Viral Infections of the Nervous System

Question 1

Causes of viral encephalitis and myelitis in adults

Answer 1

herpes simplex virus is the
most common cause of sporadic encephalitis

Question 2

Viral encephalitis: clinical findings

Answer 2

Acute or subacute onset of fever, headache, and altered mental status are the cardinal features of acute viral encephalitis.

The altered mental state may range from mild delirium to
frank coma.
Personality change, perceptional disturbance
(illusions and hallucinations), and disorientation are common and can be the heralding symptoms.

Most commonly associated with encephalitis is evidence of meningeal inflammation (meningoencephalitis), which may manifest with Kernig or Brudzinski signs.
Less common syndromes include rhomboencephalitis (involvement of the brainstem) or encephalomyelitis (spinal cord involvement), which can be concomitantly involved in patients with encephalitis.

Additional clinical features related to involved areas include aphasia, ataxia, hemiparesis, movement disorders, visual field deficits, cranial nerve deficits, focal seizures (with or without secondary generalization), and pathologic reflexes.

++ signs and symptoms of ICP!

Question 3

Viral encephalitis: laboratory findings

Answer 3

CSF: lymphocytic pleocytosis (10–500 cells/μL) and moderately elevated protein (50-150mg/dL).

Early infection may reveal a predominance of neutrophils! (In the latter setting, a repeat CSF cell count eight hours later will generally show a shift from neutrophils to lymphocytes)

The CSF glucose level may be normal or mildly decreased, and the opening pressure mildly high (20–30 cm H2O).

The immunoglobulin G (IgG) synthesis rate and CSF:serum oligoclonal bands in the CSF are typically elevated, indicating the intrathecal production immunoglobulins

Film array!!

Question 4

Role of serologic testing in viral encephalitis

Answer 4

Serologic testing is most important for patients who are not improving and who do not have a diagnosis based upon PCR.

MOST VIRAL ETIOLOGIES REQUIRE PAIRED SERA FOR DIAGNOSIS!
thus it is prudent to save serum in the setting of acute illness that can later be used if necessary.
CONVALESCENT (Ανάρρωση) serology should be obtained no sooner than three weeks after the onset of the clinical illness

(As an example, the presence of IgM antibodies in a single serum provides presumptive evidence of St. Louis encephalitis; however, a significant rise or fall between appropriately timed acute convalescent or early-late convalescent sera is diagnostic)

Serology may be helpful in diagnosis of:
* West Nile (a single specimen looking for IgM antibodies in the serum or CSF is sufficient for diagnosis)
* mumps (παρωτίτιδα)
* Epstein-Barr virus infection

Question 5

CSF findings in immunocompromised patients with viral encephalitis

Answer 5

Immunocompromised patients, including HIV/AIDS and transplant patients, often have atypical CSF patterns with acellular or a very high CSF white blood cell count.

Question 6

Which test is more sensitive for the diagnosis of West Nile encephalitis

Answer 6

For West Nile virus, PCR testing is not as sensitive as IgM serology (the preferred test)

Question 7

In which case of viral encephalitis there is low glucose in CSF

Answer 7

moderately reduced values are occasionally seen with HSV1, VZV, mumps (παρωτίτιδα), lymphocytic choriomeningitis virus, or some enteroviruses

Question 8

Specific findings in HSV-1 encephalitis CSF

Answer 8

Xanthochromia, red blood cells and low glucose

Question 9

Viral encephalitis imaging

Answer 9

Typical findings in acute viral encephalitis include:
* increased signal on T2-weighted images in both gray and white matter
* Infected areas and the meninges usually enhance with gadolinium

Question 10

Specific imaging patterns in viral encephalitis
(HSV1, HHV6, CMV, West Nile)

Answer 10

1) HSV-1
On MRI, the most characteristic pattern is unilateral T2/fluid-attenuated inversion recovery hyperintensity involving the insula, medial temporal and inferior frontal lobes with or without involvement of the adjacent limbic structures.

2) HHV-6
also has a predilection for the temporal lobes, most commonly involving the uncus, amygdala, and hippocampal body.

3) CMV
periventricular enhancement may be seen indicative of underlying ventriculoencephalitis.

4) Japanese encephalitis
primarily affects the thalamus, basal ganglia and brainstem.

