Marie Studahl

Influenza virus and CNS manifestations.

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 Reyes syndrome, acute necrotising encephalopathy (ANE), and myelitis as well as autoimmune conditions, such as Guillain-Barres syndrome, may occur during the course of influenza infection. Virological diagnosis is essential and based on virus isolation, 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.

Varicella-zoster virus CNS disease - viral load, clinical manifestations and sequels.

BACKGROUND Real-time polymerase chain reaction (PCR) analysis of cerebrospinal fluid (CSF) samples has improved the diagnosis of varicella-zoster virus (VZV) infection of the central nervous system (CNS). The VZV viral load in the CSF obtained from VZV-related neurological syndromes is not known. OBJECTIVES To investigate VZV viral loads associated with VZV-related neurological syndromes, and to describe the clinical manifestations and sequels in patients with VZV DNA in the CSF. STUDY DESIGN Patients in the Western Gotaland region of Sweden with CNS symptoms and VZV DNA in the CSF, during 1995-2006 were retrospectively identified. The diagnoses, laboratory tests (including virus quantity), antiviral treatment, and neurological complications were studied. RESULTS Ninety-seven patients with VZV DNA in the CSF detected by PCR were identified. In 66 patients in whom VZV DNA levels were determined, significantly higher viral loads were found in those with encephalitis and acute aseptic meningitis compared to patients with cranial nerve affection (including Ramsay Hunt syndrome). Fifty patients had a follow-up; 34 (68%) had neurological symptoms 1 month after acute disease and 25 (50%) had neurological complications 3 months after discharge. A minimum yearly incidence of 1.8 per 100,000 of PCR diagnosed VZV CNS infections was estimated. CONCLUSIONS VZV was the most common alpha-herpesvirus detected in CSF samples from patients with CNS symptoms in the Western Gotaland region of Sweden. CSF viral loads were higher in patients with encephalitis and acute aseptic meningitis than in other CNS syndromes caused by VZV. A majority of the patients that were seen in follow-up had neurological symptoms and sequels.

Herpesvirus DNA Detection in Cerebral Spinal Fluid: Differences in Clinical Presentation between Alpha-, Beta-, and Gamma-Herpesviruses

To evaluate the role of 6 human herpesviruses (cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus-6 (HHV-6), herpes simplex virus (HSV) types 1 and 2 and varicella zoster virus (VZV)) in infections of the nervous system, cerebrospinal fluid (CSF) samples from 662 patients with suspected viral aetiology to neurological symptoms were investigated for presence of herpesviral DNA in a PCR-based study. Of the 69 patients (2 patients had 2 herpesvirus DNA detected in CSF) who had herpesvirus DNA detected in the CSF, 60 (87%) were non-immunocompromised (CMV 7; HHV-6 6; EBV 16; HSV-1 18; HSV-2 9 and VZV 6) and 9 (13%) were immunocompromised (CMV 3; HHV-6 0; EBV 5; HSV-1 0; HSV-2 1 and VZV 0). The study was performed in a retrospective/prospective manner. The HSV-1, HSV-2, VZV and CMV DNA-positive patients usually had typical clinical syndromes, such as encephalitis/myelitis and meningitis, but also other neurological conditions were associated with findings of these viruses. HHV-6 and EBV DNA were detected in patients presenting with a variety of neurological symptoms, and in some of the cases, concurrent with diagnosis of other infections of the central nervous system. Despite the overall variability of clinical conditions seen, a pattern associated with each investigated herpesvirus was discernable as regards clinical presentation.To evaluate the role of 6 human herpesviruses (cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus-6 (HHV-6), herpes simplex virus (HSV) types 1 and 2 and varicella zoster virus (VZV)) in infections of the nervous system, cerebrospinal fluid (CSF) samples from 662 patients with suspected viral aetiology to neurological symptoms were investigated for presence of herpesviral DNA in a PCR-based study. Of the 69 patients (2 patients had 2 herpesvirus DNA detected in CSF) who had herpesvirus DNA detected in the CSF, 60 (87%) were non-immunocompromised (CMV 7; HHV-6 6; EBV 16; HSV-1 18; HSV-2 9 and VZV 6) and 9 (13%) were immunocompromised (CMV 3; HHV-6 0; EBV 5; HSV-1 0; HSV-2 1 and VZV 0). The study was performed in a retrospective/prospective manner. The HSV-1, HSV-2, VZV and CMV DNA-positive patients usually had typical clinical syndromes, such as encephalitis/myelitis and meningitis, but also other neurological conditions were associated with findings of these viruses. HHV-6 and EBV DNA were detected in patients presenting with a variety of neurological symptoms, and in some of the cases, concurrent with diagnosis of other infections of the central nervous system. Despite the overall variability of clinical conditions seen, a pattern associated with each investigated herpesvirus was discernable as regards clinical presentation.

