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Viral meningitis and encephalitis
NERVOUS SYSTEM INFECTIONS
Viral meningitis and encephalitis
Key points C
The diagnosis of encephalitis should involve testing blood and other bodily samples in addition to cerebrospinal fluid (CSF)
C
Herpes simplex encephalitis is a life-changing diagnosis, and immediate antivirals are mandatory until the diagnosis can be excluded
C
Viral meningitis is usually benign and, apart from primary herpes simplex virus (HSV) meningitis, requires no specific antiviral treatment
C
The laboratory CSF findings found in varicella-zoster virus and HSV meningitis can mimic those of tuberculous meningitis
C
Patients with recurrent HSV meningitis derive no benefit from either acute or suppressive aciclovir treatment
Philip Rice
Abstract Viral meningitis and encephalitis occur at all stages of life. They can represent disease at its primary site of replication (e.g. rabies) or be part of an infection syndrome (e.g. HIV). A large proportion of cases go unconfirmed by laboratory diagnosis despite use of all available laboratory techniques. They can be sporadic or epidemic, but with changing environmental and societal conditions, infective agents can emerge for the first time (e.g. Nipah, Hendra and Zika viruses) or reappear after a period of good control through vaccination (e.g. mumps virus, poliovirus). Specific antiviral treatment is currently limited. Prevention is by public health measures and vaccination.
Keywords Enteroviruses; Hendra; herpes simplex encephalitis; HSV; Japanese encephalitis; MRCP; Nipah; rabies; viral encephalitis; viral meningitis; West Nile virus; Zika
symptoms include arthralgia, myalgia, sore throat, rash and lethargy. Other symptoms and signs are specific to the causative agent. Clues to the possible organism can be obtained from other information revealed in the history, such as sexual exposure, travel, vaccination status and animal exposure.
Viral meningitis Enteroviruses There are >70 serotypes of enterovirus, including poliovirus, coxsackievirus A and B, and echovirus; replication is in the gastrointestinal tract. Most infections are asymptomatic and occur seasonally in late summer and autumn. Outbreaks can occur in nurseries and day-care centres. Rarely, outbreaks in neonatal units have been described, with occasionally high mortality. A rash may be seen, often subtle; this can be erythematous, maculopapular or vesicular. When on the palms or soles and inside the mouth, it is termed hand, foot and mouth disease. An enanthem in the oral cavity is seen in herpangina. Enterovirus serotype 70/71 can cause acute flaccid paralysis identical to that caused by poliovirus; this became apparent during an extensive outbreak in South-East Asia in 1997 several years ago. Aside from this neurological complication, full recovery is the rule. In patients with agammaglobulinaemia, chronic, relapsing meningitis can result, requiring administration of intravenous immunoglobulin. No antiviral agents are licensed for this indication. The antiviral agent pleconaril failed to demonstrate clinical benefit and was rejected because of side effects.
Definition and epidemiology e the term ‘aseptic meningitis’ was introduced because it seemed to represent a specific aetiological entity, namely patients with symptoms and signs of meningitis in whom bacterial cultures were negative. It is now known that almost all cases are caused by one of a wide range of viruses (Table 1), most commonly enteroviruses (70e90%), herpes simplex virus (HSV-1, HSV-2), varicella-zoster virus (VZV) and mumps virus. The exact incidence of viral meningitis is unknown, but it is grossly under-reported. In the UK in 2005e2006, 2898 patients were admitted to hospital with the diagnosis, >10 times the number formally notified to the Health Protection Agency.1 Although any age group can be affected, childhood disease is most common: a Finnish study found an annual incidence of 219 per 100,000 in infants aged <1 year compared with 28 per 100,000 in 1e14-years-olds. Transmission occurs by droplet infection, close personal and kissing contact, or faeco-orally. Zoonotic infection is seen with lymphocytic choriomeningitis virus, an arenavirus related to Lassa fever virus that is excreted in the urine of small rodents; transmission occurs by inhalation when changing bedding contaminated with urine. Clinical features e the typical viral meningitis syndrome comprises a triad of symptoms and signs of acute onset: fever, headache and accompanying signs of meningeal irritation (photophobia, neck stiffness, Kernig’s sign). Non-specific
Herpes simplex and varicella-zoster viruses Primary HSV infection can occur with either HSV-1 or HSV-2. The risk of clinically apparent meningitis is greatest in a primary infection of the genital tract, with approximately 30% of women and 13% of men developing it. However, clinical meningitis is unusual with a non-primary genital infection (infection with one virus type in an individual with pre-existing antibody to the other type). As the prevalence of childhood oral HSV-1 infection appears to be decreasing, more cases of HSV-induced meningitis are likely.
Philip Rice BSc MB BS FRCPath is a Consultant Virologist at the Norfolk and Norwich University Hospitals NHS Trust, Norwich, UK. Competing interests: none declared.
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NERVOUS SYSTEM INFECTIONS
More commonly recognized causes of viral meningitis and encephalitis Meningitis
Encephalitis
Geographical distribution
Virus HSV VZV Enterovirus EV 70/71 Poliovirus Mumps
þþþ HSV-2a þþþ þþþ þ/ þþ þþþ
þþþ HSV-1a þ þ/ þþþ þ/ þ/
HIV Rabies
þþ (Primary infection) þ/
þ (Dementia) þþþ
W/E/VEE Nipah/Hendra WNV TBE
þ þ
þþþ þþþ þþþ þþþ
Worldwide Worldwide Worldwide South-East Asia Nigeria, Somalia, Afghanistan, Pakistan Underdeveloped countries and age-restricted outbreaks in USA/UK Worldwide Africa, Indian sub-continent, South-East Asia, South and Central America, USA The Americas Malaysia/Singapore Worldwide (USA e emerging pathogen) Russia, Balkans, Scandinavia
EV, enterovirus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; TBE, tick-borne encephalitis; VZV, varicella-zoster virus; W/E/VEE, Western/Eastern/Venezuelan equine encephalitis; WNV, West Nile virus. a Predominant virus type.
