Göran Stiernstedt

ACYCLOVIR VERSUS VIDARABINE IN HERPES SIMPLEX ENCEPHALITIS: Randomised Multicentre Study in Consecutive Swedish Patients

One hundred and twenty-seven patients with suspected herpes simplex encephalitis were entered in a randomised, controlled comparative study of therapy with acyclovir 10 mg/kg, 8-hourly, versus vidarabine, 15 mg/kg daily, for 10 days. Consecutive patients were included and nearly all diagnosed cases of HSV-encephalitis in Sweden were enrolled in the study. The diagnosis of HSV-encephalitis was verified by demonstration of intrathecal herpes simplex virus (HSV) antibody production and by HSV cultivation, or antigen detection, in brain biopsy or necropsy material. Of 53 confirmed cases of HSV-encephalitis (corresponding to 2.3 cases per million inhabitants per year in Sweden), 51 (27 acyclovir, 24 vidarabine) were evaluable for therapeutic efficacy. The mortality was 19% in the acyclovir-treated group versus 50% in the vidarabine group (p = 0.04). At 12 month of observation 15 of 27 (56%) acyclovir recipients had no, or mild, sequelae compared with 3 of 24 (13%) vidarabine recipients (p = 0.002). Nineteen of 24 (79%) vidarabine-treated patients died or suffered severe sequelae, compared with 9 of 27 (33%) acyclovir-treated patients (p = 0.005). The effect of treatment was influenced by the level of consciousness at the start of therapy. The outcome for 20 vidarabine-treated patients above 30 years of age with HSE was similar to that for the 53 patients reported by an American collaborative study.

Clinical Manifestations and Diagnosis of Neuroborreliosis

Lyme borreliosis has in a few years turned out to be a health problem not only in the United States, but also in many European countries. When it affects the nervous system, Lyme borreliosis acts as the great disease imitator. Because of this characteristic it is often difficult to diagnose on clinical grounds. Patients with neuroborreliosis might appear within all medical disciplines. Clinical markers, such as preceding tick bite and/or ECM, are important clues to the diagnosis. Mononuclear pleocytosis and elevated CSF protein are present in most patients with neuroborreliosis. Final evidence for the diagnosis is the demonstration of specific antibodies in serum and/or CSF. Measurement of antibody titers should be carried out in both serum and CSF, since these methods are complementary when trying to obtain a serological diagnosis of neuroborreliosis.

Prevalence of Tick-borne Encephalitis and Lyme Borreliosis in a Defined Swedish Population

Sera from 346 individuals living on Lisö, an area south of Stockholm, endemic for tick-borne encephalitis (TBE) and Lyme borreliosis, were tested for antibody activity to TBE-virus (TBEV) and Borrelia burgdorferi, using a sonicate antigen, by haemagglutination-inhibition and ELISA, respectively. 10/346 (3%) individuals had a history of previous serologically confirmed TBE with encephalitic symptoms, and 33/346 (10%) had a history of previous erythema chronicum migrans (ECM). Four individuals (1%) had been treated for neuroborreliosis and another 4 (1%) for acrodermatitis chronica atrophicans (ACA). Antibodies to TBEV and B. burgdorferi were detected in 40/346 (12%) and 89/346 (26%) individuals, respectively. The seroprevalence of Lyme borreliosis increased with age, time spent on Lisö, and number of reported tick-bites. For TBE there was a correlation between seropositivity and time spent on Lisö only. In sera from 50 healthy blood-donors, living in a non-endemic area, no antibody activity to TBEV could be detected and only 1/50 (2%) had antibodies to borrelia. In sera from 150 age and sex matched control individuals, living in the city of Stockholm, antibody activity to TBEV and borrelia was found in 8/150 (5%) and 13/150 (9%), respectively.

CHRONIC MENINGITIS CAUSED BY A PENICILLIN-SENSITIVE MICROORGANISM?

21 patients studied had persistent or progressive chronic meningitis not associated with a demonstrable infectious or other disease, except Streptococcus milleri antigen in the cerebrospinal fluid of 1 patient. The cerebrospinal-fluid (CSF) abnormalities consisted of a moderate, predominantly mononuclear, pleocytosis, a sharp rise in CSF protein (mean 2.3 g/l), intrathecal synthesis of considerable quantities of oligoclonal immunoglobulin G, and, in half the patients, a fall in the CSF-glucose/blood-glucose ratio. In all patients symptoms began during summer or autumn. In 4 patients the onset was preceded by localised cutaneous lesion, described as erythema chronicum migrans. 4 more patients had been bitten by ticks in the weeks before onset of symptoms. The patients had profound fatigue, malaise, and weight-loss. Half had fever, usually moderate. The neurological abnormalities included aseptic meningitis, cranial neuropathy (mostly facial-nerve paralysis), motor and sensory peripheral radiculoneuropathy, and myelitis. The patients improved or recovered, sometimes dramatically, during a 2-week course of intravenous penicillin G.

Septicemia in patients with hematological disorders and neutropenia a retrospective study of causative agents and their resistance profile

In order to identify the cause of septicemia and the resistance patterns of bacteria in Swedish patients with hematological disorders, all positive blood cultures collected at a hematological ward during 1980-1986 were evaluated retrospectively. 198 episodes of septicemia in 129 patients were recorded. 54% were males and 46% women with a median age of 67 years (range 16-88). Patients with acute leukemia (46%), lymphoma (19%) and myeloma (19%) dominated. The absolute neutrophil count (ANC) was less than 0.5 x 10(9)/l in 76% of the bacteremic episodes. A total of 253 consecutive isolates were found with 53% Gram-negatives and 47% Gram-positives. The dominating pathogens were Escherichia coli (27%), klebsiella/enterobacter (15%), pseudomonas (7%), coagulase negative staphylococci (13%), alpha-streptococci (13%), Staphylococcus aureus (10%) and anaerobes (6%). Coagulase negative staphylococci showed a significant increase in isolation rate during the study period. The majority of E. coli were resistant to ampicillin. The susceptibility of klebsiella/enterobacter to ceftazidime and cefuroxime was reduced, while no imipenem resistant strains occurred. Among coagulase negative staphylococci 61% were resistant to isoxazolylpenicillin, none to vancomycin. No dramatic changes in the etiology of septicemia or the susceptibility pattern during the study period were noticed. Coagulase negative staphylococci, S. epidermidis in particular, constitute an increasing problem among granulocytopenic patients.

