We describe four patients with acute visual loss, noticed by the patients immediately after a surgery or a drug application. The literature reports visual loss after a variety of nonocular surgeries, among which spinal surgery, cardiac surgery and radical neck dissection held the greatest risk for this devastating complication [1, 2, 9, 10].
The final steps in the pathogenetic chain of events of perioperative visual loss in adults are mainly retinal vascular occlusion, ischemic optic neuropathy and ischemic cerebral lesions [3, 11]. High sensitivity of the retina to hypoxia, precipitated by hemodilution, may play a crucial role, particularly if the blood loss is significant and if the blood is replaced by crystalloid and colloid fluids only, rather than being complemented by blood transfusions or packed red blood cells.
The roles of intraoperative arterial hypotension/hypertension or increased IOP with consecutive reduction of the ocular perfusion pressure have also been discussed.
In our case series, low perfusion pressure, combined with disturbed autoregulation of the ocular blood flow, together with increased drug sensitivity seem to have played a central role in the pathogenesis of ocular hypoxia. The perfusion pressure (PP) of the eye depends on the difference between the mean arterial pressure and the retinal venous pressure (RVP). In healthy subjects, RVP is equal or slightly above the IOP. However, in patients with Flammer syndrome RVP is often distinctly above the IOP [12]. Therefore, the PP is lower than estimated just on Blood Pressure and IOP alone [13]. According to the anesthetic protocol, the MAP of Patient 1 was consistently around the lower limit of the normal range throughout the entire surgery. Together with an increased IOP (as for instance, when Ketamine is used) and an even higher RVP, PP can drop to very low values which are particularly relevant if at the same time the autoregulation is disturbed. A potential influence of a mechanical compression of the eye in prone position during scoliosis surgery (Patient 1) or during peribulbar steroid application (Patient 3) can not be ruled out. Postoperatively fundus examination revealed ocular hypoxia, which involved the retina (Patient 1), the optic nerve head (Patients 1, 3 and 4) and the choroid (Patients 1 and 4).
The trilateral link between anaesthesia, perioperative visual loss and Flammer syndrome
All four patients reported visual loss immediately after systemic surgery, ophthalmic surgery, or ocular interventions, while all of them suffered simultaneously from Flammer syndrome. Our hypothesis is that FS may increase the risk for perioperative visual loss, and is based on the following facts:
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As it is now well established, and further exemplified in our case series, that subjects with Flammer syndrome have intrinsically insufficient and unstable blood flow autoregulation.
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Flammer syndrome subjects tend to react to a number of stimuli, such as cold, physical or emotional stress, and systemic medication, like adrenalin, with marked vasoconstriction [14, 15]. The most noteworthy problem in FS subjects seems to be an arterial vasospasm [16].
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Subjects with FS often suffer from systemic hypotension [14], partly due to reduced sodium reabsorption in the proximal tubules of the kidneys [17, 18]. The latter in turn is due to prostaglandin E2 release, following increased systemic or local production of endothelin-1.
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Subjects with FS often exhibit further blood pressure dips; therefore they have a lower perfusion pressure.
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Subjects with FS have impaired autoregulation of their ocular blood flow, in which vascular endotheliopathy plays an important role [14].
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Subjects with FS have, on average, higher retinal venous pressure [12, 19]. This contributes further to a decrease of the perfusion pressure in the central retinal vein and in the optic nerve head, which has its venous outflow again via the central retinal vein.
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Subjects with FS have altered drug sensitivity, which is linked to altered expression of the ABC transport proteins [20]. This in turn may lead to yet unknown side effects during anaesthesia.
To note well, the complete vascular workup in our patients was positive for history of cold extremities, increased reactivity to cold (in all patients), and findings of increased plasma Endothelin-1 levels (Patient 1). Furthermore, the capillary blood flow cessation, registered through Nailfold Capillaroscopy with cold provocation test (Patients 1, 2 and 3) [22] and the other diagnostic signs (Table 2) [23] pointed toward unstable blood flow autoregulation as part of Flammer syndrome.
We will summarise here some prominent signs and symptoms, in order to complete the profile of such patients. Subjects with FS tend to have cold extremities [14] and reduced feeling of thirst [21]. They require longer time to fall asleep, especially when they are cold [22], as warm feet are generally a prerequisite for falling asleep. FS subjects also suffer more often from atypical headaches and migraines [23] and have increased pain sensations, since ET-1 decreases the pain perception threshold [24]. The flow cessation in nailfold capillaries after cold provocation is prolonged [23]. Reportedly, they have altered gene expression in the circulating lymphocytes [25] and slightly increased plasma Endothelin-1 level [21]. The syndrome occurs more often in females than in men, more often in thin than in obese, and - in young than in older subjects [26]. The systemic oxidative stress in such individuals is increased, most probably due to the unstable blood flow.
