Clinical manifestations

Presentation and course

The classical clinical features of this disorder are as follows (01):

	(1) Onset before 18 months of age;
	(2) Recurrent attacks of hemiplegia involving either side of the body;
	(3) Other paroxysmal episodes, including tonic spells, dystonia, chorea, nystagmus, dyspnea, and autonomic disturbances, occurring in association with the episodes of hemiplegia or independently;
	(4) Episodes of bilateral hemiplegia either at the onset of the attack or as the attack shifts from one side of the body to the other;
	(5) Resolution of the hemiplegia with the onset of sleep and prolonged episodes of recurrence 10 to 20 minutes after awakening;
	(6) Evidence of developmental delay and other neurologic abnormalities such as choreoathetosis, dystonia, and ataxia.

The presence of all of these criteria is not necessary to make the diagnosis in an otherwise typical case. Eighty-five percent of patients have paroxysmal eye movements within the first 3 months of life, which often herald the onset of symptoms. Thirty-two percent of patients had abnormal eye movements, often nystagmus, noted within 1 to 2 days of birth (37; 30). The patient may have episodes of head and eye deviation with ipsilateral limb extension associated with crying. Nystagmus and dyspnea may also occur. Hemiplegia of the affected side may follow. Consciousness is preserved. The duration of these attacks may vary from minutes to days. Hemiplegia is aborted with sleep but may recur on awakening. Episodes of quadriparesis may occur. The patients are usually flaccid unless there is superimposed dystonia. Episodes of dystonia, nystagmus, dyspnea, and autonomic symptoms, such as flushing or pallor, may occur independently of hemiplegic episodes. Some children may develop normally initially; however, developmental delay is usual. Chronic ataxia and choreoathetotic movements may develop during the course of the disorder and remain (22; 44).

According to a published series of 44 patients (16), the course of the disorder appears to consist of 3 phases. The first phase, lasting about 1 year, is characterized by mild developmental delay, intermittent nystagmus or eye deviation, and dystonic episodes. During the second phase, evolving over 1 to 5 years, patients experience episodes of hemiplegia and quadriplegia, lose developmental milestones, and begin to exhibit fixed neurologic deficits, choreoathetosis, and ataxia. During the third phase, patients continue to have episodes of hemiplegia, although at a lesser frequency, and neurologic deterioration plateaus. Earlier onset of the disorder appears to portend a poorer neurologic prognosis. A few patients, typically those with later onset or fewer spells, may maintain normal or near-normal intellect.

A study of 187 patients in the United States AHCF Registry (45) demonstrated a mean age of onset of paroxysmal symptoms of between 1.9 and 12.2 months of age, depending on the causative mutation involved. Between 50% and 80% of patients develop epilepsy, and most have developmental delay and cognitive impairment of variable severity, and genotype-phenotype correlations are relevant to these manifestations as well, although they are not reliable enough to provide prognostic information for the individual patient or family (18; 45).

In view of the genotypic and phenotypic heterogeneity of children with alternating hemiplegia of childhood, Mikati and colleagues have proposed assigning the diagnosis to children who manifest both of the essential criteria, plus either 3 major or 2 major and 3 minor criteria, as defined below (17):

	(1) Essential criteria
		(a) Paroxysmal episodes of hemiplegia that alternate between the 2 sides and/or of quadriplegia
		(b) Evidence of abnormal baseline neurologic development
	(2) Major criteria
		(a) Onset before 18 months of age
		(b) Episodes of dystonia
		(c) Different types of episodes occur independently or together at the same time with evolution from 1 or more symptoms to others during that 1 episode
		(d) Paroxysmal episodes of abnormal eye movements such as nystagmus and especially monocular nystagmus
		(e) ATP1A3 mutation
		(f) Plegic spells improve with sleep
	(3) Minor criteria
		(a) Epileptic spells alone or in combination with nonepileptic spells
		(b) Nonepileptic episodes of altered consciousness alone or in combination with other spells
		(c) Abnormal tone and/or motor function, often including coexistent hypotonia and dystonia, ataxia, choreoathetosis, and poor oral motor control
		(d) Episodes of autonomic dysfunction

Diagnostic workup at onset, including brain imaging, routine EEG, serum amino acid studies, urine organic acid assays, mitochondrial studies, and muscle biopsy, is normal. Ictal EEG can be normal as well (37).

