Infectious Diseases of the Brain and Meninges 111

Infectious Diseases of the Brain and Meninges

The intracranial structures, like the rest of the body, can be infected by bacteria, viruses, parasites, and other microorganisms. Different organisms tend to infect either the meninges or the brain substance itself. Thus, there are two main forms of intracranial infection, meningitis and encephalitis (cf. Fig. 6.25). Mixed forms also occur: a meningeal infection can spread to the brain (and/ or spinal cord), or vice versa, causing meningo- (myelo)encephalitis. The latter term is only used if the patient unequivocally manifests clinical signs of both meningeal and cerebral involvement.

Infectious diseases of the central nervous system can be classified, broadly speaking, into three basic clinical situations: a predominantly meningitic syndrome, which can be either acute or subacute to chronic, and a predominantly encephalitic syndrome. These three syndromes, and the organisms that cause each, will be discussed individually in this section.

In addition, focal infections of the brain parenchyma can lead to the formation of brain abscesses, which will also be discussed below.

Fig. 6.25 Sites and nomenclature of intracranial (a) and spinal (b) infections.

					6
	a			superior	Meninges
				sagittal sinus
		6		dura
					and
		5		mater
	1			arachnoid	Brain
				subarachnoid
					the
		3		space
	2
			4	pia mater	of
	b			cerebral cortex	Diseases
				white matter
				periosteum
				epidural space
	5
		1		dura mater
	2			arachnoid
				subarachnoid space
		6
				pia mater
		Brain:		Spinal cord:
		1=meningitis		1=arachnoiditis
		2=encephalitis		2=myelitis
	brain abscess	3=cerebritis (=early stage)
		4=abscess (=late stage)		5=spinal subdural abscess
		5=subdural empyema
		6=epidural abscess		6=spinal epidural abscess

