eMedicine Specialties > Pediatrics: Developmental and Behavioral > Medical Topics

Pervasive Developmental Disorder: Rett Syndrome

Bettina E Bernstein, DO, Assistant Professor, Department of Psychiatry, Philadelphia College of Osteopathic Medicine; Private Practice at the Wynnewood House, Consultant to Child Guidance Resource Centers, Early Elementary Education Program
Joseph H Schneider, MD, Clinical Assistant Professor of Pediatrics, Section of Neonatology, Univ. Texas Southwestern at Dallas and Childrens Medical Center; Daniel G Glaze, MD, Medical Director, Blue Bird Circle Rett Center; Associate Professor, Departments of Pediatrics and Neurology, Baylor College of Medicine

Updated: Mar 13, 2008

Introduction

Background

Rett syndrome (RS) is a pervasive developmental disorder first reported in 1966 by Andreas Rett, an Austrian pediatric neurologist. RS occurs almost exclusively in females and has a typically degenerative course. Before the discovery of RS, incidents were mistaken for many other neurologic disorders, especially in females. The gene related to RS (methyl-CpG binding protein-2 [MECP2]) was identified late in 1999.^{1,2,3,4,5,6,7,8,9,10}

Patients with RS initially have seemingly healthy development. However, in retrospect, girls are frequently reported to have been placid as infants, with low tone and subtle slowing of development. An early clinical feature is deceleration of head growth that begins when the individual is aged 2-4 months. A period of developmental stagnation is followed by a period of regression. Males with this disorder also manifest a spectrum of symptomatology, ranging from severe congenital encephalopathy, dystonia apraxia, and retardation to psychiatric illness with mild mental retardation. Individuals who are less severely affected may tolerate or even prefer interpersonal contact, show affection to others, and suffer from learning disabilities and speech fragmentation related to breathing irregularity.

The regression phase in individuals with RS may occur acutely over a period of days or, more insidiously, over months. Regression is characterized by loss of purposeful hand skills and oral language and the development of hand stereotypies and gait dyspraxia. Other problems include breath holding and apnea during wakefulness with normal breathing during sleep, epilepsy, oral-motor dysfunction with gut motility problems (eg, constipation, gastroesophageal reflux [GER]), scoliosis, autonomic dysfunction (cold, blue extremities), and somatic growth failure. During the regression period, individuals with RS demonstrate screaming episodes, sleep disturbances, and poor social interactions.

Following the regression period, people with RS demonstrate no further cognitive decline, become more interactive with their environment and other persons, and may demonstrate some improvements in hand and communication skills. They progress through puberty and survive to adulthood; however, they never regain significant purposeful hand use or oral language skills.

Currently, diagnosis of RS is made if the patient meets defined clinical criteria. The diagnosis is supported by a positive mutational analysis of MECP2. However, as many as 20% of females who meet the full clinical criteria for RS may have no identified mutation. Because no cure is available, treatment is palliative and supportive. A multidisciplinary approach to care for persons with RS is recommended.

Pathophysiology

RS is a genetic disorder of neurodevelopmental arrest rather than a progressive process. The gene for RS is located on the X chromosome. Females with one mutated MECP2 gene are more likely to survive because one X chromosome is activated randomly in each cell. The symptoms and severity of RS may depend on both the percentage of activated defective genes and the type of mutation. Multiple mutation types have been found in the 3 coding regions of the MECP2 gene, with most mutation types causing truncations and missense proteins. Mutations have been found in as many as 80% of analyzed cases of classic RS.

RS is the first human disease discovered that is caused by defects in a protein that regulates gene expression through interaction with methylated DNA. Therefore, RS involves abnormal chromatin structure, with broad-ranging effects on expression of genes that are otherwise not mutated. The normal MECP2 gene encodes a protein (also called MeCP2) that binds to methylated DNA in conjunction with a corepressor. This causes activation of histone deacetylase. Mutations in the MECP2 gene produce loss of function of this protein and unregulated expression of the genes that it normally affects, some of which, apparently, are crucial in nervous system development beyond the initial stages. Although the nervous system is the primary site, the specific target genes are not known.

Frequency

United States

The incidence has been reported to be approximately 1 per 23,000 live female births.¹¹

International

Wide variations in the incidence of RS have been reported among various countries. Rates as high as 1 per 10,000 live female births have been reported.¹² One study in Japan found an incidence of 1 per 45,000 girls aged 6-14 years.¹³ Variations in incidence may be partly accounted for by the inclusion of atypical or variant forms of RS. These atypical forms include congenital RS, milder forms with later onset of regression,¹⁴ and preserved speech variants.

Mortality/Morbidity

Most patients with RS survive into the fifth or sixth decade of life, often with severe disabilities. Survival rates of RS decline in individuals older than 10 years; the 35-year survival rate is 70%. Death may be sudden and often is secondary to pneumonia. Risk factors include seizures, loss of mobility, and difficulties with swallowing. The life expectancy is more favorable in patients with RS than in other individuals with profound mental retardation, which is associated with a 35-year survival rate of only 27%.

Race

No racial variations have been reported. In a study by Kozinetz et al, which included Latin Americans, Caucasians, and African Americans in Texas, no variation in incidence or prevalence of RS was found.¹⁵

Sex

Most patients identified are female because the disease is X-linked. Many males with RS are believed to die in utero. However, a few reports have detailed males with mutations in MECP2 and RS-like symptoms.^2,5,7 Excess male fetal loss has not been demonstrated in families with a history of RS; thus, an alternative explanation for female predominance may be noted.

Age

RS generally becomes clinically evident by the time the individual is aged 2-4 years; however, the underlying neurodevelopmental arrest probably starts in children aged 6-18 months or younger.

