Clinicalneurology-InfoPage - CNS Infections

8/12/2019 Clinicalneurology-InfoPage - CNS Infections

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Introduction to Clinical Neurology: Infections of the Central Nervous System

Lecturer: Maulik Shah, MD, MHS

UCSF Neurology Department

Syllabus and Overview

Learning Objectives: Given the breadth of pathogens, presentations, and complexities

of infections that can affect the central nervous system, it is impossible to cover all

topics and details in an introductory lecture. This lecture will focus on describing

common entities that lead to significant neurologic morbidity and mortality across the

world and familiarize the learner with disease labels, typical clinical presentations and

examination findings, diagnostic testing and interpretation or results, and strategies for

treatment and management. Specifically, we will review bacterial meningitis,

encephalitisand aseptic meningitis, cerebral abscess, and selected topics in diseasesof the nervous system in patients with human immunodeficiency virus (HIV) infection. In

the lecture itself, we will also review a case study of a patient presenting to the

Emergency Department with signs and symptoms concerning for bacterial meningitis

and discuss step-by-step management decisions.

I. BACTERIAL MENINGITIS

Approximately 1.2 million cases of bacterial meningitis occur annually worldwide, with at

least 135,000 deaths each year, and many of the survivors experiencing permanent

long-term neurologic complications. Meningitisrefers to any condition in which there isinflammation of the leptomeningesthe tissue around the brain and spinal cordand is

defined by an abnormal number of cells in the cerebrospinal fluid (CSF). Bacterial

pathogens are an important cause of meningitis and typically present acutely with rapid

progression of symptoms and neurologic deterioration. Bacterial meningitis develops

when the virulence factors of the bacteria overcome the host (human) defense

mechanisms, allowing for bacteria to colonize and then invade the central nervous

system by crossing the blood-brain barrier and multiplying within the CSF. Meningitis

can occur in both immunocompetent and immunocompromised patients, and may be

related to spread of infection via the bloodstream or direct extension from infections of

the head and neck.

The classic triad of presenting symptoms for patients with acute bacterial meningitis is:

fever, neck stiffness, and altered mental status. Other symptoms or signs that can be

seen include headache with photophobia and phonophobia, nausea and vomiting,

seizures, focal neurologic deficits and cranial nerve abnormalities, and ischemic stroke.


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Fulminant skin changes including petechiae and purpura can also be seen, especially in

cases of Neisseria meningitidis. Neurologic examination findings include nuchal rigidity

and neck stiffness; these are also appreciated by testing for Brudzinskis sign

(spontaneous flexion of the hips during passive flexion of the neck) and Kernigs sign

(inability or reluctance to allow full extension of the knee when the hip is flexed at 90

degrees), but it is important to know that these signs are not sensitive for the diagnosis

of acute bacterial meningitis. Patients are often encephalopathic and can have focal

neurologic deficits.

Management of acute bacterial meningitis requires an understanding of the patients

risk for specific pathogens and knowledge of the prevalence of pathogens in your

practice and area. The most common community-acquired pathogens in adults

between the ages of 18-50 are Streptococcus pneumonaieand Neisseria meningitidis.

Listeria monocytogenesshould also be considered as a common pathogen in patients

over the age of 50, pregnant woman, and patients who are immunocompromised.Healthcare-associated (nosocomial) meningitis is usually associated with Staphylococci

species and aerobic gram negative bacteria and can occur after neurosurgery or CNS

invasive procedures.

Given the high mortality and morbidity of acute bacterial meningitis, empiric antibiotics

are often started prior to testing and confirmation of diagnosis. After stabilizing the

patient in terms of hemodynamics and respiratory function, empiric antibiotics should be

given while preparing for diagnostic testing. It is important to collect blood cultures prior

to antibiotics as many patients have bacteremia. Antibiotic choice across the world

depends on formulary availability and pathogen prevalence in each area, but, forexample, in areas where S.pneumoniaeand N. meningitidisare the most common

causes of community-acquired meningitis, antibiotic coverage should include:

Ceftriaxone 2 grams given via IV every 12 hours to cover for Neisseriaand Vancomycin

15-20 mg/kg IV every eight hours to cover for S. pneumoniae given high rates of

penicillin-resistance. If Listeriais a concern, Ampicillin 2 grams IV every four hours

should also be added. Antibiotics should be adjusted once pathogen and sensitivity to

antibiotics are identified via culture and treatment should last at least 14 days.