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	112 6		Diseases of the Brain and Meninges
	Infections Mainly Involving the Meninges								lumbar puncture should be performed at once, as soon as
									papilledema (a sign of intracranial hypertension) has
		General manifestations of a meningitic syndrome							been ruled out by ophthalmoscopy. The CSF is typically
		are:headache;							turbid, with 1000 to several thousand cells/mm3 (mainly
		fever (though elderly and immune-deficient patients							granulocytes), the protein concentration markedly ele-
			are often afebrile);						vated (positive Pandy test), and the glucose concentra-
			nausea and vomiting due to intracranial hyperten-						tion diminished. CSF examination enables confirmation
			sion;						of the diagnosis of meningitis and, in two-thirds of
		meningism, which, in severe cases, may be evident as							patients, demonstration of bacteria by Gram stain and
			a spontaneous extended posture of the neck, or						identification of the causative organism by CSF culture.
			opisthotonus;						Treatment begins with antibiotic therapy, with a single
			positive meningeal signs with neck extension, i. e.,
			the Lasègue, Brudzinski, and Kernig signs (p. 16).						drug, or multiple drugs, chosen for their effectiveness
									against the most likely causative organisms in the given
		The clinical aspects of individual types of meningitis de-							clinical setting. Once the organism has been identified by
		pend on the inciting organism and the immune state of							CSF culture and its antibiotic sensitivity spectrum has
		the host.							been determined, the antibiotic treatment can be
									tailored for maximum effectiveness against this or-
		Acute Meningitis							ganism.
		Acute Bacterial Meningitis								The antibiotic treatment of bacterial meningitis must
									! be started immediately after the lumbar puncture,
			Acute bacterial meningitis is caused by bacteria
										without waiting, e. g., for a CT or MRI to be performed
			that can reach the meninges by any of three routes:							(if these or other tests are planned). The elapsed time
			hematogenous spread (e. g., from a focus of infec-							between the clinical presentation and the beginning of
			tion in the nasopharynx), continuous extension							treatment is the most important prognostic factor!
			(e. g., from the middle ear or paranasal sinuses), or
			direct contamination (through an open wound or
			CSF fistula). The clinical onset of purulent mening-						Acute Viral Meningitis
			itis is usually acute or subacute and patients very						A number of viruses can cause so-called aseptic or lym-
			quickly become severely ill. The initiation of antibi-
									phocytic meningitis, which usually presents acutely
			otic therapy as rapidly as possible is essential for a
									(less commonly, subacutely) after a nonspecific prodro-
			good outcome.
									mal stage with flulike or gastrointestinal symptoms. The
									more common causative viruses are enteroviruses
	Etiology. The organisms that most commonly cause								(polioand Coxsackie viruses), arboviruses, and HIV;
									other, rarer ones include lymphocytic choriomeningitis
		acute, purulent meningitis are:
									virus (LCV), cytomegalovirus, type II herpesvirus, and the
			in neonates, Escherichia	coli, group B streptococci,
									mumps, Epstein−Barr, and influenza viruses. The main
			and Listeria monocytogenes;
									clinical manifestations are headache, fever, meningism
		in children, Hemophilus influenzae, pneumococci, and
									(often mild), and general symptoms such as fatigue and
			meningococci (Neisseria meningitidis);
									myalgia. The causative virus is identified by serologic
			in adults, pneumococci, meningococci,				and, less
									testing. The natural course of aseptic meningitis is usu-
			commonly, staphylococci and gram-negative entero-
									ally favorable, provided the brain is not involved (i. e.,
			bacteria.
									provided there is no encephalitic component). Antiviral
		Clinical manifestations.		The	course	of	purulent		treatment is given if the causative virus is found to be
									one for which an effective treatment exists. Residual
		meningitis is characterized by the meningitic signs and
									neurological deficits, such as deafness, are rare.
	symptoms listed above, as well as by:
			myalgia, back pain;
			photophobia;						Chronic Meningitis
			if the infection is mainly located over the cerebral
			convexity, with irritation of		the underlying brain					Chronic meningitis is caused by different or-
			parenchyma, epileptic seizures (40 %);
										ganisms from the pus-forming bacteria that cause
			cranial nerve deficits (10 to 20 %, sometimes per-
										acute meningitis and therefore takes a less acute
			manent deafness, particularly after			pneumococcal
										and dramatic course, at least initially: the mening-
			infection);
										itic symptoms arise gradually, often fluctuate, and,
		variably severe impairment of consciousness;
										depending on the causative organism, may pro-
		in infection with Neisseria meningitidis, there may be
										gressively worsen over a long period of time. Fever
			petechial cutaneous hemorrhages and hemorrhagic
										and other clinical and laboratory signs of infection
			necrosis of the adrenal cortex due to endotoxic shock
										(elevated ESR and CRP, blood count abnormalities,
			(Waterhouse−Friderichsen syndrome).
										general symptoms such as fatigue and myalgia) are
	Diagnostic evaluation. The most important and most									common but may be absent. There may be variably
										severe neurological deficits. The spectrum of
		urgent component of the diagnostic evaluation is lumbar
										causative organisms is very wide.
		puncture. Whenever acute meningitis is suspected, a

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Infectious Diseases of the Brain and Meninges 113

Fig. 6.26 Tuberculous meningitis. a Typical contrast enhancement surrounding the brainstem. b This T1weighted MR image shows the typical meningeal contrast enhancement along the course of the middle cerebral a. (arrows).

a

b

Tuberculous Meningitis

Etiology. Mycobacterium tuberculosis bacilli reach the meninges by hematogenous spread, either directly from a primary complex (early generalization), or else from a focus of tuberculosis in an internal organ (late generalization). The site of origin may be clinically silent.

Clinical manifestations. Meningitic symptoms usually develop gradually. Febrile bouts and general symptoms (see above) are often but not always present. Because the infectious process typically centers on the base of the brain (so-called basal meningitis [Fig. 6.26], in contrast to bacterial meningitis, which is typically located around the cerebral convexities), cranial nerve palsies are common, particularly of the nerves of eye movement and the facial n. Moreover, arteritis of the cerebral vasculature may result in focal brain infarction. The protein concentration in CSF is typically markedly elevated and gelatinous exudates in the subarachnoid space, including the basal cisterns, cause progressive hardening of the meninges and malresorptive hydrocephalus.

Diagnostic evaluation. The most important part of the evaluation is the detection of the causative organism in the CSF or other bodily fluids (sputum, tracheal secretions, gastric juice, urine). In the past, the detection of mycobacteria in the CSF often required weeks of culture; at present, it can be done relatively quickly with PCR. Occasionally, a Ziehl−Neelsen stain of the CSF will directly and immediately reveal acid-fast bacilli (mycobacteria).

