Viral Encephalitis - Springer · 2017. 8. 26. · Whitley and 90% specific within 3 days of the onset of ill ness. Nevertheless, if properly performed, brain bi opsy remains the most

PRACTICAL THERAPEUTICS

Viral Encephalitis Diagnosis and Treatment

Richard J. Whitley

eNS Drugs 2 (5). 355-366. 1994 1172-7047/94/0011-0355/S0600/0

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Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA

Contents Summary 1. Pathogenesis 2. Epidemiology ... 3. Clinical Manifestations and Diagnosis . 4. Representative Diseases and Therapy.

4.1 Herpes Viruses . . .. ..... . 4.2 Other Viruses .... . .... .

5. General Treatment Guidelines for Viral Encephalitis. 5.1. Supportive Care

355 355 356 356 358 358 362 363 364 364 6. Conclusion .

Summary Viral infections of the eNS are typically associated with mortality and mor-bidity. These infections are caused by a variety of both DNA and RNA viruses, and occur in individuals of all ages. Worldwide, disease burden is most frequently attributed to herpes simplex virus, varicella zoster virus, cytomegalovirus, Jap-anese encephalitis and measles infection of the eNS. The epidemiology and pathogenesis of these infections varies according to the organism and the locale of occurrence.

Importantly, therapy has only been identified for herpes simplex encephalitis, varicella zoster virus and cytomegalovirus infections of the eNS. The utilization of aciclovir l,lnd ganciclovir will improve the morbidity and mortality for these diseases. For the other eNS viral infections for which no therapy is presently available, supportive care is essential.

Viral infections of the eNS have attracted the attention of historians and physicians for millen-nia,lI,2] With the exception of herpes simplex en-cephalitis (HSE)pA] identification of the organ-isms that causes viral eNS syndromes has been difficult, if not impossible. With the advent of anti-viral therapy, increased attention has focused on prompt and specific diagnosis, and implementation of treatment. This review focuses on the pathogen-

esis of and general diagnostic approach to patients with presumed eNS viral infections. The appropri-ate therapy of those infections that are treatable is discussed.

1. Pathogenesis

Encephalitis is generally an unusual complica-tion of a common viral infection,lS-71 Thus, of the

356

large number of individuals with systemic viral in-fection, very few develop clinical CNS complica-tions. Most viral infections cause either meningeal involvement, namely aseptic meningitis, or a mild clinical syndrome of meningoencephalitis rather than encephalitis.

In general, viral encephalitis can be subdivided into distinctive categories on the basis of aetiology and pathogenesis. There are 4 broad categories: (i) acute encephalitis; (ii) post-infectious encepha-litis; (iii) slow viral infections of the CNS; and (iv) chronic degenerative diseases of the CNS of presumed viral aetiology. This review only dis-cusses acute viral encephalitis.

In acute viral encephalitis, capillary and endo-thelial inflammation of cortical vessels is a striking pathological finding. It is accompanied by peri-vascular lymphocytic infiltration and neuronopha-gia early in the disease and astrocytosis and gliosis during later stages. Unique histopathological fea-tures include Cowdry type A intranuclear inclu-sions and Negri bodies associated with herpes vi-ruses and rabies infections, respectively.

Access of viruses to the CNS generally occurs by one of 2 routes, either haematogenous or neuro-nal (reviewed in detail elsewhere[2,5,6,8- 141) Haem-atogenous spread is most common and can result in an altered blood-brain barrier,[1l,12,15, 161 as ex-emplified by arthropod-borne viral disease)9, I 0, 16] Alternatively, viruses can access the nervous sys-tem by intraneuronal routes as occurs with herpes simplex virus (HSV) accession from peripheral sites) 17, 18] It is not known whether HSV can exist in a latent state within the CNS. Another example of intraneuronal transmission of a virus to the CNS is rabies, with ultimate involvement of the limbic system) 19]

Once a virus has reached the brain, subsequent replication can remain intraneuronal or result in either cell-to-cell or extracellular transmission.

