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Ethosuximide

Ethosuximide is a succinimide anticonvulsant, used mainly in absence seizures. It is sold by Pfizer under the name Zarontin®. more...

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Mechanism of Action

There is some controversy over the exact mechanism by which ethosuximide prevents absence seizures. While the "ethosuximide is a T-type calcium channel blocker" gained widespread support following its proposal, attempts to replicate the initial finding were inconsistent.

In March of 1989, Coulter, Huguenard and Prince showed that ethosuximide and dimethadione, both effective anti-absence agents, reduced low-threshold Ca2+ currents in T-type Ca2+ channels in freshly removed thalamic neurons. In June of that same year, they also found the mechanism of this reduction to be voltage-dependent, using acutely neurons of rats and guinea pigs; it was also noted that valproic acid, which is also used in absence seizures, did not do that. The next year, they showed that anticonvulsant succinimides did this and that the proconvulsant ones did not. The first part was supported by Kostyuk et al in 1992, who reported a substantial reduction in current in dorsal root ganglia at concentrations ranging from 7 μM to 1 mM.

That same year, however, Herrington and Lingle found no such effect at concentrations of up to 2.5 mM. The year after, a study conducted on human neocortical cells removed during surgery for intractable epilepsy, the first to use human tissue, found that ethosuximide had no effect on Ca2+ currents at the concentrations typically needed for a therapeutic effect.

In 1998, Slobodan M. Todorovic and Christopher J. Lingle of Washington University reported a 100% block of T-type current in dorsal root ganglia at 23.7 ± 0.5 mM&mdashfar higher than Kostyuk reported. That same year, Leresche et al reported that ethosuximide had no effect on T-type currents, but did decrease noninactivating Na+ current by 60% and the Ca2+-activated K+ currents by 39.1 ± 6.4% in rat and cat thalamocortical cells. It was concluded that the decrease in Na+ current is responsible for the anti-absence properties.

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Cerebral palsy
From Gale Encyclopedia of Medicine, 4/6/01 by Richard Robinson

Definition

Cerebral palsy (CP), or static encephalopathy, is the name for a collection of movement disorders caused by brain damage that occurs before, during, or shortly after birth. A person with CP is often also affected by other conditions caused by brain damage.

Description

The affected muscles of a person with CP may become rigid or excessively loose, or the person may lose control of muscles, or have problems with balance and coordination. A combination of these is also possible. The person may be primarily affected in the legs (paraplegia or diplegia), or in the arm and leg of one side of the body (hemiplegia), or all four limbs may be involved (quadriplegia).

A person with CP may also be affected by a number of other problems, including seizure disorder, visual deficits, hearing problems, mental retardation, learning disabilities, and attention-deficit/hyperactivity disorder. None of these is necessarily part of CP, however, and a person with CP may have no other impairments except for the movement disorder.

CP affects approximately 500,000 children and adults in the United States, and is diagnosed in more than 6,000 newborns and young children each year. CP is not an inherited disorder, and as of yet there is no way to predict with certainty which children will develop it. It is not a disease, and is not communicable. CP is a nonprogressive disorder, which means that symptoms neither worsen nor improve over time. However manifestation of the symptoms may become more severe over time; for example, rigidity of muscles can lead to contractures and deformities that require a variety of interventions.

Causes & symptoms

Causes

Cerebral palsy is caused by damage to the motor control centers of the brain. When the nerve cells (neurons) in these regions die, the appropriate signals can no longer be sent to the muscles under their control. The resulting poor control of these muscles causes the symptoms of CP.

This brain damage may be caused by lack of oxygen (asphyxia), infection, trauma, malnutrition, drugs or other chemicals, or hemorrhage. In most cases it is impossible to determine the actual cause, although prematurity is recognized as a significant risk factor. Although it was once thought that difficult or prolonged delivery was responsible for many cases of CP, most researchers now believe that the great majority of cases result from brain damage occurring before birth. The same injury that damages the motor areas can harm other areas as well, leading to other problems commonly associated with CP.

