Eye for an eye: near-fatal outcome of fungal infection in a young, diabetic girl

Abstract

In this report, we describe the case of a young, diabetic girl with ketoacidosis who suffered sudden loss of vision of the right eye. The loss of vision was caused by an invasive rhino-orbital-cerebral fungal infection (mucormycosis) with extensive periorbital thrombosis. Despite maximal antifungal and surgical treatment (including exenteration of the right orbit), the clinical situation deteriorated. It was only after overcoming the difficulties of managing her hyperglycaemia that the patient’s condition stabilised and her life was saved. Another factor contributing to this girls’ survival was the swift diagnosis of mucormycosis, which was made soon after the onset of symptoms. Because of this, treatment could be started almost immediately.

Background

We consider this case to be a powerful illustration of the challenges doctors face in the diagnosis and treatment of mucormycosis. Swift recognition of symptoms is paramount, and as initial complaints are most often presented to general practitioners, specialists of internal medicine, otolaryngologists or ophthalmologists, we regard this case report of interest to a broad group of doctors.

Case presentation

We describe the case of an 18-year-old woman with diabetes mellitus type I, which was poorly regulated for several years, due to incompliance. Without any accompanying symptoms like fever or malaise, she noticed a small and painful swelling of the skin on the side of her nose. The moderate swelling spread to her right eye within 3 days, still without any discomfort, and was interpreted by the patient as being a harmless eye infection. She did not experience diplopia. After 6 days, she woke with a sudden and complete loss of vision of the right eye and massive swelling, making it impossible to actively open her eye. There were no nasal complaints or signs of sinusitis (rhinorrhoea, nasal congestion, headache or facial pain). Directly after being admitted in a large local hospital, an accompanying ketoacidosis was established as well.

Investigations

A ketoacidosis was diagnosed with glucose levels of 22 mmol/L (normal 4–10 mmol/L) and an glycated haemoglobin level of 134 mmol/mol (target HbA1c <53 mmol/mol). C-reactive protein and leucocyte levels were 146 mg/L and 13.2×10⁹/L, respectively (normal <8 mg/L and 4–10×10⁹/L, respectively). Further physical examination showed a fixated right eye with proptosis (figure 1) and periorbital redness. The sensory examination showed periorbital numbness, and examination of the eye showed a dilated pupil unresponsive to light. CT imaging (figure 2A) expressed orbital cellulitis on the right side and partial opacity of the ethmoid and right maxillary sinus. All bony structures were intact. Crusts without any signs of tissue necrosis were observed in the nasal cavity at endoscopy.

Figure 1.

Initial presentation with fixation and proptosis of the right eye.

Figure 2.

(A) CT scan showing partial opacity of the nasal cavity, ethmoid and right maxillary sinus. All bony structures were intact. (B) A typical sign of mucormycosis: homogenous signal intensity of the opacified ethmoid sinus on T1 imaging (arrow), while the same plane on the T2 image displays heterogeneous signal intensity. (C) Absent flow void on MRI (right) in the right ophthalmic artery and the cavernous sinus (a sign of thrombosis) and diffusion restriction (left) of the right optic nerve (a sign of ischaemia).

