Solomon, Hart, Beeching 285

REVIEW Pract Neurol 2007; 7: 285–302 Viral : a clinician’s guide Tom Solomon, Ian J Hart, Nicholas J Beeching

T Solomon Professor of and MRC Senior Clinical Fellow, University of Liverpool Divisions of Neurological Science and Medical Microbiology, and The Walton Centre for Neurology and , Liverpool, UK

I J Hart Consultant Clinical Microbiologist, Division of Medical Microbiology and Genitourinary Medicine, Royal Liverpool University Hospital, Liverpool, UK

N J Beeching Senior Lecturer and Clinical Lead, Tropical and Infectious Unit, Royal Liverpool University Hospital, Liverpool, UK

Correspondence to: Professor T Solomon University of Liverpool Divisions of Neurological Science and Medical Microbiology, 8th Floor Duncan Building, Daulby Street, Liverpool L69 3GA, UK; [email protected]

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The management of patients with suspected has been revolutionised in recent years with improved imaging and viral diagnostics, better antiviral and immunomodulatory therapies, and enhanced neuro- intensive care. Despite this, disasters in patient management are sadly not uncommon. While some patients are attacked with all known antimicrobials with little thought to investigation of the cause of their illness, for others there are prolonged and inappropriate delays before treatment is started. Although viral encephalitis is relatively rare, patients with suspected central (CNS) , who might have viral encephalitis, are not. In addition, the increasing number of immunocompromised patients who may have viral CNS infections, plus the spread of encephalitis caused by -borne , present new challenges to clinicians. This article discusses the Liverpool approach to the investigation and treatment of adults with suspected viral encephalitis, and introduces the Liverpool algorithm for investigation and treatment of immunocompetent adults with suspected viral encephalitis (available at www.liv.ac.uk/braininfections).

here can be few things more frightening enkephalon, . Encephalitis can be caused than seeing an adult or child who was directly by a range of viruses, the herpes perfectly fit and well, progress from a viruses and some being especially T flu-like illness to confusion, and important (table 1). Other microorganisms death within a few days, despite the best can also cause encephalitis, particularly treatment efforts. Even when treatment is such as , and successful and patients survive apparently such as monocytogenes and intact, in many cases the family say that the Mycobacterium (table 2). For person they took home with them is not the viruses such as HIV that infect the brain but same as the one they brought to hospital, with without causing , the term changes in personality, irritability, and poor ‘‘encephalitis’’ is not usually used. short-term memory. The management of Encephalitis can also occur as an immune- patients with suspected encephalitis has been mediated phenomenon—for example, acute revolutionised in recent years with improved disseminated (ADEM, imaging and viral diagnostics, better antiviral which follows infections or vaccinations), and immunomodulatory therapies, and paraneoplastic , and vol- enhanced neurointensive care settings. Despite tage gated potassium channel limbic ence- this, disasters in patient management are sadly phalitis.1 not uncommon. Although viral encephalitis is Strictly speaking, encephalitis is a patho- relatively rare, patients with suspected central logical diagnosis that should only be made if nervous system (CNS) infections, who might there is tissue confirmation, either at autopsy have viral encephalitis, are not. In addition, the or on brain biopsy. However, in practice most increasing number of immunocompromised patients are diagnosed with encephalitis if patients, who may have viral CNS infections, they have the appropriate clinical presenta- plus the spread of encephalitis caused by tion (febrile illness, severe reduced arthropod-borne viruses, present new chal- consciousness (see below)) and surrogate lenges to clinicians. This review aims to provide markers of brain inflammation, such as a rational approach to the investigation and inflammatory cells in the treatment of a patient with suspected viral (CSF), or inflammation shown on imaging, encephalitis. especially if an appropriate organism is detected. Encephalitis must be distinguished WHAT IS ENCEPHALITIS? from , the clinical syndrome Encephalitis means inflammation of the brain of reduced consciousness, which can be parenchyma, and comes from the Greek caused by viral encephalitis, other infectious 10.1136/jnnp.2007.129098 Solomon, Hart, Beeching 287 diseases, metabolic disorders, drugs and alcohol. Metabolic and toxic causes of TABLE 1 Causes of acute viral encephalitis (modified from Solomon and 58 encephalopathy can usually be distinguished Whitley ) from viral encephalitis by the lack of any acute febrile illness, more gradual onset, lack Sporadic causes of viral encephalitis (not geographically restricted) listed by of a CSF pleocytosis and absence of focal group l changes on brain MRI.2 Herpes viruses – Herpes simplex types 1 & 2, , Epstein-Barr Some of the organisms that cause ence- virus, , human herpes virus types 6 & 7 phalitis often also cause an associated l meningeal reaction (), – Coxsackie viruses, echoviruses, enteroviruses 70 & 71, parechovirus, inflammation (), or nerve root invol- vement (radiculitis); these terms are some- l Paramyxoviruses times used in various combinations to reflect – virus, virus, whichever part of the neuraxis is affected—for l Others (rarer causes) example. , encephalo- – viruses, adenovirus, parvovirus, lymphocytic choreomeningitis myelitis, meningoencephalomyelitis, myelora- virus, diculitis, meningoencephaloradiculitis. The Geographically restricted causes of encephalitis—mostly arthropod-borne* term ‘‘limbic encephalitis’’ refers to encepha- l The Americas – West Nile, La Cross, St Louis, Rocio, , litis of the temporal lobes (and often of other Venezuelan, eastern & western , Colorado tick limbic structures), while rhombencephalitis virus, dengue, means hindbrain, or brainstem encephalitis. l Europe/Middle East – Tick-borne encephalitis, West Nile, Tosana, rabies, (dengue virus, PATHOGENESIS virus) l Africa Depending on the virus, the pathogenesis – West Nile, ( virus, Crimean-Congo haemorrhagic fever, consists of a mixture of direct viral cyto- dengue, ), rabies pathology (that is, viral destruction of cells) l Asia and/or a para- or post-infectious inflamma- – , West Nile, dengue, Murray Valley encephalitis, tory or immune-mediated response (fig 1). For rabies, (chikungunya virus, Nipah) most viruses, the brain parenchyma and l Australasia neuronal cells are primarily infected, but for – Murray Valley encephalitis, Japanese encephalitis (kunjin, dengue) some the blood vessels can be attacked giving a strong vasculitic component. Demyelination Rarer or suspected arboviral causes are shown in brackets. *All viruses are arthropod-borne, except for rabies and Nipah. following can also contribute. (HSV) for example, primarily targets the brain parenchyma in around the mouth) or be asymptomatic the temporal lobes, sometimes with frontal or (serological studies show that up to 90% of parietal involvement. can cause healthy adults have been infected with HSV- an acute viral encephalitis, or a delayed 1). Following primary infection the virus immune mediated encephalitis. Measles virus travels centripetally along the trigeminal causes a post-infectious encephalitis, which nerve to give latent infection in the trigeminal can sometimes have a severe haemorrhagic ganglion, in most if not all those infected. component (acute haemorrhagic leukoence- About 30% of infected people have clinically phalitis). With , diffuse apparent herpes labialis, but even asympto- cerebral oedema is a major component in matic individuals have episodes or viral the pathogenesis, while for varicella zoster shedding. About 70% of cases of HSV-1 virus (VZV), is a major pathogenic encephalitis already have present, process. indicating that reactivation of virus must be How and when the virus crosses the blood the most common mechanism;3 however, it is brain barrier is a key issue in the pathogenesis not clear whether this is due to reactivation of any viral encephalitis. of virus in the trigeminal ganglion, or virus For example, primary infection with HSV that had already established latency in the type 1 (HSV-1) occurs in the oral mucosa, and brain itself.4 Why HSV sometimes reactivates may cause herpes labialis (vesicles and ulcers is not known. In contrast to adults, in younger www.practical-neurology.com 288 Practical Neurology

