Central nervous system infections: Pathology review

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Case study0:00–1:15

At the emergency department. 17 year old Mike is brought in by his parents.
He has a fever headache and photophobia on clinical examination. Mike has neck stiffness and Kernig and beiny signs are positive.
Lumbar puncture reveals a predominantly neutrophilic pleocytosis, elevated protein and low glucose. Next to Mike is 27 year old Helen who came in with a fever headache and confusion for the past 72 hours.
Kernig and beiny signs are negative. Head ct reveals patchy temporal lobe enhancements.
Finally, there's 60 year old Lucia who was brought in by her family because of a seizure. She also complains of headache and has a mild fever.
There's no neck stiffness and Kernig and beiny signs are negative. Two weeks ago.
Lucia had an episode of otitis media for which she was treated with anti pyretic and analgesics. She has no history of epilepsy.
Head ct reveals a single ring enhanced lesion in the right temporal lobe. Ok.
So all three people suffer from a central nervous system. Infection.

Pathology1:15–1:42

CNS, infections include meningitis, which is when pathogens infect the meningeal layers, encephalitis. When the pathogens infect the brain, parenchyma, meningoencephalitis where the infection starts in the meninges and then spreads into the brain parenchyma and abscess, which is when pathogens wall themselves off in the brain.

Meningitis1:42–4:29

Ok. So let's take a closer look at the various forms of CNS infections.
Starting with meningitis. Meningitis can be caused by any pathogen that infects the meninges when it's caused by viruses.
Mycobacteria fungi or parasites. It's called aseptic meningitis.
Because routine bacterial cultures of the cerebrospinal fluid are negative. The most common cause of aseptic meningitis is a group of viruses called enteroviruses like echovirus and Coxsackievirus.
Despite viral meningitis being much more common. Acute bacterial meningitis is more life threatening the bacteria that is most likely to be responsible will depend on the individual's age.
For example, in infants, less than three months, the most common causes in descending order are group B, streptococci Escherichia coli and listeria monocytogenes.
In adolescents 13 to 17 years old, the most common causes are Neisseria meningitis followed by streptococcus pneumoniae and haemophilus influenza.
In non adolescent Children, three months to 12 years and in adults, streptococcus pneumoniae is the most common cause followed by Neisseria men ritis and haemophilus influenza.
It's also important to consider listeria monocytogenes in adults over the age of 50 or those who are immunocompromised. Also, staphylococcus aureus is more common in individuals with a history of neurosurgical procedures or trauma to the head.
Other rare but extremely important bacterial causes include mycobacterium, tuberculosis, lyme meningitis, rocky mountain spotted fever and neurosyphilis.
These are separated from the other causes because they're usually associated with a specific risk factor. For example, tuberculosis meningitis.
Biggest factor is traveling to an endemic area or working with a high risk population. Lyme meningitis is caused by the spirochaete Borrelia Berra.
And individuals can have a history of travel to an endemic region like the northeast of the United States. Finally, Rocky Mountain spotted fever is caused by rickettsia, rickettsii and is carried by Dermacentor dog tick.
It is endemic to Central and South America as well as the Southeast United States. Neurosyphilis is rare but it can arise in individuals with a history of untreated syphilis, especially in immunocompromised individuals.
All right. Now, let's move on to viruses which can cause aseptic meningitis, meningoencephalitis or pure encephalitis.

