The use of pan-retinal photocoagulation to treat recurrent vitreous haemorrhage with neovascularisation in the context of Epstein syndrome: an MYH9-related disorder

Abstract

A female patient presented with stable chronic thrombocytopaenia with large platelets, sensorineuronal deafness and renal impairment. Her treatment was refractory to intravenous immunoglobulins (IVIG) and steroids for a putative diagnosis of immune thrombocytopaenic purpura (ITP). She underwent genetic testing which revealed a MYH9 mutation in-keeping with a diagnosis of Epstein Syndrome. Subsequently to this she developed globally constricted fields on Goldmann visual field testing. MRI pituitary was unremarkable but she was diagnosed with a pituitary microprolactinoma secondary to raised prolactin in the blood responsive to carbegoline therapy. She subsequently developed retinal haemorrhages and recurrent vitreous haemorrhages due to neovascularisation. Fluorescein angiography revealed the extent of the neovascularisation and microvascular ischaemia. She underwent pan-retinal photocoagulation (PRP) to treat the ischaemic stimulus which resulted in regression of the new vessels and cessation of vitreous haemorrhages. There are no previous reported cases of microvascular retinal disease in the literature in the context of Epstein Syndrome, and this is the first report of successful treatment with PRP.

Background

Epstein syndrome is a rare genetic disease leading to thrombocytopaenia with large platelets, sensorineuronal deafness and renal failure. This is the first reported case of microvascular retinal disease with neovascularisation leading to recurrent vitreous haemorrhage in the context of this disease. It was successfully treated with pan-retinal photocoagulation (PRP) and may offer a treatment option for patients with microvascular retinal disease in the context of a hereditary MYH9 mutations.

Case presentation

The patient presented to medical services with a significant haematoma at 2 years of age with significant thrombocyotpaenia of <10×10⁹/L. Blood film demonstrated giant platelets and as such overall platelet mass was much higher than the platelet count suggested. This was suspected to be immune thrombocytopaenic purpura (ITP) and she was treated with intravenous immunoglobulins (IVIG) and steroids. There was variable to no response to IVIG and steroids and she continued to have stable thrombocytopaenia. Investigations for autoimmune diseases, platelet glycoprotein expression and Bernard Soulier Screen were all unremarkable.

During school years she developed progressive hearing difficulties. Pure tone audiometry revealed moderate-to-severe sloping symmetric bilateral sensorineuronal hearing loss treated with cochlear implants. At this stage her management was discussed with the clinical genetics department and this lead to her first contact with ophthalmology services, which excluded retinitis pigmentosa (at first encounter with ophthalmology Snellen visual acuity was 6/5 bilaterally).

At the age of 24 she received a genetic diagnosis of Epstein’s Syndrome with a heterozygous single base change c.2104C>T in MYH9 gene resulting in a mutation of p.Arg702Cys within the MYH9 protein. Blood testing results at this stage continue to demonstrate renal impairment and thrombocytopaenia (table 1). Her renal function at this point continued to deteriorate until starting peritoneal dialysis later that year. Following an episode of bacterial peritonitis she switched to haemodialysis three times a week. During an admission for management of a hepatic adenoma, it was incidentally noted that she had galactorrhoea and associated hyperprolactinaemia. This triggered a second referral to ophthalmology services.

Table 1.

Blood test results on diagnosis of Epstein Syndrome

Analyte		Units	Analyte		Units	Constituent		Units
Sodium	141	mmol/L	Albumin	34	g/L	Haemoglobin	83	g/L
Potassium	4.3	mmol/L	Bilirubin	7	μmol/L	White blood cells	6.8	x109/L
HCO3	24	mmol/L	Alkaline phosphatase	160	IU/L	Platelets	10	x109/L
Urea	18.2	mmol/L	Alanine aminotransferase	39	IU/L
Creatinine	535	μmol/L	C-reactive protein	1	mg/L
Adj. Ca2+	2.28	mmol/L	Cholesterol	7.0	mmol/L
Phos	1.52	mmol/L

At this time she developed subjective worsening gradually of her peripheral vision over the preceding 6 months with associated deterioration of night vision and sporadic peripheral photopsia bilaterally. Visual acuity was stable centrally. Visual field on confrontation was found to be restricted bitemporally. On examination the anterior segment and the retina were unremarkable with a normal optic nerve head appearance and no evidence of macular oedema or retinal hyper/hypopigmentation and the intraocular pressures were normal. Goldmann visual field testing revealed severe peripheral visual field loss. There was gross constriction in all quadrants with no tendencies to respect a midline, horizontal or vertical meridian. Electroretinogram results suggested diffuse rod and cone dystrophy. At this stage, the patient declined further investigations. The endocrinology team, following an unremarkable MRI pituitary, started carbegoline for a suspected microprolactinoma, which lead to a dramatic fall in prolactin, but no change in visual fields.