Table 1
The syndrome of benign recurrent aseptic meningitis is caused by reactivation of genitally acquired HSV infection, most commonly HSV-2. Episodes occur predominantly in women (female:male ratio 6:1), separated by intervals of months or years. The average number of episodes that patients record is four. In one study, the recurrence rate in those presenting with a first episode of HSV meningitis was 19%. Headache can be associated with genital recurrences, but the host and viral factors underlying this association are not understood. Aciclovir has not been shown to affect the course of illness and, when used to suppress attacks, can cause an increased frequency of episodes once therapy has ceased. Reactivation of VZV usually presents as cutaneous shingles but can also present as meningitis without a skin component. Such patients can suffer excruciating headaches of very sudden onset, mimicking subarachnoid haemorrhage.
HIV Headache occurs in about 50% of patients during primary HIV infection, with symptoms of meningitis in 17%. Higher HIV RNA concentrations in the CSF also correlate with neurological symptoms. Early diagnosis of primary infection in cases with a high clinical index of suspicion, by either fourth-generation antigen/antibody assays or viral load testing, may enable postexposure prophylaxis to be given to sexual contacts. Furthermore, initiation of anti-HIV drugs during the primary infection can prevent wider virus dissemination within the central nervous system (CNS) and preserve immune control of HIV.
Viral encephalitis Definition and epidemiology e encephalitis is an uncommon outcome of many common viral infections (Figure 1, Table 1). Infection of the brain parenchyma can have devastating consequences; mortality is high, and there is long-term morbidity in many survivors. Many different viruses are responsible, and the condition can arise from either primary infection or reactivation of latent infection. Acute encephalitis is a notifiable disease in the UK, with an estimated 700 cases annually. In the USA, the estimated incidence is 20,000 per year, probably because of infection by arthropod-borne (ARBO) viruses, such as West Nile virus (WNV) and St Louis virus. The largest UK prospective survey of encephalitis detected infectious agents in 42% of cases and an immune-mediated cause in 21%, leaving 37% still with no proven aetiology. Pathogenesis of infection e viruses can reach the CNS by the haematogenous or neuronal route: The haematogenous route is used by arthropod-borne viruses (arboviruses), after injection into capillary blood by a tick or mosquito bite. Local replication in surrounding
Mumps virus Mumps meningitis occurs in 1e10% of cases of mumps, typically about 5 days after onset of parotitis; however, cerebrospinal fluid (CSF) abnormalities are seen in approximately 50% of infections. Meningitis can precede parotitis by a week or even follow it after 2 weeks. Symptoms last 7e10 days, but the condition is essentially benign with no long-term complications. The epidemiology of viral meningitis has changed dramatically since 1988, following the introduction of the MMR (measles, mumps, rubella) vaccine in the UK. Before this, mumps virus was the most common cause of meningitis (annual incidence 5e11/100,000 population, 1200 hospital admissions each year); the current incidence is about 0.3 per 100,000 population. Outbreaks still occur despite good vaccine uptake rates in the UK and USA. This is thought to be because of a mixture of primary and secondary vaccine failure, the relatively high transmissibility of mumps virus and the low immunogenicity of the Jeryl Lynn strain of mumps virus in the vaccine.
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NERVOUS SYSTEM INFECTIONS
Viral causes of encephalitis
Western equine encephalitis Louping ill Venezuelan equine encephalitis Eastern equine encephalitis Tick-borne encephalitis (Western subtype) Tick-borne encephalitis (Eastern subtype) Japanese encephalitis Murray Valley encephalitis Worldwide
Rabies – South Asia, Africa, South East Asia, Central and South America Dengue fever – South East Asia, South Asia, Africa, Central and South America, Southern USA Figure 1
reactivation, the risk factors for which are unknown; the remaining one-third are caused by primary infection in the neonatal period (when HSV transmission occurs during labour or shortly thereafter) or later in childhood. It is believed that the virus accesses the CNS via the olfactory ganglia, but there is evidence for direct reactivation of latent virus within the brain. Entry via viraemia is seen only in disseminated infection. The presence of a cold sore is almost always coincidental and merely a sign that the patient is very unwell. HSV has a particular affinity for the temporal lobes, which is reflected in the symptoms e temporal lobe seizures, speech disorders, personality changes and altered behaviour. The parietal and frontal lobes are also involved in approximately 30% and 10% of cases, respectively, and because it is a cytolytic agent, considerable destruction of nervous tissue occurs. This destruction can take some time, as on admission the median Glasgow Coma Scale score has been shown to be 14, and a subset (around 5%) have no objective abnormal findings on neurological examination. It is important to note that, in cases of HSE, brain computed tomography (CT) at presentation is normal in >40% of patients, compared with only 11% assessed by magnetic resonance imaging; electroencephalography is also normal in around 20%.
