a case report and review of orbital aspergillosis treatment with voriconazole in the english language literature .
amphotericin b with debridement is the current standard of care for orbital aspergillosis ; however , its prognosis is unfavorable . when compared to amphotericin b , voriconazole demonstrates a survival benefit , has less systemic toxicity , and is better tolerated by patients .
while a prospective trial comparing amphotericin b to voriconazole in orbital aspergillosis is not feasible , there is evidence to support the use of voriconazole as primary therapy .
orbital aspergillosis is a rare and often fatal condition in healthy patients . due to its vague initial symptomatology
, it is often misdiagnosed and improperly treated which , in turn , facilitates disease progression .
once proper treatment is initiated , the therapy is often poorly tolerated and the mortality rate remains high . in this case report , we will discuss a patient whose symptoms began in july 2010 and follow the historical , clinical , radiographic , and histological course until the diagnosis of invasive orbital aspergillosis was made in november 2010 .
we will then discuss treatment options presented to this patient and summarize treatment options in the context of the available literature .
a 68-year - old white man with a past medical history of glaucoma with remote bilateral trabeculectomies , hypertension , depression , and sinusitis presented with a 1-month history of headaches and pain around his right eye .
the patient described the pain as a constant ache behind his right eye which , over the course of the month , had intensified to become a sharp , stabbing pain . during the third week , he began to have blurred vision and ptosis of the right lid .
he sought treatment at his local hospital where he was admitted and had a head ct , a head mri , and bilateral temporal artery biopsies .
no pathology was seen on imaging , and the temporal artery biopsies were negative . as a result , the patient was presumptively diagnosed with giant cell arteritis ( gca ) and treated with corticosteroids .
the patient presented in our neuro - ophthalmology clinic 4 weeks after the initial onset of his symptoms . at this time , the patient 's medications consisted of amlodipine , valsartan , paroxetine , omeprazole , and oxycodone .
his best - corrected visual acuity was 20/60 od and 20/25 os ; his color vision tested with ishihara plates was 1/11 od and 11/11 os . on examination
, he had a trace right relative afferent pupillary defect , complete ptosis of the right lid , and a frozen right eye due to paralysis of cranial nerves iii , iv , and vi ( fig .
the combination of the visual and clinical findings led to the diagnosis of orbital apex syndrome .
fundus examination demonstrated pink optic nerves with a cup / disc ratio of 0.8 od and 0.9 os .
laboratory testing revealed a c - reactive protein level of 7.9 mg / l , erythrocyte sedimentation rate of 46 mm / h , and white blood cell count of 6,900/l with 93% neutrophils . an mri and ct of the head were ordered which demonstrated an infiltrative process centered in the right pterygopalatine fossa and involving the soft tissues of the nasal posterolateral recess , right orbital apex , right sphenoid sinus , and dura adjacent to the clinoid process ( fig .
the department of otolaryngology was consulted , and a right trans - sphenoid orbital biopsy was performed .
preliminary pathology from the biopsy demonstrated an infiltrate consisting of a mixture of granulocytes , giant cells , and small mature lymphocytes without evidence of infection .
the slides were considered suggestive of a nonspecific inflammatory etiology , such as tolosa - hunt syndrome , and were sent for further staining .
the patient was discharged on prednisone 80 mg / day ( 1 mg / kg / day ) . the following morning ,
the patient 's best - corrected visual acuity had deteriorated to 20/100 od , and his right eye remained frozen . according to recommendations provided by the division of infectious diseases , he was started on voriconazole 4 mg / kg i.v .
the patient 's ophthalmoplegia and visual acuity improved dramatically within 72 h , and after 6 days of therapy the patient 's visual acuity was 20/40 od .
after 6 weeks of treatment , the patient returned to our clinic with full extraocular movements , full color vision , and a visual acuity of 20/30 od .
the divisions of infectious diseases and dermatology were consulted , and it was found that the patient had developed a drug - induced photosensitivity rash secondary to voriconazole . his therapy was changed to daily intravenous micafungin 150 mg , which he has tolerated well for the last month .
the best - established risk factor for orbital aspergillosis is sinusitis of a paraorbital sinus ; however , there is no consensus on which loci confer the greatest risk [ 1 3 ] .