TABLE 2 Diseases that may mimic viral meningoencephalitis (modified from Solomon and Whiteley58)

Central nervous system infections Para/post-infectious causes Bacteria Guillain-Barre´ syndrome* –Bacterial meninigitis –Tuberculosis Viral illnesses with febrile convulsions – Shigella –Typhoid fever Systemic viral illnesses with febrile convulsions –Parameningeal infection Systemic viral illnesses associated with swollen –Lyme fontanelle

–Syphilis Non-infectious diseases –Relapsing fever Vascular – –Vasculitis – –Systemic lupus erythematosus – –Behc¸et’s disease –Brucellosis Neoplastic –Subacute bacterial endocarditis –Primary brain tumour –Whipple’s disease –Metastases –Nocardia –Paraneoplastic limbic encephalitis –Actinomycosis Metabolic – Fungi –Renal encephalopathy –Candidiasis –Hypoglycaemia –Cryptococcus –Reye’s syndrome –Coccidiomycosis – (alcohol, drugs) –Histoplasmosis Other –North American blastomycosis –Drug reactions –Subarachnoid and subdural haemorrhage Parasites Ischaemic –Cerebral malaria – –Toxoplasmosis –Hysteria –Cysticercosis –Voltage gated K channel limbic encephalitis –Trypanosomiasis –Echinococcus –Trichinosis –Amoebiasis

Rickettsiae –Rocky Mountain spotted fever – –Q fever –Erlichiosis (anaplasma) –Cat-scratch fever

*Guillain-Barre´ syndrome and acute disseminated encephalomyelitis may follow viral or bacterial infections or vaccinations.

patients, particularly children, HSV-1 ence- meningitis, especially recurrent meningitis, phalitis occurs during primary infection. encephalitis, particularly in neonates, and HSV type 2 (HSV-2) is usually transmitted lumbosacral radiculitis. Most cases of recur- via the genital mucosa, causing genital herpes rent meningitis that were previously called in adults. In the USA approximately 20% of Mollaret’s meningitis are now thought to be individuals are sero-positive for HSV-2. The due to HSV-2, although some feel the term neurological syndromes it causes include Mollaret’s should still be reserved for those 10.1136/jnnp.2007.129098 Solomon, Hart, Beeching 289

Figure 1 Histopathological picture of the temporal cortex of a man who died from herpes simplex virus encephalitis. (A) Intense perivascular inflammatory infiltrate consisting of activated , and (H&E staining, 620). (B) High power view showing microglia and dead neurons with nuclear dissolution (karyolysis) and hypereosinophilia within the cytoplasm retaining the original pyramidal contour (H&E 640). (Pictures courtesy of Dr Daniel Crooks.) with recurrent meningitis in whom the cause morbillivirus (in the same family as is still not known. Neonates can also be measles) that was recognised for the first infected with HSV-2 during delivery to cause time in 1998 when it caused encephalitis 8 neonatal herpes, a disseminated infection— in humans in Malaysia. This virus has also caused disease in Bangladesh and often with CNS involvement. appears to be spreading. The other major route by which viruses N Encephalitis caused by vaccine preventa- enter the nervous system is during a viraemia ble viruses such as measles and mumps is and subsequent spread across the blood brain less common in industrialised nations; barrier. This occurs with enteroviruses such as however, in the UK reduced vaccine poliovirus and arboviruses such as West Nile uptake in recent years has been asso- virus. ciated with a resurgence of these viruses.9

EPIDEMIOLOGY OF VIRAL Incidence of viral encephalitis ENCEPHALITIS It is difficult to determine the incidence of Changing encephalitis because the various studies have While HSV-1 encephalitis occurs with used different case definitions and viral dependable regularity across the globe, there diagnostic capabilities. However, most studies have been notable changes in the epidemiol- report an annual incidence of 5–10 per ogy of other viral causes: 100 000,10, 11 highest in the young and elderly. N Cytomegalovirus (CMV) and Epstein-Barr Higher incidences are found in areas with virus (EBV), and to some extent human arthropod-borne viruses. A lower annual herpes virus (HHV)-6, are being seen more incidence of 1.5 per 100 000 has been often because they occur in patients reported in England, based on hospitalisation immunocompromised by HIV, transplant data,12 although this was probably an under- or cancer . estimate. HSV encephalitis is the most N Arboviruses such as and commonly diagnosed viral encephalitis in Japanese encephalitis virus are spreading industrialised nations, with an annual inci- 5 to new areas. West Nile virus has caused dence of 1 in 250 000 to 500 000.13 Most HSV outbreaks in the Americas and southern encephalitis is due to HSV-1, but about 10% Europe, and there is evidence suggesting are HSV-2. The latter typically occurs in the virus has reached the UK,6 although it immunocompromised individuals, and neo- has not yet caused human disease there. The contribution of climate change to the nates, in whom it causes a disseminated spread of these viruses is not clear. Other infection. viruses that have caused large unex- pected outbreaks in Asia and are spread- WHEN SHOULD ENCEPHALITIS ing include 71, and Nipah virus. Enterovirus 71 has caused massive BE SUSPECTED? outbreaks of hand foot and mouth The classical presentation of viral encephalitis disease in Asia in recent years, which is is generally as an acute flu-like prodrome, often associated with , developing into an illness with high fever, encephalitis or myelitis.7 Nipah virus is a severe headache, nausea, vomiting and www.practical-neurology.com 290 Practical Neurology

