Intracranial invasive mycosis mimicking hepatic encephalopathy in a patient with cirrhosis

Abstract

A 45-year-old man with alcohol-related decompensated cirrhosis presented with jaundice, fever, headache and altered sensorium. At presentation, he had tachycardia, disorientation to time and place, asterixis, icterus and upgoing plantar response. Investigations showed anaemia, thrombocytopenia, leucocytosis, hyperbilirubinemia and elevated arterial ammonia. Despite management with antihepatic coma measures and normalisation of ammonia, broad-spectrum antibiotics, 20% albumin, the patient worsened. On day 3, the patient developed generalised tonic–clonic seizure prompting mechanical ventilation. Examination showed right proptosis, chemosis and pupillary anisocoria. MRI brain showed multifocal infarcts in the right temporal lobe, right cerebellum and brainstem with inflammation in the right orbit, infratemporal fossa with right internal carotid artery thrombosis, and suspicious maxillary sinus thickening. Nasal scrapings showed aseptate fungal hyphae and serum galactomannan index was positive. Despite receiving liposomal amphotericin-B, patient had an unfavourable outcome. Intracranial invasive mycosis can mimic hepatic encephalopathy and is associated with high mortality in cirrhotics. A high index of suspicion, positive biomarkers and diagnostic radiology may provide the key to the diagnosis.

Background

Cirrhosis represents a state of heightened susceptibility to infections, which in turn is associated with high liver-related complications and mortality.¹ Cirrhosis-associated immune dysfunction, gut dysbiosis and associated malnutrition are the fundamental defects that predispose to a multitude of infections.² Although bacterial infections are more frequent, invasive fungal infections (IFIs) are increasingly recognised in hospitalised patients with cirrhosis.^{3 4} IFIs are often difficult to diagnose among cirrhotics due to lack of suspicion, lack of invasive tissues for proven diagnosis, low yield of cultures, poor differentiation from colonisation and delayed diagnosis due to conventional cultures. Non-specific clinical presentation often represents a significant challenge in early diagnosis of IFI in cirrhosis. We report a case of invasive intracranial mycosis mimicking hepatic encephalopathy in a patient with alcohol-related liver cirrhosis highlighting the importance of clinical examination and clinical suspicion in medicine.

Case presentation

A 45-year-old male farmer presented to the emergency department with jaundice for 3 months, fever and headache for 10 days and altered sensorium for 2 days. He was alcohol consumer in cirrhogenic doses (100–120 g/day for 14 years) with a recent consumption till 3 months ago. He had a history of ascites with spontaneous bacterial peritonitis, and two episodes of constipation precipitated hepatic encephalopathy in the last 1 year. There was no history of diabetes, hypertension or other chronic medical comorbidities. At presentation, examination was remarkable for fever (38.1°C), tachycardia (119/min), disorientation to time and place, asterixis, icterus and upgoing plantar response. There was no neck stiffness, and Kernig’s sign was negative. A clinical diagnosis of acute decompensation of alcohol-related cirrhosis, due to alcoholic hepatitis with sepsis was made.

Investigations

Baseline investigations showed anaemia (10.2 g/dL), thrombocytopenia: 50 000/mm³, leucocytosis (12 200/mm³), hyperbilirubinemia (total/conjugated bilirubin: 5.3/3.4 mg/dL), elevated aminotransferases (aspartate transaminase (AST)/alanine transaminase (ALT): 172/100 U/L; gamma glutamyl transferase (GGT): 105 U/L) hypoalbuminemia (3.1 mg/dL), coagulopathy (International Normalized Ratio (INR): 2.1) and elevated arterial ammonia levels (110 µmol/L). Ultrasonography of abdomen showed features of cirrhosis with moderate ascites. Ascitic fluid workup revealed high serum ascites albumin gradient (1.5), with no evidence of spontaneous bacterial peritonitis (cell count 20 cells/mm³ predominantly lymphocytes, protein 1.2 g/dL, glucose 92 mg/dL). On sepsis screening, chest radiograph was normal, urine microscopy showed 4–5 pus cells/high power field (HPF), bacterial blood and urine cultures were sterile, and procalcitonin levels were elevated at 1.79 pg/mL. The cerebrospinal fluid examination was deferred because of coagulopathy and thrombocytopenia. His initial prognostic scores were Child-Turcotte Pugh score of 11 (Class-C) and Model for End-Stage Liver Disease score of 22.

