eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases

Movement Disorders in Individuals with Developmental Disabilities

Author: Norberto Alvarez, MD, Assistant Professor, Department of Neurology, Harvard Medical School; Consulting Staff, Department of Neurology, Boston Children's Hospital
Contributor Information and Disclosures

Updated: May 6, 2009

Introduction

Background

Mental retardation is a condition in which intellectual capacity is limited significantly. Developmental disability describes a condition that limits an individual's ability to perform activities and roles as expected in a certain social environment. Mental retardation and developmental disabilities are often present simultaneously as a consequence of brain damage. The American Association for Mental Retardation defines 4 categories of risk factors for mental retardation: biomedical, social, behavioral, and educational.¹ Movement disorders almost always are associated with the biomedical category. However, some movement disorders might be seen in children in whom delay is related mostly to social deprivation.

Although several genetic and metabolic disorders are associated with movement disorders and mental retardation, most instances of movement disorder are the result of a static brain injury, which is a consequence of prenatal, perinatal, or early postnatal factors. Even though the brain lesion is static, the clinical picture is characterized, especially in children, by progression of the motor disorder.² In many cases, the onset of movement disorder is delayed. In persons with developmental disabilities, motor disorders are often seen in association with other deficits, either sensory or cognitive.

Pathophysiology

The cause of mental retardation is unknown in 24-40% of individuals with an intelligence quotient (IQ) below 50 (ie, severe mental retardation) and in almost 60% of those with an IQ of 50-70 (ie, mild mental retardation).³ Developmental disabilities are the result of a heterogeneous group of disorders. No unifying hypothesis explains mental retardation. In general, mild mental retardation is not associated with brain abnormalities, whereas severe mental retardation is usually associated with major brain malformations (eg, agyria, lissencephaly, pachygyria, hemimegalencephaly). Microcephaly is a common predictor of mental retardation.

Cytoarchitectonic techniques and new neuroimaging procedures have helped to define neuronal migration disorders, a group of prenatal causes of mental retardation that result from deficiencies in organization of the brain during intrauterine life.⁴ These malformations are frequently but not always associated with mental retardation. The malformations typically occur in the cerebral cortex and related structures. Anomalies in dendritic arborizations and synapses are described in the brains of individuals with developmental disabilities but no obvious malformations.

In a small subgroup of persons with mental retardation, defined clinical disorders, mostly congenital or metabolic, can be identified.^5,6 The pathophysiology of mental retardation is best understood in these patients. In patients with Down syndrome, for example, the dendritic spines and number of synapses are reduced. In those with Rett syndrome, the size of individual neurons is reduced, and the packing density in the cerebral cortex, thalami, and basal ganglia is increased. In those with fragile X syndrome, dendritic spine abnormalities are noted.⁴

In cerebral palsies (CPs), certain pathophysiologic findings are correlated with specific clinical presentations. Periventricular leukomalacia, characterized by necrosis of the white matter around the lateral ventricles, is the most common cause of cerebral palsy (CP) in low-birth-weight infants and most often associated with spastic diplegia. Severe asphyxia in the full-term infant is associated with diffuse brain damage in the cortex, mostly in the parasagittal area. It also affects the brainstem and the basal ganglia. This brain damage is associated with spastic quadriplegia that may or may not be associated with dyskinetic disorders. Periventricular hemorrhagic infarction in preterm infants, usually unilateral, results in hemiparesis in which the leg is typically more involved than the arm.

Abnormalities of the middle cerebral artery result in congenital spastic hemiplegia. The dyskinetic form of cerebral palsy (CP) can result from hyperbilirubinemia in the neonatal period (ie, kernicterus). In these cases, deposition of pigment and loss of neurons in the basal ganglia are observed. This disorder may also be associated with severe acute perinatal asphyxia; the lesions in the basal ganglia and thalamus may have a marbled appearance (ie, status marmoratus).

Frequency

United States

Children: The Education for All Handicapped Children Act defines "handicap" broadly; 10% of the nation's children fit the criteria.⁷ This legislation included children with disabilities that are not necessarily associated with motor disorders, for example, epilepsy, learning disabilities, or emotional or behavior disorders. The Metropolitan Atlanta Developmental Disabilities Study revealed a 1.2% prevalence of mental retardation among 10-year-old children; 0.84% had mild mental retardation and 0.36% had severe mental retardation.⁸ A reasonable estimate of the prevalence of developmental disabilities for all ages in the general population is 1%.

Adults: The number of adults with developmental disabilities and movement disorders is unknown. The United Cerebral Palsy Association estimates that approximately 400,000 adults have cerebral palsy (CP), which is usually associated with motor disorders and developmental disabilities. A recent study conducted to evaluate the medical and functional status of adults with CP showed that 52 of 101 subjects had a movement disorder (eg, athetosis, chorea, dystonia).⁹ Eighty had dysarthria resulting from pseudobulbar CP, and 26 persons who were ambulatory could no longer walk. Prevalences of various movement disorders in 1227 persons with developmental disabilities living in institutions were as follows: dyskinesia 48%, dystonia 29%, akathisia 13%, parkinsonism 3%, and other paroxysmal movement disorders 4%. Overall, 72% of the subjects had at least one movement disorder, and some had more than one.¹⁰

International

Reports from European countries indicate that rates are similar to those in the United States.

