Bacterial, Fungal, & Parasitic Infections of the Nervous System 2

Question 1

Infectious causes of chronic meningitis

Answer 1

Question 2

Noninfectious causes of aseptic meningitis

Answer 2

Question 3

Chronic meningitis: definition and clinical findings

Answer 3

Meningitis over 4 weeks

Patients with chronic meningitis usually have a subacute onset of symptoms including fever, headache, and vomiting.

The symptoms can remain static, fluctuate, and/or slowly worsen.

Question 4

Tests for chronic meningitis

Answer 4

https://www.uptodate.com/contents/image?imageKey=ID%2F64041&topicKey=ID%2F1275&search=chronic%20meningitis&rank=1~72&source=see_link

Question 5

Management of chronic meningitis of unknown cause

Answer 5

If a diagnosis is not established despite a thorough search and if symptoms are severe or fail to improve after a period of observation, empiric therapy with antituberculous therapy may be useful.
Empiric antituberculous therapy may also be warranted for patients with less severe symptoms if epidemiologic factors or clinical findings suggest a high risk for TB (eg, in patients with a past history of direct contact with others with TB or a prior positive tuberculin skin test).

Empiric glucocorticoid therapy may be useful in selected patients who fail to improve during follow-up, despite the absence of carefully controlled studies demonstrating benefit in patients with chronic meningitis.

Question 6

Clinically useful or important clues to the cause of chronic meningitis

Answer 6

Question 7

Mollaret meningitis

Answer 7

Mollaret meningitis is a form of recurrent benign lymphocytic meningitis (RBLM), characterized by greater than three episodes of fever and meningismus lasting two to five days, followed by spontaneous resolution
One-half of patients can also exhibit transient neurological manifestations, including seizures, hallucinations, diplopia, cranial nerve palsies, or altered consciousness.

The most common etiologic agent of Mollaret meningitis is herpes simplex virus (HSV)-2; some patients may have evidence of genital lesions at the time of presentation.
HSV-1 and Epstein Barr virus can rarely be the cause of RBLM.

Question 8

Causes of recurrent bacterial meningitis

Answer 8

A) Recurrent bacterial meningitis can result from a breach in the cranial vault congenital or acquired (post-traumatic or post-neurosurgical, especially in the setting of cerebrospinal fluid [CSF] rhinorrhea or other CSF leak).
Recurrent meningitis also occurs with the use of indwelling medical devices (eg, Ommaya reservoirs, ventricular shunts, and cochlear implants) placed into the central nervous system.

B) Abnormalities in both complement and opsonizing antibodies have also been associated with recurrent bacterial meningitis:

1) Deficiency of one or more of the terminal complement components (C5, C6, C7, C8, C9) has been associated with recurrent Neisseria meningitidis meningitis.
Low complement levels may be due to either congenital complement deficiency or acquired diseases, such as systemic lupus erythematosus.

2) Immunoglobulin deficiency disorders or impaired reticuloendothelial function resulting from splenectomy or hemoglobinopathy are associated with an increased risk of bacteremia and meningitis due to encapsulated pathogens.

Question 9

Tuberculous meningitis: pathogenesis

Answer 9

1) hematogenous spread of infection from the lungs or lymph nodes to the brain parenchyma, forming small tubercles that rupture into the subarachnoid space or ventricle in the initial weeks following airborne mycobacterial acquisition.

2) spread from nearby otitis or skull infection (less often)

3) reactivation of latent infection (less often)

Question 10

Tuberculous meningitis: Complications

Answer 10

1) a ruptured tuberculoma may cause fulminant meningitis

2) Stroke may result from arteritis in the large vessels passing through the infected adhesive material at the base of the brain.

3) If meningeal fibrosis occludes the arachnoid villi, communicating hydrocephalus slowly develops

4) acute obstructive hydrocephalus develops if subependymal fibrosis or midbrain swelling interfere with CSF flow through the ventricles.

5) Hyponatremia, found in about half of meningitis patients
Hypernatremia from diabetes insipidus (άποιος διαβήτης) is much less common

6) Syringomyelia occasionally develops many years after tuberculous meningitis, probably as a result of spinal cord vasculitis.

7) Optic atrophy can complicate tuberculosis infection or its treatment.

8) immune reconstitution inflammatory syndrome (30% severely immunosuppressed patients)

Question 11

Tuberculous meningitis: clinical findings

Answer 11

Systemic symptoms (headache, anorexia, low-grade fever, personality change including apathy, and overall “poor health” or malaise) can be present for many weeks before meningeal signs such as back and neck pain or stiffness develop.

Lymphadenopathy is common

Cranial nerve involvement, especially of nerves III, IV, and VI, is present at the time of diagnosis in one third of patients.

Gradual cognitive impairment may progress to coma; dementia has been described rarely

Seizures and hydrocephalus are more common in children

Extrapyramidal signs are unusual, although posturing may be seen as cerebral edema progresses.

