NEUROLOGY OF INFECTIOUS DISEASES

Bacterial Meningitis S. pneumoniae and N. meningitidis: most common pathogens in adults

L. monocytogenes: possible pathogen in neonates, the elderly, alcoholics, and immunosuppressed patients; these patients need empiric treatment with ampicillin

An appropriate empiric treatment for adults with acute bacterial meningitis is vancomycin and a third-generation cephalosporin, such as ceftriaxone, with or without ampicillin

(through a burr hole) or excision, followed by prolonged course of antibiotics

c. Corticosteroids for marked surrounding vasogenic edema, mass effect, or increased ICP

d. Antiepileptic medicines for treatment of seizures

C. Cranial Epidural Abscess 1. Develops between inner aspect of the skull and dura

mater 2. Typically, local spread from cranial infection (orbit, ear,

sinus, mastoid process, surrounding bone), but can also develop postoperatively (craniotomy) or after trauma

3. Usual pathogens: Staphylococcus aureus, aerobes, anaerobes, and gram-negative organisms

4. Clinical presentation: fever, severe unilateral headache, focal neurologic signs

5. Diagnosis: characteristic MRI features-epidural collection, increased signal on both T1 and T2 sequences, often with marked dural enhancement

6. Treatment a. Neurosurgical drainage: culture and Gram staining of

collection should be performed b. Empirical treatment with antibiotics: third-or fourth-

generation cephalosporin and vancomycin

D. Subdural Empyema 1. Collection of pus between dura mater and arachnoid 2. Typically due to local spread from cranial infection,

e.g., paranasal sinusitis, mastoiditis, or otitis media 3. Usual pathogens: aerobic, microaerophilic, and anaero-

bic streptococci 4. Clinical presentation: fever, headache, increased ICP

and change in level of consciousness, focal brain ischemia, focal neurologic deficits, seizures

5. Diagnosis a. Lumbar puncture contraindicated b. MRI characteristics: crescent-shaped fluid collections in

subdural space, with increased signal intensity on T1 and T2 sequences

6. Treatment: neurosurgical evacuation and empirical treatment with antibiotics to include penicillin G or third-or fourth-generation cephalosporin, metronidazole, and vancomycin

E. Spinal Epidural Abscess 1. Bacterial infection in spinal epidural space 2. Pathogenesis often involves spread from local infection

(e.g., osteomyelitis, soft tissue infection), trauma, intravenous drug use, postoperative, or after epidural

catheter placement 3. Most epidural abscesses: posterior to spinal cord 4. Most common pathogens: Staphylococcus aureus, then

gram-negative bacilli, and Streptococcus 5. Clinical presentation: subacute (hours-days) or more

chronic (several weeks) localized back pain, radicular symptoms, myelopathy, paralysis, fever

6. Most common location: thoracic spine (>50% of cases) 7. Diagnosis with emergent MRI showing an enhancing

epidural collection, often posterior to spinal cord, with varying degrees of mass effect

8. Treatment: surgical drainage of abscess and empirical treatment with antibiotics

F. Most Common Pathogens of Meningitis and Abscess

1. Streptococcus pneumoniae a. Gram-positive coccus b. Acquired via inhalation c. Causes disease in immunocompetent patients, but high-

er risk if immunocompromised d. Most common cause of bacterial meningitis e. Treatment: vancomycin and cefepime (or ceftriaxone)

for penicillin-resistant organisms, and penicillin G for the penicillin-sensitive organisms

f. Vaccination available 2. Neisseria meningitidis

a. Gram-negative diplococcus b. Second most frequent cause of bacterial meningitis in

adults c. Also very frequent in young adults d. Petechial rash (usually in lower trunk, lower extremities)

is common e. Treatment: third-generation cephalosporin or penicillin

G or ampicillin f. Close contacts should be treated with ciprofloxacin or

rifampin g. Vaccine is available h. Increased risk in patients with complement deficiency

3. Haemophilus influenzae a. Gram-negative coccobacillus b. Acquired via inhalation c. Much less common cause of meningitis since advent of

vaccine d. Optimal treatment: ceftriaxone, cefotaxime, or cefepime e. Rifampin prophylaxis for household contacts if other

young children 4. Listeria monocytogenes

a. Gram-positive bacillus, found widely in nature b. May cause acute or chronic meningitis

c. Most common in children younger than 1 year, adults older than 60 years, immunosuppressed patients, and in the setting of alcoholism and pregnancy

d. Best covered by ampicillin 5. Group B streptococcus (Streptococcus agalactiae)

a. Gram-positive coccus b. Most common in infants, usually within first month of

life (may occur in immunosuppressed elderly) c. Pathogenesis typically involves passage through colonized

birth canal (note: many asymptomatic women have vaginal colonization)

d. Treatment: ampicillin or penicillin G 6. Enterobacteriaceae (such as Klebsiella or E. coli)

a. Gram-negative bacillus b. Most common in infants within first month of life c. Treatment: ceftriaxone, cefotaxime, or cefepime

G. Lyme Disease: neuroborreliosis 1. Pathogenic agent: Borrelia burgdorferi (a spirochete) 2. Transmitted via bite of Ixodes tick in nymph stage, usu-

ally acquired in the summer 3. Regional predilection for the Northeast, Midwest, and

Northwest United States 4. Early infection (3-32 days): erythema migrans

a. “Bull’s-eye rash”: center of the lesion is site of tick bite, surrounded by a migrating erythematous ring that expands outward

b. Present in most, but not all patients c. Often nonspecific symptoms such as fever, malaise, mus-

cle aches, headache 5. Second stage (several weeks after onset of the rash)

a. Systemic signs: additional skin lesions, arthralgias, and cardiac abnormalities (arrhythmias, myopericarditis, ventricular dysfunction)

Lyme Disease Caused by B. burgdorferi

Three major stages: 1st (primary) stage: erythema migrans (bulls-eye rash)

2nd stage: systemic manifestations, including arthralgias, cardiac involvement, and multiple types of neuropathies and/or meningitis

3rd stage: neuropathy, encephalopathy, encephalomyelopathy

b. Headache, stiff neck, aseptic meningitis c. Radiculitis: dermatomal distribution of pain and sensory

loss, and corresponding myotomal weakness and reflex changes

d. Cranial neuropathies: especially cranial nerve (CN) VII (facial nerve)

e. Polyneuropathy (peripheral neuropathy, polyradiculoneuropathy, or mononeuritis multiplex)

f. Brachial plexopathy or lumbosacral plexopathy may be first manifestation

6. Third stage (many months after second stage) a. Systemic features, including large-joint arthritis, carditis b. Any of the aforementioned peripheral nerve manifesta-

tions, especially long-standing and indolent lengthdependent, symmetric peripheral neuropathy

c. Neurologic features may also include chronic encephalomyelopathy: many cases termed “mild encephalopathy” may encompass “memory dysfunction” that may be attributed to other causes, including psychiatric disease rather than organic brain disease

7. Diagnosis a. Serologic testing is negative early in disease course:

patients with classic skin lesions and negative for antibodies should be treated

b. Enzyme-linked immunosorbent assay (ELISA): high false-positive rate because of cross-reactivity

c. Western blot: higher specificity than ELISA (less sensitivity), used as a confirmatory test for positive ELISA

d. CSF: lymphocytic pleocytosis (mean cell count, 166 WBCs/mm3), normal or increased protein (8-400 mg/dL), and oligoclonal bands (may remain positive for decades while the other markers normalize)

e. CSF polymerase chain reaction (PCR): high specificity, limited sensitivity

f. MRI: normal or may show leptomeningeal enhancement in patients with meningitis

8. Treatment a. Doxycycline for patients with nonneurologic manifesta-

tions only b. Ceftriaxone (intravenous) for neuroborreliosis (better

central nervous system [CNS] penetration)

H. Neurosyphilis 1. Pathogen: Treponema pallidum (a spirochete) 2. Transmission through exposure to infected skin or

mucous membrane lesion (usually during sexual contact); may also occur from passage through birth canal

3. Clinical features a. Primary syphilis

1) Usually occurs within few weeks after exposure

2) Manifests as painless chancre at initial site of infection (usually genitalia)

b. Chancre 1) Painless 2) Appears at site of inoculation, with raised border and

ulcerated center (resolves without intervention) c. Most patients with primary syphilis develop secondary

syphilis d. Secondary syphilis (weeks to months after primary

syphilis): nonspecific symptoms-fever, headache, rash (including palms and soles), condyloma latum, generalized lymphadenopathy (resolves without intervention)

e. Syphilitic meningitis may occur in secondary syphilis stage (within first 2 years after primary infection) and responds well to treatment

f. Syphilitic meningitis is often characterized by headache, nausea, vomiting, meningismus, altered mentation, seizures, cranial neuropathies

g. Latent syphilis: absence of clinical signs and symptoms, but persistent serologic evidence (may last several years, and may eventually progress to tertiary syphilis)

h. Tertiary syphilis: gummatous syphilis, cardiovascular (including aortitis) and CNS complications, iritis

i. Major neurologic complications occur in tertiary syphilis, which can occur up to decades after primary infection

j. CNS involvement 1) Tabes dorsalis (involvement of posterior columns of

spinal cord) a) Usually manifests as proprioceptive loss, sensory

ataxia, lancinating and lightning-like pains, and areflexia

b) Patients may develop trophic changes because of sensory loss, including Charcot joints

2) Meningovascular syphilis (peaks about 7 years after primary infection): characterized by inflammation of intracerebral blood vessels, which can lead to strokes in different arterial distributions (may also affect arterial vasculature of spinal cord)

3) Parenchymatous neurosyphilis (paretic neurosyphilis, general paresis of the insane): chronic meningoencephalitis characterized by slowly progressive syndrome of dementia and neuropsychiatric symptoms with prominent personality change, emotional lability, easy fatigability, sleep disturbance, and poor judgment (with progression)

4) Gummatous neurosyphilis a) Rare b) CNS gummas often arise from meninges c) Symptoms often due to local mass effect or

parenchymatous extension

5) Argyll Robertson pupils a) Result from brainstem damage b) Poor direct and consensual pupillary reflexes, but

preserved constriction to accommodation 4. Diagnosis

a. Dark field microscopy: used for direct examination of infective organisms in chancre of primary syphilis (insensitive for demonstrating organism in CSF)

b. CSF in acute syphilitic meningitis: mild mononuclear pleocytosis, mildly increased protein, normal or slightly decreased glucose, positive VDRL

c. CSF in meningovascular syphilis: mild lymphocytic pleocytosis with increased protein

d. Magnetic resonance angiography or conventional cerebral angiography in meningovascular syphilis: may show focal narrowing of affected vasculature

e. CSF VDRL 1) High specificity with low sensitivity for CNS syphilis

(in the absence of blood contamination by traumatic lumbar puncture)

