**1. Introduction**

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20 Encephalitis

MD†

1999, Pages 583-586

### **1.1. Etiological factors for viral encephalitis**

Encephalitis is defined as the presence of an inflammatory process of the brain in association with clinical manifestation of neurological system of the individual. In other words, onset of central nervous system (CNS) symptoms due to infections of the brain. Described pathogens reported as to be the causative agents for encephalitis, the majority of them are viral in ori‐ gin, but sometimes bacteria or fungi or a postinfectious process. Inspite of the fact that mo‐ lecular biology researches advance, new era of essentials elements in diagnosis commences, extensive tests are being used widely, the etiology of encephalitis remains unclear and un‐ known in a considerable degree of the patients [1-3].

Acute encephalitis includes a medical emergency. In most cases, the presence of focal neurological signs and mostly focal seizures will distinguish an encephalitic situation from an encephalopathic process. The diagnosis of encephalitis is suspected in a febrile patient who comes with altered conciousness and signs of cerebral dysfunction. The lat‐ ters are so wise, therefore the dilemma of diagnosis starts with the beginning, and con‐ tinues with the determination of the relevance of an infective agent. These agents may play a role in the neurologic manifestations of illness, but not necessarily by directly in‐ vading the CNS. Apart from this, there is a big challenge in distinguishing between in‐ fectious encephalitis and posinfectious encephalomyelitis. Vaccination programs were completed in the Western world already; therefore postinfectious or posimmunizative type encephalitis or encephalomyelitis (mainly acute disseminated encephalomyelitis [ADEM]) should be different in etiological aspect, since ADEM is mediated by an immu‐ nologic response to antigenic stimuli from infecting microorganisms or immunization. Noninfectious CNS diseases (e.g., fibroelastic tissue diseases, vasculitis, collagenous dis‐ eases, and paraneoplastic syndromes) can mimic encephalitis, or present with similar

outcomes to those of encephalitis and should be account in the differential diagnosis. Herpes simplex encephalitis (HSE) is the commonest sporadic acute viral encehalitis in developed countries. The emergence of unusual forms of zoonotic encephalitis have an important public health problem all over the world. Vaccination and vector control meas‐ ures are useful preventive strategies in the management of certain arboviral and zoonotic encephalitis [4].

**Epidemiology or risk factors Possible infectious agent(s) for encephalitis**

Ticks Tick-born encephalitis virus, Powassan virus,

Physicians and health care workers VZV, HIV, Influenza virus, measles virus,

Recent vaccination Acute disseminated encephalomyelitis,

Exposure to animals Rabies virus, Expoure to horse Hendra virus, Exposure to old World primates B virus

Veterinarians Rabies virus,

Sexual contact HIV, Spelunking Rabies virus, Swimming Enterovirus,

Winter Influenza virus

Middle East West Nile virus

**Table 1.** Possible Etiology of Viral Encephalitis [1]

Africa Rabies virus, West Nile virus,

Russia Tick-born encephalitis virus,

Europe West Nile virus, Tick-born encephalitis virus, India, Nepal Rabies virus, Japanese encephalitis virus,

Rubella virus

Laboratory workers West Nile virus, HIV,

Occupation

Recreational activities

Seasons

Travel

Mosquitoes Eastern equine encephalitis virus, Western equine encephalitis virus,

Person to person transmission HSV (neonatal), VZV, Venezuelan equine encephalitis virus (rare),

Camping/hunting All agents transmitted by mosquitoes and ticks (see above)

(transplantation), Influenza virus,

Late summer/early fall All agents transmitted by mosquitoes and ticks (see above), Enterovirus

Australia Murray Valley encephalitis virus, Japanese encephalitis virus, Hendra virus Central America Rabies virus, Eastern equine encephalitis virus, Western equine encephalitis

South America Rabies virus, Eastern equine encephalitis virus, Western equine encephalitis virus, St Louis encephalitis virus, Southeast Asia, China, Pasific Rim Japanese encephalitis virus, Tick-born encephalitis virus, Nipah virus Unvaccinated status VZV, Japanese encephalitis virus, Poliovirus, Measles virus, Mumps virus,

Venezuelan equine encephalitis virus, St Louis encephalitis virus, Murray Valley encephalitis virus, Japanese encephalitis virus, West Nile virus

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Poliovirus, nonpolio Enterovirus, Measles virus, Nipah virus, Mumps virus, Rubella virus, Epstein-Barr virus (EBV), Human herpesvirus 6, B virus, West Nile virus (transfusion, transplantation, breast feeding), HIV, Rabies virus

virus, Venezuelan equine encephalitis virus, St. Louis encephalitis virus,

Since the medical situation is emergent, in the approach to the patient with encephalitis, the main attempt should be carried out to build a reliable etiological diagnosis. Although, there are no definitive effective treatment – with few exceptions, no specific therapy is avaliable for most forms of viral encephalitis – in many cases, identification of a spesific agent – if pos‐ sible – may be important for prognosis, potential prophylaxis, counseling of patients and family members, and public health issues [1].

