Sudden deafness turned out to be cryptococcal meningitis! | case sharing

Cryptococcal meningitis, mainly caused by Cryptococcus neoformans and C. gattii, is the most common opportunistic fungal disease of the central nervous system (CNS) and has a relatively high mortality rate. The most common manifestation of cryptococcal meningitis is headache, followed by nausea, vomiting, impaired consciousness, meningeal signs, and cranial nerve injury. Sensorineural hearing loss (SNHL), which is usually bilateral, is a complication of cryptococcal meningitis with an incidence of 27.0% to 30.8%. Let's study today a case of cryptococcal meningitis with sudden deafness as the first symptom.

Male, 52 years old, sudden left hearing loss for 17 days

Male, 52 years old, from Hainan, China, complained of sudden 17 days of sudden hearing loss on the left side, accompanied by a persistent squeaking sound accompanied by severe recurrent rotational vertigo attacks lasting several minutes, accompanied by unexplained nausea and vomiting. There is no history of associated headache, earache, or ear secretions. Previously had 10 years of chronic hepatitis B and 2 years of diabetes, there was neither conventional antiviral therapy nor glycemic control therapy.

Physical examination: vital signs are normal. No meningeal irritation. No spontaneous nystagmus was observed. Dix-Hallpike motion and supine roll tests have no characteristic results.

Adjunctive examination: magnetic resonance imaging (MRI) of the skull: no significant pathological changes were found.

Otoscopy found no abnormalities.

Pure audiometry: heavy SNHL on the left, thresholds above 120dB HL at frequencies of 0.5, 1, 2, and 4kHz, and moderate SNHL on the right, pure mean (PTA) of 50dB HL. Speech hearing tests with monosyllabic Mandarin words showed that the speech recognition threshold (SRT) was 40dB HL and the text recognition score (WRS) was 100% at 70dB HL in the right ear, while the speech recognition threshold (SRT) was 0% even at 100dB HL in the left ear. The bilateral tympanic pattern is Of type As. Aberration product otoacoustic emission (DPOAE) once again confirms bilateral hearing loss. At 99dB nHL, there is no click-evoked potential (ABR) in both ears.

Laboratory tests: aspartate aminotransferase (AST) 64 U/L, total bilirubin 30.41 μmol/L, albumin 37 g/L, suggesting mild hepatic insufficiency. Serological tests showed significant increases in HBsAg, HBeAg, and anti-HBc, and HBV DNA was elevated by 1.99 ×107copies/ml. Fasting blood glucose (FPG) 8.50 mmol/L, glycosylated hemoglobin (HbA1c) 9.1%. Yu did not see any abnormalities.

In summary, this patient was initially diagnosed with sudden onset of sexogenic neurotic deafness (SSNHL) on the left side, SNHL on the right side, and was accompanied by diabetes mellitus and chronic hepatitis B.

In view of its uncontrolled blood glucose, intra-tympanic corticosteroid treatment was initially used. According to guidelines approved by the Chinese Society of Otolaryngology Head and Neck Surgery, vasoactive drugs such as prostaglandin E1 and ginkgo biloba leaf extract, as well as fibrinolytic baltrase, were also used in an attempt to save the patient's hearing. Vestibular suppression drugs are used to relieve the symptoms of vertigo in patients. Use appropriate insulin therapy to control the patient's hyperglycemia, use long-acting insulin glargine (starting at 14 U, once daily at bedtime) to maintain basal insulin levels, and use rapid-acting insulin aspartate (starting at 10 U before three meals a day) to mimic the physiological peak of insulin after meals. Monitor blood glucose levels on an empty stomach and 2 hours after meals daily to help adjust insulin doses. Entetavir (0.5 mg once a night) in combination with immunomodulatory drugs, thymic fascin (1.6 mg once daily) is used to suppress HBV DNA.

