Diabetic papillopathy

INTRODUCTION — Diabetic papillopathy (DP) is a term that is used to characterize a finding of unilateral or bilateral optic disc edema with variable visual loss seen in patients with diabetes. It can occur in patients with type 1 diabetes mellitus (DM) and type 2 DM irrespective of metabolic control or severity of diabetic retinopathy.

Specific criteria for the diagnosis of DP and a clear differentiation of this entity from nonarteritic anterior ischemic optic neuropathy (NAION) have not been established [1]. While DP has a generally favorable prognosis and does not usually require treatment, it must be distinguished from the more dangerous causes of optic disc swelling such as papilledema, other infectious and inflammatory causes causing bilateral disc swelling, and those causing increased intracranial pressure.

This topic discusses DP. NAION and other conditions causing optic disc swelling are discussed separately. (See "Nonarteritic anterior ischemic optic neuropathy: Epidemiology, pathogenesis, and etiologies" and "Nonarteritic anterior ischemic optic neuropathy: Clinical features and diagnosis" and "Nonarteritic anterior ischemic optic neuropathy: Prognosis and treatment" and "Overview and differential diagnosis of papilledema".)

EPIDEMIOLOGY — The estimated incidence of DP has been reported to be 0.5 percent [2] to 3 percent [3].

Initially described in younger patients with type 1 diabetes [4-8], subsequent publications have reported that DP also occurs in older individuals (up to 79 years old) with type 2 diabetes [9-11].

PATHOPHYSIOLOGY — The pathogenesis of DP is uncertain. A diabetic microangiopathy has been proposed as an etiology, but no pathologic studies of DP have been reported to confirm or refute this theory. There is no clear association between DP and the state of metabolic control of the diabetes or with the stage of diabetic retinopathy [6,10]. Most reported cases of DP occur in patients with long-standing diabetes, but duration of diabetes is not proven to be a risk factor for DP [5,6,8,10].

Most authors believe that DP represents a mild form of nonarteritic anterior ischemic optic neuropathy (NAION) with reversible ischemia of the prelaminar and inner surface layer of the optic nerve head [7,12]. The following observations support this theory:

●Diabetes is a risk factor for NAION as well as DP. (See "Nonarteritic anterior ischemic optic neuropathy: Epidemiology, pathogenesis, and etiologies".)

●The small optic cup or crowded optic nerve head (the so-called "disc-at-risk") is frequently seen in the fellow eye in both DP and NAION [9,11,13-15].

●Patients may develop both DP and NAION [11,14,16]. Patients with NAION may demonstrate asymptomatic disc edema in the fellow eye either at presentation or in follow-up [16]. In one series, 43 percent of patients with DP had a history of NAION in the other eye [14].

●Some patients with DP develop irreversible visual loss and optic disc pallor similar to NAION [7]. Approximately 30 percent develop NAION in the same or fellow eye in follow-up [14,17].

One author described an entity of so-called incipient NAION (ie, disc edema without significant visual loss) in 54 patients who were seen in follow-up after a previous episode of NAION in the other eye or for unrelated conditions (eg, diabetic retinopathy) [16]. In this series, 63 percent of patients had diabetes mellitus and therefore met the usual clinical definition of DP. Perhaps somewhat atypical was that only 11 percent of these patients had bilateral disease. A high proportion of these patients, 45 percent, went on to develop NAION in that eye [16].

Arguments that support a pathogenesis for DP distinct from that of NAION include the observation that disc edema persists longer in DP than in NAION. While disc edema usually resolves by 2 to 3 months in NAION, a duration of 10 months or more is not unusual in DP. DP is also more frequently bilateral at presentation than NAION, and is more often described in younger age groups [12,18] (see 'Epidemiology' above and 'Clinical features' below). Despite these qualitative differences, there is substantial overlap in the clinical features of DP and NAION [12].

One author proposes that diabetes influences the course of NAION in a manner that explains the apparent clinical differences between NAION and DP. In their experience, patients with NAION and diabetes had several clinical and demographic features that were distinct from patients with NAION without diabetes, including a longer duration of optic disc edema and a better visual outcome [1]. However, it can be argued that this case series used a more inclusive definition of NAION that included patients whom others might have labeled as DP and not NAION, making their argument somewhat circular.

