Thieme Mumenthaler, Neurology - part 2 ppt

Suspicion of meningitisPapilledema or focal neurologic deficits Specific antibiotic treatment Gram stain, antigen tests, cultures Immediate empirical antibiotic treatment Meningitis conf

Fig 2.15a, b Chronic meningitis.

The patient is a 49-year-old woman The pathogenic organism could not be identified a Coronal T1-weighted MRI with contrast b Axial T1-weighted MRI with contrast Note the

abnormal contrast enhancement in the meninges

Fig 2.16a, b Acute bacterial meningitis.

The patient is a 10-year-old boy a Coronal T1-weighted MRI with contrast demonstrates

sphenoid sinusitis (arrows) spreading in the epidural space under the left temporal lobeand causing meningitis by direct extension with involvement of the temporal lobe (arrow-

heads) b T1-weighted MRI with contrast in a coronal section posterior to a shows a

prob-able epidural empyema over the left temporal lobe (arrowheads) There is also extensivesignal change in the left thalamus, probably due to an arterial infarction as a complication

of meningitis

The prognosis of acute bacterial

men-ingitis depends on:

> the pathogenic organism,

> the severity of the infection,

Mortality is highest in the newborn

(over 50%) Meningitis accompanied

by meningococcal sepsis also confers

a high mortality, because it is

fre-quently complicated by bilateral

ad-renal hemorrhage and subsequent

circulatory collapse

(Waterhouse-Friderichsen syndrome) The

mortal-ity of other forms of meningitis is

ap-proximately 20% (1014) Surviving

patients often suffer from permanent

sequelae including deafness,

malre-sorptive hydrocephalus, epilepsy, and

intellectual deficits, particularly in

children

Treatment (Fig 2.17) (777a)

If a lumbar puncture cannot be formed immediately because ofclinical signs of intracranial hyper-tension, “blind” parenteral antimi-crobial treatment should be initi-

per-ated at once, as a few minutes may make the difference between life and death If the pathogenic organism is

unknown, the antimicrobial ment is chosen empirically (Ta-

treat-ble 2.23) It can then be modified in

accordance with the findings of thecerebrospinal fluid and blood cul-tures, including sensitivity and re-sistance testing

The duration of treatment is based

on the findings of serial clinical amination and cerebrospinal fluidanalysis Some general recommen-dations are:

ex-> for meningococci and H zae, 7–10 days;

influen-> for pneumococci, 10–14 days;

> for Listeria and Gram-negativeaerobes, 3 weeks

Steroids (dexamethasone 0.4 mg/kg

every 12 hours in the first 2 days oftreatment) favorably affect thecourse of the inflammatory process

in children and probably also inadults, and should be given in addi-tion to antimicrobial agents (560,831)

Suspicion of meningitis

Papilledema or focal neurologic deficits

Specific antibiotic treatment

Gram stain, antigen tests, cultures

Immediate empirical antibiotic treatment

Meningitis confirmed, or normal; no evidence of intracranial hypertension

Blood cultures

CT or MRI

Other diagnosis found

Other specific therapy Other diagnosis

Fig 2.17 Management flowchart for meningitis.

The essential element of treatment is immediate institution of antimicrobial therapy, atfirst empirical and then tailored to the specific pathogen identified by culture

Patient group Most likely organism Agent(s) of first choice 1 Alternatives

Listeria monocytogenes Ampicillin and cefotaxime

2 Ampicillin and aminoglycoside

Infants 1–3 months Same and H influenzae,

menin-gococci, pneumococci Ampicillin and ceftriaxone orcefotaxime Chloramphenicol and aminogly-coside

Infants G 3 months, toddlers H influenzae, meningococci,

pneumococci Ceftriaxone or cefotaxime Chloramphenicol and ampicillin

Children and adults Pneumococci, meningococci,

Adults G 60 years, alcoholics,

patients with systemic

disease

Pneumococci, E coli, lus influenzae, Listeria monocyto- genes, Pseudomonas aeruginosa,

Haemophi-anaerobes3

Vancomycin and ceftriaxone2

and rifampicin Chloramphenicol andtrimethoprim-sulfamethoxazole

Traumatic brain injury,

neurosurgical procedures Staphylococcus aureus, E coli, Pseudomonas aeruginosa,4

pneumococci

Vancomycin and ceftriaxone

1 Unless otherwise specified, these recommendations are applicable to the most likely pathogens affecting the group of patients in tion If the responsible pathogen is known, the treatment should be correspondingly tailored Dosages may be found in drug compendia

ques-2 Or other (third-generation) cephalosporin

Fig 2.18 Tuberculous meningitis.

This contrast-enhanced T1-weighted MRimage reveals enhancement of the in-flamed meninges at the basal cisterns andanterior to the brainstem The asymmetri-cal extension of inflammation along thecourse of the middle cerebral artery is alsotypical

Prevention

The administration of Haemophilus

vaccine to infants confers 90%

protec-tion against this type of meningitis

Inoculation against the

meningococ-cus is recommended for travelers to

endemic areas After exposure to

Haemophilus or meningococcus,

anti-microbial prophylaxis is

recom-mended (10 mg/kg in children or

600 mg in adults, b.i.d for 2 days)

Mycobacterium tuberculosis causes a

chronic bacterial infection

character-ized by granuloma formation The

lung is usually affected The

menin-ges may become involved during the

primary infection in children, or years

afterward in adults Meningitis comes

about by reactivation of clinically

si-lent granulomas and secondary

de-posits in the subarachnoid space,

even in the absence of simultaneous

pulmonary tuberculosis HIV-positive

persons are at particularly high risk of

infection both by M tuberculosis and

by atypical mycobacteria

Pathological Anatomy

An exudative basilar meningitis and

vasculitis is found, particularly in the

vicinity of the anterior and middle

ce-rebral arteries Meningeal

involve-ment and vasculitis may lead to

cra-nial nerve deficits and to cerebral

in-farction Hydrocephalus is commonly

seen

Clinical Features

Over the course of several days or,

more rarely, weeks, these patients

ex-hibit progressive symptoms and signs

including subfebrile temperature,

fatigue, depression, personality

changes, and (sometimes) confusion

One-third of patients develop

head-ache, meningism, asymmetrical nial nerve deficits, and ischemicstroke Coma is a bad prognostic sign.For miliary tuberculosis, see p 91

cra-Diagnosis

Cerebrospinal fluid examination veals a picture of chronic meningealinflammation with at first granulo-cytic and then monocytic pleocytosis

re-of 100–500 cells, elevated proteinconcentration, and low glucose con-centration The diagnosis is con-firmed by the demonstration of acid-fast bacilli by the Ziehl-Neelsenmethod or with auramine–rhodamine staining, either in thefresh cerebrospinal fluid sample orafter 4–6 weeks of culture

In addition to the cerebrospinal fluid,

the sputum, gastric juice, and urine

should be examined and cultured for

acid-fast bacilli Contrast-enhanced

CT and MRI reveal meningeal

involve-ment at the skull base and along the

course of the middle cerebral artery

(151) (Fig 2.18).

Differential Diagnosis

The differential diagnosis includes all

types of chronic lymphocytic

menin-goencephalitis (see below)

Treatment

The treatment consists of a

combi-nation of four tuberculostatic

medi-cations: rifampicin, isoniazid,

pyra-zinamide, and ethambutol At the

same time, steroids and vitamin B 6

should be given The latter

pre-vents the pyridoxine deficiency

that may otherwise result from

long-term use of isoniazid

This therapy should be continued

until the results of culture are

available If culture is positive for

tubercle bacilli, a combination of

three medications is given for a

fur-ther 2 months, and then two

medi-cations for 8–10 months more

Once the culture results are

nega-tive and the cerebrospinal fluid

pic-ture has renormalized, treatment

may be discontinued

If the patient fails to improve on

this regimen, other etiologies of

chronic meningitis should be

sought, and, even if cultures for M.

tuberculosis are negative, it is

pru-dent to continue the

tuberculo-static therapy The currently used

tuberculostatic agents have only

minor side effects even in

long-term use

Prognosis

Tuberculous meningitis is fatal if treated, curable without sequelae iftreated in time The diagnosis should

un-be made, and treatment initiated,before the onset of cranial nerve defi-cits or of impaired consciousness

Thus: when tuberculous meningitis is strongly suspected, obtain fluid sam- ples for culture and then begin antitu- bercular therapy immediately.

Listeria are aerobic or facultativelyanaerobic bacilli that are usually in-gested orally in food They preferen-tially infect the newborn, diabetics,alcoholics, and aged or immune-suppressed persons The clinical pic-ture is generally that of a typical bac-terial meningitis, but the cerebrospi-nal fluid cell count may be so low as

to arouse suspicion of viral tis Listeria also causes encephalitis,often with brainstem manifestations,

meningi-as well as meningoencephalitisand cerebral or spinal abscesses

(Fig 2.19).

Treatment

The antimicrobial agents of first

choice are ampicillin and penicillin

G An alternative is trimethoprim/ sulfamethoxazole Cephalosporins

do not eliminate Listeria

Brucellosis is transmitted in milk orother animal products and usuallypresents nonspecifically with fever,arthralgias and myalgias, though itcauses localized disease in somecases, and its manifestations aresometimes restricted to the central

Fig 2.19 Listeria meningoencephalitis.

A 45-year-old woman with multiple cranial nerve deficits and left ataxia

a The FLAIR sequence reveals a plate-like signal abnormality in the brainstem and left

cer-ebellar hemisphere

b The T1-weighted image shows several foci of contrast enhancement.

Fig 2.20 Miliary tuberculosis.

A 28-year-old woman with miliary losis Cerebrospinal fluid examination re-vealed a mild monocytic pleocytosis, amarkedly elevated protein concentration,and a low glucose concentration The MRIreveals multiple pinhead-sized foci of con-trast enhancement in the brain paren-chyma and mild contrast enhancement ofthe meninges as well

tubercu-nervous system These usually consist

of subacute or chronic meningitis,

more rarely meningoencephalitis,

myeloradiculitis or neuritis

Twenty to 500 cells are found in the

cerebrospinal fluid The diagnosis is

confirmed by the demonstration of

specific antibodies in the CSF

Treatment

The treatment consists of

doxycy-cline and rifampicin for 4 months,

with surveillance of the

cerebrospi-nal fluid

Tuberculosis

In miliary tuberculosis,

hematoge-nous spread of tubercle bacilli leads

to the formation of millet-seed-sized

granulomas throughout the body The

clinical manifestations are not

spe-cific to this disease but rather reflect

the predominantly involved organ(s).

