- Email: [email protected]
Seeing the difference—Painless progressive vision loss in a vasculopath
Accepted Manuscript Seeing the Difference - Painless progressive Vision loss in a Vasculopath Jenny L. Lauschke, BSc(Med) MBBS (Hon) PhD, Katherine Masselos, MBBS (Hons) B. Optom (Hons) MPH FRANZCO, Jennifer Sandbach, MBBS FRANZCO, Clare L. Fraser, MBBS, MMed, FRANZCO PII:
S0039-6257(17)30229-1
DOI:
10.1016/j.survophthal.2017.09.001
Reference:
SOP 6750
To appear in:
Survey of Ophthalmology
Received Date: 29 August 2017 Accepted Date: 11 September 2017
Please cite this article as: Lauschke JL, Masselos K, Sandbach J, Fraser CL, Seeing the Difference - Painless progressive Vision loss in a Vasculopath, Survey of Ophthalmology (2017), doi: 10.1016/ j.survophthal.2017.09.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Calciphylaxis - Survey Clinical Challenge
Seeing the Difference - Painless progressive Vision loss in a Vasculopath
TITLE:
Corresponding Author
Jenny L Lauschke email: [email protected]
1. Department of Ophthalmology, Prince of Wales Hospital, Sydney NSW Australia
SC
Institution:
RI PT
Jenny L Lauschke (1) - BSc(Med) MBBS (Hon) PhD Katherine Masselos (1) - MBBS (Hons) B. Optom (Hons) MPH FRANZCO Jennifer Sandbach (1) - MBBS FRANZCO Clare L Fraser (2) – MBBS, MMed, FRANZCO
Authors:
M AN U
2. Save Sight Institute, University of Sydney, Sydney, NSW, Australia
Case Report:
TE D
A 78-year-old Caucasian man reported sudden onset of reduced vision during a routine woundcare appointment for non-healing necrotic leg ulcers. He described painless blurring of vision with grey shapes “like Chinese characters” within his central field of vision in the right eye. His other eye had a traumatic optic neuropathy sustained as a child. He reports some photophobia, but denies any headache, neck pain, jaw claudication or scalp tenderness. He denies any new systemic symptoms and recent trauma.
EP
He has a history of hypertension, hyperlipidemia, ischemic heart disease, atrial fibrillation on Warfarin, aortic valve replacement, triple coronary artery bypass graft, gout, and end-stage renal failure for which he receives hemodialysis.
AC C
On presentation to a peripheral hospital his acuity right eye pin holed to 20/20 and was 1/36 left eye with a left RAPD. Anterior segment examination was unremarkable. His right fundus showed mild optic disc swelling with a nerve fiber layer hemorrhage and cotton-wool-spots (CWS). The left fundus showed a pale optic disc and normal macular appearance. His temporal arteries were palpable with some nodularity, but were non-tender.
What is your differential diagnosis? What investigations would you order? Comments by Clare Fraser, MBBS MMed FRANZCO We have a patient with painless visual loss in his only seeing eye, with optic fundus changes suggestive of an optic neuropathy and ischemia. This is on the background of multiple cardiac and vascular issues. In any patient over 50 with sudden onset of visual disturbance, I think of giant cell arteritis (GCA) as my first differential diagnosis. In particular, if there is a history of “geographic” visual scotoma, I am concerned about ischemia affecting the choroidal circulation. This
ACCEPTED MANUSCRIPT
process also affects the retinal circulation producing disc edema and cotton wool spots. The combination of choroidal and retinal circulation pathology is almost pathognomonic for GCA. We know that up to 20% of GCA patients will not have any systemic features of GCA,9 so the lack of jaw claudication and headache does not concern me in listing this as my first diagnosis. The nodularities on the temporal arteries may be due to co-exisiing atherosclerotic disease. I would request blood work including a CBC, ESR and CRP, as well as arranging a temporal artery biopsy. Given my own personal interest in the topic, I would do a chewing gum test to assess more objectively for jaw claudication. 14
RI PT
This would all occur concurrently to the patient receiving 1 gram of intravenous methylprednisolone;however, there are many other comorbidities to consider in this case. Other vasculitides can mimic GCA, including the changes in the choroidal circulation. In particular I would like to find out more about the cause of his renal failure – does he have lupus or ANCA positive disease for example. I would include tests for other non-GCA vasculitidies in my blood work-up.
M AN U
SC
Next, this patient has an aortic valve replacement and a non-healing ulcer, so there is a possibility of an infectious embolus as the cause for his symptoms. I would look for other stigmata of infectious endocarditis clinically, and request cardiology consultation with a view to an echocardiogram. His INR levels should also be checked. As part of the work-up for other vasculitis and embolic phenomenon, I would request an MRI of the brain and orbits with contrast. Finally given that he has a pale optic disc in his fellow eye, while this fits with a history of childhood traumatic optic neuropathy, thought must be given to Foster-Kennedy syndrome particularly as the disc swelling in his right eye hasn’t resulted in a significant loss of vision, it could be due to raised intracranial pressure.
Case Report (Continued)
TE D
So while treating and assessing for GCA, I would like to more carefully assess his cardiovascular status and I would perform neuro-imaging.
AC C
EP
Due to the appearance of right disc swelling and left optic atrophy, a CT brain was performed that showed no mass or hemorrhage. Incidental findings were calcium plaques in the vessels and mild cerebral atrophy (Fig 1). Hematological investigations revealed anemia with hemoglobin of 79 g/L, platelets 219 x109/L, normal white cell count and elevated inflammatory markers (erythrocyte sedimentation rate 89, C-reactive protein 45mg/L). The INR was sub therapeutic at 1.8, and the remaining blood tests showed borderline elevated calcium and phosphate, low albumin of 30 g/L, and GFR of 13ml/min. Treatment for the presumptive diagnosis of arteritic anterior ischemic optic neuropathy (AION) was begun with intravenous methylprednisone. The patient was referred to our institution for temporal artery biopsy. Repeat examination the next day confirmed right optic disc swelling with a hemorrhage and fine telangiectasia in addition to the CWS. The macula showed a loss of the foveal reflex. There were no emboli or peripheral retinal hemorrhages visible and no rubeosis (Fig 2). Optical coherence tomography (OCT) showed increased thickness and signal of the inner retinal layers (Fig 3). Humphrey visual fields (HVF) showed patchy peripheral field loss (Figure 4a). This clinical picture was more consistent with retinal ischemia than AION. A further vasculitic screen was also arranged, and he was booked for temporal artery biopsy.
