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Pathogenesis of hypertensive retinopathy: a review'

Professor A Garner MD MRCPath
Professor N Ashton CBE FRS DSC
Department of Pathology, Institute of Ophthalmology
Judd Street, London WCIH 9QS

Although retinal vascular changes occur in benign hypertension, the term hypertensive
retinopathy usually refers to the more florid retinal changes found in the malignant or
accelerated phase. Indeed, examination of the fundus is a useful way of detecting at a very early
stage the potentially disastrous transition of benign hypertension to a malignant phase.
Clinical picture
The earliest clinical features of accelerated hypertension are small linear haemorrhages
accompanied by cotton-wool spots close to the optic disc and posterior pole. Exudates are
inconspicuous at first but common a few weeks later: they are often found in the macular
region where they tend to be arranged in a star-figure but may also occur in other parts of the
posterior retina.
Increasing haziness of the posterior retina commonly presages oedema of the disc, which
becomes congested and swollen.
Direct changes in the retinal vessels include diffuse arteriolar narrowing, widened and
enhanced light reflexes due to increased thickness of the vessel wall, and arteriovenous crossing
changes. Nipping of the veins is commonly an illusion related to the effect of arteriolar mural
sclerosis in concealing blood flow through the vein as it passes behind the arteriole. However,
none of these vascular changes is peculiar to malignant hypertension, identical appearances
developing in the benign phase and in a proportion of ageing normotensive people.
Conversely, some hypertensive individuals may have insignificant arteriolar changes as gauged
by ophthalmoscopy.
Pathogenesis of the vascular disorder
While systemic arteries respond to increases in blood pressure by hypertrophy and even
hyperplasia of their smooth muscle coat, the smaller arterioles are liable to develop destructive
as well as adaptive changes, since it is here that the main step down from arterial to capillary
pressure takes place.
Arteriolar smooth. muscle responds to increases in intraluminal tension by contracting and
consequently, although such vasoconstriction tends to be more pronounced in the malignant
phase where pressures are higher, it is not peculiar to malignant hypertension. The distinctive
manifestation of the malignant phase occurs when the constricted vessel succumbs to
disruptive forces. The resultant necrosis is usually focal and, in the retina, occurs principally
within the terminal precapillary arterioles. Experimental studies using cynomolgus monkeys
with blood pressure increase secondary to induced renal ischaemia have shown that the
essential feature of these arterioles in hypertensive retinopathy is leakage of plasma into the
vessel wall, the leakage being related to breaks or holes in the endothelial lining (Ashton 1972,
Garner et al. 1975). This accumulation of plasma in the vessel wall has been termed an insudate
and is the basis of fibrinoid necrosis, long recognized in histological sections as the hallmark of
the malignant phase. Incidentally, since the material includes fibrinogen polymerized to form
banded fibrin it is probably more appropriate to speak of fibrinous necrosis.
1 Paper read to Section of Ophthalmology, 13 October 1977. Accepted 11 November 1977
0 1 41-0768/79/050362-04/$O 1.00/0

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1979 The Royal Society of Medicine

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The initial break in the endothelial lining of the vessel appears to be caused by stretching and
attenuation related in turn to degeneration of the surrounding smooth muscle coat (Figure 1).
Loss of support from the muscle coat allows focal rupture of the lining endothelium. In studies
of tissues other than those of the eye separation of the junctions linking individual endothelial
cells has been described (Ooneda et al. 1965, Giacomelli et al. 1970), but we saw no evidence of
this in our studies of the retinal vasculature: nor did we see any convincing sign of increased
pinocytotic transport of plasma across intact endothelium. Although it is conceivable that
transient separation of the intercellular junctions occurred, we were not surprised that
permanent separation was not found since, in contrast to vessels outside the central nervous
system, the endothelial cells of the retinal vessels are joined by tight encircling junctions which
are unusually resistant to disruption.
Once gaps within the cytoplasm of attenuated endothelial cells have been created plasma
seeps into the wall, displacing the degenerate muscle cells as it does so, and the mural
thickening which results narrows the lumen and further impedes blood flow.
The steps we have outlined are essentially beyond dispute. The only matter for debate is the
cause of the muscle degeneration preceding and disposing to the endothelial damage. On the
basis that the arteriolar constriction is an adaptive response to the rising blood pressure, it is
conceivable that beyond a certain level the capacity to adapt will be exceeded and that the
muscle coat will yield to further stress. This concept is supported by some clinical studies on the
cerebral circulation (Lassen & Agnoli 1972, Strandgaard et al. 1973) and has been referred to
as 'breakthrough of autoregulation'. Alternatively, one explanation of this failure might be
that the muscle degenerates as a result of ischaemic damage from prolonged and excessive focal
vasoconstriction with its attendant metabolic aberrations. Support for this second possibility