2) Not reliable for following treatment response f. Rapid plasma reagin (RPR) test: variation of VDRL

(used only in serum, not suitable for CSF) g. Fluorescent treponemal antibody (FTA) test

1) Is called “FTA-ABS” when antigen preparation is absorbed

2) High false-positive rate when used on CSF: very little blood contamination can cause positive reaction

3) More sensitive than VDRL 4) Negative CSF FTA test essentially excludes neuro-

syphilis, but a positive test is not diagnostic 5) May remain positive for many years: a positive FTA-

ABS and negative VDRL may be seen in successfully treated syphilis

h. T. pallidum hemagglutination assay: another treponemal serologic test

5. Pathology a. Parenchymatous neurosyphilis (paretic neurosyphilis,

general paresis of the insane): thickened leptomeninges, atrophied gyri, granular appearance of ependymal lining, scanty meningeal and perivascular lymphocytic infiltrates

b. Meningovascular neurosyphilis: leptomeningeal and perivascular parenchymal lymphocytic infiltrates

6. Treatment a. Aqueous crystalline penicillin G 18 to 24 million units

daily, administered as 3 to 4 million units intravenously every 4 hours for 2 weeks or a continuous infusion, or

b. Procaine penicillin 2.4 million units intramuscularly once daily and probenecid 500 mg orally 4 times daily for 10 to 14 days

I. CNS Tuberculosis 1. Pathogen: Mycobacterium tuberculosis, a gram-positive

aerobic bacterium with very slow growth and associated with subacute to chronic meningitis

2. Usual route of transmission: inhalation of aerosolized droplet nuclei; may spread hematogenously to extrapulmonary sites, including CNS

3. Incidence of tuberculosis in United States has increased since advent of HIV

4. Subacute to chronic meningitis a. Clinical features

1) Most common CNS presentation 2) Prodrome of 2 to 4 weeks: nonspecific symptoms of

fatigue, malaise, and possibly fever 3) Mental status

a) Fully alert and oriented (first stage) b) Confused, disoriented, and inattentive (second

stage) c) Comatose or stuporous (third stage)

4) Fever, meningismus, headache, nausea, vomiting, and often basilar signs, such as cranial nerve palsies (CN VI most commonly affected)

5) Ophthalmoscopic examination may show papilledema or choroidal tubercles (latter observed only in small fraction of patients)

6) Other possible features: seizures, hydrocephalus (more frequently in children than adults)

7) Similar presentation for CNS tuberculosis in setting of HIV infection

8) Complications may include hydrocephalus and cerebral infarctions (the latter due to vascular involvement of the leptomeningeal and pachymeningeal inflammation)

b. Diagnosis 1) Acid-fast bacilli (AFB) smear: positive in 10% to

30% of cases 2) Purified protein derivative (PPD): false positive in

patients who have received the BCG vaccine, and false negative in patients with severe immunosuppression

3) Chest radiograph: possible presence of lymphadenopathy and Ghon’s complex or miliary lesions

4) Neuroimaging: meningeal enhancement of basal cisterns, especially interpeduncular fossa and ambiens cisterns

5) CSF profile: lymphocytic pleocytosis, decreased glucose, increased protein

6) CSF PCR: specificity, 94% to 100%; sensitivity, 54% to 100%

7) CSF amplified Mycobacterium tuberculosis direct test:

rapid (available within 24 hours) and probably highly specific and sensitive nucleic acid amplification assay

c. Treatment 1) First-line antimicrobial agents: isoniazid (INH),

rifampin, ethambutol, pyrazinamide, streptomycin 2) Second-line antimicrobial agents: ethionamide,

cycloserine 5. Parenchymal tuberculosis: tuberculoma and tubercu-

loid abscess a. Clinical features

1) May be found in cerebral or cerebellar parenchyma and deep gray matter; may involve epidural, subdural, or subarachnoid space

2) Clinical presentation a) Depends on location of lesion b) May include headaches, seizures, increased ICP,

and papilledema 3) Clinical course of an underlying tuberculoid abscess is

usually more precipitous and marked with rapid progression compared with indolent chronic progression of tuberculoma

b. Diagnosis 1) Neuroimaging

a) Tuberculomas: appear as isointense to parenchyma on T1-weighted images; may have central hyperintense region on T2-weighted images, with surrounding ring enhancement characteristics; there may be central calcification in mature tuberculomas (Fig. 15-4)

b) Multiple small lesions: characteristic of miliary spread

2) CSF may be normal 3) Response to antituberculosis antibiotics

c. Pathology: central caseation necrosis surrounded by collagenous capsule with multinucleated giant cells, epithelioid cells, fibroblasts, and mononuclear inflammatory infiltrates (to be differentiated from acute tuberuous abscess, which is liquefactive necrosis with neutrophilic inflammatory infiltrates); vasogenic edema and gliosis may occur outside the tuberculoma

d. Treatment 1) Antimicrobial agents and dexamethasone 2) Surgical resection when medical treatment fails or if

diagnosis is uncetain 6. Spinal tuberculosis

a. Spinal tuberculous meningitis 1) Rare, may be caused by dissemination of disease in

context of intracranial meningitis 2) Subacute or chronic onset of radiculomyelitis, due to

involvement of the spinal cord and roots

3) Imaging characteristics: leptomeningeal enchancement; clumping and enhancement of the roots

4) May rarely present as tuberculomas in the intradural or intramedullary space

b. Pott’s disease: vertebral tuberculosis infection 1) Most often involves low thoracic and thoracolumbar

region 2) Usually starts in anterior aspect of vertebral bodies

(often more than one segment) and spreads to adjacent intervertebral disks, causing softening and collapse of the vertebrae, producing kyphosis

3) May involve paravertebral tissues; may give rise to paravertebral abscesses

4) May result in pronounced spondylosis and spinal cord compromise: myelopathic or radicular symptoms and signs

5) Clinical features a) Gradual onset b) Back pain: may be present for several weeks before

presentation c) Paraspinal muscle spasms d) Kyphotic deformity of spine e) Constitutional symptoms may be present: fever,

weight loss

f) Retropharyngeal abscess when upper cervical spine is involved

6) Treatment: antimicrobial agents; surgical treatment for patients with progressive neurologic deficits, spinal instability, and poor response to antimicrobial agents

J. Leprosy (Hansen’s disease) 1. Pathophysiology

a. Etiologic agent: Mycobacterium leprae, AFB, responsible for infection of peripheral nerves and overlying skin

b. Most likely route of transmission: respiratory or cutaneous

c. Directly infects Schwann cells, producing demyelination of peripheral nerves

d. There may be granulomatous damage of the perineurium

e. Rare in United States, usually occurs in immigrants from endemic areas (e.g., Southeast Asia)

2. Clinical features a. Chronic infection, marked by very slow growth of the

bacillus b. Peripheral nerve trophism with preference for cooler

body regions, 7-10°C cooler than core temperatures c. Skin lesions: multiple, multifocal hypopigmented, anes-

thetic patches d. Peripheral nerve involvement: loss of pain and tempera-

ture and soft sensation in the hypopigmented, anhidrotic skin lesions involving the distal cutaneous sensory branches, with relative preservation of vibratory and proprioceptive sensation

e. Clinical syndrome of mononeuritis multiplex occurs when there is proximal involvement of the individual peripheral nerves

f. Peripheral nerves are more predisposed to entrapment at the common sites of compression

g. Tuberculoid leprosy 1) Occurs in setting of good host immunity

2) Well-demarcated lesions with raised erythematous borders and central clearing

3) Limited form of leprosy, but antibiotic treatment is often required

4) Most frequently affected peripheral nerve is ulnar nerve

h. Lepromatous leprosy 1) Occurs in setting of inadequate host immunity 2) Ongoing bacteremia, organisms deposit throughout

the body and establish infection in cooler body regions

3) Skin lesions are poorly demarcated and may appear as diffuse, infiltrative, nodular, and erythematous lesions

4) Initially, often a painful, purely sensory neuropathy, with preferential involvement of extensor surfaces of upper and lower limbs, pinnae of the ears, and zygomatic arch bilaterally

5) With progression: nerve trunk involvement, with enlargement and damage of peripheral nerves; motor and sensory loss in the distribution of individual nerves

i. Intermediate form: features of both tuberculoid and lepromatous types

3. Diagnosis a. Tissue diagnosis with skin smears or nerve biopsies:

weakly AFB positive b. Lepromin skin test: similar to PPD, Fernandez reaction

read at 48 hours (indicative of infection), and Mitsuda reaction read at 4 to 5 weeks (indicative of resistance)

4. Treatment: dapsone, clofazimine, rifampin

K. Rickettsial Infections 1. Pathogens: Rickettsia rickettsii, R. conorii, R. prowazekii,

and Orientia tsutsugamushi 2. Clinical features of neurologic disease

a. Headaches, altered mentation, coma, seizures, focal neurologic deficits

b. Aseptic meningitis is a common presentation; CSF polymorphonuclear cells may be prominent in some patients

c. Rocky Mountain spotted fever 1) Pathogen: R. rickettsii 2) Headache, high fever, nausea, myalgias, arthralgias,

malaise, conjunctival injection 3) Maculopapular, petechial, and ecchymotic rash (often

first appearing as macular, “small red dots,” then becoming petechial): appears first on wrists and ankles, then spreads to involve the soles and palms, and then the trunk

4) Meningitis or meningoencephalitis may follow severe cases

Mycobacteria M. tuberculosis can present neurologically with chronic basilar meningitis

M. leprae presents with hypopigmented, anesthetic patches of skin and multiple mononeuropathies

Both types of mycobacteria require long-term multidrug therapy

5) Organisms are angioinvasive and may cause microangiopathy a) May produce CNS microinfarcts, retinal vasculitis b) Conjunctival injection and skin rash may be

explained on basis of this microangiopathy d. Scrub typhus

1) Pathogen: O. tsutsugamushi 2) Transmitted by bites of larvae of mites (larvae live in

soil and mites live in rodents) 3) Two-week incubation period 4) Fever, headache, painful adenopathy, scab at original

bite site 5) Neurologic complications uncommon, but may cause

aseptic meningitis e. Endemic, or murine, typhus

1) Pathogen: R. typhi 2) Presentation: fever, nausea, maculopapular truncal

rash, myalgias, and malaise 3) Neurologic complications uncommon

f. Epidemic typhus 1) Pathogen: R. prowazekii 2) Clinical features: 12-to 14-day incubation period fol-

lowed by a) Headache, fever, macular rash first appearing in

upper trunk and axillae and sparing the face, palms, and soles

b) Meningitis, meningoencephalitis: unrelenting fever, delirium, confusion, coma, focal deficits

c) Organisms invade endothelial cells d) May be complicated by brainstem microinfarctions

