Alternating hemiplegia of childhood
Encyclopedia
Alternating hemiplegia of childhood (AHC) is a rare neurological disorder of uncertain etiology
, which is named for the transient episodes, often referred to as attacks, of hemiplegia
from which those with the disorder suffer. These hemiplegic attacks can cause anything from mild weakness to complete paralysis
on one or both sides of the body, and they can vary greatly in duration. Attacks may also alternate from one side of the body to the other, or alternate between affecting one or both sides during a single attack. AHC is associated with many symptoms besides hemiplegia, and the majority of these become apparent in early infancy. AHC is considered normal if symptoms are present before 18 months of age. Normally, hemiplegia and other associated symptoms cease completely with sleep, but they may re-occur upon waking. The disorder was only recently discovered, having first been characterized in 1971. AHC is also extremely rare – approximately 1 in 1,000,000 people have this disorder. Besides hemiplegia, symptoms of the disorder include an extremely broad range of neurological and developmental impairments which are not well understood. Much of the literature about AHC is purposefully vague in this respect due to a lack of information on the disorder.
, which is also considered a paroxysmal symptom, plays an important role in the progression and diagnosis of AHC.
, dysarthria
, and respiratory difficulty. Paralysis is also often accompanied by changes in skin color and temperature, sweating, restlessness, tremor, screaming, and the appearance of pain. Hemiplegic attacks happen irregularly and can occur with speech, eating, and swallowing impairment. Patients with AHC are frequently underweight due to these side effects. The average age of onset for hemiplegic episodes has been found to be 6–7 months of age. This early onset gives the name of this disorder the slightly misleading ending 'of childhood'. AHC is not exclusively limited to childhood – attacks become milder after the first ten years of life, but they never completely disappear.
, tonic-clonic, or myoclonic limb movements, dystonic posturing, choreoathetosis
, occular nystagmus
, and various other ocular motor abnormalities. Almost half of all people have dystonic symptoms prior to experiencing hemiplegia. These symptoms generally begin before 8 months of age. Ocular motor abnormalities occur early, and these are the most frequent early symptoms of AHC, particularly nystagmus. Almost 1/3 of people with this disorder had episodic ocular motor features within 1–2 days of birth. Many also experienced hemiplegia and dystonia before 3 months of age. A final symptom that may be considered paroxysmal is a temporary change in behavior - some patients will become unreasonable, demanding, and aggressive either before or after an attack
Not all patients have all of these symptoms, and it is not known whether they are caused by AHC. Symptoms usually manifest in the first 3 months of the child's life, with an average onset of 2.5 months. Frequently, some of these symptoms will manifest in the neonatal period. These paroxysmal symptoms are often used to help diagnose AHC, since there is no simple test for it.
In some cases, EEGs taken during these paroxysmal events were characterized by a generalized background slowing. Overall however, ictal EEGs and other investigative methods such as MRIs, TACs, angiographic MRIs and CFS have normal results.
), and cognitive deficits. These deficits become more apparent over time and include developmental delays, social problems, and retardation. It is rare for someone with AHC not to have cognitive deficits, but a study in Japan did find two patients who met all of the diagnostic criteria for AHC but who were not mentally impaired. It is not know whether AHC is a progressive disease, but severe attacks are suspected to cause damage which result in permanent loss of function. 100% of children studied in the USA have had some form of mental impairment, which is usually described as mild to moderate, but varies greatly among individuals.
, and AHC is often misdiagnosed as epilepsy because of this. These epileptic events are distinguished from other episodes by an alteration of consciousness, as well as frequent tonic
or tonic-clonic activity. Epileptic episodes are generally rare, though they do increase with age. Due to the rarity of epileptic episodes, there are few EEG confirmations of them.
The following descriptions are commonly used in the diagnosis of AHC. The initial four criteria for classifying AHC were that it begins before 18 months of age, includes attacks of both hemiplegia on either side of the body, as well as other autonomic problems such as involuntary eye movement (episodic monocular nystagmus), improper eye alignment, choreoathetosis
, and sustained muscle contractions (dystonia). Finally, patients suffer from mental retardation, delayed development, and other neurological abnormalities. These diagnostic criteria were updated in 1993 to include the fact that all of these symptoms dissipate immediately upon sleeping. Diagnostic criteria were also expanded to include episodes of bilateral hemiplegia which shifted from one side of the body to the other.
