3-22 Infections in the CNS

Question 1

How are infectious diseases of the CNS classed? (2 categories)

Answer 1

Class of organism - prion, viral, bacterial, fungal, protozoal, helminths, post-infectious/autoimmune disease

Site of infection - epidural or subdural abscess, subdural empyema, brain abscess, meningitis, encephalitis, meningo-encephalitis

Question 2

For localized infections in the CNS, name the tissue layers between:

epidural abscess

subdural abscess

subdural empyema

brain abscess

meningitis

Answer 2

epidural abscess - between bone and dura

subdural abscess, empyema - between dura & arachnoid

brain abscess - parenchyma

meningitis - between pial and arachnoid membranes, in subarachnoid space

Question 3

Infections in the CNS from pyogenic bacteria often spread from what original sites of infection?

Answer 3

Extradural or subdural infections from sinusitis, otitis, open skull fractures, endocarditis or lung abscesses are usually caused by pyogenic bacteria.

Question 4

Infection in subdural space is called what?

Answer 4

meningitis

(The same word is used for neoplastic spread in the subarachnoid space as in “lymphomatous meningitis” or “carcinomatous meningitis”).

Question 5

A localized infection in the brain can often appear as….?

Answer 5

localized infection may occur as an intracerebral abscess

Question 6

What do the following mean:

encephalitis/cerebritis

myelitis

encephalomyelitis

Answer 6

All are diffuse infections in the CNS

encephalitis/cerebritis - diffuse brain infection

myelitis - diffuse spinal cord infection

encephalomyelitis - diffuse infection involving brain and spinal cord

Question 7

Encephalitis literally means an infection/inflammation of the brain, but what is it’s conventional meaning?

Answer 7

By convention, the term encephalitis refers to viral infections of the brain

Question 8

What is meningoencephalitis?

Answer 8

Many infections involve both the subarachnoid space and the brain parenchyma. They are called meningoencephalitis

Question 9

Why is subdural empyema often due to infections elsewhere? Why is it hard to treat?

Answer 9

• Infection may spread to the subdural space from air sinuses or from the middle ear.
• The subdural space is traversed by bridging arteries and veins but has no vascular network of its own.

Therefore, antibiotics have no access to this space.

Question 10

How do you treat subdural empyema?

Answer 10

Treatment of the subdural abscess consists of evacuation plus intravenous antibiotics

Question 11

An abscess is what? Why are they problematic in the CNS?

Answer 11

• Epidural and subdural abscesses are collections of pus.
• If they are large enough, they compress the brain and spinal cord, resulting in loss of function and increased intracranial pressure.

Question 12

What are risk factors for meningitis in children & adults?

Answer 12

–Local infection

–Recent brain surgery

–Recent head injury

–Spinal abnormalities

–CSF shunt placement

–Urinary tract infections/UT abnormalities

–Weakened immune system

Question 13

Bacterial meningitis includes infection of what structures in the CNS?

Answer 13

infection of the arachnoid membrane,

subarachnoid space, and

cerebrospinal fluid by bacteria

Question 14

What is the subarachnoid space bounded by? What are its boundaries?

Answer 14

The subarachnoid space is bounded externally by the arachnoid membrane and internally by the pia, and dips into the brain along blood vessels in the perivascular (Virchow-Robin) spaces.

It extends from the optic chiasm to the cauda equina and surrounds the brain and spinal cord completely.

Question 15

How do bacteria reach the meninges to cause infection?

Answer 15

The infection may spread to the meninges from an adjacent infected area such as sinusitis, otitis media, and mastoiditis or from the environment through a penetrating injury or congenital defect, such as aa menigomyelocele. Most commonly, however, meningitis results from hematogenous dissemination of bacteria.

The organisms that cause bacterial meningitis colonize the nasopharynx. From there, they get into the blood stream and enter the subarachnoid space through complex interactions with endothelial cells. The porous structure of choroid plexus capillaries facilitates their spillage into the CSF.

