Hearing impairment as an unusual presenting sign of Cryptococcus gattii meningoencephalitis

Abstract

Hearing loss is an unusual presenting feature of Cryptococcus gattii meningoencephalitis. Two cases of HIV-negative patients who presented with hearing loss are discussed and a literature review of published cases was conducted. Possible mechanisms for hearing loss with C. gattii infection are explored. This case series aims to raise awareness among clinicians that hearing loss can be a concerning feature in patients with persistent headache necessitating further investigation.

Background

Cryptococcus gattii is an encapsulated fungal pathogen. While it is commonly diagnosed in Australia, cases are also widely spread geographically, having been reported in British Columbia, Canada and the US Pacific Northwest.¹ In contrast to Cryptococcus neoformans, it predominantly affects immunocompetent hosts.²

C. gattii infection most often manifests as a meningoencephalitis with or without pulmonary involvement.³ Seizures, altered mental status, cerebellar abnormalities and cranial nerve deficits are also common. This case series highlights prediagnosis hearing loss in C. gattii meningoencephalitis, a condition which often has delayed diagnosis due to its non-specific presenting features and insidious clinical progression. A patient recently cared for by the authors’ infectious diseases service is described. Additionally, a more clinical description of a patient obtained from a recently published study at the same hospital is provided.⁴

Case presentation

Case 1

A 50-year-old HIV-negative woman from rural North Queensland presented with sudden onset bilateral hearing loss and vertigo following a 6-month history of intermittent headache. Her medical history included chronic obstructive pulmonary disease, hypertension, ischaemic heart disease, hypothyroidism and idiopathic Raynaud’s syndrome. The patient had a distant history of excessive alcohol use and was an active smoker. She was not using any immunosuppressive medications.

She presented to her general practitioner who arranged audiometry, cerebral imaging, and referred her to an otolaryngologist for further opinion. She had a presumptive diagnosis of metastatic malignancy and underwent further investigations (see Investigations). Almost 2 months after the onset of her hearing loss, she then presented to hospital with visual hallucinations, vomiting and confusion. She had neck stiffness and was generally hyper-reflexic.

Case 2

The second case is a more detailed clinical description from the medical records of a patient mentioned in Aye et al’s⁴ retrospective chart review. A 50-year-old HIV-negative woman from regional North Queensland presented with a 2-month history of unsteadiness, short-term memory loss, headache and blurred vision. She also had progressive confusion and hearing loss. Her background included active alcohol dependence, 60 pack-year smoking history and previous physical abuse. On neurological examination, she had an ataxic gait, a positive Rhomberg’s sign, bilateral hyper-reflexia, clonus and upgoing plantar reflex on her left side. She was found to have hearing loss. Bilateral papilloedema and right horizontal nystagmus were also noted. The remainder of her physical examination was unremarkable.

Investigations

Case 1

Audiometry confirmed bilateral sensorineural hearing loss of approximately 70 dB at all frequencies. MRI of the brain showed extensive leptomeningeal thickening and enhancement with multiple small enhancing nodules up to 5 mm within the cerebellar hemispheres bilaterally. There was abnormal enhancing soft tissue filling the internal auditory canals bilaterally (figure 1), likely representing invasion by infectious organisms. There was no evidence of hydrocephalus on this initial MRI.

Figure 1.

MRI head T2 image demonstrating abnormal enhancing soft tissue filling the internal auditory canals bilaterally (marked by *).

CT of the chest/abdomen/pelvis revealed a peripheral right upper lobe lesion suggestive of a primary lung cancer. A lung biopsy performed 2 weeks later showed relatively large encapsulated yeasts consistent with Cryptococcus. The mucopolysaccharide coat surrounding the Cryptococcus cell membranes was well highlighted by Periodic acid-Schiff and Alcian blue stains.

On presentation to hospital, her initial lumbar puncture showed an elevated opening pressure of 34 cm H2O. Cerebrospinal fluid (CSF) showed an elevated protein level of 3300 mg/L (normal 150–500 mg/L), glucose <0.3 mmol/L (normal 2.2–3.9 mmol/L) and culture grew C. gattii. Cryptococcal antigen was reactive in serum and CSF (1:2048 and 1:4096, respectively).

Case 2

A chest X-ray showed left lower lobe consolidation. An MRI head demonstrated generalised dilation of the ventricles and subarachnoid spaces. The postcontrast enhancement sequence showed a subtle ependymal and meningeal enhancement particularly around the basal regions of the brain and into the left Sylvian fissure. These findings were in keeping with a basal meningitis with possible associated communicating hydrocephalus. Formal audiometry was not performed. CSF and serum cryptococccal antigen were reactive at 1:2048 and 1:256, respectively. CSF cultures grew C. gattii.