ACCEPTED MANUSCRIPT
What would be your diagnosis now? Is there anything else you would do at this stage? Do you think hyperbaric is a good idea? Comments by Dr. Fraser (Continued)
RI PT
He has an elevated ESR and CRP, which are in keeping with GCA. A normochromic, normocytic anemia is also frequently found in GCA patients, though is thought to be associated with a reduced risk of ischemic events, and I would have expected elevated platelets.12 Giant cell arteritis can also cause retinal ischemia,8 so I would continue with the treatment and management plan – steroids and a temporal artery biopsy.; however, the appearance of telangiectasia does suggest a more chronic type of retinal ischemia which I would not expect to see at this stage of a GCA process.
M AN U
SC
With regards to further management, given that there seems to be progressive changes on fundus examination despite steroids, and his INR is sub-therapeutic, his anti-coagulation needs to be managed in conjunction with his other physicians . Switching him to a heparin infusion that can be reversed for the biopsy would be a reasonable option. Unfractionated heparin is relatively safe in chronic renal failure. Thrombus emboli from the heart wall (atrial fibrillation) or the aortic valve in the ophthalmic artery could result in this mixed choroidal/retinal picture, and I would not expect to see emboli within the retinal circulation. Managing the anti-coagulation will cover this potential differential diagnosis. The anemia will be worsening any ischemia, so blood transfusion may help his retinal oxygenation. Hypotension from medication or during hemodialysis should also be addressed in conjunction with the renal physicians. It would be best to keep the perfusion pressure up.
TE D
Calcification of the cerebral vessels is most commonly associated with primary atherosclerosis in the elderly. Patients on hemodialysis with high calcium are at risk of accelerated atherosclerosis and higher mortality.18 Therefore, given that there are signs of chronic retinal ischemia, his cerebral and ocular circulation should be assessed further.
EP
A fundus fluorescein angiogram (FFA) can be very helpful to clarify the circulatory issues. Is there a prolonged arm to eye time? Is there delayed choroidal filling and are there areas of retinal non-perfusion or vasculitis? Small fluorescein doses can be given with digital photographic systems; however, the renal physicians would need to be consulted about safety. It may be best to do the FFA just before his next hemodialysis.
AC C
I would request an MRI scan to look for further evidence of cerebral vasculitis and ischemia. A formal CT or MR angiogram would also cover the origin of the ophthalmic artery – looking for atherosclerotic stenosis or aneurysm. Ophthalmic artery aneurysms cause symptoms within the both the choroidal and retinal circulations.4 Carotid Doppler ultrasound to look for critical stenosis causing ocular ischemia on the right side should also be requested. CWS can also be seen in infective retinopathies including syphilis, bartonella henselae, HIV, herpes viruses, and hepatic virus infections. In particular varicella zoster vasculitis has been documented to cause ophthalmic artery occlusions.11 Given the findings pointing more to retinal ischemia, viral serology should be added to the vasculitis blood screen, if they haven’t already been done. Hyperbaric oxygen may be of benefit in patients with central retinal artery occlusion by increasing oxygenation in the choroidal circulation which may then diffuse through to the inner retina. If this patient is still within 24 hours of the onset of visual loss, then discussion with the hyperbaric oxygen team may be worthwhile. Papers on the subject specifically discuss hyperbaric oxygen for non-arteritic occlusions.17,22 Given that arteritic pathology is
ACCEPTED MANUSCRIPT
still the primary differential diagnosis, this would need to be considered as part of this discussion. It would not be part of my typical management in a case like this, however we do not have hyperbaric oxygen available at the institutions where I work. Case Report (Continued)
RI PT
His vision subsequently worsened to 6/60 OD and repeat examination showed a deteriorated fundus appearance with ongoing disc swelling and increased numbers of CWS. Repeat OCT showed signal increase of the inner retina with loss of distinction of the inner retinal layers and loss of GCL; repeat HVF showed significant deterioration. (Fig 4b). Fluorescein angiography showed significant delays in retinal perfusion, vascular pruning and late patchy venous staining but no optic disc hyperfluorescence (Fig 5). His ESR had increased to 102 and the CRP to 98 mg/L. The vasculitic screen and investigation for syphilis, sarcoidosis and tuberculosis were negative.
M AN U
SC
Electrophysiology showed a negative b-wave on scotopic ERG and a reduction in b-wave amplitude on photopic ERG as well as reduction in amplitude and delay in the flicker ERG. This was thought to be consistent with generalized and especially inner retinal dysfunction. He underwent a session of hyperbaric oxygen therapy, which had not previously been approved and was delayed due to patient anxiety, without any visual improvement. Further treatments were not authorised. Do you agree with the treatment so far? Would you suggest any other systemic treatments or specifically for management of this only eye? Comments by Dr. Fraser (Continued)
TE D
The treatment so far has included IV steroids and hyperbaric oxygen.
EP
The electronegative ERG is in keeping with inner retinal ischemia as seen on OCT and FFA.16 Autoimmune retinopathy and cancer associated retinopathy (particularly melanoma associated) can also cause an electronegative waveform, however, I think it still fits best with retinal ischemia. Therefore, at this time I would still pursue the vascular side of this case. I would chase the temporal artery biopsy results and ask them to be processed urgently. I would liase with pathology to look for other non-GCA vascular changes.