Question 16

What organisms cause most cases of bacterial meningitis in children and adults?

Answer 16

The most common organisms of bacterial meningitis in children and adults are

• Streptococcus pneumoniae* and
• Neisseria meningitidis*

Question 17

How has bacterial meningitis and the organisms responsible for it changed in pedes over the years?

Answer 17

• Streptococcus pneumoniae* is declining after the introduction of conjugated vaccines.
• Hemophilus influenzae*, once very common in children, is now rare thanks to vaccination.

Question 18

What are the most common organisms for bact. meningitis in newborns? Babies?

Answer 18

In newborns, the most common organisms are beta hemolytic Streptococcus group B (Streptococcus agalactiae) and Escherichia coli.

In babies, group B streptococcal infection is frequently acquired during passage through the birth canal but meningitis may also develop a few days or weeks after birth.

Question 19

What are some nosocomial sources of bact. meningitis?

Answer 19

craniotomy,

internal and external ventricular shunts,

penetrating cranial fractures,

closed head injuries with CSF-leaking basilar skull fractures,

external lumbar catheters, and

rarely lumbar puncture

Question 20

What are the CSF findings for normal, purulent (bact or fungal), or aseptic (viral) meningitis? List pressure, protein, glucose, and WBCs

Answer 20

Normal - < 200 mm H2O, 14-45 mg% protein, >50% serum glucose, 0-10 WBCs

Purulent - high >>200, high protein 45-200, very low -0 glucose, polys + 1000s WBCs

Aseptic - normal/slight increase pressure and protein, normal glucose, mono 10-100s

Question 21

What does a lumbar puncture provide in terms of samples and information?

Answer 21

Lumbar puncture is an important procedure that provides direct access to the subarachnoid space of the lumbar cistern.

It can be used to obtain samples of CSF, measure CSF pressure, to remove CSF in cases of suspected normal pressure hydrocephalus, and occasionally to introduce drugs (such as antibiotics or cancer chemotherapy) or radiological contrast material into the CSF

Question 22

What should you evaluate someone for before doing a lumbar puncture?

Answer 22

Before a lumbar puncture is performed, the patient should be evaluated for evidence of elevated intracranial pressure, and the safest practice is to perform a CT scan first to avoid risk of herniation.

In addition, caution should be used in cases of impaired coagulation because of the risk of iatrogenic spinal epidural hematoma, which can compress the cauda equina.

Question 23

What is the procedure of doing a lumbar puncture?

Answer 23

The lumbar puncture procedure is performed with sterile technique under local anesthesia.

A hollow spinal needle is introduced through the skin with a stylet occluding the lumen to prevent the introduction of skin cells into CSF during needle insertion. The needle passes through subcutaneous tissues, ligaments of the spinal column, dura, and arachnoid, to finally encounter CSF in the subarachnoid space of the lumbar cistern.

Note that the lumbar cistern is normally in direct communication with CSF in the ventricles and CSF flowing over the surface of the brain.

The procedure may be done in the lying or seated position.

A manometer tube is used to measure CSF pressure. Pressure measurements are more reliable in the lying position because in the seated position the entire column of CSF in the spinal canal adds to the pressure measured in the lumbar cistern

Question 24

What is normal CSF pressure in adults?

Answer 24

less than 20 cm H2O

Question 25

Why are lumbar punctures commonly done at LV-4LV5 interspace in adults?

Answer 25

Note that the bottom portion of the spinal cord, or conus medullaris, ends at about the L1 or L2 level of the vertebral bones, and the nerve roots continue downward into the lumbar cistern, forming the cauda equina, meaning “horse’s tail”.

To avoid hitting the spinal cord, the spinal needle is generally inserted at the space between the L4 or L5 vertebral bones.

As the tip of the needle enters the subarachnoid space, the nerve roots are usually harmlessly displaced.

The posterior iliac crest serves as a landmark to determine the approximate level of the L4–L5 interspace.

Question 26

Study this:

Answer 26

What color is CSF with herpes? It’s yellow. Flip the card if you don’t believe me.

