Double Vision and Gait Ataxia in an Immunocompetent 9-Year-Old Girl With Intracranial Phaeohyphomycosis

A 9-year-old girl presented with morning headaches associated with vomiting, gait ataxia, and facial and ocular motor nerve palsies. Her initial imaging was concerning for demyelinating disease. After extensive infectious and rheumatologic workup returned negative, she was treated twice with intravenous immunoglobulin and intravenous steroids with near-complete resolution each time. She returned, however, with worsening neurologic deficits and imaging revealing focal ischemic infarction in the brainstem as well as new-onset hydrocephalus. A multispecialty workup was initiated without conclusive diagnosis. A novel, noninvasive test for plasma cell-free DNA established a diagnosis of Cladophialophora bantiana that was confirmed and validated by a brain biopsy taken during a clinical decompensation. Treatment was initiated with systemic voriconazole and intraventricular amphotericin B.

Clinical-Pathological Case Study Section Editors: Daniel R. Gold, DO Marc Levin, MD, PhD Double Vision and Gait Ataxia in an Immunocompetent 9-Year-Old Girl With Intracranial Phaeohyphomycosis Aishwarya V. Pareek, MD, Timothy E. Lotze, MD, Gail Demmler, MD, Carrie A. Mohila, MD, PhD, Brandon Tran, MD, Veeral S. Shah, MD, PhD Abstract: A 9-year-old girl presented with morning headaches associated with vomiting, gait ataxia, and facial and ocular motor nerve palsies. Her initial imaging was concerning for demyelinating disease. After extensive infectious and rheumatologic workup returned negative, she was treated twice with intravenous immunoglobulin and intravenous steroids with near-complete resolution each time. She returned, however, with worsening neurologic deficits and imaging revealing focal ischemic infarction in the brainstem as well as new-onset hydrocephalus. A multispecialty workup was initiated without conclusive diagnosis. A novel, noninvasive test for plasma cell-free DNA established a diagnosis of Cladophialophora bantiana that was confirmed and validated by a brain biopsy taken during a clinical decompensation. Treatment was initiated with systemic voriconazole and intraventricular amphotericin B. Journal of Neuro-Ophthalmology 2021;41:399–403 doi: 10.1097/WNO.0000000000001204 © 2021 by North American Neuro-Ophthalmology Society Drs. Pareek, Lotze, and Shah: A 9-year-old, previously healthy and normal developing girl presented to the emergency department with occipital headache, vision disturbance, and gait ataxia. Two weeks before presentation, and in the setting of a resolved viral Department of Pediatrics, Divisions of Neurology and Developmental Neuroscience (AVP, TEL), Infectious Disease (GD), Pathology (CAM), and Radiology (BT), Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas; and Department of Ophthalmology and Neurology (VSS), Cincinnati Children’s Hospital, University of Cincinnati, Cincinnati, Ohio. Supported in part by the clinical programs at Texas Children’s Hospital-Baylor College of Medicine, Houston, TX. The authors report no conflicts of interest. Address correspondence to Veeral S. Shah, MD, PhD, Cincinnati Children’s Hospital Medical Center, Abrahamson Pediatric Eye, Institute/Division of Pediatric Ophthalmology, 3333 Burnet Avenue, MLC 7003, Cincinnati, Ohio; E-mail: [e-mail] Pareek et al: J Neuro-Ophthalmol 2021; 41: 399-403 upper respiratory illness, she began experiencing intermittent occipital headaches on waking with associated vomiting and dizziness. Given her symptoms, she was initially evaluated at an urgent care on Day 7 of illness and diagnosed with allergic sinusitis. She was treated with azithromycin and prednisolone. On Day 14, the patient’s symptoms progressed to include unsteady gait, inability to smile on the right, and left gaze deviation. On initial examination, the patient was awake and alert in bed. Ocular examination revealed 20/20 uncorrected vision in the right and 20/40 in the left eye. Pupils were bilaterally symmetric, reactive, without afferent pupillary defect, but with light-to near dyskinesis in both eyes. Motility examination revealed a right hypertropia with (presumed) compensatory left head tilt and right inferior oblique overaction, mild right eye abduction deficit, and moderate bilateral supraduction deficits. In addition, there was moderate left eye adduction limitation with a contralateral abducting nystagmus in the right eye. Convergence eye movements were preserved, and there was no convergence-retraction nystagmus. Dilated fundus examination showed sharp optic discs without optic nerve edema. Her neurologic examination showed normal tone and symmetric strength bilaterally with no evidence of atrophy or fasciculations. On finger-to-nose and heel-to-shin testing, she displayed right-sided dysmetria. Collectively, her examination was consistent with right fourth, sixth, and seventh cranial nerve palsies, plus a left internuclear ophthalmoplegia and incomplete dorsal midbrain (Parinaud) syndrome causing supraduction paresis bilaterally and pupillary lightnear dissociation. Dr. Tran: MRI of the brain and spine with and without contrast revealed lobular enhancing slightly ill-defined mass lesion involving the right middle cerebellar peduncle, dorsal midbrain, dentate and peridentate region (Fig. 1), and no involvement of the