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Influenza virus and CNS manifestations
Journal of Clinical Virology 28 (2003) 225 /232 www.elsevier.com/locate/jcv
Influenza virus and CNS manifestations M. Studahl * ¨ stra SE-41685 Go Department of Infectious Diseases, Sahlgrenska University Hospital/O ¨ teborg, Sweden Received 13 March 2003; received in revised form 26 March 2003; accepted 29 April 2003
Abstract Neurological involvement during influenza infection has been described during epidemics and is often consistent with serious sequelae or death. An increasing incidence of influenza-associated encephalitis/encephalopathy has been reported in Japan, mainly in children. A variety of other clinical CNS manifestations, such as Reye’s syndrome, acute necrotising encephalopathy (ANE), and myelitis as well as autoimmune conditions, such as Guillain-Barre’s syndrome, may occur during the course of influenza infection. Virological diagnosis is essential and based on virusisolation, antigen detection, RNA detection by PCR, and serological analyses. Neuroimaging with CT and MRI of the brain are of prognostic value. The pathogenic mechanisms behind the influenza CNS complications are unknown. The treatment is symptomatic, with control of vital functions in the intensive care unit, antiepileptic medication and treatment against brain oedema. # 2003 Published by Elsevier B.V. Keywords: Influenza; CNS; Encephalitis; Encephalopathy; Reye’s syndrome; Diagnosis; Prognosis; Treatment
1. Virology and epidemiology of influenza Influenza viruses are important human pathogens that throughout history have caused epidemics and pandemics. Both Influenza A and B are associated with high mortality and morbidity, although Influenza B does not cause pandemics due to its antigenic stability (Nguyen-Van-Tam, 1998). New pandemic strains of Influenza A, to which the population lacks immunity, emerge either by acquisition of new gene segments in cells simultaneously infected by a human and an animal influenza A virus, or by direct transmission of an * Tel.: /46-31-343-4000; fax: /46-31-84-7813. E-mail address: [email protected] (M. Studahl). 1386-6532/03/$ - see front matter # 2003 Published by Elsevier B.V. doi:10.1016/S1386-6532(03)00119-7
animal strain to humans. The various subtypes of influenza present with new combinations of the surface glycoproteins haemagglutines (HA) (H1 / H15) and neuraminidases (NA) (N1 /N9). Historically, these antigenic shifts have resulted in pandemics every 10 /40 years (Webster et al., 1992). Epidemics on a smaller scale occur yearly or every few years and are caused by minor changes in antigenicity of influenza virus (antigenic drift) by amino acid changes in the surface antigen (HA and NA) due to point mutations of the genome. It has been suggested that Influenza A H3N2 generates more severe illness than Influenza A H1N1 and that the illness caused by influenza B is intermediate in severity (Hayden and Palese, 1997).
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2. Clinical features of influenza The spectrum of influenza may range from asymptomatic infection or mild to severe respiratory tract infection to systemic disease (‘‘flu’’) with abrupt onset of fever. The incubation period is 1/5 days. The illness, with fever and cough, sore throat, headache, anorexia, and myalgia affecting the back and limbs, may last for 1/5 days. Children often present with non-specific symptoms such as vomiting, diarrhoea in addition to high fever, cough and rhinorrhea. Paediatric influenza may provoke febrile convulsions, and give rise to otitis media and pneumonia and sometimes croup (Brocklebank et al., 1972; Price et al., 1976; Peltola et al., 2003). Symptoms in neonates are lethargy, poor feeding, apnea, and interstitial pneumonia (Meibalane et al., 1977). Complications of influenza especially affect certain risk groups, such as patients with chronic heart and lung disease, the elderly, transplant recipients, smokers, children with underlying medical conditions, and pregnant women. Viral and bacterial pneumonia are frequent complications, whereas myositis, myoglobulinuria and renal failure, myocarditis, and CNS symptoms develop more rarely. The most common causes of death are respiratory complications or cardiovascular diseases.
