Color Atlas of Neurology (Thieme 2004)

CNS Infections

		! Tuberculous Meningitis
		Pathogenesis.		Mycobacterium	tuberculosis
		transmission in man is usually by transfer of
		droplets from and to the respiratory tract (rarely
		orally or through skin lesions). The pathogen
		replicates in the lungs (primary infection), either
		in the lung tissue itself or within alveolar mac-
		rophages.	Macrophages can		only destroy
		tubercle bacilli after they have been activated by
		T cells; the course of the infection thus depends
	System	on the state of the immune system, i.e., on the
		ability of	activated macrophages to hold the
		bacilli in check. The stage of primary infection
		lasts 2–4 weeks, is not necessarily symptomatic
	Nervous	(if it is, then with nonspecific symptoms such as
		fever, anorexia, and lethargy), and cannot be de-
		tected by immune tests performed on the skin.
		The inflammatory process may also involve the
	Central	regional (hilar) lymph nodes (primary complex).
		Calcified foci in the primary complex are easily

seen on plain radiographs of the chest. The bacilli may remain dormant for years or may be reactivated when the patient’s immune defenses are lowered by HIV infection, alcoholism, diabetes mellitus, corticosteroid therapy, or other factors (reactivated tuberculosis). Spread from the primary focus to other organs (organ tuberculosis) can occur during primary infection in immunocompromised patients, but only after reactivation in other patients. The bacilli presumably reach the CNS by hematogenous dissemination; local extension to the CNS from tuberculous bone (spinal cord, base of skull) is rare.

Symptoms and signs. The type and focus of CNS involvement (neurotuberculosis) vary, depending mainly on the age and immune status of the host.

Tuberculous meningoecephalitis. The prodromal stage lasts 2–3 weeks and is characterized by behavioral changes (apathy, depression, irritability, confusion, delirium, lack of concentration), anorexia, weight loss, malaise, nausea, and fever. Headache and neck stiffness reflect meningeal involvement. Finally, cerebral involvement manifests itself in focal signs (deficits of CN II, III, VI, VII, and VIII; aphasia, apraxia, central

232paresis, focal epileptic seizures, SIADH) and/or general signs (signs of intracranial hypertension,

hydrocephalus). The focal signs are caused by

leptomeningeal adhesions, cerebral ischemia due to vasculitis, or mass lesions (tuberculoma). Chronic meningitis most likely reflects inadequate treatment, or resistance of the pathogen, rather than being a distinct form of the disease. Diagnosis: CSF examination for initial diagnosis and monitoring of disease course. The diagnosis of tuberculous meningitis can only be confirmed by detection of mycobacteria in the CSF with direct microscopic visualization, culture, or molecular biological techniques. As the prognosis of untreated tuberculous meningitis is poor, treatment for presumed disease should be initiated as soon as the diagnosis is suspected from the clinical examination and CSF findings; the latter typically include high concentrations of protein (several grams/liter) and lactate, a low glucose concentration (!50% of blood glucose), a high cell count (over several hundred), and a mixed pleocytosis (lymphocytes, monocytes, granulocytes).

Tuberculoma is a tumorlike mass with a caseous or calcified core surrounded by granulation tissue (giant cells, lymphocytes). Tuberculomas may be solitary or multiple and are to be differentiated from tuberculous abscesses, which are full of mycobacteria and lack the surrounding granulation tissue. Diagnosis: CT or MRI.

Spinal tuberculosis. Transverse spinal cord syndrome can arise because of tuberculous myelomeningoradiculitis, epidural tuberculous abscess associated with tuberculous spondylitis/ discitis, or tuberculoma. Diagnosis: MRI.

Antibiotic treatment. One treatment protocol specifies a combination of isoniazid (with vitamin B6), rifampicin (initially i. v., then p.o.), and pyrazinamide (p.o.). After 3 months, pyrazinamide is discontinued, and treatment with isoniazid and rifampicin is continued for a further 6–9 months. The treatment for HIVpositive patients includes up to five different antibiotics.