2. Epidemiology

Many human viral pathogens cause CNS infec-tions,l21 The Centers for Disease Control suggest that approximately 20 000 cases of encephalitis oc-

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Whitley

cur in the US each year, most being mild. 120,211 The 2 endemic causes of encephalitis in the US are HSV and rabies virus. Rabies virus causes only encepha-litis and is more common in developing countries. HSV accounts for approximately lO% of all en-cephalitic cases in the US,l22,23] Japanese enceph-alitis is probably the most common epidemic infec-tion outside North America. In China alone, there are over lO 000 cases annually, despite childhood immunisation. [9, 1 0]

The development of effective vaccines for con-trol of diseases such as measles, mumps, rubella and yellow fever has significantly decreased the inci-dence of both acute encephalitis and post-infec-tious encephalitis in countries where vaccination is routine. Vaccination has decreased significantly the incidence of poliovirus infections of the CNS;[24] however, sporadic cases occur as a con-sequence of vaccine-associated infection with type 2 or type 3 virus.] 251

Other members of the picornavirus family clearly have the potential to infect the brain, these includ-ing Coxsackie and Echo viruses.[2,26-281 Usually, these latter agents cause a benign aseptic meningitis.

The arthropod-borne viruses, that cause disor-ders such as St. Louis encephalitis, Eastern equine encephalitis, Venezuelan equine encephalitis and La Crosse virus infections, are causes of spo-radic and epidemic CNS viral infection in the US. [12,29-311 Early identification and recognition of the specific infection may lead to interventive strategies to prevent burgeoning mosquito popula-tions that serve as vectors for transmission of in-fection. [32]

3. Clinical Manifestations and Diagnosis

The hallmark of viral encephalitis is the acute onset of a febrile illness. The clinical findings as-sociated with viral encephalitis are shown in table I. These findings distinguish a patient with enceph-alitis from one with viral meningitis, who usually has only headache, nuchal rigidity and fever.

Clinical findings reflect disease progression and the cells of the CNS that are infected. The tropism of select viruses for different cell types illustrates

eNS Drugs 2 (5) 1994

Treatment of Viral Encephalitis

Table I. Clinical features associated with viral encephalitis

Headache

Fever

Altered consciousness

Disorientation

Behavioural disturbances

Speech disturbances

Neurological signs (sometimes focal but generally diffuse) e.g. hemiparesis and/or seizures

this point)2,5-7] For example, poliovirus preferen-tially infects motor neurons, rabies selects neurons ofthe limbic system and mumps can infect ependy-mal cells of neonates. Infection of cortical neurons can lead to abnormal electrical discharges, result-ing in seizures or focal neurological deficits. De-myelination may follow destruction of oligo-dendroglia cells, while involvement of ependymal cells can result in hydranencephaly. The predispo-sition ofHSV for the temporal lobe leads to clinical findings of aphasia, anosmia, temporal lobe sei-zures and focal neurological findings)22]

The diagnosis of viral infections of the CNS is difficult at best. Patient and general history may reveal a characteristic epidemiology, such as a his-tory of an animal bite, season of year and prevalent community diseases. The Morbidity and Mortality Weekly Report identifies prevalent diseases and responsible pathogens in the US and, therefore, may be valuable in the identification of aetiologi-cal agents locally responsible for encephalitic syn-dromes.

Physical examination usually does not lead to an aetiological diagnosis. However, a few considera-tions are essential when performing such an exam-ination. In patients with acute viral encephalitis, the distinction between generalised and focal neuro-logical findings is important. The most common cause of focal encephalopathic findings is HSV.£33,34] However, when signs and symptoms of patients with biopsy-proven HSE are compared with those who did not have HSV infection, there are no dis-tinguishing characteristics for patients ultimately proven to have HSE.£33] Viruses that are usually responsible for diffuse encephalitic diseases can,


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on occasion, localise to one area of the brain and, therefore, mimic HSE (table 11))34,35] Apprecia-tion of these data is essential for the development of diagnostic and therapeutic approaches in such patients.

