Full-Thickness Skin Grafting of Eyelids in a Patient with Generalized

CASE REPORTS AND SMALL CASE SERIES

ily review disclosed 2 brothers who band’s mother revealed a B wave of Clinical Phenotype had decreased central visual acu- reduced amplitude but within nor- Associated With the ity, in one of whom it was associ- mal limits. Similar testing of the pro- Arg141His Mutation in the ated with esotropia (Table). Exami- band’s sister was normal. The B/A ra- nation of the proband and his tio, which shows the relative X-linked Retinoschisis Gene siblings revealed bilateral, bullous relationship of B-wave to A-wave X-linked retinoschisis (XLRS) is a schisis cavities, more prominent in amplitude and should be between rare hereditary disorder character- the inferior quadrants, and foveal 1.5 and 1.7 for most normal indi- ized by bilateral stellate maculopa- changes consistent with a diagno- viduals,5 was severely abnormal in thy and peripheral retinoschisis. The sis of XLRS (Figure 1). No retinal the 3 male siblings (0.77, 0.58, and schisis cavities are usually first noted breaks or dialyses were noted. Fun- 0.66), borderline normal in the in the inferotemporal quadrant and duscopic examination results of the mother (1.4), and clearly normal in often progress to involve the entire proband’s mother and sister were the sister (2.1). peripheral retina. This process of- normal. A peripheral blood sample was ten commences within the first year Abbreviated standardized elec- obtained from each family member of life and is associated with a wide troretinograms were recorded from and genomic DNA was isolated by range of phenotypic expression.1 each participant in accordance with proteinase-K incubation followed by Histopathologic studies have dem- international standards for pediat- phenol/chloroform extraction. Oli- onstrated a splitting of the retina at ric patients4 (Figure 2). The full- gonucleotide polymerase chain re- the nerve fiber layer.2 A gene respon- field mesoscopic electroretino- action primers, able to amplify each sible for XLRS, XLRS-1, which maps grams described here were elicited exon of the XLRS-1 gene, were syn- to Xp22.2, has been cloned and se- after 20 minutes of dark adaptation thesized (sequences available on re- quenced. The predicted protein se- using a 10-microsecond xenon quest). Fluorescent-labeled dideoxy- quence contains a highly con- strobe (model PS-22; Grass Instru- nucleotides were used in direct served motif implicated in cell-cell ments, Quincy, Mass) at an inten- sequencing of polymerase chain re- interaction and, thus, may be ac- sity of 2.4 candelas/m2 and a rate of action products to study the XLRS-1 tive in cell adhesion processes.3 We 0.3 Hz (4 responses averaged). All gene for each family member. Each report the clinical and electrodiag- electroretinograms were recorded exon was aligned to wildtype se- nostic phenotype associated with a with Burian-Allen contact lens elec- quence available on the Entrez missense point mutation within the trodes (Hansen Ophthalmic Devel- nucleotide database (Accession No. fifth exon of this gene that replaces opment Laboratories, Iowa City, AF018958).AGtoAtransition re- the normal arginine residue with a Iowa) using the Neuroscan electro- sulted in the substitution of a histi- histidine residue at codon 141 in a diagnostic system v3.0 (Neurosoft dine residue for an arginine resi- family of Hispanic origin. Inc, Herndon, Va). The A wave was due at codon 141 of exon 5 for each of normal amplitude for all partici- affected male sibling (Figure 2). The Report of Cases. The proband was pants; however, the B waves were re- proband’s mother and sister were initially seen at age 1 year 5 months, duced in each of the 3 male siblings noted to be heterozygous for this after his parents noted the evolu- under mesoscopic conditions. Elec- mutation. No other mutation or tion of an alternating esotropia. Fam- trodiagnostic testing of the pro- polymorphism was identified in any

Clinical, Electroretinographic (ERG), and DNA Analysis Findings*

Visual Acuity

Patient Pedigree No.† Age, y OD OS Fundus Status ERG DNA I-2 29 20/25 20/20 Normal OU Reduced B wave Heterozygote II-1 9 20/80 20/200 Mild RS OU Absent B wave Arg141His II-2 5 20/100 20/70 Mild RS OD; Absent B wave Arg141His severe RS OS II-3 2 1/30‡ 3/30‡ Severe RS OU Absent B wave Arg141His II-4 10 20/20 20/20 Normal OU Normal Heterozygote

*OD indicates right eye; OS, left eye; OU, both eyes; and RS, retinoschisis. †See Figure 2. ‡Indicates Allen Card visual acuity.

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 other exon. This mutation was not trum of mutations in the XLRS-1 gene clearly associated with early clini- seen in 32 control chromosomes. in patients from a variety of ethnic cal, visual, and electrophysiologic backgrounds.6 The mutation we re- changes, as the affected proband Comment. The Retinoschisis Con- port has been previously identified by had central and peripheral retinal sortium has described a wide spec- the Retinoschisis Consortium6 and is changes, as well as strabismus and electroretinographic changes, by the age of 17 months. In addition, DNA sequence analysis permitted the iden- tification of the proband’s sister as a carrier prior to the development of electoretinographic changes. The ability to determine carrier status by molecular techniques is important as many female carriers of XLRS achieve childbearing age prior to the detec- tion of electroretinographic changes. Useful family counseling is enhanced by the development of rapid, reliable genotype assays.

Jeong-Hee C. Park, MD Sandra H. Ott, BA Xiaoguang Wang, MD, PhD Binoy Appukuttan, PhD Reshma J. Patel, PhD Gretchen B. Van Boemel, PhD J. Timothy Stout, MD, PhD Los Angeles, Calif

We have no proprietary interest in any Figure 1. Fundus photograph of a 5-year-old patient with X-linked retinoschisis—characteristic stellate material relating to this research maculopathy and bullous peripheral retinoschisis in the inferior quadrants with vitreous veils. project.

