AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Familial dysautonomia (FD) is an inherited disorder of the nervous system that affects the development and survival of autonomic and some sensory neurons. Originally reported by Riley et al in 1949, FD is recognized now as one of several hereditary sensory and autonomic neuropathies. Evidence of the disorder may be noted from birth, although neurologic deterioration progresses with age. The transmission is autosomal recessive with complete penetrance, and with the exception of one patient, all proven cases have been of Ashkenazi Jewish extraction.

Pathophysiology

Pathologic studies have shown marked reduction in nonmyelinated neuronal populations as well as reduction in small diameter myelinated axons. This reduction seems to indicate a developmental arrest in the sensory and autonomic systems and, in the latter, principally in the sympathetic fibers. Sympathetic ganglia have been found to be one third of the normal size, and the neuronal population has been found to be one tenth of the normal number.

Hypersensitivity to sympathomimetic and parasympathomimetic drugs occurs. Norepinephrine synthesis is diminished while dopamine products are excreted in normal amounts. During physical and emotional stress, plasma norepinephrine and dopamine are elevated and autonomic storms or "crises" may develop.

Frequency

United States

One in 30 Ashkenazi Jews is presumed to be a carrier, which results in a disease incidence of 1 in 3600 live births to this population.

International

Since its original description in 1949, more than 600 patients have been identified and registered with the Dysautonomia Center in New York, an international registry with patient distribution reflecting Jewish dispersion. Of these patients, 30% reside in the New York area, and 30% reside in Israel.

Mortality/Morbidity

With greater understanding of the disorder and development of treatment programs, survival statistics have improved markedly and increasing numbers of patients are reaching adulthood. Survival statistics prior to 1960 reveal that there was a 50% probability of patients dying before age 5 years. Current survival statistics indicate that a newborn with FD has a 50% probability of reaching age 40 years.

Many FD adults have been able to achieve independent function. Both men and women with FD have married and reproduced. All offspring have been phenotypically normal despite their obligatory heterozygote state. Although pregnancies were tolerated well, at time of delivery blood pressures were labile.

Causes of death less often are related to pulmonary complications, indicating that aggressive treatment of aspirations has been beneficial. Of recent concern have been patients who have succumbed to unexplained deaths that may have been the result of unopposed vagal stimulation or a sleep abnormality. A few adult patients have died of renal failure.

Other clinical signs encountered include tachycardia, hypertension, delayed development and poor growth, drooling and dysphagia, breath-holding with cyanosis, spinal curvature, and progressive ataxia. These children usually have a pleasant personality, although they may have excessive anxiety. Neurologic function deteriorates with time.

Race

FD is an autosomal recessive disorder with complete penetrance but variable expression.

In 1993, using genetic linkage, the gene for FD was localized to the distal long arm of chromosome 9(q31) with sufficient DNA markers to permit prenatal diagnosis and carrier identification for families in which an individual had been affected.

In 2001, mutations were discovered in the IKB kinase-complex-associated protein (IKBKAP) gene, with a major haplotype mutation located in the donor splice site of intron 20. This mutation can result in the skipping of exon 20 in the mRNA of specific subsets of cells, such as peripheral neurons. The major haplotype accounts for more than 99.5% of the FD chromosomes, corresponding to a founder defect. The second mutation is a missense mutation that affects the phosphorylation of IKAP and has been identified in 4 unrelated patients heterozygous for the major splice mutation.

In 2003, the first non-Jewish IKBKAP mutation wasdescribed, which was a proline to leucine missense mutation in exon 26. This mutation was inherited from a parent without Ashkenazi Jewish ancestry. The patient affected was also heterozygous for the major splice mutation that he received from his single Jewish parent.

Because the 2 Jewish mutations causing FD have been identified, DNA diagnosis and general population screening for the Ashkenazi Jewish population are now feasible. If both members of a couple are shown to be carriers by genetic testing, prenatal diagnosis by amniocentesis (14-17 wk) or chorionic villus sampling (10-11 wk) is possible.

Sex

No sex predilection exists in either affected individuals or carriers. Both sexes have demonstrated capability to conceive, and pregnancies have been brought successfully to term.

