Low Frequency Centromedian Thalamic Nuclei Deep Brain Stimulation for the
treatment of Super Refractory Status Epilepticus: A Case Report and a review of the
Ioannis Stavropoulos, Richard Selway, Harutomo Hasegawa, Elaine Hughes, Chris
Rittey, Diego Jiménez-Jiménez, Antonio Valentin
Reference: BRS 1875
To appear in: Brain Stimulation
Received Date: 4 November 2020
Revised Date: 26 November 2020
Accepted Date: 28 December 2020
Please cite this article as: Stavropoulos I, Selway R, Hasegawa H, Hughes E, Rittey C, Jiménez-
Jiménez D, Valentin A, Low Frequency Centromedian Thalamic Nuclei Deep Brain Stimulation for the
treatment of Super Refractory Status Epilepticus: A Case Report and a review of the literature, Brain
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© 2020 The Author(s). Published by Elsevier Inc.
Low Frequency Centromedian Thalamic Nuclei Deep Brain
Stimulation for the treatment of Super Refractory Status
Epilepticus: A Case Report and a review of the literature
, Richard Selway
, Harutomo Hasegawa
, Chris Rittey
, Diego Jiménez-Jiménez
, Antonio Valentin
Department of Clinical Neurophysiology, King’s College Hospital, London, UK
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and
Neuroscience, King's College London, London, UK
Department of Neurosurgery, King's College Hospital, London, UK
Department of Paediatric Neurosciences, King’s College Hospital, London, UK
Department of Neurology, Sheffield Children’s NHS Foundation Trust, Sheffield, UK
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, and
Epilepsy Society, Chalfont-St-Peter, Buckinghamshire, United Kingdom, London, UK
• Centromedian thalamic DBS can be considered as a “rescue” treatment of sRSE
• High frequency CMN-DBS can improve generalised seizures reducing intensive care time
• CMN-DBS could potentially help to avoid serious side effects of srSE medication
• Low frequency CMN-DBS can reduce severity and frequency of focal/multifocal seizures
AV, EH, RS and HH designed the DBS implantation and the stimulation parameters. IS, CR
and DJJ reviewed and analysed the seizures’ data. IS and AV wrote the manuscript and
prepared the seizure graph. All authors reviewed and approved the final version of the
AV has received honorary for lectures and consultancy from Medtronic. The rest of authors
declare that they have no competing interests.
This work was supported by Epilepsy Research UK (grant number: P1503) and by a jointly
grant from both Action Medical Research and Great Ormond Street Hospital Children’s
charity (grant number: GN2380).
Epilepsy, super refractory status epilepticus (srSE), deep brain stimulation (DBS),
neuromodulation, centromedian thalamic nuclei, low frequency stimulation
Super refractory status epilepticus (srSE) refers to a SE that fails to respond to 1
line treatments and persists after 24 hours of anaesthesia carrying increased risk of
mortality, morbidity, and disability. Centromedian Thalamic Nucleus DBS (CMN DBS)
appears to provide some benefit in refractory generalized epilepsy[1, 2], but its efficacy and
the best stimulation parameters for this condition remain unclear. We report the case of a
15-year-old right-handed girl with normal development and no family history of epilepsy.
Bilateral tonic-clonic seizures (BTCS) started at the age of 5 leading to srSE with Paediatric
Intensive Care Unit (PICU) admission and thiopentone coma induction. The possibility of
hemophagocytic lymphohistiocytosis/macrophage activation syndrome (MAS) was raised
and she was discharged 4 weeks later on levetiracetam, steroids and cyclosporine with
cognitive, language and behavioural difficulties.
She developed brief asymmetric tonic seizures with occasional clusters of 20-30
seizures/day. Multiple AEDs (phenytoin, levetiracetam, carbamazepine, lacosamide,
lamotrigine, perampanel, zonisamide, stiripentol) and ketogenic diet provided limited benefit.
A second srSE occurred aged 9 with a 6-week PICU admission and further regression in
cognition. Following discharge, she had significant sleep issues and clusters of daytime focal
seizures and unresponsiveness. Brain MRI was normal. An extensive presurgical work-up
with scalp telemetry, PET scan and ictal-SPECT suggested multiple potential epileptogenic
regions and excluded suitability for epilepsy surgery leading to VNS implantation.
A 3rd srSE occurred aged 14, with uncontrolled, up to 30 brief seizures/hour, requiring
further admission to PICU. Thiopentone and several other drugs (felbamate, stiripentol, IVIG,
steroids, anakinra, and cannabinoids) were unhelpful. Most seizures started with left head-
eye deviation and flickering for 1 minute, followed by arm stiffening. She also had focal tonic
seizures with clonic elements and BTCS. Respiratory depression caused by infections and
high drug doses complicated her condition.
Repeat scalp telemetry showed focal ictal onset over the left/midline parietal region, followed
by right anterior quadrant build-up of ictal activity. After 80 days in the PICU she was
transferred to King’s College Hospital for CMN DBS implantation in an attempt to terminate
the srSE. The New Clinical Procedure Committee approved the technique, and the family
provided informed consent.
DBS (Medtronic 3389 electrodes) was activated on the implantation date with bipolar
stimulation contact 1 negative, contact 2 positive, 130Hz, 90µs, 1.5 mA. After initial minor
improvement in seizure frequency, seizure control worsened and DBS parameters were
changed to bipolar; contacts 0, 1, 2 negative, contact 3 positive, 60Hz, 90µs, 3V. Impedance
was checked with each parameter adjustment. A 12-hour pause of DBS caused clinical
deterioration leading from focal to bilateral tonic-clonic seizures (graph 1). The DBS was re-
started with the same stimulation parameters and an increase of stimulation intensity to 5V.
