Paroxysmal extreme pain disorder
Encyclopedia
Paroxysmal extreme pain disorder (PEPD), originally named familial rectal pain syndrome, is a rare disorder whose most notable features are pain
in the mandibular, ocular
and rectal
areas as well as flushing
. PEPD often first manifests at the beginning of life, perhaps even in utero
, with symptoms persisting throughout life. PEPD symptoms are reminiscent of primary erythromelalgia
, as both result in flushing and episodic pain, though pain is typically present in the extremities for primary erythromelalgia. Both of these disorders have recently been shown to be allelic, both caused by mutations in the voltage-gated sodium channel NaV1.7 encoded by the gene SCN9A. PEPD also shares a genetic basis with channelopathy-associated insensitivity to pain, which causes hypo-sensitivity to pain.
, ocular
and mandibular regions. It should be stressed that while pain often originates or is centered in these areas it can also spread or be diffuse in nature. Pain experienced by patients with this disorder should not be underestimated as women with the disorder who have also given birth describe PEPD pain as worse than labor pain. Furthermore, nearly all patients have suggested a willingness to abort affected fetuses to prevent others from enduring such attacks. Concomitant with this pain is typically flushing
, often in an area associated with the pain.
During attacks in infants, the child often looks startled or terrified and can scream inconsolably. These attacks can be precipitated by injections, defecation, wiping of the perineum
, eating, or the consumption of oral medication. When attacks occur due to such precipitation, pain and flushing are often present in the area of attack precipitation, though symptoms may also be diffuse in nature.
Other symptoms may include hypersalivation when attacks are localized in the mandibular region, or leg weakness after foot trauma. A prominent non-physical symptom are tonic non-epileptic seizures. Such seizures are more common in infancy and childhood than during adulthood. In older children, inconsolable screaming usually precedes such attack, followed by apnea
, paleness, and stiffness. Such stiffness can last from seconds to a few minutes.
Attack precipitants are usually physical in nature, such as defecation, eating, or taking medicine. Some less common precipitants are micturition, coitus, and painful stimuli. There are also non-physical precipitants, such as the thought or sight of food. In general attacks tend to occur in the precipitated area, though this is not always the case. While some individuals have described a build-up to attacks, in general they tend to be abrupt. The duration of these attacks can be from a few seconds to two hours.
Patients are largely normal between attacks. The only notable interictal problem is constipation, likely due to apprehension of precipitating an attack. This symptom often decreases with age, likely due to coping mechanisms such as the use of stool softeners.
and EKG recordings. EKG recordings during attacks show sinus tachycardia
. CT
, MRI, EMG
and nerve conduction studies produce normal results. EEG
recordings are normal between attacks but show early-onset tachycardia
during attacks. On the Neuropathic Pain Questionnaire patients indicated that pain during attacks is extremely unpleasant and typically felt deep, though also superficial on occasion. Aside from presentation of typical symptoms (see Signs and symptoms above) mutation of the gene SCN9A aids in appropriate diagnosis as this gene is mutated in 8 of 14 studied families.
and sympathetic neurons
, where it aids in action potential
creation and regulation. The mutations in this gene that have received study all alter the channel's ability to inactivate. Sodium channel inactivation is vital for the proper cessation of action potentials. The decreased inactivation caused by these mutations, then, is expected to cause prolonged action potentials and repetitive firing. Such altered firing will cause increased pain sensation and increased sympathetic nervous system activity, producing the phenotype observed in patients with PEPD.
is at least partly effective at reducing the number or severity of attacks in the majority of PEPD patients. High doses of this drug may be required, perhaps explaining the lack of effect in some individuals. While other anti-epileptic drugs, gabapentin
and topiramate
, have limited effect in some patients, they have not been shown to be generally effective. Opiate
derived analgesics are also largely ineffective, with only sporadic cases of beneficial effect.
who are later determined to have PEPD. This suggests that rates of PEPD may be higher than currently believed.
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
in the mandibular, ocular
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
and rectal
Rectum
The rectum is the final straight portion of the large intestine in some mammals, and the gut in others, terminating in the anus. The human rectum is about 12 cm long...
areas as well as flushing
Flushing (physiology)
For a person to flush is to become markedly red in the face and often other areas of the skin, from various physiological conditions. Flushing is generally distinguished, despite a close physiological relation between them, from blushing, which is milder, generally restricted to the face, cheeks or...
