the management of people with type 1 diabetes mellitus largely focuses on the prevention and management of acute complications such as ketoacidosis , and long - term complications of retinopathy , nephropathy , and diabetic foot disease . it is also well known that there is a higher risk of infections in diabetes , but there is a lower level of awareness of rare infections such as mucormycosis , a rapidly progressive and invasive fungal infection with significant mortality rates . the following case highlights an example of mucormycosis in diabetes that challenges our understanding of the mechanism of its spread . a 44-year - old chinese female with type 1 diabetes mellitus ( t1 dm ) was hospitalised with diabetic ketoacidosis ( dka ) ( day 0 ) . she had a history of recurrent dka , foot ulcers with osteomyelitis , retinopathy and albuminuria . her serum glucose was 30.8  mmol / l , ketones 5.8  mmol / l , ph 6.90 , hco3 5  mmol / l , creatinine 65 there was leukocytosis ( 15.410 ) and a c - reactive protein ( crp ) of 234  mg / l . at presentation she was afebrile though tachycardic ( hr 125bpm ) with a blood pressure of 140/95  mmhg . respiratory rate was 25/min and oxygen saturation was normal on room air ( 100% ) . examination revealed foot ulcers on the plantar aspect of the first and third metatarsal phalangeal joints . three months prior , her serum hba1c had measured > 16% ( > 151  mmol / mol ) . her history was also notable for recent hospital admission six weeks prior with osteomyelitis of the foot due to methicillin resistant staphylococcus aureus ( mrsa ) and group b streptococcus and concurrent bilateral pneumonia . at the time of this presentation there was no evidence of rhinorrhoea , facial swelling , headache or fever . on day 3 , computerised tomography ( ct ) of the skull and orbits showed right - sided pansinusitis with evidence of preseptal orbital cellulitis and soft tissue inflammatory changes in the malar region of the face ( fig . ciprofloxacin was also commenced as pseudomonas aeruginosa was grown in sputum cultures . on day 5 , as there had been no improvement , an exploration under anaesthesia was performed with discovery of necrotic eschar in the right maxillary sinus a right medial maxillectomy and anterior ethmoidectomy was performed and intravenous ( iv ) liposomal amphotericin ( l - amb ) 5  mg / kg / day was commenced . ribbon - like non - septate fungal hyphae were seen on microscopy of debrided tissue . culture of tissue specimens grew floccose grey colonies within 24  h of incubation at 30  c which were identified as rhizopus arrhizus by conventional morphology . the species identity was confirmed by dna sequence analysis of the internal transcribed spacer ( its ) 1 , 5.8s and its2 regions , and the d1/d2 region of the 28s ( large subunit ) ribosomal dna gene cluster , using published primers and standard sequencing methodologies . on day 6 , the patient developed a right - sided proptosis , visual loss ( visual acuity 3/24 ) , a non - reactive pupil , and restricted eye movements in the right eye in addition to sensory loss in the region of v1 and v2 of the trigeminal nerve . a magnetic resonance imaging ( mri ) scan of the head demonstrated evidence of perineural spread of infection with enhancement of the right trigeminal nerve and meckel 's cave and enlargement of right infra - orbital nerve . on microscopy , fungi were seen within the infraorbital nerve and within the walls and lumen of numerous infarcted vessels . amphotericin soaked gauze was used for topical antifungal delivery to the orbit and iv caspofungin 50  mg daily was added . a progress mri on day 10 exhibited a right cavernous sinus filling defect and a new left lentiform nucleus and thalamus rim enhancing lesion ( fig . posaconazole was changed from oral to 300  mg iv daily . on day 15 , the patient underwent further right orbital debridement after macroscopic orbital bone necrosis was noted on examination ( fig . 3 ) . caspofungin was ceased day 18 . on day 40 , iv posaconazole was changed to oral posaconazole in tablet formulation 300  mg daily route and l - amb ceased . she was discharged on day 55 . as an outpatient she continued to be managed with the combination of oral posaconazole ( serum level 1094  ng / ml ) and amphotericin soaked gauze dressings for the orbit wounds . falling insulin requirements with episodic hypoglycaemia prompted testing for adrenal insufficiency . a short synacthen test confirmed inadequate adrenal response at 60  min ( cortisol 422  nmol / l ) . posaconazole was considered a probable cause for primary adrenal insufficiency given the known association between azole antifungals and impaired cortisol synthesis , and negative anti - adrenal antibody testing ( indicating