Surprisingly, after admission, patients began to complain of intermittent headaches, which gradually worsened over the next few days. Patients began to develop neck stiffness, and Kernig's and Brudzinski's signs were positive. Immediate head MRI scan shows only mild ischemic signals in both frontal lobes. Lumbar puncture, colorless and transparent cerebrospinal fluid, white blood cells 230×106/L, protein 0.72 g/L, glucose 1.37 mmol/L, pressure exceeding 330 mmH2O all strongly support the diagnosis of meningitis. Ink stains of CSF deposits are positive. Subsequent microbial cultures further confirmed infectious meningitis caused by Cryptococcus novelis. Antifungal susceptibility tests have shown that the strain is sensitive to amphotericin, flucytosine, fluconazole, and voriconazole.

Adequate triple antifungal therapy is given immediately. According to the results of the antifungal susceptibility test, intravenous fluconazole is given 400 mg per day for 9 weeks. On day 4 of treatment, additional intravenous amphotericin B8 weeks, starting at 5 mg per day, increasing at a rate of 10 mg to 130 mg per day, and then reducing the dose to 50 mg per day to maintain adequate blood concentrations. For the past two weeks, supplementation with 4 grams of adjuvant oral flucytosine per day. Lumbar punctures are performed approximately every 10 days to assess the antifungal effect. 20% mannitol is used as a dehydrating agent to reduce intracranial pressure.

Adverse events, such as secondary bacterial infection, metabolic acidosis, hypokalemia, elevated aminotransferase levels, hypercretinine, and anemia, were due to an increase in amphotericin B doses and gradually resolved by reducing amphotericin B doses plus appropriate potassium supplementation, antimicrobial, and bicarbonate therapy.

Finally, the headache finally got better, but there was still intermittent dizziness. Meningeal signs turn negative. Lumbar puncture shows that the WBC count, protein, and glucose levels of the CSF are normalizing, while the CSF open pressure has dropped to normal. Microbial culture further confirmed the absence of Cryptococcus. However, audio-only audiometry showed no significant improvement in bilateral hearing thresholds.

After a 71-day course of treatment, the patient was discharged from the hospital. Fluconazole (200 mg daily) is required for half a year, with long-term use of insulin and entecavir. After two years of follow-up, although the patient's hearing did not improve, there was no recurrence of cryptococcosis.

discuss

Diagnosis of cryptococcal meningitis can be difficult and is often delayed due to its non-specific clinical features. In this case, the patient's occult manifestations make the diagnosis more difficult. The patient is fever-free, complains only of sudden deafness on the left side, accompanied by tinnitus and dizziness, and is admitted to the hospital without any mental changes or meningeal signs, which misleads the initial misdiagnosis of SSNHL.

Another misleading factor is the non-specific manifestation on the HEAD MRI. Cranial MRI manifestations associated with cryptococcal meningitis have been reported in the literature, including leptometrial enhancement, cerebral infarction, hydrocephalus, cryptococcalomas, dilated Verchow-Robin (VR) lumen or pseudocysts, "dirty CSF" signs, and brain abscesses. In this patient, the head MRI showed only bilateral frontal mild lacunar infarction, which is not sufficient evidence to predict cryptococcal meningitis.

A systematic review was conducted of cases of cryptococcal meningitis in adults with hearing loss. Between 1970 and 2020, a total of 22 eligible case reports were identified. SSNHL is rarely reported in the literature as a manifestation of cryptococcal meningitis, usually a bilateral sudden onset ranging in severity from mild to severe. Most published cases are immunocompromised. The 9 cases reported were mainly HIV infection. Other conditions include idiopathic CD4 lymphopenia, chronic lymphocytic leukemia, kidney transplantation, and diabetes. Cryptococcus neoformis is the main pathogen identified in the inclusion report. Consistent with this case, amphotericin B, flucytosine, and fluconazole are the three first-line antifungal agents used, usually in combination. Nearly half of the cases had improved hearing. However, 7 patients deteriorated their condition during treatment and eventually died, indicating a high mortality rate from cryptococcal meningitis.

