Brittany A Oster, BS, Montefiore Medical Center
111 East 210th Street Bronx, NY 10467
Phone: (818) 294-2748 Email: firstname.lastname@example.org
The authors report no relevant financial relationships.
Division of Geriatrics, Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY
Cryptococcosis primarily affects patients with HIV but can also occur in patients who are immunosuppressed by other means. In patients with impaired mental status at baseline, clinical signs of cryptococcal meningitis may not be obvious. We present a case of a 72-year-old nursing home resident who was being treated with steroids for giant cell arteritis and developed progressive altered mental status. There were challenges in making a diagnosis of cryptococcal meningitis in this older patient who had cognitive impairments at baseline.
Key words: cryptococcal meningitis, altered mental status, cognitive impairment, nursing home
Cryptococcus neoformans is an encapsulated yeast that can precipitate the development of cryptococcosis.1 The two most common manifestations of the disease are fungemia and meningitis, with pulmonary disease occurring less often.2,3 The majority of patients affected are seropositive for HIV, usually with advanced disease.4 The annual incidence of cryptococcosis in the United States is estimated to be 0.4 to 1.3 cases per 100,000 people and increases to 2 to 7 cases per 1000 in people with AIDS – with a case-fatality ratio of approximately 12%.5 Cryptococcosis also affects other immunocompromised individuals, many of whom are undergoing long-term treatment for the management of other diseases. These patients include those with long-term corticosteroid use, solid-organ transplantation, hematologic malignancy, sarcoidosis, and other disorders of immune dysfunction.6 Though there is data describing cryptococcal meningitis in patients undergoing long-term treatment for the management of other diseases, there have been fewer reports of cryptococcosis in older adults and residents of long-term care (LTC) facilities.
This article presents a case of cryptococcal meningitis in a 72-year-old resident of an LTC facility who was being treated with steroids for giant cell arteritis (GCA) and subsequently developed progressive altered mental status. There were challenges in making a diagnosis of cryptococcal meningitis in this older patient due to previously documented cognitive impairments at baseline. This case highlights the need for meticulous evaluation of risk factors and diagnosing of cryptococcal meningitis, particularly in older adults.
A 72-year-old female nursing home (NH) resident presented to the emergency department (ED) with a 1-day history of fever, chills, lethargy, altered mental status, and poor oral intake. Her past medical history was significant for atrial fibrillation not on anticoagulation due to a history of gastrointestinal bleeding, stage 3 chronic kidney disease, a left parietal cerebral vascular accident 4 months prior with residual right-sided weakness and expressive aphasia, probable vascular dementia, GCA on prednisone (20 mg daily for the past 10 months), and a left thigh abscess treated with levofloxacin 1 week prior to presentation. Her family mentioned that she was intermittently febrile with waxing and waning mental status for 5 months requiring several hospitalizations with antibiotic therapy prior to the NH admission in October 2018.
Her mental status on admission in the NH was reported as being alert, able to speak in short sentences, though incoherently at times, often vocalizing sounds loudly, and capable of feeding herself from time-to-time. She was not ambulatory. Monthly notes from the first 5 months of NH residency indicated that she remained neurologically unchanged until the day she was transferred to the ED.
Upon arrival in the ED, she was febrile to 100.5°F. The initial neurologic examination demonstrated an arousable, inattentive, minimally verbal patient who intermittently mumbled incoherently and answered some questions with “yes” or “no” responses. She was able to track objects with her eyes but otherwise did not demonstrate any purposeful movements. The remainder of the exam was notable for 3-plus dependent edema up to the posterior thighs bilaterally. The left posterior thigh had a 2 to 3 cm area of soft tissue swelling with surrounding induration and eschar. There was also a smaller stage 2 sacral ulcer with clean appearance.
Investigation and Treatment
The patient’s laboratory tests (Table 1) were significant for a WBC count of 11.7 k/uL, hemoglobin of 10.1 g/dL, BUN of 32 mg/dL, creatinine of 1.6 mg/dL, glucose of 185 mg/dL, and calcium of 8.1 mg/dL. Initial infectious work-up revealed negative blood and urine cultures and an unremarkable chest x-ray, chest computerized tomography (CT) scan, lower extremity duplex, and abdominal ultrasound. She was treated empirically with broad spectrum antibiotics (vancomycin, aztreonam, and ciprofloxacin) for 48 hours.
Article continues after Table 1
The patient was given the provisional diagnosis of “fever of unknown origin” after initial infectious work-up was negative. Antibiotics were later deescalated, and the patient completed a 5-day course of ceftriaxone. After the patient’s leukocytosis had normalized, her mental status returned to baseline, and she was afebrile for 48 hours. She was subsequently discharged back to the NH on hospital day 11.