AC C
I would also chase the carotid Doppler results, CT or MR angiography results and the cardiology consultation. PET scans are also of value in assessing GCA and non-GCA vasculitis.12 I would keep him heparinized, control the anemia, and keep the blood pressure up. His head should be kept slightly lower than his heart. The patient has continued to worsen despite steroid treatment, with further elevation of his ESR and CRP. Despite steroid treatment, some GCA patients will continue to have visual deterioration;5 however, I am surprised that the ESR and CRP are getting worse. This makes me think again about infective causes for his symptoms, and now I would start considering malignancy. I would liase with infectious diseases about whether antibiotic and anti-viral cover is warranted. In particular, I would want to discuss covering with valcyclovir for possible varicella zoster virus vasculitis. Blood cultures, urine cultures and ulcer swabs may help isolate a cause.
ACCEPTED MANUSCRIPT
This is most likely a systemic process, working out what that process is and treating that is what will save his eye. Case Report (Concluded)
RI PT
Carotid Doppler revealed bilateral 80-99% internal carotid artery stenosis and vertebral artery stenosis. This was corroborated on CT angiogram that found a 12mm long calcific plaque at both carotid bulbs, causing focal stenosis >90% and generalized extensive calcification of subcutaneous vessels. (Fig 6). The temporal artery biopsy showed focal myxoid degeneration and extensive concentric calcium deposition in the tunica media with no features suggestive of GCA (Fig 7). MRI showed chronic microvascular disease but no focal cerebral ischemia. A SPECT scan was performed which showed markedly reduced cerebral perfusion.
SC
The clinical picture of non-healing necrotic ulcers, acute retinal ischemia with ischemic optic neuropathy, and the histopathological findings were consistent with calciphylaxis (calcific uremic arteriolopathy).
M AN U
Following extensive evaluation by the vascular, neurology and renal teams, surgical management for the severe carotid stenosis was deemed too a high risk. The patient was managed conservatively with adjustment of Warfarin to low-molecular-weight-heparin and aspirin, cessation of his vitamin D supplements, optimization of the medical treatment of hypercholesterolemia and hypertension, and changing to low-calcium replacement fluid in his hemodialysis. He is alive at 18 months post-presentation, and his vision remains stable.
TE D
Discussion
EP
Calciphylaxis is traditionally characterized by diffuse calcification of the media tunica of small arterioles. It classically presents with ischemia and necrosis of subcutaneous tissues, such as skin ulcers, and signs of infarction elsewhere, such as myocardial infarction, phalangeal necrosis, penile necrosis, and subepithelial necrotic nodules in the extremities.23
AC C
Ophthalmic presentations reported in the literature include ischemic optic neuropathy mimicking GCA.10 Review of records usually reveal end stage renal disease (ESRD) with hyperphosphatemia, hyperparathyroidism, and hypoalbuminemia. The pathogenesis of calciphylaxis is poorly understood and likely multifactorial. It is hypothesized that the hyperphosphatemia associated with ESRD leads to vascular smooth muscle cells calcifying under the influence of vitamin D, as happens in normal osteoblasts. This calcification is usually inhibited by Matrix GLa protein; however, that is vitamin K dependent, so is thus diminished in patients undergoing anticoagulation treatment with Warfarin or other vitamin K inhibitors.6 Risk factors for developing calciphylaxis include chronic end-stage renal failure, obesity, diabetes, hypotension, Warfarin therapy, hypoalbuminemia and deranged calciumphosphate metabolism.7,15 Although this constellation of co-morbidities is common in patients with ESRF, calciphylaxis is relatively rare, with an incidence of 1-4% of the population with ESRD.23 The reason for this is unknown.
ACCEPTED MANUSCRIPT
The onset of calciphylaxis is often preceded by a ‘trigger event’ within a minimally buffered homeostatic system, such as sudden weight-loss, liver disease, concomitant vascular disease and use of Warfarin therapy or immunosuppressant agents such as corticosteroids.7 The disease has a poor prognosis, with mortality of 60-80% in patients with ulcerative disease. Currently, the 1- and 5-year survival rates are estimated to be 45% and 35%, respectively.21
RI PT
There is no standardized treatment for this disease; however, a multidisciplinary approach including surgical parathyroidectomy, wound debridement, and aggressive medical management may improve survival. Medical management strategies include lowering of the calcium-phosphate product and serum calcium and phosphate concentrations using treatment with cinacalcet and sodium thiosulphate, cessation of vitamin D supplements, use of bisphosphanates, supplementation of albumin, and daily hemodialysis with use of low-calcium bath dialysate as well as removal of any aggravating agents such as Warfarin and corticosteroid therapy.2,20,23
M AN U
SC
There are some reports suggesting improvement in peripheral ulceration with the initiation of sodium thiosulphate, which is hypothesized to work by improving the aqueous solubility of calcium deposits and aid in their clearance.3 Daily hemodialysis is advocated as it prevents large fluctuations in blood pressure, a risk factor previously identified in non-arteritic anterior ischemic optic neuropathy (NAION) and hypothesized to play a causal role in the development of visual loss in calciphylaxis.13,20 Hyperbaric oxygen therapy has been shown to be of use in healing calciphylaxis ulcers. Supplemental oxygen is thought to maintain retinal function and restore vision via diffusion from the choroidal branches to the inner layers of the retina.1,19
TE D
Disclosures
There are no conflicts of interest to disclose
References
EP
1. Basile C. Hyperbaric oxygen therapy in the treatment of calciphylaxis? Yes, more than hope. Kidney international. 2002;62(6):2300-2300.
AC C
2. Borges L, Rosa P, Dias E, Cássio I. Successful treatment of calciphylaxis by a multidisciplinary approach. BMJ Case Rep. 2014 Jul 17;2014. 3. Burnie R, Smail S, Javaid MM. Calciphylaxis and sodium thiosulphate: a glimmer of hope in desperate situation. Journal of renal care. 2013;39(2):71-76. 4. Choi BK, Lee TH, Choi CH, Lee SW.Fusiform Intracanalicular Ophthalmic Artery Aneurysm; Case Report and Review of Literature. J Korean Neurosurg Soc. 2008 Jul; 44(1): 43–46. 5. Danesh-Meyer H, Savino PJ, Gamble GG. Poor prognosis of visual outcome after visual loss from giant cell arteritis. Ophthalmology. 2005 Jun;112(6):1098-103. 6. Eiser AR. Warfarin, Calciphylaxis, atrial fibrillation and patients on dialysis: outlier subsets and practice guidelines. The American journal of medicine. 2014;127(4):253-254. 7. Hayashi M. Calciphylaxis: diagnosis and clinical features. Clinical and experimental nephrology. 2013;17(4):498-503. 8. Hayreh SS, Podhajsky PA, Zimmerman B. Ocular manifestations of giant cell arteritis. Am J Ophthalmol. 1998 Apr;125(4):509-20
ACCEPTED MANUSCRIPT
9. Hayreh SS, Podhajsky PA, Zimmerman B. Occult giant cell arteritis: ocular manifestations. Am J Ophthalmol 125: 521–526, 1998 10. Huerva V, Sánchez MC, Ascaso FJ, Craver L, Fernández E. Calciphylaxis and bilateral optic neuropathy. J Fr Ophtalmol. 2011 Nov;34(9):651.