Clinical

History

History varies by clinical stage as follows:

• Stage I - Developmental arrest (typically in children aged 6-18 mo)
  • Parents may report gross motor development delay, disinterest in play, and loss of eye contact.
  • Hypotonia may be noted.
  • Hand wringing, a hallmark of the disease, typically appears.
  • Infants may be reported as placid and calm when compared with healthy infants.
  • Early symptoms are often very vague and nonspecific.
• Stage II - Rapid deterioration or regression (typically in children aged 1-4 y)
  • Deterioration may be rapid.
  • Sometimes, parents can report specific dates after which their child was no longer healthy.
  • In other cases, deterioration may be slow in onset.
  • This stage can last weeks to months and may be characterized by reports of autisticlike behavior, such as a loss of social interaction and communicative skills, loss of oral language, and loss of purposeful finger and hand use.
  • Parents may note stereotypic hand movements during wakefulness. These are usually midline and consist of hand wringing, clapping, washing, or hand-to-mouth movements.
  • Parents or caregivers may also report episodes of breathing irregularities, such as hyperventilation¹⁶ or breath holding.
  • Patients with Rett syndrome (RS) may also have seizures and vacant spells that resemble seizures.
  • Other problems that may be noted are sleep disorders, intermittent strabismus, and irritability.
• Stage III - Pseudostationary (typically in children aged 2-10 y)
  • Some improvement in behavior, hand use, and communication skills may occur.
  • Patients may make good eye contact and make their intent known with whatever communicative skills that remain.
  • Despite the improvement, mental impairment and hand stereotypies continue.
  • Increasing rigidity, bruxism, and involuntary tongue movements may be reported.
  • Motor dysfunction and seizures are frequently reported.
  • Episodes of hyperventilation or breath holding may continue.
  • Although the child has a good appetite, weight gain is poor.
  • Feeding may become more difficult, and almost all individuals with RS have some degree of oral motor dysfunction.
• Stage IV - Late motor deterioration (typically >10 y).
  • No additional deterioration of cognitive skills, communication skills, or hand skills occurs; however, increasing motor problems may occur, including hypertonia, dystonia, and Parkinson symptoms (eg, bradykinesia, rigidity, retropulsion).
  • Some patients stop walking.
  • Seizure frequency may be reduced.

Physical

Disease development progresses through 4 stages, which are typically reached at the ages indicated below. Physical findings vary by clinical stage as follows:

• Stage I - Developmental arrest (typically in children aged 6-18 mo)
  • Findings may include gross motor development delay, loss of eye contact, deceleration in head growth (can occur by age 3 mo), deceleration in weight growth (can occur by age 4 mo), deceleration of height growth (can occur by age 16 mo), hypotonia, and hand wringing.
  • Infants with RS may appear placid and calm when compared with healthy infants.
  • Cutaneous findings, such as the presence of hypopigmented macules, are not observed when examined with a Wood lamp.
• Stage II - Rapid deterioration or regression (typically in children aged 1-4 y)
  • Findings may include autisticlike behavior (ie, loss of social interaction and communicative skills with no oral language).
  • Midline hand wringing, clapping, hand washing, or hand-to-mouth movements may be present, along with episodes of hyperventilation or breath holding.
  • Seizures and vacant spells that resemble seizures may also occur, along with intermittent strabismus and irritability.
• Stage III - Pseudostationary (typically in children aged 2-10 y): Findings may include hand stereotypies, rigidity, hyperventilation, breath holding, bruxism, involuntary tongue movements, poor weight gain, and scoliosis.
• Stage IV - Late motor deterioration (typically in individuals >10 y)
  • Findings may include dystonia, rigidity, muscle wasting, quadriparesis, scoliosis or kyphoscoliosis, loss of ambulation, growth retardation, hyperventilation, and seizures.
  • Improvements may be observed in frequency and intensity of hand movements.
  • Eye contact continues to be preserved and may be the only avenue by which emotions and needs can be communicated.
• Rett syndrome diagnostic criteria: Diagnosis of classic RS requires that patients meet certain necessary, supportive, and exclusionary characteristics as outlined below.
• Atypical or variant incidents of RS may occur because of the heterogeneity of the syndrome. Inclusion criteria for these are presented below. In a girl aged 10 years or older with mental retardation of unexplained origin who does not demonstrate the exclusion criteria listed below, atypical or variant RS can be diagnosed if at least 3 of the 6 primary criteria are present. In addition, at least 5 of 11 supportive manifestations must be met.

Causes

See Pathophysiology. Mutations that cause RS are almost all sporadic. In families with a girl who has RS, the increased risk of having a second girl with RS is reportedly less than 0.4%. However, recurrence in families can occur through mechanisms such as germline mosaicism.

Differential Diagnoses

Other Problems to Be Considered

Differential diagnosis varies by clinical stage as follows:

Stage I - Developmental arrest (typically in children aged 6-18 mo)
Benign congenital hypotonia
Cerebral palsy
Prader-Willi syndrome
Angelman syndrome
Metabolic disorders (eg, fetal alcohol syndrome, trisomy 13)

Stage II - Rapid deterioration or regression (typically in children aged 1-4 y)
Autism
Angelman syndrome
Encephalitis
Hearing and/or visual disturbance
Landau-Kleffner syndrome
Psychoses
Slow virus panencephalopathy
Tuberous sclerosis
Metabolic disorders (eg, phenylketonuria, ornithine transcarbamoylase deficiency)
Infantile neuronal ceroid lipofuscinosis

Stage III - Pseudostationary (typically in children aged 2-10 y)
Spastic ataxia
Cerebral palsy
Spinocerebellar degeneration
Leukodystrophies
Neuroaxonal dystrophy
Lennox-Gastaut syndrome
Angelman syndrome (likely not Kabuki because patients would have macrocephaly)

Stage IV - Late motor deterioration (typically in patients >10 y)
Other degenerative disorders

Workup

Laboratory Studies

Females who meet the clinical diagnostic criteria should undergo genetic testing.