Prognosis and complications

In typical cases of alternating hemiplegia of childhood with early childhood onset, motor and cognitive disability occurs. Many patients with this disorder develop intellectual impairment, spasticity, seizures, ataxia, and choreoathetosis. Developmental delay is a variable feature at onset. In a series of 9 patients, seizures typically developed after 2 years of age (31). The occurrence of status epilepticus correlated with poorer neurologic outcome. Patients in this group frequently show cerebellar atrophy and high signal in the hippocampus on MRI over time. However, 1 comprehensive longitudinal study of 157 patients with a mean onset of symptoms of 3.5 months showed no progression of clinical manifestations over up to 52 years. Most of the data for this study were collected retrospectively, but all patients were followed prospectively for 2 years. In addition, in this study, no statistically significant correlation between a history of severe paroxysmal hemiplegic/dystonic episodes and a worse neurologic outcome was identified (20). A longitudinal study underscores the progressive potential of this disorder in some patients (26).

Premature mortality has been described in patients with alternating hemiplegia of childhood and is unexplained by seizures or neurologic dysfunction alone. A study of 52 DNA-confirmed cases of alternating hemiplegia of childhood and 52 disease controls with epilepsy suggested that electrocardiographic abnormalities are more common in patients with alternating hemiplegia than in control patients with epilepsy, and have characteristics reflecting those of inherited cardiac channelopathies and most likely relate to impaired repolarization reserve (08).

Clinical vignette

A family was described by Rodriguez-Quiroga and colleagues and the vignette below is derived from this description (29).

A 19-year-old man first came to medical attention with anarthria, mild dysphagia, hypotonia, and severe bradykinesia involving all 4 limbs, and affecting face greater than arms and greater than legs. Tremor and stooped posture, frequently seen in Parkinson disease, were notably absent. Twelve other family members were interviewed and examined and the family was found to include individuals with episodic hemiplegia, epilepsy, mild cognitive impairment, developmental delay, dystonia, parkinsonism, and/or bulbar dysfunction. The pedigree of all neurologic dysfunction in this family was consistent with an autosomal dominant inheritance pattern. The affected family members were found to have a novel missense mutation in the gene ATP1A3.

Biological basis

Etiology and pathogenesis

Alternating hemiplegia is caused by mutations in the ATP1A3 gene. This gene codes for the alpha3 subunit of the Na,K-ATPase, a protein that is neuron-specific and highly expressed in the basal ganglia, cortex, hippocampus, and thalamus (13). Two mutations, D801N and E815K, predominate and a more severe phenotype generally is seen in the E815K cohort. For example, patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment, and a higher prevalence of status epilepticus. Of 34 unique mutations found by Viollet and colleagues in a study of 187 subjects, 31 (91%) were missense. Most of these mutations are clustered in exons 17 and 18 (45).

In a study of 155 patients meeting clinical criteria for alternating hemiplegia of childhood, Panagiotakaki and colleagues identified 132 patients with, collectively, 34 different mutations of ATP1A3 (19). In addition to finding differences in overall disease severity and age at onset of epilepsy, they found that mutations clustered in 5 distinct regions of the ATP1A3 gene, and there was some correlation between the region in which the mutation occurred and disease phenotype.

Development of a Xenopus oocyte model of mutant alpha3 expression has given rise to the functional correlate of this mutation with aberrant forward cycling in neurons. Forward cycling refers to the process by which ATP hydrolysis is used to drive the exchange of 3 Na+ outward for 2 K+ inward at the cell membrane. Under some conditions, this protein also serves as an ATP-driven H+ pump. In the oocyte model, the D801N, G947R, and E815K mutants of the alpha3 subunit are dominant negative and result in loss of forward cycling and consequent proton pumping by the Na+,K+ ATPase. It is not yet known how loss of forward cycling contributes to the clinical findings in alternating hemiplegia of childhood (13).

