The Pathogenesis of Optic Nerve Drusen A

Hypothesis

Joel G. Sacks, MD; Richard B. O'Grady, MD; Earl Choromokos; Jan Leestma, MD

\s=b\Myriads of tiny perivascular drusen were found at histologic examination of the eyes of a 19-year-old patient who had pseudopapilledema and who died of a ruptured intracranial aneurysm. The possibility that they arose from constituents leaking from abnormal blood vessels prompted a review of 53 fluorescein retinal angiograms of patients with optic nerve drusen. As compared to a control group, many of these angiograms revealed the following abnormalities: (1) an abnormal branching pattern on the disc; (2) the presence of relatively large blood vessels connecting the superficial and deep disc circulations; and (3) Increased disc capillarity. We believe that the to develop optic nerve drusen results, at least in part, from a congenitally abnormal disc vasculature that allows transudation of plasma proteins that In turn serve as a nidus for the deposition of extracellular materials.

tendency

(Arch Ophthalmol 95:425-428, 1977)

optic Although line bodies) -

°phthalmologists,

drusen (hyawell known to little is known

nerve are

about their pathogenesis.

°f

We histologically examined the eyes

patient with optic

nerve drusen. the patient was young, we *ere afforded an unusual opportunity t° study the early formation of the abnormal material that led us to conclude that drusen are not static in s,ze, but rather appear to grow from m¡croscopic, subclinical particles. a

Because

Accepted for publication Sept 13,

1976.

From the Departments of Ophthalmology (Drs

Sacks and O'Grady and Mr Choromokos), Neurology (Drs Sacks and Leestma), and Pathology (Dr

Leestma), School,

Northwestern

Chicago.

Reprint

requests

to

University Medical

Department

of

Ophthal-

University Medical mology,303 Northwestern School, E Chicago Ave, Chicago, IL 60611 (Dr

Sacks).

Since our findings suggested that drusen are of vascular origin, we studied the fluorescein retinal angiograms of 53 eyes with optic nerve drusen. Therein we found certain other abnormalities of the disc vasculature that may be either secondary to the drusen or that may antecede them. REPORT OF A CASE A 19-year-old man came for neurological evaluation on March 22, 1971. In August 1970 he had had the sudden onset of vertigo, inability to walk, and impaired speech. These symptoms disappeared within two weeks. At the time of admission, the relevant physical findings were flattening of the right nasolabial fold and hypesthesia with minimal weakness in the right upper extremity. The optic discs were elevated and had blurred margins, but no hemorrhages were present (Fig 1 and 2). A fluorescein retinal angiogram showed no late stain; it was our impression that this was pseudopapilledema due to buried drusen. The CSF pressure was 290 mm HsO, and a left internal carotid angiogram showed no abnormalities. No diagnosis was made. In early April 1971 he returned, having had a sudden, marked exacerbation of the same symptoms that he had had approximately eight months earlier; he recovered within one day. The optic discs were unchanged and a repeat fluorescein retinal angiogram showed no papilledema although the CSF pressure continued to be elevated at 270 mm Uft. Another left internal carotid angiogram showed vascular changes in the left opercular area suggestive of a cerebral vascular accident. On Aug 3,1971, the patient developed an excruciating headache and was again hospitalized. Although the CSF pressure was 310 mm H20, the optic discs were unchanged. Vertebral angiography showed

Downloaded From: http://archopht.jamanetwork.com/ by a University of Michigan User on 05/19/2015

two previously undetected aneurysms. The first measured 20 x 15 x 10 mm and arose

from the proximal portion of the basilar artery; the second was 30 mm in diameter and was attached to the midportion of the basilar artery. The patient's condition rapidly deteriorated due to aneurysmal rupture and he died April 9,1971. Because he was an organ donor, respiration was mechanically maintained until his kidneys could be removed. At autopsy the brain was found to be edematous, diffusely discolored, and soft. There was a massive subarachnoid hemorrhage with a hematoma about the base of the brain and brain stem. The larger basilar artery aneurysm had become largely thrombosed but had ruptured laterally and dissected into the pons. Histologically there were autolytic changes which when coupled with the gross findings typified the "respirator brain." There were no abnormal microvessels in the brain and no mineralization of the basal ganglia, temporal lobo, or dentate nuclei of the cerebellum. The eyes were enucleated several hours after death.

OCULAR HISTOLOGIC FINDINGS Gross and microscopic examination of both eyes revealed no abnormalities other than changes in the optic nerve heads. While a few superficial disc vessels appeared dilated and mild hydropic degeneration of the prelaminar portion of the nerve head and peripapillary retina had occurred, the usual histologie features of papilledema (hemorrhage, exúdate, vascular congestion, obliteration of the cup, and peripapillary retinal displace-

ment)

were

lacking.