• Several laboratories provide diagnostic sequencing of the MECP2 gene. Specifics of how to obtain this testing can be found on the International Rett Syndrome Association Web site.
• Patients with positive MECP2 mutational gene analysis need no further diagnostic testing.
• Patients in whom no mutation is found should undergo other diagnostic tests to identify other possible causes of their signs and symptoms. These include tests for serum lactate, ammonia, pyruvate, and amino acids as well as urine organic acids and chromosomal studies, including specific tests for Angelman syndrome (chromosome 15). Rarely, urinary tests for uroporphobilinogen to rule out intermittent porphyria can be helpful.
• Mutations in the MECP2 gene have been identified in a wide spectrum of clinical phenotypes, including girls with classic Rett syndrome (RS), girls with RS variant forms, girls with autism, healthy females (carriers), males with severe infantile encephalopathies, males with classic RS, and males with X-linked neurologic problems (eg, motor deficits, communication deficits).^17,18

Imaging Studies

Neuroimaging may be useful.

• MRI may help include or exclude other causes of a patient's signs and symptoms.
• Although RS is associated with a significant decrease in cerebral cortex size, cerebellar atrophy, and a brain weight that is approximately 70-90% of normal, these findings are not specific for the diagnosis of RS.
• Changes may also be observed in the corticospinal tracts with reduced myelin and some gliosis.

Other Tests

• Electrocardiography
  • Findings may include an inverted T wave and a prolonged QT interval.¹⁹
  • Studies have demonstrated that the incidence of sudden death in persons with RS is greater than that of the general population.
  • Patients with RS may also have significantly lower heart rate variability.
  • These cardiac abnormalities may increase with advancing stages of RS.
• Barium swallow study or overnight pH probe study
  • These tests can be used to document GER, which is present in approximately 15% of patients with RS. GER may cause weight loss, discomfort with meals, vomiting after eating, obstructive apnea, or recurrent respiratory congestion and problems.
  • Swallowing studies frequently document poor oral motor skills and risk of aspiration.
• EEG
  • Abnormal results are common.²⁰
  • Seizures are reported in 60-90% of patients with RS.
  • Differentiation from Landau-Kleffner syndrome should be made clinically and secondary to response to therapy.
  • Patients also frequently have epileptiform abnormalities that appear to be age related with greatest frequency during clinical stage III and with abnormalities that can be noted earlier during nonrapid eye movement (NREM sleep).
  • Video-EEG polygraphic monitoring may be required to determine whether antiepileptic therapy is indicated because many reported seizure episodes are nonepileptic behavioral events, whereas actual seizures may be underrecognized because they occur during sleep.
• Neurophysiologic testing
  • Auditory brainstem-evoked response testing generally demonstrates normal hearing with a delayed conduction time.
  • Somatosensory-evoked responses demonstrate spinal cord and brainstem conduction abnormalities.
  • Electromyographic studies are typically normal and need not be completed, except to exclude other conditions.
• Electroretinography
  • Electroretinography plus the EEG and the continued decline of children with infantile neuronal ceroid lipofuscinosis can help differentiate RS from infantile neuronal ceroid lipofuscinosis.
  • Both disorders cause rapid regression of psychomotor development and the development of hand and finger stereotypes in children aged 1-2 years.
• Polygraphic respiratory recordings
  • These studies may demonstrate a pattern of disorganized breathing characterized by periods of apnea and/or hyperventilation and significant oxygen desaturation and clinical cyanosis.
  • Normal breathing occurs during sleep in persons with RS.
  • Total sleep time may be decreased in patients with RS.
  • Individuals with RS may demonstrate prolonged periods (³ 18 h) of wakefulness or sleep.
  • Nighttime awakenings with frequent laughing are reported.
  • Screaming episodes may also occur at night; however, consider the possibility of other medical problems (eg, GER).
• Psychometric testing
  • Generally, results in psychometric testing scores are indicative of profound mental retardation.
  • However, standard instruments that depend on the use of hands and oral language may be inadequate to fully assess individuals with RS.
  • Specialized tests such as the Gilliam Autism Rating Scale or the Children's Autism Rating Scale can be helpful to detail autisticlike symptomatology.

Histologic Findings

Morphologic features include reduced brain weight, including reduced volume of the frontal cortex and caudate, reduced neuronal size, and dendritic arborizations in certain areas (frontal correlates, motor correlates, limbic correlates) with preservation in the visual cortex and decreased organ weights proportional to height and weight.

Neurochemical findings include the following:

• Reduced levels of catecholamines in the substantia nigra
• Reduced dopamine D2 receptors and dopamine reuptake in the caudate nucleus
• Reduced choline acetyltransferase in the hippocampus, caudate, and thalamus
• Reduced acetylcholine vesicles or transporters in the putamen and thalamus
• Reduced benzodiazepine receptor binding in the frontal and temporal cortex
• Reduced beta-endorphins in the thalamus and cerebellum but increased beta-endorphins in the cerebrospinal fluid (CSF)
• Increased glutamate in the CSF
• Reduced melanin in the substantia nigra
• Decreased substance P levels in the CSF

Diagnostic Criteria 

• Necessary criteria
  • Apparently normal prenatal and perinatal period
  • Apparently normal development through at least the first 5-6 months of life
  • Normal head circumference at birth
  • Deceleration of head growth (age 3 mo to 3 y)
  • Loss of acquired skills (age 3 mo to 3 y), including learned purposeful hand skills, acquired babble and/or learned words, and communicative abilities
  • Appearance of obvious mental deficiency
  • Appearance successively of intense hand stereotypies, including hand wringing or squeezing; hand washing, patting, or rubbing; and hand mouthing or tongue pulling
  • Gait abnormalities among ambulant girls, including gait apraxia, dyspraxia, or both and jerky truncal ataxia, body dyspraxia, or both
  • Diagnosis tentative until the individual is aged 2-5 years
• Supportive criteria
  • Breathing dysfunction, including periodic apnea during wakefulness, intermittent hyperventilation, breath-holding spells, and forced expulsion of air or saliva
  • Bloated and/or marked air swallowing
  • EEG abnormalities, including slow waking background and intermittent rhythmic slowing (3-5 Hz) and epileptiform discharges, with or without clinical seizures
  • Epilepsy (various seizure forms)
  • Spastic signs, later muscle wasting, and/or dystonic traits
  • Peripheral vasomotor disturbances
  • Neurogenic scoliosis
  • Hypotrophic small and cold feet
  • Growth retardation
• Exclusion criteria
  • Organomegaly or other signs of storage disease
  • Retinopathy or optic atrophy
  • Microcephaly at birth
  • Existence of identifiable metabolic or other neurodegenerative disorder
  • Acquired neurologic disorder resulting from severe infections, head trauma, or toxic ingestion
  • Evidence of intrauterine growth retardation
  • Evidence of perinatally acquired brain damage