Figure 2 Liverpool algorithm for investigation and treatment of immunocompetent adults with suspected viral encephalitis.

altered consciousness, often associated with lethargy, drowsiness, confusion, disorienta- and focal neurological signs (fig 2). tion and coma. With the advent of CSF PCR Eighty five (91%) of 93 adults with HSV-1 more subtle presentations of HSV encephalitis encephalitis in one recent study were febrile have been recognised;15 low grade pyrexia on admission.14 Disorientation (76%), speech rather than a high fever, speech disturbances disturbances (59%) and behavioural changes (dysphasia and ), and behavioural (41%) were the most common features, and changes which can mistaken for psychiatric one third of patients had seizures.14 illness, or the consequences of drugs or Alterations in higher mental function include alcohol, occasionally with tragic consequences.

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Seizures can sometimes be the initial presenting feature of a patient with encephalitis. Any adult TABLE 3 Why encephalitis may be missed with a in the context of a febrile illness, or a seizure from which they do not recover, l Wrongly attributing a patient’s fever and confusion to a urinary tract must be investigated for possible CNS infection. infection (based on a urine dipstick) or a chest infection (based on a few There are several reasons why one may not crackles in the chest) without strong evidence l think of encephalitis, particularly a failure to Failure to realise that a patient has a febrile illness, just because they are not febrile on admission appreciate the importance of altered con- l Ignoring a relative’s complaint that a patient is ‘‘not quite right’’, sleepy or sciousness in the context of a febrile illness, lethargic, just because the Glasgow coma score is 15 (the coma score is a or failure to investigate these symptoms very crude tool) properly when they are recognised (table 3). l Wrongly attributing clouding of consciousness to drugs or alcohol, One of the commonest failings is delay in without good evidence to do so performing a in patients l Failure to properly investigate a patient with a fever and seizure, with an acute confusional state, which has following which they do not recover consciousness been incorrectly attributed to a systemic l Failure to do a lumbar puncture, even though there are no infection.16 Although most viral encephalitis contraindications presents acutely, subacute and chronic pre- sentations can be caused by CMV, VZV and HSV, especially in patients immunocompro- from eating snails carrying the rat lungworm mised as a result of HIV, or immunosuppres- Angiostrongylus cantonensis. Cerebral malaria 15 sive drugs (table 4). should also be considered in returning travellers, especially from Africa.17 IMPORTANT FEATURES IN THE Ask if there has been any contact with HISTORY animals, or whether there are sick animals in As well as being crucial in determining who the neighbourhood. In the USA some out- needs investigation for encephalitis, the breaks of West Nile virus were heralded by history can provide useful clues to aetiology. sick birds falling from the sky.18 The history of Never accept that the ‘‘history is not avail- a dog bite in a rabies endemic area may be able’’ for a confused patient; track down a important,19 as may a bite or scratch from a relative or neighbour on the phone. bat; in the UK and Europe, Daubenton’s bats Comments from relatives that a patient ‘‘does carry rabies-like viruses (European bat lyssa- not seem right’’, should not be ignored, even viruses).20 Other risk factors are related to if the Glasgow Coma Score is 15; remember occupation and recreational activities: this is a very crude tool that was devised for assessing patients with head injuries. Ask about recent rashes such as measles. TABLE 4 Causes of subacute and chronic viral encephalitis Even if there is no such history in the patient, ask whether others in the family or in the In immunocompromised patients (HIV, organ transplant recipients, cancer community have been affected (these viruses patients, those on immunosuppressive therapy, including steroids) occasionally cause encephalitis without the l Measles (inclusion body encephalitis) l Varicella zoster virus (causes a multifocal leukoencephalopathy) obvious stigmata). In children, a recent rash l Cytomegalovirus may suggest , parvovirus or HHV-6. l Herpes simplex virus (especially HSV-2) Parotitis, testicular or abdominal pain due l Human herpes virus 6 to may suggest mumps virus as the l Enterovirus causative organism. If the patient is conscious, l JC/BK* virus (causes progressive multifocal leukoencephalopathy) ask about any strange smells, which may be In immunocompetent patients olfactory hallucinations reflecting frontotem- l JC/BK* virus (causes progressive multifocal leukoencephalopathy) poral involvement in HSV-1 encephalitis. l Measles virus (subacute sclerosing panencephalitis, years after primary A travel history is essential, as are vaccination infection) details. Travellers from Asia with fever and l Rubella virus (causes progressive rubella panencephalitis, very rare) reduced consciousness may be infected with *JE and BK viruses are named after the initials of the patients from whom dengue or Japanese encephalitis viruses; they they were first isolated. may also have acquired meningoencephalitis www.practical-neurology.com 292 Practical Neurology

