Venkateswaran KJ, et al., BAOJ Neurol 2017, 3: 33: 038

BAOJ Neurology

Case Report

BAOJ Neurology, an open access journal Volume 3; Issue 3; 038

*Corresponding author: Venkateswaran KJ, Resident in Neurology, Institute of Neurology, Madras Medical College,India, E-mail: wertykj@gmail.com

Sub Date: May 18, 2017, Acc Date: May 25, 2017, Pub Date: May 25, 2017.

Citation: Venkateswaran KJ, Prabaharan U, Lakshmi Narasimhan R, Thamil Pavai N, Bharathi Vidhya Jayanthi, et al. (2017) Dual Fungal Etiology in Orbital Cellulitis. BAOJ Neurol 3: 038.

Copyright: © 2017 Venkateswaran KJ, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Dual Fungal Etiology in Orbital Cellulitis

Venkateswaran KJ1*, Prabaharan U1, Lakshmi Narasimhan R2, Thamil Pavai N3, Bharathi Vidhya Jayanthi4, Veeraraghavan Gurusamy5, Thasneem Banu S6, Sripriya CS7 and Guhan R1

1Resident, Institute of Neurology, Madras Medical College, India2Professor in Neurology, Institute of Neurology, Madras Medical College, India

3Assistant professor, Institute of Neurology, Madras Medical College, India4Professor, Institute of pathology, Madras Medical College, India5Resident, Institute of pathology, Madras Medical College, India

6Professor, Institute of microbiology, Madras Medical College, India7Assistant professor, Institute of microbiology, Madras Medical College, India

Introduction

The invasive fungal infection has varied clinical presentation and in immunocompromised individuals is detrimental. Systematic manifestations can be varied at the time of presentation. Mucor-mycosis and Aspergillosis are important causative organisms im-plicated in the invasive fungal infections. Here we discuss a case with dual fungal infection in a diabetic patient.

Case Report

47 year old male was brought with complaints of high grade fever associated with left sided headache for the past 1 week. The headache was progressive, pricking nature in the frontal region. The patient also complaints of abnormal protrusion of left eyeball with gradual progressive loss of vision for 4 days. No history suggestive of aural or other cranial nerve involvement, weakness, incoordination, sensory symptoms, neck pain and trauma. Patient is a diabetic for 2 years on irregular treatment and chronic alcoholic.

General examination revealed left sided nasal discharge. Higher mental function was normal. Cranial nerve examination revealed proptosis of the left eye with conjunctival chemosis. Visual acuity was limited to perception of light in the left eye. Pupil on the left side was in mid dilated position with absent direct and consensual light reflex. Fundus was not visualised in the left eye and was normal in the right eye. There was complete ophthalmoparesis in the left eye. sensation was impaired over first division of trigeminal nerve on the left side. Examination of other cranial nerves, spinomotor system, sensory system and cerebellum were normal. No signs of meningeal irritation were present. Examination of other systems was normal. Investigations revealed poor glycemic control with HbA1c of 10.1. Urine acetone was negative. Echocardiogram and chest X ray was normal. HIV and other viral marker negative. Visual evoked potential was not obtained in left eye and normal in right eye. Neuroimaging with MRI of brain and orbits revealed left sphenoid sinus mucosal thickening, fluid within the sinus with

soft tissue thickening. Contrast enhancement was noted along left sphenoid sinus extending into left orbital fissure and left optic nerve sheath. Minimal soft tissue enhancement and thickening noted along left lateral border of cavernous sinus (Figure 2,3,4). KOH mount of nasal discharge suggestive of broad aseptate hyphae. FESS was performed with orbital and optic nerve decompression. Tissue specimen from right maxillay sinus and left sphenoid sinus were sent for biopsy and culture (Figure 1).

Figure 1. Broad septate hyphae with conidia are visualised suggestive of aspergillus flavus.

Citation: Venkateswaran KJ, Prabaharan U, Lakshmi Narasimhan R, Thamil Pavai N, Bharathi Vidhya Jayanthi, Veeraraghavan Gurusamy, Thasneem Banu S, Sripriya CS and Guhan R(2017), Dual Fungal Etiology in Orbital Cellulitis. BAOJ Neurol 3: 038.

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Figure 2. MRI T2 / FLAIR imaging of the brain showing hyper intensities in the left cavernous sinus suggestive of cavernous sinus thrombosis.

Figure 3. MRI with Gadolinium contrast enhancement showing left sphenoid sinus mucosal thickening, fluid within the sinus with soft tissue thickening and enhancement along left sphenoid sinus extending into left orbital fissure left optic nerve sheath enhancement

Figure 4. MRI imaging of the brain T2 sequence - hyperintensity noted in left cavernous sinus

Figure 5. showing colonies of aspergillus flavus

Citation: Venkateswaran KJ, Prabaharan U, Lakshmi Narasimhan R, Thamil Pavai N, Bharathi Vidhya Jayanthi, Veeraraghavan Gurusamy, Thasneem Banu S, Sripriya CS and Guhan R(2017), Dual Fungal Etiology in Orbital Cellulitis. BAOJ Neurol 3: 038.