Differential diagnosis

Case 1

Differentials for this patient’s initial presentation with sudden onset bilateral sensorineural hearing loss include structural causes such as intracranial space occupying lesions (e.g., acoustic neuroma) or vascular abnormalities such a posterior circulation aneurysm. Metabolic causes such as hypothyroidism and diabetes mellitus should also be considered (the patient had known hypothyroidism and could have had undiagnosed diabetes). Viral infection of the cochlear nerves was another possibility. At the time, other infections causing meningitis and encephalitis were less likely as the patient was otherwise clinically well. Melioidosis and neurocysticercosis, while uncommon sources of meningoencephalitis, were possible given the tropical location. Inflammatory causes could include autoimmune inner ear disease or neurosarcoidosis; however, these were less likely due to the sudden rather than progressive onset of symptoms.

Following the MRI findings of multiple enhancing intracranial nodules, the primary differential was metastatic malignancy. A pulmonary primary was thought to be most likely given the history of smoking and subsequent finding of a right upper lobe lesion on CT chest, abdomen, and pelvis. Lymphoma or breast carcinoma are also potential causes in this age group.

Case 2

The primary differential for this patient was an intracranial space occupying lesion given the progressive history of memory loss, headache, blurred vision, confusion and hearing loss. She has also had evidence of raised intracranial pressure on examination such as bilateral papilloedema, hyper-reflexia and clonus. A chronic subdural haematoma was also a possibility given her prior history of repeated head trauma from physical abuse. The patient’s history of smoking and findings of hyponatraemia and pleural effusion on chest x-ray supported a pulmonary primary as the initial differential. As with case 1, other sources could include breast carcinoma and lymphoma in this age group. Other than malignancy, differentials also include Wernicke’s encephalopathy given her excessive alcohol use or early onset dementia as a result of both alcohol and previous head trauma.

Treatment

Case 1

The patient was started on intravenous liposomal amphotericin B and intravenous flucytosine (5-FC). She subsequently developed neutropenia due to 5-FC treatment. She had daily lumbar punctures with persistent opening pressures exceeding 30 cm H₂O for over 2 weeks. She was initially managed with a lumbar and then extra-ventricular drain. Due to persistent hydrocephalus, a permanent ventriculoperitoneal shunt was inserted. She continues on oral fluconazole as part of consolidation and eradication therapy for a total of at least 18 months from initiation of treatment.

The patient concurrently developed pulmonary nocardiosis during admission, thought to be related to dexamethasone therapy used for cerebral oedema. This resolved following treatment with linezolid. She was eventually admitted to the rehabilitation unit for intensive allied health input over the course of several months.

Case 2

The patient was treated with intravenous amphotericin deoxycholate and oral 5-FC for induction therapy. She continued on oral fluconazole as her consolidation and eradication therapy.

Outcome and follow-up

Case 1

The patient eventually became neurologically stable although with persistent deafness and visual impairment. She developed a seizure disorder secondary to her severe acquired brain injury, which was eventually controlled on levetiracetam and carbamazepine. She was transferred to the rehabilitation unit 4 months after her initial presentation. A percutaneous endoscopic gastrotomy was inserted due to severe dysphagia. She had a long-term indwelling catheter due to ongoing urinary retention and required a bowel regimen. She had ongoing severe cognitive impairment including minimal speech output. She was discharged 6 months later under the care of her supportive husband along with ongoing community rehabilitation and nursing services. She has ongoing follow-up by infectious diseases and neurology and she is awaiting a repeat audiometry.

Case 2

The patient made a slow recovery over 2 months with residual upper motor neuron signs, deafness and mild horizontal nystagmus. She died of an unrelated cause 5 months after her initial presentation.

Discussion

Hearing loss as a presenting feature of C. gattii meningoencephalitis is rare. PubMed was searched using (“cryptococcus gattii”) OR “C. gattii” AND (“hearing loss” OR “deafness” OR “vestibulocochlear” OR “cranial nerve VIII”) in all fields, yielding only six existing publications that describe hearing impairment as a prominent presenting symptom (including Aye et al’s⁴ paper in which case 2 was briefly described). Table 1 summarises these cases^4–9 as well as the main patient (case 1) described in this report.

Table 1.