Increased intracranial pressure in adults leads to nausea, vomiting and papilledema

Focal signs are usually attributable to stroke due to vasculitis in large vessels crossing through fibrotic debris in the basilar meninges

obtundation and seizures (caused by hyponatremia)

Question 12

Tuberculous meningitis: laboratory findings

Answer 12

• CSF analysis shows white cell counts ranging from 50–1000 cells/μL,
  Lymphocytes predominate, although neutrophils are seen early in the disease course in many patients.
  The fluid is clear or has a “ground-glass” appearance, with a clot of sediment (ίζημα) formed at the top of the collection tube.
  Glucose level is usually less than half of the serum level, or 30 mg/dL, but may be normal.
  Protein concentration is elevated, often more than 150 mg/dL
  Elevated lactate levels correlate adversely with prognosis.
• CSF smear (of sediment after centrifuge) with Ziehl- Neelsen staining can be done rapidly, but results are positive in less than 20% of patients.
• Because of low bacillary load in CSF, three large-volume collections for culture are recommended and special media must be used.
  Eight weeks of no growth are required to confirm a negative culture. Even so, culture is positive only half of the time.

Therefore, speed of diagnosis is much improved with nucleic acid–based amplification (PCR) tests, which have a variable sensitivity of 50–90% but excellent specificity of 98%.

Question 13

Do all patients with meningitis have white blood cells in CSF?

Answer 13

Elderly and immunocompromised patients have fewer WBCs in the CSF, which may even be acellular

Question 14

Tuberculous meningitis: imaging

Answer 14

• CT and MRI scans show hydrocephalus in 80% of children and up to 23% of adults.
• Basal meningeal enhancement is present, and thick “en plaque” meninges are sometimes seen even without contrast administration in the basal cisterns.
• Stroke (15–30%)
• tuberculomas (5–10%)
  (Mild to moderate round or lobulated ring-like enhancement around a non-enhancing center is the most typical pattern)
• Chest radiograph demonstrates the existence of tubercular infection by apical scarring, hilar lymphadenopathy, and infiltrates or miliary tuberculosis in 40–50% of patients

Question 15

Neurologic complications of antibiotic therapy in tuberculosis

Answer 15

Isoniazid induced neuropathy

Ethambutol-induced optic neuritis or other visual dysfunction

Streptomycin-induced ototoxicity and vestibular toxicity and

Cycloserine-induced seizures

Question 16

Tuberculous meningitis: Treatment

Answer 16

Treatment should be initiated when the diagnosis is suspected and not deferred until a diagnosis is established

● Antituberculous therapy – In general, treatment of CNS TB consists of an intensive phase (four drugs administered for two months) followed by a continuation phase (2 drugs administered for an additional 7 to 10 months), for a total treatment duration of 9 to 12 months

Intensive phase
consists of four drugs (isoniazid, rifampin, pyrazinamide, and ethambutol) administered for two months.

Continuation phase
consists of two drugs (isoniazid and rifampin); we suggest a duration of 7 to 10 months over a shorter duration

● Glucocorticoids – The approach to use of glucocorticoids depends on the clinical presentation:

Meningitis

For patients with tuberculous meningitis (established or suspected) with HIV infection or in the absence of HIV infection, we recommend adjunctive glucocorticoid therapy

Tuberculoma – For patients with tuberculoma, we suggest adjunctive glucocorticoid therapy for patients with cerebral edema (particularly when edema is out of proportion to mass effect in the setting of associated altered mental status or focal neurologic deficits), and/or elevated intracranial pressure

Spinal arachnoiditis – For patients with spinal arachnoiditis, we suggest adjunctive glucocorticoid therapy for patients with spinal block (cerebrospinal fluid protein ≥500 mg/dL) and/or patients with acute cord compression

Transverse myelitis – For patients with tuberculous transverse myelitis (established or suspected), we suggest adjunctive glucocorticoid therapy

● Antiretroviral therapy – For patients with HIV infection and CNS TB who are not already on antiretroviral therapy (ART), we suggest deferral of ART until eight weeks after starting TB treatment, regardless of CD4 count

Question 17

Isoniazid resistant tuberculous meningitis management

Answer 17

treatment with daily rifampin, ethambutol, pyrazinamide, and a fluoroquinolone

In addition, the duration of therapy should be extended to 18 to 24 months, taking into account the severity of illness, clinical response to therapy, and the patient’s immune status

Question 18

TB-associated IRIS: management

Answer 18

Development of immune reconstitution inflammatory syndrome (IRIS) occurs in approximately one-third of patients with CNS TB
it typically manifests with paradoxical worsening within three months of antituberculous therapy and may cause severe or fatal neurologic complications

IRIS is usually self-limited and in general does not require alteration or interruption of the antituberculous or antiretroviral regimens.
Initial management consists of nonsteroidal anti-inflammatory drugs, if symptoms persist, a short course of corticosteroids is warranted

For patients with IRIS that is not responsive to corticosteroids, particularly patients with neurological manifestations of TB, tumor necrosis factor alpha inhibitors may be a useful treatment tool