Some hypothesize that the pathogenesis of DP may be similar to the phenomena of early worsening of diabetic retinopathy sometimes observed after improvement in metabolic control. In a study of 2066 patients with type 1 diabetes followed for a mean of 4.85 years (10,020 patient-years), bilateral DP developed in five patients [19]. During the year preceding this incident, all five patients had experienced a decrease in glycosylated hemoglobin A_1c at a maximum rate of -2.5 percentage points per quarter year, which was significantly different from the changes observed in the remainder of the study population. Photographs recorded before the onset of bilateral DP showed that all five patients had small cup-to-disc diameter ratios in both eyes. Limitations of the study are its retrospective design and the low frequency of events. Other case reports describe the occurrence of DP after starting or intensifying insulin treatment [15,20,21]. The proposed mechanism was hypothesized to be cellular stress as a result of a rapid change in metabolic and glycemic balance.

An alternative, but speculative, theory proposes that DP is a distinct form of diabetic microangiopathy that primarily affects capillary integrity [11].

CLINICAL FEATURES

Visual complaints — Patients with DP typically present with nonspecific visual complaints such as mild blurring or distortion of vision [8]. Alternatively, DP may be an incidental (asymptomatic) finding on routine ophthalmologic examination [10,14].

Visual acuity is often normal or only mildly abnormal. When abnormal, acuity deficits are usually explained by comorbid pathology including diabetic retinopathy and/or macular edema [11,14]. Associated macular edema is usually related to diabetic retinopathy. Visual fields may be normal or demonstrate a slightly enlarged blind spot; other visual field deficits usually reflect comorbid pathology rather than DP [10].

Funduscopic examination — Funduscopic examination demonstrates optic disc swelling, often with hyperemia and a striking dilation of the inner optic disc vasculature (picture 1) [7-10]. The surface telangiectasia may be so prominent in some patients that it can be mistaken for neovascularization of the optic disc. However, the vessels on the optic disc are radially distributed in DP as opposed to the random branching pattern of neovascularization [22]. Another distinctive feature is that the abnormal-appearing vessels are limited to the disc surface and do not protrude into the vitreous cavity.

The optic disc edema may be unilateral or bilateral; when bilateral, the involvement may be simultaneous or sequential. Bilateral optic disc features are described in 11 to 60 percent of patients [6,10,14-16].

Macular edema is a frequent comorbid finding, occurring in 70 to 100 percent of patients [9,23,24]. The etiology of macular edema may be related to breakdown of the blood-retinal barrier and leakage from retinal capillaries. Serous macular detachment has also been described as a result of capillary leakage from the swollen optic nerve head in the absence of retinal capillary leakage [25].

Other manifestations of diabetic retinopathy, usually of the nonproliferative type, are seen in the affected or unaffected eye in 35 to 90 percent of patients [10]. Examination of the fellow eye usually reveals a small optic disc cup [9,11]. (See "Diabetic retinopathy: Classification and clinical features".)

Optic disc abnormalities resolve spontaneously after a mean of four to eight months [9,10]. The optic disc then appears normal, only rarely demonstrating mild optic neuropathy [6,7].

Fluorescein angiography — Fluorescein angiography usually demonstrates optic disc staining [14,24]. The dye leakage into the disc substance and peripapillary retina seen in DP contrasts with leakage into the anterior vitreous that occurs from optic disc neovascularization found in patients with proliferative diabetic retinopathy. Fluorescein angiography also more clearly demonstrates the radial pattern of dilated vessels typical of DP and helps distinguish it from neovascularization [22]. Capillary nonperfusion is variably seen [9,10]. A less common finding in DP is a delay in filling that is similar to that seen in nonarteritic anterior ischemic optic neuropathy (NAION) [22].

Optical coherence tomography — Optical coherence tomography (OCT) images the retina and optic nerve. In patients with DP, OCT demonstrates similar changes in the retinal nerve fiber layer and the macular ganglion cell layer that are observed in NAION [26].

Swept-source OCT angiography (SS-OCTA) provides an image of the vasculature. In one patient with DP, SS-OCTA displayed blood flow signals in the retinal nerve fiber layer and not above the vitreoretinal interface; this helped distinguish these vessels from neovascularization of the disc [27].

DIFFERENTIAL DIAGNOSIS — DP is a diagnosis of exclusion; other entities such as papilledema, optic disc neovascularization, malignant hypertension, papillitis, and NAION must be considered in the differential diagnosis (table 1). (See "Overview and differential diagnosis of papilledema", section on 'Differential diagnosis'.)