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Biopsy Report

Right Maxillary Sinus

Predominantly inflammatory exudates composed of slender fungal septate hyphae and inflammatory cells composed of lymphocytes, plasma cells, eosinophils suggestive of aspergillosis.

Left Maxillary Sinus

Section shows lesion lined by respiratory epithelium. Fibro-collegenous stroma shows edema, inflammatory cells composed of plasma cells, lymphocytes, eosinophils, multiple granulomas, few multinucleate giant cells and langerhan giant cells along with broad aseptate hyphae, suggestive of invasive mucormycosis.

Treatment

Patient was treated with amphotericin injection 50mg IV od for 3 weeks, insulin was given according to blood sugar and FESS with orbital and optic nerve decompression was performed.

Discussion

Invasive fungal infection with extensive spread portends a poor prognosis. The presence of dual fungal infection worsens the prognosis, is a rarity and is being under reported. The invasive nature of mucormycosis and aspergillosis are individually aggressive and together are additive. In our patient, uncontrolled diabetes mellitus served as a nidus for dual fungal infections (aspergillosis, mucormycosis). Early diagnosis and treatment resulted in the prevention of life threatening complications. Either

of the fungus have angioinvasive properties, which further validates the initiation of early therapy.

Aspergillosis and mucormycosis are most common fungal infections causing orbital cellulitis [1,2]. The classification of the fungi is summarized in Table 1. Table 1. The classification of Mucormycosis and Aspergillosis

Aspergillosis Mucormycosis (rhino-orbital cerebral mucormycosis)

Order Order Eurotiales genus Aspergillus order Mucorales

Species

Aspergillus fumigatusAspergillus flavusAspergillus niger

Rhizopus orzae(most common-90%)Absidia Mucor Rhizomucor pusillus Apophysomyces elegans

Hyphae

Septate with dichomatous branches at 45 degree

Non septate filamentous fungi branched at 45 degree

Mode of spread

The most common mode of spread is direct inoculation from adjacent paranasal sinus and direct traumatic inoculation from sinus. Less common mode of spread haematogenous and droplet inhalation [1].

Figure 6. Varied clinical manifestations of aspergillosis and mucormycosis

Citation: Venkateswaran KJ, Prabaharan U, Lakshmi Narasimhan R, Thamil Pavai N, Bharathi Vidhya Jayanthi, Veeraraghavan Gurusamy, Thasneem Banu S, Sripriya CS and Guhan R(2017), Dual Fungal Etiology in Orbital Cellulitis. BAOJ Neurol 3: 038.

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Risk Factors

Diabetes mellitus, neutropenia, steroids, immunosuppressive therapy are common risk factors for both mucormycosis and aspergillosis. Iron is required in the pathogenesis and virulence of mucormycosis. Hence desferrioxamine therapy and iron overload (hemochromatosis and hemodialysis) are risk factors for mucormycosis [3,4]. In diabetic ketoacidosis, phagocytosis is defective and in acidic medium iron content is more, hence mucormycosis is common. Immunocompromised patients and smoking marijuana increases the risk for sino-orbital aspergillosis (Figure 7).

Figure 7. Aseptate fungal hyphae showing mucormycosis

Alcoholism and Fungal Infections

Leukotrienes regulate the adhesion ability of neutrophils. Alcohol interferes with leukotrienes production there by interfering with neutrophil function and also interferes with monocytes and macrophages activity there by results in defective phagocytosis.

Alcoholism increases the risk for fungal infection.

Clinical features

The most common symptoms in mucormycosis are sinusitis, nasal discharge with mucosal ulceration and necrosis. Symptoms specific to orbital involvement include complete external opthalmoplegia. Less common symptoms include sudden blindness. Black eschar in Mucormycosis is a late and inconsistent feature but characteristic feature. Most dreaded complication includes carotid artery occlusion that leads to cerebral infarction Table 2.

The most common clinical manifestation in aspergillosis is allergic rhinitis and chronic nasal discharge Table 3 (Figure 7).

Investigations [6,7,8]

Potassium hydroxide stain (KOH) of tissue from nasal or oral mucosa shows branched septate hypahae in aspergillosis and branched aseptate hyphae in mucormycosis. Other stains used are periodic acid schiff stain, gomori methenamine silver, hematoxylin and eosin, calcofluor white.

Culture

Even positive cultures are not diagnostic; mucorales are common laboratory contaminant and are also grown in uninfected mucosa. Sabouraud’s agar without cycloheximide is culture media. HPE shows arterial involvement with relative sparing of the veins. Thrombosing arteritis with vessel wall invasion with fungal hyphae is seen. Aspergillus fumigatus shows grey-green colonies. Aspergillus flavus shows yellow-green colonies. Aspergillus niger shows black colonies [9,10,11].

