Human parechovirus and the risk of type 1 diabetes.

Human parechoviruses (HPeVs) are RNA viruses associated mainly with mild gastrointestinal and respiratory infections in children and also cause neonatal sepsis and CNS infections. Human enteroviruses, close relatives of HPeVs, associate with the development of type 1 diabetes. In this study, the potential role of HPeV infections in promoting beta cell autoimmunity was investigated by analyzing stool samples of 54 prediabetic case and 134 healthy control children for the presence of HPeV RNA and comparing the derived infection frequencies. All 188 children were participants of the Finnish prospective Diabetes Prediction and Prevention study. Viral RNA was screened for using an HPeV-specific RT-PCR method coupled to liquid hybridization of the PCR product. The overall HPeV infection frequency did not differ between prediabetic case and control children. However, case boys had more HPeV positive samples in the 6-month period before becoming autoantibody positive, when compared to the matching time-period in controls (P < 0.01). HPeV infection at a young age does not appear to play a major role in the development of beta-cell autoimmunity. In boys, however, HPeVs showed time-dependent association with the first detection of diabetes-associated autoantibodies. Thus, in boys, HPeV infections cannot be excluded as a gender-specific risk factor which promotes the development of type 1 diabetes.

Viral meningoencephalitis: a review of diagnostic methods and guidelines for management.

BACKGROUND: Viral encephalitis is a medical emergency. The prognosis depends mainly on the pathogen and host immunologic state. Correct immediate diagnosis and introduction of symptomatic and specific therapy has a dramatic influence upon survival and reduces the extent of permanent brain injury. METHODS: We searched the literature from 1966 to 2009. Recommendations were reached by consensus. Where there was lack of evidence but consensus was clear, we have stated our opinion as good practice points. RECOMMENDATIONS: Diagnosis should be based on medical history and examination followed by CSF analysis for protein and glucose levels, cellular analysis, and identification of the pathogen by polymerase chain reaction amplification (recommendation level A) and serology (level B). Neuroimaging, preferably by MRI, is essential (level B). Lumbar puncture can follow neuroimaging when immediately available, but if this cannot be performed immediately, LP should be delayed only under unusual circumstances. Brain biopsy should be reserved only for unusual and diagnostically difficult cases. Patients must be hospitalized with easy access to intensive care units. Specific, evidence-based, antiviral therapy, acyclovir, is available for herpes encephalitis (level A) and may also be effective for varicella-zoster virus encephalitis. Ganciclovir and foscarnet can be given to treat cytomegalovirus encephalitis, and pleconaril for enterovirus encephalitis (IV class evidence). Corticosteroids as an adjunct treatment for acute viral encephalitis are not generally considered to be effective, and their use is controversial, but this important issue is currently being evaluated in a large clinical trial. Surgical decompression is indicated for impending uncal herniation or increased intracranial pressure refractory to medical management.

HHV-6 infection in multiple sclerosis. A clinical and laboratory analysis.

BACKGROUND AND PURPOSE: To elucidate the role of human herpesvirus-6 (HHV-6) in the development of multiple sclerosis (MS). PATIENTS AND METHODS: Nine patients with MS and with acute or chronic HHV-6 infection were evaluated. RESULTS: Intrathecal antibody production to HHV-6 and oligoclonal IgG bands in the cerebrospinal fluid (CSF) was observed in two patients with a clinically definite MS and chronic HHV-6 infection (based on the presence of HHV-6 specific antibodies in the CSF). A temporal association between the symptoms of clinically possible MS and acute primary HHV-6A infection (based on avidity of HHV-6 specific antibodies) was observed in two patients. CONCLUSIONS: Human herpesvirus-6 infection may be an associated agent in some MS cases. Viral studies are needed to identify a possible viral etiology and give specific therapy.

Evidence for human herpesvirus 6 variant A antibodies in multiple sclerosis: diagnostic and therapeutic implications.