Question 19

TB-associated IRIS: risk factors and CNS clinical manifestations

Answer 19

Among patients with TB, IRIS has been described in 8 to 43 percent of cases

The risk is increased in HIV+ patients with:
* an initial CD4 count <100/microL and
* a significant reduction in viral load and a large increase in CD4 count

IRIS usually occurs approximately three weeks after starting ART, though it can occur later.
Clinical manifestations of IRIS in patients with HIV infection with TB include meningitis, intracranial tuberculoma, brain abscess, radiculomyelitis, and spinal epidural abscess

Question 20

Tuberculoma clinical findings and imaging

Answer 20

Patients with tuberculomas present with
* seizures
* focal signs
* in cases of multiple lesions, increased intracranial pressure, cognitive dysfunction, and progressive obtundation

Tuberculomas can occur anywhere in the brain with enhancement patterns ranging from ring to diffuse enhancement

MRI shows a hypointense core and hyperintense rim on T2-weighted or FLAIR images, and hypointense or isointense (to brain) lesion on T1-weighted images, which correlates with necrosis and increased cellularity.

Before the lesion becomes encapsulated, hypodensity with no enhancement is seen.
Hydrocephalus is present in 37% of patients and is dependent on the location of the tuberculoma at a site that blocks CSF flow.

(Abscesses cause a greater mass effect and surrounding edema and are hypodense on CT and hyperintense on T2-weighted MRI scans)

Question 21

Tuberculoma management

Answer 21

Treatment includes the same combination of four antimycobacterial drugs (isoniazid, rifampin, pyrazinamide, and ethambutol) described for tuberculous meningitis but with more prolonged courses, determined by radiographic response.
Because of their toxicity pyrazinamide and ethambutol can be stopped in 2 months but the others continued for up to 1 year.

Large lesions (>4 cm in diameter) have a worse response to medication and may require surgery.
Permanent ventriculoperitoneal shunting may be needed for persistent hydrocephalus.

Accompanying steroids help with increased intracranial pressure, spinal block, and cerebral edema surrounding tuberculomas

Question 22

Tetanus pathogenesis

Answer 22

Tissue necrosis and suppuration allow the bacteria to germinate and produce the toxin (tetanospasmin), which is taken up by peripheral nerve terminals and ascends intra-axonally to the spinal cord or brainstem.

Tetanospasmin blocks inhibitory interneurons, resulting in excessive discharge of motor neurons and, in severe cases, autonomic dysfunction.

Question 23

Tetanus clinical findings

Answer 23

The usual incubation period from injury to first symptoms is 7–21 days.
Trismus (“lockjaw”) and stiffness of the neck and
paraspinal muscles are prominent early symptoms, spreading as the disease progresses to the limbs.
Stiffness of facial muscles produces risus sardonicus and paraspinal rigidity can produce opisthotonus.

Superimposed paroxysmal painful tonic spasms (tetanospasms) occur spontaneously or are triggered by tactile stimuli or sound.

Pharyngeal muscle spasm causes dysphagia and laryngeal and respiratory muscle spasm cause asphyxia.

Diplopia and ptosis are common.

Autonomic dysfunction can cause fever, blood pressure swings, severe diaphoresis, and cardiac arrhythmia even when body spasms are controlled.

Most patients remain mentally clear.

Question 24

Tetanus management

Answer 24

Supportive care – Supportive care is the mainstay of management to avoid complications such as respiratory failure, nosocomial infections, and thromboembolism

Halting and neutralizing toxin production – Since tetanus is mediated by a toxin, a crucial aspect of therapy is to eliminate ongoing toxin production.
This includes debriding the wound and administering antimicrobial therapy (eg, metronidazole 500 mg intravenously every six to eight hours for 7 to 10 days).
In addition, patients should receive passive immunization with antitoxin (eg, human tetanus immune globulin) to neutralize unbound toxin.

Infusion of magnesium sulfate may be useful

Control of muscle spasms – Muscle spasms are controlled with sedation (usually benzodiazepines) or neuromuscular blockade.

Autonomic dysfunction –
Autonomic hyperactivity can be treated with labetalol or morphine sulfate.
Beta blockade without concomitant alpha blockade should be avoided.

Question 25

Fungal infections of CNS: most common parthogens

Answer 25

Cryptococcus neoformans is the most common pathogen

followed by Candida, Coccidioides immitis, and Histoplasma

Question 26

Causes of cryptococcal meningitis

Answer 26

Most cases of cryptococcal meningitis represent
reemergence of existing infection in immunosuppressed patients, especially those with AIDS, when T-cell counts fall below 200 cells/μL.

Other causes of immunosuppression
* use of antirejection drugs in organ transplant recipients
* chemotherapy- induced neutropenia
* diabetes mellitus
* malignancy
* alcoholism
* corticosteroid use
* pregnancy
* prematurity

all predispose to recrudescence (αναζωπυρωση) of latent infection.

