Familial Dysautonomia 

Updated: Sep 11, 2018
Author: Robert A D'Amico, MD, FACS; Chief Editor: Hampton Roy, Sr, MD 

Overview

Background

Familial dysautonomia (FD) is an inherited disorder of the nervous system that affects the development and survival of autonomic and some sensory neurons.[1, 2] Originally reported by Riley et al in 1949,[3] familial dysautonomia is now recognized as one of several hereditary sensory and autonomic neuropathies. Evidence of the disorder may be noted from birth, although neurologic deterioration progresses with age.[1, 2] The transmission is autosomal recessive with complete penetrance, and with the exception of one patient, all proven cases have been of Ashkenazi Jewish extraction.[4, 5, 6]

Pathophysiology

Pathologic studies have shown marked reduction in nonmyelinated neuronal populations as well as reduction in small diameter myelinated axons.[1, 7] 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. There is a unique pattern of plasma catechols with low plasma levels of dihydroxyphenylglycol (DHPG), high DOPA and dopamine (DA) levels, and high norepinephrine (NE):DHPG, DA:NE, and DOPA:DHPG ratios.[2] During physical and emotional stress, plasma norepinephrine and dopamine are elevated and autonomic storms or "crises" may develop.

Epidemiology

Frequency

United States

Approximately 1 in 30 Ashkenazi Jews is presumed to be a carrier, which results in a potential disease incidence of 1 in 3600 live births to this population. However, since identification of the gene and institution of population screening, the actual birth rate has decreased.

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.[8] Survival statistics prior to 1960 reveal that there was a 50% probability of patients dying before age 5 years.[9] Current survival statistics indicate that a newborn with familial dysautonomia has a 50% probability of reaching age 40 years.[8]

Many adults with familial dysautonomia have been able to achieve independent function. Both men and women with familial dysautonomia have married and reproduced. All offspring have been phenotypically normal despite their obligatory heterozygote state. Although pregnancies were tolerated well, blood pressures were labile at time of delivery.[10]

Causes of death are less often 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. Some adult patients have died of renal failure.[8, 11]

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 and generally normal intelligence, although they may have excessive anxiety.[12, 13, 14] Neurologic function deteriorates with time.[15]

Race

Familial dysautonomia is an autosomal recessive disorder with complete penetrance but variable expression. With the exception of only one patient, all affected individuals have had both parents of Ashkenazi Jewish extraction.[4, 5, 6]

In 1993, using genetic linkage, the gene for familial dysautonomia 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.[16]

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.[4, 6] 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 familial dysautonomia 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.[17, 18]

Because the 2 Jewish mutations causing familial dysautonomia 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 some patients have survived into their 60s.

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 decreased the 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, scleral lenses) when topical medications are not sufficient.

 

Presentation

History

Although the diagnostic signs may be evident at birth, considerable variation exists in the expression of the disease at any time.[1, 2] 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 flushing of the skin and profuse drooling, as well as 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 vital dyes, such as fluorescein or rose bengal, is a common finding, and it is 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 cornea. Persistent epithelial erosions lead to progressive corneal thinning and repair by fibrovascular scarring.

Erosion and scarring of the inferior cornea due to Erosion and scarring of the inferior cornea due to incomplete lid closure during sleep.

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 may be mild, and a border of hazy epithelium usually surrounds the defect.

Neurotrophic corneal ulcer. Neurotrophic corneal ulcer.

Stromal opacification due to degenerative changes in the collagen as well as calcium deposition in the bed can occur.

Corneal stromal opacification. Corneal stromal opacification.

Superinfection must be guarded against but has been less frequent than might be anticipated, possibly because of the irrigating effect of frequent tear instillations and excellent family support.[19, 20] When bacterial superinfection occurred, staphylococci were the most common agents.

However, resistant strains and gram-negative contamination must be considered when patients are hospitalized for respiratory complications.

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 familial dysautonomia than in the general population.

Optic neuropathy characterized by nerve pallor and decrease in best corrected visual acuity is frequent and increases with age. It can be detected in the early stage by abnormal visual-evoked potential (VEP) and later by generalized visual field depression particularly in the cecocentral region.[21, 22, 23] Red-green color impairment is present on almost all cases. In a 2017 study, pathologic confirmation of optic nerve fiber loss, as well as retinal ganglion cell loss, was obtained from autopsy specimens from three patients.[24]

Systemic findings

The diagnosis is confirmed by ascertaining the presence of 5 cardinal criteria, as follows:

  • 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 decreased responses to both hot and cold.

Pain and temperature perceptions are more affected in the trunk and lower extremities, 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 patient with familial dysautonomia 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 familial dysautonomia 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.

