Ronny Wickström

Childhood encephalitis in Sweden: etiology, clinical presentation and outcome.

Acute encephalitis is a relatively uncommon but potentially harmful CNS inflammation usually caused by infection. The diagnosis is difficult to establish and the etiology often remains unclear. Furthermore, the long-term prognosis of acute encephalitis in children is poorly described. In this study, we characterize childhood encephalitis from a Swedish perspective in regard to etiology, clinical presentation and sequele. We retrospectively studied all children (n=93) who were admitted for acute encephalitis at Karolinska University Hospital in Stockholm during 2000-2004. A confirmed etiological agent was identified in eight cases and a probable one in 37; in 48 cases no etiological agent could be found. Tick-borne encephalitis virus, enterovirus, respiratory syncytial virus, varicella zoster virus and influenza virus predominated and represented 67% of all the confirmed or probable etiologies. Encephalopathy was present in 80% of the children, 81% had fever, 44% had focal neurological findings, and seizures occurred in 40%. EEG abnormalities were seen in 90% and abnormal neuroimaging was present in 30%. The cerebrospinal fluid showed pleocytosis in 55%. There was no mortality, but 60% of the children had persisting symptoms at the time of discharge, 41% of which were moderate to severe. We conclude that the etiology of encephalitis among Swedish children is at large the same as in other European countries with similar vaccination programs. Fever and encephalopathy were seen in a majority of children and the most sensitive tool for making the diagnosis was EEG examination. Furthermore, many children display persisting sequele at discharge for which the strongest predictive factor was focal neurological findings at presentation.

Long-term outcomes of acute encephalitis in childhood.

OBJECTIVES: The aims of this study were to investigate the long-term outcomes of childhood encephalitis and to examine possible prognostic factors. METHODS: Of 93 children who were treated for acute encephalitis in 2000–2004, 71 were eligible for follow-up evaluations. A structured interview, using 2 questionnaires, was conducted with the parents. Fifteen of the children with the most-severe symptoms at the time of discharge also underwent electroencephalographic recording and tests of reaction times and working memory. RESULTS: Persisting symptoms were reported by 54% of children. The predominant symptoms were personality changes and cognitive problems. Children who made a complete recovery did so within 6 to 12 months. The only significant risk factor for sequelae was disease severity leading to admission to the ICU. The risk of subsequent epilepsy was increased for children with seizures at presentation. Most follow-up electroencephalograms showed improvement, but results had not normalized for 9 of 15 children. Children with encephalitis had slower reaction times, compared with control subjects, but no difference in working memory could be seen. CONCLUSION: Persisting symptoms after childhood encephalitis were present for a substantial number of children. Seizures increased the risk of subsequent epilepsy; the only other prognostic marker was admission to the ICU. Even children who were considered fully recovered at discharge reported persisting symptoms at follow-up evaluations. Children who made a full recovery did so within 6 to 12 months, which suggests that all children with encephalitis should be monitored for 1 year after the acute illness.

Tick-borne encephalitis carries a high risk of incomplete recovery in children.

OBJECTIVE To examine long-term outcome after tick-borne encephalitis (TBE) in children. STUDY DESIGN In this population-based cohort, 55 children with TBE with central nervous system involvement infected during 2004-2008 were evaluated 2-7 years later using the Rivermead post-concussion symptoms questionnaire (n = 42) and the Behavior Rating Inventory of Executive Functioning for parents and teachers (n = 32, n = 22, respectively). General cognitive ability was investigated in a subgroup (n = 20) using the Wechsler Intelligence Scale for Children, 4th edition. RESULTS At long-term follow-up, two-thirds of the children experienced residual problems, the main complaints being cognitive problems, headache, fatigue, and irritability. More than one-third of the children were reported by parents or teachers to have problems with executive functioning on the Behavior Rating Inventory of Executive Functioning, mainly in areas involving initiating and organizing activities and working memory. Children who underwent Wechsler Intelligence Scale for Children, 4th edition testing had a significantly lower working memory index compared with reference norms. CONCLUSION A large proportion of children experience an incomplete recovery after TBE with central nervous system involvement. Cognitive problems in areas of executive function and working memory are the most prevalent. Even if mortality and severe sequelae are low in children after TBE, all children should be followed after TBE to detect cognitive deficits.

