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Pediatric Retinal
Vascular Diseases
123
Pediatric Retinal Vascular Diseases
Ulrich Spandau • Sang Jin Kim
This Springer imprint is published by the registered company Springer Nature Switzerland AG.
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
Preface
Dear reader,
This book provides comprehensive and up-to-date information on diagnosis,
medical, and surgical treatments for pediatric retinal vascular conditions, which are
leading causes of childhood blindness throughout the world. Experienced ophthal-
mologists in this field discuss basic knowledge about these diseases, practical
aspects of management such as exam under anesthesia, up-to-date diagnostic
approaches including spectral-domain handheld optical coherence tomography
(OCT), and OCT angiography. A high emphasis is placed on recent advances in
medical and surgical treatments for pediatric retinal vascular diseases. Step-by-step
instructions are given for the surgical treatment with anti-VEGF treatment, laser
photocoagulation, and vitrectomy. Both the general ophthalmologist who cares for
children with retinal diseases and the specialist (pediatric ophthalmologists and
vitreoretinal surgeon) will find this book to be an informative resource in providing
best care for children with pediatric retinal vascular conditions.
The book includes many videos, which demonstrate the surgeries step-by-step.
All videos are listed in the Video list and can be accessed under http://extras.
springer.com/Search. Enter the ISBN number of your book and download the
videos.
Alternatively, the online version of every chapter contains the videos. Note the
following footmark at the beginning of every chapter:
“Electronic Supplementary Material The online version of this chapter
(https://doi.org/10.1007/978-3-030-13701-4_16) contains supplementary material,
which is available to authorized users.” Copy and paste the https address in your
browser and you can access the videos.
v
Acknowledgments
I want to thank my family and especially my wife Katrin for her never-ending
patience with a husband who spends so much time with his books.
Ulrich Spandau
vii
Contents
ix
x Contents
Part II Examination
Part III Assessment
FA fluorescein angiography
FEVR familial exudative vitreoretinopathy
GA gestational age
LE left eye
LIO laser indirect ophthalmoscopy
PHPV persistent hyperplastic primary vitreous
PMA postmenstrual age
RE right eye
ROP retinopathy of prematurity
xvii
List of Videos
xix
Part I
Pediatric Retinal Diseases
Chapter 1
Coats Disease
1.1.1 Introduction
1.1.2 Pathogenesis
1.1.2.1 Histopathology
A histologic study on enucleated eyes with Coats disease revealed macrophage infil-
tration and cholesteric clefts in the subretinal space [4]. Retinal vascular abnormali-
ties were also demonstrated including dilated vessels with hyalinized vessel walls
[4]. Immunoreactivity for VEGF was observed in the detached retina, dilated ves-
sel, and macrophages infiltrating the subretinal proliferative tissue [4]. VEGFR-2
immunoreactivity was also observed in endothelial cells located in abnormal retinal
vessels and inner layer of the detached retina, but not in macrophages infiltrating
the subretinal space [4].
1.1.3 Genetics
Previous studies reported mutations in several genes including NDP [5], CRB1 [6],
TINF2 [7], PANK2 [8], and ABCA4 [9] in patients with Coats disease or Coats-like
retinal phenotype. However, the exact molecular mechanisms remain to be elucidated.
Retinal vascular telangiectasis (Figs. 1.1 and 1.2) develop most commonly in
the inferior and temporal quadrants between the equator and the ora serrata [12].
Affected vessels show irregular and aneurysmal dilations. Vascular leakage from
the abnormal vessels result in lipid-rich exudation (Figs. 1.3 and 1.4) and pro-
gressive fluid accumulation with subsequent serous retinal detachment (Figs. 1.5,
1.6, and 1.7) [11]. Macular edema or subretinal fluid is a common cause of visual
symptom.
Retinal pigment epithelial cells that proliferate and migrate into the subretinal
space may develop subretinal fibrous proliferation [11].
The vitreous usually remains clear [11]. Vitreoretinal traction, fibrosis, or pro-
liferative vitreoretinopathy are not common but epiretinal membrane may develop
[11].