Treatment generally begins with a combination of four tuberculostatic drugs (isoniazid, rifampicin, pyrazinamide, and myambutol), followed by a combination of three drugs, and then of two, for at least 12 months. Untreated tuberculous meningitis is lethal.

Other Causes of Chronic Meningitis. A number of other organisms can rarely cause chronic meningitis, usually accompanied by variably severe encephalitis.

Fig. 6.27 Sarcoidosis. This MR image of a 31-year-old woman with sarcoidosis shows infiltration of the basal meninges. There is marked signal abnormality in the basal ambient cistern.

Fungal meningitis mainly affects immune-deficient patients, though not exclusively; the causative species include Cryptococcus neoformans, Candida albicans, and aspergilli. Further causative organisms include protozoa (Toxoplasma gondii) and parasites (cysticerci, echinococci).

The noninfectious causes of the chronic meningitic syndrome include sarcoidosis, which, like tuberculous meningitis, is mainly found around the base of the brain (Fig. 6.27), and seeding of the meninges with metastatic carcinoma or sarcoma (carcinomatous or sarcomatous meningitis).

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114 6 Diseases of the Brain and Meninges

Infections Mainly Involving the Brain

Infections with a predominantly encephalitic, rather than meningitic, syndrome typically cause focal neurological and neuropsychological deficits as well as a variably severe impairment of consciousness. Encephalitis, like meningitis, can be of viral, bacterial, fungal, protozoal, or parasitic origin. Prion diseases are a special category of encephalitis.

These infectious processes often involve other structures in the nervous system simultaneously with the brain (e. g., the peripheral nerves and plexuses, nerve roots, spinal cord, and meninges). In particular, the three important clinical varieties of spirochetal infection (syphilis, borreliosis, and leptospirosis) often present initially with meningitic or polyradiculitic and polyneuritic manifestations.

General signs and symptoms of an encephalitic syndrome are:

fever,

headache,

impairment of consciousness,

personality changes and neuropsychological abnormalities,

epileptic seizures,

focal neurological deficits.

Viral Encephalitis

Herpes Simplex Encephalitis

Herpes simplex encephalitis is a serious infectious condition caused by the herpes simplex virus, type I.

Pathogenesis. This viral disease is characterized by hemorrhagic−necrotic inflammation of the basal portions of the frontal and temporal lobes, combined with severe cerebral edema. The inflammatory foci are found in both hemispheres, but one is usually more strongly affected than the other.

Clinical manifestations. After a nonspecific prodromal phase with fever, headache, and other general symptoms, the disease presents with progressive impairment of consciousness, epileptic seizures (usually of complex partial type, with or without secondary generalization, because of the temporal localization of the disease), and focal neurological and neuropsychological deficits, particularly impairment of memory and orientation. Aphasia and hemiplegia may ensue.

Diagnostic evaluation. CSF examination reveals up to 500 cells/mm3, mainly lymphocytes but also granulocytes; the CSF is sometimes bloody or xanthochromic. Viral DNA can be identified in the CSF by the polymerase chain reaction (PCR) in the first few days of illness and, two weeks later, IgG specific for herpes simplex virus can be identified in the CSF as well. The EEG, in addition to nonspecific changes, may reveal characteristic focal

Fig. 6.28 Herpes simplex encephalitis affecting both temporal lobes.

findings over one or both temporal lobes. The CT scan is usually normal at first but, within a few days, reveals temporal or frontal hypodense areas, which may contain foci of hemorrhage (Fig. 6.28). MRI may reveal corresponding signal changes even earlier.

Treatment. Acyclovir is given intravenously. Corticosteroids are given to combat cerebral edema and antiepileptic drugs to prevent seizures.

!If there is good reason to suspect herpes simplex encephalitis (progressive impairment of consciousness, aphasia, epileptic seizures [particularly of the complex partial type], an inflammatory CSF profile, focal EEG abnormalities), intravenous acyclovir therapy must be started immediately.