Definitive treatment also involves identification of any nidus of infection (e.g. mastoiditis)

and appropriate targeted treatment to prevent persistent or recurrent infection.

In addition to antibiotics, randomized controlled trials have shown that administration of

high-dose IV steroids (e.g. Decadron) with or prior tofirst antibiotic dosing was

associated with reduced mortality and neurologic complications compared to placebo in

patients who had S.pneumoniae.Given the prevalence of this pathogen, it has become


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common practice to start steroids empirically and then continue or discontinue them

once the pathogen has been identified.

Definitive diagnosis of acute bacterial meningitis typically involves identification of the

pathogen from CSF culture with demonstration of inflammation within the CSF. This is

achieved by lumbar puncture and collection of CSF for analysis. Prior to lumbar

puncture, practitioners should consider obtaining CT scans of the brain in certain

populations given the risk of precipitating cerebral herniation after lumbar puncture if

there is an intracranial pressure gradient due to mass effect. This is not absolutely

necessary in all cases and may not be feasible in all health care settings, but should be

considered, according to guidelines from the Infectious Disease Society of America, in

patients who are 1) immunocompromised, 2) have a history of CNS mass or focal

disease, 3) have a seizure at onset of illness, 4) have optic disc edema on fundoscopic

examination, or 5) have a clear focal deficit on neurologic examination. Evaluation for

cerebral edema in the posterior fossa of the skull and ruling out subdural process orfocal mass can be achieved via CT scans of the head and these would be relative

contra-indications to pursuing lumbar puncture.

When lumbar puncture is obtained, the opening pressure should be noted, as it is often

elevated (normal is less than 20 cm H20). CSF studies should be sent for gram stain

and culture, cell count, protein, and glucose levels, and other specific pathogen testing

depending on clinical suspicion. In acute bacterial meningitis, there should be a

pleocytosis of WBC, often ranging from 100 to 100,000 cells, with neutrophil

predominance in terms of cell type. CSF glucose is typically decreased to below 40% of

serum glucose and CSF protein is typically markedly elevated. Gram stain and cultureoften grow the pathologic bacteria, but cultures may be sterile if lumbar puncture is

delayed following administration of antibiotics. If CSF studies are not consistent with

bacterial meningitis, then consideration should be given for discontinuation of antibiotics

at meningeal dosing and stopping steroids in the appropriate clinical setting.

In the United States, the overall mortality of bacterial meningitis is 16% and is higher in

older patients and those with hospital-acquired infection. There is a high rate of

neurologic complications and deficits including cognitive deficits, recurrent seizures and

epilepsy, hydrocephalus requiring shunting, venous sinus thrombosis, cranial nerve

injury including hearing loss, and immediate and delayed cerebral vasculopathy leading

to ischemic stroke. Given the high rate of complications after even a few hours or days

of illness, acute bacterial meningitis is an important clinical disease to immediately

recognize and empirically treat, as it is preferable to discontinue antibiotics later after

diagnostic testing reveals alternative diagnosis rather than delay definitive treatment

because of delayed recognition or diagnosis.


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II. ENCEPHALITIS

Encephalitisdiffers from meningitisin that patients exhibit symptoms and signs

indicative of cerebral dysfunction, which are often focal in nature. The term implies that

there is inflammation as cause of CNS injury, often captured by elevation of

inflammatory markers in CSF, but does not imply an infectious etiology. In truth, acute

bacterial meningitis should be considered a form of meningoencephalitis as patients

typically have evidence of cerebral dysfunction, but the nomenclature is inconsistent in

the literature, and acute bacterial infection is often referred to as meningitis. In

addition, the term aseptic meningitisis often used to describe patients with abnormal

CSF with pleocytosis but without neurologic symptoms or signs; in these cases, CSF

culture does not grow bacteria pathogens (hence the term, aseptic) but infectious

etiologies remain of primary concern and are the most common cause. This module will

help clarify how to distinguish these entities clinically and review common etiologies.

Numerous infectious and non-infectious pathogens can cause encephalitis, and as

such, there is a broad array of presentations. It is also difficult, given its broad

definition, to quantify the overall incidence and prevalence of infectious encephalitis

especially as definitive diagnosis requires specialized laboratory testing. Viral

pathogens are a common cause of encephalitis, and can lead to cerebral dysfunction

either via direct invasion of viral particles into the central nervous system or via post-

infectious immune-mediated injury, often weeks or even years after the initial systemic

viral infection.