Age

The disorder is present throughout life. Expression of the disease varies among individuals and even in the same individual at different ages. At the present time, more than 40% of the surviving patients are older than 20 years, and patients in their early 50s have been cared for.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Although the diagnostic signs may be evident at birth, considerable variation exists in the expression of the disease at any time. The earliest signs are feeding difficulties with uncoordinated swallowing and risk of aspiration pneumonia. The lack of tears with emotional crying may be noted after age 7 months when infants normally show evidence of tear production. Additionally, the affected child may show severe reactions to physical and emotional stress termed dysautonomic crises. These events are characterized by intractable vomiting, sweating, tachycardia, hypertension, and personality changes. During these episodes, parents of young patients may notice conjunctival congestion, loss of corneal luster, or corneal opacification. Older patients report loss of vision without pain when the integrity of the ocular surface is compromised.

Physical

• Ocular findings
• • Absence of overflow tears with emotional crying is noted in all cases.
  • Baseline moisture and reflex tearing varies among individuals and even in the same individual at different periods, although the overall tear volume usually is reduced. This reduction places the integrity of the corneal epithelium at greater risk in the presence of fever or dehydration or in an overly dry environment.
  • Corneal anesthesia usually is present, increases susceptibility to minor trauma, and may delay repair when epithelial defects occur.
  • Diffuse punctate conjunctival and corneal epithelial staining with fluorescein is a common finding, particularly increased during crisis episodes.
  • During crisis periods the blink rate, which usually is reduced, is slowed further.
  • The palpebral fissure often is widened, possibly due to unopposed activity of the lid retractors, increasing the surface drying.
  • Incomplete lid closure during sleep also may cause erosions of the inferior periphery. Persistent epithelial erosions lead to progressive corneal thinning or repair by fibrovascular scaring.
  • Neurotrophic corneal ulcers are usually circular or horizontally oval in contour with rolled epithelial edges and located in the central or inferior cornea. The surrounding inflammatory reaction as well as the anterior chamber reaction is mild, but a border of hazy epithelium usually surrounds the defect.
  • Stromal opacification due to edema and degenerative changes in the collagen as well as calcium deposition in the bed can occur.
  • Superinfection must of course be guarded against but has been less frequent than anticipated in FD, possibly because of the irrigating effect of frequent tear instillations and excellent family support. When bacterial superinfection occurred, staphylococci were the most common agent.
  • However, resistant strains and gram-negative contamination must be considered when patients are hospitalized for respiratory complications requiring tracheotomy.
  • Herpes simplex and herpes zoster infections have not been noted, raising speculation of a relationship to the reduction in the neuronal population of the ganglia.
  • Exotropia and myopia have been noted more commonly in FD than in the general population.
  • Optic neuropathy is frequent and increases with age. It can be detected in the early years by abnormal visual-evoked potential (VEP) and later by frank nerve pallor and generalized visual field depression particularly in the cecocentral region. It may be responsible for decreased visual acuity, exodeviation, and abnormal color vision other than that caused by corneal scarring.
• Systemic findings
• • The diagnosis is confirmed by ascertaining the presence of 5 cardinal criteria.
    • Absence of overflow emotional tears
    • Absent lingual fungiform papillae
    • Depressed patellar reflexes
    • Lack of an axon flare following intradermal histamine
    • Documentation of Ashkenazi Jewish extraction
  • Further supportive evidence is provided by findings of decreased response to pain and temperature, orthostatic hypotension, periodic erythematous blotching of the skin, and increased sweating.
  • In addition, cineesophagrams may reveal delay in cricopharyngeal closure, tertiary contractions of the esophagus, gastroesophageal reflux, and delayed gastric emptying.
  • Other clinical signs include manifestations of sensory and autonomic nervous system dysfunction.
• Sensory system
• • Although pain sensation is decreased, it is not completely absent, and palms, soles of feet, neck, and genital areas usually are spared; these areas often are exquisitely sensitive.
  • Temperature appreciation is affected.
  • With both pain and temperature perceptions, the trunk and lower extremities are more affected and older individuals have greater losses than younger individuals.
  • In the older individual, vibration sense and occasionally joint position become abnormal and rombergism may be noted.
  • Visceral sensation is intact, so patients are able to perceive discomfort with pleuritic or peritoneal irritation.
  • Peripheral sensory deprivation makes the FD patient prone to self-injury.
  • In addition to inadvertent trauma to joints and long bones causing Charcot joints, aseptic necrosis, and unrecognized fractures, some patients self-mutilate by picking at their fingers to the point of bleeding.
  • Spinal curvature abnormality can be early and pernicious in its course.
  • Central sensory deficits include decreased pain perception along the branches of the trigeminal nerve, diminished corneal reflexes, and decreased taste perception, especially in recognition of sweet, which corresponds to the absence of fungiform papillae on the tip of the tongue.
  • Although the motor system is spared, the young child with FD is frequently hypotonic, which may be due to a combination of central deficits and decreased tone of stretch receptors.