Encephalitis4:29–7:55

Pure encephalitis without meningitis is usually caused by viruses. Most commonly entero viruses.
Herpes simplex virus or HSV is another very high yield cause of viral encephalitis. It can result from a primary infection but more commonly happens during reactivation.
This is when an HSV infection is being suppressed by the immune system and only the latent virus that settled in the sensory ganglia survives in the body.
When the immune system is compromised. Like when the individual is taking corticosteroids, the latent HSV can escape into the bloodstream and reach the brain where it will typically affect the temporal lobes.
Ok. Now, other viruses that can cause C NS infections include arboviruses like West Nile virus which use a mosquito vector.
Although mumps is quite rare due to vaccination in unvaccinated individuals, it can cause viral meningitis as well as encephalitis.
Measles can also cause encephalitis during the acute phase of the illness. However, even after the acute infection has resolved, a form of encephalitis called subacute sclerosing panencephalitis or sspe can appear up to 10 years later and is typically fatal varicella zoster virus or VZ V can also cause a lifethreatening form of encephalitis, particularly in immunocompromised individuals.
Ok. Now, when it comes to fungi, remember that they typically cause CNS infections only in immune compromised people.
So first, we have cryptococcus neoformans, which is found in soil and bird droppings. It is transmitted via the respiratory root where it could colonize the lungs.
However, in HIV positive individuals with a CD four positive T cell counts below 100 cryptococcus Neoformans can spread to the brain causing meningitis or encephalitis.
Another very similar fungi is Coccidioides immitis, which is also a soil dwelling fungi transmitted via the respiratory route.
In HIV positive individuals with a CD four positive T cell count below 200. It could cause a disseminated infection resulting in meningitis as for parasites, a particularly fatal form of meningoencephalitis is called Naegleria fowleri, which is an amoeba.
This organism is called the brain eating amoeba and it's usually acquired from fresh water. It makes its way to the brain through the nasal passages like when someone dives into water and it rushes up through the cribriform plate.
Now, another parasite that can cause CNS infection is a protozoan trypanosoma bros, which is transmitted via the sets fly.
Also a dangerous complication of malaria is cerebral malaria, a type of meningoencephalitis. Finally, it's important to remember that the same pathogens that can cause meningitis can also cause meningoencephalitis.
All right. Now, in some situations, bacteria fungi and parasites can wall off from the rest of the brain parenchyma forming an abscess.

Brain abscesses7:55–10:23

Brain abscesses can also develop from other infections in nearby structures like otitis media and mastoiditis that usually cause abscesses on the temporal lobe and the cerebellum.
There are also sinusitis and dental infections that usually cause abscesses on the frontal lobe. Bacterial brain abscesses are usually polymicrobial.
Gram positive. Bacteria include streptococcus viridans and staphylococcus aureus.
While gram negative bacteria include klebsiella e coli and anaerobes like bacteroides. Species pathogens can also come from a hematogenous source like dissemination from a lung abscess or endocarditis.
Now, bacteremia typically leads to multiple abscesses while single lesions are usually caused by infections that spread from a nearby organ.
Other causes include nocardiosis caused by nocardia which is found in soil and usually develops in immunocompromised individuals.
Individuals with no cardios present with tuberculosis like symptoms including fever, weight loss, night sweats and pulmonary infiltrates the presence of skin lesions and brain abscesses distinguishes it from tuberculosis.
Now, when it comes to fungi, mucor and rhizopus species are important causes of brain abscesses. They cause a serious infection of the sinuses in individuals with diabetes or neutropenia called mucormycosis.
From the sinuses, fungi can spread to the surrounding blood vessels and bones and enter the brain causing a brain abscess of the frontal lobe.
As for parasites, the tapeworm taenia solium can cause neurocysticercosis, especially in those who have been exposed to contaminated pork.
Most individuals with neurocysticercosis are either diagnosed incidentally or they present with epileptic seizures. Uniquely in HIV infected individuals with a CD four positive T cell count of less than 100 toxoplasma gondii can cause multiple brain abscesses.