Human herpesvirus 6 (HHV-6) has been linked to the pathogenesis of multiple sclerosis (MS). HHV-6 antibodies in serum and cerebrospinal fluid (CSF) of 27 patients with clinically definite MS (CDMS) were compared with age- and sex-matched controls, including various other neurological diseases and symptoms (OND). In addition, we studied a series of 19 patients with clinically or laboratory supported possible MS (CPMS). Seroprevalence to HHV-6A was 100% in patients with MS, both in CDMS and CPMS, compared to 69.2% in patients with OND (P = .001 and .007). The mean immunoglobulin G (IgG) titers were significantly higher in patients with CDMS and CPMS than in controls (P = .005 and .00002). The proportion of acute primary infections without CSF involvement was similar in all groups; however, primary infections with intrathecal HHV-6 antibody production were more frequent in MS. In CSF, HHV-6A-specific antibodies were present in three (11.5%) and four (21.1%) patients with CDMS and CPMS, compared to none with OND (P = .06 and .01, respectively). Serological suggestions to HHV-6A infection occurred more often in both CDMS and CPMS than in OND (14.8% versus 21.1% versus 3.8%). We conclude that a subpopulation of MS patients, and even a greater proportion of possible MS subjects, has serological evidence of HHV-6A infection, which might provide new markers for diagnosis and therapy.

Confirmed primary HHV-6 infection in children with suspected encephalitis.

HHV-6 infection has been associated with neurological symptoms in children. Two variants of human herpes virus 6, HHV-6A and HHV-6B, have been identified. Their role in neurological infections is poorly understood. We studied 53 children with suspected encephalitis for HHV-6A (strain GS) and HHV-6B (strain Z29) antibodies using an indirect immunofluorescence test. Primary infection was separated from past infection by an IgG-avidity test. The identified primary infections were studied for HHV-6 specific DNA by PCR. Forty-one children of 53 had IgG antibodies to HHV-6. Six children had low avidity of HHV-6 IgG antibodies indicating acute primary infection; four to type A, one to B, and one to both types. By serology, HHV-6 viral etiology was suggested in 6/53 (11.3%) of cases. One of the six patients with primary infection had HHV-6 DNA in serum and two in CSF. The children with primary HHV-6 infection were significantly younger than the whole series, 2.3 years vs. 6.4 years. We conclude that primary HHV-6 infection appears to be an important associated or causative agent in neurological infections of young children, and it can be confirmed from a single serum specimen using the IgG-avidity test.

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.

Tissue plasminogen activator as a key effector in neurobiology and neuropathology.

Tissue plasminogen activator (tPA) is expressed by many types of neurons in the developing and adult rodent brain. We have now mapped tPA transcripts and protein in the human central nervous system using tissue arrays and find widespread expression, in particular in neocortical mantle, thalamus, amygdala, and hippocampal pyramidal neurons. The abundant presence of tPA protein in cellular vesicles implies that its acute release, e.g. upon ischaemic stroke or trauma, could play a role in neuronal damage. We also found in patients with multiple sclerosis (MS), and to a lesser extent patients with leukaemia and encephalitis, prominently elevated tPA activity in the cerebrospinal fluid and in MS in neurons in the proximity of areas of demyelination elevated tPA mRNA and antigen levels. In addition, we observed up-regulation of tPA expression in a mouse model of MS, experimental autoimmune encephalomyelitis. Accumulating evidence implies roles for tPA in normal neural function, as well as in neurodestructive processes in humans, such as occur in MS and brain tumours and warrant further studies on expression of tPA and its regulatory molecules in neurodegenerative diseases.

Antibody status to HHV-6 in children with leukaemia.

Forty children with acute lymphoblastic (33) or myeloid leukaemia (seven) were studied for IgG and IgM antibodies and IgG avidity against human herpesvirus 6 (HHV-6) at the time of diagnosis, and compared with age-, sex- and season-matched children with various neurological diseases of suspected viral origin. Of the children with leukaemia, 97.5% had IgG antibodies and 40% IgM antibodies to HHV-6 compared with 92.3% and 7.7% of reference subjects (P = 0.005). A seronegative child with leukaemia seroconverted 3 weeks after the diagnosis. The avidity of IgG antibodies (based on the resistance to urea treatment) was high in all children with leukaemia. One reference child had HHV-6-specific IgG antibodies with low avidity, which together with his positive IgM indicated an acute infection. The presence of specific IgM antibodies in 40% of children with leukaemia and the high avidity of IgG suggest a reactivation or an inaproppriate primary response to HHV-6 infection. The results support the conclusion of the role of the HHV-6 infection at the onset of childhood leukaemia.

Infections of the central nervous system of suspected viral origin: a collaborative study from Finland.

