Familial Dysautonomia Treatment & Management

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 hypercapnea, 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 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. 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.
  • 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.
  • 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 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.^[25] 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.^[26]
  • Punctal occlusion helps maintain the tear volume, and cautery of all 4 puncta is usually recommended.^[27]
  • 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, which would tend to absorb water, 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.
  • Fluid-ventilated, high-gas permeable scleral lenses have also been used successfully for the long-term treatment of neurotrophic and dry eye disease by maintaining a chamber of oxygenated tears over the compromised cornea.^[28]
• 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 and topical murine epidermal growth factor have been previously reported to promote epithelial healing of persistent neurotrophic corneal ulcers.^[29]
• 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.^[30] 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.

• 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.
  • 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 nasal corneal scarring or perforation is threatened.
• Corneal surgical procedures

  • Cryopreserved human amniotic membrane (Bio-Tissue, Inc, Miami) has been used with and without tarsorrhaphy to promote rapid epithelial healing and to suppress secondary corneal scarring.^[31] 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.^[32]
  • This may be valuable both in the treatment of the neurotrophic ulcer and in the failure to reepithelialize following keratoplasty procedures in familial dysautonomia (FD).
  • Cryopreserved amniotic membrane is also supplied on a plastic ring mount that is stabilized in the fornices without sutures but maintaining it in contact with the cornea (ProKera, Bio-Tissue, Inc). The membrane dissolves in about 2 weeks and requires replacement, but the authors have obtained healing in 2 cases of corneal ulceration that failed to respond to other modalities.
  • Recently, a topical extract of amniotic membrane (AMX) has been prepared and used successfully in Europe in corneal epithelial healing.^[33]
  • 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 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 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.^[34]
  • 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^[35] :
    • 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 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.

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.

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.