In the right eye particularly, several deeply basophilic, accllular, laminated bodies of varying size distorted the optic nerve anterior to the lamina cribrosa without extending to the disc

(Fig 3). Few were intact, however, having been either fractured surface

by

the microtome knife

or

washed

during laboratory processing. Adjacent to, and sometimes blending with, the large laminated bodies were numerous small basophilic granules that, for the most part, were grouped about dilated vascular channels (Fig 4). While generally uniform in shape, away

their size varied from small bodies to

larger and larger structures, some of which appeared laminated, similar to fully developed drusen. In one particularly fortuitous section, a ever

blood vessel

appeared outlined by perivascular granules (Fig 5); that this structure is indeed

a vascular channel confirmed by the presence of intraluminal erythrocytes in an adja-

was

a normal control series we used the number of fluorescein retinal angiograms of young adults who were recently discovered to be diabetic, but who had no substantial diabetic rctinopathy.

For

same

cent section.

RESULTS

MATERIAL AND METHODS The fluorescein retinal angiograms of all eyes diagnosed as having optic disc drusen within the files of the Retina Laboratory of the Department of Ophthalmology at Northwestern University Medical School reviewed. There were 53 such eyes within our collection.

were

Fig 1—Fundus of right eye showing blurred disc other signs of papilledema are present.

margins. No

Fig 3.—Large, fractured, partially dissolved drusen distort prelam¡nar optic nerve, while superficial nerve fibers are. undergoing hydropic degeneration (hematoxylin-eosin, original magnification x4).

reviewing the fluorescein retinal angiograms, we discovered three distinctly unusual findings in the paIn

tients who had drusen of the optic disc. The first of these was an unusual pattern of branching of the vessels on the optic nerve head. In particular, the

Fig 2.—Fundus of left eye, similar to right. Fig 4.—Several confluent, laminated, acellular drusen are present to the right (arrow), while nearby blood vessels are surrounded by small and large basophilic granules. Largest of these have begun to take on a laminated pattern (hematoxylin-eosin, original magnification x400).

Downloaded From: http://archopht.jamanetwork.com/ by a University of Michigan User on 05/19/2015

branchings appeared

much "earlier" one would expect (Fig 6). In order to evaluate this more accurately, we counted the number of vessels crossing the disc border that were obviously branches of the central retinal artery or tributaries of the «entrai retinal vein. We found the average number to be 30 in the drusen

than

series while it was only 23 in the controls. This was significant beyond the 0.01 level of confidence. The second abnormality that we observed was the presence of large vessels, filling early in the course of angiography, and which seemingly interconnected the superficial disc circulation with that of the deeper

F¡g 5.-Numerous small perivascular drusen granules surround a longitudinally sectioned vessel. Large space represents a site formerly occupied by fully developed drusen (wedge) (hematoxylin-eosln, original magnification

x

200).

early branching pattern of retinal vessels. Capil^ilaries g 6.—Typical unusually promitemporal side of this right disc nent.

on

are

of the optic nerve (Fig 7). Because these vessels seem to curve backward, we call them "circumflex." These abnormal vessels were visible in 62% of the experimental group and in none of the controls. The third abnormality that we found, and which is admittedly far more difficult to quantitate, is an increased "capillarity" of the optic disc. In such cases, the capillaries were far more prominent and seemingly increased in number, but did not leak such as one would expect with papilledema and were unassociated with any hemorrhages (Fig 6 and 7). We judged this to be present in 89% of the eyes with drusen and in none of the controls.

portions

COMMENT We do not believe that the histologie appearance of the optic discs of ouipatient can be reasonably attributed to chronic disc swelling due to elevated intracranial pressure. The repeatedly normal fluorescein retinal angiograms, the absence of change in the discs' appearance over months, and the lack of hemorrhages or exudates all point away from this explanation. It has long been known that papilledema is not present in all

Fig 7.-Circumflex vessel (arrow) in early venous phase of fluorescein retinal angiogram. Both number and size of disc capillaries are increased.

Downloaded From: http://archopht.jamanetwork.com/ by a University of Michigan User on 05/19/2015

patients with

increased intracranial

pressure.1

The modest degree of disc swelling that was observed histologically can be explained by the fact that the patient had been maintained on a respirator.- The brain showed profound edema, autolytic changes, and numerous hypoxic neurons in all portions examined. These and other changes observed are commonly noted in the so-called respirator brain. The changes appear to result from impaired perfusion or total circulatory block and represent autolysis of the brain even though the patient may still possess heart action. Having the opportunity to examine the eyes of a young patient with optic nerve drusen, both clinically and histopathologically, allowed us to observe what we believe to be an unusually early stage in the development of hyaline bodies. Cibis' was the first to report the perivascular distribution of drusen; his patient was 38 years old. All or most other eyes with drusen have come from older patients: they show fully developed drusen, but no longer give a clue as to the pathogenesis of the hyaline material. Because of the presence of drusenlike material within the perivascular space of the optic discs of our patient, we propose that the drusen originate from the leakage of nonformed elements from the blood, such as plasma proteins, and that these elements in

