Hello everyone. Welcome to this lecture on neuroinfections. My name is Shweta Mainali and I'm an Associate Professor of Neurology, Director of Clinical Research for the Division of Stroke and Neurocritical Care at the Virginia Commonwealth University. I have no disclosures relevant to this talk. The learning objectives of this talk is to learn about the common bacterial, viral, and fungal pathogens involved in CNS infection, learn about the clinical presentation and initial diagnostic evaluation of CNS infection, to learn about some basic principles of management of acute CNS infection, and also learn about some common healthcare associated CNS infections. How do we define meningitis and encephalitis? So, meningitis is the inflammation of the leptomeninges where the underlying brain parenchyma is not involved. Therefore, the key feature of meningitis, it could be headache or even lethargy, but their cerebral and cognitive function remain normal. In contrast, in patients with encephalitis, they have significant cognitive impairment, they may have motor or sensory deficit, they could have behavior or personality changes, or even speech disorder or movement disorder. Seizures or postictal state can be seen both with meningitis and also encephalitis. So, just because someone has seizure, it should not be construed as a definitive evidence of encephalitis. Looking at the consensus statement from the International Encephalitis Consortium regarding the diagnostic criteria for encephalitis. So, the table here is from the consensus statement, and there is a requirement of one major criteria, which is patient has to present to the medical attention with altered mental status that could be either alteration of consciousness, lethargy, or personality change lasting greater than or equal to 24 hours without any other etiology to attribute to that presentation. And there are minor criteria, and patient has to have at least two of these minor criteria for possible encephalitis, and if there's three or more of these minor criteria present, then patient is thought to have probable or confirmed encephalitis. Now, there should be, for minor criteria, fever, a documented fever up to 100.4 degree Fahrenheit within 72 hours before or after presentation. Patient could have generalized or partial seizure that is not attributable to other pre-existing seizure conditions. Patient could have a new onset focal neurological deficit. The CSF study should show white count greater than five cubic millimeters. There should be abnormality of brain parenchyma or neuroimaging suggesting encephalitis that is either new from prior studies or appears to be acute on imaging if it's the first study done. And another minor criteria is also EEG abnormality that is consistent with encephalitis that is not attributable to other causes such as metabolic derangements, etc. Let us now look into some of the common causes of meningitis. Some common pathogens causing meningitis include bacteria causing acute bacterial meningitis. There could be partially treated bacterial meningitis if patients received a couple of doses of antibiotics prior to obtaining CSF. Another type of meningitis is the viral meningitis or meningoencephalitis. Some uncommon causes in the United States include tuberculous meningitis, fungal meningitis, syphilis or leptospirosis meningitis, amoebic meningitis such as naegleria, which is a very fulminant type of meningitis. You could also have meningitis from parainfectious processes such as brain abscesses, epidural empyema, epidural abscess or epidural empyemas, and you may have a secondary meningitis from chemical such as drugs, intrathecal drugs or dermoid cysts causing chemical meningitis in patients who have died for myelogram that could also result in a form of chemical meningitis. In terms of management of these patients, a clinical approach is to consider brain infection in all patients who present with headache, neck stiffness, fever, altered sensorium or diffuser focal neurological findings. In some patients, the alteration in mental status may be a result of increased ICP. Hence, that's why fundoscopic exam is a useful component of physical evaluation in these patients to rule out papilledema. In addition to fundoscopy, it's important to do a focused neurological exam with specific special attention to cranial nerves as some basilar meningitis can affect cranial nerve and would lead to cranial nerve neuropathies. CSFC sampling is the only reliable method of assessing the presence or absence of meningitis and in the absence of any contraindications when there is high index of suspicion for meningitis, a lumbar puncture should be performed. It is very important to provide critical care monitoring in these patients and providers should be aware of the rapid risk of decline and rapid deterioration in these patients. This is a nice algorithm about approach to management of patients with CNS infection that was recently published that's referenced below. That's basically if there is no contraindication to a lumbar puncture, then we should go ahead get the lumbar puncture, start the first dose of antibiotics along with dexamethasone if there is bacterial meningitis suspected and the final therapy should be tailored based on CSF profile and analysis. If there is a contraindication to lumbar puncture, that should not hold starting antibiotics or dexamethasone if there's concern for bacterial meningitis, especially if there's focal neurological deficit. Neuroimaging should be obtained to rule out large mass effect that could put patients at risk of herniation during lumbar puncture, which can may be fatal. Hence, it's