The diagnostic criteria for atypical or variant RS syndrome are as follows:

• Primary criteria
  • Loss of (partial or subtotal) acquired fine finger skills in late infancy or early childhood
  • Loss of acquired single words or phrases and/or nuanced babble
  • RS hand stereotypies, hands together or apart
  • Early deviant communicative ability
  • Deceleration of head growth of 2 standard deviations (SD), even when within the reference range
  • RS disease profile (ie, a regression period [stage II] followed by a certain recovery of contact and communication [stage III] in contrast to slow neuromotor regression through school age and adolescence)
• Supportive criteria
  • Breathing irregularities (hyperventilation and/or breath holding)
  • Bloating and/or marked air swallowing
  • Characteristic RS teeth grinding
  • Gait dyspraxia
  • Neurogenic scoliosis or high kyphosis (ambulant girls)
  • Development of abnormal lower limb neurology
  • Small blue and/or cold impaired feet, autonomic and/or trophic dysfunction
  • Characteristic RS EEG development (as noted)
  • Unprompted sudden laughing and/or screaming spells
  • Impaired and/or delayed nociception
  • Intensive eye communication with eye pointing

Treatment

Medical Care

• Adopt a comprehensive team approach to maximize the abilities of patients with Rett syndrome (RS).
• If seizurelike activity is noted, video-EEG monitoring may be necessary to identify epileptic seizures for which antiepileptic drugs (AEDs) are appropriate. Vacant spells of patients with RS may not be seizures, and seizures may be less common than reported. However, true seizures may go unrecognized during sleep. Various treatments have been used to manage epilepsy in persons with RS. Treatments range from conventional AEDs (eg, carbamazepine, valproic acid) to newer AEDs (eg, topiramate, lamotrigine), a ketogenic diet, and a vagal nerve stimulator (VNS). Vagal nerve stimulation has generally been safe and well tolerated, with few surgical complications, increased alertness, and improved ability to participate in activities.²¹
• If seizures are well controlled, consider the addition of the Snoezelen multisensory approach, with or without hydrotherapy.^22,23,24

Surgical Care

• If the patient with RS cannot manage oral intake of food, consider a gastrostomy tube (G-tube) to minimize the risk of aspiration or recurrent pneumonias. Many girls with RS may experience significant somatic growth failure. Girls aged 4-8 years with RS may demonstrate poor or no weight gain despite apparently adequate caloric intake. In such persons, supplemental feeding is warranted either orally or by G-tube.
• If GER is refractory to medical treatment, a fundoplication may be necessary.
• Scoliosis in individuals with RS often does not respond to orthotics. Consider surgery in patients with Cobb angles more than 40-45° or curves that cause pain or loss of function.

Consultations

Patients with RS need early multidisciplinary evaluation and therapy, including the following:

• Communication assessment
  • Most girls with RS lose expressive language; however, some may retain one-word expressions, and others may attempt to communicate through eyes and body language.
  • Careful assessment of the patients' communication abilities and the parents' response to the patients' communication is important to maximize their potential.
  • Devices such as picture boards may be helpful.
• Oral motor assessments
  • Feeding disorders occur in more than 80% of patients with RS when aged 4-8 years.
  • Factors include abnormal tongue movements and tone, skeletal misalignment, and rigidity.²⁵
  • Treatments may range from simple positioning and therapy to decrease rigidity to more complex interventions.
• Other assessments and therapy
  • Music, hydrotherapy, hippotherapy (ie, horseback riding), and massage are noted by some to be helpful.
  • Other needs include psychosocial support for families and the creation and implementation of an appropriate educational plan with schools.
  • Parents may require help accessing community resources for items (eg, wheelchairs, ramps) and services that allow home care of patients with RS.

Diet

Despite excellent appetites, weight gain is poor in many patients with RS.

• Improved weight gain and better seizure control have been reported when girls were given a high-calorie diet, with approximately 70% of calories from fats and 15% each from carbohydrates and proteins (see Surgical Care).
• Osteoporosis is common in persons with RS. Osteoporosis in individuals with RS may need to be treated with vitamin D, calcium supplements, and bisphosphonate.

Activity

Therapy that promotes ambulation, balance, and hand use is important.

• Hand splints and other devices that decrease hand stereotypies may make girls with RS more focused and may decrease agitation and self-injurious behavior.
• Hinged ankle-foot orthoses and physical therapy may be beneficial in treating toe walking that results from increased heel cord tone.

Medication

No medications are available to treat persons with Rett syndrome (RS). Bromocriptine and carbidopa-levodopa, which are dopamine agonists, have been tried as a treatment for motor dysfunction in persons with RS; however, benefits are neither substantial nor long lasting. Case reports have suggested the effectiveness of levocarnitine.

Individuals with GER may respond to conservative medical treatment with antireflux agents (eg, metoclopramide), thickened feeding solutions, and semiupright positioning at bedtime (see Gastroesophageal Reflux). AEDs may be prescribed to control seizurelike activity.

Antiepileptic agents

These agents are used to control seizure activity.

Carbamazepine (Tegretol)

May block posttetanic potentiation by reducing summation of temporal stimulation. Following therapeutic response, may reduce dose to minimum effective level or discontinue treatment at least once q3mo.