RI PT
11. Jayaram H, Stanescu-Segal D, Holder GE, Graham EM. Bilateral ophthalmic artery occlusions due to probable varicella-zoster virus vasculopathy. Arch Ophthalmol. 2012 Nov;130(11):1492-4. 12. Kawasaki A, Purvin V. Giant cell arteritis: an updated review. Acta Ophthalmol 2009 Feb; 87(1):13-32 13. Korzets A, Marashek I, Schwartz A, Rosenblatt I, Herman M, Ori Y. Ischemic optic neuropathy in dialyzed patients: a previously unrecognized manifestation of calcific uremic arteriolopathy. American Journal of Kidney Diseases. 2004;44(6):e93-e97.
SC
14.Kuo CH, McCluskey P, Fraser CL. Chewing Gum Test for Jaw Claudication in GiantCell Arteritis. N Engl J Med. 2016 May 5;374(18):1794-5 15. Lal G, Nowell AG, Liao J, Sugg SL, Weigel RJ, Howe JR. Determinants of survival in patients with calciphylaxis: a multivariate analysis. Surgery. 2009;146(6):1028-1034.
TE D
M AN U
16. Lima LH, Cella W, Brue C, Tsang SH. Unilateral electronegative ERG in a presumed central retinal artery occlusion. Clin Ophthalmol. 2010 Nov 17;4:1311-4. 17. Menzel-Severing J, Siekmann U, Weinberger A, Roessler G, Walter P, Mazinani B. Early hyperbaric oxygen treatment for nonarteritic central retinal artery obstruction. Am J Ophthalmol. 2012 Mar;153(3):454-459.e2. 18. Obi Y, Mehrotra R, Rivara MB, Streja E, Rhee CM, Lau WL, Kovesdy CP, KalantarZadeh K. Hidden Hypercalcemia and Mortality Risk in Incident Hemodialysis Patients. J Clin Endocrinol Metab. 2016 Jun;101(6):2440-9. 19. Podymow T, Wherrett C, Burns KD. Hyperbaric oxygen in the treatment of calciphylaxis: a case series. Nephrology Dialysis Transplantation. 2001;16(11):2176-2180.
EP
20. Vedvyas C, Winterfield LS, Vleugels RA. Calciphylaxis: a systematic review of existing and emerging therapies. Journal of the American Academy of Dermatology. 2012;67(6):e253-e260. 21. Weenig RH, Sewell LD, Davis MD, McCarthy JT, Pittelkow MR. Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol. 2007 Apr. 56(4):569-79.
AC C
22. Weiss JN. Hyperbaric oxygen treatment of nonacute central retinal artery occlusion.Undersea Hyperb Med. 2009 Nov-Dec;36(6):401-5. 23. Wilmer WA, Magro CM. Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment. Semin Dial. 2002 May-Jun. 15(3):172-86
7. Abstract:
A 78-year-old Caucasian man with significant vascular disease reported sudden onset of worsened vision during a routine wound-care appointment for non-healing necrotic leg ulcers. He described painless blurring of vision with grey scotomas in his RE, his only wellseeing eye, following trauma to the LE as a child. He presented with retinal ischemia, a cotton-wool spot and optic nerve swelling. Temporal artery biopsy showed myxoid degeneration and extensive calcium deposition which also was shown on imaging throughout his carotid and vertebral arterial system, the clinical picture of calciphylaxis.
ACCEPTED MANUSCRIPT 8. Keywords:
painless vision loss, retinal ischemia, ischemic optic neuropathy, calciphylaxis
RI PT
Figure Legends Fig 1: Plain CT brain and orbits shows normal ventricles (asterix) and CSF spaces with no evidence of cerebral infarction or space occupying lesion. There is diffuse calcification of the vessels ( ).
M AN U
SC
Fig 2: Fundus photos showing right mild optic disc swelling with a nerve fiber layer hemorrhage (arrow), fine telangiectasia and a cotton wool spot (asterix) . There is a dulling of the foveal reflex. There are no emboli or peripheral retinal hemorrhages visible and no neovascularization. The left fundus shows mild temporal optic disc pallor and a otherwise healthy macula. Fig 3: Optical coherence tomography (OCT) scan through the right fovea showing increased thickness (bar) and signal intensity (asterix) of the inner retina layers with no evidence of intra- or sub retinal fluid. The left macula shows inner retinal thinning with normal signal. Fig 4: 24-2 Humphrey Visual fields (HVF) at presentation (a) showing patchy peripheral field loss and after several days (b) showing worsening of field loss with predominantly nasal scotoma.
TE D
Fig 5: Fluorescein Angiogram showing significant delays in retinal perfusion through the right fundus with late venous phase not reached till 1.06 minutes. There are areas of blocked fluorescence secondary to the CWS (asterix) and some late patchy venous staining ( ) but no optic disc leak or evidence of vascular sheathing. The left fundus is normal.
EP
Fig 6: CT angiogram from aortic arch to circle of Willis shows and a calcified plaque at both carotid bulbs extending into the origins of the internal carotid arteries (arrow). This is causing marked bilateral stenosis >90%. There is significant generalized calcification with a focus of heavy calcification at the aortic arch, common carotid and both vertebral artery origin which is also causing marked stenosis.