Two years later during routine follow-up examination revealed retinal haemorrhage with peripheral pigmentory changes. Visual fields were stable compared with previous. She continued to report floaters in her vision for the next 2 years but her visual acuity remained stable as did her fundus examination findings. She then presented with an acute episode of sudden disturbance of her vision in her left eye. Visual acuity deteriorated only a small amount to 6/6 in the right eye and 6/9 in the left eye, but examination revealed scattered blot retinal haemorrhages in the right eye (figure 1A) and a subhyaloid haemorrhage in the left eye (figure 1B). This was also evident on infrared imaging of the retina (figure 1C,D). Fluorescein angiography was performed at this stage revealing neovascularisation at the disc with profusely leaking vessels bilaterally (figure 2). After this she suffered two vitreous haemorrhages in her right eye in quick succession and her vision deteriorated to 6/36 on the right and 6/12 on the left.

Figure 1.

Fundus photographs during episode of sudden visual loss in 2012. (A) Several areas of retinal haemorrhage in the right eye on colour imaging and (C) on infrared imaging. (B) Colour fundus photography demonstrating vitreous and subhyaloid haemorrhage in the left eye and (D) demonstrated on infrared imaging.

Figure 2.

Fluorescein angiography at the time of the vitreous haemorrhage demonstrating (A) neovascularisation and leaking vessels around the optic disc on the right eye, and (B) profuse leaking vessels and neovascularisation around the optic disc.

PRP was used as initial therapy with a second session of fill-in laser therapy 4 weeks after the initial therapy. Her visual acuity improved to 6/9 bilaterally as the vitreous haemorrhage resorbed. Six months after this initial therapy she presented with a sudden loss of vision in her right eye with acuity of 6/35—examination revealed a right vitreous haemorrhage with no evidence of retinal detachment. No further laser therapy was offered at this stage and the haemorrhage resolved. She was noted to develop bilateral subcapsular posterior cataracts, which were removed over the following 12 months. She experienced stable vision until 2 years after the initial PRP when she experience three successive left vitreous haemorrhages within 6 months and her visual acuity dropped to counting fingers in that eye. She was treated with further PRP at this stage as evidenced on her repeat retinal imaging (figure 3). This final session of laser therapy has resulted in no further bleeding and stable vision for the last 3 years with the resolution of the leaking neovascularisation on repeat angiography. Her visual acuity has remained stable at 0.3 in the right eye and 0.48 in the left eye throughout this period. The only notable developments on continued follow-up has been of epiretinal membrane bilaterally.

Figure 3.

Fundus photography following pan-retinal photocoagulation demonstrating no further haemorrhage and scarring in the periphery of the retina on colour imaging in (A) the right eye and (B) the left eye. This is highlighted on infrared imaging of (C) the right fundus and (D) the left fundus.

Outcome and follow-up

For 4 years after the last session of PRP the patient’s vision remains stable (logMAR right 0.3 and left 0.48) with no recurrence of any vitreous haemorrhages.

Discussion

In the context of Epstein Syndrome previous published cases have highlighted formation of dense presenile cataracts as well as congenital cataracts in other MYH9 mutations.^1–3 However, there are no previous reports of either recurrent vitreous haemorrhage or microvascular retinal disease in the context of Epstein Syndrome specifically. There is a report of non-specified vitreous lesions in Fechtner Syndrome⁴—another disease from the constellation of MYH9-related disorders. The authors do not elaborate beyond this non-specific description and there is no description of the fundus itself.⁴

MYH9-related disorders have been categorised into four major disease phenotypes⁵:

• Epstein syndrome.

• Fechtner syndrome.

• May-Hegglin anomaly.

• Sebastian’s syndrome.

Each disorder fundamentally demonstrates macrothrombocytopaenia—a reduced platelet count but with increased individual platelet volumes—and a combination of other clinical features: sensorineuronal deafness, deranged liver enzymes, renal impairment, presenile cataract and small or large inclusion bodies within leukocytes.^{2 6} These diseases are due to an autosomal dominant mutation within MYH9 gene encoding the cytoskeletal protein non-muscular myosin heavy chain IIA (NMMHCIIA).⁷ The mutations in NMMHCIIA affect the same signalling pathway in which the mutated proteins of von Willebrand factor and glycoprotein Ib cause the hereditary thrombocytopaenic diseases of von Willebrand’s disease type IIB and Bernard-Soulier syndrome respectively.⁶ Although a family history may point to a diagnosis of an MYH9-related disorder, absence of this does not exclude the disease: approximately 35% of cases demonstrate de novo mutations leading to sporadic forms of these diseases.^{2 8}