skin is followed by primary viraemia that seeds the major organs. A second bout of multiplication produces secondary viraemia; if of sufficient magnitude, this can lead to the virus crossing the bloodebrain barrier via infected leucocytes or locally in vascular endothelia. The neuronal route of entry is exemplified by rabies and HSV, which are transported directly into the brain by retrograde axoplasmic flow. This is a viral immune evasion mechanism e once inside the axon, the virus is invulnerable to immune control. Clinical features e the onset of viral encephalitis is commonly acute, with fever and headache. However, fever can be absent at presentation in 10% of patients. Because the injury is directly to the brain, there are disturbances in higher mental function (e.g. confusion, delirium, behaviour changes, dysphasia/aphasia, temporal lobe seizures, focal neurological signs proceeding to coma). These distinguish viral encephalitis from meningitis, in which there is no nervous parenchymal tissue involvement. It is essential that the collateral history from carers and relatives is listened to carefully and not dismissed as signs of CNS involvement can sometimes be subtle. The overall case fatality rate is 7%, although this is probably an underestimate. Herpes simplex encephalitis (HSE) In developed countries, the most common and important cause of viral encephalitis is HSV, although such cases are rare (incidence 1 in 250,000e500,000 per year); most cases (>85%) are caused by HSV-1.2 One-third occur in the under-20s and one-half in the over-50s. About two-thirds of cases are caused by virus
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Infection in immunocompromised individuals A slightly different group of (mostly latent) viruses is responsible for encephalitis in immunocompromised individuals. Cytomegalovirus and VZV can cause encephalitis and granulomatous arteritis, with spinal cord myelopathy caused by cytomegalovirus
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NERVOUS SYSTEM INFECTIONS
encephalitis, the cells are predominantly lymphocytes, although a neutrophil predominance, even beyond the first 24 hours the illness, is seen in patients acutely ill with viral meningitis. Peripheral blood lymphocytosis, lymphopenia or thrombocytopenia and elevated liver enzymes can also suggest a virus infection. Polymerase chain reaction (PCR) analysis e diagnosis of viral meningitis and encephalitis has been transformed by the use of PCR, which has made brain biopsy almost obsolete. The technique has replaced conventional cell culture as it is significantly more sensitive and rapid.3 PCR can also detect non-culturable enterovirus serotypes, with multiplex PCR capable of detecting as many as 20 different viruses simultaneously. Used in a timely manner, PCR can be cost-effective by reducing unnecessary investigations and antibiotic treatment, and consequently the length of stay in hospital.4 Audits of CSF microscopy and PCR testing have shown that the positive predictive value of PCR is significantly increased by targeting cellular CSF samples for testing. Cell culture e this is now obsolete. PCR of relevant samples such as throat swabs, stool and vesicular fluid or lesions should also be attempted when CSF PCR is negative as an aetiological diagnosis still be possible. Clotted blood samples e these may be useful, and still have a role in demonstrating seroconversion to HIV and HSV, and detecting virus-specific antibodies (e.g. in Japanese encephalitis, WNV or mumps).
in HIV-infected patients. Patients with HIV can also suffer unrestricted replication of EpsteineBarr virus and JC virus, leading to primary CNS lymphoma and progressive multifocal leucoencephalopathy (PML), respectively. Both diagnoses can have a poor prognosis despite the introduction of highly active antiretroviral therapy. Biological agents, such as natalizumab to treat multiple sclerosis, greatly increase the risk of PML. Encephalitis in travellers A history of recent travel should always be obtained from patients with suspected encephalitis. Viruses to consider include rabies, Japanese and tick-borne encephalitis, Nipah and Hendra ARBO viruses from Singapore and Malaysia, and WNV, now endemic in New York and New England, USA. Zika virus, a previously obscure ARBO virus, now occupies an almost unique position in causing widespread damage to the developing brain in utero. It has also been linked to GuillaineBarre syndrome. Neither treatment nor vaccine prophylaxis is currently available. Rabies is only very rarely imported into the UK, although worldwide it is responsible for an estimated 50,000 deaths annually. Most of the disease burden falls on the Indian subcontinent and Africa. It is almost universally fatal, although one survivor has recently been reported after treatment with ribavirin. Virus entry is often via a bite, but rare cases have been said to occur after inhaling virus from bat guano in caves, or when a fresh wound is licked by an animal excreting virus in its saliva. Pre-exposure vaccination is advisable in travellers spending longer periods in endemic areas; post-exposure active and passive vaccination is advisable after significant exposure in previously unimmunized individuals. Another lethal form of viral encephalitis acquired by animal bite is simian herpes virus B, which can occur after a bite from a macaque monkey. Postexposure aciclovir prophylaxis should be considered. Japanese encephalitis is commonly asymptomatic. When symptomatic encephalitis develops, mortality is 20e30%, with severe morbidity is 30% of survivors. The virus is transmitted by culicine mosquitoes, which acquire virus from pig or bird reservoirs. Tick-borne encephalitis is present in forested and rural areas in Scandinavia, Europe east of France, the Balkans and Russia. It is common in forestry workers and shepherds, and a risk among travellers in the peak season of late spring and summer. A bite from a tick of the genus Ixodes is responsible. Fatalities are uncommon (1e2%).
Management and prognosis Viral meningitis e the outlook for most patients with viral meningitis is excellent. Serious complications include unilateral deafness after mumps, chronic enterovirus meningitis in patients with agammaglobulinaemia, and hydrocephalus after intrauterine infection with lymphocytic choriomeningitis virus. Treatment is supportive and must include adequate analgesia. Herpes simplex encephalitis e aciclovir should be used to treat meningitis associated with primary genital herpes infection, but its usefulness in recurrent meningitis is unclear. Before the introduction of aciclovir, the outlook (in HSE) was poor: 70% of patients died, and only 2.5% regained normal function. Even with treatment, it remains a serious condition: mortality is 50% 2 years after diagnosis, only about 15% of patients completely recover, and persistent problems with short-term memory are particularly prevalent. The best predictor of good outcome is early therapeutic intervention within 3e4 days of symptom onset. As the median time from symptom onset to hospital admission is 3e3.5 days, antiviral treatment should be started as soon as it is suspected clinically. High-dose aciclovir, 10 mg/kg intravenously 8-hourly for 21 days should be used. Strict attention to fluid balance must be adhered to as dehydration increases the likelihood of aciclovir-induced renal toxicity. Relapse occurs in up to 5% of patients, requiring continuation of treatment for an additional 7 days.5 In neonatal CNS infection, the long-term neurological outcome in survivors after the acute treatment phase has completed shows no improvement compared with the preaciclovir era. This may change as experience widens with use of suppressive aciclovir therapy for 6 months after intravenous treatment has stopped. This has been shown to reduce the rate of CNS recurrence and progression of damage.