Question 27

What is the clinical picture of acute bacterial meningitis?

Answer 27

acute onset (hours), fever, lethargy, headache, altered mental status, signs of meningeal irritation, such as neck stiffness

Question 28

What is the most common infection in the CNS?

Answer 28

acute purulent (bacterial) leptomeningitis is the most common

Question 29

What is the mortality of meningitis?

Answer 29

Purulent leptomeningitis (often simply called meningitis) still has an overall mortality of 10-15%, often as a result of diffuse cerebral edema and herniation.

In survivors, long-term sequelae are not uncommon

Question 30

What are the initial clinical symptoms of meningitis? What are the signs that can be seen?

Answer 30

The initial symptoms of meningitis are fever, severe headache, and stiff neck.

The inflamed spinal structures are sensitive to stretch, and pain can be elicited by maneuvers that stretch the spine, such as bending the leg with an outstretched knee (Kernig sign) or bending the neck (Brudzinski sign).

Question 31

What symptoms are present with progression of meningitis? Why?

Answer 31

As the disease progresses, confusion, coma, and seizures develop.

These complications are due to HIE, increased intracranial pressure, and a toxic metabolic encephalopathy.

HIE is due to shock.

The toxic metabolic encephalopathy is probably caused by unknown diffusible substances (perhaps cytokines) that have a neurotoxic action.

Question 32

What are the SSXs of meningitis in infants?

Answer 32

In infants, meningitis may present with nonspecific signs such as a depressed state, apneic spells, changes in heart rate, and atypical seizures.

Question 33

What test is most helpful in diagnosing bacterial meningitis? What abnormal findings are expected?

Answer 33

The cornerstone in the diagnosis of bacterial meningitis is CSF examination. The CSF in meningitis shows hundreds, even thousands of neutrophils and is teeming with organisms. CSF protein is elevated and glucose is low (because it is consumed by inflammatory cells). The CSF:blood glucose ratio is lower than 50%.

Question 34

Why is CSF an ideal medium for spread of bacteria?

Answer 34

The CSF is an ideal medium for the spread of bacteria because it provides enough nutrients for their multiplication and has few phagocytic cells, and low levels of antibodies and complement.

Initially, bacteria multiply uninhibited and can be identified in smears, cultures, or by ELISA detection of their antigens before there is any inflammation

Question 35

Why does bacterial meningitis cause increased intracranial pressure? What other SSXs does it cause?

Answer 35

Bacterial toxins cause neuronal apoptosis and

cell wall lipopolysaccharide, released from bacteria, damages the blood brain barrier (BBB).

Increased vascular permeability from BBB damage, in turn, causes cerebral edema, increased intracranial pressure, decreased cerebral perfusion, hypoxia, and neuronal necrosis.

Question 36

Brain damage in bacterial meningitis is caused in part by the direct action of bacteria and in part by the antibacterial inflammatory response. Outline the inflammatory response, and resulting sequelae.

Answer 36

Cells of the innate immune system of the brain, located in the BBB, choroid plexus, and ependyma, detect bacteria and secrete cytokines, chemokines, and complement, which attract circulating neutrophils into the CSF.

Neutrophils have powerful lysosomal enzymes and free radicals, which they use to kill bacteria, but have a short life span. As they lyse, these compounds are spilled and can destroy everything in their way.

If neutrophils accumulate, they can damage brain tissue, nerves, and blood vessels. Vasculitis and clotting cause cerebral infarcts.

Question 37

How are CNs damaged in bacterial meningitis?

Answer 37

Neutrophils in the subarachnoid space infiltrate and damage cranial nerves resulting in cranial nerve deficits, and invade leptomeningeal vessels causing phlebitis and arteritis with thrombosis and ischemic infarction. Sinovenous thrombosis may also occur.

Question 38

How does hydrocephalus happen in meningitis?