3. Treatment: chloramphenicol, tetracycline, doxycycline

L. Whipple’s Disease 1. Pathogen: Tropheryma whippelii 2. Multisystem involvement, but almost always involves

gastrointestinal tract: arthralgias, weight loss, diarrhea, abdominal pain, low-grade fever, lymphadenopathy

3. Neurologic manifestations a. Altered mentation, encephalopathy, coma, seizures b. Dementia from chronic and recurrent meningitis c. Involvement of hypothalamic-pituitary axis: polydipsia,

polyuria, hypogonadism, hyperinsomnia d. Supranuclear ophthalmoplegia e. Cerebellar ataxia f. Myelopathy g. Oculomasticatory myorhythmia: characterized by slow

and smooth convergent-divergent pendular nystagmus associated with synchronous rhythmic myoclonic movements of tongue and mandible

h. Oculofacial-skeletal myorhythmia: similar rhythmic

movements involving different muscle groups in face and limbs

4. Diagnosis a. CSF PCR for T. whippelii b. Small-bowel biopsy c. Neuroimaging: often normal, may show parenchymal

T2 hyperintensities in middle cerebellar peduncle and other parenchyma

5. Treatment a. Trimethoprim-sulfamethoxazole: for initial therapy, also

for recurrent disease b. Alternative treatments: combination of penicillin and

streptomycin or parenteral ceftriaxone

A. Viral Meningitis (aseptic meningitis) 1. Clinical features: fever, chills, headaches, photophobia,

nuchal rigidity, nausea, anorexia, myalgias, with or without rash

2. Most common pathogens and specific features a. Enteroviruses

1) Most common cause of aseptic meningitis 2) Coxsackieviruses, echoviruses, polioviruses, and

human enteroviruses 68 to 71 3) Infection transmitted by fecal-oral contamination,

respiratory droplets 4) Seasonal peak in late summer 5) May be a respiratory or gastrointestinal prodrome 6) Benign form of viral meningitis, except in immuno-

suppressed patients (in which case may be protracted or recurrent)

b. La Crosse (California) encephalitis 1) Most common cause of arbovirus meningoencephali-

tis in United States 2) Clinical presentation is aseptic meningitis, often

occurring concurrently with encephalitis 3) Mild disease, predominantly affecting children

(>85% of cases in children <12 years old) 4) Seizures are common (distinguishing feature): gener-

alized and partial seizures develop with approximately equal frequency; status epilepticus occurs in 25%

5) Focal signs or symptoms in 20% 6) Serologic tests may not be positive until 2 to 4 weeks

after acute illness 7) Seasonal peak in late summer 8) Usually self-limited and uncomplicated: mortality

less than 1%, persistent sequelae in ~10% to 15%

(memory and behavioral disturbance, aphasia, seizures, cranial nerve palsies)

9) Rarely may have fulminant presentation, with fever, headache, obtundation progressing to coma, and sometimes status epilepticus

c. Mumps (see below, under “C. Specific Viral Entities”) d. Herpes simplex type 2

1) Herpesvirus, a DNA virus 2) May cause viral meningitis concurrent with, or after,

primary genital infection by reactivation from sacral dorsal root ganglia

3) The most common agent believed to cause benign recurrent lymphocytic meningitis (Mollaret’s meningitis)

4) Genital lesions may not be observed in recurrent meningitis

5) Diagnosis a) CSF: positive PCR for herpes simplex virus

(HSV) type 2, protein normal or mildly increased, glucose normal or mildly decreased, lymphocytic pleocytosis (may be mainly polymorphonuclear neutrophils if CSF obtained within first 48 hours), usually WBC <1,000 cells/mm3

b) Neuroimaging: may be normal or show leptomeningeal enhancement

e. Varicella-zoster virus (VZV) 1) Syndrome of meningoencephalitis, usually in context

of zoster, with dermatomal distribution of vesicular rash, accompanying pain, and possibly dermatomal neurologic deficits (most often as a complication of ophthalmic zoster)

2) May also cause self-limited cerebellar ataxia, brainstem encephalitis, transverse myelitis, granulomatous arteritis, and small-vessel angiopathy, sometimes producing cerebral infarction

3) Mild lymphocytic pleocytosis may be present in context of uncomplicated dermatomal zoster, without clinical features of aseptic meningitis

4) Good prognosis 5) Recommended treatment with acyclovir, especially in

immunosuppressed patients f. HIV-1: may spread to CSF and meninges during time

of acute infection and cause aseptic meningitis g. Lymphocytic choreomeningitis

1) Rodent-borne virus transmitted to humans through exposure to rodent urine, feces, saliva, or blood

2) Often asymptomatic or mild but can cause aseptic meningitis, encephalitis, life-threatening infections in immunosuppressed persons

3) May cause severe congenital defects

h. Arboviruses (other than La Crosse encephalitis): much more common cause of encephalitis or meningoencephalitis (discussed below)

B. Viral Encephalitis 1. Viral infection of brain parenchyma 2. Most common nonepidemic viral cause: HSV-1 3. Pathogenesis

a. Viruses may penetrate mucosal surfaces, skin, or gastrointestinal or genitourinary barriers

b. Pathogens seed CNS via hematogenous (most common route) or neuronal spread by reactivation from neural ganglia, followed by retrograde axonal transmission

c. Hematogenous dissemination is most common method of viral entry to CNS; involves transient viremia shortly after inoculation and viral replication at site of inoculation

d. Pathogenic virus tends to spread to reticuloendothelial organs (lymph nodes, liver, spleen, bone marrow), where viral replication continues and second wave of increased viremia occurs

4. Clinical features a. Encephalitis usually occurs concurrent with meningitis

as meningoencephalitis b. Acute onset of febrile illness, headache, nuchal rigidity,

altered mental status with disorientation, and behavioral disturbance

c. HSV encephalitis: aphasia, complex partial seizures, characteristic electroencephalographic (EEG) findings (periodic lateralized epileptiform discharges [PLEDs])

5. Pathology a. Lymphocytic infiltration of brain parenchyma and

meninges, with edema and necrosis b. Microglial nodules c. There may be virus-specific inclusions d. Immunohistochemistry for organism identification

6. Most common pathogens and specific features a. HSV-1

1) Most common nonepidemic cause of viral encephalitis

2) Predilection for inferior frontal and temporal lobes: causes behavioral dysfunction, personality change, aphasia, complex partial seizures, and PLEDs localized to involved parenchyma

3) Fever with or without nuchal rigidity 4) CSF may show red blood cells (because of underlying

hemorrhagic necrosis of involved parenchyma) 5) CSF PCR

a) Highly sensitive and specific; useful for early detection

b) Influenced by antiviral therapy: 98% remain positive within first week of treatment (47% with 1-2 weeks of treatment, 21% with >2 weeks of treatment)

6) Serologic testing a) May be used after at least 2 weeks of illness; largely

replaced by CSF PCR b) Increased serum titers: nonspecific c) Serum:CSF ratio less than 20:1 (after at least 2

weeks of infection) strongly favors primary CNS antibody production and indicates CNS infection

7) Pathology (Fig. 15-5) a) Perivascular mononuclear infiltrates b) Necrotizing inflammation c) Foci of hemorrhage d) Intranuclear viral inclusions

8) Neuroimaging (Fig. 15-6): T2 hyperintense lesions predominantly involving frontotemporal regions, variable enhancement, with or without hemorrhagic component

9) Treatment: intravenous acyclovir should be started as soon as possible because of high mortality rate

10) Mortality: 70% of untreated patients b. Arboviruses

1) Arthropod-borne 2) Common epidemic encephalitis of summer months 3) Usually cause meningoencephalitis: seizures, focal

neurologic deficits 4) Benign illness without sequelae, good prognosis 5) La Crosse (California) encephalitis (discussed above) 6) Japanese encephalitis virus (Flavivirus)

a) Most common cause of arbovirus encephalitis worldwide

b) Route of transmission: from Culex mosquito bite (mosquitoes acquire it from infected birds or pigs), hematogenous spread to CNS

c) Predominantly affects children in endemic regions d) Most infected patients do not develop CNS

symptoms e) Typical clinical presentation in symptomatic cases:

febrile headache, aseptic meningitis, or encephalitis f) Prodrome of viral illness: headache, nausea, vomit-

ing, low-grade fever, other constitutional symptoms, behavioral change, and often seizures

g) Virus can spread to and establish infection in various regions of brain via hematogenous dissemination: cerebral cortex, deep gray matter (thalamus, basal ganglia, substantia nigra), brainstem, and cerebellum

h) Clinical features depend on part of CNS involved

i) Extrapyramidal features: tremors, axial rigidity, cogwheel appendicular rigidity, choreoathetosis from involvement of basal ganglia

j) Spinal cord involvement: asymmetric flaccid paralysis from involvement of anterior horn cells, affecting lower more than upper extremities

k) Brainstem involvement (rhombencephalitis): cranial nerve palsies, diffuse weakness, long tract signs

l) Cerebellar involvement: ataxia m) Mortality is 30%; approximately half of survivors

continue to have severe neurologic sequelae 7) St. Louis encephalitis virus (SLEV)

a) Most common in southern, western, and midwestern United States; mainly occurs in late summer and autumn months

b) Route of transmission: from Culex mosquito bite c) Patients are usually older than those with other

arboviral illnesses d) Frank encephalitis with psychotic features occurs in

older patients e) Aseptic meningitis in 25% of patients, usually in

younger patients f) Labial, lingual, and hand tremors in 50% of

patients

g) Slow progression of encephalitis, generalized fatigue, malaise, and tremors characterize syndrome

h) Mortality rate: 20% 8) West Nile virus

a) Usually asymptomatic in areas of endemic disease b) Elderly and immunosuppressed persons are at risk

for encephalitis c) Severe neurologic manifestations are more com-

mon in young children and elderly d) Febrile viral illness occurs after incubation period

of 3 to 15 days: pharyngitis, headache, conjunctivitis, malaise and fatigue, back pain

e) May be gastrointestinal symptoms: nausea, abdominal pain, diarrhea

f) Prominent and distinguishing feature of West Nile virus infection: tremor (up to 94% of patients)

g) May be other extrapyramidal symptoms: myoclonus (40%) and parkinsonism (75%)

h) Direct infection of anterior horn cells causes poliomyelitis-like acute flaccid paralysis characterized by acute onset of asymmetric muscle weakness and hyporeflexia with minimal sensory abnormalities

i) CSF profile: mild lymphocytic pleocytosis (27-51 cells), normal or increased protein (38-899 mg/dL), usually normal glucose

j) CSF anti-West Nile virus IgM antibodies by ELISA: IgM antibodies do not cross blood-brain barrier; their presence indicates intrathecal antibody production and CNS infection

k) CSF PCR: low sensitivity, high specificity l) Neuroimaging: may show meningeal, thalamus, or

basal ganglia abnormalities 9) Eastern equine encephalitis virus

a) Responsible for most severe arboviral encephalitis b) Clinical presentation marked by abrupt onset of

fever, convulsions, altered mentation, with rapid progression to coma

c) Encephalitis may be preceded by viral prodrome of constitutional symptoms

d) There may be focal lesions in basal ganglia and thalamus (less often, brainstem)

