Markku Päivärinta

Homozygous W748S mutation in the POLG1 gene in patients with juvenile-onset Alpers syndrome and status epilepticus.

Purpose: Polymerase gamma (POLG) is the sole enzyme in the replication of mitochondrial DNA (mtDNA). Numerous mutations in the POLG1 gene have been detected recently in patients with various phenotypes including a classic infantile‐onset Alpers‐Huttenlocher syndrome (AHS). Here we studied the molecular etiology of juvenile‐onset AHS manifesting with status epilepticus and liver disease in three teenagers.

Decreased raphe serotonin in rabbits with experimental herpes simplex encephalitis

Increased monoamine metabolism in experimental herpes simplex virus (HSV) encephalitis is well established. Both serotonin (5-HT) and dopamine (DA) systems are affected. HSV invades the raphe nuclei after its entry into the brain stem. However, no studies have been published concerning influences of HSV on the neurotransmitters in the raphe. In the present study, concentrations of 5-HT and DA and their metabolites in the raphe nuclei and related brain regions in rabbits with fulminant HSV encephalitis have been analyzed using high-pressure liquid chromatography. Encephalitis was induced by corneal inoculation with HSV. Homovanillic acid (HVA) and dihydroxyphenyl acetic acid (DOPAC) concentrations and HVA/DA ratios were increased in the raphe nuclei suggesting increased DA turnover. The most substantial changes were bilaterally decreased 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the raphe nuclei. The decrease in the raphe 5-HT was reflected also to the projection areas in the hemispheres, where 5-HT concentrations were lower in HSV-inoculated rabbits than in controls. The changes strongly suggest a direct influence of HSV on serotoninergic neurons. Since the ventral parts of the limbic system have rich serotoninergic afferents from the raphe, this also suggests that HSV may reach hemispheres in HSV encephalitis from the brain stem via the ascending serotoninergic system.

Decrease in mesencephalic dopamine autoreceptors in experimental herpes simplex encephalitis

Brain dopamine receptors were determined in experimental herpes encephalitis using an animal model, where herpes simplex virus type 1 was inoculated onto the cornea of rabbits. The animals exhibit an asymmetric posture and circling to the side of inoculation, which appears to be connected to the altered dopamine transmission in the mesostriatal system. In this study striatal and mesencephalic D-1 and D-2 dopamine receptors were measured by radioligand techniques using3H-SCH 23390 and3H-spiroperidol as ligands. In the striatal D-1 and D-2 receptors there were no significant differences between HSV-inoculated and control rabbits. In the substantia nigra-ventral tegmental area there was a significant decrease in the D-2 receptors (Bmax) on the side contralateral to the primary virus inoculation and the direction of the rotational behaviour, without any changes in the D-1 receptors. Thus experimental herpes simplex virus infection seems to affect the mesencephalic dopamine autoreceptors, leading to unilateral activation of the mesostriatal dopamine system and rotational behaviour.

Nervous system inflammatory lesions and viral nucleic acids in rabbits with herpes simplex virus encephalitis-induced rotational behaviour

Rabbits with herpes simplex virus (HSV) encephalitis induced by corneal virus challenge exhibit rotational behaviour linked with altered brain dopamine functions. The neuropathology and the distribution of the HSV-specific nucleic acids were studied, using probes for the viral trans-inducing factor αTIF and for the latency-associated transcript LAT-1 RNA to detect productive and latent infections, respectively. The rotational behaviour began 4 days after inoculation, and at that time the inflammatory process was observed only in the brain stem and the productive infection, revealed by in situ hybridisation, was seen in the trigeminal entry and nuclei. No HSV-specific nucleic acids or neural destruction were observed in the regions of the serotoninergic raphe or dopaminergic substantia nigra. At 8 days after inoculation, when the rotational behaviour was beginning to attenuate, the inflammatory lesions spread into the hemispheres, involving particularly the ventral parts of the limbic system including the olfactory system. In no cases were HSV-specific nucleic acids detected in the olfactory system. The inflammation in the limbic system was also detectable in animals without inflammatory lesions in the olfactory bulbs or tracts, suggesting that the infection had spread from the brain stem. The present study shows that in this model the altered neurotransmitter functions observed previously, appearing as rotational behaviour, occur without productive infection or necrosis, suggesting specific interaction of HSV with monoaminergic neurons. Additionally, the results suggest that HSV could reach the limbic system via ascending serotoninergic projections from the raphe neurons.

