Download Ocular Responses to Autonomic Drugs in Familial

Ocular responses to autonomic drugs in
familial dysautonomia
Alfred A. Smith, Joseph Dancis, and Goodwin Breinin
Familial dysautonomia presents a tetrad of symptoms referable to the eye which are quite
regularly present and which, in association, are distinctive and virtually diagnostic. These are
alacrima, corneal hypesthesia or anesthesia, exodeviation, and pupillary constriction following
the local administration of 2.5 per cent methacholine. These manifestations appear to be related
to other symptoms of the disease.
E
Materials and methods
amilial dysautonomia is a rare, inherited
disease affecting the motor, autonomic, and
sensory nervous systems. The patients suffer from postural hypotension, emotional
lability with hypertensive and vomiting episodes, excessive sweating, and blotching of
the skin. The presenting symptoms may involve the eyes—alacrima, corneal anesthesia, and trophic lesions of the cornea.1
In the present study, dysautonomic children have been examined in order to define better the ophthalmologic disorder and
possibly gain further insight into the
mechanisms of the disease. In the course of
the study, an abnormal response to methacholine has been recognized which may
serve as a diagnostic test.*
Methacholine hydrochlori.de (Mecholyl) was
freshly prepared as a 2.5 per cent solution in distilled water just prior to use. The epinephrine
solution (USP) contained a small quantity of
norepinephrine. Cocaine hydrochloride and neostigmine were employed as 5 per cent solutions.
Phospholine iodide was provided by Campbell
Pharmaceuticals.
The subjects with dysautonomia ranged in ages
between 6 and 24 and presented the clinical characteristics of the disease. In addition, they had
an abnormal resjoonse to intradermal histamine3
and demonstrated deficient taste discrimination.4
For the response to local administration of
pharmacologic agents, one drop of the test solution was placed in the conjunctival sac and held
for 10 seconds. The pupils were then examined
periodically over the next 30 minutes. Pupillary
sizes were examined initially by means of a transparent ruler and at constant illumination. The
diameter of the pupils ranged from 4 to 5 mm.
The response to methacholine was usually marked
(greater than 2 mm. change) so that the majority
of the studies were subsequently done by simple
comparison with the control eye. The corneas of
2 of the children who had a marked miotic
response to methacholine were examined by means
of a slit lamp and fluorescein stain, but no abnormalities were detected. None of the dysautonomic subjects tested with drugs showed gross
evidence of corneal abnormality. The response to
methacholine was also tested in 14 persons having
a variety of corneal lesions, and in 5 children
tested immediately after tonometry.
Methacholine was administered systemically to
6 control and 6 dysautonomic subjects by in-
From the Departments of Psychiatry, Pediatrics,
and Ophthalmology, New York University
Medical Center, New York, N. Y.
Aided by grants from the Dysautonomia Association of New York, the National Foundation, and
the United States Public Health Service (MH01434-08 and HD-00462-11).
This study was done in the Special Clinical Unit,
New York University Medical Center. Dr.
Dancis is a Career Investigator of the United
States Public Health Service.
•A preliminary report of this finding was presented at a
meeting of the American Pediatric Society, May, 1963,
Atlantic City, N. J.2
358
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Number 3
Autonomic drugs in familial dijsautonomia
travenous infusion at controlled rates in solutions
of 25 to 100 fig per milliliter of isotonic saline.
An increase in the flow of tears was determined by
inspection. Ocular deviation was evaluated by Miss
H. Dendy, orthoptist in the Department of
Ophthalmology.
Results
The instillation of 0.1 per cent 1-epinephrine ordinarily produces no pupillary
change. Cocaine, however, does produce
mydriasis in normal individuals.5 These
findings indicate an intact sympathetic innervation to the dilator muscles of the iris.
As shown in Table I, patients with dysautonomia give the normal responses.
In contrast with the normal/1 16 of 18
patients with dysautonomia developed miosis within 30 minutes following installation of methacholine, 2.5 per cent. The
miosis was marked in 14 (more than 2 mm.
change in diameter) and moderate but
easily seen in 2 others when compared
with their untreated eye. The remaining
2 patients failed to respond even after repeated instillations of methacholine. These
last subjects also showed a much milder
form of the disease than the others.
The cholinesterase inhibitors, neostigmine and phospholine, constricted the pupils in each of the 7 dysautonomic subjects
tested. The miosis induced by phospholine
persisted for many hours.
To determine whether the presence of
inapparent corneal lesions in the dysautonomic enhanced the penetration of methacholine into the anterior chamber, a group
of 14 adults with a variety of corneal lesions
and a group of 5 children just examined
with a tonometer were tested with methacholine, 2.5 per cent. In these individuals
existing corneal lesions and tonometry did
not induce a miotic response to this solution.