We studied 3231 patients with acute central nervous system (CNS) symptoms of suspected viral origin to elucidate the current etiologic spectrum. In 46% of the cases, a viral finding was observed. Varicella-zoster virus (VZV) was the main agent associated with encephalitis, as well as meningitis and myelitis. VZV comprised 29% of all confirmed or probable etiologic agents. Herpes simplex virus (HSV) and enteroviruses accounted 11% each, and influenza A virus 7%. VZV seems to have achieved a major role in viral infections of CNS. In encephalitis in our population, VZV is clearly more commonly associated with these neurological diseases than HSV. The increase in VZV findings may in part be a pseudophenomenon due to improved diagnostic methods, however, a true increase may have occurred and the pathogenetic mechanisms behind this should be elucidated.

Congenital varicella-zoster virus infection after maternal subclinical infection: clinical and neuropathological findings.

OBJECTIVE: It is known that varicella-zoster virus (VZV) can cause asymptomatic infections, but it has not been described that congenital infection can be caused by maternal subclinical infection. The purpose of this study is to evaluate clinical and neuropathologic findings of infants with neonatal seizures and cerebrospinal fluid (CSF) VZV antibodies, but no maternal clinical VZV infection during the pregnancy. STUDY DESIGN: Screening of 201 neonates were studied for congenital viral infections, because of neurologic problems of unknown origin. Antibodies to 16 different microbes were investigated from the CSF and the serum of the neonates, as well as from the first trimester and postpartum serum of their mothers. Clinical symptoms and signs as well as neuropathology of those infants with antibodies to VZV in CSF were evaluated in this study. RESULTS: Four neonates with antibodies to VZV in CSF were identified and CSF findings were reported earlier. Their mothers had laboratory evidence of infection, based on a significant rise in serum VZV antibody level during pregnancy in three mothers, and a constantly high antibody level to VZV in one mother. All four children had seizures and abnormalities in muscular tone during the neonatal period, but no typical manifestations of a congenital VZV infection. One child died at the age of 4 months. At autopsy, neuropathologic examination showed foci of astrocytic hyperplasia and hypertrophy but no specific signs of viral infection. CONCLUSION: Maternal subclinical VZV infection can cause congenital infection with neurologic symptoms and signs in the child.

Acute encephalitis from 1967 to 1991.

We studied all the adult patients with acute encephalitis, 322 in all, in the Helsinki area, Finland, during the years 1967--1991. The average incidence was 1.4/100000 adults/year. The proportion of known and suggested etiologies in 5-year periods has risen from 36 (1967--71) to 59% (1987--91). Herpes simplex virus was identified most often (16%), followed by varicella-zoster (5%), mumps (4%), and influenza A viruses (4%). In addition, 20 other agents were identified. The leading cause of encephalitis in patients aged 65 years or more was varicella-zoster virus. Eighteen patients (5.6%) died. It appears that the etiology of encephalitis changes with age and with time. It is important to establish the etiological pattern, as this assists in prompt diagnosis, which is a prerequisite for successful therapy.

A major role of viruses in convulsive status epilepticus in children: a prospective study of 22 children.

UNLABELLED: A group of 22 previously healthy children with their first convulsive status epilepticus (SE), treated at Kuopio University Hospital, Finland, were prospectively studied. Eleven children had febrile and 11 afebrile SE. Polymerase chain reaction was used to detect specific DNA from CSF, enzyme immunoassays and immunofluorescence assays to detect specific antibodies in serum and CSF, viral cultures were obtained from CSF, throat and stool and antigen detection from throat specimens. Viral infection was identified in 10 of 11 children with febrile SE (91%) and in 7 of 11 with afebrile SE (64%). Human herpes virus 6 infection was identified in 12 children (55%), and in at least six of them the infection was primary. Single cases of human herpes virus 7, parainfluenza 3, adenovirus 1, echovirus 22, rota, influenza A and Mycoplasma pneumoniae infection were diagnosed. CONCLUSION: Viruses, human herpes virus 6 in particular, seem to be major associated factors in convulsive status epilepticus, both febrile and afebrile. Human herpes virus 7 and Mycoplasma pneumoniae are novel agents associated with status epilepticus.

Chlamydia trachomatis infection in mothers with preterm delivery and in their newborn infants.