In a large-scale case series (n = 150 patients) study by Shields et al. in 2001
[10], median age at the diagnosis was 5 years. Among the 150 patients, 114 (76%)
were males and 142 (95%) showed unilateral involvement [10]. The most common
referral diagnoses were Coats disease in 64 (41%) followed by retinoblastoma in
43 (27%) patients [10]. Visual acuity at presentation was 20/200 or worse in 121
eyes (76%) [10]. The retinal telangiectasia involved the midperipheral or peripheral
fundus in 98% of eyes [10]. Retinal exudation was present in six or more clock
hours in 115 eyes (73%) [10]. Total retinal detachment was seen in 74 eyes (47%)
and neovascular glaucoma in 12 eyes (8%) [10].
and blocked fluorescence from exudates (Figs. 1.8, 1.9, 1.10, and 1.11) [11].
Fluorescein angiography is essential in early detection of vascular abnormalities
especially in eyes with telangiectasia only.
In Coats disease, OCT is useful in identifying macular edema and subretinal fluid
and to evaluate response to treatment. Subretinal fluid and exudate may be visible
with OCT in patients with Coats disease (Figs. 1.12 and 1.13). It should be noted
8 1 Coats Disease
Fig. 1.12 SD-OCT showing macular edema and exudates in a patient with Coats disease
Fig. 1.13 SD-OCT showing intraretinal lipid deposits in a patient with Coats disease
that in eyes with large amount of subretinal fluid, the amount of subretinal fluid
seen on OCT scans taken in a sitting position may be different from that in a supine
position due to fluid shifting.
Shields et al. proposed a classification system of Coats disease based on their clini-
cal observations in 150 consecutive patients in 2001 [10]. Their proposed classifi-
cation system is now being widely-used and very helpful for selecting treatment
methods and predicting the visual outcomes (Table 1.1 and Fig. 1.14).
10 1 Coats Disease
Eyes with stage 1 disease can be managed by either regular follow-up exams or
laser photocoagulation [10]. In stage 1 disease, there is high probability that the eye
can be salvaged and the visual prognosis is usually favorable [10]. However, stage 1
disease is rare in a real clinical practice probably due to no symptoms.
Eyes with stage 2 disease can be managed by laser photocoagulation or cryo-
therapy, depending on the extent and location of the disease [10]. In stage 2A, the
visual prognosis is generally good [10]. Eyes with stage 2B are usually salvaged
and the visual prognosis is fairly good [10]. Visual prognosis of eyes with a dense
yellow gray nodule by the foveal exudation is usually worse [10].
Eyes with stage 3A disease can generally be managed by photocoagulation or
cryotherapy [10]. Some of the patients with stage 3A1 disease (extrafoveal subto-
tal retinal detachment) in a sitting position can reveal subfoveal fluid in a supine
position (thus stage 3A2). Even if the retinal detachment involves the fovea, it will
resolve when the telangiectasias are treated [10]. Laser photocoagulation is less
effective in areas of retinal detachment, and cryotherapy is often preferable in such
instances [10]. However, Levinson and Hubbard reported good anatomical outcome
of 577 nm yellow laser photocoagulation in 16 patients including 5 patients with
stage 3B disease [13]. Patients with stage 3B with bullous detachment may require
surgical treatment (e.g. external subretinal fluid drainage).
Patients who present with stage 4 disease are often best managed by enucleation
to relieve the severe ocular pain [10]. Patients with stage 5 disease generally have a
blind, but comfortable eye and require no aggressive treatment [10].