5) West Nile virus encephalitis
most commonly affects the basal ganglia, thalami, medial temporal lobes, and brainstem

**
Involvement of the thalamus or basal ganglia may be observed in the setting of encephalitis due to respiratory viral infection, Creutzfeldt-Jakob disease, arbovirus, and tuberculosis

MRI during postinfectious encephalitis may demonstrate multifocal lesions mainly involving supratentorial white matter

Question 11

Life-threatening manifestations of HSV-1 encephalitis

Answer 11

hemorrhage and/or cerebral edema

Question 12

EEG findings in HSV encephalitis

Answer 12

Focal electroencephalographic changes may be seen, such as:
* periodic lateralizing epileptiform discharges
* focal temporal lobe spikes
* slow waves

Question 13

Viral encephalitis treatment

Answer 13

Acyclovir, 10 mg/kg intravenously every 8 hours, reduces morbidity and mortality associated with HSV encephalitis and therefore should be initiated as soon as the diagnosis of encephalitis is considered.
Dosing should be adjusted for renal insufficiency.
Acyclovir is also effective in patients with varicella-zoster virus (VZV) vasculitis and encephalitis.

Both ganciclovir, 5 mg/kg intravenously every 12 hours, and foscarnet, 90–120 mg/kg/day, have demonstrated efficacy in the treatment of CMV infections of the CNS

Immunocompromised patients with HHV-6 encephalitis should be treated with ganciclovir or foscarnet.

Treatment of West Nile encephalitis remains supportive.

Patients should be monitored closely for signs of raised
intracranial pressure

Evidence on the management of raised ICP in viral encephalitis is limited. All of the “standard” therapeutic interventions for lowering CSF pressure (eg, steroids, mannitol) have been used in this setting, but none have been shown to have well-established benefit.

Question 14

Suggested initial therapy for agents that cause encephalitis

Answer 14

https://www.uptodate.com/contents/image?imageKey=ID%2F69990&topicKey=ID%2F1284&search=viral%20encephalitis&rank=1~88&source=see_link

Question 15

Differential diagnosis of viral meningitis and encephalitis

Answer 15

Question 16

Difference between encephalitis and meningitis

Answer 16

The presence or absence of normal brain function is the important distinguishing feature between encephalitis and meningitis.
Patients with meningitis may be uncomfortable, lethargic, or distracted by headache, but their cerebral function remains normal.
In encephalitis, however, abnormalities in brain function are a differentiating feature, including altered mental status, motor or sensory deficits, altered behavior and personality changes, and speech or movement disorders.
Other neurologic manifestations of encephalitis may include hemiparesis, flaccid paralysis, and paresthesias.

Seizures and postictal states can be seen with meningitis alone and should not be construed as definitive evidence of encephalitis.

Question 17

Types of viral encephalitis

Answer 17

Viral encephalitis can be either primary or postinfectious

● Primary infection is characterized by viral invasion of the CNS. Neuronal involvement can be identified on histologic examination, which may show inclusion bodies on light microscopy or viral particles on electron microscopy. The virus can often be cultured from brain tissue.

● In postinfectious encephalitis (also called acute disseminated encephalomyelitis, or ADEM), a virus cannot be detected or recovered, and the neurons are spared. However, perivascular inflammation and demyelination are prominent in this entity. The inability to recover a virus and the type of histologic abnormalities observed suggest that postinfectious encephalitis is an immune-mediated disease

Question 18

West Nile infection: clinical findings

Answer 18

WN neuroinvasive disease can present as
* encephalitis
* meningitis
* acute asymmetric flaccid paralysis
* Other neurologic manifestations: tremor, myoclonus, and Parkinsonian features such as rigidity, postural instability, and bradykinesia

Encephalitis that is associated with muscle weakness and flaccid paralysis is particularly suggestive of WN virus infection

After the acute infection, many patients with WN virus infection experience persistent symptoms, such as fatigue, memory impairment, weakness, headache, and balance problems

Question 19

Typical CSF findings in CNS infections

Answer 19

Question 20

Do enteroviruses cause more often encephalitis or meningitis

Answer 20

Meningitis

Question 21

Potentially treatable diseases mimicking viral CNS infection

Answer 21

https://www.uptodate.com/contents/image?imageKey=ID%2F77933&topicKey=ID%2F1284&search=viral%20encephalitis&rank=1~88&source=see_link

Question 22

Increased intracranial pressure management in viral encephalitis

Answer 22

All of the “standard” therapeutic interventions for lowering CSF pressure (eg, steroids, mannitol) have been used in this setting, but none have been shown to be of well-established benefit.
Although dexamethasone has been shown to reduce brain edema and improve neurologic outcomes in patients with pneumococcal meningitis, there are only limited retrospective data on the use of steroids in viral encephalitis

Question 23

Causes of viral meningitis (and which are the most common)

Answer 23

Question 24

Clinical considerations in meningitis caused by lymphocytic choriomeningitis virus

Answer 24

Meningeal signs + upper respiratoy symptoms

A minority of patients with LCMV develop orchitis, parotitis, myopericarditis, or arthritis.