10) Western equine encephalitis virus a) Asymptomatic infections are common b) Viral prodrome, presenting with pharyngitis, myal-

gias, fever, and other constitutional symptoms c) Convulsions and progression to coma develops in

some patients 11) Epstein-Barr virus (EBV) (see below) 12) Cytomegalovirus (CMV) (see below)

C. Specific Viral Entities 1. Herpesviruses

a. HSV-1 and HSV-2 (discussed above) b. VZV

1) Chickenpox: primary infection, usually without neurologic sequelae; the virus becomes latent in dorsal root ganglia

2) Pathogenesis of herpes zoster virus infection

a) Due to reactivation of latent virus in dorsal root ganglia

b) Reactivation after trauma or with reduced cellmediated immunity with age or concurrent immunosuppression

c) Radicular pain and paresthesias in cranial or spinal dermatomes, followed by vesicular rash involving same distribution

d) Usually involves mid to low thoracic (less commonly, cranial and lumbosacral) segments

e) Possible sequelae: postherpetic neuralgia f) Ophthalmic zoster: involvement of first division

of trigeminal ganglion, may be complicated by aseptic meningitis or granulomatous arteritis

g) Ramsey Hunt syndrome: painful facial weakness accompanied by vesicular eruption involving external auditory canal

h) Cranial nerve involvement in older patients: high risk for developing meningoencephalitis, all should be treated with antiviral agents

3) Aseptic meningitis and meningoencephalitis (discussed above)

4) Zoster myelitis (spinal cord involvement): poor prognosis for recovery of encephalomyelitis, especially if underlying immunosuppression

5) Self-limited cerebellar ataxia 6) Granulomatous arteritis and small-vessel

microangiopathy a) May complicate ophthalmic zoster b) Multifocal ischemic and occasional hemorrhagic

infarcts c) Hyperplasia of blood vessel intima and media and

superimposed thrombus formation d) Small-vessel arteritis, microangiopathy: may cause

multifocal deep white matter lesions 7) Reye’s syndrome: may rarely occur in children, par-

ticularly with use of aspirin; characterized by encephalopathy, renal failure, and liver dysfunction

8) Postinfectious multifocal, demyelinating leukoencephalomyelitis: rare, demyelination due to infection of oligodendrocytes, with Cowdry type A intranuclear inclusions

9) Treatment: supportive measures, intravenous acyclovir or famciclovir

c. CMV 1) Largest human herpesvirus 2) A DNA virus 3) Ubiquitous presence in asymptomatic persons, with

widespread exposure among population: 80% of individuals are seropositive for CMV by adulthood

West Nile Encephalitis Two most common presentations

Meningoencephalitis: typical encephalitic features Flaccid paralysis: poliolike clinical features with anterior horn cell damage

Rare cases of parkinsonism, myoclonus, and other clinical presentations

4) Predominantly a disease of immunocompromised host and infected newborns

5) Can infect several organs, including nervous system; infection may remain latent or be persistent

6) Immunocompetent persons: acute infection may be asymptomatic or, uncommonly, person may present with aseptic meningitis or mononucleosis syndrome

7) Acute meningitis of CMV 8) CMV encephalitis

a) Occurs in immunocompromised adults (rare in immunocompetent patients)

b) Fever, headache, mental status changes, cranial nerve palsies, cognitive dysfunction

c) Multifocal CNS disease with involvement of spinal cord, nerve roots, ventricular and subependymal regions, and both gray and white matter (with predilection for deep gray matter structures)

d) Variable presentation: acute encephalitis or slowly progressive ventriculoencephalitis with necrotizing ependymitis or ventriculitis

e) Myeloradiculitis: patients may have predominance of polymorphonuclear cells and low glucose level (a profile more typical of bacterial infections)

f) Common presentation in context of HIV: ventriculitis or ependymitis with subacute progression, polymorphonuclear CSF pleocytosis with low CSF glucose level

9) Diffuse ependymitis and ventriculitis a) Presentation: subacute to chronic meningitis b) Cauda equina may be involved c) CSF: prominent mononuclear pleocytosis and

increased protein d) Subependymal enhancement outlining ventricular

system 10) CMV polyradiculopathy (discussed below) 11) Congenital CMV

a) Most common congenital infection b) Transmission to infant from infected mother: ver-

tical transmission through birth canal at time of delivery or breast milk in perinatal period

c) Most primary maternal infections transmitted to infants are acquired in first trimester

d) 90% of CMV-infected infants born to mothers with primary CMV infection have no clinical features of infection at birth; these infants carry lifetime risk up to 15% for sensorineural hearing loss

e) 10% of CMV-infected infants have clinical features of infection at birth: jaundice, hepatosplenomegaly, petechial rash, growth retardation, sensorineural hearing loss, microcephaly, micro-

gyria, seizures, cerebral calcifications, choreoretinitis, and death in perinatal period (5% of patients)

f) Children with very mild disease may only have sensorineural hearing loss

12) Pathology (Fig. 15-7) a) Involvement predominantly of ependymal cells

and microglia b) Cowdry type A intranuclear inclusions c) Microglial nodules (dense focal aggregates of

microglial cells and macrophages) d) Severity of inflammatory infiltrates depends on

degree of immunocompetence e) CMV ventriculitis: necrosis of ventricular surface f) CMV polyradiculopathy: necrosis of nerve roots,

inflammatory infiltrate 13) Diagnosis

a) Serologic testing: unreliable because of fluctuating titers

b) CSF PCR: sensitivity reported up to 95%, specificity of 99%

c) Infants symptomatic with congenital CMV: thrombocytopenia, direct hyperbilirubinemia, abnormal liver function enzymes, periventricular calcifications on CT (50% of symptomatic infants), and sometimes parenchymal neural migration abnormalities (when infection occurs during period of neural migration, e.g., polymicrogyria, lissencephaly, schizencephaly)

d) Other radiographic characeristics: ventriculomegaly because of parenchymal loss; focal areas of contrast enhancement (especially periventricular) apparent in the active infection, replaced later by nonenhancing calcification

14) Treatment: ganciclovir with or without foscarnet d. EBV

1) Infection spread through saliva; establishes latent infection in B cells

2) Acute infection

Congenital cytomegalovirus infection Phenotype varies from very mild (only sensorineural hearing loss) to severe cerebral injury, including developmental delay, microcephaly, microgyria, seizures, cerebral calcifications, choreoretinitis, and death in the perinatal period in 5% of patients

a) Asymptomatic b) Nonspecific febrile viral illness c) Infectious mononucleosis: cervical lymph-

adenopathy, pharyngitis, and splenomegaly 3) Neurologic complications in less than 1% of acute

EBV infections a) Aseptic meningitis: may occur at time of primary

infection, along with acute mononucleosis b) Encephalitis c) Cerebellitis d) Transverse myelitis e) Guillain-Barré syndrome f) Optic neuritis g) Cranial neuropathies, including facial palsy

4) May have a pathogenic role in development of primary CNS lymphoma in immunocompromised patients: EBV genome has been found in up to 100% of lymphomas in immunocompromised patients, including those with HIV infection (only 16% of lymphomas in immunocompetent patients)

5) Diagnosis by serologic studies a) Acute, acquired infection: presence of IgM anti-

bodies against EBV viral capsid antigen (VCA) or combination of IgG antibodies against both VCA and early antigen (EA-diffuse)

b) CSF IgM antibodies persist for several months and are sensitive and specific markers for acute CNS infection

c) Past exposure: presence of IgG antibodies against VCA and EBV nuclear antigen (EBNA), observed

in serum specimens collected as early as approximately 1 month after onset of illness

d) EBNA antibodies may remain positive for person’s lifetime; when present alone, they indicate remote infection

e) Heterophil antibody and Monospot tests: are unreliable and frequently negative in patients with EBV infections of CNS

6) Diagnosis by CSF PCR a) Not positive in patients with latent EBV infection b) Sensitivity and specificity for diagnosis of acute

EBV infections of the CNS: unknown c) EBV CSF PCR: often positive in patients with

acquired immunodeficiency syndrome (AIDS)- associated primary CNS lymphoma (PCNSL); test appears to be sensitive indicator of the presence of tumor

7) Treatment: data are largely anecdotal, successful use of ganciclovir has been reported

e. Human herpesvirus 6 (HHV-6) 1) Ubiquitous virus: 2/3 of children are seropositive by

1 year and up to 95% by adulthood 2) Responsible for roseola infantum in infants and

young children (also called sixth disease or exanthema subitum): high fever, malaise, irritability, and pharyngitis, followed by macular or maculopapular rash that starts on trunk

3) ~1/3 of babies with primary HHV-6 infection have seizures; common presentation is febrile seizures some time before the characteristic rash appears

4) After acute primary infection, HHV-6 becomes latent; it can reactivate in infants and young children, causing recurrent febrile seizures; can reactivate during immunosuppression

5) Recurrent HHV-6 should be considered as pathogenic agent in setting of recurrent febrile seizures (even without the characteristic rash)

6) Meningoencephalitis may occur in immunocompromised patients; can be severe in this setting

