A previously healthy 42-year-old man is brought to the ED by his wife who noticed that he was stumbling and almost fell down on two occasions over the past few hours. He had been having nausea and vomiting for the last few days followed by global headaches and subjective fevers. This morning he woke up complaining of double vision, and his wife noticed that he was limping when he got up from his bed. In the ED, his vital signs are:
On examination, he was alert and oriented. Cardiovascular, respiratory, and abdominal examination were normal. He did not have nuchal rigidity, but lateral gaze of the right eye was restricted; he had mild left-sided hemiparesis and decreased sensation on the left side of the body. Laboratory data included a hemoglobin of 12.3 g/dL, WBC count 16 000/dL (90% neutrophils), platelets 235 000/dL, sodium 126 mmol/L, creatinine 1.5 mg/dL (no prior data available), aspartate aminotransferase 37 U/L, alanine aminotransferase 26 U/L, and total bilirubin 1.0 mg/dL. A CT head without contrast was obtained, which did not show any acute abnormality. He was empirically started on vancomycin and ceftriaxone for community-acquired bacterial meningitis and transferred to the floor. Overnight, his level of consciousness decreased and respiratory status deteriorated resulting in the need for intubation before being transferred to the medical ICU. Bedside electroencephalography did not show any seizure activity. He continued to spike high-grade fevers and eventually underwent an LP, which showed mild neutrophilic pleocytosis and mildly elevated protein, suggestive of aseptic meningitis but was otherwise normal. A brain MRI with contrast was planned; however, before this could happen, the patient’s neurological status worsened with loss of cranial nerve reflexes and the family decided to withdraw care. Blood cultures from admission showed growth of gram-positive bacteria in two of two bottles at 48 hours, about 24 hours after the patient’s death. Final pathology from autopsy reported severe inflammation of the brainstem, which led to herniation.
Which of the following is true regarding the management of this patient?
Correct Answer: B
Listeria monocytogenes can cause invasive CNS disease in otherwise healthy individuals requiring a very high level of suspicion for diagnosis. Early administration of ampicillin, which is the treatment of choice, significantly alters morbidity and mortality.
Inflammation of the brainstem, also known as rhomboencephalitis, is a well-described syndrome that can result from a variety of infectious and noninfectious insults. In immunocompromised individuals such as those with HIV and slowly progressing infections such as Cryptococcus and tuberculosis are seen more commonly, but HSV-1 and Listeria monocytogenes can affect immunocompentent individuals as well. In contrast to its other manifestations, Listeria monocytogenes rhomboencephalitis typically occurs in young healthy individuals. This syndrome is distinct from the more commonly seen Listeria meningitis in neonates, in the immunosuppressed and elderly. It classically presents as a biphasic illness with 72 to 96 hours of prodromal symptoms consisting most commonly of fevers, headaches, nausea, and vomiting, which are followed by rather rapid progression of focal neurological deficits involving the brainstem. Meningeal signs may be completely absent in these patients, and CSF analysis may or may not be suggestive of meningoencephalitis. Blood cultures are positive in up to half of these cases, and CSF PCR for Listeria monocytogenes (as part of multiplex panels) may aid in diagnosis. The treatment of choice is ampicillin, with trimethoprim-sulfamethoxazole as an alternative in the setting of penicillin allergy. Mortality without early initiation of adequate therapy is up to 50%. Even with treatment, high mortality and morbidity from persistent neurological deficits have been reported. As this syndrome occurs in young, otherwise healthy individuals in whom Listeria is not usually considered a causative organism of meningitis and for whom Listeria coverage is not usually included in empiric antimicrobial regimen for CNS infections, the diagnosis requires high index of suspicion and early initiation of empiric treatment while awaiting diagnostic studies.
Consideration should also be given to noninfectious etiologies of rhomboencephalitis including multiple sclerosis and autoimmune or paraneoplastic syndromes; however, antimicrobial therapy should be started early while workup is in process for other noninfectious etiologies. Although HSV can cause rhomboencephalitis, the presence of bacteremia with Listeria argues against this being the etiological agent. The addition of dexamethasone during treatment of invasive Listeriosis was associated with a trend toward worsened outcomes in a large French study and is therefore discouraged.