Symptoms and signs may include

fe-ver, night sweats, anorexia,

general-ized weakness and fatigue,

hepato-splenomegaly, lymphadenopathy,

and (if the brain is affected) headache

and progressive impairment of

con-sciousness Miliary tuberculosis

usually affects the brain parenchyma

more than the meninges The

cere-brospinal fluid findings are the same

as for tuberculous meningitis, except

that pleocytosis is usually only

mild MRI reveals multiple

pinhead-sized, contrast-enhancing nodules

(Fig 2.20).

For diagnosis and treatment, see

“Tu-berculous meningitis,” above (p 90)

(148, 315, 819)

Neurological symptoms and signs

de-velop in at least one-third of patients

with infectious endocarditis and may

be the presenting manifestations of

the disease

Streptococcus is the most common

pathogen, followed by

staphylococ-cus and Gram-negative bacilli

Cen-tral nervous manifestations arise by

several different pathogenetic

mecha-nisms:

> occlusion of cerebral arteries by

septic and thrombotic emboli

aris-ing from heart valve vegetations;

> infection of the meninges, brain

parenchyma, or vascular walls by

septic emboli or by bacteremia;

> “toxic” and probably also

immune-mediated injury

Pathological Anatomy

There may be bland or hemorrhagic

cerebral infarcts, intracerebral,

sub-arachnoid or subdural hemorrhage,

meningitis, abscesses, mycotic

aneu-rysms, or any combination of theseentities

a diffuse encephalopathy with ioral and cognitive disturbances, im-pairment of consciousness, focal orgeneralized seizures, and sometimesheadache and meningism Importantdiagnostic clues include subfebrile or(in acute endocarditis) septic temper-ature, a feeling of severe illness andprostration, anemia, splenomegaly,subungual, palmar and retinal pete-chiae, and heart murmur

behav-Diagnosis

The complete blood count revealsacute inflammation, and the erythro-cyte sedimentation rate and C-reactive protein are elevated The re-sponsible organism can usually be

demonstrated by blood culture, and endocarditis by transesophageal echo- cardiography (212) The cerebrospinal

fluid may be sterile, purulent or orrhagic, depending on the nature ofCNS involvement (772)

hem-MRI is particularly useful for the

demonstration of embolic and tious processes affecting the central

infec-nervous system Angiography is the

most reliable way to demonstratemycotic aneurysms, but need not beperformed routinely in every patient(819)

The most important initial step is

the prompt institution of empiric

antimicrobial treatment

Penicil-linase-resistant penicillins (e.g.,

flu-cloxacillin or methicillin) are given

together with gentamicin until the

results of culture are available,

whereupon the treatment can be

specifically tailored Vancomycin

should be given with gentamicin

initially whenever the presence of

penicillinase-resistant

staphylococ-cus is likely on clinical grounds (e.g.,

in intravenous drug users and

pa-tients with artificial heart valves)

If emboli continue to form despite

antimicrobial treatment, surgical

heart valve replacement may be

necessary Anticoagulants should be

withheld till at least 48 hours after

the procedure, unless the infected

valve is itself a previously

im-planted prosthesis, in which case

anticoagulation should generally

not be interrupted

Mycotic aneurysms pose a special

problem Many regress

spontane-ously under antimicrobial therapy,

but persistent aneurysms may need

This is a bacterial infection of the

in-testinal mucosa, mesenteric lymph

nodes, and reticuloendothelial

sys-tem The responsible pathogen,

Tro-pheryma whippelii, generally cannot

be cultured

Clinical Features

The manifestations include

arthral-gias, diarrhea, intestinal

malabsorp-tion and weight loss Some 40% of tients show neurological signs, whichare the sole finding in 5% These con-sist of a progressive encephalopathywith personality changes, apathy,memory impairment, and cognitivedeficits that may reach the severity ofdementia Extrapyramidal signs,ataxia, ophthalmoplegia, and hypo-thalamic dysfunction may also befound Oculomasticatory myorhyth-mia with a frequency of 1 Hz is char-acteristic

pa-Diagnosis

These clinical signs are the quence of a perivascular nodular en-cephalitis that is well seen in CT andMRI The cerebrospinal fluid may benormal, or there may be pleocytosis

conse-of up to 200 cells/‘ L and an elevatedprotein concentration of up to 2 g/L.The diagnosis rests on the demon-stration of PAS-positive material inthe mucosa of the small intestine or(in cases of isolated CNS disease) inthe brain

Treatment

Clinical improvement followstreatment with trimethoprim- sulfamethoxazole (Bactrim), which

must be given for 1 year

Focal Purulent Infections

A brain abscess is a focal purulentprocess in the brain parenchyma.These rarely occurring lesions arefound more commonly in personswith HIV (see p 117), bronchiectasis,hereditary hemorrhagic telangiecta-sia (Osler-Weber-Rendu disease), orcongenital heart anomalies with aright-to-left shunt

Pathogenesis, Sites and Responsible

Organisms

Approximately one-half of brain

ab-scesses arise by contiguous spread of

infection, generally from otitis media

or sinusitis; the means of spread is

hematogenous in a further

one-quarter of cases, and undetermined in

the remainder Dental abscesses are

found in 10% of patients Direct

inoc-ulation of pathogens into the brain is

relatively rare Abscesses are multiple

in 10% to 50% of cases (the numbers

in published series vary)

Hematoge-nous abscesses are commonly found

at the junction of gray and white

matter in the territory of the middle

cerebral artery, but may be anywhere

in the brain The source of infection is

commonly the lungs, abdomen,

pel-vis, or bones (osteomyelitis)

Tempo-ral lobe abscesses most commonly

re-sult from otitis media, mastoiditis,

and sphenoid sinusitis, and frontal

lobe abscesses from frontal and

eth-moidal sinusitis or dental abscess

Cerebellar abscesses are otogenic in

90% of cases Two-thirds of the

re-sponsible organisms are aerobic, and

one-third anaerobic; different flora

are typically associated with each

source of infection In general,

strep-tococci, Gram-negative bacilli, and

Staphylococcus aureus are the most

common aerobes, and Bacteroides sp.

and streptococci the most common

anaerobes Some 30–60% of

ab-scesses contain mixed flora (two or

more species)

Pathology

An abscess develops through

succes-sive stages of early and late cerebritis

followed by early and late capsule

formation At first, there is cerebritis

with a necrotic focus, marked edema,

and a perifocal zone of inflammation

Table 2.24 Differential diagnosis of

ring-enhancement on CT and MRIPrimary brain tumorMetastasisAbscessGranulomaHematoma in the process of being re-sorbed

InfarctThrombosed arteriovenous malformationThrombosed aneurysm

Plaque of demyelination

The focus then becomes demarcated

as surrounding neovascularizationand fibrosis gradually lead to the for-mation of a capsule Over the course

of several weeks or months, the crotic center is replaced by granula-tion tissue and correspondinglyshrinks in size An abscess may alsogive rise to satellite abscesses or rup-ture into a ventricle or the subarach-noid space, causing an acute ventri-culitis or meningitis

ne-Neuroradiology

The stages of abscess developmentcan be followed with CT or MRI(282) CT initially shows a poorly de-marcated area of hypodensity withdiffuse contrast enhancement Thecentral hypodense zone is sur-rounded by edema with consequentmass effect Later, ring-enhancementappears and the abscess capsule be-comes visible in the nonenhancedviews as well On the MRI, cerebritis

is T2-hyperintense and enhances fusely with contrast Necrosis andedema are hypointense on T1- andhyperintense on T2-weighted ima-

dif-ges, while the abscess capsule is

isointense or mildly hyperintense on

T1-weighted and isointense or mildly

hypointense on T2-weighted images

The capsule is visible as a marked

ring-enhancement (1049), which,

however, is not specific for brain

ab-scess and carries an extensive

differ-ential diagnosis (Table 2.24).

Clinical Features

The clinical manifestations of brain

abscess include:

> general manifestations of the

pri-mary or generalized infectious

pro-cess, when present,

> general signs of intracranial

hyper-tension,

> focal signs depending on the site of

the abscess in the brain (Table

2.25).

Fever, prostration, and shaking chills

may be, but need not be present

Headache, nausea and vomiting, and

papilledema indicate the presence of

intracranial hypertension Local

ef-fects of the abscess on the brain

in-Table 2.25 Clinical manifestations of

brain abscess (1031)

(%)

Triad of fever, headache, and

focal neurological deficit X 50

Laboratory Findings and Diagnosis

The blood leukocyte count, cyte sedimentation rate, and C-reactive protein are usually, but by nomeans always, elevated Blood cul-tures are positive in only about 10% ofcases The cerebrospinal fluid is nor-mal or else shows the same picture as

erythro-in chronic menerythro-ingitis, usually with anormal glucose concentration Ifsigns of intracranial hypertension arepresent, lumbar puncture should not

be performed, or only with a very fineneedle if necessary CT or MRI dem-onstrates the focal lesion As the ra-diologic picture is not pathogno-monic, the diagnosis must be based

on the combination of clinical, ratory, and radiologic findings

Epidural Abscess (140)

