19.1 History of Orbital Exenteration

George Bartisch, a German physician, considered by many as the “father of modern ophthalmology,” first reported orbital exenteration in 1583 [1]. The modern total orbital exenteration was reported by Golovine [2], and Coston and Small in 1981 simplified the technique [3]. Since then, several variations in the surgical procedure have been reported [4,5,6,7,8,9,10,11,12,13,14].

19.2 Changing Trends in Orbital Exenteration

Orbital exenteration is a potentially lifesaving yet mutilating surgery with permanent cosmetic blemish leaving the patients socially uncomfortable. It has been primarily reserved for extensive and infiltrative eyelid, ocular surface, adnexal, and intraocular malignancies with orbital extension and for advanced primary orbital malignancies where conservative treatment is not feasible [15,16,17]. Non-neoplastic conditions including ROCM constituted only a minority of indications in the previously published reports [4,5,6,7,8,9,10,11,12,13,14].

The COVID-19 pandemic led to an unfortunate rapid rise in the number of cases of ROCM undergoing orbital exenteration. It is possible that some of these patients could be conservatively managed without compromising on life salvage. On the contrary, inappropriate attempts at conservation may have implications on life salvage. Therefore, the treating clinicians need to understand the thin line between adopting conservative management and resorting to radical surgical interventions. The decision to conserve versus exenterate becomes logical if we were to follow a system of staging to evaluate the severity and triage the patients for management as appropriate.

19.3 Stages of ROCM

ROCM typically follows a sequence of evolution from the point of entry (nasal mucosa) to the point of proliferation (paranasal sinuses) with contiguous progression to involve the orbit and intracranial structures. There are non-contiguous routes of spread as well, though rare. Before outlining the management protocol, the clinicians must understand the stages of ROCM as described in Fig. 19.1 [18] which provides a logical representation of clinical severity. Stage 3 and stage 4 constitute orbital mucormycosis.

Fig. 19.1
figure 1

Stages of ROCM 18

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Optimal management of ROCM requires concerted action and rapid response by a multidisciplinary team of experts in diagnosis (radiology, microbiology, pathology, molecular biology), and medical (infectious disease, neurology, critical care), and surgical (otorhinolaryngology, ophthalmology, neurosurgery) care. Establishing a clinico-radiological assessment to ascertain the extent of disease and confirmation by direct microscopy are the primary steps that help plan the management approach.

19.4 Medical Management of ROCM

Comprehensive guidelines for the medical management of ROCM have been issued by the European Confederation of Medical Mycology (ECMM) and the Mycoses Study Group Education and Research Consortium (MSGERC) [19]. Immediate induction therapy includes intravenous liposomal Amphotericin B 5–10 mg/kg BW with strict metabolic control. In cases with contraindication to Amphotericin B due to impaired renal function, Isavuconazole IV 200 mg thrice a day on days 1–2, 200 mg once a day from day 3; or Posaconazole IV 300 mg twice a day on day 1, 300 mg once a day from day 2 must be given. Continuation of induction therapy with intravenous liposomal Amphotericin B 5–10 mg/kg BW is required for a minimum of 4 weeks, followed by step-down treatment (oral Isavuconazole 200 mg thrice a day on days 1–2, 200 mg once a day from day 3; or oral Posaconazole 300 mg twice a day on day 1, 300 mg once a day from day 2) for 3–6 months or a minimum of 6 weeks following clinico-radiological regression or stabilization [18]. Amphotericin B Deoxycholate or Amphotericin B Lipid Complex may be utilized in patients with good renal function.

19.5 Recommended Treatment Protocol for ROCM with Orbital Involvement

Aggressive debridement of the involved paranasal sinuses constitutes the primary surgical management in cases of ROCM [20]. It can be combined with conservative management of the orbital component, primary orbital exenteration, or deferred orbital surgical intervention. Stage-wise management of orbital mucormycosis has been depicted in Fig. 19.2.

Fig. 19.2
figure 2

Stage-wise management of orbital mucormycosis

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19.6 Conservative Management in ROCM

There are clear indications for conservative management of the orbital disease as follows:

Stage 3a (involvement of the nasolacrimal duct and medial orbit, with unaffected vision): Stage 3a as shown in Fig. 19.3 describes localized orbital involvement, in which it is possible to treat the disease conservatively with medical management as described above along with intraorbital Amphotericin B injection (Deoxycholate Amphotericin B 3.5 mg/mL, Liposomal Amphotericin B 1 mg/mL) specifically to the area of involvement as confirmed by imaging. A series of 7 injections are provided daily or on alternate days depending on clinical severity and response, with clinico-radiological monitoring of response.