In all of the presented patients the vascular dysregulation dynamics were supposedly influenced by pharmaceuticals, with known side effects.
The pharmacological agents used during the surgery of Patient 1 were: Fentanyl, Remifentanil, Morphine, Thiopental, Atracurium, Ketamine, Propofol, Ringer’s lactate, HAES, Cefazolin, Paracetamol and Oxygen. Hypotension is observed after Morphine and Remifentanil medication. Thiopental and Atracurium may have hypotonic effect, mediated by histamine release [27, 28]. Ketamine has a well-pronounced hypertensive effect and is also known to increase the IOP, thus negatively influencing the ocular blood flow by decreasing the perfusion pressure.
Raynaud-like phenomenon has been described in a 14-year-old girl after Propofol medication [28]. Cerebral vasoconstriction has also been reported with Propofol intake [29].
In Patient 2 the anaesthetic protocol comprised Meperidine, Propofol, Ringer’s lactate, Hydroxyethyl Starch (HAES), Cefazolin, Paracetamol and Oxygen. Here the medications given to an individual with pre-existing Flammer syndrome and normal tension glaucoma produced the so dreaded outcome of visual loss. On the contrary, to our knowledge, a betamethasone-vascular dysregulation interaction (patient 3) has not been reported so far [29, 30].
Regarding Patient 4, during cardiac surgery a catecholamine (Norepinephrine) is routinely used to preserve the vessel tonus under open-air conditions. However, Norepinephrine is known to produce peripheral vasoconstriction [7].
Studying four patients with Flammer syndrome, in which seemingly different influences exacerbated the vascular disturbance, increased our understanding of this condition and the precautions to be taken, if a surgery or an invasive treatment, such as peribulbar or retrobulbar medication is to be performed.
Our findings shed new light on the pathogenesis of perioperative visual loss, while we ought to point out the limitations of our study, stemming from the small number of observed patients. While thankfully this complication is quite rare, further reports and observational prospective studies would be necessary, in order to establish the rate of perioperative visual loss among subject with FS, compared to the general population undergoing anaesthesia and surgery, and how the perioperative management of such subjects can promote a more favourable outcome in terms of vision preservation.
In Summary, we observed perioperative visual loss in four consecutive patients, and all data pointed toward episodes of ocular hypoxia. All four patients also had Flammer syndrome, therefore we presume that the syndrome may distinctly increase the risk for this devastating complication. A preoperative screening for FS would identify the patients in need of preventive measures. The screening can be done through thorough history taking, sensitive for data pointing toward probability for Flammer syndrome, such as prominent cold sensitivity, increased sleep latency, low blood pressure and other features of the syndrome (Table 2).
Identifying patients with FS may allow undertaking preventive measures, such as avoidance of: low blood pressure, cold provocation and vasoconstrictors, while implementing pre-treatment with magnesium [31] and low dose Calcium-channel blockers [14]. Calcium-channel blockers in adapted lower doses are preferred for their higher lipid affinity, which leads to better penetration through cerebral vessels, as well as for their milder effect on retinal vessels. Very productive and cost-effective approach to a patient with known or presumed FS is to administer omega-3 fatty acids supplementation and/or a diet containing them [32, 33], together with magnesium preparations, during the last two weeks preceding the surgical treatment.
Finally, in our case series, we assume a disturbed blood flow autoregulation, and a hyperreactivity toward pharmacological stimuli, to be the etiological bases of the unstable blood supply during the respective interventions. This process leads to significant and rapid increase of free radicals and enormous oxidative stress in individuals with Flammer syndrome. In our patients, based on all presented findings, we also hypothesise a hyperactivity of the sympathetic nervous system during or immediately after the surgery, or procedure, which resulted in massive vasospasm of the retinal, choroidal and/or peribulbar vessels, thus producing a visual loss.
The presented herein in-depth analysis of vascular dysregulation factors in a diverse group of patients, including an adolescent individual, has promoted our understanding of the pathological mechanisms leading to visual loss after uncomplicated (from systemic point of view) anesthesia or surgery, and was crucial for identifying effective preventive strategies.