Mortality/Morbidity

Although the life span of individuals with developmental disabilities has increased steadily in the past few years, these individuals generally have a life span shorter than that of individuals without developmental disabilities.

• In one study, the average age of 123 individuals with mental retardation who died in a residential institution between 1988 and 1998 was 63.8 years (range, 41-95 y). The average age of people living in the institution was 53 years (range, 32-89 y). In the same institution, the average age of 112 individuals who died in from 1999-2008 was 66 years. The mean age of the individuals living in the institution as of December 2008 was 61 years. Most of these individuals had a severe to profound degree of mental retardation.(Personal information)
• The role of movement disorders in an individual's life span has not been researched fully, but these disorders are expected to affect functions such as eating and drinking and to limit mobility in ways that may negatively affect both morbidity and mortality.
• Immobile individuals have a life expectancy shorter than that of people who can move around. Moreover, children with developmental disability with fair motor and eating skills have good survival rates; 90% or more reach adulthood.

Sex

More male individuals have mental retardation than female individuals, but the male predominance does not necessarily extend to the subgroup with movement disorders.

Age

No age preponderance is known in patients with movement disorders related to developmental disorders, though the clinical presentation of an individual may change over time.

Clinical

History

Although the prevalence of motor disorders varies among people with mental retardation and developmental disabilities, some generalizations are possible. The following are clinical disorders that are frequently associated with movement disorders:

• Cerebral palsy (CP) - General considerations
  • CP comprises all conditions for which the main disability is motor. CP also implies that the injury to the brain is nonprogressive and that it occurred before the brain was fully mature.
  • CP is an expression of a continuum of CNS dysfunction. It is frequently associated with other deficits: mental retardation in 60% of cases, epilepsy in 30%, and hearing and visual deficits in 10-15%.
  • The number of children younger than 18 years with CP is nearly 100,000,¹¹ and approximately 5000 new cases are discovered per year.¹²
  • Despite improvements in obstetrical and neonatal care, the incidence of CP has not decreased. Data suggest that the combination of CP and mental retardation may be increasing in frequency. This might be the result of the increasing survival rate of fragile premature infants.
  • In almost 50% of patients, the cause of brain damage cannot be identified. Low birth weight, perinatal asphyxia, and multiple births are major risk factors. About 28% of children with CP were born weighing less than 1.5 kg.¹² CP is more frequent in twin and triplet births than in single births.
  • Birth asphyxia is responsible for CP in only 5-10% of otherwise normal newborns with no other risk factors for CP. The usual type of CP in these patients is spastic quadriparesis, especially that associated with dyskinesia.
  • Among newborns with a low Apgar score and low pH, the incidence of congenital malformations is high. This finding suggests that prenatal factors can contribute to perinatal problems in these patients. (A mnemonic for the Apgar score is the acronym APGAR, which stands for appearance, pulse, grimace, activity, and respiration.)
  • Kernicterus due to Rh incompatibility and subsequent hyperbilirubinemia was the most common cause of athetoid CP before the introduction of exchange transfusions.
• At present, serious birth asphyxia is the most common cause of choreoathetotic movement disorders.¹³ This is often associated with spastic quadriplegia and mental retardation.
• Cerebral palsy (CP) - Types of motor disorders
  • The 2 main motor disorders associated with CP are pyramidal (or spastic) and extrapyramidal (or dyskinetic). The rigid and the ataxic forms are relatively infrequent. Pure motor forms are the exception. Finding the proper diagnostic term is sometimes difficult. Most, if not all, cases of CP have some mixed symptoms.
  • CP - Pyramidal (spastic) type
    • Approximately 70-80% of cases of CP are of the spastic type. The clinical presentation of the CPs was historically classified according to the topography of the motor deficits.
    • In the hemiplegic form, only 1 side is involved, and the arm is usually more involved than the leg. In the diplegic type, all 4 extremities might be affected, but symptoms are predominant in the legs.
    • When 4 limbs are involved extensively, the term used is quadriplegia. The term bilateral (double) hemiplegia is reserved for cases in which 4 extremities are involved but the upper extremities are more involved than the lower extremities.
    • The topography and type of CP might suggest the etiology, associated deficits, and prognosis. For example, children with unilateral hemiplegia have only minimal cognitive deficits, if any, but they have a high frequency of sensory deficits (eg, homonymous hemianopsia, deficits in stereognosis and position sense) and a high incidence of epilepsy. Children with quadriplegia have epilepsy and cognitive deficiencies that are more severe than those of children with other types of CP. Spastic diplegia occurs in premature more often than in term children.
    • Regarding muscle tone in spasticity, resistance to passive movement is increased. This change is elicited by rapidly moving a joint with subsequent sudden stretching of the tendon. The resistance classically increases to a point and is followed by a sudden give (ie, clasp-knife phenomenon). Changes in muscle tone and posture are most constant during the day and are not affected by the patient's emotional state.
  • Extrapyramidal cerebral palsy (CP)
    • This type is characterized by a variety of movement disorders, predominantly dystonic posturing and choreoathetoid movement. Derangement of muscle tone also occurs.
    • In extrapyramidal hypertonicity, muscle tone is characterized by the lead-pipe phenomenon, which is a persistent uniform increase in resistance observed throughout slow, passive joint movement. A combination of the lead-pipe and the clasp-knife phenomena might be seen in the same patient, especially when brain damage is extensive. Muscle tone might markedly decrease when the patient is sleeping or relaxed.
    • Postures vary greatly and are not markedly affected by the patient's emotional state.
    • Dystonias are characterized by persistent involuntary contractions of a muscle or muscle group that result in a fixed position.
    • In the athetotic form, involuntary activity is often produced as an overflow phenomenon from attempted voluntary movement. This feature is characterized by excessive muscular activity, mostly in muscles that are not involved with the task and that are directly antagonistic.¹⁴
• Cerebral palsy (CP) - Deep tendon reflexes
  • Deep tendon reflexes are exaggerated in both pyramidal and extrapyramidal CP and are not useful in differentiating these 2 forms of abnormal muscle tone.
  • Sustained ankle clonus is seen more often in the spastic form, but it can also be seen in the extrapyramidal form.
  • A prominent Babinski sign can be used to differentiate CP from other types of developmental delays.
• Clinical picture - Early
  • Defining the type of CP in young patients is difficult. Symptoms change with age, and many infants with suspected CP may be asymptomatic at the age of 7 years.
  • Children who developed spastic CP are hypotonic at birth and might remain hypotonic for the first 6-8 months of life.
  • In many cases, the exact clinical picture is not defined until the child is aged 2-3 years.
  • In the first week of life, newborns with bilirubin encephalopathy and kernicterus present with opisthotonos and a high-pitched cry. Their muscle tone might be normal by the sixth week of life.
  • Subtle signs are predictive of CP. Examples are lying asymmetrically in bed; asymmetrically opening of the mouth; or having difficulty in maintaining a symmetric posture, difficulty extending the neck and supporting the weight with the arms, poor stability of the neck and trunk, and difficulty flexing the neck in traction response.¹⁵