Early Summer Meningoencephalitis (ESME)

This disease is caused by an arbovirus and transmitted by tick bites. In endemic areas (e. g., Austria and southern Germany), it affects one in every 100 to 1000 tickbite victims. After an incubation period of one to four weeks, in which there are nonspecific prodromal manifestations such as fever and flulike or gastrointestinal symptoms, about 20 % of patients develop headache, meningism, and focal neurological deficits referable to the brain and spinal cord. Peripheral nerve deficits may also appear some time later. When the patient has recovered from the acute illness, residual paresis and, less commonly, neuropsychological deficits may remain. The essential diagnostic test is the demonstration of virus-specific IgM antibodies. ESME can be effectively prevented by exposure prophylaxis (adequate clothing in endemic forest areas) and active immunization. Immune serum given within 48 hours of a tick bite is protective.

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Infectious Diseases of the Brain and Meninges

HIV Encephalitis and Opportunistic Infections in

HIV-positive Persons

Nearly 50 % of persons infected with HIV have a clinically evident infection of the brain or other parts of the nervous system at some point in the course of their illness. The nervous system can be infected with HIV itself, other, opportunistic pathogens, or both. In severe cases, patients may suffer from encephalitis, myelopathy, mono- and polyneuropathy, and/or myopathy. Encephalitis presents with neuropsychological abnormalities including delirium, personality change, and dementia.

Other Types of Viral Encephalitis

Herpes zoster encephalitis is accompanied by a segmental vesicular rash in the territory of a peripheral nerve (cranial nerve). CSF examination reveals lymphocytic pleocytosis up to 200 cells/mm3. The disease may appear in particularly severe form after a generalized herpes zoster infection.

Rarer types. Other, rarer viruses causing meningoencephalitis, some of which are specific to particular regions, are listed in Table 6.16 in addition to those already discussed. Fig. 6.29 concerns one such virus (papovavirus encephalitis in an HIV-positive man).

Table 6.16 Viruses that cause meningoencephalitis

Virus	Route of	Season of	Persons at risk	Clinical features	Special aspects of
	infection	peak inci-			diagnostic evalua-
		dence			tion
Echovirus	fecal−oral	summer/fall	children and family	M, rash, gastrointestinal	virology
			members living with	symptoms
			them
Coxsackie virus A	fecal−oral	summer/fall	children and family	M, rash, gastrointestinal	virology
			members living with	symptoms
			them
Coxsackie virus B	fecal−oral	summer/fall	children and family	M, rash, pleuritis, peri-	virology
			members living with	carditis, myocarditis, or-
			them	chitis, gastrointestinal
				symptoms
Mumps virus	inhalation	late winter/	children, mainly boys	M, parotitis, orchitis,	elevated amylase,
		spring		oophoritis, pancreatitis	CSF cell count, and
					CSF glucose
Adenovirus	inhalation		infants and children	M, pharyngitis, pneu-
				monia
Lymphocytic chorio-	mice	late winter/	laboratory personnel	M, pharyngitis, pneu-
meningitis virus		spring		monia
Hepatitis viruses	fecal−oral,		mainly intravenous	M, jaundice, arthritis	hepatic dysfunction
	sexual inter-		drug abusers, homo-
	course, blood		and bisexuals,
	transfusion		recipients of blood
			transfusions
Epstein−Barr virus	oral		teenagers and young	M, lymphadenopathy,	atypical lymphocytes,
(infectious mono-			adults	pharyngitis, rash,	Paul−Bunnell reac-
nucleosis)				splenomegaly	tion, hepatic dysfunc-
					tion
Echovirus				M, enanthem and exan-
				them
ESME virus (early	tick bite,	early summer,	persons who go into	M, E, myelitis, menin-	serology
summer meningo-	cutaneous	fall	a forest in an en-	goradiculitis
encephalitis)			demic area
Varicella-zoster	inhalation		children and persons	M, radiculitis; M, E, and	demonstration of in-
virus			who come in contact	myelitis: pain, vesicular	trathecal antibodies,
			with them	eruption	PCR
Cytomegalovirus			HIV-positive persons	E, epileptic seizures,	detection of HIV in
(CMV)				radiculitis	the CSF or urine, PCR
					of CSF or EDTA blood,
					CMV-specific intra-
					thecal IgG synthase,
					CMV retinitis

Continued

*M = predominantly meningitic manifestations, E = predominantly encephalitic manifestations

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Diseases of the Brain and Meninges