AC C
Fig 7: Specimen of right temporal artery in low and high magnification showing focal myxoid edema (arrow) and extensive concentric medial calcification (asterix) consistent with Calciphylaxis. There is no significant inflammation and no giant cells are identified.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S0039-6257(17)30229-1
DOI:
10.1016/j.survophthal.2017.09.001
Reference:
SOP 6750
To appear in:
Survey of Ophthalmology
Received Date: 29 August 2017 Accepted Date: 11 September 2017
Please cite this article as: Lauschke JL, Masselos K, Sandbach J, Fraser CL, Seeing the Difference - Painless progressive Vision loss in a Vasculopath, Survey of Ophthalmology (2017), doi: 10.1016/ j.survophthal.2017.09.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Calciphylaxis - Survey Clinical Challenge
Seeing the Difference - Painless progressive Vision loss in a Vasculopath
TITLE:
Corresponding Author
Jenny L Lauschke email: [email protected]
1. Department of Ophthalmology, Prince of Wales Hospital, Sydney NSW Australia
SC
Institution:
RI PT
Jenny L Lauschke (1) - BSc(Med) MBBS (Hon) PhD Katherine Masselos (1) - MBBS (Hons) B. Optom (Hons) MPH FRANZCO Jennifer Sandbach (1) - MBBS FRANZCO Clare L Fraser (2) – MBBS, MMed, FRANZCO
Authors:
M AN U
2. Save Sight Institute, University of Sydney, Sydney, NSW, Australia
Case Report:
TE D
A 78-year-old Caucasian man reported sudden onset of reduced vision during a routine woundcare appointment for non-healing necrotic leg ulcers. He described painless blurring of vision with grey shapes “like Chinese characters” within his central field of vision in the right eye. His other eye had a traumatic optic neuropathy sustained as a child. He reports some photophobia, but denies any headache, neck pain, jaw claudication or scalp tenderness. He denies any new systemic symptoms and recent trauma.
EP
He has a history of hypertension, hyperlipidemia, ischemic heart disease, atrial fibrillation on Warfarin, aortic valve replacement, triple coronary artery bypass graft, gout, and end-stage renal failure for which he receives hemodialysis.
AC C
On presentation to a peripheral hospital his acuity right eye pin holed to 20/20 and was 1/36 left eye with a left RAPD. Anterior segment examination was unremarkable. His right fundus showed mild optic disc swelling with a nerve fiber layer hemorrhage and cotton-wool-spots (CWS). The left fundus showed a pale optic disc and normal macular appearance. His temporal arteries were palpable with some nodularity, but were non-tender.
What is your differential diagnosis? What investigations would you order? Comments by Clare Fraser, MBBS MMed FRANZCO We have a patient with painless visual loss in his only seeing eye, with optic fundus changes suggestive of an optic neuropathy and ischemia. This is on the background of multiple cardiac and vascular issues. In any patient over 50 with sudden onset of visual disturbance, I think of giant cell arteritis (GCA) as my first differential diagnosis. In particular, if there is a history of “geographic” visual scotoma, I am concerned about ischemia affecting the choroidal circulation. This
ACCEPTED MANUSCRIPT
process also affects the retinal circulation producing disc edema and cotton wool spots. The combination of choroidal and retinal circulation pathology is almost pathognomonic for GCA. We know that up to 20% of GCA patients will not have any systemic features of GCA,9 so the lack of jaw claudication and headache does not concern me in listing this as my first diagnosis. The nodularities on the temporal arteries may be due to co-exisiing atherosclerotic disease. I would request blood work including a CBC, ESR and CRP, as well as arranging a temporal artery biopsy. Given my own personal interest in the topic, I would do a chewing gum test to assess more objectively for jaw claudication. 14
RI PT
This would all occur concurrently to the patient receiving 1 gram of intravenous methylprednisolone;however, there are many other comorbidities to consider in this case. Other vasculitides can mimic GCA, including the changes in the choroidal circulation. In particular I would like to find out more about the cause of his renal failure – does he have lupus or ANCA positive disease for example. I would include tests for other non-GCA vasculitidies in my blood work-up.
M AN U
SC
Next, this patient has an aortic valve replacement and a non-healing ulcer, so there is a possibility of an infectious embolus as the cause for his symptoms. I would look for other stigmata of infectious endocarditis clinically, and request cardiology consultation with a view to an echocardiogram. His INR levels should also be checked. As part of the work-up for other vasculitis and embolic phenomenon, I would request an MRI of the brain and orbits with contrast. Finally given that he has a pale optic disc in his fellow eye, while this fits with a history of childhood traumatic optic neuropathy, thought must be given to Foster-Kennedy syndrome particularly as the disc swelling in his right eye hasn’t resulted in a significant loss of vision, it could be due to raised intracranial pressure.
Case Report (Continued)
TE D
So while treating and assessing for GCA, I would like to more carefully assess his cardiovascular status and I would perform neuro-imaging.
AC C
EP
Due to the appearance of right disc swelling and left optic atrophy, a CT brain was performed that showed no mass or hemorrhage. Incidental findings were calcium plaques in the vessels and mild cerebral atrophy (Fig 1). Hematological investigations revealed anemia with hemoglobin of 79 g/L, platelets 219 x109/L, normal white cell count and elevated inflammatory markers (erythrocyte sedimentation rate 89, C-reactive protein 45mg/L). The INR was sub therapeutic at 1.8, and the remaining blood tests showed borderline elevated calcium and phosphate, low albumin of 30 g/L, and GFR of 13ml/min. Treatment for the presumptive diagnosis of arteritic anterior ischemic optic neuropathy (AION) was begun with intravenous methylprednisone. The patient was referred to our institution for temporal artery biopsy. Repeat examination the next day confirmed right optic disc swelling with a hemorrhage and fine telangiectasia in addition to the CWS. The macula showed a loss of the foveal reflex. There were no emboli or peripheral retinal hemorrhages visible and no rubeosis (Fig 2). Optical coherence tomography (OCT) showed increased thickness and signal of the inner retinal layers (Fig 3). Humphrey visual fields (HVF) showed patchy peripheral field loss (Figure 4a). This clinical picture was more consistent with retinal ischemia than AION. A further vasculitic screen was also arranged, and he was booked for temporal artery biopsy.