• Clinical picture - Childhood and beyond
  • Full chorea syndrome can be seen by the end of the third year of life.
  • In teenagers or young adults, dystonia, more than choreoathetosis, is the predominant movement disorder.
  • When choreoathetosis is a consequence of kernicterus, the cognitive deficit is not severe. However, deafness is present in 70% of affected patients.
  • In a young child, the choreoathetotic form is more likely than other types to be associated with diffuse brain damage and severe cognitive deficiencies.
  • Epilepsy is a frequently associated condition.
  • Many medical complications, such as progressive scoliosis, nerve entrapments, secondary muscle atrophy, and contractures, can interfere with movement.
  • Contractures (usually in limb joints) are common. The temporomandibular joints are also affected and might be responsible for a slow, progressive deterioration of feeding skills.¹⁶
  • Individuals with a dystonic choreoathetoid disorder are prone to have cervical spondylosis, radiculomyelopathy, and carpal tunnel syndrome.^17,18
• Delayed-onset movement disorder in individuals with developmental disabilities
  • In individuals with nonprogressive brain lesions due to perinatal hypoxia-ischemia, the movement disorders might not present until years after the insult. The mean latency for the development of movement disorders could be as much as 27 years. The mean latency is independent of the cause of the injury and decreases with age at the time of injury. It could be more than 27 years if the initial insult occurs when the patient is younger than 2 years.²
  • The type of movement disorder also is related to age at the time of injury. Generalized dystonia is most often seen in patients in whom the brain injury occurred before age 2 years. Tremor, parkinsonism, and myoclonus are other movement disorders observed in these patients. Spasticity and cognitive deficiencies can present before these movement disorders. The pathophysiology is poorly understood.
• Mild neuromotor disabilities
  • Affected children present with fine and gross motor skills and cognitive functions that are mildly impaired relative to those of their same-aged peers. Labels such as clumsy-child syndrome, minimal CP, and minimal brain damage, have been used to describe this condition.^19,20
  • Early in life, patients usually have a marked deficit in motor performance and, often a mild dyskinesia.
  • They might present with productive speech delay in the presence of good understanding.
  • Certain motor milestones, such as walking or riding a tricycle or bicycle, may be delayed. Patients may have difficulties learning tasks, such as buttoning and unbuttoning a shirt, tying shoes, or holding a pencil. Infants may never even crawl. Sports, mostly those that require good fine visual-motor coordination (eg, baseball, football) are particularly difficult for children with mild neuromotor disabilities.
  • Deficiencies become more obvious with age.
  • Hypotonia is seen in some cases.
  • Learning disabilities, and not necessarily mental retardation, might be present.
  • Some children present with attention-deficit/hyperactivity disorder.
  • Children usually do not have focal neurologic signs, but laterality may develop later in life.
  • The incidence of these disorders in children aged 5-7 years is 5-15%.²⁰
  • No clear organic basis is found in most cases. Perinatal complications might play a role. Some studies indicate clumsiness in close relatives.
  • Teenagers who presented with these symptoms when they were aged 6-7 years have more motor disorders and behavior problems, increased substance abuse, and greater difficulty in social adaptation than others.^19,21 They are less competent academically than teenagers with no history of clumsiness. Teenagers who have clumsiness in childhood have a decreased tolerance for the stress of intense military training.
• Drug-induced movement disorders -Tardive dyskinesia (TD)
  • TD is a well-recognized complication of long-term use of psychotropic medications. As many as 50% of people with mental retardation living in institutions and 30% of those living in community settings are taking psychotropic medications.²²
  • The Abnormal Involuntary Movement Scale (AIMS), the Dyskinesia Identification System Condensed User Scale (DISCUS), and the Rockland/Simpson Tardive Dyskinesia Rating Scale are frequently used to document the movement disorders of TD. Each scale results in a different prevalence in the same population.²³ This variation is probably related to poor cooperation²⁴ from patients and the presence of other chronic movement disorders.
  • In a population of individuals with mental retardation, the incidence of signs and symptoms of TD was 16% in those younger than 18 years; 30% in those aged 18-40 years and 42% in those older than 40 years. However, in many instances, signs and symptoms of TD were present in individuals never exposed to psychotropic medications (67% of those <18 y, 29% of those aged 18-40 y, and 15% of those >40 y).
  • In other studies of individuals with mental retardation never exposed to neuroleptics, orofacial movements were observed in 50%.²⁵ Movements of the head, trunk, and limbs were observed in 32%, and perioral facial movements were found in 27%. Brain damage alone may play a role in these movement disorders. However, some of the abnormal movements might be the result of nonpsychotropic medications that also have a dopamine-blocking effect. Metoclopramide, which is often used to treat the frequent gastrointestinal disorders observed in this population, causes as many movement disorders, as do other typical psychotropic medications.²⁶
  • One particular drug-induced TD is characterized by an insidious dystonic reaction. This involves mostly the trunk and produces a bend to 1 side, with rotation in the same direction. Some patients have a turn opposite to their walking direction. This TD was described in individuals with mental retardation and abnormal findings on brain CT. Symptoms were related to the use of antipsychotic drugs and improved with anticholinergic therapy.²⁷
  • In patients treated with neuroleptics, orofacial movements are observed in 71%, and movements of the head, trunk, and limbs in 53%; and perioral facial movements are observed in 34%.²⁵
  • Among patients with psychiatric disorders, the prevalence of akathisia is 12-75%.²⁸ In persons with mental retardation, it is 7-13%.^29,10 Akathisia is probably underreported because of its subjective component.
