Elsevier

Pediatric Neurology

Volume 103, February 2020, Pages 12-20
Pediatric Neurology

Topical Review
Management of Alternating Hemiplegia of Childhood: A Review

https://doi.org/10.1016/j.pediatrneurol.2019.10.003Get rights and content

Abstract

Alternating hemiplegia of childhood is a severe neurological disorder with infantile-onset recurrent episodes of hemiplegia on either side of the body and other paroxysmal events such as seizures, dystonia, tonic episodes, abnormal eye movements or autonomic dysfunction, primarily due to de novo pathogenic mutations in the ATP1A3 gene. The burden of neuromorbidities is significant and includes epilepsy; attention-deficit/hyperactivity disorder; behavioral difficulties; motor, cognitive, adaptive, and learning impairment; ataxia; movement disorders; and migraine. Comprehensive multispecialty clinic with the availability of various specialists with considerable experience in alternating hemiplegia of childhood is beneficial. A comprehensive treatment plan including strict maintenance of a diary about different paroxysmal events is helpful. Disease-modifying therapy of alternating hemiplegia of childhood does not exist, and several agents such as benzodiazepines, flunarizine, topiramate, ketogenic diet, triheptanoin, steroid, amantadine, memantine, aripiprazole, oral ATP, coenzyme Q, acetazolamide, dextromethorphan, and vagus nerve stimulator have been tried with various rates of success by aborting attacks or reducing the frequency or severity of paroxysmal spells. The apparent efficacy of flunarizine is based on its use in hundreds of patients, albeit in open-label experience, but most of the other agents’ reports of efficacy were from single case reports or case series of only a handful of patients. Besides reviewing existing data about individual agent active against paroxysmal events, we also review the management principles for coexisting neurological issues. However, with rapid advancement in the understanding of molecular pathogenesis and network abnormality of this disease, the treatment paradigm of alternating hemiplegia of childhood may significantly alter over the next decade.

Introduction

Alternating hemiplegia of childhood (AHC) is a severe neurological disorder with infantile-onset recurrent episodes of hemiplegia on either side of the body. Verret and Steele described this entity in 1971 in eight patients.1 Clinical features were clarified by Krägeloh and Aicardi with further distillation in later publications and formation of the generally accepted diagnostic criteria of AHC2,3 (Table 1). However, only in 2012, molecular abnormality of ATP1A3 had been discovered as the primary etiology of this rare disease.4,5 Some other genetic abnormalities such as pathogenic variants of ATPA12, SLC2A, and CACN1A can produce clinical manifestations closely mimicking those of AHC. Disease-modifying therapy of AHC does not exist, and several agents have been tried with various rates of success to ameliorate symptoms. However, with the rapid advancement in the understanding of molecular pathogenesis and network abnormality of this disease, the treatment paradigm of AHC may significantly alter over the next decade.

Section snippets

Comprehensive clinic and treatment plan

AHC is a rare disease with an annual incidence of less than 1/100,000 newborns. Thus, specialists with unique expertise in the management of AHC are scarce. However, a comprehensive multispecialty-dedicated AHC clinic can provide significant benefits by providing continuing care or intermittent consultation on an as needed basis.6 A detailed treatment plan including strict maintenance of a diary about different paroxysmal events can be useful. Physicians should teach caretakers how to maintain

Pathophysiology of AHC related to treatment implication

Different agents have been used over the years to counteract AHC symptoms. Researchers hypothesized several different mechanisms (improvement in glucose metabolism, normalization of serotonin, or dopamine abnormality) to explain the beneficial effect of these agents. However, since the discovery of the molecular etiology, the probable effectiveness of an agent was primarily explained by its action on the Na+/K+ pump, other channels present on the cell membrane, or an effect on the signal

Acute management of paroxysmal events

The most worrisome features of AHC are recurrent episodes of paroxysmal episodes, lasting for minutes to several days. Sometimes specific triggers can be identified. Patients should avoid modifiable triggers such as sleep deprivation, physical or mental exhaustion, and excessive stimulation, if possible. Triggers that are difficult to alter such as sickness, fever, menstrual cycles, accidental head trauma, and weather change may alert the caregiver to monitor for potential recurrence and

Benzodiazepines, Non-Benzodiazepine Sedatives, and Sodium oxybate

Several different benzodiazepines such as diazepam, midazolam, clonazepam, and lorazepam have been utilized. As the glutamatergic-GABAergic imbalance can be responsible for paroxysmal spells in AHC, benzodiazepines can be useful for epileptic and nonepileptic spells. The superiority of one type of benzodiazepine over others has not been studied. Pisciotta et al.16 reported 25 patients who were treated with diazepam with effectiveness reported in three-quarters of the patients. Approximately,

Flunarizine

At present, flunarizine is the most commonly used therapy; it is a nonselective calcium channel blocker, and rather than direct action on the pump, it may inhibit intracellular calcium accumulation.

