Marjaleena Koskiniemi

Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1)

Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is an autosomal recessive inherited form of epilepsy, previously linked to human chromosome 21q22.3. The gene encoding cystatin B was shown to be localized to this region, and levels of messenger RNA encoded by this gene were found to be decreased in cells from affected individuals. Two mutations, a 3′ splice site mutation and a stop codon mutation, were identified in the gene encoding cystatin B in EPM1 patients but were not present in unaffected individuals. These results provide evidence that mutations in the gene encoding cystatin B are responsible for the primary defect in patients with EPM1.

PROGRESSIVE MYOCLONUS EPILEPSY

The clinical picture and the progression of the disease in 93 cases of progressive myoclonus epilepsy in Finland were analysed. The disease was familial in 25 out of 67 families. The incidence was calculated to be one in 27000 live‐born children, i.e. three new cases each year. The early development and health of the patients was normaI. The first obvious symptom of the disease occurring at the age of 6 to 15 years was either myoclonus or grand mal seizures, the other following later. The characteristic clinical picture also included ataxia, intention tremor, dysarthria as well as emotional lability, but only a slight decrease in the intelligence level. Raised arterial pressure was seen in 14 per cent of cases. Symptoms from other organs were generally lacking. Resistance to infectious diseases seemed to be lower than normally. The thickness of the skull was increased but other disturbances of hone were not found. The pneumoencephalograms did not show any clear atrophy of the brain. The most essential feature of the disease was myoclonus which was provoked by light, touch and other stimuli and it was an important sign for the diagnosis. The increase of myoclonus finally made the patient unable to move unaided and to take care of himself and rendered him bedridden and helpless, most frequently at the age of 17 to 18 years. The average age at death was 24 years, about 14 years after the appearance of the first symptoms. In some patients the progress of the disease came to a halt after many years and these patients sometimes lived for up to 20–30 years after the beginning of the disease. A thorough neuropathological examination was made in one case and in five other cases some autopsy specimens from the brain were examined. Biopsy specimens from other tissues such as peripheral nerves, liver and muscle were examined in 26 cases. The most outstanding feature of the brain was loss of Purkinje cells. No Lafora bodies were found and no other signs of pathological accumulating material. Thus the Finnish cases of progressive myoclonus epilepsy do not belong to the Lafora body type of the disease. Clinically they differ from this type mainly on the basis of the fairly high intelligence level.

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.

CNS Manifestations Associated with Mycoplasma pneumoniae Infections: Summary of Cases at the University of Helsinki and Review

Abstract CNS manifestations appear in one of 1,000 patients with Mycoplasma pneumoniae-associated infections. Encephalitis is the most frequent manifestation, but cases of meningitis, myelitis, and polyradiculitis, as well as many other symptoms (e.g., coma, ataxia, psychosis, and stroke), have been reported. The onset of these manifestations is usually acute, with lowered consciousness, convulsions, pareses, and other neurological signs. Severe, even fatal, cases are known. The pathophysiology of CNS manifestations is unknown. To our knowledge, M. pneumoniae has never been isolated from brain tissue, but instead it has been recovered from CSF specimens in at least seven cases. Besides direct invasion of M. pneumoniae into the brain, neurotoxic or autoimmune reaction within the brain tissue is suspected. At neuropathological examination, edema, demyelination, and microthrombi have been described. Improved diagnostic methods may reveal the pathophysiology of CNS manifestations associated with M. pneumoniae infection.

Progressive myoclonus epilepsy: genetic and nosological aspects with special reference to 107 Finnish patients

In 107 Finnish patients with progressive myoclonus epilepsy (PME), belonging to 74 families, autosomal recessive inheritance was evident. The sex ratio was 48:51, the corrected proportion of affected sibs being 0.260. Of 68 marriages 15, or 22 %, were consanguineous; several of the parents were related and the geographical distribution was of the uneven type typical of young, isolated populations in Finland. The incidence in Finland was estimated to exceed 1:20,000.

Epidemiology of encephalitis in children. A prospective multicentre study

Abstract We found 175 cases with acute encephalitis in a population of 791,712 children aged 1 month – 15 years during a 2-year surveillance period in 1993–1994. The overall incidence was 10.5/100,000 child-years with the highest figure in children < 1 year of age, 18.4/100 000 child-years. The microbial diagnosis was considered proven or suggested in 110 cases (63%); varicella zoster, respiratory and enteroviruses comprised 61% of these, and adeno, Epstein Barr-, herpes simplex and rota viruses comprised 5% each. A clearcut change seems to have occurred in the aetiology of encephalitis. Mumps, measles, and rubella virus associated encephalitides have been almost eliminated. Varicella zoster, respiratory, and enteroviruses have increased in frequency and occur in younger age groups. New causes were identified, especially Chlamydia pneumoniae and HHV-6. Our data should assist in making a specific diagnosis and defining appropriate antimicrobial therapy. ConclusionThe spectrum of encephalitis in children has changed due to vaccination programs. The incidence, however, appears to be about the same due to increasing frequency of other associated old and new microbes.

