Macular Halos Associated with Niemann-Pick Type B Disease JOHN D. MATTHEWS, MD,* JOHN J. WElTER, MD, PhD,t EDWIN H. KOLODNY, MDt

Abstract: Macular halos describe a striking clinical finding of bilaterally elevated, doughnut-shaped, white rings around the fovea. This paper presents the third well-documented report of the association of macular halos with Niemann-Pick type B disease, demonstrated by color photographs and subtle fluorescein angiographic findings. The systemic association with Niemann-Pick type B dis­ease was confirmed by bone marrow biopsy and enzyme assay. Of 13 family members examined, only the proposita had macular halos; 10 were found to be carriers by sphingomyelinase assay. Recognition of this pathognomonic eye finding warrants more widespread awareness as a presenting sign of Niemann­Pick type B disease. [Key words: cherry-red spot, Iysozomal storage disease, macula, macular halo, Niemann-Pick disease.] Ophthalmology 93:933-937, 1986

Macular cherry-red spots are known to be associated with the sphingolipidoses, specifically Tay-Sachs and Niemann-Pick disease. A more subtle type of cherry-red spot, termed "macular halo," has recently been identified.' This unique ophthalmoscopic finding has been shown to be associated with Niemann-Pick type B disease.' This report documents a new family with this disease. Thirteen family members in four generations were examined; one had the pathognomonic finding of macular halos and 10 were found to be carriers of the trait for this autosomal recessive disease.

CASE REPORT

A 19-year-old white woman of French and American Indian (maternal) and English (paternal) ancestry presented in May 1983 with no visual complaints. A peculiar foveal lesion had been noted on routine examination, and she was referred for further evaluation. Best corrected visual acuity was 20/20 in

From the Southeastem Eye Center, Greensboro: the Eye Research Institute of Retina Foundation and Retina Associates, Boston,t and the Eunice Kennedy Shriver Center, Waltham.:\:

Presented at an Annual Meeting of the American Academy of Ophthal­mology.

Reprint requests to John D. Matthews, MD, Southeastem Eye Center, 3312 Battleground Avenue, Greensboro, NC 27410.

each eye. The pupils were equal, round, and reactive to light. Extraocular movements were intact. The anterior segments were normal, and there were no lens opacities. On ophthalmoscopy, a discrete white ring was noted around the fovea of each eye (Figs 1, 2). The ring was 0.5 disc diameter at its outer edge and appeared slightly elevated by contact lens examination. The ma­terial causing the ring was in the superficial layers of the retina, and the edge was feathered. Findings of the ocular examination were otherwise unremarkable.

Color vision by Farnsworth dichotomous (D = IS) test was normal. No defect was noted on central visual field examination. Monochromatic photographs (Fig 3) and early fluorescein an­giographic study (Fig 4) revealed masking of the perifoveal vessels by the lesion. The late-phase angiogram showed no staining or pooling of dye from leakage (Fig 5). Visual evoked response, electroretinogram, and electro-oculogram were within normal limits for each eye.

The patient had a short stature (61 in) but was otherwise nor­mal in appearance. Although not mentally retarded, she had significantly more difficulty with her 12 grades of school than did her siblings. A raised macular skin rash was noted, on the extremities and neck, which was chronic by history. She had adult secondary sexual characteristics and had recently delivered a child. Although her spleen was enlarged to 4 cm below the left costal margins, no liver or lymph node enlargement was noted. The neurologic examination failed to reveal any generalized or focal abnormalities. Complete blood count, platelets, electro­phoresis, and chest x-ray were within normal limits.

Because of the eye findings, a lipid storage disease was sus­pected, and a bone marrow aspirate and biopsy specimen were obtained. A Wright-Giemsa preparation demonstrated sea-blue

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OPHTHALMOLOGY • JULY 1986 • VOLUME 93 • NUMBER 7

Fig l.Top left. right eye posterior pole demonstrating macular halo. Fig 2. Top right. left eye posterior pole demonstrating mac­ular halo. Fig 3. Second row left. right eye monochromatic (red­free) photograph highlights feathered appearance in nerve fiber layer. Fig 4. Second row right. right eye fluorescein angiogram, early phase. Note masking of peri foveal vasculature implying ac­cumulation of sphingomyelin in ganglion cell layer. Fig 5. Third row left. right eye fluorescein angiogram, late phase. No staining or pooling of dye from leakage. Fig 6. Third row right. sea-blue histiocyte (arrow) in bone marrow aspirate. Wright-Giemsa stain. Fig 7. Bottom left. foam cell (arrow) in bone marrow biopsy. Ziehl-Neelsen stain.

