Acute viral infections

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Acute viral infections

Classifications of viral infections of the CNS such as those shown in Table 12.1 are of help in making an accurate diagnosis. In practice, a combination of approaches is generally used to classify and diagnose these disorders.

Table 12.1

Viral infections of the central nervous system

These may be classified according to:

Course of disease

Acute

Subacute or chronic

Most severely involved/target tissue

Meningitis

Poliomyelitis, polioencephalomyelitis

Viral leukoencephalopathy

Panencephalitis

Patient age group

Fetal

Neonatal

Child

Adult

Patient immune status

Etiologic agent

ASEPTIC MENINGITIS

This is a benign, usually short-lived, syndrome of meningeal inflammation that is not attributable to any of the common bacterial pathogens. A wide range of viruses can cause aseptic meningitis (Table 12.2); much less common causes include some bacteria (e.g. in syphilis and Lyme disease) and other microorganisms, non-infective inflammatory disorders (e.g. Behçet’s disease), tumors (e.g. epidermoid and dermoid cysts), and drugs (e.g. ibuprofen). One form of recurrent aseptic meningitis (Mollaret’s) that was previously regarded as non-infective has been linked to infection with herpes simplex virus (HSV), especially HSV-2.

Table 12.2

Common viral causes of aseptic meningitis

Echovirus

Coxsackie B

Coxsackie A

Herpes simplex virus (HSV)-2

Mumps

Human immunodeficiency virus (HIV)

Lymphochoriomeningitis virus

Arboviruses

Measles

Parainfluenza virus

Adenovirus

The causes of aseptic meningitis show considerable geographic and seasonal variation. The peak incidence of cases due to enteroviral infection, which is the commonest overall cause of this syndrome, is during late summer and fall.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Since aseptic meningitis is by definition benign, reports of the neuropathologic findings are uncommon. Occasionally, patients with aseptic meningitis die as a result of a concurrent systemic illness (e.g. viral myocarditis). Histologic examination of the CNS then reveals a scanty infiltrate of lymphocytes in the meninges, in the perivascular space surrounding some of the superficial cortical blood vessels (Fig. 12.1), and in the choroid plexus.

12.1 Aseptic meningitis.
This section shows a meningeal and scanty perivascular infiltrate of lymphocytes in a child who died of coxsackievirus myocarditis. (Courtesy of Dr David Hilton, Derriford Hospital, Plymouth, UK.)

POLIOMYELITIS

This disorder is characterized by lytic infection of motor neurons. The destructive effects may be confined to the spinal cord or may also involve neurons within the brain (polioencephalomyelitis).

POLIOMYELITIS

Polioviruses are small RNA viruses of the genus Enterovirus (along with group A and B coxsackieviruses, echoviruses, and enteroviruses). Spread of the virus is feco–oral, and is facilitated by crowding and poor sanitation.

There are three antigenic types of poliovirus: types 1, 2, and 3. Until the development and widespread use of poliovirus vaccines, these viruses were responsible for almost all cases of poliomyelitis, including the epidemics of paralytic poliomyelitis in Europe and North America in the latter half of the nineteenth century.

The introduction of the Salk vaccine containing inactivated virus in the 1950s, and of the Sabin vaccine comprising live attenuated poliovirus in the early 1960s, caused a sharp decline in the incidence of poliomyelitis.

Outbreaks of paralytic infection by wild-type (i.e. unmodified) poliovirus still occur in a few developing parts of the world and in communities that refuse vaccination (e.g. for religious reasons). However, in vaccinated populations poliomyelitis is usually caused by the rare reversion to neurovirulence of attenuated vaccine-related strains of poliovirus; by other enteroviruses, especially group A coxsackieviruses and enterovirus 71; or by arboviruses – Japanese encephalitis virus, West Nile virus, or tick-borne encephalitis virus.

CNS infection by poliovirus and other enteroviruses is hematogenous. After initial intestinal infection and viral replication, there is a primary viremia with spread to the reticuloendothelial system, where further replication leads to a secondary viremia, during which the virus enters the CNS.

MACROSCOPIC APPEARANCES

Acute phase

It is unusual to see macroscopic lesions. In severe cases, vascular congestion, petechial hemorrhages, and focal necrosis may be evident in the spinal gray matter or brain stem.

MICROSCOPIC APPEARANCES

Acute phase

The extent of histologic involvement almost always exceeds that predicted by the clinical manifestations. The distribution of lesions is variable. The spinal gray matter is usually involved, particularly the anterior horn cells. The disease also shows a predilection for the motor nuclei in the pons and medulla, the reticular formation, and deep cerebellar nuclei (Fig. 12.2). Apart from the precentral gyrus, the cerebral cortex is usually spared.

12.2 Schematic illustration of the regions of the CNS that are susceptible to poliomyelitis.

There is intense inflammation in the leptomeninges and affected gray matter (Fig. 12.3). Neutrophils are found initially, but lymphocytes soon predominate. Lymphocytic cuffing of blood vessels is a conspicuous feature.

12.3 Poliomyelitis.
(a) and (b) show mixed inflammatory infiltrate in the spinal gray matter in coxsackievirus poliomyelitis. (Courtesy of Dr David Hilton, Derriford Hospital, Plymouth, UK.)

The histologic hallmark of the viral infection of neurons is neuronophagia (aggregation of microglia and macrophages around dead neurons, Fig. 12.4). Clusters of microglia (microglial nodules) mark the sites of destroyed neurons for several weeks after their resorption.

12.4 Neuronophagia and microglial nodule formation in poliovirus infection.
(a) Florid brain stem inflammation and neuronophagia in poliovirus poliomyelitis. (b) Microglial nodule in the brain stem in coxsackievirus polioencephalomyelitis.

There is often congestion of small blood vessels in the areas of inflammation. This may be associated with perivascular hemorrhage and, occasionally, focal necrosis. Enterovirus 71 infection has been associated with widespread inflammation in the spinal gray matter, brain stem, hypothalamus, subthalamic and dentate nuclei, and necrotizing lesions in the dorsomedial pons and medulla.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Chronic phase

In patients coming to necropsy several years after the acute illness, there is wasting of the affected muscles, and thinning and gray discoloration of the corresponding anterior spinal nerve roots.

Examination of the affected regions shows an obvious loss of motor neurons (Fig. 12.5) and atrophy and fibrosis of anterior nerve roots. There may be scanty residual inflammation. These changes apart, the parenchyma of the affected spinal cord or brain stem is usually remarkably well preserved.

12.5 Chronic phase of poliomyelitis.
Marked depletion of anterior horn cells from the spinal cord of a long-term survivor of poliomyelitis.