Subdural empyema is a collection ofpus in the virtual space between thedura mater and the arachnoid, whileepidural abscess is one in the virtualspace between the dura mater andthe inner table of the skull When anepidural abscess is present, there isusually a subdural empyema as well,because the two spaces are spanned

by the emissary veins Subdural pyema can spread more or less un-hindered in the subdural space; onlythe tentorium serves as a barrier be-tween the supra- and infratentorialcompartments Epidural abscessescannot spread across the cranial su-tures

em-Both of these types of infection

usu-ally arise as complications of sinusitis

Penicillin G and ceftazidime2andmetronidazole Penicillin G, chloramphenicol

Frontal abscess and sinusitis Anaerobic streptococci,

pneumo-cocci, Haemophilus Penicillin G

3and metronidazole Penicillin G, chloramphenicol

Traumatic brain injury,

neurosurgical procedures Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa4 Penicillinase-resistant penicillin

and ceftriaxone2and rifampicin Vancomycin and ceftriaxone

ques-2 Or other (third-generation) cephalosporin

3 In young adults, penicillinase-resistant penicillin in place of penicillin G

4 Often mixed flora

Cerebritis is treated with

antimicro-bial therapy with serial

neuroradio-logical follow-up If the lesion

im-proves, the treatment should be

continued; if not, a stereotactic

bi-opsy should be performed for

his-tological confirmation of the

diag-nosis and the obtaining of a

speci-men for culture

Brain abscess is usually initially

treated by stereotactic biopsy and

aspiration (with or without

drain-age), to reduce the infectious mass

and obtain material or culture

Thereafter, specific antimicrobial

therapy is given (or empiric

ther-apy until culture results are

avail-able; Table 2.26) If the abscess is

small (X 2.5 cm in diameter), the

source of infection is known, and

the presumed pathogenic organism

has already been identified by

cul-ture from that source, it may be

possible to dispense with biopsy

and proceed directly to specific

an-timicrobial therapy

Parenteral antimicrobial therapy is

continued for 4–6 weeks A further

2–6 months of oral antimicrobial

therapy is often given, but is of

un-certain benefit

or otitis, though they are sometimes

the result of trauma and rarely of

he-matogenous spread of infection

else-where in the body They are most

of-ten due to a single organism, and

their spectrum is comparable to that

of otorhinogenic brain abscesses

(streptococci, staphylococci,

Gram-negative bacilli)

Clinical Features

The appearance of neurological signs

and symptoms in a patient suffering

from sinusitis, otitis, or mastoiditisshould arouse suspicion of a subduralempyema or epidural abscess Some-times, however, the sinusitis or otitismay be discovered only after presen-tation with neurologic manifestations.The latter include fever, headache,meningism, seizures, and focal signs,

usually hemiparesis (Table 2.27) Diagnosis

A cerebrospinal fluid pleocytosis with6–500 cells/‘ L, an elevated proteinconcentration, and a normal glucoseconcentration are found The patho-genic organism can be identified bycerebrospinal fluid culture in only10% of cases The diagnosis is estab-lished by imaging studies (CT or MRI)

in conjunction with the clinical ings and elevated laboratory parame-ters of inflammation The images re-veal a crescentic or lentiform fluidcollection over a cerebral hemisphere

find-Table 2.27 Clinical manifestations of

46

or in the interhemispheric fissure.

The adjacent gyri are inflamed and,

therefore, contrast-enhancing (1010)

Course

Epidural abscess may take a relatively

protracted course, but subdural

em-pyema is a fulminant and

life-threatening disease with mortality

between 10% and 30%

Spinal Epidural and Subdural

Abscesses

The spinal sub- and epidural spaces,

unlike the corresponding intracranial

spaces, are real, rather than virtual

Infections in these areas are acute

emergencies and are discussed on

p 414

Acute Viral Infections (470)

A bewildering variety of viruses can

cause acute or chronic infection of the

central nervous system (see p 104)

The clinical presentation depends on

which structure is predominantly

in-volved: the meninges (meningitis),

the brain (encephalitis), the spinal

cord (myelitis, p 416), or the nerve

roots (radiculitis and polyradiculitis,

pp 575 ff.)

(Serous) Meningitis

This term refers to an acute

meningi-tis caused by a viral pathogen The

di-Treatment

Both of these entities are treated by

immediate intravenous

antimicro-bial therapy and immediate

neuro-surgical evacuation The choice of

antimicrobial agent follows the

same principles as in the case of

infec-> enteroviruses,

> arboviruses,

> the human immunodeficiency rus (HIV), and

vi-> herpes simplex viruses (HSV)

Rarer pathogens include:

> lymphocytic choriomeningitis rus (LCMV),

vi-> mumps virus,

> adenoviruses,

> cytomegalovirus (CMV),

> Epstein-Barr virus (EBV),

> influenza viruses (types A and B),

irri-Diagnosis

The blood leukocyte count and rocyte sedimentation rate are mildly

eryth-elevated, and the differential white

cell count is usually dominated by

lymphocytes and monocytes The

ce-rebrospinal fluid is clear or mildly

turbid and contains up to a few

hun-dred mononuclear lymphocytes,

though granulocytes may initially

predominate The protein and glucose

concentrations are normal, or, at

most, mildly elevated (see

Ta-ble 2.21) The cerebrospinal fluid may

exhibit oligoclonal bands, disruption

of the blood-brain barrier, or both

Viral infection is definitively

demon-strated by serology: seroconversion

usually occurs in the blood,

cerebro-spinal fluid, or both between the

acute illness and the convalescence

phase Typically, CNS infections

pro-duce a steeper rise in antibody titers

in the cerebrospinal fluid than in

se-rum Serologic testing is of little

clini-cal help, however, because it enables

only a retrospective diagnosis A few

viruses, including Coxsackie virus,

echoviruses, LCMV and mumps virus,

can be cultured or demonstrated by

PCR PCR results are sometimes

falsely positive

Differential Diagnosis

Viral lymphocytic meningitis must be

differentiated from parameningeal

infections, partially treated bacterial,

chronic, or neoplastic meningitis, and

noninfectious inflammation due to

vasculitis The possibility of HIV

men-ingitis should be considered in

indi-viduals at risk, and evidence of

sero-conversion should be sought when

the patient is in the convalescent

phase

Prognosis

Viral meningitis is usually a

self-limited illness that passes without

permanent sequelae

Prevention

All infants and children should beroutinely immunized against mumps,poliomyelitis, and measles For pre-vention of HIV meningitis, see p 119

Treatment

The treatment is symptomatic and

consists of bed rest, analgesia against headache, and antipyretic medication Acyclovir is used to

treat HSV, EBV, and VZV; the latter

can also be treated with famciclovir

or valaciclovir (51a).

In these disorders, viral infection volves either the brain exclusively(encephalitis) or both the brainand the meninges (meningoencepha-

in-litis) The more common pathogens

Clinical Features

Most varieties of viral encephalitispresent, like meningitis, with fever,headache, and meningism These are

Table 2.28 Clinical manifestations of viral

encephalitis (1021)

(%) Impairment of

Cranial nerve deficits 33

Visual field defects 13

practically always accompanied by

impairment of consciousness, and

of-ten also by personality changes,

dys-phasia, autonomic dysfunction,

ataxia, hemiparesis, generalized or

focal seizures, cranial nerve deficits,

visual field defects, and papilledema

(Table 2.28) A history of animal bite

raises the possibility of rabies; a

flac-cid paralysis, that of poliomyelitis or

early summer meningoencephalitis

(ESME) Homonymous upper

quad-rantanopsia is indicative of temporal

lobe involvement and thus suggests

HSV-I encephalitis (1021)

Diagnosis

The diagnosis is based on the

cere-brospinal fluid examination and on

neuroimaging studies The findings in

the cerebrospinal fluid are the same

as those of viral meningitis (seeabove), although the pleocytosis may

at first be only mild, or even absent inrare cases In the latter situation, ifpleocytosis is still not found 24 hourslater, another etiology should besought

CT and MRI enable a differentiation

between diffuse and focal tis; MRI is the examination of choicebecause of its higher sensitivity (854).Characteristic findings are hypoden-sity on CT, T1-hypointensity and T2-hyperintensity on MRI

encephali-The EEG shows generalized and

sometimes also focal abnormalities

Serologic testing may reveal

anti-bodies against various neurotropic ruses in the blood or cerebrospinalfluid and thus indicate the presence

vi-of a specific infection, whose coursecan then be followed with serial ti-

ters PCR methods are also available

for the detection of some viruses

by the feco-oral route and reach thecentral nervous system through thebloodstream For poliomyelitis, see

p 414 Coxsackie virus and viruses seldom produce permanentsequelae, except in the case of perina-tal infection

Arboviruses (an acronym for

“arthropod-borne viruses”) are

classi-fied into alphaviruses, flaviviruses,

and bunyaviruses and are transmitted

to man by ticks and mosquitoes

En-demic and epiEn-demic arboviral

en-cephalitis occurs in many parts of the

world, in a regional and seasonal

pat-tern reflecting the habitat and life

cy-cle of their specific arthropod vectors

They usually arise from early summer

to fall In the United States, western

and eastern equine encephalitis, St.

Louis encephalitis, and California

en-cephalitis are found; in Central and

South America, Venezuelan equine

en-cephalitis; and, in Europe, Russian

spring-summer meningoencephalitis

and central European tick-borne

en-cephalitis or early summer

meningo-encephalitis (ESME) The latter

typi-cally appears as an encephalitis

com-bined with a predominantly focal

polyradiculitis or

polyradiculomyeli-tis, which may severely and

perma-nently damage the central and

pe-ripheral nervous system Protection

against ESME may be conferred by

both active and (with prompt

inter-vention) passive immunization

Rabies exclusively attacks the

mam-malian central nervous system and is

transmitted to man by the bite of a

ra-bid animal Affected animals include

dogs and cats (urban type), as well as

wild animals such as foxes, badgers,

bats, and raccoons (sylvatic type) The

virus arrives in the CNS by retrograde

transport through peripheral nerves

and may then spread

transsynapti-cally to the entire nervous system

Af-ter a nonspecific prodromal phase, an

encephalitis appears that is initially

indistinguishable from other types of

viral encephalitis but then goes on to

attack the brainstem, practically

al-ways causing death

The diagnosis is suspected on the sis of a history of animal bite and con-firmed by serology and by immuno-fluorescence staining of a specimen

ba-of skin obtained by biopsy Active andpassive immunization are feasible inpersons bitten by an abnormally be-having animal Persons at special risk,such as veterinarians, should be pro-phylactically actively immunized

The paramyxoviruses include themeasles, mumps, and parainfluenzaviruses Mumps may lead, 3–10 daysafter the parotitis, to a meningoen-cephalitis of generally benign course.Measles does not affect the CNS dur-ing the acute infection, but is fol-lowed in approximately one in a

thousand cases by a postinfectious toimmune encephalomyelitis Sub- acute sclerosing panencephalitis (p.

au-124) appears years after the infection

in approximately one child per lion (468)

Lymphocytic choriomeningitis (LCM) and Lassa fever are both produced by

arenaviruses LCM usually appears inthe winter months and is transmitted

by rodents The clinical illness is ther a meningitis or a meningoen-cephalitis Lassa fever is an often fatalhemorrhagic fever occurring in WestAfrica, which may lead, in survivors,

ei-to cognitive disturbances and ness

The family of herpes viruses includes:

> herpes simplex virus, types I and II(HSV-I and HSV-II),

> varicella-zoster virus (VZV),

> cytomegalovirus (CMV), and

> Epstein-Barr virus (EBV)

a b Fig 2.21a, b Herpes simplex encephalitis.