Diagnosis Lumbar puncture e before performing lumbar puncture in suspected meningitis or encephalitis, it is now common to undertake CT of the head to exclude space-occupying lesions and reveal radiographic evidence of raised intracranial pressure. The typical CSF findings in viral meningitis and encephalitis are pleocytosis, mildly elevated protein (0.5e1.5 g/litre) and normal CSF:plasma glucose ratio. In VZV and HSV meningitis, CSF protein is often >1 g/litre, which can cause confusion with tuberculosis as a possible diagnosis. A raised cell count is often much more prominent in meningitis, whereas in HSV and VZV encephalitis, white cells are absent in up to 10% of patients. In both meningitis and
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NERVOUS SYSTEM INFECTIONS
Prevention
KEY REFERENCES 1 Logan SAE, MacMahon E. Viral meningitis. Br Med J 2008; 336: 36e40. 2 Solomon T, Hart IJ, Beeching NJ. Viral encephalitis: a clinician’s guide. Pract Neurol 2007; 7: 288e305. 3 Jeffrey KJ, Read SJ, Peto TE, Mayon-White RT, Bangham CR. Diagnosis of viral infections of the central nervous system: clinical interpretation of PCR results. Lancet 1997; 349: 313e7. 4 Raschilas F, Wolff M, Delatour F, et al. Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study. Clin Infect Dis 2002; 35: 254e60. 5 Solomon T, Michael BD, Smith PE, et al. Management of suspected viral encephalitis in adults e Association of British Neurologists and British Infection Association National Guidelines. J Infect 2012; 64: 347e73.
Vaccination has almost eliminated wild-type poliovirus worldwide, except in Pakistan, Afghanistan and parts of Africa, especially Nigeria. There is now an effective vaccine against enterovirus (70/71), an important advance as, in South-East Asia, mortality in hospitalized children was 17%. Prophylactic vaccination remains the ultimate goal in preventing the disease burden caused by genital HSV infections, but Phase III trials have consistently failed to demonstrate efficacy. Prevention of viral encephalitis is possible only in rabies, Japanese encephalitis and tick-borne encephalitis. The Japanese encephalitis vaccine is unlicensed in the UK, but the disease is rare in travellers. Tick-borne encephalitis and rabies may be prevented by pre-exposure and post-exposure prophylaxis in the form of vaccine and virus-specific immunoglobulin. A
TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here.
Question 1
Question 2
A 17-month-old boy presented with a febrile convulsion. He had been pyrexial and off his food for 3 days. There was no rash. He was being looked after by foster parents as there was a history of ‘shaken baby syndrome’ from when he had been with his biological parents. This had led to a traumatic brain injury resulting in cerebral palsy. A magnetic resonance scan of the brain had previously been reported as normal. Clinical examination was unremarkable. A lumbar puncture was performed.
A 49-year-old woman presented with the ‘worst headache in my life’. She had had two very similar episodes in the previous 3 years. She was otherwise well, and there was no significant past history. Clinical examination was normal. A lumbar puncture was performed. Investigations CSF White cell count 328/microlitre (<5) Lymphocytes 95% Neutrophils 5% Red cell count 5/microlitre (0) Protein 2.25 g/litre (0.15e0.45) Glucose 2.3 mmol/litre (3.3e4.4) (serum glucose 6.1)
Investigations CSF: Appearance: clear and colourless White cell count: 2/microlitre (<5) Red cell count 4/microlitre (0) Protein 0.11 g/litre (0.15e0.45) Glucose 3.1 mmol/litre (3.3e4.4)
Bacterial culture showed no growth after 24 hours CSF polymerase chain reaction (PCR): Varicella-zoster virus DNA PCR þve (weak positive) Herpes simplex virus DNA PCR ve Enterovirus RNA PCR ve
What is the most likely diagnosis? A Recurrent HSV meningitis B Primary HSV meningitis C Primary HSV encephalitis D TB meningitis E Migraine with asymptomatic HSV shedding in cerebrospinal fluid
Which interpretation of the CSF PCR is most likely to be correct? A False-positive varicella-zoster virus PCR B Acute varicella meningitis C Acute varicella encephalitis D Congenital varicella syndrome E Zoster encephalitis
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CSF PCR: Varicella-zoster virus (VZV) DNA not detected Herpes simplex virus (HSV)-1 DNA not detected HSV-2 DNA detected Enterovirus RNA not detected
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NERVOUS SYSTEM INFECTIONS
Which test is the most likely to provide the most useful diagnostic information? A Cerebrospinal fluid microscopy B Viral polymerase chain reaction of a swab from the skin rash C Serological tests for acute viral hepatitis D Serological testing for HIV E Computed tomography scan of the brain
Question 3 A 37-year-old man presented with a 2-day history of increasing headache associated with cough, fever and sore throat, He was otherwise well, having recently returned from a 3-week holiday in Ibiza. He had a 20 pack-year smoking history. On clinical examination, his temperature was 38.5 C, heart rate 98 beats/minute and blood pressure 134/78 mmHg. There was widespread lymphadenopathy, and a few widely distributed macular skin lesions. Investigations Haemoglobin 162 g/litre (130e180) White cell count 5.6 109/litre (4e11) Neutrophil count 5.1 109/litre (1.5e7.0) Lymphocyte count 0.4 109/litre (1.5e4.0) Platelet count 104 109/litre (150e400) Serum Alanine Transaminase 87 IU/litre (5e35)
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Viral meningitis and encephalitis
Key points C
The diagnosis of encephalitis should involve testing blood and other bodily samples in addition to cerebrospinal fluid (CSF)
C
Herpes simplex encephalitis is a life-changing diagnosis, and immediate antivirals are mandatory until the diagnosis can be excluded
C
Viral meningitis is usually benign and, apart from primary herpes simplex virus (HSV) meningitis, requires no specific antiviral treatment
C
The laboratory CSF findings found in varicella-zoster virus and HSV meningitis can mimic those of tuberculous meningitis
C
Patients with recurrent HSV meningitis derive no benefit from either acute or suppressive aciclovir treatment
Philip Rice
Abstract Viral meningitis and encephalitis occur at all stages of life. They can represent disease at its primary site of replication (e.g. rabies) or be part of an infection syndrome (e.g. HIV). A large proportion of cases go unconfirmed by laboratory diagnosis despite use of all available laboratory techniques. They can be sporadic or epidemic, but with changing environmental and societal conditions, infective agents can emerge for the first time (e.g. Nipah, Hendra and Zika viruses) or reappear after a period of good control through vaccination (e.g. mumps virus, poliovirus). Specific antiviral treatment is currently limited. Prevention is by public health measures and vaccination.