3. CNS manifestations CNS involvement during influenza includes a variety of syndromes, more often described in children than in adults (Nicholson, 1998). The major clinical entities are encephalitis or encephalopathy. In etiological studies of encephalitis, Influenza A and/or B have been identified in up to 8.5% of adult patients with positive virological findings (Koskiniemi et al., 2001) and in up to 10% of paediatric cases (Kolski et al., 1998). Reye’s syndrome and acute necrotising encephalopathy (ANE) are special forms of encephalopathies with high mortality and sequelae. More rare conditions are myelitis caused by influenza virus (Salonen et al., 1997) and, even more seldom, autoimmune
diseases elicited by influenza such as GuillainBarre’s syndrome (Jacobs et al., 1998). Historically, Encephalitis lethargica (EL) was associated with the 1918 /1920 influenza pandemics (von Economo, 1931), but a recent study has failed to detect the genome of influenza from archival brain specimens (McCall et al., 2001). During the decades following the isolations of influenza A, B and C viruses in the 1930 /1940 (Nicholson, 1998) and especially during the Asian influenza in 1957 /1958, cases of CNS complications were reported in association with influenza virus infection (Flewett and Hoult, 1958; Horner, 1958). 3.1. Reye’s syndrome Reye’s syndrome is characterised by non-inflammatory encephalopathy with rapid onset of lowered consciousness, vomiting, convulsions, and cerebral oedema in association with hepatic fatty infiltration. It affects children and adolescents (Reye et al., 1963). Influenza A, or more often B, infection and varicella as well as other viral infections may precede Reye’s syndrome (Norman et al., 1968; Hall et al., 1969; Corey et al., 1976). A decrease in incidence has been noted during the last 20 years, which may be partly related to the avoidance of giving acetylsalicylic acid to children with viral illness. Reye’s syndrome is diagnosed by means of exclusion, and a plasma ammonia or serum aspartate or serum aminotransferases more than three-times above the normal limit is required if liver pathology is not shown (Belay et al., 1999). The liver pathology seen in Reye’s syndrome is compatible with a hepatotoxic picture caused by mitochondrial failure (Pessayre et al., 1999). The CSF is normal. CT scan of the brain may show diffuse brain swelling but usually no focal lesions. The pathogenesis of the CNS symptoms in Reye’s syndrome is not fully understood, but a nonpermissive influenza virus infection of cerebral capillary endothelial cells has been discussed on the basis of findings in experimental mice models (Davis et al., 2000). Factors associated with high mortality are deep coma on admission, increased intracranial pressure, and high blood ammonia levels. The mortal-
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ity is up to 40 /50% of hospitalised patents, and survivors often develop neurological sequelae (Corey et al., 1977). The treatment of Reye’s syndrome is intensive supportive care with control of intracranial pressure. 3.2. Influenza encephalitis/encephalopathy and acute nectrotising encephalopathy (ANE) Encephalitis and encephalopathy are not always distinguishable from each other (Davis, 2000), and there is probably a continuum and/or an overlap between these clinical syndromes, including the more severe condition acute nectrotising encephalopathy (Yoshikawa et al., 2001). Influenza A is most frequently reported, especially H3N2 and H1N1, although Influenza B is associated with encephalitis/encephalopathy as well. The onset of neurological symptoms is usually within a few days to a week after the first signs of influenza infection (Table 1). Fever, decreased consciousness, and seizures are common symptoms, and among the less common are focal neurological signs such as paresis, aphasia, cranial nerve palsies and choreoathetosis (Hattori et al., 1983; Protheroe and Mellor, 1991; Ryan et al., 1999). Encephalitis/encephalopathy is most frequently reported in children although adults cases
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are described (Mihara et al., 2001; Rose and Prabhakar, 1982; Kurita et al., 2001; Hakoda and Nakatani, 2000). Reports of influenza virus-associated encephalitis/encephalopathy with high fatality rate, especially among children, have increased in Japan (Okabe et al., 2000) with estimates of about 200 patients during 1998/1999 and 100 during 1999 / 2000 (Okabe, personal communication, 2001). The children, mainly B/6 years, present with high fever, convulsions and impaired consciousness often leading to coma within 24 h (Yoshikawa et al., 2001). The mortality is approximately 30%, and the risk of neurological sequelae is high (Sugaya, 2002). ANE, which is found in a minor part of cases, is characterised by a fulminant and monophasic course, with multifocal brain lesions in the bilateral thalami, brainstem, periventricular white matter, and cerebellar medulla, often associated with brain oedema (see Fig. 1 described in Studahl et al. manuscript). Influenza, as well as other viral infections, may elicit this condition. ANE has been reported mostly from Japan (Mizuguchi et al., 1995), but a few European cases have also been described (Protheroe and Mellor, 1991; Voudris et al., 2001; Studahl et al., manuscript).
Table 1 Characteristics of patient with influenza-associated encephalitis/encephalopathy with normal contra pathological radiologic findings Number of Age, mean (med- CSF lekocytes/ml, cases ian, range) mean (median, (years) range) Normal CT/MRI of 15 the brain Pathological CT/ 25 MRI of the brain
Onset of neurological symptoms Outcome after ‘‘flu’’/days mean (median, range)
22.5 (31, 2 /50)
15 (2, 0 /73)
3.6 (3, 0 /7)
5.2 (3, 0.9 /14)
38.8 (2, 0 /318)
3.7 (2, 0 /20)
Nine recovered, five sequel, one N.D. Six recovered, ten sequelea, four deaths, five N.D.