DIAGNOSIS — DP is a diagnosis of exclusion; thus, diagnostic testing is usually required to exclude other conditions:

●When the disc edema is bilateral, papilledema secondary to increased intracranial pressure is a potentially life-threatening cause. Neuroimaging, usually with magnetic resonance imaging (MRI), followed by a lumbar puncture (LP) if the MRI is normal, should proceed expeditiously.

●Patients with unilateral optic disc edema and other clinical and ancillary test results consistent with DP may not require MRI or LP. Ophthalmologic evaluation with visual field testing and fluorescein angiography can be helpful in excluding other causes and providing confirmatory evidence of DP.

All patients should have ophthalmologic follow-up to monitor for vision loss and confirm the expected resolution of the optic disc edema. (See "Overview and differential diagnosis of papilledema", section on 'Diagnostic testing'.)

PROGNOSIS — Because DP produces mild or no visual loss, the prognosis is understood to be benign. However, some patients with a presentation consistent with DP develop vision loss over the next few weeks, because of either progression to nonarteritic anterior ischemic optic neuropathy (NAION), worsening macular edema, or progression of diabetic retinopathy [14,28,29]. In one series that included 19 diabetic patients with asymptomatic disc edema, NAION developed in 30 percent over a few weeks to a few months, as well as in an additional patient at 80 weeks, after the initial presentation [14]. In this series, the presence of retinopathy or a previous episode of NAION in the fellow eye did not affect the incidence of NAION. Similarly, DP does not appear to influence the progression of the underlying diabetic retinopathy, although this does occur in up to 25 percent of patients [6,10,28].

TREATMENT — In general, no treatment is required or recommended for patients with DP. Patients should be followed to confirm the expected resolution of the optic disc findings and to monitor for vision loss.

Some clinicians advocate the routine use of corticosteroids in patients with DP to ameliorate progression to nonarteritic anterior ischemic optic neuropathy (NAION) and/or clinically significant macular edema. However, in one observational cohort, oral corticosteroid therapy did not influence progression to NAION [16]. The use of intravitreal and periocular (sub-Tenon) injection of steroids has been reported in a small number of patients who developed severe optic nerve dysfunction from either the papillopathy or macular edema [23,29,30]. These patients subsequently had substantial and rapid resolution of both disc and macular edema, as well as visual function after treatment. Intravitreal steroid therapy is also a treatment option for macular edema associated with diabetic retinopathy. (See "Diabetic retinopathy: Prevention and treatment", section on 'Intravitreal glucocorticoids'.)

Intravitreal injection of vascular endothelial growth factor inhibitors (anti-VEGF; bevacizumab, ranibizumab) with or without steroids have been reported to cause rapid resolution of optic disc swelling and visual improvement in a number of published case reports of DP [2,30-39]. Others have reported resolution of the optic disc swelling with panretinal photocoagulation [34,40]. Many of these patients also had macular edema in association with optic nerve head swelling. Larger clinical studies are needed to further evaluate the efficacy of these agents.

SUMMARY AND RECOMMENDATIONS

●Definition – Diabetic papillopathy (DP) is a term that is usually used to characterize a finding of unilateral or bilateral optic disc edema with mild or no visual loss in a patient with either type 1 or type 2 diabetes. (See 'Epidemiology' above.)

●Pathogenesis – DP likely represents a mild form of nonarteritic anterior ischemic optic neuropathy (NAION), although this is not certain. (See 'Pathophysiology' above.)

●Clinical features – DP usually presents with very mild vision loss or as an incidental finding of unilateral or bilateral optic disc edema. Macular edema and other features of diabetic retinopathy are common findings. A small optic disc cup in the fellow eye is also usual. (See 'Clinical features' above.)

●Diagnosis and differential diagnosis – DP is a diagnosis of exclusion. Increased intracranial pressure and other causes of optic disc swelling must be excluded. (See 'Differential diagnosis' above and 'Diagnosis' above.)

●Natural history – Up to 30 percent of patients who initially present with DP may develop subsequent vision loss from NAION or from macular edema or other forms of diabetic retinopathy. (See 'Prognosis' above.)

●Treatment – Uncomplicated DP does not require treatment. No treatment is known to prevent subsequent vision loss from either NAION or diabetic retinopathy. However, some clinicians do treat with corticosteroids based on anecdotal evidence. (See 'Treatment' above.)