Orbital apex syndrome in a man with rhino-ocular cerebral mucormycosis: a case report

Abstract

Background

Orbital apex syndrome is a symptom complex of visual loss and ophthalmoplegia resulting from a disease involving the orbital apex. It can be caused by inflammation, infection, and malignancies. Mucormycosis is an infection caused by filamentous saprophytes of the order Mucorales. It is ubiquitous, and the infection can occur from ingesting contaminated food, inhaling spores, or injecting the disrupted skin or wounds. It is mainly a disease of the immunocompromised, affecting patients with poorly controlled diabetes, organ transplant recipients, and patients with hematological malignancies. We present the case of a man with orbital apex syndrome resulting from rapidly spreading rhino-ocular cerebral mucormycosis, who had a poor outcome despite an aggressive combined medical and surgical treatment. This is an unusual cause of orbital apex syndrome.

Case presentation

A 46-year-old Bangladeshi man presented to the emergency department with a history of toothache and pain in the left eye. On examination, the patient had a left-sided periorbital edema, ptosis, and proptosis. He had complete ophthalmoplegia and absent direct pupillary response in the left eye. Magnetic resonance imaging of the brain and orbit showed bilateral ethmoidal, left frontal, maxillary, and sphenoidal sinusitis with left orbital cellulitis. His left orbit was surgically decompressed and histology confirmed mucormycosis. Despite aggressive treatment, the patient had only a partial improvement in his symptoms.

Conclusions

Mucormycosis is a rare disease that can easily be misdiagnosed, leading to delayed treatment and disease dissemination. Clinicians must be suspicious of mucormycosis in patients presenting with multiple cranial nerve palsy.

Background

Orbital apex syndrome (OAS) is a symptom complex of visual loss and ophthalmoplegia resulting from a disease involving the orbital apex [1]. It can be caused by inflammation, infection, and malignancies. OAS must be distinguished from superior orbital fissure syndrome and cavernous sinus syndrome to which it is closely related. The main distinguishing difference between the three is the involvement of the optic nerve in OAS, which is absent in the other two syndromes.

Mucormycosis is a fungal infection caused by filamentous saprophytes of the orders Mucorales and Entomophthorales. Mucorales are ubiquitous and are found in various habitats, including dust, soil, decaying vegetables, and bread. Infection can occur from ingesting contaminated food, inhaling spores, or injecting the disrupted skin or wounds. Low oxygen, high glucose, acidic pH, and a high iron level favor the germination of spores and encourage fungal growth by impairing phagocytosis [2, 3]. The prevalence of mucormycosis is approximately 910,000 cases worldwide, and 99% occur in India alone [4]. Mucormycosis is uncommon in the Arab League nations, with annual incidences of less than 1 per 100,000 people [5]. As an emerging disease, increased awareness and better diagnostic tools have led to increased reported cases [6]. Mucormycosis is mainly a disease of the immunocompromised; however, cutaneous, rhino-orbital, and rarely disseminated infections have been reported in immunocompetent patients after soft tissue trauma. Poorly controlled diabetes is the most common risk factor for the disease in Africa, India, Iran, and Mexico. However, organ transplant recipients and hematological malignancies are the risk factors in Europe and North America [6]. We present the case of a man with orbital apex syndrome due to advanced rhino-ocular cerebral mucormycosis. This case is unique because six cranial nerves were affected, causing diagnostic challenges.

Case presentation

A 46-year-old Bangladeshi man presented to the emergency department with a 5-day history of “toothache and pain in the left eye.” He had a 15-year history of type 2 diabetes with poor compliance to medications. The patient had a poor socioeconomic status and limited access to healthcare facilities. He had no relevant family or social history.

During the clinical examination, the patient was alert and oriented. He was afebrile, his blood pressure was 137/83mmHg, his heart rate was 75 beats per minute, his respiratory rate was 22 breaths per minute, and his oxygen saturation was 98% on room air. Random blood glucose was 17 mmol/L [4,5,6].