N.D., no data. Influenza infections are virologically verified by positive PCR or virusisolation from CSF, and/or significant titerrise in serum, and/or virus isolated from nasopharynx/throat, and/or intrathecally produced antibodies against influenza. Data abstracted from Delorme and Middleton, 1979; Sulkava et al., 1981; Rose and Prabhakar, 1982; Hattori et al., 1983; Hawkins et al., 1987; Protheroe and Mellor, 1991; Fujii et al., 1992; Nagai et al., 1993; Kimura et al., 1995; Hayase and Tobita, 1997; Kimura et al., 1998; Ryan et al., 1999; McCullers et al., 1999; Shinjoh et al., 2000; Fujimoto et al., 2000; Tsuchiya et al., 2000; Hakoda and Nakatani, 2000; Sugaya, 2000; Yokota et al., 2000; Tokunaga et al., 2000; Munakata et al., 2000; Mihara et al., 2001; Voudris et al., 2001. a Three mild, seven severe.
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3.3. Pathogenesis of influenza encephalitis/ encephalopathy The pathogenic mechanisms of the various neurological syndromes during influenza infection in humans are largely unknown. Influenza replicates in the respiratory tract and is more seldom isolated from the brain (Frankova et al., 1977; Flewett and Hoult, 1958; Kapila et al., 1958). However, detection of influenza virus (Paisley et al., 1978; Okabe et al., 2000) or viral RNA in the CSF (Fujimoto et al., 1998; Togashi et al., 2000) has indicated penetration of virus into the CNS. Although most viral infections are thought to spread to the brain hematogenously (Johnson and Mims, 1968), this route has been doubted in influenza encephalitis/encephalopathy since viremia is sparsely reported in humans, where it has been found only during the incubation period and initial stage of disease (Stanley and Jackson, 1969; Khakpour et al., 1969; Xu et al., 1998). The neuronal pathway, shown in animal models via the olfactory and trigeminal nerve system (Reinacher et al., 1983), may be favoured by the free nerve endings near the influenza-infected epithelial cells in the upper respiratory tract (Mori and Kimura, 2001). Different routes of virus entry to the brain, studied experimentally in mice, are linked to infection of different cells and regions of the CNS (Reinacher et al., 1983) and might result in diverse clinical pictures and neuroimaging findings. Influenza infection in ependymal cells, positive for virus antigen by immune staining, has been shown in a post-mortem study of immunosuppressed patients (Frankova et al., 1977). The hypothesis of a vascular endothelial infection (Ito et al., 1999) is supported by studies on mice, where wild influenza strains replicate primarily in ependymal cells in the CNS (Johnson and Mims, 1968). However, a limited direct invasion of neurons is not excluded. Virus-antigen positivity has been shown in Purkinjecells in the cerebellum and in several neurons in the pontine nuclei in a 2-yearold girl who died from influenza encephalopathy (Takahashi et al., 2000). Another hypothesis has recently suggested that cytokine release from virus-stimulated glial cells may be responsible for
a neurotoxic effect on the brain and a rapid breakdown of the blood /brain-barrier (Yokota et al., 2000). Autopsy studies of patients with CNS complications associated with influenza are generally scarce. Fatal cases with brain pathology have shown congestion and hyperemia of the brain without inflammatory cell infiltration (Flewett and Hoult, 1958; Takahashi et al., 2000; Frankova et al., 1977; Oseasohn et al., 1959), and in rare cases demyelination (Horner, 1958; Flewett and Hoult, 1958) and neuron degeneration (Kapila et al., 1958).