Answer 38

The thick fibrinopurulent exudate in the subarachnoid space organizes into fibrous tissue that blocks the exits of the fourth ventricle and impairs CSF circulation around the cerebral convexities. This causes hydrocephalus.

Question 39

Why is meningitis so devastating in neonates?

Answer 39

. The effects of HIE and cerebral infarction are especially devastating in newborn babies in whom the brain can literally melt away.

Question 40

Why is brain abscess as a complication of meningitis rare?

Answer 40

The glia limitans, a thick tight mesh of astrocytic processes, joined by dense junctions and covered by basement membrane, resists penetration by bacteria and neutrophils

Undamaged, it provides an effective barrier that prevents the infection from spreading into brain tissue.

Thus, brain abscess as a complication of meningitis is rare.

Question 41

How is CSF brought deep into brain parenchyma? How is the brain still protected normally?

Answer 41

The CSF flows/bathes the brain surface and fills the “Virchow-Robbin space”. This space, which surrounds the vessels, ends at the level of the capillaries.

Thus, whatever is in the CSF is brought deep into the brain parenchyma (such as inflammatory cells).

Under normal circumstances, the BB barrier is intact throughout this system

Question 42

Why are the endothelial cells lining the brain capillaries so unusual?

Answer 42

the endothelial cells that line brain capillaries have no fenestrations or pinocytotic (transportation) vesicles and have tight and adherens junctions that almost fuse adjacent endothelial cells.

Moreover, these endothelial cells have different receptors and ion channels on their surface facing the lumen than on the surfaces facing the brain, an arrangement that facilitates transcellular transport.

This anatomy is the basis of the blood-brain barrier (BBB).

Question 43

Without reading the caption, what’s this? What pathology is pictured?

Answer 43

meningitis

Virchow-Robbin space filled with neutrophils.

Because the BB barrier is altered secondary to the inflammation, the brain parenchyma is altered and edematous (note pale zone) and scattered neutrophils are entering the brain tissue.

Question 44

What disorders are associated with BBB dysfxn?

Answer 44

A wide variety of disorders including stroke, trauma, CNS infections, demyelinative diseases, metabolic disorders, degenerative diseases, and malignant brain tumors are associated with BBB dysfunction.

Question 45

What is the common end result of BBB dysfxn? How does BBB dysfxn sustain yet more damage/pathological processes?

Answer 45

The common end result of BBB dysfunction in many of these disorders is increased vascular permeability leading to vasogenic edema.

Cytokines generated during infectious and inflammatory processes enhance transmigration of circulating leukocytes and may even loosen tight junctions, thus facilitating the migration of inflammatory cells into the brain.

HIE disrupts the BBB. More subtle BBB dysfunction may result in impaired glucose transport and accumulation of Aβ.

Question 46

What is a common cause of meningitis at birth - 2 mo.?

Answer 46

E. coli, Group B Streptococcus, Listeria

Question 47

What are the common causes of meningitis at 2mo- 5 yrs.?

Answer 47

Streptococcus pneumoniae, meningococcus.

H. flu was a very common cause prior to development of a vaccine.

Question 48

What are common causes of bacterial meningitis in older children - adults?

Answer 48

Streptococcus pneumoniae, Neisseria meningitidis (Meningococcus).

Note: only form of bacterial meningitis that may occur in epidemics

Question 49

What are some common causes of bacterial meningitis in the elderly?

Answer 49

Streptococcus pneumoniae (Pneumococcus), E. coli, Group B Streptococcus, Listeria

Question 50

What is a brain abscess? What is often the result of?

Answer 50

• A Brain abscess is a collection of neutrophils and pus usually from bacterial or fungal infection.
• A brain abscess rarely results from meningitis.
• Usually it results from hematogenous dissemination of an infection.
• Primary site of infection often not found.
• Primary site often is lung.

Question 51

What are the SSXs of cerebral abscess??

Answer 51

•Headaches, fever, seizures, focal signs

Question 52

What is the mortality of cerebral abscess?