Dosing

Adult

200 mg PO bid (100 mg PO qid if susp)
Increase at weekly intervals by increments not to exceed 200 mg/d tid/qid (bid with ER) until best response obtained, not to exceed 1600 mg/d

Pediatric

10 mg/kg/d PO divided tid/qid initial; may increase over 2-3 wk to 15-20 mg/kg/d

Interactions

Serum levels may increase significantly within 30 d of danazol coadministration (avoid whenever possible); do not coadminister with MAOIs; cimetidine may increase toxicity, especially if taken in first 4 wk of therapy; may decrease primidone and phenobarbital levels (their coadministration may increase carbamazepine levels); erythromycin may increase levels (sometimes very quickly and to very high ranges); can decrease potency of PO contraceptives because of protein-binding changes and/or metabolism

Contraindications

Documented hypersensitivity; history of bone marrow depression; administration of MAOIs within last 14 d

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution with increased intraocular pressure; obtain CBC counts and serum iron baseline prior to treatment, during first 2 mo, and yearly or every other year thereafter; can cause drowsiness, dizziness, and blurred vision; caution while driving or performing other tasks requiring alertness

Valproic acid (Depakote)

Chemically unrelated to other drugs that treat seizure disorders. Although mechanism of action is not established, activity may be related to increased brain levels of GABA, or enhanced GABA action. Valproate may also potentiate postsynaptic GABA responses, affect potassium channel, or have direct membrane-stabilizing effect. For conversion to monotherapy, concomitant AED dosage ordinarily can be reduced by approximately 25% q2wk. This reduction may start at initiation of therapy or be delayed by 1-2 wk if concern that seizures may occur with reduction is noted. During this period, closely monitor patients for increased seizure frequency. As adjunctive therapy, divalproex sodium may be added to patient's regimen at 10-15 mg/kg/d. May increase by 5-10 mg/kg/wk to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses <60 mg/kg/d.

Dosing

Adult

Monotherapy: 10-15 mg/kg/d PO divided bid/tid and increased by 5-10 mg/kg/wk, not to exceed 60 mg/kg/d until seizures are controlled or adverse effects prevent further increases; if total daily dose >250 mg, administer in divided doses
Monitor plasma concentration before morning dose 3-4 d after initiating or changing therapy

Pediatric

Administer as in adults

Interactions

Coadministration with cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin significantly may reduce valproate levels; in pediatric patients, protein binding and metabolism of valproate decrease when taken concomitantly with salicylates; coadministration with carbamazepine may result in variable changes of carbamazepine concentrations with possible loss of seizure control; valproate may increase diazepam and ethosuximide toxicity (monitor closely); valproate may increase phenobarbital and phenytoin levels while either one may decrease valproate levels; valproate may displace warfarin from protein-binding sites (monitor coagulation tests); may increase zidovudine levels in patients seropositive for HIV

Contraindications

Documented hypersensitivity; hepatic disease and/or dysfunction

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Thrombocytopenia and abnormal coagulation parameters have occurred; risk of thrombocytopenia increases significantly at total trough valproate plasma concentrations >110 mcg/mL in females and 135 mcg/mL in males; at periodic intervals and prior to surgery, determine platelet counts and bleeding time before initiating therapy; reduce dose or discontinue therapy if hemorrhage, bruising, or hemostasis and/or coagulation disorder occurs; hyperammonemia may occur, resulting in hepatotoxicity; closely monitor patients for appearance of malaise, weakness, facial edema, anorexia, jaundice, and vomiting; may cause drowsiness

Topiramate (Topamax)

Sulfamate-substituted monosaccharide with broad-spectrum antiepileptic activity that may have state-dependent sodium channel-blocking action, which potentiates inhibitory activity of neurotransmitter GABA. May block glutamate activity.
Not necessary to monitor topiramate plasma concentrations to optimize therapy. Coadministration with phenytoin may require adjustment of phenytoin dose to achieve optimal clinical outcome.

Dosing

Adult

50 mg/d PO; titrate by 50 mg/d at 1-wk intervals to target dose of 200 mg bid, not to exceed 1600 mg/d

Pediatric

1 mg/kg/d PO divided bid; increase q1-2wk by 1 mg/kg/d to range of 3-10 mg/kg/d; sometimes even higher

Interactions

Phenytoin, carbamazepine, and valproic acid can decrease levels significantly; reduces digoxin and norethindrone levels when administered concomitantly; avoid concomitant use with carbonic anhydrase inhibitors, which may increase risk of renal stone formation; use extreme caution when administering concurrently with CNS depressants because may have additive effect in CNS depression as well as other cognitive or neuropsychiatric adverse events

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Risk of developing kidney stone formation is increased 2-4 times that of untreated population; risk may be reduced by increasing fluid intake; caution in renal or hepatic impairment

Lamotrigine (Lamictal)

Phenyltriazine that is unrelated chemically to existing AEDs. Mechanism of action is unknown. Studies suggest it inhibits voltage-sensitive sodium channels, stabilizing neuronal membranes and modulating presynaptic transmitter release of excitatory amino acids. Round dose down to nearest 5 mg.

Dosing

Adult

Monotherapy:
Initial: 50-100 mg/d PO bid
Maintenance: 100-400 mg/d PO qd or divided in 2 doses; not to exceed 500 mg/d
Adjunct therapy with valproic acid:
Initial dose: 25 mg PO qod
Maintenance: 50-200 mg/d PO qd or divided in 2 doses; not to exceed 200 mg/d

Pediatric

<17 kg: Not recommended
2-12 years:
Monotherapy:
Weeks 1-2: 0.6 mg/kg/d PO divided bid
Weeks 3-4: 1.2 mg/kg/d PO divided bid
Maintenance: 5-15 mg/kg/d, not to exceed 400 mg/d PO divided bid; to achieve maintenance dose, increase doses q1-2wk by calculating 1.2 mg/kg/d and adding this amount to previously administered qd dose
Concomitant therapy with valproic acid:
Weeks 1-2: 0.15 mg/kg/d PO qd or divided bid; if initial calculated daily dose is 2.5-5 mg, administer 5 mg on alternate days for first 2 wk
Weeks 3-4: 0.3 mg/kg/d PO qd or divided bid, rounded down to nearest 5 mg
Maintenance: 1-5 mg/kg/d PO qd or divided bid, not to exceed 200 mg/d; to achieve maintenance dose, increase doses q1-2wk as follows by calculating 0.3 mg/kg/d and adding amount to previously administered qd dose
>12 years:
Monotherapy:
Weeks 1-2: 50 mg/d PO
Weeks 3-4: 100 mg/d PO divided bid
Maintenance: 300-500 mg/d PO divided bid; to achieve maintenance, increase doses by 100 mg/d q1-2wk
Concomitant therapy with valproic acid:
Weeks 1-2: 25 mg PO qod
Weeks 3-4: 25 mg PO qd
Maintenance: 100-400 mg/d PO qd or divided bid; to achieve maintenance dose, may increase by 25-50 mg/d q1-2wk

