The neuropsychiatric aspects of influenza/swine flu: A selective review

Abstract

The world witnessed the influenza virus during the seasonal epidemics and pandemics. The current strain of H1N1 (swine flu) pandemic is believed to be the legacy of the influenza pandemic (1918-19). The influenza virus has been implicated in many neuropsychiatric disorders. In view of the recent pandemic, it would be interesting to review the neuropsychiatric aspects of influenza, specifically swine flu. Author used popular search engine ‘PUBMED’ to search for published articles with different MeSH terms using Boolean operator (AND). Among these, a selective review of the published literature was done. Acute manifestations of swine flu varied from behavioral changes, fear of misdiagnosis during outbreak, neurological features like seizures, encephalopathy, encephalitis, transverse myelitis, aseptic meningitis, multiple sclerosis, and Guillian-Barre Syndrome. Among the chronic manifestations, schizophrenia, Parkinson's disease, mood disorder, dementia, and mental retardation have been hypothesized. Further research is required to understand the etiological hypothesis of the chronic manifestations of influenza. The author urges neuroscientists around the world to make use of the current swine flu pandemic as an opportunity for further research.

Influenza is a viral infectious disease commonly referred as ‘flu’. Influenza viruses are RNA viruses and belong to the family ‘orthomyxoviridae’ with three genera: Influenza Virus A, Influenza Virus B and Influenza Virus C.[1] Among these, Type A is the most virulent human pathogen and causes the most severe form of the disease. This genus has one species, influenza A virus. The wild aquatic birds are the natural hosts for a large varieties of influenza A. Occasionally, viruses are transmitted to other species and may cause devastating outbreaks in domestic poultry or human influenza pandemics.[2] Influenza A is further sub-typed into 16 distinct H types and 9 distinct N types based on hemagglutinin and neuraminidase antigens on the surface of the virus.[3] The confirmed serotypes (in order of deaths) in human pandemics are: H1N1 (caused Spanish flu-1918 and swine-flu-2009), H2N2 (Asian Flu-1957), H3N2 (Hong Kong Flu-1968), H5N1 (highly pathogenic avian influenza virus; there is a threat of the pandemic now), H7N7 and others.[4]

The recent swine origin of the influenza virus (H1N1 strain) underwent triple reassortment and contains genes from avian, swine and human viruses.[5] It is believed to be a legacy of the influenza pandemic (1918-19) and has now acquired the ability to infect and spread within the human host after adapting over the last 91 years.[3]

Influenza usually causes an acute and self-limiting febrile illness but may cause severe complications in medical conditions[6] and has the potential of significant morbidity in the community.[7] The most common symptoms of influenza are chills, fever, sore throat, muscle pains, severe headache, coughing, weakness/fatigue and general discomfort.[8] In serious cases, influenza may cause pneumonia which can be fatal in the young, and particularly in the elderly. Although it is often confused with other influenza-like illnesses, especially with common cold, it is a much more severe disease than common cold.[9]

Seasonal influenza occurs every year. The Center for Disease Control and Prevention (CDC) reported the first identified cases of respiratory infection with H1N1 virus in the United States on 15 and 17 April, 2009.[10] On 11 June, 2009, the World Health Organization (WHO) declared the first pandemic of the 21st century by swine flu (H1N1).[11] The clinical features of hospitalized swine flu cases were generally similar with the seasonal influenza.[12,13]

NEUROPSYCHIATRY OF INFLUENZA AND SWINE FLU

Karl A. Menniger was the first researcher to link influenza with neuropsychiatry in 100 influenza patients admitted with behavioral changes in Boston between 15 September and 15 December 1918 (Spanish flu).[14] This pandemic was also linked with Parkinsonism.[15]

The influenza virus most commonly affects the respiratory system, but the burden in neuropsychiatric diseases are under-recognized.[16] Hence a selective review was carried out on the neuropsychiatric aspects of human influenza and especially of the current swine flu pandemic which may helpful for prevention, early recognition and treatment. From the point of view of research this review of the swine flu pandemic may provide some opportunity for future research of many neuropsychiatric disorders.[17]

The aim of the paper is to do an educational review to sensitize the neuropsychiatric community about the implication of the swine flu pandemic in their clinical practice and discuss the implication for further research.

METHODOLOGY

The authors conducted an electronic search of articles published in ‘Pubmed’ from 1950 to March 2010. The MeSH terms such as “Influenza, Human” [Mesh] were combined with various terms using Boolean operator (AND). The first author (NM) also screened the cross-references of major articles, and reviews, whenever relevant. The author found a wide scatter of published articles. To arrive at a meaningful discussion, only relevant articles were selected (selective review) based on relevance and hierarchy of scientific evidence.

The hierarchy followed in this review was prospective studies, retrospective studies, systematic reviews, case series followed by case reports (from higher to lower level of evidence) in human beings. Whenever findings from a higher level of evidence are reviewed, similar findings from a lower level of evidence are not repeated in this review. When there was no evidence from human beings, we considered findings from animal studies (taken from cross-references).

RESULTS AND DISCUSSION

The neuropsychiatric aspects of influenza/swine flu, for convenience of discussion, are classified into clinical manifestations-related and treatment-related. The clinical manifestations-related aspects were further subdivided into acute (within six months) and chronic (more than six months) manifestations. Treatment-related neuropsychiatric aspects were further subdivided into neuropsychiatric aspects of medication used and of its vaccination. A brief note on the pathogenesis of neuropsychiatric aspects of influenza is also discussed at the end.

ACUTE NEUROPSYCHIATRIC MANIFESTATIONS OF INFLUENZA AND PRESENT SWINE FLU PANDEMIC

Influenza

The reports of influenza-associated acute neurological syndromes are available from 1385 onwards.[18–20] Acute neurological manifestations have been reported during epidemics and are often consistent with serious sequelae or death. An increased incidence of influenza-associated encephalitis/encephalopathy (IAE) has been reported in Japan, mainly in children. Other acute clinical neurological manifestations include seizures, Reye's Syndrome (RS), acute necrotizing encephalopathy, transverse myelitis, and aseptic meningitis as well as autoimmune conditions, such as Guillian-Barre Syndrome (GBS), which may occur during the course of influenza infection.[21–26] There is evidence that influenza can directly lead to acute encephalitis.[27] In recent times, a range from mild encephalitis to motor disturbances to coma has been reported with H5N1 infections in poultry[28] and in humans.[29]

In a retrospective chart review, Maricich et al.,[21] reported a range of neurologic complications such as seizures (n-4), mental status changes (n-3), and mutism (n-1) with seasonal influenza A in eight admitted unimmunized US children (age 5 months to 9 years) in 2003. Investigations revealed the presence of influenza A viral antigen in nasal wash samples (in all patients), isolation of influenza A virus from the cerebrospinal fluid (in only one), and no serum metabolic or cerebrospinal fluid abnormalities (in all). Abnormalities in brain imaging were found in three patients. Among these eight patients, six survived with complete recovery and two of them had sequelae.

Toovey[16] (in review) found that febrile seizure was the most common clinical presentation in influenza (occurrence is one in five children with complete recovery but has increased risk of subsequent afebrile seizure), whereas, IAE was less common but potentially life-threatening (more in Japan). They also found that clinical manifestations were diverse, typically involving febrile seizures and abnormal behaviors (in mild cases), with rapid evolution through decreased consciousness to coma (in severe forms) and the prognosis was often poor (in serious cases), with outcomes including death or severe neurological sequelae. Toovey[16] also found that influenza was also known to trigger a number of rarely encountered, but often serious central nervous system (CNS) diseases like encephalopathy of RS, a peripheral neuropathy of GBS, and the lesser known Kleine-Levin syndrome and post-encephalitic Parkinson's disease. Sivadon-Tardy et al.,[30] found the serological evidence for influenza viruses playing a role during outbreaks of GBS . In a 30-year study, Kazmierski et al.,[31] supported the hypothesis that influenza infection could precipitate the onset of multiple sclerosis (MS). De Keyser et al.,[32] reported that 33% and 5% of exacerbations in 180 patients with relapsing MS was associated with influenza illness and post-influenza vaccination respectively.

Others

There are case reports of acute psychosis following influenza.[33,34] A case report describes an ischemic stroke in a four-year-old male associated with acute influenza A infection.[35]

Present swine flu pandemic

The acute manifestations of swine flu are simply the behavioral reactions, misdiagnosis/over-treatment and other acute neurological manifestations. In a nationwide cross-sectional telephonic survey of 997 adult citizens of England, Scotland, and Wales after swine flu was declared as pandemic, Rubin et al.,[36] found significant behavioral changes (as precautionary measures) such as following ‘some recommended behavior’ (increases in hand washing and surface cleaning or plans made with a “flu friend”) in about 38% of participants over the past four days, and nearly 5% carried out ‘some avoidance behavior’ (engaged in one or more of six behaviors such as avoiding large crowds or public transport). These behavioral changes were correlated with a high level of anxiety.[36] There is a report of misdiagnosis at the height of the fear of the swine flu pandemic even for a case of sore throat and prescribed unnecessary oseltamivir by health professionals.[37] There is a report of bizarre neuropsychiatric behavioral changes in one adolescent with novel H1N1.[38]

For the first time, the neurological complications due to H1N1 were reported on 24 July 2009 from US Center for Disease Control and Prevention (CDC).[39] These cases presented as encephalopathy (defined operationally as altered sensorium lasting for >24 h) in four children confirmed in nasopharyngeal swabs with enzyme immunoassay method. These four patients, aged 7 to 17 years, were admitted with signs of influenza-like illness and neurological complications. i.e., two had seizures (on third day) and three had abnormal electroencephalograph recordings. H1N1 virus was detected in the nasopharyngeal specimens in all cases but not in the cerebrospinal fluid (CSF). There was complete recovery without any neurologic sequelae in all four patients at the time of discharge. These findings confirmed that, similar to seasonal influenza, the neurologic complications can also occur with novel H1N1 virus after respiratory tract infection, but severity is lesser than that seen in seasonal influenza. This report called for participation of the Neurology community in the surveillance of the current swine flu pandemic for possible involvement of the central nervous system (CNS).[40]

CHRONIC NEUROPSYCHIATRIC MANIFESTATIONS OF INFLUENZA AND SWINE FLU

A significant numbers of papers from long times demonstrated interest in the chronic manifestations of the influenza virus. The viral hypothesis of influenza has been proposed for many neuropsychiatric disorders, particularly in schizophrenia, Parkinson's disease, Alzheimer's disease and mental retardation.[41] However, the evidence for this influenza hypothesis is available from animal studies and retrospective human studies with presumptive causation.

Parkinson's disease

The earlier linkage of Parkinsonism with influenza infection was reported after the 1918 influenza pandemic with observation that a number of people are shown diminished mobility and other neurological symptoms suggestive of Parkinson's disease (PD).[15] Subsequent evidence is also available for this linkage from epidemiological data[19,20] and findings of the presence of Type A influenza antigens in Encephalitis lethargica (EL) patients.[42] The lack of viral RNA from brains of post-encephalic Parkinsonian patients[43] and the absence of any known mutations of direct infection[44] are the major drawbacks in the understanding the role of influenza as a Parkinsonian agent.

In a recently published animal study by Jang et al.,[45] elevated levels of alpha-synuclein, loss of 17% dopaminergic neurons in the substantia nigra and persistent inflammation in areas of the brain infected with H5N1 influenza strain have been reported. All experimental mice developed tremors and movement difficulties suggestive of PD. However, there is no report of PD in human survivors of the H5N1 flu so far and it is too early to know whether those infected are at an increased risk as only a few years have passed since the report of the first cases. Researchers also acknowledge that 70% or more loss of dopaminergic neurons is required for full-blown PD to manifest and the observed 17% reduction in dopaminergic neurons alone may not be sufficient to cause PD, but it may make the brain more susceptible, especially in combination with other factors such as genetic, other environmental triggers, or simply old age. Miller[46] believes that bird flu may trigger PD in this pandemic as there is a possibility of fear of pandemic with H5N1 serotype). With these evidences, there is a possibility of recurrence of EL in this influenza pandemic.[47] In view of the reemergence of the highly pathogenic virus Avian influenza A (H5N1) in 2003,[48] authors call for long-term follow-up studies among survivors of H5N1-infected individuals if it occurs as a pandemic before concluding that it is the causative agent for PD.

Schizophrenia

Karl A. Menninger first reported “mental disturbances” in 80 patients of influenza admitted in a psychiatric hospital, of whom 16 were diagnosed with delirium, 25 with dementia praecox, 23 with “other types of psychosis,” and 16 who could not be classified.[14] He considered that the Spanish pandemic of influenza (1918) could have led to the development of dementia praecox, but neither he nor his contemporaries raised the possibility of influenza as an etiological agent for schizophrenia that could occur in utero.