A murine knock-in model of mutant ATP1A3 expression demonstrates abnormal impulsivity, memory, gait, motor coordination, tremor, motor control, endogenous nociceptive response, paroxysmal hemiplegias, diplegias, dystonias, spontaneous recurrent seizures, and predisposition to sudden unexpected death. Electrophysiologically, hippocampal slices from these animals demonstrate hyperexcitable responses to 1 Hz pulse-trains of electrical stimuli delivered to the Schaffer collaterals and significantly longer duration of K+-induced spreading depression responses than controls (07).

Clinically, there is an expanding array of phenotypes associated with mutations in ATP1A3, suggesting that the specific mutation involved and/or epigenetic factors may modulate the manifestations of the genetic abnormality in a given patient and family (02; 32). One study of 39 Italian patients divided the cohort into 3 groups according to genotype and found evidence for correlation between genotype and phenotype in the disorder (03). In this cohort, 92.3% of the patients had a mutation of ATP1A3. Those with a p.Glu815Lys mutation constituted 23% of the sample and demonstrated earlier onset of plegic episode, were more frequently hypotonic and nonambulatory, more frequently had epilepsy, and had more severe dystonia than those with an p.Asp801Asn mutation (26% of the sample). The remaining patients with mutations of ATP1A3 had a variety of other mutations with generally later onset of symptoms and less severe disease. Patients with a p.Glu815Lys mutation were the most responsive to flunarizine in this study (03). A child with hemidystonia and polymicrogyria has been shown to have a de novo single nucleotide missense mutation (12).

A meta-analysis of studies collectively including 902 patients with ATP1A3 mutations demonstrated no consistent phenotype-genotype correlations; however, some interesting trends emerged. Complex rearrangements were found only in alternating hemiplegia of childhood. More than half of subjects with alternating hemiplegia of childhood had p.D801N or p.E815K mutation of ATP1A3; these mutations were not seen in any of the subjects with CAPOS. Patients who had both alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism tended not to have either of these two mutations either (14).

Epidemiology

The incidence of alternating hemiplegia of childhood has been estimated to be 1 in 1,000,000 live births (17). Most cases are sporadic, although occasional familial clusters have been reported.

Differential diagnosis

Confusing conditions

Early in the course of the disorder, when dystonic rather than hemiplegic episodes are more common, the differential diagnosis is broad. Diagnostic considerations often include partial epilepsy, which may require routine EEG and prolonged EEG to differentiate. Idiopathic torsion dystonia, an inherited condition characterized by episodes of dystonia that may begin in early childhood, may mimic the early dystonic episodes of alternating hemiplegia of childhood. However, these children do not experience the developmental decline seen in alternating hemiplegia of childhood. Similarly, dopa-responsive dystonia, a disorder nearly identical in manifestation to idiopathic torsion dystonia, may also resemble alternating hemiplegia of childhood; however, these patients respond dramatically to levodopa. Children with paroxysmal dystonic choreoathetosis, an autosomal dominant disorder, may present in infancy with spells of dystonia lasting minutes to hours but remain neurologically normal. Children with paroxysmal kinesigenic choreoathetosis exhibit numerous, very brief episodes of dystonia or chorea that are provoked by movement. They also remain developmentally normal. In benign dystonia of infancy, dystonic episodes of an arm or leg occur; these are not associated with any other neurologic symptoms and resolve by 5 years of age. Secondary causes of dystonia in young children include glutaric aciduria, GM1 and GM2 gangliosidoses, Hartnup disease, pantothenate kinase-associated neurodegeneration (PKAN), mitochondrial cytopathy, and congenital and acquired lesions of the basal ganglia (41). A syndrome consisting of alternating hemiplegia and epilepsia partialis continua has been ascribed to mutations in the TBC1D24 gene (28). In addition, GLUT1 deficiency has occasionally been associated with paroxysmal hemiplegia and contralateral EEG slowing (25; 46). Children with mutations in ATP1A2 have also been reported to demonstrate alternating hemiplegia and familial hemiplegic migraine of childhood. One case report suggests that NMDA receptor antagonists can be helpful in this disorder and are thought to involve glutamatergic toxicity (40). Gene sequencing studies, imaging, metabolic studies, and clinical course can help to differentiate these disorders from alternating hemiplegia of childhood. For example, one study demonstrated that adding consideration of the Combined Annotation Dependent Depletion score, an algorithm-based mutation analysis tool that integrates consideration of many different aspects of mutation pathogenicity, can increase diagnostic certainty over consideration only of clinical phenotype (44).