ACCEPTED MANUSCRIPT
What would be your diagnosis now? Is there anything else you would do at this stage? Do you think hyperbaric is a good idea? Comments by Dr. Fraser (Continued)
RI PT
He has an elevated ESR and CRP, which are in keeping with GCA. A normochromic, normocytic anemia is also frequently found in GCA patients, though is thought to be associated with a reduced risk of ischemic events, and I would have expected elevated platelets.12 Giant cell arteritis can also cause retinal ischemia,8 so I would continue with the treatment and management plan – steroids and a temporal artery biopsy.; however, the appearance of telangiectasia does suggest a more chronic type of retinal ischemia which I would not expect to see at this stage of a GCA process.
M AN U
SC
With regards to further management, given that there seems to be progressive changes on fundus examination despite steroids, and his INR is sub-therapeutic, his anti-coagulation needs to be managed in conjunction with his other physicians . Switching him to a heparin infusion that can be reversed for the biopsy would be a reasonable option. Unfractionated heparin is relatively safe in chronic renal failure. Thrombus emboli from the heart wall (atrial fibrillation) or the aortic valve in the ophthalmic artery could result in this mixed choroidal/retinal picture, and I would not expect to see emboli within the retinal circulation. Managing the anti-coagulation will cover this potential differential diagnosis. The anemia will be worsening any ischemia, so blood transfusion may help his retinal oxygenation. Hypotension from medication or during hemodialysis should also be addressed in conjunction with the renal physicians. It would be best to keep the perfusion pressure up.
TE D
Calcification of the cerebral vessels is most commonly associated with primary atherosclerosis in the elderly. Patients on hemodialysis with high calcium are at risk of accelerated atherosclerosis and higher mortality.18 Therefore, given that there are signs of chronic retinal ischemia, his cerebral and ocular circulation should be assessed further.
EP
A fundus fluorescein angiogram (FFA) can be very helpful to clarify the circulatory issues. Is there a prolonged arm to eye time? Is there delayed choroidal filling and are there areas of retinal non-perfusion or vasculitis? Small fluorescein doses can be given with digital photographic systems; however, the renal physicians would need to be consulted about safety. It may be best to do the FFA just before his next hemodialysis.
AC C
I would request an MRI scan to look for further evidence of cerebral vasculitis and ischemia. A formal CT or MR angiogram would also cover the origin of the ophthalmic artery – looking for atherosclerotic stenosis or aneurysm. Ophthalmic artery aneurysms cause symptoms within the both the choroidal and retinal circulations.4 Carotid Doppler ultrasound to look for critical stenosis causing ocular ischemia on the right side should also be requested. CWS can also be seen in infective retinopathies including syphilis, bartonella henselae, HIV, herpes viruses, and hepatic virus infections. In particular varicella zoster vasculitis has been documented to cause ophthalmic artery occlusions.11 Given the findings pointing more to retinal ischemia, viral serology should be added to the vasculitis blood screen, if they haven’t already been done. Hyperbaric oxygen may be of benefit in patients with central retinal artery occlusion by increasing oxygenation in the choroidal circulation which may then diffuse through to the inner retina. If this patient is still within 24 hours of the onset of visual loss, then discussion with the hyperbaric oxygen team may be worthwhile. Papers on the subject specifically discuss hyperbaric oxygen for non-arteritic occlusions.17,22 Given that arteritic pathology is
ACCEPTED MANUSCRIPT
still the primary differential diagnosis, this would need to be considered as part of this discussion. It would not be part of my typical management in a case like this, however we do not have hyperbaric oxygen available at the institutions where I work. Case Report (Continued)
RI PT
His vision subsequently worsened to 6/60 OD and repeat examination showed a deteriorated fundus appearance with ongoing disc swelling and increased numbers of CWS. Repeat OCT showed signal increase of the inner retina with loss of distinction of the inner retinal layers and loss of GCL; repeat HVF showed significant deterioration. (Fig 4b). Fluorescein angiography showed significant delays in retinal perfusion, vascular pruning and late patchy venous staining but no optic disc hyperfluorescence (Fig 5). His ESR had increased to 102 and the CRP to 98 mg/L. The vasculitic screen and investigation for syphilis, sarcoidosis and tuberculosis were negative.
M AN U
SC
Electrophysiology showed a negative b-wave on scotopic ERG and a reduction in b-wave amplitude on photopic ERG as well as reduction in amplitude and delay in the flicker ERG. This was thought to be consistent with generalized and especially inner retinal dysfunction. He underwent a session of hyperbaric oxygen therapy, which had not previously been approved and was delayed due to patient anxiety, without any visual improvement. Further treatments were not authorised. Do you agree with the treatment so far? Would you suggest any other systemic treatments or specifically for management of this only eye? Comments by Dr. Fraser (Continued)
TE D
The treatment so far has included IV steroids and hyperbaric oxygen.
EP
The electronegative ERG is in keeping with inner retinal ischemia as seen on OCT and FFA.16 Autoimmune retinopathy and cancer associated retinopathy (particularly melanoma associated) can also cause an electronegative waveform, however, I think it still fits best with retinal ischemia. Therefore, at this time I would still pursue the vascular side of this case. I would chase the temporal artery biopsy results and ask them to be processed urgently. I would liase with pathology to look for other non-GCA vascular changes.
AC C
I would also chase the carotid Doppler results, CT or MR angiography results and the cardiology consultation. PET scans are also of value in assessing GCA and non-GCA vasculitis.12 I would keep him heparinized, control the anemia, and keep the blood pressure up. His head should be kept slightly lower than his heart. The patient has continued to worsen despite steroid treatment, with further elevation of his ESR and CRP. Despite steroid treatment, some GCA patients will continue to have visual deterioration;5 however, I am surprised that the ESR and CRP are getting worse. This makes me think again about infective causes for his symptoms, and now I would start considering malignancy. I would liase with infectious diseases about whether antibiotic and anti-viral cover is warranted. In particular, I would want to discuss covering with valcyclovir for possible varicella zoster virus vasculitis. Blood cultures, urine cultures and ulcer swabs may help isolate a cause.