The T2-weighted MR images reveal extensive signal changes in the left and (to a lesser tent) right temporal lobes

ex-a Axiex-al spin-echo sequence.

b Parasagittal spin-echo sequence.

Herpes simplex encephalitis Herpes

simplex encephalitis is the most

com-mon sporadic form of acute focal

en-cephalitis and is almost always

caused by HSV-I (1020) It remains

unclear whether this illness

repre-sents a new infection by way of the

olfactory system or the reactivation of

a latent infection already present

Fe-ver, headache, confusion, bizarre

be-havior, lethargy, meningism, epileptic

seizures (generalized or complex

par-tial), dysphasia, focal motor and

sen-sory deficits, and upper homonymous

quadrantanopsia make up the typical

clinical picture HSV encephalitis,

however, cannot be distinguished

from other viral encephalitides and

other illnesses in the differential

di-agnosis on clinical grounds alone

(1021), or by the findings of the CSF

examination

CT and, especially, MRI help to

estab-lish the diagnosis (853) CT reveals

hypodensity, and MRI reveals signal

changes, in the medial temporal areas

with extension to lateral portions of

the basal ganglia and to the insular

cortex (Fig 2.21).

At the same time, there is cerebraledema with mass effect that may besevere enough to cause transtentorialherniation The inflamed brain areasoften become hemorrhagic The brain

is usually asymmetrically affected,and the differentiation from a cere-brovascular insult can be difficult.Unlike the latter, however, herpessimplex encephalitis may simulta-neously affect the vascular distribu-tions of the middle cerebral artery(insular cortex, basal ganglia) and ofthe posterior cerebral artery (medial

temporal lobe) The EEG reveals

peri-odic sharp waves every 2–3 secondsover the temporal regions on one orboth sides (889) A rise in the anti-body titer can be documented by se-rology, but occurs too late to be usefulfor therapeutic decision-making Thediagnosis can be established earlywith the use of PCR or brain biopsy(808), although the latter is seldomnecessary (895)

The agent of choice is acyclovir

(10 mg/kg i.v q8h for 10 days)

(886) Treatment with acyclovir

re-duces mortality from 60–70% to

less than 30% (1019) Foscarnet is

also effective

HSV-II infections HSV-II, the

causa-tive organism of genital herpes, can

also lead to aseptic meningitis,

zoster-like neuropathies, urinary

re-tention (cf Elsberg syndrome, p 582),

and, in immunocompromised

pa-tients, to a diffuse encephalitis

Varicella-zoster virus VZV is the

cause of chickenpox (varicella)

(344a) Reactivation of a childhood

infection in adulthood results in

her-pes zoster (p 739), which is more

common in immunocompromised

patients Herpes zoster, in turn, can

be complicated by encephalitis or by a

granulomatous vasculitis infecting

the larger arteries of the central

ner-vous system Small-vessel vasculitis

can also occur (28a) For VZV myelitis,

cf pp 416 and 739

Treatment

Acyclovir is the first line of therapy;

valaciclovir and famciclovir are also

effective

Cytomegalovirus CMV may produce

a congenital infection, Guillain-Barr ´e

syndrome (see p 575), or, rarely, an

acquired encephalitis In

immuno-compromised patients, particularly

AIDS patients, CMV is a frequent

cause of encephalitis, myelitis,

poly-radiculitis, and retinitis The CMV

en-cephalitis of AIDS mainly affects the

periventricular white matter and

takes a subacute course with

progres-sive dementia, headache, cranialnerve deficits, focal and generalized

weakness, and seizures CMV retinitis

is characterized by a painless, gressive visual loss that usually ap-pears bilaterally and can be treatedwith ganciclovir and foscarnet

pro-Treatment

Acyclovir, ganciclovir and vir are used for the prophylaxis andsuppressive treatment of CMV in-fection in immunocompromisedpatients

valaciclo-Epstein-Barr virus EBV is the cause of

infectious mononucleosis and, rarely,

of encephalitis or myelitis

JC virus, the causative organism of

progressive multifocal encephalopathy (PML), belongs to the family of papo-

vaviruses (91) PML typically affectspatients whose cellular immune re-sponse is compromised (because oflymphoma, leukemia, AIDS, etc.) and

is pathologically characterized by myelination of white matter in thebrain and, to a lesser extent, in thespinal cord Its clinical manifestationsinclude cortical blindness, dysphasia,confusion, dementia, hemi- andquadriparesis, ataxia, and other focalneurologic disturbances The diseaseestablishes itself rapidly and leads todeath within a few months

de-The cerebrospinal fluid is normal CTreveals the foci of demyelination ashypodense areas Altered signal in-tensity is always present on MRI

sig-Fig 2.22 Progressive multifocal

leu-koencephalopathy.

A 75-year-old man with leukemia and

corti-cal blindness The signal change in the

white matter is typical, as are the

un-changed signal intensity and thinning of

the adjacent gray matter (arrows)

Chronic Meningitis (955)

Chronic meningitis is diagnosed

when the clinical signs and

symp-toms of meningitis, including

inflam-matory changes of the cerebrospinal

fluid, persist for at least 4 weeks The

various etiologies are summarized in

Table 2.29 Their frequency varies

highly in immune-competent and

immunocompromised patients (p

120) Relevant aspects of the patient’s

history include earlier illnesses,

oper-ations and malignancies, travel, tick

bites, sexual behavior, and eating

habits

Clinical Features

The most prominent manifestations

are headache, fever, and nuchal

rigid-ity, but these may be very mild, and

Treatment

The viral encephalitides are treatedsymptomatically, with the goal ofpreventing medical complications

Temporary hospitalization in an tensive care unit is often necessary,

in-especially when respiratory function arises If HSV encephalitis

dys-is suspected, acyclovir should be

given (see above for dosage) OtherCNS infections entering into thedifferential diagnosis that may re-quire other kinds of specific treat-ment should be ruled out with cer-

tainty Cerebral edema exerting

mass effect must be treated (p 72)whenever there is clinical or radio-logical evidence for its presence.Decisions whether to give anticon-vulsants or ulcer prophylaxisshould be made on an individualbasis

other relevant physical findings orsuggestive history may be absent.Occasionally, erythema chronicummigrans will point to a diagnosis ofborreliosis (Lyme disease), or the fun-duscopic examination will revealsigns of chorioretinitis Rarely (e.g., insarcoidosis), there may be signs ofhypothalamic or pituitary dysfunc-tion Cranial nerve deficits are foundmore often in tuberculous, sarcoid,luetic, fungal, and neoplastic menin-gitis, all of which preferentially affectthe basilar meninges

Diagnosis

A complete blood count, serum zymes, antinuclear antibodies, serol-ogy for HIV, syphilis, and cryptococ-cus, and a chest roentgenogramshould be obtained in every patient.Cutaneous lesions may point to thecorrect diagnosis in borreliosis, sar-

en-Table 2.29 Common etiologies and differential diagnoses of chronic meningitis (after

Vogt-Koyanagi-Harada syndrome

Differential diagnosis Parameningeal inflammation—e.g., epidural abscess,

osteomyelitis

coidosis, secondary syphilis,

tubercu-losis, or disseminated fungal

infec-tion The cerebrospinal fluid

exami-nation should include cell count,

protein, glucose, Gram and

Ziehl-Neelsen stains, syphilis and Borrelia

serologies, a touch prep for the

dem-onstration of cryptococcus, and

cytol-ogy for the detection of neoplastic

cells (p 79)

Further, the cerebrospinal fluid

should be cultured for aerobic and

anaerobic bacteria, fungi, and

tuber-cle bacilli These tests should be

per-formed at least three times, both to

increase the diagnostic yield and to

assess the dynamics of the disease

over time

A CT or, preferably, MRI scan may

in-dicate a lesion of the brain

paren-chyma (e.g., in cysticercosis, mosis, and tuberculosis), and thechronically inflamed meninges en-hance with intravenously adminis-

toxoplas-tered contrast (see Fig 2.15) Imaging

studies are also necessary to rule outthe presence of parameningeal foci ofinfection, hydrocephalus complicat-ing chronic basilar meningitis, andmultiple infarcts due to vasculitis.Vasculitis can be ruled out by angiog-raphy Because chronic meningitismay be the central nervous manifes-tation of an infection involving otherorgans as well, the lymph nodes, liver,and bone marrow may need to be bi-opsied, and the gastric juice, sputumand urine may need to be cultured formycobacteria and other pathogens,depending on the specific clinical

Table 2.30 Diagnostic questions and investigations to be considered in chronic

meningitis

MRI of brain with contrast, possibly CT

(parenchymal lesion, meningeal or parameningeal involvement?)

MRI of spinal cord with contrast, possibly CT

(parenchymal lesion, meningeal or parameningeal involvement?)

Plain radiographs of skull and spine (bone destruction?)

Cerebrospinal fluid examination, at least 3 times

(cell count, protein, isoelectric focusing, glucose, Gram stain, touch prep, Neelsen stain, cytology for neoplastic cells, cultures for aerobic and anaerobic

Ziehl-bacteria, fungi, and mycoZiehl-bacteria, PCR studies, possibly also antibody tests)

Funduscopy with contact lens (chorioretinitis?)

Serological studies

(borreliosis, syphilis, HIV, brucellosis, cryptococcosis, toxoplasmosis, cysticercosis,echinococcosis, antinuclear antibodies, etc.)

Medication history

(medication-induced aseptic meninigitis? intravenous immunoglobulins?)