As focal seizures remained almost continuous, 48 hours later the DBS parameters were
changed to bipolar stimulation contact 1 negative, contact 2 positive, 6Hz, 300µs, 3V. No
clear stimulation artefacts or recruitment rhythm was noted at the scalp EEG at any
After 4 days, the seizure frequency decreased significantly and she was more alert, enjoying
uninterrupted seizure-free sleep periods. She was discharged from HDU to the paediatric
ward on the 17
day. Seizures remained focal over left parietal and midline region without
spreading anteriorly. On the 22
day, a deterioration in sleep pattern was noted, and the
stimulation parameters were set to 60Hz/90µs during the night and 6Hz/300µs during
daytime, without sleep improvement and with re-emergence of 5-6 focal seizures/hour.
Based on prominent focal EEG activity after DBS implantation, a review of brain MRI and
PET suggested an area of possible focal cortical dysplasia over the left parietal region.
Stereo-EEG (SEEG) exploration was agreed and DBS was switched off on the 27
before the implantation of depth electrodes. Detailed description of the SEEG implantation
strategy is out of the scope of this letter but SEEG recorded clinical and electrographic
seizures with onset over the left temporoparietal region. Resection of the area led to more
than 90% reduction in clinical seizures and the patient was discharged home with a
rehabilitation plan. Neuropathology showed possible, but non-conclusive, cortical dysplasia.
DBS can be considered as a potential “rescue” treatment for patients with super-refractory
status epilepticus. Seven cases have been reported describing the efficacy of DBS for srSE
(Table 1-supplementary material). The timing of DBS implantation after srSE onset is
variable (28-59 days) and the ideal DBS target for srSE has not been established. In three
cases, the DBS was implanted at the anterior nucleus of the thalamus for absence srSE,
convulsive srSE and non-convulsive rSE. In four cases, the CMN was targeted either
due to common variable immunodeficiency-associated encephalomyelitis, possible
encephalitis (autoimmune/ infectious) complicated with cardiac arrest, or febrile infection-
related epilepsy syndrome (FIRES). In a previous case implanted at KCH and in one of
the two FIRES cases at another institution, the srSE terminated with a vegetative state
probably due to hypoxic-ischaemic brain injury in the 1
case, and prolonged status in the
case. Based on these outcomes, earlier DBS implantation could be considered to reduce
time in srSE and avoid permanent neurological injury.
There is a lack of consensus regarding the best DBS parameters. High-frequency
stimulation (130Hz[4, 8], 145Hz[3, 5], or 180Hz, with a 70-90µs pulse width) appeared to
be effective in the treatment of generalised seizures, successfully resolving the srSE (table
1). Occasionally, improvement in frequency of generalised seizures evolve to frequent focal
or multifocal seizures. In order to reduce the severity and burden of focal seizures, low-
frequency stimulation (6Hz, 300µs) have been tried in three previously reported cases[7, 8]
and in our patient, reducing focal/multifocal seizures after a stimulation period of 5-10 days
(Graph 1). Other variations in DBS parameters such as monopolar/bipolar, current/voltage or
continuous/discontinuous stimulation have not been properly studied in these cases.
One potential hypothesis for the apparent benefit of CMN low-frequency stimulation is that
CMN thalamic nuclei are functionally connected with the fronto-parietal structures of the
cortex and this could cause highly-synchronized brain activity, facilitating inhibitory
mechanisms which could be involved in the termination of focal seizures during srSE.
Continuous low-frequency stimulation of these nuclei may disrupt seizure generation in
connected cortical epileptogenic regions, reducing number and/or severity of focal seizures.
In summary, srSE is a life-threatening condition with a complicated standard treatment and
CMN-DBS could be considered a “rescue” therapeutic option. High-frequency stimulation
appears effective in controlling generalised seizures and may be considered as a clinical
option for substantially reducing intensive care time, limiting the potential side effects of srSE
medication, and preventing further neurological damage. Low-frequency CMN DBS
stimulation could provide an additional clinical benefit reducing the severity and frequency of
The writing of this article was supported in part by a grant from Epilepsy Research UK and
by a jointly grant from both Action Medical Research and Great Ormond Street Hospital
The authors would like to thank the patient’s parents and referring clinicians without whom
this work would not have been possible. We would also like to thank Dr Zaloa Agirre-
Arrizubieta, Prof Alexander Hammers, Dr Josef Jarosz, Dr Nandini Mullatti, Dr Franz
Brunnhuber, Dr Robert Elwes, the ward nurses and the neurophysiologist team for their
extraordinary assistance in the clinical care of the patient.
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Figure 1: Figure 1: A) Axial view of pre-implantation MRI fused with post-implantation CT; B)
coronal view of pre-implantation MRI fused with post-implantation CT showing the final
position of the DBS electrodes. Note that the left DBS electrode is slightly lateral to the
target, but within stimulation distance of the CMN; C) Retrospective count of seizures by IS
and DJ who were blind to treatment. Seizures were summation for every 24 hours. The
different DBS stimulation parameters and the lorazepam injection for severe clinical seizures
are marked through the graph. At the time of DBS implantation her medication was
Melatonin, Brivaracetam, Clonazepam Sodium Valproate and Cannabidiol. No changes in
medication were done during the whole period of DBS stimulation apart from PRN
lorazepam doses given for prolonged or frequent tonic clonic seizures; D) Typical EEG
recording before DBS implantation; E) EEG recording during DBS stimulation at 6 Hz (day
Supplementary Material Table 1: The previously reported cases with the DBS target,
parameters used (Hz/μsecs) and outcome.