I1 2 3

II 1 23 4

A G G G G C G C T AAG G G G C CTAAGGGGCCTAAGGGGCCTAGGGGCNCTAGGGGCNCT

50-µm V 25 ms

Mesoscopic ERG 2.4 cd/m2

–50 –25 0 25 75 50 100 125 150 175 –50 –25 0 25 75 50 100 125 150 175 –50 –25 0 25 75 50 100 125 150 175 –50 –25 0 25 75 50 100 125 150 175 –50 –25 0 25 75 50 100 125 150 175 B/A Ratio 0.77 0.58 0.66 1.4 2.1

Figure 2. Family pedigree. Corresponding DNA sequence for exon 5 and electroretinographic data are aligned beneath each individual. Arrows point to the nucleotide of interest. ERG indicates electroretinogram; B/A ratio, the relationship of B-wave to A-wave amplitude (reference range, 1.5-1.7).

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Corresponding author: J. Timo- band) was referred to our hospital capillaries. The crystals did not show thy Stout, MD, PhD, 4650 Sunset Blvd, in 1991 for a 1-year history of night up on the angiogram. No neovascu- Mail Stop 88, Los Angeles, CA 90027 blindness, metamorphopsia, and lar membrane, gross leakage and (e-mail: [email protected]). slowly progressive visual loss. The pooling of fluorescein dye from ves- left eye was more severely affected. sels, or gross macular edema was 1. George NDL, Yates JRW, Moore AT. Clinical features in affected males with X-linked retinoschisis. He was the second child in his fam- seen. Full-field electroretinogra- Arch Ophthalmol. 1996;114:274-280. ily and his parents were not related phy recorded diminishment in am- 2. Yanoff M, Rahn EK, Zimmerman LE. Histopa- (Figure 1). He was not obese and plitude of all waveforms, especially thology of juvenile retinoschisis. Arch Ophthal- mol. 1968;79:49-53. findings from the medical and drug the cone response. Findings from 3. Sauer C, Gehrig A, Weber B. Positional cloning history were normal. On examina- electro-oculographic examination of the gene associated with X-linked juvenile retinoschisis. Nat Genet. 1997;17:164-170. tion, visual acuity was 20/70 OD and showed subnormalities with de- 4. Marmor MF, Zrenner E. Standard for clinical 20/100 OS. The cornea was clear creased dark to light ratio. electroretinogaphy (1994 update). Doc Ophthal- with no crystals. Findings from fun- Values from routine blood bio- mol. 1995;89;199-210. 5. Birch DG. Clinical electroretinography. Oph- dus examination showed multiple chemistry tests, including fasting tri- thalmol Clin North Am. 1989;2:469-497. fine yellow-white refractile crystal- glycerides, total cholesterol, low- and 6. The Retinoschisis Consortium. Functional im- high-density lipoprotein choles- plications of the spectrum of mutation found in line flecks scattered throughout both 234 cases with X-linked juvenile retinoschisis. of the posterior poles and the pe- terol, and apolipoprotein B were nor- Hum Molec Genet. 1998;7:1185-1192. riphery of the fundi. They situated mal. Oxalic acid and amino acid in all layers of the neurosensory analysis in 24-hour urine samples retina, and some crystals lay on top also gave normal results. Leuko- Bietti Crystalline of the retinal vessels. Several areas cyte cystine level and ␣-galactosi- Retinopathy Affecting of blotchy pigment clumping were dase A activity were within refer- All 3 Male Siblings noticed in the mid-periphery. The ence intervals. The expression of the in a Family optic discs and retinal vessels were ornithine aminotransferase gene was normal. A left subretinal scar lying also normal. The patient had been Three male siblings of a nonconsan- 1–disc diameter temporal and infe- followed up in our hospital for 7 guineous Chinese family exhibited rior to the fovea and a similar but years. His vision remained stable, but characteristic retinal crystalline flecks somewhat fainter right scar lying the retinopathy showed advance- of Bietti crystalline retinopathy about 2–disc diameters temporal to ment in atrophic changes over the (BCR). The main proband suffered the fovea were evident (Figure 2). retinal pigment epithelial layer, and from blurred and distorted vision and Visual field testing using the also had bilateral submacular scars. Humphrey Field Analyzer showed To our knowledge, the presence of bilateral paracentral scotomas. Color BCR in this family demonstrated the vision tested with the Ishihara color Male Female Crystalline Retinopathy strongest male preponderance among chart was normal. Findings from the reported cases in the English lit- fluorescein angiography of the late erature. The mode of inheritance venous phase showed areas of hy- could be X-linked recessive, but no perfluorescence interspersed with conclusion could be made because hypofluorescent regions and the as- 123 the pedigree studied was too small. sociated prominent choroidal vessels. These features suggested atro- Report of Cases. Case 1. A 38-year- phic changes of both the retinal Figure 1. Pedigree chart of the family. Numbers old Chinese man (the main pro- pigment epithelium and the chorio- 1, 2, and 3 indicate patients 1, 2, and 3.

Figure 2. Patient 1 (the main proband). Color fundus photographs of the right (left) and left (right) eyes showing glistening crystals scattered throughout the posterior fundus and extended into the periphery, patches of pigment clumping, and retinal pigment epithelial hypopigmentation and atrophy. Subretinal scars (arrows) were found in the macular area of both eyes.

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Figure 3. Patient 2. Color fundus photographs of the right (left) and left (right) eyes showing many tiny reflective crystals mainly over the posterior poles. The retinal pigmented epithelial atrophy was not marked.

