Viral infections of the central nervous system - technical article
Enteroviruses are responsible for 80 to 90% and mumps for 10 to 20% of diagnosed cases of viral meningitis, with many other viruses sometimes incriminated with considerable geographical and seasonal variation.
Clinical features and prognosis—typical presentation is with sudden onset of fever, headache, change in conscious level, and (occasionally) a stiff neck and vomiting. The specific cause may be suggested by characteristic signs outside the nervous system, e.g. swelling in the parotid region (mumps). Prognosis is excellent.
Japanese encephalitis is the commonest cause of encephalitis in Asia: other causes—with considerable geographical and seasonal variation—include dengue viruses, Enteroviruses (EV71) rabies, Nipah virus, herpes simplex, West Nile virus, and mumps.
Clinical features and prognosis—most patients present with the symptoms of meningitis followed by altered consciousness, convulsions, and sometimes focal neurological signs, signs of raised intracranial pressure, or psychiatric symptoms. Some manifestations suggest particular viruses, e.g. temporal lobe features in herpes simplex encephalitis; hydrophobia in rabies; Parkinsonian and extrapyramidal features in Japanese encephalitis. Mortality and morbidity vary according to cause, but are high, e.g. mortality 10 to 40% in Japanese encephalitis, with neurological sequelae in 5 to 75% of survivors.
Viral ‘paralytic’ myelitis is classically caused by poliovirus, which has now been virtually eliminated from the Americas: other causes—with considerable geographical and seasonal variation—include Japanese encephalitis and various coxsackieviruses, echoviruses, enteroviruses and flaviruses.
Clinical features—following a nonspecific episode of influenza-like symptoms, poliomyelitis typically presents with features of viral meningitis preceding or accompanying the development of lower motor neurone (flaccid) paralysis. Respiratory and bulbar paralysis is life-threatening. Mortality in adults is more than 20%.
The most important investigation is lumbar puncture to allow examination of the cerebrospinal fluid, with typical findings of (1) pleocytosis—ranging from tens to thousands of cells/µl, with lymphocytes and other mononuclear cells usually predominating; (2) modest increase in protein concentration; (3) normal glucose concentration. Some viruses can be isolated from the cerebrospinal fluid, and viruses can sometimes be cultured from distant sites, but polymerase chain reaction (PCR) technology is now used routinely for diagnosis of viral central nervous system infection.
Aside from supportive care, aciclovir is effective in treating herpes simplex encephalitis, and hyperimmune plasma reduces mortality of Argentine haemorrhagic fever (Junin virus) and Congo Crimean haemorrhagic fever, but there is no effective specific treatment for most viral infections of the central nervous system.
Prophylactic vaccination is available against poliomyelitis, measles, Japanese encephalitis, and rabies. Postexposure rabies vaccination is effective in preventing rabies encephalitis. Hyperimmune immunoglobulin has been used for prophylaxis of measles, herpes zoster virus, HSV-2, vaccinia, rabies, and some other infections in high-risk groups.
Other neurological disorders in which viruses play a role
These include (1) Reye’s syndrome—an acute encephalopathy affecting children aged 2 to 16 years, associated with use of salicylates during the preceding viral illness. (2) Subacute sclerosing panencephalitis—caused by measles virus; typically presents with very gradual onset of altered behaviour, mild intellectual deterioration, and loss of energy and interest; periodic involuntary movements then appear; further progression is marked by intellectual deterioration, rigidity, spasticity, and increasing helplessness; there is no effective treatment; 40% of patients die within a year. (3) Progressive multifocal leucoencephalopathy—caused by opportunistic infection by papovaviruses, most commonly JC virus and the simian virus SV40; onset is usually with progressive evidence of a focal lesion of one cerebral hemisphere, before gradual development of more widespread signs; there is no effective treatment; most patients die within 6 to 12 months.
Viruses invade and damage the central nervous system in two ways: directly, by infecting the leptomeninges, brain, and spinal cord; and, indirectly, by inducing an immunological reaction resulting in para- and postinfectious diseases. In both cases, the terms ‘meningitis’, ‘encephalitis’, and ‘myelitis’ are used alone or in combination. Meningitis implies inflammation of the meninges without alteration of consciousness, convulsions, or the production of focal neurological abnormalities; in encephalitis there is impairment of cerebral function, usually with an altered state of consciousness and often with convulsions and focal neurological signs; while myelitis indicates involvement of the spinal cord. Retroviral and prion diseases of the central nervous system are dealt with elsewhere.
There is considerable geographical and seasonal variation in the kinds of viruses causing meningitis, myelitis, and encephalitis. Vulnerability varies with age and immunocompetence.
Enteroviruses are responsible for 80 to 90% of diagnosed cases of viral meningitis. Almost all the serotypes have been implicated in sporadic cases, and outbreaks have been associated with coxsackieviruses A7 and A9, EV71, all the coxsackievirus B types, and many of the echoviruses, especially 4, 6, 9, 11, 14, 16, and 30. Echovirus 13, a rare type, has caused cases in the United States of America, Australia, and Europe, and there has been an increase in echovirus 30 cases. Mumps is responsible for about 10 to 20% of cases of viral meningitis. Other causes include herpes zoster (HZV), herpes simplex virus (predominantly type 2, HSV-2), measles, adenoviruses, Epstein–Barr virus (EBV), and, in the United States of America, togaviruses, such as St Louis, eastern and western equine encephalitis, and West Nile and bunyaviruses, such as California (La Crosse) encephalitis viruses.
Poliovirus has long been considered the major cause of viral ‘paralytic’ myelitis throughout the world, but has now been virtually eliminated from the Americas. A confusingly similar syndrome of acute flaccid paralysis caused by Japanese encephalitis (JE) has been reported from Vietnam. Coxsackievirus A7 (AB IV) has caused occasional outbreaks, and other coxsackieviruses A and B, echoviruses, enterovirus 71, and flaviruses (tick-borne encephalitis) have all been implicated as causes of flaccid paralysis. HZV, paralytic rabies virus, EBV, and herpesvirus simiae (B virus) can cause myelitis or ascending paralysis, and HSV-2 can cause lumbosacral myeloradiculitis.
Viruses causing encephalitis vary from country to country. JE virus is the major cause of encephalitis in Asia. There are at least 50 000 cases of JE with 15 000 deaths annually (case fatality 0.3 to 60%). The virus is transmitted by culex mosquitoes and is endemic across much of Asia and the Indian subcontinent. Dengue viruses have been implicated as a cause of encephalitis in both south-east Asia and Latin America. Rabies remains an important cause of fatal encephalomyelitis, especially in the Indian subcontinent and Africa (see Chapter 7.5.10).
In 1999 an outbreak of an encephalitic illness among pig farm and abattoir workers was reported from Singapore and Malaysia. There were 258 cases of encephalitis, with a case fatality rate of almost 40%. Subsequently, Nipah has become endemic in Bangladesh. The causative agent was a new paramyxovirus, Nipah virus, closely related to the Hendra and Manangle viruses described in Australia. Nipah virus encephalitis is a zoonosis infecting pigs and flying foxes (Pteropus spp.). Almost all patients infected in this outbreak had direct contact with pigs. Hendra virus has caused a few cases of equine and human encephalitis with a human fatality in Brisbane, Australia in 2008.