spinal cord. 399 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study Drs. Pareek, Lotze, Demmler, and Shah: An infectious workup included blood and cerebrospinal fluid (CSF) cultures as well as laboratory studies for atypical infections most likely to cause cerebellar ataxia and cranial nerve abnormalities in immunocompetent hosts. These included Epstein–Barr virus, herpes simplex virus, arboviridae including West Nile virus, and fungal etiologies. Testing however returned negative for these etiologies. The patient was initiated on a course of high dose intravenous methylprednisolone (IVMP) at 30 mg/kg/day for suspected acquired demyelinating disease based on the findings of enhancing lesions on MRI and absence of evidence to support alternate etiology. By Day 5 of IVMP, the patient had shown slight improvement in her right gaze palsy with persistence of her other focal neurologic deficits. Given this only modest improvement, IVMP treatment was extended for a total of 7 days, after which a 3-day course of intravenous immunoglobulin was initiated. At the completion of these treatments, the patient showed considerable improvement in deficits with nearly complete resolution of her right gaze palsy, facial asymmetry, and gait ataxia, and improvement in her ability to ambulate independently. She was discharged home with outpatient physical therapy and plans to repeat an MRI of the brain in 3 weeks. Three days after discharge, she returned to the emergency room with worsening occipital headache, vomiting, and double vision. She was alert and oriented, and examination was notable for marginal improvement of ocular motor abnormalities and cranial neuropathies compared with examination on day of discharge from her first admission. FIG. 2. Contrast MRI brain during the second admission for worsening occipital headache associated with vomiting and ataxic gait. Compared with initial MR brain (Fig. 1), there has been an interval change in appearance of the parenchymal abnormality involving the brainstem and cerebellum. A. Axial T2-weighted image shows significant interval decrease in T2 hyperintense signal in the right dorsal pons and middle cerebellar peduncle. B. Axial postcontrast image shows an increase in ependymal enhancement with extension to the contralateral side (arrow). extending contralaterally (Fig. 2). On day 5 of admission, the patient continued to have headache, emesis, and poor appetite and developed spontaneous upbeat nystagmus, which prompted an acute MRI. The neuroimaging revealed interval progression of underlying disease with mildly increased T2/FLAIR hyperintensity involving dorsal aspects of the pons and pontomedullary junction and a new T2/ FLAIR hyperintense punctate focus in the peripheral right cerebellar hemisphere. Drs. Pareek, Lotze, and Shah: Dr. Tran: Repeat MRI Brain with and without contrast revealed interval change in the appearance of the parenchymal abnormality of the brainstem and cerebellum. Specifically, it showed significant decrease in parenchymal enhancement and interval improvement of hyperintense T2 signal abnormality, but an increase in ependymal enhancement Given her previous clinical and neuroimaging response to high-dose corticosteroids and her negative infectious workup, the primary diagnosis remained an acquired demyelinating disorder. She was initiated again on IVMP and demonstrated clinical improvement in her gait and near-complete resolution of her facial palsy. She was discharged after 10 days with an oral steroid taper. FIG. 1. A 9-year-old girl presents with right fourth, fifth, and seventh cranial nerve palsies, left INO, and dorsal midbrain syndrome. Contrast MRI brain on the day of presentation. A. Axial T2-weighted image shows hyperintense T2 signal involving the right middle cerebellar peduncle (arrow) and dorsal pons (star), extending around the lateral recess of the fourth ventricle and involving dentate and peridentate region (asterisk). B, C. Postcontrast axial images show marked enhancement including the ependymal lining of the fourth ventricle and right facial colliculus (arrow). INO, internuclear ophthalmoplegia. 400 Pareek et al: J Neuro-Ophthalmol 2021; 41: 399-403 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study Four days after discharge, she was readmitted to the neurology service for persistent occipital headache and recurrent gait ataxia. On examination, although she was alert and oriented, she appeared very fatigued. Pupils were equal and reactive, and there was sustained abducting nystagmus with rightward gaze and right-sided seventh nerve palsy but otherwise normal symmetric tone and strength. Dr. Tran: On follow-up MRI brain with and without contrast, there was interval development of focal restricted diffusion in the left upper pons (with diffusion-weighted imaging [DWI]) consistent with focal infarct, interval worsening of signal abnormality in the right cerebellum, dentate and peridentate regions, dorsal pons and brainstem in conjunction with interval development of an acute communicating hydrocephalus (Fig. 3). Drs. Pareek, Lotze, Demmler, and Shah: Given new and worsening radiographic findings, investigation was reinitiated based on a broader differential diagnosis including demyelinating disease, infection, malignancy, and vasculitis. The patient initially presented with a clinical image of