Recent criteria have been proposed for screening for AHC early, in order to improve the diagnostic timeline. These screening criteria include focal or unilateral paroxysmal dystonia in the first 6 months of life, as well as the possibility of flaccid hemiplegia either with or separate from these symptoms. Paroxysmal ocular movements should also be considered, and these should include both binocular and monocular symptoms which show in the first 3 months of life.
because of strong family histories of migraine reported in AHC cases. AHC has also been considered to be a movement disorder or a form of epilepsy. Suggested causes have included channelopathy
, mitochondrial dysfunction, and cerebrovascular dysfunction. The disorder most closely related to AHC is familial hemiplegic migraine
, and this was recently discovered to be caused by a mutation in a gene for calcium channel receptors. It is suspected that AHC may be caused by a similar channelopathy, and this is a current area of investigation into the cause of AHC. An association with ATP1A2
mutation has been found in some patients, but other studies have found no mutations and thus a lack of evidence that mutations which cause AHC are in the same genes as mutations which cause familial hemiplegic migrane.
Because alternating hemiplegia of childhood is so rare, there is no increased risk of AHC for the children of siblings of someone with AHC, but it is believed to be autosomal dominant, by which a person with AHC has a 50% change of passing the disorder on to their children. AHC is questionably a progressive disease, because cognitive abilities do appear to decline over time. This cannot be completely determined however, because the mechanism of AHC's progression is unknown. It is likely that it is caused by a generalized cellular dysfunction caused by a mitochondrial disorder. However, studies involving mechanisms of AHC have been inconclusive. Experts currently researching this disorder believe that the cause of AHC is a mutated ion channel. This would make the cause difficult to find because one disrupted channel may be represented differently in different tissues. This mutation is suspected because the most closely related disease, FHM, is also caused by a mutated ion channel. A small number of genes which were suspected to carry a mutation for AHC have been screened for sodium channel protein mutations, ATP
pump mutations, and excitatory amino acid
transmitter mutations. None of these have yet been successful in determining the underlying cause of AHC.
. Flunarizine functions by acting as a calcium channel
blocker. Other drugs, in order of frequency of use are benzodiazepines, carbamazapine, barbiturates, and valproic acid. Flunarizine is prescribed for the purpose of reducing the severity of AHC attacks and the number of episodes, though it rarely stops attacks altogether. Minimizing the attacks may help reduce damage to the body from hemiplegic attacks and improve long-term outcomes as far as mental and physical disabilities are concerned.
Experts differ in their confidence in flunarizine's effectiveness. Some studies have found it to be very effective in reducing the duration, severity, and frequency of hemiplegic attacks. It is generally considered the best treatment available, but this drug is thought by some to be of little benefit to AHC patients. Many patients suffer adverse effects without seeing any improvement. Flunarizine also causes problems because it is difficult for patients to obtain, because it is not readily available in the United States.
is an effective treatment for AHC. Thus far, only a small number of patients have been sampled, and no conclusive results are yet available. While some success has been had thus far with the drug, AHC patients have been known to respond well initially to other drugs, but then the effectiveness will decline over time. Currently, sodium oxybate is used as a narcolepsy
-cataplexy
treatment, though in the past it has been used controversially in nutritional supplements. This drug was chosen to test because of a possible link between the causes of narcolepsy-cataplexy and AHC.
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
, which is named for the transient episodes, often referred to as attacks, of hemiplegia
Hemiplegia
Hemiplegia /he.mə.pliː.dʒiə/ is total paralysis of the arm, leg, and trunk on the same side of the body. Hemiplegia is more severe than hemiparesis, wherein one half of the body has less marked weakness....
from which those with the disorder suffer. These hemiplegic attacks can cause anything from mild weakness to complete paralysis
Paralysis
Paralysis is loss of muscle function for one or more muscles. Paralysis can be accompanied by a loss of feeling in the affected area if there is sensory damage as well as motor. A study conducted by the Christopher & Dana Reeve Foundation, suggests that about 1 in 50 people have been diagnosed...
on one or both sides of the body, and they can vary greatly in duration. Attacks may also alternate from one side of the body to the other, or alternate between affecting one or both sides during a single attack. AHC is associated with many symptoms besides hemiplegia, and the majority of these become apparent in early infancy. AHC is considered normal if symptoms are present before 18 months of age. Normally, hemiplegia and other associated symptoms cease completely with sleep, but they may re-occur upon waking. The disorder was only recently discovered, having first been characterized in 1971. AHC is also extremely rare – approximately 1 in 1,000,000 people have this disorder. Besides hemiplegia, symptoms of the disorder include an extremely broad range of neurological and developmental impairments which are not well understood. Much of the literature about AHC is purposefully vague in this respect due to a lack of information on the disorder.