Figure 4. Patient 3. Color fundus photographs of the right (left) and left (right) eyes showing only a few crystals around the macula.

the crystals became less promi- Comment. The normal drug and cases are not consistent with any of nent. medical history, results of ophthal- these disorders. Case 2 and Case 3. Cases 2 and mologic examination, biochemis- There are about 90 reported 3, aged 34 and 36 years, respec- try tests, and molecular analysis sup- cases of BCR with considerable varia- tively, were the younger brothers of port the diagnosis of BCR without tion in symptoms and retinopa- the main proband. Both of them corneal involvement. We have con- thy.1-5 Some have characteristic fun- were asymptomatic, had an unre- ducted comprehensive ocular ex- dal pictures as originally described markable medical or drug history, aminations for all other family mem- by Bietti.6,7 Some have simulta- and their visual acuity was 20/20 bers as shown in the pedigree tree neous corneal and retinal involve- OU. Findings from ocular examina- (Figure 1). Findings from these ex- ment. Pure retinal involvement ap- tion were normal except for the pres- aminations were normal. pears to be more common in Asian ence of bilateral multiple crystal- The presence of refractile bod- than white people.1,2 This intrafa- line flecks in the retinas. These ies and crystalline deposits over both milial phenotypic variability typi- retinal flecks were confined to the retinas may be owing to primary eye fies the heterogeneity of BCR and has posterior pole. There were fewer de- diseases or secondary effects of in- been well shown in our cases. posits when compared with that of herited or acquired metabolic dis- Our main proband had nei- the proband (Figure 3), and the eases. Differential diagnosis is im- ther high myopia nor a history of youngest brother had the fewest de- portant for appropriate treatment. choroiditis. He had bilateral crystal- posits (Figure 4). Both corneas Diffuse crystalline retinal deposits line retinopathy with subretinal fi- were clear with no deposits. Find- may occur in systemic oxalosis, cys- brosis in the posterior poles. Macu- ings from systemic and ocular test- tinosis, hyperornithinemia, talc reti- lopathy in Bietti dystrophy is ing, including blood biochemis- nopathy, Sjo¨gren-Larsson syn- uncommon. Macular holes have tries, molecular analyses, visual field, drome, and excessive intake of been reported in 2 cases in which 1 electroretinogram, and electro- tamoxifen or canthaxantine. Clini- was highly myopic.1-3 The submacu- oculogram, were all normal. cal and biochemical features of our lar scar in the first patient could be

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 the result of a subretinal neovascu- This study was supported in part by hole surgery has not been reported. lar membrane, which, to our knowl- the W. K. Lee Eye Foundation, Sha- We describe 3 patients with promi- edge, could represent the first case tin, Hong Kong. nent macular drusen and idiopathic reported in the English literature and Corresponding author: Dennis S. macular holes. Macular hole surgery highlights the clinical diversity of C. Lam, FRCS, FRCOphth, Chair- was performed and a follow-up of at BCR. However, whether it is re- man, Department of Ophthalmology least 3 months was obtained. lated to the dystrophy and the and Visual Sciences, The Chinese Report of Cases. Case 1. An 83- mechanism of its formation is not University of Hong Kong, Prince of year-old white woman was seen with clear. Wales Hospital, Shatin, Hong Kong a 2-month history of decreased vision The proportion of male and fe- (e-mail: [email protected]). in her left eye. Best-corrected visual male patients with BCR is similar, acuity was 20/50 OD and 20/400 OS. 1. Bagolini B, Ioli-Spada G. Bietti’s tapetoretinal de- but there was segregation of male generation with marginal corneal dystrophy. Am The anterior segment examination and female patients in some fami- J Ophthalmol. 1968;65:53-60. showed 1+ nuclear sclerosis in both lies. In one reported family, 8 of 9 2. Bernauer W, Daicker B. Bietti’s corneal-retinal eyes. The posterior segment exami- 4 dystrophy: a 16-year progression. Retina. 1992; of those affected were women. In 12:18-20. nation of the right eye showed mul- general, however, BCR usually oc- 3. Saatci AO, Yaman A, Berk AT, Soylev MF. Macu- tiple drusen in the macula. Examina- lar hole formation in Bietti’s crystalline retinopa- curs sporadically and is more com- thy: a case report. Ophthalmol Genet. 1997;18: tion of the left eye revealed multiple mon among siblings or in families 139-141. drusen with a 200-µm stage 4 macu- with consanguineous marriage; an 4. Richards BW, Brodstein DE, Nussbaum JS, Fer- lar hole and surrounding cuff of sub- encz JR, Maeda K, Weiss L. Autosomal domi- autosomal recessive mode of inher- nant crystalline dystrophy. Ophthalmology. 1991; retinal fluid (Figure 1, A). The itance is generally regarded.1 Rich- 98:658-665. Watzkesignwaspositive.Fluorescein ards et al4 described an autosomal 5. Wilson DJ, Weleber RG, Klein ML, et al. Bietti’s crystalline dystrophy: a clinicopathologic cor- angiogramshowedhyperfluorescence dominant inheritance of high pen- relative study. Arch Ophthalmol. 1989;107:213- corresponding with the hole. The pa- etrance in a family with BCR. They 221. tient underwent pars plana vitrecto- 6. Bietti GB. Su alcune forme atipiche o rare di de- even suggested that it should be re- generazione retinica: degenerazione tappetoret- my, membrane peeling, fluid-air ex- garded as a new disease entity. In our iniche e quadri morbosi similari. Boll Oculist. change, and injection of 16% perfluo- family, all of the male siblings (3) in 1937;16:1159-1244. 7. Bietti GB. Ueber familia¨res Vorkommen von ropropane (C3F8) gas. Two weeks of the second generation were af- “Retinitis punctata albescens” (verbunden mit prone positioning was accomplished fected despite the different magni- “Dystrophia marginalis cristallinea corneae”): and the hole was closed. One year tudes, while their unrelated par- Glitzern des Glasko¨rpers und anderen degen- erativen Augenvera¨nderungen. Klin Monatsbl Au- later, her best-corrected visual acu- ents and the only sister were genheilkd. 1937;99:737-756. ity was 20/30 OS (Figure 1, B). unaffected. The X-linked recessive Case 2. An 82-year-old woman mode of inheritance is possible, but was referred for possible choroidal no conclusion could be made as the Macular Hole Surgery in neovascularization from age-related pedigree of the current family is too the Presence of Prominent macular degeneration in her left eye. small. Macular Drusen She had noticed decreased visual acuity in the affected eye for a few Wai-Man Chan, FRCS weeks and had previous cataract ex- Chi-Pui Pang, DPhil Current vitreoretinal surgical tech- traction in both eyes 2 years ear- Alfred T. S. Leung, FRCS niques often achieve good visual acu- lier. The best-corrected visual acu- Dorothy S. P. Fan, MBChB ity outcomes in eyes with idiopathic ity was 20/30−2 OD and 20/200 OS. Arthur C. K. Cheng, MBBS macular holes.1,2 However, the effect There were macular drusen in both Dennis S. C. Lam, FRCS, FRCOphth of concurrent prominent macular eyes. Contact lens biomicroscopy of Shatin, Hong Kong drusen on the outcome of macular the left eye showed a small macular

