Patient presents with unilateral vision loss, ptosis, pain
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A 37-year-old Native American man presented at the hospital complaining of painful left eye with vision loss and a drooping eyelid for the past 2 days.
He described the pain as a constant pressure, rated 4/10 at the appointment. The pain radiated from below the left orbit along the ipsilateral side of his nose and above his eye. Four days earlier he had multiple maxillary teeth on the left side extracted due to considerable infection. After his dental visit the patient was prescribed acetaminophen and codeine phosphate (Tylenol #3, Johnson & Johnson) every 6 hours for 2 days, ibuprofen 400 mg every 2 hours for 4 days and clindamycin 150 mg four times a day for 7 days.
The patient had no known ocular conditions and denied any previous ocular surgery or trauma. The patient also denied all medical history, aside from his recent dental infections.
Entering visual acuities were 20/20 OD and hand motion at 2 feet in the left eye. Confrontation fields were full to finger count in the right eye and restricted inferior temporal and inferior nasal in the left eye; the patient could appreciate hand motion in the superior field of the left eye. Extraocular movements were full and smooth with no increase in pain. The right pupil was round and reactive to light. The left pupil was round, minimally reactive to light, with a 4+ afferent pupillary defect.
Exophthalmometry measured 18 mm both eyes. Goldmann tonometry measured 12 mm Hg OU. Anterior segment exam revealed a moderate 3 mm to 4 mm ptosis of the left eye. Fundus exam was unremarkable. OCT of the macula and optic nerve head was taken for both eyes (Figures 1, 2). No frank swelling of the optic nerve was detected. Outside normal limits measurements superior temporal does not explain severe vision loss.
What’s your diagnosis?
A number of differentials were considered in this case of sudden unilateral vision loss with a normal fundus appearance.
Optic neuritis is a demyelinating condition most often affecting women between 20 and 50 years old, although one-third of patients are men. The first symptom may be retro-orbital pain worsened by eye movement. Two-thirds of patients have retrobulbar inflammation with no disc edema. Sudden vision loss occurs rapidly over the course of 1 week and recovers within 1 month.
Although ptosis and hand motion vision are not consistent with optic neuritis, it remained a differential after the initial examination, pending MRI results.
Neuromyelitis optica is a chronic disease of the brain and spinal cord that can result in severe vision loss. Episodes of inflammation lead to unilateral or bilateral vision loss less than 20/200 with associated pain in and behind the eye. Episodes are separated by periods of remission that can last from weeks to years. MRI reveals necrotizing, demyelinating lesions of the optic nerve and spinal cord. Retinal nerve fiber layer OCT imaging often shows profound thinning less than 60 m in the affected eye. Pain in neuromyelitis optica is often less than typical optic neuritis, although vision loss is much more profound. It also remained an unlikely differential pending MRI results.
Leber’s hereditary optic neuropathy arises from mitochondrial DNA mutations and begins to reduce vision in males 10 to 30 years old. Half of cases result in bilateral vision loss at presentation. In unilateral cases the fellow eye is involved within 9 months. Circumpapillary telangiectasia are often noted, though not always present. Vision loss is permanent with variable prognosis based on the specific mutation. We eliminated this condition from the list of differentials due to a lack of family history.
Posterior ischemic optic neuropathy presents with acute optic nerve dysfunction due to lack of blood supply. It is often seen during severe blood loss or after long surgical procedures. Although the fundus appears normal, lack of recent injury or surgery eliminated this possibility.
Compressive lesions can cause variable vision loss, pain and ptosis. Vision loss is not sudden in these situations, but patients may notice the symptoms all at once. In other cases, aneurysm or pituitary apoplexy may expand rapidly, causing an acute decline. This was not the primary diagnosis but needed to be ruled out with imaging of the head and orbit.
Infectious optic neuropathies have been documented in a variety of conditions including syphilis, varicella zoster, Lyme disease, HIV, as well as opportunistic infections including toxoplasmosis, cytomegalovirus, Cryptococcus, mucormycosis, and aspergillosis. Due to the recent dental infections, the patient was suspected to have infectious optic neuropathy and sent for further testing and possible inpatient treatment.