focal neurologic deficits in the setting of recent nonspecific upper respiratory infection, all consistent with an acute demyelinating process. However, her initial laboratory workup and imaging were not typical for most demyelinating diseases. Her CSF studies showed a white blood cell count greater than 300, which would be atypical for demyelinating disease, and more typical of an infectious process. Furthermore, there was MR contrast-enhancement of the cerebellum extending into the fourth ventricle and DWI-restricted diffusion within the fourth ventricle. Such MRI findings are not typically seen with demyelination. In this 9-year-old immunocompetent girl who was up to date with vaccinations and had no relevant travel history (e.g., to endemic Lyme regions), her initial (unrevealing) infectious workup centered on pathogens that may present with cerebellar ataxia and cranial nerve abnormalities. Given her brainstem involvement, tuberculosis meningitis, varicella, and listeria rhombencephalitis were considered and subsequently excluded. The patient showed no clinical improvement despite treatment with meningitic dosing of empiric antibiotics on numerous occasions during her hospitalizations. Central nervous system (CNS) malignancy was entertained as a possibility at the outset when the patient presented with progressive headache and emesis, followed by cranial nerve deficits and ataxia. Imaging of the brain revealed a large lesion that demonstrated rapid growth on serial MRI, also consistent with malignancy. However, despite the large lesion size, only minimal mass effect was seen, CSF cytology showed mixed acute and chronic inflammatory cells without malignant cells, and computed tomography (CT) of the chest, abdomen, and pelvis was unrevealing, making malignancy less likely. The patient’s new focal ischemic infarction of the pons increased suspicion for primary CNS vasculopathy. Secondary CNS vasculopathy due to systemic lupus erythematosus, antiphospholipid antibody syndrome, and deficiency of adenosine deaminase 2 (DADA2) were also considered. CT angiogram followed by conventional angiography did not demonstrate beading or other arterial abnormalities to suggest vasculitis. Because of a negative laboratory work-up, exclusion of other etiologies, as well as the clinical and imaging response to steroids, she was presumed to have demyelinating disease. By the patient’s third admission, her illness had followed a relapsing course without systemic symptoms such as fever. Further diagnostic evaluation focused on identifying a possible underlying immune defect, which could predispose to a more subacute and indolent CNS infection such as Aspergillus or Nocardia. FIG. 3. Contrast MRI brain during the third admission for with slurred speech, diplopia, ataxia, and severe occipital headache. A, B. Axial DWI and postcontrast images show interval development of focal ischemic infarction in the left upper pons with interval worsening of signal abnormality in the right dentate and peridentate regions, dorsal pons and surface of the brainstem. C. Axial T2weighted image shows development of hydrocephalus with transependymal flow of CSF (arrow), and diffuse sulcal effacement, which is concerning for increased intracranial pressure. DWI, diffusion-weighted imaging; CSF, cerebrospinal fluid. Pareek et al: J Neuro-Ophthalmol 2021; 41: 399-403 401 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study Noninvasive laboratory and imaging workup proved to be insufficient in narrowing the differential, leading finally to the need for a brain biopsy to definitively rule out a number of possible etiologies. Because of signs of CNS decompensation, she underwent emergent endoscopic third ventriculostomy and external ventricular drain (EVD) replacement, and biopsies were collected. Two days before the surgery, a novel plasma detection test for microbial cellfree DNA (cfDNA) was sent. Dr. Mohila: Specimens were collected from within the cistern where the surgeons were able to visualize fibrinous pus–like material around the basilar artery, as well as from within the fourth ventricle where they found multiple bales of black pigmented arachnoid-type tissue (Fig. 4A). These specimens were sent for microscopic evaluation which revealed pigmented, septate fungal hyphae with rare acute and rightangle branching (Fig. 4B). Drs. Pareek, Lotze, Demmler, and Shah: Three days from collection, the results from the microbial cell-free DNA (cfDNA) identified fungal CNS infection due to Cladophialophora bantiana (Fig. 5). In addition, culture of the fourth ventricle biopsy specimen grew C. bantiana after 7 days. Treatment was initiated with systemic combination antifungal treatment with liposomal amphotericin B, flucytosine, and voriconazole. However, after treatment initiation, repeat imaging of the brain showed interval increase in diffusion restriction in the fourth ventricle because of fungal debris. This, along with the patient’s clinical deterioration, prompted a trial of intraventricular administration of amphotericin B and continuation of systemic voriconazole and flucytosine. Final Diagnosis Multifocal CNS phaeohyphomycoses with ventriculitis due to C. bantiana. Discussion The differential diagnosis for a child presenting with acuteonset focal neurologic deficits and multiple enhancing lesions of the brain is