AHC has some phenotypic similarity with familial hemiplegic migraine (FHM), and CACN1A is the most commonly known mutation associated with FHM. As flunarizine had been used effectively in FHM, it was first studied in AHC by Casaer and Azou.18 Soon afterward, Curatolo and Cusmai reported another

Ketogenic diet

Isolated case reports and case series describe a potential beneficial effect of the ketogenic diet. Initially, the diet had been used fortuitously due to a mistaken diagnosis of glucose transporter type 1 deficiency syndrome (GLUT-1 deficiency disorder) in which the ketogenic diet is the treatment of choice. Some authors proposed the ketogenic diet’s effect on transient glucose hypometabolism in AHC as a potential mechanism for improvement. Glucose hypometabolism in the positron emission

Triheptanoin

Triheptanoin is an artificially produced triglyceride oil composed of odd-carbon fatty acids; it is converted to ketone bodies in the liver and crosses the blood-brain barrier. In addition, it provides key intermediate substrates of the tricarboxylic acid cycle to function as an anaplerotic agent. However, a recent double-blind crossover placebo-controlled trial of triheptanoin in 10 patients with AHC failed to show improvement in the occurrence of paroxysmal events (seizures and nonepileptic

Topiramate

Although its precise mechanism of action is unknown, topiramate can block neuronal voltage-dependent sodium channels, enhances GABA(A) activity, antagonizes α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate glutamate receptors, and weakly inhibits carbonic anhydrase. Di Rosa et al.27 described a 10-year-old patient with AHC who did not respond to flunarizine but had a remarkable response from topiramate. Topiramate was started at 1 mg/kg/day and gradually increased to 4 mg/kg/day

Steroids

Wong et al.34 described a Chinese girl who had AHC secondary to D801 variant of ATP1A3 and hemiplegic attacks refractory to antiepileptic drugs, antimigraine drugs, and calcium channel blockers. However, her attacks completely stopped with a four-week course of betamethasone and promptly relapsed after stopping the steroid. However, her mother declined to restart steroid due to fear of side effects. Although glucocorticoid has demonstrated modulatory activity on the Na-K ATPase in animal

Amantadine

Amantadine is an N-methyl-d-aspartate (NMDA) glutamate receptor antagonist and has been used to counteract previously described glutamate-induced excitotoxic injury. Dextromethorphan and memantine have similar NMDA antagonist activity. Sone et al.35 reported two patients with AHC who had a reduction in the frequency and duration of paroxysmal episodes with treatment with amantadine. Neither patient responded to flunarizine and both had a persistent response over two years after amantadine

Memantine

Memantine is a noncompetitive NMDA receptor antagonist and effectively blocks receptor function during prolonged activation of the receptor in an excitotoxic state. Korinthenberg reported a child with AHC who responded to memantine (10 mg two times daily) with reduction of frequency, severity, and duration of the paroxysmal spells over 15 months period.36 The child previously had been refractory to several other medicines including flunarizine, acetazolamide, clobazam, and chloral hydrate. He

Aripiprazole

Aripiprazole is an atypical antipsychotic and has a novel mechanism of action with dopamine D2 receptor partial agonism. However, it binds other receptors in the brain such as serotonin receptors. Increased serotonin synthesis during and after hemiplegic attacks in PET studies (using l-tryptophan) was noted, as well as an increase in tyrosine in the cerebrospinal fluid during the acute presentation.8 Some researchers postulated that agents with a combination of activity against both serotonin

Oral ATP

Ju et al.39 reported the use of oral ATP in a six-year-old child with AHC (de novo ATP1A3 mutation). Dose-dependent reduction of frequency, duration, and severity of the hemiplegic episodes were noted during one-year follow-up when authors increased the oral ATP dose from 2 to 25 mg/kg/day. The child tolerated this well except for an occasional mild increase of the serum uric acid level. The authors hypothesized that ATP supplementation might help the dysfunctional ATPase and ATP might increase

Coenzyme Q

There are rare reports of mitochondrial dysfunction in individuals with AHC. Bhatt et al.40 reported a 17-year-old with AHC and complex IV deficiency who had a favorable response from coenzyme Q10; it has also been used in combination therapy with other agents.