  • Older patients are not weak but develop a broad-based and mildly ataxic gait with special difficulties in performing rapid movements or turning. Gait abnormalities can be severe enough to require use walkers or wheelchairs.
• Autonomic dysfunction: Pervasive autonomic dysfunction results in protean functional abnormalities affecting other systems and yielding a myriad of clinical manifestations. As the disorder has variable expression, individual variations exist. Some of these manifestations are apparent at birth and others become more prominent and problematic as a function of age.
• • Gastrointestinal system
    • Oropharyngeal incoordination is one of the earliest signs of FD. Poor suck or uncoordinated swallow is observed in 60% of infants in the neonatal period.
    • Oral incoordination also results in tendency to drool.
    • Liquids are more apt to be aspirated.
    • If nutrition cannot be maintained or respiratory problems persist, then gastrostomy is recommended.
    • The most prominent manifestation of abnormal gastrointestinal dysmotility in individuals with FD is the propensity to vomit. Vomiting can occur intermittently as part of a systemic reaction to physical or emotional stress, or it can occur daily in response to the stress of arousal.
    • Because vomiting often is associated with hypertension, tachycardia, diffuse sweating, and even personality change, this constellation of signs has been termed the dysautonomic crisis.
    • Gastroesophageal reflux (GER) is another common problem and should be considered in individuals with FD who frequently vomit.
  • Respiratory system
    • Aspiration is the major cause of lung infections and is due to oral incoordination and or gastroesophageal reflux.
    • Ventilatory response to lung infection often is altered because of insensitivity to hypoxia and hypercapnia.
    • Low oxygen saturations do not stimulate tachypnea and can cause syncope as hypoxia induces both hypotension and bradycardia.
    • Dysautonomic patients must be cautious in settings where the partial pressure of oxygen is decreased, such as at high altitudes or during airplane travel. When the airplane's altitude exceeds 39,000 feet, the cabin pressure will be equivalent to more than 6000 feet, and supplemental oxygen probably will be necessary.
    • Diving and underwater swimming can be potential hazards.
  • Cardiovascular irregularities
    • Consistent with sympathetic dysfunction, patients exhibit rapid and severe orthostatic decreases in blood pressure, without appropriate compensatory increases in heart rate.
    • Clinical manifestations of postural hypotension include episodes of lightheadedness or dizzy spells.
    • Some patients complain of weak legs.
    • On occasion, syncope may occur. Symptoms tend to be worse in the morning, in hot or humid weather, when the bladder is full, before a large bowel movement, after a long car ride, coming out of a movie theater, or with fatigue.
    • Symptoms referable to hypotension become more prominent in the adult years and can limit function and mobility.
    • General anesthesia has the potential for inducing severe hypotension. With greater attention to stabilization of the vascular bed by hydrating the patient before surgery and titrating the anesthetic to continuously monitored arterial blood pressure, anesthetic risk has been reduced greatly.
    • In older patients, supine hypertension can become prominent despite the retention of severe responses to orthostatic challenge.
    • Hypertension also can occur intermittently in response to emotional stress or visceral pain or as part of the crisis constellation. The hypertension responds to the same medications recommended for crisis management.
    • Hypertension also can exist without any other symptoms. Because blood pressure is so labile in individuals with FD, asymptomatic hypertension usually is not treated because the hypertension usually is transitory and appears to be better tolerated than hypotension.
    • As part of the progressive nature of FD, worsening of sympathetic dysfunction and development of parasympathetic dysfunction occurs.
  • Renal problems
    • Azotemia is frequently prerenal in origin.
    • Although clinical signs of dehydration may not be present, blood urea nitrogen values often can be reduced by simple hydration.
    • Renal function appears to deteriorate with advancing age, so that about 20% of adult patients have reduced renal function.
    • Renal biopsies performed on individuals with noncorrectable azotemia revealed significant ischemic-type glomerulosclerosis and deficient vascular innervation.
    • Renal hypoperfusion secondary to cardiovascular instability has been suggested as the cause of the progressive renal disease.
  • Central nervous system features (intelligence/emotion/seizures)
    • Emotional lability has been considered one of the prominent features of FD and was emphasized in its original description. Now, behavioral abnormalities are acknowledged as part of the crisis constellation and may be secondary to periodic catecholamine imbalance. The prompt normalization of personality in response to benzodiazepines supports this hypothesis.
    • Most affected individuals are of normal intelligence.
    • About 25% of patients with FD have abnormal EEGs but less than 10% actually have a true seizure disorder.
    • Prolonged breath-holding with crying can be severe enough to result in cyanosis, syncope, and decerebrate posturing and has been believed to represent a type of seizure activity.
    • Breath-holding is frequent in the early years, occurring at least one time in 63% of patients. This phenomenon probably is a manifestation of insensitivity to hypoxia and hypercapnia. It can become a manipulative maneuver with some children. The episodes are self-limited, cease by age 6 years, and have never been fatal.
    • Metabolic seizures, induced by hyponatremia, have been observed during extremely hot weather when fluid and salt intake have failed to compensate for the excessive sweating manifested by these patients.
    • Hyponatremic seizures also have occurred with severe infections.