When methacholine is infused into
normal individuals, tearing usually occurs.
In our study (Table II), tearing began at
infusion rates of 2.5 to 11.7 p,g per kilogram
per minute, with a mean of 6.0. The dysautonomic response contrasted sharply; the
onset of tearing appeared at rates as low
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359
Table I. Pupillary responses to instillation
of drugs into one eye of patients with
familial dysautonomia
No. of
patients Miosis Mydriasis None
Drug
4
4
Epinephrine,
0.1%
5
Cocaine, 2%
5
2
16
18
Methacholine,
2.5%
5
5
Neostigmine, 5%
2
2
Phospholine,
0.125%
The untreated eye served as a control for pupillary size.
Table II. Infusion rates of methacholine
required to initiate tearing in dysautonomic
and control subjects
Normals
Age/
Subject
R. D.
F. P.
M. P.
M. G.
L.J.
J.M.
Sex
22/M
28/F
25/F
13/F
12/M
23/M
Mean
Infusion
rates
(fg/Kg/min.)
2.5
4.0
5.8*
6.0"
6.0
11.7
6.0
Dysautonomic ,mbjects
Infusion
rates
Age/ (Pg/KgSubject
/min.)
Sex
H. R. 21/M
0.5
2.8
R. L. 14/F
K. E. 21/M
1.3
1.0
J.S. 14/F
M. W. 14/M
1.3
0.4
K.S. 25/F
1.2
"Lacrimation was not evident at the highest infusion
rates employed. The normal subjects are listed as
responders at these rates for convenience of iJiesentation.
as 0.4 and with a mean of 1.4 ^ig per kilogram per minute. Overflow tearing was
commonly observed only in the dysautonomic subjects.
The difference from normal in the dose
of methacholine required to initiate tearing, and the fact that tearing ordinarily
does not occur in dysautonomia, suggests
denervation supersensitivity of the lacrimal
gland.
A further ocular disorder which appears
to be part of the dysautonomic syndrome
is exodeviation. As shown in Table III, of
15 patients examined by the orthoptist, 12
showed some form of this disorder.
Discussion
A disease with widespread effects on the
motor, sensory, and autonomic nervous
360
Investigative Ophthalmology
June 1965
Smith, Dancis, and Breinin
Table III. Ocular deviation and acuity in 15 children with dysautonomia
Visual acuity
Subject
Age/Sex
OS
Abnormality
S. F.
D. B.
6/M
9/M
OD
Not tested
20/40°
20/40
D. S.
B. R.
J.S.
6/F
8/F
12/F
15/M
20/70f
20/50
20/50
20/70°
20/40
20/50°
Not tested
Myopia
Myopia
Myopia
B. L.
E.G.
L. S.
16/F
8/F
10/F
20/70
20/70
20/40
20/50*
20/20!
20/40!
Myopia
Myopia
M. W.
S.A.
15/M
19/F
20/20
20/200
20/30!
20/100°
None
Myopia
B. M.
E. H.
A. K.
5/F
10/F
7/F
14/F
10/40
20/400
2/200
20/30
10/30°
20/40°
20/30
4/200
Corneal ulcers, bilateral
Corneal ulcer, left
Corneal opacity, left
Right amblyopia
s. s.
J.K.
"Examined with glasses,
f Examined without glasses.
systems is likely to have manifestations in
the eye. In fact, the tetrad of ophthalmologic findings—alacrima, corneal hypesthesia or anesthesia, exodeviation, and pupillary constriction following methacholine,
2.5 per cent—is so distinctive as to suggest strongly the diagnosis of familial dysautonomia. The diagnosis can be readily
confirmed by the intradermal histamine
test3 and by the absence of fungiform and
vallate papillae on the tongue.7
Previous studies have demonstrated an
exaggerated response in dysautonomia to
intravenous infusions of norepinephrine9
and of methacholine.7 It was suggested8
that the exaggerated response to norepinephrine may be the result of supersensitivity following deficient synthesis or release of norepinephrine, this suggestion
being supported by the finding of reduced
urinary vanillyl-mandelic acid.10 However,
it was also pointed out that a deficiency in
parasympathetic compensatory response to
norepinephrine could also explain the results. Such a parasympathetic deficiency
would also account for the supersensitive
pupillary responses to methacholine, 2.5
per cent, and for the alacrima correctable
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Myopia
Deviation
None
Alternating intermittent exotropia
Right exotropia
Exophoria
Left intermittent exotropia
Alternating intermittent exotropia
Exophoria
Left intermittent exotropia
Alternating intermittent exotropia
None
Alternating intermittent exotropia
None
Exophoria
Left exotropia
Right exotropia
by methacholine, first reported by Kroop.11
In fact, the lacrimal gland appears to share
the supersensitivity to methacholine.