7) Most primary HHV-6 infections are self-limited and do not require treatment

8) HHV-6 infection has been associated with multiple sclerosis, but its pathogenic role has not been established

f. HHV-7 1) Clinical features of the acute infection are similar to

those of HHV-6 infection 2) Treatment: most isolates resistant to acyclovir but

sensitive to cidofovir, foscarnet, and ganciclovir (foscarnet may be more efficacious than ganciclovir)

2. Rabies virus a. Caused by rabies virus (an RNA virus) in genus

Lyssavirus, in rhabdovirus family b. Pathophysiology

1) Often due to bite of infected animal (e.g., skunk, bat, or raccoon); risk of CNS disease is 50 times higher with bite than scratch

2) Many cases do not have known exposure; this may be secondary to prolonged incubation of virus

3) Virus multiplies in muscle at inoculation site and is taken up by nerve endings in muscle spindles or at neuromuscular junction; is retrogradely transported to CNS

4) Centripetal spread to CNS: fast retrograde axonal transport results in widespread CNS infection; symptoms can occur years after infection

5) Some evidence that virus undergoes replication in dorsal root ganglia and anterior horn cells

6) Centrifugal spread from CNS: after infection is established in CNS, the virus can spread to different regions of head and neck

7) Bites at sites with high concentrations of nicotinic acetylcholine receptors (e.g., head or face) have greater chance of causing CNS infection and have shorter incubation periods

c. Clinical features 1) Incubation period: usually 1 to 2 months after expo-

sure (may be as early as 5 days if peripheral nerves directly inoculated)

2) Prodrome: nonspecific illness with fever, headache,

myalgias; possibly with local symptoms of paresthesias, numbness, dysesthesias, pruritis at site of exposure

3) Local symptoms start at site of the bite and spread to involve entire limb or ipsilateral face a) Onset of local symptoms marks end of incubation

period b) Condition progresses into acute neurologic infec-

tious phase, and most patients die within next 2 weeks

4) Acute neurologic phase: takes the form of two different syndromes, either classic or nonclassic rabies

5) Classic rabies is categorized as furious rabies and paralytic rabies a) Furious classic rabies

i) Fluctuations in mentation, behavior, and consciousness

ii) Persistent fever iii) Psychiatric disturbance, including depression

and agitation iv) Hydrophobia or aerophobia due to spasms of

pharyngeal muscles (which may be triggered by swallowing or environmental stimuli)

v) Hypersalivation: combination of autonomic hyperactivity and dysphagia

vi) Other autonomic features: hyperhidrosis, priapism, spontaneous ejaculation, anisocoria, fixed pupils

b) Paralytic classic rabies i) Ascending weakness, axonal polyradiculo-

neuropathy ii) Weakness in both lower extremities in ascending

fashion develops in all patients, with early loss of tendon reflexes

iii) Myoedema 6) Nonclassic rabies: various symptoms localizing to

CNS, including signs of brainstem deficits, hemiparesis, hemisensory loss, ataxia, and vertigo

7) Coma: associated with inspiratory spasms and tachycardia

8) MRI: normal or nonspecific T2 hyperintense lesions, with or without enhancement

9) Skin biopsy from neck: frozen sections of skin with fluorescent antibody technique show rabies virus antigen in subcutaneous nervous tissue

10) CSF: normal or minimal pleocytosis 11) Pathology

a) Leptomeningeal and perivascular lymphocytic infiltrates, relative paucity of inflammatory response

b) Inclusion bodies: Negri bodies usually found in

Purkinje cells and in hippocampus 12) Postexposure prophylaxis

a) Immediate cleansing site of the wound b) Rabies immune globulin: inject locally around

wound and at intramuscular site close to wound c) Vaccination: intramuscular and intradermal

3. Measles a. Pathogen: measles virus, a paramyxovirus (an RNA virus) b. Virus generally spreads through infected respiratory

secretions; may cause neurologic manifestations through spread to CNS during initial infection, but also may have CNS effects years after initial infection

c. Acute infection 1) Constitutional symptoms, including fever 2) Maculopapular rash: appears first on head and shoul-

ders and spreads downward (and disappears in same sequence)

3) Koplik’s spots: small erythematous lesions with pale centers in mucosal surface of oropharynx; develop shortly after onset of the rash

4) Cough, coryza 5) Incidence has decreased significantly with advent of

vaccination, but new cases possibly due to immunization have been reported

6) May be associated with acute encephalitis, aseptic meningitis, transverse myelitis

d. Measles inclusion body encephalitis: rapidly progressive dementing illness developing 1 to 6 months after inoculation; associated with myoclonus, seizures, coma

e. Subacute sclerosing panencephalitis 1) Rare, delayed complication: 5 to 10 of every 1 mil-

lion cases of measles 2) Delayed onset after acute infection: 2 to 12 years

(median, 8 years) 3) Gradual onset of behavioral disturbance, followed by

seizures, dementia, spasticity, and various movement disorders (myoclonus, choreoathetosis, ataxia) and progressing to akinetic mutism and eventually coma and death

4) EEG: generalized, stereotyped, repetitive, polyphasic sharp and slow wave-high voltage complexes, 0.5 to 2 seconds in duration and usually recurring every 4 to 15 seconds (usually bisynchronous, but may be asymmetric), often occurrring in conjunction with myoclonic jerks

5) Pathology: parenchymal and leptomeningeal perivascular lymphocytic infiltrates in cerebral cortex, white matter, thalamus, and basal ganglia, with loss of neurons and myelinated fibers, gliosis, and intranuclear inclusions (Fig. 15-8)

4. Mumps a. Pathogen: mumps virus, a paramyxovirus b. Replicates in respiratory tract and regional lymph nodes;

hematogenous spread to distant sites c. May infect parotid gland (parotitis) and testes (orchitis) d. Aseptic meningitis or encephalitis may occur in nonim-

munized persons e. Prevention with live, attenuated vaccine

5. Papovaviruses and progressive multifocal leukoencephalopathy (discussed below)

6. Human T-lymphotropic virus (discussed in Chapter 20)

7. HIV infection (discussed below) 8. Poliovirus (discussed in Chapter 20)

A. Pathogen 1. Retrovirus in the lentivirus family

a. Two forms are pathogenic in humans: HIV-1 and HIV-2 b. HIV-1 is more common in United States; HIV-2 has

been identified mainly in West Africa and Indian subcontinent

2. Major components include the p24 antigen (most HIV tests detect antibodies to p24), reverse transcriptase, integrase, protease, and RNA; its lipid layer comes from host cells

3. Preferential infection of CD4+ cells; typically affects T cells (CD4+), dendritic cells, and macrophages

4. An HIV envelope protein, gp120, binds to CD4; next step is binding of gp120 to either CCR5 or CXCR4 receptors on host cell, giving virus ability to enter host cell

5. Virus then spreads to other host cells; death of host cells leads to development of severe immunodeficiency

6. Virus migrates into CNS early in course of infection; major viral reservoirs in CNS are macrophages and microglia

B. Routes of Transmission 1. Main routes of transmission are via blood and genital

secretions, typically by sexual contact, intravenous drug use, or maternal-fetal transfer

2. Currently, sexual contact is most common mode of transmission

3. Many hemophiliacs developed disease before blood products were screened for HIV

4. May also spread through breast milk and, in rare cases, via occupational exposure

C. Epidemiology 1. Over 60 million people have been infected with HIV

worldwide; currently over 40 million people worldwide are HIV infected

2. Almost 1 million of these cases are in United States

D. Natural History 1. At time of primary infection, there may be seroconver-

sion-related illness, which can include fever, maculopapular rash, malaise, myalgias, primary meningitis

2. Usually a subsequent clinical, but not virologic, latent period of 10 years (average); many patients develop lymphadenopathy during this period

3. Eventually, fevers, mild signs, and symptoms suggestive of reduced cell-mediated immunity develop

4. With progressive decrease of CD4 count, opportunistic infections and AIDS develop

5. Most neurologic complications of HIV are symptomatic during latter stages of infection; about 50% of people with HIV develop related neurologic symptoms in the course of disease

E. Aseptic Meningitis 1. Monophasic illness that occurs within first 6 weeks

after seroconversion or later in course of HIV infection 2. Acute viral syndrome of constitutional symptoms of

fever, headache, lethargy, nausea, anorexia; also diffuse

arthralgias, maculopapular rash, pharyngitis, lymphadenopathy

3. Neurologic syndromes other than aseptic meningitis: encephalitis, meningoencephalitis, seizures, myelopathy, peripheral neuropathy

4. CSF in aseptic meningitis of acute HIV infection is marked by mild lymphocytic pleocytosis (<25 cells/μL), increased protein, and normal glucose

5. May have HIV antibodies in blood, but may only be positive for p24 antigen if early in the course of infection

6. MRI of head: normal or shows meningeal enhancement

7. Typically self-limited disease, recovery expected within a few months

F. HIV-Associated Dementia 1. Thought to be related to HIV infection rather than

opportunistic infection 2. Usually occurs late in HIV infection, when CD4 count

is <200 cells/mm3 3. Incidence among HIV-infected patients: about 1%

since HIV treatment has been available 4. Minor cognitive motor disorder: a mild form occurs in

approximately 20% of patients with HIV infection (not necessarily progressive)

5. Based on one review, 35% of asymptomatic HIVinfected patients have been shown to have neuropsychologic deficits (compared with 12% of seronegative controls) (Grant and White et al, HNRC group)

6. Before era of HIV treatment: up to 60% of patients developed some cognitive impairment

7. Prevalence may be increasing because more HIV-infected patients live longer

8. Risk factors for HIV-associated dementia: anemia, low peripheral blood CD4 T-cell count, high viral load (i.e., high plasma HIV RNA), history of injection drug use, history of hepatitis C infection, female gender, and older age

9. Clinical features a. Cognitive impairment, behavioral changes, and motor

dysfunction b. Cognitive impairment: slowness in thinking (bradyphre-

nia), poor attention and concentration, impairment in short-term and working memory, and reduced psychomotor speed and cognitive flexibility on formal testing

c. Personality changes: apathy, inertia, social withdrawal, irritability; occasionally, agitation, psychosis, mania, obsessive-compulsive behavior

d. Motor impairment: nonspecific gait disturbance characterized by “clumsiness,” incoordination, and slowed movements; usually develops after onset of cognitive deficits

e. Progressive syndrome: at end stage, patient can become bedbound, severely demented, with minimal responsiveness and profoundly slow psychomotor function

f. Minor cognitive motor disorder: mild or equivocal neurocognitive symptoms, patients need to be monitored closely and periodically for development of HIVassociated dementia

g. Children infected with HIV: onset as early as age 2 months, with microcephaly, developmental delay and regression, progressive encephalopathy, weakness, ataxia, hyperreflexia, and spasticity; basal ganglia calcification