Causes

FD is an autosomal recessive genetic disorder caused by mutations in the IKBKAP gene.

DIFFERENTIALS

Section 4 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Isolated lacrimal gland hypoplasia
Hereditary congenital alacrima
Alacrima and aptyalism syndromes
Anhydrotic ectodermal dysplasia syndromes
Allgrove syndrome or achalasia, alacrima, and adrenocorticotropic hormone (ACTH) insensitivity
Cranial nerve and/or nuclear dysplasia
Moebius syndrome
Cri du chat
Congenital sensory neuropathies or hereditary sensory autonomic neuropathies (HSAN)
FD (HSAN type 3)
Congenital autonomic dysfunction with universal pain loss
Congenital sensory neuropathy (HSAN type 2)
Progressive panneuropathy with hypotonia

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• DNA diagnosis is now available, and documentation of the IKBKAP mutation is the criterion standard to confirm the diagnosis. However, in a patient in whom this diagnosis is suspected, a tentative diagnosis can be made using a constellation of clinical criteria. Traditionally, 5 cardinal criteria should be present for a firm diagnosis.
• • Parents of Ashkenazi Jewish ancestry: Both parents should have a history of being of Eastern European extraction.
  • Absence of fungiform papillae on the tongue: The highly vascularized fungiform papillae on the anterior third of the tongue are absent resulting in a smooth and glistening tongue tip. See Image 1.
  • Decreased deep tendon reflexes: In 95% of patients with FD, knee jerks cannot be elicited.
  • Lack of axon flare following intradermal histamine: Histamine phosphate in a 1:10,000 dilution injected intradermally does not produce pain or an axon flare. See Image 2.
  • No overflow tears with emotional crying: Normally overflow emotional tearing can be delayed until age 7 months, but Schirmer tear testing usually shows diminished baseline tear flow.

TREATMENT

Section 6 of 11  

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• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Medical Care

The disease cannot be arrested and ongoing systemic and ocular therapy is directed toward the specific problems encountered. Dehydration due to excessive sweating and drooling is exacerbated by poor fluid intake and fever associated with aspiration pneumonia. Gastrostomy and fundal plication allow improved nutrition and reduction of pneumonia episodes. Pulmonary hygiene by bronchodilation, postural drainage, and suction of tracheal secretions is also important. Monitor and treat systemic hypertension and postural hypotension. Diazepam is used to ameliorate the vomiting during crisis episodes, and clonidine is used to control the hypertension.

