Table 2 Descriptions and representative quotes from parents characterizing the phases of the irritability episodes

Prodromal phase:

Occurs 1–2 days prior to the peak of the irritability episode

Families describe their children as having behavioral or physical changes indicating the impending onset of an irritability episode (13/14). They describe increase in vocalization (7/14), movements (6/14) and stiffness/spasticity (6/14); development of agitation (6/14), jaw clenching (5/14), inappropriate smiles/laughter (7/14), clammy hands and feet (7/14), an unusual smell (3/14), and decreased sleep (6/14)

There are several behavioral and movement symptoms that precede his bad episodes or storms as we call them. We start to notice 1–2 days prior to the cycle these symptoms: sleep disturbances, trouble sleeping, red clammy hands/feet, grinding his teeth, slight increased spasticity, and more sensitivity to his environment such as him giving us warning yells or the inappropriate laughter. The sensitivity to his environment includes not being able to tolerate people talking to him and responding with an inappropriate crazy laughter that actually then turns into a pout and a cry. It's his way of saying, "this is too much loud and too much input and I can't take it anymore, stop." Family 1

We can understand the bad cycle upcoming when we see a different gaze in the eyes of [our son]. He becomes disoriented, starts to contract muscles, puts his hands in his mouth, increases the salivation, his hands and feet have a cold sweat. Family 8

Stiffness in limbs, involuntary movement of arms and legs (dystonia) vomiting and nausea and retching, sleeplessness, not wanting to eat or drink. Manic laughing, restless and not sleeping. Family 5

I notice clammy hands, hot/sweating forehead, more rigidity in his arms and legs, constipation, serious/no smiles. Family 9

For a while she had a smell, coming from her breath/head, that we'd call the bad day smell. She'd get it the day before the bad days. It was a weird acidic sort of smell. Family 11

She starts with her right ear getting red and blotches of red on arms, chest, and face which usually signals one coming. She get very stiff and yells, cries, or laughs uncontrollably. Family 12

Peak phase:

The peak of the irritability episode lasts from 1 to 5 days, with the longest reported at 10 days

Parents describe the escalation of the episodes in various terms, including “storms”, “bad cycles”, “hypercycle”, “panic attacks”, “spells”, and “bad days”.^a The child’s vocalizations become screams/yells (14/14), abnormal movements increase including rolling, thrashing, and posturing (11/14), with stiffness and spasticity (11/14). Signs of agitation (8/14) and gastric symptoms (6/14) increase with some children not being able to eat or drink (5/14). Parents note that their child is unfocused and disengaged (5/14)

It is a painful scream and sometimes more fierce like a neurological crazy cry, like something is driving him crazy/mad and he cannot stop it. Family 1

When the bad cycle became worst, we lose him, he seems to be absent, and seems to be concentrated only on his pain. He is in another dimension, and we can do very little to calm him, to resolve the situation. Family 8

Behaviors that emerge or are more severe during an episode—biting or chewing of himself, temperature disregulation (he gets hot very quickly), GI discomfort. He goes from using communication techniques (nods or raising eyebrows) to not communicating at all (except to scream) Family 4

Irritability getting worse over time, will not sleep without sedative medications, thrashing hands, stomping feet, arching back, lifts head and swing back violently, wriggling around, restless body, turning head side to side, rubbing face -causing skin irritation, stiff, wants to be flat—does not want to sit. Eyes not focusing on anything in particular. Increase work of breathing, stridor is worse. Increased heart rate. Doesn't smile or laugh. Doesn't interact with family/carers. Sometimes bites fingers. Grinding teeth. Dry cracked lips. Head becomes very sweaty. Body temperature increases. Family 10

During these episodes, she is very irritated, it is better to leave her alone in the dark without noise. She can't stand being touched, talked to, cuddled… No communication is possible. Family 15

During a hypercycle (irritable cycle), he has involuntary movements and can roll in his bed for hours on end. There is a lack of sleep and that sometimes that lasts about 2–3 days maximum. Exercise (therapy), loud noises, chaos and light will only intensify his involuntary movements. He screams and makes a lot of loud noises. This escalates over 2–3 days till it reaches a peak and then it ends with a sleeping cycle. Family 7

We have noticed temp changes and he will be diaphoretic, clammy and have low grade fevers that are resolved once the cycle has stopped. Family 1

Resolving phase:

The episodes often end with the onset of sleep, tiredness, and lethargy, typically lasting 1–2 days

In the following days after the bad part of the cycle, [he] sleeps a lot, he is in general sloppy and with a very low tone, he eats and drinks with no rush…. we say that he is recovering from his marathon, from his endurance race. Family 8

The cyclic bad days would last 3–4 days often culminating in an evening of extreme nausea (nonstop gagging and retching) and then we knew the bad days were ending. She'd sleep that night and wake up better the next day. Often she'd sleep a day or two straight to recover from the bad days. Family 11

Since she doesn't sleep much during an episode, when she calms down she sleeps a lot for a couple of days. Family 12