior similar scientific reports. The pharmacological action of anti-epileptic medication in ASD is not entirely unexpected because the conditions may have a common neurodevelopment origin, although a precise link between these two pathologies is still undetermined. The ability of a low dose of an anti-epileptic medication to rescue autistic behavior in an animal model has already been established. Dravet's syndrome (DS) is a form of autism and epilepsy in which there is a SCN1A mutation that encodes for VGSC type-1 (NaV1.1), the primary sodium channel in the GABAergic interneurons. An SCN1A haplo-insufficiency results in a reduction of GABAergic transmission. Han et al. reported that treatment with low-dose (1/40th of the therapeutic dose) clonazepam, a positive allosteric modulator of GABAA receptors, completely rescued the abnormal social behaviors and deficits in fear memory in the mouse model of DS, demonstrating that they are both caused by impaired GABAergic function and sensitive to very low (sub-therapeutic) doses of an anti-epileptic medication.
ASDs are increasingly thought to be characterized by a disruption in the excitatory and inhibitory balance of neural activity. Mutations in genes involved in the expression of excitatory and inhibitory neurotransmitters (for example, glutamate and gamma-aminobutyric acid (GABA)) have been identified in individuals with ASD. This has been supported by increasing evidence that autism and related developmental conditions involve a GABA deficit. More recently, strong evidence has been building for a role of lesions in neuronal voltage-gated sodium channel (VGSC) alpha subunits in typical polygenic ASD. These channels are also the therapeutic targets of phenytoin in the brain. The VGSC gene family comprises nine homologous members, SCN1A to SCN11A, that encode the sodium-selective ion channels NaV1.1 to NaV1.9. SCN1A, SCN2A, SCN3A, SCN7A and SCN8A are associated with ASD. Whole-exome sequencing of nearly 1000 individuals identified SCN2A as the sole gene in which two independent probands had non-sense variants that disrupted the same gene, a highly significant result. The importance of VGSCs in typical polygenic ASD was also supported by a separate large sequencing study that found de novo protein-altering mutations in the gene in probands with ASD.
I hypothesize that, in a similar mechanism to the low-dose clonazepam in this animal model of autism, low-dose phenytoin may enhance GABA neurotransmission, thereby correcting the imbalance between the GABAergic and glutaminergic systems.
Discussion
ASDs are characterized by social deficits and communication difficulties, and stereotyped or repetitive behaviors and interests. The social deficits have been noted in autism as a failure to understand the intentions and mental states of others. The treatment of ASD has remained difficult. The only psychotropic interventions with research data strong enough to obtain a rating of 'established evidence' have been within the antipsychotic class and are for the treatment of the behavioral manifestations of ASDs.
In this case report I have described the clinical presentation of a patient with ASD who benefited clinically with increased social functioning from treatment with low-dose phenytoin. The initial sublingual test dose provided a more rapid onset of therapeutic effect compared with the variable absorption often associated with oral phenytoin, although the speed of response was consistent with other pharmaceuticals agents. The medication was well tolerated and resulted in improvements in multiple domains including the core social deficits associated with ASD. Perhaps the most significant social change was my patient's ability to establish and maintain eye contact during conversation. This provided an enhanced and more comfortable social engagement and a sense of real-time feedback on the outcome of conversation that previously had not occurred. His ability to sustain eye contact and interpret non-verbal communication may have contributed to a reduction in social anxiety and the improvement in quality of life reported by my patient and his family.
This clinical case report provides potential evidence that a low dose of a widely used anti-epileptic medication, phenytoin, may be capable of modifying the core social cognitive deficits associated with ASDs. These clinical improvements were reflected and maintained for over seven months in the AQ and DASS.
My previous clinical observations in similar patients led to use of sub-therapeutic doses of an anti-epileptic medication to improve social cognition. This discovery was unexpected and I am unaware of prior similar scientific reports. The pharmacological action of anti-epileptic medication in ASD is not entirely unexpected because the conditions may have a common neurodevelopment origin, although a precise link between these two pathologies is still undetermined. The ability of a low dose of an anti-epileptic medication to rescue autistic behavior in an animal model has already been established. Dravet's syndrome (DS) is a form of autism and epilepsy in which there is a SCN1A mutation that encodes for VGSC type-1 (NaV1.1), the primary sodium channel in the GABAergic interneurons. An SCN1A haplo-insufficiency results in a reduction of GABAergic transmission. Han et al. reported that treatment with low-dose (1/40th of the therapeutic dose) clonazepam, a positive allosteric modulator of GABAA receptors, completely rescued the abnormal social behaviors and deficits in fear memory in the mouse model of DS, demonstrating that they are both caused by impaired GABAergic function and sensitive to very low (sub-therapeutic) doses of an anti-epileptic medication.
ASDs are increasingly thought to be characterized by a disruption in the excitatory and inhibitory balance of neural activity. Mutations in genes involved in the expression of excitatory and inhibitory neurotransmitters (for example, glutamate and gamma-aminobutyric acid (GABA)) have been identified in individuals with ASD. This has been supported by increasing evidence that autism and related developmental conditions involve a GABA deficit. More recently, strong evidence has been building for a role of lesions in neuronal voltage-gated sodium channel (VGSC) alpha subunits in typical polygenic ASD. These channels are also the therapeutic targets of phenytoin in the brain. The VGSC gene family comprises nine homologous members, SCN1A to SCN11A, that encode the sodium-selective ion channels NaV1.1 to NaV1.9. SCN1A, SCN2A, SCN3A, SCN7A and SCN8A are associated with ASD. Whole-exome sequencing of nearly 1000 individuals identified SCN2A as the sole gene in which two independent probands had non-sense variants that disrupted the same gene, a highly significant result. The importance of VGSCs in typical polygenic ASD was also supported by a separate large sequencing study that found de novo protein-altering mutations in the gene in probands with ASD.
I hypothesize that, in a similar mechanism to the low-dose clonazepam in this animal model of autism, low-dose phenytoin may enhance GABA neurotransmission, thereby correcting the imbalance between the GABAergic and glutaminergic systems.