Question 27

Percentage of HIV mortality caused by cryptococcus

Answer 27

causes 20% of HIV-related mortality overall

Question 28

Risk factors for fungal infection

Answer 28

Spores are inhaled during childhood or invade through the skin, mucous membranes, sinuses, or wounds.

Immunocompetent hosts can suffer chronic meningitis from Coccidioides, but most fungal infection occur in T-cell immunodeficient hosts.

Other at-risk patients include:
1) those exposed to large amounts of bat or bird guano (περιττώματα) (Cryptococcus)
2) those requiring chronic antibiotics or very young patients (Candida)
3) uncontrolled diabetics or those with IV drug use or burns (Mucor)
4) those exposed to dirt containing Aspergillus, Coccidioides, or Histoplasma spores

Question 29

Fungal infection clinical findings

Answer 29

• Headache, which may become severe, develops slowly over weeks or months.
• Meningeal signs, fever, and altered mental
  state, are usually less frequent and less pronounced in fungal than in bacterial or tuberculous meningitis
• Coma implies severe intracranial hypertension, hydrocephalus, or hyponatremia due to inappropriate antidiuretic hormone secretion.
• Papilledema, diplopia, and focal findings are seen in 10% of patients.
• Seizures and stroke are occasional complications.
• Fever is usually low grade.

Question 30

Fungal infection clinical findings (pathogen specific)

Answer 30

Candida, Aspergillus, and rarely Blastomycosis infections tend to invade the brain more often than they cause meningitis, where they cause microabscesses.

Mucormycosis, is often seen in neutropenic or diabetic patients with hyperglycemic ketoacidosis or in normal hosts who have smoked contaminated marijuana.
This fungal infection causes orbital cellulitis and nasal destruction, followed by cavernous sinus thrombosis and frontal abscess that is highly necrotic.

Aspergillus usually is intraparenchymal and can produce sudden focal symptoms as a result of hemorrhage into a mass.
Lung infection can invade adjacent vertebrae to cause cord compression.

Coccidioidal meningitis is difficult to treat and has significant morbidity (hydrocephalus, vasculitis, abscess, or infarct) and mortality.

Question 31

Fungal infections CSF findings

Answer 31

Diagnosis is made by CSF examination, which shows moderately low glucose (median ratio to serum 0.4), high protein content (median 80 mg/mL), and more than 20 WBCs/μL, mostly lymphocytes.

Coccidioidomycosis may produce eosinophils or neutrophils in CSF.
Neutrophilic predominance can also be found in
* histoplasmosis
* blastomycosis
* Candida
* Aspergillus
* Zygomycetes
* P boydii

Nonspecific causes of elevation of protein and white cells, such as diabetes and untreated HIV infection, must be considered;
(reduced CSF:serum glucose ratio is more reliably associated with infection)

Question 32

Specific fungal infection diagnosis
Cryptococcus, Candida, Coccidioides, Histoplasma

Answer 32

Cryptococcus: definite diagnosis with culture of the organism from the CSF
CSF: additional India ink evaluation
cryptococcal antigen testing : A positive cryptococcal polysaccharide antigen in the CSF or serum strongly suggests the presence of infection well before the cultures become positive in high-risk patients
++ PCR (film Array)

Candida: Lumbar puncture to obtain CSF for culture and analysis is essential for establishing the diagnosis.
The beta-D-glucan assay using CSF might be a useful adjunct to CSF culture and analysis.

Coccidioides: A definitive diagnosis of coccidioidal meningitis is supported by isolating Coccidioides species from CSF or other central nervous system specimens; however, most cases are presumptively diagnosed by identifying anticoccidioidal antibodies in the CSF

Histoplasma: The diagnosis is often based upon detection of antigen or antibody in the CSF, CSF cultures are often not positive.
Establishing the diagnosis of meningitis due to histoplasmosis can be difficult; thus, for patients with suspected meningitis, cerebrospinal fluid (CSF), serum, and urine antigen testing, CSF and serum antibody testing, and CSF and blood cultures should be obtained.

Question 33

Fungal infections of the CNS: imaging

Answer 33

Imaging can show hydrocephalus caused by ependymitis or blockage of subarachnoid space.

Meningeal enhancement is almost always present, especially in the basilar meninges.

Small areas of cryptococcoma can be present adjacent to ventricles and subsequently disappear with medical treatment.

MRI with contrast can reveal candidal microabscesses, which are ring shaped, hemorrhagic, and usually multiple and widespread in the brain.
Less common are infarcts due to vasculitis.

Hemorrhage is a common finding in patients with Aspergillus infection.

Necrosis with infarction is seen in those with Zygomycetes (mucormycosis) infection.

Blastomyces infection causes epidural abscess as well as intracranial abscess.

