Bumetanide to Ameliorate Tuberous Sclerosis Complex Hyperexcitable Behaviors

Neurological and behavioural problems are central features of children with
tuberous sclerosis complex (TSC). Much attention in the treatment of TSC
patients is given to seizure management, while cognitive and behavioural
problems are often under evaluated. At present, treatments to reduce the
tremendous behavioural burden associated with TSC are lacking. There is an
urgent need to develop novel targeted treatment options.

It has been shown that the structural brain abnormalities in TSC, notable the
tubers, constitute a source of excessive and dysfunctional brain activity.
Different studies have shown that the balance between excitatory (via the
neurotransmitter glutamate), and inhibitory (via the neurotransmitter GABA)
brain activity is disturbed in tubers, a phenomenon also referred to as the
balance between excitation-inhibition (E / I). The inhibitory quality of GABA
depends on chloride concentration in neuronal cells, when chloride is high then
GABA is excitatory instead of inhibitory. Disturbances in chloride maintenance
have been linked to epilepsy and autism spectrum disorders, both highly
prevalent in TSC. Landmark studies have shown that the diuretic agent
bumetanide can lower chloride levels and may reinstate GABAergic inhibition in
these conditions. This may be extremely relevant to TSC as disturbances in
chloride maintenance were shown in surgically resected tuber specimens of TSC
patients.

Before a randomized controlled trial in TSC cohorts can become feasible,
positive effects of bumetanide need to be confirmed in children with TSC and
appropriate endpoints need to be established. We propose to conduct a pilot
study to establish the efficacy of bumetanide as add-on treatment to reduce
irritability and other behavioural symptoms typical in children and adolescents
with TSC, with and without mental retardation. In addition, we will perform EEG
measurements to assess the effect of treatment on measures of hyperexcitability
and to identify neurophysiological characteristics that may improve and specify
future application of bumetanide treatment.

In sum, this mono-centre pilot study will prepare the repositioning of a common
diuretic drug with limited side effects to treat the severe lifelong cognitive
and behavioural problems associated with TSC that have no medical therapy at
present.

Primary aim: to confirm that treatment with bumetanide improves daily life
functioning and reduces behavioral symptoms related to hyperexcitability in
children and adolescents with TSC.
Secondary aim: to identify neurophysiological and cognitive characteristics
that relate to efficacy of bumetanide treatment.

We will conduct a 91 day monocenter pilot study with bumetanide, followed by a
28 day wash-out period.

Patients will be treated with bumetanide, which will be provided as an add-on
treatment, supplementary to the regular use of AEDs or other (allowed)
co-medications. Patients will be given a dose between 0.5 mg and 1.0 mg twice a
day (before breakfast and at the end of the afternoon, at least 2.5 hours
before bedtime) for 91 days. Bumetanide will be administered in the formulation
of half a 1.0 mg Bumetanide tablet, containing 0.5 mg bumetanide, and taken
orally. Starting dosage will be 0.5 mg twice a day, then the dose will be
increased to 1.0 mg twice a day, if blood electrolytes are normal and no signs
of dehydration are present in the clinic visit at day 7. The treatment period
will be followed by a 28 day wash-out period to evaluate return of
symptomatology and reversibility of treatment effect.

The burden and risks associated with participation are acceptable while the
intervention may greatly improve quality of life for patients and caregivers.
Bumetanide has been used as a diuretic drug for decades. Since the 1970s, the
safety and tolerability of bumetanide after short and prolonged treatment has
been established in both children and adults. The main adverse events are
related to the diuretic activity of the molecule leading to a decrease in
electrolytes, notably mild hypokalaemia are frequently reported. To monitor the
diuretic effects, physical examination (8 times in total) and blood testing (6
times in total) and urine test (1 time) will be performed with negligable and
known risks. To prevent hypokaliemia, potassium suppletion will be adminstered
in during the 91 treatment days. To monitor treatment effect, questionnaires,
cognitive tasks and EEG measurements will be performed three times. These tests
are generally well tolerated and are all non-invasive.

Importantly, neurobehavioral problems pose one of the greatest burdens in daily
life of patients with TSC and their caregivers and until now, targeted
treatments are lacking. The study proposed here is therefore relevant for
several reasons. Our application builds on existing pre-clinical and clinical
research on the application of bumetanide in neurodevelopmental disorders,
including ASD, epilepsy and TSC. Bumetanide has shown a long known safety and
has proven effective to reinstate GABA inhibitory properties, which may restore
important developmental capacities. Treatment with bumetanide may constitute a
rational treatment for cognitive and behavioural disruptions. If bumetanide
treatment is confirmed to be effective this intervention will ultimately
improve quality of life for patients and caregivers.