Answer 52

• Mortality 10 - 30% (even with appropriate therapy)
• ~50% of survivors with complications

Question 53

The infections in a brain abscess are introduced into the cranium in what ways?

Answer 53

•Direct extension

–Trauma, surgery

•Hematogenous

–Endocarditis, other infections

Question 54

Why abscess is not a common complication of meningitis:

• A. Because different bacteria are involved in the two processes.
• B. Because the immune system prevent the spread of the infection to the brain.
• C. Because the Glia Limitans protects the brain from the spread of the infection.
• D. Because the Dura protects the brain from the spread of the infection.
• E. Because the blood – brain membrane protects the glia from the spread of the infaction.

Answer 54

Correct answer is C, glia limitans, see question 40 or:

• The brain is protected from bacterial invasion from the environment by the skull, the dura, the arachnoid membrane, the pia, and the glia limitans, which is a dense mesh of astrocytic processes on the surface of the brain. Consequently, most bacterial infections spread to the brain by the bloodstream. Bacteria can penetrate into the brain from the environment if there is a break in the continuity of these protective layers. Such a discontinuity may be due to congenital defects (encephalocele, meningomyelocele) or may be caused by trauma or a shunt. Bacteria can also spread to the brain from infected adjacent air sinuses, the middle ear and the mastoids. They can reach the brain either directly through the bone, especially in areas where the bone plate is thin, or through veins (diploic veins, dural venous sinuses, intracerebral veins). The various protective layers may also help contain infections within certain spaces or planes.
• In the case of meningistis the glia limitans is the only barrier to the spread of the infection.

Question 55

What’s this:

Answer 55

Cerebral abscess

Question 56

What’s this?

Answer 56

Cerebral abscess

Question 57

Try to name some common pathogens and treatment for bacterial meningitis based on age.

Answer 57

Question 58

What’s this:

Answer 58

Acute Pneumococcal meningitis

. Note the thick exudate, distributed here mainly at the vertex, coating the surface of the brain and obscuring the sulci. This material represents the accumulation of many acute inflammatory cells (neutrophils) in the subarachnoid space. These neutrophils would also appear in the cerebrospinal fluid removed by lumbar puncture. The CSF glucose is typically decreased with acute bacterial meningitis

Question 59

What’s this? Describe the pathology:

Answer 59

Microscopically, there is a thick layer of polymorphonuclear leukocytes in the subarachnoid space (arrow) in acute bacterial meningitis. The molecular layer of the cerebellum can be seen to the left in this micrograph. The presence of inflammatory cells in the subarachnoid space can lead to cerebral edema.

Question 60

What’s this:

Answer 60

venous thrombosis d/t bacterial meningitis

Question 61

What is the clinical picture of acute aseptic/viral meningitis?

Answer 61

•Clinical picture – Similar to bacterial meningitis with fever, lethargy, headache, altered mental status and signs of meningeal irritation.

Question 62

What are the most common organisms that cause acute viral meningitis? What’s the mortality like?

Answer 62

•Enteroviruses are the most common organism

•

•Low mortality

Question 63

What are the common agents that cause viral encephalitis in the real world? On boards?

Answer 63

•Common agents:

–Arboviruses

–CMV(intranuclear inclusions)

–Herpes(intranuclear inclusions)

–HIV

•Rare in the real world, but common on tests:

–Rabies

–PML (Progressive Multifocal Leukoencephalopathy) - intranuclear inclusions

–SSPE (Subacute Sclerosing Panencephalitis)

Question 64

Generally, what viruses cause meningitis versus encephalitis?

Answer 64

A wide variety of different viruses can infect the CNS. Most viruses are capable of causing either meningitis or encephalitis, although in general, a given virus is more likely to cause one syndrome than the other.

A subset of these viruses, including mumps, measles, varicella-zoster virus (VZV), rubella, and influenza have also been associated with postinfectious encephalitis.

Question 65

How do you diagnose viral encephalitis and find the causative agent?

Answer 65

For many viral diseases the histologic changes are subtle and the diagnosis is made serologically (by a rise in specific antibody titers).