Mycobacterial culture of sputum, gastric juice, and urine

Angiotensin-converting enzyme (sarcoidosis?)

Tuberculin test (sarcoidosis, tuberculosis?)

Chest radiograph (sarcoidosis, tuberculosis, or other specific change?)

Cerebral angiography (vasculitis?)

Tissue biopsy for histology, possibly also microbiological examination and culture(skin, liver, bone marrow)

Biopsy and possibly also microbiological examination and culture of radiologicallydetectable abnormalities in the meninges or brain

suspicion in each case If the

diagno-sis remains unclear, the

neuroradiolo-gically visible changes in the

menin-ges or brain should be directly

inves-tigated by biopsy and culture The

neurosurgeon should also take this

opportunity to obtain ventricular

fluid for culture (Table 2.30).

Recurrent Meningitis

The syndrome of recurrent aseptic

meningitis with symptom-free

inter-vals is known as Mollaret’s meningitis

(622) In a recent study, PCR analysisdemonstrated the presence of HSV-II

in patients’ cerebrospinal fluid ing, but not between, the meningiticepisodes; this illness is thus thought

dur-to represent an initial infection withHSV-II followed by one or more epi-sodes of reactivation It remains un-clear whether virustatic therapy canshorten the meningitic episodes Itseems reasonable to treat frequentlyrecurring episodes with famciclovir,

500 mg p.o b.i.d., for 10 days

Allergic reactions to medications,

usually nonsteroidal

anti-inflam-matory agents, can also produce

re-current meningitis (195) Further

causes include acquired or congenital

dural defects, epidermoid cyst, or a

parameningeal infection that

repeat-edly breaks into the subarachnoid

space

Treatment

When chronic meningitis is due to

a known pathogenic organism, the

treatment is directed at its

eradica-tion Usually, however, the etiology

is not yet known when a

therapeu-tic decision must be taken When

borreliosis is suspected, ceftriaxone

can be given for 3 weeks If the

pa-tient’s condition worsens despite

this treatment, tuberculostatic

treatment should be given without

hesitation In such situations, a

possible fungal infection should be

sought by all available diagnostic

means, even while tuberculostatic

treatment is in progress, and, if

dis-covered, should be treated If fungi

are not found, and if the level of

clinical suspicion for a fungal

infec-tion is not very high, then

empiri-cal antifungal therapy should not

be given, in view of its high toxicity

Fungal Meningoencephalitis

The clinical features of fungal

infec-tion cover a broad spectrum (Table

2.31) The immune status of the

pa-tient is a crucial variable

Cryptococ-cus neoformans is the most common

pathogen in the patient with normal

immune status, while Candida sp and

Aspergillus sp are more common in

the immunocompromised host In

general, fungal illness plays a greater

role in arid geographic zones than

Table 2.31 Types of fungal infection in

the CNS (after Bell and McGuinness, 80)Meningitis (acute, subacute, chronic)Granulomatous meningoencephalitisAbscess (solitary, multiple, microabscess)Granuloma (microgranuloma, mass le-sion)

Infarct due to arterial or venous bosis

throm-in Europe Coccidioides immitis is found only in the Americas, Histo- plasma capsulatum worldwide but

with a particular concentration in the

Americas, and Blastomyces dis in North America, Africa, and the

dermatiti-Middle East

Cryptococcus neoformans mainly

af-fects patients with AIDS or other temic illnesses impairing the cellularimmune response (lymphoma, post-transplantation, steroid therapy), and,more rarely, patients with normal im-mune status (231, 1050) The primaryinfection occurs in the lungs CNS in-fection is usually subacute or chronicand appears as a combination ofmeningitis and multifocal granulo-matous encephalitis (the clinicalsigns of either of these two may pre-dominate in individual cases) Themajor symptom is headache, and as-sociated signs of encephalitis includepersonality changes, confusion, andfocal neurological deficits In somecases, a mild cognitive deficit is theonly manifestation of disease The ce-rebrospinal fluid examination usuallyreveals a chronically inflammatory

sys-picture (p 84 and Table 2.22), which

may be only mild in the presence of

Table 2.32 Fungi causing CNS infections,

in order of frequency (after Bell and

immunosuppression The touch prep

directly reveals cryptococci in more

than half of all patients; when it does

not, the demonstration of

anticrypto-coccal antibodies in the serum and

cerebrospinal fluid is necessary for

rapid diagnosis CSF cultures are

posi-tive by 4–6 weeks in three-quarters of

all patients Blood, sputum, urine, and

stool cultures may also be helpful

Treatment

The treatment consists of

amphote-ricin B and flucytosine

Immuno-compromised patients require

long-term treatment with

flucyto-sine for the prevention of a relapse

Candidiasis is seldom restricted to

the central nervous system and

gen-erally is found in the CNS as a local

expression of systemic disease It is

usually a consequence of visceral

sur-gical procedures, intravenous terization, steroid treatment, intrave-nous drug use, and the like It maytake an acute or chronic course, with

cathe-or without fever, and lead to gitis or meningoencephalitis, withcorresponding clinical features Thecerebrospinal fluid examination usu-ally reveals a chronically inflamma-

menin-tory picture (see Table 2.21), with cell

count rarely above 2000/‘ L Thediagnosis rests on the demonstration

of spores in the cerebrospinal fluid,either directly or by culture

Toxoplasma gondii is an intracellular

parasite Infection may be congenital,

or it may be acquired at any agethrough the consumption of infectedmeat or contact with the feces of do-mestic animals or pets

Congenital toxoplasmosis produces a

granulomatous meningoencephalitis(p 36)

Acquired toxoplasmosis is typicallyasymptomatic or else a mono-nucleosis-like illness with lymphade-nopathy, fever, rash, myalgias, andhepatosplenomegaly In rare cases,meningoencephalitis may be seen,with up to 500 lymphocytes per mi-croliter of cerebrospinal fluid (948).Patients with AIDS or under pharma-cological immunosuppression are atincreased risk of severe toxoplasmo-

sis infections, which may arise de novo or as a reactivation of latent dis-

ease

b Fig 2.23a, b Cerebral cysticercosis.

a Parasagittal T1-weighted image Two

cysts are visible as hypodense areas inthe parietal lobe A larva can be seen inthe larger cyst

b Axial T2-weighted image Two cysts can

be seen as areas of increased signal eral to the left posterior horn

lat-Clinically, there may be a diffuse

me-ningoencephalitis, or else solitary or

multiple intracerebral masses (698)

Gradually worsening headache,

leth-argy, seizures, and focal neurologic

signs are typical manifestations CT

and MRI reveal solitary or multiple

ring-enhancing lesions (464, 806),

which may become calcified The

di-agnosis is established by serology or

by the direct demonstration of

organ-isms in tissue or cerebrospinal fluid

Treatment

The treatment of choice is a

combi-nation of pyrimethamine and

sulfa-diazine, together with leucovorin

(see Table 2.26).

Trypanosomal Infections

These protozoal illnesses affecting

the brain are mainly found in Africa

and the Americas

Cysticercosis is endemic to Central

and South America and parts of

Af-rica, Asia, and Eastern Europe Is

caused by the pork tapeworm

(ces-tode), Taenia solium Man is the only

known definitive host for the adult

form of the organism (the tapeworm

itself, which resides in the intestine)

Man may also be infected as an

inter-mediate host, harboring the larvae of

the organism in skeletal muscle and

in the brain (cerebral cysticercosis)

The commonest intermediate hosts

are domestic animals such as pigs,

dogs, cats, and sheep When a human

being eats the flesh of an infected

an-imal that contains larvae, an

intesti-nal infection with the adult

tape-worm results The tape-worm produces

eggs, which then develop into bryos; the latter penetrate the intesti-nal wall and spread through thebloodstream to the distant soft tis-sues, including the brain, where theymature further to larvae (cysticerci)

em-The cysticerci may be several

milli-meters to 2 cm in size Their clinical

manifestations are a function of their

size, number, localization, and stage

of development, together with the

re-action of the surrounding cerebral

tissue (833) They most commonly

cause epileptic seizures (224),

head-ache, papilledema, and vomiting, and

more rarely hydrocephalus,

meningi-tis, or spinal cord involvement

CT and MRI are essential for the

diag-nosis (173) and reveal single or

multi-ple cystic lesions, sometimes

contain-ing radiologically identifiable larvae

(Fig 2.23).

The dying cysticercus causes an

in-flammatory tissue reaction with

edema and then becomes calcified

The cerebrospinal fluid may be

nor-mal or show chronic inflammation,

with eosinophils The diagnosis is

es-tablished by serology or by direct

demonstration of cysticerci in

biop-sied tissue

Treatment

Praziquantel and albendazole are

given in combination with

cortico-steroids (albendazole is more

effec-tive against neurocysticercosis

than praziquantel) Cysts must

oc-casionally be removed

neurosur-gically (190)

The larval form of other tapeworms

(cestodes) may cause infections in

man, including coenurosis,

spargano-sis, and echinococcosis

Echinococcosis This disease is caused

by the larvae of tapeworms for which

dogs and foxes are the definitive

hosts Echinococcus granulosus gives

rise to solitary cysts, Echinococcus

multilocularis to locally invasive cyst

agglomerates that are usually found

in the liver, lungs, and skeletal cle The larvae may rarely stray intothe brain, where they form solitarymass lesions that progress over sev-eral months and cause epilepsy,headache, papilledema, personalitychanges, and focal neurologic deficits.The diagnosis is made on the basis ofthe neuroradiologic findings and se-rology, which is usually, though notalways, positive

mus-Treatment

Cysts should be neurosurgically sected whenever possible If the cyst is unresectable, albendazole

re-can be given

Trichinosis is the most common matoid infection affecting man and isusually contracted by the consump-tion of undercooked pork The in-gested larvae spread through thebloodstream to the soft tissues After

ne-an initial diarrheal phase, the diseasemanifests itself by fever, prostration,myalgias due to myositis, periorbitaledema, and, in 10% of cases, meningi-tis, encephalitis, or meningoencepha-litis Eosinophilia in the peripheralblood is present, indicating a parasiticinfection The diagnosis is established

by serology or muscle biopsy

Treatment

Steroids (prednisone, 1 mg/kg, for

5 days) are effective against tis, but antihelminthic agents areineffective against the larvae in thesoft tissues

myosi-| Rickettsial Infections (1034)