important to evaluate these patients with caution, although withholding antimicrobial therapy should not be done if lumbar puncture cannot be obtained. Nice table from the source referenced below of various parameters of opening pressure, color, white blood cell, different shells, blood glucose, CSF glucose and protein levels in patients with various types of meningitis, bacterial, viral, tuberculosis and fungal. I will leave this on the slide for you guys to review, but I just wanted to point out that most centers in the United States use a protein value of milligram per deciliter. So for example, normal would be 0.45 gram per liter or 45 gram per less than 45 milligram per deciliter. Looking at a table again from the Intensive Care Medicine Journal by Mayfreud et al. Common pathogens for bacterial meningitis. The most common ones are strep pneumonia and neisseria meningitides. It affects all ages. More common in older individuals is the strep pneumonia. Neisseria is more common in younger individuals. Listeria monocytogenes is most commonly seen in adults over 50 years of age and usually more common in patients that are immunocompromised, pregnant or alcoholic, malignancy or liver disease. As for coagulase negative staph and staph aureus, it affects all ages. It's commonly seen in patients with neurosurgical intervention or foreign bodies such as shunt. The gram negative bacilli infection such as pseudomonas meningitis can be seen in immunocompromised hosts with foreign bodies or post-operative state who are critically ill and important to have high effects of suspicion and gram negative coverage in these individuals. Haemophilus influenzae can be found in all ages but they're also more common in patients that are immunocompromised with compromised humoral immunity or unvaccinated children. Here quickly goes over different age groups and different pathogens that are more common in different age groups. For neonates less than one month of age, strep agalachy, E. coli, listeria or eclepsia are most common pathogens. Hence, we should use ampicillin plus ceftazepam or aminoglycosides in this patient. In patients from one month up to a year, common pathogens include strep pneumonia, neisseria, strep agalachy, haemophilus influenzae or E. coli. Hence, we should add vancomycin plus a third generation encephalosporin as empiric therapy. In patients above one year up to 50 years of age, most common pathogens are neisseria meningitis and strep pneumonia. Again, as we said earlier, neisseria tends to be found more commonly in younger individuals, strep pneumonia in older individuals. For this age group, the common empiric therapy is vancomycin and a third generation cephalosporin such as ceftazepam or cefepime. In patients who are greater than 50 years of age, in addition to neisseria and strep pneumonia, there is additional risk of listeria monocytogenes and aerobic gram-negative bacilli. So, we need to add ampicillin in addition to vancomycin and third generation cephalosporin when we're covering these individuals empirically. This slide mostly reviews what we just discussed, but one of the things that I wanted to point out is bacterial meningitis can really be fatal. As you can see here, strep pneumonia is one of the two leading causes of bacterial meningitis in adults with mortality up to 30 percent. So, it's really important to have high index of suspicion and start early antibiotic therapy to have effective treatment for these patients. So, in summary, the treatment of bacterial meningitis includes early initiation of empiric antimicrobial therapy. It is preferable to have a lumbar puncture done prior to the first dose of antimicrobial. However, if there's any clinical reason to delay a lumbar puncture or neuroimaging to guide the safety of lumbar puncture, then we should not hold back the first dose of antimicrobials. If patients present with Neisseria meningitidis or H. influenza, we should offer their close contacts chemoprophylaxis. If patients have other systemic infections like pneumonia or UTI and present with neurological symptoms, then it is common to assume co-infection with the same pathogen. It's the most common first-line treatment for bacterial meningitis is ceftriaxone and vancomycin in adults greater than 50. We like to add epazolite to cover for listeria monocytogenes. If there is suspicion of meningoencephalitis, acyclovir is recommended in those patients until the CSF profile is back with HSP analysis. Dexamethasone is recommended prior to treatment with antibiotics in adults with suspected bacterial meningitis. Let us now talk about fungal meningitis. Here is the NICE table reviewing the various types of fungal pathogens responsible for meningitis, meningoencephalitis, and CNS involvement. The reference is cited below where you are able to find this table. So the common fungal pathogens involving CNS include candida species, aspergillosis, blastomyces, histoplasma species, coccidioides, cryptococcus, zygomycetes species, which include mucor and rhizopus that are more common in patients with immunocompromised or uncontrolled diabetes and often tend to be fatal. They present in various forms including meningitis, meningoencephalitis, brain abscesses, may have spinal cord epidural abscesses or paraspinal abscesses, may present with meningoencephalitis or stroke-like symptoms. Let us look into this young 46-year-old HIV-positive male who presented with headache, nausea, vomiting, and found to have cryptococcal meningitis. His symptoms initially improved after lumbar puncture. He was promptly started on amfotericin B and flucitazine. However, two days later, he had records of these