Exposure history and epidemiologic information are often important in establishing a presumptive diagnosis.

A common cause of sporadic encephalitis is herpes simplex virus type 1. Other diagnostic considerations will depend on geographic location (eg, St. Louis encephalitis in North America and Japanese encephalitis in Asia) and epidemiologic clues such as exposure history (eg, bat exposure or dog bite and rabies), regional outbreaks (eg, enterovirus type 71 in Denver, Colorado), and clinical clues such as profound weakness and rash with West Nile.

Question 66

What are the SSXs of herpes encephalitis?

Answer 66

•Headache, fever, neck stiffness, drowsiness, coma or focal neurologic signs (e.g. dysphasia, hemiparesis, seizures) ​

Question 67

What is the mortality and outlook for herpes encephalitis?

Answer 67

•Without treatment, the disease progresses rapidly over the course of a few days and is usually fatal (~20%).

•Fatal without immediate Rx in days

•25-50% die regardless of Rx

•Some patients do survive, with behavioral abnormalities, memory disturbances, and other neurologic deficits of varying severity.

Question 68

What are the gross and histological findings in a brain with advanced HSV encephalitis?

Answer 68

The brain in advanced HSV encephalitis shows diffuse softening and edema, accentuated by hemorrhagic necrosis of the inferior frontal and temporal lobes.

Microscopical examination in the acute phase shows meningeal and perivascular mononuclear cells, activated microglia, microglial nodules, and intranuclear inclusions.

Question 69

What is the gross and histo pattern of HSV encephalitis without treatment? How are the end stages detected?

Answer 69

Without treatment, extensive necrosis, macrophage reaction and neovascularization develop. The end-stage is brain atrophy and gliosis.

The degree of brain destruction (especially in the frontal and temporal lobes) and the inflammatory and reactive changes are more severe than any other viral encephalitis and can be detected by imaging.

Question 70

What is seen with atypical cases of HSV encephalitis?

Answer 70

Atypical cases may have asymmetric pathology, mass-like necrotic and hemorrhagic fronto-temporal lesions, and a wider anatomical distribution, including myelitis and brainstem encephalitis.

Some cases may be mild, causing only a mild reduction of consciousness

Question 71

How does HSV infection cause encephalitis?

Answer 71

Most people become primarily infected with HSV in their teens or twenties. HSV type I is transmitted by the saliva. The initial infection causes a stomatitis. Following this, the virus remains latent in the trigeminal ganglion.

From this location , reactivated virus can spread or to the brain, infecting the meninges of the anterior and middle cranial fossae.

From the meninges, the virus extends to the adjacent brain where it affects the temporal and inferior frontal lobes first and more severely, and then spreads to the rest of the brain.

Question 72

. Adult HSV encephalitis is limited to the brain. Its symptoms are fever, confusion, coma, and seizures. What are the additional sequelae that can develop due to involvement of the frontal and temporal lobes?

Answer 72

because of the involvement of the frontal and temporal lobes, patients often display bizarre behavior, personality changes, anosmia, and gustatory hallucinations.

Survivors may have Korsakoff’s amnesia, because of bilateral damage of the hippocampus, dementia, and seizures.

Question 73

What’s this?

Answer 73

In this picture of herpes simplex virus (HSV) encephalitis note the petechial hemorrhages in the temporal lobe on the right side (black arrow).

There are also petechial hemorrhages in the rectus gyrus (red arrow).

Question 74

What’s this?

Answer 74

:These coronal sections of brain demonstrate the marked destructive nature of herpes simplex virus (HSV) encephalitis.

This patient survived some 10 years after herpes simplex encephalitis. Note the complete loss of the temporal lobes bilaterally. This patient had severe memory problems and lived in a chronic care hospital

Question 75

What’s this? How is this different from many path slides we’ve seen so far on this disease?