10. Pathology (Fig. 15-9) a. Diffuse, patchy, and confluent rarefaction and pallor of

white matter, due to neuronal loss b. Microglial nodules c. Activated macrophages and astrocytes and multinucleat-

ed giant cells with immunophenotype of microglia or macrophages; predilection for perivascular aggregation

d. Perivascular and periventricular parenchymal lymphocytic infiltrates

11. Diagnosis a. Clinical examination and formal neuropsychologic test-

ing: opportunistic infections or drug effects must be excluded

b. CSF analysis: may be mild lymphocytic pleocytosis, nonspecific

c. MRI of head: diffuse, confluent periventricular white

matter T2 hyperintense lesions, with normal T1 images (Fig. 15-10)

G. HIV-Associated Vacuolar Myelopathy 1. Observed in 50% of autopsies of all patients with AIDS 2. Most common cause of myelopathy in HIV-infected

persons 3. Uncommon in HIV-infected children 4. Subacute onset and progression of spastic paraparesis

a. Painless upper motor neuron pattern of weakness (especially legs), spasticity, urinary incontinence, erectile dysfunction, Babinski’s sign

b. Progressive sensory deficits in lower extremities, although a sensory level often cannot be determined

5. Often occurs concomitantly with HIV-associated dementia

6. HIV-associated vacuolar myelopathy needs to be differentiated from the rare acute or subacute HIV (transverse) myelitis

7. Pathology a. Spongiform change with vacuolization of myelin sheaths b. Lipid-laden macrophages c. Aggregation of activated and foamy macrophages and

microglia d. Multinucleated giant cells e. Changes predominantly involve posterior and lateral

columns (anterolateral tracts with progression), most commonly in thoracic segments

8. Treatment: predominantly symptomatic; highly active antiretroviral therapy (HAART) usually indicated because of profound immunosuppression at this stage of infection

H. HIV-Associated Neuromuscular Disease 1. Distal sensory polyneuropathy

a. Painful, symmetric, predominantly sensory axonal polyneuropathy

b. Gradual onset of pain, dysesthesias, paresthesias, deep pain, hyperalgesia in feet (distal > proximal); predominantly decreased pain, temperature, and vibratory sensation and relatively preserved proprioception until later in disease course

c. Progression marked by gradual proximal spread of symptoms

2. Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) a. Distinguishing feature from idiopathic Guillain-Barré

syndrome: lymphocytic pleocytosis b. Usually occurs in early stages of HIV infection as result

of immune dysregulation

c. Clinical presentation in HIV patients similar to that of noninfected patients: may have lower extremity sensory paresthesias, followed by progressive ascending weakness and areflexia

d. Predominantly sensory symptoms, infrequently causes sphincter disturbance

e. CSF: increased protein, but often also mild mononuclear pleocytosis

f. Nerve conduction studies (NCS) and electromyography (EMG): demyelinating features, with prolonged distal latencies and F-wave latencies and slowed conduction velocities

g. Treatment 1) Intravenous immunoglobulin or plasma exchange

may be given to patients with AIDP: recovery is the norm but may be slow

2) Chronic inflammatory demyelinating polyradiculopathy may require longer term treatment, but benefits of iatrogenic immunosuppression must be weighed against the risks in these patients

3. Antiretroviral-associated neuropathy

a. Pathophysiology 1) Often associated with use of nucleoside analog HIV

treatment, such as ddI (didanosine), ddC (zalcitabine), or d4T (stavudine); may occur in up to 1/3 of patients taking these agents

2) Believed to be related to mitochondrial dysfunction induced by these agents

b. Clinical presentation: length-dependent peripheral neuropathy, with primarily sensory symptoms; weakness is less common

c. Electrophysiologic characteristics: axonal length-dependent neuropathy, decreased sural amplitude, may show mild EMG changes of denervation in distal leg muscles

d. Often can be distinguished from primary HIV neuropathy only by withdrawal of drug: there may be significant lag time between drug withdrawal and symptom improvement

e. Treatment: symptomatic treatment and withdrawal of offending agent if possible

4. Cranial mononeuropathies or mononeuritis multiplex occur early in course of HIV infection

5. HIV-associated lumbosacral plexopathy 6. Motor neuron disease-like illness may occur late in

course of HIV infection 7. CMV polyradiculopathy

a. Caused by CMV, usually reactivation of latent virus in patient

b. Usually occurs in severe immunosuppression, with CD4 count <50 cells/mm3

c. Clinical features: slow onset of progressive flaccid paraparesis (often rapidly evolving and asymmetric), sphincter dysfunction, lower extremity sensory loss (in absence of definite sensory level), and pain in back and radicular distributions

d. NCS/EMG: active denervation and axonal loss in polyradicular distribution, usually only in lumbosacral roots

e. CSF: increased protein, polymorphonuclear pleocytosis; positive CMV PCR and/or viral cultures

f. Neuroimaging: normal or thickened lumbosacral nerve roots seen with gadolinium enhancement

g. Pathology: necrotizing inflammation of nerve roots, with positive CMV immunohistochemistry staining of Schwann cells

8. HIV-associated myopathy a. Pathophysiology: cause of this rare disorder is unclear,

but may be muscle fiber damage from immune dysregulation or inflammatory cytokines

b. Characterized by proximal weakness and myalgias c. Variable increase in creatine kinase d. NCS/EMG: consistent with myopathy, short-duration

motor unit potentials in proximal musculature e. Pathology: degeneration of muscle fibers, with variable

amounts of mononuclear inflammation 9. AZT-associated myopathy

a. Caused by exposure to antiretroviral drug zidovudine b. Believed to be caused by mitochondrial damage from

zidovudine

I. Progressive Multifocal Leukoencephalopathy (PML)

1. Caused by JC virus, a human polyomavirus, that exists asymptomatically in up to 70% of immunocompetent persons

2. PML: thought to result from reactivation of virus in most cases, not new infection

3. PML is either result of reactivation of virus in the brain or of virus transported from other organs to brain

4. Often occurs in immunosuppressive illness (e.g., AIDS or other immunocompromised states)

5. Affects approximately 4% of AIDS patients, usually occurs when CD4 count is <200 cells/mm3

6. Pathology and pathogenesis (Fig. 15-11) a. Caused by direct lytic infection of brain oligodendro-

cytes and astrocytes; produces multifocal and confluent demyelinating lesions

b. Predominantly involves frontal, parietal, and occipital lobes (predilection for parieto-occipital region); also described in cerebellum and brainstem (80%-90% are supratentorial lesions, 10%-20% are infratentorial)

c. Viral products may be seen as “inclusions” within oligodendrocytes

7. Clinical features a. Variable, depends on localization and extent of lesions b. Unusual to present with fever or headache; absence of

mass effect or meningitis c. Most common features: altered mentation and cognitive

deficits, focal paralysis or generalized weakness, homonymous hemianopia (most common manifestation in AIDS patients: hemiparesis)

d. Visual disturbance (e.g., visual field deficits); posterior subcortical white matter frequently affected

e. Other neurologic deficits: gait abnormalities, sensory deficits

8. Diagnostic evaluation a. CT: multiple foci of hypoattenuation, insensitive b. MRI

1) Hyperintense T2 superficial, subcortical white matter multifocal lesions beginning at gray-white matter junction and coalescing to form confluent lesions

2) Lesions appear hypointense in T1 images; may appear bright on diffusion-weighted imaging

3) Typically, there is little or no enhancement c. EEG: diffuse or focal slowing, nonspecific d. CSF: normal or nonspecific mild mononuclear pleocy-

tosis and increased protein

e. CSF JC virus PCR: sensitivity of more than 80%, specificity of more than 90%; a negative test does not exclude diagnosis

9. Pathology a. Macroscopic appearance: confluent demyelination pre-

dominantly at juxtacortical white matter or near the deep gray matter (in contrast to multiple sclerosis lesions, which have predilection for periventricular white matter)

b. Enlarged oligodendrocytes (filled with virions) c. Relative sparing of axons in areas of demyelination d. Reactive astrocytosis, with bizarre appearance of giant

astrocytes

10. Treatment a. HAART: mainstay of treatment; concomitant use of

other therapies is debated b. Some success reported with other agents: cytosine ara-

binoside, amantadine, vidarabine, acyclovir, and interferon alpha

J. Cytomegalovirus (discussed above)

K. Toxoplasmosis 1. Pathogenic agent: Toxoplasma gondii, an obligate intra-

cellular protozoa 2. Usually occurs in patients with CD4 count <100

cells/mm3, resulting from reactivation of latent infection

3. Approximately 1/3 of adult population is seropositive for T. gondii: seroprevalence varies from country to country

4. May be acquired in utero: congenital toxoplasmosis 5. Pathogenesis

a. Primary mode of inoculation is oral-fecal: ingestion of oocytes or cysts in feline feces-contaminated food or uncooked meet (usually pork or lamb)

b. Parasites are released from cysts after ingestion and are disseminated via hematogenous and lymphatic spread to different organs

c. Organism may remain latent and cause infection when person is immunocompromised

6. Clinical presentation varies, depending on the location of lesion or lesions a. Acute mass lesion with focal (or multifocal) signs and

symptoms due to focal parenchymal abscess or abscesses: headache, seizures, hemiparesis, hemianopia, aphasia, ataxia

b. Subacute encephalitis (with or without acute mass lesions): fever, headaches, subacute onset of confusion, inattention, disorientation, and behavioral disturbance

7. Diagnosis a. IgG antibodies to T. gondii at time of presentation (IgM

antibodies are uncommon); may be difficult to interpret because of seroprevalence in general population

b. CSF: increased protein, lymphocytic pleocytosis, PCR for T. gondii very specific (>95%), but not very sensitive (only about 50%-60%)

c. Lumbar puncture may be contraindicated in the setting of focal mass lesion with mass effect

d. Neuroimaging: one or more ring-enhancing lesions (about 2/3 of patients have multiple lesions at presentation), often with central necrosis and mass effect, with ring enhancement and surrounding vasogenic edema

e. Main differential diagnosis: PCNSL 1) Thallium-201 single photon emission CT (SPECT)

and positron emission tomography (PET) may distinguish the two conditions

2) Most clinicians decide to treat for toxoplasmosis and consider alternate diagnosis in nonresponders