In North America, herpes simplex virus is the most common cause of sporadic fatal viral encephalitis, followed by the California encephalitis group, St Louis encephalitis virus, HZV, enteroviruses, mumps, measles, and, most recently, the West Nile virus. In the United States of America, herpes simplex encephalitis has an estimated incidence of 2.3 per million population each year; HSV-1 accounts for 95% of cases; HSV-2 causes encephalitis mainly in neonates and those who are immunosuppressed, such as transplant recipients, and those with HIV infection. In 1999 there was an outbreak of West Nile infection in the eastern United States of America with a cluster of cases of encephalitis in New York and 16 human deaths. West Nile virus is a mosquito-borne flavivirus closely related to JE. It has been known to cause encephalitis in Africa, the Middle East, and southern and eastern Europe, but this was the first appearance of this virus in the New World. In endemic areas, infection with West Nile virus is usually asymptomatic or associated with a mild flu-like illness. Only occasionally does it cause encephalitis, with a case fatality rate for patients admitted to hospital in New York of 12%. The virus has now become established in migrant bird populations across the United States of America and Central America, and in 2008 there were 1370 cases with 37 fatalities in the United States of America reported by the Centers for Disease Control (CDC), Atlanta.
In the United Kingdom, mumps is the most frequently diagnosed viral encephalitis, followed by echoviruses, coxsackieviruses, measles, HSV, HZV, EBV, and adenoviruses (especially adenovirus 7). Louping ill is the only indigenous arthropod (tick)-borne encephalitis in the United Kingdom. In central and eastern Europe and Scandinavia, tick-borne encephalitis virus and Russian spring–summer encephalitis viruses are endemic. Usutu, a flavivirus, has been isolated in birds in Austria. In many developing countries rabies is an important cause of viral encephalitis. Other regional causes are Rift Valley fever virus in Africa and the Middle East, arenaviruses (Junin, Guanarito, Sabiá, Lassa, and Machupo) in Latin America and Africa, Marburg and Ebola viruses in Africa, Colorado tick fever virus in North America, and Murray Valley encephalitis virus in Australia.
Postinfectious encephalomyelitis most commonly follows measles, vaccinia, varicella, rubella, mumps, and influenza. Guillain–Barré syndrome, a sensorimotor polyneuropathy (see Chapter 24.16), has been associated with infections by EBV, cytomegalovirus (CMV), coxsackievirus B, and HZV. The decreasingly used nervous tissue vaccines for rabies may give rise to postvaccinal encephalomyelitis (see below), whereas immunization against influenza, rabies, hepatitis B, measles, and poliomyelitis has been complicated by Guillain–Barré syndrome.
Immunodeficient patients are particularly vulnerable to some viral infections. Those with depressed cell-mediated immunity (Hodgkin’s disease) may develop HZV encephalitis, and CMV may cause a subacute encephalitis in patients with AIDS. In children or adults with hypogammaglobulinaemia, enteroviruses, including live-attenuated polio vaccine, may produce a progressive and fatal meningoencephalitis. Progressive multifocal leucoencephalopathy, a chronic and fatal papovavirus infection in patients with impaired cell-mediated immunity, is described below. HIV infection of the brain and meninges may be responsible for acute meningoencephalitis at the time of seroconversion and for subacute chronic encephalopathies and dementia in patients with AIDS.
Many viral infections of the central nervous system (CNS) occur in seasonal peaks or as epidemics, whereas others, such as herpes simplex encephalitis, are sporadic. Epidemics of JE occur in the summer or rainy season in northern India, Nepal, northern Thailand, Korea, Taiwan, and China. However, in southern Vietnam, Indonesia, Malaysia, southern India, and the Philippines the disease can occur all the year round, although the peak is at the start of the rainy season. This variation in the incidence of disease is an important consideration when recommending immunization. In endemic areas it is mostly a disease of children, but as the disease spreads to new regions, or nonimmune travellers visit endemic regions, nonimmune adults are also affected. The major vector is Culex tritaeniorhynchus mosquitoes that have been infected by first feeding on the bird (cattle egrets, herons) or mammal reservoir species. Indigenous children and nonimmune (immigrant) adults are most susceptible. Euro-Siberian tick-borne encephalitidese occur in spring and early summer when the ticks are most active but can also be acquired by drinking unpasteurized dairy products, especially goat’s milk. Mumps encephalitis is most common in the late winter or early spring, whereas enterovirus infections occur most often in the summer and early autumn. Rodent-related encephalitides, such as the arenaviruses, are most common when the rodent population is at its peak, either in the fields (Machupo and Junin viruses) or in the home (lymphocytic choriomeningitis virus). Zoonotic viral infections, such as Rift Valley fever, survive periods of cold weather, during which the invertebrate–vertebrate cycle is suspended by ‘overwintering’ in their arthropod vectors (e.g. in the bottom of dried-up ponds) or hibernating vertebrate reservoirs. Rabies, the classic zoonosis (see Chapter 7.5.10), occurs sporadically or in microepidemics although, in Europe, historically the greatest risk of dogs becoming mad with rabies was believed to be associated with the hot weather, the ‘dog days’, when Sirius the dog star was in the ascendant (20 July to 15August).
Invasion of the CNS seems to be a rare event in most viral infections. In the case of some infections, such as JE, there may be only 1 case of encephalitis for every 300 to 500 asymptomatic infections. Eastern equine encephalitis virus produces a much higher proportion of encephalitic cases than other togaviruses.
Infections by many neurotropic viruses are most frequent and severe in children and older people. Herpes simplex encephalitis affects all age groups but shows peaks of incidence in those aged between 5 and 30 years and over 50 years. When HSV-2 invades the CNS it is likely to cause a benign lymphocytic meningitis in adults, but in neonates it usually produces a severe encephalitis. Among mosquito-borne epidemic encephalitides, California encephalitis and JE are most common in children, St Louis and West Nile encephalitis in older people, whereas eastern and western equine encephalitis affect both very young and older people. Postinfectious encephalitis is most frequent in children, because it complicates the common childhood exanthematous viral infections. It is the most common demyelinating disease in the world.
Most viral infections reach the CNS from the primary site of infection and multiplication via the bloodstream, but the rabies virus enters peripheral nerves through acetylcholine and other receptors and travels to the CNS in axoplasm, employing the microtubular dynein motor system. Viruses inoculated through the skin include those transmitted by arthropods, rabies virus, herpes simplex virus, herpesvirus simiae (B virus), and lymphocytic choriomeningitis virus. Arthropod-borne viruses are presumed to replicate in local lymph nodes, the vascular endothelium, and circulating fixed macrophages, in order to sustain viraemia. Rabies virus may multiply locally in the cytoplasm of muscle cells before entering peripheral nerves. Viruses that enter through the respiratory tract (e.g. measles, mumps, varicella) or gut (enteroviruses) multiply in local lymphoid tissue before entering the bloodstream. Viraemia is a feature of most viral infections, yet invasion of the CNS is rare in most cases. The explanation for this is not known, but the CNS contains a number of intrinsic physical barriers to infectious agents such as viruses. These include the blood–brain barrier with its ‘tight junctions’, virus-resistant cells, and the absence of lymphatic drainage. Nonspecific mechanisms at or near the site of virus entry, such as gastric acidity and cilia in the respiratory tract, also play a protective role. In the case of rabies, HSV, and HZV, the virus enters the CNS through the peripheral nerves. Although the subarachnoid space surrounding the olfactory nerves projects through the cribriform plate and is directly beneath the nasal mucosa, this route of infection seems to be extremely rare in humans and has been proven only in a few cases of inhaled rabies virus infection and herpes simplex encephalitis. Viruses have been inoculated directly into the CNS by infected corneal transplant grafts (rabies) and prions through infected brain-surface electrodes (Creutzfeldt–Jakob disease). Herpes simplex encephalitis may complicate primary HSV infection in children and young adults, but in most cases of herpes simplex encephalitis the cause is thought to be reactivation of latent virus (HSV-1) in the trigeminal nerve, autonomic nerve roots, or brain.