There are no specific clinical features to distinguish encephalitis from other causes of

neurologic dysfunction. The presentation depends on the part of the nervous system

that has been affected, although altered mental status, ranging from mild confusion to

comatose states, is common. Patients can have seizures and focal neurologic

symptoms including language, cerebellar, motor, sensory, and visuospatial deficits. In

evaluating a patient with suspected encephalitis, it is important to ask about recent

illnesses, vaccinations, travel, or exposures as this often helps narrow the differential

diagnosis. For example, arboviruses, which are associated with illnesses such as

Japanese encephalitis and dengue fever, are most prevalence during mosquito and

monsoon seasons given that these insects are the vector for viral transmission to

humans. Rabies encephalitis follows animal exposure and bite, and several zoonotic

exposures are associated with specific atypical bacterial infections which can cause

encephalitis. It is also important to know which types of infections are endemic in your

area.


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Physical examination may reveal signs and symptoms indicative of specific etiologies.

Systemic viral infections are often associated with skin exanthema and rash; these may

not be present at the time of presentation of neurologic symptoms so it is important to

ask about preceding symptoms and signs. Flaccid paralysis of limbs is suggestive of

West Nile virus neuro-invasive disease and rabies encephalitis is also associated with

limb weakness along with hydrophobia, aerophobia, and pharyngeal spasms. Another

example would be the parotitis that is associated with mumps infection. In general,

however, there are no specific neurologic examination findings when evaluating a

patient with suspected encephalitis.

Diagnostic testing is helpful in demonstrating inflammation within the central nervous

system. Lumbar puncture is usually obtained after CNS imaging to rule out focal mass

and high risk for herniation. CSF analysis typically shows elevated WBC count with

predominance of lymphocytes, elevated CSF protein, and normal CSF glucose. Brain

imaging, both CT and MRI scan, and electroencephalography (EEG) are oftenabnormal, demonstrating focal injury to specific parts of the brain as well as global

dysfunction. Specific diagnosis of etiologies is made by testing for specific pathogens;

for example, laboratories can test for evidence of viral DNA or antibodies to viral

pathogens from CSF or serum samples; as there are numerous causes of encephalitis,

specific pathogen testing depends on the clinical presentation, exposure and patient risk

history, and CSF and imaging testing results described above.

The most important cause of viral encephalitis to recognize acutely is herpes simplex

virus (HSV) encephalitis. It is the most common cause of sporadic fatal encephalitis

worldwide, and, unlike some other forms of encephalitis, has a targeted treatment that isvital to prevent death and serious neurologic injury. HSV has a predilection for the

temporal lobes of the brain, and EEG and/or CNS imaging that suggests focal temporal

lobe dysfunction should raise high suspicion for HSV encephalitis. CSF typically shows

elevated pleocytosis (lymphocyte predominance) and high CSF protein; specific

diagnosis is made by testing for HSV DNA from CSF samples. Untreated, HSV

encephalitis has a mortality rate approaching 70%, and even with treatment, there is a

20-30% rate of mortality and survivors have a very high rate of neurologic complications

including epilepsy, amnesia, and prominent personality and behavioral change.

In addition, to direct viral infection, encephalitis can also occur via immune and

antibody-mediated injury followingsystemic infection. For example, acute disseminated

encephalomyelitis (ADEM) is a syndrome of widespread demyelinating injury to the

brain parenchyma and spinal cord which often follows a viral syndrome such as EBV

infection or upper respiratory syndrome. It is most common in pediatric populations and

is a monophasic illness that is treated with high-dose steroids. Following VZV infection


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such as chicken pox or shingles, patients can develop a cerebrovascular arteriopathy

leading to ischemic stroke and parenchymal injury. Another example, in which the

neurologic condition often occurs years after the initial infection, is subacute sclerosing

panencephalitis (SSPE), in which a progressive neurodegenerative condition

characterized by periodic myoclonus develops due to re-activation of latent CNS

measles infection. In all these cases, host immune system activity is felt to be altered

by initial infection, contributing to development of post-infectious CNS injury.

As discussed above, the term aseptic meningitisrefers to any cause of meningeal

inflammation (defined as elevated CSF white cell count) with negative bacterial cultures.