Keywords Enteroviruses; Hendra; herpes simplex encephalitis; HSV; Japanese encephalitis; MRCP; Nipah; rabies; viral encephalitis; viral meningitis; West Nile virus; Zika
symptoms include arthralgia, myalgia, sore throat, rash and lethargy. Other symptoms and signs are specific to the causative agent. Clues to the possible organism can be obtained from other information revealed in the history, such as sexual exposure, travel, vaccination status and animal exposure.
Viral meningitis Enteroviruses There are >70 serotypes of enterovirus, including poliovirus, coxsackievirus A and B, and echovirus; replication is in the gastrointestinal tract. Most infections are asymptomatic and occur seasonally in late summer and autumn. Outbreaks can occur in nurseries and day-care centres. Rarely, outbreaks in neonatal units have been described, with occasionally high mortality. A rash may be seen, often subtle; this can be erythematous, maculopapular or vesicular. When on the palms or soles and inside the mouth, it is termed hand, foot and mouth disease. An enanthem in the oral cavity is seen in herpangina. Enterovirus serotype 70/71 can cause acute flaccid paralysis identical to that caused by poliovirus; this became apparent during an extensive outbreak in South-East Asia in 1997 several years ago. Aside from this neurological complication, full recovery is the rule. In patients with agammaglobulinaemia, chronic, relapsing meningitis can result, requiring administration of intravenous immunoglobulin. No antiviral agents are licensed for this indication. The antiviral agent pleconaril failed to demonstrate clinical benefit and was rejected because of side effects.
Definition and epidemiology e the term ‘aseptic meningitis’ was introduced because it seemed to represent a specific aetiological entity, namely patients with symptoms and signs of meningitis in whom bacterial cultures were negative. It is now known that almost all cases are caused by one of a wide range of viruses (Table 1), most commonly enteroviruses (70e90%), herpes simplex virus (HSV-1, HSV-2), varicella-zoster virus (VZV) and mumps virus. The exact incidence of viral meningitis is unknown, but it is grossly under-reported. In the UK in 2005e2006, 2898 patients were admitted to hospital with the diagnosis, >10 times the number formally notified to the Health Protection Agency.1 Although any age group can be affected, childhood disease is most common: a Finnish study found an annual incidence of 219 per 100,000 in infants aged <1 year compared with 28 per 100,000 in 1e14-years-olds. Transmission occurs by droplet infection, close personal and kissing contact, or faeco-orally. Zoonotic infection is seen with lymphocytic choriomeningitis virus, an arenavirus related to Lassa fever virus that is excreted in the urine of small rodents; transmission occurs by inhalation when changing bedding contaminated with urine. Clinical features e the typical viral meningitis syndrome comprises a triad of symptoms and signs of acute onset: fever, headache and accompanying signs of meningeal irritation (photophobia, neck stiffness, Kernig’s sign). Non-specific
Herpes simplex and varicella-zoster viruses Primary HSV infection can occur with either HSV-1 or HSV-2. The risk of clinically apparent meningitis is greatest in a primary infection of the genital tract, with approximately 30% of women and 13% of men developing it. However, clinical meningitis is unusual with a non-primary genital infection (infection with one virus type in an individual with pre-existing antibody to the other type). As the prevalence of childhood oral HSV-1 infection appears to be decreasing, more cases of HSV-induced meningitis are likely.
Philip Rice BSc MB BS FRCPath is a Consultant Virologist at the Norfolk and Norwich University Hospitals NHS Trust, Norwich, UK. Competing interests: none declared.
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NERVOUS SYSTEM INFECTIONS
More commonly recognized causes of viral meningitis and encephalitis Meningitis
Encephalitis
Geographical distribution
Virus HSV VZV Enterovirus EV 70/71 Poliovirus Mumps
þþþ HSV-2a þþþ þþþ þ/ þþ þþþ
þþþ HSV-1a þ þ/ þþþ þ/ þ/
HIV Rabies
þþ (Primary infection) þ/
þ (Dementia) þþþ
W/E/VEE Nipah/Hendra WNV TBE
þ þ
þþþ þþþ þþþ þþþ
Worldwide Worldwide Worldwide South-East Asia Nigeria, Somalia, Afghanistan, Pakistan Underdeveloped countries and age-restricted outbreaks in USA/UK Worldwide Africa, Indian sub-continent, South-East Asia, South and Central America, USA The Americas Malaysia/Singapore Worldwide (USA e emerging pathogen) Russia, Balkans, Scandinavia
EV, enterovirus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; TBE, tick-borne encephalitis; VZV, varicella-zoster virus; W/E/VEE, Western/Eastern/Venezuelan equine encephalitis; WNV, West Nile virus. a Predominant virus type.