Some viruses, such as the enteroviruses and mumps, usually infect the meninges rather than the parenchyma of the CNS, whereas others, such as the togaviruses, usually cause encephalitis. Different neural cells are selectively vulnerable to different neurotropic viruses. Examples are the predilection of polioviruses for motor neurons of the anterior horns of the spinal cord, and of rabies for neurons of the limbic system and cerebellar Purkinje cells. The pathological effects of viral infections on the CNS include:
- ◆ the destruction and phagocytosis of neurons (neuronophagia) as a result of either viral invasion itself or immune lysis
- ◆ demyelination
- ◆ inflammatory oedema with the compressive effects of raised intracranial pressure
- ◆ in some cases, vascular lesions
In rabies, a universally fatal encephalitis, neuronolysis is relatively mild. However, rabies virus may interfere with neurotransmission at central and peripheral synapses. It also produces severe systemic effects, following its centrifugal spread (e.g. myocarditis and cardiac arrhythmias) or its focal effects on vasomotor and respiratory centres in the brainstem and in the temporal lobes and amygdala (compare Klüver–Bucy syndrome) (see Chapter 7.5.10).
Postinfectious encephalitis and the Guillain–Barré syndrome are thought to result from sensitization to central and peripheral myelin, respectively. The animal model for the former is experimental allergic encephalomyelitis, which can be produced in a variety of animals after immunization with myelin basic protein. A similar animal model for Guillain–Barré syndrome is known as experimental allergic neuritis. It is uncertain how the preceding viral infection induces this autoimmune response. In the case of postvaccinal encephalomyelitis resulting from old-fashioned nervous tissue antirabies vaccines containing homogenized animal brain, the mechanism is still not clear. The antimyelin basic protein is not always present and is probably not the direct cause of demyelination.
The host’s immune responses to viruses play a crucial role in combating infection. They may be directed against either the virus particle or the virus-infected cell, and may be humorally or cell mediated. An important local immune response at infected surfaces is provided by IgA antibody, which is present in secretions in the gut, saliva, and respiratory tract. This is important, for example, in the early stages of poliovirus infection where the antibody neutralizes the virus by combining with viral surface proteins. The systemic viral infection may also be limited by means of circulating IgG and IgM antibodies, which can neutralize the virus in a variety of different ways. Immune responses may also occur locally within the CNS, where local synthesis of immunoglobulins in response to virus infection, sometimes in an oligoclonal pattern, may be evident. Such antibody elevations may be of considerable diagnostic value (see below). Under certain conditions immune responses to viruses may themselves set in train immunopathological processes leading to disease. This may occur in a number of different ways, such as through the deposition in blood vessels of immune complexes formed between an antiviral antibody and viral antigen. In other cases, such as lymphocytic choriomeningitis virus infection, the induction of virus-specific cytotoxic T lymphocytes is itself responsible for the production of encephalitis.
The basal leptomeninges, ependyma, and choroid plexus are infiltrated with mononuclear cells but the parenchyma is normal. In mumps meningitis there may be exfoliation of ependymal cells.
Virus is distributed widely throughout the brain and spinal cord, possibly even in nonparalytic cases, but usually the only cells to suffer chromatolysis and phagocytosis are motor neurons in the anterior horns of the spinal cord, medulla, and grey matter of the precentral gyrus.
Most viral encephalitides are characterized by lymphocytic infiltration of the meninges and perivascular cuffing (in the Virchow–Robin spaces) in the cortex and underlying white matter, by lymphocytes, plasma cells, histiocytes, and some neutrophils, and proliferation of microglia with the formation of glial nodules. Neuronolysis and demyelination are variable in their degree and location. Infected neurons may show characteristic inclusion bodies in their nuclei (measles, HSV, and adenoviruses) or cytoplasm (Negri’s bodies in rabies). Microhaemorrhages and foci of necrosis may be found.
Herpes simplex encephalitis
Characteristic features of this condition are gross cerebral oedema and severe haemorrhagic and necrotizing encephalitis, which is often asymmetrically localized to the inferior and medial parts of the temporal lobe, the insula, and the orbital part of the frontal lobe. Histological sections show eosinophilic Cowdry type A intranuclear inclusions with margination of chromatin in neurons, oligodendrocytes, and astrocytes, inflammatory and haemorrhagic perivascular reactions, but no demyelination. Cowdry type A inclusions are also found in HZV and CMV encephalitides. The unique cerebral localization of herpes simplex encephalitis has not been satisfactorily explained, but is probably the result of viral spread along specific neural pathways rather than a differential susceptibility of particular cell populations. A popular idea is that HSV spreads along olfactory pathways to the base of the brain and temporal lobes, but it is also possible that virus may spread from the trigeminal ganglia through sensory fibres innervating the dura near these regions. This latter mechanism is consistent with the discovery of latent HSV-1 in the trigeminal, superior cervical, and vagal ganglia in a high proportion of normal individuals, irrespective of whether they have a history of mucocutaneous herpes infections (‘cold sores’). Latent HSV-1 might be reactivated by a variety of stimuli, such as sunlight, fever, trauma, and stress; however, the actual mechanisms underlying its latency and reactivation in the nervous system are not yet fully understood. If herpes simplex encephalitis is caused by the reactivation of latent virus, its rarity, despite ubiquitous asymptomatic infection in humans, is hard to explain.
Microscopic appearances are typical of other viral encephalitides: there is oedema, congestion, and focal haemorrhages of the brain and meninges, and perivascular cuffing, neuronophagia, and glial nodules of the brain parenchyma. Neuronolysis and neuronophagia are unusually widespread in the thalamus, basal ganglia, brainstem, cerebellum (where there is marked destruction of Purkinje’s cells), and the spinal cord. Viral antigen is localized to neurons, especially in the brainstem, thalamus, and basal ganglia.
Nipah virus encephalitis
Pathological studies on the brains of fatal cases demonstrated that the endothelium of small blood vessels in the CNS was particularly susceptible to infection. This led to disseminated endothelial damage and syncytium formation, vasculitis, thrombosis, ischaemia, and microinfarction. There was also evidence of neuronal infection by the virus that may have contributed to neurological dysfunction.
West Nile virus encephalitis
Pathological changes include varying degrees of neuronal necrosis in the grey matter, with infiltrates of microglia and polymorphonuclear leucocytes, perivascular cuffing, neuronal degeneration, and neuronophagia. Viral antigens were demonstrated in neurons and in areas of necrosis. No antigen was detected in other major organs, including lung, liver, spleen, and kidney. The major pathological lesions were seen in the brainstem and spinal cord.
There is severe perivascular cuffing, parenchymal inflammation, and neuronophagia in the spinal cord, brainstem, and diencephalon, and in focal areas in the cerebellum and cerebrum. Although no viral inclusions were detected, immunohistochemistry showed viral antigen in the neuronal cytoplasm. Inflammation was often more extensive than neuronal infection, suggesting that other indirect factors may be involved in tissue damage in addition to the effects of direct viral invasion.
A feverish illness accompanied by myalgia, headache, and fatigue develops 4 to 28 days after the tick bite. Between 1 and 33 days later, about one-third of the patients will develop meningitis, meningoencephalomyelitis, myelitis, or meningoradiculitis.
A prodromal influenza-like illness, followed by a brief remission of symptoms, is typical of lymphocytic choriomeningitis viral infection, and some outbreaks of enteroviral meningitis (e.g. echovirus 9), but in most cases of viral meningitis symptoms start suddenly. There is usually fever, headache, change in conscious level, and occasionally a stiff neck, and vomiting, especially in children. Nausea, anorexia, abdominal pain, myalgias, and sore throat are particularly common in enteroviral meningitis. Myalgia is particularly severe with coxsackievirus B infections. As in acute bacterial meningitis, infants usually present with vague irritability and a tense fontanelle, and young children with fever and irritability or lethargy. Conjunctival injection, pharyngitis, and cervical lymphadenopathy may be found. Macular or petechial exanthems or enanthemas are seen with coxsackievirus A and B and echovirus infections (especially echovirus 9). Vesicles on the hands, feet, and mouth have been reported with coxsackievirus A16 and enterovirus 71 infections. By definition, the level of consciousness is normal in simple meningitis. Neurological features include vertigo, nystagmus, cerebellar ataxia, facial spasms, and involuntary movements.