MATTHEWS, et al • MACULAR HALOS

Table 1. Sphingomyelinase Activity (nmoles/mg protein/hour)

Normals Niemann-Pick (disease) Niemann-Pick (carrier) Paternal grandmother Maternal grandmother Father Paternal aunt Maternal uncle Mother Brother #1 Brother #2 Brother #3 Brother #4 Proposita

Pedigree Location Leukocytes

3.5 ± 1.1 0.18 ± 0.14 0.91 ± 0.35

0.8 1.5 0.4 1.0 2.4 1.1 1.0 1.0 0.5 1.2 0.0

histiocytes (Fig 6), and a Ziehl-Neelsen preparation demonstrated many foam cells (Fig 7). An assay for sphingomyelinase revealed a total absence of activity (Table 1), confirming the clinical di­agnosis of Niemann-Pick type B disease.2

Thirteen family members in four generations were subse­quently studied (Fig 8); only the proposita had macular halos. Nine of the 13 were shown to be carriers by sphingomyelinase assay. One individual (lIh) refused the assay, and the child (lV1),

not tested, can be assumed to be an obligate carrier. The ten carriers ranged in age from 6 months to 84 years, and were physically and neurologically normal. There was no family his­tory of blindness, neurologic disease, or infant death that might be associated with Niemann-Pick disease.

DISCUSSION

Cherry-red spots have classically been described in as­sociation with Tay-Sachs, Niemann-Pick, and other lipid storage diseases.3

,4 They are also seen in central retinal arterial occlusion. The cherry-red spot appearance is due to an opacity at the level of the nerve fiber layer. The opacity is an intracellular accumulation of the lipid ma­terial in the case oflipid storage diseases, and an abnormal swelling of the nerve fibers in the case of retinal arterial occlusion. Since no ganglion cells are present in the central fovea, this normal area stands out as unduly red in contrast to the surrounding affected retina. The size of the whitened area is determined by the density of the ganglion cells and the quantity of lipid material present.

The macular halo appears to be a forme fruste, or a mild expression, of the cherry-red spot. It has been de­scribed as "silver-grey rings with moderately sharp edges ... with a brown-reddish sunken center," "thin opaque ring around which punctate white deposits (lipids?) could be detected," "doughnut-shaped grey discoloration," "fine white stipples," and "granular or crystalloid opacities about the foveolas.,,1,5-9 Although these scattered reports were in the literature (Table 2), it was Cogan who clearly identified the lesion and made the association with Nie­mann-Pick type B disease. 1,9 The foveal lesion in our pa-

tient is similar in size and appearance to the fundus pho­tographs published by Cogan. On the basis of stereo biomicroscopy and contact lens examination, we locate the lesion in the most superficial (ganglion cell) layer of the retina. The masking effect that the lesion has on the perifoveal vasculature in the early fluorescein angiogram confirms that the accumulated material is in the ganglion cell layer (Fig 4). This is consistent with known histology specimens of cherry-red spots which place the abnormal accumulation in the nerve fibers and ganglion cell layers. Thus, we propose that the macular halo is the smallest or mildest form of a cherry-red spot.

These findings are in conflict with those of Cogan, who suggests that the accumulated material is an abnormal xanthophyll and locates the lesion in or beneath Henle's layer. 1 He further suggests that the opacity may even be located deep to the photoreceptors. As noted above, we locate the abnormal material in the ganglion cell layer. Since macular xanthophyll has its highest concentration in the fovea, we do not feel that an abnormality of xan­thophyll accounts for the lesion's appearance. lO Further­more, an accumulation of an abnormal material around or beneath the photoreceptors would most surely inter­fere with vision, and no such finding has been re­ported. 1,5-9.1 1,13

Niemann-Pick is a group of diseases (Fig 9) character­ized by a deficiency of the enzyme sphingomyelinase.4

This results in the abnormal accumulation of sphingo­myelin, a phospho-sphingolipid that is a normal com­ponent of all cell membranes. Sphingomyelin accumulates in all body tissues, but the amount is different in each tissue.3 The rate of accumulation and the amount to which the material interferes with normal body function deter­mine the clinical course of the disease.