4. Diagnosis of CNS infection The suspicion of CNS infection is ascertained by neuroimaging with MRI/CT of the brain, EEG pathology, and virological analyses of CSF (Table 2). 4.1. CT and MRI of the brain and electroencephalogram (EEG) Neuroimaging findings on CT or MRI may be normal initially, but pathological changes can develop after a few days of neurological symptoms (Kimura et al., 1998). The neuroimaging pictures include diffuse involvement of cerebral cortex and subcortical white matter with various localisations or symmetrical involvement of the thalamus and Table 2 Diagnosis of influenza CNS infection MRI/CT of the brain EEG Lumbar puncture Cells, glucose, lactate, protein Virusisolation cell culture on green monkey kidney cells (GMK) RT-PCR influenza Blood samples Serological analyses (ELISA, IF, KB, HI) (acute and convalescent sera 14 /21 days later) ( /4-fold or greater titre rise of specific IgG is required) Throat or nasopharyngeal swabs or nasal washings Rapid antigen detection by IF or ELISA Virusisolation
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lesions in brain stem, basal ganglia, and cerebellar white matter with or without brain oedema (Kimura et al., 1998). Diffusion-weighted imaging (DWI) may demonstrate lesions more clearly than conventional MRI (Tokunaga et al., 2000; Tsuchiya et al., 2000). Electroencephalogram (EEG) is usually nonspecific with pathological, diffuse slowing of brain waves consistent with encephalitis/encephalopathy (Flewett and Hoult, 1958; Protheroe and Mellor, 1991; Hattori et al., 1983; Delorme and Middleton, 1979; Sulkava et al., 1981; Rose and Prabhakar, 1982). 4.2. CSF findings In influenza virus-associated encephalopathy or encephalitis CSF analyses will often reveal a lack of pleocytosis or merely a discrete elevation of mononuclear leukocytes. Protein and glucose content are usually normal, although a slightly increased protein level may be present. 4.3. Virological analyses Virological analyses are essential for the diagnosis of CNS complications of influenza and a prerequisite for expanding the knowledge in the field. Positive CSF virusisolation is rarely reported (Paisley et al., 1978; Okabe et al., 2000), maybe because the virus has disappeared by the time of sampling or because CSF may contain low amounts of virus. Furthermore, virus isolations from the CSF might not be widely performed. RTPCR analyses with detection of influenza virus Aand B-specific RNA fragments in CSF/brain specimens have been documented in cases with a rapid onset of encephalitis/encephalopathy after 1 /2 days of influenza infection (Fujimoto et al., 1998; Ito et al., 1999; McCullers et al., 1999; Togashi et al., 2000; Takahashi et al., 2000; Okabe et al., 2000). Virus isolation or antigen detection from nasopharyngeal aspirates and/or throat/ bronchial washing are complementary analyses, which are especially valuable in cases where lumbar puncture is contraindicated. Analysis by serology (haemagglutination inhibition (HI), enzyme immunoassay (EIA), complement fixation (CF) or neutralisation tests (NT)), showing sig-
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nificant titre rise between acute and convalescent sera may indicate that influenza has elicited the concurrent CNS disease. Detection of intrathecally produced antibodies against influenza in diagnostics has not been evaluated in studies (Salonen et al., 1997; Fujimoto et al., 2000).
5. Prognosis The outcome in encephalitis/encephalopathy depends mainly on age and presence of CT/MRI pathology. Neuroimaging studies in influenza encephalitis/encephalopathy reveal that patients with pathological CT/MRI are significantly younger and have more severe sequelae or fatal disease in comparison with patients with normal CT/MRI, the majority of whom recover or have mild sequelae (Table 1). However, severe sequelae such as choreoathetosis, altered personality, spastic quadriparesis, and persistent vegetative state may occur also in cases with normal imaging findings (Rose and Prabhakar, 1982; Ryan et al., 1999; Hakoda and Nakatani, 2000). A diffuse severe brain oedema is associated with severe brain damage or death (Yokota et al., 2000).
6. Treatment The therapy in CNS complications of influenza is supportive with supervision of vital functions in the intensive care unit including control of intracranial pressure, antiepileptic treatment against seizures, and treatment against brain oedema. Mild hypothermia (34 /35 8C) therapy has been tried for suppressing brain oedema (Yokota et al., 2000; Munakata et al., 2000) in addition to corticosteroid treatment. Whether antiviral treatment in CNS complications of influenza may have beneficial effect is unknown. Oral administration of amantadine, an antiviral compound with effect against Influenza A infection, and good bioavailability (Tominack and Hayden, 1989), as well as efficient penetration into the CSF (Kornhuber et al., 1995), has been used experimentally in single cases (Munakata et al., 2000; Sugaya, 2000). Prevention with older drugs (amantadine, riman-
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tadine), newer drugs (zanamivir, oseltamivir) or immunisations is associated with reduction in numbers of deaths from influenza-related complications (Long et al., 2000; Anon, 1998), but none of these therapies has so far been scientifically documented as playing a protective role in CNS syndromes.
7. Conclusions CNS complications during influenza virus infection are diverse, and the pathogenesis is mostly unknown. The phenomenon of frequent reports of influenza-associated encephalitis/encephalopathy from Japan, and infrequent reports from other parts of the world is puzzling. Virological analyses with virusisolation or detection of viral RNA by PCR from the CSF and respiratory tract, antigen detection, and serological analyses are important for establishing the diagnosis of influenza virus infection. Increased knowledge of host-virus interaction in the brain during influenza infection, necropsy studies of cases with CNS involvement as well as controlled treatment studies with antiviral agents are warranted.