The specific cause of viral meningitis may be suggested by characteristic signs outside the nervous system, such as genital or rectal vesicles in the sexually active age group (HSV-2), HZV skin lesions, swelling in the parotid region (mumps, and occasionally coxsackie-, lymphocytic choriomeningitis, and EBV), orchitis (mumps and lymphocytic choriomeningitis virus), and arthritis (lymphocytic choriomeningitis virus). However, potentially helpful features, such as gastrointestinal symptoms associated with enteroviral infections and parotitis associated with mumps, may be completely absent in patients with meningitis.
Mollaret’s meningitis (benign recurrent aseptic meningitis or benign recurrent lymphocytic meningitis)
This is a sporadic condition presenting between the ages of 5 and 60 years. The symptoms are typical of acute meningitis—malaise, fever, vomiting, neck stiffness, convulsions, and coma. There is complete spontaneous recovery, usually within a few days, and symptom-free intervals lasting from a few days to years. About half the patients develop other neurological disturbances including hallucinations, diplopia, cranial nerve lesions, and signs of an upper motor neuron lesion. Pleocytosis is usually less than 3000/µl, with a predominance of lymphocytes, monocytes, and large endothelial (Mollaret’s) cells, but occasionally neutrophils are in the majority. The protein level in cerebrospinal fluid is mildly increased, with increased gammaglobulin. The cerebrospinal fluid glucose concentration may be decreased. HSV-2 and HSV-1, human herpesvirus 6, and EBV have been implicated by polymerase chain reaction (PCR) detection. However, some argue that the term ‘Mollaret’s meningitis’ should be restricted to idiopathic recurrent aseptic meningitis.
Differential diagnosis of recurrent meningitis
An important differential diagnosis is recurrent purulent meningitis that is often attributable to a congenital or traumatic defect providing access to the subarachnoid space, such as congenital occult spina bifida or fracture of the base of the skull. A cerebrospinal fluid leak may be apparent in about 50% of the cases with post-traumatic recurrent meningitis. The head trauma may have occurred many years earlier and a connection with the subarachnoid space may be clinically inapparent. Rarely, recurrent meningitis may arise from episodes of recurrent sepsis of a parameningeal focus (e.g. sinusitis or mastoiditis) or from a complement deficiency. Deficiency in a number of the components of the complement pathway has been detected in patients with recurrent meningitis. Neisseria meningitidis meningitis caused consecutively by different serogroups is the usual presentation in these cases.
Other causes of recurrent meningitis include Behçet’s syndrome, Vogt–Koyanagi–Harada syndrome, sarcoidosis, and systemic lupus erythematosus, and undiagnosed viral meningitis (e.g. that due to encephalomyocarditis virus).
Poliomyelitis is acquired by droplet spread from the respiratory tract or by the faecal–oral route. The ‘minor illness’, coinciding with viraemia, is a nonspecific episode of influenza-like symptoms—fever, headache, sore throat, malaise, and mild gastrointestinal symptoms—which resolves in a few days. Most of those infected have no further symptoms but, in a minority, the ‘major illness’ follows, sometimes after a few days’ remission of symptoms. The features are those of viral meningitis: muscle pain, spasms, and sensory disturbances may precede or accompany the development of lower motor neuron (flaccid) paralysis. Any combination of motor unit deficits may be seen. Respiratory and bulbar paralysis is life threatening. Encephalitis is rare. The most common causes of death are aspiration and airway obstruction, resulting from bulbar paralysis and paralysis of respiratory muscles. Disturbances of respiratory and cardiac rhythm, thought to be the result of damage to medullary vasomotor and respiratory centres, are extremely uncommon. Other complications include impaired control of body temperature and blood pressure, gastrointestinal haemorrhage, aspiration pneumonia, and paralysis of the bladder and bowel.
Most patients with viral encephalitis present with the symptoms of meningitis (fever, headache, neck stiffness, vomiting), followed by altered consciousness, convulsions, and sometimes focal neurological signs, signs of raised intracranial pressure, or psychiatric symptoms.
Herpes simplex encephalitis
This relatively common sporadic encephalitis may occur in any age group. In neonates, it is caused by HSV-2.
As well as the usual clinical features of severe viral encephalitis, patients with herpes simplex encephalitis have symptoms related to the focal nature of the encephalitis (frontal and temporal cortex and limbic system). These include behavioural abnormalities, olfactory and gustatory hallucinations, anosmia, amnesia, expressive aphasia, and temporal lobe seizures. Herpetic skin or mucosal lesions are rarely found, except in the case of acute genital HSV-2 infection, or proctitis, and a past history of ‘cold sores’ does not affect the chances of the infection being due to HSV. Most deaths occur within the first 2 weeks.
After an incubation period of 7 to 14 days, patients develop nonspecific prodromal symptoms (fever, headache, malaise, and nausea) lasting 2 to 3 days. Neurological symptoms begin with headache, deteriorating level of consciousness, and generalized convulsions, which may result in status epilepticus. Fever persists for 6 to 7 days and, in survivors, neurological symptoms may persist for several weeks. Parkinsonian and extrapyramidal features occur frequently and choreoathetoid movement disorders or severe dystonias can last for many months. The case fatality rate is 30% in those admitted to hospital. Most deaths occur in the first 7 to 10 days from respiratory failure, aspiration pneumonias, intracranial hypertension, and uncontrolled seizures. Up to 50% of survivors suffer from intellectual impairment, psychiatric problems, persistent epilepsy, or a vegetative state with spastic quadriparesis and evidence of basal ganglia involvement, such as dystonia of the limbs and trunk, rigidity, and tremor.
Nipah virus encephalitis
The main clinical features of Nipah virus encephalitis are fever, headache, dizziness, reduced consciousness, and prominent brainstem dysfunction. Distinctive signs included myoclonus, areflexia, hypotonia, hypertension, and tachycardia, suggesting extensive brainstem and spinal cord involvement. MRI during the acute illness shows widespread focal lesions in subcortical and deep white matter and, to a lesser extent, in grey matter on T2-weighted sequences. Long-term sequelae are common in Nipah encephalitis.
West Nile virus encephalitis
The most common clinical features are encephalitis, meningitis, fever, weakness, and headache following an incubation period of 3 to 15 days. Infection usually results in an acute febrile episode with no CNS involvement. In unusual cases or, as in the United States of America, when the virus is introduced into a naïve population, the incidence of encephalitis rises particularly in older people. An erythematous rash of the neck, trunk, and limbs is present in 20% of cases. Patients over 50 years of age were most at risk of developing encephalitis, but all age groups are affected in endemic areas. Muscle weakness, areflexia, and diffuse flaccid paralysis in association with an axonal polyneuropathy were also reported. MRI of the brain demonstrated enhancement of the meninges and periventricular areas. There is no specific treatment.
As the goal of poliomyelitis eradication appears more achievable, another enterovirus is emerging as a significant cause of acute neurological disease in Asia. Enterovirus 71 (EV71) was first recognized in 1969 and is responsible for a variety of clinical manifestations, including: hand, foot, and mouth disease; aseptic meningitis; meningoencephalitis; and acute flaccid paralysis. In an outbreak of hand, foot, and mouth disease in Malaysia, a number of young children developed fatal encephalomyelitis, dying within a few hours of presentation with cardiovascular instability and severe pulmonary oedema. Postmortem examination in four cases revealed major involvement of the brainstem and spinal cord, with EV71 being isolated from brain tissue in all cases; there was no apparent cardiac pathology and the virus was not isolated from the myocardium. Molecular characterization of these four viruses and others isolated concurrently suggest that at least two potentially virulent EV71 strains were circulating during the outbreak. An adenovirus was also thought to have complicated the infection in 60% of the children dying with a similar clinical picture. It is possible that coinfection with the two viruses may have resulted in severe disease.