Question 34

Fungal infection of the CNS: treatment

Answer 34

Antifungal agents fall into five classes:
* polyenes (amphotericin)
* triazoles (ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole)
* pyrimidine analog (flucytosine)
* echinocandins (caspofungin, micafungin, anidulafungin)
* allylamine (terbinafine)

Most work by disrupting aspects of fungal cell membrane or wall formation
5-flucytosine interferes with pyrimidine metabolism in the nucleus

In immunosuppressed patients, after initial treatment of any cryptococcal infection, secondary prophylaxis with fluconazole, 200 mg/day orally, is continued for 1 year until the CD4+ lymphocyte count recovers to 100 cells/μL and viral load is undetectable for at least 3 months.

Supportive management includes control of elevated intracranial pressure by repeated lumbar puncture or ventricular drain.
Although it acts as a potential locus of future infection, a permanent shunt is necessary if hydrocephalus persists.

Removal of a fungus ball surgically may avoid the expense, toxicity and ineffectiveness of longterm medication use.

Question 35

How to prevent IRIS in HIV patients with cryptococcal infection

Answer 35

To avoid immune reconstitution syndrome (IRIS) in cryptococcal infection, antiretroviral therapy should be delayed at least 4 weeks.

Question 36

Stages of syphilis

Answer 36

Question 37

Neurosyphilis pathogenesis

Answer 37

Spirochete arrives in the CNS through the meninges.
In early stages, stroke occurs due to involvement of the vessels, and asymptomatic meningitis is found on lumbar puncture.
Historic but rarely encountered tertiary syphilis syndromes:
i) invasion of the frontal lobes (general paresis and dementia - προϊούσα γενική παράλυση)
ii) upper brainstem (Argyll Robertson pupils)
iii) spinal cord dorsal columns (tabes dorsalis)

Rarely, an inflammatory mass or gumma develops near the dura, with symptoms corresponding to the location; these may include seizures.

Question 38

Neurosyphilis clinical findings

Answer 38

The CNS may be involved at any stage of syphilis.

Meningitis occurs any time after healing of the chancre, usually at least 4–10 weeks later.
During this early stage, meningeal signs such as photophobia and headache are accompanied by a highly variable, potentially infectious, rash that tends to involve the palms and soles.

5% of patients develop symptoms of cranial nerve dysfunction, especially of vestibular or auditory nerves, with tinnitus or deafness.
Ocular symptoms: visual impairment due to uveitis or retinitis.
Gait and balance dysfunction is present in some.

Stroke involving medium-sized vessels, is caused by inflammatory reactions in vessels much more commonly than emboli from syphilitic aortitis

Gumma: focal signs such as seizures

Late neurosyphilis: tabes dorsalis, general paresis (dementia paralytica)

Question 39

Neurosyphilis: occular and otologic findings

Answer 39

Ocular syphilis —
Ocular syphilis can involve almost any eye structure, but posterior uveitis (ραγοειδίτιδα) and panuveitis are the most common and present with diminished visual acuity.
Additional manifestations may include optic neuropathy, interstitial keratitis, anterior uveitis, and retinal vasculitis.
Ocular syphilis is often, but not always, accompanied by syphilitic meningitis.
Ocular syphilis may worsen when the diagnosis is not considered and patients are treated with systemic or topical corticosteroids.

Otosyphilis —
Hearing loss, with or without tinnitus
Like ocular syphilis, hearing loss may or may not be accompanied by meningitis.

In patients with positive serum FTA:
Patients with otologic symptoms should be evaluated by an otolaryngologist and patients with ocular symptoms should be evaluated by an ophthalmologist, and if findings are consistent with otologic or ocular syphilis, these patients should be treated for neurosyphilis even if the CSF is normal

Question 40

Neurosyphilis diagnosis (no HIV)

Answer 40

https://www.uptodate.com/contents/image?imageKey=NEURO%2F57300&topicKey=NEURO%2F7599&search=neurosyphilis&rank=1~72&source=see_link

Question 41

Neurosyphilis diagnosis (+HIV infection)

Answer 41

https://www.uptodate.com/contents/image?imageKey=NEURO%2F71518&topicKey=NEURO%2F7599&search=neurosyphilis&source=outline_link&selectedTitle=1~74

Question 42

Treponemal and Non treponemal tests for syphilis

Answer 42

Treponemal (Specific): Fluorescent treponemal antibody, absorbed (TA-Abs), Treponema pallidum hemagglutination (TPHA), microhemagglutination—Treponema pallidum (MHA-TP)

Non treponemal (Nonspecific): VDRL, rapid plasma reagin (RPR), and immunoglobulin G (IgG) tests

Question 43

Neurosyphilis: CSF findings

Answer 43

Lymphocytic or monocytic pleocytosis can persist throughout the course of syphilis infection, with several hundred cells in the secondary, meningeal stage.
Glucose level is usually normal or mildly decreased
CSF protein concentration may be elevated as high as 100 mg/dL
oligoclonal bands are often present.

Patients with AIDS who are treated for neurosyphilis should undergo a repeat lumbar puncture at 6 months to identify those who do not respond to standard courses of antibiotics. Lymphocytes can be present in chronic HIV infection at any stage.

The less sensitive RPR test should not be used!!!