test score. The general medical examination TABLE 5 Brainstem encephalitis (rhombencephalitis): clues and causes should include a search for other possible explanations of the coma. Suggestive clinical features Look for a purpuric (meningococcal) rash l Lower cranial nerve involvement and other exanthema, bites and stigmata that l may suggest an aetiology; is there the rash of l Autonomic dysfunction ? Are there injection sites that might l Locked-in syndrome indicate intravenous drug use? Look for l MRI changes in the brainstem, with gadolinium enhancement of basal seborrhoeic dermatitis, oral candida or oral Causes—viral and other hairy leukoplakia in the mouth, or Kaposi’s l Enteroviruses (especially EV71) sarcoma on the skin indicative of undiag- l Flaviviruses, eg West Nile virus, Japanese encephalitis virus nosed HIV infection. In patients with HIV look l Listeria for mouth ulcers or umbilicated skin papules l Tuberculosis suggestive of disseminated histoplasmosis or l Brucella . Look at the genitals for the l Borrelia ulcers of HSV and chancres of syphilis. l Paraneoplastic syndromes Examine also the chest, ears and urine for infection. However, beware ascribing reduced consciousness to a urinary or chest infection, N leptospirosis can be acquired from rat especially in someone who is otherwise fit urine during fresh water activities and well. Such patients need a lumbar N lymphocytic choreomeningitis virus puncture to rule out a CNS infection. (LCMV) is transmitted in rodent faeces; Look for seizures including subtle motor humans are exposed when cleaning out seizures, and examine the side of the tongue barns, etc or inside cheek for bites indicating that a N hikers in the forests of Austria, , seizure has occurred. Test for , and and Eastern Europe are at risk of tick- look for focal neurological signs, including borne encephalitis virus (TBEV) hemispheric signs that could indicate an N a related virus, Louping ill virus, causes abscess, or suggestive of occasional encephalitis in sheep in the spinal cord involvement. and abnor- Scottish Highlands, and very rarely in mal movements are seen in some forms of humans encephalitis, particularly those that involve N hikers in the New Forest in the UK are at the , such as West Nile virus and risk of . other flaviviruses, or toxoplasmosis. An acute Ask about risk factors for HIV, including febrile encephalopathy with lower cranial previous blood transfusions, and high-risk neuropathies and myoclonus suggests a behaviours such as intravenous drug use, sex rhomboencephalitis or basal meningoence- between men, and multiple sexual partners, phalitis, as seen with some enteroviruses, or especially with people from high-risk areas of listeria (table 5). Deafness is quite common in the world such as sub-Saharan Africa and mumps and some rickettsial infections. Upper Thailand. limb weakness and fasciculation suggest a cervical myelitis, for example in tick-borne encephalitis. Encephalitis associated with IMPORTANT EXAMINATION radiculitis is seen in CMV and EBV. FINDINGS On examination the first priorities are to check that the airway is protected, assess and INITIAL INVESTIGATIONS document the level of consciousness, using a N A peripheral blood count may show a quantitative scale such as the Glasgow Coma or leukopenia. Atypical lym- Scale (GCS), and treat any immediate com- phocytes are seen in EBV infection, and plications of infection such as generalised in eosinophilic meningitis. seizures. For patients with mild behavioural N Hyponatraemia due to the syndrome of abnormalities or disorientation, document the inappropriate antidiuretic hormone odd behaviour, and record the mini-mental (SIADH) is common in encephalitis. 10.1136/jnnp.2007.129098 Solomon, Hart, Beeching 293

N A raised serum amylase is common in mumps virus infection. N If there has been a respiratory component to the presentation check for cold agglu- tinins, which occur in mycoplasma infec- tion, and order appropriate serological investigations for mycoplasma and chla- mydia (atypical respiratory infections). N Blood cultures should be taken as part of the investigation of possible bacterial causes, and PCR of the blood for meningococcus considered. N Bacterial testing of CSF and urine may be helpful. N A chest x ray is essential to look for pulmonary infiltrates in atypical pneu- monia, for example in mycoplasma pneu- monia, legionella or LCMV. N HIV testing should also be considered, especially if the cause of CNS infection is sometimes associated with the raised pres- Figure 3 uncertain. Our practice is to perform the sure, so the pressure is not the same in all the CT scan with contrast of a middle-aged man with a one-week history of a flu- test in all such patients, because if CSF compartments. For this reason patients like illness, severe headache and positive it makes such a difference to should be assessed for clinical features which increasing confusion, who had HSV the differential and management. might indicate a space-occupying lesion, encephalitis confirmed by CSF PCR. (A) A low density area in the left temporal brain swelling or shift, and who should then lobe, with swelling and some contrast THE LUMBAR PUNCTURE have computed tomography (CT) before enhancement. (B) The same patient four CONTROVERSY lumbar puncture (fig 3); focal neurological days later with more marked changes. Few topics have led to as much confusion, signs (for example a hemiparesis), new onset contradiction and controversy as the role of seizures, papilloedema and deep coma. CT is lumbar punctures in patients with suspected also recommended for immunocompromised CNS infection.21 A lumbar puncture is an patients, who may lack the clinical signs of an 24 essential investigation because the initial CSF inflammatory mass lesion. Opinions vary as findings (especially the cell count, differential to what level of ‘‘deep coma’’ necessitates a and glucose ratio) reveal firstly whether or CT scan before lumbar puncture. To some not there is infection, and secondly whether it extent it depends on how quickly imaging can is likely to be bacterial or viral infection, be organised. If a CT scan can be performed which thus informs the initial antimicrobial promptly, so that it will not delay lumbar therapy. Subsequent studies such as culture puncture for more than an hour or two, then and PCR confirm precisely what the organism it is reasonable to do this first. However, in a is, which allows the therapy to be tailored and patient who is only mildly confused with no appropriate public health measures, including focal neurological signs, than a lumbar disease notification, to be organised. puncture should be done straight away, However, if patients have a space-occupy- without the unnecessary delay of a CT.24 ing lesion, marked brain swelling, or brain If a CT is going to cause a delay of several shift (for example herniation across the hours, then presumptive treatment for both midline, the tentorium or the foramen bacterial and/or viral should be magnum), then a lumbar puncture may of started. There are no hard and fast rules course make things worse. Raised intracranial about how long a delay is acceptable before pressure itself is not a problem—indeed treatment is initiated. For bacterial meningitis patients with idiopathic intracranial hyper- a delay of more than six hours between tension are treated by lumbar punctures, and arrival in hospital and initiation of in most patients with CNS infection the CSF treatment is associated with a worse out- opening pressure is raised to some degree.22, 23 come.25 If patients have a purpuric rash The problem is the swelling or shift which is suggestive of meningococcal septicaemia, or www.practical-neurology.com 294 Practical Neurology