8. Pathology (Fig. 15-12) a. Toxoplasmic abscess is referred to as “gold coin lesion”

because of discoloration from central coagulative or hemorrhagic necrosis

b. Microscopic appearance: encysted T. gondii bradyzoites or free organisms (tachyzoites) typically found at borders of the lesions

c. Organized abscesses have typical histologic appearance of coagulative necrosis

9. Treatment a. Primary induction therapy with oral pyrimethamine and

oral sulfadiazine for minimum of 6 weeks, followed by maintenance therapy of reduced doses of same regimen

b. Folinic acid is often added to counteract bone marrow toxicity of pyrimethamine

c. Relapses are very common if maintenance therapy is discontinued (persistence of parenchymal cysts despite treatment may be responsible for reactivation and may be cause of relapses)

d. Maintenance therapy may be continued for life in absence of retroviral therapy (may be discontinued when the CD4 counts are sustained above 200 cells/μL)

e. Primary prophylaxis with trimethoprim-sulfamethoxazole indicated for severely immunocompromised patients with CD4 cell counts less than 100 cells/μL

f. Primary prophylaxis should also include avoidance of ingestion of uncooked meat, contact with material potentially contaminated with cat feces

L. Cryptococcal Meningitis 1. Most frequent primary cause of meningitis in AIDS

patients (affects approximately 10% of these patients) 2. Caused by Cryptococcus neoformans, an encapsulated

yeast widely present in nature (often found in soil and pigeon droppings)

3. Clinical features a. Chronic basilar meningitis with cranial neuropathies and

slow onset of altered mentation, behavioral disturbance, change in personality, psychiatric manifestations, obtundation, and coma

b. Other manifestations: focal signs and symptoms (e.g., hemiparesis, seizures)

c. Relative absence of nuchal rigidity because of mild inflammatory reaction

4. Diagnostic evaluation a. CSF profile: normal or mild mononuclear pleocytosis

with slightly increased protein and decreased glucose b. CSF fungal cultures: high sensitivity (>90%) and speci-

ficity (almost 100%), but may take several weeks; sensitivity of serum fungal cultures is much less

c. Increased serum and CSF cryptococcal capsular polysaccharide antigen titer (often determined by latex agglutination)

d. India ink stain: detects pathogen and demonstrates typical morphology in 70% to 90% of cases; positive test is helpful, but negative test does not exclude diagnosis

e. Neuroimaging characteristics: normal or nonspecific abnormalities, including nonspecific small T2 hyperin-

tense lesions (typically nonenhancing); there may or may not be sulcal or basilar leptomeningeal enhancement, with occasional parenchymal involvement (Fig. 15-13)

5. Pathology a. Macroscopic appearance: thick, fibrotic, and opacified

meninges of chronic meningitis covering the brain; there may be multiple small cysts and cryptococcomas (Fig. 15-14)

b. Leptomeningeal inflammatory infiltrates in cryptococcal meningitis (mononuclear inflammatory cells and multinucleated giant cells)

c. Cryptococcal cysts: enlarged cystic spaces (often perivascular) filled with the organism; may be encapsulated or in form of budding yeast

6. Treatment a. Induction therapy with intravenous amphotericin B for

2 weeks (with or without flucytosine), followed by 8 to 10 weeks of maintenance therapy with oral fluconazole

M. Primary CNS Lymphoma (discussed in Chapter 16)

A. Pathogenesis 1. Fungal meningitis is characterized by infection of pia

mater and arachnoid membrane by a fungus, without associated involvement of brain parenchyma

2. Primary inoculation usually by inhalation, often followed by hematogenous spread to CNS; an exception is Candida, which penetrates mucosal surface it normally colonizes and gains access to deep tissue

3. Much more common in immunocompromised patients, either by primary disease (e.g., HIV/AIDS, diabetes mellitus) or by iatrogenic immunosupression (corticosteroid use, chemotherapy, transplant recipients who receive immunosuppressant therapy)

4. Recent surgery or foreign body (e.g., ventriculoperitoneal shunt) can provide direct means of fungal entry

B. Clinical Features 1. Subacute to chronic meningitis: malaise, fever,

headaches, nausea, meningismus, failure to thrive, cranial nerve findings, seizures

2. Usually not as ill as patient with bacterial meningitis 3. Lethargy and confusion with progression 4. Immunocompromised patients have more rapid course

than immunocompetent patients and may have rapid progression to severe, permanent neurolgic deficits, coma, or death

C. Diagnosis 1. Typical CSF profile

a. Lymphocytic pleocytosis (usually <1,000 cells/mm3), increased protein, decreased glucose

b. Eosinophilic pleocytosis: suggests coccidioidal meningitis

2. India ink stain to observe encapsulated yeasts of Cryptococcus (discussed above)

3. Cryptococcal antigen test: sensitive and specific, rapid test

4. Fungal cultures a. Most useful in cryptococcal meningitis b. Time-consuming, often do not yield the organism

(growth occurs in 50% of cases of blastomycosis, histoplasmosis, or coccidioidomycosis)

c. Cultures of large volume of CSF may have better yield d. Limited by contamination by normal flora

5. Serologic testing a. Nonspecific, there is cross-reactivity b. Difficult to interpret

6. Neuroimaging (MRI more sensitive than CT) a. Leptomeningeal enhancement, often involving basal

cisterns b. Space-occupying lesions with mass effect (abscess or

granulomas) c. Hemorrhagic infarcts may indicate underlying vasculitis

D. Pathology 1. Varies greatly depending on organism 2. Abscesses, with necrotic centers and hemorrhage, in

cases of angioinvasive fungi 3. Thick exudates, inflammatory meningeal infiltrates

consisting of neutrophils, plasma cells, lymphocytes, and macrophages

4. Caseating or noncaseating granulomas with multinucleated giant cells, epithelioid cells, and activated macrophages

5. Yeasts, hyphae, molds are often visible with PAS or silver stain

6. Endospores of Coccidioides immitis within spherules: rupture of the spherules may induce acute inflammatory response

Fungal meningitis Usually subacute or chronic

Cerebrospinal fluid usually has mononuclear pleocytosis, increased protein, and normal or decreased glucose

Most infections acquired via inhalation

More common in immunosuppressed patients

Common pathogens to be considered are Cryptococcus, Histoplasma, Aspergillus, Coccidioides, Blastomyces, Candida

Usual treatment is amphotericin B (watch for renal toxicity)

7. Aspergillosis: infiltraton of blood vessels by fungal hyphae (Fig. 15-15)

E. Treatment 1. Amphotericin B

a. Usually first-line agent for fungal infections of CNS b. Administration: systemic or intrathecal (latter reserved

for refractory cases) c. Broad antifungal spectrum d. Associated with nephrotoxicity (minimized by use of

lipid preparations) e. Lipid preparations have reduced CSF penetrance com-

pared with standard formulations 2. Flucytosine

a. Good antimicrobial activity against Candida and Cryptococcus neoformans

b. Drug resistance may develop c. Often given in conjunction with amphotericin B d. Eliminated unchanged in urine: renal insufficiency can

cause drug accumulation e. Adverse effects: rash, diarrhea, eosinophilia, liver dys-

function, bone marrow toxicity when given in combination with amphotericin B

3. Fluconazole and itraconazole a. Not recommended as first-line agents, inferior to

amphotericin for primary therapy b. Main role as maintenance therapy and lifelong secondary

preventive therapy for immunocompromised patients c. Advantages: good CNS penetrance, few adverse effects

F. Individual Pathogens 1. Aspergillosis (Fig. 15-15)

a. Causative agents: Aspergillus fumigatus or A. flavus b. Filamentous fungus (mold) c. Acquired through inhalation, then subsequent fungemia,

which may spread to CNS; may also spread directly from Aspergillus sinusitis

d. Angioinvasive, infiltration of blood vessels by hyphae; associated with blood vessel thrombosis, infarcts, parenchymal and subarachnoid hemorrhages

e. Neurologic disease most common in immunosuppressed patients

f. Almost all patients have associated pulmonary manifestations

g. Neurologic manifestations 1) Result from direct, contiguous parenchymal invasion

(e.g., from focus of sinusitis) or intravascular invasion (vasculitis)

2) Usually consist of multiple focal deficits with fever (multiple infarcts, abscesses)

3) Potential for rapid progression in immunocompromised host

2. Yeasts a. Cryptococcal neoformans (discussed above) b. Candida

1) Yeast, in form of coherent budding, oval chains, or pseudohyphae; may also produce true hyphae

2) Normal flora of mucosal and skin surfaces in the immunocompetent host

3) Systemic infection may follow penetration of fungus into deeper tissues

4) Predisposing factors: underlying immunosuppression and neutropenia (neutrophils are primary effector cells), indwelling ventriculostomy tubes or shunts

5) Angioinvasive: associated with blood vessel thrombosis, infarcts, parenchymal and subarachnoid hemorrhages

3. Systemic fungal infections a. Pathogens: Coccidioides immitis, Blastomyces dermatitidis,

Histoplasma capsulatum b. Dimorphic fungi: found as mycelia (at room tempera-

ture) and yeasts (at core body temperature) c. Primary inoculation by inhalation, local pulmonary

infection, followed by hematogenous dissemination d. Majority of infected patients are asymptomatic e. May present with pulmonary infection (calcified granu-

lomas may follow primary infection) f. Disseminated disease: commonly occurs in immuno-

compromised host; may cause fungal infection of CNS and subacute to chronic meningitis; may occur after primary infection or reactivation of old infection

g. May be mass lesions and granulomas along neuroaxis h. C. immitis

1) Most prevalent in southwestern U.S. and Mexico 2) Common symptom at presentation: headache, often

accompanying other symptoms of chronic meningitis i. H. capsulatum

1) Nonencapulated organism 2) Endemic areas: Mississippi and Ohio River valleys,

Central and South America 3) Present in bird and bat droppings; primary infection

by inhalation of aerosolized contaminated soil 4) Most cases are self-limiting 5) Systemic manifestations: hepatosplenomegaly,

lymphadenopathy, diffuse pulmonary infiltrates, mucosal ulcerations

6) CNS disease usually in form of subacute meningitis and/or cerebral abscess

j. B. dermatitidis 1) Neurologic involvement seen in up to 1/3 of cases of

disseminated disease; meningitis may be marked by rapid deterioration; some patients may develop blastomycomas (mass lesions, abscess)

