Archives of Academic Emergency Medicine. 2021; 9(1): e54 CA S E RE P O RT Facial Nerve Palsy with Total Ophthalmoplegia; a Novel Presentation of Fungal Invasion Zainab Mehdi1∗, Nidhi Bhardwaj1, Jyoti Aggarwal1, Narinder Kaur2, Brijdeep Singh3 1. Department of General Medicine, Government Medical College and Hospital, Sector -32 Chandigarh, India. 2. Department of Radio diagnosis, Government Medical College and Hospital, Sector -32 Chandigarh, India. 3. Department of Pathology, Government Medical College and Hospital, Sector -32 Chandigarh, India. Received: May 2021; Accepted: May 2021; Published online: 28 July 2021 Abstract: Mucormycosis is an expeditious invasion of a fungus of angioinvasive nature, predominant in immunocompro- mised individuals, often leading to organ malfunction and loss. Facial nerve involvement and total ophthalmo- plegia are its rare presentations. Early detection and treatment can alter natural disease course and prevent po- tential catastrophic outcomes in diabetic patients. Facial nerve palsy is mostly attributed to peripheral neuropa- thy in patients with advanced diabetes mellitus. It rarely raises alarm about an invasive fungal infection. Here, we report the case of a 38-year-old male with type 2 diabetes mellitus, who presented to us with left lower motor neuron type facial palsy and left-sided total ophthalmoplegia due to invasive rhino-orbito-cerebral mucormyco- sis (ROCM). Despite aggressive measures, including antifungal therapy and repeated endoscopic debridement, he subsequently developed central retinal artery occlusion (CRAO) and underwent left eye exenteration. Keywords: Mucormycosis; diabetes mellitus; facial paralysis; retinal artery occlusion Cite this article as: Mehdi Z, Bhardwaj N, Aggarwal J, Kaur N, Singh B. Facial Nerve Palsy with Total Ophthalmoplegia; a Novel Presentation of Fungal Invasion. Arch Acad Emerg Med. 2021; 9(1): e54, DOI: https://doi.org/10.22037/aaem.v9i1.1305. 1. Introduction Mucormycosis, coined and reclassified by R.D.Baker, is an insidious fungal infection caused by ubiquitous mold, mu- cormycetes, which belongs to family of mucoraceae, order Mucorales, class zygomycetes (1, 2). Since being reported first in 1885 by German pathologist Pal- tauf, they have increasingly manifested themselves primar- ily among immunocompromised individuals (1, 2). A 2009 French study reviewing 10-year trends of mucormycosis re- ported 7.4% annual amplification of such cases (3). Diabetes mellitus is the most common predisposing factor, the rest in- clude hematological neoplastic diseases, iron overload, and steroid and deferoxamine therapy (4, 5). The clinical presentation has been broadly divided into five main categories: rhino-orbital-cerebral, pulmonary, cuta- neous, gastrointestinal, and disseminated. Rhino-orbital- cerebral mucormycosis (ROCM) can be acute or the lesser- ∗Corresponding Author: Zainab Mehdi; Area-21, Emergency Medicine, A block, Government Medical College and Hospital, Sector -32 Chandigarh, In- dia. Email: ir.zainab@gmail.com, Tel: +919582432774, ORCID: 0000-0002- 8920-3300. known chronic form. Acute form spreads aggressively in- volving nose, sinus, orbit, and other cranial entities within a short period of time, typically manifesting as orbital swelling, headache, ophthalmoplegia, or visual loss (6). Facial nerve palsy is a relatively lesser-known and unusual presentation of ROCM. It has the potential of being misdiagnosed as a vas- cular event, causing delayed detection and treatment, while adversely affecting the outcome (7). Similarly, central reti- nal artery occlusion (CRAO), lower cranial nerves palsy (IX, X CN), and cavernous sinus thrombosis have also been docu- mented as rare presenting symptoms of unilateral ROCM (8, 9). Here, we report a case of a 38-year-old male with type II di- abetes mellitus who had advanced intracranial and intraor- bital mucormycosis. The presence of unilateral lower motor neuron (LMN) type facial palsy and ipsilateral total ophthal- moplegia as presenting features of fungal infection make this case unique. 2. Case presentation A 38-year-old male presented to the emergency medicine de- partment of our urban academic tertiary care center with painless left eye swelling for the last seven days. He also com- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Z. Mehdi et al. 2 plained of progressive limitation of left eye movement with drooping of left eyelid, ultimately causing inability to open left eye over last week. He complained of having double vi- sion while looking sideways. While looking himself in mir- ror two days ago, he also noticed his mouth deviating to- wards the right side of his body. He had history of high-grade fever, mostly at night time, in the last fifteen days, which was responsive to oral antipyretics, as well as few episodes of bloody sputum. His wife also noticed his body excessively sweating