Raili Riikonen

Favourable prognostic factors with infantile spasms

The following aspects are reviewed: Does the aetiology influence the outcome of infantile spasms? Does the treatment influence the outcome? Can the outcome be predicted? Can we improve the prognosis? Favourable factors are the following: cryptogenic aetiology, age at onset > or =4 months, absence of atypical spasms and partial seizures, and absence of asymmetrical EEG abnormalities, short treatment lag, and an early and sustained response to treatment. Not only patients with a cryptogenic aetiology have a favourable outcome. We can already at the first clinical evaluation tell the parents if the prognosis looks favourable. The final goal of the treatment is improved mental outcome. Steroids and vigabatrin are the first-line drugs for infantile spasms in Europe. In a prospective study from the United Kingdom short-term outcome was better with hormonal than with vigabatrin therapy (tuberous sclerosis excluded). However, the numbers of patients who were seizure-free at 3-4 months in different studies have been very similar. Moreover, an early response to treatment seems to be of predictive value for the cognitive outcome in children with cryptogenic spasms. The long-term outcome is known only after hormonal therapy. The side effects of steroids are usually treatable and reversible. In Finland ACTH therapy is given at the minimum effective dose and for the minimum effective time with minimal side effects. The risks of VGB are irreversible visual field defects. As of yet there is no method to examine the visual fields in patients with infantile spasms. Early treatment of infantile spasms seems to be important. Prevention of infantile spasms with some aetiological groups might be possible.

Deep Serotonergic and Dopaminergic Structures in Fetal Alcoholic Syndrome: A Study with nor-β-CIT-Single-Photon Emission Computed Tomography and Magnetic Resonance Imaging Volumetry

BACKGROUND In prenatally alcohol exposed children, the relationship between brain structure and function is highlighted to be important to study. METHODS We studied 12 children with fetal alcoholic syndrome (FAS) and fetal alcoholic effects (FAE) by magnetic resonance imaging volumetry and by single-photon emission computed tomography with iodine-123 labeled 2beta-carbomethoxy-3beta-(4-iodophenyl) ([123I]nor-beta-CIT) and related these findings to those from neuropsychological and psychiatric tests. RESULTS The absolute volumes of studied nuclei, including the brain volume, were significantly smaller in FAS/FAE children than in control patients. After normalization of volumes, significant differences were not found. Left hippocampus was smaller than the right (p<.003) but did not significantly differ from the control subjects. The children with FAS/FAE showed reduced serotonin (p=.02) in the medial frontal cortex and slightly increased striatal dopamine transporter binding. All FAS/FAE children had attention-deficit/hyperkinetic disorder (ADHD). None had depression. The internalization scores correlated with dopamine transporter binding (r=-.65; p=.03). CONCLUSIONS The results indicate that the serotonin (5-HT) system may be vulnerable to the effects of ethanol in utero. The high dopamine transporter levels may correlate with the ADHD findings. Reduced serotonin and increased binding of dopamine transporter are also seen in type 2 alcoholism. Some behavioral problems of FAS/FAE might be preventable by early intervention and treatment.

Treatment of infantile spasms: Emerging insights from clinical and basic science perspectives

Infantile spasms is an epileptic encephalopathy of early infancy with specific clinical and electroencephalographic (EEG) features, limited treatment options, and a poor prognosis. Efforts to develop improved treatment options have been hindered by the lack of experimental models in which to test prospective therapies. The neuropeptide adrenocorticotropic hormone (ACTH) is effective in many cases of infantile spasms, although its mechanism(s) of action is unknown. This review describes the emerging candidate mechanisms that can underlie the therapeutic effects of ACTH in infantile spasms. These mechanisms can ultimately help to improve understanding and treatment of the disease. An overview of current treatments of infantile spasms, novel conceptual and experimental approaches to infantile spasms treatment, and a perspective on remaining clinical challenges and current research questions are presented here. This summary derives from a meeting of specialists in infantile spasms clinical care and research held in New York City on June 14, 2010.

Recent Advances in the Pharmacotherapy of Infantile Spasms

Adrenocorticotrophic hormone (ACTH), oral corticosteroids and vigabatrin are now first-line treatments for infantile spasms in the US and Europe. There is now increased knowledge regarding the role of ACTH, corticosteroids and vigabatrin (e.g. efficacy, doses, side effects, treatment in specific aetiological subtypes of infantile spasms), and other antiepileptic drugs (i.e. topiramate, valproate, zonisamide, sulthiame, levetiracetam, lamotrigine, pyridoxine, ganaxolone), as well as adjunctive flunarizine and novel drugs not yet in clinical use for infantile spasms (i.e. pulse rapamycin and melanocortin receptor agonists). The existence of a latent period, weeks to months following a precipitating brain insult, raises the possibility of preventive interventions. Recent experimental data emerging from animal models of infantile spasms have provided optimism that new and innovative treatments can be developed, and knowledge that drug treatment can affect long-term cognitive outcome is increasing. The aim of this article is to review recent developments in the pharmacotherapy of infantile spasms and to highlight the practical implications of the latest research.

WONOEP appraisal: Molecular and cellular biomarkers for epilepsy.