A B

Figure 1. Case 1. A, Prominent macular drusen with full-thickness macular hole (arrow). Preoperative visual acuity was 20/400. B, Twelve months after macular hole surgery. The macular hole is closed without progression of macular drusen and the visual acuity is 20/30.

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Figure 2. Case 2. A, Prominent macular drusen with stage 4 macular hole (arrows). The foveal area was digitally enhanced to better define the macular hole (inset). Preoperative visual acuity was 20/200. B, Fluorescein angiography revealed a discrete area of hyperfluorescence corresponding to the macular hole (arrow). The area of hyperfluoroscence superotemporal to the fovea corresponded to the cluster of drusen seen in part A. C, Three months following macular hole surgery. The macular hole is closed and the visual acuity is 20/60.

1,2 hole, surrounded by a cuff of sub- sual acuity improvement. After Corresponding author: Harry W. retinal fluid (Figure 2, A). The successful surgery, macular hole clo- Flynn, Jr, MD, Bascom Palmer Eye In- Watzke sign was positive. There was sure is believed to result from glial 3 stitute, 900 NW 17th St, University of also evidence of a superonasal proliferation and contraction, and Miami School of Medicine, Miami, FL branch vein occlusion, which was the visual acuity may return to near- 33136. distant from the macula. Fluores- normal function. cein angiography revealed a dis- Prominent macular drusen may 1. Wendel RT, Patel AC, Kelly NE, et al. Vitreous crete area of hyperfluorescence cor- sometimes mask the presence of a surgery for macular holes. Ophthalmology. 1993; 100:1671-1676. responding with the macular hole full-thickness macular hole (Fig- 2. Smiddy WE, Pimentel S, Williams GA. Macular (Figure 2, B). Pars plana vitrec- ure 2, A). Case 2 was referred with hole surgery without using adjunctive addi- tomy, membrane peeling, and fluid- the diagnosis of exudative macular tives. Ophthalmic Surg Lasers. 1997;28:713- 717. gas exchange with 16% C3F8 gas was degeneration. The correct diagno- 3. Funata M, Wendel RT, de la Cruz Z, Green WR. performed, followed by 2 weeks of sis of macular hole and prominent Clinicopathologic study of bilateral macular holes prone positioning. The macular hole macular drusen was made with the treated with pars plana vitrectomy and gas tam- ponade. Retina. 1992;12:289-298. was closed and the visual acuity im- aid of contact lens biomicroscopy. 4. Banker AS, Freeman WR, Kim JW. Vision- proved to 20/60 at the 3-month fol- The effect of prominent macu- threatening complications of surgery for full- thickness macular holes. Ophthalmology. 1997; low-up examination (Figure 2, C). lar drusen on the anatomic and func- 104:1442-1453. Case 3. A 74-year-old white tional success of macular hole sur- 5. Park SS, Marcuss DM, Duker JS, et al. Posterior woman was seen for a 1-month his- gery has not been previously reported. segment complications after vitrectomy for macu- tory of decreased vision in her right Banker and associates4 correlated lar hole. Ophthalmology. 1995;102:775-781. eye. Six months earlier, she was di- macular retinal pigment epithelium agnosed as having prominent macu- changes with poorer visual out- lar drusen in both eyes by another comes. The described retinal pig- Synkinesis Following retina specialist and had received ment epithelium alterations presum- Diabetic Third Nerve Palsy grid laser treatment in both eyes with ably result from light toxicity or partial resolution of the drusen. She anatomic debridement during macu- A 59-year-old man developed a left also had cataract extraction in both lar hole repair.4,5 pupil-sparing third nerve palsy re- eyes 1 year earlier. Best-corrected vi- In the present report, all 3 pa- lated to diabetes that recovered sual acuity was 20/200 OU and 20/30 tients had prominent preoperative gradually over 5 months; the only OS. Dilated fundus examination of macular drusen, which remained es- deficit remaining at 8 months was a the right eye showed prominent dru- sentially unchanged following macu- trace underaction of adduction. Ocu- sen with a stage 4 macular hole. Ex- lar hole surgery. Although these 3 pa- lomotor synkinesis was evident at this amination of the left eye revealed tients represent a limited experience, time, manifest as left upper lid re- prominent macular soft drusen. Pars patients with prominent macular dru- traction on adduction and on down- plana vitrectomy, membrane peel- sen and a macular hole can achieve gaze. There were no signs of oculo- ing, fluid-air exchange, and injec- similar anatomic and visual success motor or pupillary synkinesis. High- tion of 16% C3F8 gas was per- compared with patients without dru- resolution magnetic resonance formed on the right eye. The macular sen. Therefore, the presence of promi- imaging of the third nerve pathway hole was closed after 2 weeks of nent drusen in the macula does not revealed no abnormality. Oculomo- prone positioning. At 18-month fol- constitute a contraindication to macu- tor synkinesis following diabetic third low-up, best-corrected visual acu- lar hole surgery. nerve palsy is extremely rare, with ity was 20/25 OD. only one report in the literature to date. Comment. With current vitreoreti- Nauman A. Chaudhry, MD Synkinesis may occur during the nal techniques, anatomic closure rate Harry W. Flynn, Jr, MD recovery phase of a traumatic third in macular hole surgery has been re- William E. Smiddy, MD nerve palsy or after long-standing ported in up to 91% of cases and the Miami, Fla compression. The abnormal move- majority of anatomically successful John T. Thompson, MD ments that constitute synkinesis may cases achieve 2 or more lines of vi- Baltimore, Md involve the upper lid, oculomotor