Interactions

Coadministration with acetaminophen, primidone, phenobarbital, phenytoin, or carbamazepine may decrease concentrations; steady-state concentration is increased with valproic acid, and steady-state valproic acid concentration is decreased

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause dizziness, somnolence, and signs of CNS depression; photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; rash like Stevens-Johnson syndrome is reported (if occurs, evaluation is required, and drug may have to be stopped)

Vagal nerve stimulators

These agents are amino acid derivatives synthesized from methionine and lysine. They are required in energy metabolism.

Levocarnitine (Carnitor)

Can promote excretion of excess fatty acids in patients with defects in fatty acid metabolism or specific organic acidopathies that bioaccumulate acyl CoA esters.

Dosing

Adult

1-3 g/d/50 kg body-weight PO divided bid/tid

Pediatric

50-100 mg/kg/d PO divided bid/tid, not to exceed 3 g/d

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Monitor blood chemistries, plasma carnitine concentrations, vital signs, and overall clinical condition; nausea, vomiting, abdominal cramps, and diarrhea may occur

Prokinetic agents

These agents are used to augment cholinergic activity and improve motility in the GI tract for treatment of reflux.

Metoclopramide (Reglan)

GI prokinetic agent that increases GI motility, increases resting esophageal sphincter tone, and relaxes pyloric sphincter.

Dosing

Adult

5-10 mg PO or 5-20 mg IV/IM tid

Pediatric

<6 years: 0.1 mg/kg/dose PO/IV/IM, not to exceed qid
6-14 years: 2.5-5 mg/dose PO/IV/IM; not to exceed qid
>14 years: Administer as in adults

Interactions

Opiate analgesics may increase metoclopramide toxicity in CNS; may cause dystonias

Contraindications

Documented hypersensitivity; pheochromocytoma or GI hemorrhage, obstruction, or perforation; history of seizure disorders

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in history of mental illness and Parkinson disease

Sedative and hypnotic agents

These agents are used to induce sleep.

Zaleplon (Sonata)

Nonbenzodiazepine hypnotic from pyrazolopyrimidine class. Chemical structure is unrelated to benzodiazepines, barbiturates, or other hypnotic drugs but interacts with GABA-BZ receptor complex. Binds selectively to omega1 receptor situated on alpha subunit of GABA-A receptor complex in brain. Potentiates t-butyl-bicyclophosphorothionate binding. Has preferential binding to omega1 receptor of GABA receptor family.

Dosing

Adult

10 mg PO hs; may increase to 20 mg prn if tolerated
Start with 5 mg PO hs in patients who are elderly and debilitated

Pediatric

Not established; limited data suggests 5 mg PO hs

Interactions

Cimetidine significantly increases levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Failure of insomnia to remit after 7-10 d of treatment may indicate need for evaluation of primary psychiatric or medical illness; limit treatment to 7-10 d and reevaluate patient if prescribed for >2-3 wk (do not prescribe in quantities exceeding 1-mo supply); in hepatic function impairment, reduce dose to 5 mg PO hs; caution in patients exhibiting signs or symptoms of depression

Zolpidem (Ambien)

Structurally dissimilar to benzodiazepine but similar in activity with exception of having reduced effects on skeletal muscle and seizure threshold.

Dosing

Adult

10 mg PO hs, not to exceed 10 mg/d

Pediatric

Not established; limited data suggests 5 mg PO hs

Interactions

Increases toxicity of alcohol and CNS depressants

Contraindications

Documented hypersensitivity; lactation

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor elderly individuals for impaired cognitive or motor performance

Follow-up

Further Outpatient Care

• Agitation and screaming
  • Perhaps as attempts to communicate, agitation and screaming are common and are often distressing to families.
  • Patients with Rett syndrome (RS) need gradual transitions and may have great difficulty communicating physical problems to physicians.
  • The clinician should perform careful evaluation to exclude clinical problems and pain.
  • If a clinical reason cannot be found for agitation, treatment may include warm baths, massage, music, or a quiet less-stimulating environment.
• Sleep disturbances
  • For management of sleep disturbances, short-acting nonbenzodiazepine receptor agonists (eg, zaleplon, zolpidem) may be helpful without untoward effects on daytime functioning.
  • Other approaches to sleep problems have included use of melatonin with dosage range of 2.5-7.5 mg and behavioral techniques.
• Constipation
  • Constipation is common in patients with RS.
  • Order adequate fluid intake, high fiber intake, and exercise.
  • Stool softeners may be necessary; however, avoid continuous laxatives, suppositories, and enemas.
  • Long-term mineral oil use interferes with the absorption of certain fat-soluble vitamins.
  • Regular oral milk of magnesia can be used.
• Scoliosis
  • Scoliosis occurs in more than one half of patients with RS, usually when aged 8-11 years.
  • Scoliosis may progress rapidly, especially if early hypotonia, dystonia, or loss of ambulation is present.
  • Close monitoring is necessary to determine if bracing or surgery is needed.
• Osteopenia with possible fractures: Possibly occurring for multiple reasons, osteopenia with possible fractures can be minimized through physical therapy, good nutrition, and close observation.²⁶
• Birth control
  • In most girls with RS, puberty occurs at the same age as girls without RS.
  • Discussions of birth control should occur with the patient's guardians.