In subsequent studies, a high prevalence of schizophrenia was documented in children born in winter and early spring that witness influenza infections.[49] There are controversial reports on the influenza virus in the etiology of schizophrenia from population-based, retrospective studies[50–52] with ecological design (i.e., the information on actual individual exposure was not available) that might have led to high false-positives.[53] Approximately 50% of studies have reported positive associations among 25 incidence studies of schizophrenia in the offspring of women who were thought to have contracted influenza during pregnancy.[54] The reliability of the documentation of exposure about maternal influenza in these studies are questionable as it is generally based on self-reports of participants or on occurrences of influenza epidemics contemporaneous with their pregnancies. To counter this problem, Brown et al.,[55] analyzed influenza antibodies in a case-control study in a population-based birth cohort (in sera drawn from pregnant women whose children later developed schizophrenia, and compared with a matched control group of women whose children did not develop schizophrenia) and found a dramatic sevenfold increase in the risk of schizophrenia among the offspring of women who were exposed to influenza during their first trimester of pregnancy, but not during the second and third trimester. The data collected from actually infected pregnant women in two studies have found no increase in risk of schizophrenia among their children.[56,57] Polymerase chain reaction-based studies in pregnant women have not detected influenza virus-specific nucleic acid sequences in brain tissue or CSF.[58,59] These evidences along with indirect evidence from animal studies suggest that human influenza viruses may have caused inherent immunological distortions in mind.[60]

Despite these evidences in the scientific literature for more than a century, there is no conclusive evidence for the influenza/viral etiology of schizophrenia.[17] Researchers advised to do further studies to get answer for many unanswered viral etiology of schizophrenia in this pandemic[61,62] as the data from pregnant women has started available in this pandemic.[63]

Dementia and mental retardation

Nabeshima et al.,[64] reported a case of progressive dementia and prolonged gait disturbance after initial presentation of delirium correlated with serologically confirmed influenza A/H3N2 infection in a 91-year-old female patient. Increased risk of mental retardation (MR) was observed in adulthood in children of prenatal exposure to Hong Kong flu[65] during the winter of 1969-70 especially in third to fourth month of gestation.[66] Jancar[67] also observed an association of influenza with MR.

Mood disorders: Depression

A retrospective Australian study with participation of 2514 adolescents/young adults reported an increased prevalence of suicidal and depressive symptoms in people who were born during flu peak in the Southern hemisphere, in comparison with those born in the Northern hemisphere,[68] but a prospective study by influenza antibody titer disapproved this correlation.[69]

Mood disorders: Mania

A case of mania induced by influenza B infection has been reported with hypothesis of connection between the locus ceruleus and influenza virus.[70] Steinberg et al.,[71] also reported a manic psychosis in influenza.

Mood disorders: Bipolar disorder vs. Unipolar disorder

In comparison with bipolar disorder, a case-control study found that the risk of occurrence of uniploar affective disorders is increased in people who were exposed to an influenza epidemic during the second trimester which supports the neuro-developmental hypothesis of affective disorder.[72]

However, Morgan et al.,[73] found no increased incidence of schizophrenia, affective psychoses and neurotic depression, but a possible effect was found for MR in males exposed in the first and second gestational trimester.

NEUROPSYCHIATRIC ASPECTS OF INFLUENZA AND SWINE FLU TREATMENT (TAMIFLU)

Oseltamivir, a neuraminidase inhibitor, is the most commonly used and generally well tolerated medication for swine flu worldwide and encouraging results have been observed if treated within 48 h of detection.[74] Oseltamivir (Tamiflu) is effective for treating both seasonal flu and H1N1 infection.

Behavioral problems such as jumping and falling from balconies has been reported in young Japanese patients treated with oseltamivir;[75] that lead authorities to issue warning against the prescription of oseltamivir.[76] A case of oseltamivir-induced mania was reported in an 18-year-old Chinese lady who was admitted for H1N1 in Hong Kong with family history of bipolar disorder.[77] There is also a report of oseltamivir-induced delirium in a geriatric patient.[78]

In an internet-based cross-sectional survey,[79] 18% of oseltamivir-treated H1N1 UK schoolchildren had mild neuropsychiatric side-effects and reported one or more following symptoms: poor concentration/unable to think clearly, problems in sleeping, feeling dazed/confused, bad dreams/nightmares, and behaving strangely.

In post-marketing surveillance of tamiflu, the following transient neuropsychiatric adverse effects were reported mainly from Japan: delusions, hallucinations, sleep problems, abnormal behavior leading to injury, convulsions, encephalitis and delirium to suicide (mainly documented in teenagers).[80,81] US Food and Drug Administration (FDA) suggested that the increased reports of neuropsychiatric events in Japanese children are most likely related to an increased awareness of influenza-associated encephalopathy, increased access to Tamiflu in that population, and a coincident period of intensive monitoring of adverse events.[81] These prompted the inclusion of precautions to the US product label for oseltamivir.[82]

A retrospective cohort study[82] funded by Roche (who make Tamiflu) noted a higher rate of episodic mood disorders among those aged 17 years and below receiving oseltamivir compared to those who received no antiviral treatment.