Niemann-Pick disease is usually subdivided into four types. 3,4 Type A is the most severe and devastating. This acute neuronopathic form affects non-neurologic and neurologic function, and usually leads to death before the age of 4 years. Type A patients have the classic cherry­red spot and are sphinogomyelinase deficient. Type B, the mildest form, is chronic and progressive, usually with massive hepatosplenomegaly, bony changes, and diffuse infiltration of both lungs. Although there is no functional involvement of the central nervous system, the macular halo is present. Sphingomyelinase is usually greatly defi­cient in the leukocytes and, as with other forms of Nie­mann-Pick disease, there are foam cells in the bone mar­row. These patients are usually teenagers or adults when the disease is detected. Type C is a subacute form. After normal development for a year or more, affected children then undergo rapid involvement of their nervous system and die within a few years. Their eyes are reported to be normal. Type 0 is clinically identical to type C except that the patients are descendants of an Acadian couple born in Yarmouth, Nova Scotia, in the early 1600s.4 Al­though tissue storage of sphingomyelin occurs in types C and 0 , sphingomyelinase activity in these patients is normal.

Our patient has a chronic skin rash. Sebestyen and Galfi and Wewalka also reported skin findings in their pa-

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OPHTHALMOLOGY • JULY 1986 • VOLUME 93 • NUMBER 7

t t

II

III

IV

00 60 00 ()[)

••

Not examined

Normal eye exam

Sphingomyelinase normal

Carrier

Homozygous

Fig 8. Pedigree. Note arrow indicating proposita. X in­dicates other family members examined and having normal ophthalmologic findings. Of pedigree members examined, only II5 was not a carrier. III7 refused testing. IV 1 cross­hatching indicates that the child was not studied enzy­mati cally, but is at least an obligate carrier.

Table 2. Reported Macular Halo Cases

Author Date Eye Findings Tissue Findings

Wewalka8 1950 Fine white Bone marrow, stipples Gaucher cells,

Cogan & 1964 Halos (photo) Spleen with Federman9 sphingomyelin

Sebestyn & 1969 Silver-grey Foam cells in Galfi5 rings, spleen

brown-red center (photo)

Saidi et all 1970 Doughnut- Foam cells in shaped liver and bone grey marrow opacities (photo)

Harzer et al 6 1978 Thin, opaque Foam cells in ring (photo) bone marrow

Hammersen 1979 Grey-yellow Foam cells in et al 13 ring, bone marrow

Punctate deposits (photo)

Cogan et all 1983 Granular Foam cells in opacities spleen/liver above fovea (photo)

Matthews et al 1985 White ring Foam cells and (this paper) (photo) sea-blue

histiocytes in bone marrow

tients.5,8 Type B patients are not known to have significant

functional impairment. When Cogan's patient was reex­amined 20 years later, after having four children, no change was found. 1 Since reproduction is such a complex endocrine function, the ability to bear children is a relative measure of normal body function. One of us (EHK) has

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Family Members Sphingomyelinase Affected Comment

Not done No POW malaria, TB malnutrition,

Skin fibroblasts 3% 2 children, not Assay done 20 yr of normal seen after diagnosis

Not done None seen Mental retardation, Skin rash

Not done Parents, 2 sisters, Patchy pig men-not seen tat ion on face

Leukocytes 10% of No mention Mental retardation normal

Leukocytes 1 % of No mention normal, Skin fibroblasts 1-3% of normal

Skin fibroblasts 50- 4 siblings, 3 half-60% of normal siblings, no

exam

Lymphocytes & 2 grandmothers, 2 Skin rash 10 WBC 0% of parents, 4 carriers normal siblings, 1

aunt, 1 uncle, 1 cousin, all examined and assayed. 1 sibling, 1 child, no assay

studied post-mortem tissues from two patients with type B disease who died of causes unrelated to Niemann-Pick at ages 55 and 29 years. (Unfortunately, histopathologic study of the eyes was not allowed.) In some patients, how­ever, the pulmonary changes shorten life.

Patients with Niemann-Pick disease can be subdivided

MATTHEWS. et al • MACULAR HALOS

Oi ......

GM, GANGLIOSIDOSIS

TAY-SACHS

FABRY'S

KRABBE'S

METACHROMATIC

LEUKOPYS1ROPHY

NIEMANN-PICK

GAUCHER 'S

FARBER 'S

SPHINGOLIPIDOSES

Major Sphingolipid Accumulated

'~" -=----.1--< ooc G.I ; o. ...... c

.~

~CM2

'v::::\ ----'-"'-_-_-_--"I....;\:';

'M ~==rl~

, 0.0,

c... ..... pCac'_ -J ..... , ... u

Enzyme Defect

B-Galactosidas.

