Eric Lemonnier

A randomised controlled trial of bumetanide in the treatment of autism in children

Gamma aminobutyric acid (GABA)-mediated synapses and the oscillations they orchestrate are altered in autism. GABA-acting benzodiazepines exert in some patients with autism paradoxical effects, raising the possibility that like in epilepsies, GABA excites neurons because of elevated intracellular concentrations of chloride. Following a successful pilot study,1 we have now performed a double-blind clinical trial using the diuretic, chloride-importer antagonist bumetanide that reduces intracellular chloride reinforcing GABAergic inhibition. Sixty children with autism or Asperger syndrome (3–11 years old) received for 3 months placebo or bumetanide (1 mg daily), followed by 1-month wash out. Determination of the severity of autism was made with video films at day 0 (D0) and D90 by blind, independent evaluators. Bumetanide reduced significantly the Childhood Autism Rating Scale (CARS) (D90−D0; P<0.004 treated vs placebo), Clinical Global Impressions (P<0.017 treated vs placebo) and Autism Diagnostic Observation Schedule values when the most severe cases (CARS values above the mean±s.d.; n=9) were removed (Wilcoxon test: P-value=0.031; Student’s t-test: P-value=0.017). Side effects were restricted to an occasional mild hypokalaemia (3.0–3.5 mM l−1 K+) that was treated with supplemental potassium. In a companion study, chronic bumetanide treatment significantly improved accuracy in facial emotional labelling, and increased brain activation in areas involved in social and emotional perception (Hadjikhani et al., submitted). Therefore, bumetanide is a promising novel therapeutic agent to treat autism. Larger trials are warranted to better determine the population best suited for this treatment.

Does pet arrival trigger prosocial behaviors in individuals with autism

Alteration of social interactions especially prosocial behaviors – an important aspect of development – is one of the characteristics of autistic disorders. Numerous strategies or therapies are used to improve communication skills or at least to reduce social impairments. Animal-assisted therapies are used widely but their relevant benefits have never been scientifically evaluated. In the present study, we evaluated the association between the presence or the arrival of pets in families with an individual with autism and the changes in his or her prosocial behaviors. Of 260 individuals with autism - on the basis of presence or absence of pets - two groups of 12 individuals and two groups of 8 individuals were assigned to: study 1 (pet arrival after age of 5 versus no pet) and study 2 (pet versus no pet), respectively. Evaluation of social impairment was assessed at two time periods using the 36-items ADI-R algorithm and a parental questionnaire about their child-pet relationships. The results showed that 2 of the 36 items changed positively between the age of 4 to 5 (t0) and time of assessment (t1) in the pet arrival group (study 1): “offering to share” and “offering comfort”. Interestingly, these two items reflect prosocial behaviors. There seemed to be no significant changes in any item for the three other groups. The interactions between individuals with autism and their pets were more – qualitatively and quantitatively - reported in the situation of pet arrival than pet presence since birth. These findings open further lines of research on the impact of pet’s presence or arrival in families with an individual with autism. Given the potential ability of individuals with autism to develop prosocial behaviors, related studies are needed to better understand the mechanisms involved in the development of such child-pet relationship.

The diuretic bumetanide decreases autistic behaviour in five infants treated during 3 months with no side effects

The inhibitory transmitter GABA has been suggested to play an important role in infantile autistic syndrome (IAS), and extensive investigations suggest that excitatory actions of GABA in neurological disorders are because of a persistent increase of [Cl−]I.

Emotional contagion for pain is intact in autism spectrum disorders

Perceiving others in pain generally leads to empathic concern, consisting of both emotional and cognitive processes. Empathy deficits have been considered as an element contributing to social difficulties in individuals with autism spectrum disorders (ASD). Here, we used functional magnetic resonance imaging and short video clips of facial expressions of people experiencing pain to examine the neural substrates underlying the spontaneous empathic response to pain in autism. Thirty-eight adolescents and adults of normal intelligence diagnosed with ASD and 35 matched controls participated in the study. In contrast to general assumptions, we found no significant differences in brain activation between ASD individuals and controls during the perception of pain experienced by others. Both groups showed similar levels of activation in areas associated with pain sharing, evidencing the presence of emotional empathy and emotional contagion in participants with autism as well as in controls. Differences between groups could be observed at a more liberal statistical threshold, and revealed increased activations in areas involved in cognitive reappraisal in ASD participants compared with controls. Scores of emotional empathy were positively correlated with brain activation in areas involved in embodiment of pain in ASD group only. Our findings show that simulation mechanisms involved in emotional empathy are preserved in high-functioning individuals with autism, and suggest that increased reappraisal may have a role in their apparent lack of caring behavior.