This patient’s management
After the initial visit, the patient was referred to the emergency department emergently. He did not go the same day, as planned, eventually arriving 1 week later. Initial lab results found high blood glucose 470 mg/dL and abnormally high anion gap, alkaline phosphate and AST.
The patient was diagnosed with diabetes and started on metformin therapy 1,000 mg twice daily. MRI of the brain and orbit showed left ethmoid sinusitis and left post-septal orbital cellulitis, with possible fungal disease (Figures 3, 4). MRA showed left superior ophthalmic artery occlusion or stenosis (Figure 5). The patient declined being admitted to hospital for further testing, instead opting for follow-up with ophthalmology. He was sent home on Augmentin and Bactrim DS for suspected infectious optic neuropathy and metformin to reduce blood glucose levels.
At the ophthalmology visit, the patient was told to return to the emergency department for likely admission and treatment with IV antibiotics or antifungals. He underwent left-sided ethmoid sinus surgery and was placed on IV antibiotics. Cultures revealed mucormycosis infection, and the patient was switched to IV amphotericin B.
He suffered an anaphylactic reaction to amphotericin B, and the IV was stopped. As an alternative, he was prescribed isavuconazole 200 mg three times daily for 6 days followed by long-term 200 mg for a period of 3 or more months. The patient was also started on insulin during his hospital stay to further control newly diagnosed diabetes. Since initiating therapy, the patient reports less pain, but no improvement in vision in the left eye.
Fungal infection
Mucormycosis is a rare, often fatal fungal infection most commonly affecting the paranasal sinuses, orbit and brain. Infection leads to tissue necrosis.
This opportunistic pathogen often targets individuals with diabetes, the immunocompromised and trauma patients. The infection almost always leads to vision loss due to either compressive or inflammatory optic neuropathy.
A variety of causative Mucorales genera have been identified. Rhizopus is the most common, followed by Mucor. A related but distinct – and less fatal – infection is caused by fungi of the Entomophtorales family and leads to subcutaneous and intestinal disease.
Mucormycosis is categorized based on the location of the infection. Rhino-orbital-cerebral mucormycosis (ROCM) is the most common – approximately 34% of cases – followed by cutaneous (22%) and pulmonary (20%). Less common manifestations include disseminated disease (13%) and gastrointestinal infection (8%) (Jeong et al., Clin Microbiol Infect).
Pulmonary infection is related to hematological malignancy, such as leukemia and lymphoma. Disseminated disease occurs after solid organ transplantation. An increase in trauma-related cutaneous cases has been documented in tornado, tsunami and fire survivors (Jeong et al., Clin Microbiol Infect).
ROCM is significantly associated with diabetes, occurring more commonly in those with poorly controlled blood sugar or ketoacidosis. Infection begins with the inhalation of fungal spores that directly inoculate nasal mucosa. From there, fungal hyphae invade and propagate along arteries. The infection can quickly spread to the orbit and brain, although ocular involvement is rare, as the avascular sclera serves as a natural barrier. Infection of arteries leads to localized ischemia. During biopsy, patients often show an abnormal lack of bleeding during the procedure. Cerebral involvement leads to difficult-to-treat and deadly infections.
Diagnosis of mucormycosis involves imaging and laboratory studies. Computed tomography (CT) will show nodular, mucosal thickening in the affected sinuses. In later disease it may show bony destruction of the orbital wall and invasion of rectus muscles. MRI better visualizes invasion of soft tissue and vascular obstruction and is often used to rule out other causes of unilateral vision loss. Biopsy and direct microscopy of sinus tissue reveal fungal hyphae and allow a definitive diagnosis of mucormycosis.
Clinical manifestations
Initial signs of infection include fever, unilateral facial edema, proptosis and palatal or palpebral fistula. In diabetic patients, facial pain or numbness, headache, sinusitis, proptosis, ophthalmoplegia and orbital apex syndrome may occur.