POLIOVIRUS INFECTION

Most patients experience no more than a minor nonspecific illness at the time of the primary viremia, 1–5 days after exposure to the virus. Symptoms include: gastrointestinal upset, mild pyrexia, headache, and general malaise.

Some days after resolution of the nonspecific illness or approximately 10 days after the initial exposure, a small percentage of patients develop paralytic polioencephalomyelitis. In children, paralytic disease is usually heralded by pyrexia, headache, vomiting, neck stiffness, and irritability. In adults, these prodromal symptoms may be less pronounced.

Patients may experience muscle pain or stiffness before the development of paralysis.

The distribution of the paralysis depends on that of the lesions within the CNS. The spinal cord is usually involved. The paralysis is typically asymmetric, and the lower limbs are involved more often than the upper limbs or trunk. Bulbar disease manifests with cranial nerve palsies, and involvement of the reticular formation with cardiac arrhythmias and abnormal patterns of breathing.

Post-polio syndrome

This is a syndrome of increasing weakness or muscular atrophy developing many years later in survivors of poliomyelitis who do not have any other neuromuscular disease. The cause is not known.

Chronic enteroviral meningoencephalitis

Patients with depressed humoral immunity, due to X-linked agammaglobulinemia or combined variable immunodeficiency, rarely develop a chronic encephalopathy or myelopathy due to persistent enteroviral infection of the CNS (see Chapter 13).

CAUSES OF POLIOMYELITIS AND POLIOENC EPHALOMYELITIS

Whilst most cases of poliomyelitis are caused by enteroviruses (mainly coxsackievirus A4, A7, or B3, echovirus 2, 9, or 30, and enterovirus 70 or 71), arboviruses are sometimes responsible and should also be considered, particularly in older age groups. The types of arbovirus that are potentially responsible will depend on the geographical context (see Arbovirus infections, below) but include:

Tick-borne encephalitis virus

Japanese encephalitis virus

West Nile virus.

The differential diagnosis of polioencephalomyelitis includes infection due to these and other arboviruses (see below), rabies (see below) and non-infective encephalitides, particularly Rasmussen’s encephalitis (see Chapters 7 and 13) and paraneoplastic (autoimmune) encephalitis (see Chapter 47).

HERPESVIRUS INFECTIONS

The herpesviruses are relatively large, enveloped, double-stranded DNA viruses. The group includes several that are human pathogens and can cause CNS disease (Fig. 12.7), including herpes simplex virus type 1, herpes simplex virus type 2, Epstein–Barr virus, cytomegalovirus, and human herpesvirus 6. The simian herpesvirus, B virus, can also infect humans and cause CNS disease. When these viruses invade the CNS they tend to cause necrotizing destruction of both gray and white matter (i.e. panencephalitis or panmyelitis).

12.7 Patterns of herpesvirus infections in children and adults.

HERPES SIMPLEX VIRUS INFECTION

CLASSICAL HERPES SIMPLEX ENCEPHALITIS (HSE)

This is one of the commonest forms of acute necrotizing encephalitis. Approximately 50 cases are reported in the United Kingdom each year, but there are probably more cases that are not recognized and therefore not reported.

HERPES SIMPLEX ENCEPHALITIS

Patients present with a combination of:

• nonspecific features of encephalitis (e.g. headache, pyrexia, neck stiffness, drowsiness, coma)

• focal neurologic signs (e.g. dysphasia, hemiparesis, focal seizures).

Without treatment, the disease progresses rapidly over the course of a few days and is usually fatal. Some patients do survive, with behavioral abnormalities, memory disturbances, and other neurologic deficits of varying severity.

Since the introduction of vidarabine and later aciclovir, the mortality and morbidity rates have fallen substantially, although ~20% of patients still die despite treatment, the risk being greatest in the elderly and in those whose level of consciousness is severely depressed when treatment is started.

MACROSCOPIC APPEARANCES

Acute phase

Most cases show obvious congestion and hemorrhagic necrosis involving the temporal lobes (Fig. 12.9) and, to a greater or lesser extent, the insulae, cingulate gyri, and posterior orbital frontal cortex (Fig. 12.9). The lesions are often somewhat asymmetric. Occasionally, in very early disease, the brain may appear macroscopically normal. In contrast, in patients dying some weeks after the onset of disease the liquefactive necrosis in these regions will have progressed to cavitation and atrophy.

12.9 HSE.
(a) Undersurface of unfixed brain from a patient with subacute HSE showing hemorrhagic necrosis of the temporal lobes. (b) Coronal slice through the fixed brain of a patient with HSE. The brain shows temporal, orbital frontal, and focal insular necrosis.

MICROSCOPIC APPEARANCES

Acute phase

The earliest lesions contain relatively scanty parenchymal inflammation, although there are moderate numbers of lymphocytes and macrophages in the overlying leptomeninges (Fig. 12.10). The lesions extend from the pial surface through the cerebral cortex and into the white matter. The affected neurons, glia, and endothelial cells tend to have slightly hypereosinophilic cytoplasm. Many of the nuclei are pyknotic or disintegrating; others contain homogeneous eosinophilic inclusions (Fig. 12.10), some surrounded by an irregular rim of condensed marginated chromatin. Clumps of eosinophilic inclusion material may also be visible in the cytoplasm. Inclusions are usually best seen in cells towards the edge of lesions.

12.10 Early HSE.
(a) Meningeal, perivascular, and scanty parenchymal inflammation. (b) This section shows scanty perivascular inflammation and scattered cells containing viral inclusions (arrows). (c) Towards the edge of the affected region of the temporal lobe, intranuclear viral inclusions (arrow) are visible.

Most lesions are usually at a more advanced stage, containing sheets of necrotic cells, foci of hemorrhage, and an intense perivascular and interstitial infiltrate of lymphocytes and macrophages (Fig. 12.11). There may be neuronophagia and, later, microglial nodules. Nuclear inclusions are sparse at this stage.

12.11 Necrotizing inflammation in HSE.
Sheets of foamy macrophages and perivascular cuffing by lymphocytes in a case of HSE.

Herpesvirus nucleocapsid particles are approximately 100 nm in diameter and may be seen within the nuclei of infected cells by electron microscopy (Fig. 12.12). Viral antigen is readily demonstrable by immunohistochemistry (Fig. 12.13) for up to approximately 3 weeks after the onset of encephalitis, and viral DNA can be detected in frozen or paraffin sections by in situ hybridization (Fig. 12.14) or polymerase chain reaction (PCR) amplification with suitable primers.