Prognosis

• Development
  • Developmental potential for patients with RS is difficult to predict.
  • Some individuals with RS achieve and maintain some functional skills.
  • Of patients with RS, as many as 60% may retain their abilities to ambulate; the remainder lose ambulation or never walk because of atrophy, dystonia, and scoliosis.
• Lifespan
  • In a case study by Hagberg et al of 54 patients, the median age at death was 24 years.²⁷ In most cases, death was sudden and unexpected.
  • However, more recent experiences based on longer follow-up care indicate that, with attention to nutritional needs and comprehensive programs of physical and occupational therapies, individuals with RS can be expected to survive long into adulthood.
  • Reports of women with RS in their sixth and even eighth decade of life are now available.
• Diagnosis
  • Although no cure for RS is available, accurately identifying the diagnosis has many advantages. For example, girls with RS may be able to retain some communicative skills with proper assistance.
  • Because persons with RS are at significant risk of malnutrition, enact steps to adjust their diets to avoid malnutrition.
  • Individuals with RS are at risk of sudden death, possibly from long-QT sequelae; therefore, identifying patients with this condition is important.
  • Finally, diagnosis can bring relief to parents and help to identify the scope of clinical problems that can be anticipated.

Patient Education

• International Rett Syndrome Association
  • International Rett Syndrome Association, Clinton, MD (800-818-7388), supports international research and meetings of parents and professionals to improve knowledge of RS.
  • The Rett Syndrome Web site is available in multiple languages.
  • The Web site provides overviews of RS and highlights individuals living with RS.
  • The site also provides a discussion group for parents, doctors, and researchers, updated research findings, research contacts, an online library, and links to other RS-related sites.
  • Several laboratories provide diagnostic sequencing of the MECP2 gene. Specifics of how to obtain this testing can be found on the International Rett Syndrome Association Web site.
• Blue Bird Circle Rett Center
  • The Blue Bird Circle Rett Center of Baylor College of Medicine (Houston, TX; 713-798-RETT [7388] or 888-430-RETT), operates one of the largest RS clinics in the world.
  • The Blue Bird Circle Rett Center Web site contains additional information.
  • The Blue Bird Circle Rett Center is part of a Rett Consortium with the University of Alabama at Birmingham and the University of California at Los Angeles.
• The Rett Program: The Rett Program at the Kennedy-Krieger Institute, Johns Hopkins University School of Medicine (Baltimore, MD; 800-873-3377) can provide additional information.

Miscellaneous

Medicolegal Pitfalls

• Diagnosis of Rett syndrome (RS) is initially difficult; however, the observant pediatrician may note deceleration of head, weight, and height growth.
• Although no cure is available for this disorder, early identification of RS may help with parental concerns and maximize the girl's potential, which is influenced by an active lifestyle, good nutrition, and the amount of effective physical therapy received.
• In view of expected survival into adulthood, discuss provisions for guardianship and long-term care with parents and caregivers of individuals with RS.

References

1. Amir RE, Van den Veyver IB, Wan M, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CpG-binding protein 2. Nat Genet. Oct 1999;23(2):185-8. [Medline].

2. Dayer AG, Bottani A, Bouchardy I, et al. MECP2 mutant allele in a boy with Rett syndrome and his unaffected heterozygous mother. Brain Dev. Jul 14 2006;[Medline].

3. Hoffbuhr K, Devaney JM, LaFleur B. MeCP2 mutations in children with and without the phenotype of Rett syndrome. Neurology. Jun 12 2001;56(11):1486-95. [Medline].

4. Huppke P, Laccone F, Kramer N, et al. Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. Hum Mol Genet. May 22 2000;9(9):1369-75. [Medline].

5. Kankirawatana P, Leonard H, Ellaway C, et al. Early progressive encephalopathy in boys and MECP2 mutations. Neurology. Jul 11 2006;67(1):164-6. [Medline].

6. Kerr AM, Archer HL, Evans JC, et al. People with MECP2 mutation-positive Rett disorder who converse. J Intellect Disabil Res. May 2006;50(Pt 5):386-94. [Medline].

7. Moog U, Smeets EE, van Roozendaal KE, et al. Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2). Eur J Paediatr Neurol. 2003;7(1):5-12. [Medline].

8. Moretti P, Zoghbi HY. MeCP2 dysfunction in Rett syndrome and related disorders. Curr Opin Genet Dev. Jun 2006;16(3):276-81. [Medline].

9. Philippe C, Villard L, De Roux N, et al. Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update. Eur J Med Genet. Jan-Feb 2006;49(1):9-18. [Medline].

10. Wan M, Lee SS, Zhang X, et al. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet. Dec 1999;65(6):1520-9. [Medline].

11. Glaze DG, Schultz RJ. Rett Syndrome: Meeting the Challenge of This Gender-Specific Neurodevelopmental Disorder. Medscape Womens Health. Jan 1997;2(1):3. [Medline].

12. Sampieri K, Meloni I, Scala E, et al. Italian Rett database and biobank. Hum Mutat. Apr 2007;28(4):329-35. [Medline].

13. Terai K, Munesue T, Hiratani M, Jiang ZY, Jibiki I, Yamaguchi N. The prevalence of Rett syndrome in Fukui prefecture. Brain Dev. Mar-Apr 1995;17(2):153-4. [Medline].

14. Huppke P, Maier EM, Warnke A, et al. Very mild cases of Rett syndrome with skewed X inactivation. J Med Genet. May 11 2006;[Medline].

15. Kozinetz CA, Skender ML, MacNaughton N, et al. Epidemiology of Rett Syndrome: a population-based registry. Pediatrics. 1993;91(2):445-50. [Medline].

16. Kerr AM, Julu PO. Recent insights into hyperventilation from the study of Rett syndrome. Arch Dis Child. Apr 1999;80(4):384-7. [Medline].

17. Amir RE, Sutton VR, Van den Veyver IB. Newborn screening and prenatal diagnosis for Rett syndrome: implications for therapy. J Child Neurol. Sep 2005;20(9):779-83. [Medline].

18. Ham AL, Kumar A, Deeter R. Does genotype predict phenotype in Rett syndrome?. J Child Neurol. Sep 2005;20(9):768-78. [Medline].