Autonomic dysfunction

Pervasive autonomic dysfunction results in protean functional abnormalities affecting other systems and yielding myriad 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 familial dysautonomia. 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 gastrointestinal dysmotility in individuals with familial dysautonomia 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.

Vomiting is often 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 familial dysautonomia 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.[25, 26]

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. On occasion, syncope may occur.

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.

In older patients, supine hypertension can become prominent despite the retention of severe orthostatic hypotension, which increases treatment 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 familial dysautonomia, 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 familial dysautonomia, 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.[11]

Renal biopsies performed on individuals with noncorrectable azotemia revealed significant ischemic-type glomerulosclerosis and deficient vascular innervation.[27]

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 familial dysautonomia 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.[14]

About 25% of patients with familial dysautonomia 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.

Causes

Familial dysautonomia is an autosomal recessive genetic disorder caused by mutations in the IKBKAP gene.[4, 6]

 

DDx

 

Workup

Laboratory 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 following image.

Absence of fungiform papillae on the tongue. The h 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.

Decreased deep tendon reflexes: In 95% of patients with familial dysautonomia (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 following image.

Lack of axon flare following intradermal histamine 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.

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

Medical Care

The disease cannot be arrested, and ongoing systemic and ocular therapy is directed toward the specific problems encountered.[19, 20] 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.

Because of insensitivity to hypoxia and hypercapnia, and poor coordination of breathing with a tendency to hypoventilate during sleep, patients may be advised to use noninvasive assisted ventilation during sleep. These positive pressure systems may threaten corneal integrity, as an ill-fitting mask can allow airflow to further dry the eye.

Central agents, such as benzodiazepines and clonidine, are used to ameliorate the vomiting, hypertension, and general agitation associated with the dysautonomic crisis. Blood pressure management is complex, as fludrocortisone and midodrine are used to combat orthostatic hypotension,[20] while benzodiazepines, clonidine, and calcium channel blockers are used in conjunction with positioning to treat supine hypertension.

General dehydration

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.

Environmental dryness

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.

Corneal anesthesia

The decrease in blink rate noted with corneal anesthesia also accentuates the drying.

Mueller muscle contraction

During crisis episodes, the catecholamine surge causes a sustained contraction of Mueller muscle with eyelid retraction causing increased corneal exposure and drying.

Tear substitute therapy

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. Hydroxypropyl cellulose is also available in 5-mg rods (Lacrisert, Merck) that may be placed in the lower cul-de-sac, where they slowly dissolve, thickening and stabilizing the precorneal tear film. However, the decreased blink rate may interfere with the uniform dissolution of the cellulose rod, resulting in a ”clumping” effect.

Fortifying tear supplements with sodium hyaluronate prolong corneal surface coating, increasing tear break-up time; such products are now commercially available outside of the United States.[28]

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 hourly.

Nonpreserved solutions in unit dose packaging are preferred when frequent instillations are necessary.

Ointments may be 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 polyethylene film of ordinary kitchen cling wrap to the periorbita. The use of a room humidifier and the avoidance of hot air type heating are also of value.

Surface drying problems

Surface drying problems may range from conjunctival hyperemia with conjunctival and 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 has been shown to increase the dryness, and a nonsteroidal immunomodulator may be helpful.[29] Restasis (cyclosporine ophthalmic emulsion) 0.05% used twice daily is well tolerated and often provides 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.[29, 30]

Punctal occlusion helps maintain the tear volume, and cautery of all 4 puncta is usually recommended.[30, 31]

Puncta sometimes recanalize in children, requiring the procedure to be repeated.

Moisture chamber spectacle attachments/swim goggles

Moisture chamber spectacle attachments reduce evaporation, and swim goggles have been used 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 include a gauze pad, which would tend to be absorbent, but rather a moisture chamber, which may be 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.

Therapeutic contact lens

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.

Therapeutic soft lenses are used only until reepithelialization is obtained and 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.

High–gas-permeable scleral lenses have been used successfully for the long-term treatment of neurotrophic and dry eye disease by maintaining a chamber of oxygenated fluid over the compromised cornea.

The Boston Scleral lens, a fluid-filled gas-permeable (fluorosilicone/acrylate polymer) scleral contact lens was introduced in 1994 for the treatment of persistent corneal epithelial erosions in patients with severe ocular surface disease. Its fitting was structured with a computer-aided design to have the lenses rest entirely on the sclera, with maintenance of a shallow but continuous clearance of the cornea and limbus. Channels were created at the posterior interface to permit exchange of fluid, but not air, into the lens reservoir.[32]

The therapeutic fitting system now known as PROSE (Prosthetic Replacement of the Ocular Ecosystem) has had singular success in various patients, including many with dysautonomia at risk because of their corneal anesthesia and alacrima. It has also been used after keratoplasty in these patients as a daily-wear lens, and sometimes it is combined with the overnight use of a soft contact lens or modified scleral lens.[32, 33]

Temporary Tarsorrhaphy

Temporary tarsorrhaphy is a very effective treatment of the decompensated neurotrophic cornea.