Signs and symptoms
AHC patients exhibit a wide range of symptoms in addition to hemiplegic attacks. These can be further characterized as paroxysmal and non-paroxysmal symptoms. Paroxysmal symptoms are generally associated with hemiplegic attacks and may occur suddenly with hemiplegia or on their own. Paroxysmal symptoms may last for variable amounts of time. Non-paroxysmal symptoms tend to be side effects of AHC which are present at all times, not just during episodes or attacks. 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...
, which is also considered a paroxysmal symptom, plays an important role in the progression and diagnosis of AHC.
Hemiplegic attacks
Chronologically, hemiplegic attacks are not always the first symptom of AHC, but they are the most prominent symptom, as well as the symptom for which the disorder is named. Hemiplegic attacks may affect one or both sides of the body, and attacks which affect both sides of the body may be referred to as either bilateral or quadriplegic attacks. One of the unique characteristics of AHC is that hemiplegic attacks, as well as other symptoms which may co-occur with hemiplegia, cease immediately upon sleep. During strong attacks, the symptoms may reoccur upon waking. Hemiplegic attacks can occur suddenly or gradually, and the severity of an attack can vary over its duration. The attacks may alternate from one side of the body to another, though this is rare. The length of attacks may also vary from minutes to weeks, though length of attacks varies more greatly between people than between attacks for one person. Both bilateral and hemiplegic attacks are associated with pseudobulbar features such as dysphagiaDysphagia
Dysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....
, dysarthria
Dysarthria
Dysarthria is a motor speech disorder resulting from neurological injury of the motor component of the motor-speech system and is characterized by poor articulation of phonemes...
, and respiratory difficulty. Paralysis is also often accompanied by changes in skin color and temperature, sweating, restlessness, tremor, screaming, and the appearance of pain. Hemiplegic attacks happen irregularly and can occur with speech, eating, and swallowing impairment. Patients with AHC are frequently underweight due to these side effects. The average age of onset for hemiplegic episodes has been found to be 6–7 months of age. This early onset gives the name of this disorder the slightly misleading ending 'of childhood'. AHC is not exclusively limited to childhood – attacks become milder after the first ten years of life, but they never completely disappear.
Paroxysmal symptoms
AHC patients have exhibited various paroxysmal symptoms which manifest to different degrees in each person. Paroxysmal symptoms include tonicTonic (physiology)
Tonic in physiology refers to a physiological response which is slow, and may be graded. This term is typically used in opposition to a fast response...
, tonic-clonic, or myoclonic limb movements, dystonic posturing, choreoathetosis
Choreoathetosis
Choreoathetosis is the occurrence of involuntary movements in a combination of chorea and athetosis ....
, occular nystagmus
Nystagmus
Nystagmus is a condition of involuntary eye movement, acquired in infancy or later in life, that may result in reduced or limited vision.There are two key forms of Nystagmus: pathological and physiological, with variations within each type. Nystagmus may be caused by congenital disorders,...
, and various other ocular motor abnormalities. Almost half of all people have dystonic symptoms prior to experiencing hemiplegia. These symptoms generally begin before 8 months of age. Ocular motor abnormalities occur early, and these are the most frequent early symptoms of AHC, particularly nystagmus. Almost 1/3 of people with this disorder had episodic ocular motor features within 1–2 days of birth. Many also experienced hemiplegia and dystonia before 3 months of age. A final symptom that may be considered paroxysmal is a temporary change in behavior - some patients will become unreasonable, demanding, and aggressive either before or after an attack
Not all patients have all of these symptoms, and it is not known whether they are caused by AHC. Symptoms usually manifest in the first 3 months of the child's life, with an average onset of 2.5 months. Frequently, some of these symptoms will manifest in the neonatal period. These paroxysmal symptoms are often used to help diagnose AHC, since there is no simple test for it.
In some cases, EEGs taken during these paroxysmal events were characterized by a generalized background slowing. Overall however, ictal EEGs and other investigative methods such as MRIs, TACs, angiographic MRIs and CFS have normal results.