  • Significant risk factors are profound degree of mental retardation, increasing age, and length of the exposure.
  • Studies have yielded contradictory results in regard of prognostic factors, such as dosages of neuroleptics, for example.
  • Long-term outcomes vary, and the role of mental retardation in the persistence of the TD after drug discontinuation is not clear. Investigators agree that abnormal movements increase when the offending drugs are withdrawn and that they tend to normalize after the drugs are totally withdrawn. However, common screening instruments used to evaluate TD (eg, DISCUS) might not enable documentation of subtle and persistent changes in postural motion and of the sequential pattern of postural movement that remains even 1 year after drug withdrawal.
  • Second-generation antipsychotics improve the safety profile in terms of TD and are used in persons with mental retardation more commonly now than before.³⁰ However, studies in persons with mental retardation are insufficient to document this point.
  • The fatality rate of neuroleptic malignant syndrome, a severe and potentially fatal complication of psychotropic medication, is 21% in persons with developmental disabilities.³¹ This rate is approximately twice that in the general population. Neuroleptic polypharmacy was a factor in 55% of patients who developed this syndrome.
• Other drug-induced movement disorders
  • Patients with brain damage are at increased risk of toxicity from long-term use of antiepileptic drugs (AEDs).
  • Phenobarbital increases hyperactive behavior, especially in children who were previously hyperactive.
  • Persons with brain damage can acquire a phenytoin-induced choreoathetotic movement disorder. The risk is increased with a combination of phenytoin and lamotrigine.
  • Gabapentin produces a disorder similar to TD that is associated with facial dyskinesia in individuals with severe neurologic deficit and chronic epilepsy. New-onset myoclonus has been observed in several individuals with refractory epilepsy after gabapentin therapy was started.³² All of these individuals were taking other AEDs; however, the myoclonus improved or resolved after gabapentin was stopped. The myoclonus might be mild; if so, the medication need not be discontinued.
  • Long-term use of valproic acid as monotherapy produced a reversible parkinsonism syndrome in several patients with epilepsy. Choreic movements are also described in individuals with brain damage who were receiving valproic acid long term.³³
  • Oculogyric crisis was reported in a patient with mental retardation during therapy with carbamazepine and valproic acid.
  • Levetiracetam induced choreoathetosis in some children with refractory epilepsy. Improvement of the choreoathetosis was observed after the dosage of levetiracetam was decreased.
• Bruxism
  • Grinding of the teeth is an involuntary movement during sleep (ie, sleep bruxism) and common in the general population.
  • Bruxism in the awake state is associated frequently with severe to profound mental retardation.
  • Bruxism was observed in almost all patients with Rett syndrome who were evaluated in a dental clinic. In these individuals, the bruxism resulted in marked dental attrition. The bruxism was observed mostly during the day, and it was associated with an increase in the stereotypical hand behavior.³⁴
• Stereotypies and self-injurious behavior (SIB)
  • Stereotypies are repetitive, patterned involuntary movements that have no apparent function. They have some rhythmicity, and they also might have a ritualistic quality. Examples include body rocking; waving and flapping the hands; staring; head banging; and touching, feeling, and smelling different objects. Seeing several stereotyped behaviors in the same individual is not unusual.³⁵
  • The prevalence of stereotypies and SIB in people with severe-to-profound mental retardation living in institutions is 32-60%.^36,37 In non-institutionalized persons with mental retardation, it is 8-10%, and in persons with mental retardation and autistic psychosis living in community settings, the prevalence can be as high as 22%.³⁸
  • Stereotyped behaviors are also seen in healthy individuals. For example, body rocking,³⁹ head banging, and thumb sucking are common behaviors in healthy toddlers that can persist into childhood.^40,41 Studies showed that body rocking might be seen in 25% of adults without mental retardation. However, this body rocking might be different from that seen in persons with mental retardation, in whom the behavior may have increased amplitude and decreased association with situational factors.
  • Motor stereotypies may persist for many years, especially those affecting hands and arms and observed in early life in children without mental retardation or pervasive developmental disorder. Other comorbid conditions including attention deficit hyperactivity disorder, tics, and obsessive compulsive disorders are also seen in these children. Some of these children have family history of stereotypies.⁴²
  • The causes of stereotyped behaviors are not clear and might differ from person to person. Several theories have been explored to explain the stereotyped behaviors observed in persons with mental retardation.
    • Because many stereotyped behaviors are similar to rhythmic habit pattern in healthy infants, one theory speculates that the stereotyped behaviors are simply a delayed presentation of these otherwise normal patterns.
    • Stereotyped behaviors can be induced and then maintained by the sensory perceptions that occurred at the time of the behavior, in a self-perpetuating circle. In individuals with this finding, the behaviors can be controlled by removing the perceptions.
    • Stereotyped behaviors might result from central motor-control disorders secondary to damage to the basal ganglia.
    • The repetitive and sometimes rhythmic nature of the behavior might be related to normal physiologic rhythmicity (eg, linked to the heart rate).
    • Some form of stereotyped behavior might be internally regulated (like having an internal pacemaker). In some individuals, the stereotyped behaviors might occur consistently over long periods. This observation suggests that, in these individuals, external environmental factors are not relevant in the expression of the behavior.
    • In other individuals, behavior is opposite to that described above. The behavior decreases in frequency when these individuals are exposed to enriched environments and increase when their environments are barren.