at night for the last few weeks and his significant weight loss in the last few months. The patient had suffered from diabetes mellitus for the last seven years, non-compliant to orally administered anti- hyperglycemic agents (OHA) treatment. His past medical history revealed having been diagnosed with pulmonary tu- berculosis two years back, for which he took regular treat- ment only for four months. He has smoked (30 pack years), consumes alcoholic beverages four days a week, and occa- sionally uses opium. There was no history of trauma, in- voluntary body movements, pus or watery discharge from ear, epistaxis, alteration in sensorium or behavior, dyspha- gia, or change in voice. No history of any recent surgery was present. The patient was conscious with Glasgow coma score (GCS) of E3V4M6, afebrile (temp 99.6 F), blood pressure of 100/80 mmHg, pulse rate of 89/min, and respiratory rate of 22/min, cooperative with physician. Neurological examination re- vealed deviation of angle of mouth to the right side with ab- sent wrinkling of forehead on left side, abnormal grimace with hypoesthesia in distribution of V1, V2 branches of left trigeminal nerve (Figure 1). On blowing of mouth air, leak was present from left side. Left eye ptosis, immobility, fixed mid-dilated non-reactive pupil and complete loss of accom- modation, and loss of left corneal sensation were noted. Fun- doscopy revealed normal disc and macula. He had bilateral lower and upper limb power of 5/5 with normal reflexes and no other cranial nerve deficit was noted. Nasal discharge from left nostril was seen, which was not blood stained. No infraorbital necrosis, ulcer, or perforation of hard palate were present. Gag reflex was intact. Based on clinical findings, after ruling out possibility of trauma, a differential diagnosis of cerebrovascular accident (CVA), intracranial space occupying lesion, tuberculoma or diabetes mellitus-related neuropathy with tuberculosis re- activation were considered. Initial Non-Contrast computed tomography (CT) scan (NCCT) of the head revealed left maxillary sinusitis. Hematological and biochemical workup done in emergency department revealed anemia, raised to- tal leukocyte count (TLC), and high random blood glucose without ketoacidosis (Table 1). Cerebrospinal fluid exami- nation was unremarkable. Electrocardiogram (ECG) was not suggestive of any abnormality. Urine and blood culture were sterile. Sample for assessing KOH mount of nasal secretion was sent. His sputum was sent for acid fast bacilli (AFB) staining as well as fungal evaluation. Patient was admit- ted to the emergency medicine ward and started on intra- venous (IV ) antibiotics empirically, and insulin for glycemic control, as further diagnostic evaluations continued. As per local guidelines, his high nasal and oropharyngeal swab were sent for RTPCR for COVID-19 which came negative. His chest radiograph revealed fibrotic bands along with cavitary lesion with surrounding consolidation and air crescent sign present in both hemi thoraces (figure 2). Contrast-enhanced magnetic resonance imaging (CEMRI) of brain, orbit, and paranasal sinuses (PNS) was done to look for intracranial pathology. It demonstrated acute left maxillary sinusitis with posterolateral wall erosion, prominent left op- tic nerve sheath, and skull base osteomyelitis with cavernous sinus thrombosis (Figure 2). In view of chest X-ray findings, after pulmonary consultation contrast-enhanced CT scan (CECT) of chest was performed to aid in decision regarding initiation of anti-tubercular therapy, which suggested tuber- culosis reactivation (Figure 2). Patient’s KOH mount of nasal secretion showed non-septate ribbon-like hyphae. Based on cumulative results of initial evaluation, a primary diagnosis of invasive rhino-orbito-cerebral mucormycosis with pulmonary tuberculosis reactivation was made. Anti- tubercular treatment (ATT) was started and ear, nose, throat (ENT) review was sought for assessing need for urgent en- doscopic debridement, taking in account intra-orbital and intracranial fungal extension causing multiple cranial nerve palsies threatening vision. Nasal endoscopic debridement and left orbital decompression were performed the next day. Histopathological examination (HPE) of excised tissue re- vealed broad aseptate hyphae with right angle branching in- vading both nerves and vessel wall, confirming diagnosis of invasive mucormycosis (Figure 2). Patient was started on amphotericin B, optimal anticoag- ulation, and insulin therapy for optimization of glycemic control. His biochemistry was regularly monitored for any nephrotoxicity, hematotoxicity, and other infusion-related adverse effects. A repeat endoscopic debridement was per- formed after a period of seven days. Meanwhile, serial fun- doscopy was performed by ophthalmologist to look for pos- sible optic nerve involvement, any optic disc