Non-paroxysmal symptoms
In the long term, many paroxysmal symptoms occur along with AHC, and while these symptoms vary in strength depending on the person, they are consistent features of AHC. It is thought that some of these symptoms are brought on or worsened by hemiplegic attacks, though it is not known for certain. Patients suffer persistent motor, movement (ataxiaAtaxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
), and cognitive deficits. These deficits become more apparent over time and include developmental delays, social problems, and retardation. It is rare for someone with AHC not to have cognitive deficits, but a study in Japan did find two patients who met all of the diagnostic criteria for AHC but who were not mentally impaired. It is not know whether AHC is a progressive disease, but severe attacks are suspected to cause damage which result in permanent loss of function. 100% of children studied in the USA have had some form of mental impairment, which is usually described as mild to moderate, but varies greatly among individuals.
Epilepsy
Approximately 50% of AHC sufferers also suffer from 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...
, and AHC is often misdiagnosed as epilepsy because of this. These epileptic events are distinguished from other episodes by an alteration of consciousness, as well as frequent tonic
Tonic (physiology)
Tonic in physiology refers to a physiological response which is slow, and may be graded. This term is typically used in opposition to a fast response...
or tonic-clonic activity. Epileptic episodes are generally rare, though they do increase with age. Due to the rarity of epileptic episodes, there are few EEG confirmations of them.
Diagnosis
As of 1993 only approximately 30 people with AHC had been described in scientific literature. Due to the rarity and complexity of AHC, it is not unusual for the initial diagnosis to be incorrect, or for diagnosis to be delayed for several months after the initial symptoms become apparent. The average age of diagnosis is just over 36 months. Diagnosis of AHC is not only difficult because of its rarity, but because there is no diagnostic test. Instead, there are several generally accepted criteria which define this disorder. Due to these diagnostic difficulties, it is possible that the commonness of the disease is underestimated.The following descriptions are commonly used in the diagnosis of AHC. The initial four criteria for classifying AHC were that it begins before 18 months of age, includes attacks of both hemiplegia on either side of the body, as well as other autonomic problems such as involuntary eye movement (episodic monocular nystagmus), improper eye alignment, choreoathetosis
Choreoathetosis
Choreoathetosis is the occurrence of involuntary movements in a combination of chorea and athetosis ....
, and sustained muscle contractions (dystonia). Finally, patients suffer from mental retardation, delayed development, and other neurological abnormalities. These diagnostic criteria were updated in 1993 to include the fact that all of these symptoms dissipate immediately upon sleeping. Diagnostic criteria were also expanded to include episodes of bilateral hemiplegia which shifted from one side of the body to the other.
Recent criteria have been proposed for screening for AHC early, in order to improve the diagnostic timeline. These screening criteria include focal or unilateral paroxysmal dystonia in the first 6 months of life, as well as the possibility of flaccid hemiplegia either with or separate from these symptoms. Paroxysmal ocular movements should also be considered, and these should include both binocular and monocular symptoms which show in the first 3 months of life.
Etiology
The cause of AHC is unknown. It was initially thought to be a form of complicated migraineMigraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
because of strong family histories of migraine reported in AHC cases. AHC has also been considered to be a movement disorder or a form of epilepsy. Suggested causes have included channelopathy
Channelopathy
Channelopathies are diseases caused by disturbed function of ion channel subunits or the proteins that regulate them. These diseases may be either congenital or acquired .There are a large number of distinct dysfunctions known to be caused by ion channel...
, mitochondrial dysfunction, and cerebrovascular dysfunction. The disorder most closely related to AHC is familial hemiplegic migraine
Familial hemiplegic migraine
Familial hemiplegic migraine is an autosomal dominant classical migraine subtype that typically includes hemiparesis during the aura phase. It can be accompanied by other symptoms, such as ataxia, coma and epileptic seizures...
, and this was recently discovered to be caused by a mutation in a gene for calcium channel receptors. It is suspected that AHC may be caused by a similar channelopathy, and this is a current area of investigation into the cause of AHC. An association with ATP1A2
ATP1A2
ATPase, Na+/K+ transporting, alpha 2 polypeptide, also known as ATP1A2, is a protein which in humans is encoded by the ATP1A2 gene.- Function :...
mutation has been found in some patients, but other studies have found no mutations and thus a lack of evidence that mutations which cause AHC are in the same genes as mutations which cause familial hemiplegic migrane.