As opposed to encephalitis, in these cases patients do not have signs of parenchymal

brain injury. They can present with headache, stiff neck, and fever, but without focal

neurologic deficits. Patients often have a self-limited course lasting days to a few

weeks, with no long-term complications, and not requiring any specific treatment.

Often, given this natural history, a specific etiology is never found. It is important toknow about possible etiologies, however, as some of them do have specific implications

or require treatment, and diagnostic testing should involve specific testing of these

entities. For example, acute HIV infection can cause meningitis and should be

screened for in all patients if possible. Herpes simplex virus type 2 can cause recurrent

aseptic meningitis (sometimes termed Mollarets meningitis) and can be treated with

oral antiviral therapy. In addition, atypical bacterial infection, especially spirochete

infections such as syphilis, can cause meningitis and should be treated with antibiotics;

these are diagnosed by evaluation for antibodies as pathogens do not grow from routine

cultures. In addition, neoplastic, fungal, and parasitic infections can also present as

chronic aseptic meningitis and require specific treatments. As such, follow-upevaluation of these patients is important in ensuring resolution of symptoms as

persistent symptoms should imply a process that will require specific treatment to

eradicate.

III. CEREBRAL ABSCESS

A cerebral abscess refers to a focal collection of infection within the brain parenchyma.

Subdural empyema refers to infection within a subdural collection. Bacteria are

common causes of cerebral abscess and can invade the brain via direct spread from

contiguous sites or via hematogenous spread. For example, direct spread to brain

parenchyma can occur from sinus, dental, otitis media infection, or after penetrating

trauma. Infection can spread from the bloodstream in patients with endocarditis and

bacteremia, with abscesses often forming at the grey matter and white matter junction

of the brain.


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Abscess cultures often showed mixed pathogens with anaerobic bacteria and aerobic

gram positive cocci among the most common. Specific sites of infection are associated

with certain bacteria. For example, abscesses from sinus infection are often associated

with Streptoccocus, Haemophilus, and Bacteroides; Staphylococcusand gram negative

bacteria are common pathogens after neurosurgery; and Viridans streptococciand

Staphylococcusare associated with endocarditis. In patients with immune deficiencies,

atypical pathogens and non-bacterial etiologies should also be considered including

Listeria and Nocardiainfections, fungal abscesses, and toxoplasmosis.

Presenting symptoms in patients with cerebral abscess depend on the location of focal

collection. Patients often present with headaches, seizures, or focal neurologic deficits,

but only 50% of patients have fever at onset. Patients may also have signs of high

intracranial pressure on examination including optic disc edema and encephalopathy.

Imaging characteristics of cerebral abscess depend on the stage of infection. In itsearly stages, an abscess is termed cerebritis, in which lesions are poorly demarcated

with local edema. On imaging, CT scans show irregular low density areas within the

brain parenchyma that do not enhance during the cerebritis stage. After few weeks,

necrosis and liquefaction of brain parenchyma occurs with formation of surrounding

fibrotic capsule. At this time, contrast-enhanced CT scan imaging shows ring

enhancement. Where available, MRI Brain scans are more sensitive than CT scans for

diagnosis and evaluation of cerebral abscesses. Lesions are bright or hyperintense on

diffusion weighted sequences, there is ring enhancement on gadolinium enhanced

sequences, and imaging more accurately depicts the degree of surrounding edema.

Identification of the pathogen is usually done via abscess culture via imaging-guided

surgical aspiration of brain parenchyma or primary site of infection (such as an adjacent

sinus). In cases of hematogenous spread, blood cultures may allow speciation of

pathogen. Lumbar puncture is usually not pursued and is often contra-indicated given

the presence of mass effect and risk for herniation, but, if collected, often shows

elevated cell count and protein with low glucose. Asides from its role in obtaining

culture data, surgical aspiration and drainagewhen technically feasibleis part of

definitive abscess management. In addition, patients must be treated with antibiotics,

which are often chosen empirically depending on the most likely pathogens in relation to

the likely etiology of abscess. For example, sinus or oral infection sources are treated

with Metronidazole and Penicillin or Cetriaxone in order to cover for anaerobic flora and

Streptococcusspecies. Patients with infection after penetrating trauma may be treated

with Vancomycin and Ceftriaxone; after neurosurgery, Vancomycin and Ceftazidime or

Cefepime to cover gram negative species are recommended. Antibiotics should be

narrowed once a definitive pathogen has been identified.