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 system, and the pupil. Synkinesis is the left upper lid on adduction was withtheuseofmagneticresonanceim- rare when the cause is ischemia1 and unchanged and there was a new in- aging, it is now apparent that isolated we have found only one previous re- complete descent of the left upper lid thirdnervepalsy(withorwithoutpain port of synkinesis following dia- by 2 mm on downgaze (Figure). andwithoutpupillaryinvolvement)in betic third nerve palsy.2 Our report Although the patient’s third adiabeticindividualmayuncommonly adds a second to the literature. nerve palsy had recovered almost be due to midbrain infarction or hem- completely, definite signs of oculo- orrhage.7 It should be noted that if the Report of a Case. A 59-year-old man motor synkinesis were evident. These third nerve palsy in a diabetic patient with type 2 diabetes mellitus was synkinetic movements were un- fails to recover, it is likely to be due to seen with a 2-week history of left changed at the last examination, 8 a coexistent compressive lesion such ocular and retro-orbital pain, pro- months after the onset of symptoms. as a tumor or an aneurysm. gressive left upper lid ptosis, and dip- Recovery of third nerve palsy in lopia in all directions of gaze. Dia- Comment. Third nerve palsy is the diabetes usually occurs within 3 betes was well controlled and there commonest cranial mononeuropathy months.8-10 The mechanism of re- was no history of hypertension or inpatientswithdiabetes.3 Althoughthe covery is not known, but almost cer- previous neurologic disturbance. precise etiological role of diabetes- tainly involves remyelination, pres- Medication consisted of oral hypo- relatedthirdnervepalsyisuncertain,4,5 ent at 6 months11 and complete by glycemic agents only. diabetes-relatedischemiaoftheperiph- 3 years.12 Synkinesis may occur dur- The examination revealed cor- eral nerve may be important.6 And, ing recovery of any third nerve palsy, rected visual acuity of 20/30 OU, nor-

mal color vision, and full visual fields. A The pupils were 4 mm in diameter and reacted briskly to light. There was no proptosis. The upper lid and duc- tions in the right eye were normal. On the left side, there was complete ptosis with no levator function. The left eye was exotropic, adduction and elevation were absent, and depression was markedly limited. Intorsion on attempted downgaze was present. The remainder of the cranial nerves were normal. A diagnosis of diabetic left pupil-sparing third nerve palsy was made and the patient was B observed. At 2 months, his pain had re- solved completely, and left upper lid ptosis was only 3 mm with 5 mm of levator function. The left eye could be adducted just beyond the mid- line and there was improved but still limited upgaze and inferior rectus function. There was 2 mm of left upper lid retraction on attempted adduction, with the right upper lid remaining stationary on right gaze. There was complete descent of the left C upper lid on downgaze at this time. Because of the signs of oculomotor synkinesis, a magnetic resonance scan of the third nerve pathway was obtained, but no intracranial abnormality from the midbrain to the orbit was found. At 5 months, the patient was asymptomatic and had almost completely recovered. The patient had no ptosis or pupillary abnormality, normal levator function, and full motil- A, Right gaze demonstrates slight underaction of left medial rectus and elevation of left upper lid. B, Left ity except for a trace underaction of gaze demonstrates the normal lower position of the left upper lid. C, On downgaze, the left upper lid does adduction on the left. Retraction of not descend fully.