symptoms with blurring of vision and severe headache. What is the most likely reason for return of his symptoms? On the right-hand side here, you can see this image A, which is a T2-weighted image, and image B, which is a T1-weighted image showing multiple cystic CSFL dilated perivascular spaces, which is a common MRI finding in cryptococcus meningitis. Let us now move on to reviewing cerebral abscesses. Here, we have a 40-year-old male with history of IV heroin abuse who presented with one-week history of fever, chills, headache, and three days of mild ataxia and homonymous hemianopsia. Upon presentation, he was febrile with a temperature of 101.5 with normal respiration, heart rate, and blood pressure. MRI brain is shown over here. What is the most likely diagnosis? As you can see on the top panel here, you're seeing a contrasted, very nicely ring-enhancing lesion in the left inferior temporal region. This lesion appears to have restricted diffusion on the DWI image in panel B with corresponding dark area in ADC. Here, we have very strong suspicion, especially given fever, history of IV abuse of cerebral abscess. How do we manage cerebral abscesses? The general principle is the empiric therapy should be guided by your principle of whether or not the drug penetrates the CNS and trying to cover the most likely pathogen. For example, if the source is dental or sinus abscesses, then you probably want to treat with a gram-negative coverage as well as anaerobic coverage such as metronidazole. If the abscess is related to trauma or a neurosurgical procedure, you would like to cover for gram-positive bacteria. Probably, the empiric therapy should include coverage for MRSA unless it comes back negative. Patients with very high risk for tuberculosis, fungal, or parasitic abscesses should, again, their antibiotic therapy should be guided or antimicrobial therapy should be guided by the most likely pathogen being considered. Remember, steroids should not be routinely used. It's only used in an acute period when there is suspicion of a very severe bacterial infection, inflammation with cerebral edema. Routine use can actually increase mortality, so we should avoid routine or delayed use of steroids. Small multiple abscesses are usually treated medically, but if the abscesses are surgically accessible or large solitary abscesses, whenever possible, surgical drainage should be considered. Generally, location, size, the total number of abscesses is what dictates whether or not the patient should get medical management, surgical management, or a combination of these. Moving on to viral meningitis. The picture of viral meningitis can look similar to aseptic meningitis, and the term aseptic meningitis refers to patients who have clinical and lab evidence for meningeal inflammation, but their cultures are negative. The viral pathogens most commonly responsible for viral encephalitis include HSV1 and 2, and that accounts for about 50 to 75 percent of identifiable cases of viral meningitis. Other common causes include VCV, enterovirus, dengue, Zika, West Nile virus, EBV, CMV, measles, mumps, etc. Again, this table is an excerpt from this paper referenced below. Looking at this case here of a 53-year-old female who was brought to the emergency department with new-onset seizure. Her husband reported she has been confused and lethargic for the past three days. Vitals include a temperature of 101, normal heart rate, respiratory rate, and oxygen saturation. Upon exam, she's outtunded, requires repeated stimulation to open eyes. She is only oriented to self and intermittently able to wiggle toes to command. However, she has minimal verbal output and not following complex commands. A lumbar puncture revealed protein of 66-glucose-62, white count 84, RBC 118. CT scan of the brain is shown. What is the most likely etiology for seizure? As you can see here, patient has this hypodensity with intermixed hyperdensity in the left temporal region. This is a common area and a common presentation in patients with HSV meningoencephalitis. So HSV encephalitis is the leading cause of sporadic non-endemic encephalitis in children and adults in the United States. It can produce acute necrotizing infection generally involving the frontal, temporal, cortex, limbic system beyond the neonatal period, and it's almost always HSV-1. The infection may manifest as nonspecific findings like fever, headache, nuchal rigidity, nausea, vomiting, generalized seizures, or alteration of consciousness. If there's injury to frontal cortex, temporal cortex, or limbic system, patient may have have symptoms of anosmia, memory loss, peculiar behavior, aphasia, other hallucinations, focal seizures, or speech difficulties. It is important to note that HSV encephalitis, if untreated, can lead to progressive coma and death in up to 75% of cases, in contrast to HSV meningitis, which can be have a slow smoldering course with spontaneous resolution. Examination of CSF typically for herpes encephalitis shows moderate number of mononuclear cells and polymorphonuclear leukocytes. There's slight elevation of protein. The glucose can be normal, or maybe it may even be slightly low, and there's often a moderate number of erythrocytes. We treat this with acyclovir with a dose of 10 milligram per kilogram every eight hours for 14 to 21 days. HSV is a common cause of aseptic meningitis, and sometimes may even present as recurrent aseptic meningitis, also known as molar-raised meningitis. It is important to know that up to 20% of patients with HSV encephalitis may manifest autoimmunity within two to six weeks of infection, and some of these may even have positive anti-NMDA