Development of CO2-response in the early newborn period in rat

We examined the respiratory response to moderate hypercapnia in rat pups during the first 10 days after birth and also studied immediate early gene expression to investigate whether areas described as chemosensitive in the adult rat are activated also in the early postnatal period. Breathing frequency increased in 1- and 3-day-old pups, but decreased in older animals in response to hypercapnia. Tidal volume and ventilation increased significantly in all age groups but relatively more in the 10-day-old pups as compared to younger animals. In situ hybridisation for c-fos mRNA revealed increased expression in several of the areas assigned as chemosensitive in the adult, including the caudal nucleus tractus solitarii and the ventral lateral medulla. In contrast, locus coeruleus and the majority of midline raphe neurons did not exhibit increased expression of c-fos mRNA. We conclude that the hypercapnic respiratory response tends to decrease during the first postnatal week, but thereafter increases on day 10 due to increased tidal volumes rather than changes in respiratory timing. We also speculate that differences in activation of chemosensitive brainstem neurons may be part of the maturation of the hypercapnic ventilatory response.

Relationship of Maternal Snuff Use and Cigarette Smoking With Neonatal Apnea

BACKGROUND: Maternal smoking is associated with disturbed cardiorespiratory control in the infant. Despite lacking knowledge of whether the harmful effects of smoking are caused by combustion products in tobacco smoke or by nicotine, it has been argued that nicotine-replacement therapy during pregnancy is safer than smoking. OBJECTIVE: The goal of this study was to investigate if the disturbances in cardiorespiratory control associated with maternal smoking are also seen in infants prenatally exposed to snuff. We hypothesized that prenatal nicotine exposure (via moist snuff) causes disturbances in autonomic control and thereby increases the risk of apnea in the newborn. METHODS: In a nationwide Swedish cohort study, we studied associations between maternal tobacco use during pregnancy and neonatal apnea. Of 609 551 live-born singleton infants, 7599 were born to snuff-using mothers, 41 391 and 16 928 were born to light (1–9 cigarettes per day) and heavy (≥10 cigarettes per day) smokers, respectively. Logistic regression was used to calculate odds ratios, using 95% confidence intervals. RESULTS: Compared with infants of nontobacco users, infants with prenatal exposure to snuff were at an increased risk of apnea even after adjustment for differences in gestational age (odds ratio: 1.96 [95% confidence interval: [1.30–2.96]) Smoking was associated with increased risk of apnea before, but not after, adjusting for gestational age. CONCLUSIONS: Snuff use during pregnancy is associated with a higher risk of neonatal apnea than smoking. Maternal use of snuff or nicotine-replacement therapy cannot be regarded as an alternative to smoking during pregnancy.

Efficacy and safety of lidocaine for treatment of neonatal seizures.

Treatment of neonatal seizures still relies primarily on phenobarbital, despite an estimated efficacy of less than 50% and concern over neurodegenerative side effects. The objective of this study was to evaluate the efficacy and safety of lidocaine as second‐line treatment of neonatal seizures in infants following benzodiazepine treatment but without previous treatment with phenobarbital.

Viral triggering of anti-NMDA receptor encephalitis in a child - an important cause for disease relapse.

Herpes simplex encephalitis (HSE) in children is a potentially devastating condition which is occasionally complicated by a clinical relapse. An autoimmune component has long been suspected in these relapses and recent findings suggest that antibodies against N-methyl-D-aspartate receptors (NMDARs) may be part of this mechanism. We here report an 11 months old girl with acute HSE and with negative NMDAR antibody serology at presentation who after an initial response to antiviral treatment deteriorated with seizures, abnormal movements, focal neurologic deficits and psychiatric symptoms. We show that this relapse occurred as production of NMDAR antibodies developed and that clinical improvement followed immunotherapy with a concomitant decrease in NMDAR antibody titers in CSF. She also developed a characteristic 15-20 Hz activity over both hemispheres which has been previously described as an electroencephalographic presentation of anti-NMDAR encephalitis. We conclude that relapse or persisting symptoms in HSE in children may represent an immune-mediated mechanism rather than a viral reactivation and that NMDAR antibodies should be analyzed as this may be of importance for the choice of therapy.