Improving emotional face perception in autism with diuretic bumetanide: A proof-of-concept behavioral and functional brain imaging pilot study:

Clinical observations have shown that GABA-acting benzodiazepines exert paradoxical excitatory effects in autism, suggesting elevated intracellular chloride (Cl–)i and excitatory action of GABA. In a previous double-blind randomized study, we have shown that the diuretic NKCC1 chloride importer antagonist bumetanide, that decreases (Cl–)i and reinforces GABAergic inhibition, reduces the severity of autism symptoms. Here, we report results from an open-label trial pilot study in which we used functional magnetic resonance imaging and neuropsychological testing to determine the effects of 10 months bumetanide treatment in adolescents and young adults with autism. We show that bumetanide treatment improves emotion recognition and enhances the activation of brain regions involved in social and emotional perception during the perception of emotional faces. The improvement of emotion processing by bumetanide reinforces the usefulness of bumetanide as a promising treatment to improve social interactions in autism.

It's All in the Eyes: Subcortical and Cortical Activation during Grotesqueness Perception in Autism

Atypical face processing plays a key role in social interaction difficulties encountered by individuals with autism. In the current fMRI study, the Thatcher illusion was used to investigate several aspects of face processing in 20 young adults with high-functioning autism spectrum disorder (ASD) and 20 matched neurotypical controls. “Thatcherized” stimuli were modified at either the eyes or the mouth and participants discriminated between pairs of faces while cued to attend to either of these features in upright and inverted orientation. Behavioral data confirmed sensitivity to the illusion and intact configural processing in ASD. Directing attention towards the eyes vs. the mouth in upright faces in ASD led to (1) improved discrimination accuracy; (2) increased activation in areas involved in social and emotional processing; (3) increased activation in subcortical face-processing areas. Our findings show that when explicitly cued to attend to the eyes, activation of cortical areas involved in face processing, including its social and emotional aspects, can be enhanced in autism. This suggests that impairments in face processing in autism may be caused by a deficit in social attention, and that giving specific cues to attend to the eye-region when performing behavioral therapies aimed at improving social skills may result in a better outcome.

Treating Fragile X syndrome with the diuretic bumetanide: a case report.

We report that daily administration of the diuretic NKCC1 chloride co‐transporter, bumetanide, reduces the severity of autism in a 10‐year‐old Fragile X boy using CARS, ADOS, ABC, RDEG and RRB before and after treatment. In keeping with extensive clinical use of this diuretic, the only side effect was a small hypokalaemia. A double‐blind clinical trial is warranted to test the efficacy of bumetanide in FRX.

Autism spectrum disorders: head circumference and body length at birth are both relative.

Although the body length and weight of an infant are related to head circumference, little research on ASDs has examined these factors. Our study compared the head circumferences of neonates who were later diagnosed with ASD with a control group. Additional comparisons on morphological disproportions at birth included the head circumference‐to‐height and head circumference‐to‐weight ratios.

Treating Schizophrenia With the Diuretic Bumetanide: A Case Report.

Administration of the diuretic and NKCC1 chloride cotransporter antagonist bumetanide reduces the severity of autism spectrum disorders in children, and this effect is mediated by a reduction of the elevated intracellular chloride concentrations and a reinforcement of GABAergic inhibition (Lemonnier et al Transl Psychiatry. 2012;2:e202; Tyzio et al Science. 2014;343:675-679). Here, we report that this treatment also reduces the severity of symptoms in an adolescent with schizophrenia. Long-term treatment reduced hallucinations significantly, suggesting that this treatment may also be useful to treat schizophrenia. Further clinical trials and experimental studies are warranted to test this hypothesis.

Failure of the Nemo Trial: Bumetanide Is a Promising Agent to Treat Many Brain Disorders but Not Newborn Seizures

The diuretic bumetanide failed to treat acute seizures due to hypoxic ischemic encephalopathy (HIE) in newborn babies and was associated with hearing loss (NEMO trial, Pressler et al., 2015). On the other hand, clinical and experimental observations suggest that the diuretic might provide novel therapy for many brain disorders including Autism Spectrum Disorders (ASD), schizophrenia, Rett syndrome, and Parkinson disease. Here, we discuss the differences between the pathophysiology of severe recurrent seizures in the neonates and neurological and psychiatric disorders stressing the uniqueness of severe seizures in newborn in comparison to other disorders.