  • Environmental or emotional factors might induce stereotypies.
  • SIBs often consist of repetitive behaviors that might be considered extreme versions of stereotypies. The harmful consequences of the behavior (eg, head or body banging, eye poking, self-cutting, self-biting), and not necessarily the topography, differentiate this behavior from other stereotypies.
  • The reported prevalence is 10-15% in institutionalized individuals, but it may be as high as 38% in individuals in public residential facilities. The rate is 1-2.5% in the population with mental retardation living outside of institutions.⁴³ The degree of mental retardation is correlated with the prevalence of self-injury. Also, the presence of SIB is associated with a high degree of institutionalization.³⁵
  • Stereotypies are twice as frequent in persons with SIB than in others, suggesting an association. Compulsive behavior is also associated with SIB and stereotypies.
  • The biologic bases of these behaviors are unknown, but they are not necessarily the result of mannerisms or psychological events. These behaviors are frequently observed in individuals with mental retardation, and they may be the result of a neurochemical imbalance. A growing body of evidence suggests that endogenous factors that interfere with pain-regulatory systems might play a role in the development and persistence of these behaviors in certain individuals.
  • Brain damage at early age, hypodopaminergic function,³⁷ failure of dopamine D2 and serotonin receptors, dysfunction of the basal ganglia or the mesolimbic system, and neuropeptide or endorphin dysfunction are implicated in the pathogenesis of these stereotypies.
  • Some studies showed that individuals with mental retardation, stereotypies, and SIB had morning beta-endorphin levels that were higher than those of control subjects with mental retardation.⁴⁴
  • Evaluation of plasma cortisol levels in individuals with mental retardation with or without SIB yielded contradictory results. Some studies showed no difference, whereas others revealed lowered plasma cortisol values in persons with SIB.
  • Substance P, a neuropeptide released from sensory fibers of peripheral nerves after noxious stimulation, modulates the transmission of peripheral pain impulses to the brain. In individuals with mental retardation and SIB, salivary substance P content is decreased in the morning compared with the afternoon.⁴⁵
  • Different theories have been presented to explain SIB. One theory suggests that decreased pain perception is responsible for SIB. Others suggest that seeking opiate euphoric effects, which are induced by release of beta-endorphins at the time of SIB, is the basis of the abnormal behavior. This theory implies that SIB is equivalent to an addiction.
  • Given the theory described above, the use of opiate antagonists (eg, naltrexone, naloxone) may be helpful. The variation in responses suggests dysregulation of the beta-endorphin system in some cases.
    • Researchers quantitatively analyzed peer-reviewed publications from 1983-2003 that reported the use of naltrexone in people with developmental disabilities and other related condition (eg, autism) to treat SIB.⁴⁶ About 80% of the subjects treated this way had improvement, and, in 47%, SIB was reduced by at least 50%.²² Male subjects responded better than female subjects, and no significant correlation was found between the type of SIB or the presence of autism.
    • Studies with naltrexone showed improvement in SIB and in some stereotypies but no improvement or even an increase in other stereotypies. This finding suggests that the biochemical mechanism for these 2 behaviors might be different.^{44,47,48,49,50}
  • Use of medications to treat these behaviors is controversial. In general, neuroleptics seem to be most effective in suppressing specific stereotyped behaviors, but they do not appear to improve SIB. Other drugs used to treat stereotypic behavior include benzodiazepines, methylphenidate, amphetamines, reserpine, fenfluramine, naltrexone, and clonidine. The efficacies of these medications vary; however, in general, they are not effective.
  • Reducing sensory input results in improvement in some individuals. For example, playing a hand-held video game or wearing safety goggles reduced eye poking, and applying a topical anesthetic to the cheek reduced self-slapping.⁵¹
• Autism
  • Clinical features usually manifest in early infancy. Disorders of language and social communication, poor response to external stimulation, tendency to isolation, and poor eye-to-eye contact are well-recognized symptoms.
  • For many years, the motor system was thought to be unaffected; however, recent data clearly show that motor deficiencies can be demonstrated as early as the first trimester of life.
  • Individuals with autism have various degrees of clumsiness, difficulties in using utensils and dressing themselves, and delayed development of motor milestones.
  • Some children and adults with autism have difficulties with organized movements and sequential tasks. Children with autism have difficulty with goal-directed motor tasks. Visual control of movement may be impaired.
  • Hyperactivity and irritability are common, as are stereotyped, ritualistic, and SIBs.
  • Gait acquisition may be delayed, and unusual gait patterns are frequently observed. Steps might be shortened, and the associated movement of the limbs may be slower than in that in individuals without autism. Toe walking is not unusual.
  • Poor facial expression, which was initially thought to be secondary to withdrawal behavior, might be an expression of a generalized motor dyspraxia.
  • The anatomic basis of these abnormalities is unclear.
• Special cases
  • Behavioral phenotypes - Syndrome-specific behaviors: Few syndromes are associated with typically pathognomonic behaviors (eg, hand wringing observed in individuals with Rett syndrome, hand biting in those with Lesch-Nyhan syndrome, face hitting in those with Cornelia de Lange syndrome). These behaviors are not exclusive of these particular syndromes; however, clinical experience shows that individuals with certain syndromes are likely to have a given set of behaviors more often than individuals without the syndrome, though the behaviors might not be unique to the syndrome. Because some syndromes are associated with specific genes or metabolic abnormalities, the evaluation of syndrome-specific behavior offers a unique opportunity to correlate abnormal behaviors with potential biochemical abnormalities.