Difference in pathogenesis between herpes simplex virus type 1 encephalitis and tick-borne encephalitis demonstrated by means of cerebrospinal fluid markers of glial and neuronal destruction

Abstract We determined the extent of neuronal and glial cell destruction in 13 patients with herpes simplex type 1 (HSV-1) encephalitis, 15 patients with tick-borne encephalitis (TBE), and 20 noninfectious controls by analyzing the cerebrospinal fluid (CSF) concentrations of neurofilament protein (a marker of neurons, mainly axons), neuron-specific enolase (a marker of neurons, mainly somas), glial fibrillary acidic protein, and S-100 protein (markers of astrocytes). In addition, in patients with HSV-1 encephalitis CSF samples were collected serially before 7, 8–14, and 18–49 days and 3–10 months after the onset of neurological symptoms. In the acute stage of HSV-1 encephalitis we found markedly higher CSF levels of the cell damage markers than in patients with TBE. The concentration of cell damage markers in HSV-1 encephalitis decreased within 45 days after acute infection, except for neurofilament protein. The CSF concentrations of neurofilament protein increased during the second week, remained extremely high throughout the next month, and decrease thereafter. The changes in these markers of neuronal and glial destruction demonstrate the neuronal and astroglial cell damage during the first month after HSV-1 encephalitis. In contrast, most patients with TBE had signs only of slight astrogliosis, except for two patients with paresis.

Late-Onset Posttraumatic Skin and Soft-Tissue Infections Caused by Rapid-Growing Mycobacteria in Tsunami Survivors

BACKGROUND In the tsunami catastrophe in Thailand in 2004, several thousand Swedish tourists were injured, with contaminated crush trauma of the legs being the main cause of injury among the survivors. METHODS Patient and laboratory data for those who received hospital care in Stockholm and Gothenburg and contracted late-onset infections due to rapid-growing mycobacteria were reviewed retrospectively. Also, concomitant infections were recorded. RESULTS Fifteen patients with late-onset skin and soft-tissue infections due to rapid-growing mycobacteria are described here. Mycobacterium abscessus was isolated in 7 cases, Mycobacterium fortuitum was isolated in 6 cases, and Mycobacterium peregrinum and Mycobacterium mageritense were isolated in 1 case each. The infections appeared after a delay of 20-105 days (median, 60 days) after the trauma, targeting undamaged skin located near primary sutured wounds or skin grafts. Antimycobacterial drugs were given to 9 (60%) of the patients. The course of infection was protracted, but all infections due to rapid-growing mycobacteria healed within 12 months. Concomitant subcutaneous infections due to other microorganisms, such as Burkholderia pseudomallei or Cladophialophora bantiana, appeared early or late after the trauma. CONCLUSIONS Repeated cultures of abscess and wound specimens for Mycobacterium species may be needed to find the etiologic agents causing contaminated skin and soft-tissue infections, such as those that developed after traumas that occurred during the tsunami. These cultures are especially necessary when symptoms appear late and when conventional bacterial culture results are negative. A biopsy is recommended for the best yield and for complementary histopathological examination.

Long-term Valacyclovir Suppressive Treatment After Herpes Simplex Virus Type 2 Meningitis: A Double-Blind, Randomized Controlled Trial

BACKGROUND Herpes simplex virus type 2 (HSV-2) is a common cause of acute and recurrent aseptic meningitis. Our aim was to determine the impact of antiviral suppression on recurrence of meningitis and to delineate the full spectrum of neurological complications. METHODS One hundred and one patients with acute primary or recurrent HSV-2 meningitis were assigned to placebo (n = 51) or 0.5 g of valacyclovir twice daily (n = 50) for 1 year after initial treatment with 1 g of valacyclovir 3 times daily for 1 week in a prospective, placebo-controlled, multicenter trial. The primary outcome was time until recurrence of meningitis. The patients were followed up for 2 years. RESULTS The first year, no significant difference was found between the valacyclovir and placebo groups. The second year, without study drugs, the risk of recurrence of verified and probable HSV-2 meningitis was significantly higher among patients exposed to valacyclovir (hazard ratio, 3.29 [95% confidence interval, 10.06-10.21]). One-third of the patients experienced 1-4 meningitis episodes during the study period. A considerable morbidity rate, comprising symptoms from the central, peripheral, and autonomous nervous system, was found in both groups. CONCLUSIONS Suppressive treatment with 0.5 g of valacyclovir twice daily was not shown to prohibit recurrent meningitis and cannot be recommended for this purpose after HSV meningitis in general. Protection against mucocutaneous lesions was observed, but the dosage was probably inappropriate for the prevention of HSV activation in the central nervous system. The higher frequency of meningitis, after cessation of active drug, could be interpreted as a rebound phenomenon.