. PEPD often first manifests at the beginning of life, perhaps even in utero
In utero
In utero is a Latin term literally meaning "in the womb". In biology, the phrase describes the state of an embryo or fetus. In legal contexts, the phrase is used to refer to unborn children. Under common law, unborn children are still considered to exist for property transfer purposes.-See also:*...
, with symptoms persisting throughout life. PEPD symptoms are reminiscent of primary erythromelalgia
Erythromelalgia
Erythromelalgia, also known as Mitchell's disease , acromelalgia, red neuralgia, or erythermalgia, is a rare neurovascular peripheral pain disorder in which blood vessels, usually in the lower extremities , are episodically blocked , then become hyperemic and inflamed...
, as both result in flushing and episodic pain, though pain is typically present in the extremities for primary erythromelalgia. Both of these disorders have recently been shown to be allelic, both caused by mutations in the voltage-gated sodium channel NaV1.7 encoded by the gene SCN9A. PEPD also shares a genetic basis with channelopathy-associated insensitivity to pain, which causes hypo-sensitivity to pain.
Symptoms and Signs
The most distinctive feature of PEPD is episodic burning pain of the rectumRectum
The rectum is the final straight portion of the large intestine in some mammals, and the gut in others, terminating in the anus. The human rectum is about 12 cm long...
, ocular
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
and mandibular regions. It should be stressed that while pain often originates or is centered in these areas it can also spread or be diffuse in nature. Pain experienced by patients with this disorder should not be underestimated as women with the disorder who have also given birth describe PEPD pain as worse than labor pain. Furthermore, nearly all patients have suggested a willingness to abort affected fetuses to prevent others from enduring such attacks. Concomitant with this pain is typically flushing
Flushing (physiology)
For a person to flush is to become markedly red in the face and often other areas of the skin, from various physiological conditions. Flushing is generally distinguished, despite a close physiological relation between them, from blushing, which is milder, generally restricted to the face, cheeks or...
, often in an area associated with the pain.
During attacks in infants, the child often looks startled or terrified and can scream inconsolably. These attacks can be precipitated by injections, defecation, wiping of the perineum
Perineum
In human anatomy, the perineum is a region of the body including the perineal body and surrounding structures...
, eating, or the consumption of oral medication. When attacks occur due to such precipitation, pain and flushing are often present in the area of attack precipitation, though symptoms may also be diffuse in nature.
Other symptoms may include hypersalivation when attacks are localized in the mandibular region, or leg weakness after foot trauma. A prominent non-physical symptom are tonic non-epileptic seizures. Such seizures are more common in infancy and childhood than during adulthood. In older children, inconsolable screaming usually precedes such attack, followed by apnea
Apnea
Apnea, apnoea, or apnœa is a term for suspension of external breathing. During apnea there is no movement of the muscles of respiration and the volume of the lungs initially remains unchanged...
, paleness, and stiffness. Such stiffness can last from seconds to a few minutes.
Attack precipitants are usually physical in nature, such as defecation, eating, or taking medicine. Some less common precipitants are micturition, coitus, and painful stimuli. There are also non-physical precipitants, such as the thought or sight of food. In general attacks tend to occur in the precipitated area, though this is not always the case. While some individuals have described a build-up to attacks, in general they tend to be abrupt. The duration of these attacks can be from a few seconds to two hours.
Patients are largely normal between attacks. The only notable interictal problem is constipation, likely due to apprehension of precipitating an attack. This symptom often decreases with age, likely due to coping mechanisms such as the use of stool softeners.
Diagnosis
Hematological, biochemical and metabolic investigations on blood and urine between attacks are normal, as are karyotypingKaryotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
and EKG recordings. EKG recordings during attacks show sinus tachycardia
Sinus tachycardia
Sinus tachycardia is a heart rhythm with elevated rate of impulses originating from the sinoatrial node, defined as a rate greater than 100 beats/min in an average adult. The normal heart rate in the average adult ranges from 60–100 beats/min...
