Peter G. E. Kennedy

The neurotropic herpes viruses: herpes simplex and varicella-zoster

Herpes simplex viruses types 1 and 2 (HSV1 and HSV2) and varicella-zoster virus (VZV) establish latent infection in dorsal root ganglia for the entire life of the host. From this reservoir they can reactivate to cause human morbidity and mortality. Although the viruses vary in the clinical disorders they cause and in their molecular structure, they share several features that affect the course of infection of the human nervous system. HSV1 is the causative agent of encephalitis, corneal blindness, and several disorders of the peripheral nervous system; HSV2 is responsible for meningoencephalitis in neonates and meningitis in adults. Reactivation of VZV, the pathogen of varicella (chickenpox), is associated with herpes zoster (shingles) and central nervous system complications such as myelitis and focal vasculopathies. We review the biological, medical, and neurological aspects of acute, latent, and reactivated infections with the neurotropic herpes viruses.

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.

Human African trypanosomiasis of the CNS: current issues and challenges

Human African trypanosomiasis (HAT), also known as sleeping sickness, is a major cause of mortality and morbidity in sub-Saharan Africa. Current therapy with melarsoprol for CNS HAT has unacceptable side-effects with an overall mortality of 5%. This review discusses the issues of diagnosis and staging of CNS disease, its neuropathogenesis, and the possibility of new therapies for treating late-stage disease.

Miller Fisher syndrome is associated with serum antibodies to GQ1b ganglioside.

A recent report described serum anti-GQ1b ganglioside antibodies in Miller Fisher syndrome (MFS), a clinical variant of Guillain-Barré syndrome (GBS). Four consecutive cases of MFS all had high titre anti-GQ1b antibodies which were absent from all control sera including those of patients with GBS.

Herpes simplex encephalitis

Herpes simplex virus encephalitis still has an unacceptably high mortality Herpes simplex virus (HSV) is a human herpesvirus that causes HSV encephalitis (HSE), which is the commonest fatal sporadic encephalitis in humans.1,2 About 90% of all HSE cases in adults and children are due to HSV-1, while HSV-2 is associated with HSE in neonates, in which there is a disseminated infection, and in immunocompromised patients, such as those with renal transplants or HIV infection.3,4 While the exact incidence of HSE is not known, it has been estimated at about one case per million per year.4,5 This figure is probably an underestimate since about 2000 cases occur annually in the United States.1 The neuropathological picture of HSE is characteristic, consisting of an acute necrotising encephalitis that almost always localises, often asymmetrically, to the orbitofrontal and temporal lobes with involvement of the cingulate and insular cortex; neonatal HSE tends to produce a more diffuse pathology.1 Untreated, HSE has an extremely high mortality rate at about 70% with fewer than 3% of survivors returning to normal function.2,6 Among common central nervous system (CNS) viral infections, mortality in HSE is disproportionately high, taking into account a recent study that showed that HSV infections are responsible for only 11% of cases compared with 29% for varicella-zoster virus,7 another human herpesvirus that is not associated with such a high mortality. The neuropathogenesis of HSE has intrigued clinicians and scientists for many years, with two of the key questions relating to, firstly, the very low incidence of the condition in the presence of the widespread carriage of latent HSV in ganglionic tissues in healthy people and, secondly, the propensity of the disease process to localise to the frontotemporal region. About 90% of normal people are seropositive …

Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness).

Human African trypanosomiasis, or sleeping sickness, is caused by infection with parasites of the genus Trypanosoma, transmitted by the tsetse fly. The disease has two forms, Trypanosoma brucei (T b) rhodesiense and T b gambiense; and is almost always fatal if untreated. Despite a recent reduction in the number of reported cases, patients with African trypanosomiasis continue to present major challenges to clinicians. Because treatment for CNS-stage disease can be very toxic, diagnostic staging to distinguish early-stage from late-stage disease when the CNS in invaded is crucial but remains problematic. Melarsoprol is the only available treatment for late-stage T b rhodesiense infection, but can be lethal to 5% of patients owing to post-treatment reactive encephalopathy. Eflornithine combined with nifurtimox is the first-line treatment for late-stage T b gambiense. New drugs are in the pipeline for treatment of CNS human African trypanosomiasis, giving rise to cautious optimism.

EFNS guideline on the management of community-acquired bacterial meningitis : report of an EFNS Task Force on acute bacterial meningitis in older children and adults

Acute bacterial meningitis (ABM) is a potentially life‐threatening neurological emergency. An agreed protocol for early, evidence‐based and effective management of community‐acquired ABM is essential for best possible outcome. A literature search of peer‐reviewed articles on ABM was used to collect data on the management of ABM in older children and adults. Based on the strength of published evidence, a consensus guideline was developed for initial management, investigations, antibiotics and supportive therapy of community‐acquired ABM. Patients with ABM should be rapidly hospitalized and assessed for consideration of lumbar puncture (LP) if clinically safe. Ideally, patients should have fast‐track brain imaging before LP, but initiation of antibiotic therapy should not be delayed beyond 3 h after first contact of patient with health service. In every case, blood sample must be sent for culture before initiating antibiotic therapy. Laboratory examination of cerebrospinal fluid is the most definitive investigation for ABM and whenever possible, the choice of antibiotics, and the duration of therapy, should be guided by the microbiological diagnosis. Parenteral therapy with a third‐generation cephalosporin is the initial antibiotics of choice in the absence of penicillin allergy and bacterial resistance; amoxicillin should be used in addition if meningitis because of Listeria monocytogenes is suspected. Vancomycin is the preferred antibiotic for penicillin‐resistant pneumococcal meningitis. Dexamethasone should be administered both in adults and in children with or shortly before the first dose of antibiotic in suspected cases of Streptococcus pneumoniae and H. Influenzae meningitis. In patients presenting with rapidly evolving petechial skin rash, antibiotic therapy must be initiated immediately on suspicion of Neisseria meningitidis infection with parenteral benzyl penicillin in the absence of known history of penicillin allergy.