Evaluation of the cerebrospinal fluid (CSF) is essential, unless its collection is contraindicated because of marked increased intracranial pressure. Careful assessment of the CSF formula is helpful. Findings indicative of encephalitis generally in-clude pleocytosis, predominately mononuclear cells and elevated protein levels (glucose levels are usually normal). Nevertheless, a small percentage of patients (approximately 3 to 5%) with severe viral infections of the CNS, such as HSE, have completely normal CSF)33] Unfortunately, cul-tures ofCSF are of little value for isolation of HSV, except under unusual circumstances (see section 4.1.1).[35] However, cultures may be positive early after the onset of some viral meningitis.

Neurodiagnostic tests, including the electro-encephalogram (EEG), and computed tomographic (CT) technetium brain and magnetic resonance im-aging (MRI) scans, can provide useful information for the evaluation of patients with altered menta-tion and fever.

Laboratory confirmation of disease aetiology is of therapeutic value for only a few pathogens, but is always of prognostic value. For most diseases, antibodies identified in the CSF are not useful diagnostically unless evaluated sequentially, in or-der to demonstrate increasing quantities. Routine evaluation of acute and convalescence sera (to as-sess seroconversion or seroboosting) is of no prac-tical value in the decision to institute therapy for viral CNS infections. Such studies may be helpful, retrospectively, to clarify the aetiology of infec-tion, as has been done for HSE.£35-37]

The development of new diagnostic assays that utilise CSF can accelerate the diagnosis of viral infections of the brain. Japanese encephalitis and HSE can be detected using these systems. An enzyme-linked immuno-sorbent assay (ELISA) that detects immunoglobulin M (IgM) antibodies in the CSF from patients with presumed Japanese encephalitis


358

Table II. Diseases found in 432 patients that mimic herpes simplex encephalitis (reproduced from Whitley et al.,[34] with permission)

Disease

Treatable diseases 1. Infection

Abscess or subdural empyema

bacterial

listerial

fungal

mycoplasmal

Tuberculosis

Cryptococcal

Rickettsial

Toxoplasmosis

. Mucormycosis

Meningococcal meningitis

2. Tumour

3. Subdural haematoma

4. Systemic lupus erythematosus

5. Adrenoleukodystrophy

Untreatable diseases 1. Nonviral

Vascular disease

Toxic encephalopathy

Reye's syndrome

2. Viral

Togavirus infection

St Louis encephalitis

Western equine encephalomyelitis

California encephalitis

Eastern equine encephalomyelitis

Other herpesvirus infections

Number of patients

38

5

1

2

2

6

3

2

1

1

5 2

1

6

57

11

5

1

7

3

4

2

Epstein-Barr virus 8

cytomegalovirus

Other

echovirus infection 3

influenza A 4

mumps 3

adenovirus infection 1

progressive multifocal leukoencephalopathy

lymphocytic choriomeningitis

subacute sclerosing panencephalitis 2

is sensitive and specific.£38] Most patients have IgM antibodies at the time of hospitalisation and virtually all acquire them by day 3 of illnessJ38,39] The polymerase chain reaction (PCR) has been de-veloped to detect viral DNA in the CSF of patients with HSE.£40-42] This assay is over 90% sensitive


Whitley

and 90% specific within 3 days of the onset of ill-ness.

Nevertheless, if properly performed, brain bi-opsy remains the most sensitive and specific means for diagnosis of HSE and diseases that mimic HSE.£33-35] Brain tissue is submitted for culture, histopathological and electron microscopic evalu-ations. Currently, brain biopsy is generally re-served for patients who deteriorate on aciclovir therapy and have an unknown abnormality on CT or MRI evaluation.