Differential diagnosis

Unilateral swelling of the eye, redness and pain are signs of ocular inflammation and may represent a diagnostic challenge to many clinicians. The differential diagnosis is broad and includes both non-emergent and emergent diagnoses. Conjunctivitis and blepharitis are common eye infections usually treated by primary care physicians. Acute and complete loss of vision and/or extraocular involvement suggests serious orbital inflammation/abscess and/or cavernous sinus thrombosis, warranting diagnosis and treatment to proceed as rapidly as possible. An orbital abscess was discarded after CT imaging in which there was no sign of an abscess. The minimal signs of inflammation in the sinus complex and the localisation of mucosal swelling solely in the ethmoid and maxillary sinus, made a cavernous sinus thrombosis unlikely. An invasive fungal infection was considered to be a probable diagnosis because of the decreased immune status in this diabetic young woman. Patients with ketoacidosis are specifically at risk for invasive fungal infections, due to an altered iron and ketonic metabolism. These considerations together with the very rapid clinical course of events made a fungal infection the most likely diagnosis. More importantly, it was a diagnosis that needed to be confirmed or excluded immediately, due to its notorious outcome. MRI was performed (figure 2B), which showed the typical sign of mucormycosis: homogenous signal intensity of the opacified ethmoid sinus on T1 imaging, while the same plane on the T2 image displays heterogenous signal intensity. A diagnostic ethmoidectomy was performed at the referring hospital, during which white and gritty biopsies were obtained, suspect for fungal infection. Rhizopus arrhizus (formerly known as Rhizopus oryzae) was isolated from these biopsies, after culture according to standard laboratory procedures. Pathology results from material retrieved during extensive sinus surgery at our centre also describe branched hyphae, suspect for mucormycosis.

Treatment

A starting dose¹ of 7 mg/kg intravenous liposomal amphotericin B (Ambisome) was administered 1 day after presentation (making it the seventh day after the initial symptom of a small and painful swelling on the side of the nose). This was increased up to 10 mg/kg¹ and is considered to be the first line of pharmacological therapy. An echinocandin in the form of micafungin (100 mg/kg) was added to increase efficacy of therapy and as a step prior to further escalating the amphotericin dosage, because of toxicity.¹ It was, however, difficult to adequately control the diabetes. In order to administer amphotericine B not only systemically but also locally and in order to debulk infected and necrotic tissue, extensive sinus surgery was performed. The orbit was left intact and amoxicillin with clavulanic acid was added to the pharmacological treatment regimen to prevent superinfection of necrotic tissue.

Postoperatively, there was no clinical improvement as the orbital cellulitis remained and vision of the right eye was concluded to be definitely lost. Repeated MRI (figure 2C) now showed an absent flow void in the right ophthalmic artery and the cavernous sinus (a sign of thrombosis), diffusion restriction of the right optic nerve (a sign of ischaemia) and dural enhancement. Above all, after a short-lived improvement, glucose levels were still difficult to manage.

The difficulty in managing glucose levels in this patient was largely explained by the accessory ketoacidosis and infection. Glycogen levels were very high due to unregulated diabetes (leading in turn to ketoacidosis). In order to decrease these levels, a high dose of intravenous insulin needed to be administered. After treatment with insulin and glucose, pH normalised and insulin treatment was switched to subcutaneous treatment. The patient, however, remained acidotic showing low levels of bicarbonate whereas pH remained normal. Urinary ketosis was still demonstrable. When this state of non-acidotic ketosis was confirmed, the patient was switched back to high-dose intravenous insulin and treated until a normalisation of bicarbonate was achieved. Potentially, the underlying infection, in this case the mucormycosis, supported and maintained the ketoacidosis.

This created a vicious cycle in which ketoacidosis and hyperglycaemia-induced infection, which in turn, destabilised the management of diabetes.

The definitive diagnosis of rhino-orbital-cerebral mucormycosis due to ketoacidosis with extensive periorbital thrombosis (and subsequent blindness) was made. On the 10th day after initial symptoms, a third, and final, operation was performed where the right orbit was exenterated. Furthermore, it was finally possible to adequately control glucose levels. In the following weeks, the patients’ condition improved and she was discharged with oral antifungal treatment and stringent follow-up of her diabetes.

Outcome and follow-up

After 17 months of follow-up, she is clinically stable, has ceased oral antifungal treatment and is adjusting to monocular life.