If brain cells do not get enough oxygen because of poor circulation, they may die. Defects in circulation in the developing brain may cause CP in some cases. Asphyxia during birth is also possible, and about half of newborns known to have suffered asphyxia during birth (perinatal asphyxia) develop CP. However, asphyxia during birth is usually considered a symptom of an underlying neurological problem in a newborn, rather than its cause, and the resulting CP may be another sign of that problem. Asphyxia after birth can be caused by choking, poisoning (such as from carbon monoxide or barbiturates), or near-drowning.

The fetal brain may be damaged by an infection contracted by the mother. Infections correlated with CP include rubella (German measles), toxoplasmosis (often contracted from cat feces or undercooked meat), cytomegalovirus (a herpes virus), and HIV (the virus that causes AIDS). Encephalitis and meningitis, infections of the brain and its coverings, can also cause CP when contracted by infants.

Physical trauma to the pregnant mother or infant may cause brain damage. Blows to the infant's head, as from a motor vehicle accident, violent shaking, or other physical abuse can damage the infant's brain. Maternal malnutrition may cause brain damage, as can the use of drugs, including cocaine or alcohol. Although these factors may cause CP, they may be more likely to cause mental retardation or other impairments.

Incompatibility between the Rh blood types of mother and child was once a major cause of athetoid CP, one type of movement impairment seen in cerebral palsy. In some cases, this incompatibility can cause the mother's defense (immune) system to attack and destroy the child's blood cells during the pregnancy, a condition called erythroblastosis fetalis. High levels in the child's circulation of a blood cell breakdown product called bilirubin can result, leading to yellowish pigmentation of the skin caused by bile (jaundice) and causing brain damage. This condition is now rare because of testing procedures that identify potential Rh incompatibility, and treatment procedures that prevent the mother's immune system from attacking the child's blood cells. Jaundice that does occur can be treated with special lights that help the breakdown of bilirubin. Blood transfusions for the child are also possible in extreme cases. Despite the virtual elimination of this cause of CP in the last few decades, CP rates have not declined, largely because of the increase of survival of premature babies.

Prematurity is one of the most significant risk factors for CP. About 7% of babies weighing less than 3 lbs at birth develop CP, and the risk increases dramatically as weight falls. Prematurity may increase the risk of CP because of the increased likelihood of hemorrhaging in the brain associated with low birth weight. Brain hemorrhage is most common in babies born weighing less that 4 lbs, and the risk increases as weight decreases. The hemorrhage may destroy brain tissue, either through asphyxia or release of toxic breakdown products.

Symptoms

The symptoms of CP are usually not noticeable at birth; as children develop through the first 18 months of life, though, they progress through a predictable set of developmental milestones. Children with CP will develop these skills more slowly because of their motor impairments, and delay in reaching milestones is usually the first symptom of CP. The more severe the CP, the earlier the diagnosis is usually made.

Selected developmental milestones, and the ages at which a child will normally acquire them, are given below. There is some cause for concern if the child does not acquire the skill by the age shown in parentheses.

  • Sits well unsupported--6 months (8-10 months)
  • Babbles--6 months (8 months)
  • Crawls--9 months (12 months)
  • Finger feeds, holds bottle--9 months (12 months)
  • Walks alone--12 months (15-18 months)
  • Uses one or two words other than dada/mama--12 months (15 months)
  • Walks up and down steps--24 months (24-36 months)
  • Turns pages in books; removes shoes and socks--24 months (30 months).

Children do not consistently favor one hand over the other before 18 months, and doing so may be a sign that the child has difficulty using the other hand. This same preference for one side of the body may show up as an asymmetric crawling effort, or continuing to use only one leg for the work of stair climbing after age three.

It must be remembered that children normally progress at somewhat different rates, and slow beginning accomplishment is often followed by normal development. There are also other causes for delay in reaching some milestones, including problems with vision or hearing. Because CP is a nonprogressive disease, loss of previously acquired milestones indicates that CP is not the cause of the problem.

The impairments of CP become recognizable in early childhood. The type of motor impairment and its location are used as the basis for classification. There are five generally recognized types of impairment:

  • Spastic--Muscles are rigid, posture may be abnormal, and fine motor control is impaired
  • Athetoid--Marked by slow, writhing, involuntary movements
  • Hypotonic--Muscles are floppy, without tone
  • Ataxic--Balance and coordination are impaired
  • Dystonic--Mixed.

