Pearls & Oy-sters: Alternating hemiplegia of childhood mimics focal epilepsy and paroxysmal dyskinesia in infancy

Discussion

AHC is a rare disorder with an incidence of 1 in 1 million individuals.² Most cases are sporadic; however, in the rare familial cases, the inheritance is autosomal dominant.³ The most common mutation involves the ATP1A3 gene.¹ ATP1A3 is a part of the α subunit of Na⁺/K⁺ adenosine triphosphatase (ATPase) protein, which is responsible for normal transport of ions across neuronal membrane. The mutation reduces the activity of Na⁺/K⁺ ATPase without affecting the protein levels, resulting in impaired functioning. Mutation in the ATP1A3 gene is also associated with 2 other movement disorders: rapid-onset dystonia-parkinsonism and the syndrome of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS).⁴

The spectrum of clinical symptoms of AHC is broad and consists of episodic hemiplegia or quadriplegia, dystonic posturing, choreoathetoid movements, abnormal ocular movements, developmental delay, and progressive cognitive impairment.⁵ The first attack usually occurs between 3.5 and 7 months of age, although symptoms can be seen as early as the second day of life.^5,6 The diagnostic criteria for AHC have been defined below.⁵ Of these, criteria 1, 2, 3, and 7 are required for a definitive diagnosis of “typical” AHC.

1. Onset of paroxysmal events before 18 months of age

2. Repeated attacks of hemiplegia with attacks on right and left side of the body

3. Episodes of bilateral hemiplegia or quadriplegia starting either as generalization of hemiplegia attack or bilateral from the onset

4. Other paroxysmal events, such as tonic/dystonic attacks, nystagmus, strabismus; dyspnea or autonomic disturbances during the hemiplegia attack or in isolation

5. Disappearance of the symptoms with sleep followed by recurrence upon awakening

6. Evidence of developmental delay, cognitive impairment

7. Not attributable to any other cause

Hemiplegic attacks as the first sign of AHC is seen in only one-third of cases, whereas in the remainder, it is often followed by dystonic episodes or ocular abnormalities such as nystagmus. In fact, the incidence of dystonic episodes preceding the hemiplegic attacks is highest during the first 3 months of life.⁶ In our patient, the dystonic attacks preceded the hemiplegic attacks by 4 months. He was also noted to have transient abnormal ocular movements. Because of the variability in presenting symptoms, the diagnosis is challenging and can often be delayed or misdiagnosed as epilepsy. Although tonic gaze is a common presenting symptom of AHC,^6,7 it is a hallmark of focal seizures and presents a diagnostic challenge that is aided by video EEG. Co-occurrence or late occurrence of epileptic seizures with autonomic features is seen in 40% to 53% of patients with AHC. These patients often have autonomic dysfunction causing flushing, sweating, mydriasis, and sometimes respiratory distress with cyanosis, again mimicking seizures. However, features of bilateral episodic nystagmus or gaze deviation and periods of intermittent and alternating stiffening of extremities lasting minutes to hours with preserved responsiveness differentiate dystonic spells from seizures and should prompt the investigations toward this condition.

Treatment of AHC is challenging. The spells often abate with sleep, and efforts to identify and reduce triggers such as unexpected stimuli and stress are required. Treatment of AHC is symptomatic and is directed toward reducing the severity and duration of the paroxysmal spells. Anticonvulsant and calcium channel blockers are often used with variable success.² Alternatively, drugs such as acetazolamide or the ketogenic diet that may modify cellular pH, γ-aminobutyric acid, or metabolic pathways have been attempted.⁸ Such treatments may modify the neuronal membrane potential or the probability of neurotransmitter release but the mechanism is indirect and their efficacy remains unproven. The severity of the disease appears to be related to the genetic mutation, and whether treatment improves developmental outcome in addition to the frequency of the spells remains unclear.