other risk factors include trauma , facial surgery , high - exposure professions ( demolition , yard work , or working in endemic areas of aspergillus flavus such as the sudan ) , and immunocompromised states including aids , absolute neutrophil count < 1,000 , leukemia , and diabetes mellitus .
the two most common pathogens in humans are a. flavus and a. fumigatus . in the orbit
, a. flavus causes an invasive granulomatous infection , whereas a. fumigatus may present as a noninvasive or an invasive necrotizing - fulminate infection .
noninvasive orbital aspergillosis is typically found in diabetics , corticosteroid users , and immunocompetent individuals .
patients often present with a chronic , dull retrobulbar pain present for months , headache , red eyes , and proptosis . over time
, these symptoms may progress to include sharp pain , cranial nerve palsies , amaurosis , and orbital apex syndrome .
as the disease progresses , aspergillus may invade the vasculature resulting in necrotizing angiitis , mycotic aneurysms , dissemination , and thrombosis of the cavernous sinus , leading to mortality within days [ 2 , 4 ] . as a result ,
invasive orbital aspergillosis presents similarly but with a more rapid progression and is uniformly fatal if untreated .
invasive aspergillosis typically manifests in immunocompromised individuals and is characterized by a granulomatous or fulminate immune response with a centrifugal invasion of adjacent tissues , vasculature , and bone .
invasive orbital aspergillosis may result in orbital apex syndrome , necrotizing angiitis , mycotic aneurysms , thrombosis , systemic dissemination , erosion of the orbit , and direct invasion of the central nervous system .
when the disease is limited to the orbit , there is a 28% mortality rate for patients receiving standard treatment with amphotericin b .
however , once orbital apex syndrome has manifested , the mortality rate increases to 7080% despite standard treatment , and if the central nervous system is involved , the mortality rate increases to 80100% [ 4 , 5 , 6 , 7 ] .
the diagnosis of orbital aspergillosis is difficult to confirm and is often delayed 210 months from the initial presentation of symptoms .
however , since its initial symptoms are vague , similar to more prevalent conditions , and respond to steroids , aspergillosis is often misdiagnosed as orbital pseudotumor or gca ( table 1 ) .
many patients , including ours , are presumptively started on corticosteroids and demonstrate a subsequent improvement resulting in a premature conclusion to the workup .
steroids decrease the inflammation in the orbit and transiently improve symptoms but may hasten the course of aspergillosis . when a diagnosis of orbital aspergillosis is suspected , an mri of the orbit is indicated .
mri is useful for evaluating the optic nerve , cerebral dura , paraorbital sinuses , and masses .
any sinusitis ( > 8-mm thickening of the sinus mucosa ) with an enhancement of the optic nerve or erosion of the orbital bones should prompt suspicion for orbital aspergillosis .
a ct of the orbit without contrast may aid in the diagnosis by screening for bony erosion and examining for intraluminal calcification , which is pathognomonic . to confirm the diagnosis ,
fungal cultures of the nares have been shown to be unreliable and should not be used for screening . if imaging reveals a paraorbital sinusitis , an anterior rhinoscopy as well as a biopsy may be performed .
while anterior rhinoscopy is the least invasive approach , 50% of cases require a second biopsy [ 1 , 8 ] .
alternative approaches include orbital fine needle aspiration or trans - sinus orbital biopsy ; these approaches have a higher yield but are more invasive than anterior rhinoscopy .
the tissue should be sent for both frozen and permanent sections to look for fungi as well as other pathology .
in addition , slides should be sent for periodic acid - schiff stain and gomori methenamine silver stain to look for haemotoxophilic organisms with 45 branching septate hyphae 24 m in width .
if pathological testing is initially negative but a high suspicion of aspergillosis is maintained , corticosteroids should be held until cultures are known and empiric treatment for aspergillosis should be initiated .