The location of the impairment usually falls into one of three broad categories:

  • Hemiplegia--One arm and one leg on the same side of the body involved
  • Diplegia--Both legs; arms may be partially involved
  • Quadriplegia--All four extremities involved.

Therefore, a person with CP may be said to have spastic diplegia, or ataxic hemiplegia, for instance. CP is also termed mild, moderate, or severe, although these are subjective categories with no firm boundaries.

Loss of muscle control, especially of the spastic type, can cause serious orthopedic problems, including scoliosis (spine curvature), hip dislocation, or contractures. A contracture is a shortening of a muscle, caused by an imbalance of opposing force from a neighboring muscle. Contractures begin as prolonged contractions, but can become fixed or irreversible without regular range of motion exercises. A fixed contracture occurs when the contracted muscle adapts by reducing its overall length. Fixed contractures may cause postural abnormalities in the affected limbs, including clenched fists, tightly pressed or crossed thighs, or equinus. In equinus, the most common postural deformity, the foot is extended by the strong pull of the rear calf muscles, causing the toes to point. The foot is commonly pulled inward as well, a condition called equinovarus. Contractures of all kinds may be painful, and may interfere with normal activities of daily living, including hygiene and mobility.

As noted, the brain damage that causes CP may also cause a large number of other disorders. These may include:

  • Mental retardation
  • Learning disabilities
  • Attention-deficit/hyperactivity disorder
  • Seizure disorder
  • Visual impairment, especially strabismus ("cross-eye")
  • Hearing loss
  • Speech impairment.

These problems may have an even greater impact on the child's life than the physical impairment of CP, although not all children with CP are affected by other problems. About one-third of children with CP have moderate-to-severe mental retardation, one-third have mild mental retardation, and one-third have normal to above average intelligence.

Diagnosis

The tracking of developmental progress is the most important test the physician has in determining whether a child has cerebral palsy. Most children with CP can be confidently diagnosed by 18 months. However, diagnosing CP is not always easy, since variations in child development may account for delays in achieving milestones, and since even children who are obviously delayed may continue to progress through the various developmental stages, and attain a normal range of skills later on. Serious or prolonged childhood illness may cause delays that are made up later on.

Evidence of other risk factors may aid the diagnosis. The Apgar score, evaluated immediately after birth, measures the newborn's heart rate, cry, color, muscle tone, and motor reactions. Apgar scores of less than 3 out a possible 10 are associated with a highly increased risk for CP. Presence of abnormal muscle tone or movements may signal CP, as may the persistence of infantile reflexes. A child with seizures or congenital organ malformation has an increased likelihood of CP. Ultrasound examination, a diagnostic technique that creates a two-dimensional image of internal body structures, may help to identify brain abnormalities, such as enlarged ventricles (chambers containing fluid) or periventricular leukomalacia (an abnormality of the area surrounding the ventricles), which may be associated with CP.

X rays, MRIs, and CT scans are often used to look for scarring, cysts, expansion of the cerebral ventricles (hydrocephalus), or other brain abnormalities that may indicate the cause of the symptoms. Blood tests and genetic tests may be used to rule out other possible causes, including muscular dystrophy (a disease characterized by the progressive wasting of muscles), mitochondrial (cellular) disease, other inherited disorders, or infection.

Treatment

Cerebral palsy cannot be cured, but many of the disabilities it causes can be managed through planning and timely care. Treatment for a child with CP depends on the severity, nature, and location of the impairment, as well as the associated problems the child has. Optimal care of a child with mild CP may involve regular interaction with only a physical therapist and occupational therapist, whereas care for a more severely affected child may include a speech-language therapist, special education teacher, adaptive sports therapist, nutritionist, orthopedic surgeon, and neurosurgeon. Since CP is not a progressive disorder, its symptoms will not worsen with time. Nonetheless, the way in which those symptoms affect the growing child will change over time, and may require new strategies for treatment, adaptation, and compensation.