Clinical manifestations of Borrelia infections of the nervous system

Clinical, treatment and laboratory parameters were analyzed in 46 consecutive Swedish patients with Borrelia infections of the nervous system. The importance of age in the clinical symptoms, the wide spectrum of disease, and the chronic behaviour of the Borrelia infection of the nervous system was stressed, as well as the benefit of high-dose intravenous antibiotics, especially penicillin G. Borrelia infection of the nervous system can imitate other diseases. When associated with meningitis it can mimic psychosomatic disorders, when associated with radiculoneuritis it may imitate herniated discs and when central nervous involvement of the Borrelia infection occurs, it can mimic a non-infectious, thrombotic or haemorrhagic cerebro-vascular disease.

Erythema Chronicum Migrans in Sweden: Clinical Manifestations and Antibodies to Ixodes ricinus Spirochete Measured by Indirect Immunofluorescence and Enzyme-linked Immunosorbent Assay

26 Swedish patients with erythema chronicum migrans (ECM) were studied regarding associated clinical symptoms and antibodies to Swedish Ixodes ricinus spirochete. 11/26 (42%) of the patients had associated symptoms, compared to more than 90% of 314 American patients with ECM, as described by Steere et al. Only 2/26 (8%) had multiple skin lesions, compared to 48% of the American patients. Elevated erythrocyte sedimentation rate and circulating immune complexes were demonstrated in 6/25 (24%) and 8/25 patients (32%), respectively, as against in 53% and 84%, respectively, of the American patients. The antibody response to Ixodes ricinus spirochete was measured by indirect immunofluorescence (IFA) and enzyme-linked immunosorbent assay (ELISA). Compared to the 95% percentile of controls, significantly high antibody titers were demonstrated in 3/25 (12%) by IFA, and 7/25 (28%) by ELISA. The ELISA antibody titers differed significantly (p less than 0.05) between ECM-patients and controls. The spirochetal antibody response in ECM was also compared with that in spirochete-associated disease of the central nervous system.

Serological Follow-up after Treatment of Borrelia Arthritis and Acrodermatitis Chronica Atrophicans

To study the serological response to Borrelia burgdorferi after treatment of late Lyme borreliosis, consecutive serum samples from 20 patients with Borrelia arthritis and 21 with acrodermatitis chronica atrophicans were analysed with capture IgM ELISA and indirect IgG ELISA, both using B. burgdorferi flagella as antigen. Seven patients had positive IgM OD values, whereas all 41 had positive IgG OD values before therapy. In the majority, highly elevated IgG OD values were seen. All patients improved after antibiotic therapy, 32 recovering completely, while 9 had sequelae. At follow-up after 6 months to 5 years, 4/7 patients became negative IgM ELISA, whereas 3 still had slightly elevated IgM OD values 6 months, 1 year and 4.5 years, respectively, after therapy. Only one patient became negative in IgG ELISA during follow-up, although a significant decline in IgG OD values was seen in 22 of the remaining 40 initially IgG-positive patients. The serological response after successful treatment of Borrelia arthritis and acrodermatitis chronica atrophicans may persist for several years even with highly elevated IgG OD values in patients who have recovered completely.

Characterization of antibody response in patients with Borrelia meningitis

Abstract Western blot analysis was used to characterize the antibody response of 38 patients with Borrelia meningitis to different strains of Borrelia spirochetes. Eight strains of Borrelia spirochetes were analysed by SDS-PAGE which showed major proteins of 60, 41, 31·5–34 and 22–23 kD. Immunoblots of all sera, and all except one CSF from patients with clinically active disease showed IgG and/or IgM antibodies to at least one Borrelia protein. Antibodies to a 41 kD protein was the first to appear and patients with a longer duration of neurological disease had antibodies to as many as 19 different proteins. Some of the 40 controls showed weak bands, in some cases with the same location as in the Borrelia infected patients. In comparison with an ELISA assay based on a whole cell sonicate as antigen, western blot was more sensitive in detecting an early antibody response, especially in serum. We conclude that Western blot might be used as a complement for immunological diagnosis of Borrelia infection in selected cases with low or border-line ELISA titers. However, a more sensitive/specific ELISA assay might be developed with a single protein as antigen.

Treatment of Lyme Borreliosis with Emphasis on Neurological Disease

We have studied 113 patients with neurologic Lyme borreliosis and meningitis who were treated with intravenous high-dose antibiotics (penicillin G, 12 g, mostly for 14 days in 47 patients; penicillin G, 9 g, mostly for 10 days in 58 patients; doxycycline, 200 mg, in 5 patients; and cefuroxime, 4.5-9 g, in 3 patients). Seventy percent of the patients had peripheral nerve symptoms and 13% had central nervous symptoms. Almost half of the patients were treated more than 4 weeks after the onset of symptoms and 15% of the patients had persisting or progressive symptoms between 4 and 11 months. There seemed to be clinical benefit as well as a decrease of spinal fluid pleocytosis and spinal proteins. No significant symptoms of Herxheimer reaction were demonstrated.