12.12 Ultrastructural appearance of HSV.
Electron micrograph showing intranuclear herpesvirus nucleocapsid particles.

12.13 Immunohistochemical demonstration of HSV antigen, some of which is clearly within neurons (arrows).

12.14 Detection of HSV DNA by in situ hybridization with a biotinylated probe.

HERPES SIMPLEX ENCEPHALITIS

Classical herpes simplex encephalitis (HSE) is caused by herpes simplex virus type 1 (HSV-1), which is spread by direct contact with infected secretions, usually from orolabial vesicles (‘cold sores’).

Primary mucocutaneous infection

In most patients, initial infection by HSV-1 involves the mucocutaneous border of the lips or the oropharyngeal mucosa.

Establishment of latency in the trigeminal ganglion

After local replication the virus is conveyed by retrograde axonal transport along sensory fibers to the trigeminal ganglion, where, after further replication, latent infection is established (Fig. 12.8). (In contrast, HSV-2 causes genital herpes infection and establishes latency in the sacral dorsal root ganglia.) HSV-1 genome and latency-associated transcripts (the only viral mRNAs produced during latent infection) can be detected in the trigeminal ganglia in 50–75% of adults.

12.8 Spread of HSV-1 (upper diagram) and HSV-2 (lower diagram), and possible routes of entry of virus into the CNS.

Reactivation of virus

Reactivation of the virus within the trigeminal ganglia results in its anterograde axonal transport to the skin or mucosa and the development of cold sores. Reactivation may occur spontaneously, or be precipitated by local mucocutaneous trauma or ultraviolet irradiation, or by systemic factors such as pyrexia, emotional stress, physiologic fluctuations in estrogen and progesterone concentrations during the menstrual cycle, and immunosuppression.

Involvement of the olfactory pathway

HSV-1 DNA has been detected in the olfactory bulbs in approximately 15% of adults, suggesting that retrograde transport of the virus along the olfactory nerve fibers may occur after primary nasopharyngeal infection. It is not known whether the virus in the olfactory bulbs is susceptible to reactivation. In experimental studies, attempts at reactivation from central nervous tissue have been unsuccessful.

Entry of HSV-1 into the CNS

The mechanism of entry of HSV-1 into the CNS to cause HSE has been much debated. Proposals include:

Spread along olfactory nerve fibers and tracts either during primary nasopharyngeal infection or after reactivation of latent virus in the olfactory bulbs. This route would explain the predilection of the disease for the posterior orbital, frontal, and limbic regions.

Reactivation of latent virus in the trigeminal ganglia and axonal spread along either centrally projecting fibers into the brain stem or peripheral trigeminal sensory fibers innervating the dura. This route would not account for the restricted distribution of lesions in herpes encephalitis, the lack of correlation between the development of herpes labialis and herpes encephalitis, or the occasional difference in the strain of virus isolated from cold sores and the brain.

Reactivation of virus that has previously established latent infection within the temporal lobes or other parts of the CNS affected by herpes encephalitis. This is the most speculative proposal, although there are reports that tiny amounts of HSV DNA can be detected in the brains of many adults without neurologic disease.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Chronic phase

In long-term survivors of untreated or unsuccessfully treated herpes encephalitis, affected parts of the brain are shrunken and cavitated and show yellow-brown discoloration (Fig. 12.15).

12.15 ‘Burnt out’ HSE.
(a) Marked atrophy and yellow-brown discoloration affect the temporal lobes and insulae. (b) Cavitated temporal lobe in a long-term survivor of HSE. (c) Scattered aggregates of lymphocytes persist in the meninges or brain parenchyma for many years. Note also the cortical gliosis and microcystic change.

The normal gray and white matter is replaced by cavitated glial scar tissue (Fig. 12.15). Occasional clusters of lymphocytes are still seen in the meninges and brain parenchyma (Fig. 12.15).

Although virus is no longer demonstrable by culture, electron microscopy, or immunohistochemistry, in most cases viral DNA is readily detectable, even in paraffin-embedded material, by PCR. It should be noted, however, that on using highly sensitive nested PCR techniques, very small amounts of herpesvirus DNA have been detected in apparently normal brain tissue.

ATYPICAL HERPES SIMPLEX ENCEPHALITIS

In occasional patients, HSE predominantly involves the brain stem or follows a more subacute clinical course than usual (Fig. 12.16). Although the likelihood of developing HSE is probably not increased by immunosuppression, immunosuppression predisposes to atypical forms of the disease.

12.16 Atypical HSE.
Immunohistochemical demonstration of atypical non-necrotizing HSV-1 infection of the brain stem in a patient with AIDS.

CHRONIC GRANULOMATOUS HERPES SIMPLEX ENCEPHALITIS

Very rarely, children who have experienced an otherwise typical attack of acute herpes encephalitis develop focal or multifocal chronic granulomatous encephalitis, sometimes after an intervening symptom-free period of months or years. Histology reveals a patchy cortical and leptomeningeal infiltrate of chronic inflammatory cells and scattered, well-circumscribed granulomas that contain epithelioid macrophages and giant cells, with surrounding lymphocytes, macrophages, and plasma cells. Foci of necrosis and mineralization may be prominent. In some patients, HSV DNA or antigen is demonstrable by PCR or immunohistochemistry (Fig. 12.17).

12.17 Chronic granulomatous herpes simplex encephalitis.
(a) Histology of partial temporal lobectomy specimen from a 10-year old boy with chronic granulomatous inflammation complicating herpes simplex virus encephalitis at 4.5 months of age reveals multiple granulomas, some including multinucleated giant cells, with a surrounding infiltrate of lymphocytes and macrophages. The arrow indicates a focus of mineralization. Postoperatively, HSV-1 DNA and elevated titers of HSV IgM antibodies were detected in the CSF. (b) Higher magnification view of the granulomas and foci of mineralization (arrows).

NECROTIZING MYELOPATHY

Both HSV-1 and HSV-2 can cause this rare disorder. Histology shows extensive necrosis and inflammation involving the spinal gray and white matter (Fig. 12.18). Herpesvirus is usually demonstrable within the cord by immunohistochemistry (Fig. 12.18).

12.18 Necrotizing myelopathy due to HSV-1 infection.
(a) There is extensive necrosis within the spinal cord and perivascular inflammation in the leptomeninges. (b) Immunohistochemical demonstration of HSV-1 in the necrotic spinal cord. (Courtesy of Professor Clayton Wiley, University of Pittsburgh.)

NEONATAL HSV ENCEPHALITIS

Neonatal HSE differs in its pathogenesis and clinical and pathologic manifestations from the adult disease.

PATHOGENESIS OF NEONATAL HSV ENCEPHALITIS

Most cases of neonatal HSV infection are due to HSV-2 and are acquired during delivery by contact between the fetus and infected maternal genital lesions. The disease can, however, be acquired from the mother in utero, even during early gestation, or by contact with infected secretions from the mother or another source during the postnatal period.