• General dehydration is probably the most overlooked factor in the development of corneal complications in dysautonomia.
  • It may be subclinical and may be combined with a low-grade systemic infection.
  • Ensure adequate hydration not only during crisis episodes but also in apparently stable periods.
  • Adequate hydration has been better achieved since the introduction of gastrostomy and fundal plication.
• Consider the dryness of the environment.
  • Corneal drying may occur during car travel with an open window, direct air current from a fan, home hot air heating, or exposure to the dry air of an airplane cabin.
  • Even the steady air current from an oxygen mask or nasal cannula blowing upward toward the eye may accentuate dryness and increase the risk of corneal epithelial breakdown.
• The decrease in blink rate noted with corneal anesthesia also accentuates the drying.
• During crisis episodes, the catecholamine surge causes a sustained contraction of Mueller muscle with eyelid retraction causing increased corneal exposure and drying.
• As in any dry eye condition, the regular use of a tear substitute is important in maintaining the integrity of the corneal and mucous membrane surfaces, thereby reducing the incidence of surface inflammation and infection.
  • The lubricating and irrigating effect of frequent instillations may be achieved with any of the many over-the-counter products available, although a longer surface coating is obtained with the more viscous products. These more viscous products usually contain a cellulose base of 0.5-1% concentrations.
  • Light mineral oil also can be used as an ocular lubricant, is included in some over-the-counter products, but should be reserved for eyes with punctal occlusion because of the risk of aspiration of the oil.
• The frequency of instillation of a tear substitute varies with the need and may range from a few times a day to every half hour.
  • Nonpreserved solutions in unit dose packaging are preferred when frequent instillations are necessary.
  • Ointments usually are reserved for nighttime use because of blurring.
  • Many dysautonomic patients have incomplete lid closure during sleep, accentuating the corneal dryness. This can be helped considerably by the application of a thin polyethylene film of ordinary kitchen cling wrap after instillation of lubricant ointment at bedtime. The use of a room humidifier and the avoidance of hot air type heating are also of value.
• Surface drying problems may range from conjunctival hyperemia with corneal epithelial erosions to confluent epithelial defects and stromal ulcerations.
  • Topical steroids, by their anti-inflammatory action, suppress conjunctival congestion and give a false picture of improvement. Nevertheless, the inflammatory cascade invoked by the dry eye state does appear to increase the dryness, and a nonsteroidal immunomodulator may be helpful. Restasis (cyclosporine ophthalmic emulsion) 0.05% used twice daily is well tolerated and often shows a beneficial effect.
  • Avoid long-term steroid use due to increased risk of intraocular pressure, cataract formation, and decreased resistance to secondary infection.
  • Tocotrienol, a Vitamin E analog that appears to have a neuroprotective effect from the oxidative damage of free radicals, seems to coincidentally increase tear flow in some patients.
  • Punctal occlusion helps maintain the tear volume, and cautery of all 4 puncta usually is carried out.
  • Puncta sometimes recanalize in children, requiring the procedure to be repeated.
• Moisture chamber spectacle attachments reduce evaporation and swim goggles may be necessary in more severe cases.
  • Again, an occlusive dressing at night may be helpful in the treatment of a persistent epithelial defect.
  • This dressing should not be a gauze pad but rather a moisture chamber such as may be fashioned with a 4-inch square of polyethylene cling wrap applied to the periorbital margins and stabilized by skin moisture and a small strip of adhesive.
• The compromised neurotrophic cornea requires not only lubricant but also surface protection for adequate repair. This protection sometimes can be achieved with a therapeutic (bandage) contact lens.
  • Frequent tear supplements must be continued as well as a prophylactic antibiotic.
  • The therapeutic lenses are used only until reepithelialization is obtained, and lenses are not used in the presence of clinical infection. A temporary tarsorrhaphy may be necessary to keep the lens in place until healing is completed.
  • Rarely, in the presence of a low tear volume and an infrequent blink rate, a relative anoxia develops beneath the lens. In this event, sterile corneal infiltrates, sterile hypopyon, and even interstitial vascularization may develop within the cornea requiring this line of therapy to be abandoned.
• The most effective treatment of the decompensated neurotrophic cornea is tarsorrhaphy.
  • Since repair of the corneal surface often can be obtained within a week, a glue tarsorrhaphy combined with a bandage lens may be sufficient.
  • In this procedure, a thin line of cyanoacrylate glue is applied to the skin about 1-2 mm below the lash line of the lateral half of the lower eyelid.
  • The patient is directed to squeeze the lids together tightly for about 10 seconds for an adequate adhesion of the lashes and external skin margins to be obtained.
  • If it is well applied to a clean eyelid margin and no forceful effort is made to pull the lids apart, it will stay in place for about a week.
  • Eye medications should be continued and instilled at the nasal canthus.
  • When the adhesion loosens, remaining glue may be removed with ointment. Some lashes may be removed along with the glue but rapidly grow back.
• Topical fibronectin from autologous or bank plasma and topical murine epidermal growth factor have been previously reported as beneficial to the healing of persistent neurotrophic corneal ulcers.
  • In a limited trial, a significant reduction in the time to healing in patients treated with bank plasma fibronectin was not found.
  • Recently, the use of topical murine nerve growth factor over a 4-week period was reported as very effective in healing neurotrophic corneal ulcers of various causes. The authors have not had the opportunity to monitor patients with this treatment modality.