Sudden convulsions, coma, fever, or pareses appear 10 to 14 days after the start of immunization (vaccinia or nervous tissue rabies vaccine) or after infection with measles, varicella, rubella, mumps, or influenza. In the case of measles, varicella, and rubella, encephalitic symptoms develop 2 to 12 days after the rash has appeared, and in mumps before or after parotid swelling. Involuntary movements, cranial nerve lesions (VII and III), pupillary abnormalities, nystagmus, ataxia, and upper motor neuron signs are common.
Clinical and epidemiological details
The time of year, known current epidemics, the patient’s age, occupation, animal contacts, and countries or states visited recently may help to narrow down the possibilities. A specific diagnosis may be suggested by distinctive clinical features of the encephalitis itself (e.g. hydrophobia in rabies, temporal lobe features in herpes simplex encephalitis) or of the associated infection (e.g. mumps parotitis, measles rash, skin and mucosal lesions of herpesviruses, and gastrointestinal symptoms associated with enteroviral infections).
These should aim to demonstrate a specific viral agent (particularly important for the potentially treatable herpesvirus infections) or exclude potentially treatable nonviral causes of meningitis or encephalomyelitis. The most important investigation is examination of the cerebrospinal fluid. Contraindications to lumbar puncture are the same as for acute bacterial meningitis. If there are lateralizing neurological signs or evidence of raised intracranial pressure, a CT or MRI scan should be performed to exclude an intracranial mass lesion before contemplating a lumbar puncture. Cerebrospinal fluid pressure is especially increased in herpes simplex encephalitis, where there is intense cerebral oedema. Pleocytosis ranges from tens to thousands of cells per microlitre. Lymphocytes and other mononuclear cells predominate, except in the early stages of some infections (e.g. enteroviruses, herpes simplex encephalitis). The cerebrospinal fluid contains erythrocytes or is xanthochromic in haemorrhagic encephalitides such as herpes simplex encephalitis and acute necrotic leucoencephalitis. Protein concentration is usually increased in the range of 50 to 150 mg/dl with an increasing proportion of IgG as the disease progresses. Leakage of serum IgG into the cerebrospinal fluid and intrathecal IgG synthesis, indicated by a monoclonal band, are responsible. Cerebrospinal fluid glucose concentration is usually normal or increased towards the level in a blood sample taken simultaneously, but low levels are occasionally reported, especially in mumps and lymphocytic choriomeningitis virus infections. Cerebrospinal fluid examination may be misleading if it is normal: as it is at the first examination in 10 to 15% of patients with herpes simplex encephalitis; if there is a predominantly neutrophil pleocytosis; or if the glucose concentration is low.
|Table 1 Causes of aseptic meningitis,a with or without encephalitis or myelitis, other than viruses and postinfectious/postvaccinal syndromes|
|Cause||Diagnostic clinical feature or investigation|
|Acute bacterial meningitis (partially treated)||CSF antigen detection (CIE, LA), repeated CSF examination|
|Intracranial/spinal abscess or empyema (parameningeal infections)||Physical examination (exclude otitis media, trauma, dermoid sinus, etc.), radiographs, CT/MRI, myelogram|
|Brucella spp.||CSF, blood culture, serology|
|Cat-scratch disease bacillus||Warthin–Starry stain of skin and lymph nodes, skin test|
|Mycobacteria||CSF microscopy, LA, culture; Mantoux test, chest radiograph|
|Mycoplasma spp.||CSF and serum IgM (IFA)|
|Relapsing fevers||Blood smear, mouse inoculation|
|Lyme disease||Serology (EIA, IFA), culture, skin biopsy, CSF IgG (EIA IFT)|
|Syphilis||Serology (FTA-abs test) serum and CSF|
|Spirillum minus||Microscopy of wound or lymph-node aspirates, mouse inoculation|
|(Rocky Mountain spotted fever, murine, epidemic, scrub typhus)||Serology (Weil–Felix), skin biopsy IFT (RMSF)|
|Blastomyces spp.||CSF culture, EIA, demonstration at other sites, lung, skin, biopsy|
|Candida spp.||CSF culture (repeated)|
|Coccidioides spp.||CSF CFT, culture, microscopy|
|Cryptococcus spp.||CSF India ink, LA—beware false positive with surface condensate on agar|
|Histoplasma spp.||CSF culture (repeated), demonstration at other sites, blood smear (buffy coat) serum, urine, CSF antigen detection (RIA)|
|Amoeba (Acanthamoeba spp., Naegleria spp., Balamuthia spp.)||CSF microscopy (fresh wet preparation + India ink), culture|
|Malaria (cerebral)||Blood smears|
|Toxoplasma spp.||(Immunocompromised patients—AIDS) CSF animal inoculation, serology, brain biopsy|
|Trypanosomiasis (African and South American)||Blood smear (buffy coat), lymph node aspirate, CSF microscopy, and IgM, serology, xenodiagnosis|
|Angiostrongylus cantonensis||CSF larvae, eosinophilia|
|Cysticercosis||CT/MRI, radiographs, examination for subcutaneous cysts, CSF CFT, histology|
|Gnathostoma spinigerum||Cutaneous migratory swelling, CSF eosinophilia|
|Hydatid disease||Casoni test, serology, CT/MR scan, radiographs|
|Paragonimus spp.||CSF ova, eosinophils, serology, CT/MR scan or skull radiograph, histology|
|Schistosomiasis||Low transverse myelitis, ova in urine or stool, CT/MRI, CSF eosinophilia, myelogram, histology|
|Sparganosis||Histology, CT/MR scan|
|Strongyloides stercoralis||(Immunocompromised patients) larvae, ova in stool, duodenal fluid, etc.|
|Behçet’s syndrome||Clinical syndrome|
|Carcinomas, cysts, leukaemias, lymphomas||CSF cytology, evidence of condition elsewhere|
|Chemical||Recent lumbar puncture, spinal anaesthesia, myelography, isotope cisternography|
|Drugs||Nonsteroidal anti-inflammatory agents immunomodulators, antimicrobials (e.g. trimethoprim)|
|Kawasaki’s disease||Clinical features, echocardiography, coronary angiography, etc.|
|Lead encephalopathy||Blood lead, blood smear, urinary coproporphyrins|
|Mollaret’s meningitis||Recurrence, CSF ‘Mollaret’s’ cells (PCR for HSV)|
|Sarcoidosis||Histology, Kveim’s test, Mantoux test, serum Ca2+, ACE|
|Systemic lupus erythematosus and other collagen/vascular diseases||Antinuclear antibodies, DNA antibodies, lupus erythematosus cells|
|Vogt–Koyanagi–Harada syndrome||Clinical syndrome|
|Whipple’s disease||Clinical features, jejunal histology|
a Aseptic meningitis: CSF pleocytosis but no bacteria stainable by Gram’s method and no growth on standard bacterial culture media.
ACE, angiotensin-converting enzyme; CFT, complement fixation test; CIE, countercurrent immunoelectrophoresis; CSF, cerebrospinal fluid; EIA, enzyme immunoassay; FTA-abs, fixed treponema antibody absorption test; HSV, herpes simplex virus; IFA, immunofluorescent antibody; LA, latex agglutination; PCR, polymerase chain reaction; RIA, radioimmunoassay; RMSF, Rocky Mountain spotted fever.