Primary maternal HSV-2 infection during pregnancy and prolonged rupture of the membranes in a woman with active genital infection are particular risk factors for fetal infection.

Approximately 15–20% of neonatal HSV infections are due to HSV-1 and these are predominantly acquired postnatally.

NEONATAL HSV INFECTION

In approximately 45% of neonates with HSV infection the disease is confined to the skin, eyes, and mouth.

In ~35% there is also (or only) encephalitis.

Approximately 20% show evidence of widely disseminated disease, usually involving the brain, liver, and adrenal glands, and, less consistently, other internal organs.

Vesicular skin lesions and keratoconjunctivitis are usually but not always present.

CNS involvement usually manifests nonspecifically, with poor feeding, irritability, lethargy, and seizures.

Treatment with aciclovir has reduced the mortality of localized neonatal HSE to approximately 15% and nearly 50% of survivors develop normally.

The mortality of disseminated infection is much higher (~50%), but ~85% of the survivors develop normally.

MACROSCOPIC APPEARANCES

The brains of neonates or infants dying of disease acquired intrapartum or postnatally are usually swollen, with generalized softening and variable congestion and hemorrhage. Intrauterine infection may produce severe cystic encephalomalacia.

MICROSCOPIC APPEARANCES

The lesions of HSE in neonates do not show a predilection for any one part of the brain and can involve gray and white matter in the cerebrum, cerebellum, and brain stem (Fig. 12.19). As in adults, the features are of a necrotizing encephalitis, associated with meningeal and parenchymal infiltration by lymphocytes and macrophages. Nuclear inclusions, viral antigen, and DNA are usually demonstrable in abundance, particularly during the first few days of infection.

12.19 Neonatal HSV-1 encephalitis.
(a) There is a mixed inflammatory infiltrate at the edge of a zone of necrosis within the cerebral cortex. (b) Immunohistochemistry reveals abundant HSV-1 antigen within the necrotic tissue. (c) There are typical herpesvirus intranuclear inclusions in this case of neonatal HSE. (d) Immunohistochemical demonstration of periventricular HSV-1 infection. (e) Section adjacent to that in (d) showing in situ hybridization of a biotinylated probe for HSV DNA.

VARICELLA-ZOSTER VIRUS (VZV) INFECTION

VZV is the cause of varicella (chickenpox) and herpes zoster (shingles).

VARICELLA CEREBELLITIS

This complicates approximately 1 in 4000 cases of chickenpox and is usually a benign short-lived illness manifesting with meningism and ataxia. Viral antigen and DNA have been identified in the CSF, which shows mild to moderate lymphocytosis.

VARICELLA-ZOSTER VIRUS

After presumed upper respiratory infection, primary viremic spread to the reticuloendothelial system, and secondary viremia, the virus spreads throughout the body, including to the skin, to cause the typical manifestations of chickenpox.

Latent infection is subsequently established in the dorsal root or trigeminal ganglia or both, probably after retrograde axonal transport of virus from the periphery.

Reactivation of latent virus usually manifests as shingles, which may involve the head and neck (the ophthalmic division of the trigeminal nerve is commonly involved), trunk, or extremities.

Reactivation often occurs without an obvious precipitating event, but there are recognized risk factors, including cancer, lymphoma (especially Hodgkin’s disease), ionizing radiation, and immunosuppression.

The CNS may be involved during the primary infection (varicella) or the recrudescent disease (herpes zoster) (Table 12.3).

Table 12.3

CNS disease associated with VZV infection

VARICELLA MENINGOENCEPHALITIS

Less commonly, varicella is complicated by an encephalitic illness in which seizures and impaired consciousness are often prominent features. The onset of the encephalitis may precede or follow development of the skin rash. There are conflicting reports concerning its pathology and probable pathogenesis. Some describe only scanty lymphocytic cuffing and edema; others record changes resembling those of acute disseminated encephalomyelitis. In most reports, virus has not been identified within the CNS, suggesting that the neurologic damage is immunologically mediated. Although most patients make a good recovery, a small percentage die during the acute illness or suffer permanent neurologic disability.

REYE SYNDROME

Of the several exanthematous illnesses that are occasionally complicated by this encephalopathic, predominantly childhood, illness, varicella is much the commonest. In children with exanthematous illnesses, the development of Reye syndrome can be precipitated by the ingestion of salicylates. The presentation is with severe headache, vomiting and seizures, often progressing to coma. Reye syndrome is fatal in ~20% of cases; autopsy reveals microvesicular steatosis of the liver and cerebral edema.

ZOSTER ENCEPHALITIS AND MYELORADICULITIS

These conditions usually occur in immunosuppressed patients. Many of the descriptions of zoster encephalitis and myeloradiculitis in the scientific literature relate to patients with AIDS.

ZOSTER ENCEPHALITIS AND MYELORADICULITIS

A zosteriform skin rash usually (although not always) occurs 1–2 weeks before the development of the encephalitis or myeloradiculitis.

Encephalitis presents nonspecifically with altered mentation, seizures, and variable neurologic deficits. Depending on the pattern of infection (see text), visual or bulbar symptoms may predominate.

In myeloradiculitis, the presenting neurologic symptoms are usually ipsilateral to the rash. Paralysis is more prominent than sensory loss.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Several patterns are described, including:

multifocal lesions that resemble the demyelinating plaques of multiple sclerosis and predominantly affect cerebral white matter

ventriculitis (Fig. 12.20)

12.20 VZV ventriculitis in a patient with AIDS.
(a) Periventricular edema and scanty lymphocytic inflammation. (b) At higher magnification, intranuclear viral inclusions (arrows) are clearly visible within the ependyma.

encephalitis involving the visual system

brain stem encephalitis

myeloradiculitis.

The first two patterns of infection are probably caused respectively by hematogenous and ventricular spread of virus, the third by spread from conjunctival and corneal lesions of ophthalmic zoster, and the last two by direct spread from the trigeminal or dorsal root ganglia. In all cases, the infection is typically necrotizing and associated with perivascular and interstitial infiltration by lymphocytes and macrophages. Intranuclear viral inclusions may be seen, and viral antigen and DNA are usually demonstrable. Neuronophagia and microglial nodules tend to be prominent features of brain stem zoster encephalitis. Parenchymal infection may be associated with a necrotizing or granulomatous vasculitis involving small or large intracranial blood vessels and causing infarcts or hemorrhages. These manifestations of VZV infection have been largely confined to patients with AIDS.