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 particularly following traumatic and synkinesis following diabetic third 21. Blake PY, Mark AS, Kattah J, Kolsky M. MR of 13-15 oculomotor nerve palsy. AJNR Am J Neurora- compressive lesions, but only nerve palsy remains a diagnosis of diol. 1995;16:1665-1672. rarely when the nerve palsy ap- exclusion. 22. Dreyfus PM, Hakim S, Adams RD. Diabetic oph- pears to be due to microvascular dis- thalmoplegia: report of a case, with postmor- 1 tem study and comments on vascular supply ease or ischemia related to giant cell Dai Barr, FRCOphth of human oculomotor nerve. Arch Neurol Psy- arteritis.16 Oculomotor synkinesis is Mark Kupersmith, MD chiatry. 1957;77:337-349. manifest as abnormal movements of Roger Turbin, MD the upper lid, globe, or pupil, oc- Sherry Yang, MD curring in isolation or in a variety of Raymond Iezzi, MD combinations that may be subtle and New York, NY Oral Ivermectin Therapy easily missed by the examiner. for Phthiriasis Palpebrum There are currently 3 contest- Corresponding author: Mark J. Kuper- ing theories on the pathogenesis of smith, MD, INN at Beth Israel North, Pediculosis pubis, as well as phthi- oculomotor synkinesis (see review riasis palpebrum, is caused by the 17 170 East End Ave, New York, NY 10128 by Sibony et al ): (1) Aberrant re- (e-mail: [email protected]). cosmopolitan crab or Pthirus pubis. generation of injured nerve fibers in This wingless, blood-sucking which regenerating axons that grow 1. Zorrilla E, Kozak GP. Ophthalmoplegia in dia- insect not only infests eyelashes betes mellitus. Ann Intern Med. 1967;67:968- into the wrong nerve sheaths are di- 976. and pubic regions, but occasionally rected to incorrect targets. (2) “Re- 2. Weinstein EA, Dolger H. External ocular muscle inhabits the hair of the face, axil- lease” phenomenon or synaptic re- palsies occurring in diabetes mellitus. Arch Neu- lae, chest, and rectal regions. rol Psychiatry. 1948;60:597-603. organization of the third nerve 3. Rush JA, Younge BR. Paralysis of cranial nerves Unlike the head louse, the pubic prenuclear or nuclear complex.18,19 III, IV, and VI. Arch Ophthalmol. 1981;99:76- crab has a serrated surface on its (3) Abnormal signal conduction 79. first tarsal claws, allowing this 4. Teuscher AU, Meienberg O. Ischaemic oculo- (ephaptic transmission) between pe- motor nerve palsy. J Neurol. 1985;232:144- organism traction on flat, hairless ripheral axons where there is a sec- 149. surfaces.1 Thus, this louse species 5. Watanabe K, Hagura R, Akanuma Y, et al. Char- ondary partial or complete loss of acteristics of cranial nerve palsies in diabetic pa- can navigate over the entire skin myelin. tients. Diabetes Res Clin Pract. 1990;10:19-27. surface. Although docile when In our patient, it is assumed that 6. Smith BE, Dyck PJ. Subclinical histopathologi- exposed to light, P pubis can be cal changes in the oculomotor nerve in diabe- the third nerve palsy was due to a le- tes mellitus. Ann Neurol. 1992;32:376-385. rather mobile in the dark. These sion of the peripheral nerve since 7. Hopf HC, Gutmann L. Diabetic 3rd nerve palsy: characteristics explain the promi- magnetic resonance imaging re- evidence for a mesencephalic lesion. Neurol- nent role that fomite transmission ogy. 1990;40:1041-1045. vealed no evidence of a brainstem, 8. Goldstein JE, Cogan DG. Diabetic ophthal- plays with crab lice, as well as its cavernous sinus, or subarachnoid le- moplegia with special reference to the pupil. occasional migration to the eyelids. Arch Ophthalmol. 1960;64:144-152. sion along the third nerve pathway. 9. Green WR, Hackett ER, Schlezinger NS. Neuro- Pubic lice have been challeng- Magnetic resonance imaging is un- ophthalmic evaluation of oculomotor nerve pa- ing to eradicate, as they often in- helpful in confirming the peripheral ralysis. Arch Ophthalmol. 1964;72:154-167. habit several hairy areas on indi- 10. Capo H, Warren F, Kupersmith MJ. Evolution location of the lesion in diabetic third of oculomotor nerve palsies. J Clin Neurooph- vidual patients. Lice need host hair nerve palsy since, as occurred in our thalmol. 1992;12:21-25. to cling to when sleeping, and for at- patient and in other studies,20,21 the 11. Weber RB, Daroff RB, Mackey EA. Pathology tachment of their eggs. In children, of oculomotor palsy in diabetics. Neurology. third nerve did not enhance. 1970;20:835-838. the tendency to inhabit eyelashes re- Histological studies of diabetic 12. Asbury AK, Aldredge H, Herschberg R, Fisher lates to specific temperature and CM. Oculomotor palsy in diabetes mellitus: a third nerve palsies may provide in- clinico-pathological study. Brain. 1970;93:555- moisture requirements, as well as the sight about the pathogenesis of syn- 566. lack of terminal hairs on most body kinesis in our patient. These stud- 13. Krohel GB. Blepharoptosis after traumatic third- regions in children of prepubetal 11,12,22 nerve palsies. Am J Ophthalmol. 1979;88:598- 2 ies found that the dominant 601. age. Thus, topical therapy may fail feature was central focal demyelin- 14. Hamer J. Prognosis of oculomotor palsy in pa- if one does not apply insecticide to ation of the subarachnoid, intracav- tients with aneurysms of the posterior com- all hairy areas, including the peri- municating artery. Acta Neurochir (Wien). 1982; ernous third nerve with relative axo- 66:173-185. rectal region. nal sparing. The fascicles and nuclei 15. Elston JS. Traumatic third nerve palsy. Br J Oph- Numerous insecticide formula- thalmol. 1984;68:538-543. were normal in two of the examina- 16. Sibony PA, Lessell S. Transient oculomotor syn- tions in aqueous vehicles and ap- tions. These findings mitigate against kinesis in temporal arteritis. Arch Neurol. 1984; plied with cotton sticks have been the misdirection and central theo- 41:87-88. suggested for phthiriasis palpe- 17. Sibony PA, Lessell S, Gittinger JW. Acquired 3 ries but favor the ephaptic theory of oculomotor synkinesis. Surv Ophthalmol. 1984; brum, including lindane, mala- electrotonic conduction between bare 28:382-390. thion,4 and pyrethrin.5 Additionally, axons in our case. 18. Wartenberg R. Associated movements in the various other reported treatments for oculomotor and facial muscles. Arch Neurol Psy- In conclusion, this case report chiatry. 1946;55:439-488. pediculosis ciliaris include mechani- is the second of synkinesis follow- 19. Lyle DG. Experimental oculomotor nerve re- cal removal with fine forceps,6 yel- generation. Am J Ophthalmol. 1966;61:1239- 7 ing diabetic third nerve palsy. It is 1243. low mercuric oxide eye ointment, 8 emphasized that signs of oculomo- 20. Mark AS, Blake P, Atlas SW, Ross M, Brown D, cryotherapy, 20% fluorescein solu- tor synkinesis may be subtle and Kolsky M. Gd-DTPA enhancement of the cis- tion,9 physostigmine ointment,10 pe- ternal portion of the oculomotor nerve on MR 11 thus easily missed unless specifi- imaging. AJNR Am J Neuroradiol. 1992;13:1463- troleum jelly, and argon laser pho- cally looked for, but the diagnosis of 1470. totherapy.12 Alcoholic formulations