Fig. 19.3
figure 3

Stage 3a ROCM (a) Clinical picture showing left periocular edema, ptosis and proptosis. (b) Endoscopy picture showing necrosed left periorbita (arrow). (c, d) Coronal and axial CT, respectively, showing left eye proptosis with diffuse bilateral paranasal sinus and left medial orbital involvement (Courtesy: Sen M et al. [21])

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Stage 3b (diffuse orbital involvement, >1 quadrant or >2 structures, and unaffected vision): Stage 3b as seen in Fig. 19.4 was managed with intraorbital amphotericin B injections to the areas involved along with concomitant medical management and assessment of response clinico-radiologically and has responded remarkably well. In patients with a suboptimal response after 7 injections, limited orbital debulking is recommended, along with orbital irrigation with Amphotericin B 1 mg/mL.

Fig. 19.4
figure 4

Stage 3b ROCM: (a) A 56-year-old lady presented to us with left eye BCVA of light perception only, ptosis of 3 mm, restriction of movements in all directions with radiological evidence of involvement in the superomedial and inferomedial aspect. (b) After a series of seven injections of intraorbital Amphotericin B, she had complete resolution of symptoms and signs along with BCVA of 20/40 at the latest follow-up 5 months and interval decrease in the medial orbital involvement on MRI

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Results of this approach are variable. Kohn and Helper have established that timely and accurate diagnosis of the extent of involvement attributes to favorable outcomes with conservative management thus avoiding mutilating surgeries and preserving visual acuity [22], and the same has been supported by Pelton et al. [23]. As per Sen et al., in the orbit, diffuse involvement predominated in 40% (674 of 1731) followed by involvement of the medial orbit in 27% (469). Orbital apex was involved in 21% (371) patients [21]. Kashkouli et al. have reported that out of the 34 eyes without exenteration, 41% progressed to complete loss of vision with a final vision survival of 25% in their series [24]. We believe that an accurate assessment of the extent of involvement and intraorbital Amphotericin B targeted to the area of involvement, early identification of poor responders and orbital exenteration in that subset are the keys to the success of this approach. Murthy et al. have reported 111 cases of ROCM treated conservatively with no recurrence for 3 months and not requiring orbital exenteration despite complete loss of vision (in five cases), thus avoiding mutilating surgeries [25].

19.7 Orbital Exenteration in ROCM

There are specific indications for orbital exenteration as follows:

Stage 3c (central retinal artery or ophthalmic artery occlusion or superior ophthalmic vein thrombosis; involvement of superior orbital fissure, inferior orbital fissure, orbital apex, loss of vision): This stage (Fig. 19.5) is a specific indication for orbital exenteration with continued medical management. Moorthy et al. have ascertained that an aggressive surgical approach reduces disease burden in these cases with irreversible blindness [26].

Fig. 19.5
figure 5

Stage 3c ROCM (a) Clinical picture showing right eye ptosis, periocular edema, and ecchymosis. (b) Severe conjunctival congestion and chemosis. (c) Axial MRI (T1) of orbit and paranasal sinuses showing diffuse orbital involvement along with diffuse paranasal sinus involvement (s/p right paranasal sinus debridement and turbinectomy). (d) Coronal MRI (T2) showing unilateral diffuse right orbital involvement (Courtesy: Sen M et al. [21])

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Stage 3d (bilateral orbital involvement): This stage requires a comparative analysis of orbital involvement (Fig. 19.6). Bilateral exenteration is not recommended and therefore, intraorbital Amphotericin B to the relatively better orbit along and exenteration of the more severely involved orbit is advised. Kashkouli et al. have reported four such patients in whom two cases were operated on for unilateral exenteration and another eye was left as blind eye and in the other two cases both eyes were left without any surgical intervention [24].