Patients in this study reported only left-sided hearing loss when admitted to the hospital, but subsequent hearing tests confirmed that moderate right-sided hearing loss was also confirmed. There are two assumptions that can explain this inconsistency. Hearing loss in the right ear may be a congenital disorder or insensitive compared to severe hearing loss in the left ear. Previously reported histopathology showed that spiral ganglion neurons and cochlear fibers in Corti organs were severely damaged and felt normal hair cells, which was associated with SNHL in cryptococcal meningitis. The route of cryptococcus infection of the cochlea may be blood transmission or direct meningeal infiltration. The prognosis for hearing loss appears to be unpredictable, although varying degrees of hearing recovery have been reported in several studies. In this case, 2 years of follow-up repeated audiometry showed persistent bilateral hearing loss. Vestibular dysfunction is milder and completely relieved after treatment compared to irreversible hearing impairment, which is consistent with previous reports of the vestibular nerve against Cryptococcus invasion.

Underlying diabetes and chronic hepatitis B predispose to cryptococcosis, although HIV is seropositive.

Diabetes mellitus has been identified as an independent factor in the incidence and mortality of cryptococcosis. A retrospective study reported that nearly two-thirds of diabetics in China had untreated or poorly controlled hyperglycemia prior to infection with Cryptococcus. In line with this, the patient had a two-year history of diabetes without any appropriate treatment. The glucose-rich blood of the patient becomes an excellent medium for cryptococcus growth. Hyperglycemia impairs the chemotaxis and phagocytic function of neutrophils, leading to cell-mediated immunodeficiency, which is critical to the host's response to Cryptococcal infection.

Hepatitis B virus (HBV) has also been reported as a predisposing factor for Cryptococcal infection, accounting for about 37.8%, while cirrhosis and HBV DNA > 103copies/ml suggest a poor prognosis. A 10-year history of untreated chronic hepatitis B, combined with HBV DNA > 107 copies/ml at the time of admission, made the patient more susceptible to Cryptococcus infection. As with diabetes, HBV infection can also disrupt cell-mediated immunity, hindering the eradication of Cryptococcus through host defenses.

Clinical practice guidelines for cryptococcal therapy recommend induction therapy for 4 weeks with amphotericin B (0.7-1.0 mg per day) plus fluorocytosine (100 mg per day), consolidation therapy for 8 weeks with fluconazole (400 mg per day), and maintenance therapy for 6-12 months with fluconazole (200 mg per day). Amphotericin B liposomes (3-4 mg/kg per day) can be used as an alternative to amphotericin B intolerance. To reduce nephrotoxicity, the patient in this case of 65 kg was switched to amphotericin B liposomes, starting at 5 mg per day and gradually reaching 120 mg per day after 6 weeks. Due to concomitant dose-related adverse events, the dose of amphotericin B liposomes was reduced to 50 mg per day for the next two weeks. Given the low incidence of adverse events, good permeability to cerebrospinal fluid, low cost and easy availability, fluconazole (400 mg per day) in this case is treated with fluorouracil for 9 weeks. Oral flucytosine (4 g daily) for 2 months, plus oral fluconazole (200 mg per day) for 6 months, is used for maintenance therapy. Adverse events such as secondary bacterial infection, metabolic acidosis, and hypokalemia can lead to death. Fortunately, with prompt and appropriate supportive care, the current patient has finally survived and returned to health.

In summary, when cryptococcal meningitis is presented to the Department of ENT with sudden hearing loss or vestibular dysfunction, it is easily misdiagnosed. While cryptococcal meningitis usually occurs in HIV-positive patients, patients with other modes of immune damage, including diabetes mellitus and viral hepatitis, remain susceptible to infection. Prior to steroid therapy, patients with sudden hearing loss with underlying conditions that may lead to immunosuppression should be differentiated from cryptococcal meningitis. A timely sterilization regimen and appropriate supportive care are essential for a good prognosis.

医脉通编译自：Zhu Y, Zhao Z, Dong C, Jiang H. Cryptococcal meningitis presented as sudden hearing loss: A case study. J Mycol Med. 2021 Mar;31(1):101084. doi: 10.1016/j.mycmed.2020.101084. Epub 2020 Nov 16. PMID: 33276295.