ZOSTER INTRACRANIAL VASCULOPATHY AND VASCULITIS

Vasculitis may be a feature of VZV infections of the CNS. However, VZV may be associated with a CNS vasculopathy in the absence of parenchymal infection. Viral particles and antigen have been demonstrated in the walls of intracranial blood vessels in some cases and it has been postulated that an autoimmune process accounts for others.

A well-recognized, albeit rare complication of ophthalmic zoster is the development of contralateral hemiplegia. Angiography may demonstrate cerebral infarction due to inflammation (which may be granulomatous), focal necrosis, and thrombosis of the ipsilateral internal carotid artery or a major parenchymal artery (Fig. 12.21). In other patients the infarction is due to vasculitis involving smaller intracerebral arteries (Fig. 12.21).

12.21 Zoster vasculitis.
(a) Fibrinoid necrosis in the wall of the posterior cerebral artery in VZV infection. This is associated with an infiltrate of lymphocytes, macrophages, and multinucleated cells. (b) Infarct in the basal ganglia due to necrotizing vasculitis in a patient with ophthalmic zoster.

FETAL AND NEONATAL INFECTION

Maternal varicella during the first 20 weeks of pregnancy is occasionally complicated by varicella embryopathy, a syndrome of limb hypoplasia, CNS abnormalities (cerebral cortical atrophy, microcephaly, or hydrocephalus), cicatricial skin lesions, and ocular defects (chorioretinitis, cataracts, microphthalmia, optic atrophy). Neuropathologic examination usually reveals foci of cystic degeneration, glial scarring, and microcalcification, but no viral inclusions or antigen. There may be inflammatory infiltrates. Very rarely, there is evidence of active necrotizing infection with viral inclusions and antigen (Fig. 12.22). Fetal infection after 20 weeks of gestation tends to be subclinical but can lead to infantile zoster. Neonatally acquired varicella is usually a severe infection with multiple organ involvement.

12.22 Congenital VZV infection.
Many of the nuclei in the cerebral cortex, deep gray matter, and brain stem contained viral inclusions. This unusual case complicated maternal chickenpox at 12 weeks’ gestation. (Courtesy of Dr L R Bridges, University of Leeds, UK.)

EPSTEIN–BARR VIRUS (EBV) INFECTION

EBV is the etiologic agent of infectious mononucleosis. It is also associated with Burkitt’s lymphoma and nasopharyngeal and other poorly differentiated or lymphoepithelioma-like carcinomas of the stomach, salivary gland, lung, and thymus. EBV probably contributes to the development of a range of B cell lymphoproliferative disorders, particularly in immunosuppressed patients, in whom it also causes oral hairy leukoplakia, and may play a role in the development of smooth muscle neoplasms.

EBV is present in the saliva during infectious mononucleosis and is usually spread in droplets and by direct contact. It establishes latent infection in B cells and causes their immortalization in vitro. Latent virus has also been detected in EBV-associated carcinomas and at necropsy in a wide range of tissues without EBV-related disease.

EBV may be associated with several peripheral nervous system disorders, including Guillain–Barré syndrome, mononeuritis, and polyneuritis (see Fig. 12.7). CNS complications of EBV infection are much less common and include aseptic meningitis, acute disseminated encephalomyelitis, and an acute cerebellitis resembling that associated with VZV. Rarely, the virus causes an encephalitis or myelitis, which may be combined with peripheral neurologic manifestations of infection. Most patients make a good recovery.

CYTOMEGALOVIRUS (CMV) INFECTION

In immunocompetent children and adults, CMV infection causes an infectious mononucleosis-like syndrome. The virus may be spread through saliva, urine, sexual contact, or blood transfusion. Spread is facilitated by crowded living conditions and, as a result, infection tends to occur at an earlier age in lower socioeconomic groups. Latent infection is probably established in granulocyte-macrophage progenitor cells in the bone marrow, and reactivated infection disseminated hematogenously by progeny myelomonocytic cells. Endothelial cells may also harbor latent CMV.

CMV ENCEPHALITIS AND MYELORADICULITIS

Although CMV may cause encephalitis and myeloradiculitis, these complications of infection are uncommon in patients with normal immune function. Much of the literature on CMV encephalitis and myeloradiculitis concerns patients with AIDS (see Chapter 13), in whom several patterns of infection may occur (see below). The majority (~90%) of patients with AIDS and CMV encephalitis also have CMV retinitis; conversely, ~40% of those with CMV retinitis also have CMV encephalitis. Although CMV retinitis usually responds well to ganciclovir or foscarnet, these agents do not prevent the development of CMV encephalitis. The development of symptoms of CMV encephalitis (i.e. impaired mentation, confusion, disorientation, and, in some patients, nystagmus and cranial nerve palsies) carries a poor prognosis in patients with AIDS.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Several patterns are described (Fig. 12.23):

12.23 CMV encephalitis and myelitis in patients with AIDS.
(a) Low-grade, non-necrotizing encephalitis, with scattered cytomegalic inclusion cells (arrow) in the white matter. (b) and (c) illustrate examples of more severe encephalitis, with moderate (b) and more severe (c) white matter damage. Apoptotic bodies (arrows) containing fragments of nuclear DNA are particularly prominent in (b). In (c) there is an associated mixed inflammatory infiltrate. (d) CMV myeloradiculitis, with numerous cytomegalic inclusion cells in the spinal white matter.

low-grade encephalitis, with cytomegalic inclusion cells, usually but not always within microglial nodules

encephalitis with inclusions that are predominantly within microvascular endothelium

necrotizing encephalitis, with large cystic foci resembling infarcts

ventriculoencephalitis, with hemorrhagic necrosis of periventricular brain tissue

lumbosacral myeloradiculitis.

CMV infection of the CNS is further discussed and illustrated under HIV infection (see Chapter 13).

CONGENITAL CMV INFECTION

This is the commonest of the known intrauterine viral infections, affecting 0.2–2.2% of live births.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The neuropathologic features are of a necrotizing encephalitis or ventriculoencephalitis with infiltration by lymphocytes and macrophages, microglial nodules, and typical cytomegalic inclusion cells (Fig. 12.24). Neurons, glia, and endothelial cells may be infected. Immunohistochemistry or in situ hybridization reveals that many more cells than show cytomegalic change are infected by virus.

12.24 Congenital CMV encephalitis.
(a) Note the ventricular dilatation and periventricular calcification. (Courtesy of Dr Helen Porter, Bristol Children’s Hospital, UK.) (b) Large focus of periventricular calcification due to CMV encephalitis. (c) Scattered cytomegalic inclusion cells are seen within the germinal matrix. (d) Immunohistochemical demonstration of CMV in scattered cells in the disrupted basal ganglia. Not all of the virus-containing cells have a cytomegalic appearance.