Table 1
The syndrome of benign recurrent aseptic meningitis is caused by reactivation of genitally acquired HSV infection, most commonly HSV-2. Episodes occur predominantly in women (female:male ratio 6:1), separated by intervals of months or years. The average number of episodes that patients record is four. In one study, the recurrence rate in those presenting with a first episode of HSV meningitis was 19%. Headache can be associated with genital recurrences, but the host and viral factors underlying this association are not understood. Aciclovir has not been shown to affect the course of illness and, when used to suppress attacks, can cause an increased frequency of episodes once therapy has ceased. Reactivation of VZV usually presents as cutaneous shingles but can also present as meningitis without a skin component. Such patients can suffer excruciating headaches of very sudden onset, mimicking subarachnoid haemorrhage.
HIV Headache occurs in about 50% of patients during primary HIV infection, with symptoms of meningitis in 17%. Higher HIV RNA concentrations in the CSF also correlate with neurological symptoms. Early diagnosis of primary infection in cases with a high clinical index of suspicion, by either fourth-generation antigen/antibody assays or viral load testing, may enable postexposure prophylaxis to be given to sexual contacts. Furthermore, initiation of anti-HIV drugs during the primary infection can prevent wider virus dissemination within the central nervous system (CNS) and preserve immune control of HIV.
Viral encephalitis Definition and epidemiology e encephalitis is an uncommon outcome of many common viral infections (Figure 1, Table 1). Infection of the brain parenchyma can have devastating consequences; mortality is high, and there is long-term morbidity in many survivors. Many different viruses are responsible, and the condition can arise from either primary infection or reactivation of latent infection. Acute encephalitis is a notifiable disease in the UK, with an estimated 700 cases annually. In the USA, the estimated incidence is 20,000 per year, probably because of infection by arthropod-borne (ARBO) viruses, such as West Nile virus (WNV) and St Louis virus. The largest UK prospective survey of encephalitis detected infectious agents in 42% of cases and an immune-mediated cause in 21%, leaving 37% still with no proven aetiology. Pathogenesis of infection e viruses can reach the CNS by the haematogenous or neuronal route: The haematogenous route is used by arthropod-borne viruses (arboviruses), after injection into capillary blood by a tick or mosquito bite. Local replication in surrounding
Mumps virus Mumps meningitis occurs in 1e10% of cases of mumps, typically about 5 days after onset of parotitis; however, cerebrospinal fluid (CSF) abnormalities are seen in approximately 50% of infections. Meningitis can precede parotitis by a week or even follow it after 2 weeks. Symptoms last 7e10 days, but the condition is essentially benign with no long-term complications. The epidemiology of viral meningitis has changed dramatically since 1988, following the introduction of the MMR (measles, mumps, rubella) vaccine in the UK. Before this, mumps virus was the most common cause of meningitis (annual incidence 5e11/100,000 population, 1200 hospital admissions each year); the current incidence is about 0.3 per 100,000 population. Outbreaks still occur despite good vaccine uptake rates in the UK and USA. This is thought to be because of a mixture of primary and secondary vaccine failure, the relatively high transmissibility of mumps virus and the low immunogenicity of the Jeryl Lynn strain of mumps virus in the vaccine.
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Viral causes of encephalitis
Western equine encephalitis Louping ill Venezuelan equine encephalitis Eastern equine encephalitis Tick-borne encephalitis (Western subtype) Tick-borne encephalitis (Eastern subtype) Japanese encephalitis Murray Valley encephalitis Worldwide
Rabies – South Asia, Africa, South East Asia, Central and South America Dengue fever – South East Asia, South Asia, Africa, Central and South America, Southern USA Figure 1
reactivation, the risk factors for which are unknown; the remaining one-third are caused by primary infection in the neonatal period (when HSV transmission occurs during labour or shortly thereafter) or later in childhood. It is believed that the virus accesses the CNS via the olfactory ganglia, but there is evidence for direct reactivation of latent virus within the brain. Entry via viraemia is seen only in disseminated infection. The presence of a cold sore is almost always coincidental and merely a sign that the patient is very unwell. HSV has a particular affinity for the temporal lobes, which is reflected in the symptoms e temporal lobe seizures, speech disorders, personality changes and altered behaviour. The parietal and frontal lobes are also involved in approximately 30% and 10% of cases, respectively, and because it is a cytolytic agent, considerable destruction of nervous tissue occurs. This destruction can take some time, as on admission the median Glasgow Coma Scale score has been shown to be 14, and a subset (around 5%) have no objective abnormal findings on neurological examination. It is important to note that, in cases of HSE, brain computed tomography (CT) at presentation is normal in >40% of patients, compared with only 11% assessed by magnetic resonance imaging; electroencephalography is also normal in around 20%.