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CNS Infections

Prodromal phase

Spinal cord compression

Abducens palsy

Focal disturbances

(patient looking to right)

Hydrocephalus

Central Nervous System

Ischemic lesion				Leptomeningeal
(tuberculous			contrast enhance-
arteritis)				ment in MRI
III						II

Tuberculoma in

brain stem

VI Tuberculous V spondylitis,

gibbus deformity

Leptomeninges full of exudate; cranial nerves barely visible

233

Caseating meningitis (basal exudate)

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234

CNS Infections

Viral Infections

! Viral Meningoencephalitis

Aseptic meningitis is characterized by a meningitic syndrome (p. 222) that arises acutely and takes a benign course over the ensuing 1 or 2 weeks, in the absence of signs of generalized or local infection (otitis media, craniospinal abscess, sinusitis). CSF findings: A mild granulocytic pleocytosis is seen in the first 48 hours and is then transformed into a mild lymphomonocytic pleocytosis which can persist as long as 2 months after the clinical findings have regressed. The CSF protein and lactate concentrations are normal or only slightly elevated, while the CSF glucose concentration is normal or mildly decreased. The term “viral meningitis” is often used synonymously with aseptic meningitis, though, strictly speaking, the clinical picture of aseptic meningitis can also be produced by fungal, parasitic, or even bacterial infection (e. g., mycobacteria, mycoplasma, Brucella, spirochetes, Listeria, rickettsiae, incompletely treated bacterial meningitis). Aseptic meningitis may be postinfectious (HIV, rubella, measles, zoster) or postvaccinial or a sequela of sarcoidosis, Behçet disease, Vogt–Koyanagi–Harada syndrome, Mollaret meningitis, connective tissue diseases, and other, noninflammatory disorders

(meningeal carcinomatosis, contrast agents, medications, subarachnoid hemorrhage, lead poisoning).

Pathogens. Their seasonal peak frequency is shown in the following table.

Viral meningitis. Frontal or retro-orbital headache, fever, and low-grade neck stiffness usually begin acutely and last for 1–2 weeks. The CSF findings are those of aseptic meningitis, described above; the IgG index or oligoclonal IgG may be elevated.

Viral encephalitis. The meninges are usually involved concomitantly (meningoencephalitis). Acute encephalitis mainly affects the gray matter and perivascular areas of the brain. Behavioral changes, psychomotor agitation, and focal epileptic seizures may be the leading symptoms (p. 192). The CSF findings are generally as listed above for aseptic meningitis, though pleocytosis may be absent at first. Diffuse and focal EEG changes are usually seen. CT and MRI often reveal pathological changes.

Acute demyelinating encephalomyelitis (ADEM) predominantly affects perivenous regions and the cerebral white matter (leukoencephalitis). The disease takes a variable course (a monophasic course with complete resolution is among the possibilities). ADEM can occur during or after a bout of infectious disease (measles, chickenpox, rubella, influenza) or after a vaccination (smallpox, measles, mumps, polio). Both encephalitic and myelitic syndromes can occur (spastic paraparesis or quadriparesis). The white-matter lesions are demonstrated best by MRI, less well by CT.

Summer, Early Spring	Autumn, Winter	Winter, Spring	All Year Round
Arboviruses, ente-	Lymphocytic chorio-	Mumps	HIV, herpes simplex
roviruses	meningitis virus		virus, cytomegalovirus

The viral pathogens that most commonly cause meningitis differ from those most commonly causing encephalitis and myelitis (cf. Table 30, p. 376).

Identification of pathogen: Serologic tests or isolation of the virus from throat smears (poliovirus, coxsackievirus, mumps virus; ade-

novirus, HSV type 1), stool samples (coxsackievirus, polio virus), CSF (coxsackievirus, mumps, adenovirus, arbovirus, rabies, VZV, LCMV, HSV type 2), blood (arbovirus, EBV, LCMV, CMV, HSV type 2), urine (mumps, CMV), or saliva (mumps, rabies).

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CNS Infections

Personality change

(perseveration, apraxia, aphasia)	Confusion
	(hallucinations, psychomotor hyperactivity,
	loss of coordination, fluctuating level of
	consciousness)

Clonus

Focal signs
(partial epileptic seizure)	Extrapyramidal motor
	dysfunction
	(tonic upward gaze deviation)

Loss of drive (anxiety, apathy, mutism)