These are often not easy diagnoses to make and there are numerous reported cases of misdiagnosis for a number of years.^{9 10} ITP tend to be the most common alternate diagnosis.^10–13 This often leads to inappropriate and ineffective treatment with repeated courses of intravenous corticosteroids and immunoglobulins as well as in some cases splenectomy.^{10 11} If patients present with a predominance of renal failure and hearing loss they can be confused as Alport’s Syndrome—indeed this is the likeness suggested by Epstein and colleagues on their original description of the disease.¹⁴

The neovascularisation noted in this rare disease is postulated to be secondary to occlusive capillary disease, possibly due to the haematological abnormalities present in Epstein syndrome. Loss of the capillary network, resulting in retinal hypoxia may be akin to the occlusion resulting from sickle cell disease or diabetic retinopathy, hence the features of multiple retinal haemorrhages, peripheral retinal hyperpigmentation and neovascularisation. The link between these features and subsequent preretinal or vitreous haemorrhage is suspected to be similar to that described in other diseases: the neovascularisation is triggered predominantly by proangiogenic growth factors, such as vascular endothelial growth factor (VEGF)—the concentrations of which are raised within the vitreous secondary to ischaemia in the peripheral retina.¹⁵ This results from the hypoxic stimulus stimulating VEGF production by the Muller cells, retinal ganglion cells and retinal astrocytes within the peripheral retina.¹⁶ This does not lead to beneficial revascularisation—rather it induces preretinal blood vessel formation which predispose to vitreous haemorrhage.¹⁷ The mechanisms of pathological neovascularisation are not exclusive to diabetic retinopathy or sickle cell disease and are shared with several other disease situations that result in pathological aberrant angiogenesis.

There are a plethora of rare diseases that result in aberrant neovascularisation following retinal ischaemia or vaso-occulsive disease such as that seen in this case. Idiopathic retinal vasculitis, aneurysms and neuroretinitis syndrome demonstrates a further rare disease with multiple microvascular pathologies coexist that lead to neovascularisation and further accelerated deterioration in vision.¹⁸ Similarly, vaso-occlusive disease secondary to systemic lupus erythematosus (SLE) demonstrates neovascularisation and vitreous haemorrhages that can manifest as the initial presentation of SLE.^{19 20} There is also reported vitreous haemorrhage following retinal neovascularisation secondary to Susac syndrome—a systemic disease which results in vaso-occlusive disease.²¹ All of these diseases result in aberrant vasculature within the retina as a result of ischaemic drive, which is suspected to underlie the pathogenesis of the vitreous haemorrhage in this case of Epstein’s Syndrome.

In all of these scenarios the use of PRP appears effective in suppressing proangiogenic drive and facilitating the prevention of the complications of aberrant vessel formation^21–24 a principle that allowed for effective treatment in this case of Epstein’s syndrome with repeated vitreous haemorrhage.

It is notable that this patient demonstrated some features of retinitis pigmentosa, but there was no confirmation of this aspect of the patient’s ocular disease, given they refused further investigation. Although the authors do not suspect this is related to the proliferative retinopathy and neovascularisation, it is interesting to note that retinitis pigmentosa is associated with the similar but aetiologically distinct Alport’s syndrome.^{25 26} In the context of MYH9-related diseases there is no current literature describing features of retinitis pigmentosa as an ocular manifestation of the disease, and there is not conclusive evidence of this in the current patient. Further follow-up with other patients with MYH9-related diseases may be beneficial to establish whether this could affect such patients.

In conclusion this case highlights an unusual presentation of vitreous haemorrhage secondary to neovascularisation in the context of the rare genetic disease of Epstein Syndrome. This is the first reported incidence of proliferative retinopathy within the MYH9 related disorders and successfully treated with PRP—a strategy that may be beneficial across a broad range of rare diseases and unique that result in a common pathway of aberrant angiogenesis within the retina.

Learning points.

• MYH9-related disorders are frequently misdiagnosed, frequently as immune thrombocytopaenic purpura (ITP). If patients have macrothrombocytopaenia further investigation may be warranted to exclude a mutation in MYH9.

• Visual symptoms within Epstein syndrome may represent microvascular pathology within the eye and not solely presenile cataract.

• The mechanism of proliferative retinopathy in the context of Epstein syndrome is thought to be due to vaso-occulsive disease promoting aberrant angiogenesis.

• Pan-retinal photocoagulation offers a potentially effective and simple treatment for microvascular disease with evidence of neovascularisation in the context of Epstein syndrome.