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 should be avoided owing to ocular ir- mate and GABA are the neurotrans- 8. Awan KJ. Cryotherapy in phthiriasis palpebrum. Am J Ophthalmol. 1977;83:906-907. ritation, and allergic reactions can oc- mitters for peripheral motor func- 9. Mathew M, D’Souza P, Mahta DK. A new treat- cur in people sensitized to excipient tion. The neuromuscular system in ment of phthiriasis palpebrum. Ann Ophthal- components. Of note, delayed cor- humans does not operate via gluta- mol. 1982;14:439-441. 10. Couch JM, Green WR, Hirst LW, De La Cruz neal damage has been reported with mate or GABA, and thus is not af- ZC. Diagnosing and treating Phthirus pubis pal- insecticidal use.13 fected by the presence of this drug. pebrum. Surv Opthalmol. 1982;26:219-225. 11. Mutavdzic A. Head lice infestations and their Oral ivermectin (Stromectol; As ivermectin has a half-life of treatment. S Afr Med J. 1984;66:923-924. Merck and Co Inc, Whitehouse Sta- 16 hours, a single dose of ivermec- 12. Awan KJ. Argon laser phototherapy of phthi- tion, NJ) has been purported to be tin does not allow sufficient drug lev- riasis palpebrum. Ophthalmic Surg. 1986;17: 14 813-814. the solution to pubic lice, but to our els in the bloodstream to kill nymphs 13. Pe’er J, BenEzra D. Corneal damage following knowledge no case reports of its use as they hatch from their nit capsule the use of the pediculocide A-200 pyrinate. Arch 1 week later.16 Pubic lice feed on hu- Ophthalmol. 1988;106:16-17. for phthiriasis palpebrum have been 14. Burkhart CG, Burkhart CN. An assessment of reported. For this reason, we re- man blood several times during each the topical and oral prescription and over-the- port our experience with 4 cases of day and young lice require a blood counter treatments for head lice. J Am Acad Der- matol. 1998;38:979-982. phthiriasis palpebrum. meal soon after hatching from the 15. Aubin F, Humbert P. Ivermectin for crusted 2 egg. Ivermectin has no ovicidal ac- (Norwegian) scabies. N Engl J Med. 1995;132: Report of Cases. Four patients, rang- tivity, and requires the louse to ob- 612. 16. Burkhart CN, Burkhart CG. Another look at ing in age from 3 to 10 years, had com- tain the drug via blood meals. Simi- ivermectin in the treatment of scabies and head plaints of itching and irritation of the lar to our experience with pubic lice lice. Int J Dermatol. 1999;38:235-236. in the groin, 2 doses of ivermectin, 17. Meinking T, Burkhart CG, Burkhart CN. Ec- eyes for several weeks. On clinical ex- toparasitic diseases in dermatology: reassess- amination, all revealed reddened, given a week apart, are required to ment of scabies and pediculosis. In: James W, crusty lid margins with grayish dis- eradicate phthiriasis palpebrum. ed. Advances in Dermatology. Vol 15. St Louis, Mo: Mosby; 1999. coloration at their bases. On closer There are 2 caveats with ivermec- 18. Barkwell R, Shields S. Death associated with examination, numerous nits and mo- tin. First, one needs to avoid treat- ivermectin treatment of scabies. Lancet. 1997; tile parasites were noted on the eye- ing persons weighing less than 15 kg, 349:1144-1145. lashes. All 4 patients had bilateral in- and to use caution in use in preg- volvement, with 1 additionally hav- nant or breastfeeding women.16,17 ing infestation with crab lice in the This restriction is based on the drug’s scalp hair. Three of the 4 patients had ability to potentially cross poorly de- Full-Thickness Skin been previously unsuccessfully veloped blood-brain barriers. Sec- Grafting of Eyelids treated with 1% gamma benzene ond, there has been one report of in a Patient With hexachloride shampoo and topical possibly increased incidence of death Generalized Morphea 18 physostigmine. All patients were in elderly patients. However, there Taking Thalidomide treated with two 200-µg/kg doses of have been more than 10 million oral ivermectin (Stromectol) given a people treated worldwide for on- Thalidomide, formerly a medical week apart. No topical treatments chocerciasis and strongyloidiasis “outcast,” has enjoyed a resur- were applied to the eyelids. without any reported ramifications gence of interest as a drug capable All 4 patients were cured with in older populations.17 of treating many medical condi- this therapy. All adult lice were tions by the same mechanisms that eradicated within 2 days, while the Craig N. Burkhart once demonized it. With its anti- nits remained attached to the eye- Craig G. Burkhart, MSPH, MD inflammatory and antiangiogenic ef- lashes but dissipated during the fol- Sylvania, Ohio fects, thalidomide is now being ef- lowing month as the eyelid hairs fectively applied to a variety of grew out. Corresponding author: Craig G. autoimmune and dermatologic dis- Burkhart, MSPH, MD, Department of orders such as erythema nodosum Comment. Ivermectin is an anthel- Medicine, Medical College of Ohio at leprosum, discoid lupus erythema- mintic agent that has proved to be Toledo, 5600 Monroe St, Suite 106B, tosus, Behc¸et syndrome, and Langer- an excellent antiparasitic drug for Sylvania, OH 43560. hans cell histiocytosis.1 Addition- veterinary medicine since its intro- ally, more and more research is 1. Ubelaker JE, Payne E, Allison VF, Moore DV. duction in 1981. Approved by the Scanning electron microscopy of the human pu- exploring the effects and applica- Food and Drug Administration for bic louse, Pthirus pubis. J Parasitol. 1973;59: tions of thalidomide to angiogenesis- human use for onchocerciasis and 913-919. dependent medical conditions such 2. Burgess IF. Human lice and their manage- strongyloidiasis in 1996, ivermec- ment. Adv Parasitol. 1995;36:271-342. as diabetic retinopathy, certain can- tin has also been effective for loia- 3. Kincaid MC. Phthirus pubis infestation of the cers, and wound healing. This case sis, bancroftian filariasis, cutane- lashes. JAMA. 1983;249:590. report is followed by a discussion of 4. Burns DA. The treatment of human ectopara- ous larva migrans, scabies, and site infection. Br J Dermatol. 1987;117:741-743. the effects of thalidomide on fac- lice.14,15 Ivermectin acts by block- 5. Klaus S, Shvil Y, Mumcuoglu KY. Generalized tors involved in wound healing. infestation of a 3-year old girl with pubic louse. ing chemical transmission across Pediatr Dermatol. 1994;1:26-28. nerve synapses that use glutamate or 6. Ronchese F. Treatment of pediculosis cilio- Report of a Case. A 50-year-old ␥-aminobutyric acid (GABA). In- rum in an infant. N Engl J Med. 1953;249:897- white woman was referred for evalu- 898. vertebrates, like lice, are selectively 7. Perlman HH, Fraga S, Medina M. Phthiriasis pal- ation of severe cicatricial eyelid re- paralyzed by ivermectin, as gluta- pebrum. J Pediatr. 1956;49:88-90. traction and ectropion (Figure 1)