Symptoms10:23–15:11

All right. Now, all forms of meningitis present with a triad of fever, neck rigidity or resistance to flexion of the head and headache.
Other common symptoms include photophobia, nausea and vomiting. Helpful signs include the Kernig and binky signs to elicit the Kernig sign, place the individual in a supine position, flex the hip to 90 degrees and attempt to extend the knee.
If the individual has pain with full extension of the knee, that's a positive Kernig sign to elicit the Brezinsky sign, you have to passively flex the neck and if there's involuntary flexion of the hips due to pain, then that's a positive binky sign.
Now, these signs aren't particularly sensitive. So, negative Kernig and bins signs don't exclude meningitis.
Sometimes fundoscopy of the eye can reveal pal edema which indicates an increased intracranial pressure. There can also be focal neurological deficits like cranial nerve motor or sensory deficits.
Ok. Now the various forms of meningitis have a difference in the time course, acute bacterial meningitis and HSV meningoencephalitis usually present within hours to a few days.
Viral meningitis, cryptococcal meningitis, lyme disease and Rocky Mountain spotted fever usually present over the course of days to weeks while tuberculosis, Coccidioides and syphilis tend to present over the course of months.
Additionally, some clinical clues on physical examination can point towards a specific cause. For example, pete are characteristic of Neisseria meningitis.
A red maculopapular rash on the wrists and ankles that spreads towards the body may indicate Rocky Mountain spotted fever, a bull's eye appearing rash called erythema chronica migrans, bilateral facial nerve palsy or cardiac arrhythmias, like ATRIO ventricular node block point towards lyme meningitis, flaccid paralysis of the extremities is characteristic of West Nile virus which occurs because the virus can also cause concomitant myelitis which is inflammation of the spinal cord keratitis may suggest mumps and a group of vesicles in a dermatomal distribution suggests VZ V features of disseminated tuberculosis, like pulmonary infiltrates lymphadenopathy and a positive tuberculin skin test should prompt consideration of tuberculosis meningitis, especially in infants.
Now, features of meningitis along with erythema nodosum or multiform and arthralgias suggest Coccidioides immitis as a cause as for parasites.
Trypanosoma brucei causes a disease called African trypanosomiasis which presents with lymphadenopathy fever and neurological symptoms such as confusion.
It can also cause sleep disturbances and that's why it's also known as African sleeping sickness, what distinguishes pure encephalitis from meningitis is an abnormal brain function like a change in behavior and personality and the absence of meningeal irritation.
Symptoms like neck rigidity and Kernig and binky signs, seizures can occur in both meningitis and encephalitis and both can eventually lead to an altered mental status and even coma or death.
Ok. Now, HSV encephalitis also has specific symptoms since HSV involves primarily the temporal lobe.
So in the exams to diagnose HSV encephalitis, look for symptoms like aphasia, olfactory hallucinations and personality changes.
All right. So individuals with brain abscesses can have a headache and focal neurological deficits with or without fever.
Additionally, there may be signs of increased intracranial pressure such as vomiting and papilledema as well as the cushing triad, which includes bradycardia, irregular respiratory pattern and hypertension mucormycosis can present with pain in the face and scars with black necrotic tissue.
Ok. Now, let's switch gears and talk about diagnosis and treatment when meningitis or encephalitis is suspected.