TABLE 6 Typical cerebrospinal fluid findings in infections

Viral meningo- Acute bacterial Tuberculous encephalitis meningitis meningitis Fungal Normal Opening pressure Normal/high High High High–very high 10–20 cm* Colour ‘‘Gin’’ clear Cloudy Cloudy/yellow Clear/cloudy Clear Cells/mm3 Slightly increased High–very high Slightly increased Normal–high 5–1000 100–50000 25–500 0–1000 ,5{ Differential Lymphocytes Neutrophils Lymphocytes Lymphocytes Lymphocytes CSF/plasma glucose Normal Low Low–very low Normal–low 66%{ ratio (,30%) (g/l) Normal–high High High–very high Normal–high ,0.45{ 0.5–1 .1 1.0–5.0 0.2–5.0 *Normal CSF opening pressure is generally ,20 cm for adults, ,10 cm for children below age 8, but may be as high as 25 cm (Whiteley et al, Neurology 2006;67:1690–1). {A bloody tap will falsely elevate the CSF white cell count and protein. To correct for a bloody tap, subtract 1 white cell for every 700 red blood cells/mm3 in the CSF, and 0.1 g/dl of protein for every 1000 red blood cells. {A normal glucose ratio is usually quoted as 66%, though only values below 50% are likely to be significant. Some important exceptions: N In viral CNS infections, an early lumbar puncture may give predominantly neutrophils, or there may be no cells in early or late lumbar punctures. N In patients with acute bacterial meningitis that has been partially pre-treated with (or patients ,1 year old) the CSF cell count may not be very high and may be mostly lymphocytic. N may have predominant CSF polymorphs early on. N Listeria can give a similar CSF picture to tuberculous meningitis, but the history is shorter. N CSF findings in bacterial abscesses range from near normal to purulent, depending on location of the abscess, and whether there is associated meningitis, or rupture. N A cryptococcal antigen test and India ink stain should be performed on the CSF of all patients in whom cryptococcus is possible.

are deteriorating rapidly, antibiotics should be treatment has been started, it is still essential to started immediately.26 In HSV-1 encephalitis, a perform a lumbar puncture, because this bad outcome is associated with a delay of two informs the diagnosis and guides subsequent days or more between hospitalisation and management.28 Giving blind antibacterial and starting treatment.14 In practice, HSV ence- antiviral treatment to all patients with sus- phalitis is rare, and most suspected cases turn pected CNS infection, and then not investigat- out to have something different.27 While one ing with lumbar puncture because it ‘‘makes no would not advocate unnecessary delays, difference to the management’’ is unacceptable together these data suggest that for patients practiceandshouldbediscouraged.21 This with suspected encephalitis the emphasis approach risks missing other diagnoses that should be on investigating promptly where may require alternative treatments,29 and possible before starting treatment. For most increases the risk of adverse effects of the patients with no contraindication, it should be unwarranted and unnecessary drugs. For HSV-1 possible to perform a lumbar puncture, and encephalitis, PCR of the CSF remains positive in get the result back within a few hours to then about 80% of patients even a week after guide the management. If there are delays or starting antiviral therapy.13 a patient appears to be deteriorating, then presumptive treatment with is CEREBROSPINAL FLUID appropriate, at least while investigations FINDINGS proceed. In encephalitis, the CSF opening pressure is For patients with suspected bacterial menin- often slightly raised, and there is usually a gitis or viral encephalitis, even if antimicrobial mild to moderate CSF pleocytosis of 5–1000 10.1136/jnnp.2007.129098 Solomon, Hart, Beeching 295 cells/mm3, with predominant lymphocytes (table 6). However, early in the infection the TABLE 7 Staged approach to microbiological investigation of viral CSF white cell count may be normal, or encephalitis neutrophils may predominate, as they do in .30 The CSF red cell count is CSF PCR usually normal, or slightly raised, but it may l All patients be markedly raised in HSV-1 encephalitis, – HSV-1, HSV-2, VZV which can be haemorrhagic, or in acute – Enterovirus, parechovirus, l If indicated necrotising haemorrhagic leukoencephalitis. – EBV/CMV (especially if immunocompromised) The glucose ratio is usually normal in viral – HHV 6,7 (especially if immunocompromised, or children) CNS infections, though it may be a little – Adenovirus, influenza A & B, (children) reduced—for example, in mumps or enter- – Measles, mumps (if clinically indicated) ovirus infection.31 The CSF protein is often – Parvovirus B19 slightly raised, between 0.5 and 1.0 g/l. – Chlamydia (if clinically indicated) l Special circumstance DIAGNOSTIC VIROLOGY – Rabies, West Nile virus, tick-borne encephalitis virus (if appropriate exposure) The definitive diagnosis of a viral CNS infection – Antibody testing (where indicated—see text) * is based on demonstrating the virus in the CNS, l Viruses: IgM and IgG in CSF and serum (acute and convalescent), for either from culture or PCR of brain tissue or CSF, against HSV 1 & 2, VZV, CMV, HHV6, HHV7, enteroviruses, RSV, or by demonstrating a specific antibody parvovirus B19, adenovirus, influenza A & B;* response in the CSF. Less strong evidence l Antibody detection in the serum identifies infection (past or recent comes from detecting virus elsewhere in the depending on the type of antibodies) but does not necessarily mean this body of a patient with a CNS syndrome (for virus has caused the CNS disease example, from throat, rectal or vesicle swabs), or l If associated with atypical pneumonia, test serum for showing an antibody response to the virus in – Mycoplasma and cold agglutinins the serum (the organism is then presumed to be – Chlamydia serology Ancillary investigations (these establish systemic infection, but not responsible for the clinical presentation, necessarily the cause of the CNS disease) although there is always the possibility that it l Throat swab, nasopharyngeal aspirate, rectal swab is a coincidental infection). – PCR/culture of throat swab, rectal swab for enteroviruses – PCR of throat swab for mycoplasma, chlamydia PCR of CSF – PCR/antigen detection of nasopharyngeal aspirate for respiratory The diagnosis of viral encephalitis used to rely viruses, adenovirus, influenza virus (especially children) l Vesicle electron microscopy, PCR and culture on brain biopsy,27 but many important viruses – Patients with herpetic lesions (for HSV, VZV) can now be detected with PCR.32, 33 PCR tests – Children with hand foot and mouth disease (for enteroviruses) for HSV have overall sensitivity and specificity l Brain biopsy .95%, but may be negative in the first few – For culture, electron microscopy, PCR and immunohistochemistry days of the illness, or after about 10 days.34, 35 Initial investigation of immunocompetent patients with encephalitis should include PCR for both HSV and VZV because these syncitial virus (RSV), and influenza virus A and are potentially treatable with aciclovir (see B; and parvovirus B19 are also below) (table 7). Enterovirus PCR is often occasionally associated with CNS disease, included at this stage, because it is a relatively especially in children.36, 37 PCR can also be used common cause of viral meningitis, especially to detect Chlamydia pneumoniae in the CSF. in the summer/autumn. In immunocompro- CSF viral culture is now rarely performed, mised patients, EBV and CMV PCR should also although it has the potential advantage over be performed, and HHV-6 and HHV-7 con- PCR of being able to detect any virus, whereas sidered. Measles and mumps should be looked PCR only detects the viruses being targeted by for if there is a suggestive clinical indication, the panel of PCR assays used. Newer more although they can occasionally cause ence- sensitive PCR methods, such as ‘‘real-time’’ and phalitis in patients with no other features. quantitative PCR have improved the clinical Other viruses to consider, especially in children, utility of this test, and are becoming available include adenoviruses, HHV-6, respiratory for herpes viruses and enteroviruses.38 www.practical-neurology.com 296 Practical Neurology