Residual lesions in those surviving the acute neonatal illness include microcephaly, microgyria, porencephalic cysts, hydrocephalus, and periventricular calcification.

CONGENITAL CMV INFECTION

In most cases, congenital CMV infection is due to transplacental spread of virus from an infected mother.

The risk of fetal transmission is approximately 40% during primary maternal infection, but less than 2% during recrudescent maternal disease.

As women in lower socioeconomic groups living in crowded conditions are more likely to have been exposed to CMV in childhood, only approximately 10% of these women are susceptible to primary infection during pregnancy compared with up to 50% of women from higher socioeconomic groups in developed countries.

The risk of fetal complications is related to the gestational age at the time of infection, and is highest when infection occurs during the first trimester.

Neonatal infection is occasionally acquired postnatally by contact with infected genital secretions, saliva, or breast milk.

MANIFESTATIONS OF CONGENITAL CMV INFECTION

Only 10–15% of infected neonates develop symptomatic infection although careful examination of ‘asymptomatic’ cases often discloses minor neurologic impairment, particularly sensorineural hearing loss.

The manifestations of symptomatic neonatal infection include hepatosplenomegaly with liver dysfunction and consumptive coagulopathy, microcephaly with intracranial calcifications, and chorioretinitis.

Up to 30% of infants die during the acute illness.

Most survivors have residual neurologic defects, including mental retardation, microcephaly, learning difficulties, seizures, sensorineural hearing loss, chorioretinitis, and optic atrophy.

HUMAN HERPESVIRUSES 6 AND 7

Human herpesvirus 6 (HHV-6) and, less frequently HHV-7, cause exanthem subitum (roseola infantum), a benign disease of infants and children characterized by a high fever and, as the fever subsides, a faint maculopapular rash. The pre-eruptive stage of the disease may be complicated by febrile seizures or, rarely, an encephalitic illness. Viral DNA has been detected in the CSF of some patients. Most make a good recovery.

B VIRUS

This herpesvirus is indigenous to Old World monkeys, but can cause human infection. Transmission to humans is usually by monkey bite, but rare cases of monkey-to-human spread are presumed to have been mediated by infected respiratory droplets and human-to-human transmission has occurred. In humans, B virus tends to cause a rapidly progressive necrotizing infection of the CNS (i.e. ascending myelitis leading to widespread panencephalitis).

ADENOVIRUS

This is a rare cause of necrotizing panencephalitis, almost exclusively in patients who are immunosuppressed. Histology reveals focal infiltrates of lymphocytes, macrophages, and microglia, associated with foci of necrosis, sometimes hemorrhagic. Neurons and glia may have enlarged nuclei containing basophilic inclusions.

PARAMYXOVIRUSES

This family includes mumps virus, measles virus, Hendra virus, and Nipah virus (Figs 12.25, 12.26).

12.25 Acute Nipah encephalitis.
(a) The virus infects endothelial cells, causing necrosis and thrombosis of small blood vessels, including those in the brain. (b) The microangiitis, vascular thrombosis and spread of virus to adjacent neurons produce foci of parenchymal brain necrosis, as illustrated here. (Images courtesy of Dr K T Wong, University of Malaya.)

12.26 Relapsing Nipah encephalitis.
In these cases, there is more abundant virus within the brain, foci of necrosis tend to be larger, sometimes taking the form of concentric bands. (a) Neurons may contain eosinophilic nuclear and cytoplasmic inclusions (the arrows indicate two cytoplasmic viral inclusions). (b) There is abundant viral antigen within the infected neurons, shown here by immunoperoxidase labeling. (Images courtesy of Dr K T Wong, University of Malaya.)

Mumps virus is one of the commoner causes of aseptic meningitis (see Table 12.2). Rarely, mumps is complicated by the development of transverse myelitis or acute disseminated encephalomyelitis (Chapter 20).

Measles can cause aseptic meningitis or, much less frequently, acute disseminated encephalomyelitis (Chapter 20). It is also responsible for two rare, subacute or chronic neurological diseases, measles inclusion body encephalitis and subacute sclerosing panencephalitis, that are considered in Chapter 13.

Hendra virus, first identified in 1994 in Australia, is a very rare cause of human encephalitis. The natural hosts are species of Pteropid (fruit bat). Horses are the intermediate hosts. The encephalitis may be part of an acute systemic illness, in which the virus causes vasculitis involving lung, kidney, brain and other organs, as well as necrotizing neuronal infection. Relapse, with severe necrotizing panencephalitis, has been reported months after resolution of the initial clinical illness.

Nipah virus (now placed with Hendra virus in a new genus, Henipavirus) was identified as the cause of outbreaks of encephalitis in Malaysia and Singapore between 1997 and 1999. Subsequent outbreaks have occurred in Bangladesh and India. As for Hendra virus, the natural hosts are species of Pteropid. In most human outbreaks, pigs have been the intermediate hosts. Close proximity of pigs and humans in affected populations has probably been critical in facilitating pig to human transmission. In man, infection may be asymptomatic or manifest with ’flu-like symptoms but can also cause a severe vasculitic illness, most pronounced within the brain but also affecting heart, kidney, and lung. The virus infects endothelial cells, causing formation of occasional syncytia, endothelial necrosis, thrombosis and parenchymal necrosis. In the brain, infection also spreads to adjacent neurons. Some patients have suffered from relapses of encephalitis after resolution of the acute episode. In these cases, foci of necrosis tend to be larger, some form concentric bands, and some may become confluent. Viral nuclear and cytoplasmic inclusions, antigen and RNA can be demonstrated within neurons in affected regions.

RUBELLA ENCEPHALITIS

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Macroscopic abnormalities are usually a consequence of first-trimester infection. The commonest are microcephaly, hydrocephalus, and foci of cavitation in the cerebral white matter.

Microscopically, the ‘expanded’ rubella syndrome may be associated with active meningoencephalitis. Much more commonly, histology reveals only chronic lesions, consisting of vascular and parenchymal mineralization, particularly in the basal ganglia and thalamus (Fig. 12.27).

12.27 Congenital rubella syndrome.
Foci of calcification and necrosis in the basal ganglia of an infant with first trimester infection, who also had cardiac malformations and cataracts.

ETIOLOGY AND PATHOGENESIS OF RUBELLA

Rubella virus is a small enveloped RNA virus and is the only member of the genus Rubivirus in the Togavirus family.

In children and adults, this virus causes German measles, which is a benign exanthematous disease complicated in some cases by arthritis, and rarely, by postinfectious acute disseminated encephalomyelitis. It is, however, the fetus that is most at risk from rubella virus.

