Alternating Hemiplegia of Childhood

Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder of children that was first reported in the 1970s and is characterized by recurrent “attacks” or episodes of loss of muscle tone, thereby resulting in weakness or paralysis on one or both sides of the body. These episodes are often triggered by various stressors and can be classified as either a hemiplegic attack (i.e., if one side of the body is affected) or a quadriplegic attack (i.e., both sides of the body are affected).  

A hallmark feature of AHC is that these paralyzing attacks often alternate from one side to the other, and in rare cases, affect both sides. Patients with AHC may also experience epileptic seizures, developmental delays, intellectual disability, and long-term neurocognitive impairments.

AHC is caused by genetic mutations in the ATP gene, most commonly mutations in the ATP1A3 gene, which is responsible for encoding proteins involved in a variety of biological processes including brain development and maintenance of sodium-potassium (Na+/K+) ATPase ion channel pumps. Na+/K+ ATPase ion channels help drive sodium and potassium ions across cellular membranes in the body and are an integral part of balancing ion concentrations in cells intra- and extracellularly. If ion concentrations are not well maintained, cells cannot produce action potentials, which are crucial for the release of neurotransmitters. Furthermore, mutations in the ATP1A3 gene are also associated with familial hemiplegic migraine, a complicated migraine (i.e., accompanied by neurologic deficits including hemiplegia and/or aphasia) inherited in an autosomal dominant fashion (i.e., requires only one mutated gene to cause disease) that usually occurs in the first or second decade of life. 

Other mutated genes including ATP1A2, CACNA1A, SLC1A3, and SLC2A1 have also been associated with the development of AHC. For example, the CACNA1A, SLC1A3, and SLC2A1 genes play a role in modulating neurotransmission and energy metabolism, and similar to the ATP genes, they help make up part of several voltage-gated ion channels. 

Diagnosis of AHC is primarily one of exclusion and it begins with a thorough review of symptoms, and medical and family history. A focused ocular and neurologic exam can help evaluate abnormal oculomotor symptoms and neurologic signs, respectively.  
 
The seven proposed diagnostic criteria of AHC include: 
(1) Onset of symptoms before 18 months of age 

(2) Recurrent hemiplegic or quadriplegic attacks 

(3) Quadriplegia that occurs as an isolated incident or as part of a hemiplegic attack 

(4) Absence of symptoms during sleep 

(5) Additional paroxysmal symptoms including dystonia, nystagmus, gaze deviation, or autonomic dysfunction 

(6) Evidence of neurocognitive sequelae including intellectual disability and developmental delay, or neurologic symptoms such as choreoathetosis and ataxia 

(7) Clinical presentation cannot be attributed to other neurologic disorders or causes
 
Routine and specialized laboratory testing can help exclude metabolic disorders that can also present with similar symptoms. For example, the presence of organic acids in the urine may suggest an inborn error of metabolism (i.e., a group of genetic diseases that occur due to mutations in metabolic pathways), which can be misdiagnosed as AHC since these genetic diseases present in a similar fashion. Additionally, a variety of imaging tests can be used to rule out other conditions. For example, magnetic resonance imaging (MRI) or computed tomography (CT) of the head can help identify potential structural etiologies (e.g., neoplasm) that may be causing neurologic symptoms. Additional specialized tests such as electroencephalogram (EEG), which measures electrical activity in the brain, are used to identify seizure disorders. Finally, molecular genetic testing through targeted gene sequencing, can help identify a pathologic variant within the several implicated genes (e.g., ATP1A3).

Currently, there is no cure for AHC, therefore management consists of supportive care measures aimed at improving the individual’s quality of life. Affected individuals may benefit from a multidisciplinary care team of medical professionals, special education specialists, physical therapists, and speech and occupational therapists. The goal of treatment is to reduce the frequency and severity of hemiplegic attacks. Non-pharmacologic strategies may include avoiding triggers (i.e., avoiding bright light exposure, excessive temperatures, foods, or odors) and maintaining a consistent sleep schedule with naps built in during the day.  

Pharmacotherapy with fluphenazine (i.e., antipsychotic with calcium channel blocking activity) has been shown to reduce the frequency, duration, and severity of non-epileptic episodes. Anticonvulsant medications (e.g., topiramate) have also been shown to reduce seizures, dystonia, and involuntary movements. Benzodiazepines (e.g., midazolam or rectal diazepam) can also be used to prematurely induce sleep in individuals as well as improve symptoms. Severe cases (e.g., quadriplegic attacks) where individuals have severe clinical impairments (e.g., difficulty swallowing, breathing, and paralysis) may warrant hospitalization for higher level care, especially if the airway is compromised or if the individual is unable to maintain nutritional status due to inability to eat and drink by mouth.