Answer 75

HSV encephalitis - shows gross image of neonate’s brain

Neonatal HSV encephalitis. The patient died 4 weeks after the onset of symptoms, despite treatment with Acyclovir. A necrotizing encephalitis that caused a diffuse melt down of the brain, without predilection for the frontal and temporal lobes (different than adults).

Question 76

How is HSV infection established in neonates?

Answer 76

Neonatal HSV encephalitis. About seventy percent of neonatal HSV infections are caused by HSV-2 (herpes genitalis) and thirty percent by HSV-2.

HSV-1 is most commonly aquired during vaginal delivery by contact with secretions in the infected birth canal. Most infected mothers are symptomatic. Cesarean delivery before rupture of membranes prevents these infections.

In a few cases, HSV is transmitted across the placenta. A few babies also acquire the infection after birth, in the newborn nursery or at home.

Question 77

What organs are affected by neonatal HSV infection?

Answer 77

Untreated, neonatal HSV infection disseminates and involves the brain in most cases.

The generalized infection affects the skin, eyes, liver, adrenal glands and other organs and presents clinically as neonatal sepsis.

Encephalitis (lethargy progressing to coma, seizures, mononuclear CSF pleocytosis with elevated protein) develops one or two weeks after birth, sometimes later.

Question 78

What is the course of neonatal HSV infection? Dx and Tx?

Answer 78

A few cases of neonatal HSV encephalitis are mild but most cause a devastating diffuse necrotizing pathology, without predilection for the frontal and temporal lobes.

In time, the lesions evolve into cystic encephalomalacia with microcephaly. The diagnosis is made by PCR of CSF. Treatment with Acyclovir significantly reduces mortality

Question 79

What’s this?

Answer 79

Fetal CMV encephalitis. Microcephaly, abnormal gyral pattern, hydrocephalus, and perivantricular calcificatiions.

Question 80

What’s this?

Answer 80

Head CT of neonate with congenital CMV. Periventricular calcifications, ventriculomegaly and an abnormal gyral pattern

Question 81

How does a fetus become infected with CMV?

Answer 81

A pregnant mother who carries CMV may transmit the virus to the fetus, causing a generalized fetal CMV infection. This infection may develop at any stage during pregnancy and may continue after delivery. Infants with congenital CMV infection have variable involvement of the brain and other organs.

Question 82

What does prenatal CMV infection cause? How is it detected?

Answer 82

Prenatal CMV infection often causes necrosis of brain tissue, especially of the walls of the lateral ventricles.

Necrotic areas calcify and can be detected by imaging.

Question 83

What are some of the sequelae of prenatal CMV infection?

Answer 83

Infection before mid-gestation may derange the process of neuronal migration, causing microcephaly and cortical dysplasia.

In some cases, fetal CMV infection destroys large parts of the brain, causing porencephaly, or schizencephaly. These lesions are thought to be caused by ischemia induced by the infection

Question 84

What is the genus name for rabies virus? What is its reservoir?

Answer 84

• Rhabdovirus
• Endemic in animals (foxes, raccoons, skunks, bats, dogs)

Question 85

How is rabies spread? What is its incubation?

Answer 85

• Animal bites, aerosols
• Variable incubation period (10 days to a year)

Question 86

Where does rabies replicate in the body? What are the forms, symptoms, and progression of infection?

Answer 86

• Muscular replication
• Centripetal axonal transport to CNS
• Headaches, fever and malaise, swallowing difficulty
• Furious form and “dumb” forms
• Progresses to stupor, coma and death

Question 87

What’s this?

Answer 87

Negri bodies, seen in Purkinje cell

Rabies infection

Question 88

What’s this?

Answer 88

eosinophilic and oval Negri body in Purkinje cells

Question 89

What’s this?

Answer 89

Negri body in pyramidal cells of hippocampus

Question 90

What’s this? Why have you seen this image before?

Answer 90

Rabies is still prevalent in many parts of the world.

This microscopic view demonstrates a Negri body (arrows) which can be found in the cytoplasm of affected cells.