CSF findings are typical of other causes of viral meningitis except that low glucose concentrations are observed in 20 to 30 percent of patients with LCMV meningitis and CSF WBC counts of greater than 1000/microL are not unusual

Question 25

Clinical considerations in meningitis caused by HSV-2

Answer 25

Meningeal signs +

herpetic rash in genital area, sometimes accompanied by polyradiculitis

Question 26

Which cause should be suggested in flaccid paralysis with meningitis

Answer 26

West Nile virus

Question 27

Viral Meningitis CSF findings

Answer 27

CSF analysis is characterized by lymphocytic pleocytosis
(10–500 cells/mm3), mild elevation of protein concentration,
and normal glucose level.
In the hyperacute stage, polymorphonuclear granulocytosis may predominate.
Virus-specific PCR, antibody titers, and culture should
be obtained
Other serum analysis is often not helpful during the acute
infection.
Saliva, throat washings, and stool can be examined for virus, although the diagnostic yield is low except for some enteroviruses

Question 28

Viral meningitis treatment

Answer 28

Viral meningitis is a self-limited disease that requires only
supportive treatment with analgesics, antiemetics, and intravenous hydration.
The exceptions are HIV and HSV-2, in which treatment (antiretroviral therapy and acyclovir, respectively) may be initiated, although probably without direct influence on the course of meningitis itself.
Full recovery usually occurs within 1–2 weeks.

Question 29

Which patients are at higher risk for CNS VZV vasculitis

Answer 29

immunosuppressed

Question 30

VZV vasculopathy clinical findings

Answer 30

• ischemic stroke (most common)
• hemorrhagic stroke
• aneurysm
• subarachnoid hemorrhage
• arterial ectasia
• carotid dissection

Question 31

Strokes related to VZV infection location

Answer 31

Strokes related to VZV infection tend to affect the deep structures of the brain, including the basal ganglia and internal capsules, as well as the cerebral cortex supplied by the branches of the middle cerebral artery.

Question 32

Timing of VZV vasculopathy in relation to infection

Answer 32

VZV can lead to a vasculopathy either as an acute infection (chickenpox) or as a reactivation.
Approximately two-thirds of patients have a history of zoster or varicella rash within the last few months prior to presentation.

Question 33

Which virus can cause temporal artery infection with features of giant cell arteritis

Answer 33

VZV

Question 34

VZV vasculitis laboratory findings

Answer 34

CSF:
pleocytosis, usually fewer than 100 cells/mm3, predominantly mononuclear cells, is seen in approximately two-thirds of patients. CSF protein is usually elevated, whereas glucose is normal and oligoclonal bands are frequently present.
Testing for anti-VZV IgG antibody in the CSF generally has a higher yield than testing for VZV DNA.

Only negative results in both anti-VZV IgG antibody testing and VZV PCR in the CSF would exclude the diagnosis of VZV vasculopathy

Question 35

VZV vasculopathy imaging

Answer 35

VZV vasculopathy involves both large and small arteries.

Brain imaging shows ischemic or hemorrhagic infarction in virtually all cases of virologically confirmed VZV vasculopathy.

MRI typically demonstrates both superficial and deep-seated lesions, in both gray and white matter, and particularly at the gray–white matter junction.
Ischemic or hemorrhagic infarction at the gray–white matter junction should prompt consideration of vascular studies, such as magnetic resonance arteriogram, CT angiography, or conventional contrast dye angiography in conjunction with virologic testing.
Typical angiographic changes produced by VZV include segmental constriction, often with poststenotic dilatation.

Question 36

VZV vasculopathy treatment

Answer 36

Prompt treatment in suspected cases of VZV vasculopathy is important to minimize morbidity and mortality.

When the diagnosis of VZV vasculopathy is being considered, and one is awaiting CSF studies that detect anti-VZV IgG antibody or VZV DNA in CSF to confirm the diagnosis, it is advisable to begin treatment immediately with intravenous acyclovir (10 to 15 mg/kg three times daily).

The duration of treatment depends on the clinical response.
Patients should be treated for a minimum of 14 days, with close monitoring of clinical and neuroimaging findings.
If there is a lack of clinical response, the development of new lesions, or has a persistently elevated CSF pleocytosis, there should be consideration of further treatment for 2–4 weeks.