The patient had a left-sided periorbital edema, ptosis, and proptosis. He had a partial facial nerve palsy and decreased sensations over the distribution of the ophthalmic branch of the trigeminal nerve. He had complete ophthalmoplegia and absent direct pupillary response in the left eye. Visual acuity in the left eye was 6/60 and 6/6 in the right. No other focal motor or sensory deficit was found.

A computed tomography scan (CT) of the brain showed opacification of the left maxillary sinus, ethmoidal sinus, and frontal sinus (Figs. 1 and 2). There was no brain infarct or bleeding. An urgent head CT with venogram was ordered, which showed a filling defect surrounding the cavernous segment of the left internal carotid artery (ICA), suggestive of thrombosis.

Fig. 1

Computed tomography of the brain with arrow pointing at sinusitis of the maxilla and ethmoid sinuses

Fig. 2

Computed tomography of the brain with an arrow pointing at frontal sinusitis

Computed tomography angiogram of the head and neck showed bilateral multiple small cervical lymph nodes and no occlusion or stenosis.

Based on the physical examination and CT findings, differential diagnoses of orbital cellulitis, orbital myositis, cavernous sinus infection, and venous thrombosis were made.

Laboratory results on admission showed a total leukocyte count of 11.6 × 10⁹/L (4.0–11.0), and differential leukocyte count was 71% neutrophils, 19% lymphocytes, and 1.6% eosinophils. C-reactive protein level of 164 mg/L (normal < 5) and random glucose level of 17.5 mmol/L (4–6) was found. The serum creatinine level was 84 micromol/L (60–110) and urea was 5.31 mmol/L (2.5 – 7.0). His serum sodium and potassium were 129 mmol/L (137–144) and 4.5 mmol/L (3.5–4.9), respectively. His human immunodeficiency virus (HIV), hepatitis B, hepatitis C, and syphilis screen were negative.

An urgent magnetic resonance imaging (MRI) of the brain and orbit, with and without contrast, was done for the patient. These showed bilateral ethmoidal, left frontal, left maxillary, and left sphenoidal sinusitis with left orbital cellulitis. In addition, there was patchy enhancement of the intraconal space of the left orbit with peripheral enhancement of the left optic nerve (Fig. 3). There was no cavernous sinus thrombosis. A fiberoptic nasopharyngoscopy was done on the patient. This showed a palatal ulcer and a soft tissue mass from which a biopsy was taken. Histology of the biopsy and hematoxylin and eosin stain revealed a fungal organism consisting of aseptate branching hyphae with a diameter ranging from 9 to 17 μm, consistent with mucormycosis (Fig. 4). Beta-d-glucan was negative.

Fig. 3

MRI of the brain and orbit with arrow pointing at peripheral enhancement of the optic nerve

Fig. 4

Hematoxylin and eosin (H & E) staining: short arrows pointing at aseptate hyphae of mucormycosis, long arrow showing inflammatory cells

A final diagnosis of orbital apex syndrome caused by rhino-orbital cerebral mucormycosis (ROCM) causing multiple cranial nerve palsies was made.

The patient was admitted to the ward and started on empirical liposomal amphotericin B 300 mg intravenously once a day and oral posaconazole 300 mg with daily monitoring of serum creatinine and serum potassium levels. Blood sugar was controlled with glimepiride 2 mg, insulin aspart, and insulin glargine.

The surgeons did left functional endoscopic sinus surgery (FESS) with orbital decompression under general anesthesia.

On day 7 of admission, the patient developed acute kidney injury (AKI), possibly from antifungal medication. This was managed with adequate fluid balance and reduction of the antifungal therapy. Despite aggressive antifungal therapy and strict control of glucose, the patient only had a slight improvement in his left eye vision and orbital cellulitis. There was no improvement in the extraocular muscle movements, ptosis, proptosis, and facial nerve palsy. We arranged a transfer to a specialized facility for further extensive facial debridement. However, the patient discharged himself against medical advice for personal and socioeconomic reasons. He failed to keep his follow-up appointments in our facility. Several attempts were made to contact him by telephone to no avail.