4. Representative Diseases and Therapy

4.1 Herpes Viruses

4. 1. 1 Herpes Simplex

Incidence and Diagnosis HSE is the most common cause of nonepidemic,

sporadic, acute focal encephalitis in the US. The estimated incidence is 1 in 250 000 to 1 in 500 000 individuals per year.£22,43] Occurring throughout the year, approximately one-third of the cases of HSE develop in patients less than 20 years of age and one-half in individuals over the age of 50 years)22] The disease does not occur more com-monly in immunosuppressed patients,[44] but may be increasing in individuals with HIV infection.£45]

In the absence of antiviral therapy, the mortality for HSE is in excess of 70%. Furthermore, only approximately 2.5% of untreated individuals re-turn to normal functioning)46,47]

A distinction must be made between HSV infec-tions of the CNS that occur during the neonatal and other periods. HSE in neonates is caused either by HSV type 1 or type 2, while infection in older chil-dren and adults is overwhelmingly the conse-quence of HSV type 1.£48,49] During the neonatal period, HSV type 2 infection of the brain in patients with multi-organ disseminated neonatal HSV in-fection is likely to be blood-borne. It is associated with a diffuse encephalitic process, resulting in generalised encephalomalacia)50] In contrast, when the disease only involves the CNS of neonates, neuronal transmission of the virus to the CNS tends to result in unitemporal and, then, bitemporal



disease as illness progresses. This latter pattern of evolution is also encountered in older children and adults. Interestingly, HSV type 2 (which is the most common cause of genital herpes and, not in-frequently, viral meningitis) rarely results in en-cephalitis in adults. The reasons for the differences in the pathogenesis of HSV type I and type 2 are unknown.

HSV can be retrieved from the CSF of babies with encephalitis or disseminated disease in ap-proximately 15 and 40% of patients, respectively. [50] Thus, CSF viral cultures are indicated in neonates. This is in contrast to older individuals in whom isolation of the virus from this site is uncommon. In older patients, it becomes necessary to obtain a brain biopsy or utilise CSF for the detection of HSVby PCR.

Treatment Studies A series of trials has evaluated therapy of HSE

in older children and adultsP2,46,47,51-53]

The first clinical trials to indicate therapeutic success used vidarabine 15 mg/kg/day. Mortality was decreased from 70% in placebo recipients to 28% in drug-treated patients 1 month after institu-tion of therapy and to 44% 6 months later for pa-tients with biopsy proven disease.l46]

However, the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group and investigators in Sweden found aciclovir to be superior to vidarabine.[52,53] Mortality was reduced to 28% in the aciclovir-treated patients 18 months after the onset of treatment compared with 50% in vidarabine recipients, as shown in figure l.l52] Three factors influenced outcome with aciclovir therapy. First, a low level of conscious-ness, as measured by a Glasgow coma score of 6 or less, was associated with a poor therapeutic out-come. This was irrespective of the age of the pa-tient (or the agent administered). Secondly, if dis-ease was present for 4 days or less before initiation of therapy, the likelihood of survival increased from 72 to 92% during the 18 months following treatment. Finally, patients less than 30 years of age had a more favourable outcome than older in-dividuals.


359

100

~ 80 ACV (n =32)

'" c: :~ 60 2: :::l !J)

i1 ARA·A n=37 CI> '@ 40 c. '0 0 z 20

o 3 6 9 12 15 18 Time (months)

Fig. 1. Comparison of survival in patients with biopsy-proved herpes simplex encephalitis treated with vidarabine (ARA-A) or aciclovir (ACV) [reproduced from Whitley et al.,[52] with per-mission].

Two years after treatment, 30% of aciclovir re-cipients were judged to be normal or to have mild impairment, 17% had moderate neurological se-quelae (such as speech impediment and gait distur-bance) and 53% were dead or had severe impairment. This outcome was better than that of vidarabine re-cipients, of whom only 15 to 20% were found to be neu-rologically normal on long-term follow-up.l22,52-54] Obviously, these data indicate the need for further improvement in therapy of HSV infections of the brain.

When vidarabine and aciclovir were compared directly in neonates with HSV infection, no differ-ence in morbidity or mortality was detected be-tween the 2 drugs (see fig. 2 and table III).l55,56] Neonates with HSV infections can be classified as having disease that is localised to the skin, eyes and mouth, affecting the CNS, or that is disseminated.