Maternal Snuff Use and Smoking and the Risk of Oral Cleft Malformations - A Population-Based Cohort Study

Objective To determine if maternal use of snuff (containing high levels of nicotine, low levels of nitrosamines and no combustion products) is associated with an increased risk of oral cleft malformations in the infant and whether cessation of snuff use or smoking before the antenatal booking influences the risk. Method A population-based cohort study was conducted on all live born infants, recorded in the Swedish Medical Birth Register from 1999 through 2009 (n = 1 086 213). Risks of oral clefts were evaluated by multivariate logistic regression analyses (using adjusted odds ratios, with 95% confidence intervals [CI]). Results Among 975 866 infants that had information on maternal tobacco use, 1761 cases of oral clefts were diagnosed. More than 50% of the mothers who used snuff or smoked three months prior pregnancy stopped using before the antenatal booking. Almost 8% of the mothers were smoking at the antenatal booking and 1,1% of the mothers used snuff. Compared with infants of non-tobacco users, the adjusted odds ratios (95% CI) of any oral cleft for infants of mothers who continued to use snuff or to smoke were 1.48 [1.00–2.21] and 1.19 [1.01–1.41], respectively. In contrast, in infants of mothers who stopped using snuff or stopped smoking before the antenatal booking, the corresponding risks were not increased (adjusted odds ratios [95% CI] were 0.71 [0.44–1.14] and 0.88 [0.73–1.05], respectively). Conclusion Maternal snuff use or smoking in early pregnancy is associated with an increased risk of oral clefts. Infants of mothers who stopped using snuff or stopped smoking before the antenatal booking had no increased risk of oral cleft malformations. Oral snuff or other sources of nicotine should not be recommended as an alternative for smoke-cessation during pregnancy.

Prenatal exposure to nicotine affects substance p and preprotachykinin-A mRNA levels in newborn rat.

Prenatal nicotine exposure influences neuronal development including effects on several neurotransmitter systems. It also attenuates the ventilatory response to hypoxia, known to require a functional substance P-ergic system. Previous studies have shown that nicotine increases the risk for sudden infant death syndrome (SIDS) by 4-fold, and that SIDS-victims have elevated brainstem levels of substance P. We, therefore, studied the effect of prenatal nicotine exposure on the levels of substance P-like immunoreactivity by RIA in the brain in newborn rat pups. The expression of the substance P precursor preprotachykinin A mRNA was also determined by real-time reverse transcriptase-polymerase chain reaction in carotid body, in petrosal/jugular and trigeminal ganglia, in cervical and lumbar dorsal root ganglia, and in the brainstem. We found that prenatal nicotine exposure increased levels of substance P-like immunoreactivity in the brainstem without changing levels in other parts of the brain or in the adrenals. Furthermore, mRNA levels were increased in the carotid bodies and in the petrosal ganglia, in contrast to the decreased levels in the cervical dorsal root ganglia. We conclude that nicotine causes alterations in the substance P-ergic system in the brainstem, possibly linked to the increased risk for SIDS after prenatal nicotine exposure.

Characterising seizures in anti-NMDA-receptor encephalitis with dynamic causal modelling

We characterised the pathophysiology of seizure onset in terms of slow fluctuations in synaptic efficacy using EEG in patients with anti-N-methyl-d-aspartate receptor (NMDA-R) encephalitis. EEG recordings were obtained from two female patients with anti-NMDA-R encephalitis with recurrent partial seizures (ages 19 and 31). Focal electrographic seizure activity was localised using an empirical Bayes beamformer. The spectral density of reconstructed source activity was then characterised with dynamic causal modelling (DCM). Eight models were compared for each patient, to evaluate the relative contribution of changes in intrinsic (excitatory and inhibitory) connectivity and endogenous afferent input. Bayesian model comparison established a role for changes in both excitatory and inhibitory connectivity during seizure activity (in addition to changes in the exogenous input). Seizures in both patients were associated with a sequence of changes in inhibitory and excitatory connectivity; a transient increase in inhibitory connectivity followed by a transient increase in excitatory connectivity and a final peak of excitatory–inhibitory balance at seizure offset. These systematic fluctuations in excitatory and inhibitory gain may be characteristic of (anti NMDA-R encephalitis) seizures. We present these results as a case study and replication to motivate analyses of larger patient cohorts, to see whether our findings generalise and further characterise the mechanisms of seizure activity in anti-NMDA-R encephalitis.