The Continuing Problem of Human African Trypanosomiasis (Sleeping Sickness)

Human African trypanosomiasis, also known as sleeping sickness, is a neglected disease, and it continues to pose a major threat to 60 million people in 36 countries in sub‐Saharan Africa. Transmitted by the bite of the tsetse fly, the disease is caused by protozoan parasites of the genus Trypanosoma and comes in two types: East African human African trypanosomiasis caused by Trypanosoma brucei rhodesiense and the West African form caused by Trypanosoma brucei gambiense. There is an early or hemolymphatic stage and a late or encephalitic stage, when the parasites cross the blood–brain barrier to invade the central nervous system. Two critical current issues are disease staging and drug therapy, especially for late‐stage disease. Lumbar puncture to analyze cerebrospinal fluid will remain the only method of disease staging until reliable noninvasive methods are developed, but there is no widespread consensus as to what exactly defines biologically central nervous system disease or what specific cerebrospinal fluid findings should justify drug therapy for late‐stage involvement. All four main drugs used for human African trypanosomiasis are toxic, and melarsoprol, the only drug that is effective for both types of central nervous system disease, is so toxic that it kills 5% of patients who receive it. Eflornithine, alone or combined with nifurtimox, is being used increasingly as first‐line therapy for gambiense disease. There is a pressing need for an effective, safe oral drug for both stages of the disease, but this will require a significant increase in investment for new drug discovery from Western governments and the pharmaceutical industry. Ann Neurol 2008;64:116–126

VIRAL ENCEPHALITIS: CAUSES, DIFFERENTIAL DIAGNOSIS, AND MANAGEMENT

Encephalitis refers to an acute, usually diffuse, inflammatory process affecting the brain. While meningitis is primarily an infection of the meninges, a combined meningoencephalitis may also occur. An infection by a virus is the most common and important cause of encephalitis, although other organisms may sometimes cause an encephalitis. An encephalitic illness caused by alteration of normal immune function in the context of a previous viral infection or following vaccination is also well recognised (acute disseminated encephalomyelitis, ADEM). An infectious encephalitis may also be difficult to distinguish from an encephalopathy that may be associated with numerous metabolic causes. Among the factors which have helped to focus attention on viral encephalitis over the last few years have been: This article will address three broad areas of viral encephalitis—its causes, differential diagnosis, and management. While the approach will be a general one, I shall focus particularly on HSE which is the most frequent cause of sporadic fatal encephalitis in humans in the western world. The various causes of acute infectious viral encephalitis are shown in table 1. While precise figures for the incidence of encephalitis following these various viruses are not available, estimates have been given for some of them. For example, it has been estimated that HSE, the most important treatable viral encephalitis, has an incidence of about one case per million per year.1 About 2000 cases occur annually in …

Varicella-Zoster Virus Gene Expression in Latently Infected and Explanted Human Ganglia

ABSTRACT A consistent feature of varicella-zoster virus (VZV) latency is the restricted pattern of viral gene expression in human ganglionic tissues. To understand further the significance of this gene restriction, we used in situ hybridization (ISH) to detect the frequency of RNA expression for nine VZV genes in trigeminal ganglia (TG) from 35 human subjects, including 18 who were human immunodeficiency virus (HIV) positive. RNA for VZV gene 21 was detected in 7 of 11 normal and 6 of 10 HIV-positive subjects, RNA for gene 29 was detected in 5 of 14 normal and 11 of 11 HIV-positive subjects, RNA for gene 62 was detected in 4 of 10 normal and 6 of 9 HIV-positive subjects, and RNA for gene 63 was detected in 8 of 17 normal and 12 of 15 HIV-positive subjects. RNA for VZV gene 4 was detected in 2 of 13 normal and 4 of 9 HIV-positive subjects, and RNA for gene 18 was detected in 4 of 15 normal and 5 of 15 HIV-positive subjects. By contrast, RNAs for VZV genes 28, 40, and 61 were rarely or never detected. In addition, immunocytochemical analysis detected the presence of VZV gene 63-encoded protein in five normal and four HIV-positive subjects. VZV RNA was also analyzed in explanted fresh human TG and dorsal root ganglia from five normal human subjects over a period of up to 11 days in culture. We found a very different pattern of gene expression in these explants, with transcripts for VZV genes 18, 28, 29, 40, and 63 all frequently detected, presumably as a result of viral reactivation. Taken together, these data provide further support for the notion of significant and restricted viral gene expression in VZV latency.