116	6 Diseases of the Brain and Meninges
		Table 6.16 Viruses that cause meningoencephalitis (Continued)
		Virus	Route of	Season of	Persons at risk	Clinical features	Special aspects of
			infection	peak inci-			diagnostic evalua-
				dence			tion
		Herpes simplex	person-to-	all year	all persons	E, focal neurological	MRI, virus detection,
		virus type I	person			deficits, epileptic	PCR of the CSF, EEG
						seizures, impairment of	with periodic steep
						consciousness	waves, intrathecal
							HSV-specific IgG syn-
							thesis
		Herpes simplex	person-to-	all year	neonates and child-	E (in neonates);
		virus type II	person		ren, rarely adults	M in others
		Arboviruses	mosquitoes		children and adults in	E, rash	virology
		(Eastern equine,			the Americas
		Western equine,
		Venezuelan equine)
		Human im-	sexual inter-	all year	sexual partners of	E, AIDS dementia, my-	serology
		munodeficiency	course, blood		HIV-positive persons,	elopathy, poly-
		virus (HIV)	transfusion		mother−child, in-	neuropathy, myopathy,
					travenous drug	opportunistic infections
					abusers, homosexuals
	Papovaviruses			all year	immunocom-	E, myelitis, clinical pic-	MRI with subcortical
					promised persons	ture of progressive	T2-hyperintensities,
					(AIDS, lymphoma)	multifocal leuko-	virology
						encephalopathy

*M = predominantly meningitic manifestations, E = predominantly encephalitic manifestations

Fig. 6.29 Asymmetrical encephalitis, probably due to papovavirus, in a 42-year-old, HIV-positive man. MRI reveals involvement of the occipital lobes bilaterally.

Fungal, Parasitic, and Protozoal Encephalitis

Some of the fungi mentioned above as causes of meningitis can also cause encephalitis. In persons with normal immune competence, encephalitis can be caused by Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, and Blastomyces dermatitidis. Persons with reduced immune competence due to disease or pharmacotherapy may develop encephalitis due to any of these or to Candida, Aspergillus, or Zygomycetes. Parasites, particularly Toxoplasma gon-

dii, and protozoa (amebae, plasmodia, trypanosomes, cysticerci, and echinococci) can also infect the brain.

Spirochetal (Meningo-)encephalitis

Neurosyphilis

Etiology. Syphilis is caused by the sexually transmitted spirochete, Treponema pallidum.

Clinical manifestations. Hematogenous spread of treponemes in the secondary phase of syphilis may lead to meningeal irritation or early syphilitic meningitis with cranial nerve palsies (basal meningitis).

In the tertiary phase (usually one or two years after the primary infection and secondary seeding of treponemes), cerebrospinal syphilis mainly affects the mesenchymal structures (blood vessels, meninges) of the brain and, often, the spinal cord. Inflammatory changes of vascular walls, particularly in the arteries of the skull base and the middle cerebral a., cause stenoses and multiple ischemic strokes. Meningitis, mainly in the region of the skull base, presents with fluctuating headache and cranial nerve palsies. Occasionally, tertiary syphilis gives rise to polyneuropathic and polyradicular manifestations. In the rare gummous variant of tertiary syphilis, large granulomatous masses may form within the cranial cavity, producing mass effect and intracranial hypertension.

In the quaternary phase of syphilis, the inflammatory process extends into the parenchyma of the brain and spinal cord, producing tabes dorsalis (spinal cord involvement) and/or progressive paralysis (chronic meningoencephalitis).

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Infectious Diseases of the Brain and Meninges 117

Tabes dorsalis appears in 7 % of untreated syphilitics eight to 12 years after the primary infection. It is characterized, above all, by progressive degeneration of the posterior columns and posterior roots. Its clinical manifestations include progressively severe ataxia, lancinating pains, bladder dysfunction, diminished reflexes, loss of pupillary reactivity (p. 193), diminished sensitivity to pain, hypotonia of the musculature, and joint deformities.

Progressive paralysis appears 10−15 years after the primary infection and is caused by parenchymal meningoencephalitis with formation of caseating granulomas. Its major clinical sign is progressive dementia, with typical features including impaired judgment, lack of social inhibition, and, in some patients, expansive agitation (megalomania, nonsensical and delusional ideas). In other cases, patients may develop flattening of drive and affect, become depressed, or manifest schizophreniform phenomena (hallucinations, paranoia).

