What is AHC?

Signs & Symptoms

Whilst the name of the disease highlights its most characteristic symptom (recurrent attacks of hemiplegia that alternates between limbs and can include full-body quadriplegia), this condition encompasses a vast and wide-ranging complex constellation of neurological symptoms.[4, 5]  These neurological symptoms will vary and fluctuate during an individual’s life.
Some symptoms are episodic (also called paroxysmal, i.e having a sudden onset, a duration, and a conclusion, either spontaneous or induced by drugs) and some others are permanent manifestations, even if fluctuating in severity and intensity, and comorbidities.

Episodes

There are many types of paroxysmal symptoms in AHC including:

• seizures (both epileptiform and non-epileptiform) and episodes of status epilepticus
• dystonic (painful muscle rigidity) attacks (which can include full body dystonia),
• plegic (floppy/flaccid paralysis) attacks,
• episodes of nystagmus and other abnormal ocular movements,
• episodes of reduced awareness spells (RAS), tremor, chorea, migraines, and dysautonomia
• episodes of pain, either in association to other types of episodes or isolated 

Any and all of these types of paroxysmal symptoms occurring in an AHC person are referred to as ‘episodes.’  An episode can be a combination of several types of symptoms in one time period and vary greatly in frequency, severity, intensity, and duration between individuals as well as with age and with different seasons, without a specific pattern.

Epileptic seizures and seizure-like episodes may appear at different ages, from early infancy to late adulthood.[7]

Sleep plays a peculiar and critical role in AHC. A key part of the clinical diagnositc criteria is resolution of the plegic attacks during sleep. Therefore, inducing sleep during an attack is paramount to ending it.  However, it is recognised that on waking the attacks can re-occur within the first hour.  Parents usually take advantage of this short time of relief after a long-lasting attack, to feed and hydrate their children. Unfortunately, for some who have prolonged or frequent AHC episodes this is not adequate and supplemental feeding via a gastrostomy is required.

The triggers for episodes in AHC are vast and wide-ranging.[5, 8]  This makes it a very complex condition to manage in everyday life.  Common triggers include excitement, fatigue, temperature change, water, pain, constipation, fever or illness, sunlight …… Many attacks, however, appear without a specific trigger and are totally unpredictable.
The live of families living with AHC is unpredictable. A child can be happy and playing and suddenly, often with little to no warning, an AHC episode can be triggered that can be a mild paralysis to full-blown life-threatening episodes. An episode can last few minutes or hours and even days/weeks, interrupted only briefly by sleep or by drugs.  Parents spend their lives trying to minimise triggers, but the condition is sometimes described as a timebomb where they are “just waiting, waiting for it to go off.”

Genetic Causes

In 2012 a group of mutations in the ATP1A3 gene (located on chromosome 19) was identified as causing AHC in approximately 70-80% of cases[2, 14, 15]  The ATP1A3 gene encodes a protein functioning as a sodium-potassium ion pump at the neuronal level (Na+, K+-ATPase)[3]  and has a critical role in the regulation of the nervous system.  Recently, it has also been found to be expressed in the heart.[11, 16]  Prior to this, the cause of AHC was unclear with many theories hypothesised.  This genetic mutation is now included in rare epilepsy genetic panels, no doubt leading to more individuals being correctly diagnosed.
Currently around one hundred different ATP1A3 mutations are reported to cause AHC: some of them are more frequent (D801N and E815K), some others are single-case mutations. Almost always the mutations are de-novo, i.e not inherited from the parents. Additionally, for a minority, the mutation is within the ATP1A2 gene.[17, 18]
For the remaining approximately 20% of patients with a clinical diagnosis of AHC the genetic basis is yet unknown.  Research is still ongoing searching for an additional gene(s) involved.  Other genetic mutations have been proposed as causing AHC, but are either not yet conclusively linked or don’t fit the full AHC diagnostic criteria and are instead a differential diagnosis.[19, 20, 21, 22]

Several large-scale genotype-phenotype studies have been carried out showing that some ATP1A3 mutations are associated with more severe phenotypes (E815K, pGlu815Lys), some intermediate phenotypes (D801N, pAsp801Asn), and some milder phenotypes (G947R, pGly947Arg).[6, 23, 24, 25, 34] However, the variation in the different mutations does not fully explain the clinical variation with the varied phenotypes, leaving researchers with many unanswered questions about the possible role of other genes/variation across the whole genome or epigenetic factors influencing pathogenic variation or protein misfolding/varied ratio of normal to mutant ATP1A3 proteins.[26, 27]

Treatment & Management

There is no regulatory approved treatment for AHC.

Antiepileptic drugs are used for those patients with confirmed seizures and episodes of status epilepticus.
For AHC-specific episodes, several drugs are used both as prophylaxis, to reduce the frequency, duration, and severity of the episodes, and as acute treatment, to interrupt an ongoing episode.

For prophylaxis, Flunarizine is the only drug effective for most patients, albeit in open-label experience.[35, 36, 37, 38, 39]. Other drugs are used for prophylaxis (topiramate, acetazolamide, memantine, aripiprazole, and more recently, ketogenic diet, oral ATP, and anecdotally cannabinoids), but most of these other drugs’ reports of efficacy are from single case reports (e.g. oral ATP) or case series of only a handful of patients. [37, 40, 41, 42, 43].

Treatment for dystonia can sometimes include medications such as benzodiazepines, trihexyphenidyl, gabapentin, clonidine, and baclofen.

For acute treatment, the most effective reported drugs are benzodiazepines and chloral hydrate. Other drugs like niaprazine and melatonin are used to induce sleep, either for a more regular sleep pattern or to interrupt an ongoing episode.

For severe and long-lasting plegic/dystonic episodes, and for seizures or status epilepticus, hospitalization may be necessary, and more specific treatment and measures may be adopted.

In addition to pharmacological treatment, with the aim to reduce their frequency, a preventive measure can be to limit the exposure to the most known triggering factors for AHC episodes.

Cardiac abnormalities should be properly treated and monitored, while irregular sleeping patterns should be avoided as much as possible. 

A multispecialty reference center with the availability of various specialists with considerable experience in AHC should take charge of patients, directly or through a local centre.

The multispecialty team should provide regular follow-up visits, including:

• a neurological and neuropsychological assessment
• an ophthalmological and a gastroenterological assessment.
• sleep and respiratory assessment
• cardiac assessment and allied healthcare professional assessments (physiotherapy, occupational therapy, and Speech, and Language Therapy assessments)

They should also coordinate and support any other involved local service: rehabilitation, education, and schooling, social and home assistance, psychologic support,  emergency services for the treatment of prolonged dystonic/plegic attacks and seizures/episodes of status epilepticus …

Adult patients and their families need to be supported in the transition from pediatric neurology to neurology for adults. There is far less knowledge of AHC amongst the adult physicians given it is a relatively new disease.