The most common site to find Negri bodies is within the Purkinje cells of the cerebellum or in the pyramidal cells of the hippocampus. This virus travels intra-axonally from the site of the animal bite to the CNS and then spreads widely to cause the symptoms.

Question 91

What causes Progressive Multifocal Leukoencephalopathy?

Answer 91

•Caused by a polyomavirus (one of two ubiquitous viruses, JC and BK)

PML is an opportunistic infection seen in immunocompromised patients (for example AIDS patients or transplant patients). Many of the reactive astrocytes are large with bizarre nuclei

Question 92

Describe the infectious process of polyomavirus and PML.

Answer 92

• Infection in humans is generally asymptomatic.
• Latent in kidneys and B-cells in tonsils of most adults and in the brains of some.
• Reactivation within CNS or in peripheral tissues, with impaired immunity leading to widespread damage of the white matter.
• Infects/destroys oligodendrocytes

Question 93

Describe the symptoms and progression of PML.

Answer 93

• Focal neurologic deficits (dysarthria, limb weakness, visual disturbances, ataxia, personality changes, and occasionally seizures)
• Usually progresses relentlessly over a few months, with increasing cognitive impairment
• Almost invariably fatal

Question 94

How is PML treated?

Answer 94

•Treatment of underlying immunosuppression (e.g. of AIDS, with highly active anti-retroviral therapy) can lead to remission

Question 95

What is the cellular appearance of PML?

Answer 95

Ultrastructurally, the nuclei are completely filled with virions in progressive multifocal leukoencephalopathy (PML).

Each small dot in the nucleus represents a virion. This gives the nucleus a stippled, or finely granular, appearance by electron microscopy.

Many of the reactive astrocytes are large with bizarre nuclei

Question 96

What is PML a disease of? What cells does it predominantly affect?

Answer 96

Progressive multifocal leukoencephalopathy (PML) is a disease of the white matter of the brain, caused by a virus infection that targets cells that make myelin–the material that insulates nerve cells (neurons).

Polyomavirus JC (often called JC virus) is carried by a majority of people and is harmless except among those with lowered immune defenses.

Question 97

Who is affected by PML?

Answer 97

The disease is rare and occurs in patients undergoing chronic corticosteroid or immunosuppressive therapy for organ transplant, or individuals with cancer (such as Hodgkin’s disease or lymphoma). Individuals with autoimmune conditions such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosis – some of whom are treated with biological therapies that allow JC virus reactivation – are at risk for PML as well. PML is most common among individuals with HIV-1 infection / acquired immune deficiency syndrome (AIDS).

Question 98

What is the relationship of PML to AIDS dx?

Answer 98

PML is most common among individuals with HIV-1 infection / acquired immune deficiency syndrome (AIDS). Studies estimate that prior to effective antiretroviral therapy, as many as 5 percent of persons infected with HIV-1 eventually develop PML that is an AIDS-defining illness.

However, current HIV therapy using antiretroviral drugs (ART), which effectively restores immune system function, allows as many as half of all HIV-PML patients to survive, although they may sometimes have an inflammatory reaction in the regions of the brain affected by PML.

Question 99

What are the symptoms of PML? What do they reflect?

Answer 99

The symptoms of PML are diverse, since they are related to the location and amount of damage in the brain, and may evolve over the course of several weeks to months The most prominent symptoms are clumsiness; progressive weakness; and visual, speech, and sometimes personality changes. The progression of deficits leads to life-threatening disability and (frequently) death.

Question 100

How is PML dx’ed?

Answer 100

A diagnosis of PML can be made following brain biopsy or by combining observations of a progressive course of the disease, consistent white matter lesions visible on a magnetic resonance imaging (MRI) scan, and the detection of the JC virus in spinal fluid

Question 101

Answer 101

PML affecting white matter

Question 102

What’s this?

Answer 102

PML destroying white matter

Question 103

What’s this?

Answer 103

PML affecting white matter, oligodendrocytes

Question 104

What’s this?

Answer 104

EM of intranuclear viral particles in PML