. CT
Computed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
, MRI, EMG
Electromyography
Electromyography is a technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an instrument called an electromyograph, to produce a record called an electromyogram. An electromyograph detects the electrical potential generated by muscle...
and nerve conduction studies produce normal results. EEG
EEG
EEG commonly refers to electroencephalography, a measurement of the electrical activity of the brain.EEG may also refer to:* Emperor Entertainment Group, a Hong Kong-based entertainment company...
recordings are normal between attacks but show early-onset tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
during attacks. On the Neuropathic Pain Questionnaire patients indicated that pain during attacks is extremely unpleasant and typically felt deep, though also superficial on occasion. Aside from presentation of typical symptoms (see Signs and symptoms above) mutation of the gene SCN9A aids in appropriate diagnosis as this gene is mutated in 8 of 14 studied families.
Cause
The voltage-gated sodium channel NaV1.7 is expressed in nociceptiveNociception
Nociception is defined as "the neural processes of encoding and processing noxious stimuli." It is the afferent activity produced in the peripheral and central nervous system by stimuli that have the potential to damage tissue...
and sympathetic neurons
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
, where it aids in action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
creation and regulation. The mutations in this gene that have received study all alter the channel's ability to inactivate. Sodium channel inactivation is vital for the proper cessation of action potentials. The decreased inactivation caused by these mutations, then, is expected to cause prolonged action potentials and repetitive firing. Such altered firing will cause increased pain sensation and increased sympathetic nervous system activity, producing the phenotype observed in patients with PEPD.
Pathophysiology
There are a total of 8 mutations that account for the disorder in 8 of 14 studied families. These mutations are clustered in four regions throughout the channel: the linker between domains 2 and 3 (D2-3), the intracellular segment linking segments 4 and 5 in domain 3 (D3S4-5), the linker between domains 3 and 4 (D3-4) and the intracellular segment linking segments 4 and 5 in domain 4 (D4S4-5). The mutations in the D3S4-5 region (I1461T, F1462V and T1461I) are located in or next to an IFM motif that is conserved across all voltage-gated sodium channels. Mutagenesis studies of this region have shown that it acts as part of the inactivation gate, pivoting to block the central pore. Not surprisingly then, the two of these mutations that have received further study show incomplete inactivation. When the IFM motif pivots to block the central pore it interacts with residues in the D3S4-5 region. There are three mutations in this region (V1298F, F1298D and V1299F) that are believed to alter the interaction with the inactivation gate. While this region has been studied by mutagenesis these specific mutations have not all received attention, though they are expected to produce changes similar to the aforementioned IFM region mutations. The M1627K mutation in the D4S4-5 region may also affect a residue involved in interacting with the IFM inactivation motif. This would explain the observed alteration of inactivation and the broadening of a window current. One of the affected families with the R996C mutation, pedigree 12, has a single individual who also has the V1298D mutation. The individual in this family with the compound mutation is the most severely affected, suggesting that the R996C mutation may cause a less severe phenotype. The less severe phenotype of the pedigree 4 family is in concordance with this theory. It is unclear how the R996C mutation affects channel function.Treatment/Management
CarbamazepineCarbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
is at least partly effective at reducing the number or severity of attacks in the majority of PEPD patients. High doses of this drug may be required, perhaps explaining the lack of effect in some individuals. While other anti-epileptic drugs, gabapentin
Gabapentin
Gabapentin is a pharmaceutical drug, specifically a GABA analogue. It was originally developed for the treatment of epilepsy, and currently is also used to relieve neuropathic pain...
and topiramate
Topiramate
Topiramate is an anticonvulsant drug. It was originally produced by Ortho-McNeil Neurologics and Noramco, Inc., both divisions of the Johnson & Johnson Corporation. This medication was discovered in 1979 by Bruce E. Maryanoff and Joseph F. Gardocki during their research work at McNeil...
, have limited effect in some patients, they have not been shown to be generally effective. Opiate
Opiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...
derived analgesics are also largely ineffective, with only sporadic cases of beneficial effect.
Epidemiology
PEPD is an extremely rare disorder with only 15 known affected families. There are some cases, however, of individuals originally diagnosed with epilepsyEpilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
who are later determined to have PEPD. This suggests that rates of PEPD may be higher than currently believed.