Full laboratory resources allow a specific virus to be implicated in 70 to 75% of cases of lymphocytic meningitis and in 30 to 40% of patients with meningoencephalitis (Table 2). At appropriate stages of the illness, a rapid diagnosis by direct immunofluorescence may be made of HSV (skin and brain), HZV (skin lesion scrapings), rabies (skin sections and brain), measles (nasopharyngeal aspirate), and some nonviral causes such as Rocky Mountain spotted fever (skin). Electron microscopy of skin lesions will identify a herpesvirus. Some viruses can be isolated from the cerebrospinal fluid (e.g. mumps, enteroviruses, lymphocytic choriomeningitis virus, central European encephalitides, louping ill, and HIV). Virus cultured from a distant site may help with the diagnosis (e.g. polio and other enteroviruses from stool, or arthropod-borne viruses from blood culture), but they may not be related to the neurological symptoms (e.g. CMV from the pharynx or urine, HSV from skin or mucosa, or adenovirus seen in stool by electron microscopy). Specific viral IgM can be detected in serum for mumps, EBV, CMV, or measles, or using a µ-capture technique in the cerebrospinal fluid for JE virus. This method is being used increasingly to detect IgM to other viruses. The viraemia associated with JE is very brief and isolation from cerebrospinal fluid difficult. Virus can occasionally be isolated from postmortem material. A viral diagnosis is often delayed until a rising convalescent antibody titre is found by an appropriate technique. This is usually the case for mumps, coxsackieviruses, and most arthropod-borne viruses.
An important diagnostic advance has been the introduction of PCR technology for the routine diagnosis of a viral infection of the CNS. PCR greatly amplifies the amount of viral nucleic acid in the test sample, enabling the identification of HSV in the cerebrospinal fluid of suspected cases of herpes simplex encephalitis within a short time of the onset of symptoms. PCR is now the investigation of choice for the rapid diagnosis of HSV encephalitis, having a sensitivity of 95% and a specificity of 100%. The application of microchip and real-time PCR technology may further aid the rapid diagnosis of encephalitis. It is hoped that molecular techniques may aid the early diagnosis of a greater variety of CNS viral infections in the future (Table 2).
|Table 2 Specimens for the virological diagnosis of acute meningitis or meningoencephalomyelitis|
|Virus||Specimens for virus isolation/identification||Serology|
|Throat swab||Stool||CSF||Blood||Other specimens||PCR CSF||Acute||Convalescent|
|Lymphocytic choriomeningitis||–||–||+++||+||?b||+||+2–3 months|
|Coxsackievirus and echovirusesf||+||+++||+++||–||+||+|
|Type 2||–||–||+||–||Vesicular fluid||+||+a||+|
|Herpesvirus simiae (B)||–||–||–||–||Vesicular fluid||–||+a||+|
|Herpes varicella-zoster||–||–||+||–||Vesicular fluid||+b||+a||+|
|Rabies||–||–||+||–||Skin biopsy, saliva, brain||+||+||+|
CSF, cerebrospinal fluid; HTLV, human T-lymphotropic virus; PCR, polymerase chain reaction.
a Isolations or antibody responses may represent non-specific activation
b Too few data to indicate general usefulness in diagnosis
c Also serum/blood
d Also stool
e Also brain tissue
f Some Coxsackie A serotypes (especially A1–6) cannot be grown on cells.
For the rapid diagnosis of viral encephalitides such as progressive multifocal leucoencephalopathy there is still no substitute for brain biopsy, but few would regard this inherently risky procedure as being justified. Electroencephalography (EEG), CT or MRI, angiography, or technetium scans can help to direct the surgeon towards the affected area of brain.
Imaging of the brain and spinal cord
MRI of the brain and spinal cord can be extremely useful for the diagnosis of the site, nature, and extent of mass lesions and associated oedema, sub- and epidural empyemas, meningitis, cerebritis, and ventriculitis, the presence of intracranial hypertension, hydrocephalus, cerebral and brainstem herniation, demyelination, and other anatomical abnormalities).
Some viral encephalitides do have characteristic lesions on MRI. Some 94% of patients with HSV have high-signal T 2-hyperintense lesions in the medial and inferior temporal regions, and JE is associated with characteristic lesions in the basal ganglia. More discrete high-signal intensity 2- to 7-mm lesions, particularly in the subcortical and deep white matter of the cerebral hemispheres, have been associated with Nipah virus infection. However, these classic descriptions often overlap and the general features of oedema, infarction, and high signal on the T 2-weighted images are commonly seen in a variety of viral infections of the CNS.
Viral infections of the CNS must be distinguished from the many other conditions that produce similar clinical features and cerebrospinal fluid abnormalities (see Table 1). The differential diagnosis of viral meningitis includes the other causes of aseptic meningitis, such as partially treated bacterial meningitis, tuberculous meningitis, spirochaetal infections (leptospirosis, borreliosis, Lyme disease, and syphilis), and fungal, amoebic, neoplastic, granulomatous, and idiopathic meningitides. Viral myelitides must be distinguished from other causes of transverse myelitis and the Brown–Séquard syndrome. These include spinal compression by tumours, abscesses, helminths or their ova, or vertebral disease.
The differential diagnosis of paralytic poliomyelitis includes: postinfectious and other immunopathic polyneuroradiculopathies, such as Guillain–Barré syndrome and Landry’s ascending paralysis; metabolic neuropathies such as acute porphyria; paralytic rabies; neoplastic polyradiculopathies; and rarities, such as tick paralysis and herpesvirus simiae (B virus) infection. The lack of objective sensory loss in poliomyelitis usually distinguishes it from these other entities.
The differential diagnosis of viral encephalitis includes other infective encephalopathies: bacterial, fungal, protozoal, and parasitic; intracranial abscesses and neoplasms; toxic and metabolic encephalopathies; and heat stroke. The diagnosis of ‘viral encephalitis’ should not be made too hastily, because it may condemn the patient with concealed cerebral malaria or some other curable encephalopathy to delayed treatment or even death.
Aciclovir is effective in treating herpes simplex encephalitis. In view of the remarkable lack of serious toxicity of aciclovir, treatment can be started as soon as herpes simplex encephalitis is suspected clinically. Therapy with aciclovir should be started immediately on suspicion of encephalitis. Aciclovir is also the treatment for CNS associated V2V infections. There is no convincing evidence for its efficacy in CMV infections of the CNS. For CMV infections garciclovir or toscarnet should be considered. The rare, but very dangerous, encephalomyelitis caused by herpesvirus simiae B should be treated with aciclovir. Ribavirin is effective against some RNA viruses, such as those causing Lassa fever, haemorrhagic fever with renal syndrome, and possibly Argentine haemorrhagic fever, Rift Valley fever, and Congo Crimean haemorrhagic fever.
Interferons have been used by intravenous, intrathecal, or intraventricular routes in the treatment of JE, rabies, HZV, and other herpesvirus encephalitides, but have not proved effective.
Hyperimmune plasma given within 8 days of the start of symptoms has reduced the mortality rate of Argentine haemorrhagic fever (Junin virus) from between 20% and 30% to 1% and 3%. Hyperimmune human globulin has also proved effective in the treatment of Congo Crimean haemorrhagic fever. It is widely used in Asia for the treatment of enterovirus 71, although evidence from randomized controlled trials is lacking.
Corticosteroids have been used in the treatment of most of the viral encephalomyelitides, both in an attempt to combat cerebral oedema (especially in herpes simplex encephalitis) and for their other anti-inflammatory effects. Convincing evidence of benefit from controlled trials is lacking, but the immunosuppressive effects of corticosteroids have not led to obvious clinical deterioration. Corticosteroids or ACTH has also been used for postinfectious and postvaccinal encephalomyelitides, but the evidence for their efficacy is not convincing and, as they may exacerbate latent rabies in experimental animals, should be used only in life-threatening cases of rabies postvaccinal encephalomyelitis. Severe intracranial hypertension should be treated with intravenous mannitol or mechanical hyperventilation. Nursing and general care are the same as for acute bacterial meningitis and tuberculous meningitis. Seizures should be controlled with phenytoin or phenobarbital, fever lowered by cooling, respiratory failure treated by mechanical ventilation, and attention given to fluid, electrolyte, and acid–base balance. Hyponatraemia is attributable to inappropriate secretion of antidiuretic hormone in some cases.