The staging system of Coats disease is helpful for selecting treatment and predict-
ing the ocular and visual outcomes. In a case series study including 150 patients
from 1975 to 1999, the visual outcome was generally poor [10]. The proportion of
1.2 Classification of Coats Disease 11
a b
c d
e f
Fig. 1.14 Examples of stages of Coats disease. (a) Stage 1, retinal telangiectasia only. (b) Stage
2A, telangiectasia and extrafoveal exudation. (c) Stage 2B, foveal exudation. (d) Stage 3A1, sub-
total retinal detachment inferiorly, sparing the fovea. (e) Stage 3A2, subtotal retinal detachment
extending beneath the fovea. (f) Stage 3B, total exudative retinal detachment. (g) Stage 4, total
exudative retinal detachment behind the lens in eye with secondary glaucoma. (h) Stage 5,
advanced end stage disease with chronic inflammation, posterior synechia and cataract, secondary
to longstanding retinal detachment. (Reprinted from Shields et al. [12]. Copyright (2001), with
permission from Elsevier)
12 1 Coats Disease
g h
poor visual outcome (20/200 or worse) was high in eyes with stage 2B through 5
(Table 1.2). Recently, Ong et al. [14] compared visual outcome between two time
periods (decade 1, 1995–2005 and decade 2, 2006–2015), and showed that (1)
there was a trend for the mean initial presenting VA for decade 1 eyes to be worse
than for decade 2 eyes; (2) from initial to final follow-up visit, mean VA also
worsened for decade 1 eyes, but remained stable for decade 2 eyes; (3) at the end
of follow-up, there was a trend for mean VA for decade 1 eyes to be worse than
for decade 2 eyes; and (4) decade 2 eyes had a higher average number of proce-
dures per eye compared with decade 1 eyes (Table 1.2). In conclusion, this study
showed that the earlier presentation of disease in decade 2 suggests improvements
in disease detection over time, and there was a trend for eyes to have better final
VA in decade 2.
References 13
References
1. Coats G. Forms of retinal diseases with massive exudation. Graefes Arhiv für Ophthalmologie.
1912;17:440–525.
2. Blair MP, Ulrich JN, Elizabeth Hartnett M, Shapiro MJ. Peripheral retinal nonperfusion in fel-
low eyes in coats disease. Retina. 2013;33:1694–9.
3. Jung EH, Kim JH, Kim SJ, Yu YS. Fluorescein angiographic abnormalities in the contralat-
eral eye with Normal fundus in children with unilateral Coats’ disease. Korean J Ophthalmol.
2018;32:65–9.
4. Kase S, Rao NA, Yoshikawa H, Fukuhara J, Noda K, Kanda A, Ishida S. Expression of
vascular endothelial growth factor in eyes with Coats’ disease. Invest Ophthalmol Vis Sci.
2013;54:57–62.
5. Black GC, Perveen R, Bonshek R, Cahill M, Clayton-Smith J, Lloyd IC, McLeod D. Coats’
disease of the retina (unilateral retinal telangiectasis) caused by somatic mutation in the NDP
gene: a role for norrin in retinal angiogenesis. Hum Mol Genet. 1999;8:2031–5.
6. Hasan SM, Azmeh A, Mostafa O, Megarbane A. Coat’s like vasculopathy in leber congenital
amaurosis secondary to homozygous mutations in CRB1: a case report and discussion of the
management options. BMC Res Notes. 2016;9:91.
7. Gupta MP, Talcott KE, Kim DY, Agarwal S, Mukai S. Retinal findings and a novel TINF2
mutation in Revesz syndrome: clinical and molecular correlations with pediatric retinal vascu-
lopathies. Ophthalmic Genet. 2017;38:51–60.
8. Sohn EH, Michaelides M, Bird AC, Roberts CJ, Moore AT, Smyth D, Brady AF, Hungerford
JL. Novel mutation in PANK2 associated with retinal telangiectasis. Br J Ophthalmol.
2011;95:149–50.
9. Saatci AO, Ayhan Z, Yaman A, Bora E, Ulgenalp A, Kavukcu S. A 12-year-old girl with bilat-
eral Coats disease and ABCA4 gene mutation. Case Rep Ophthalmol. 2018;9:375–80.
10. Shields JA, Shields CL, Honavar SG, Demirci H, Cater J. Classification and management of
Coats disease: the 2000 Proctor Lecture. Am J Ophthalmol. 2001;131:572–83.
11. Sigler EJ, Randolph JC, Calzada JI, Wilson MW, Haik BG. Current management of Coats
disease. Surv Ophthalmol. 2014;59:30–46.
12. Shields JA, Shields CL, Honavar SG, Demirci H. Clinical variations and complications of
Coats disease in 150 cases: the 2000 Sanford Gifford Memorial Lecture. Am J Ophthalmol.
2001;131:561–71.
13. Levinson JD, Hubbard GB 3rd. 577-nm yellow laser photocoagulation for Coats disease.
Retina. 2016;36:1388–94.