Heltolaminidaee A

A -Galactosidase

B -Galactosidas.

Arylsulfatase A

Sphingomyelinase

Glucocerebrosidase

Ceramidase

car = ce<amide Gic = glucose Gal = galactose GaiNAc = N-Acetytgalactosamine NANA = N-Acetytneuraminic Acid PChoI = Phosphorytcholine

Fig 9. Outline of biochemical defect in 5phingolipidoses.

into two groups according to the presence or absence of the macular halo. Curiously, in the few cases where it has beep observed, there have been no other signs of central nervous system dysfunction. The sphingomyelinase de­ficiency characteristic of this disease is also present in the brain, yet there is no measurable accumulation of sphin­gomyelin in the brain tissue. 12 In an autopsy study of a 29-year-old patient with Niemann-Pick type B disease, one of us (EHK) found a 33-fold increase in liver sphin­gomyelin, whereas the lipid content in brain gray and white matter was similar to the normal control (unpub­lished observation). Whatever mechanism for sphingo­myelin clearance persists, sparing the brain in Niemann­Pick type B disease, may be absent from the retinal gan-

glion cells of these patients. Yet preservation of their central vision indicates that the macular change, which may be present even in early childhood, is not functionally significant. 13

Macular halos are a pathognomonic ocular finding of Niemann-Pick type B disease. The disease is compatible with normal vision and subtle physical findings, which are consistent with otherwise normal adulthood. Once the diagnosis is suspected, it can be confirmed by a sphin~ gomyelinase assay. This assay is the only method of de­tecting carriers of this autosomal recessive condition.

REFERENCES

1. Cogan DG, Chu FC, Barranger JA, Gregg RE. Macular halo syndrom~; variant of Niemann·Pick disease. Arch Ophthalmol 198~; 101: 1698-700.

2. Glew RH, Peters SP, eds. Practical Enzymology of the Sphingolipi· doses. New York: Alan R. Liss, 1977; 39-70.

3. Beeson PB, McDermott W, Wyngaarden JB, eds. Cecil Textbook of Medicine, 15th ed. Philadelphia: WB Saunders, 1979; 2014-5.

4. Fredrickson OS, Sloan HR: Sphingomyelin lipidoses: Niemann-Pick disease. In: Stanbury JB, Wyngaarden JB, Fredrickson OS, eds. Met· abolic Basis of Inherited Disease, 3d ed. New York: McGraw-Hili, 1972; 783-807.

5. Sebestyen J, Galli I. Retinal functions in Niemann-Pick lipidosis; ophthalmological aspects of the chronic form of sphyngomyelin lipi­dosis. Ophthalmologica 1969; 157:349.,.56.

6. Harzer K, Ruprecht KW, Seuffer-Schulze D, Jans U. Morbus Niemann­Pick Typ B-enzymatisch gesichert-mit unerwarteter retinaler Be­teiligung. Albrecht von Graefes Arch Klin Exp Ophthalmol 1978; 206: 79-88.

7. Saidi P, Azizi SP, Sar1ati R, Sayar N. Rare variant lipid storage disorders. Blood 1970; 35:533-8.

8. Wewalka F. Zur Frage der "blauen Pigmentmakrophagen" im Ster­nalpunktat. Wi en Klin Wochenschr 1950; 62:788-91.

9. Cogan DG, Federman DO. Retinal involvement with reticuloendothe­liosis of unclassified type. Arch Ophthalmol 1964; 71 :489-91.

10. Snodderly OM, Brown PK, Delori FC, Auran JD. The macular pigment. I. Absorbance spectra, localization, and discrimination from other yel­low pigments in primate retinas. Invest Ophthalmol Vis Sci 1984; 25: 660-73.

11 . Hartwig H, Kolling G, Best W. Kirschroter Fleck im Makulabereich ohne sicheren Hinweis auf Sphingolipidose. Klin Monatsbl Augenheilkd 1978; 173:716-9.

12. Wenger DA. Kudoh T, Sattler M, et al. Niemann-Pick disease type B: prenatal diagnosis and enzymatic and chemical studies on fetal brain and liver. Am J Hum Genet 1981; 33:337-44.

13. Hammersen G, Oppermann HC, Harms E. et al. Oculo-ne\.lral involve­ment in an enzymatically proven case of Niemann-Pick disease type B. Eur J Pediatr 1979; 132:77-84.

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