The two late forms of neurosyphilis can also be present in combination.

Diagnostic evaluation. The diagnosis of neurosyphilis is established by various serologic tests: the TPHA and FTA−ABS tests for the demonstration of previous contact with Treponema pallidum, the VDRL test for the assessment of current disease activity (though this test is not specific for Treponema pallidum), and the 19-S-IgM−FTA− ABS test for the demonstration of treponeme-specific IgM antibodies, which indicate an active or florid infection. Neurosyphilis also causes an inflammatory CSF picture with elevated leukocyte count and protein concentration, a positive VDRL test in the CSF, and an elevated CSF concentration of treponeme-specific IgG.

Treatment. All forms of neurosyphilis are treated with penicillin G; if the patient is allergic to penicillin, tetracycline or erythromycin can be given instead. The success of treatment depends on the time at which it is begun: improvement is less likely if the brain and spinal cord parenchyma have already sustained considerable damage.

Prognosis. The prognosis of early syphilitic meningitis is good. In the other phases of neurosyphilis, progression can be prevented by appropriate treatment, but residual deficits are common.

Neuroborreliosis

Etiology. Borreliosis is caused by Borrelia burgdorferi, a spirochete transmitted by bites of the tick Ixodes ricinus.

Fifteen percent of patients who reach this stage without treatment go on to develop neurological manifestations, typically lymphocytic meningitis combined with radiculoneuritis, causing weakness, very unpleasant, often burning, dysesthesia, and severe pain in the distribution of the affected nerve roots (Bannwarth syndrome). Cranial nerve involvement is also common and may cause facial diplegia, a condition that should always arouse suspicion of borreliosis. Less commonly, plexus neuritis, encephalitis, or myelitis can develop at this stage or later.

Other possible complications of advanced borreliosis are vasculitis of the cerebral vessels and, outside the central nervous system, myopericarditis, acrodermatitis chronica atrophicans, arthralgia, and liver involvement.

In the United States, borreliosis is commonly known as “Lyme disease,” after the town of Lyme, Connecticut, in which an outbreak was described.

Diagnostic evaluation. A clinical suspicion of neuroborreliosis can be supported, though not definitively confirmed, by the demonstration of specific IgG and, above all, IgM antibodies in the serum and cerebrospinal fluid.

!Serologic testing for Borrelia is positive in at least 10 % of asymptomatic individuals. Thus, the demonstration of antibodies against Borrelia is no reason to ascribe an unclear neurological condition to florid borreliosis.

The diagnosis of neuroborreliosis can only be made if there is an inflammatory CSF profile (elevated cell count and protein concentration, positive Borrelia titer in the CSF). A normal CSF profile makes the diagnosis questionable, even if the serologic tests are positive.

Treatment. If a borrelial infection is suspected after a tick bite (overt erythema chronicum migrans, flulike symptoms), doxycycline is given orally. In all later stages of the disease, third-generation cephalosporins (ceftriaxone, cefotaxime) are given intravenously.

Leptospirosis

Leptospirosis in its initial stage often causes acute lymphocytic meningitis. In a more advanced stage, there may be signs of encephalitis (epileptic seizures, delirious psychosis) or myelitis. The brain can also be damaged by vasculitis of the cerebral vessels. Outside the nervous system, leptospirosis can affect the liver (causing jaundice) and kidneys and cause a bleeding diathesis.

Clinical manifestations. Borrelia burgdorferi can attack the nervous system, joints, cardiovascular system, liver, and skin. Its clinical manifestations are equally varied: after transfer of the organism by a tick bite, one-quarter of patients locally develop erythema chronicum migrans, a red, annular rash that expands centrifugally around the site of the tick bite, clearing in the central area as it grows outward. If the spirochetes are then disseminated systemically, headache, fever, arthralgia, and sometimes generalized lymphadenopathy will follow.

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Encephalitis in Prion Diseases

Prions are infectious particles composed of protein that replicate within the body’s cells even though they possess no genetic material (nucleic acids) of their own. They can arise in situ by mutation of the host’s genetic material or reach the body from outside and incorporate themselves into its cells, where they replicate.

Neurons in the brain that have been infected by prions may die after a latency period of years or even decades. The typical pathological findings in prion infection are

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Diseases of the Brain and Meninges