Treatment

He was managed with nutritional support, antihepatic coma measures (oral lactulose and rifaximin), broad-spectrum intravenous antibiotics (intravenous ceftriaxone, and piperacillin–tazobactam), intravenous albumin (20%) and other supportive measures.

Outcome and follow up

On day 3, patient continued to have encephalopathy and fever. Following an episode of generalised seizure, sensorium of the patient deteriorated (E1M1Vt), and he was intubated and mechanically ventilated. Intravenous lorazepam and levetiracetam were given to control seizures. Electrolytes including sodium, calcium, magnesium and phosphorus were normal. Arterial ammonia was normal (45 µmol/L). Meticulous clinical examination showed right proptosis, chemosis and pupillary anisocoria. Subsequently, non-contrast CT head followed by a contrast MRI brain was done. Contrast MRI brain (figure 1) showed multifocal infarcts (straight arrows) in right medial-temporal, right cerebellum and brainstem with extensive inflammation in the right orbit/infratemporal fossa with right internal carotid artery (ICA) thrombosis and suspicious maxillary sinus thickening. Nasal scrapings (figure 2) showed aseptate fungal hyphae, and serum galactomannan index came to be positive: 0.8 (Platelia Aspergillus; Bio-Rad laboratories, France). He received intravenous liposomal amphotericin-B with a possibility of invasive intracranial mycosis. Despite all measures, the patient had worsening bilirubin, development of renal failure, coagulopathy and shock requiring increasing vasopressors and succumbed to his illness on day 7 of hospital stay. Blood fungal cultures were sent which came out to be sterile (posthumously). Fungal cultures from tissue and subsequent antifungal susceptibility tests could not be carried out due to lack of sampling and adverse outcomes of the patient. Autopsy could not be performed due to lack of consent from the relatives.

Figure 1.

CEMRI brain showing multifocal infarcts (straight arrows) in right medial-temporal, right cerebellum brainstem with extensive inflammation in the right orbit/infratemporal fossa with right ICA thrombosis (bold arrow). CEMRI, Contrast Enhanced Magnetic Resolution Imaging; ICA, internal carotid artery.

Figure 2.

KOH mount of the nasal scrapings of the patient (40x magnification) demonstrating scant aseptate fungal hyphae. KOH, potassium hydroxide.

Discussion

Patients with cirrhosis are frequently exposed to repeated hospitalisations, instrumentations, broad-spectrum antibiotics, which in addition to immune dysfunction and malnutrition predisposes them to acquire drug-resistant and opportunistic fungal infections. IFIs are increasingly recognised cause of morbidity, mortality and treatment failures in patients with cirrhosis.^{3 5} Such infections have recently been described in patients with acute on chronic liver failure (ACLF) that carries a very high short-term mortality.⁴

A recent American study showed a reasonably high prevalence of 4.8% (134 out of 2743 patients) of fungal infections inpatients with cirrhosis.³ A study in 185 patients with cirrhosis and culture-positive infections demonstrated that 6% patients had fungal infections alone while 4.3% had combined bacterial and fungal infections. In the subgroup of patients with fungal infections, 58% had spontaneous fungal peritonitis, and 42% had fungemia.⁶ In another study with patients in intensive care setting, the incidence of both fungal colonisation and IFI was reported to be higher in patients with liver disease.⁷ Another study with 264 patients with ACLF showed an incidence of IFI in 14.7% of the patients with the most frequent sites being was respiratory, followed by renal and spontaneous fungal peritonitis.⁴