When hemiplegic spells and cognitive deterioration become manifest, the differential may broaden to include stroke and moyamoya disease in addition to epilepsy and mitochondrial disease. Imaging (including MRI and MRA) may help to exclude these possibilities, although the increasing availability and decreasing cost of gene sequencing testing may make these unnecessary.

Associated or underlying disorders

Complications of anesthesia, whether for diagnostic procedures or surgery, are particularly prevalent in children with alternating hemiplegia. They include cardiac arrhythmias, hypotension, seizures, dystonic spells, and apnea (21). The possibility of a link between anesthetic complications and autonomic dysfunction in alternating hemiplegia has been raised (24).

Diagnostic workup

In the evaluation of a child suspected of having alternating hemiplegia of childhood, careful physical and ophthalmologic examinations should first be performed in consideration of lysosomal storage disorders that can cause similar clinical presentations. Further evaluation should include ictal EEG monitoring (to look for epilepsy) and MRI with MRA (to look for structural or vascular lesions or white matter disease). It should be noted that the absence of epileptiform discharges on first ictal EEG does not preclude subsequent diagnosis of epilepsy. Although epileptic seizures can be the first paroxysmal symptom, an epileptiform EEG may be seen only subsequently (39). Whole exome sequencing should be performed if available, and, if negative for known causative mutations in ATP1A3, chromosomal analysis, urine organic acids (to rule out glutaric aciduria type 1), lactate and pyruvate, MR spectroscopy, and muscle biopsy should also be considered.

Management

Although a curative treatment is not known, several medications appear to have some efficacy in preventing hemiplegic spells. Flunarizine, a calcium channel blocker used for migraine in Europe but not available in the United States, is felt to be the most effective agent for preventing hemiplegic spells and has also been purported to improve neurologic prognosis (16; 33; 27). No specific dosing guidelines have been established; however, doses ranging from 5 mg/kg every other day to 12 mg/kg per day have been used. No prospective studies have been published. Benzodiazepines and chloral hydrate have also been used as prophylactic agents, although it is not clear whether or not the response seen is secondary to the hypnotic effects of these agents (35; 42). Amantadine and memantine, noncompetitive NMDA receptor antagonists, have also been reported to reduce the frequency of hemiplegic spells in patients unresponsive to flunarizine (10; 36). Treatment with older anticonvulsants has not been found to be fruitful for episodes of hemiplegia, and even patients with epileptiform ictal EEGs are often drug-resistant (39); however, several case reports have reported efficacy of topiramate, an anticonvulsant and migraine prophylactic agent, both in patients who have failed flunarizine and as a first line agent (04; 09). Unfortunately, in the largest series published, only 1 of 16 patients treated with topiramate showed improvement (38). In a small observational study, 6 patients in whom a vagal nerve stimulator was implanted noted decreased seizure frequency and a modest, but not statistically significant decrease in dystonic episode (39). Another group reported reduction in the frequency, duration, and severity of hemiplegic episodes in a teenage patient with an established diagnosis of alternating hemiplegia of childhood and treated with aripiprazole, an antipsychotic. The patient was inadvertently given an inactive drug and had deterioration, with subsequent improvement on reinitiation of active drug. Several reports of improvement with ketogenic diet therapy suggest that this approach should be considered (34). In addition, a single case report suggests that aripiprazole may be of use in patients whose symptoms are refractory to flunarizine (05).

Optimal management of children with alternating hemiplegia of childhood is best accomplished with a multidisciplinary team-based approach (15).