Figure 1. Electron micrograph showing smooth muscle

(SM) degeneration in the wall of a retinal arteriole which is
associated with attenuation and focal necrosis of the lining
endothelium (arrow). x 7500

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comes from our own electron microscopical studies, in which we observed pronounced
arteriolar constriction with incipient degenerative changes in the cytoplasm of some individual
muscle cells (Garner & Ashton 1970, Garner et al. 1975).
To summarize (Figure 2), we consider that the sequence of events in the production of
fibrinous necrosis in retinal arterioles is: (1) A phase of intense vasoconstriction affecting
chiefly the precapillary arterioles. (2) Smooth muscle degeneration leading to a loss of support
for the endothelium. (3) Focal breaks in the endothelium allowing plasma to seep into the
vessel wall. (4) Mural necrosis and plasmatic insudation leading to obliteration of the lumen.

Figure 2. Possible sequence in the pathogenesis of hypertensive fibrinous necrosis. After an initial phase of extreme
vasoconstriction smooth muscle necrosis supervenes in the
face of continued rise in blood pressure. This leads to
dilatation and leakage of plasma into the necrotic wall
through focal breaks in the unsupported endothelial lining

Pathogenesis of the extravascular changes

Haemorrhages
Bleeding occurs through the walls of necrotic arterioles and, since vessels of this type are
located within the nerve-fibre layer, the haemorrhages assume a linear or flame-shaped
distribution.
Cotton-wool spots
Occlusion of precapillary arterioles as a result of fibrinous necrosis gives rise to focal ischaemia
in the dependent capillary bed. Increasing metabolic embarrassment occurs over the next few
hours within the inner layers of the retina, culminating in a zone of nerve fibre swelling.
Eventually many swollen axons disrupt because of ischaemic necrosis, and the residual stumps
undergo further swelling and form bulbous structures recognized in histological sections as
cytoid bodies (Ashton & Harry 1963). The swelling, which in part is likely to be due directly to
anoxia and intracellular oedema, is compounded by interference with axoplasmic transport
(McLeod 1976). Tracer studies indicate that there is interruption of flow in both orthograde
and retrograde directions, axoplasm entering the disrupted regions and accumulating because
the local source of energy required to propel fluid away is lacking. The swollen region
eventually undergoes extensive necrosis, with the lipoprotein membranes of degenerate
organelles congregating in the centre of the terminal bulb to constitute the pseudonucleus of
the cytoid body. Subsequently the necrotic axons are removed by retinal macrophages and
replaced by glial tissue.

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Exudates

Although exudates almost certainly originate along with the haemorrhages they tend to
present somewhat later in the course of the retinopathy. This is because initially their
consistency is little different from that of transudative oedema and only later, as they pool in
the outer plexiform layer or in Henle's layer at the macula, do they become progressively
inspissated and recognizable as hard creamy-yellow exudates.
Papilloedema
Swelling of the optic nerve head is associated with plasma leakage, as fluorescein studies
confirm, but the major factor appears to be swelling of the nerve fibres as they pass through the
disc region. Like the cotton-wool spot, this represents ischaemic swelling and consequent
interference with axoplasmic flow in the nerve head. Both the exudation and the ischaemia are
related to fibrinous necrosis of the smaller arterioles supplying the optic disc, although other
factors, such as impeded venous outflow, complicate the pathogenetic mechanism of the
papilloedema.
References
Ashton N (1972) Transactions of the American Academy of Ophthalmology and Otolaryngology 76, 17-40
Ashton N & Harry J (1963) Transactions of the Ophthalmological Societies of the United Kingdom 83, 91
Garner A & Ashton N (1970) XXI Concilium Ophthalmologicum, Mexico, Excerpta Medica, Amsterdam; pp 583-600
Garner A, Ashton N, Tripathi R, Kohner E M, Bulpitt C J & Dollery C T (1975) British Journal of Ophthalmology 59,
3-44
Giacomelli F, Wiener J & Spiro D (1970) American Journal of Pathology 59, 133-159
Lassen N A & Agnoli A (1972) Scandinavian Journal of Clinical and Laboratory Investigation 30, 113-116
McLeod D (I1976) Transactions of the Ophthalmological Societies of the United Kingdom 96, 313-316
Ooneda G, Ooyama Y, Matsuyama K, Takatama M, Yoshida Y, Sekiguchi M and Arai I (1965) Angiology 16, 8-17
Strandgaard S, Olesen J, Skinhoj E & Lassen N A (1973) British Medical Journal i, 507-510