changes, pa- pilledema, or decrease in visual acuity and field. A week after the second debridement and thirteen days of amphotericin B cumulative dose 1425 milligrams, patient complained of severe pain in left side of face, predominant in the orbital region with increased swelling on waking up from sleep. Fundus examination revealed a cherry red spot, optic disc edema with complete retinal opacification, suggesting cen- tral retinal artery occlusion in left eye. Patient was started on topical timolol 0.5% and systemic acetazolamide along- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2021; 9(1): e54 side intermittent digital ocular massage with the aim of re- ducing intraocular pressure. He did not respond to the above measures and decision for left eye exenteration alongside repeat decompression and debridement was made. Post- exenteration monitoring for involvement of right eye and other signs of raised intraocular and intracranial pressures continued alongside antifungal therapy. His condition re- mained satisfactory and gradual improvement followed. His right eye vision remained unaltered and serial fundoscopy did not reveal any alarming features. Optimal glycemic con- trol was achieved with insulin therapy. He was ultimately dis- charged home after 48 days of hospital stay in a stable state with residual left facial nerve palsy, written advice to follow up for dressing, ocular prosthesis, and further treatment op- timization. 3. Discussion Mucormycosis, a deadly fungal infection by Mucorales, nearly invariably involving immunocompromised patients, especially diabetics, can disseminate to paranasal sinuses, retro orbital regions, and brain. Its ability to extensively and uniformly invade vessels facilitates hematogenous spread to various areas leading to vessel thrombosis and tissue necro- sis in multiple organs (10). Factors that render diabetics more prone to fungal invasion include pre-existing nerve ischemia and injury, abnormal en- doneurial and epineural vessels, resistant arteries, reduced chemotaxis and phagocytic efficiency, and favorable acidic and high-sugar environment helping hyphae production (7, 11). Pterygopalatine fossa plays a key role in involvement of facial nerve and retro global area. Its numerous vascular and neural connections facilitate cranial invasion and lower cranial nerve palsies (7). Our patient had fungal skull base osteomyelitis, which may have facilitated facial nerve inva- sion via pterygopalatine fossa, cavernous sinus thrombosis causing ipsilateral involvement of third, fourth and sixth cra- nial nerves manifesting as total ophthalmoplegia and sen- sory loss in distribution of V1 and V3 divisions of the fifth cra- nial nerve. Prognosis of mucormycosis with intracranial and intra- orbital extension is disastrous and usually fatal. Amalgama- tion of surgical debridement and amphotericin B has im- proved patient survival to 85% from 24% in those untreated (12). Our patient was managed with early and multiple- staged endoscopic debridement. He received a total dose of 4125 milligrams of amphotericin B. Due to advanced fun- gal invasion of left optic nerve and subsequent thrombosis of ophthalmic artery, his left eye could not be salvaged. Knowing that unilateral facial nerve palsy can be a present- ing feature of intracranial spread of fungal infection and considering it in the initial workup of all immunocompro- mised patients presenting with peripheral neuropathy can help early cessation of disease advancement and salvage of organs. Multiple cranial nerve palsies in an immunocompro- mised patient without history of trauma should alarm emer- gency physician of possible intracranial fungal infection. It is of outmost importance to assess KOH mount of nasal se- cretions, keep a low threshold for CEMRI of brain, orbit, and PNS and start antifungal treatment as early as possible. Long duration of amphotericin therapy demands close monitoring and intervention for any drug side effects. Continual mon- itoring for any new sign and symptom is recommended as patients tend to develop other complications while on treat- ment, like CRAO in our case. 4. Conclusion Mucormycosis infection in immunocompromised individu- als can diverge considerably: from being a simple acute fun- gal sinusitis to deadly orbital and cranial extension. There- fore, an approach based on early suspicion, detection, and intervention, resulting in favorable outcome and preventing complications, is commendable. 5. Declarations 5.1. Ethical considerations and patient’s consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal the identity, but anonymity cannot be guaranteed. 