Central Nervous System

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236

CNS Infections

! Herpes Simplex Virus Infection

Pathogenesis. Herpes simplex virus type 1 (HSV- 1) is usually transmitted in childhood through lesions of the oral mucosa (gingival stomatitis, pharyngitis). The virus travels centripetally by way of nerve processes toward the sensory ganglia (e. g., the trigeminal ganglion), where it remains dormant for a variable period of time until reactivated by a trigger such as ultraviolet radiation, dental procedures, immunosuppression, or a febrile illness. It then travels centrifugally, again over nerve processes, back to the periphery, producing blisterlike vesicles (herpes labialis). HSV-1 also causes eye infection (keratoconjunctivitis), as well as (meningo)encephalitis when it spreads via CN I and leptomeningeal fibers of CN V. There is no association between herpes labialis and HSV-1 encephalitis. Herpes simplex virus type 2 (HSV-2) reaches the lumbosacral ganglia by axonal transport from a site of (asymptomatic) urogenital infection. Its reactivation causes genital herpes. In adults, HSV-2 infection can cause (aseptic) meningitis and, occasionally, polyradiculitis or myelitis. HSV-2 virus can be transmitted to the newborn during the birth process, causing encephalitis. HSV-1 encephalitis is very rare in neonates, and HSV-2 encephalitis is very rare in adults.

Symptoms and signs. Herpes simplex encephalitis (HSE) in adults begins with local inflammation of the caudal and medial parts of the frontal and temporal lobes. Uncharacteristic prodromal signs such as fever, headache, nausea, anorexia, and lethargy last a few days at the most. Focal symptoms including olfactory and gustatory hallucinations, aphasia, and behavioral disturbances (confusion, psychosis) then appear, along with focal or complex partial seizures with secondary generalization. There is usually repeated seizure activity, but status epilepticus is rare. Intracranial hypertension causes impairment of consciousness or coma within a few hours. In neonates, the inflammation spreads throughout the CNS.

The diagnosis of HSE can be difficult, especially at first. The clinical findings include neck stiffness, hemiparesis, and mental disturbances. CSF examination reveals a lymphomonocytic pleocytosis (granulocytes may predominate initially) with an elevated protein concentration;

low glucose and high lactate concentrations are only rarely found. Xanthochromia and erythrocytes may be present (hemorrhagic necrotizing encephalitis). In the first 3 weeks, the virus can almost always be detected in the CSF by polymerase chain reaction; brain biopsy is only rarely needed for identification of the viral pathogen. Lumbar puncture carries a risk if intracranial hypertension is present (p. 162). EEG reveals periodic high-voltage sharp waves and 2–3 Hz slow wave complexes as a focal or diffuse finding in one or both temporal lobes. In the acute stage of HSE, CT is normal or reveals only mild temporobasal hypointensity without contrast enhancement. Hemorrhage may appear as a hyperdense area. Sharply defined areas of hypodensity appear on CT only in the later stages of HSE. T2-weighted MRI, however, already reveals inflammatory lesions in early HSE. Thus, MRI is used for early diagnosis, CT for the monitoring of encephalitic foci and cerebral edema over the course of the disease.

Meningitis. The clinical manifestations are those of aseptic meningitis (p. 234).

Myelitis. Low back pain, fever, sensory deficit with spinal level, flaccid or spastic paraparesis, bladder and bowel dysfunction. These manifestations usually regress within 2 weeks.

Radiculitis. Inflammation of the lumbosacral nerve roots produces a sensory deficit and bladder and bowel dysfunction.

Virustatic agents. HSV infection of the CNS is treated with acyclovir 10 mg/kg (i. v.) q8h for 14–21 days. Particularly in HSE, it is important to begin treatment as soon as possible.

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CNS Infections

Migration of virus (olfactory bulb)

Olfactory epithelium

Route of HSV-1 infection (in encephalitis)

Spaceoccupying lesion (herpes simplex encephalitis of left temporal lobe)

Viral invasion (olfactory epithelial cell)

HSV-1

Prodromal signs,	MRI
behavioral changes	(contrast-enhanced T1-weighted image)

	Periodic slow-wave complexes, left temporal
1s	50 V
	EEG

Central Nervous System

237

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238

CNS Infections

! Varicella-Zoster Virus Infection

Pathogenesis. In children, primary infection with varicella-zoster virus (VZV) usually causes chickenpox (varicella). The portals of entry for infection by droplets or mucus are the conjunctiva, oropharynx, and upper respiratory tract. The virions replicate locally, then enter cells of the reticulohistiocytic system by hematogenous and lymphatic spread (primary viremia). There, they replicate again and disseminate (secondary viremia). VZV infection is followed by immunity. VZV travels by centripetal axonal transport through the sensory nerve fibers of the skin and mucous membranes to the spinal and cranial ganglia and may remain latent there for years (ganglionic latency phase). The thoracic and trigeminal nerve ganglia are most commonly affected, but those of CN VII, IX, and X can also be involved. Spontaneous viral reactivation in the ganglia (ganglionitis) is most common in the elderly, diabetics, and immunocompromised persons (HIV, lymphoma, radiotherapy, chemotherapy, etc.). The reactivated virus travels over the axons centrifugally to the dermatome corresponding to its ganglion of origin, producing the typical dermatomal rash of herpes zoster. It may also spread to the CNS via the spinal dorsal roots (radiculitis), causing herpes zoster myelitis or meningoencephalitis. VZV attacks cerebral blood vessels by way of axonal transport from the trigeminal ganglion. Postherpetic neuralgia is thought to be due to disordered nociceptive processing in both peripheral and central structures.