14. Ong SS, Buckley EG, McCuen BW 2nd, Jaffe GJ, Postel EA, Mahmoud TH, Stinnett SS, Toth
CA, Vajzovic L, Mruthyunjaya P. Comparison of visual outcomes in Coats’ disease: a 20-year
experience. Ophthalmology. 2017;124:1368–76.
Chapter 2
Norrie Disease
2.1 Introduction
2.2 Genetics
Fig. 2.1 Dysplastic retinas demonstrating the unique retinal structure associated with Norrie disease.
Note the vascularized dysplastic retinal mass, called as “pumpkin” lesions. (Reprinted from Drenser
et al. [2]. https://journals.lww.com/retinajournal/Abstract/2007/02000/A_CHARACTERISTIC_
PHENOTYPIC_RETINAL_APPEARANCE_IN.16.aspx. Copyright (2007), with permission from
Wolters Kluwer Health, Inc.)
A knock-out mouse model with an Ndp gene disruption suggested that one of the
principal functions of norrin in the ear is to regulate the interaction of the cochlea
with its vasculature [5]. NDP mutations with subsequent defective norrin may cause
progressive loss of vessels in the stria vascularis of the cochlea and lead to senso-
rineural hearing loss. Studies showed that almost all patients will eventually suffer
some degree of hearing loss [6, 7].
Smith et al. study on 56 patients with IP showed that about one-third of patients
had cognitive impairment. Also, behavioral disorders (such as autism) and chromic
seizure disorder were also common [7].
Another random document with
no related content on Scribd:
“Une pareille conduite ne mène pas rapidement à la fortune.
Cependant le cabinet de Danton s’améliora en très peu de temps.
En dirigeant dignement ses affaires, il gagnait de vingt à vingt-cinq
mille francs par an; son sort de père de famille était assuré.
“Dans ce temps où la France était encore divisée en provinces, les
classes inférieures pouvaient se réclamer des grands seigneurs de
leur pays, et ceux-ci aimaient souvent par vanité autant que par
humanité à protéger leurs vassaux. La maison de Brienne était de
Champagne, près Arcis-sur-Aube. Danton était connu du comte de
Brienne, ancien ministre de la guerre, et de l’archevêque de Sens,
alors premier ministre. Il comptait parmi ses clients M. de Barentin. Il
avait des conférences avec lui pour ses affaires particulières, et
plusieurs fois, après les avoir traitées, M. de Barentin s’entretenait
avec son avocat des affaires publiques. La manière supérieure dont
Danton voyait les choses avait frappé M. de Barentin et lui avait
laissé une vive impression de sa capacité.
“Devenu garde des sceaux, M. de Barentin se souvint aussitôt de
son avocat et lui fit demander s’il voulait être secrétaire de la
chancellerie? Danton, dans un long entretien qu’il eut avec ce
ministre, lui exposa avec détails un plan qu’il croyait pouvoir éloigner
les déchirements que l’opposition des parlements allait enfanter.
Quelques-uns de ces parlements venaient d’être exilés: Danton
pensait que leur rappel n’était pas une chose de la plus grande
urgence. Il fallait avant tout les enlacer dans la participation aux
réformes; ils en étaient autant les adversaires que la noblesse et le
clergé, dont ils faisaient en quelque sorte partie et dont ils avaient
les privilèges. Tous les privilégiés enfin, quels que fussent leurs
costumes, qu’ils eussent un manteau de noblesse, une soutane de
prêtre ou une robe de palais, tous, selon l’opinion de Danton,
devaient contribuer aux charges qui ne pesaient que sur le tiers État,
c’est-à-dire sur l’immense majorité; la nation attendait l’allégement
du fardeau intolérable qu’elle ne pouvait plus supporter, la
résignation était épuisée....
“Si ces idées étaient acceptées, le roi, étant à leur tête, se
trouverait conquérir dans l’intérêt de tous une puissance supérieure
à tous les intérêts particuliers. Il pourrait réaliser les demandes de la
raison et donner, par un progrès réel, toute satisfaction aux lumières
du siècle et à la philosophie, interprète des vrais besoins de
l’humanité.