In a comparative study, aciclovir was as effec-tive as (but not superior to) vidarabine treatment in neonates with HSV infections (fig. 2)[55] Overall, no baby with disease localised to the skin, eyes or mouth died, while 18% of babies with CNS infec-tion and 55% of those with disseminated infection died. Among babies with HSV infections of the


360 Whitley

Table III. Assessment of morbidity after 12 months in infants with neonatal herpes simplex virus infection treated with vidarabine or aciciovir (reproduced from Whitley et al.,155] with permission)

Extent of disease Morbidity after 12 months (number of infants) AI ive after 12 Dead within Total normal mild moderate severe

Skin, eye or mouth infection

Vidarabine 22 1 1 Aciclovir 45 0 0

eNS infection Vidarabine 13 1 5 11 Aciclovir 8 5 6 9

Disseminated disease Vidarabine 7 0 4 Aciclovir 3 0

Total 98 9 13 26

skin, eyes and mouth, 90% of those treated with vidarabine and 98% of those treated with aciclovir were developing normally 2 years after infection. The comparable values were 50% and 43%, respec-tively, among babies surviving CNS infection (en-cephalitis) and 62% and 57%, respectively, among babies surviving disseminated infection.

Thus, unlike the results of therapy in older patients with HSE, there were no significant differences in either morbidity or mortality among infants treated with aciclovir and vidarabine. Clearance of the virus was slower in babies who received aciclovir than in immunocompromised adults, implying a require-ment for host defense for recovery. To improve out-come, therapy must prevent progression of infection to the CNS or disseminated disease.

Factors that influence outcome of CNS disease in neonates include prematurity, level of conscious-ness at initiation of therapy, HSV-I for mortality, and seizures and HSV-2 infection for morbidity. As an example, differences in outcome are dependent on the HSV type. Babies with HSV type 1 CNS infection have been noted[46,47J to have a signifi-cantly better neurological outcome than those with HSV type 2 infection of the brain,l52]

Therapeutic Recommendations Because of the ease of administration and rela-

tive absence of toxicity, aciclovir is recommended by most authorities as the medication of choice for


subtotal months (morbidity 12 months unknown)

25 6 0 31 46 8 0 54

30 1 5 36 28 2 5 35

12 2 14 28 5 2 11 18

146 21 35 202

treatment of neonatal, child and adult HSV infec-tionJ48] It should be administered intravenously at a dosage of 10 mg/kg 3 times daily for a period of 10 to 14 days. Longer periods of administration and higher dosages of medication are being investi-gated. There is no established therapeutic value to the concomitant administration of steroids.

Relapse of HSV infection of the brain following either aciclovir or vidarabine therapy has been doc-umented. From studies of neonatal HSE, approxi-mately 8% of children who received aciclovir had a documented virological relapse if treated for 10 days at a dosage of 10 mg/kg every 8 hours. [55] The exact percentage of adults with biopsy proven HSE who experience relapse is unknown. However, re-ports have suggested that relapse can occur[57,58] following therapy with either vidarabine or aciclovir, and may be as high as 5%.[59,601

At this time, HSV isolates have not been routinely obtained from patients with neurological deteriora-tion. In a few cases when HSV isolates were obtained and tested for resistance to aciclovir, they remained sensitive. Retreatment at a higher dosage of aciclovir (15 mg/kg every 8 hours) or in combination with vidarabine 15 mg/kg/day has been utilised in a few patients and for a longer course (21 days).

4.1.2 Other Herpes Viruses Other herpes viruses can cause acute encepha-

litic syndromes, including varicella zoster virus



(VZV), cytomegalovirus (CMV) and Epstein-Barr virus.l34] The occurrence offocal encephalopathic disease caused by Epstein-Barr virus is of particu-lar interest; recovery was complete without treat-ment. The role of human herpesvirus-6 (HHV-6) as a cause of encephalitis in under investigation. This entity is difficult to diagnose and does not rou-tinely warrant therapy.