Peripheral biomarkers have myriad potential uses for treatment, prediction, prognostication, and pharmacovigilance in epilepsy. To date, no single peripheral biomarker has demonstrated proven effectiveness, although multiple candidates are in development. In this review, we discuss the major areas of focus including inflammation, blood–brain barrier dysfunction, redox alterations, metabolism, hormones and growth factors.

Brain derived neurotrophic factor and serotonin transporter binding as markers of clinical response to fluoxetine therapy in children with autism

Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), has shown favorable effects in some children with autism. There are no previous studies evaluating the connection between clinical outcome and markers of clinical response to fluoxetine treatment. We examined serum brain derived neurotrophic factor (BDNF) concentrations and serotonin transporter (SERT) binding in the medial frontal cortex and midbrain, measured by single photon emission computed tomography (SPECT) scanning, in a group of 13 autistic children and adolescents (12 males, one female; age 5-16 years), who were treated for six months with fluoxetine at a dose range of 10-40 mg/day. Clinical response was evaluated by the Autism Treatment Evaluation Checklist (ATEC). Serum concentrations of BDNF and SERT binding were measured at baseline and two months after termination of fluoxetine treatment. At baseline, before starting fluoxetine treatment, the serum concentration of BDNF had a bimodal distribution in the autism group with either a low concentration (n = 8, mean 1497 pg/mL) or a high concentration (n = 5, mean 14062 pg/mL) with respect to controls (n = 15, mean 9652 pg/mL), and SERT binding was uniformly low in the autistic subjects in medial frontal cortex and midbrain. Fluoxetine treatment led to positive effects in several aspects of communication, socialization and cognitive awareness, with 6 out 13 subjects being particularly good responders. These six also had a significant decrease in BDNF (p = 0.03) and minimal change in SERT binding after therapy. The other 7 subjects showed a trend towards an increase in BDNF and SERT binding. Our results indicate that fluoxetine may improve core autistic symptoms, and that this clinical response is linked to a decrease in serum BDNF.

Cerebrospinal fluid insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein (IGFBP-2) in children with acute lymphoblastic leukemia

Insulin‐like growth factor‐1 (IGF‐1) has specific effects on axonal growth and myelination, low CSF IGF‐1 levels being found in some severe neurologic diseases. We studied the levels of CSF IGF‐1 and IGF binding protein‐2 (IGFBP‐2) in children with ALL to find out whether these levels correlated with any of the neurological deficits observed.

Treatment of autistic spectrum disorder with insulin-like growth factors

There are no treatments for the core symptoms of autistic spectrum disorder (ASD), but there is now more knowledge on emerging mechanisms and on mechanism-based therapies. In autism there are altered synapses: genes affected are commonly related to synaptic and immune function. Dysregulation of activity-dependent signaling networks may have a key role the etiology of autism. There is an over-activation of IGF-AKT-mTor in autism spectrum disorders. Morphological and electro-physiological defects of the cerebellum are linked to system-wide ASD-like behavior defects. The molecular basis for a cerebellar contribution has been demonstrated in a mouse model. These have led to a potential mechanism-based use of drug targets and mouse models. Neurotrophic factors are potential candidates for the treatment. Insulin-like growth factor-1 (IGF-1) is altered in autism. It reduces neuro-inflammation: by causing changes of cytokines such as IL-6 and microglial function. IGF-1 reduces the defects in the synapse. It alleviates NMDA-induced neurotoxicity via the IGF-AKT-mTor pathway in microglia. IGF-1 may rescue function in Rett syndrome and ASD caused by changes of the SCHANK3 gene. There are recently pilot studies of the treatment of Rett syndrome and of SCHANK3 gene deficiency syndromes. The FDA has granted Orphan drug designations for Fragile X syndrome, SCHANK3 gene deficiency syndrome and Rett syndrome.

Long‐term mortality of patients with West syndrome

To study long‐term survival and mortality among patients with West syndrome.

CBP011 Cerebrospinal fluid insulin-like growth factors IGF-1 and IGF-2 in infantile autism

There has been little exploration of major biologic regulators of cerebral development in autism. We measured insulin-like growth factors (IGF) -1 and -2 from cerebrospinal fluid (CSF) by radio immunoassay in 25 children with autism (median age 5y 5mo; range 1y 11mo-15y 10mo; 20 males, 5 females), and in 16 age-matched comparison children without disability (median age 7y 4mo; range 1y 1mo-15y 2mo; eight males, eight females). IGF-1 and -2 concentrations were further correlated with age of patients and head size. CSF IGF-1 concentration was significantly lower in patients with autism than in the comparison group. The CSF concentrations of children with autism under 5 years of age were significantly lower than their age-matched comparisons. The head circumferences correlated with CSF IGF-1 in children with autism but no such correlation was found in the comparison group. There was no difference between the two groups in CSF IGF-2 concentrations. No patients with autism had macrocephaly. We conclude that low concentrations of CSF IGF-1 at an early age might be linked with the pathogenesis in autism because IGF-1 is important for the survival of Purkinje cells of the cerebellum. The head growth might be explained by the actions of IGF-1 and -2 reflected in CSF concentrations.