“En résumé, le plan conçu par Danton tendait à faire accomplir par
le roi une réforme progressive qui, laissant en place les pouvoirs
établis, les rendit, à leur insu ou malgré eux, les instruments de cette
équité pratique qui aurait fortifié à la fois tous les organes du
mécanisme social. M. de Barentin parla du projet de Danton à
l’archevêque de Sens. On parut l’approuver. Dans l’intervalle, la cour
répudia ce système trop net et trop décisif pour ses allures. Le
parlement fut rappelé. Brienne croyait en avoir gagné les principaux
membres.
“Mais trois mois après—novembre 1787—lorsque le roi fut obligé
de venir à Paris tenir un lit de justice à ce même parlement pour
obtenir l’enregistrement d’un édit portant création de divers emprunts
jusqu’à concurrence de 450 millions, Louis XVI rencontra la plus
violente opposition dans cette cour qu’on croyait réduite. Il voulut
vaincre l’opposition en exilant les plus récalcitrants, les conseillers
Fréteau, Sabatier, de Cabre et le duc d’Orléans.... Au mois de mai
suivant, 1788, le même parlement rendit un arrêt qui réclama avec
véhémence ‘les lois fondamentales de l’État; le droit de la nation
d’accorder des subsides, le droit des cours du royaume de vérifier
les édits, de vérifier dans chaque province les volontés du roi, et de
n’en accorder l’enregistrement qu’autant qu’elles seraient conformes
aux lois constitutives de la province, ainsi qu’aux fondamentales de
l’État; l’immovabilité et l’indépendance des magistrats, le droit pour
chaque citoyen de n’être jamais traduit en aucune manière devant
d’autres juges que ses juges naturels désignés par la loi; le droit,
sans lequel tous les autres sont inutiles, de n’être arrêté, par
quelque ordre que ce soit, que pour être remis sans délai entre les
mains des juges compétents; protestant la cour du parlement contre
toute atteinte qui serait portée aux principes exprimés.’
“M. de Barentin proposa de nouveau a Danton d’être secrétaire du
sceau. Celui-ci remercia en disant que l’état de la question politique
était changé. ‘Nous n’en sommes plus aux réformes modestes; ceux
qui les ont refusées ont refusé leur propre salut; nous sommes, dit-il
plus nettement que jamais, à la veille d’une révolution. Eh quoi! ne
voyez-vous pas venir l’avalanche?...
A. R. C. de Saint-Albin.”
VI
EXTRACTS FROM DOCUMENTS
Showing the Price Paid for Danton’s Place at the Conseils du Roi, the
Sources from which he Derived the Money for its Payment, and the
Compensation Paid on its Suppression in 1791.
The three documents from which I quote below are of the utmost
importance to a special study of Danton, because they give us most
of our evidence as to the value of his post at the Conseils du Roi,
and permit us to understand his financial position during the first
years of the Revolution.
They are three in number:—
(a) The deed of sale by which Danton acquired the post from Me.
Huet de Paisy. This deed was discovered by Dr. Robinet (from
whose “Vie Privée de Danton” I take all the documents quoted) in the
offices of a Parisian solicitor, Me. Faiseau-Jaranne of the Rue
Vivienne. This gentleman was the direct successor in his business of
the M. Dosfant who drew up the deed seventy years before.
I have quoted only the essential portions of this exceedingly
interesting piece of evidence. They give us the date of the
transaction (March 29, 1787), the price paid, 78,000 livres, or rather
(seeing that Danton acquired the right to collect a debt of 11,000)
67,000 livres net (say £2600); the fact that some £2000 of this was
paid down out of a loan raised for him by his relations in Champagne
and his future father-in-law, while some £160 he paid out of his
savings, and the rest remained owing. The receipt of 1789, which I
have attached at the end of the extract, shows us that by that time
the balance had been paid over to Me. Huet de Paisy, including
interest at 5 per cent. Incidentally there is mention of Danton moving
to the Rue de la Tissanderie, whence we shall find him drawing up
his marriage-contract.
(b) The marriage-contract between Danton and Antoinette
Charpentier, contains all the customary provisions of a French
marriage-contract, and is witnessed by the usual host of Mends,
such as we find witnessing Desmoulins’ contract, three or four years
later. It tells us, among other things, the position of his stepfather
Recordain and the well-to-do connections of the Charpentiers; but
the point of principal interest is the dowry—20,000 livres, that is,
some £800—of which the greater part (£600) went to pay his debt on
the place he held as Avocat ès Conseils, and the fact that he had
remaining a patrimony of some £500.