Varicella Zoster Virus VZV can result in CNS disease, causing

symptoms including cerebellar ataxia, meningo-encephalitis, transverse myelitis and aseptic meningitis. During chickenpox in otherwise healthy individuals, cerebellar ataxia is a com-mon clinical finding and is usually benign. In the US, between 200 and 400 child deaths yearly are attributed to chickenpox, many of which in-volved the CNS. In older individuals, herpes zoster encephalitis and granulomatous arteritis can occur.l7,61] This latter condition has been re-ported following zoster ophthalmicus. Other CNS syndromes associated with VZV infection include myelitis, encephalitis, polyradiculitis, and cranial and peripheral nervous palsies.

The diagnosis of VZV infection of the CNS re-sides, for the most part, on supportive evidence of cutaneous clinical disease. The patient with al-tered mentation or evidence of myelitis with either chickenpox or shingles should be presumed to have VZV infection of the CNS. Evaluation can include CSF examination, EEG and either CT or MRI scans. A MRI scan can be useful in establishing the diag-nosis of transverse myelitis and granulomatosis arteritis. However, findings with other diagnostic tools may be nonspecific. Assessment of CSF by PCR may detect VZV-DNA.

The treatment of VZV infections of the CNS with both aciclovir and vidarabine has been evalu-ated in limited numbers of patients.l62] The treat-ment of choice is aciclovir administered intrave-nously at a dosage of 500 mg/m2 given every 8 hours for 7 to lO days.

Cercopithecine Herpes Virus 1 (8 Virus) B virus has caused several cases of severe and

fatal encephalitis,[63] with fewer than 40 cases re-


1.0

0.9

Cl 0.8 c .:;; .~

:::J 0.7

UJ

~ 0.6 Ql

~ 0.5 c.

15 0.4 c 0 t 0.3 0 c. e 0.2 0..

0.1

0 0

I!!I Skin, eye or mouth infection, vidarabine (n = 31) or aciclovir (n = 54)

+ CNS infection, vidarabine (n = 36) • CNS infection, aciclovir (n = 35) • Disseminated infection, vidarabine (n = 28) o Disseminated infection, aciclovir (n = 18)

361

60 120 180 240 300 360

Survival (days)

Fig. 2. Survival of babies with neonatal herpes simplex viral infection, according to treatment and extent of disease (repro-duced from Whitley et al.,[55J with permission).

ported in the literature. This virus is transmitted by monkey bite, and is a preventable disease if proper animal handling precautions are employed.l63] In-fection can be confirmed by virus isolation, a pro-cedure not routinely performed, or seroconversion.

Aciclovir or ganciclovir may be of value in the therapy of CNS disease; however, therapeutic ex-perience in this condition is limited. Nevertheless, early therapy has resulted in survival in the ab-sence of neurological impairment.[64] Because of the near fatal outcome of CNS disease, therapy with aciclovir should be initiated at dosages used for the treatment of HSE (see section 4.1.1). If disease progression occurs, treatment should be changed to ganciclovir at 5 mg/kg administered intravenously every 12 hours for at least 14 days. Because of the life-threatening potential ofinfec-tion, some authorities recommend long term sup-pressive aciclovir therapy (at a dosage of 250 mg/m2

3 times daily) for survivors of disease.


362

Cytomegalovirus CMV infection of the CNS is most commonly

associated with congenital CMV infection, occur-ring with a prevalence of approximated 1 % in de-veloped countries. However, CMV also occurs in patients with HIV infection, and so CMV neuro-logical disease is being reported more frequently in this patient population.

One of 10 children with congenital CMV infec-tion will have evidence of clinical symptoms, in-cluding microcephaly (50%), psychomotor impair-ment (70%) and hearing loss (60%). Intracranial calcification is also common. Disease is confirmed by isolation of CMV from the urine within the first 2 weeks of life.

In the immunocompromised host, clinical find-ings are less specific than in children. Meningitis, encephalitis and polyradiculitis are all attributed to CMV infection of the CNS. The appearance ofCSF proteinosis and leucocytosis in the absence of bac-terial, parasitic or fungal evidence of disease and clinical evidence of polyradiculitis is highly sug-gestive of CMV infection. Disease can be con-firmed by PCR evaluation of CSF for CMV-DNA.