All cases in literature relating to hearing loss on presentation of Cryptococcus gattii

Reference	Age	Sex	Ethnicity	Organism	Country	Travel Hx	Auditory symptoms	Duration of auditory symptoms to presentation	Time to diagnosis from auditory symptom onset	Other symptoms	Total duration (all symptoms)*	Duration of antifungal treatment	Auditory response to treatment
														Case 1	53	F	Indigenous Australian	C.gattii, Nocardia sp.	Australia	None	Bilateral hearing loss	1 week	7 weeks	Headache	7 months	18 months	Ongoing treatment
Aye et al4	48	F	Caucasian	C. gatti, Nocardia spp	Australia	None	Hearing loss	2 months	2 months	Headache, memory loss, fatigue, blurred vision, haemoptysis	2 months	5 months	Unknown - deceased unrelated cause
														Chen et al5	37	F	Caucasian	C. gattii	Australia	Unknown	Hearing loss	1 month	1 month	Headache	1 month	12 months	Unknown
														Walraven et al6	56	M	Hispanic	C. gattii	USA	None	Tinnitus and hearing loss	4 days	6 days (postmortem)	Progressively worsening headache, severe weakness, neck stiffness	3 months	None	None - deceased 2 days into admission
														Cookman and Hugi7	60	M	Caucasian	C. gattii	Canada	Vancouver Island	Hearing loss	2 months	2 months	Headache, fatigue, weight loss, low grade fever	2 months	Not specified	Ongoing mild bilateral hearing loss
Lee et al8	60	M	Asian	C. gattii	Taiwan	None	Hearing loss	2 weeks	2 weeks	Headache, non-productive cough, vision loss	2 months	3 weeks	Unknown
Panos et al9	24	F	Unknown	C. gattii, HTLVsI/II	Greece	Amazon, Caribbean, Antarctica	Sudden hearing loss	Several days	Several days	Grand mal seizures, generalised weakness, peripheral paresthaesias	Several days	Not specified	Clinical improvement, not otherwise specified

*Total duration of symptoms: from any symptom onset to diagnosis.

Additionally, Lalloo et al¹⁰ mention two patients who presented with hearing impairment in their retrospective cohort study. However, there is no further information about these symptoms or the patients’ demographic details. Hughes et al¹¹ report two cases of hearing loss as an adverse outcome, but none presenting with this feature.

Among the known cases, patients varied in geographical location (urban, regional and rural), age, ethnicity and background medical history (table 1). The median age was 53 years. The median duration of auditory symptoms was 14 days and the median time to diagnosis from onset of auditory symptoms was 30 days. The auditory symptoms were generally poorly characterised, with no reports (other than the index case) describing objective measurements such as audiometry.

Cases of hearing loss on presentation of C. neoformans meningoencephalitis have also been reported,^12–20 particularly by Wang et al who have studied the prognosis of auditory symptoms in detail.²¹ As with C. gattii, hearing loss is also an infrequent presenting clinical feature in C. neoformans with only 13 cases described. Among these cases, the approximate median duration of auditory symptoms to presentation (where specified) for C. neoformans is 7 days, compared with a median of 14 days for C. gattii. This could be due to a more fulminant disease process with more profound hearing loss in C. neoformans. Of note, prior to 2002, all cases would have all been identified as C. neoformans prior to recognition of C. gattii as a separate species.²² Therefore, some of the cases reported as C. neoformans could have been cases of C. gattii.

Cryptococcal meningitis causes sensorineural hearing loss through several mechanisms. These include direct invasion of the temporal bone, damage of the spiral ganglion and cochlear nerve fibres or meningeal infiltration.²¹ Some authors have reported nervous system involvement extending to the vestibulocochlear system, while others have found end-organ sparing as summarised in a report by Low.¹⁵ The common factor between these studies is that there appears to be retrocochlear damage. One of the two cases in this report had internal auditory canal involvement, likely to be indicative of infectious collections. Both patients described had basal enhancement on cerebral imaging. In addition to basal meningitis causing bilateral sensorineural hearing loss, hypoacousia is likely to have occurred via spread of infection to the inner ear through the modiolus and cochlear aqueduct, which in turn triggers an immune response within nearby associated structure.^{17 23}

Other than direct inflammatory involvement of the auditory structures, hydrocephalus may indirectly cause hearing loss due to the anatomical relationship between the inner ear and CSF spaces. The pressure in the perilymph is controlled via the cochlear aqueduct connecting to the subarachnoid space. Hydrocephalus could then increase the pressure within the scala vestibuli, reducing the transduction of vibration along the perilymph from the ossicular chain.²⁴

Patient’s perspective.

The patient of Case 1 was unable to be interviewed due to severe neurological impairment. Her partner and father have expressed their frustration with the duration from initial presentation to achieving a diagnosis (nearly two months), at which stage the patient’s condition had significantly deteriorated. They both commend her general practitioner for coordinating her care between specialists during this time and for making an urgent referral to infectious diseases as soon as her biopsy results were available. They hope that her case will raise awareness within the medical community of hearing loss as an unusual presenting symptom and that this will facilitate more rapid diagnosis for future patients.

Learning points.

• Although uncommon, hearing loss may be an early presenting sign of Cryptococcus gattii meningoencephalitis.

• This case series aims to raise awareness among clinicians that hearing loss in patients with chronic headache is a concerning feature necessitating investigating with neuroimaging and lumbar puncture.

• As C. gattii causes infection in immunocompetent rather than immunocompromised individuals, it is often missed as a potential differential diagnosis.