Rickettsiae are intracellular parasites

that cause a number of illnesses

in-cluding Rocky Mountain spotted

fe-ver, louse-born typhus, Q fefe-ver, and

trench fever These illnesses are

transmitted by ticks, lice, and fleas

Central nervous system involvement

is indicated by the presence of

head-ache and other neurologic

manifesta-tions and may dominate the clinical

picture Serologic tests are available

for most of the rickettsioses

Treatment

Tetracycline and chloramphenicol

are the antimicrobial agents of first

choice

Encephalopathies Caused by

Immune Reaction (469)

Certain infectious diseases and

im-munizations rarely provoke immune

reactions leading to complications in

the central nervous system An

in-flammatory, demyelinating

encepha-lomyelitis typically arises days to

weeks after the infection or

immuni-zation, with a monophasic course

Post-vaccinial and post-infectious

en-cephalomyelitides are most often

seen after rabies and measles

immu-nizations or after a measles infection

(p 130), mumps, chickenpox, or

ru-bella (360)

Cerebrospinal fluid pleocytosis is

usually present, and MRI reveals

mul-tifocal signal changes (509) The

dif-ferential diagnosis between one of

these entities and the initial phase of

multiple sclerosis may be impossible

at first and become clear only after

spirochete Treponema pallidum Its

three phases are known as primary,secondary, and tertiary syphilis.Syphilitic meningitis may occur asearly as the secondary phase, but typ-

ical neurosyphilis occurs in the

ter-tiary phase Neurosyphilis may be

meningeal, meningovascular, or chymal; in the latter form, it is associ-

paren-ated with the classical syndromes of

general paresis (earlier known as

“general paresis of the insane”) and

tabes dorsalis If the patient is

clini-cally asymptomatic and serologictests are positive only in the blood,then one speaks of seropositive latentsyphilis; if serologic tests are positive

in the cerebrospinal fluid as well, onespeaks of asymptomatic neurosyphi-lis Cerebrospinal fluid changes ap-pear in one-third of all syphilitic in-fections, usually between 12 and

18 months after the primary tion, at which time meningovascularsyphilis is also most frequent Generalparesis or tabes dorsalis appearsyears or even decades after the pri-mary infection in 7% of all untreatedsyphilitics

Meningeal syphilis may affect themeninges of either the brain or thespinal cord and manifests itself asheadache, vomiting, meningism, cra-nial nerve deficits, papillitis, seizures,and occasionally mental changes It is

a predominantly basal, chronic ingitis It occasionally affects the ver-tex region and can lead to malre-sorptive hydrocephalus

men-| Cerebrovascular Syphilis (426)

Cerebrovascular syphilis produces a

marked inflammation of the

menin-ges and cerebral blood vessels,

lead-ing to infarction, usually in the

distri-bution of middle-sized arteries

In-farction is preceded by prodromal

manifestations such as headache,

personality change, dizziness, sleep

disturbances and other nonspecific

symptoms The vascular narrowing

and parenchymal infarcts are

re-vealed by imaging studies The

cere-brospinal fluid displays chronic

in-flammatory changes

Tabes dorsalis arises on average

8–12 years after the primary infection

and is characterized by “lancinating”

pain, ataxia, and bladder dysfunction

Physical examination reveals

hypo-reflexia and abnormal pupillary

reac-tions (Argyll Robertson pupil, p 665)

Tabetic patients account for some

30% of patients with neurosyphilis

Men are four to seven times more

commonly affected than women, in

keeping with their higher rate of

pri-mary infection

Symptoms

Pain of sudden onset, lasting several

seconds or minutes, and shooting

(“lancinating”) into the legs or other

parts of the body is a characteristic

early complaint Painful tabetic crises

are often felt in the epigastrium,

rec-tum, penis, bladder, and elsewhere

Other common phenomena include

paresthesias, sensory disturbances

and associated gait difficulties

(“walking on cotton wool”), as well as

ataxic gait Bladder dysfunction often

appears early and is usually

irrevers-ible; the bladder is typically atonic

and enlarged, with a large voiding residual volume, but withoutpain Impotence is another earlymanifestation

post-Clinical Findings and Course

Sensory abnormalities can always befound at the time of presentation Vi-bration sense and, later, positionsense are either impaired or exagger-ated Sensitivity to painful stimuli islessened in deep and visceral struc-tures (no pain on squeezing of thetesticle or Achilles tendon) Perinealpain sensation is delayed The im-pairment of position sense leads togait ataxia, which may be disabling,

in about one-third of patients Ataxia

is particularly severe when the eyesare closed or in darkness, and thetandem gait and Romberg test areabnormal Involvement of muscle af-ferents in the posterior roots leads tohypotonia, which may be severe,causing abnormal mobility of thejoints The deep tendon reflexes dis-appear in more than half of all pa-tients, first the Achilles reflexes, andthen the patellar reflexes Pyramidaltract signs are rarely seen as well.Sooner or later, 90% of tabetics havepupillary abnormalities The pupilsare usually unequal, constricted, andmisshapen and react to light weakly

or not at all All transitional states arefound up to the classic Argyll Robert-son abnormality, which is seen insome 20% of tabetics About thesame number of patients suffer fromoptic atrophy, which usually leads toblindness regardless of treatment.Oculomotor disturbances are rarer.Trophic manifestations includechronic perforating ulcer of the sole

of the foot and tabetic arthropathywith severe joint destruction (Char-cot joint)

Thinning and sclerosis of the

poste-rior columns of the spinal cord is

ap-preciable on gross examination

Mi-croscopically, a degeneration of fibers

entering via the posterior horn is

seen The fibers of the posterior

col-umns are demyelinated, with

spo-radic axonal degeneration, and gliosis

is present

General paresis appears 10–15 years

after the primary infection, and

sometimes even later It is associated

with a progressive dementia and is

the clinical correlate of a

parenchy-mal meningoencephalitis with

case-ating granulomatous inflammation

(gumma or gummata) Men are more

commonly affected than women

Clinical Features

Progressive dementia is the most

prominent manifestation and is often

associated with lack of judgment,

ex-pansive features, epileptic seizures,

dysarthria, pupillary dysfunction,

myoclonus, and variable focal

neuro-logic signs

The initial symptoms are often

non-specific: headache, fatigability, and

sleep disturbances Some 10% of

pa-tients go on to have seizures In rare

cases, there are transient focal signs,

such as hemiparesis Pupillary

dys-function, as in tabes dorsalis, is

char-acteristic (p 664), as is a slurred,

“syl-labic” form of dysarthria best brought

out with certain test phrases

(“around the rugged rocks the ragged

rascal ran,” “hopping hippopotamus,”

“Methodist Episcopal”) Muscular

jerks known as “sheet lightning” may

be seen, particularly around the

mouth The reflexes are often brisk,

and a Babinski sign is often present

Optic atrophy, posterior column function, and other signs of tabes dor-salis may be used, in which case theterm “taboparalysis” is applied Mal-resoptive hydrocephalus is occasion-ally seen (p 39)

of dementia

Neuropathology

Gross examination reveals thickening

of the meninges, brain atrophy, tricular enlargement, and granuloma-tous ependymitis Microscopically, asubacute encephalitis is found, withmany inflammatory cells in the peri-vascular spaces and in the brain pa-renchyma itself Neuronal loss andglial proliferation are seen, and spiro-chetes can be detected with the use

ven-of special stains

Prognosis

General paresis usually leads to deathwithin 3 years if untreated Spontane-ous improvement is rare

The neurologic expression of syphilis

is by no means limited to tabes lis and general paresis and may take

dorsa-on many other forms, often

mimick-ing other neurologic diseases

Exam-ples include syphilitic optic atrophy,

which leads to progressive blindness,

first in one eye, and then in the other;

and syphilitic sensorineural deafness.

For congenital syphilis, see p 37

Diagnosis of Neurosyphilis

The diagnosis is based on serology

and on the cerebrospinal fluid

exami-nation

As for serology, a number of

nonspe-cific screening tests (such as the VDRL

test) and specific treponemal tests

(such as FTA-ABS and TPHA) are

avail-able The nonspecific tests are

ade-quate for routine testing of large

numbers of serum samples Their

re-sults are expressed as a quantitative

antibody titer, which provides

infor-mation about the possible presence

and activity of the syphilis-producing

organisms Specific tests are used to

confirm the diagnosis in patients

with positive nonspecific tests, or in

whom there is an elevated clinical

suspicion The cerebrospinal fluid

dis-plays the features of chronic

meningi-tis (see Table 2.22) The most

pro-nounced CSF changes, with the

high-est cell counts, are found in syphilitic

meningitis, the least pronounced in

tabes dorsalis The CSF protein

con-centration rarely exceeds 200 mg/dL

and is usually below 100 mg/dL The

glucose concentration is normal or

mildly low The CSF abnormalities are

very mild in some cases; rarely

(usu-ally in cases of tabes dorsalis), the cell

count is normal CSF-specific

oligo-clonal bands are found in ca 50% of

cases Every patient with syphilis

should also be tested for HIV, and vice

versa.