Discussion

Our patient presented with symptoms consistent with palsy of cranial nerves II, III, IV, V, VI, and VII. This posed diagnostic challenges and various differential diagnoses, such as acute stroke, orbital cellulitis, and cavernous sinus thrombosis, were considered. Extensive investigations confirmed rhino-orbital cranial mucormycosis (ROCM) as the cause of the patient’s symptoms and signs. Mucormycosis is classified into six types, based on the involved anatomical body part, namely pulmonary, which constitute 20% of reported cases, cutaneous (22%), gastrointestinal (8%), diffuse (13%), atypical sites (3%), and ROCM (34%) [1]. Patients with ROCM are often asymptomatic, but they can present with unilateral facial edema, headache, sinus pain, and serosanguinous nasal discharge. In advanced stages, patients can develop proptosis, diplopia, cranial nerve palsies, and palatine ulcer due to rapid intracranial progression through direct extension or angioinvasion. Our patient presented with facial nerve palsy and was misdiagnosed as a stroke and cavernous sinus thrombosis. Misdiagnosis is common in mucormycosis and can potentially lead to a delay in treatment and poor outcomes [7].

The most prevalent signs and symptoms of orbital apex syndrome are proptosis, ophthalmoplegia, and vision impairment resulting from the involvement of cranial nerves II, III, IV, VI, and the maxillary division of V [8]^. Our patient’s symptoms were more extensive than that seen in OAS with the involvement of cranial nerve VII and the ophthalmic division of cranial nerve V. Multiple cranial nerve palsies in a patient with no history of trauma should raise the possibility of intracranial fungal infection.

A definitive diagnosis of ROCM requires a tissue biopsy of the focal lesion and staining with periodic acid Sciff (PAS) and Grocott–Gomori methenamine silver [3]. The broad nonseptate ribbon-like hyphae, 10–20 μm in diameter with branches at 90 degrees, in tissue specimens are characteristic findings. Grocott–Gomori staining was not done in our patient because the H&E staining was sufficiently diagnostic. Radiological imaging, including magnetic resonance imaging (MRI) and computed tomography (CT), are essential in determining the extent of the disease spread.

Evidence for the best treatment options for mucormycosis is limited. Lipid formulation of amphotericin B (LFAB) is the mainstay of treatment. High-dose LFAB (5–10 mg/kg/day) is recommended as first-line treatment for a minimum of 6–8 weeks. LFAB can cause severe systemic side effects such as infusion-related reactions and nephrotoxicity, as in our patient. Isavuconazole and conazole posa have Mucorales action and have been used as induction and salvage therapy in those intolerant or refractory to LFAB. Partial and complete remission of 75% and 65%, respectively, have been reported. Combination therapy of two or more antifungal medications is recommended in refractory cases [2, 9].

Surgical debridement has an important supplementary role, especially in patients with ROCM. The survival rate is 3% in untreated cases while combining LFAB and surgery improves survival to 70% [2]. It is important to manage underlying risk factors such as diabetes, neutropenia, and reduction or discontinuation of glucocorticoids, immunosuppressants, and deferoxamine [2, 9].

The disease site and patient comorbidities significantly influence the mortality rate of mucormycosis. Patients with hematological malignancies and recipients of hematopoietic stem cell transplants have the highest mortality rates. In contrast, the best prognosis is found in patients with isolated cutaneous disease. In a review of 929 cases of mucormycosis, the mortality rate was 96% in those with disseminated disease, and 85% and 76% in patients with involvement of the gastrointestinal tract and lungs, respectively [2]. Another review of 174 cases in renal transplant recipients reported a mortality rate of 76% in disseminated disease, 55.6% in renal graft infection, 42.2% in pulmonary mucormycosis, 31% in ROCM, and 23% for cutaneous infection [9]. Our patient could have had a better outcome based on the affected site, but his late presentation, the rapid progression of his disease, and his inability to complete the treatment led to a poor prognosis.

Conclusions

Mucormycosis is a rare disease that can easily be misdiagnosed, leading to delayed treatment and disease dissemination. It can disseminate rapidly with a very high fatality, hence the need for prompt diagnosis and treatment. Clinicians must be suspicious of mucormycosis in patients presenting with multiple cranial nerve palsy.