Parents of a child newly diagnosed with CP are not likely to have the necessary expertise to coordinate the full range of care their child will need. Although knowledgeable and caring medical professionals are indispensable for developing a care plan, a potentially more important source of information and advice is other parents who have dealt with the same set of difficulties. Support groups of parents of physically or mentally impaired children can be significant sources of both practical advice and emotional support. Many cities have support groups that can be located through the United Cerebral Palsy Association or a local hospital or social service agency. Children with CP are also eligible for special education services. The diagnosing doctor should refer parents to the local school district for these services. Even children aged 0-3 years are eligible through "early intervention."

The influence of CP on development

Much of a child's normal intellectual, physical, and social development occurs through play and exploration of the environment. The ability to reach for and grasp objects, to move about, to explore the properties of toys, and to communicate with others are all central activities in the child's growth. CP may restrict a child's ability to engage in these activities, and therefore prevent the acquisition of motor skills, knowledge of the world, and social competence. The family can do much to overcome these restrictions by adapting the child's environment to meet his or her needs and providing challenges within the child's abilities to accomplish. The advice and direction of an occupational therapist can be critical to promoting normal development of the child with CP.

Posture and mobility

Spasticity, muscle coordination, ataxia, and scoliosis are all significant impairments that affect the posture and mobility of a person with cerebral palsy. The physical therapist works with the family to maximize the child's ability to move affected limbs, to develop normal motor patterns, and to maintain posture. Adaptive equipment may be needed, including wheelchairs, walkers, shoe inserts, crutches, or braces. The need for adaptive equipment may change as the person develops, or as new treatments are introduced. The parents or other caregivers are taught safe transfer techniques to aid the person who cannot move independently from wheelchair to bed, for example.

Spasticity

Spasticity causes muscles to shorten, joints to tighten, and postures to change. Spasticity can affect the ability to walk, use a wheelchair, and sit unaided; and it can prevent independent feeding, dressing, hygiene, or other activities of daily living. Contracture and dislocations are common consequences of spasticity.

Mild spasticity may be treated by regular stretching of the affected muscles through their full range of motion. This usually is done at least daily. Moderate spasticity may require bracing to keep the limb out of the abnormal position, or serial casting to return it to its normal position. Ankle-foot braces (orthoses) made of lightweight plastic are often used to increase a child's stability and to promote proper joint alignment. Before fixed contracture develops, botulinum toxin (a highly active neurotoxin; Botox) injections can help loosen the affected muscles. Alcohol or phenol injection into the nerve controlling the muscle is also done; these injections are less costly than botulinum toxin, but they may cause more serious side effects, including pain, loss of sensation, and excess weakness. Fixed contractures are usually treated with either serial casting or tenotomy surgery. In this surgery, the tendons of the affected muscle are cut. The limb is then cast in a more normal position while the tendon regrows. Tenotomy is commonly done to prevent hip dislocation and to correct equinus. Another type of surgery available is dorsal rhizotomy. In this procedure, selected nerve roots in the spinal cord are cut to prevent them from stimulating the spastic muscles.

Spasticity may also be treated with muscle relaxing drugs, including diazepam (Valium), dantrolene (Dantrium), and baclofen (Lioresal). A baclofen pump can also be implanted to deliver the drug directly to the spinal cord, its site of action, allowing more effective spasticity reduction with fewer side effects.

A variety of experimental surgeries have been tried for people with cerebral palsy, most often to control spasticity. Most of these have not proved effective for most people. A new procedure implants an electrode into the brain to control the tremors found in some forms of CP, but as of 1998 the procedure was too new for its success to be fully evaluated.

Ataxia and coordination

Ataxia, or lack of balance control, is another factor affecting mobility. Physical therapy is an important tool to help the child with CP maximize balance. Coordination can be worsened if one member of a muscle pair is overly strong; bracing or surgical transfer of the muscle to a less overpowering position may help.

Scoliosis

Scoliosis, or spine curvature, can develop when the muscles that hold the spine in place become either weak or spastic. In either case, an imbalance of forces pulls the vertebrae (bones making up the spinal column) out of alignment. This can cause pain, as well as interfere with normal posture and internal organ function. Scoliosis may be treated with a trunk brace. If this proves unsuccessful, spinal fusion surgery may be needed to join the vertebrae together, which keeps the spine straight.