Most cases of fetal infection are associated with symptomatic maternal infection during pregnancy, but in approximately 35% of cases the maternal infection is subclinical.

The risk of teratogenic fetal damage declines from approximately 50% during the first month of pregnancy to 5% by the fourth month.

Congenital rubella is now rarely seen in countries with vaccination programs for female children, but remains a health problem in developing countries.

RUBELLA INFECTION

The classic rubella syndrome of cardiac and vascular malformations, cataracts, mental retardation, microcephaly, and deafness occurs only after first trimester infections.

In second trimester infections, fetal damage, when it occurs, is usually limited to mental retardation and deafness.

Neonates may manifest an ‘expanded’ syndrome of continuing rubella infection, which includes pneumonitis and hepatosplenomegaly with severe thrombocytopenia. This syndrome may persist for several months after birth. Occasionally, it develops after an initial period of apparent quiescence.

Very rarely, congenital or postnatal rubella infection manifests up to a decade or more later as a slowly progressive panencephalitis (see Chapter 13).

RABIES

ETIOLOGY AND PATHOGENESIS OF RABIES

Rabies virus is an RNA virus of the genus Lyssavirus in the Rhabdovirus family (Fig. 12.28).

12.28 Schematic illustration of rabies virus.

Etiology

The disease is endemic in animals in the Americas, large parts of Europe, Africa, and Central Asia. Rabies-free countries include the United Kingdom, Sweden, Portugal, Japan, Australia, and New Zealand.

Rabies is usually transmitted by the bite of a rabid animal. Dogs are still an important source of human rabies in many parts of the world.

In most developed countries, however, vaccination programs have limited or eradicated rabies in domestic dogs; as a result, wild animals are usually responsible for transmitting the disease. These include foxes (particularly in Europe, but also in North America), skunks, raccoons, and lynx (in North America), the silver-haired/eastern pipistrelle bat (since 1990, the most frequent cause of fatal rabies in the United States), vampire bats (particularly in South America), wolves (in Asia and parts of Europe), jackals (in Africa), and mongooses (in Africa and parts of Asia).

The disease may also be spread by nonimmune domestic cats.

Aerosol transmission is a recognized but rare consequence of visiting caves populated by infected bats.

Pathogenesis

In most cases, rabies virus replicates within skeletal muscle at the site of inoculation before being taken up by axons and transported centripetally to the CNS. At this stage, the virus replicates and spreads within the CNS through the spinal cord and brain stem to the cerebrum and cerebellum.

Virus is also transported centrifugally within nerve fibers to peripheral tissues, including the salivary and lacrimal glands, from which virus is shed in saliva and tears. Transmission has occurred by corneal transplantation.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The brain and spinal cord may appear swollen, but are usually macroscopically normal.

Microscopically, the appearances are of a widespread polioencephalomyelitis. The classic histologic feature is the presence of Negri bodies, which are sharply delineated, round or oval, eosinophilic inclusions in the neuronal cytoplasm (Fig. 12.29). Some neurons contain less well-defined (although ultrastructurally similar) eosinophilic inclusions, termed lyssa bodies. There may occasionally be coarse vacuolation of the cytoplasm of infected neurons. The inclusions can occur in most parts of the CNS, but tend to be easiest to find in Purkinje cells, hippocampal pyramidal cells, and brain stem nuclei.

12.29 Rabies encephalitis.
(a) This section shows a Purkinje cell containing two Negri bodies (arrows). Note the absence of inflammation. (b) Cluster of microglia (arrowheads) in the parahippocampal gyrus. One of the remaining neurons contains a Negri body (arrow). (c) The red immunolabeling product highlights the abundant rabies virus antigen in the cytoplasm of infected Purkinje cells. (Courtesy of Professor Francoise Gray, Hôpital Raymond Poincare, Paris.)

Although there are usually leptomeningeal and perivascular lymphocytic infiltrates and neuronophagia, there may be a striking disparity between the abundance of virus and the limited degree of inflammation. The clusters of microglia that remain after neuronal destruction are known as Babès’ nodules (Fig. 12.29).

Immunostaining of virus usually shows it to be much more abundant than is evident on conventional microscopy (Fig. 12.29). Virus can be identified by immunofluorescence in corneal cells and in cutaneous nerve fibers. The disease can therefore be confirmed by examining corneal impressions or nuchal skin biopsies.

RABIES INFECTION

Incubation period

The incubation period ranges from as little as 10 days to as long as 1 year, or, very rarely, longer. The incubation period is shorter in children than adults and also varies according to the proximity of the site of inoculation to the CNS, the onset of symptoms being most rapid after bites on the head.

Prodrome

The onset of CNS disease is heralded by a 2–10-day period of ‘flu-like symptoms (i.e. headache, fever, malaise) and occasionally pain or paresthesia at the site of the bite.

Acute neurologic disease

The acute neurologic disease lasts 2–7 days. This takes one of two forms, which may overlap:

‘Furious’ rabies is the commoner form and is characterized by agitation, insomnia, aggressive behavior (which may include biting), hallucinations, hydrophobia, and brain stem dysfunction (including dysphagia, dysarthria, nystagmus, and cardiorespiratory disturbances).

‘Dumb’ rabies, the other form, is characterized by paralysis of one or more limbs and sometimes ascending paralysis simulating Guillain–Barré syndrome, sensory loss, and incontinence.

Terminal stage

The acute neurologic disease progresses to stupor, coma, and death. Complications that may occur during this terminal stage include inappropriate ADH secretion, diabetes insipidus, cardiac and respiratory failure.

ARBOVIRUS INFECTIONS

Arboviruses (i.e. arthropod-borne viruses) are small enveloped RNA viruses transmitted predominantly by arthropod vectors. Most arbovirus infections are asymptomatic or produce only a mild febrile illness. Although some arboviruses are capable of causing hemorrhagic fever or encephalitis, these occur in only a small proportion of infections. Arbovirus encephalitis is rarely encountered in neuropathologic practice. Four virus families harbor arboviruses: Togaviridae, Flaviviridae, Bunyaviridae, and Reoviridae. Only those arboviruses that are capable of causing encephalitis are considered here.

MACROSCOPIC APPEARANCES

The brain tends to be moderately congested and swollen (Fig. 12.30). There may be petechial hemorrhages. The most severely affected parts of the nervous system are:

12.30 Coronal slice through the brain in a case of Japanese encephalitis.
The brain is congested and there is mottled dusky discoloration of the thalamus and upper part of the midbrain. (Courtesy of Professor Francesco Scaravilli, Institute of Neurology, Queen Square, London.)