A 76-year-old male with rheumatoid arthritis managed with rituximab infusions is brought in to the ED with altered mental status. Four days before presentation, he developed fevers up to 103°F and headaches about a week after he returned from a camping trip in rural Wyoming. He was seen in his primary care physician’s office 2 days ago for these symptoms and was noted to have a nonblanchable maculopapular rash over the left side of his trunk. He was managed symptomatically with antipyretics, but his headaches worsened and he was found to be confused this morning. On examination, he has limited ability to move his left lower extremity, which appears floppy. The rest of his examination is unremarkable, and no rash is seen. His complete blood profile and chemistry is normal. He has no risk factors for human immunodeficiency virus (HIV). Diagnostic workup is started for stroke, and he is empirically started on IV vancomycin, ceftriaxone, ampicillin, and acyclovir for possible meningoencephalitis. A CT head without contrast does not show an acute abnormality. An LP is performed, which reveals:
Gram stain is negative, and culture is pending. Brain MRI with gadolinium shows nonspecific enhancement of left basal ganglia. PCR for HSV on CSF is negative. Over the next 24 hours, his fevers persist, level of consciousness worsens, and he requires intubation for airway protection.
Which of the following laboratory tests is MOST likely to reveal the etiology of his presentation?
Correct Answer: C
The patient has a classical presentation for West Nile virus meningoencephalitis. The diagnostic test of choice is measurement of West Nile IgM in the CSF unless there is concern for impaired antibody production in which case PCR on CSF can be helpful.
West Nile is the most common mosquito-borne illness in the United States. It was first reported in an outbreak in New York City in 1999, but the disease has spread rapidly across the continent and has now been reported from almost all continental states in the United States. Culex mosquitoes are primary vectors of transmission, which occurs seasonally in summer and fall. Transmission has also been reported via blood transfusion, organ transplantation, breastfeeding, and even transplacentally. Eighty percent of infections are asymptomatic and if present, symptoms are usually limited to a brief flulike illness with or without a nonspecific maculopapular rash, which is present for hours to days. Neuroinvasive disease is seen in less than 1% of cases and has three distinct presentations–acute flaccid paralysis, encephalitis, and meningitis (very rare in isolation)–although a combination of these presentation may also be seen. Meningismus is often absent, and LP usually reveals a mild aseptic meningitis picture without any predilection for lymphocyte or neutrophil predomination. When history is suggestive, diagnosis is usually made by West Nile virus IgM in the CSF. Serum IgM can also be supportive. Serologies may be negative early on in the disease, and a convalescent titer should be checked if suspicion remains high. IgM is not an option in the answers for this question; IgG in CSF or serum is insensitive in the acute phase. The next best diagnostic option is West Nile virus PCR in CSF. West Nile virus is notable in that unlike most other viruses, PCR is less sensitive and becomes negative very early on in the disease process. In patients who have known impairment of antibody production—either from an underlying disease such as chronic lymphocytic leukemia or iatrogenic (as in this case) from rituximab, antibody testing is not reliable and therefore PCR is very useful. It should be noted that West Nile virus is not included in most commercially available viral PCR panels and West Nile virus–specific PCR needs to be specifically sent to a reference laboratory. Most state labs and the Centers for Disease Control and Prevention (CDC) offer West Nile virus testing.
The above presentation of encephalitis with aseptic meningitis and flaccid paralysis following a prodrome of fevers, headaches, and transient maculopapular rash after a camping trip is not consistent with Echovirus or Coxsackie virus infection—these viruses typically cause self-limited aseptic meningitis.