Epidemiological clues that may help in directing the investigations for an etiologic diagnosis include season, geographical localization, travel history, occupational status, insect and ani‐ mal contact, vaccinations, immunization of the insult. Therefore clinic approach should be carried out for etiology. Possible etiological agents of encephalitis – mainly viral – based on epidemiology and related risk factors are represented in Table 1. This table is revised from Infectious Diseases Society of America (IDAS) Guidelines 2008:



**Table 1.** Possible Etiology of Viral Encephalitis [1]

outcomes to those of encephalitis and should be account in the differential diagnosis. Herpes simplex encephalitis (HSE) is the commonest sporadic acute viral encehalitis in developed countries. The emergence of unusual forms of zoonotic encephalitis have an important public health problem all over the world. Vaccination and vector control meas‐ ures are useful preventive strategies in the management of certain arboviral and zoonotic

Since the medical situation is emergent, in the approach to the patient with encephalitis, the main attempt should be carried out to build a reliable etiological diagnosis. Although, there are no definitive effective treatment – with few exceptions, no specific therapy is avaliable for most forms of viral encephalitis – in many cases, identification of a spesific agent – if pos‐ sible – may be important for prognosis, potential prophylaxis, counseling of patients and

Epidemiological clues that may help in directing the investigations for an etiologic diagnosis include season, geographical localization, travel history, occupational status, insect and ani‐ mal contact, vaccinations, immunization of the insult. Therefore clinic approach should be carried out for etiology. Possible etiological agents of encephalitis – mainly viral – based on epidemiology and related risk factors are represented in Table 1. This table is revised from

Neonates Herpes simplex virus (HSV) type 2, Cytomegalovirus (CMV), Rubella virus, Infant and children Eastern equine encephalitis virus, Japanese encephalitis virus, Murray

Elderly persons Eastern equine encephalitis virus, St Louis encephalitis virus, West Nile

Valley encephalitis virus, Influenza virus, La crosse virus

Eastern equine encephalitis virus, Western equine encephalitis virus,

virus, sporadic Creutzfeldt –Jacob disease (sCJD)

encephalitis [4].

22 Encephalitis

Age

Animal contacts

Insect contact

family members, and public health issues [1].

**Agammaglobulinemia Enterovirus**

Bats Rabies virus, Nipah virus

Cats Japanese virus, Dogs Rabies virus, Horses Rabies virus,

Skunks Rabies virus,

Infectious Diseases Society of America (IDAS) Guidelines 2008:

**Epidemiology or risk factors Possible infectious agent(s) for encephalitis**

Birds West Nile virus, Eastern equine encephalitis virus,

Hendra virus

HIV, JC virus

Immunocompromised persons Varicella zoster virus (VZV), CMV, Human herpesvirus 6, West Nile virus,

Swine Japanese encephalitis virus, Nipah virus

Unpasteurized milk Tick-born encephalitis virus,

Clinical findings (physical and specific neurological signs and symptoms) may indicate cer‐ tain causative agents in patients with encephalitis (Table 2). This table is again revisely taken from the same guideline mentioned in the previous paragraph [1];

early period leads to at once, differentiation of central pathologies from systemic ones, of in‐ fectious etiologies from noninfectious causes, and getting data concerning the character of a possible central nervous system infection; therefore CSF analysis maintains its importance

Lumbar puncture is performed generally from L4-5 intervertebral space. However L3-4 and L5-S1 intervertebral spaces are also utilized. Sufficient CSF sample should be obtained for routine laboratory tests, and a certain amount should be spared for advanced tests. Initially, protein and glucose levels are analysed from obtained sample, white blood cell count is done, and cultural analyses are performed. Opening pressure and protein concentration are increased, and glucose levels are decreased in bacterial menengitis. Polymorphonuclear cells (PNL) are usually found. Opening pressure is normal or mildly increased however in viral encephalitis and menengitis. In a classical viral encephalitis glucose levels are normal, but protein concentration is found to be mildly or moderatly increased. CSF findings in several

**Pressure** Increased Normal-mildly increased Normal-mildly increased Increased **Glucose** Low Normal Low Low

**Protein** High High High High

**Cell count** PNL Mononuclear Mononuclear PNL/mononuclear

In viral encephalitis, a more important problem is to find out the etiological agent and to apply therefore the appropriate antiviral agent beginning from the early period of the disease. Nevertheless, CSF findings, as they are analysed by routine tests, are not specific in viral encephalitis, and couldn't be heplfull to distinguish different etiological agents. These findings combined with radiological data could also not be assistant, and determi‐ nation of etiology may be delayed. As a matter of fact, various serological methods, cell cultures and genom analyses are widely utilised currently. Methods to apply should be adapted to geographical factors, to epidemyological data, and to travel history in a spe‐ cific individual. Negative results does not always rule out a certain agent, therefore re‐

A hemorhagic CSF could be seen in Herpes simplex type I encephalitis [5]. Lymphositic

found [6]. However, in immuncompromised patients especially, one could not encounter typical pleocytosis. Thus, CSF findings could be misleading in such situations; before ruling out the disease or an etiological agent, a wider CSF screen is needed in these patients. Deter‐ mination of HSV-DNA with polymerase chain reaction (PCR) is a widely utilised method today. As a gold diagnostic standart currently, PCR's sensitivity is 95 % in Herpes simplex

) and increased protein concentrations are usually

**Viral encephalitis Fungal menengitis Tuberculose menengitis**

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as a valid method currently, for searching brain infections.

infectious situations is summarized in Table 3.

**Table 3.** General characteristics of various CNS infections

peated tests could be needed.

pleocytosis (10-500 mononuclear cell/mm3

**Bacterial menengitis**


**Table 2.** Possible etiological agents of viral Encephalitis based on clinical findings