Western and Eastern equine encephalitis – basal ganglia, thalamus, brain stem

St Louis encephalitis – midbrain, thalamus

Japanese encephalitis – thalamus, substantia nigra, brain stem, spinal cord

West Nile fever – thalamus, cerebellum, substantia nigra, pons, medulla, spinal cord. Predominantly gray matter involvement. Abundant viral antigen demonstrable in neurons.

ETIOLOGY OF ARBOVIRUS INFECTIONS

Togaviridae

Genomes comprise positive-sense, single-stranded, polyadenylated, non-segmented RNA.

Only the genus Alphavirus includes arboviruses, three of which are important causes of mosquito-borne encephalitis: Eastern equine encephalitis, Western equine encephalitis, and Venezuelan equine encephalitis (VEE); the related VEE II Everglades virus is readily spread in aerosol form.

The genus Rubivirus is also in the Togavirus family and includes rubella virus, which is not an arbovirus and is considered on p. 316.

Reoviridae

Genomes comprise double-stranded RNA.

Colorado tick fever virus in the genus Orbivirus is the only significant cause of human tick-borne encephalitis in this family.

Flaviviridae

Genomes comprise positive-sense, single-stranded, non-polyadenylated, non-segmented RNA.

Causes of mosquito-borne encephalitis in this family include: St Louis encephalitis, Japanese encephalitis, Murray Valley encephalitis, West Nile virus, and Rocio virus.

This family also includes a group of closely related tick-borne encephalitis-causing viruses such as the viruses that cause Powassan encephalitis and Russian spring–summer encephalitis.

Bunyaviridae

Genomes comprise segmented, single-stranded, non-polyadenylated RNA that is negative-sense (apart from the genus Phlebovirus, which contains ambisense RNA, the 5′-end being positive-stranded and the 3′-end negative-stranded).

Two genera in this family (i.e. Bunyavirus and Phlebovirus) include arboviruses that cause mosquito-borne human encephalitis.

Bunyavirus encephalitides include those caused by California serogroup viruses (especially La Crosse virus), Tahyna virus, and Jamestown Canyon virus. Another bunyavirus, Toscana virus, is a major cause of meningitis (and a rare cause of encephalitis) in Mediterranean European countries.

The Phlebovirus most often associated with human encephalitis is Rift Valley fever virus, which can be spread in aerosol form.

EPIDEMIOLOGY OF ARBOVIRUS INFECTION

The geographic distribution of different arboviruses reflects that of the natural hosts and insect vectors (Table 12.4).

Table 12.4

The geographic distribution of different arboviruses

Virus	Geographic distribution
Eastern equine encephalitis	Eastern and Gulf coast states of USA, Caribbean, and South America, rarely further inland
Western equine encephalitis	Predominantly western and midwestern USA
VEE	South and Central America, Florida, and southwestern USA
St Louis encephalitis virus	USA, Central and South America
Japanese encephalitis	Southeast Asia, Bangladesh, and Pakistan
Murray valley encephalitis	Southwestern Australia, New Guinea
West Nile virus	Africa, Eastern Europe, West Asia, Middle East, North America (since 1999)
Rocio virus	Brazil
Powassan encephalitis	Canada, northern USA, and Russia
Russian spring-summer encephalitis	Russia, East Asia
La Crosse virus	Mainly midwestern USA
Tahyna virus	Czech Republic, Slovakia
Jamestown Canyon virus	Canada and northern USA

There is marked seasonal variation in the incidence of most arbovirus infections corresponding to the fluctuation in quantity of insect vectors. Infections are most numerous in the summer and early fall months. The number of cases also varies considerably from year to year.

Some types of infection have a predilection for the young: Western equine encephalitis usually infects children less than 1 year of age; Eastern equine encephalitis infects children and the elderly; La Crosse virus encephalitis is the commonest pediatric arbovirus encephalitis in the USA.

PATHOGENESIS OF ARBOVIRUS INFECTIONS

The virus enters the vector (usually a mosquito or tick) while it is feeding on the blood of an infected host. It is then transmitted to other hosts in the salivary secretions of the vector as it feeds. The natural hosts of most arboviruses are birds or small mammals, such as rodents. Pigs may be amplifying hosts (e.g. for Japanese encephalitis virus). Humans (and horses, in the case of the equine encephalitides) are dead-end hosts.

The virus replicates at the site of host inoculation and then spreads to regional lymph nodes and other lymphoreticular tissues (primary viremia) where it proliferates before disseminating hematogenously (secondary viremia) to systemic tissues, including, in some cases, the CNS.

West Nile fever has been spread by transfusion of infected blood and organ transplantation from an infected donor.

ARBOVIRUS INFECTION

The incubation period is usually <1 week but can be up to 3 weeks.

Patients present acutely with fever (sometimes marked), malaise, and myalgias.

Manifestations of neurologic disease are relatively nonspecific and include:

• headache, vomiting, diarrhea

• an altered level of consciousness, disorientation

• flaccid or spastic paralysis

• seizures.

Progression to coma may occur rapidly.

In some cases the neurological features are solely of aseptic meningitis.

The precise viral etiology is usually determined by serologic tests or by isolation of virus or specific viral RNA from the CSF.

The mortality and morbidity of the encephalitis caused by different arboviruses vary considerably (Table 12.5).

Table 12.5

Mortality and morbidity of arbovirus encephalitis

Causative virus	Mortality	Morbidity
Eastern equine encephalitis	50–75%	90% of survivors have persistent neurologic disability
Western equine encephalitis and VEE	Less than 5%
St Louis encephalitis	Less than 5%	Persistent neurologic disability in approximately 25% of survivors
Japanese encephalitis	Up to 50%	Persistent neurologic disability in a high proportion of survivors
West Nile virus	3–15% (higher in the elderly)	50–75% of survivors of West Nile encephalitis/encephalomyelitis have residual neurologic disability
La Crosse virus	Less than 1%
Tick-borne encephalitides	Varies from less than 1% to over 10%	A small proportion of patients with Russian spring–summer encephalitis who recover from the acute illness later develop a chronic encephalitis with intractable epilepsy and progressive paralysis

MICROSCOPIC APPEARANCES

Histology reveals leptomeningeal, perivascular, and parenchymal infiltration, predominantly by lymphocytes and microglia or macrophages (Figs 12.31, 12.32). Affected gray matter regions contain perivascular cuffs of mononuclear inflammatory cells, especially lymphocytes, perivascular hemorrhages, and microglial nodules, often surrounding degenerating neuronal cell bodies (neuronophagia) (Fig. 12.32). The perivascular inflammation in the white matter is associated with focal necrosis of myelinated fibers. Other features include thrombosed small blood vessels and, rarely, large regions of necrosis.