19. Ellaway CJ, Sholler G, Leonard H, et al. Prolonged QT interval in Rett syndrome. Arch Dis Child. May 1999;80(5):470-2. [Medline].

20. Glaze DG, Schultz RJ, Frost JD. Rett syndrome: characterization of seizures versus non-seizures. Electroencephalogr Clin Neurophysiol. Jan 1998;106(1):79-83. [Medline].

21. Wilfong AA, Schultz RJ. Vagus nerve stimulation for treatment of epilepsy in Rett syndrome. Dev Med Child Neurol. Aug 2006;48(8):683-6. [Medline].

22. Chung JC, Lai CK, Chung PM, French HP. Snoezelen for dementia. Cochrane Database Syst Rev. 2002;CD003152. [Medline].

23. Lavie E, Shapiro M, Julius M. Hydrotherapy combined with Snoezelen multi-sensory therapy. Int J Adolesc Med Health. Jan-Mar 2005;17(1):83-7. [Medline].

24. Lotan M. Management of Rett syndrome in the controlled multisensory (Snoezelen) environment. A review with three case stories. ScientificWorldJournal. 2006;6:791-807. [Medline].

25. Motil KJ, Schultz RJ, Browning K, et al. Oropharyngeal dysfunction and gastroesophageal dysmotility are present in girls and women with Rett syndrome. J Pediatr Gastroenterol Nutr. Jul 1999;29(1):31-7. [Medline].

26. Leonard H, Thomson MR, Glasson EJ, et al. A population-based approach to the investigation of osteopenia in Rett syndrome. Dev Med Child Neurol. May 1999;41(5):323-8. [Medline].

27. Hagberg B, Berg M, Steffenburg U. Rett Syndrome - an odd handicap afffecting girls. A current 25-year follow-up in western Sweden. Lakartidningen. 1999;96(49):5488-90. [Medline].

28. Armstrong DD. Review of Rett syndrome. J Neuropathol Exp Neurol. Aug 1997;56(8):843-9. [Medline].

29. Ellaway C, Williams K, Leonard H, et al. Rett syndrome: randomized controlled trial of L-carnitine. J Child Neurol. Mar 1999;14(3):162-7. [Medline].

30. Motil KJ, Schultz R, Brown B, et al. Altered energy balance may account for growth failure in Rett syndrome. J Child Neurol. Jul 1994;9(3):315-9. [Medline].

31. Motil KJ, Schultz RJ, Abrams S, et al. Fractional calcium absorption is increased in girls with Rett syndrome. J Pediatr Gastroenterol Nutr. Apr 2006;42(4):419-26. [Medline].

32. Renieri A, Meloni I, Longo I, et al. Rett syndrome: the complex nature of a monogenic disease. J Mol Med. Jun 2003;81(6):346-54. [Medline].

33. Schultz RJ, Glaze DG, Motil KJ, et al. The pattern of growth failure in Rett syndrome. Am J Dis Child. Jun 1993;147(6):633-7. [Medline].

34. Stauder JE, Smeets EE, van Mil SG, Curfs LG. The development of visual- and auditory processing in Rett syndrome: An ERP study. Brain Dev. Apr 26 2006;[Medline].

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Keywords

pervasive developmental disorder, PDD, Rett syndrome, RS, cerebroatrophic hyperammonemia, neurologic disorder, neurodevelopmental arrest, genetic disorder, severe congenital encephalopathy, dystonia apraxia, retardation, epilepsy, oral-motor dysfunction, somatic growth failure, gastroesophageal reflux, GER, scoliosis, sleep disturbances, MECP2, congenital RS, hypotonia, hand wringing, strabismus

Contributor Information and Disclosures

Author

Bettina E Bernstein, DO, Assistant Professor, Department of Psychiatry, Philadelphia College of Osteopathic Medicine; Private Practice at the Wynnewood House, Consultant to Child Guidance Resource Centers, Early Elementary Education Program
Bettina E Bernstein, DO is a member of the following medical societies: American Academy of Child and Adolescent Psychiatry and American Psychiatric Association
Disclosure: Nothing to disclose.

Coauthor(s)

Joseph H Schneider, MD, Clinical Assistant Professor of Pediatrics, Section of Neonatology, Univ. Texas Southwestern at Dallas and Childrens Medical Center
Joseph H Schneider, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, Texas Medical Association, and Texas Pediatric Society
Disclosure: Nothing to disclose.

Daniel G Glaze, MD, Medical Director, Blue Bird Circle Rett Center; Associate Professor, Departments of Pediatrics and Neurology, Baylor College of Medicine
Daniel G Glaze, MD is a member of the following medical societies: American Clinical Neurophysiology Society, American Neurological Association, and Child Neurology Society
Disclosure: Nothing to disclose.

Medical Editor

Carol Diane Berkowitz, MD, Executive Vice Chair, Department of Pediatrics, Professor, Harbor-University of California at Los Angeles Medical Center
Carol Diane Berkowitz, MD is a member of the following medical societies: Alpha Omega Alpha, Ambulatory Pediatric Association, American Academy of Pediatrics, American College of Emergency Physicians, American Medical Association, American Pediatric Society, and North American Society for Pediatric and Adolescent Gynecology
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

CME Editor

Carrie Sylvester, MD, MPH, Director of Education in Child and Adolescent Psychiatry, Professor, Departments of Psychiatry and Pediatrics, Northwestern University Medical School
Carrie Sylvester, MD, MPH is a member of the following medical societies: American Academy of Child and Adolescent Psychiatry, American Academy of Pediatrics, American Medical Women's Association, American Psychiatric Association, and American Society for Adolescent Psychiatry
Disclosure: Nothing to disclose.

Chief Editor

Caroly Pataki, MD, Professor of Clinical Psychiatry, Department of Psychiatry and Biobehavioral Sciences, Division Chair of Child and Adolescent Psychiatry, Director of Training, Child and Adolescent Psychiatry Residency Program, University of Southern California Keck School of Medicine
Caroly Pataki, MD is a member of the following medical societies: American Academy of Child and Adolescent Psychiatry, New York Academy of Sciences, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

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