2) Osteolytic lesions of vertebral bodies may occur 3) Infection not significantly more frequent in immuno-

compromised hosts 4. Mucormycosis

a. Opportunistic, aggressive infection of brain vessels b. Caused by zygomycete fungi, including Rhizopus

arrhizus and Mucor species c. Predisposing conditions: diabetes mellitus, organ trans-

plant recipient, hematologic malignancies, intravenous drug use, AIDS

d. CNS infection often due to contiguous spread from adjacent paranasal sinuses or orbital or retro-orbital space

e. Rhinocerebral infection may progress slowly or precipi-

tously; high index of suspicion and urgent surgical removal of infected tissue are required

f. Presentation may be that of cerebral infarction: angioinvasive hyphae causing arterial thrombosis and hemorrhagic infarctions and direct parenchymal invasion causing brain abscess

g. Presentation may also be that of cavernous sinus syndrome due to thrombosis of cavernous sinus

h. Only effective therapy: surgical removal of the infected tissue; amphotericin B may be used as adjunctive therapy

A. Cerebral Malaria 1. Protozoal infection caused by Plasmodium, species; in

most cases, CNS involvement is due to P. falciparum (rare cases of cerebral malaria due to P. vivax have been reported)

2. Life cycle a. Sporozoites: carried by mosquito, injected into host,

enter bloodstream, and invade and inhabit hepatocytes b. Each sporozoite then undergoes multiple nuclear divi-

sions, forming a multinuclear body (schizont) c. Each nucleus inside the schizont acquires cytoplasm and

becomes a small body (merozoites) d. Merozoites rupture and enter other hepatocytes and

bloodstream

e. After entering bloodstream, merozoites invade erythrocytes and form a trophozoite

f. Trophozoite undergoes nuclear division and is transformed into a multinuclear schizont, containing multiple merozoites

g. Erythrocyte ruptures and merozoites enter bloodstream, eliciting immune reaction responsible for recurrence of fever and constitutional symptoms

h. Phagocytic cells of reticuloendothelial system, including liver and spleen, engulf debris from the destroyed erythrocytes; this produces hepatosplenomegaly

3. Incubation period: depends on immune status and Plasmodium species, usually 1 to 2 weeks (may vary from 9 days to >3 months)

4. Prodrome of headache, malaise, chills 5. Periodic high-grade fever (one every third day) associat-

ed with chills and diaphoresis 6. Systemic manifestations: nausea, abdominal pain,

hepatosplenomegaly, jaundice, azotemia, anemia, tachycardia, arthralgias

7. Neurologic manifestations: focal deficits, retinal hemorrhages, abnormal extraocular movement, focal or generalized seizures, status epilepticus, delirium, proceeding to coma

8. Mortality: up to 50% reported 9. Diagnosis

a. Examine peripheral blood smear for trophozoites; if initial smear is negative, repeat smear

b. CSF: usually normal, may show mild lymphocytic pleocytosis

c. Increased serum and CSF levels of lactate d. MRI: usually normal

10. Treatment: quinine, quinidine, and artemisinin derivatives

B. Amebic Infections of CNS 1. Often fatal protozoa infection

2. Primary amebic meningoencephalitis a. The protozoa is found in warm freshwater b. Trophozoite and flagellate forms enter nasal cavity, pene-

trate epithelium and cribriform plate, and enter parenchyma causing necrotizing inflammation

c. Meningoencephalitis: acute onset of fever, headache, photophobia, stiff neck, impaired consciousness, seizures

d. May be focal signs and symptoms e. Possible complications: hydrocephalus, diffuse brain

edema, increased ICP f. Death may occur within 1 week after onset of symptoms g. Treatment

1) Poor therapeutic response 2) Best with combination of antimicrobial agents

amphotericin B, rifampin, miconazole 3. Granulomatous amebic encephalitis

a. Predisposing factors: immunocompromised state, HIV infection, splenectomy, long-term corticosteroid therapy, diabetes mellitus, chronic alcoholism

b. Primary infectious focus may be skin or respiratory or olfactory epithelium

c. Trophozoites invade CNS by hematogenous spread and set up multiple necrotic abscesses, with some predilection for posterior fossa

d. Clinical features: often nonspecific but may include focal signs and symptoms (focal seizures) or deficits related to focal lesions

e. Progression is gradual, but disease often progresses to coma and death in 2 to 3 weeks

4. Amebic brain abscess a. Rare, late complication of intestinal, pulmonary, or

hepatic amebiasis b. Metastatic CNS abscess produced by hematogenous

spread of organism, usually at gray-white matter junction c. Fever, altered mentation, focal signs and symptoms,

seizures d. Treatment: both medical (metronidazole) and surgical

resection

C. Toxoplasmosis (discussed above)

D. American Trypanosomiasis: Chagas’ disease 1. Protozoal pathogen is Trypanosoma cruzi: disease of the

Americas, including southern U.S. and Central and South America

2. Vector: reduviid bug (kissing bug) 3. Organism multiplies in intestinal tract of vector and

transforms in rectum into infective trypomastigotes, which are abundant in feces

4. When the vector takes a blood meal, it also defecates

Mucor Most commonly causes disease in immunosuppressed persons; common in diabetes mellitus

Usually has rhinocerebral presentation, with sinusitis and local extension into bone, brain, and involvement of cranial nerves

Usually requires debridement and amphotericin B

and releases trypomastigotes, which enter bloodstream of human host (Fig. 15-16)

5. Shortly after entering the bloodstream, the organism transforms into the amastigote form after losing the undulating membrane and flagellum and rapidly multiplies, forming pseudocyst

6. Pseudocysts are present in multiple host tissues, including skeletal muscle, reticuloendothelial cells, and CNS

7. Acute illness: marked by erythema and swelling at site of inoculation (chagoma), cardiac involvement (including arrhythmias), and, uncommonly, meningoencephalitis (more common in infected children or HIVinfected persons)

8. Chronic phase: dilated cardiomyopathy (most common neurologic manifestation of chronic phase is cardioembolic stroke); megacolon and megaesophagus (from involvement of enteric nervous system); organisms leave the bloodstream but serologic tests remain positive

E. African Trypanosomiasis: sleeping sickness 1. Protozoal pathogen, T. brucei subspecies, transmitted by

tsetse fly 2. Following the bite, flagellated motile trypomastigote

form of the organism travels in bloodstream to lymph nodes and reticuloendothelial system and CNS

3. Initial manifestations a. Erythematous, painful skin ulcer (chancre) at bite site b. Appearance of chancre is followed by systemic illness

occurring after incubation period of less than 3 weeks: cyclic fever, headache, lymphadenopathy, malaise (fever occurs in cycles of hours to days)

c. Initial stage may last for several months 4. Second stage of meningoencephalitis

a. Organism crosses blood-brain barrier and causes CNS infection marked by headaches, ataxia, extrapyramidal symptoms, slurred speech, behavioral changes, dementia, lethargy and hypersomnolence (hence, “sleeping sickness”)

b. May be rapid deterioration to coma and death c. Duration of this stage may be as long as 1 year

F. Cysticercosis 1. Helminthic infection 2. Pathogen is pork tapeworm, Taenia solium 3. Acquired via fecal-oral route from other infected indi-

viduals or by ingestion of food contaminated with the eggs

4. Eggs are ingested by human host; in small intestine, hatch into larvae, which migrate in bloodstream to effector organs, including CNS

5. Cysticerci may remain in vesicular state for years and either induce an inflammatory reaction or undergo destruction and calcification by host’s immune response

6. Degeneration of the cysts induces inflammatory response (more severe with large parasitic load); inflammatory response is accompanied by vasogenic edema and reactive gliosis

7. Intense inflammatory reaction may cause fulminant meningoencephalitis

8. Neurologic manifestations a. Most common: seizures (partial or generalized) b. Increased ICP: headaches, vomiting, neurocognitive

deficits c. Infarcts: may be due to vasculitis d. Obstructive hydrocephalus may be due to intraventricu-

lar cysts or proliferation of ependymal cells or thickened leptomeninges due to local inflammatory response at foramina

9. Neuroimaging may show characteristic cystic lesions, with or without enhancement or surrounding edema (active disease), characteristic parenchymal calcifications (of the cysts), hydrocephalus, possibly leptomeningeal enhancement; cyst location may be meningobasal, parenchymal, or intraventricular

10. Treatment

a. Antiparasitic agents for active parenchymal disease: albendazole or praziquantel

b. Surgical resection may be required

c. Supportive therapy, including ventriculoperitoneal shunt for hydrocephalus

d. Long-term anticonvulsant

1. A 32-year-old man, human immunodeficiency virus (HIV)-positive, presents with a 3-week history of upper quadrantanopia, right arm weakness, and fatigue. His recent laboratory evaluation shows a CD4 count of 50 cells/mm3. Brain MRI shows multiple areas of white matter lesions, mostly posterior, without mass effect, and nonenhancing. What is the most likely cause of this man’s symptoms? a. Cytomegalovirus (CMV) ventriculitis b.Progressive multifocal leukoencephalopathy (PML) c. Primary central nervous system lymphoma d.Toxoplasmosis

2. A 28-year-old woman, human immunodeficiency virus (HIV)-positive, presents with a several-week history of mild bifrontal headache, neck stiffness, and low-grade fevers. Also a facial palsy developed sometime before she presented. Brain MRI shows mild enhancement of the basilar cisterns. The CD4 count is 150 cells/mm3. What organism is of particular concern in this patient and why? a. Toxoplasma gondii b.Staphylococcus aureus

c. Neisseria meningitidis d.Cryptococcus neoformans

3. A 13-year-old boy has a 4-day history of headache, mild neck stiffness, vomiting, and diarrhea. Cerebrospinal fluid (CSF) examination at presentation showed a mild lymphocytic pleocytosis and mild increase in protein. Neuroimaging findings are unremarkable. A viral meningitis is diagnosed. What are the most common etiologic agents? a. Herpes simplex virus type 2 b.Cytomegalovirus c. Non-polio enterovirus d.Varicella-zoster virus

4. A 62-year-old woman from New York experienced fevers, skin rash, and myalgias for 1 week. West Nile virus infection was diagnosed. What is the chance that this will progress to neurologic disease? a. 1% b.10% c. 50% d.75%

1. Answer: b. PML is an opportunistic infection caused by JC virus. Multifocal, confluent signal abnormality related to demyelination is the most typical neuroimaging characteristic. It usually occurs in late stages of HIV infection, and the prognosis is poor, with no known effective long-term treatment. CMV also tends to be pathogenic in patients with low CD4 counts, notoriously causing ventriculitis. Primary central nervous system lymphoma and cerebral toxoplasmosis can appear as mass lesions, often with enhancement.