Brain monoamine metabolism and rotational behaviour induced by experimental herpes simplex virus encephalitis

The motor behaviour and brain concentrations of dopamine, noradrenaline, serotonin and their metabolites have been examined in rabbits with experimental herpes simplex virus (HSV) brain infection achieved by unilateral corneal inoculation. The animals showed altered motor behaviour, consisting of a posture tilting to the side of inoculation and circling in the same direction, that began on day 4–5 post inoculation, and was most vigorous on day 7 post inoculation. Compared with controls, the concentration of 5-hydroxyindoleacetic acid was increased in the caudate nucleus on both sides and that of serotonin was decreased in the nucleus accumbens on the side of inoculation. The circling of the animals correlated positively with the ratio of homovanillic acid concentrations between the left and right caudate nucleus, although the actual concentrations did not differ from the controls. The posture asymmetry correlated with the ratio of the left and right nucleus accumbens homovanillic acid concentrations. The results demonstrate that experimental HSV infection in the brain alters motor behaviour, in association with changes in brain dopamine and serotonin metabolism in the major ascending monoamine systems.

Dopaminergic neurotransmission in chronic herpes simplex virus brain infection in rabbits

In this study we have examined brain concentrations of monoamine neurotransmitters and striatal and mesencephalic D-2 receptors in a chronic model of herpes simplex virus (HSV) encephalitis. The HSV-inoculated rabbits were killed two months after inoculation. Dopamine (DA), noradrenaline, serotonin and their metabolites were determined in the substantia nigra, caudate nucleus, putamen, nucleus accumbens, and olfactory tubercles using HPLC with electrochemical detection. The Bmax and Kd values of D-2 receptors were studied in the striatum and in the mesencephalon using3H-spiroperidol as ligand. The animals showed rotational behaviour, consisting of posture tilting to the inoculated side and circling in the same direction during the first week, then slowly subsiding. Compared with controls, the concentration of homovanillic acid (HVA) was reduced in the ascending DA system on both sides. Neither in the number nor affinity of D-2 receptors were there any differences between the HSV-inoculated and control rabbits. The decreased HVA concentrations suggest that dopaminergic hypofunction can develop as a consequence of previously experienced acute HSV brain infection.

Steroid-responsive encephalopathy with a peculiar CSF biomarker profile in an 89-year-old man

Abstract Being treatable, steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), or Hashimoto’s encephalopathy, should be distinguished from untreatable conditions. Our patient was a previously healthy 89-year-old man, who presented with cognitive and balance deterioration over several months. His cerebrospinal fluid (CSF) examination was positive for protein 14-3-3 but no other test suggested Creutzfeldt–Jacob disease. His condition improved markedly, although not fully, with intravenous corticosteroids. In control CSF sampling, protein 14-3-3 was negative but a biomarker signature consistent with Alzheimer’s disease was observed. SREAT should be considered also in the very elderly in case of subacute encephalopathy.

Why We Still Need More Research on the Epidemiology of Huntington's Disease.

to agree upon as partial explanations for the rise in prevalence. They are also compatible with the stated finding that there has been no change in HD incidence at least in the UK. Increased awareness complemented by the availability of genetic testing is also compatible with this argument provided that it does not lead to ascertainment of completely new cases that otherwise would not have been diagnosed except to persons at risk being diagnosed earlier and thus live longer with diagnosed HD. Considering that the HTT mutation is not a disease in itself but an autosomal dominantly inherited trait and the subjective element inherent in contemporary diagnostic criteria of manifest HD, this is quite possible. On the other hand, incidence studies from other Caucasian populations seem to suggest an increasing trend [1, 3] and data concerning new mutation rates are incomplete. Furthermore, while we do not know the impact the introduction of genetic testing has had upon case ascertainment and diagnosis, it feels sensible to assume that making a diagnosis in uncertain and improbable cases has become easier and even more common. Many studies have indeed recently noted that a considerable number of new patients have no family history of HD and proportions of late-onset cases (at least 60 years of age at motor onset) have increased (for instance [4–6] ). This is also Nearly a quarter of a century ago, the mutation underlying Huntington’s disease (HD), a dynamic cytosine-adenine-guanine (CAG) repeat expansion of the Huntingtin (HTT) gene located in chromosome 4, was discovered. We have learned much since then, but more work remains if we are to find a cure for this disease. Perhaps, surprisingly, 144 years after George Huntington gave his speech on chorea, this is also true concerning HD epidemiology. Like earlier studies, a recent review found HD prevalence to be highest in populations of Caucasian descent at 5.7 per 100,000 [1] . However, a rise has been postulated and both estimates in the traditional prevalence range, but considerably higher figures have also been published recently. In their paper, in this issue of Neuroepidemiology , Rawlins et al. [2] review all prevalence studies published to date and provide a meta-analysis confirming a trend of increasing HD prevalence in most populations of Caucasian descent. While their results also confirm that the disease is most prevalent in Caucasian populations, they also point out that more studies of HD epidemiology are needed, not only in South America and Africa but also in Asia and even Central and Eastern Europe. Increase in population longevity and possibly longer survival of HD patients due to better treatment are easy Published online: February 3, 2016