Neuroimaging studies (CT, MRI) reveal

infarcts or gummata appearing as

well-demarcated contrast-enhancingmasses Cranial nerve and meningealinvolvement may also be visible, par-ticularly on MRI (92, 942)

Treatment

Patients with neurosyphilis, even ifasymptomatic, should be treatedwith high-dose penicillin G (12–24million units i.v qd for 10 days), oralternatively with ceftriaxone (1 gi.v q.i.d for 14 days)

Successful treatment results in adecline of the VDRL antibody titer,which should be rechecked at 1, 3,

6, and 12 months after treatment.Nonspecific tests for syphilis oftenbecome negative, but the specifictests do not The cerebrospinalfluid should be reexamined every3–6 months for 3 years to docu-ment the expected fall in cell countand somewhat slower fall of the el-evated protein concentration

Borrelia burgdorferi, afzelii, and garinii

are the etiological agents of the pean Garin-Bujadoux-Bannwarth

Euro-syndrome, and Borrelia burgdorferi

that of North American Lyme disease(which takes its name from the town

of Lyme, Connecticut) These isms are spirochetes related to thetreponemes that cause syphilis (159)and are transmitted to human beings

organ-by tick bites The initial infection ismarked by local cutaneous erythema,typically in the form of an enlarging

ring (erythema chronicum migrans),

sometimes accompanied by flu-like

symptoms Acute disseminated liosis may appear very early, but chronic borreliosis may not be evident

borre-until much later The clinical picture

is so varied, and the rate of

seroposi-Fig 2.24 Cranial polyradiculitis in borreliosis, in a 38-year-old man This axial

T1-weighted spin-echo image reveals contrast enhancement of the meninges and cranialnerves, particularly well seen in the leptomeninges around the medulla and in the hypo-glossal nerves bilaterally

tivity so high in the normal

popula-tion (10–15%), that practically every

manner of presentation of neurologic

disease has been ascribed to

borrelio-sis in at least one case report (734)

Clinical Features (595, 735)

The early stage of infection (stage I),

in which the infection is still local, is

characterized by erythema

chroni-cum migrans or, less commonly, by

cutaneous erythema with

lymphohis-tiocytic infiltration Such skin

changes are seen, however, in fewer

than 25% of patients with borreliosis

The disseminated infection (stage II)

makes itself known with headache,

fever, musculoskeletal pain,

arthral-gias, and sometimes a generalized

lymphadenopathy Multifocal

ery-thema may arise in this stage 15% of

patients with disseminated

borrelio-sis suffer from neurologic syndromes

including meningitis, cranial neuritis,

radiculoneuritis, plexus neuritis,

en-cephalitis, and combinations of these

entities (Fig 2.24).

The most common form of neurologicinvolvement is a lymphocytic menin-gitis with uni- or bilateral facial palsy

or radiculoneuritis Uni- or multifocalencephalitis or vasculitis is rarer Ra-diculoneuritis is typically very painfuland may dominate the clinical pic-ture Within weeks of presentation,cardiac involvement may become ev-ident in the form of intracardiac con-duction abnormalities or, more rarely,myopericarditis with ventricular dys-function In the chronic, generalizedstage of infection (stage III), arthral-gias (60%) and cutaneous abnormali-

ties (acrodermatitis chronica cans) are typical Late-stage neuro-

atrophi-logic abnormalities include a mild,nonspecific encephalopathy withmild memory loss and mood changes,

or else leukoencephalopathy withspastic paraparesis and bladder dys-function

Acute borreliosis is associated with a

cerebrospinal fluid pleocytosis of up

to 100 cells/‘ L The cell count is

lower, or even normal, in chronic

bor-reliosis The diagnosis is established

by serological demonstration of IgG

and IgM antibodies and is most

reli-able when seroconversion is found to

have occurred over a time span of a

few weeks IgM titers are highest a

few weeks after the onset of disease,

IgG titers only months or years later

The presence of intrathecal

anti-bodies is pathognomonic of

neuro-borreliosis (193, 380) When

inter-preting positive findings, the

diag-nostician must remember that

10–15% of the normal population

possesses IgG antibodies and will

therefore have false-positive

serol-ogy, that cross-reactions with other

spirochetal diseases, such as syphilis,

do occur, and that collagen-vascular

diseases may also lead to falsely

posi-tive tests If a test for serum antibody

is positive, neuroborreliosis must be

ruled in or out by lumbar puncture

and cerebrospinal fluid serology

The leptospiroses are acute systemic

illnesses with vasculitis The

organ-isms are transmitted through the

fe-ces of infected animals

Clinical Features

The leptospiroses generally present,

much like a viral illness, with

lym-phocytic meningitis Rare cases

pre-sent with hepatic and renal failure

as-sociated with visceral hemorrhage

(Weil disease due to Leptospira

ictero-haemorrhagiae).

Treatment (215)

Acute neuroborrelioses are treated

parenterally with ceftriaxone (2 g i.v./day), cefotaxime (2 g i.v t.i.d.),

or penicillin G (20–24 million units

i.v./day) for 2 weeks Lymphocyticmeningoradiculitis may also be

treated with doxycycline 100 mg

p.o b.i.d for 2 weeks (492) Chronicneuroborreliosis requires at least3–4 weeks of treatment with ceftri-axone, cefotaxime, or penicillin inthe above doses Isolated facial

palsy can be treated with cline 100 mg p.o b.i.d or amoxicil- lin 500 mg p.o t.i.d for 3 weeks.

doxycy-Steroids are useful in the treatment

of painful neuroborreliosis

Diagnosis

The cerebrospinal fluid cell count andprotein concentration tend to behigher than in viral meningitis; theglucose concentration is normal Thediagnosis can be made in the earliestphase of the illness by direct demon-stration of leptospirae in the blood,cerebrospinal fluid, or urine, or6–12 days later by serology

Treatment

Doxycycline and penicillin G shorten

the course of illness

Chronic Viral Infections of the Central Nervous System

Many different viruses can produceinfections of the central nervous sys-tem that persist for years or decades.The most common such diseases are

listed in Table 2.33.

| HIV Infection and AIDS

(290, 422, 881)

HIV-1 in North America and Europe,

and HIV-2 in West Africa, are

retrovi-ruses (RNA viretrovi-ruses possessing the

en-zyme reverse transcriptase) that

at-tack and destroy CD4+ T-lymphocytes

and macrophages They thereby

pro-duce immune deficiency leading to

severe opportunistic infection,

Ka-posi’s sarcoma, and lymphoma

Epidemiology and History

The acquired immune deficiency

syn-drome (AIDS) was first described in

homosexual men in 1981 It soon

be-came clear that this was a viral illness

transmitted by sexual intercourse,

blood transfusion, or exchange of

blood components by other means

(intravenous drug use, administration

of blood products to treat hemophilia,

childbirth in HIV-positive mothers)

Throughout the 1980s, AIDS largely

remained a disease of homosexual

men, intravenous drug users, and

he-mophiliacs Since then, however, it

has become increasingly common in

the general population and has,

in-Table 2.33 Chronic viral infections of the

Progressive rubella

encephalopathy Rubella virus

deed, become a worldwide pandemic.The international agency dealingwith AIDS (UNAIDS) reports that thenumber of HIV-infected personsworldwide has increased from 13 mil-lion in 1993 to 34.3 million in 2000

Clinical Manifestations and Definition of Disease Stages

The clinical manifestations of HIV fection run a typical course from theprimary infection, through a pro-longed asymptomatic period, to theadvanced disease (AIDS) A standarddefinition of the stages of disease hasbeen issued by the Centers for Dis-ease Control (CDC) of the UnitedStates and was last revised in 1993

in-(Tables 2.34 and 2.35) Staging is

based on the CD4+ T-lymphocytecount and on the clinical findings.AIDS is present, by definition, in anypatient in clinical category C (Ta-

ble 2.35) or with fewer than 200

CD4+ cells per microliter, regardless

of clinical condition It is further ulated that clinical improvement(successfully treated infections, etc.)does not entail reclassification in abetter category

stip-In 50–70% of cases, the event bywhich HIV is transmitted to the pa-tient is followed within a few weeks

by a mononucleosis-like illness withfever, pharyngitis, headache and ret-roorbital pain, lymphadenopathy,prostration, arthralgia, and myalgia.There may also be a maculopapularrash, mucosal ulcers, acute lympho-cytic meninigitis, or, more rarely, en-cephalitis, myelopathy, or plexusneuritis At the time of seroconver-sion, most patients manifest CSF ple-ocytosis This stage of primary infec-tion is followed by an asymptomaticphase, with or without lymphade-nopathy, during which the virus mul-

Table 2.34 Revised CDC classification of HIV infection

Asymptomatic primaryHIV infection or pro-gressive generalizedlymphadenopathy

Clinical tions are present,but neither A nor Bsymptoms

manifesta-AIDS-definingclinical manifes-tations

> Asymptomatic HIV infection

> Progressive generalized lymphadenopathy

> Acute primary HIV infection

> Disseminated or extrapulmonary coccidioidomycosis or cryptococcosis

> Cytomegalovirus infection other than in the liver, spleen, and lymph nodes

tiplies and the CD4+ lymphocyte

count steadily falls The first sign of

the subsequent phase of

symptom-atic HIV infection may be herpes

zoster, thrombocytopenia, oral

le-sions, or the regression of previous

lymphadenopathy The risk of an

op-portunistic infection is high if the

CD4+ cell count is below 200 per

microliter

Neurologic Manifestations of HIV

Infection

Neurologic manifestations are

pre-sent at some time in 60–80% of

pa-tients infected with HIV They reflect

direct damage to the central and

pe-ripheral nervous system by the virus

itself, as well as indirect damage

Table 2.36 Neurologic manifestations of HIV infection

ests, apathy, and progressive deficits

of attention and memory Later on,

the behavioral and cognitive

abnor-malities worsen, the patient becomes

disoriented, and the complete picture

of subcortical dementia is produced

By the time this stage is reached,

mo-tor function is slow and ataxic

Fi-nally, these patients lose the ability to

walk, become incontinent of urine

and stool, and lapse into a vegetative

state

The cerebrospinal fluid contains a

mild mononuclear pleocytosis, a

mildly elevated protein

concentra-tion, and oligoclonal bands CT and

MRI reveal a nonspecific brain

atro-phy MRI usually reveals symmetric

bilateral white matter changes (398)

Unless CT or MRI is performed, AIDS

dementia cannot be reliably

distin-guished from the effects of

opportu-nistic infections and tumors on the

brain

Treatment

Antiretroviral therapy with

zidovu-dine or didanosine can improve

cognitive function in the short

term, but AIDS dementia

neverthe-less remains an inexorably fatal

condition

Aseptic Meningitis

Aseptic meningitis may appear at any

stage of HIV infection, but does so

most commonly during the acute

pri-mary infection It resolves

spontane-ously over a few weeks but may later

recur or undergo a transition to

chronic meningitis or

meningoen-cephalitis Cranial nerve deficits,

par-ticularly involving the trigeminal,

fa-cial, and vestibulocochlear nerves, are

common

The cerebrospinal fluid examinationreveals lymphocytic pleocytosis, anelevated protein concentration, and anormal glucose concentration

Myelopathy

Some 20% of AIDS patients sufferfrom HIV myelopathy The most com-

mon form is a vacuolar myelopathy, in

which a combined degeneration ofthe long tracts leads to spasticity,ataxia, and bladder and bowel dys-function Cognitive disturbances arealmost always present as well Lesscommonly, an isolated degeneration

of the posterior columns results insensory ataxia or in isolated pares-thesiae and dysesthesiae in the lowerextremities

The differential diagnosis of HIV lopathy includes spinal cord involve-ment by opportunistic infection ortumors, which may be treatable

mye-Treatment

Antiretroviral therapy has shown

some success to date in the ment of HIV myelopathy

treat-Neuropathy

Neuropathy is a common tion of HIV infection and may appear

complica-at any stage of the disease

Acute demyelinating polyneuropathy.