VDRL of CSF is 100% specific, assuming the lumbar puncture is atraumatic
CSF FTA is 30% specific, but almost 100% sensitive

Question 44

Neurosyphilis CSF tests interpretation

Answer 44

A positive CSF VDRL means the patient does have neurosyphilis but a negative CSF VDRL does not rule it out;
whereas a negative CSF FTA does rule out neurosyphilis but a positive CSF FTA does not make that diagnosis.

Because the FTA will remain positive throughout the patient’s life, even after treatment, it should not be used to follow a patient’s response to treatment.

Question 45

Are VDRL and RPR serum titers stable througout the years?

Answer 45

VDRL and RPR titers decrease as infection advances over years, leading to false-negative results in older patients.
Similarly, serology is unreliable in immunosuppressed HIV positive patients
successful therapy accelerates the pace of antibody decline

Question 46

Neurosyphilis serum tests interpretation

Answer 46

• Positive nontreponemal and treponemal test –
  For patients without a history of prior syphilis, a diagnosis of syphilis is made when both nontreponemal and treponemal tests are reactive. All persons who are diagnosed with a new syphilis infection should be treated.

For patients with a history of treated syphilis, the presence of a positive nontreponemal test can indicate:
-a new infection
-an evolving response to recent treatment
-treatment failure
In some cases, a patient may have had an adequate decline in titers but nontreponemal titers do not serorevert.

• Positive nontreponemal and negative treponemal test – Patients who have a positive nontreponemal test followed by a negative treponemal test are generally considered to have a false-positive syphilis result. However, testing should be repeated in those with a recent high-risk exposure

False-positive tests are particularly common during pregnancy. Other reasons for a false-positive test include acute infection, recent immunization, and autoimmune conditions.

• Positive treponemal and negative nontreponemal test –
  This scenario is usually seen in patients with a history of previously treated syphilis.
  However, it can occasionally occur in very early syphilis or in late syphilis when nontreponemal tests have become nonreactive over time.
• Negative nontreponemal test in persons with evidence of early syphilis –
  Patients with clinical signs and symptoms of early syphilis (eg, ulcer, rash) who are tested for syphilis using an initial nontreponemal test may have a false-negative result. For such patients, a false-negative test is typically due to testing prior to antibody formation or secondary to a prozone effect.

● Latent syphilis –
Latent syphilis is diagnosed in a patient who has no clinical signs or symptoms of syphilis but has serologic evidence of infection.
Early latent syphilis is diagnosed if an asymptomatic patient has serologic evidence of T. pallidum infection that was acquired within the last 12 months.
All others are assumed to have late latent syphilis.

Question 47

Which test correlates with disease activity in syphilis?

Answer 47

Nontreponemal (RPR, VDRL) serum tests

Question 48

Are CSF treponemal tests specific?

Answer 48

CSF treponemal tests are less specific and do not distinguish between previously treated neurosyphilis and active infection

Question 49

Neurosyphilis imaging

Answer 49

Signs of meningeal inflammation on enhanced CT or MRI
scan are suspicious for meningovascular lues.

MRI visualization of a gumma (rare)

Magnetic resonance angiography or routine angiography can demonstrate vascular occlusion.

Question 50

Neurosyphilis treatment

Answer 50

Patients who have a serious penicillin allergy must first undergo desensitization prior to penicillin therapy.

For patients who have a mild penicillin allergy, we suggest ceftriaxone (2 g intravenous daily) for 10 to 14 days with careful observation for cross-reactivity

Question 51

Neurosyphilis: how to monitor treatment success

Answer 51

Lumbar puncture should be performed three to six months after treatment and every six months thereafter until the CSF white blood cell count is normal and the CSF-VDRL is nonreactive.

We suggest retreatment if the CSF white blood cell count does not decrease six months after therapy or the CSF-VDRL does not decline fourfold (or to nonreactive if the initial titer is <1:2) one year after therapy.
In addition, we suggest retreatment if there is an increase in the CSF white blood cell count, or a fourfold increase in CSF-VDRL titer, in any follow-up CSF sample.

In immunocompetent patients or patients with HIV who are taking antiretroviral agents and in whom a follow-up lumbar puncture cannot be performed, normalization of the serum RPR titer can be used as a surrogate for success of neurosyphilis treatment.

Question 52

Leptospirosis: cause, clinical findings, diagnosis and treatment

Answer 52

Leptospirosis is an acute and often severe infection that affects the liver and other organs and is caused by the spirochete Leptospira interrogans, which affects rats, dogs, cattle, and swine, among other animals.
Humans may contract the infection by consuming food contaminated by urine of a reservoir (infected) animal, or from infected soil or water.

Symptoms: from mild meningeal signs similar to aseptic meningitis, with conjunctivitis, chills, fever, headache and meningismus, to septicemia with liver and cardiac failure. All symptoms start 1–2 weeks after exposure and may recur after resolution.

Analysis of CSF (initially acellular) eventually shows some monocytes and an elevated protein concentration, with seroconversion manifested as immune complexes and IgM antibody to Leptospira subtypes.
Occasionally the organism can be grown in CSF culture.