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, P5.001. 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.

Acute central nervous system complications in varicella zoster virus infections

BACKGROUND In a previous multicenter study on central nervous system (CNS) viral infections varicella zoster virus (VZV) appeared the most frequent etiologic agent and appeared often without rash. OBJECTIVE To evaluate the appearance and diagnostics of VZV in CNS more thoroughly, we studied the cases systematically by using sensitive and specific methods to learn the best diagnostic approach in order to start specific therapy. STUDY DESIGN We analyzed all serum and cerebrospinal fluid samples of 174 patients, 88 females and 86 males, with acute CNS symptoms associated with VZV infection diagnosed in the multicenter study on viral CNS infections. RESULTS About 38 patients (22%) had chickenpox, 59 (34%) had shingles, and 77 (44%) had no cutaneous symptoms at all. The mean age of chickenpox patients was 8.6 years, of the others 46.6 and 41.4 years. VZV-specific nucleic acid was detected in the CSF in one fourth of the patients in all groups, primarily during the first week of illness. In serum specimens, specific IgM was present in two thirds of the patients with chickenpox, whereas in the others in one third of the cases. In CSF, specific IgM was present in 15-17% of patients with skin manifestations, compared with 6% of those without rash. CONCLUSIONS The role of VZV infections in CNS complications seems remarkable, often presenting without rash. Even these cases should be promptly recognized in order to conduct proper antiviral therapy. In children, a combination of PCR and IgM tests is the best approach. In adults, PCR, together with the measurement of intrathecal antibody production yields best results.

Epidemiology of encephalitis in children: a 20-year survey.

Four hundred five children from the Helsinki area who were 1 month to 16 years old were treated for acute encephalitis at the Childrens Hospital, University of Helsinki, from January 1968 through December 1987. Encephalitis occurred most commonly in children 1 to 1.9 years of age, among whom the incidence was 16.7 per 100,000 child‐years. The incidence remained quite high until the age of 10 years, and then gradually declined to 1.0 per 100,000 child‐years at the age of 15 years. Since 1983, when mumps, measles, and rubella vaccination eradicated the encephalitides associated with these microbes, the major associated agents have been varicella‐zoster, Mycoplasma pneumoniae, and respiratory and enteroviruses. In infants younger than 1 year of age, the major agents were enteroviruses, herpes simplex virus, and the group of “others,” whereas in older children, respiratory viruses and Mycoplasma Pneumoniae as well as varicella‐zoster virus, dominated. In children aged 1 to 11 months, the causal agent could not be identified in one‐half of all cases, whereas in children who were at least 10 years old, the etiology remained unknown in only one‐fourth of cases. Male dominance was most evident in the 4‐ to 9‐year age group. The difference in etiology between males and females was significant (p = 0.02); mumps and varicella were more common in boys, and adenovirus and Mycoplasma pneumoniae were more common in girls. The overall male‐to‐female ratio was 1.4:1. Characteristic seasonal variation occurred in encephalitides associated with mumps, measles, and entero‐ and respiratory viruses. In the whole series, some accumulation appeared in February and March. Less than one‐half of this number appeared in July and August.

EFFECT OF MEASLES, MUMPS, RUBELLA VACCINATION ON PATTERN OF ENCEPHALITIS IN CHILDREN

462 patients (269 males, 193 females, aged from 1 month to 16 years) with encephalitis were treated at the Childrens Hospital, University of Helsinki, over a 20-year period. The incidence of encephalitis was 8.3/100,000 child-years (range 19.8 in 1974 to 2.5 in 1985 and 1986). The organisms most commonly associated with encephalitis in children were mumps, measles, and varicella viruses, and Mycoplasma pneumoniae. After the start of the nationwide measles, parotitis, and rubella (MPR) vaccination programme in 1982 in Finland, encephalitides associated with these viruses seem to have totally vanished. Currently the pathogens most often associated with childhood encephalitides are varicella-zoster, M pneumoniae, and enteroviruses. 3% of the 462 patients died from their illness, and 7% became severely damaged, with the poorest outcome occurring after multiple infections, and herpes simplex virus, cytomegalovirus or M pneumoniae infections. The decline in the total number of cases of encephalitis was not accompanied by a decrease in number of patients with a poor outcome. Patients with treatable encephalitides due, for example, to M pneumoniae and herpes viruses, need prompt attention.