ACCEPTED MANUSCRIPT
This is most likely a systemic process, working out what that process is and treating that is what will save his eye. Case Report (Concluded)
RI PT
Carotid Doppler revealed bilateral 80-99% internal carotid artery stenosis and vertebral artery stenosis. This was corroborated on CT angiogram that found a 12mm long calcific plaque at both carotid bulbs, causing focal stenosis >90% and generalized extensive calcification of subcutaneous vessels. (Fig 6). The temporal artery biopsy showed focal myxoid degeneration and extensive concentric calcium deposition in the tunica media with no features suggestive of GCA (Fig 7). MRI showed chronic microvascular disease but no focal cerebral ischemia. A SPECT scan was performed which showed markedly reduced cerebral perfusion.
SC
The clinical picture of non-healing necrotic ulcers, acute retinal ischemia with ischemic optic neuropathy, and the histopathological findings were consistent with calciphylaxis (calcific uremic arteriolopathy).
M AN U
Following extensive evaluation by the vascular, neurology and renal teams, surgical management for the severe carotid stenosis was deemed too a high risk. The patient was managed conservatively with adjustment of Warfarin to low-molecular-weight-heparin and aspirin, cessation of his vitamin D supplements, optimization of the medical treatment of hypercholesterolemia and hypertension, and changing to low-calcium replacement fluid in his hemodialysis. He is alive at 18 months post-presentation, and his vision remains stable.
TE D
Discussion
EP
Calciphylaxis is traditionally characterized by diffuse calcification of the media tunica of small arterioles. It classically presents with ischemia and necrosis of subcutaneous tissues, such as skin ulcers, and signs of infarction elsewhere, such as myocardial infarction, phalangeal necrosis, penile necrosis, and subepithelial necrotic nodules in the extremities.23
AC C
Ophthalmic presentations reported in the literature include ischemic optic neuropathy mimicking GCA.10 Review of records usually reveal end stage renal disease (ESRD) with hyperphosphatemia, hyperparathyroidism, and hypoalbuminemia. The pathogenesis of calciphylaxis is poorly understood and likely multifactorial. It is hypothesized that the hyperphosphatemia associated with ESRD leads to vascular smooth muscle cells calcifying under the influence of vitamin D, as happens in normal osteoblasts. This calcification is usually inhibited by Matrix GLa protein; however, that is vitamin K dependent, so is thus diminished in patients undergoing anticoagulation treatment with Warfarin or other vitamin K inhibitors.6 Risk factors for developing calciphylaxis include chronic end-stage renal failure, obesity, diabetes, hypotension, Warfarin therapy, hypoalbuminemia and deranged calciumphosphate metabolism.7,15 Although this constellation of co-morbidities is common in patients with ESRF, calciphylaxis is relatively rare, with an incidence of 1-4% of the population with ESRD.23 The reason for this is unknown.
ACCEPTED MANUSCRIPT
The onset of calciphylaxis is often preceded by a ‘trigger event’ within a minimally buffered homeostatic system, such as sudden weight-loss, liver disease, concomitant vascular disease and use of Warfarin therapy or immunosuppressant agents such as corticosteroids.7 The disease has a poor prognosis, with mortality of 60-80% in patients with ulcerative disease. Currently, the 1- and 5-year survival rates are estimated to be 45% and 35%, respectively.21
RI PT
There is no standardized treatment for this disease; however, a multidisciplinary approach including surgical parathyroidectomy, wound debridement, and aggressive medical management may improve survival. Medical management strategies include lowering of the calcium-phosphate product and serum calcium and phosphate concentrations using treatment with cinacalcet and sodium thiosulphate, cessation of vitamin D supplements, use of bisphosphanates, supplementation of albumin, and daily hemodialysis with use of low-calcium bath dialysate as well as removal of any aggravating agents such as Warfarin and corticosteroid therapy.2,20,23
M AN U
SC
There are some reports suggesting improvement in peripheral ulceration with the initiation of sodium thiosulphate, which is hypothesized to work by improving the aqueous solubility of calcium deposits and aid in their clearance.3 Daily hemodialysis is advocated as it prevents large fluctuations in blood pressure, a risk factor previously identified in non-arteritic anterior ischemic optic neuropathy (NAION) and hypothesized to play a causal role in the development of visual loss in calciphylaxis.13,20 Hyperbaric oxygen therapy has been shown to be of use in healing calciphylaxis ulcers. Supplemental oxygen is thought to maintain retinal function and restore vision via diffusion from the choroidal branches to the inner layers of the retina.1,19
TE D
Disclosures
There are no conflicts of interest to disclose
References
EP
1. Basile C. Hyperbaric oxygen therapy in the treatment of calciphylaxis? Yes, more than hope. Kidney international. 2002;62(6):2300-2300.
AC C
2. Borges L, Rosa P, Dias E, Cássio I. Successful treatment of calciphylaxis by a multidisciplinary approach. BMJ Case Rep. 2014 Jul 17;2014. 3. Burnie R, Smail S, Javaid MM. Calciphylaxis and sodium thiosulphate: a glimmer of hope in desperate situation. Journal of renal care. 2013;39(2):71-76. 4. Choi BK, Lee TH, Choi CH, Lee SW.Fusiform Intracanalicular Ophthalmic Artery Aneurysm; Case Report and Review of Literature. J Korean Neurosurg Soc. 2008 Jul; 44(1): 43–46. 5. Danesh-Meyer H, Savino PJ, Gamble GG. Poor prognosis of visual outcome after visual loss from giant cell arteritis. Ophthalmology. 2005 Jun;112(6):1098-103. 6. Eiser AR. Warfarin, Calciphylaxis, atrial fibrillation and patients on dialysis: outlier subsets and practice guidelines. The American journal of medicine. 2014;127(4):253-254. 7. Hayashi M. Calciphylaxis: diagnosis and clinical features. Clinical and experimental nephrology. 2013;17(4):498-503. 8. Hayreh SS, Podhajsky PA, Zimmerman B. Ocular manifestations of giant cell arteritis. Am J Ophthalmol. 1998 Apr;125(4):509-20
ACCEPTED MANUSCRIPT
9. Hayreh SS, Podhajsky PA, Zimmerman B. Occult giant cell arteritis: ocular manifestations. Am J Ophthalmol 125: 521–526, 1998 10. Huerva V, Sánchez MC, Ascaso FJ, Craver L, Fernández E. Calciphylaxis and bilateral optic neuropathy. J Fr Ophtalmol. 2011 Nov;34(9):651.