One problem is that the high sensitivity of 1/200th of the serum concentration; hence in a some of the recent PCR assays for herpes primary acute CNS infection, IgG rises later than viruses, such as EBV and CMV, can make IgM both in CSF and serum. In reactivations and positive results difficult to interpret. Most of secondary infections, IgG tends to rise earlier the adult population have been infected with andtoagreaterextentthanIgM. these viruses and carry them in their The detection of oligoclonal bands is lymphocytes. Therefore, there is debate about sometimes a useful non-specific indicator whether detection of the viruses by PCR of that a patient has an inflammatory process in the CSF represents true pathogenic infection, the CNS, rather than a non-inflammatory rather than just the presence of infected cause of encephalopathy. Immunoblotting of lymphocytes.39 Where there is uncertainty the bands against viral has been about the significance of a result, the amount used, but mostly as a research tool to help of virus in the CSF compared with the blood determine the cause of the inflammation—for (determined by quantitative PCR) usually example, HSV-1 or HSV-2.29, 34 However, the helps resolve it. For example, in a patient detection of intrathecal anti-HSV antibody with HIV, a CSF CMV PCR titre that is higher has a sensitivity of 50% by 10 days after than that in the serum is usually significant. clinical presentation, and is thus only con- sidered useful for . Antibody testing Our practice, at least for diagnosing HSV infections, is to ask for PCR on CSF acutely. If Antibody testing continues to play an impor- this is negative, but suspicion remains high, tant role in the diagnosis of many viral CNS PCR of the CSF is repeated after a few days infections. Traditional techniques required the (as indicated above PCR can sometimes be demonstration of a fourfold rise in antibody negative if the sample is taken early in the between acute and convalescent serum illness). If two CSFs are negative for HSV by samples collected 2–4 weeks apart, and thus PCR then it is unlikely that the patient has are not helpful in making an early diagnosis. HSV infection. If for logistic reasons CSFs And in practice convalescent samples are were not taken at this time, or were not sent often forgotten. for HSV PCR, then testing a late CSF (for Newer enzyme immunoassays can detect example, later than 10 days of hospitalisa- immunoglobulin (Ig)-M and IgG antibodies in tion) for the production of intrathecal anti- the serum and CSF against most of the bodies against HSV, by IgM, IgG or antibody- important viruses, as well as Mycoplasma mediated immunoblotting of oligoclonal pneumoniae. Specific anti-viral IgM is often bands, can be useful. produced within a few days of a primary infection and can be measured by IgM enzyme immunoassays. The detection of virus INVESTIGATION OF OTHER specific IgM antibodies in the CSF in higher SAMPLES titres than in serum indicates local production Other investigations include: of antibody in the CNS in response to N PCR and/or culture of throat and rectal infection. IgM does not normally cross the swabs for enteroviruses, mumps virus or blood-brain barrier because of its size. measles virus. However, if there is inflammation the barrier N PCR or antigen detection and culture of is leaky to IgM, and other immunoglobulins. nasopharyngeal aspirates for respiratory In this circumstance, the ratio of CSF to viruses such as adenoviruses, RSV, para- serum for the specific IgM antibody can be influenza viruses or influenza viruses. compared to the ratio for immunoglobulin as N a whole, to decide if this is local production Urine culture for mumps virus. rather than leak across an inflamed blood- N Chlamydia pneumoniae and Mycoplasma brain barrier. IgM detection is especially pneumonia can also be detected in throat useful for flavivirus infections, but less so swabs using PCR. for herpes virus infections, which are often N Vesicles, for example in hand foot and reactivations. In contrast to IgM, IgG is mouth disease, should be aspirated for normally found in the CSF at a ratio of culture or PCR, for enteroviruses. 10.1136/jnnp.2007.129098 Solomon, Hart, Beeching 297

N VZV or HSV can be detected in herpetic Figure 4 rashes by cell culture, antigen detection T2-weighted MRI brain scan showing by immunofluorescence or PCR. Electron right hyperintensity in a microscopy of vesicle fluids may also patient with herpes encephalitis. demonstrate herpes viruses. In general, a virus detected in sterile sites, such as vesicles, is more likely to be causal than a virus from non-sterile sites. For example, enteroviruses detected in vesicle swabs indicate that they are temporally associated with the acute infection, whereas shedding from the rectum occurs for several weeks after an acute infection.40 The list of all possible investigations for causes of viral CNS disease is clearly very long. Our practice is to do the initial CSF PCR for HSV and VZV as soon as the samples are received, because of their importance for early management. PCR for enteroviruses and parechoviruses is also usually done at this stage. In addition, patients that are immuno- compromised are investigated with CMV and EBV PCR. Further investigations are guided by the clinical picture, especially the patient’s immune competence and the initial CSF findings. The opinion of a clinical virologist in assessing such patients is invaluable. With the advent of PCR, brain biopsy of patients with suspected encephalitis has become less common. Previously it was considered the gold standard for diagnosis of HSV-1 encephalitis. It may still have a role in undiagnosed patients that are deteriorat- early.41 Diffusion-weighted MRI may be ing. In one study approximately half of especially useful for demonstrating early patients with suspected HSV-1 encephalitis changes.42 who had a brain biopsy had an alternative An EEG usually shows non-specific diffuse 27 diagnosis, of which 40% were treatable. high amplitude slow waves of encephalo- pathy, but can be useful to look for subtle IMAGING AND EEG epileptic seizures. Periodic lateralised epilepti- As described above, in patients with ence- form discharges were once thought to be phalopathy and fever, a CT scan is generally diagnostic of HSV encephalitis, but have since done before the lumbar puncture if there are been seen in other conditions.43 clinical features of brain shift or a space- occupying lesion. In HSV the scan may be MANAGEMENT normal initially, or there may be subtle There are three elements to the management swelling of the frontotemporal region with of patients with encephalitis: loss of the normal gyral pattern (fig 1). Subsequently there is hypodensity, or there N the first is to consider whether there is may be high signal change if haemorrhagic any antiviral or immunomodulatory treat- transformation occurs. MRI is generally more ment to halt or reverse the disease sensitive, showing high signal intensities in process; the brain areas affected (fig 4), but even MRI N the second is to control the immediate scans can look normal if performed very complications of the encephalitis; www.practical-neurology.com 298 Practical Neurology