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Figure 1. Patient with generalized morphea with right upper cicatricial eyelid Figure 2. Postoperative appearance after successful full-thickness skin retraction associated with exposure-induced ulcerative keratitis and left grafting to the right upper (14 months later), left upper, and left lower eyelids upper and lower eyelid cicatricial ectropion prior to surgery. (10 months later). The right corneal ulcer is healed with residual scarring.

due to generalized morphea—a sodes of corneal exposure despite liability in successful wound heal- scleroderma variant of progressive disease progression. ing. This patient healed well after systemic sclerosis without sys- skin grafting while taking thalido- temic involvement.2 The patient had Comment. This case is an example mide, further illustrating the remark- been taking 800 to 1000 mg/d of tha- of successful skin grafting per- ably complex relationship between lidomide for several months prior to formed on a patient taking thalido- integrins, cytokines, normal cellu- repair, and continued taking the mide who has a degenerative, fi- lar processes, and disease states. drug for the duration of our involve- brotic dermatologic disorder such as ment in her care. Given her skin con- generalized morphea. Other reports Laura M. Periman, MD dition and the lack of literature de- of skin grafts on nonhealing periph- Bryan S. Sires, MD, PhD scribing skin grafting in patients eral skin ulcers in patients with Seattle,Wash taking thalidomide, we initiated a scleroderma have been published.3 staged repair. Using the only normal- However, to our knowledge, this is appearing patch of skin from the left the first case report of a successful This study was supported in part by scapula, full-thickness skin graft- skin grafting procedure performed on an unrestricted departmental award ing to the patient’s right upper eye- a patient taking thalidomide. from Research to Prevent Blindness lid was performed first, because of The precise mechanism(s) of Inc, New York, NY. the presence of an exposure- thalidomide’s anti-inflammatory, an- Corresponding author: Bryan S. induced corneal ulcer. The pa- tiangiogenic, and teratogenic ef- Sires, MD, PhD, University of Wash- tient’s wounds healed satisfacto- fects are still under investigation. ington, Ophthalmology, Box 356485, rily. Eight months later, a 3-mm However, thalidomide seems to in- Seattle, WA 98195-6485 (e-mail: lateral tarsorrhaphy was added to the hibit the fibrotic effects of tumor ne- [email protected]). ␣ right lateral eyelids. Four months crosis factor , antagonize the an- 1. Tseng S, Pak G, Washenik K, Pomeranz MK, Sh- later, the patient underwent simi- giogenic effects of beta fibroblast upack JL. Rediscovering thalidomide: a review of its mechanism of action, side effects and poten- lar repair of the left upper and lower growth factor, and inhibit the ex- tial uses. J Am Acad Dermatol. 1996;35:969-979. eyelids. Normal-appearing skin from pression of certain beta integrin sub- 2. Isselbacher AB, ed. Harrison’s Principles of In- the left scapula was again used to units.4,5 Integrins are cell surface pro- ternal Medicine. 13th ed. New York, NY: McGraw- Hill Co; 1994:1654-1656. cover the defects that remained af- teins involved in important cell- 3. Hafner J, Kohler A, Enzler M, Brunner U. Suc- ter dissection, undermining, and re- cell and cell-matrix interactions. By cessful treatment of an extended leg ulcer in sys- approximation of the eyelid to the decreasing the expression of inte- temic sclerosis. Vasa. 1997;26:302-304. 4. McCarty MF. Thalidomide may impede cell mi- globe. Again, the wound healed sat- grins, cell migration–dependent pro- gration in primates by down-regulating inte- isfactorily (Figure 2). One year cesses such as inflammation, angio- grin beta-chains: potential therapeutic utility in solid malignancies, proliferative retinopathy, in- after the procedure, the patient con- genesis, and embryogenesis would flammatory disorders, neointimal hyperplasia, tinues to have good eyelid approxi- thus be limited. Theoretically, tha- and osteoporosis. Med Hypotheses. 1997;49:123- mation to the globe (3 mm of lag- lidomide’s therapeutic anti- 131. 5. DAmato RJ, Loughnan MS, Flynn E, Folkman ophthalmos on the right and 2 mm inflammatory, antifibrotic, and an- J. Thalidomide is an inhibitor of angiogenesis. on the left) and no further epi- tiangiogenic effects could become a Proc Natl Acad SciUSA. 1994;91:4082-4085.

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