Key-words:
Cerebral phaeohyphomycosis - fungal - onychomycosis
Introduction
CPHM with onychomycosis is extremely rare. Authors report a case and discuss treatment.
Case Report
History and examination
A 37-year-old male, farmer presented with forgetfulness and altered behavior for 3 months. There is a history of blackish discoloration of all nails 1 year back, which improved after 3 months of medical treatment. On examination, his right thumb's nail was black and irregular.
Routine laboratory investigations were within normal limits, and Western blot test was negative for HIV. Noncontrast computerized tomography (NCCT) scan chest and NCCT scan par nasal sinus were normal. NCCT head revealed ill-defined hyperdense lesion in the left frontal region [[Figure 1]]a. Contrast-enhanced magnetic resonance imaging (MRI) of his brain revealed large ill-defined gray-white area of altered signal intensity involving left frontal region [[Figure 1]]b with involvement of left basal ganglia and anterior part of the corpus callosum showed T2-weighted, fluid-attenuated inversion recovery (FLAIR) hyperintense signal with no significant restricted diffusion. Lesion demonstrated intense heterogeneous enhancement as postcontrast T1-weighted image. No perifocal edema is noted.
Figure 1: Radiological imaging (a) preoperative noncontrast computerised tomography head showing irregular hyperdense lesion (black arrow) seen in left frontal region; (b) preoperative magnetic resonance imaging (fluid-attenuated inversion recovery) of the brain (axial section) showing irregular lesion (black arrow) seen in the left frontal region. (c) Postoperative (day 1) contrast-enhanced computerized tomography scan of the brain (axial section) showing postoperative cavity with substance defect; (d) postoperative (3 months) magnetic resonance imaging (contrast enhanced T1 image) of the brain (axial section) showing near-total nonvisualization of lesion
The patient underwent surgery for resection and biopsy of the lesion.
Operation
Craniotomy was done. Dura mater was incised. Intraoperatively, a blackish, ill-defined lesion was noted invading the cerebral tissue. The lesion was infiltrating the cerebral tissue. Resection of the lesion was done. Immediate and delayed postoperative periods were uneventful.
Histopathological examination
On gross examination, the biopsy comprised of blackish tissue admixed with pieces of gray-white soft tissue. On microscopic examination, the necrotic debris, spore, and septate-pigmented and branching hyphae with giant cell [[Figure 2]] were noted. Fontana Masson stain confirmed the presence of dematiaceous hyphae. The gross and microscopic findings of the lesion we describe are characteristic features of cerebral phaeohyphomycosis (CPHM). Potassium hydroxide staining and fungal culture were not done as fungal etiology was not suspected pre- and intra-operatively.
Figure 2: Photomicrographs showing (a) light blue-colored round spores (black arrow) (H and E, x40); (b) brown-pigmented fungal hyphae (black arrow) (H and E, x100); (c) fungal hyphae (black arrow) in giant cell (H and E, x100)
The patient was started on antifungal drug voriconazole after histopathology reports. On 6 months follow-up, the patient has neither nail discoloration nor any neurological deficits.
Postoperative contrast-enhanced computerized tomography scan head (at day 1) revealed postoperative cavity with substance defect [[Figure 1]]c.
Postoperative contrast MRI brain (at 3 months) revealed large postoperative cavity with substance defect and perilesional gliosis and hemosiderin staining in the left frontal region with peripheral nodular shaggy enhancement, likely due to postoperative granulation tissue. There is near-total nonvisualization of the left frontal lesion [[Figure 1]]d.
Discussion
Ajello et al. coined the term phaeohyphomycosis (PHM) in 1974 to describe cutaneous, subcutaneous, and systemic infection caused by hyphomycetous fungi, which develop as dematiaceous, septated hyphae in the host tissue.[[1]] The presence of melanin in the fungal cell walls gives a dark color to the hyphae.[[2]] Melanin is considered a major virulence factor[[2]] as melanin provides advantage in evading host defense and crossing the blood–brain barrier by binding to hydrolytic enzymes.[[3]] Such fungi are soil inhabitant, a true pathogen that are known for their neurotrophism.