skin is followed by primary viraemia that seeds the major organs. A second bout of multiplication produces secondary viraemia; if of sufficient magnitude, this can lead to the virus crossing the bloodebrain barrier via infected leucocytes or locally in vascular endothelia. The neuronal route of entry is exemplified by rabies and HSV, which are transported directly into the brain by retrograde axoplasmic flow. This is a viral immune evasion mechanism e once inside the axon, the virus is invulnerable to immune control. Clinical features e the onset of viral encephalitis is commonly acute, with fever and headache. However, fever can be absent at presentation in 10% of patients. Because the injury is directly to the brain, there are disturbances in higher mental function (e.g. confusion, delirium, behaviour changes, dysphasia/aphasia, temporal lobe seizures, focal neurological signs proceeding to coma). These distinguish viral encephalitis from meningitis, in which there is no nervous parenchymal tissue involvement. It is essential that the collateral history from carers and relatives is listened to carefully and not dismissed as signs of CNS involvement can sometimes be subtle. The overall case fatality rate is 7%, although this is probably an underestimate. Herpes simplex encephalitis (HSE) In developed countries, the most common and important cause of viral encephalitis is HSV, although such cases are rare (incidence 1 in 250,000e500,000 per year); most cases (>85%) are caused by HSV-1.2 One-third occur in the under-20s and one-half in the over-50s. About two-thirds of cases are caused by virus
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Infection in immunocompromised individuals A slightly different group of (mostly latent) viruses is responsible for encephalitis in immunocompromised individuals. Cytomegalovirus and VZV can cause encephalitis and granulomatous arteritis, with spinal cord myelopathy caused by cytomegalovirus
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encephalitis, the cells are predominantly lymphocytes, although a neutrophil predominance, even beyond the first 24 hours the illness, is seen in patients acutely ill with viral meningitis. Peripheral blood lymphocytosis, lymphopenia or thrombocytopenia and elevated liver enzymes can also suggest a virus infection. Polymerase chain reaction (PCR) analysis e diagnosis of viral meningitis and encephalitis has been transformed by the use of PCR, which has made brain biopsy almost obsolete. The technique has replaced conventional cell culture as it is significantly more sensitive and rapid.3 PCR can also detect non-culturable enterovirus serotypes, with multiplex PCR capable of detecting as many as 20 different viruses simultaneously. Used in a timely manner, PCR can be cost-effective by reducing unnecessary investigations and antibiotic treatment, and consequently the length of stay in hospital.4 Audits of CSF microscopy and PCR testing have shown that the positive predictive value of PCR is significantly increased by targeting cellular CSF samples for testing. Cell culture e this is now obsolete. PCR of relevant samples such as throat swabs, stool and vesicular fluid or lesions should also be attempted when CSF PCR is negative as an aetiological diagnosis still be possible. Clotted blood samples e these may be useful, and still have a role in demonstrating seroconversion to HIV and HSV, and detecting virus-specific antibodies (e.g. in Japanese encephalitis, WNV or mumps).
in HIV-infected patients. Patients with HIV can also suffer unrestricted replication of EpsteineBarr virus and JC virus, leading to primary CNS lymphoma and progressive multifocal leucoencephalopathy (PML), respectively. Both diagnoses can have a poor prognosis despite the introduction of highly active antiretroviral therapy. Biological agents, such as natalizumab to treat multiple sclerosis, greatly increase the risk of PML. Encephalitis in travellers A history of recent travel should always be obtained from patients with suspected encephalitis. Viruses to consider include rabies, Japanese and tick-borne encephalitis, Nipah and Hendra ARBO viruses from Singapore and Malaysia, and WNV, now endemic in New York and New England, USA. Zika virus, a previously obscure ARBO virus, now occupies an almost unique position in causing widespread damage to the developing brain in utero. It has also been linked to GuillaineBarre syndrome. Neither treatment nor vaccine prophylaxis is currently available. Rabies is only very rarely imported into the UK, although worldwide it is responsible for an estimated 50,000 deaths annually. Most of the disease burden falls on the Indian subcontinent and Africa. It is almost universally fatal, although one survivor has recently been reported after treatment with ribavirin. Virus entry is often via a bite, but rare cases have been said to occur after inhaling virus from bat guano in caves, or when a fresh wound is licked by an animal excreting virus in its saliva. Pre-exposure vaccination is advisable in travellers spending longer periods in endemic areas; post-exposure active and passive vaccination is advisable after significant exposure in previously unimmunized individuals. Another lethal form of viral encephalitis acquired by animal bite is simian herpes virus B, which can occur after a bite from a macaque monkey. Postexposure aciclovir prophylaxis should be considered. Japanese encephalitis is commonly asymptomatic. When symptomatic encephalitis develops, mortality is 20e30%, with severe morbidity is 30% of survivors. The virus is transmitted by culicine mosquitoes, which acquire virus from pig or bird reservoirs. Tick-borne encephalitis is present in forested and rural areas in Scandinavia, Europe east of France, the Balkans and Russia. It is common in forestry workers and shepherds, and a risk among travellers in the peak season of late spring and summer. A bite from a tick of the genus Ixodes is responsible. Fatalities are uncommon (1e2%).
Management and prognosis Viral meningitis e the outlook for most patients with viral meningitis is excellent. Serious complications include unilateral deafness after mumps, chronic enterovirus meningitis in patients with agammaglobulinaemia, and hydrocephalus after intrauterine infection with lymphocytic choriomeningitis virus. Treatment is supportive and must include adequate analgesia. Herpes simplex encephalitis e aciclovir should be used to treat meningitis associated with primary genital herpes infection, but its usefulness in recurrent meningitis is unclear. Before the introduction of aciclovir, the outlook (in HSE) was poor: 70% of patients died, and only 2.5% regained normal function. Even with treatment, it remains a serious condition: mortality is 50% 2 years after diagnosis, only about 15% of patients completely recover, and persistent problems with short-term memory are particularly prevalent. The best predictor of good outcome is early therapeutic intervention within 3e4 days of symptom onset. As the median time from symptom onset to hospital admission is 3e3.5 days, antiviral treatment should be started as soon as it is suspected clinically. High-dose aciclovir, 10 mg/kg intravenously 8-hourly for 21 days should be used. Strict attention to fluid balance must be adhered to as dehydration increases the likelihood of aciclovir-induced renal toxicity. Relapse occurs in up to 5% of patients, requiring continuation of treatment for an additional 7 days.5 In neonatal CNS infection, the long-term neurological outcome in survivors after the acute treatment phase has completed shows no improvement compared with the preaciclovir era. This may change as experience widens with use of suppressive aciclovir therapy for 6 months after intravenous treatment has stopped. This has been shown to reduce the rate of CNS recurrence and progression of damage.