Seizures

Seizures occur in 30-50% of children with CP. Seizures may be restricted to one limb (focal) or generalized. Grand mal seizures are the most common type of generalized seizure for people with CP. Seizures may be treated with drugs, most commonly carbamazepine (Tegretol) or ethosuximide (Zarontin). A combination of a ketogenic diet and fasting may also be used to control seizures. Although the need for antiseizure medication is temporary in some children, it may be required throughout life for others.

Strabismus

Strabismus occurs in nearly half of all people with spastic CP. Strabismus may be treated with patching and corrective lenses. When these do not work, it may be treated with either surgery on the eye muscles causing the problem or by injection of botulinum toxin.

Nutrition

The person with CP may not be able to feed easily, because of poor coordination of the tongue and mouth muscles, or inability to hold and move utensils independently. The person may not take in adequate nutrition for full growth and development, worsening the results of the disorder. Careful attention to nutritional needs can prevent these problems. Nutritional supplements may be needed. Poor swallowing coordination may lead to aspiration, or inhaling of food or saliva. A speech-language therapist may be able to teach the person more effective movement patterns to avoid aspiration. In severe cases, a gastrostomy tube may be required to provide adequate nutrition directly into the digestive system while preventing aspiration. Nutrition may need to be monitored throughout childhood and adolescence, since meeting the increased food demands of a growing body may become difficult.

Other common medical problems

Drooling, dental caries (cavities), and gum disease are more common in people with CP than in the general population, partly because of lowered coordination and increased muscle tightness in the mouth and jaw. Each of these can be prevented to some degree, either through behavioral changes alone or in combination with drug therapy. Constipation is more common as well, and may be treated through dietary changes, or with enemas or suppositories when necessary.

Communication

Poor coordination of the tongue and mouth muscles can also affect speech. The inability to be understood can influence the child's intellectual development, especially if parents don't take the extra time needed to understand their child's attempts at speech. Children may benefit from picture boards or other communication devices that allow them to point to make their desires known. For school-age children or older persons with CP, there are a large number of augmentative communication devices, including shorthand typing programs and computer-assisted speech devices. A speech-language therapist can offer valuable advice on the types of equipment available.

Education

The best choice of school for the child with CP depends on the presence and degree of mental impairment and physical impairment, as well as the facilities available in the area. "Inclusion," or mainstreaming the child in a regular public school classroom, may work well for the child with mild physical impairment. Separate classrooms or special schools may be needed for more severely involved children. Schooling for disabled students is governed by the Individuals with Disabilities Education Act (IDEA) at the federal level and state special education rules at the local level. An educational specialist either within the school system or from the community social services agency may be able to help the family navigate the various bureaucratic pathways that will ensure the best schooling available.

The process of developing an educational plan for a child with CP begins with an assessment of the child's needs. The assessment is carried out under state guidelines by a team of medical professionals. After the assessment, the school district works with the parents and others involved in the child's education and treatment to develop an Individualized Educational Plan (IEP). The IEP states the child's specific needs for special instruction and indicates what services will be provided. The special services may be as simple as allowing extra time to travel between classes or as extensive as individualized instruction, adapted classroom equipment, and special testing procedures. More information about assessments and IEPs is available through the National Information Center for Children and Youth with Disabilities. The United Cerebral Palsy Assocation is another resource for advocacy, information, and legal rights.

Behavioral and mental health services

The child with CP may have behavioral problems or emotional issues that affect psychological development and social interactions. These may require special intervention or treatment, including behavior modification programs or individual and family counseling. Attention-deficit/hyperactivity disorder is common in children with CP, and may require behavioral, educational, and medical intervention.

Alternative treatment

A number of people with cerebral palsy, both children and adults, have found systematic relief and enhanced quality of life from a combination of alternative and complementary treatments, including homeopathy, massage therapy, vitamin treatments, herbal medicine, and acupuncture.

Prognosis

Cerebral palsy can affect every stage of maturation, from childhood through adolescence to adulthood. At each stage, the person with CP and his or her caregivers must strive to achieve and maintain the fullest range of experiences and education consistent with the person's abilities. The advice and intervention of professionals remains crucial for many people with CP.