Acetazolamide

Occasional patients may respond to acetazolamide. Camfield et al.41 reported two patients with long-term benefit from the use of acetazolamide (187.5 and 500 mg/day) with the reduction of episodes of hemiplegic attacks.

Vagus nerve stimulation

Helseth et al.45 investigated the role of vagus nerve stimulation in epilepsy and other paroxysmal spells in four patients with AHC. During the follow-up period of one to three years, all four patients had a more than 85% reduction of seizure frequency. Interestingly, both hemiplegic and dystonic spells also decreased in frequency in all four patients in the range of 60% to 92% and 60% to 90%, respectively. Side effects were mild, such as cough, hoarseness, and a mild increase of the

Management of epilepsy

Approximately 50% of patients with AHC develop epilepsy. No particular antiepileptic drug is superior to others. However, due to topiramate’s probable effect on the hemiplegic episodes, it has been used earlier for the management of epilepsy. Owing to disproportionate GABA dysregulation, a GABAergic medication such as clobazam can be used. Other antiepileptics with the various mechanisms of action such as phenobarbital, phenytoin, valproic acid, felbamate, ethosuximide, and levetiracetam have

Management of attention-deficit/hyperactivity disorder

A child diagnosed with AHC should have a detailed neuropsychiatric evaluation at the time of the diagnosis and then at periodic intervals. Different neuropsychiatric pathologies are prevalent including attention-deficit/hyperactivity disorder (ADHD), anxiety, mood dysregulation, obsessive-compulsive disorder, intellectual impairment, and global or specific domain cognitive delay. ADHD should be managed as with any other patients without AHC. Younger children can be started initially on

Management of behavior

Behavioral abnormalities are common in AHC. Other than ADHD, these patients can commonly have disruptive behavior and anxiety disorder.47 In some children, aggressive psychiatric management becomes necessary. Anecdotal report suggests that aripiprazole is better than risperidone or haloperidol for this purpose. However, aripiprazole still may worsen dystonia. Management of anxiety can be challenging. Selective serotonin reuptake inhibitors are usually not effective, and fluoxetine can induce

Management of motor, cognitive, adaptive, and learning impairments

Patients with AHC have significant difficulties related to impairments in these domains, and intensive physical, occupational, speech, and cognitive therapy may be useful for these individuals.48 Individualized education plan, and if necessary home-based therapy, becomes necessary. Therapists with knowledge and experience in managing patients with AHC can be helpful. As these patients may be quite friendly in between their acute attacks and also have better receptive language skill than

Management of movement disorders (choreoathetosis and dystonia)

Many children with AHC develop hyperkinetic involuntary movement disorders, sometimes slow and continuous choreoathetotic pattern, or more sustained and twisting dystonic pattern. A dopamine-depleting agent or a dopamine receptor blocker is more suited for such movements. Dopaminergic agents such as levodopa-carbidopa or dopamine agonists are useful for dystonia, but the response rate is poor in ATP1A3 mutation-related dystonia (personal observation). Tetrabenazine, a monoamine-depleting and

Management of migraine

Patients with AHC may develop disabling episodic headaches, consistent with migraines. International Headache Society classification system included AHC (A1.6.5) as an episodic syndrome that may be associated with migraine, along with infantile colic and vestibular migraine.50 Hemiplegic migraine was reported with overlapping symptoms of hemiplegic migraine and AHC, with ATP1A2 and SLC2A1 mutations.51 Management of headaches is standard; however, topiramate, CoQ, and valproate are most commonly

Directions for future research

The most frequently used medicine for AHC is flunarizine. A large number of patients were treated with flunarizine, but most studies evaluated effectiveness of flunarizine retrospectively. One prospective study was not successful as previously described. Flunarizine is not approved for any indication in the United States. To further improve the research related to flunarizine in AHC, interested sponsors should use two programs of the US Food and Drug Administration: the Orphan Drug Designation

Conclusion

A multidisciplinary team within a comprehensive program can provide an optimum treatment plan with both symptomatic and preventive treatment of this challenging condition. So far, only limited evidence exists for the use of currently popular agents. The level of evidence for most agents except flunarizine is of lower level as it came from a single or smaller number of a descriptive or qualitative study. Even for flunarizine, the evidence, although involves its use in hundreds of patients, is

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    Conflicts of interest: The author declares no potential conflicts of interest concerning the research, authorship, and publication of this article.

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