Diagnosis & Treatment15:11–24:43

The key diagnostic procedure is a lumbar puncture to obtain a CSF sample. However, before that, it's important to know the contraindications.
First, there's increased intracranial pressure because it could cause a fatal cerebral herniation. Look for signs like pall edema.
But the best way to rule it out is with a CT to look for the CNS masses like abscesses or tumors. Also, this procedure is contraindicated in people with thrombocytopenia.
Since there's a risk of uncontrolled bleeding if there are no contraindications, lumbar puncture is done right away to obtain a cerebrospinal fluid sample for analysis and culture.
If there are contraindications, get a blood sample for culture instead. Once this is done, the next step is to start IV dexamethasone and empiric antibiotics, we need to get the CSF sample first.
Since antibiotics will decrease the yield on cultures. The logic behind giving IV dexamethasone before IV antibiotics is that it reduces the inflammatory response that usually occurs when antibiotics destroy the bacteria, steroids, decrease mortality and the risk of complications like hearing loss, cranial nerve palsies and seizures if the individual has symptoms of encephalitis such as confusion change in personality or drowsiness in an adult or fussiness, lethargy and a bulging fontanel in an infant, then empiric intravenous acyclovir should be started to treat HSV encephalitis, especially if there's patchy temporal lobe enhancement on CT scan.
It's important to do so in order to prevent permanent neurological defects. So, treatment is started before the diagnosis is confirmed with PCR.
After empiric treatment is started, we can now look at our CSF sample. A high yield concept is that the bacteria, viruses and fungi cause different changes in the cerebrospinal fluid.
And this can help you narrow down the pathogen. So the first thing to know is that with meningitis, the opening pressure will be increased the most in bacterial meningitis.
There's moderate or slight increase in fungal and tuberculosis infections and normal or slightly increased pressure in most viral meningitis if the cause of the infection is bacterial.
A good indicator is dramatically increased white blood cell count. With neutrophil predominance, mild leukocytosis with a lymphocyte predominance is likely due to viral tuberculosis or fungal infections.
Next, let's look at protein level. This tends to be highly elevated in bacterial and tuberculosis infections as they tend to disrupt the blood brain barrier.
More causing serum protein to leak into the CSF fungal and viral infections cause a mild elevation or even normal protein level.
For glucose level. Bacteria, fungi and tuberculosis cause a large decrease.
This is because both the pathogens and the immune cells they attract, use the glucose as an energy source. Additionally, bacteria interfere with the normal glucose transport to the brain reducing its levels in the CSF even further.
On the other hand, since viruses don't metabolize glucose, the glucose levels remain normal or slightly decreased if it's a viral infection.
Next, we have the gram stain, gram positive bacteria such as streptococcus pneumoniae and listeria monocytogenes stain purple.
While gram negative bacteria such as Neisseria meningitis turn red or pink. All right.
Now, in bacterial meningitis, the gram stain result can be done immediately whereas the culture can take up to five days.
Although most pathogens grow within 48 hours. So if the culture is negative, then this effectively rules out acute bacterial meningitis.
When it comes to viruses. Tuberculosis and fungi, specific tests will be needed since they won't show up on gram stain in tuberculosis meningitis.
It's possible to detect the pathogens with an acid fast stain since culture can take weeks. ATB PCR is preferred because it's faster and more sensitive.
If cryptococcal meningitis is suspected. An India ink stain is obtained on the cerebrospinal fluid which shows broad budding yeast and a thick fungal capsule that does not take up the stain.
Also a brain ct or MRI can reveal lesions that look like soap bubbles. However, the latex agglutination test that detects the cryptococcal capsular antigen is more sensitive and specific in coccidioidal meningitis.
Microscopic examination of the cerebrospinal fluid may reveal sproles that include Coccidioides endospores. However, serum serology is the mainstay of diagnosis as for the parasites in Naegleria fowleri meningoencephalitis CSF is obtained to look for amoebas.
While in trypanosoma bros infection trypomastigote can be found on the blood smear to look for viral meningitis. PCR for HSV, enteroviruses and in some cases, VZV can be done.
Also the presence of red blood cells in the cerebrospinal fluid suggests herpes simplex encephalitis due to hemorrhagic destruction of the temporal lobes.
Additionally, if West Nile virus is suspected, then a serology of the cerebrospinal fluid is obtained for the west Nile virus IgM antibody in the right clinical context.
PCR for other viruses like measles, mumps or influenza may also be obtained. Finally, since pure encephalitis is mainly caused by viruses.
The same viral investigations sent for meningitis can also be sent here because of the high chance of increased intracranial pressure.
A lumbar puncture is always contraindicated in an individual with a brain abscess. The first step is to get a head CT or MRI which will show a brain abscess as a ring enhancing lesion with central necrosis.
The MRI is more sensitive than CT in detecting brain abscesses but A CT is usually easier to obtain emergently to diagnose and treat brain abscesses.
A combination of surgical drainage and antibiotics are needed. The preferred method of drainage is stereotactic aspiration, which is a CT or MRI guided needle aspiration of the abscess.
This is both diagnostic and therapeutic because a sample can be sent off for gram stain and culture and aspiration shrinks.
The abscess. Now, toxoplasmosis can be diagnosed based upon serology and biopsy showing tachyzoite in mucormycosis biopsy demonstrates broad irregular nonseptate hyphae branching at 90 degrees which are pathognomic for mucormycosis.
Ok. So once the blood cultures are obtained, empiric antibiotics can be started to treat the most likely pathogens.
One regimen includes vancomycin to cover methicillin resistant staphylococcus, aureus and streptococci ceftazidime to cover the gram negatives, including pseudomonas and metroNIDAZOLE to cover the anaerobes because the infection is walled off.
Antibiotics need to be given for 4 to 8 weeks. Additionally, steroids may be added if there are signs of increased intracranial pressure.
There are rarer causes that are not treated by empiric antibiotic therapy such as nocardiosis, which is classically treated with trimethoprimsulfamethoxazole and neurocysticercosis, which is most often treated with albendazole.
Now, the approach to HIV infected individuals with a CD four positive T cell count, less than 100 is quite unique, primary central nervous system, lymphoma and toxoplasmosis can cause ring enhancing lesions in this population.
If there is a single ring enhancing lesion, then the likelihood of lymphoma is high and a brain biopsy is done. However, if there are multiple ring enhancing lesions, then it's more likely to be toxoplasmosis.
An empiric treatment with pyrimethamine and sulfADIAZINE is started after two weeks of treatment. If there's clinical improvement, then this confirms that it was indeed toxoplasmosis and treatment is continued.
However, if there is no improvement, then the diagnosis is likely lymphoma and the lesion is biopsied to confirm the suspicion.
Finally, mucormycosis is treated with amphotericin B or is of econazole. All right.