We studied Chlamydia trachomatis infection in mothers with preterm delivery and intrauterine transmission of the infection to their offspring. Forty-one mothers with preterm labour and their newborn infants (n=50) were studied for the presence of C. trachomatis infection using microimmunofluorescence test for detection of serum antibodies against C trachomatis and polymerase chain reaction for detection of C. trachomatis-specific DNA in mucosal swabs. Antibodies to C trachomatis were found in serum of 12 mothers (29%). Five of fourteen mothers had C. trachomatis DNA in cervical specimens. Eighteen neonates were born to the 14 mothers with positive serology and/or C. trachomatis DNA. C. trachomatis DNA was detected in specimens from 10 of the 18 neonates (55.5%). Three of the available cord blood samples contained C trachomatis IgM antibodies. Our results strongly suggest that mothers and their preterm babies may benefit from screening for active C. trachomatis infection.

Chlamydia trachomatis seropositivity is associated both with stillbirth and preterm delivery.

The cause of stillbirth and preterm delivery is often unknown. We studied the prevalence of Chlamydia trachomatis antibodies in mothers with stillbirth and preterm labor. Serum specimens from 72 mothers with stillbirth after the 21st gestational week, and from 48 mothers with preterm delivery between gestational weeks 23 and 29, both from the greater Helsinki area, and cord blood from 96 consecutive liveborn deliveries at the Department of Obstetrics and Gynecology, the University of Helsinki, were studied for antibodies to C. trachomatis immunotypes CJHI, GFK and BED by microimmunofluorescence test. The prevalence of C. trachomatis antibodies was highest, 33.3%, in mothers with stillbirth, 18.8% in mothers with preterm delivery, and 10.4% in cord blood. The IgM seropositivity rate was high among mothers with preterm delivery (8.3%). We conclude that C. trachomatis IgG antibodies are frequently detected in sera from mothers with stillbirth, suggesting past infection, while mothers with preterm delivery often have serum IgM antibodies, suggesting of acute infection.

Human cytomegalovirus seroprevalence in three socioeconomically different urban areas during the first trimester: a population-based cohort study.

BACKGROUND: To re-evaluate the impact of socioeconomic status and human cytomegalovirus (HCMV) seroprevalence during pregnancy, we carried out a population-based cohort study. METHODS: IgG and IgM antibodies to HCMV and IgG avidity were studied by enzyme-linked immunosorbent assay (ELISA) in three different socioeconomic areas (SEA) in the 9-12th week of pregnancy of 1088 consecutive mothers. RESULTS: The overall IgG seropositivity was 70.7%, ranging from 60.9 to 76.4% in 'upper' to 'lower' SEA (P = 0.0004). The HCMV IgM seropositivity was 4.0%, ranging from 3.8% in the 'upper' and 'intermediate' SEA to 4.6% in the 'lower' SEA. Serologically acute cases, defined by low avidity of IgG, represented 1.7% of the pregnancies in the 'upper' SEA compared with 1.0 and 1.1% in the other two areas. In the 'lower' SEA there were twice as many recurrent infections as in the others, 3.6 versus 1.7%. The low impact of age did not increase after elimination of the effects of SEA and parity. Miscarriages were associated neither with IgG nor with IgM positivity, although the percentage of >/=2 miscarriages was 8.8% in seronegative women compared with 11.2% and 13.6% in IgG- and IgM-positive women. CONCLUSIONS: Social environment seems to be the most powerful factor, predicting both IgG seroprevalence and recurrences during pregnancy.

Human herpesvirus-6 associated encephalitis with subsequent infantile spasms and cerebellar astrocytoma.

A 14-month-old girl presented after 3 days of fever, floppiness, and diffuse urticarial exanthem. She developed encephalitis and carditis and 1 week later, intractable seizures. Initial CT and MRI showed no changes in the brain parenchyma. On days 14 and 34 after the onset of symptoms, a human herpesvirus-6 (HHV-6) genome in cerebrospinal fluid was identified by polymerase chain reaction (PCR). Convulsions became more frequent and 11 weeks from the onset, they changed to typical infantile spasms with hypsarrhythmic electroencephalogram. She gradually lost her social contact and ability to walk and sit. Eleven months after the primary infection, a repeated MRI of the brain revealed a cystic tumour of 2 cm in diameter near the vermis. The tumour was surgically removed, and shown to be a pilocytic astrocytoma on histopathological examination. HHV-6 DNA was detected by PCR in new tumour tissue. This is the first reported case of HHV-6 encephalitis associated with carditis, infantile spasms, and a subsequent brain tumour containing the HHV-6 genome.