Prognosis and sequelae
Viral meningitis has an excellent prognosis, but some patients with HSV-2 infection have recurrent attacks with spinal cord or nerve root involvement. Case fatality rates of some viral encephalomyelitides are as follows: rabies 100%; herpes simplex encephalitis (untreated) 40 to more than 75% (highest in neonates and those over 30 years old); eastern equine encephalitis 50%; JE 10 to 40%; measles 10 to 20%; varicella 10 to 30%; western equine encephalitis 8%; St Louis encephalitis 3%; California encephalitis, Venezuelan encephalitis, and mumps less than 1%. The mortality rate of paralytic poliomyelitis increases from 5% in young children to more than 20% in adults. Postinfectious and postvaccinal encephalomyelitides carry case fatality rates of 15 to 40%.
Neurological sequelae are found in 5 to 75% of survivors of JE and herpes simplex encephalitis, and are common in infants. They include intellectual impairment, loss of memory, speech abnormalities (including subtle expressive aphasias), hemiparesis, ataxia, dystonic brainstem and cranial nerve lesions, recurrent convulsions, and various behavioural and personality disturbances. Sequelae are common with postinfectious encephalomyelitis. An unusual sequel to paralytic poliomyelitis developing after an interval of many years is a condition characterized by progressive muscle weakness and wasting, attributable to depletion of anterior horn cells, which has some similarities to motor neuron disease.
Prophylactic immunization against poliomyelitis and measles has virtually eradicated encephalitides caused by these viruses in many communities. Postexposure rabies immunization has also proved effective in preventing rabies encephalitis, and tissue-culture rabies vaccines are used increasingly for pre-exposure prophylaxis. A formalin-inactivated, adult mouse-brain vaccine is manufactured in Osaka for JE. It is effective and carries a very low risk of objective neurological complications (one in a million courses). An alternative live-attenuated vaccine, SA 14-14-2, has been developed in China, and has been shown to be both safe and effective in over 200 million Chinese and Indian children. Promising future vaccine candidates are currently being evaluated in nonhuman primate models, including a chimaeric live-attenuated JEV/yellow fever virus combination and two poxvirus-vectored recombinant JE vaccines. Travellers to endemic regions should be immunized.
Since the outbreak of West Nile infection in the United States of America, several vaccine candidates have already been identified and immune protection against infection demonstrated in several animal models: human trials have been planned. There have been no reports of such success against Nipah virus. Vaccines for use in humans have been prepared against a number of other arthropod-borne viruses (e.g. European tick-borne encephalitis).
Hyperimmune immunoglobulin has been used for prophylaxis (and in some cases attempted treatment) of measles, HZV, HSV-2, vaccinia, and rabies, and some other infections in high-risk groups. Immunocompromised patients, such as those with leukaemia, who are household contacts of a case of HZV infection, should be given prophylactic hyperimmune globulin and, if they develop skin lesions, they should be treated with aciclovir to prevent the development of severe disease.
Interferons have been used with some success to prevent herpesvirus infections, e.g. CMV in high-risk groups such as renal transplant recipients. However, the evidence does not yet justify their recommendation.
Caesarean section before rupture of the membranes in a full-term pregnant woman with genital herpes may prevent HSV-2 encephalitis in the neonate. If the herpetic lesions are discovered during or after vaginal delivery, topical aciclovir should be applied to the eyes of the neonate, as they are the most likely portal of entry.
Arthropod-borne viral encephalitides can be prevented by avoiding or controlling the arthropod vectors (e.g. by the use of mosquito nets, insect repellents, insecticides), by attempting to control the numbers of wild vertebrate reservoir species, or by immunizing domestic animals, such as horses (eastern and western equine encephalitides) and pigs (JE). To control rabies, the principal wild mammalian vectors can be immunized (e.g. wild foxes, racoons, and black-backed jackals have been immunized by distributing oral vaccine in bait). Domestic dogs and cats should be immunized. To prevent the viral encephalitides transmissible from laboratory animals (e.g. lymphocytic choriomeningitis from mice and rats, herpesvirus simiae b from monkeys) their screening, quarantine, handling, and housing should be strictly controlled.
Reye’s syndrome is an acute encephalopathy affecting children between the ages of 2 and 16 years. It is rapidly fatal in 10 to 40% of cases. The defining characteristics are sudden impairment of consciousness, increase in serum aminotransferase concentrations (or, if a biopsy is done, a fatty liver), and the exclusion of other diseases. Symptoms develop a few days after varicella or an upper respiratory tract or gastrointestinal illness. Clusters of cases (median age 11 years) have been associated with influenza B epidemics, although sporadic cases (median age 6 years) have followed varicella, coxsackievirus, dengue, and other viral infections. Studies in the United States of America have demonstrated an association between Reye’s syndrome and the use of salicylates, but not of paracetamol, during the preceding viral illness. This has led the United Kingdom Committee on Safety of Medicines to recommend that aspirin should not be given to children under 12 years of age, unless specifically indicated for childhood rheumatic conditions. Aflatoxin has been implicated in Thailand. In the United States of America, the annual incidence of Reye’s syndrome in those under 18 years old is 0.42 per 100 000 urban dwellers and 1.8 per 100 000 rural and suburban dwellers.
The child is nauseated and retches or vomits for 1 or 2 days before becoming confused or comatose and requiring admission to hospital. Most are afebrile and have hepatosplenomegaly but no jaundice at presentation. Fever develops later. The cerebrospinal fluid is usually normal or contains a few mononuclear cells. Irritability, extreme agitation, aggression, and delirium are succeeded by coma and death in 2 to 3 days. Decorticate and decerebrate posturing and convulsions may be partly attributable to hypoglycaemia, which occurs in most cases. There is rapid neurological deterioration with loss of pupillary and oculovestibular reflexes, evidence of increased intracranial pressure, deepening coma, and death. Neurological sequelae are common in survivors. Blood ammonia is increased in almost all cases. The characteristic histological abnormality is fatty droplets in the liver cells. Mitochondrial abnormalities, but no inflammatory changes, have also been seen in neurons and hepatocytes.
The differential diagnosis includes inborn errors of metabolism, acute hepatic encephalopathy, especially associated with poisoning, infective encephalopathies such as cerebral malaria (usually distinguishable by a positive blood smear), or bacterial, viral, and fungal meningoencephalitides (distinguished by characteristic cerebrospinal fluid abnormalities).
There is no specific treatment, but mortality can be reduced by treating hypoglycaemia, cerebral oedema, respiratory failure, fluid and electrolyte disturbances, and other complications.
Other viral infections or disorders in which viruses play a role in the pathogenesis of neurological disease
Subacute sclerosing panencephalitis
This disorder is a form of subacute encephalitis affecting children and young adults due to persistent infection with the measles virus. The cumbersome title, usually abbreviated to SSPE, is derived from the conditions formerly known as subacute sclerosing leucoencephalitis and inclusion-body encephalitis, now known to be the same disease.
An infective cause was long suspected and there is now conclusive evidence to incriminate the measles virus. Measles virus antibody titres are extremely high in the blood and cerebrospinal fluid, measles antigen has been demonstrated in the brain, and the virus has sometimes been isolated, but only with difficulty. Most affected children have had measles at an unusually early age and there is a mean interval of some 6 years between infection and the onset of encephalitis. The disease can occur in children immunized with live measles virus, but the risk is much lower than that following the natural disease.