Review24:43–26:05

As a quick recap cns infections include meningitis, encephalitis and brain abscesses. Meningitis can be caused by bacteria like streptococcus, pneumoniae, Neisseria, meningitis and mycobacteria such as mycobacterium tuberculosis, viruses like enteroviruses fungi like cryptococcus and parasites like malaria.
The same pathogens that cause meningitis can also cause meningoencephalitis. Pure encephalitis.
Without meningitis is usually caused by viruses like HSV that primarily affect the temporal lobe. Brain abscesses can develop from nearby infections like otitis media and dental infections, but can also disseminate hematogenously from infections like endocarditis.
Diagnosis of a cns infection can be made based on clinical presentation, lumbar puncture and a head ct or M ria CSF sample should be obtained via spinal tap before starting empiric antibiotic treatment.
Except when an abscess or other causes of increased intracranial pressure is present if the infection doesn't resolve with empiric therapy, pathogen, specific treatment needs to be used after identifying the cause.
Now, back to the patients due to his clinical presentation, Mike most probably has meningitis. Key clues include the meningeal signs like neck stiffness and Kernig and bins sign.

Summary26:05–27:30

The lumbar puncture findings show leukocytosis with neutrophil predominance, high protein and low glucose. This is the typical finding for bacterial meningitis, gram stain and culture of the cerebrospinal fluid will be done to find the specific pathogen and empiric antibiotic therapy is started.
Ok. Helen and Lucia both had fever, headache and neurological symptoms without meningeal signs.
We should suspect viral encephalitis. In Helen's case, since she has a headache, fever and confusion.
Meningitis is unlikely due to the lack of meningeal signs. The patchy temporal lobe enhancement on head CT suggests HSV as the causative pathogen.
A PCR of the CSF will confirm the diagnosis but acyclovir should be started before the diagnosis is confirmed for Lucia.
The head ct showed a single ring enhanced lesion, most likely a brain abscess. Another clue is her recent history of otitis media which is the likely source of the abscess.
Remember that in her case, a spinal tap is contraindicated due to increased intracranial pressure