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. This can be reinforced by approximating and overlapping the skin at the lateral canthus with Steri-strips. 

If the adhesive is applied to a clean dry area just below the lower-lid lash line and lateral canthal area and no forceful effort is made to pull the lids apart, the temporary tarsorrhaphy will stay in place for about a week.

Eye medications should be continued and instilled at the nasal canthus.

Topical fibronectin and topical murine epidermal growth factor

Topical fibronectin and topical murine epidermal growth factor have been previously reported to promote epithelial healing of persistent neurotrophic corneal ulcers.[33]

Autologous serum eyedrops

Autologous serum eyedrops provide a significant quantity of epidermal and transforming growth factor, fibronectin, and vitamin A, all essential components of the normal tear film. These accelerate corneal epithelial healing by stimulation of cell proliferation and migration.[34] Autologous blood, 50 cc, obtained by venipuncture is centrifuged at 1500 rpm and the serum supernatant is diluted to 20% with balanced salt solution (BSS). This is aliquoted into small, tinted dropper bottles, which are refrigerated and used 6 times daily. Supplies not in current use are kept frozen at –20°C.[35, 36]

Surgical Care

Suture 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. Alternatively, a running suture of 5-0 nylon can be placed through the lid margins at the lateral half of the palpebral fissure and tied at the canthus without the use of a peg.

Permanent tarsorrhaphy limits observation and treatment of the eye and should only be undertaken as a last resort. If it 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 nasal corneal scarring or perforation is threatened.

Bipedicle tarsorrhaphy. Bipedicle tarsorrhaphy.

Corneal surgical procedures

Dry and cryopreserved human amniotic membranes have been used with soft bandage contact lenses and with and without temporary tarsorrhaphy to promote rapid epithelial healing and to avoid secondary corneal scarring.[37] While its exact mechanism of action is unclear, its matrix contains growth factors, neurotrophins, and cytokines that suppress inflammation and the fibrovascular response that threaten corneal integrity.[38]

They may be valuable both in the treatment of the neurotrophic ulcer and in the failure to reepithelialize following keratoplasty procedures.

Cryopreserved amniotic membrane is also supplied on a plastic ring mount that is stabilized in the fornices without sutures but still maintaining it in contact with the cornea (ProKera, Bio-Tissue, Inc). The membrane dissolves in about 2 weeks and may require replacement.

The corneal opacification complicating familial dysautonomia is a frequent sequela of neurotrophic disease in the dry eye state. These corneas have difficulty resurfacing and maintaining epithelial integrity, thus they have guarded prognoses 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.

Temporary 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 familial dysautonomia. 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 in a case where multiple viable corneal grafts failed.[39]

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.

If general anesthesia is required, then general principles are as follows:[40]

  • 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 to stabilize the cardiovascular status.

  • 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

Nonophthalmologic surgical procedures frequently performed in patients with familial dysautonomia 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.[41, 42]

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.

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.

Further Outpatient Care

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

 

Medication

Medication Summary

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, in conjunction with clonidine, is the most effective drug for the dysautonomic crisis. Initial dose of diazepam should be effective in stopping vomiting, normalizing the blood pressure, and decreasing agitation. However, if hypertension persists, then clonidine is added. Crisis usually resolves abruptly and is marked by normalization of personality and return of appetite.

Benzodiazepines

Class Summary

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.

Diazepam (Valium)

Suppresses crisis symptoms by enhancing GABA; secondarily decreases dopamine release.

H2 receptor antagonists

Class Summary

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.

Ranitidine (Zantac)

H2 antagonist that may be a useful adjunct in reducing emesis volume.

Alpha-adrenergic agonists

Class Summary

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.

Clonidine (Catapres)

A central alpha-adrenergic agonist that suppresses peripheral release of norepinephrine, resulting in lower blood pressure; used to control symptomatic hypertension suggested if diastolic hypertension (>85 mm Hg) persists 30 min after diazepam administration.

Midodrine (ProAmatine)

A pure peripheral alpha-adrenergic agonist, which causes peripheral vasoconstriction and raises blood pressure without stimulating cardiac receptors; used for treatment of postural hypotension.

Corticosteroids

Class Summary

These agents have profound and varied metabolic effects.

Fludrocortisone (Florinef)

A mineralocorticoid; promotes retention of sodium and water, which increases intravascular volume; used for treatment of postural hypotension.