Symptoms and signs. Chickenpox: After an incubation period of 14–21 days, crops of itchy efflorescent lesions appear, which progress through the sequence macule, papule, vesicle, scab within a few hours. The scabs detach in 1–2 weeks. Immunocompromised patients can develop severe hemorrhagic myelitis, pneumonia, encephalitis, or hepatitis. Acute cerebellitis in children causes appendicular, postural, and gait ataxia, less commonly dysarthria and nystagmus. CSF examination reveals mild pleocytosis and elevation of the protein concentration, or is normal, and the MRI is usually normal. VZV cerebellitis resolves slowly in most cases.

Herpes zoster begins with general symptoms (lethargy, fever) followed by pain, itching, burn-

ing or tingling in the affected dermatome(s), which are most commonly thoracic or craniocervical (special forms: herpes zoster ophthalmicus, oticus, and occipitocollaris). Within a few days, groups of distended vesicles containing clear fluid appear on an erythematous base within the affected dermatome. The contents of the vesicles become turbid and yellowish in 2–3 days. The rash dries, becomes encrusted, and heals in another 5–10 days. The pain and dysesthesia of herpes zoster generally last no longer than 4 weeks. They may also occur without a rash (herpes zoster sine herpete).

Complications. Elderly and immunocompromised persons are at increased risk for complications. Pain that persists more than 4 weeks after the cutaneous manifestations have healed is called postherpetic neuralgia and is most common in the cranial and thoracic dermatomes.

Cranial nerve involvement may cause unilateral or bilateral ocular complications (ophthalmoplegia, keratoconjunctivitis, visual impairment) or Ramsay–Hunt syndrome (facial palsy, hearing loss, tinnitus, vertigo). Other cranial nerves (IX, X, XII) are rarely affected. Further complications include Guillain–Barré syndrome, myelitis, segmental muscular paresis/ atrophy, myositis, meningitis, ventriculitis, encephalitis, autonomic disturbances (anhidrosis, complex regional pain syndrome), generalized herpes zoster, and vasculitis (ICA and its branches, basilar artery). The viral pathogen is detected in CSF with the polymerase chain reaction.

Virustatic therapy. Acyclovir: 5 mg/kg i. v. q8h or 800 mg p.o. 5 times daily; brivudine: 125 mg p.o. 4 times daily; famcyclovir: 250 mg p.o. 3 times dialy; or valacyclovir: 1 g p.o. 3 times daily. Treatment is continued for 5–7 days. These agents are only effective during the viral replication phase. Intrathecal administration of methylprednisolone is effective in postherpetic neuralgia.

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			CNS Infections
		Papule	Viremia
	Scab formation
	Macule	Vesicle		System
	Varicella		Portals of entry	Nervous
	(different stages of efflorescence)			Central
			Centripetal axonal
			transport
	Spread via spinal dorsal root
			Ganglionic
			latency phase
	Intraneuronal virus (spinal ganglion)		Reactivation
		Group of vesicles on
		reddened base
	Varicella	Zoster
	Acute cerebellar	Postherpetic
	ataxia	neuralgia
	Postinfectious	Cranial nerve palsy
	encephalomyelitis	Segmental paresis
	Myelitis	Aseptic
	Guillain-Barré	meningitis
	syndrome	Meningoencephalitis
	Reye syndrome	Myelitis
	Vasculitis (infarct)	Vasculitis (infarct)
	(Adapted from Johnson, 1998)		Herpes zoster	239
	Possible complications of VZV infection
			(“shingles”; dermatome T6/7, left)