Question 37

Differential diagnosis of acute myelopathy

Answer 37

Question 38

Viral causes of acute myelitis

Answer 38

Question 39

Acute viral myelitis clinical findings

Answer 39

Weakness, sensory loss below the level of the lesion, and
autonomic dysfunction are the cardinal features of most
causes of viral myelitis.

In the acute phase, tone of the affected limbs is decreased and reflexes may be absent or diminished.
Pinprick can demarcate a sensory level, usually one to two levels below the actual cord lesion.
Anal sphincter tone, cremaster reflex, anal wink, and bulbocavernosus response are lost or diminished.
Urinary retention and bowel dysfunction are the rule, and autonomic instability is common.
In the chronic phase, spasticity with pathologic reflexes in the affected limbs develops.

When the complete axial plane of the cord is involved
(transverse myelitis), all sensory and motor modalities below the lesion are affected. When only a portion of the axial cord is involved (partial myelitis), a Brown-Séquard syndrome can result

Nerve roots may also be involved, causing a radiculitis.

Question 40

Acute viral myelitis diagnostic studies

Answer 40

CSF:
mild to moderate lymphocytic pleocytosis (10–500 cells/mm3), elevated protein concentration (100–500 mg/dL), and normal or mildly depressed glucose level.
Markedly elevated protein level (>500 mg/dL) suggests spinal block (Froin syndrome) from cord swelling.
The IgG synthesis rate and oligoclonal bands in the CSF
are typically elevated, indicating the intrathecal production
of immunoglobulin, but is not specific to a cause.
Virus-specific PCR and antibody titer should be performed.

MRI spine
Affected areas typically appear swollen, enhance with gadolinium on T1-weighted images, and display high signal on T2-weighted images. The entire axial plane is usually affected, in contrast to nonviral causes of acute myelitis.

Question 41

Imaging difference between viral and other causes myelitis

Answer 41

1) In general, viruses are more likely to cause a complete (transverse) myelitis while other causes (eg, multiple sclerosis) tend to be partial and asymmetric.

2) It is uncommon for both brain and spinal cord to be involved in most viral infections, in contrast to postinfectious or autoimmune myelitis.

Question 42

Risk factors for developing herpes zoster

Answer 42

The natural history of herpes zoster is influenced by the immune status of the host.
Reactivation is influenced by
* age-related immunosenescence,
* disease-related immunocompromise,
* iatrogenic immunosuppression

age is the major risk factor for 90 percent of cases of herpes zoster
(40% occur in people at least 60 years of age)

Question 43

which division of trigeminal is most commonly affected by zoster

Answer 43

First (Zoster opthalmicus)

Question 44

Ramsay Hunt syndrome

Answer 44

typically includes the triad of ipsilateral facial paralysis, ear pain, and vesicles in the auditory canal or on the auricle.
Ipsilateral altered taste perception and tongue lesions, hearing abnormalities (decreased hearing, tinnitus, hyperacusis), and lacrimation occur in some patients; vestibular disturbances (vertigo) are also frequently reported

Ramsay Hunt syndrome reflects reactivation of latent VZV in the geniculate ganglion, with subsequent spread of the infection to the eighth cranial nerve. Ramsay Hunt syndrome may rarely occur as a component of multiple cranial nerve involvement, especially cranial nerves V, IX, and X

Question 45

Herpes zoster treatment

Answer 45

For most patients: oral valacyclovir (1000 mg three times daily) (prefered)
The duration of treatment is usually seven days.

For immunocompromised patients at high risk for dissemination (eg, hematopoietic stem cell or organ transplant recipients with significant immunosuppression or cancer patients with leukopenia), IV acyclovir (10 mg/kg every eight hours).
After initial clinical improvement, patients may be switched to an oral agent until all lesions have crusted (typically 10 to 14 days)

In patients with Ramsay Hunt syndrome, we suggest adjunctive glucocorticoids in addition to antiviral therapy

Question 46

Postherpetic neuralgia definition and management

Answer 46

Postherpetic neuralgia refers to pain persisting beyond three months from the initial onset of the rash associated with a prior acute herpes zoster episode.

Question 47

Postherpetic neuralgia: risk according to location

Answer 47

Patients with trigeminal nerve involvement especially in the V1 distribution have the highest risk of PHN whereas those with sacral or lumbar involvement have the lowest risk

Question 48

Complication of measles (ιλαρά) infection

Answer 48

Subacute sclerosing panencephalitis
chronic viral infection, usually occurs 7-10 years after the natural measles infection

SSPE has been divided into the following stages:

●Stage I – Stage I consists of insidious development of neurologic symptoms such as personality changes, lethargy, difficulty in school, and strange behavior. Stage I may last from weeks to years.