TABLE 8 Treatment options to consider in encephalitis (modified from Boos and Esiri)52

Acute viral encephalitis Herpes simplex virus 1 and 2 Aciclovir Varicella zoster virus (incluing cerebellitis) Aciclovir plus Human herpes virus-6 , Rabies Ketamine*, amantidine, ribavirin Subacute/chronic encephalitis In the immunocompromised Varicella-zoster virus Aciclovir Cytomegalovirus Ganciclovir, foscarnet, cidofovir Measles inclusion body encephalitis Ribavirin Enterovirus Pleconaril, specific immunoglobulin Progressive multifocal leukoencephalophy in HIV patients Highly active antiretroviral therapy (HAART), cidofovir In the immunocompetent Subacute sclerosing panencephalitis alpha (intraventricular), ribavirin inosiplex Progressive multifocal leukoencephalopathy Consider cytosine arabinoside (ARA-C) Progressive rubella panencephalitis Plasma exchange Rasmussen’s encephalitis IVIg Immune-mediated encephalitis Acute disseminated encephalomyelitis{ Coricoteroids/IVIg/plasma exchange Paraneoplastic Treatment of underlying tumour, consider immunosuppression Voltage gated K channel limbic encephalitis IVIg/plasma exchange plus corticosteroids

*Considered experimental. {Acute disseminated encephalomyelitis presents acutely; the others typically present with a subacute encephalitis.

N the third is to prevent some of the For example in much of Asia large outbreaks secondary and late complications. of Japanese encephalitis occur; in parts of Standard intensive care for patients with Asia and sub-Saharan Africa, HIV-associated encephalitis include oxygen via a mask, CNS infections and cerebral malaria are paying attention to fluid and hydration, common. nasogastric or parenteral feeding, and treat- Aciclovir is a nucleoside analogue that is ing the complications of infection such as highly effective against HSV and some of the pneumonia. Patients with a reduced coma other herpes viruses, such as VZV and herpes score or impaired gag reflex, should be . Intravenous administration of aciclo- assessed by an intensive care unit outreach vir at 10 mg/kg three times daily reduces the team, with a view to early transfer. risk of a fatal outcome from approximately 70% to less than 20%.44, 45 Renal function When to start aciclovir should be monitored closely and adequate In most immunocompetent patients in devel- hydration maintained, because of the rare risk oped countries aciclovir should be given as of renal failure. Other rare adverse effects soon as there is a strong suspicion of viral include local inflammation at the site of the encephalitis, based on the clinical presenta- intravenous canula, hepatitis, and bone tion and initial CSF and/or imaging findings. If marrow failure. performing these investigations is likely to lead to long delays and the clinical suspicion When to stop aciclovir is strong, then treatment should be started at Although the original aciclovir trials were for once, for both viral encephalitis and possible 10 days’ treatment, most physicians continue bacterial meningitis. The situation may be for 14 or 21 days, especially in patients with different in developing countries, where the proven herpes encephalitis, because of the cost of aciclovir may be an issue, and other risk of relapse after 10 days.46 Some advocate causes of CNS infection are more common. repeating the CSF examination at the end of 10.1136/jnnp.2007.129098 Solomon, Hart, Beeching 299 treatment and continuing with aciclovir if Other antiviral and HSV is still detected by PCR. This approach is immunomodulatory treatments being evaluated by the American There are few large, randomised controlled trials Collaborative Antiviral Study Group, which is assessing the efficacy of antiviral treatments in assessing the prognostic value of quantitative viral CNS infections, other than for HSV PCR detection of viral DNA in the CSF at the encephalitis. Nonetheless treatments for other end of three weeks’ treatment and prolonged conditions are given based on an understanding high dose oral valaciclovir for three months. of the pathogenesis, in vitro data, anecdotal If the initial CSF PCR is negative for HSV reports, or small clinical series, although these but other features are consistent with HSV sometimes provide conflicting data (table 8). encephalitis, then the aciclovir should not be If the clinical presentation and imaging stopped, because false negative PCR results findings suggest a post- or para-infectious can occur, particularly early on.47, 48 In such encephalitis such as ADEM, acute haemorrhagic patients the lumbar puncture should be leukoencephalitis or diffuse encephalopathy repeated because it may be positive 24–48 h associated with systemic viral infection, immu- later and, even if negative again, treatment nosuppressive drugs are given.52 High dose continued for at least 10 days. However, if a treatment is often the initial definitive alternative diagnosis has become treatment, followed by intravenous immuno- apparent, or it seems very unlikely that the globulin, plasma exchange, or further treatment patient has viral encephalitis, then it is with steroids, depending on the response to the reasonable to stop the acyclovir earlier. initial treatment. In some circumstances, both antiviral and A role for oral valaciclovir? immunosuppressive drugs are given. For In circumstances where ongoing intravenous example, in HSV encephalitis corticosteroids treatment is proving difficult (for example, in are sometimes used in addition to aciclovir as a child who is now fully conscious), oral described above. In VZV encephalitis cortico- valaciclovir may be reasonable,49 although we steroids are used alongside aciclovir because would only consider this after the first of the strong vasculitic component of the 10 days of intravenous treatment. disease. Valaciclovir is the valene ester of aciclovir, Severe CMV and HHV-6 infections are which is converted to aciclovir after absorp- treated with ganciclovir, foscarnet or cidofo- tion, and has good oral bioavailability. vir, severe adenovirus infections have been Although oral valaciclovir may have a role, treated with cidofovir or ribavirin and oral aciclovir should not be used in HSV Pleconaril has been used for severe enter- encephalitis, because the levels achieved in ovirus infections, particularly in the immuno- the CSF are inadequate. compromised, although its overall role remains unclear.53, 54 Interferon alpha has Ancillary treatments been used in West Nile virus and other flavivirus infections, but a randomised con- In patients with brain swelling, corticosteroids trolled trial in Japanese encephalitis showed it and mannitol are often used to control raised was not effective.55 . A recent trial suggests steroids may be beneficial even in patients without marked swelling.50 Their role in HSV Management of seizures, raised encephalitis merits further study.51 In patients intracranial pressure and other with severe brain swelling, decompressive complications hemicraniectomy is sometimes performed. Seizures are common in encephalitis, parti- Antibiotic treatment with a cephalosporin is cularly in children. In adults, seizures can be often also given, especially if the initial CSF useful in distinguishing acute viral encepha- findings could be consistent with bacterial litis from para-infectious inflammatory ence- disease (for algorithm see http://www. phalopathies. There may be obvious britishinfectionsociety.org). If listeria is sus- generalised tonic clonic seizures or subtle pected, ampicillin and gentamicin, or high motor seizures, which may manifest as dose cotrimoxazole, should be given. twitching of a digit, or around the mouth or www.practical-neurology.com 300 Practical Neurology