The present investigation of the pupillary reactivity to pharmacologic agents has
provided further information. Sympathetic
denervation results in supersensitivity of
the iris muscle to adrenergic agents, whereas parasympathetic denervation induces
supersensitivity to cholinergic agonists.
Dilute epinephrine produced no response
in the dysautonomic subjects, but cocaine,
2 per cent, which produces a sympathetic
stimulation by potentiating intrinsic norepinephrine, induced mydriasis. These results are consistent with an intact sympathetic innervation to the eye.5
In 16 of 18 dysautonomic subjects, however, methacholine, 2.5 per cent, produced
miosis. Interestingly, the 2 subjects who
failed to respond had a mild form of the
disease, clinically difficult to diagnose as
dysautonomia. The miotic response to dilute methacholine is consistent with a parasympathetic denervation.6 Whether the
postulated denervation is central or post
ganglionic is unknown, but the miotic responses to neostigmine and phospholine
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Autonomic drugs in familial dysautonomia 361
strongly suggest that the denervation is incomplete. Both substances are cholinesterase inhibitors and therefore believed
merely to augment the effect of endogenous
acetylcholine.
There is the possibility that the exaggerated response to methacholine simply
reflects increased permeability of the cornea
as a result of trophic disturbances. However, patients with definite corneal lesions
but without dysautonomia did not respond
to dilute methacholine. An abnormal response, moreover, was demonstrable in a
dysautonomic infant at the age of 2 weeks
before there had been much opportunity
for corneal damage to have occurred.11 In
this case a slightly higher concentration
of methacholine (3.5 per cent) was used.
Normal infants under 6 months of age,
however, occasionally respond to dilute
methacholine,13 so that in this age group
the diagnosis of dysautonomia requires support by other tests.3' 7
The exodeviation parallels the general
awkwardness and poor muscular control
from which these children suffer. Rombergism, which can also be elicited, suggests
a proprioceptive defect. The neurological
lesion causing this disturbance is presently
unknown, although recent evidence suggests that the widespread sensory deficits
in dysautonomia may originate at the receptor sites.7 The inability to taste dilute
sweet or sour solutions has been correlated
with a receptor defect—an absence of taste
buds. The fungiform papillae and vallate
papillae, which contain the taste buds, are
absent in the dysautonomic. The respiratory
responses to hypoxia and hypercapnea are
also subnormal.1'1 The axon reflex normally
induced by histamine injection3 is missing
in dysautonomia and suggests a peripheral
sensory defect in the vicinity of the receptor site. Perhaps the corneal hypesthesia
or anesthesia also arises from a peripheral
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sensory deficit possibly within the cornea.
Since these nerve endings can be visualized
in the cornea, it may be possible to demonstrate an anatomical basis for pain insensitivity in this organ resembling the absence
of taste buds in the tongue.
REFERENCES
1. Riley, C. M.: Familial dysautonomia, Advances Pediat. 9: 157, 1957.
2. Smith, A. A., and Dancis, J.: Physiologic
studies in familial dysautonomia, presented
at the annual meeting of the American Pediatric Society, J. Pediat. 63: 838, 1963.
3. Smith, A. A., and Dancis, J.: The response
to intradermal histamine in familial dysautonomia: A diagnostic test, J. Pediat. 63: 889,
1963.
4. Smith, A. A., and Dancis, J.: Taste discrimination in familial dysautonomia, Pediatrics
33: 441, 1964.
5. Jaffe, N. S.: Localization of lesions causing
Homer's syndrome, Arch. Ophth. 44: 710,
1950.
6. Scheie, H. G.: Site of disturbance in Adie's
syndrome, 24: 225, 1940.
7. Smith, A. A., Farbman, A., and Dancis, ].:
Absence of taste-bud papillae in familial
dysautonomia, Science 147: 1040, 1965.
8. Smith, A. A., Hirsch, J., and Dancis, J.:
Responses to infused methacholine in familial dysautonomia, J. Pediat., 1965. In press.
9. Smith, A. A., and Dancis, J.: The exaggerated
response to infused norepinephrine in familial
dysautonomia, New England J. Med. 270:
704, 1964.
10. Smith, A. A., Taylor, T., and Wortis, S. B.:
Abnormal catechol amine metabolism in familial dysautonomia, New England J. Med. 268:
705, 1963.
11. Kroop, I. G.: The production of tears in
familial dysautonomia, J. Pediat. 48: 328,
1956.
12. Geltzer, A. J., Gluck, F., Talner, N. S., and
Polesky, H. F.: Familial dysautonomia: Studies in a newborn infant, New England J.
Med. 271: 436, 1964.
13. Dodge, P. R.: Personal communication.
14. Filler, J., Smith, A. A., Stone, S., and Dancis,
J.: Respiratory control in familial dysautonomia, J. Pediat. 66: 509, 1965.