5.2. Authors’ contributions All the authors have made substantial contributions to con- ception and design, or acquisition of data, or analysis and interpretation of data. All the authors have been involved in drafting the manuscript or revising it critically for impor- tant intellectual content and have given final approval of the version to be published. Each author has participated suffi- ciently in the work to take public responsibility for appropri- ate portions of the content. The corresponding author takes responsibility for the article during the submission and re- view process. Dr Zainab Mehdi: Concept, design, intellectual content, liter- ature search, data acquisition, manuscript preparation, edit- ing, and review Dr Nidhi Bhardwaj: Concept, design, intellectual content, lit- erature search, editing, and review Dr Jyoti Aggarwal: Literature search, manuscript prepara- tion, data acquisition, manuscript editing and review Dr. Narinder Kaur: Literature search, clinical studies, data This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Z. Mehdi et al. 4 acquisition, manuscript preparation, editing, and review Dr. Brijdeep Singh: Literature search, clinical studies, data acquisition, manuscript preparation, editing, and review 5.3. Funding and support None. 5.4. Conflicts of interest None declared. 5.5. Acknowledgment None. References 1. Mohammadi R, Nazeri M, Sayedayn SMA, Ehteram H. 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Downloaded from: http://journals.sbmu.ac.ir/aaem 5 Archives of Academic Emergency Medicine. 2021; 9(1): e54 Figure 1: (A) left facial droop and deviation of mouth to right side; (B) left sided absence of forehead wrinkling and left sided ptosis; (C) inability to open eye and absent eyeball movement on left side upon being asked to look up. Figure 2: (A) Chest X-ray posteroanterior (PA) view showing right upper and lower zone cavitary lesions with radiopacity in dependant parts and air-crescent sign along the non-dependant parts. Multiple alveolar infiltrates and linear strands are seen in left upper and middle zones; (B) Axial T1-weighted contrast-enhanced MRI at the level of base of skull showing enhancement of basisphenoid, clivus, and basiocciput. Contrast enhancement was extending to left sided retroantral fat and posterolateral wall of left maxillary sinus and contents of left infratemporal fossa. Left maxillary sinus shows mucosal thickening along the posteromedial wall, air fluid level and hyperdensity along the medial wall. All these findings are suggestive of invasive fungal sinusitis; (C) Axial T1-weighted contrast-enhanced MRI at the level of cavernous sinus and orbits showing post contrast enhancement of left optic canal and optic nerve. A small filling defect is noted in left cavernous sinus as well as outward bulge of the lateral wall, which indicates thrombosis; (D) CT chest showing cavitary lesion in right middle lobe with air crescent sign along the non-dependant part and ball-like soft tissue along the dependant part of cavity. Adjacent lung parenchyma postero-laterally shows consoli- dation and thickening of abutting right oblique fissure; (E) Haematoxylin and eosin (H&E) stain (20x10) fungal profiles can be seen invading vessel wall accompanied by dense inflammatory cell infiltrate comprising neutrophils, lymphocyte, and few scattered eosinophils and plasma cells. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Z. Mehdi et al. 6 Table 1: Results of laboratory investigations performed during the hospital stay Variables Day1 Day7 Day14 Day21 Day28 Day32 Day40 Hemoglobin (g/dl) 10.7 9.8 10.2 11.7 12 11.6 12.1 Leukocyte count(109cells/L) 12.3 13.3 16.9 11.1 9.8 6.1 6.3 Polymorphs (%) 79.1 60 66 67 70 71 68 Lymphocytes (%) 8.7 8.5 8.2 7.3 8.1 6.8 7.1 Eosinophils (%) 3.2 3.2 3.1 2.9 2.9 3 3.3 Basophils (%) 1.6 1.4 1.2 1.6 1.1 1.5 1.4 Monocytes (%) 0.4 0.6 0.6 0.3 0.8 0.6 0.4 Platelet count (lac/mm3) 475 471 506 696 423 413 415 ESR* (mm/hour) 12 10 10 8 Total serum bilirubin (mg/dL) 0.1 1.3 0.7 Conjugated bilirubin (mg/dL) .3 .4 .2 Alkaline phosphatase (U/L) 70 69 70 101 72 68 66 AST (U/L) 18 40 130 135 118 98 45 ALT (U/L) 27 47 143 147 125 103 53 Total protein 6.4 7.6 5.7 5.9 Albumin 3.5 2.8 3.1 3.0 Serum sodium (mEq/L) 136 137 125 129 136 139 141 Serum potassium (mEq/L) 4.7 4.1 3.6 3.8 4.1 4.5 4.4 Chloride (mEq/L) Blood urea (mg/dL) 21 23 37 32 28 20 16 Serum creatinine (mg/dL) 0.6 0.7 0.9 0.5 0.6 0.6 0.7 Calcium (mg/dL) 9.1 8.9 8.2 8.3 8.7 9.1 9.3 Magnesium (mg/dL) 2.7 2.2 1.9 1.8 1.9 2.7 3 Phosphorus (mg/dL) 2.9 3.8 2.9 2.6 2.7 2.8 2.9 FBS (mg/dL) 286 228 237 195 121 201 198 pH* 7.34 7.34 7.23 7.24 7.34 7.35 7.41 PaO2 88 89 88 87 88 88 88 PaCO2 44 36 38 42 43 42 45 HCO3 23 28 26 24 24 22 24 SpO2 (%) 89 94 93 95 96 94 93 Lactate 1.4 1.6 1.7 .9 .9 1.0 .9 Urine ketone Nil Nil HbA1C 13 *: Arterial blood gas analysis. AST: aspartate aminotransferase, ALT: alanine transaminase, LDH: lactate dehydrogenase, SpO2: peripheral oxygen saturation, ESR: erythrocyte sedimentation rate, FBS: fasting blood sugar. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Case presentation Discussion Conclusion Declarations References