In situ hybridization detection of human herpesvirus 6 in brain tissue from fatal encephalitis.

A 23-month-old girl died after 2 days' illness with rash, fever, and convulsions. Neuropathologic findings were consistent with viral hemorrhagic encephalitis in pontine tegmentum and medial thalamic areas. Human herpesvirus 6 (HHV-6) DNA was detected in pontine nuclei by in situ hybridization. In addition, polymerase chain reaction for HHV-6 of serum and paraffin-embedded pontine tissue was positive, and serology indicated an acute primary infection. This is the first case showing HHV-6 DNA in the brain cells of an immunocompetent patient with acute encephalitis.

Cognitive indicators of vocational outcome after severe traumatic brain injury (TBI) in childhood.

Recent studies suggest that plasticity does not benefit outcome when diffuse cerebral pathology of the young child's brain is concerned. Thirty-three patients with severe traumatic brain injury (TBI) at preschool age were followed-up until adulthood. After the age of 18 years, a thorough neurological, neuropsychological and social evaluation, including detailed patient history and assessment of identity, was made by the team. When the youngest patients were 21 years old, the study was completed, with a questionnaire assessing employment status and ability to live independently. Twenty-seven per cent of the patients worked full time, 21% had subsidised work, 37% lived independently at home and 15% needed help with every-day functions. Tests measuring speed, executive and memory functions were significantly associated with vocational outcome, as was the sense identity, which was independent of the test scores. The results support the recent reports on the vulnerability of a young child's brain to early trauma. The study also strongly suggests that the final assessment of outcome after childhood TBI should be done in adulthood.

The association of the human herpesvirus-6 and MS.

Given the clinical and pathological nature of Multiple Sclerosis (MS), a viral infection has long been hypothesized as part of the etiology. In this study we investigated the possibility that the human herpesvirus-6 (HHV-6) is present in a dormant or active phase in the tissue of MS patients, specifically oligodendrocytes. Using PCR assays of MS and non-MS brain sections with primers prepared against the HHV-6 structural protein 101, the results demonstrated that 36% of MS brains were positive for the virus, while 13.5% of non-MS brains were positive. Antibody to the HHV-6 structural protein was also used in immunohistochemical experiments in brain tissue. 47% (7/15) of MS brains were positive for HHV-6, whereas 0/16 controls were positive. In addition, MS patients demonstrated high immune reactivity to this virus, even when compared to auto-immune diseases, which might cause polyclonal activation. Sera obtained from MS and control patients revealed that the IgM response to the HHV-6 virus was significantly elevated in 80% patients compared to 16% non-MS controls, P<.001. The above experiments strongly suggest that a significant number of MS brain samples contain HHV-6 antigens and genomic fragments in a dormant or active phase compared to control specimens and that MS patients mount a brisk, early IgM response.

Progressive myoclonus epilepsy of Unverricht-Lundborg type.

Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is characterized by onset at age 6-15 years, stimulus-sensitive myoclonus, tonic-clonic seizures, and typical EEG findings, with marked sensitivity to photic stimulation. Previously the course of the disease was progressive throughout the life, and no biochemical or pathologic marker existed for the diagnosis of EPM1. With modern anticonvulsive therapy, the prognosis has improved significantly, the symptoms are nowadays relatively well controlled, and the disease may not always progress. Moreover, the molecular genetic findings have now made possible an etiologic diagnosis of EPM1. The positional cloning strategy was applied to identify the gene whose defects are responsible for EPM1. The underlying gene encodes cystatin B, a cysteine protease inhibitor. The major mutation worldwide is an unstable expansion of a dodecamer minisatellite repeat unit in the promoter region of the cystatin B gene. In addition, five "minor" mutations have been described. Cystatin B mutations are now known to account for both Mediterranean myoclonus and for "Baltic" myoclonus, described mainly from Finland, thus solving a long-term controversy and proving that these two disorders are one single disease entity. The pathogenetic mechanisms in EPM1 are yet unknown, but in the majority of patients, a reduced level of the cystatin B gene product seems to be the primary mechanism in the pathology. Understanding the molecular pathogenesis of EPM1 may lead to the development of specific therapies for the disease.