low likelihood that the adrenal insufficiency was autoimmune in nature ) . due to progressive hypotension mucormycosis infection is considered a fungal emergency owing to its rapidly aggressive and invasive nature . infection can occur in various anatomical areas depending on the portal site of entry of spores , with predilection for certain sites based on comorbidities or risk factors . these include rhino - orbital - cerebral ( roc ) , pulmonary , cutaneous , gastrointestinal or disseminated forms ( defined as two or more non - contiguous sites ) . roc infection follows inhalation of fungal spores into the sinuses and is the most common form in diabetes , . it sequentially invades sinus , orbital and cerebral tissue and morbidity relates to vascular invasion , thrombosis and necrosis , the hallmarks of the disease , . the environment created by diabetic ketoacidosis is particularly promotive of the growth of mucorales due to their unique virulence traits . mucorales have an affinity for acidic environments and possess ketone reductase , an enzyme that allows them to thrive in states of diabetic ketoacidosis ( dka ) . in the largest case series to date , most infections in diabetic patients occurred in dka ( 48% of t1 dm and 34% of t2 dm ) . furthermore , these organisms survive through acquisition of iron from their hosts . in acidic environments such as dka , serum iron levels are elevated due to disruption of iron binding to transferrin , , . amongst people with diabetes , fungal acute sinusitis infection almost exclusively spreads via direct extension to surrounding structures . contiguous spread to cerebral tissue occurs through bony erosion or invasion of blood vessels , nerves and lymphatics . if cavernous sinus involvement occurs , direct cerebral seeding may occur via the ethmoidal and orbital veins draining this area . haematogenous spread has mainly been reported in patients with a history of intravenous drug use . in these patients , spores are directly inoculated into the circulation then present as cerebral infection , usually in isolation , with preference for involvement of the basal ganglia , , . there are higher levels of iron in these regions owing to increased expression of divalent metal transporter type 1 , hence the basal ganglia environment may be particularly conducive to growth , . it is also thought that there is a relationship between the size of the mucorales spore relative to the luminal size of the striatal arteries supplying the basal ganglia . in the presented case , the appearance of a non - contiguous cerebral lesion in the basal ganglia is highly atypical of traditional roc mucormycosis . in fact , dissemination of any form in diabetes is rare with the largest case series reporting an odds ratio of 0.29 for disseminated infection in this population . we infer that dissemination would have followed from significant fungal angioinvasion with development of fungaemia and subsequent cerebral seeding . the contralateral basal ganglia involvement supports this hypothesis , given the non - contiguous disease pattern . the other novel aspect of this case is the development of mild adrenal insufficiency arising from posaconazole therapy . other antifungals such as ketoconazole are known to cause adrenal insufficiency due to their effect on steroidogenesis . fluconazole has a lower affinity for steroid metabolism enzymes and has also been associated with adrenal insufficiency albeit only in case reports and in critically ill patients , . posaconazole is a relatively new extended spectrum azole that is being used with increasing success in mucormycosis infection . it inhibits fungal growth by inhibiting the enzyme lanosterol 14-methylase which is essential in ergosterol synthesis . adrenal insufficiency with posaconazole has been reported in phase iii clinical trials in patients treated for more than 6 months . there have been no case reports in the post - marketing arena and it is considered an otherwise generally well tolerated drug , . associate professor sharon chen is a member of the antifungal advisory board for msd australia , pfizer australia and gilead sciences , inc .
we document the first case of haematogenous cerebral spread in rhizopus arrhizus rhino - orbital mucormycosis , and of posaconazole related adrenal insufficiency . 
 a patient presenting with diabetic ketoacidosis and sinusitis was treated with right medial maxillectomy , ethmoidectomy and iv liposomal amphotericin . 
 orbital exenteration was performed after intraorbital spread of infection . 
 iv caspofungin and posaconazole was added but complicated by adrenal insufficiency . 
 mri revealed a new left lentiform nucleus and thalamus rim - enhancing lesion indicating haematogenous cerebral spread .