Discussion

Both diabetes and rhinosinusitis are very common ailments much encountered by general practitioners and ear, nose and throat specialists.² However, when rhinosinusitis is caused by an invasive fungus due to an underlying illness like diabetes or a haematological malignancy, the outcome is often devastating with very high mortality rates reported up to 80%.^3–5

Mucormycosis is a saprophytic fungus that naturally occurs in organic matter like bread mould, soil and rotten fruits and vegetables.⁴ R. arrhizus is part of the Rhizophoraceae (formerly Mucoraceae) family (order Mucorales) and the most common genus to cause clinical infection. Microbiological identification is most often based on colony morphology (white, cottony colonies) and microscopy (non-septate, branched sporangiophores from root-like rhizoids, with globose sporangia). These fungi are non-pathologic in normal hosts and infections occur almost exclusively in immunocompromised patients. Patients receiving solid organ or haematopoietic stem cell transplantations are also risk groups.⁴ However, the largest group of patients concerns diabetics.⁵ Diabetics are particularly at risk, not only due to a decreased immune status but also because of an altered iron and ketonic metabolism (in the case of ketoacidosis).⁵

When infected, hyphae of the fungus invade the walls of blood vessels, leading to local thrombosis. The result is extensive tissue necrosis, haemorrhage and sepsis.⁴ Rhino-orbital-cerebral mucormycosis accounts for about 50% of the reported cases.⁶ Pulmonary, cutaneous, gastrointestinal and disseminated types account for the other 50%. Mortality rates in patients with diabetes with rhino-orbital-cerebral mucormycosis are reported around 40%.^{3 5 6} However, as seen in case series and case reports,^{7 8} rapid treatment (surgical and systemic antifungal) is the determining factor, as mortality rates quickly rise if treatment is not started within days after the onset of symptoms. In most case series, patients with uncontrolled diabetes, often accompanied by ketoacidosis, comprise the largest patient group. This is specifically the case in articles that report of patient groups originating from rural areas or areas where there is no easy access to medical care. Rapid treatment is, however, not only dependent on access to medical care but also on the correct diagnosis of mucormycosis. As mucormycosis is fortunately a rare disease, this can also end in a delayed diagnosis, with deteriorating chances of survival as a result.⁸

As mentioned before, intravenous antifungal medication combined with additional debridement is the current medical golden standard to treat mucormycisis.⁶ However, maximal antifungal treatment did not cease disease progression in this case. Glucose levels were difficult to control and it was only after its adequate management that the clinical situation improved. This is illustrated in figure 3, where we see glucose levels compared with time and disease progression and the event of orbital exenteration after a renewed peak in glucose levels.

Figure 3.

Glucose levels compared with time and disease progression.

We therefore pose a take home message that is fourfold.

First, be aware that in immunocompromised patients such as uncontrolled diabetics, a small insignificant infection can evolve into a very dangerous fungal infection, especially in the nasal and ocular region.

Second, treat fungal infections like mucormycosis rapidly and aggressively; suspicion of an invasive fungal infection alone is sufficient to start treatment.

Third, realise that, when dealing with mucormycosis, you are always one step behind: clinical symptoms precede radiological findings as microinvasion and thrombosis of small vessels occur before extensive necrosis and often multiple debridements are necessary. This is illustrated by our case, where thrombosis of the ophthalmic artery and the cavernous sinus was only demonstrated on an MRI performed 5 days after the patient went blind.

Finally, and possibly most important, controlling the underlying illness is paramount. In our case, this was performed by adequate adjustment of glucose levels and ketoacidosis. For obvious reasons, this is relatively easy compared with, for instance, the neutropenic state of a patient having haematopoietic stem cell transplantations or with haematological malignancies.

Concluding this case, we would like to emphasise that every doctor should be aware of an invasive fungal infection in the patient with diabetes (and moreover ketoacidotic), when encountering rapidly evolving or a specific rhino-orbital complaints.

Learning points.

• In patients with uncontrolled diabetes, especially with ketoacidosis, a small insignificant infection can evolve into a very dangerous fungal infection.

• Treat fungal infections, like mucormycosis, rapidly and aggressively.

• You are always one step behind; clinical symptoms precede radiological findings.

• Controlling the underlying illness is paramount in the treatment of mucormycosis.