Polymerase chain reaction for fungal DNA identifies the exact species of mucormycosis. Its wide use is limited by availability and cost. Estimation of serum galactomannan and beta-D-glucan

Table 2. showing the clinical manifestations of Mucormycosis

Mucormycosis (5,6,7)

Symptoms Sinusitis, nasal discharge, epistaxis, nasal mucosal ulceration, crusting and necrosis

Orbital symptoms Decreased vision, proptosis, complete external and internal opthalmoplegia, ptosis, sudden blindness

Sudden blindness due to thrombosis of central retinal artery, posterior cilliary artery, infarction of optic nerve

Complications Infection from orbit spread to brain through cribrifomplate, orbital apex and cavernous sinus.

Carotid occlusion in cavernous sinus leads to cerebral infarction, fungal meningitis, abcess and death

Poor prognosis Hemiplegia, cavernous sinus thrombosis, periorbital necrosis

Table 3. showing the clinical manifestations of Aspergillosis

Aspergillosis (5,6,7) Symptoms

Common manifestations Allergic rhinitis,chronic nasal obstruction

Immunocompromised without AIDS Acute proptosis with visual loss and severe pain

Immunocompromised with AIDS Gradual proptosis with extraocular movements restriction(weeks to months)

Citation: Venkateswaran KJ, Prabaharan U, Lakshmi Narasimhan R, Thamil Pavai N, Bharathi Vidhya Jayanthi, Veeraraghavan Gurusamy, Thasneem Banu S, Sripriya CS and Guhan R(2017), Dual Fungal Etiology in Orbital Cellulitis. BAOJ Neurol 3: 038.

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in invasive aspergillosis has a better sensitivity than KOH mount (beta-D glucan is found in cell wall of all fungi except Zygomyces and cryptococcus). PET scan is useful in evaluating the treatment response in mucormycosis Table 4.Table 4. showing the sensitivity and specificity of various tests used in the diagnostic evaluation of Fungal infection.

Test Sensitivity Specificity

KOH mount 73%

Beta D-glucan 78-100% 88-100%

Polymerase chain reaction 100% 97%

Treatment

Treatment of invasive fungal infections involves a combination approach. Surgical debridement of the involved tissues with anti-fungal treatment is required. Risk factor that is favorable to

the growth of the organism including hyperglycemia, metabolic acidosis and neutropenia should be corrected.

Patients with invasive mucormycosis are treated with aggressive surgical debridement and medical therapy. Medical therapy includes initial administration of liposomal amphotericin B. The patient is continued until the patient has shown favorable response following which the patient is switched over to oral posaconzole. If the patient does not respond to Amphotericin B, salvage therapy with parenteral Posaconazole should be given [12] Table 5, 6.

Conclusion

Fungal infection by aspergillum and Mucor are both angioinvasive. Hence early diagnosis, appropriate aggressive anti-fungal treatment with surgical debridement can preserve vision and is lifesaving. We are highlighting this case in view of its dual pathology.

Table 5. Neuroimaging findings in Mucormycosis and Aspergillosis (10,11)

Aspergillosis Mucormycosis

CT- PNS Heterogenous lesion of soft tissue with bony erosion and calc.ification Sinusitis,bony necrosis, mucosal thickening, thrombosis of the ophthaylmic vein.

MRI Contrast enhancing lesions that are hypointense in both T1 and T2 weighted sequence images

T2 weighted image showing hyperintensity to hypointensity in all sequences with destruction and obliteration of fat planes

Table 6. Classification of anti fungal drugs by the mechanism of action.

Mechanism of action Drug class examples

Alteration in cell membrane due to interaction with ergosterol Polyenes Amphotericin B

Inhibitors of mitosis Antibiotic Griseofulvin

C14-demethylase inhibitors Azoles Fluconazole

Squalene epoxidase inhibitor Allylamines Terbinafine

Inhibition of DNA and RNA synthesis Antimetabolite flucytosine

Inhibitors of beta (1-3)-D-glucan synthesis echinocandins Caspofungin,micafungin,anidulafungin

Table 7. Drugs used in the treatment of aspergillosis and mucormycosis

Aspergillosis Mucormycosis Amphotericin B (0.5 – 1mg/kg/d) or liposomal Amphotericin B (5mg/kg/d)with surgical debridement

Amphotericin B (1 to 1.5mg/kg/d) or liposomal Amphotericin B (5mg/kg/d) with surgical debridement

Itraconazole 200-400mg/d (should not be used if there is pulmonary involvement) Oral posoconazole- 300mg every 12 hrs on the first day,then 300mg/d

Fluconazole 100- 200mg/d Isavoconazole

Voriconazole- 6mg/kg for 1 day followed by 4mg/kg/d Hyperbaric oxygen-increases oxygen, thereby reducing the acidosis environment

Rifamin 600mg/d

Granulocyte-colony stimulating factor and granulocyte-macrophage -colony stimulating factor- to increase neutrophils count

Caspofungin typically lacks CNS penetration

Citation: Venkateswaran KJ, Prabaharan U, Lakshmi Narasimhan R, Thamil Pavai N, Bharathi Vidhya Jayanthi, Veeraraghavan Gurusamy, Thasneem Banu S, Sripriya CS and Guhan R(2017), Dual Fungal Etiology in Orbital Cellulitis. BAOJ Neurol 3: 038.

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