Because alternating hemiplegia of childhood is so rare, there is no increased risk of AHC for the children of siblings of someone with AHC, but it is believed to be autosomal dominant, by which a person with AHC has a 50% change of passing the disorder on to their children. AHC is questionably a progressive disease, because cognitive abilities do appear to decline over time. This cannot be completely determined however, because the mechanism of AHC's progression is unknown. It is likely that it is caused by a generalized cellular dysfunction caused by a mitochondrial disorder. However, studies involving mechanisms of AHC have been inconclusive. Experts currently researching this disorder believe that the cause of AHC is a mutated ion channel. This would make the cause difficult to find because one disrupted channel may be represented differently in different tissues. This mutation is suspected because the most closely related disease, FHM, is also caused by a mutated ion channel. A small number of genes which were suspected to carry a mutation for AHC have been screened for sodium channel protein mutations, ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
pump mutations, and excitatory amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
transmitter mutations. None of these have yet been successful in determining the underlying cause of AHC.
Treatments and prognosis
Overall outcomes for AHC are generally poor, which is contributed to by AHC's various diagnostic and management challenges. In the long term, AHC is debilitating due to both the hemiplegic attacks and permanent damage associated with AHC. This damage can include cognitive impairment, behavioral and psychiatric disorders, and various motor impairments. There is, however, not yet any conclusive evidence that AHC is fatal or that it shortens life expectancy, but the relatively recent discovery of the disorder makes large data for this type of information unavailable. Treatment for AHC has not been extremely successful, and there is no cure. There are several drugs available for treatment, as well as management strategies for preventing and dealing with hemiplegic attacks.Management strategies
Hemiplegic attacks can be brought on by particular triggers, and management of AHC often centers around avoiding common or known triggers. While triggers vary greatly from person to person, there are also some common ones which are prevalent in many patients. Common triggers include temperature changes, water exposure, bright lights, certain foods, emotional stress, and physical activity. While avoiding triggers may help, it cannot prevent all hemiplegic episodes because many occur without being triggered. Because attacks and other associated symptoms end with sleep, various sedatives can be used to help patients sleep.Flunarizine
The most common drug used to treat AHC is flunarizineFlunarizine
Flunarizine is a drug classified as a calcium channel blocker. Flunarizine is a non-selective calcium entry blocker with calmodulin binding properties and histamine H1 blocking activity. It is effective in the prophylaxis of migraine, occlusive peripheral vascular disease, vertigo of central and...
. Flunarizine functions by acting as a calcium channel
Calcium channel
A Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...
blocker. Other drugs, in order of frequency of use are benzodiazepines, carbamazapine, barbiturates, and valproic acid. Flunarizine is prescribed for the purpose of reducing the severity of AHC attacks and the number of episodes, though it rarely stops attacks altogether. Minimizing the attacks may help reduce damage to the body from hemiplegic attacks and improve long-term outcomes as far as mental and physical disabilities are concerned.
Experts differ in their confidence in flunarizine's effectiveness. Some studies have found it to be very effective in reducing the duration, severity, and frequency of hemiplegic attacks. It is generally considered the best treatment available, but this drug is thought by some to be of little benefit to AHC patients. Many patients suffer adverse effects without seeing any improvement. Flunarizine also causes problems because it is difficult for patients to obtain, because it is not readily available in the United States.
Sodium oxybate
Current research at the University of Utah is investigating whether sodium oxybate, also known as Gamma-Hydroxybutyric acidGamma-Hydroxybutyric acid
γ-Hydroxybutyric acid , also known as 4-hydroxybutanoic acid and sodium oxybate when used for medicinal purposes, is a naturally occurring substance found in the central nervous system, wine, beef, small citrus fruits, and almost all animals in small amounts. It is also categorized as an illegal...
is an effective treatment for AHC. Thus far, only a small number of patients have been sampled, and no conclusive results are yet available. While some success has been had thus far with the drug, AHC patients have been known to respond well initially to other drugs, but then the effectiveness will decline over time. Currently, sodium oxybate is used as a narcolepsy
Narcolepsy
Narcolepsy is a chronic sleep disorder, or dyssomnia, characterized by excessive sleepiness and sleep attacks at inappropriate times, such as while at work. People with narcolepsy often experience disturbed nocturnal sleep and an abnormal daytime sleep pattern, which often is confused with insomnia...
-cataplexy
Cataplexy
Cataplexy is a sudden and transient episode of loss of muscle tone, often triggered by emotions. It is a rare disease , but affects roughly 70% of people who have narcolepsy...
treatment, though in the past it has been used controversially in nutritional supplements. This drug was chosen to test because of a possible link between the causes of narcolepsy-cataplexy and AHC.