PRACTICE POINTS limb movements will reduce the risk of limb contractures, which can occur in patients with limb weakness, and splints and braces l All patients with a febrile illness and altered behaviour or consciousness may be needed to facilitate mobilisation. should be investigated for a central nervous system (CNS) infection, unless there is very clear evidence of another diagnosis. l Patients with a suspected CNS infection need a lumbar puncture as soon as Management in the recovery possible, unless there is an indication for a brain CT first. period l Patients with a meningococcal rash and/or sepsis should receive immediate Ideally, a full neuropsychological assessment antibiotics, but for most other patients investigation with lumbar puncture should be organised at hospital discharge, or should be possible before starting treatment. soon after. This should include cognitive function, intelligence, memory and speech assessment, because these help determine the eyes, particularly in children. An EEG should extent of any damage, and the help that be performed if there is any uncertainty. might be needed. Regular out-patient assess- Uncontrolled seizures lead to raised intra- ment following encephalitis is especially cranial pressure, increased metabolic activity, important in children. Behavioural and psy- acidosis and vasodilatation, which in turn chiatric disturbances are common and may leads to further raised pressure. The resulting include depression or disinhibition. positive feedback cycle can ultimately pre- Antidepressants and mild night-time seda- cipitate brain shift and herniation. If seizures tives may be necessary. Other disabilities in are not easily controlled with and the recovery period or afterwards include low doses of , patients should seizures, post-encephalitic seen be intubated and ventilated mechanically, so after , and encephalitis that higher doses of sedating anticonvulsive caused by flaviviruses. The risk of seizures is drugs, including benzodiazepines and pheno- greatest in those who had seizures during the barbital, can be used. Electroencephalographic acute period; in one study the cumulative risk monitoring, with or without continuous of seizures at 5 years was 10% for patients function and analysing monitoring (CFAM), with no acute seizures, which increased to should be used to detect ongoing epileptic 20% for those with acute seizures.57 activity. Memory difficulties can be particularly Standard measures to control raised intra- prominent after HSV encephalitis. A range of cranial pressure include nursing the patient at practical approaches can help to overcome 30˚ head up, keeping the head straight to these difficulties such as the patient keeping ensure there is no obstruction to venous a notebook and diary, labelling items around return, and ventilating to maintain a low the house, and leaving messages as remin-

arterial pCO2. Although there are no good ders. More sophisticated aids being developed data for viral encephalitis, data from other include a neuropage system (http://www. infectious suggest that neuropage.nhs.uk), which sends pager remin- osmotic diuretics produce a short-term der messages throughout the day, and a reduction in pressure.56 The role of anti- camera, worn around the neck, which auto- inflammatory drugs in viral encephalitis is matically takes pictures throughout the day uncertain.51 To reduce the risk of deep venous as a reminder of what the patient has been thrombosis and pulmonary embolism, doing (SenseCam – http://reseach.microsoft. patients with reduced mobility should be com.sendev/). Excellent help and advice can fitted with compression stockings, and once it be obtained from patient support groups, is clear that there is no major haemorrhagic such as the encephalitis society (http://www. component to the encephalitis, they should encephalitis.info) be given prophylactic heparin. Bed sores are a risk in immobile patients, and appropriate PROGNOSTIC FACTORS AND mattresses and regular turning are needed. OUTCOME Patients with encephalitis are also at risk of Although treatment with aciclovir has secondary pneumonia, due to aspiration, and reduced the mortality of HSV, the morbidity urinary tract infections. Passive and active remains high.13 Poor prognostic factors after 10.1136/jnnp.2007.129098 Solomon, Hart, Beeching 301

HSV encephalitis include age above 60, 8. Chua KB, Goh KJ, Wong KT, et al. Fatal encephalitis 44 due to Nipah virus among pig-farmers in Malaysia. reduced coma score on admission, especially Lancet 1999;354:1257–9. if (6,45 and delays between hospitalisation 9. Bloom S, Wharton M. Mumps outbreak among and starting aciclovir treatment (especially young adults in UK. BMJ 2005;331:E363–4. delays of more than two days).14, 16 Two thirds 10. Rantala H, Uhari M. Occurrence of childhood encephalitis: a population-based study. Pediatr of survivors have significant neuropsychiatric Infect Dis J 1989;8:426–30. sequelae, including memory impairment 11. Koskiniemi M, Korppi M, Mustonen K, et al. (69%), personality and behavioural change Epidemiology of encephalitis in children. A prospective multicentre study. Eur J Pediatr (45%), dysphasia (41%) and epilepsy in up to 1997;156:541–5. 25%.16 This means that in addition to the high 12. Davison KL, Crowcroft NS, Ramsay ME, et al. Viral hospitalisation costs estimated in the USA at encephalitis in England, 1989–1998: what did we $500 million for 1983 alone, there are miss? Emerg Infect Dis 2003;9:234–40. 13. Whitley RJ. Herpes simplex encephalitis: considerable additional costs of long-term adolescents and adults. Antiviral Res care and support. If the personal tragedies 2006;71:141–8. themselves were not impetus enough, this 14. Raschilas F, Wolff M, Delatour F, et al. Outcome of and prognostic factors for herpes simplex major financial burden emphasises the need encephalitis in adult patients: results of a for a rational approach to investigation and multicenter study. Clin Infect Dis 2002;35:254–60. treatment of this devastating condition. 15. Fodor PA, Levin MJ, Weinberg A, et al. Atypical herpes simplex virus encephalitis diagnosed by PCR amplification of viral DNA from CSF. Neurology ACKNOWLEDGEMENTS 1998;51:554–9. 16. McGrath N, Anderson NE, Croxson MC, et al. 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