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Influenza virus and CNS manifestations M. Studahl * ¨ stra SE-41685 Go Department of Infectious Diseases, Sahlgrenska University Hospital/O ¨ teborg, Sweden Received 13 March 2003; received in revised form 26 March 2003; accepted 29 April 2003
Abstract Neurological involvement during influenza infection has been described during epidemics and is often consistent with serious sequelae or death. An increasing incidence of influenza-associated encephalitis/encephalopathy has been reported in Japan, mainly in children. A variety of other clinical CNS manifestations, such as Reye’s syndrome, acute necrotising encephalopathy (ANE), and myelitis as well as autoimmune conditions, such as Guillain-Barre’s syndrome, may occur during the course of influenza infection. Virological diagnosis is essential and based on virusisolation, antigen detection, RNA detection by PCR, and serological analyses. Neuroimaging with CT and MRI of the brain are of prognostic value. The pathogenic mechanisms behind the influenza CNS complications are unknown. The treatment is symptomatic, with control of vital functions in the intensive care unit, antiepileptic medication and treatment against brain oedema. # 2003 Published by Elsevier B.V. Keywords: Influenza; CNS; Encephalitis; Encephalopathy; Reye’s syndrome; Diagnosis; Prognosis; Treatment
1. Virology and epidemiology of influenza Influenza viruses are important human pathogens that throughout history have caused epidemics and pandemics. Both Influenza A and B are associated with high mortality and morbidity, although Influenza B does not cause pandemics due to its antigenic stability (Nguyen-Van-Tam, 1998). New pandemic strains of Influenza A, to which the population lacks immunity, emerge either by acquisition of new gene segments in cells simultaneously infected by a human and an animal influenza A virus, or by direct transmission of an * Tel.: /46-31-343-4000; fax: /46-31-84-7813. E-mail address: [email protected] (M. Studahl). 1386-6532/03/$ - see front matter # 2003 Published by Elsevier B.V. doi:10.1016/S1386-6532(03)00119-7
animal strain to humans. The various subtypes of influenza present with new combinations of the surface glycoproteins haemagglutines (HA) (H1 / H15) and neuraminidases (NA) (N1 /N9). Historically, these antigenic shifts have resulted in pandemics every 10 /40 years (Webster et al., 1992). Epidemics on a smaller scale occur yearly or every few years and are caused by minor changes in antigenicity of influenza virus (antigenic drift) by amino acid changes in the surface antigen (HA and NA) due to point mutations of the genome. It has been suggested that Influenza A H3N2 generates more severe illness than Influenza A H1N1 and that the illness caused by influenza B is intermediate in severity (Hayden and Palese, 1997).
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2. Clinical features of influenza The spectrum of influenza may range from asymptomatic infection or mild to severe respiratory tract infection to systemic disease (‘‘flu’’) with abrupt onset of fever. The incubation period is 1/5 days. The illness, with fever and cough, sore throat, headache, anorexia, and myalgia affecting the back and limbs, may last for 1/5 days. Children often present with non-specific symptoms such as vomiting, diarrhoea in addition to high fever, cough and rhinorrhea. Paediatric influenza may provoke febrile convulsions, and give rise to otitis media and pneumonia and sometimes croup (Brocklebank et al., 1972; Price et al., 1976; Peltola et al., 2003). Symptoms in neonates are lethargy, poor feeding, apnea, and interstitial pneumonia (Meibalane et al., 1977). Complications of influenza especially affect certain risk groups, such as patients with chronic heart and lung disease, the elderly, transplant recipients, smokers, children with underlying medical conditions, and pregnant women. Viral and bacterial pneumonia are frequent complications, whereas myositis, myoglobulinuria and renal failure, myocarditis, and CNS symptoms develop more rarely. The most common causes of death are respiratory complications or cardiovascular diseases.