extensive and includes demyelination, neoplasm, vasculitis, and infection. In this particular case, the initial neuroimaging was not particularly consistent with focal demyelination given the diffusion restriction within the fourth ventricle. However, her remarkable clinical and imaging response to treatment with corticosteroids on 2 separate occasions and the absence of findings to suggest an alternate diagnosis led to a presumptive diagnosis of a demyelinating disorder. The persistent recurrence of symptoms and progression of CNS lesions eventually necessitated 402 FIG. 4. A. Images from endoscopic brain biopsy show fibrinous, pus-like material (asterisks) adherent to the cistern and around the basilar artery. In addition, black, web-like material is discovered in the fourth ventricle. B. Histopathology of multiple biopsy specimens reveals pigmented, septate hyphal forms with rare acute and right-angle branching, concerning for invasive fungal infection (arrow). Fungal PCR identifies the pathogen as C. bantiana. PCR, polymerase chain reaction. a reassessment of the working diagnosis. Although not definitive, normal CT and conventional angiograms made vasculitis less likely and negative CSF cytology argued against neoplasm. Finally, to further expand the already extensive infectious workup, a novel plasma detection test for microbial cell-free DNA (cfDNA) was sent and identified free DNA from C. bantiana fungi. Although examination of direct specimens to identify fungal elements within tissue has long been required to establish a diagnosis of CNS phaeohyphomycoses, this next generation microbial DNA sequencing was able to noninvasively confirm this rare etiologic fungus in our patient. The diagnosis was later confirmed by histopathology, which suggests that noninvasive testing may help guide evaluation and management earlier in a patient’s clinical course. C. bantiana is a rare neurotropic fungus known to cause CNS phaeohyphomycosis with equal preference for immunocompetent and immunocompromised hosts (1). The environmental source of C. bantiana is unknown, but the occupational association with farming suggests that its origin is in the soil. A theoretical exposure in our patient could Pareek et al: J Neuro-Ophthalmol 2021; 41: 399-403 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 5. Detection of C. bantiana microbial cell-free DNA plasma. A. Diagram depicting multiple pathogens—including bacteria, fungi, viruses, and parasites—release cell-free DNA in various organs that circulate in plasma. DNA can be isolated, sequenced, and quantified (in molecules per microliter) with approximately 1-day turnaround. B. Analysis in this patient showed presence of 42 molecules of C. bantiana DNA per microliter of plasma. © Karius, Inc., used with permission. have occurred during a weekend trip to a farmhouse 2 months before symptom onset. Although it presents clinically with nonspecific symptomology and varied neurologic deficits, it is known for its radiologic findings of supratentorial brain abscesses (2). C. bantiana CNS infections have an estimated mortality rate of 70%, even with appropriate treatment. This is attributed to the need for diagnostic brain biopsy, which occurs late in the disease course and delays treatment (3). C. bantiana is a therapeutic challenge as optimal treatment is unknown because of the relative paucity of documented cases and variable outcomes in reported patients. Most patients in previous case series received high-dose amphotericin B usually in combination with a triazole or flucytosine (4). Most reported cases have involved discrete parenchymal abscesses (5), whereas our patient’s disease process was unique with multifocal lesions and significant ventriculitis with fungal debris. We opted for a trial of intraventricular amphotericin B through the patient’s EVD to target the mass of organisms in her fourth ventricle. In addition, she was administered systemic voriconazole and flucytosine, which has excellent CNS penetration (6). Considering the toxicity of amphotericin when given intraventricularly, we began at the lowest therapeutic dose and increased as tolerated. Given the propensity of C. bantiana to form abscesses, the patient was monitored closely for changes in neurologic examination and on serial MRI while undergoing treatment. Pareek et al: J Neuro-Ophthalmol 2021; 41: 399-403 Our patient’s hospital course spanned nearly 6 months and was complicated by tracheostomy and G-tube placement, multiple EVD and VP shunt revisions, and cardiac arrest requiring prolonged resuscitation. In addition, fungal cultures continued to grow positive after 3 months of aggressive treatment, prompting craniotomy and wash out of the fourth ventricle. More than 1 year after the diagnosis, she exhibits moderate residual neurologic deficits with continued rehabilitative therapies. REFERENCES 1. Chakrabarti A, Kaur H, Rudramurthy SM, Appannanavar SB, Patel A, Mukherjee KK, Ghosh A, Ray U. Brain abscess due to cladophialophora bantiana : a review of 124 cases. Med Mycol. 2016;54:111–119. 2. Ahmad M, Jacobs D, Wu H, Wolk DM, Jaffer Kazmi SA, Jaramillo C, Toms SA. A rare intracerebral fungal Abscess—case series and review of literature. Surg J (NY). 2017;03:e62–e68. 3. Shrivastava A, Tadepalli K, Goel G, Gupta K, Kumar Gupta P. 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