The measles virus in subacute sclerosing panencephalitis appears to be incomplete, as the matrix (M) protein required to attach the nucleocapsid to the cytoplasmic membrane before budding is deficient or absent. It is not known whether the absence of M protein from the brain is the result of an abnormality of the virus or of the host, and, if the latter, whether inborn or acquired. Current thought is that, during the long symptom-free interval between infection and appearance of disease, viral material accumulates, eventually leading to cell damage. The paradox of high antimeasles antibodies, except against M protein, and persistent virus has not been explained. The comparatively early age of clinical measles in affected children, often below the age of 2 years, suggests that the immature immune system permits entry and persistence of the virus in the brain.
As its name implies, both grey matter and white matter show the changes of encephalitis, with perivascular cuffing and more diffuse cellular infiltration, neuronal loss, and myelin destruction, with variable glial scarring or sclerosis. Acidophilic nuclear inclusion bodies are never profuse and may not be detected. No visceral lesions are found.
In the great majority, the onset is in the first two decades, but young adults may also be affected. The disease is twice as common in boys as in girls. Incidence has fallen sharply in countries where measles immunization is at a high level; the annual incidence in England and Wales has fallen from 20 to around 5. Subacute sclerosing panencephalitis remains relatively common in parts of eastern Europe, Egypt, and the Lebanon. No convincing predisposing factors have been identified and, in particular, immunosuppressed children are not at special risk but they may occasionally develop acute measles inclusion-body encephalitis.
The speed of onset is extremely variable, but there is usually a prolonged period of altered behaviour, mild intellectual deterioration, and loss of energy and interest, often misinterpreted as sloth or neurosis. After some weeks or months increasing clumsiness or the appearance of focal neurological symptoms draws attention to the organic nature of the disease. Periodic involuntary movements then appear, the most common form being myoclonus, consisting of a stereotyped jerk or lapse of posture involving the limbs, often asymmetrically, occurring every 3 to 6 s. The myoclonus may result in sudden falls, which are occasionally the presenting symptom. Visual signs may be prominent, with papilloedema, retinitis, optic atrophy, or cortical blindness. Choroidoretinal scarring is present in 30% of cases. In other cases the onset is relatively abrupt with no recognizable prodromal stage. There is no fever or other evidence of systemic infection.
Further progression is marked by intellectual deterioration, rigidity and spasticity, and increasing helplessness. Some 40% of patients die within a year, but a similar proportion survive for more than 2 years. A period of apparent arrest is common and in some patients, particularly at the upper end of the age range, substantial remission and prolonged survival occur. Even in such cases there may be radiological evidence of continued cerebral damage and it is probable that the disease is always eventually fatal.
There is no significant pleocytosis in the cerebrospinal fluid and total protein is not increased, but there is evidence of intrathecal synthesis of immunoglobulin and oligoclonal bands of IgG. Although the measles antibody titres in blood and cerebrospinal fluid are usually raised to high levels, occasionally they overlap control values. In established disease, the EEG shows highly characteristic periodic discharges, synchronous with the myoclonus, but persisting in the absence of the movements. The CT scan shows low-density, white-matter lesions and cerebral atrophy.
There is no effective treatment for subacute sclerosing panencephalitis. Isoprinosine 100 mg/kg daily by mouth, in divided, doses possibly prolongs survival, particularly in older patients with disease of slow onset, but adequately controlled trials are naturally difficult to mount. Interferon given by intraventricular catheter has been reported to induce partial remission.
Progressive multifocal leucoencephalopathy
This disease is caused by opportunistic infection by papovaviruses, most commonly JC virus and the simian virus SV40. A high proportion of normal adults have antibodies to the former and the agent appears to be ubiquitous. The reservoir of SV40 is in monkeys and the agent was apparently transmitted in early types of poliomyelitis vaccine, without evident ill-effects. These viruses are potentially oncogenic, but are nonpathogenic for humans unless of the immune system has been compromised.
Progressive multifocal leucoencephalopathy thus occurs in patients already affected by such conditions as lympho- or myeloproliferative diseases, sarcoidosis, and other chronic granulomatous diseases, or, more recently, AIDS, and also in those who are therapeutically immunosuppressed. Most patients are aged over 50 years but, with the spread of AIDS, younger people are being affected, with a male preponderance, and the disease is no longer rare.
The virus particularly invades the nuclei of the oligodendroglia and, as a result, there is demyelination of the white matter of the cerebral hemisphere, spreading from numerous foci. The cerebellum and brainstem are less often involved and the spinal cord is spared. Abnormal giant forms of oligodendrocytes with eosinophilic inclusions are seen microscopically, and arrays of intranuclear virus particles can often be identified by electron microscopy. JC virus antigen can be identified by immunofluorescence or immunohistochemistry. DNA probing has revealed unintegrated virus in oligodendrocytes, astrocytes, endothelial cells, and extraneural organs such as kidney, liver, lung, spleen, and lymph nodes.
The onset is usually with progressive signs of a focal lesion of one cerebral hemisphere, limb weakness, aphasia, or visual field defects such as homonymous hemianopia. More widespread signs gradually develop, leading to personality changes, intellectual deterioration, dysarthria or fluent aphasia, and bilateral weakness. Fits are rare. There is no systemic evidence of infection. Spontaneous temporary arrest or partial remission is common but eventual progression causes death in 6 to 12 months, although far more chronic cases are on record, with survival, exceptionally, to 5 years.
The cerebrospinal fluid is normal apart from occasionally a mild elevation of protein and slight pleocytosis, and is not under increased pressure. The EEG shows a bilateral excess of slow activity. The CT scan may at first show little abnormality, but eventually large, non-enhancing, low-density lesions appear in the cerebral white matter. MRI is more sensitive. Serum antibodies are of no diagnostic help but the response in the cerebrospinal fluid has not been fully evaluated. The diagnosis can be confirmed only by cerebral biopsy, but it is essential that white matter be included in the specimen. This may be important to distinguish lymphoma and, rarely, herpes simplex encephalitis involving white matter.
No treatment is of proven value, but cytosine arabinoside has sometimes appeared to induce partial remission.
Progressive rubella panencephalitis
This extremely rare disorder may follow congenital rubella or rubella in early childhood. It evolves insidiously some 10 years after the original illness and is characterized by progressive intellectual impairment with behaviour changes, fits, ataxia, spasticity, optic atrophy, and macular degeneration. Pathological changes are those of encephalitis with perivascular infiltration. The cerebrospinal fluid may show a slight rise in white cell and protein content, elevation of gammaglobulin and of antirubella antibodies to an extent greater than the rise in the serum level, suggesting local production of antibody within the CNS. The EEG may show changes similar to those seen in subacute sclerosing panencephalitis due to measles virus. The mechanism responsible for the appearance of this disorder is unknown and there is no effective treatment.
The cause of this rare syndrome is thought to be an inflammatory autoimmune reaction to an unidentified viral infection. The disorder affects tissues having a common embryological origin, the uvea and leptomeninges and the melanoblasts, ocular pigments, and auditory labyrinth pigments originating from the neural crest. The dermatological features consist of patchy whitening of eyelashes, eyebrows and scalp hair, alopecia, and vitiligo. Neurological manifestations include meningoencephalitis, raised intracranial pressure, neurosensory deafness, tinnitus, nystagmus, ataxia, ocular palsies, and focal cerebral deficits. Ocular features are those of uveitis with pain and photophobia, more generalized inflammation of the eye, retinopathy, and impaired visual acuity. The condition tends to be self-limiting but may result in serious permanent ocular and neurological deficits. Steroids and immunosuppressive drugs have been used and are said to arrest the progression of at least some features of the disorder.
Viral causes of psychiatric illness
Mental changes are common in patients with encephalitis. Influenza, infectious mononucleosis, and infectious hepatitis are sometimes followed by psychiatric sequelae, in particular a depressive reaction. Psychosis after encephalitis lethargica has been reported on occasions. Chronic fatigue syndrome has been attributed to viral encephalitis.
Acute disseminated encephalomyelitis and Behçet’s syndrome