The neurotophic fungi are often geographically restricted, such as Rhinocladiella mackenziei occurring in the Middle East and Cladophialophora bantiana mainly in India.[[2]] Although most infections with Exophiala dermatitidis are reported from East Asia, the fungus is encountered worldwide.[[2]] CPHM commonly occurs in the second and third decades of life with male predominance, except R. mackenziei which affects adults with a median age of 62 years without male predominance.[[4]] The occurrence of CPHM irrelevant to immune status of host is its most unique characteristic.[[3]] In this case, patient was 37 years old, male, and immunocompetent.
Central nervous system (CNS) seeding may occur due to hematologenous dissemination[[2]],[[3]] of inhaled spores or accidental skin inoculation[[3]] as well as direct extension from adjacent par nasal sinuses or ears. In this case, spread to brain could be hematogenous spread after accidental inoculation in nail.
Early diagnosis is a challenge due to the rarity and lack of specific signs and symptoms of disease. Brain abscess is classic CNS manifestation.[[5]] However, the patient can also present meningitis, encephalitis, myelitis, or arachnoiditis.[[3]] Clinical symptoms can vary as memory loss and hemiplegia. Headache and hemiparesis are the most common symptoms.[[3]] In this case, symptoms were memory loss and altered behavior.
Classically described MRI findings are ring-enhancing lesions on T1-weighted imaging, hypointensity of the rings on T2-weighted imaging, and low-to-high signal on diffusion-weighted imaging.[[6]] We were misled to the preoperative diagnosis of high-grade glioma in the present case due to absence of fever and other constitutional symptoms of infection and hyperintensity on T2-weighted imaging and FLAIR. Magnetic resonance spectroscopy brain can help to differentiate.[[5]] Intraoperative frozen section or crush smear can help in early diagnosis and management of CPHM.[[7]]
Culture and isolation of pathogen from the serum or cerebrospinal fluid (CSF) may not always be possible.[[8]] Diagnosis is made by surgical biopsy.[[5]] Only the tissue examination can be useful to identify irregularly swollen hyphae with yeast-like structure and to confirm the presence of dematiaceous hyphae in melanin-specific Fontana Masson stain.[[2]],[[3]] There is no standard guidelines for CPHM due to rarity of cases.[[2]] Most treatment protocols are based on sporadic case reports.[[2]] A combination of surgical and medical treatment is generally recommended.[[6]],[[9]] Complete excision of brain abscess has better outcome than only aspiration or partial excision. There are no standardized therapies, but voriconazole, posaconazole, and itraconazole demonstrate the most consistent in vitro activity against this group of fungi.[[2]] Voriconazole may presumably be superior for CNS infections because of its ability to achieve good levels in the CSF.[[2]],[[3]],[[9]],[[10]] The precision of treatment length is still not known, but long-term therapy is recommended.
For disseminated or intracranial diseases with limited surgical options, combination antifungal therapy (polyene, flucytosine, terbinafine, echinocandins, and/or extended-spectrum azoles) is frequently considered.[[2]],[[10]] In most cases in which surgery is performed, antifungal drug treatment is used to insure elimination of any residual infection[[10]] as in this case.
Therapy for pulmonary PHM consists of intravenous liposomal amphotericin B or mold-active azoles, except ketoconazole, for a prolonged period.[[2]] CPHM with pulmonary involvement should have a role of liposomal amphotericin B along with azoles. Prognosis is poor.
Conclusions
CPHM is rare disease, but challenging one with high mortality rate, particularly when the CNS is affected. Diagnosis depends on a high index of clinical suspicion along with accurate mycological findings. Detailed studies are required for deciding treatment protocols.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