0.5 mg / kg / day with debridement of focal abscesses [ 1 , 2 , 4 ] . in total ,
4060% of patients show a response to amphotericin b , including liposomal preparations . despite treatment with amphotericin b ,
once the infection has manifested as an orbital apex syndrome , the mortality rate remains 7080% [ 1 , 2 , 4 , 5 , 6 ] . due to a high rate of relapse , prolonged treatment for 2 years to life is suggested [ 1 , 2 ] .
amphotericin b has numerous side effects , including irreversible nephrotoxicity , and as a result is often poorly tolerated .
there is a case report of a patient who died as a direct result of amphotericin b therapy for invasive orbital aspergillosis .
itraconazole is better tolerated than amphotericin b , but has similar response , relapse , and mortality rates [ 1 , 4 ] .
this drug should not be used if there is pulmonary involvement because a higher mortality has been demonstrated in these cases .
concomitant induction of amphotericin b and itraconazole may increase response , and maintenance with itraconazole alone is significantly better tolerated than with amphotericin b .
fluconazole 100200 mg / kg / day and rifampin 600 mg / day have also been shown to be effective , but there are too few reports to evaluate their role in therapy [ 4 , 9 ] .
ketoconazole on the other hand has been shown to be ineffective in treating orbital aspergillosis .
voriconazole is a second - generation triazole antifungal that has become the usual treatment of extraorbital invasive aspergillosis after demonstrating a 22% survival benefit over amphotericin b in a comparative evaluation [ 10 , 11 ] .
voriconazole 6 mg / kg for 1 day , then 4 mg / kg / day , has less systemic side effects than amphotericin b , favorable bone penetration , and is better tolerated for maintenance therapy [ 10 , 11 , 12 ] . despite its favorable profile , we could only find one case report in the english literature and two abstracts in the japanese literature on voriconazole treatment of invasive orbital aspergillosis [ 10 , 13 , 14 ] . in each of these case reports
, the patients demonstrated a dramatic improvement within several days of voriconazole therapy . in the english literature ,
sasindran et al .   presented a case of an 8-year - old boy who developed an orbital apex syndrome after a trauma .
the japanese literature presented 2 cases of patients in their 70s being successfully treated for orbital aspergillosis , but the treatment protocols were not discussed in the abstracts [ 13 , 14 ] .
despite being the current standard of treatment for invasive orbital aspergillosis , amphotericin b preparations offer an unfavorable prognosis . with optimized amphotericin b therapy ,
additionally , only 4060% of patients with orbital aspergillosis will respond to treatment with amphotericin b , and patients poorly tolerate prolonged therapy .
most patients develop serious complications such as nephrotoxicity , and 1 patient is reported to have died as a direct result of the therapy .
while the role of voriconazole as the mainstay of therapy for extraorbital invasive aspergillosis is well defined , its role in orbital aspergillosis has not yet been documented .
the use of voriconazole seems intuitive for orbital aspergillosis since it confers a survival benefit , provides better bone penetration , and is better tolerated than amphotericin b preparations in extraorbital invasive aspergillosis .
the efficacy of voriconazole has been demonstrated in our patient and the 3 above - mentioned case reports found in the literature .
out of the 4 patients , only our patient reported a side effect ( photosensitive drug rash ) due to voriconazole .
our patient 's risk factors for orbital aspergillosis included type 2 diabetes and a history of previous sinusitis .
these risk factors are usually associated with noninvasive orbital aspergillosis rather than with the invasive disease as confirmed by mri in our case .
our patient may initially have had a noninvasive orbital aspergillosis that was exacerbated by the use of corticosteroids for the treatment of probable gca .
the reversible immunosuppression conferred by the steroids may explain the rapid invasive progression and the favorable response to voriconazole . while 4 patients do not demonstrate a statistical benefit , voriconazole can be considered an efficacious alternative to amphotericin b for the treatment of orbital aspergillosis that is better tolerated by patients .
 background / aimto describe a case of invasive orbital aspergillosis and evaluate treatments and outcomes.methodsa case report and review of orbital aspergillosis treatment with voriconazole in the english language literature.conclusionamphotericin b with debridement is the current standard of care for orbital aspergillosis ; however , its prognosis is unfavorable . 
 when compared to amphotericin b , voriconazole demonstrates a survival benefit , has less systemic toxicity , and is better tolerated by patients . 
 while a prospective trial comparing amphotericin b to voriconazole in orbital aspergillosis is not feasible , there is evidence to support the use of voriconazole as primary therapy . 
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Case Report
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