  • Smith-Lemli-Opitz syndrome, or RSH syndrome, is an autosomal recessive disorder caused by a genetic deficiency of the enzyme 7-dehydrocholesterol reductase. This deficiency impairs production of cholesterol from the precursor 7-dehydrocholesterol, levels of which are elevated in blood and tissues. In most patients, the concentration of cholesterol in both blood and body tissues is decreased.⁵² These biochemical abnormalities help to confirm the diagnosis.
    • Smith-Lemli-Opitz syndrome is characterized by mental retardation and multiple malformations. The level of cognitive function ranges from borderline to profound mental retardation. Affected individuals might have language impairment that is more receptive than expressive. They may also have sleep disturbances, hyperactivity, ritualistic and repetitive behaviors, trichotillomania, high prevalence of autism spectrum disorder⁵³ , and SIBs, which in many individuals consist of biting the wrist or the thenar areas. During infancy, they might have inconsolable screaming. Irritability and aggression are also part of the syndrome.
    • Some phenotypical abnormalities are frequently observed. These abnormalities help to suspect the diagnosis and include microcephaly, bitemporal narrowing of the head, ptosis, upturned nares, micrognathia, posteriorly rotated ears, prominent nasal bridge, high arched palate, syndactyly in the toes, and clinodactyly.
    • In an evaluation of 56 patients in whom the syndrome was biochemically confirmed, abnormal aggression was reported in 63%, and self-injury was reported in 89%. A particular behavior consisting of forceful and rapid backward arching of the head and trunk and backward thrusting (opisthokinesis) was present in 54%. This behavior was seen in children younger than 5 years and decreased after that. Also, arching of the neck backward was seen in another 13%. Stretching associated with a brief and rapid hand movement was observed in 27%.⁵⁴ Children who received cholesterol supplementation therapy before the age of 5 years fulfilled fewer criteria for autism than did those who started cholesterol supplementation later in life.⁵⁴ However, this improvement was not confirmed by others.⁵⁵ Treatment with simvastatin in patients with mild biochemical abnormalities did not have a positive effect on behavior.⁵⁵
  • Fragile X syndrome: This is the most common form of X-linked mental retardation. This syndrome was first described in male subjects, but we now know that both male and female individuals are affected. However, expression of the phenotype is most severe in male patients.
    • An expansion mutation in the fragile X mental retardation 1 (FMR1) gene on the long arm of the X chromosome causes this syndrome. This mutation limits the production of the fragile X mental retardation protein (FMRP), which is related to the maturation of synapsis during brain development.⁵⁶  FMRP also has a role in the regulation of cortisol. Healthy individuals have 6-50 CGG (cytosine-guanine-guanine) repeats. Individuals with typical phenotype of fragile X syndrome have more than 200 CGG repeats. Persons with 50-200 CGG repeats carry the premutation, and though they do not have the full phenotype, they might have neurocognitive signs and symptoms. Boys with fragile X have lower levels of FMRP than girls do, and the clinical manifestations of the syndrome are more severe in boys than in girls.⁵⁶
    • The typical phenotype includes mental retardation with IQ into the moderate-to-severe range. About 20-30% of the boys present with autism,⁵⁷ and 15-20% have epilepsy in childhood. Other somatic features frequently seen in boys are macroorchidism, a long and narrow face, enlarged ears and jaw, increased head circumference, and prominent supraorbital ridges. Neurologic signs and symptoms include gait disturbances, poor fine-motor performance, cerebellar ataxia, intention tremor, parkinsonism, peripheral neuropathies. An underlying defect in the connective tissue causes hyperelasticity of the joints, pes planus, and smooth skin. Physical characteristics might not be seen until after the onset of puberty. Some boys present with attention-deficit disorders, hyperactivity, and speech and language disorders.
    • Compulsive behavior has been reported in 74% of boys and 55% of girls.⁵⁶  Girls with compulsive behaviors have significantly lower levels of FMRP than those who did not show compulsive behaviors.⁵⁶  Self-injurious behavior was found in 58% of boys and 17% of girls with fragile X. Self-biting was the most prevalent form (45% of the boys and 7% of the girls).⁵⁶
    • Women with the premutation have failures in visual attention and premature ovarian failure with early menopause.
    • A syndrome with tremor and/or ataxia and progressive neurologic deterioration was described in relatives of persons with fragile X syndrome. These individuals had a triplet repeat expansion of 55-200 CGG repeats.^58,59
  • Smith-Magenis syndrome: This syndrome is the result of an interstitial deletion of the 17p11.2 chromosome subband. It is characterized by dysmorphic features, such as brachycephaly, midface hypoplasia, brachydactylia, ear malformations, and mild-to-moderate mental retardation. A typical stereotyped behavior consists of self-hugging;⁶⁰ patients either cross both arms tightly across their chest while simultaneously tensing their upper body, or they clasp their hands while interlocking their fingers and squeezing their arms against their chest. Most present with severe aggressive and self-mutilating behaviors, such as pulling out fingernails and toenails or inserting foreign bodies into bodily orifices. Head banging and hand biting are also common.
  • Lesch-Nyhan syndrome: This syndrome is associated with a gene localized on the long arm of the X chromosome (q26-q27).⁶¹ Most patients with this disorder have low or undetected levels of hypoxanthine-guanine phosphoribosyltransferase. This enzyme is present in each cell of the body but its concentration is highest in the basal ganglia. Definitive diagnosis requires measurement of levels of this enzyme. In individuals with the classic syndrome, the level is almost 0%, but it can be as high as 50-60% in people with partial variants. Clinical manifestations are inversely correlated with the severity of the symptoms.