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There are no clinical trials or specific consensus guidelines regarding the duration of

antibiotics. Most practitioners tend to treat patients for 4 to 8 weeks and determine

exact course based on clinical and radiographic response/improvement on antibiotics.

Longer treatment courses are recommended in patients with abscesses in the posterior

fossa, with multifocal lesions, and in states of immune dysfunction. Steroids are not

recommended as part of treatment course unless there is significant mass effect from

abscess-associated edema leading to clinical deterioration.

Overall, improved recognition of cerebral abscess over the last few decades and with

advances in imaging modalities, has led to improved mortality and morbidity from

cerebral abscess. Patients who present with coma or stupor, who experience rapid

clinical deterioration, and who have spread of infection into the ventricles, tend to have

a much poorer prognosis. Long-term neurologic complications in survivors are common

including focal epilepsy and neurologic deficits. As treatment often involves surgery,outcomes are also related to the immediate risks and complications of surgery and post-

operative care.

IV. HIV NEUROLOGY

In 2012, there were at least 35 million people across the world living human

immunodeficiency virus (HIV) infection. As such, it is important to appreciate and know

about the various neurologic complications and infections associated with HIV infection

and immunocompromised states in general. Other examples of immunocompromised

states include patients with systemic neoplasms on chemotherapy or patients onimmunomodulatory therapy for treatment of systemic auto-immune conditions. These

patients are risk for opportunistic infections, those which normally would not be

pathogenic in patients with normal immune system function. In addition, in patients with

HIV infection, neurologic complications can occur in relation to direct infection from the

HIV virus (as in cases of HIV encephalitis and vacuolar myelopathy) or from side effects

from anti-retroviral therapy (such as myositis). All parts of the nervous system,

including the peripheral nerves and muscles, can be affected. Knowing the patients

absolute CD4 count as a measure of degree of immune dysfunction is helpful in

understanding the risk for specific opportunistic infections, as certain infections only

develop at very low CD4 counts. It is also important to remember that patients with very

low CD4 counts can have multiple CNS infections at the same time. In this module, we

will briefly review a few selected infectious disorders which are seen as neurologic

complications of HIV infection.


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Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of

the central nervous system caused by reactivation of the JC polyomavirus. The JC

virus does not cause clinically significant disease in patients with normal immune

systems. In addition to patients with HIV, PML has been reported as a significant

infectious complication of chronic immunomodulatory therapy for disorders such as

multiple sclerosis and systemic neoplasms. In HIV infection, it is usually seen in patients

with CD4 counts less than 200. Patients present with progressive multi-focal neurologic

symptoms with multiple focal deficits on examination depending on the location of

demyelination within the brain. Imaging shows plaque-like abnormalities within the

white matter of the brain, which is often asymmetric in appearance, and does not exert

mass effect or enhance with contrast. CSF studies are often normal and the diagnosis

is made by identification of the JC virus from CSF samples or brain biopsy. There is no

specific treatment for PML and the goal of management is to start or adjust patients

anti-retroviral therapy with goal of raising CD4 count. Management also involves

symptomatic treatment of seizures which occur in up to 20% of patients and physicaltherapy for management of neurologic deficits. Survival is often less than 1 year.

Diagnostically, PML should be distinguished from HIV encephalitis, which is thought to

be caused by direct infection of HIV virus within the brain parenchyma. HIV encephalitis

is usually slowly progressive, presenting as a neurocognitive disorder without clear focal

motor or sensory deficits, and associated with symmetric periventricular white matter

changes on imaging.

When patients with HIV present with new neurologic symptoms and are found to have

enhancing lesions with associated edema on brain imaging, the differential diagnosis

should include cerebral bacterial or fungal abscess, toxoplasmosis infection, andprimary CNS lymphoma. Toxoplasmosis infection occurs in patients with CD4 < 100,

often in patients who are not taking prophylactic medications. Imaging shows multiple

ring-enhancing lesions, often involving the basal ganglia, and diagnosis can be made by

testing for antibodies to toxoplasmosis in the serum. If toxoplasmosis is suspected,

empiric treatment should be started with Pyrimethamine, Sulfadiazine, and Leucovorin

or similar regimen, and continued until there is clear clinical and radiographic

improvement. Similar to toxoplasmosis, primary CNS lymphoma presents with

progressive neurologic deterioration and with imaging showing enhancing lesions with

associated edema. Primary lymphoma is most common in patients with CD4 counts

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