If recognized early, treatment consists of high doses of intravenous penicillin G or doxycycline, oral or intravenous, in doses similar to those used for treatment of syphilis.

Most patients recover with no therapy

Question 53

Lyme disease: pathogen and stages

Answer 53

Borrelia Burgdoferi

Question 54

Lyme disease: common neurologic syndromes

Answer 54

can occur as combined or individual syndromes:

1) Meningitis – Lymphocytic/monocytic meningitis is the most common syndrome; patients present with headache, fever, photosensitivity, and neck stiffness.

2) Facial nerve palsy – Similar to idiopathic Bell’s palsy, patients with Lyme-associated facial palsy usually present with unilateral facial paralysis; some patients have bilateral involvement, either simultaneously or in rapid succession

3) Radiculoneuritis – Patients with radiculoneuritis or Bannwarth syndrome present with radicular pain in one or more dermatomes, accompanied by corresponding sensory deficits, motor weakness, and/or reflex changes.
Nerve conduction studies and electromyography help confirm the neurologic localization

Question 55

Lyme disease diagnosis

Answer 55

Lyme disease should be suspected in patients who present with one of the common clinical syndromes if they live in an endemic area and present in the spring through fall months.

Serologic testing – Serologic testing is highly sensitive and specific for Lyme disease when using the two-tier approach.
The two-tier strategy typically uses the sensitive ELISA followed by a Western blot or a second ELISA with different targets.

-If the ELISA is positive or equivocal, then the same serum sample should be tested by Western blot.
A second, orthogonal ELISA may be substituted as the second-tier assay and is as valid as a Western blot, easier to perform on large numbers of samples, and easier to standardize.

-If the initial ELISA is negative, the sample needs no further testing.

• Lumbar puncture – Cerebrospinal fluid (CSF) analysis is required for patients who present with acute meningitis to evaluate for other more dangerous causes. For certain other presentations, it may be reasonable to diagnose and treat based on serologic testing alone.

The appropriate test for Lyme disease is Borrelia burgdorferi antibody index measurement, comparing CSF with serum antibody concentrations.

Polymerase chain reaction (PCR) for B. burgdorferi is not a useful test

Question 56

Lyme disease complications

Answer 56

• chronic radiculopathy
• sleep disturbance
• headache
• fatigue
• encephalopathy
• myelopathy
• Rarely vasculitis causes permanent white matter pathology with cognitive and emotional dysfunction.
• “Post-Lyme (chronic) encephalopathy” is most likely
  to be caused by psychiatric conditions such as depression.

Question 57

Lyme disease treatment

Answer 57

Question 58

Timing of antibody presence in Lyme disease

Answer 58

Neurological manifestations can be seen prior to the appearance of IgM antibodies in the blood.

Thus antibody testing in a patient with suspected exposure within 3-6 weeks of presentation may be negative

Question 59

Toxoplasmosis: 1) which patients are at risk for CNS infection 2) clinical presentation

Answer 59

1) HIV + and a CD4 count <100 cells/microL

2) Toxoplasmic encephalitis (cerebral abscesses) —
Patients with toxoplasmic encephalitis typically present with headache and/or other neurologic symptoms.
Fever is usually, but not reliably, present.
Focal neurologic deficits or seizures are also common.
Mental status changes range from dull affect to stupor and coma and can result from global encephalitis and/or increased intracranial pressure

Question 60

Toxoplasmosis diagnosis in HIV patients

Answer 60

A presumptive diagnosis of toxoplasmic encephalitis can be made if the patient has a CD4 count <100 cells/microL, has not been receiving effective prophylaxis for toxoplasma, and has all of the following:

*A compatible clinical syndrome
*A positive serum T. gondii IgG antibody
*Brain imaging (preferably magnetic resonance imaging) that demonstrates a typical radiographic appearance (eg, multiple ring-enhancing lesions)

For patients who can safely undergo lumbar puncture, analysis of CSF should also be performed to evaluate for evidence of T. gondii.
If toxoplasmosis is identified using PCR, the diagnosis of TE is even more likely

(Anti-toxoplasma serum IgM antibodies are usually absent in HIV patients)

Question 61

Toxoplasmosis treatment in patients with HIV

Answer 61

antimicrobial therapy directed against T. gondii, as well as antiretroviral therapy (ART) for immune recovery

• Initial therapy – sulfadiazine plus pyrimethamine or trimethoprim-sulfamethoxazole.

For patients who respond to treatment, the duration of initial therapy is typically six weeks

• Maintenance therapy – For patients who complete initial therapy, we suggest maintenance therapy (ie, secondary prophylaxis) with sulfadiazine plus pyrimethamine or TMP-SMX. Relapse of infection can occur after initial therapy unless the patient has immunologic recovery.

