Paroxysmal Extreme Pain Disorder

Paroxysmal Extreme Pain Disorder

Paroxysmal Extreme Pain Disorder is a manifestation of a sodium channelopathy due to a gain of function mutation affecting the SCN9A gene. It is characterized by episodes of excruciating rectal, ocular, or submandibular pain, accompanied by erythematous skin changes. The onset typically occurs during infancy or the neonatal period, and the disorder was previously referred to as familial rectal pain.

Genetics

Paroxysmal extreme pain disorder is caused by mutations in the SCN9A gene, which encodes the alpha subunit of a voltage-gated sodium channel called Nav1.7. This channel plays a crucial role in the generation and conduction of nerve impulses (action potentials), particularly in pain-sensing neurons (nociceptors). Mutations in the SCN9A gene lead to a gain of function, causing the Nav1.7 channel to open more easily and amplify pain signals. This results in the heightened pain sensitivity observed in individuals with PEPD.

The penetrance in families with SCN9A paroxysmal extreme pain disorder reported to date is 100%.

Clinical Features

The disorder is often characterized by:

• Autonomic manifestations during infancy, including skin flushing, harlequin (patchy or asymmetric) color change, tonic non-epileptic attacks (stiffening), and syncope with bradycardia.
• Older children and adults describe the pain as excruciating, burning, or sharp.
• Pain that is initially localized but spreads during severe attacks (e.g., from the rectum to the abdomen).
• Attacks lasting from seconds to two hours.
• Constipation between episodes due to reluctance to pass stool and precipitate a painful attack.
• The number of rectal attacks can decrease with age, whereas ocular and jaw attacks may increase with age.

PEPD episodes can be triggered by:

• Defecation or perineal wiping (rectal attacks)
• Eating (jaw attacks)
• Cold wind, temperature change, or crying (ocular attacks)

Differential Diagnosis

Differential diagnosis of SCN9A paroxysmal extreme pain disorder includes:

• Epilepsy: Atonic attacks in infants can resemble epileptic seizures, but EEG during attacks shows slowing without epileptiform activity.
• Hereditary Hyperekplexia
• Cardiac arrhythmia: Bradycardia and even asystole during atonic attacks may prompt evaluation for a primary cardiac cause.
• Gastrointestinal reflux: Pain, facial erythema, and crying after eating may resemble gastroesophageal reflux.

Management

Preventative Measures

To reduce the likelihood of triggering an attack:

• Use stool softeners
• Pass stool slowly

Medication

• Carbamazepine is the most effective (though not completely effective) treatment for reducing the number and severity of PEPD attacks.
• Additional anti-seizure medications, such as lamotrigine, topiramate, tiagabine, and sodium valproate, have been reported to have varying effectiveness.
• Analgesics and opiates are ineffective in the treatment of PEPD.

Resources

GeneReviews - SCN9A Neuropathic Pain Syndromes

Literature Review

Literature Review

Reviews from the last 7 years: review articles, free review articles, systematic reviews, meta-analyses, NCBI Bookshelf

Articles from all years: PubMed search, Google Scholar search.

TRIP Database: clinical publications about evidence-based medicine.

Other Wikis: Radiopaedia, Wikipedia Search, Wikipedia I Feel Lucky, Orthobullets,