The patient returned to the ED 5 days later with a fever and worsening mental status. She was again found to have a leukocytosis of 13.1 k/uL; however, on this occasion, she was also found to have an abnormal urinalysis with many white blood cells and leukocyte esterase seen in the urine. Urine culture grew multidrug resistant Escherichia coli (E. Coli). She was also found to be weakly positive for influenza A. The patient was treated with oseltamivir (30 mg twice daily) for influenza A and meropenem (500 mg intravenous q8 for 7 days) for urinary tract infection (UTI). At this time, her fever and leukocytosis were attributed to a UTI and influenza.
The patient continued to be intermittently febrile and lethargic with poor oral intake. After 5 days in the hospital, she became hypernatremic to 150 mEq/L and was started on D5 ½ NS. Due to her lack of clinical improvement with treatment for UTI and influenza, a CT of the abdomen was performed on hospital day 7. This did not show any occult sources of infection.
A gallium scan was performed on hospital day 13 and a CT of the head and electroencephalogram (EEG) was performed on hospital day 14. It was believed that the patient may have suffered another stroke, although seizures and abscess were also on the differential. The gallium scan did not demonstrate any areas of abnormal uptake. The EEG was unrevealing, only showing diffuse slowing. The CT of the head (Figure 1) showed an age indeterminate infarct in the left parietal lobe, chronic infarct in the left temporal lobe, white matter microvascular ischemic disease, and dilated ventricles.
A brain magnetic resonance imaging (MRI) was performed on hospital day 16 to determine if the age indeterminate stroke seen on CT was acute. The MRI (Figure 2) showed multiple focal areas of restricted diffusion with suspected debris in the bilateral ventricles – suspicious for meningitis. On the same day, a lumbar puncture was performed with an opening pressure of 10 mmHg. Cerebrospinal fluid (CSF) analysis revealed a red blood cell (RBC) count of 225, WBC count of 311 with 83% lymphocytes, 3% monocytes, and 2% macrophages in Tube 1, as well as an elevated albumin and total protein (159.0 mg/dL and 216 mg/dL respectively), and low CSF glucose of less than 20 mg/dL. Tube 4 of the CSF showed a WBC count of 543 with 77% lymphocytes and 4% monocytes and an RBC count of 400. The CSF was positive for cryptococcal antigen and had a cryptococcal antigen titer of 1:2560. CSF culture grew Cryptococcus neoformans.
The patient began treatment for cryptococcal meningitis with flucytosine (250 mg orally q12 hours) and amphotericin B liposomal (350 mg IV q12 hours). Steroid treatment for GCA was maintained initially but ultimately tapered out of concern that immunosuppressive effects of steroids might interfere with her ability to clear the infection.
Outcome and Follow Up
Due to her altered mental status, the patient was unable to feed orally, and a nasogastric tube was placed on hospital day 19. Subsequently, the patient became tachycardic and was found to have food in her mouth, which led to concern for aspiration. She was treated empirically with cefepime (1 g IV q12 hours for 5 days). The patient continued to be obtunded and only responded to noxious stimuli. Her sacral ulcers continued to deteriorate, and she developed worsening anasarca. A repeat lumbar puncture was attempted to assess for response to cryptococcosis treatment but was aborted as she became severely tachycardic and tachypneic during the attempts. On hospital day 25, the patient developed progressive acute kidney injury in the setting of treatment with multiple nephrotoxic agents.
Goals-of-care discussions were continuously performed with the patient’s children regarding the poor prognosis associated with cryptococcal meningitis. The patient had previously made her wishes known to her family. She had explicitly said should would not want a feeding tube to support her for an extended period. As the patient’s mental status worsened, it became clear she was unlikely to have any meaningful neurologic recovery. Her daughter signed a Do Not Resuscitate/Do Not Intubate order, and hospice care was agreed upon by her family. The patient passed away on the 41st day of her hospital stay.
We believe that diligent assessment of mental status changes and further investigation into reason for the change can lead to earlier diagnosis of cryptococcal meningitis. In this case, daily detailed documentation of the patient’s mental status may have revealed subtle mental status changes and led to an earlier presentation to the ED. Additionally, mental status changes are very common in LTC residents who present with febrile illness and generally improves once the underlying infection is treated. A typical work-up begins with assessing for common infections in the urine and lungs. This patient’s mental status change was initially attributed to a UTI, a common cause of febrile illness and mental status change in older adults. The lack of clinical improvement with treatment of this common infection led providers to pursue further workup, including CT and MRI scans and a lumbar puncture.
The most common clinical presentation of cryptococcal meningitis includes subacute headache and confusion.7 Intracranial pressure is often elevated and may cause cranial nerve palsies or seizures. Classic features of “meningism,” including neck stiffness, occur in less than 20% of patients.7 Although these are the most common signs, cryptococcal meningitis can also present in an indolent manner, as was the case in this patient. Insidious cognitive impairment occurs in more than half of individuals with cryptococcal meningitis8 and, in retrospect, may have been present for months in this patient. Altered mental status is associated with higher mortality in these patients.9 Given these nonspecific symptoms, one could imagine the difficulty in making a diagnosis of cryptococcal meningitis in an older patient with dementia at baseline.