RI PT
11. Jayaram H, Stanescu-Segal D, Holder GE, Graham EM. Bilateral ophthalmic artery occlusions due to probable varicella-zoster virus vasculopathy. Arch Ophthalmol. 2012 Nov;130(11):1492-4. 12. Kawasaki A, Purvin V. Giant cell arteritis: an updated review. Acta Ophthalmol 2009 Feb; 87(1):13-32 13. Korzets A, Marashek I, Schwartz A, Rosenblatt I, Herman M, Ori Y. Ischemic optic neuropathy in dialyzed patients: a previously unrecognized manifestation of calcific uremic arteriolopathy. American Journal of Kidney Diseases. 2004;44(6):e93-e97.
SC
14.Kuo CH, McCluskey P, Fraser CL. Chewing Gum Test for Jaw Claudication in GiantCell Arteritis. N Engl J Med. 2016 May 5;374(18):1794-5 15. Lal G, Nowell AG, Liao J, Sugg SL, Weigel RJ, Howe JR. Determinants of survival in patients with calciphylaxis: a multivariate analysis. Surgery. 2009;146(6):1028-1034.
TE D
M AN U
16. Lima LH, Cella W, Brue C, Tsang SH. Unilateral electronegative ERG in a presumed central retinal artery occlusion. Clin Ophthalmol. 2010 Nov 17;4:1311-4. 17. Menzel-Severing J, Siekmann U, Weinberger A, Roessler G, Walter P, Mazinani B. Early hyperbaric oxygen treatment for nonarteritic central retinal artery obstruction. Am J Ophthalmol. 2012 Mar;153(3):454-459.e2. 18. Obi Y, Mehrotra R, Rivara MB, Streja E, Rhee CM, Lau WL, Kovesdy CP, KalantarZadeh K. Hidden Hypercalcemia and Mortality Risk in Incident Hemodialysis Patients. J Clin Endocrinol Metab. 2016 Jun;101(6):2440-9. 19. Podymow T, Wherrett C, Burns KD. Hyperbaric oxygen in the treatment of calciphylaxis: a case series. Nephrology Dialysis Transplantation. 2001;16(11):2176-2180.
EP
20. Vedvyas C, Winterfield LS, Vleugels RA. Calciphylaxis: a systematic review of existing and emerging therapies. Journal of the American Academy of Dermatology. 2012;67(6):e253-e260. 21. Weenig RH, Sewell LD, Davis MD, McCarthy JT, Pittelkow MR. Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol. 2007 Apr. 56(4):569-79.
AC C
22. Weiss JN. Hyperbaric oxygen treatment of nonacute central retinal artery occlusion.Undersea Hyperb Med. 2009 Nov-Dec;36(6):401-5. 23. Wilmer WA, Magro CM. Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment. Semin Dial. 2002 May-Jun. 15(3):172-86
7. Abstract:
A 78-year-old Caucasian man with significant vascular disease reported sudden onset of worsened vision during a routine wound-care appointment for non-healing necrotic leg ulcers. He described painless blurring of vision with grey scotomas in his RE, his only wellseeing eye, following trauma to the LE as a child. He presented with retinal ischemia, a cotton-wool spot and optic nerve swelling. Temporal artery biopsy showed myxoid degeneration and extensive calcium deposition which also was shown on imaging throughout his carotid and vertebral arterial system, the clinical picture of calciphylaxis.
ACCEPTED MANUSCRIPT 8. Keywords:
painless vision loss, retinal ischemia, ischemic optic neuropathy, calciphylaxis
RI PT
Figure Legends Fig 1: Plain CT brain and orbits shows normal ventricles (asterix) and CSF spaces with no evidence of cerebral infarction or space occupying lesion. There is diffuse calcification of the vessels ( ).
M AN U
SC
Fig 2: Fundus photos showing right mild optic disc swelling with a nerve fiber layer hemorrhage (arrow), fine telangiectasia and a cotton wool spot (asterix) . There is a dulling of the foveal reflex. There are no emboli or peripheral retinal hemorrhages visible and no neovascularization. The left fundus shows mild temporal optic disc pallor and a otherwise healthy macula. Fig 3: Optical coherence tomography (OCT) scan through the right fovea showing increased thickness (bar) and signal intensity (asterix) of the inner retina layers with no evidence of intra- or sub retinal fluid. The left macula shows inner retinal thinning with normal signal. Fig 4: 24-2 Humphrey Visual fields (HVF) at presentation (a) showing patchy peripheral field loss and after several days (b) showing worsening of field loss with predominantly nasal scotoma.
TE D
Fig 5: Fluorescein Angiogram showing significant delays in retinal perfusion through the right fundus with late venous phase not reached till 1.06 minutes. There are areas of blocked fluorescence secondary to the CWS (asterix) and some late patchy venous staining ( ) but no optic disc leak or evidence of vascular sheathing. The left fundus is normal.
EP
Fig 6: CT angiogram from aortic arch to circle of Willis shows and a calcified plaque at both carotid bulbs extending into the origins of the internal carotid arteries (arrow). This is causing marked bilateral stenosis >90%. There is significant generalized calcification with a focus of heavy calcification at the aortic arch, common carotid and both vertebral artery origin which is also causing marked stenosis.
AC C
Fig 7: Specimen of right temporal artery in low and high magnification showing focal myxoid edema (arrow) and extensive concentric medial calcification (asterix) consistent with Calciphylaxis. There is no significant inflammation and no giant cells are identified.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT