Review: Neuropathology of acute phase encephalitis lethargica: a review of cases from the epidemic period

Introduction: Encephalitis lethargica (EL), an epidemic disease of the early 20th century, has continued to be diagnosed sporadically since that time, including a report of 20 new cases in 2004. Many of the recent case reports state that the primary neuropathology of acute EL consists of inflammatory changes and lesions within the midbrain, basal ganglia and substantia nigra. However, the neuropathology of acute EL cases from the epidemic period was actually much more widespread. Methods: In order to characterize the neuropathology of acute phase EL, we developed a database of EL pathology based on 112 cases from the years 1915 to 1940, of which most died within 2 weeks of EL onset. Results: Our analysis revealed that cortical damage was prevalent in 75% of the 112 cases; damage to the meninges and brainstem occurred in approximately half of the cases; and the substantia nigra was damaged in only 13% of these acute cases. We also found that after 1921, damage to cranial nerve nuclei was not reported. An analysis of the neuropathology and clinical symptoms revealed little correlation. Conclusions: Based on these findings, putative modern cases of acute EL with MRI/CT indicated lesions confined solely to the midbrain, brainstem, and/or basal ganglia should not be considered, consistent with that reported during epidemic period.     

Enterovirus 71 encephalomyelitis and Japanese encephalitis can be distinguished by topographic distribution of inflammation and specific intraneuronal detection of viral antigen and RNA

K. T. Wong, K. Y. Ng, K. C. Ong, W. F. Ng, S. K. Shankar, A. Mahadevan, B. Radotra, I. J. Su, G. Lau, A. E. Ling, K. P. Chan, P. Macorelles, S. Vallet, M. J. Cardosa, A. Desai, V. Ravi, N. Nagata, H. Shimizu and T. Takasaki (2012) Neuropathology and Applied Neurobiology 38, 443–453 Enterovirus 71 encephalomyelitis and Japanese encephalitis can be distinguished by topographic distribution of inflammation and specific intraneuronal detection of viral antigen and RNA Aims: To investigate if two important epidemic viral encephalitis in children, Enterovirus 71 (EV71) encephalomyelitis and Japanese encephalitis (JE) whose clinical and pathological features may be nonspecific and overlapping, could be distinguished. Methods: Tissue sections from the central nervous system of infected cases were examined by light microscopy, immunohistochemistry and in situ hybridization. Results: All 13 cases of EV71 encephalomyelitis collected from Asia and France invariably showed stereotyped distribution of inflammation in the spinal cord, brainstem, hypothalamus, cerebellar dentate nucleus and, to a lesser extent, cerebral cortex and meninges. Anterior pons, corpus striatum, thalamus, temporal lobe, hippocampus and cerebellar cortex were always uninflamed. In contrast, the eight JE cases studied showed inflammation involving most neuronal areas of the central nervous system, including the areas that were uninflamed in EV71 encephalomyelitis. Lesions in both infections were nonspecific, consisting of perivascular and parenchymal infiltration by inflammatory cells, oedematous/necrolytic areas, microglial nodules and neuronophagia. Viral inclusions were absent. Conclusions: Immunohistochemistry and in situ hybridization assays were useful to identify the causative virus, localizing viral antigens and RNA, respectively, almost exclusively to neurones. The stereotyped distribution of inflammatory lesions in EV71 encephalomyelitis appears to be very useful to help distinguish it from JE.     

Movement disorders associated with encephalitis lethargica: a video compilation.

Encephalitis lethargica (EL; epidemic encephalitis; von Economo's disease) often presented with a movement disorder, and the motor consequences of postencephalitic parkinsonism (PEP) were characteristic of the chronic sequelae of this condition. PEP was similar to Parkinson's disease but was more variable and had some distinct features such as oculogyric crises. Although two previous publications have included video images of the movement disorders associated with EL and PEP, the sequences presented were typically short, showed only a few patients, and did not include the work of several neurologists who had the foresight to preserve filmed images of their patients. We describe the most complete record of EL and PEP moving images that have been preserved and make them available in edited form.     

Transient global amnesia as a manifestation of Epstein-Barr virus encephalitis

Summary A 43-year-old man developed severe global amnesia with uncinate fits and a single generalised convulsion 10 days after a febrile infection. CSF pleocytosis and serological findings indicated an acute Epstein-Barr virus encephalitis. All of the symptoms cleared within 2 weeks except for occasional generalised seizures. This seems to be the first observation of Epstein-Barr virus encephalitis presenting predominantly as transient global amnesia.

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Zusammenfassung Ein 43jähriger Mann erkrankte an einer schweren globalen Gedächtnisstörung, vereinzelten Uncinatus-Anfällen und einem ersten, generalisierten Krampfanfall, 10 Tage nach einem fieberhaften Infekt. Liquorpleozytose und virologisch-serologische Befunde zeigten das Vorliegen einer akuten Epstein-Barr-Virusencephalitis. Alle Symptome verschwanden innerhalb von zwei Wochen. Lediglich gelegentliche, generalisierte Anfälle blieben bestehen. Dieser Fall scheint die erste Beobachtung einer Epstein-Barr-Virus-infektion zu sein, bei der eine transiente, globale Amnesie im Vordergrund steht.

     

Rasmussen脑炎临床病理研究

目的 探讨Rasmussen脑炎的的发病机制、临床表现、神经影像学表现和病理特征.方法 结合临床、影像、HE和免疫组化方法对6例大脑半球切除的Rasmussen脑炎患者的资料进行回顾分析(手术时年龄3.5 ～11.0岁).结果 患者均为难治性癫痫,患病时间1-4年,均有不同程度偏瘫.术后随访4个月-3年8个月,预后均良好,正规服用抗癫痫药物,均无癫痫发作.组织病理学上所有6例均可见局灶软脑膜下星形胶质细胞增生,脑实质淋巴细胞及小胶质细胞结节散在分布,5例脑实质血管周围慢性淋巴细胞浸润,淋巴套袖形成,所有淋巴细胞以T淋巴细胞为主(CD3+,CD5+,CD7+),且有细胞毒性T淋巴细胞为主(CD8+,GranzymeB+,CD4-),B淋巴细胞罕见(CD79a-,CD20-).未见病毒包涵体.结论 Rasmussen脑炎中淋巴细胞为细胞毒性T细胞来源,患侧大脑半球切除是治疗Rasmussen脑炎、阻止疾病进展的有效的方法.     

A historical analysis of the relationship between encephalitis lethargica and postencephalitic parkinsonism: A complex rather than a direct relationship

Postencephalitic parkinsonism has been considered unique among disorders with parkinsonian features because it is believed to have a unitary etiology associated with the virus that presumably caused encephalitis lethargica. Careful analysis of the historical record, however, suggests that this relationship is more complex than commonly perceived. In most cases, the diagnosis of acute encephalitis lethargica was made post hoc, and virtually any catarrh‐like illness was considered to have represented encephalitis lethargica, often after an oral history‐taking that was undoubtedly subject to patient recall and physician bias. Also, postencephalitic parkinsonism and oculogyric crises were not recognized as sequelae to encephalitis lethargica until well after other sequelae such as movement disorders and mental disturbances had been identified (see previous paper). We suggest here that the relationship between encephalitis lethargica and postencephalitic parkinsonism is not simplistic, i.e., encephalitis lethargica was not solely responsible for the etiology of postencephalitic parkinsonism, thus aligning the latter with most other parkinsonian disorders that are now believed to have multiple causes. © 2010 Movement Disorder Society     

Emerging zoonotic encephalitis viruses: Lessons from Southeast Asia and Oceania

The last decade of the 20th Century saw the introduction of an unprecedented number of encephalitic viruses emerge or spread in the Southeast Asian and Western Pacific regions (Mackenzie et al, 2001; Solomon, 2003a). Most of these viruses are zoonotic, either being arthropod-borne viruses or bat-borne viruses. Thus Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, has spread through the Indonesian archipelago to Papua New Guinea (PNG) and to the islands of the Torres Strait of northern Australia, to Pakistan, and to new areas in the Indian subcontinent; a strain of tick-borne encephalitis virus (TBEV) was described for the first time in Hokkaido, Japan; and a novel mosquito-borne alphavirus, Me Tri virus, was described from Vietnam. Three novel bat-borne viruses emerged in Australia and Malaysia; two, Hendra and Nipah viruses, represent the first examples of a new genus in the family Paramyxoviridae, the genus Henipaviruses, and the third, Australian bat lyssavirus (ABLV) is new lyssavirus closely related to classical rabies virus. These viruses will form the body of this brief review.     

Viral encephalitis: a review of diagnostic methods and guidelines for management

Viral encephalitis is a medical emergency. The spectrum of brain involvement and the prognosis are dependent mainly on the specific pathogen and the immunological state of the host. Although specific therapy is limited to only several viral agents, correct immediate diagnosis and introduction of symptomatic and specific therapy has a dramatic influence upon survival and reduces the extent of permanent brain injury in survivors. We searched MEDLINE (National Library of Medicine) for relevant literature from 1966 to May 2004. Review articles and book chapters were also included. Recommendations are based on this literature based on our judgment of the relevance of the references to the subject. Recommendations were reached by consensus. Where there was lack of evidence but consensus was clear we have stated our opinion as good practice points. Diagnosis should be based on medical history, examination followed by analysis of cerebrospinal fluid for protein and glucose contents, cellular analysis and identification of the pathogen by polymerase chain reaction (PCR) amplification (recommendation level A) and serology (recommendation level B). Neuroimaging, preferably by magnetic resonance imaging, is an essential aspect of evaluation (recommendation level B). Lumbar puncture can follow neuroimaging when immediately available, but if this cannot be obtained at the shortest span of time it should be delayed only in the presence of strict contraindications. Brain biopsy should be reserved only for unusual and diagnostically difficult cases. All encephalitis cases must be hospitalized with an access to intensive care units. Supportive therapy is an important basis of management. Specific, evidence-based, anti-viral therapy, acyclovir, is available for herpes encephalitis (recommendation level A). Acyclovir might also be effective for varicella-zoster virus encephalitis, gancyclovir and foscarnet for cytomegalovirus encephalitis and pleconaril for enterovirus encephalitis (IV class of evidence). Corticosteroids as an adjunct treatment for acute viral encephalitis are not generally considered to be effective and their use is controversial. Surgical decompression is indicated for impending uncal herniation or increased intracranial pressure refractory to medical management.     

病毒性脑炎患者脑血管造影的改变

目的探讨病毒性脑炎患者脑血管造影的改变。方法应用数字减影血管造影(DSA)系统对5例单纯疱疹病毒性脑炎和2例Epstein-Barr病毒性脑炎患者进行全脑血管造影检查,并与对照组(10例头痛患者)进行比较。结果病毒性脑炎患者DSA检查均异常,表现为“激惹”式血循环速度明显加快,整个脑动静脉循环时间平均6.71s,而对照组DSA检查均正常,整个脑动静脉循环时间为10.25s,两组比较差异有显著性(P<0.05)。结论病毒性脑炎的脑血管造影检查可见脑血循环速度明显加快,其对病毒性脑炎的诊断有一定价值。     

登革热脑炎伴降钙素原升高1例报道

该文报道了1例患登革热脑炎的年轻女性患者。收集了患者的临床症状和体征、生化标志物、影像学表现、宏基因检测等资料,并查阅相关文献。该患者以“发热、头痛4 d,腹泻、呕吐3 d,全身抽搐伴意识障碍3 h”为主诉被陆军军医大学第一附属医院收入院。入院第2天脑脊液宏基因组学检测（RNA）结果显示,登革热病毒1型,且伴有降钙素原升高,明确了登革热脑炎的诊断。临床上遇到发热、头痛、腹泻、呕吐,伴随降钙素原水平升高的患者,应怀疑登革热脑炎,并进行登革热血清学检查和脑脊液登革热RNA检测。 [国际神经病学神经外科学杂志, 2024, 51(2): 69-72]     

Autoimmune encephalitis: Recent updates and emerging challenges

The knowledge of immune dysregulation and autoimmunity in neurological disorders has expanded considerably in recent times. Recognition of clinical syndromes, reliable methods of diagnosis, and early targeted immunotherapy can lead to a favourable outcome in acute and subacute neurological disorders that may be associated with significant morbidity and mortality if left untreated. This review focuses on the rapidly expanding field of autoimmune encephalitis. We describe the differences between limbic encephalitis associated with antibodies targeting intracellular antigens, and neuronal surface antibody syndromes (NSAS) where the antigens are primarily receptors or synaptic proteins located on the neuronal cell surface. We chronologically highlight important developments in NSAS by focusing on voltage gated potassium channel complex-associated antibody mediated encephalitis, anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis, and anti-dopamine 2 receptor antibody-associated basal ganglia encephalitis. Contentious issues such as the complexities of using serum antibodies as biomarkers, the initiation of central nervous system autoimmunity, and possible pathogenic mechanisms of these antibodies will be reviewed. The therapeutic challenges that clinicians face such as the timing of therapy and the role of second-line therapy will be discussed, with crucial concepts highlighted in the form of clinical vignettes. Future directions will involve the identification of novel antigens and methods to establish their pathogenicity, as well as evaluation of the most efficacious therapeutic strategies in patients with established NSAS.     

Non-herpes simplex encephalitis is early exclusion of herpes simplex etiology possible?

Summary Since effective antiviral treatment is available for herpes simplex encephalitis (HSE), early diagnosis or exclusion of herpes simplex etiology is essential for prognosis. In a retrospective study of 25 cases of acute viral encephalitis not caused by herpes simplex virus (non-HSE), we investigated whether HSE can be excluded in the early phase before serological evidence is present. Using clinical means, history, investigations of CSF (protein, cells), EEG, and CCT, HSE could not be excluded with reliability. This is because clinical signs and laboratory results are not pathognomonic for any form of viral encephalitis, even if periodic activity in EEG and temporal attenuation in CCT are more frequent in HSE than in other forms of encephalitis. Therefore, in all cases of severe encephalitis, acyclovir therapy should be initiated early.     

N-methyl D-aspartate receptor encephalitis: A new addition to the spectrum of autoimmune encephalitis

A large proportion of “encephalitis” is caused by unknown agents. Of late, a new category of disorders, “autoimmune encephalitis,” has been described, which present with features similar to viral encephalitides. A well-delineated and common entity among this group is the recently described anti-NMDAR encephalitis (NMDARE). Although this entity was initially described in young women harboring ovarian teratomas, it is now characterised as well in children and men. Approximately 60% of the patients have an underlying tumor, usually an ovarian teratoma. In 40% of the patients, no cause can be found (idiopathic NMDARE). NMDARE typically presents with psychiatric features followed by altered level of consciousness, severe dysautonomia, hyperkinetic movement disorders, seizures and central hypoventilation. Orofacial dyskinesias resulting in lip and tongue mutilation are quite common. Seizures, are common and may be difficult to treat. The disease can be confirmed by serum and cerebrospinal fluid anti-NMDAR antibodies. Titers of these antibodies can also guide response to treatment. Tumor removal is necessary if identified, followed by immunological treatment. Intravenous methylprednisolone and immunoglobulins aim to suppress/modulate immune response while plasma exchange attempts to remove antibodies and other inflammatory cytokines. Rituximab and cyclophosphamide aim to suppress antibody production. Recovery is slow and often with neurological deficits if treatment is delayed. With many distinctive clinical features, a specific antibody that aids diagnosis, and early effective treatment with commonly available drugs leading to good outcomes, NMDARE is a diagnosis that should be considered early in any case of “unexplained encephalitis.”     

Diagnosis of herpes simplex encephalitis

In a series of six cases of encephalitis caused by herpes simplex virus, type 1, the diagnostic and prognostic value of the electroencephalogram (EEG) was investigated. Special interest was focused on the time relationship between the appearance of abnormal EEG findings, the initial clinical symptoms and the changes in cranial computed tomography (CT). The characteristic periodic EEG pattern can be demonstrated within 2 days of disease, before typical structural changes appear in CT. A unilateral periodic pattern may be associated with a good prognosis, where-as all patients with bilateral changes died in spite of specific antiviral therapy.     

疱疹病毒性脑炎的早期诊断方法研究

目的探讨不同检测手段对早期诊断疱疹病毒性脑炎（ＨＶＥ）的价值。方法应用间接荧光抗体法（ＩＦＡ）、聚合酶链反应（ＰＣＲ）检测ＨＶＥ患者脑脊液中的抗疱疹病毒ＩｇＭ抗体和疱疹病毒核酸；应用免疫细胞化学（ＩＣＣ）、原位杂交（ＩＳＨ）和ＰＣＲ检测ＨＶＥ患者脑活检组织中的疱疹病毒抗原和核酸。结果６４例患者脑脊液中５４例抗疱疹病毒ＩｇＭ抗体阳性，５０例ＰＣＲ阳性，其中４０例两者均为阳性。１２例脑组织中１０例ＰＣＲ阳性，４例ＩＳＨ阳性，６例ＩＣＣ阳性。结论抗疱疹病毒ＩｇＭ抗体检测最敏感，以下依次为ＰＣＲ、ＩＣＣ、ＩＳＨ诊断疱疹病毒性脑炎，联合应用以上几种检测手段有助于提高早期诊断ＨＶＥ阳性率。     

Characterisation of a syndrome of autoimmune adult onset focal epilepsy and encephalitis

We report a series of patients with a clinical syndrome characterised by the explosive onset in adulthood of recurrent focal seizures of frontotemporal onset and features suggestive of autoimmune encephalitis. We propose that this presentation of “autoimmune adult onset focal epilepsy and encephalitis” is a recognisable clinical syndrome, and provide evidence it may be associated with heterogeneous immunological targets. Between 2008 and 2011 we encountered six patients with new-onset epilepsy in whom we suspected an autoimmune aetiology. We first characterised the clinical, electroencephalographic, cerebrospinal fluid (CSF), imaging, and pathological findings of this syndrome. We subsequently tested them for antibodies against both intracellular and neuronal cell surface antigens. All patients presented with recurrent seizures with focal frontotemporal onset, refractory to multiple anticonvulsants. Four had focal T2-weighted hyperintensities on MRI. CSF mononuclear cells were variably elevated with positive oligoclonal bands in four. Brain biopsy in one patient demonstrated perivascular lymphocytic infiltration. Two were treated with immunosuppression and went on to achieve complete seizure control and return to baseline cognition. Three of four patients who received only pulsed steroids or no treatment had ongoing frequent seizures, with two dying of sudden unexpected death in epilepsy. Subsequently, three had antibodies identified against neuronal cell surface antigens including N-methyl-d-aspartate receptor and leucine-rich glioma inactivated 1. We suggest that patients with such a presentation should be carefully evaluated for a suspected autoimmune aetiology targeting cell surface antigens and have a therapeutic trial of immunosuppression as this may improve their long-term outcome.     

Concurrent herpes simplex type 1 necrotizing encephalitis,cytomegalovirus ventriculoencephalitis and cerebral lymphoma in an AIDS patient

Unlike cytomegalovirus (CMV) ventriculoencephalitis, herpes simplex virus type 1 necrotizing encephalitis has only rarely been observed in AIDS patients. A 40-year-old bisexual man was followed for an HIV1 infection from 1987 onwards. In June 1993 he was referred for sudden confusion, left hemiparesia and fever. The blood contained less than 10 CD4 lymphocytes/mm³. The patient remained comatose and febrile, and died 4 weeks later. In coronal sections of the brain there was necrosis of the internal parts of the left temporal lobe, necrosis of certain areas of the ventricular walls and a small tumor at the top of the right frontal lobe, which proved to be a polymorphic high-grade lymphoma. CMV ventriculoencephalitis lesions were prominent in the ventricular walls of the oecipital lobes and there was a strong nuclear signal for CMV using in situ hybridization. Herpes simplex virus type 1 was shown in the nuclei and cytoplasm of certain neurons and astrocytes in the borders of the necrotized temporal lobe areas by immunohistochemistry, in situ hybridization and electron microscopy, whereas in situ hybridization and immunohistochemistry for CMV were negative in such areas. Necrotizing type 1 encephalitis must not be overlooked in immunodeficient patients.