3. CNS manifestations CNS involvement during influenza includes a variety of syndromes, more often described in children than in adults (Nicholson, 1998). The major clinical entities are encephalitis or encephalopathy. In etiological studies of encephalitis, Influenza A and/or B have been identified in up to 8.5% of adult patients with positive virological findings (Koskiniemi et al., 2001) and in up to 10% of paediatric cases (Kolski et al., 1998). Reye’s syndrome and acute necrotising encephalopathy (ANE) are special forms of encephalopathies with high mortality and sequelae. More rare conditions are myelitis caused by influenza virus (Salonen et al., 1997) and, even more seldom, autoimmune
diseases elicited by influenza such as GuillainBarre’s syndrome (Jacobs et al., 1998). Historically, Encephalitis lethargica (EL) was associated with the 1918 /1920 influenza pandemics (von Economo, 1931), but a recent study has failed to detect the genome of influenza from archival brain specimens (McCall et al., 2001). During the decades following the isolations of influenza A, B and C viruses in the 1930 /1940 (Nicholson, 1998) and especially during the Asian influenza in 1957 /1958, cases of CNS complications were reported in association with influenza virus infection (Flewett and Hoult, 1958; Horner, 1958). 3.1. Reye’s syndrome Reye’s syndrome is characterised by non-inflammatory encephalopathy with rapid onset of lowered consciousness, vomiting, convulsions, and cerebral oedema in association with hepatic fatty infiltration. It affects children and adolescents (Reye et al., 1963). Influenza A, or more often B, infection and varicella as well as other viral infections may precede Reye’s syndrome (Norman et al., 1968; Hall et al., 1969; Corey et al., 1976). A decrease in incidence has been noted during the last 20 years, which may be partly related to the avoidance of giving acetylsalicylic acid to children with viral illness. Reye’s syndrome is diagnosed by means of exclusion, and a plasma ammonia or serum aspartate or serum aminotransferases more than three-times above the normal limit is required if liver pathology is not shown (Belay et al., 1999). The liver pathology seen in Reye’s syndrome is compatible with a hepatotoxic picture caused by mitochondrial failure (Pessayre et al., 1999). The CSF is normal. CT scan of the brain may show diffuse brain swelling but usually no focal lesions. The pathogenesis of the CNS symptoms in Reye’s syndrome is not fully understood, but a nonpermissive influenza virus infection of cerebral capillary endothelial cells has been discussed on the basis of findings in experimental mice models (Davis et al., 2000). Factors associated with high mortality are deep coma on admission, increased intracranial pressure, and high blood ammonia levels. The mortal-
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ity is up to 40 /50% of hospitalised patents, and survivors often develop neurological sequelae (Corey et al., 1977). The treatment of Reye’s syndrome is intensive supportive care with control of intracranial pressure. 3.2. Influenza encephalitis/encephalopathy and acute nectrotising encephalopathy (ANE) Encephalitis and encephalopathy are not always distinguishable from each other (Davis, 2000), and there is probably a continuum and/or an overlap between these clinical syndromes, including the more severe condition acute nectrotising encephalopathy (Yoshikawa et al., 2001). Influenza A is most frequently reported, especially H3N2 and H1N1, although Influenza B is associated with encephalitis/encephalopathy as well. The onset of neurological symptoms is usually within a few days to a week after the first signs of influenza infection (Table 1). Fever, decreased consciousness, and seizures are common symptoms, and among the less common are focal neurological signs such as paresis, aphasia, cranial nerve palsies and choreoathetosis (Hattori et al., 1983; Protheroe and Mellor, 1991; Ryan et al., 1999). Encephalitis/encephalopathy is most frequently reported in children although adults cases
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are described (Mihara et al., 2001; Rose and Prabhakar, 1982; Kurita et al., 2001; Hakoda and Nakatani, 2000). Reports of influenza virus-associated encephalitis/encephalopathy with high fatality rate, especially among children, have increased in Japan (Okabe et al., 2000) with estimates of about 200 patients during 1998/1999 and 100 during 1999 / 2000 (Okabe, personal communication, 2001). The children, mainly B/6 years, present with high fever, convulsions and impaired consciousness often leading to coma within 24 h (Yoshikawa et al., 2001). The mortality is approximately 30%, and the risk of neurological sequelae is high (Sugaya, 2002). ANE, which is found in a minor part of cases, is characterised by a fulminant and monophasic course, with multifocal brain lesions in the bilateral thalami, brainstem, periventricular white matter, and cerebellar medulla, often associated with brain oedema (see Fig. 1 described in Studahl et al. manuscript). Influenza, as well as other viral infections, may elicit this condition. ANE has been reported mostly from Japan (Mizuguchi et al., 1995), but a few European cases have also been described (Protheroe and Mellor, 1991; Voudris et al., 2001; Studahl et al., manuscript).
Table 1 Characteristics of patient with influenza-associated encephalitis/encephalopathy with normal contra pathological radiologic findings Number of Age, mean (med- CSF lekocytes/ml, cases ian, range) mean (median, (years) range) Normal CT/MRI of 15 the brain Pathological CT/ 25 MRI of the brain
Onset of neurological symptoms Outcome after ‘‘flu’’/days mean (median, range)
22.5 (31, 2 /50)
15 (2, 0 /73)
3.6 (3, 0 /7)
5.2 (3, 0.9 /14)
38.8 (2, 0 /318)
3.7 (2, 0 /20)
Nine recovered, five sequel, one N.D. Six recovered, ten sequelea, four deaths, five N.D.