    • The syndrome is characterized by hyperuricemia, mental retardation (which is usually mild to moderate), CP with hypotonia in early life followed by extrapyramidal symptoms (eg, chorea, athetosis, dystonia) that appear in the first year of life. In many cases, pyramidal signs (eg, hyperreflexia, ankle clonus, Babinski sign, scissoring gait) might be seen at the age of 1 year.
    • A distinctive feature is the presence of intense self-mutilation (eg, lip biting) all sensory modalities, including pain sensation, being intact. The most common age of onset of the self-mutilating behavior is around 1 year. However, in some patients, it might be in the teens. The most common SIB is lip and finger biting. The SIB is intense and may result in loss of tissue in the lips or tongue or in partial amputation of the fingers. The patient is aware of the SIB and might help to devise strategies to decrease the behavior. They might even ask for help to stop the damaging behavior. Other abnormal behavior (eg, limb banging, pulling of fingernails, poking the eyes) may develop. Patients may also pinch or hit other people or display other aggressive behaviors.
    • Volumetric studies of the brain show markedly decreased volume in the caudate and some loss of volume in the putamen and whole brain.
    • The biochemical abnormalities of the syndrome are not clear. Data suggest a defect in the arborization of dopaminergic dendrites. Other data show a decreased striatal cholinergic activity. Increase serotonergic activity in the striatum might be related to the SIB. Reduced presynaptic dopamine transport suggests that dopamine dysfunction in the basal ganglia might be involved in the dystonia observed in some patients.
    • Medical management with allopurinol effectively reduces the high levels of acid uric and prevents gout and the lethal complications of kidney failure. However, it does not affect the behavior and has no effect on SIB. Bone marrow transplantation was tried, but it was not effective. Partial-exchange transfusion improved enzyme activity but had no effect on the behavioral and neurologic issues.
    • Several behavioral treatments have been used. Aversive techniques based on contingent electric shocks that might be useful in other SIBs are not effective in this condition. Positive reinforcement seems to be more useful than aversive techniques.
    • Use of physical restraints seems to be among the most effective techniques. Individuals with the disorder frequently participate in making the decision about using restraints, and they are usually compliant. Simple techniques, such as using bandages or wearing gloves, might be effective.
    • Stress reduction and getting involved with the child when the abnormal behaviors occur are reportedly useful.
    • Because most of the damage involves biting, several odontologic procedures have been used with some positive results. Examples are the use of mouth guards or the extraction of teeth.
    • Many drugs have been tried: benzodiazepines, haloperidol, clomipramine, L-dopa, pimozide, naltrexone, and fluphenazine. These drugs have not been useful in decreasing SIB.
    • Substantial healing in the lips was observed in 1 child treated with injections of botulinum toxin in the masseters muscles.
    • In a patient that was receiving bilateral chronic stimulation of the globus pallidus for the treatment of dystonia, SIB was unexpectedly and totally suppressed.⁶²
  • Prader-Willi syndrome: Obsessive-compulsive disorders are 20-40 times more common in Prader-Willi syndrome than in the general population with mental retardation.
  • Rett syndrome: This syndrome is a progressive neurodevelopmental disorder associated most often associated with a mutation in the X-linked gene MECP2. However, in some patients with the phenotype of Rett syndrome establishing a positive molecular diagnosis is not possible. Some differences have been observed between those patients with and those without the mutation.⁶³
    • Studies have shown evidence of neurotransmitter dysfunction involving both excitatory and inhibitory neurotransmitters.
    • The syndrome is characterized by progressive deterioration of acquired motor skills, epileptic seizures, development of an autism-like syndrome, and a particular movement disorder comprising a stereotyped hand movement (hand washing or hand wringing). These stereotyped hand movements, even though not unique to Rett syndrome, are a major diagnostic feature and a necessary diagnostic criteria. The hands are kept to the sides of the body or to the front. Finger rubbing and overlapping of fingers may also be observed. The hands are frequently kept near or inside the mouth. These behaviors are seen only when the patient is awake and are not that much affected by environmental manipulations.⁶³
    • The hand stereotypies appear early in life (2-3 y) and may precede or coincide with loss of purposeful hand movements, another distinct feature of Rett syndrome. These stereotypies are usually seen months after the child has lost social interactions.⁶³
    • The most frequent movement is the simultaneous wringing-washing-like movements of both hands. However, independent hands movement can also be seen. More than one stereotype can be seen in the same individual, and some individuals might have 5 or more stereotypic movements. The most frequent association is hand washing and bruxism.⁶³ Bruxism is observed mostly when the patient is awake.
    • The number of stereotype movements decreases after the age 10 years, and some movements (not the ones involving the hands), tend to disappear as the patient gets older.   
    • Other abnormal movements involving other body parts have also been described.⁶³  These abnormal movements include head rolling, grimacing, retropulsion, mouthing of the hands, pill rolling, flapping, toe walking, and jumping.
    • The most typical hand movements are first observed around age 2-3 years; however, closed analysis of family videotapes obtained in girls before the diagnosis of Rett syndrome showed that abnormal generalized spontaneous movements can be observed during the first 4 months of life.⁶⁴
    • Breathing irregularities, hyperventilation, breath-holding, or a combination of these also may be present. Topiramate is effective for treating the seizures and the respiratory disorder.⁶⁵
    • Motor disorders that affect swallowing lead to difficulties in feeding (and malnutrition).

Physical

Previous sections discuss the most relevant physical findings for each condition.

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