Maintenance therapy can be discontinued in asymptomatic patients who are receiving ART, have a suppressed HIV viral load, and have maintained a CD4 count >200 cells/microL for at least six months

●Antiretroviral therapy – Most patients with toxoplasmosis are not on ART at the time of diagnosis.
We initiate ART within two weeks of starting treatment for toxoplasmosis, typically as soon as it is clear that the patient is tolerating toxoplasmosis therapy

The empirical use of corticosteroids is not recommended for toxoplasmosis treatment. The addition of corticosteroids has not been shown to improve neurological outcome and may interfere with the assessment of a possible primary CNS lymphoma.

Question 62

Which is the most common CNS parasitic disease

Answer 62

Neurocysticercosis

Question 63

Neurocysticercosis: 1) pathogenesis 2) clinical findings

Answer 63

1) Cysticercosis is caused by the larval stage of the tapeworm Taenia solium
Cysticercosis is transmitted by ingestion of T. solium eggs shed in the stool of a human tapeworm carrier. Following ingestion, embryos (oncospheres) hatch in the small intestine, invade the bowel wall, and disseminate hematogenously to brain, muscles, and/or other tissues.
Humans become T. solium tapeworm carriers by ingesting undercooked pork containing cysticerci in muscle tissue.

2)
A) Intraparenchymal NCC – Intraparenchymal NCC is the most common form of cysticercosis
Onset of symptoms usually occurs three to five years following infection but can occur >30 years following infection.
Seizures and headache are the most common manifestation; less common manifestations include altered vision, focal neurologic signs, and meningitis.
In patients with massive numbers of parenchymal cysts, an intense immune response with diffuse edema can cause a clinical picture resembling encephalitis; manifestations may include seizures, headache, nausea and vomiting, impaired consciousness, reduced visual acuity, and occasionally fever.
Many cases of parenchymal NCC are asymptomatic and are identified incidentally via radiographic imaging performed for other reasons

B) Extraparenchymal NCC

*Intraventricular NCC – Intraventricular NCC (free-floating cysts in the ventricular cavity or attached to the choroid plexus) occurs in 10 to 20 percent of cases.
Typically, symptoms develop when cysticerci become lodged in the ventricular outflow tracks, with consequent obstructive hydrocephalus and increased intracranial pressure. Associated symptoms include headache, nausea and vomiting, altered mental status, and decreased visual acuity with papilledema

*Subarachnoid NCC – Subarachnoid neurocysticercosis is the most severe form of NCC; it occurs in about 5 percent of hospitalized cases.
Subarachnoid NCC may be associated with chronic arachnoiditis and/or mass effect due to cyst enlargement.
Chronic arachnoiditis may develop as a result of local inflammation; in some cases, it may be associated with communicating hydrocephalus, vasculitis, meningitis, and stroke. Mass effect and focal neurologic defects can develop in patients whose cysticerci enlarge within in the subarachnoid space, where cysts may grow to 10 cm or larger

*Other manifestations – Other clinical presentations of NCC include spinal lesions (1 percent of cases) and ocular lesions (1 to 3 percent of cases). Spinal cysticerci are usually located in the subarachnoid space where they can cause inflammatory and demyelinating changes in the peripheral nerve roots. Patients typically present with radicular pain, paresthesias, and/or sphincter disturbances. Patients with ocular cysticercosis may have involvement of the subretinal space, vitreous humor, anterior chamber, conjunctiva, or extraocular muscles.

Question 64

Neurocysticercosis: 1) diagnosis 2) treatment

Answer 64

1)
https://www.uptodate.com/contents/image?imageKey=ID%2F117226&topicKey=ID%2F5678&search=neurocysticercosis&rank=1~25&source=see_link

https://www.uptodate.com/contents/image?imageKey=ID%2F117225&topicKey=ID%2F5678&search=neurocysticercosis&rank=1~25&source=see_link

scolex= κεφάλι ενός κεστώδους σκώληκα

2)
Anticonvulsants are recommended, at least during the first several months after symptomatic seizures.
During periods of cysticidal therapy, which consists of albendazole, 400 mg orally every 12 hours for 10 days, corticosteroids are added prophylactically to prevent seizures and minimize meningeal reactions.

When retinal lesions are present, no cysticidal therapy should be given to avoid blindness from the inflammatory response.
Surgical decompression is required only in patients with giant, symptomatic, or intraventricular cysts.

Question 65

Differential of ring -enhancing lesions

Answer 65

The differential for peripheral or ring enhancing cerebral lesions includes:

Mnemonic DR MAGICAL

D: demyelinating disease (classically incomplete rim of enhancement)
R: radiation necrosis or resolving hematoma
M: metastasis
A: abscess
G: glioblastoma
I: infarct (subacute phase) or inflammatory (neurocysticercosis, tuberculoma)
C: contusion
A: AIDS-related CNS disease (e.g. toxoplasmosis, cryptococcosis)
L: lymphoma (this appearance is more common in immunocompromised)

Question 66

Difference between pachymeningitis and leptomeningitis

Answer 66

Pachymeningitis involves the dura-arachnoid
Leptomeningitis affects the pia and subarachnoid spaces