|Ahead of print
Carbamazepine-responsive chorea in a toddler with semilobar holoprosencephaly: Case report
Leonardo Ajuz do Prado Oliveira1, Izabela Mara Martins Silveira1, Thiago Ribeiro e Silva1, Daniel Almeida do Valle2
1 Pediatrics Department, Universidade Positivo, Curitiba, Brazil
2 Department of Pediatric Neurology, Hospital Pequeno Príncipe, Curitiba, Brazil
|Date of Submission||03-Sep-2020|
|Date of Decision||10-Jan-2021|
|Date of Acceptance||24-Mar-2021|
|Date of Web Publication||07-Jan-2022|
Daniel Almeida do Valle,
Department of Pediatric Neurology, Hospital Pequeno Príncipe, Rua Desembargador Mota 1070
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Introduction: Holoprosencephaly (HPE) is a central nervous system malformation defined by incomplete separation of the prosencephalon in two hemispheres and determines a broad spectrum of clinical presentations based on extension of non-separation. Case Presentation: A 1 year and 8 months’ old girl with semilobar HPE and 18p deletion syndrome was admitted to our hospital due to viral bronchiolitis. During hospitalization, she started generalized choreic movements, with face dyskinesia and without any identified aggravating factors. Haloperidol, clonazepam, and valproic acid did not achieve an attenuation of the movement disorder. Significant symptom relief was obtained with the use of trihexyphenidyl, with reduced amplitude and frequency of movements, but hyperthermia compromised its use. Control of chorea with no important side effects was only achieved after the introduction of carbamazepine. Discussion: Despite significant morbidity, there are few cases described in the literature of chorea and movement disorders in HPE and no effective treatment strategies described. Carbamazepine is an antiepileptic drug that stabilizes voltage-gated sodium channels and is the most effective treatment for paroxysmal kinesigenic dyskinesia. Although it has been used successfully in the treatment of different movement disorders, few therapeutic trials have been reported. The mechanism by which carbamazepine alleviates chorea is still unknown but may be justified through the blocking of post-synaptic dopamine receptors and stimulation of cholinergic pathways.
Keywords: Anticonvulsants, carbamazepine, case report, chorea, holoprosencephaly
| Introduction|| |
Holoprosencephaly (HPE) is a central nervous system (CNS) malformation defined by incomplete separation of the prosencephalon in two hemispheres., The main causes, after chromosomal abnormalities, are microdeletions and microduplications, corresponding to up to 10% of the cases. HPE determines a broad spectrum of clinical presentations based on the extension of the non-separation.,,
Although chorea in children usually presents with an acute or subacute onset due to an acquired cause, it can also be caused by brain malformations. The clinical presentation of movement disorders in association with HPE is complex, with different abnormal movements described.,,
In this study, we report a case of a toddler with semilobar HPE due to chromosome 18p deletion syndrome with carbamazepine-responsive chorea.
| Case Presentation|| |
A 1 year and 8 months’ old girl with semilobar HPE and 18p deletion syndrome was admitted to our hospital due to viral bronchiolitis. During hospitalization, she developed generalized choreic movements, with face dyskinesia without any aggravating factors. During the first evaluation of the paroxysmal event, a family video and an electrophysiological study of the event classified the crisis as non-epileptic, and so the diagnosis of chorea was confirmed.
The starting treatment for the condition was a combination of haloperidol and clonazepam, but an unsatisfactory response was achieved, even after dose adjustment. Facing therapeutic failure, valproic acid was started, with a maximum dose of 60 mg/kg/day, without improvement in movement disorders. Notable symptom relief was obtained with the use of trihexyphenidyl, with reduced amplitude and frequency of movements, but with significant side effects — hyperthermia — which compromised its use.
The withdrawal of trihexyphenidyl was enough to resolve the episodes of hyperthermia; however, the patient returned with severe choreic movements. Control of chorea with no important side effects was only achieved after the introduction of carbamazepine, at a dose of 20 mg/kg/day. The patient was discharged using carbamazepine (20 mg/kg/day), diazepam (0.4 mg/kg/day), and valproic acid (40 mg/kg/day).
| Discussion|| |
Although uncertain, the most likely pathophysiology of chorea in HPE is assumed to be due to incomplete separation of the basal ganglia, leading to dysfunction.,, Patients with HPE lobar form ordinarily have milder motor dysfunction when compared with those with alobar and semilobar forms. However, this hypothesis was unconfirmed in a study carried out in 68 patients with HPE, in which the degree of non-separation of the caudate and lentiform nuclei did not correlate with choreoathetosis.
Despite the significant morbidity, there are few cases described in the literature of chorea and movement disorders in HPE and no effective treatment strategies described.,, The main treatment is based on dopamine-depleting agent, because of selective inhibition of pre-synaptic vesicular monoamine transporter type 2 (VMAT2) mechanism, which results in dopamine degradation by monoamine oxidases before uptake in synaptic vesicles, leading to dopamine depletion., Tetrabenazine, the most used agent of its class for this condition, is the drug approved by the US Food and Drug Administration (FDA) for the treatment of chorea associated with Huntington’s disease and has been reported to be effective in specific etiologic subgroups of childhood-onset chorea. However, it is unavailable in our country. Instead, other drugs that target on dopamine pathway, as dopamine D2 receptor-blocking agents, such as haloperidol, have been also used for a long time in chorea. The more potent the D2 receptor-blocking action, the better is antichoreic efficacy, but there is also a considerable risk of developing tardive dyskinesia. Side effects related to this medication, such as dystonia, Parkinsonism More Details, and drowsiness, limit its use.
Trihexyphenidyl is an anticholinergic drug with good results for controlling dystonia in patients with HPE and also for controlling other movement disorders in anecdotal reports.,, Although our case describes a patient that achieved good control with trihexyphenidyl, side effects limited its use. Common adverse effects include those typically related to anticholinergic drugs such as dry mouth, dry eyes, constipation, decreased sweating, and potential for overheating. The hyperthermia presented by the patient worsened her movements, making its use unsustainable.
Valproic acid has also been reported as efficacious in treating chorea caused by kernicterus, post-traumatic, post-anoxic, and stroke and so persists as one of the first alternatives for controlling chorea in children. Despite the lack of randomized studies, there are reports of improvement in chorea with benzodiazepine use, especially clonazepam. However, none of these drugs was effective for chorea control in the case reported.
Carbamazepine is an antiepileptic drug that stabilizes voltage-gated sodium channels and is the most effective treatment for paroxysmal kinesigenic dyskinesia. Although it has been used successfully in the treatment of different movement disorders, few therapeutic trials have been reported., The mechanism by which carbamazepine alleviates chorea is still unknown but may be justified through the blocking of post-synaptic dopamine receptors and stimulation of cholinergic pathways. To our knowledge, carbamazepine had not been described with favorable results in patients with chorea due to HPE.
The present case aims to alert the presence of movement disorders, like chorea, in patients with HPE, which can manifest with prominence and severity and high impact on the quality of life of these patients and carbamazepine may be beneficial in the management of these hyperkinetic movements. Likewise, these facts emphasize the need for clinical trials, studies, and better-standardized guidelines for the treatment of chorea, especially in patients with HPE and other structural causes.
Financial support and sponsorship
No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.
Conflicts of interest
The authors declare that there are no additional disclosures to report.
Ethical compliance statement
The Hospital Pequeno Principe’s Ethics Research Committee reviewed and approved the study (CAAE: 32558420.3.0000.0097). The authors obtained written informed consent from the patient. We affirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
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