Surgical Care

• Tarsorrhaphy
  • If a longer period of lid closure is necessary, a temporary suture may be placed. A double-armed nonabsorbable suture (eg, 5-0 nylon) is passed through a rubber peg and then through the upper and lower lid margins of the lateral half of the lids without abrading the margins. This can remain in place for a few weeks.
  • If a permanent tarsorrhaphy is necessary, the lid margins are split at the grey line and only the posterior halves are sutured to avoid cicatricial distortion of the lashes.
  • Lateral tarsorrhaphy is more cosmetically acceptable, but bipedicle tarsorrhaphy may be necessary if corneal scarring or perforation is threatened.
• Corneal surgical procedures
  • Cryopreserved human amniotic membrane has been used with and without tarsorrhaphy to promote rapid epithelial healing and suppress secondary corneal scarring.
  • This may be valuable both in the treatment of the neurotrophic ulcer and in the failure to reepithelialize following keratoplasty procedures.
• • The corneal opacification complicating FD is a frequent sequela of neurotrophic disease in the dry eye state. These corneas have difficulty resurfacing and maintaining epithelial integrity, thus they are poor candidates for keratectomy or keratoplasty.
  • Penetrating keratoplasty may also show delay in stromal wound healing as well as epithelial resurfacing and should be reserved for severe vision loss or impending perforation. It can be performed under local or even topical anesthesia and mild sedation with diazepam when good patient cooperation is present. General anesthesia carries a risk of blood pressure lability and poor cortical response to hypoxia and hypercapnia.
  • When keratoplasty is undertaken, interrupted sutures should be used because delayed healing in one quadrant may compromise a continuous suture.
  • Bipedicle tarsorrhaphy should be considered as soon as initial success of keratoplasty is ascertained.
  • Incidence of immune-related graft rejection is equivalent to that of patients without FD. When multiple graft failures have occurred in both eyes, prosthokeratoplasty may be considered. It should be combined with a glaucoma shunt because of the difficulty of monitoring intraocular pressure postoperatively.
  • The Dohlman type II model keratoprosthesis has been used successfully.
  • Local anesthesia, with only diazepam as a preoperative medication, can be used with most ophthalmologic procedures if the dysautonomic patient is adolescent or adult and is cooperative. In infants or an uncooperative individual, general anesthesia can be used.
  • Large amounts of epinephrine should not be infiltrated because of the exaggerated response to sympathomimetic drugs. One of the most important factors in reducing risk is maintenance of an adequate circulating volume because vasodilatation during anesthesia may be extreme.
  • The patient should be prehydrated the night before surgery with intravenous fluids.
  • With general anesthesia, arterial blood pressures and blood gases are monitored throughout surgery via an arterial line.
  • Hypotension should be corrected by decreasing the percentage of gas anesthetic and administering volume expanders.
  • Rarely, pressor agents, such as phenylephrine hydrochloride or epinephrine, are required.
  • Gastric secretions tend to be copious during excitatory anesthetic phases. To avoid postoperative aspiration, ranitidine can be given, and the stomach should be kept decompressed. This decompression is facilitated if a gastrostomy is present.
  • Postoperative care with general anesthesia includes vigorous chest physiotherapy, because a tendency toward development of mucous plugs and exacerbation of preexisting lung disease exists. The duration of intubation may need to be extended until the respiratory status stabilizes or less reliance on pain medication exists.
  • Ophthalmologic cases require minimal pain medication postoperatively because of decreased pain perception along the branches of the trigeminal nerve.
• Nonophthalmologic surgical procedures frequently performed in patients with FD include the following:
• • Gastrostomy in 80% of patients prior to 5 years as a means for providing fluids safely (without risk of aspiration) and to provide extra calories.
  • Fundoplication in 67% of patients for gastroesophageal reflux that is refractory to medical management.
  • Spinal fusion for severe curvatures.