A 38-year-old male is brought to the ED when family noticed that he was confused. Per report, he was well until about 3 weeks ago when he developed generalized malaise and a dry cough followed by daily fevers of 100.6°F to 100.8°F. Over the last week, he had been feeling increasingly short of breath. His past medical history is significant for HIV for which he is receiving highly active antiretroviral therapy (HAART), untreated hepatitis C infection complicated by cirrhosis, and smoking-related chronic obstructive pulmonary disease (COPD) for which he has been receiving prednisone 40 mg daily for the last 2 weeks. His CD4 count 1 month ago was 640 cells/mL with an undetectable HIV viral load. He has no history of opportunistic infections. On physical examination, he has normal heart sounds, coarse crackles on the right lung base, his abdomen is soft and nontender without evidence of ascites, and his neurological examination is unremarkable except that he is not oriented to time, place, or person. In the ED, laboratory data are:
Chest x-ray shows a right lower lobar consolidation. Two sets of blood cultures are drawn, and he is started on vancomycin and piperacillin/tazobactam. Over the next 72 hours, his oxygen requirements increase to requiring 6 L via nasal cannula and he continues to spike fevers. His increasing confusion is attributed to delirium, and he is started on lactulose for possible hepatic encephalopathy. On day 5 of admission, he is transferred to the ICU with worsening hypoxia requiring intubation. He undergoes bronchoscopy for diagnostic bronchoalveolar lavage (BAL). The initial stain shows yeast with thick capsules, and the following day cultures show growth of pigmented colonies.
What is the next best step in management for this patient?
Correct Answer: D
This scenario is concerning for disseminated cryptococcosis involving the lungs and meninges. LP should therefore be performed to measure opening pressure and to establish whether CNS involvement is present as this would directly affect management.
Cryptococcus neoformans is one of the most common causes of meningitis in HIV positive individuals and usually occurs when CD4 counts fall below 100 cells/mL. Cryptococcus is being increasingly recognized as causative of lung, CNS, and disseminated disease in other immocompromised populations including organ or stem cell transplantation, receiving other forms of immunosuppression, and in patients with diabetes. Cirrhosis, which leads to impaired humoral as well as cell-mediated immunity, is also considered to be a risk factor for cryptococcosis. Even in the absence of any of these risks, immunocompetent individuals can also occasionally be affected. The primary mode of transmission is inhalation of the fungus with dissemination from the lung through hematogenous spread. Invasive cryptococcal disease classically presents as a meningoencephalitis, but lung involvement in the form of lobar pneumonia, nodules, or even cavitary lesions is common in HIV-negative individuals either alone or concomitant with CNS infection. Skin involvement may occur with a variable presentation ranging from papular rash to cellulitis and even ulceration. cryptococcal meningitis is usually an indolent and subacute process presenting with a few weeks of headache, malaise, fever, and/or altered mental status. It is uncommon to have rapid progression of disease with significant neurological impairment although that can occur. Signs of meningeal irritation may or may not be present.
Whenever a diagnosis of extraneural cryptococcosis is made, including that of isolated Cryptococcemia, an LP is indicated to establish CNS involvement. CNS cryptococcosis is treated with amphotericin ideally in combination with flucytosine, whereas fluconazole alone may otherwise be sufficient for isolated lung, skin, or other organ disease. Additionally, intracranial pressures may be very high in cryptococcal meningitis in which case repeat LPs for therapeutic drainage or drain/shunt placement may be indicated. Other than high opening pressures, the CSF analysis is usually of limited utility with low to normal glucose, mildly elevated protein, and mild, if any, pleocytosis. Culture of CSF remains the gold standard for diagnosis. The identification of cryptococcal antigen in the CSF has very high sensitivity and specificity and is also useful for monitoring the effect of treatment. Serum cryptococcal antigen is also highly sensitive for meningoencephalitis (not for other organs) and if positive, is sufficient to rule in CNS involvement in patients with an absolute contraindication to LP.
Although the patient’s HIV is well controlled, his steroid use and cirrhosis place him at risk for cryptococcosis. The presence of non-Candida yeast in the BAL, which grows with pigmented colonies (due to melanin production) on culture is characteristic of Cryptococcus neoformans. Candida, CMV, typical bacterial pneumonia, or nontuberculous mycobacterial disease would not fit this clinical picture.
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