Ganciclovir therapy should be reserved for HIV-infected patients instituted promptly at a dosage of 5 mg/kg every 12 hours for 21 days.

4.2 Other Viruses

4.2. 1 Rabies Rabies is of increasing concern worldwide, es-

pecially in the US in view of recent cases in New YorkV1 In the Southeastern US, foxes and bats are most often infected with rabies virus, while in Cali-fornia skunks are most often infected. In South and Central America, dogs and cattle are the primary carrier of rabies virus.l651 Infection is transmitted by the bite of a rabid animal. The incubation period is quite variable, ranging from days to months. While not all individuals bitten by a rabid animal develop infection, if infection does occur, it is in-variably fatal.[66,671

The best medical management is the prevention of infection by utilisation of post-exposure vaccine and immune serum, particularly in individuals bit-

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Whitley

ten by an unprovoked animal.l68-701 The vaccine should also be administered to animal handlers at risk. Post-exposure immunisation is an essential feature of the imunoprophylaxis of rabies even for individuals who have received pre-exposure rabies immunisation. Most rabies exposures occur be-cause of unanticipated animal contact (bite, scratch or mucosal contamination). In an nonimmunised indi vidual, both rabies immune globulin (of human origin) and rabies vaccine should be administered as appropriate for the circumstances of exposure. Local care should include aggressive cleaning of the wound. Active immunisation consists of the hu-man diploid cell vaccine (HDCV) or rhesus diploid cell vaccine (rabies vaccine absorbed) as a 1ml in-jection given intramuscularly in the deltoid area on the first day of treatment, with administration re-peated on days 3, 7, 14 and 28.

Recent vaccine advances, utilising rabies virus glycoproteins produced by vaccine vectors, may be a better prophylactic approach.[71-751 Vaccination of wild animals, to decrease transmission in the animal community, has been considered. [76-781 No therapy for rabies exists at this time.

4.2.2 Arthropod-Borne Viruses Arthropod-borne viruses can be a common cause

of sporadic and epidemic encephalitisV,79,801 These viruses replicate in both vertebrate and nonverte-brate species, and include members of the a-, flavi-and bunyavirus families. These agents are transmit-ted by mosquitoes and ticks. Among the a-viruses are those that cause Eastern, Western and Venezu-elan equine encephalitis. The flaviviruses cause ei-ther mosquito- or tick-borne encephalitis. Exam-ples of the former include Japanese, St. Louis, Rocio, Murray Valley and West Nile encephalitis. Examples of tick-borne diseases are Kyasuma For-est and Powassan encephalitis. The bunyavirus family includes the most common causes of arbo-viral disease in the- US, La Crosse virus, as well as Jamestown Canyon and California encephalitis vi-ruses.

Japanese encephalitis is a major medical problem in China, Southeast Asia and India where as many as 20 000 cases per year have been reported.l9,81,821 The



major vector for Japanese encephalitis in humans appears to be the colicine mosquito, which breeds in large numbers in the rice fields of the Orient. Incubation in the mosquito, known as the gesta-tional incubation period or the interval of time be-tween ingestion of infected blood and spread from the mid gut to the salivary glands, is inoculum-and temperature-dependent)lO] A predictive fac-tor for outcome is the rapid appearance of antibod-ies directed against Japanese encephalitis in the CSF.[38] These antibodies apparently ameliorate disease severity)39] Vaccination against Japanese encephalitis is effective.

No treatment exists for arboviral infections other than supportive care.

4.2.3 Enteroviruses The infrequent but devastating occurrence of

poliomyelitis caused by the type 2 or 3 strain polio-virus following vaccination is of increasing con-cern)24,25,83-85] This has led to numerous attempts to alter the vaccine)86,87] Alternative vaccines, in-cluding an enhanced inactivated vaccine and a genetically engineered vaccine, have been tested and debated as potential solutions)87]

Perinatal acquisition of echoviruses and cox-sackieviruses can lead to significant morbidity and mortality)88,89] In patients with agammaglobulin-aemia, enteroviral CNS infections can be chronic and lethal.l90]

Care of patients with enteroviral infection of the CNS is supportive, as no drugs exist for treatment.