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CNS Infections

!Human Immunodeficiency Virus (HIV) Infection

Pathogenesis. HIV type 1 (HIV-1) is found worldwide, HIV-2 mainly in western Africa and only rarely in Europe, America, and India. HIV is transmitted by sexual contact, by exposure to contaminated blood or blood products, or from mother to neonate (vertical transmission). It is not transmitted through nonsexual contact during normal daily activities, by contaminated food or water, or by insect bites. In industrialized countries, the mean incubation period for HIV is 9–12 years, and the mean survival time after the onset of acquired immunodeficiency syndrome

(AIDS) is 1–3 years. In primary infection (transmitted through mucosal lesions, etc.), the free or cell-bound organisms enter primary target cells in the hematopoietic system (T cells, B cells, macrophages, dendritic cells), CNS (macrophages, microglia, astrocytes, neurons), skin (fibroblasts), or gastrointestinal tract (goblet cells). After replicating in the primary target cells, the virions spread to regional lymph nodes, CD4+ T cells, and macrophages, where they replicate rapidly, leading to a marked viremia with dissemination of HIV to other target cells throughout the body. About 7–14 days after this viremic phase, the immune system gains partial control over viral replication, and seroconversion occurs. The subsequent period of clinical latency is characterized by a steady rate of viral replication, elimination of HIV by the immune system, and the absence of major clinical manifestations for several years. Eventually, the immune system fails to keep up with the replicating virus, various immune functions become impaired, and the CD4+ T-lymphocyte count declines sharply. The rising viral load correlates with the progression of HIV infection to AIDS. In the nervous system, HIV initially appears in the CSF, but is later found mainly in macrophages and microglia.

Symptoms and signs. Neurological manifestations can occur at any stage of HIV infection, but usually appear only in the late stages of AIDS. One-half to two-thirds of all HIV-positive individuals develop neurological disturbances as a primary or secondary complication of HIV infection or of a concomitant disease.

Primary HIV infection. Early manifestations at the time of seroconversion are rare; these in-

clude acute reversible encephalitis or aseptic meningitis (p. 234), cranial nerve deficits (especially facial nerve palsy), radiculitis, or myelitis. Neurological signs are usually late manifestations of HIV infection. HIV encephalopathy progresses over several months and is characterized by lethargy, headache, increasing social withdrawal, insomnia, forgetfulness, lack of concentration, and apathy. Advanced AIDS is accompanied by bradyphrenia, impaired ocular pursuit, dysarthrophonia, incoordination, myoclonus, rigidity, and postural tremor. Incontinence and central paresis develop in the final stages of the disease. CT of the brain reveals generalized atrophy, and MRI reveals multifocal or diffuse white-matter lesions. The CSF examination may be normal or reveal a low-grade pleocytosis and an elevated protein concentration. EEG reveals increased slow-wave activity. Other neurological manifestations include HIV myelopathy (vacuolar myelopathy), distal symmetrical polyradiculoneuropathies, mononeuritis multiplex, and polymyositis.

Secondary complications of HIV infection include opportunistic CNS infections (toxoplasmosis, cryptococcal meningitis, aspergillosis, progressive multifocal leukoencephalopathy, cytomegalovirus encephalitis, herpes simplex encephalitis, herpes zoster, tuberculosis, syphilis), tumors (primary CNS lymphoma), stroke (infarction, hemorrhage), and metabolic disturbances

(iatrogenic or secondary to vitamin deficiency). Virustatic treatment. Antiretroviral combination therapy (HAART: highly active antiretroviral therapy).

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			CNS Infections
Spread in regional			HIV replication
lymph node			(lymph node)

Primary

infection

HIV-1

Mucosal lesion

	HIV replication cycle in host cell
Chromosomal integration		Nonintegrated DNA
Cellular DNA				Viremia,
				dissemination
Integrated
proviral DNA				Genomic RNA
		rT*
Transcription
				Adsorption
of viral genome				(virus gp120 + CD4+ receptor)
Construction
of virions				Viral penetration
Release of virions	mRNA,	Protein synthesis,		Co-receptor
		processing of gp160,
	translation	envelope, capsid

Pathogenesis of HIV infection (*rT = reverse transcriptase)

CD4+ T													HIV-1 RNA
cells/ml)			Early manifestation, viremia, dissemination										copies/ml plasma)
													107
												Death
1000					Clinical latency
													106
							Opportunistic						105
							diseases
500													104
													103
100
													102
Primary	3 6 9 12			1		5						10			CNS toxoplasmosis (axial
	(Weeks)						(Years)								T2-weighted MRI scan)
infection

Course of HIV infection (number of CD4+ lymphocytes and HIV)

Central Nervous System

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