The prevalence of dementia in hospitalized patients varies from 15% to 42%.10 This number is expected to be significantly higher among those admitted from LTC facilities. It is estimated that 70% of patients in a LTC facility have some form of cognitive impairment with 29% percent having mild impairment, 23% moderate impairment, and 19% severe impairment.11 In these patients who may have varying degrees of ability to describe symptoms, it is paramount for spouses, caregivers, and NH attendants to be diligent in assessing changes in mental status because these changes may signify a serious medical problem. Providers and caregivers should use caution when attributing a change in mental status to the patient’s underlying cognitive impairment.
Documentation can be an important aspect in assessing mental status changes. Rather than simply documenting “A&Ox0,” it would be more appropriate to document the patient’s mental status in greater detail. This may include a description about what the patient is able to verbalize and comprehend, as well as the activities he/she is able to perform. This type of assessment should be performed and documented on a day-to-day basis. If there is a change in mental status, then it should be documented, and the cause of the mental status change should be investigated.
There have been multiple case reports in which cryptococcal meningitis in an older patient was misdiagnosed as Alzheimer dementia12-14 and vascular dementia.15 It is difficult to estimate the prevalence of cryptococcal meningitis as the cause of cognitive impairment because the work up for dementia traditionally does not include a lumbar puncture.14 The American Academy of Neurology practice parameter for the evaluation of dementia states that a lumbar puncture should be performed when any of the following are present: metastatic cancer, suspicion of central nervous system (CNS) infection, positive serum syphilis serology, hydrocephalus, dementia in a person younger than 55 years, a rapidly progressive or unusual dementia, immunosuppression, and suspicion of CNS vasculitis.16
Although advanced HIV infection is a known risk factor for cryptococcosis, cryptococcal disease affects many others worldwide. In developing nations, 95% of reported cases of cryptococcal meningitis affect patients with HIV.17 However, in the United States, HIV-infected individuals affected by cryptococcal meningitis accounted for only 71% of patients with 29% of patients not HIV-positive.18 Of this 29%, the majority are immunocompromised in some other capacity. Relevant to this case are those individuals being treated with corticosteroids. Corticosteroids affect the skin and mucous membranes by breaking down collagen and fibrous tissue, weakening the first line of defense.19 Corticosteroids also disrupt the function of neutrophils, lymphocytes, and monocytes.19 This culminates in a predisposition to infections.
Though this patient did not suffer from HIV, it is important to point out that there is a growing population of older adults who are HIV positive. It has been estimated that the number of people living with HIV older than 50 years has increased by 17% in the last decade,20 and these numbers are projected to rise in the coming decades.21 The morbidity and mortality of HIV has also been shown to increase in older adults. Additionally, patients older than 50 years with HIV are known to have a more rapid progression to AIDS.22,23 With this population growing, it is all the more imperative that LTC providers remain cognizant of mental status changes and keep the diagnosis of cryptococcal meningitis in mind.
Another interesting aspect of this case is cryptococcal meningitis and its relation to GCA – the most common vasculitis in older adults. It is most prominent in adults older than 50 years, with the median age of onset around 75 years.24 There have been very few reports of cryptococcal meningitis in patients with GCA. LV and Zhang25 reported a case of a 65-year-old with relapsing GCA being treated with prednisone and azathioprine. Hedderwick et al26 reported a case of a 77-year-old patient with GCA whose culture of bronchoalveolar fluid grew C. neoformans. Revest et al27 reported four cases of patients who suffered from cryptococcosis, three of which were meningitis. These patients also carried diagnoses of chronic lymphocytic leukemia, GCA, gastric neoplasm, and lupus, respectively, and were being treated with immunosuppression agents. Although it may be rare, providers caring for older adults are more likely to encounter patients with GCA and need to have a heightened awareness of cryptococcal meningitis as a possibility.
Patients with GCA may be susceptible to cryptococcal meningitis because the treatment with corticosteroids causes immunosuppression. However, it is also possible that the presence of GCA increases the susceptibility to infections. Vessels affected by GCA are known to produce specific cytokines that disrupt T-cell and macrophage function.28,29
This case highlights many important aspects when it comes to evaluating risk factors and diagnosing cryptococcal meningitis in older adults. Appropriate documentation in daily clinical practice is essential for evaluating subtle changes in mental status. Cryptococcal meningitis should be kept on the differential diagnosis for causes of worsening of mental status in immunocompromised patients. A lumbar puncture should be considered in older adults with dementia and worsening mental status or if mental status does not improve with clinical treatments. Though seldom reported, cryptococcal meningitis should be investigated in patients with GCA.
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