Influenza virus and neurological diseases

Abstract  Influenza viruses rarely cause acute encephalopathy. Post-influenzal encephalitis, which occurs a few weeks after recovery from influenza is thought to be an autoimmune process associated with demyelination and vasculopathy. It has been suggested that Economo lethargic encephalitis followed by postencephalitic Parkinsonism was associated with the influenza A epidemic of 1918 (Spanish flu). The incidence of Reye's syndrome has markedly decreased due to the avoidance of salicylates in the treatment of influenza or varicella. One inactivated flu vaccine is thought to have caused Guillain Bane syndrome due to molecular mimicry between viral protein and myelin, which triggered autoimmune responses. The persistence of influenza virus genes in neural cells as one of the causes of chronic degenerative diseases of the central nervous system by inducing apoptosis of the host cells is yet to be proven.     

Human Hendra virus infection causes acute and relapsing encephalitis

Aim : To study the pathology of two cases of human Hendra virus infection, one with no clinical encephalitis and one with relapsing encephalitis. Methods : Autopsy tissues were investigated by light microscopy, immunohistochemistry and in situ hybridization. Results : In the patient with acute pulmonary syndrome but not clinical acute encephalitis, vasculitis was found in the brain, lung, heart and kidney. Occasionally, viral antigens were demonstrated in vascular walls but multinucleated endothelial syncytia were absent. In the lung, there was severe inflammation, necrosis and viral antigens in type II pneumocytes and macrophages. The rare kidney glomerulus showed inflammation and viral antigens in capillary walls and podocytes. Discrete necrotic/vacuolar plaques in the brain parenchyma were associated with antigens and viral RNA. Brain inflammation was mild although CD68⁺ microglia/macrophages were significantly increased. Cytoplasmic viral inclusions and antigens and viral RNA in neurones and ependyma suggested viral replication. In the case of relapsing encephalitis, there was severe widespread meningoencephalitis characterized by neuronal loss, macrophages and other inflammatory cells, reactive blood vessels and perivascular cuffing. Antigens and viral RNA were mainly found in neurones. Vasculitis was absent in all the tissues examined. Conclusions : The case of acute Hendra virus infection demonstrated evidence of systemic infection and acute encephalitis. The case of relapsing Hendra virus encephalitis showed no signs of extraneural infection but in the brain, extensive inflammation and infected neurones were observed. Hendra virus can cause acute and relapsing encephalitis and the findings suggest that the pathology and pathogenesis are similar to Nipah virus infection.     

Viral encephalitis and epilepsy

Viral encephalitis presents with seizures not only in the acute stage but also increases the risk of late unprovoked seizures and epilepsy. Acute symptomatic and late unprovoked seizures in different viral encephalitides are reviewed here. Among the sporadic viral encephalitides, Herpes simplex encephalitis (HSE) is perhaps most frequently associated with epilepsy, which may often be severe. Seizures may be the presenting feature in 50% patients with HSE because of involvement of the highly epileptogenic frontotemporal cortex. The occurrence of seizures in HSE is associated with poor prognosis. In addition, chronic and relapsing forms of HSE have been described and these may be associated with antiepileptic drug-resistant seizures. Among the epidemic (usually due to flaviviruses) viral encephalitides, Japanese encephalitis (JE) is most common and is associated with acute symptomatic seizures, especially in children. The reported frequency of acute symptomatic seizures in JE is 7–46%. Encephalitis due to other flaviviruses such as equine, St. Louis, and West Nile viruses may also manifest with acute symptomatic seizures. In Nipah virus encephalitis, seizures are more common in relapsed and late-onset encephalitis in comparison to acute encephalitis (4% vs. 1.8%). Other viruses like measles, varicella, mumps, influenza, and entero-viruses may cause seizures depending on the area of brain involved. There is no comprehensive data regarding late unprovoked seizures in different viral encephalitides. Prospective studies are required to document the risk of late unprovoked seizures and epilepsy following viral encephalitis due to different viruses as well as to determine the clinical characteristics, course, and outcome of post-encephalitic epilepsy.     

Intrathecal synthesis of different alpha-interferons in patients with various neurological diseases

CSF and sera from 238 newborns and children with various neurological diseases were assayed on bovine cells for the presence of alpha-interferon (IFN). An intrathecal synthesis of pH 2-resistant alpha-IFN was recovered in all newborns and in more than 90% of children with herpes encephalitis. It was also observed in one case of mumps encephalitis and in one case of encephalitis associated with Influenza A infection. An acid-labile alpha-IFN production was detected in CSF from more than one half of patients with viral meningitis or active congenital rubella and in those with neurological complications of systemic lupus erythematosus. This alpha-IFN subtype was also detected in CSF from only 2/37 children with measles encephalitis. In contrast, no alpha-IFN (less than 2 IU) in CSF was found among patients with subacute sclerosing panencephalitis, Guillain-Barré syndrome, Reye's syndrome, acute cerebellar ataxia, infantile spasms or facial paralysis of unknown origin.     

Acute encephalitis

Acute encephalitis: etiology, clinical findings and prognosis. We studied 44 patients with acute encephalitis diagnosed in a neurological university clinic during an 11-year period. An etiology was found in 11 cases (25%). In 3 the cause was herpes simplex virus; in 2 morbilli. There were single patients in which the cause was mycoplasma pneumoniae, epidemic parotitis, ornithosis, infectious mononucleosis, influenza B-virus and recent tetanus immunization. No specific etiology was found in 33 (75%). Besides fever the most frequent sign was impairment of consciousness in 39% of cases. Four patients (9%) died. Among the survivors mental and/or focal neurological deficits persisted in 22 (55%). Most frequent was dementia in 6 cases (15% of survivors). Impaired consciousness in the acute phase indicated a worse prognosis (p < 0.005).     

VGKC complex antibodies in pediatric severe acute encephalitis: A study and literature review

Background: Antibodies to surface proteins like voltage-gated potassium channel (VGKC) complexes are increasingly found in different neurologic diseases and encephalitis in adults and recently, in children. Detecting such antibodies can help identify forms of encephalitis that may respond to immuno-therapies. However, there are few reports on VGKC complex antibodies in pediatric severe acute encephalitis. Methods: This study retrospectively reviewed antibodies to VGKC, leucine-rich glioma-inactivated 1 (Lgi1), and contactin-associated protein-like 2 (Caspr2) in 46 children with severe acute encephalitis. Published cases of VGKC complex antibodies in pediatric encephalitis in the period of 2000–2012 were also reviewed. Results: Elevated VGKC complex antibodies (>100 pM) were detected in one of the 46 children with severe acute encephalitis. The 4-year and 6-month-old girl presented with seizure and disturbed consciousness. Viral PCR/culture and serologic evidence of influenza A infection was noted. She also had complications of epilepsy, impaired cognition, and altered behavior and psychology. Antibodies to Lgi1 and Caspr2 were not detected. Ten previously published reports revealed that VGKC complex antibodies can occur in children with limbic encephalitis and acute or sub-acute encephalitis. Conclusion: The incidence of VGKC complex antibodies in pediatric severe acute encephalitis is not high with only one (2.2%) of 46 children in this study. And, this is the first report on the association of VGKC complex antibodies and patients with influenza A-related severe acute encephalitis. The mechanism of VGKC complex antibodies in pediatric severe acute encephalitis warrants further study.     

Association of Japanese encephalitis virus infection with Guillain-Barré syndrome in endemic areas of South India*

This study is a report of 34 cases of Guillain-Barré syndrome (GBS) observed in Bangalore (South India), an endemic area for Japanese encephalitis virus (JEV) infection. Virological and immunological findings suggested an antecedent and recent JEV infection in 21/34 patients. Nineteen patients among them showed high levels of JEV-specific IgM antibodies in serum and/or CSF, while the viral antigen could be demonstrated in one case and virus isolation from the CSF was successful in one patient. EMG studies revealed features of predominantly demyelinating neuropathy in 18/25 cases. Comparison of clinical findings, duration of illness and outcome in GBS patients with evidence of JEV infection and those without did not reveal any differences. Pathological findings in one patient corroborated the association of JEV with GBS. We conclude that, JEV infection may predispose to Guillain-Barré syndrome in endemic areas.     

疱疹病毒性脑炎并发视力下降二例

目的探讨疱疹病毒性脑炎和视力下降的关系。方法对2例疱疹病毒性脑炎患者腰椎穿刺,行脑脊液测压、常规、生化、细胞学及病原学检查及头颅磁共振(MRI)检查;例1患者行眼科超声检查。结果2例患者均在入院治疗过程中出现视力下降。例1为单纯疱疹病毒感染,例2为巨细胞病毒感染。2例患者头颅MRI扫描均有脑实质炎性改变,均涉及岛叶。例1眼科超声提示视网膜坏死及视网膜脱离。结论疱疹病毒感染与急性视网膜坏死综合征及视神经炎有关。对于病毒性脑炎患者应给与足够的抗病毒治疗,期间若出现视力下降,警惕合并急性视网膜坏死综合征及视神经炎。     

Clinical and radiologic manifestations of H1N1 virus infection associated with neurological complications: a case report

Encephalitis complicating novel influenza A (H1N1) viral infection is rare and has only been reported in children. We present cerebral magnetic resonance imaging findings from a confirmed adult case with H1N1 infection who presented with acute encephalitis and subsequent respiratory failure. Cerebral magnetic resonance imaging showed hyperintense abnormalities in the bilateral globus pallidus in T1-weighted images, and multiple hyperintense abnormalities in the right insular cortex, right parahippocampus, and the pontine tegmentum in fluid-attenuated inversion recovery images.     

Epidemiological study of acute encephalitis in Tottori Prefecture,Japan

Background and purpose: To conduct an epidemiological survey of acute encephalitis focusing on non‐herpetic acute limbic encephalitis (NHALE) in Tottori Prefecture, western area of Japan. Methods: A questionnaire survey on the annual number of patients aged 16 years or more with acute encephalitis from 2001 to 2005 was undertaken in 2006. Results: During the study period, 49 patients were diagnosed with acute encephalitis. The subtype of acute encephalitis was as follows: 10 patients with herpes simplex encephalitis (HSE), 12 patients with NHALE, 4 patients with paraneoplastic encephalitis, 2 patients with encephalitis associated with collagen disease, one patient with viral encephalitis other than HSE, 20 patients with encephalitis with unknown causes. The service‐based incidence rate of acute encephalitis was 19.0 per million person‐years. The incidence rate of NHALE subtype was 4.7 per million person‐years. Conclusions: Our epidemiological survey indicated an estimated 550 patients would develop NHALE per year in Japan, suggesting that NHALE may not be a rare disorder.     

Influenza A encephalitis with movement disorder.

Influenza A is an uncommon but well-recognized cause of viral encephalitis in childhood, occurring most commonly during community influenza outbreaks. The authors report four cases of influenza A encephalitis that occurred during an Australian epidemic in 1997-1998. Choreoathetosis during the acute phase of infection or basal ganglia involvement on neuroimaging was observed in three of the four patients. These findings in pediatric encephalitis are suggestive of influenza A infection and may guide investigation and early diagnosis.     

62例病毒性脑炎脑电图与临床及CT分析

为探讨病毒性脑炎（病脑）患者脑电图（EEG）与临床及CT之间的关系,将临床确诊的62例病脑患者进行EEG与CT检查,对其EEG异常的阳性率、异常程度与病程、临床表现、CT之间的关系进行比较分析,并作统计学处理。结果发现,发病10天以内EEG中、重度异常39倒（78%）,与10天以后比较有显著性差异（P＜0．001）。EET可表现为三种形式：以弥漫性异常为主（51.5％）;弥漫性异常伴局灶慢波（32．3%）;局灶性异常（16．2%）。EEG与CT之间无明显相关性（P＞0．05）。提示：EEG检查对病脑的诊断、鉴别诊断,以及动态观察病情、判断预后有重大意义。CT不能取代EEG。     

Does the historical literature on encephalitis lethargica support a simple (direct) relationship with postencephalitic Parkinsonism?

This article and the subsequent one suggest that the currently accepted view of a simplistic (direct) relationship between encephalitis lethargica (EL) and postencephalitic Parkinsonism (PEP) is based on a incomplete evaluation of the epidemic period literature. In this article we provide a detailed analysis of the literature from the period that demonstrates that Parkinsonism was not initially part of acute EL symptomatology, that PEP was not typically the prevailing type of chronic EL and that oculogyric crises were never part of acute EL symptomatology and not initially associated with PEP. The second paper uses these finding, and also examines the clinical justifications for concluding that all patients with PEP had prior acute episodes of EL, to reevaluate the presumed direct etiologic relationship between EL and PEP. © 2010 Movement Disorder Society     

Relapsing Anti-NMDAR Encephalitis after a gap of eight years in a girl from North-East India

It has been just 7 years since the discovery of anti-NMDAR encephalitis as distinct immune-mediated encephalitis and we have such cases being reported from our country. Herein, we describe a case of a 13-year-old girl who had relapsing encephalitis consisting of multiple types of difficult-to-control seizures, abnormal behavior, language disintegration, memory loss and abnormal movements eight years after the first clinical attack. In 2005, when she was 5 yearsold, anti-NMDAR encephalitis was not yet discovered and she was provisionally diagnosed as a case of viral encephalitis. During her second attack in 2013, antibodies against NMDAR were demonstrated by immunofluoresence in serum (1:10). This is the first report from our country of a case of relapsing anti-NMDAR encephalitis of such a long duration, successfully treated by immunotherapy.     

Involvement of the central nervous system in Miller Fisher syndrome: a case report

Miller Fisher syndrome (MFS) is characterised by ophthalmoplegia, ataxia and areflexia. Reports on cerebellar ataxia and supranuclear oculomotor derangement in MFS suggested an additional involvement of the central nervous system (CNS), resembling Bickerstaff's brainstem encephalitis (BBE). In the present report, a patient with a monophasic acute illness, early recovery and specific clinical-laboratory findings suggested both intrinsic brainstem and peripheral nerve disease (MFS and BBE). In pons and medulla oblangata, blurred to discrete T2-lesions were revealed by cranial MRI, while involvement of peripheral nerves was detected with EMG. The CSF showed no increase in protein or cell content, such as occurs in brainstem encephalitis.     

PET‐positive extralimbic presentation of anti‐glutamic acid decarboxylase antibody‐associated encephalitis

Anti‐glutamic acid decarboxylase (GAD) antibody‐associated autoimmune encephalitis has been reported mostly as limbic encephalitis. Only few cases with extralimbic involvement are reported with limited investigation. Here, we report an extensive investigation with MRI, PET, and pathological examination. A 66‐year‐old Japanese female with a history of hypothyroidism, colon cancer, pheochromocytoma, and thymoma‐associated myasthenia gravis presented with generalised tonic‐clonic seizures. MRI showed multiple hyperintense lesions and PET showed hypermetabolic lesions in the brain. Biopsy showed non‐specific gliosis, microglial proliferation, and perivascular lymphohistiocytic infiltrates. Various neuronal antibodies were negative, except for anti‐GAD antibody. Anti‐GAD antibody‐associated encephalitis is an increasingly recognised CNS disease. Pathophysiology of this encephalitis is unclear. While PET showed hypermetabolic lesions, the biopsy showed non‐specific changes. The treatments may include immunosuppressants, IVIg, and plasma exchange. One should consider to measure this antibody, in addition to others, when autoimmune encephalitis is suspected [Published with video sequences].     

Emerging and re-emerging epidemic encephalitis: a tale of two viruses

Two major epidemics of viral encephalitis occurred in Asia in 1997 and 1998. The first was a re-emergence of neurovirulent strains of enterovirus 71, which caused severe encephalomyelitis in children in Malaysia, Taiwan and Japan, on a background of hand, foot and mouth disease. Necropsy studies of patients who died of enterovirus 71 infection showed 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 factors, in addition to direct viral cytolysis, may be involved in tissue damage. The second epidemic of viral encephalitis was the result of a novel paramyxovirus called Nipah, which mainly involved pig handlers in Malaysia and Singapore. Pathological evidence suggested that the endothelium of small blood vessels in the central nervous system was particularly susceptible to infection. This led to disseminated endothelial damage and syncytium formation, vasculitis, thrombosis, ischaemia and microinfarction. However, there was also evidence of neuronal infection by the virus and this may also have contributed to the neurological dysfunction in Nipah encephalitis. Some patients who seemed to recover from the acute symptoms have been re-admitted with clinical findings suggestive of relapsing encephalitis. As these two epidemics indicate, the emergence and re-emergence of viral encephalitides continue to pose considerable challenges to the neuropathologist, in establishing the diagnosis and unravelling the pathogenesis of the neurological disease.     

A Case of Adult Influenza A Virus–Associated Encephalitis: Magnetic Resonance Imaging Findings

A 27-year-old man presented with fever, convulsive seizure, and sudden impairment of consciousness. Magnetic resonance imaging (MRI) abnormalities were found in the bilateral thalami, including the brain stem and white matter. The possibility of a previous influenza A virus infection was considered, and cerebrospinal fluid cells and interleukin-6 were elevated. The MRI findings closely resembled those found in cases of childhood acute necrotizing encephalopathy (ANE). The present case suggests that adult influenza A virus-associated encephalitis/encephalopathy or ANE can occur during winter influenza epidemics.     

病毒性脑炎急性期继发癫痫的临床特点

目的:分析病毒性脑炎急性期继发癫痫的临床特点。方法:1982年4月5日～2003年12月15日连续住院的374例病毒性脑炎患者,采用统一的调查表,用Microsoft Access 2002建立数据库,共51个主项内容,部分主项有下属分项。分析患者癫痫发病情况,对比观察继发癫痫患者和无癫痫发作患者脑电图结果及预后情况。结果:374例中115例(30.8％)继发癫痫,其中全面发作72例(62.6％),单纯部分发作18例,复杂部分发作11例,部分继发全面14例。115例患者中23例(20.0％)出现癫痫持续状态,14例(12.2％)继发多系统损害,普通脑电图检查20例发现痫性放电,占17.4％。继发癫痫组额叶、颞叶损害共54例,占47.0％。继发癫痫组与无癫痫发作组比较,脑电图异常程度差异有显著意义(x2=23.6,P<0.01),大脑皮质损害发生率差异有显著意义(x2=85.53,P<0.001)。继发癫痫组住院天数26.1±23.6,无癫痫发作组住院天数17.9±5.0,二者比较差异有显著意义(t=5.33,P<0.001)。结论:急性病毒性脑炎后继发癫痫发作以全面发作最为常见,大脑皮质损害易于继发癫痫,癫痫发作影响病毒性脑炎患者病情恢复。     

Individual voxel-based subtype prediction can differentiate progressive supranuclear palsy from idiopathic Parkinson syndrome and healthy controls

Voxel-based morphometry (VBM) shows a differentiated pattern in patients with atypical Parkinson syndrome but so far has had little impact in individual cases. It is desirable to translate VBM findings into clinical practice and individual classification. To this end, we examined whether a support vector machine (SVM) can provide useful accuracies for the differential diagnosis. We acquired a volumetric 3D T1-weighted MRI of 21 patients with idiopathic Parkinson syndrome (IPS), 11 multiple systems atrophy (MSA-P) and 10 progressive supranuclear palsy (PSP), and 22 healthy controls. Images were segmented, normalized, and compared at group level with SPM8 in a classical VBM design. Next, a SVM analysis was performed on an individual basis with leave-one-out cross-validation. VBM showed a strong white matter loss in the mesencephalon of patients with PSP, a putaminal grey matter loss in MSA, and a cerebellar grey matter loss in patients with PSP compared with IPS. The SVM allowed for an individual classification in PSP versus IPS with up to 96.8% accuracy with 90% sensitivity and 100% specificity. In MSA versus IPS, an accuracy of 71.9% was achieved; sensitivity, however, was low with 36.4%. Patients with IPS could not be differentiated from controls. In summary, a voxel-based SVM analysis allows for a reliable classification of individual cases in PSP that can be directly clinically useful. For patients with MSA and IPS, further developments like quantitative MRI are needed.