Orbital apex syndrome results in variable cranial nerve involvement and explains our patient’s vision loss with ptosis. Decreased mental state may also be seen as a result of prolonged pain or cerebral involvement. Half of patients with ROCM suffer from visual loss. Ocular and optic nerve ischemia can result from occlusion of the internal carotid, ophthalmic, central retinal artery or posterior ciliary artery. Vision may also decrease due to compressive/space occupying mucosal nodules and necrosis.
Treatment, management
Mucormycosis always requires prompt, aggressive treatment to increase chances of survival. Intravenous amphotericin B is the most common first-line antifungal treatment. Lipid-based IV amphotericin B formulations can be used, though they are more available in European countries. No difference in survival between traditional and lipid-based formulations has been found, although lipid-based formulations may cause less renal damage.
A newer oral medication shown to be comparable to IV amphotericin B is isavuconazole. Patients are given 200 mg oral water-soluble prodrug three times daily for 6 days, followed by 200 mg per day until disease resolution or treatment failure. Salvage therapy is initiated after lack of clinical response to first-line treatment. Most commonly an isavuconazole antifungal, including IV or oral Posaconazole, is used.
Hyperbaric oxygen therapy demonstrates fungal growth inhibition and promotes wound healing. Supplemental oxygen may be beneficial in certain cases, but no prospective clinical studies have been undertaken.
Surgical debridement, up to and including exenteration, is often warranted. International guidelines strongly support early and complete resection of infected tissue when possible, in addition to systemic antifungal therapy. Combined surgery and antifungal treatment is associated with lower 90-day mortality compared to antifungals alone (Jeong et al., Int J Antimicrob Agents).
Prognosis
All-cause mortality ranges from 40% to 80% (Cornely et al.). The highest survival rates are in those without underlying conditions. This includes untreated diabetics, like our patient, whose blood glucose is subsequently controlled. Survival is least likely in patients with blood cancers or a history of stem-cell transplants.
Death occurs at a median of 19 days post-presentation (Cornely et al.). There has been no statistically significant difference in survival with the advent of new antifungal medications (Jeong et al., Int J Antimicrob Agents). As clinicians, the most important aspect of care is initiation of prompt treatment. A 6-day delay in administration of antifungals is associated with a twofold increase in 90-day mortality (Cornely et al.).
Our patient returned for a full eye exam 64 days after the initial visit. He had multiple follow-ups with infectious disease, ENT and endocrinology in the intervening days. Vision was 20/20 OD and 20/400 OS with eccentric viewing and a 4+ afferent pupillary defect. Confrontation fields were full in the right eye and showed constriction inferotemporally in the left eye. Motility was full with no pain, and the patient’s moderate ptosis had resolved. Optic nerve pallor in the left eye was seen on fundus examination, and the retinal nerve fiber layer (RNFL) OCT showed significant thinning.
As of publication, patient is still taking 200 mg isavuconazole per day. He is aware that the vision in his left eye will never return to normal. Visual field testing may be warranted at the next visit. He has returned to work and is in good spirits.
Mucormycosis is a serious and fatal condition that often leads to decreased vision. As primary eye care providers, recognizing the initial symptoms and referring for prompt, aggressive hospital-based treatment can be the difference between life and death.
Fundus photos at 64 days.
References:
- Cornely O, et al. HemaSphere. 2019;doi:10.1097/01.hs9.0000563416.43453.d2.
- Herrera D, et al. Skull Base. 2008;doi:10.1055/s-2008-1093099.
- Jeong W, et al. Clin Microbiol Infect. 2019;doi:10.1016/j.cmi.2018.07.011.
- Jeong W, et al. Int J Antimicrob Agents. 2019;doi:10.1016/j.ijantimicag.2019.01.002.
- Sponsler TA, et al. Surv Ophthalmol. 2019;doi:10.1016/0039-6257(92)90111-6.
- Wani N, et al. J Otol. 2015;doi:10.4103/0971-7749.159700.
For more information:
Daniel Christensen, OD, completed an optometric residency in ocular disease with an emphasis in primary care in Santa Fe, N.M. He currently practices at Orcutt Eye Center in Orcutt, Calif. He can be reached at danielchristensen31@gmail.com.
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