serve as the nidus for the deposition of other materials within the perivascular space, thus producing the very fine drusen that we observed in the histopathologic examination of our patient. These granules continue to increase in size, either by progressive lamination or coalescence, until such time as they become visible

turn

ophthalmoscopically. The pathogenesis that we propose is not novel. Most neuropathologists accept the concept of plasma bleeding, also known as a dysoria or transudative vasculopathy. The term dysoria was first coined by Schürmann and McMahon' and indicates a prolonged impairment of the blood-tissue barrier. The concept has been primarily discussed in the non-English language neuropathology literature, and is thus generally not well known to Englishspeaking ophthalmologists. An excellent, readily available review of the topic has been written by Pent-

schew.'' The accumulation of perivascular acellular material resulting from a dysoria occurs in a variety of cerebral disorders. Among these are dysoric angiopathy," Fahr's disease (nonarteriosclerotic cerebral calcification),7 and the Sturge-Weber syndrome; in the latter two entities the material is laminated in a manner similar to drusen. The dysoria hypothesis could also explain the formation of drusen-like

bodies in chronic papilledema such as has been described by Okun." Why should the disc vessels permit plasma bleeding? While little is known about the biochemical or ultrastructural defects underlying any of the generally accepted transudative vasculopathies, it is possible that the abnormal vascular patterns noted on fluorescein retinal angiography may be at least contributory. The unusual pattern of ramification of the blood vessels on the disc, which was first described by Erkkilä," may be a gross sign that reflects other, subtler abnormalities of the arterial and venous trees.

Karel and co-workers'" described the circumflex vessels, as well as the

prominence of retinal capillaries. They suggested that these two findings were secondary to patchy ischemia of the optic nerve produced by the

drusen. Instead of these abnormal vascular appearances being secondary, we submit the hypothesis that they are primary, and that the formation of the drusen results from an inherited, abnormal disc vascular pattern. Because of this unusual vascular pattern, we propose that there may be abnormal pressure relationships within the microvasculature of the optic nerve head. These unusual pressures contribute to the dysoria. Sandra Olson, MD, allowed the study of her patient.

References 1. Ayer JB: Cerebrospinal fluid (lumbar) in brain tumor: Analysis of 67 cases of tumors and cysts of the brain. JAMA 90:1521-1524, 1928. 2. Lindenberg R, Walsh FB, Sacks JG: Neuropathology of Vision: An Atlas. Philadelphia, Lea & Febiger, 1973, p 8. 3. Cibis P: Zur Klinik und Anatomie der Drusenbildung in der Papille und \l=u"\berder Kombination derselben mit einem Melanosarkom der Aderhaut, Klin Monatsbl Augenheilkd 105:78-88, 1940. 4. Sch\l=u"\rmannP, McMahon ME: Die maligne Nephrosklerose, zugleich ein Beitrag zur Frage

der Bedeutung der Blutgewebeschranke. Virchows Arch (Pathol Anal) 291:47-218, 1933. 5. Pentschew A: Multidimensional neuropathology, in Walsh FB, Hoyt WF: Clinical Neuroed 3. Baltimore, Williams & Wilkins Co, 1969, pp 2732-2733. 6. Surbek B: L'angiopathie dyshorique (Morel) de l'\l=e'\corcec\l=e'\r\l=e'\brale:Etude anatamo-clinique et statistique, aspect g\l=e'\n\l=e'\tique.Ada Neuropathol 1:168-197, 1961. 7. Mouren P, Berard-Badier Mme, Giudicelli S, et al: La maladie de Fahr. Sem Hop Paris 47:1758\x=req-\ 1768, 1971.

Ophthalmology,

Downloaded From: http://archopht.jamanetwork.com/ by a University of Michigan User on 05/19/2015

8. Okun E: Chronic papilledema simulating hyaline bodies of the optic disc. Am Ophthalmol J

53:922-927, 1962.

9. Erkkil\l=a"\H: The central vascular pattern of eyeground in children with drusen of the

the

optic disc. Albrecht von Graefes Arch Klin Ophthalmol 199:1-10, 1976. 10. Karel

I, Otradovec J, Pele\l=s%v\kaM: Fluores-

angiography in circulatory disturbances in drusen of the optic disc. Ophthalmologica 164:449\x=req-\

cence

462, 1972.

The pathogenesis of optic nerve drusen. A hypothesis.

The Pathogenesis of Optic Nerve Drusen A Hypothesis Joel G. Sacks, MD; Richard B. O'Grady, MD; Earl Choromokos; Jan Leestma, MD \s=b\Myriads of tin...
6MB Sizes 0 Downloads 0 Views