Septic Arthritis of the Knee: A 10-Year Review and Long-term Follow-up using a New Scoring System

The case records of 64 patients with 65 episodes of infectious gonarthritis during 1979-88 were reviewed regarding epidemiological, clinical and laboratory data of possible relevance to the course and outcome of the disease. Long-term healing results were evaluated by means of a new scoring system 2-11 years after the acute disease in 46 patients. The infection was acquired by inoculation in 37% and by the hematogenous route in 55%. The major risk factors were trauma to the joint and arthrosis. Staphylococcus aureus was the causative agent in 58% and Streptococci in 15%. Treatment consisted of suction irrigation (86%) or intermittent aspiration (5%) combined with systemic antibiotic treatment. At follow-up, the pain and ache scores of the arthritic joint had decreased by 21% and 16% respectively, compared with the scores of the contralateral control joints. Anatomy and motility were reduced by 9% and 8% respectively. Age < 45 was associated with a greater score loss than in older patients. Treatment delayed by > 5 days was associated with increased loss of motility. We estimate that 79% of the patients had excellent or good long-term results following treatment of infectious arthritis of the knee. Evaluation of healing after infectious gonarthritis by use of a scoring system is quite feasible and allows comparison of different treatment regimes with improved accuracy.

Cutaneous melioidosis in a Swedish tourist after the tsunami in 2004

A tourist from Sweden developed cutaneous melioidosis after the tsunami in Thailand on 26 December 2004. Melioidosis is a severe, chronic infection which is endemic in Thailand and is caused by Burkholderia pseudomallei. Persons with traumatic injuries inflicted by the tsunami have increased risks of being infected by B. pseudomallei and melioidosis should be suspected if abscesses of the skin or inner organs develop in the months or years after the trauma.

Varicella-Zoster Virus (VZV) Glycoprotein E Is a Serological Antigen for Detection of Intrathecal Antibodies to VZV in Central Nervous System Infections, without Cross-Reaction to Herpes Simplex Virus 1

ABSTRACT Herpes simplex virus 1 (HSV-1) and varicella-zoster virus (VZV) cause serious central nervous system (CNS) diseases that are diagnosed with PCR using samples of cerebrospinal fluid (CSF) and, during later stages of such infections, with assays of intrathecal IgG antibody production. However, serological diagnoses have been hampered by cross-reactions between HSV-1 and VZV IgG antibodies and are commonly reported in patients with herpes simplex encephalitis (HSE). In this study we have evaluated VZV glycoprotein E (gE) as a new antigen for serological diagnosis of VZV-induced CNS infections. Paired samples of CSF and serum from 29 patients with clinical diagnosis of VZV CNS infection (n = 15) or HSE (n = 14), all confirmed by PCR, were analyzed. VZV gE and whole VZV were compared as antigens in enzyme-linked immunosorbent assays (ELISAs) for serological assays in which the CSF/serum sample pairs were diluted to identical IgG concentrations. With the gE antigen, none of the HSE patients showed intrathecal IgG antibodies against VZV, compared to those shown by 11/14 patients using whole-VZV antigen (P < 0.001). In the patients with VZV infections, significantly higher CSF/serum optical density (OD) ratios were found in the VZV patients using the VZV gE antigen compared to those found using the whole-VZV antigen (P = 0.001). These results show that gE is a sensitive antigen for serological diagnosis of VZV infections in the CNS and that this antigen was devoid of cross-reactivity to HSV-1 IgG in patients with HSE. We therefore propose that VZV gE can be used for serological discrimination of CNS infections caused by VZV and HSV-1.

The antibody response to pandemic H1N1 2009 influenza vaccine in adult organ transplant patients

Limited data are available regarding antibody response and the safety of the monovalent influenza A H1N1/09 vaccine for immunocompromised patients. In this study, the humoral response to this vaccine in solid organ transplant (SOT) recipients and healthy individuals was evaluated. Eighty‐two SOT recipients and 28 healthy individuals received two doses of the influenza A H1N1/09 AS03 adjuvanted vaccine containing 3.75 mg of haemagglutinin at a 3‐ to 4‐week interval. Serum samples were drawn at baseline and 3–4 weeks after the first and second vaccine doses. Seroprotective titres were measured with a haemagglutination inhibition. After the first dose seroprotective titres were observed in 69% of the SOT patients and in 96% of the healthy controls (P = 0.006), and increased after the second dose to 80% and 100%, respectively (P = 0.003). All controls and 77% of the SOT recipients achieved a ≥4‐fold titre rise after the first immunisation (P = 0.005). The vaccine was well tolerated and no acute rejection was observed. Influenza A H1N1/09 vaccine elicited a protective antibody response in the majority of SOT recipients, but the response was lower when compared with controls. A second dose significantly improved vaccine immunogenicity in SOT recipients. (ClinicalTrials.gov number: NCT01254955)