N.D., no data. Influenza infections are virologically verified by positive PCR or virusisolation from CSF, and/or significant titerrise in serum, and/or virus isolated from nasopharynx/throat, and/or intrathecally produced antibodies against influenza. Data abstracted from Delorme and Middleton, 1979; Sulkava et al., 1981; Rose and Prabhakar, 1982; Hattori et al., 1983; Hawkins et al., 1987; Protheroe and Mellor, 1991; Fujii et al., 1992; Nagai et al., 1993; Kimura et al., 1995; Hayase and Tobita, 1997; Kimura et al., 1998; Ryan et al., 1999; McCullers et al., 1999; Shinjoh et al., 2000; Fujimoto et al., 2000; Tsuchiya et al., 2000; Hakoda and Nakatani, 2000; Sugaya, 2000; Yokota et al., 2000; Tokunaga et al., 2000; Munakata et al., 2000; Mihara et al., 2001; Voudris et al., 2001. a Three mild, seven severe.
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3.3. Pathogenesis of influenza encephalitis/ encephalopathy The pathogenic mechanisms of the various neurological syndromes during influenza infection in humans are largely unknown. Influenza replicates in the respiratory tract and is more seldom isolated from the brain (Frankova et al., 1977; Flewett and Hoult, 1958; Kapila et al., 1958). However, detection of influenza virus (Paisley et al., 1978; Okabe et al., 2000) or viral RNA in the CSF (Fujimoto et al., 1998; Togashi et al., 2000) has indicated penetration of virus into the CNS. Although most viral infections are thought to spread to the brain hematogenously (Johnson and Mims, 1968), this route has been doubted in influenza encephalitis/encephalopathy since viremia is sparsely reported in humans, where it has been found only during the incubation period and initial stage of disease (Stanley and Jackson, 1969; Khakpour et al., 1969; Xu et al., 1998). The neuronal pathway, shown in animal models via the olfactory and trigeminal nerve system (Reinacher et al., 1983), may be favoured by the free nerve endings near the influenza-infected epithelial cells in the upper respiratory tract (Mori and Kimura, 2001). Different routes of virus entry to the brain, studied experimentally in mice, are linked to infection of different cells and regions of the CNS (Reinacher et al., 1983) and might result in diverse clinical pictures and neuroimaging findings. Influenza infection in ependymal cells, positive for virus antigen by immune staining, has been shown in a post-mortem study of immunosuppressed patients (Frankova et al., 1977). The hypothesis of a vascular endothelial infection (Ito et al., 1999) is supported by studies on mice, where wild influenza strains replicate primarily in ependymal cells in the CNS (Johnson and Mims, 1968). However, a limited direct invasion of neurons is not excluded. Virus-antigen positivity has been shown in Purkinjecells in the cerebellum and in several neurons in the pontine nuclei in a 2-yearold girl who died from influenza encephalopathy (Takahashi et al., 2000). Another hypothesis has recently suggested that cytokine release from virus-stimulated glial cells may be responsible for
a neurotoxic effect on the brain and a rapid breakdown of the blood /brain-barrier (Yokota et al., 2000). Autopsy studies of patients with CNS complications associated with influenza are generally scarce. Fatal cases with brain pathology have shown congestion and hyperemia of the brain without inflammatory cell infiltration (Flewett and Hoult, 1958; Takahashi et al., 2000; Frankova et al., 1977; Oseasohn et al., 1959), and in rare cases demyelination (Horner, 1958; Flewett and Hoult, 1958) and neuron degeneration (Kapila et al., 1958).