Although CP is not a terminal disorder, it can affect a person's lifespan by increasing the risk of infection, especially lung infections. Poor nutrition can contribute to the likelihood of infection. People with mild cerebral palsy may have near-normal lifespans. The lifespan of those with more severe forms, especially spastic quadriplegia, is often considerably shortened. However, over 90% of infants with CP survive into adulthood.

Prevention

The cause of most cases of CP is unknown, but it has become clear in recent years that birth difficulties are not to blame in most cases. Rather, developmental problems before birth, usually unknown and generally undiagnosable, are responsible for most cases. Although the incidence of CP caused by Rh factor incompatibility has declined markedly, the incidence of CP as a consequence of prematurity has increased, because of the increasing success of medical intervention in keeping premature babies alive.

The risk of CP can be decreased through good maternal nutrition, avoidance of drugs or alcohol during pregnancy, and prevention or prompt treatment of infections. Recent preliminary research suggests that magnesium sulfate may reduce the risk of CP in mothers taking it for the medical treatment for preeclampsia and preterm labor.

Key Terms

Ataxic
Ataxic refers to a condition called ataxia, in which balance and coordination are impaired.
Athetoid
Athetoid refs to a condition called athetonia, which is marked by slow, writhing, involuntary muscle movements.
Attention-deficit/hyperactivity disorder
A behavioral disorder marked by inattentiveness, hyperactivity, and impulsivity.
Augmentative communication devices
Computers, picture boards, and other devices that increase the ability to communicate, either with or without speech.

Contracture
A shortening of a muscle caused by an imbalance of force between opposing muscles.
Diplegia
Paralysis of corresponding parts on both sides of the body.
Dorsal rhizotomy
Surgical procedure that cuts nerve roots to reduce spasticity in affected muscles.
Dystonic
Dystonic refers to a condition called dystonia, in which fine motor control is confused.
Equinovarus
A condition in which the foot is commonly pulled inward.
Equinus
The most common postural deformity.
Hemiplegia
Paralysis of one side of the body.
Hypotonic
Hypotonic refers to a condition called hypotonia, in which fine motor control is floppy, without tone.
IEP
Individualized Educational Plan; a plan that guides the delivery of services to a child with special education needs.
Ketogenic diet
A specialized diet designed to increase the blood levels of breakdown products known as ketone bodies. For unknown reasons, this aids in seizure control.
Perinatal asphyxia
Asphyxia that occurs during birth.
Quadriplegia
Paralysis of all four limbs.
Serial casting
A series of casts designed to gradually move a limb into a more functional position_as opposed to doing it all at once with one cast, as would be done in setting a broken bone.
Spastic
Spastic refers to a condition in which the muscles are rigid, posture may be abnormal, and fine motor control is impaired.
Tenotomy
Surgical procedure that cuts the tendon of a contractured muscle to allow lengthening.

Further Reading

For Your Information

    Books

  • Kramer, Laura. Uncommon Voyage: Parenting a Special Needs Child in the World of Alternative Medicine. Faber & Faber, 1996.
  • Miller, Freema, and Steven J. Bachrach. Cerebral Palsy: A Complete Guide for Caregiving. Johns Hopkins University Press, 1995.
  • Vickers, Andrew. Health Options: Complementary Therapies for Cerebral Palsy and Related Conditions. Element Publications, 1994.

    Periodicals

  • Exceptional Parent Magazine 555 Kinderkamack Road, Oradell, NJ 07649-1517; 800-EPARENT, 201-634-6550.
  • Kuban, KCK, and A. Leviton. "Cerebral Palsy." New England Journal of Medicine 1994: 188-95.

    Organizations

  • National Information Center for Children and Youth with Disabilities. PO Box 1492, Washington DC 20013-1492. (800) 695-0285.
  • United Cerebral Palsy Association. 1660 L Street, NW Washington, DC 20036-5602. (800) USA-5-UCP, (202) 776-0406, (202) 973-7197 (TTY). (202) 776-0414 (fax). ucpnatl@ucpa.org. http://www.ucpa.org.

    Other

  • Electronic forum for cerebral palsy http://neuro-www.mgh.harvard.edu/forum/CerebralPalsyMenu.html.

Gale Encyclopedia of Medicine. Gale Research, 1999.

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