Diagnosis Lumbar puncture e before performing lumbar puncture in suspected meningitis or encephalitis, it is now common to undertake CT of the head to exclude space-occupying lesions and reveal radiographic evidence of raised intracranial pressure. The typical CSF findings in viral meningitis and encephalitis are pleocytosis, mildly elevated protein (0.5e1.5 g/litre) and normal CSF:plasma glucose ratio. In VZV and HSV meningitis, CSF protein is often >1 g/litre, which can cause confusion with tuberculosis as a possible diagnosis. A raised cell count is often much more prominent in meningitis, whereas in HSV and VZV encephalitis, white cells are absent in up to 10% of patients. In both meningitis and
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Prevention
KEY REFERENCES 1 Logan SAE, MacMahon E. Viral meningitis. Br Med J 2008; 336: 36e40. 2 Solomon T, Hart IJ, Beeching NJ. Viral encephalitis: a clinician’s guide. Pract Neurol 2007; 7: 288e305. 3 Jeffrey KJ, Read SJ, Peto TE, Mayon-White RT, Bangham CR. Diagnosis of viral infections of the central nervous system: clinical interpretation of PCR results. Lancet 1997; 349: 313e7. 4 Raschilas F, Wolff M, Delatour F, et al. Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study. Clin Infect Dis 2002; 35: 254e60. 5 Solomon T, Michael BD, Smith PE, et al. Management of suspected viral encephalitis in adults e Association of British Neurologists and British Infection Association National Guidelines. J Infect 2012; 64: 347e73.
Vaccination has almost eliminated wild-type poliovirus worldwide, except in Pakistan, Afghanistan and parts of Africa, especially Nigeria. There is now an effective vaccine against enterovirus (70/71), an important advance as, in South-East Asia, mortality in hospitalized children was 17%. Prophylactic vaccination remains the ultimate goal in preventing the disease burden caused by genital HSV infections, but Phase III trials have consistently failed to demonstrate efficacy. Prevention of viral encephalitis is possible only in rabies, Japanese encephalitis and tick-borne encephalitis. The Japanese encephalitis vaccine is unlicensed in the UK, but the disease is rare in travellers. Tick-borne encephalitis and rabies may be prevented by pre-exposure and post-exposure prophylaxis in the form of vaccine and virus-specific immunoglobulin. A
TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here.
Question 1
Question 2
A 17-month-old boy presented with a febrile convulsion. He had been pyrexial and off his food for 3 days. There was no rash. He was being looked after by foster parents as there was a history of ‘shaken baby syndrome’ from when he had been with his biological parents. This had led to a traumatic brain injury resulting in cerebral palsy. A magnetic resonance scan of the brain had previously been reported as normal. Clinical examination was unremarkable. A lumbar puncture was performed.
A 49-year-old woman presented with the ‘worst headache in my life’. She had had two very similar episodes in the previous 3 years. She was otherwise well, and there was no significant past history. Clinical examination was normal. A lumbar puncture was performed. Investigations CSF White cell count 328/microlitre (<5) Lymphocytes 95% Neutrophils 5% Red cell count 5/microlitre (0) Protein 2.25 g/litre (0.15e0.45) Glucose 2.3 mmol/litre (3.3e4.4) (serum glucose 6.1)
Investigations CSF: Appearance: clear and colourless White cell count: 2/microlitre (<5) Red cell count 4/microlitre (0) Protein 0.11 g/litre (0.15e0.45) Glucose 3.1 mmol/litre (3.3e4.4)
Bacterial culture showed no growth after 24 hours CSF polymerase chain reaction (PCR): Varicella-zoster virus DNA PCR þve (weak positive) Herpes simplex virus DNA PCR ve Enterovirus RNA PCR ve
What is the most likely diagnosis? A Recurrent HSV meningitis B Primary HSV meningitis C Primary HSV encephalitis D TB meningitis E Migraine with asymptomatic HSV shedding in cerebrospinal fluid
Which interpretation of the CSF PCR is most likely to be correct? A False-positive varicella-zoster virus PCR B Acute varicella meningitis C Acute varicella encephalitis D Congenital varicella syndrome E Zoster encephalitis
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CSF PCR: Varicella-zoster virus (VZV) DNA not detected Herpes simplex virus (HSV)-1 DNA not detected HSV-2 DNA detected Enterovirus RNA not detected
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Which test is the most likely to provide the most useful diagnostic information? A Cerebrospinal fluid microscopy B Viral polymerase chain reaction of a swab from the skin rash C Serological tests for acute viral hepatitis D Serological testing for HIV E Computed tomography scan of the brain
Question 3 A 37-year-old man presented with a 2-day history of increasing headache associated with cough, fever and sore throat, He was otherwise well, having recently returned from a 3-week holiday in Ibiza. He had a 20 pack-year smoking history. On clinical examination, his temperature was 38.5 C, heart rate 98 beats/minute and blood pressure 134/78 mmHg. There was widespread lymphadenopathy, and a few widely distributed macular skin lesions. Investigations Haemoglobin 162 g/litre (130e180) White cell count 5.6 109/litre (4e11) Neutrophil count 5.1 109/litre (1.5e7.0) Lymphocyte count 0.4 109/litre (1.5e4.0) Platelet count 104 109/litre (150e400) Serum Alanine Transaminase 87 IU/litre (5e35)
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