HIV-positive individuals who are stillimmune-competent may suffer from

an acute demyelinating thy with clinical features similar to

polyneuropa-those of GuillaBarr´e syndrome,

in-cluding progressive weakness, lexia, and mild sensory changes Thecerebrospinal fluid is pleocytotic, andnerve biopsy reveals a perivascularlymphocytic infiltrate, indicating

aref-an autoimmune pathogenesis

HIV-associated acute demyelinating

poly-neuropathy usually resolves

sponta-neously

Treatment

Plasmapheresis and intravenous

im-munoglobulin, and possibly also

steroids, can improve and shorten

the course of this condition

CMV-associated acute

polyradiculo-pathy This entity is in the differential

diagnosis of HIV-associated acute

de-myelinating polyneuropathy

Treatment

CMV-associated acute

polyradicu-lopathy is treated with ganciclovir

or foscarnet.

Mononeuritis multiplex Like

HIV-associated acute demyelinating

poly-neuropathy, mononeuritis affecting

one or more peripheral nerves, nerve

roots, or (typically) cranial nerves

tends to occur in the earlier stages of

HIV infection, when the immune

sys-tem is still competent, and its

patho-genetic mechanism is presumably the

same The cerebrospinal fluid is

usu-ally pleocytotic

Distal symmetric polyneuropathy/

progressive radiculopathy In

distinc-tion to mononeuritis multiplex, distal

symmetric polyneuropathy and

pro-gressive radiculopathy are both seen

almost exclusively in later stages of

HIV infection, in the presence of

im-mune deficiency

Mild sensory polyneuropathy At least

one-third of AIDS patients suffer from

a mild, mainly sensory

polyneuropa-thy that progresses over time and

may cause unpleasant or painful resthesiae, sensory loss, sensoryataxia, predominantly distal weak-ness, and autonomic disturbances.The cerebrospinal fluid is normal oronly mildly abnormal

pa-Treatment

The treatment is symptomatic and

consists of tricyclic agents, vulsants, analgesics, and combina- tions of these medications.

anticon-Progressive culomyelopathy In this entity, motor

polyradiculopathy/radi-disturbances are more pronouncedthan sensory disturbances, and thecerebrospinal fluid examination re-veals pleocytosis, elevated proteinconcentration, and low glucose con-centration

Toxic neuropathies The differential

diagnosis of these entities specific toHIV-positive patients includes notonly polyneuropathies affecting thegeneral population, but also toxicneuropathies caused by antiretroviralagents (didanosine, zalcitabine, sta-vudine) These are dose-dependentand reversible if the responsiblemedication is discontinued earlyenough

Myopathy

Myopathy may also be a complication

of HIV infection It ranges in severityfrom an asymptomatic elevation ofcreatine kinase to a marked, predom-inantly proximal muscle atrophy andweakness Muscle atrophy may resultfrom the general inanition of AIDS,from AIDS-associated inflammatorydestruction of muscle fibers, or fromlong-term use of zidovudine

Steroids are occasionally helpful.

Opportunistic Infections of the

Central Nervous System

The intracranial lesions listed in

Ta-ble 2.37 appear in at least one-third

of AIDS patients Some 30% of

pa-tients suffer from two or more of

these entities simultaneously or

sequentially

Toxoplasmosis By far the commonest

such infection is toxoplasmosis (p

108 and Table 2.26), which is

mani-fest in a CT or MRI scan of the brain as

a ring-enhancing lesion

Cryptococcosis The next most

com-mon pathogenic organism is

Crypto-coccus neoformans, which causes

meningitis or focal parenchymal

in-fection (p 107)

Other infections Candida spp.,

Myco-bacterium tuberculosis and atypical

mycobacteria, Listeria monocytogenes

and Nocardia asteroides are further

pathogenic organisms causing

men-Table 2.37 Most common causes of focal

CNS lesions in AIDS

Toxoplasmosis

Cryptococcosis

Listeriosis

Herpes viral infection (HSV, CMV, VZV)

Progressive multifocal

ab-Opportunistic viral infections

Menin-gitis, encephalitis, myelitis, and radiculitis can also result from an op-portunistic viral infection, particu-larly arising from herpes viruses(HSV-I, HSV-II, CMV, VZV) and papo-vaviruses (JC virus, see p 103) JC vi-rus is the causative agent of progres-sive multifocal leukoencephalopathy.Retinitis is typical in CMV infection.Syphilis should be considered in thedifferential diagnosis

poly-Primary CNS Lymphoma

Primary lymphoma of the central vous system is extremely rare in thegeneral population (p 71) but affectssome 2% of AIDS patients It producessubacute cognitive deficits, headache,and focal neurologic deficits (892)

ner-Systemic Lymphoma

Systemic lymphoma generally affectsthe CNS by invasion of the meningesand produces a clinical picture ofmeningitis with cranial nerve in-

volvement Kaposi’s sarcoma, a tumor

typically found in AIDS patients,rarely metastasizes to the CNS

Epileptic Seizures

Seizures are a common feature ofAIDS and are seen in primary HIV en-cephalopathy as well as in opportu-nistic infections of the brain

Diagnosis of HIV Infection

The diagnosis is made by serologictesting HIV infection may be sus-pected because the patient belongs to

a group at elevated risk, or because ofthe appearance of an infection or tu-mor associated with immune defi-ciency

Diagnosis and Treatment of the AIDS

Patient with Neurologic

Manifestations

Patients with peripheral neurologic

manifestations These patients, like

HIV-negative patients, are evaluated

by electrophysiologic studies and

ce-rebrospinal fluid examination The

treatment is directed toward the

par-ticular entity causing symptoms, as

detailed above

Patients with central nervous

mani-festations Depending on the manner

of presentation, these patients are

evaluated by imaging study,

cerebro-spinal fluid examination, or both If

the CT or MRI scan is normal or shows

nothing more than meningeal

en-hancement, a lumbar puncture must

be performed and a treatable cause

(organism) sought If the imaging

study reveals one or more mass

le-sions, empirical treatment for

pre-sumed toxoplasmosis can be given for

2–3 weeks If the lesions become

smaller, the treatment can be

contin-ued; if not, a stereotactic biopsy

should be considered, so that tissue

can be obtained for microbiological

examination and culture for the

de-termination of further therapy

Treatment

Antiretroviral Therapy

(343a, 824)

Patients with neurologic

manifes-tations or opportunistic infections

(AIDS-defining infections), as well

as HIV-positive patients with fewer

than 350 CD4+ lymphocytes/‘ L or

more than 5,000–10,000 virus

par-ticles per milliliter of plasma,

should be treated with

antiretrovi-ral medications, as long as this is

not made impossible by drug actions, unacceptable side effects,

inter-or other contraindications The rently available antiretroviralagents and their major side effects

cur-are listed in Table 2.38.

Monotherapy was preferred a fewyears ago, but is no longer recom-mended Current therapy consists

of a protease inhibitor combined with two nucleoside reverse tran- scriptase inhibitors If the CD4+

lymphocyte count falls below 50/

‘ L, acyclovir should also be given

prophylactically

Epileptic seizures in HIV-positivepatients are treated primarily withphenytoin Some 10% of patientsdevelop an allergic rash and canthen be treated alternatively with

phenobarbital or valproic acid.

Spastic Paraparesis) (728, 978)

Tropical spastic paraparesis is rare inEurope It takes a slowly progressivecourse (months) and is associatedwith bladder dysfunction Sensorydisturbances are mild, usually affect-ing only vibration sense The causa-tive organism is the human T-lymphotropic virus, type I (HTLV-I),which is transmitted in similar fash-ion to HIV Cerebrospinal fluid exami-nation reveals a mild lymphocyticpleocytosis (X 50/ ‘ L), a mildly ele-vated protein concentration, and oli-goclonal bands Demyelination andvacuolar myelopathy predominantlyaffecting the posterior columns may

be visible on MRI Periventricular nal changes in the brain may also beseen

sig-Table 2.38 Antiretroviral medications

Reverse transcriptase

inhibitors-nucleoside analogues

Abacavir Headache, hypersensitivity

Didanosine Pancreatitis, polyneuropathy,

diarrheaLamivudine Myelosuppression, polyneuro-

pathyStavudine PolyneuropathyZalcitabine Polyneuropathy, stomal ulcersZidovudine Anemia, headache, myopathy

Reverse transcriptase

inhibitors-non-nucleoside analogues

Delavirdine Rash, headache

Efavirenz Vertigo, rashNevirapine Rash

Protease inhibitors Amprenavir Rash, paresthesiae, depression

Indinavir Renal calculi, nauseaNelfinavir Diarrhea

Rifonavir Perioral paresthesiasSaquinavir Diarrhea

Treatment

The occasionally beneficial effect of

steroids is explained by a presumed

direct viral and immune-mediated

pathogenetic mechanism

Zidovu-dine should also be beneficial on

theoretical grounds

Panencephalitis (SSPE) (258)

This term designates a chronic

mea-sles infection of the brain that usually

affects school-age children, an entity

earlier known as Dawson’s

inclu-sion body encephalitis, Pette-Döring

panencephalitis, and van Bogaert’s sclerosing panencephalitis The intro-

duction of measles vaccination haslowered its incidence from 10 to oneper million per year

Pathogenesis

The pathogenesis of SSPE is notknown with certainty It has been hy-pothesized that incomplete viral rep-lication results in the persistence ofintracellular virus particles, whichthen leads to cell death

Clinical Features

The clinical manifestations arise sidiously At first, there are mild and