●Stage II – Stage II is characterized by myoclonus, worsening dementia, and long-tract motor or sensory disease. The patient eventually develops a highly characteristic form of myoclonus in which massive myoclonic jerks occur approximately every 5 to 10 seconds. Stage II usually lasts 3 to 12 months.

●Stages III and IV – Stages III and IV are characterized by further neurologic deterioration with eventual flaccidity or decorticate rigidity and symptoms and signs of autonomic dysfunction. Myoclonus is absent. Stage IV is a vegetative state. Death usually occurs during stage IV but is possible in any of the stages.

A CSF measles IgG antibody titer greater than 1:4, a serum antibody titer greater than 1:256, or a CSF-to-serum titer ratio less than 1:200 supports the diagnosis of SSPE

Pathognomonic findings in EEG: during stage II may demonstrate bursts of high-voltage complexes (300 to 1500 microvolts) of two- to three-per-second delta waves (slow waves) and sharp waves. These complexes last 0.5 to 3 seconds and occur every 3 to 20 seconds

Question 49

Progressive multifocal leukoencephalopathy: cause, pathogenesis, risk factors

Answer 49

infection by JC virus

subacute demyelinating disease

Risk factors:
- HIV and AIDS (most cases)
- immunosuppressed patients as a result of hematologic malignancies, idiopathic CD4 lymphocytopenia, and autoimmune disorders
- Medications including natalizumab for multiple sclerosis, Rituximab and chronic corticosteroid use

Question 50

Progressive multifocal leukoencephalopathy clinical findings and diagnosis

Answer 50

subacute neurologic deficits, including altered mental status, visual symptoms such as hemianopia and diplopia, hemiparesis or monoparesis, and appendicular or gait ataxia.
Seizures occur in up to 18 percent of patients

Question 51

Progressive multifocal leukoencephalopathy treatment

Answer 51

There is no specific treatment for PML. Therefore, the main approach is restoring the host adaptive immune response, a strategy that appears to prolong survival

●In patients with PML and HIV infection, initiation and optimization of effective antiretroviral therapy (ART) therapy is crucial

●For immunosuppressed patients without HIV infection who have PML, we generally stop or reduce immunosuppressive therapy (when feasible) since PML is usually a progressive, fatal disease

●For patients with multiple sclerosis who develop PML during natalizumab treatment, natalizumab should be immediately discontinued.
In addition, we suggest a course of plasma exchange.
In these patients, IRIS is likely to develop approximately three to six weeks after plasma exchange

Question 52

PML - IRIS

Answer 52

●PML may be associated with the immune reconstitution inflammatory syndrome (IRIS), which is associated with new onset or clinical worsening of PML symptoms and with contrast enhancement of PML lesions on brain MRI

PML-IRIS occurs mainly in
1) patients with HIV infection and PML who are started on ART
2) patients with multiple sclerosis who develop natalizumab-associated PML, leading to withdrawal of natalizumab therapy

• For patients who develop PML-IRIS and have both neurologic deterioration and clinical or radiologic evidence of brain swelling, we suggest high-dose glucocorticoid therapy.
  Reasonable regimens include either intravenous dexamethasone (32 mg daily given in four divided doses) for two weeks, or intravenous methylprednisolone (1 g daily for five days), both followed by a slow glucocorticoid taper. In patients with HIV infection, glucocorticoid therapy can be started without interruption of ART.
• In patients with PML-IRIS who have no clinically significant neurologic deterioration due to brain swelling, we suggest not treating with glucocorticoids

Question 53

Progressive multifocal leukoencephalopathy prognosis

Answer 53

PML is often fatal, and the median survival of patients without HIV infection (excluding those with natalizumab-associated PML) is only three months.

In patients with HIV infection and PML, the median survival for patients has increased with widespread use of ART, but the increment varies among published series.

In patients with natalizumab-associated PML, the available evidence suggests that survival with treatment is ≥80 percent at one year after PML diagnosis.
Most survivors have moderate to severe disability.

Question 54

Which complication should be suspected in recurrent symptoms after succesful treatment of HSV encephalitis

Answer 54

Anti-NMDA receptor encephalitis!!!

Question 55

Do PML lesions enhance in postcontrast MRI

Answer 55

Classic PML generally does not enhance on T1+c scans although faint peripheral rim-like enhancement occurs in 5%

The exception is hyperacute PML in the setting of IRIS and in MS patients on Natalizumab. In these cases, striking foci with irregular rim enhancement are frequently present.