Consultations

Because of the protean manifestations of this disorder and the potential for respiratory, gastrointestinal, and cardiovascular problems, many patients maintain periodic care and avail themselves of consultations regarding management from the Dysautonomia Treatment and Evaluation Center at New York University.

Diet

Liquids are more of a problem for the dysautonomic patient than solids because the former are associated with risk of aspiration. Therefore, 80% of patients younger than 5 years have required gastrostomy.

MEDICATION

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Labile autonomic status results in precarious homeostasis. Any stress, emotional or physical, may trigger a dysautonomic crisis, which can result in ocular complications as increased exposure and dehydration of the corneal surface can be associated. Diazepam is the most effective antiemetic for the dysautonomic crisis. Initial dose of diazepam should be effective in stopping vomiting, normalizing the blood pressure, and decreasing agitation. For hypertension, diazepam should be given at the same doses as for crisis. Crisis usually resolves abruptly and is marked by normalization of personality and return of appetite.

Drug Category: Benzodiazepines

By binding to specific receptor-sites these agents appear to potentiate the effects of gamma-aminobutyric acid (GABA) and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters.

Drug Category: H2 receptor antagonists

These agents are reversible competitive blockers of histamine at the H2 receptors, particularly those in the gastric parietal cells where they inhibit acid secretion. The H2 antagonists are highly selective, do not affect the H1 receptors, and are not anticholinergic agents.

Drug Category: Alpha-adrenergic agonists

These agents stimulate alpha-adrenoreceptors in brain stem, activating an inhibitory neuron, which in turn results in reduced sympathetic outflow. These effects result in a decrease in vasomotor tone and heart rate.

Drug Name	Midodrine (ProAmatine)
Description	A pure peripheral alpha-adrenergic agonist, which causes peripheral vasoconstriction and raises blood pressure without stimulating cardiac receptors; used for treatment of postural hypotension.
Adult Dose	0.01 mg/kg/dose; usually q4h while patient is erect
Pediatric Dose	Dosage in children has not been studied adequately
Contraindications	Documented hypersensitivity; acute renal disease; severe organic heart disease; pheochromocytoma urinary retention; persistent and excessive supine hypertension
Interactions	Drugs that stimulate alpha-adrenergic agonists may enhance or potentiate pressor effects of midodrine; coadministration with midodrine, cardiac glycosides, may enhance or precipitate bradycardia, psychopharmacologic agents or beta-blockers, A/V block or arrhythmia
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in diabetes or visual complications; discontinue midodrine and reevaluate if any signs or symptoms suggesting bradycardia occur

Drug Category: Corticosteroids

These agents have profound and varied metabolic effects.

FOLLOW-UP

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• Follow-up
• Miscellaneous
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Further Outpatient Care

• At New York University Medical Center, a Dysautonomia Treatment and Evaluation Center examines patients with FD on a regular schedule to provide comprehensive care plans. It serves as a resource for patients, families, and health providers.

Deterrence/Prevention

• No means of preventing the disorder exists at this time, but with symptomatic and supportive treatments, morbidity and mortality have been reduced and quality of life enhanced.