4. Diagnosis of CNS infection The suspicion of CNS infection is ascertained by neuroimaging with MRI/CT of the brain, EEG pathology, and virological analyses of CSF (Table 2). 4.1. CT and MRI of the brain and electroencephalogram (EEG) Neuroimaging findings on CT or MRI may be normal initially, but pathological changes can develop after a few days of neurological symptoms (Kimura et al., 1998). The neuroimaging pictures include diffuse involvement of cerebral cortex and subcortical white matter with various localisations or symmetrical involvement of the thalamus and Table 2 Diagnosis of influenza CNS infection MRI/CT of the brain EEG Lumbar puncture Cells, glucose, lactate, protein Virusisolation cell culture on green monkey kidney cells (GMK) RT-PCR influenza Blood samples Serological analyses (ELISA, IF, KB, HI) (acute and convalescent sera 14 /21 days later) ( /4-fold or greater titre rise of specific IgG is required) Throat or nasopharyngeal swabs or nasal washings Rapid antigen detection by IF or ELISA Virusisolation
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lesions in brain stem, basal ganglia, and cerebellar white matter with or without brain oedema (Kimura et al., 1998). Diffusion-weighted imaging (DWI) may demonstrate lesions more clearly than conventional MRI (Tokunaga et al., 2000; Tsuchiya et al., 2000). Electroencephalogram (EEG) is usually nonspecific with pathological, diffuse slowing of brain waves consistent with encephalitis/encephalopathy (Flewett and Hoult, 1958; Protheroe and Mellor, 1991; Hattori et al., 1983; Delorme and Middleton, 1979; Sulkava et al., 1981; Rose and Prabhakar, 1982). 4.2. CSF findings In influenza virus-associated encephalopathy or encephalitis CSF analyses will often reveal a lack of pleocytosis or merely a discrete elevation of mononuclear leukocytes. Protein and glucose content are usually normal, although a slightly increased protein level may be present. 4.3. Virological analyses Virological analyses are essential for the diagnosis of CNS complications of influenza and a prerequisite for expanding the knowledge in the field. Positive CSF virusisolation is rarely reported (Paisley et al., 1978; Okabe et al., 2000), maybe because the virus has disappeared by the time of sampling or because CSF may contain low amounts of virus. Furthermore, virus isolations from the CSF might not be widely performed. RTPCR analyses with detection of influenza virus Aand B-specific RNA fragments in CSF/brain specimens have been documented in cases with a rapid onset of encephalitis/encephalopathy after 1 /2 days of influenza infection (Fujimoto et al., 1998; Ito et al., 1999; McCullers et al., 1999; Togashi et al., 2000; Takahashi et al., 2000; Okabe et al., 2000). Virus isolation or antigen detection from nasopharyngeal aspirates and/or throat/ bronchial washing are complementary analyses, which are especially valuable in cases where lumbar puncture is contraindicated. Analysis by serology (haemagglutination inhibition (HI), enzyme immunoassay (EIA), complement fixation (CF) or neutralisation tests (NT)), showing sig-
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nificant titre rise between acute and convalescent sera may indicate that influenza has elicited the concurrent CNS disease. Detection of intrathecally produced antibodies against influenza in diagnostics has not been evaluated in studies (Salonen et al., 1997; Fujimoto et al., 2000).
5. Prognosis The outcome in encephalitis/encephalopathy depends mainly on age and presence of CT/MRI pathology. Neuroimaging studies in influenza encephalitis/encephalopathy reveal that patients with pathological CT/MRI are significantly younger and have more severe sequelae or fatal disease in comparison with patients with normal CT/MRI, the majority of whom recover or have mild sequelae (Table 1). However, severe sequelae such as choreoathetosis, altered personality, spastic quadriparesis, and persistent vegetative state may occur also in cases with normal imaging findings (Rose and Prabhakar, 1982; Ryan et al., 1999; Hakoda and Nakatani, 2000). A diffuse severe brain oedema is associated with severe brain damage or death (Yokota et al., 2000).
6. Treatment The therapy in CNS complications of influenza is supportive with supervision of vital functions in the intensive care unit including control of intracranial pressure, antiepileptic treatment against seizures, and treatment against brain oedema. Mild hypothermia (34 /35 8C) therapy has been tried for suppressing brain oedema (Yokota et al., 2000; Munakata et al., 2000) in addition to corticosteroid treatment. Whether antiviral treatment in CNS complications of influenza may have beneficial effect is unknown. Oral administration of amantadine, an antiviral compound with effect against Influenza A infection, and good bioavailability (Tominack and Hayden, 1989), as well as efficient penetration into the CSF (Kornhuber et al., 1995), has been used experimentally in single cases (Munakata et al., 2000; Sugaya, 2000). Prevention with older drugs (amantadine, riman-
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tadine), newer drugs (zanamivir, oseltamivir) or immunisations is associated with reduction in numbers of deaths from influenza-related complications (Long et al., 2000; Anon, 1998), but none of these therapies has so far been scientifically documented as playing a protective role in CNS syndromes.
7. Conclusions CNS complications during influenza virus infection are diverse, and the pathogenesis is mostly unknown. The phenomenon of frequent reports of influenza-associated encephalitis/encephalopathy from Japan, and infrequent reports from other parts of the world is puzzling. Virological analyses with virusisolation or detection of viral RNA by PCR from the CSF and respiratory tract, antigen detection, and serological analyses are important for establishing the diagnosis of influenza virus infection. Increased knowledge of host-virus interaction in the brain during influenza infection, necropsy studies of cases with CNS involvement as well as controlled treatment studies with antiviral agents are warranted.
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