(c) The acknowledgment of the sum due as compensation to
Danton when the hereditary and purchasable office which he had
bought was put an end to. All students of the period know the vast
pother that has been raised on this point, the rumour that Danton
was overpaid as a kind of bribe from the court, &c. &c. All the direct
evidence we have of the transaction is in these few lines. They are
just like all the other forms of reimbursement, and are perfectly
straightforward.
The amount is somewhat less than we should give in England
under similar circumstances, for (1) the State does not allow for the
entrance-fees (10,000 livres), which Danton had had to pay, and (2)
it taxes him 12 per cent. for the probable future taxation which would
have fallen by death, transference, &c., on the estate. Finally, he
gets not quite 70,000 livres for a place which cost him first and last
78,000.
To recapitulate: the general conclusions which these documents
permit us to draw with regard to Danton’s financial position are as
follows:—The price of the practice he bought was 68,000 livres; of
this, 56,000 was paid down, a sum obtained by borrowing 36,000
from Mdlle. Duhattoir (a mortgagee discovered by the family solicitor,
Millot), and 15,000 from his future father-in-law, Charpentier, the
remaining 5000 being paid out of his own pocket.
He thus remains in debt to Me. Huet de Paisy, the vendor, in a
sum of 12,000 livres at 5 per cent. interest.
To this must be added a sum of 10,000 livres entrance-fee, which
he presumably pays by recovering a debt of somewhat larger
amount (11,000) which he had bought along with the practice.
When he marries, his wife’s dowry cancels his debt to Charpentier
and leaves him 5000 livres over, he possessing at that time in land
and houses at Arcy some 12,000—in all 17,000 livres or their value
are in hand in the summer of 1787, and his total liabilities at the
same date are the 36,000 to Mdlle. Duhattoir and the 12,000 to Me.
de Paisy. He starts his practice, therefore, with 31,000 livres, or
about £1200 of net liability. The practice was lucrative; we know that
he is immediately concerned with three important chancery cases;
he becomes the lawyer of two of the wealthiest men in the kingdom;
he lives modestly. We know that he pays the 12,000 with interest in
December 1789, and though we do not possess the receipt for
Mdlle. Duhattoir’s repayment, it is eminently probable that, under
such conditions, he could easily have met a debt of less than £800
out of four years’ successful practice in a close corporation, which of
necessity dealt with the most lucrative cases in the kingdom. I think,
therefore, one may regard the reimbursement which he received in
1791 as presumably free from debt, and see him in no financial
difficulty at any period of the Revolution. This opinion has the
advantage of depending upon the support of all those who have
lately investigated the same documents—MM. Aulard, Robinet,
earlier Bougeart (but he is a special pleader), and finally Mr. Morse
Stephens in England.
Livres
In the Cellar.—Three pieces of Burgundy, 62 bottles
of claret, 92 bottles of Burgundy, a small barrel of
white wine 600
In the Kitchen.—The usual batterie de cuisine of a
French household, enumerated in detail, and
valued at 208
In the Pantry and Offices of the Kitchen.—A few
chairs, a pair of scales, cups, saucers, and so
forth 98
In a Bedroom adjoining, and giving on the Cour de
Commerce.—The usual furniture; probably a
dressing-room. Here was the watch found on
Danton after his execution, his writing-table, &c.:
the whole, including dishes in the cupboard and
a stove 264
In a larger Bedroom giving on the Rue des
Cordeliers.—After the usual furniture, a small
piano, a guitar, two looking-glasses, and a
writing-table 990
In a little Room opening out of this.—Usual furniture
of a small study or boudoir, furnished in the white
wood of the period 470
In the Drawing-room.—The furniture, mostly grey and
white, no piece worth any special mention 992
A large cupboard near the chimney contained some
summer clothes put away, and the sword which
Danton had worn in the old Bataillon of the
Cordeliers. The whole valued at 332
In a little Room looking on an inner court (evidently
used as a Library, the list of whose books will be
found on p. 380):—Furniture, chiefly bookcases,
to the value of 160
In a little Lumber-room.—Three empty trunks and a 16
bed
In two little Rooms adjoining.—Furniture (mostly put
away) 214