Fig. 19.6
figure 6

Stage 3d ROCM (a) Axial MRI (T2) and (b) contrast enhanced (T1) of the orbit and paranasal sinuses showing bilateral orbital apical involvement, more extensive on the right side (Courtesy: Sen M et al. [21])

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Stage 4 (central nervous system involvement): Sen et al. noted that in the CNS, cavernous sinus was most commonly involved in 53% (285 of 539), bilateral CNS involvement in 5% (133 of 2669) cases with cavernous sinus being the most common route of spread (70%, 299 of 430).

Even though in these cases (Fig. 19.7), the disease has progressed to involve the central nervous system, it has been observed that timely orbital exenteration results in faster recovery and halts the disease progression as is shown by Kashkouli et al. in their series of 79 eyes of 63 patients [24]. Jung et al. have stated that control of the underlying predisposing illness, prompt medical management, and aggressive surgical intervention decreases mortality [27].

Fig. 19.7
figure 7

Stage 4b ROCM (a) Clinical picture showing no significant ocular manifestation, however, (b) Axial MRI (T1) of the orbit, paranasal sinuses and brain showed diffuse paranasal sinus involvement along with (c) Coronal view (T1) showing extension into the cavernous sinus via the pterygopalatine fossa (Courtesy: Sen M et al. [21])

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19.8 Gray Zone

There are certain situations where cautious conservative measures can be employed:

  1. 1.

    Younger patients with stage 3c or 3d with good renal function can be treated conservatively with intraorbital Amphotericin B, limited orbital debulking with close clinico-radiological monitoring, which on worsening can be triaged to orbital exenteration. Those improvement or stability can be continued on conservative treatment.

  2. 2.

    Young patients with bilateral orbital involvement (stage 3d) can be treated conservatively with intraorbital Amphotericin B, limited orbital debulking with close clinico-radiological monitoring.

  3. 3.

    Patients with extensive orbital invasion who cannot undergo immediate orbital exenteration due to coexistent uncontrolled comorbidities or continuing COVID-19-associated respiratory derangements.

Sen et al. reported that ROCM covers a wide range of age groups with a mean of 51.9 years (range, 12–88 years) [21], therefore, the decision about radical surgical interventions becomes difficult for the clinicians as well as for the families. It is imperative to weigh the advantages and disadvantages before making a decision (Fig. 19.8).

Fig. 19.8
figure 8

Advantages and disadvantages of conservative treatment versus orbital exenteration

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19.9 Prognosis

Hargrove et al. in an extensive literature review have stated that patients with ROCM with age >46 years, frontal sinus involvement, and fever had bleak chances of survival whereas patients treated with Amphotericin B had a better survival rate and that exenteration increases the likelihood of survival [28]. We have observed that out of 2826 cases assessed, the ocular outcome was available for 1838 patients, 16% (289) had orbital exenteration and in 84% (1549), the eye could be salvaged. With the protocol mentioned above, eye salvage was achieved in 100% (50 of 50) in stage 3a, 98% (81 of 83) in 3b, 83% (97 of 117) in 3c, 77% (10 of 13) in 3d, 71% (24 of 34) in 4a, 79% (11 of 14) in 4b, 82% (22 of 27) in 4c, and 67% (8 of 12) in 4d [21].

Multiple case series have reported a variable outcome including no effect to increased patients’ survival [4, 23, 29, 30] to a significant decrease in survival rate [27, 28].

19.10 Challenges in Future

As the treatment entails a significant financial burden due to prolonged hospital stay, repeated radiological investigations, long recovery burden, maintenance therapy, and reconstructive surgeries, it leaves a major impact on the family. Psychological and cosmetic rehabilitation in patients undergoing orbital exenteration due to ROCM has to be handled delicately [31]. Dedicated counseling sessions are recommended for the ROCM survivors as they undergo multiple surgeries with long-term health-related issues within a short period [32].

19.11 Conclusion

Among the cases of ROCM, a stage-based treatment protocol has been advocated which includes conservative management for stage 3a, stage 3b, and orbital exenteration for cases with stage 3c, stage 3d, and stage 4. There is, however, a gray zone, wherein for young patients with stage 3c and 3d ROCM, a cautious conservative approach can be considered. A balanced approach must be followed which comprises of a multidisciplinary team, accurate primary assessment of the extent of the disease, close monitoring of treatment response and disease progression by clinico-radiological assessment coupled with holistic consideration of psychological, social, and economical aspects helping in taking the decision for conservative treatment versus orbital exenteration.