4.2.4 Retroviruses Human T-lymphotropic viruses (HTLV) are

known causes of CNS disease.l91 ,92] HTLV type I has been associated with spastic pareses in Japan and Hawaii. HIV causes dementia in nearly all pa-tients by the time of death)93-100] It is likely that HIV encephalopathy will become the most com-mon cause of CNS viral infection worldwide. Oral therapy with zidovudine 100mg 5 times a day may benefit CNS disease as it does other systemic man-ifestations of HIV infection)lOl-103] This virus, as well as other retroviral causes of CNS diseases, has been reviewed extensively in other publica-tions )93-100,104-107]


363

4.2.5 Miscellaneous Viruses Other viruses can also result in CNS disease,

and these will only be briefly mentioned. Two paramyxoviruses, mumps and measles, commonly caused CNS disease in the prevaccine era. Vacci-nation in the US has nearly eliminated this prob-lem. The arenaviruses, lymphocytic choriomenin-gitis and Lassa viruses, are rare causes of CNS disease. Ribavirin, an antiviral licensed for therapy of respiratory syncytial virus infection of infants, has been reported to be efficacious in the treatment of Lassa fever, using a dosage regimen of a 2g load-ing dose followed by 19 4 times a day for 4 days and then O.5g 3 times a day for 6 days)108]

5. General Treatment Guidelines for Viral Encephalitis

Of all the viral encephalitis currently identified, only those caused by HSV, VZV and CMV are amenable to treatment. The utilisation of aciclovir and ganciclovir in patients with these infections is described in section 4.1.

The administration of aciclovir must be as a 1 hour infusion in order to avoid potential local (thrombophlebitis) as well as renal (tubular crystal deposition) complications. Adequate hydration must be maintained and balanced against increased intracranial pressure associated with cerebral oe-dema. Evidence of bone marrow suppression, and bone marrow, hepatic and other organ dysfunction is not usually encountered with the administration of aciclovir. However, renal function must be moni-tored carefully, particularly in patients for whom excessive fluid requirements may not be well tol-erated.

Administration of ganciclovir of the treatment of CMV infection is associated with significant bone marrow suppression. Medication can usually be administered for a period of 10 to 14 days, with the appearance of neutropenia and thrombocyto-penia in approximately 10 to 15% of patients. Thus, careful monitoring of blood cell parameters should be employed in patients who receive this therapy.


364

5.1 Supportive Care

Individuals with infections of the eNS require meticulous medical management. Since a common complication of infections of the eNS is increased intracranial pressure, it is common for patients to re-quire ventilatory support. Therefore, careful atten-tion to pulmonary hygiene, adequate ventilation and judicious use of antimicrobial agents to treat sec-ondary infections are all indicate. Additionally, atten-tion to adequate nutritional status is also required.

6. Conclusion

This review has focused on the pathogenesis, diagnosis and treatment of common eNS viral en-cephalitides, with a particular focus on those caused by herpes viruses. With the recognition that at least one eNS viral disease is treatable, namely HSE, it is likely that newer specific diagnostic tests and therapies for other viral eNS infections will be de-veloped. However, it should be noted that at pres-ent most viral encephalitides are not directly treat-able with an antiviral drugs, and, therefore, care is supportive.

Acknowledgements

Studies performed by the author and herein reported were initiated and supported under a contract (NOI-AI-62554) with the Development and Applications Branch of the Na-tional Institute of Allergy and Infectious Diseases (NIAID), a Program Project Grant (PO I AI 24009), by grants from the General Clinical Research Center Program (RR-032) and the State of Alabama.

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Correspondence and reprints: Dr Richard J. Whitley, Univer-sity of Alabama at Birmingham, Department of Pediatrics, Microbiology, and Medicine, 616 Children's Hospital -ACC, 1600 Seventh Avenue South, Birmingham, AL 35233, USA.


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