receptors. And in children, they commonly present with movement disorders while in adult state, manifest with psychiatric symptoms. Let us switch gears a little bit and look into this case of a 29-year-old male with history of alcoholism, IV drug abuse, who presents with three-day history of fever, back pain, urinary retention, one-day history of progressive lower extremity weakness, and numbness. Upon presentation, his febrile up to 102.5, slightly tachycardic, slightly tachypneic with normal oxygen saturation. Brain MRI was normal. PAM culture was sensed. MRI cervical thoracic spine with and without contrast was obtained in the ED, which showed anterior spinal epidural abscess at L4. Associated with osteomyelitis of L3 and L4 and discitis at that level. What are the predisposing factors, management, and prognosis for this diagnosis? As you can see on the image here on the right, the arrow indicates epidural abscess at L4. This image was obtained from this article in NEJM from 2006 as referenced below. As for presentation of spinal epidural abscess, the triad of fever, back pain, and neurological deficit, also known as the plastic triad, is actually not that common and only present in about 2% to 33% of cases. Although back pain is a very common presenting symptom, fever may be only present in about 50% of these cases. There could be a wide range of neurological deficits occurring with this condition, ranging from focal motor weakness, sensory disturbance, up to urinary and bowel-bladder dysfunction. Some of the predisposing factors for spinal epidural abscesses include IV drug use, alcohol abuse, malignancy, uncontrolled diabetes, immunocompromised states such as HIV infection, chronic steroid use, etc. The portal of entry could be contiguous infection or hematogenous seeding or it could be iatrogenic. The neurological outcomes are actually directly related to the state of the neurological exam at the time of presentation. Early diagnosis and intervention tend to lead to better outcomes and deficits, if they're severe, like including compression of the spinal cord with cauda equinus syndrome, etc., may be permanent. Therefore, it's very important to maintain a high index of suspicion and to avoid delay in diagnosis of these patients. As for prognosis, mortality can approach up to 20% and neurological disability after recovery affects approximately half of these patients who survive. Surgical decompression within 36 hours is important as late decompression may lead to poor prognosis. As you know, lumbar puncture is generally contraindicated in these patients as we might be coursing through the site of infection. As we've already discussed, urgent surgical drainage is a priority as they usually have poor response of conservative management alone. If patients have very high risk for surgery and are neurologically intact and have abscess in the accessible location, imaging guided needle aspiration is an alternative to surgical decompression. The response to medical therapy alone is quite poor, especially in patients who are older than 65, if they already have weakness or sensory deficit, if there's definitive evidence of cord compression with cord injuries such as myelopathy or cauda equinus syndrome, if there's infection with MRSA, poorly controlled diabetes, severe inflammation with CRP greater than 115, if their white count's greater than 12,000, 12.5, if they have positive blood cultures and presence of neurological impairment related to the cord injury are all associated with 15-fold higher odds of failing medical therapy. Hence, given that medical therapy alone is quite limited in terms of efficacy, it should only be reserved for individuals that are very, very high surgical candidates, lack the above-mentioned risk factors, and have an established pathogen already from aspiration and are confirmed to be on the right type of antibiotics. Standard empiric therapy typically includes vancomycin and ceftriaxone or another cephalosporin such as cefepime. As with brain abscesses, there's a lack of control trials to guide the optimal duration of antimicrobial therapy for spinal epidural abscess. However, most patients end up receiving about four to eight weeks of medical therapy. Shorter durations can be reserved for patients with surgical drainage, and longer durations should be considered for patients who are being managed with antibiotics alone or who have associated bony infection with osteomyelitis. Last but not the least, let us review this case of a 14-year-old male with history of pineal tumor, status post resection, and ventricular peritoneal shunt placement who presented with three days history of fever, headache, and altered mental status. A shunt series in the ED showed intact shunt but suggested mild hydrocephalus compared to post-operative scans six weeks ago. The DWI and ADC sequences of the MRI is shown on the right here. What is the most likely diagnosis? As you can see, indicated by the red arrows on the left on the DWI image is bright, hyper-intense areas within the ventricle, which represents the pus, which corresponds with dark areas in the ventricles and ADC. So this, we're looking at ventriculitis. We should treat this with antibiotics until we have definitive diagnoses of the pathogen. That concludes our session for today. I'm happy to take questions that you may have, and if we don't get to all your questions today, feel free to email me at shraddha.mainali.osumc.edu, or you can also send me a message on Twitter at Mainali Shraddha. Thank you and wish you all the best.

neuroinfections

bacterial pathogens

viral pathogens

fungal pathogens

meningitis

encephalitis