Seizures have been reported variably (2%–33%) in patients with hepatic encephalopathy.⁸ Seizures may present due to hepatic encephalopathy (HE) per se or due to associated complications. Complications may include hypoglycemia, dyselectrolytemia and intracranial haemorrhages.⁸ A study has described epileptiform activity in 15% of patients with HE.⁹ Overall, the prognosis of patients with seizures with HE remains worse.^{8 9} The possible cause for seizure in our patient was presence of extensive infarcts secondary to intracranial IFI which led to an epileptogenic focus. This case emphasises the necessity of ruling out secondary causes like central nervous system (CNS) infection prior to the diagnosis of HE, in order to guide timely and appropriate treatment.

Intracranial IFI has been infrequently reported in patients with cirrhosis.¹⁰ Invasive mucormycosis and aspergillosis are the most commonly implicated fungi causing CNS infections in cirrhosis. Classically, rhinocerebral mucormycosis have risk factors, including diabetesmellitus, steroid exposure, malnutrition, immunodeficiency, neutropenia, haematological malignancies, bone marrow and/or solid organ transplantation.¹¹ Smoking and occupational exposure like fodder and livestock handling are also putative risk factors for invasive mucormycosis.¹² It frequently involves the sinuses, orbit, base of skull and intracerebral arteries causing vasculitic cerebral infarcts.¹³

On the other hand, invasive aspergillosis frequently involves both lungs and CNS. CNS involvement includes abscesses, infarcts, haemorrhages and/or dural enhancement with frequent involvement of sinuses and orbital wall.¹⁴ Maxillary sinus thickening, orbital inflammation, ICA with base of skull involvement, vascultitc cerebral infarcts, absence of abscesses or dural enhancement, and presence of aseptate hyphae on nasal scrapings favour invasive mucormycosis in our case. Low-level galactomannan positivity was not inconsistent with mucormycosis in our case as described in literature.¹¹ Invasive rhinocerebral mucormycosis in cirrhotics have been described as case reports in the literature, and presentation in our case was consistent.¹⁰ Invasive aspergillosis involving CNS (4 out of 94 patients) in the form of abscesses have recently been described among patients with alcoholic hepatitis receiving corticosteroids.¹⁵

Cirrhosis-associated immune defects—neutrophil dysfunction, alcoholism, malnutrition and farming as an occupation—were the likely risk factors for our patient. CNS involvement with mycosis is generally poor and especially in patients with cirrhosis.^{10 15}

The diagnosis of intracranial fungal infections in cirrhosis a clinical challenge, especially in the background of HE and can be missed due to lack of suspicion, inconclusive clinical signs, poor yield of the fungal cultures, the variability of fungal biomarker assays and non-specific radiology. In order to make a diagnosis of HE, one must exclude the secondary causes of altered sensorium including CNS infections. This case highlights the importance of clinical suspicion and meticulous clinical examination in diagnosing CNS infections early in the course of management.

Therapeutic options for intracranial mycosis with severe liver dysfunction are limited. Liposomal amphotericin-B is often the preferred drug due to broad-spectrum, and relative lack of toxicity in liver failure patients.¹⁶ The use of voriconazole is often limited in patients with decompensated cirrhosis due to markedly prolonged elimination, potential toxicity and drug interactions.^{17 15} Posaconazole merits the therapeutic drug monitoring, and echinocandins have limited efficacy against aspergillosis and mucroales.¹⁶ Surgical intervention for source control is often limited in patients with liver disease due to sickness profile and coexistent coagulopathy.

Learning points.

• Fungal infections in cirrhosis are becoming increasingly prevalent.

• Diagnosis in cases of intracranial invasive fungal infection (IFI) remains a challenge in the background of HE.

• In an appropriate clinical setting, combination of tissue mycology, serum biomarkers and neuroimaging is required for early diagnosis and management of intracranial IFI in cirrhosis.