There are many etiological mechanisms are proposed for neuropsychiatric side-effects of oseltamivir. Izumi et al.,[83] hypothesized that oseltamivir carboxylase, the main metabolite of oseltamivir, has an effect on the CNS with a role in CNS development and impulse conduction. Yoshino et al.,[76] found that oseltamivir increases the release of dopamine in the medial prefrontal cortex and may be the cause of abnormal behavior in young patients.

The genetic mechanism in the Japanese population may be responsible for the neuropsychiatric side-effects with oseltamivir including suicide.[75] Clinicians are asked to closely monitor this potential side-effect of suicide in every patient, especially with a positive family or personal history of mental illness.

Neuropsychiatry of influenza and oseltamivir: Overall vs. treated vs. untreated

Controversy exists regarding whether neuropsychiatric manifestations are a result of influenza per se or side-effects of oseltamivir. A retrospective cohort study of influenza in 1 to 21 years from USA found that there was no evidence of increased risk of adverse neuropsychiatric outcomes among the study population treated with oseltamivir for influenza.[84]

NEUROPSYCHIATRIC ASPECTS OF VACCINATION FOR INFLUENZA AND SWINE FLU

There are many reports of GBS (subacute/chronic, progressive, post-vaccination encephalopathy) identical to the subacute and chronic forms of polyradiculoneuropathy (very rarely) and subclinical myelopathies (a very few cases of) following vaccination for influenza.[85] Among all these, GBS is a highly controversial side-effect in view of earlier reports of GBS due to influenza infection itself.

Probably for the first time, occurrence of GBS with vaccine for influenza outbreak was reported in 1976 during a large-scale immunization campaign in New Jersey, USA which led to a cessation of this mass immunization. An estimate suggests that there was a risk of one additional case of GBS per 100,000 people vaccinated for influenza in comparison with background prevalence of GBS of 1–2·3 per 100,000 in the general population. ‘Lancet Neurology’[40] observes that the chances of detecting cases of GBS during the development phase are low since the number of participants in most clinical trials of vaccines against H1N1 is unlikely to exceed 1500. In view of reports of mass vaccination in this swine flu pandemic, the timely reporting and analysis of any neurological complications during the immunization period will be essential.

However, preliminary data from CDC[86] (1 October- 24 November 2009) suggests that there are no substantial differences noted between H1N1 and seasonal influenza vaccines in the proportion or types of serious adverse events reported after FDA gave license for H1N1 vaccines on 15 September 2009. In light of the H1N1 pandemic, the WHO recommends continuation of surveillance of acute flaccid paralysis that may represent a useful means of monitoring GBS during the pandemic.[87] In view of controversy of whether GBS is a part of influenza, or a side-effect of influenza vaccination and absence of clear evidence for either, WHO recommended collaborative active surveillance for GBS during immunization which might give better insight about the controversial etiology of GBS.

PATHOGENESIS OF NEUROPSYCHIATRIC INVOLVEMENT IN SWINE FLU

The pathogenesis of swine flu in the respiratory system is beyond the scope of this article and is dealt with elsewhere.[7]

The evidences for the involvement of the brain in the pathogenesis of influenza virus are available from animal studies. A study of the immunization of rabbits with certain H1N1 influenza viruses led to production of autoantibodies to a brain-specific protein of 37kDa, present in various species including humans.[88] These autoantibodies were produced only in the brain and not in other tissues. These antibodies were not elicited by other Influenza A or B viruses. In histological studies, the reaction with antiviral antisera was specific to gray matter and was confined to sera that recognized the 37-kDa protein. The binding of the antibody was prominent in regions comprising neuronal cell bodies in cellular layers of the dentate gyrus, hippocampus, cerebral cortex, and cerebellum and not detectable in myelin-rich regions, such as the corpus callosum. The 37-kDa protein, therefore, appears to be a neuronal antigen. Antibodies directed against this protein may be involved in the pathogenesis of one or more of the neuropsychiatric disorders that occur after infection with influenza.[88]

CONCLUSIONS

The well-documented acute neuropsychiatric manifestations of influenza and swine flu are encephalitis/encephalopathy, seizures, RS, transverse myelitis, and aseptic meningitis, and GBS. Among the chronic manifestations of influenza, the evidence for schizophrenia and PD require further scientific data. Suicide and GBS are the two controversial neuropsychiatric side-effects of oseltamivir and influenza vaccination respectively, undergoing post-marketing surveillance.

Many notable neuropsychiatric manifestations implicated with the infection of influenza/swine flu, the relation between swine flu and neuropsychiatry are yet to be understood fully, especially the chronic manifestations. The neuropsychiatric community around the world shall make use this swine flu pandemic for further research.