Prognosis

• Educate parents and patients regarding daily eye care and early warning signs of corneal problems, as well as use of punctal cautery. This education has resulted in decreased corneal scarring and need for more aggressive surgical measures such as tarsorrhaphy, conjunctival flaps, and corneal transplants.

Patient Education

• Teach patients and parents to instill topical lubricants frequently and to be alert for early warning signs of corneal erosion and infection.
• Use eye protective devices (eg, goggles, moisture chambers) when topical medications are not sufficient.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Highly suspected in strong family history

MULTIMEDIA

Section 10 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Absence of fungiform papillae on the tongue. The highly vascularized fungiform papillae on the anterior third of the tongue are absent resulting in a smooth and glistening tongue tip.
	View Full Size Image
Media type:  Photo

Media file 2:  Lack of axon flare following intradermal histamine. Histamine phosphate in a 1:10,000 dilution injected intradermally does not produce pain or an axon flare.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

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• Medication
• Follow-up
• Miscellaneous
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• Anderson SL, Coli R, Daly IW. Familial dysautonomia is caused by mutations of the IKAP gene. Am J Hum Genet. Mar 2001;68(3):753-8. [Medline].
• Axelrod FB. Familial dysautonomia. In: Burg FD, Ingelfinger JR, Polin RA, eds. Current Pediatric Therapy. 15th ed. Philadelphia, Pa:. WB Saunders Co;1996:91-94.
• Axelrod FB. Familial dysautonomia. Muscle Nerve. Mar 2004;29(3):352-63. [Medline].
• Axelrod FB, Goldberg JD, Ye XY. Survival in familial dysautonomia: Impact of early intervention. J Pediatr. Oct 2002;141(4):518-23. [Medline].
• Blumenfeld A, Slaugenhaupt SA, Axelrod FB, et al. Localization of the gene for familial dysautonomia on chromosome 9 and definition of DNA markers for genetic diagnosis. Nat Genet. Jun 1993;4(2):160-4. [Medline].
• Bonini S, Lambiase A, Rama P, et al. Topical treatment with nerve growth factor for neurotrophic keratitis. Ophthalmology. Jul 2000;107(7):1347-51; discussion 1351-2. [Medline].
• Brunt PW, McKusick VA. Familial dysautonomia. A report of genetic and clinical studies, with a review of the literature. Medicine (Baltimore). Sep 1970;49(5):343-74. [Medline].
• Chen HJ, Pires RT, Tseng SC. Amniotic membrane transplantation for severe neurotrophic corneal ulcers. Br J Ophthalmol. Aug 2000;84(8):826-33. [Medline]. [Full Text].
• Diamond GA, D''Amico RA, Axelrod FB. Optic nerve dysfunction in familial dysautonomia. Am J Ophthalmol. Dec 15 1987;104(6):645-8. [Medline].
• Dohlman C, Waller S, Netland P. Keratoprosthesis Surgery. In: Lindquist T, Lindstrom R, eds. Ophthalmic Surgery. Vol L. 1996:1-32.
• Goldberg MF, Payne JW, Brunt PW. Ophthalmologic studies of familial dysautonomia. The Riley-Day syndrome. Arch Ophthalmol. Dec 1968;80(6):732-43. [Medline].
• Ilsar M, Hartstein ME, Maayan C. Punctal occlusion in patients with familial dysautonomia. Ann Ophthalmology. 1998;30(6):375-378.
• Leyne M, Mull J, Gill SP. Identification of the first non-Jewish mutation in familial Dysautonomia. Am J Med Genet A. May 1 2003;118(4):305-8. [Medline].
• Pearson J, Pytel BA, Grover-Johnson N, et al. Quantitative studies of dorsal root ganglia and neuropathologic observations on spinal cords in familial dysautonomia. J Neurol Sci. Jan 1978;35(1):77-92. [Medline].
• Riley CM, Day RL, Greeley DM. Central autonomic dysfunction with defective lacrimation: report of five cases. In: Pediatrics. Vol. 3. 1949:468-77.
• Slaugenhaupt SA, Blumenfeld A, Gill SP. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet. Mar 2001;68(3):598-605. [Medline].

Article Last Updated: Apr 14, 2006