PMC8498587_01
Algorithm model for therapy, device block diagram and postsurgical outcome. (A) The model for the control algorithm in the device. The typical "open loop" pathway is illustrated in green. A clinician generally captures a reference value and control policy based on experience and observation, setting a stimulation state for the device that interacts with the nervous system. A "closed loop" pathway, illustrated in blue, can be constructed by adding a sensor and classifier that can then adjust stimulation accordingly through a control policy; this adaptive feedback pathway allows for continuous refinement based on immediate patient state. A feedforward pathway, illustrated in red, can help to account for variability linked to set temporal rhythms, similar to circadian cycles observed in physiology control pathways. The feedforward pathway can adjust multiple parameters in the open and adaptive loops, including reference values for measured variables, how to stimulate, which sensors to use and the classification objectives. The combination of feedforward and feedback pathways aims to optimize predictive and responsive stimulation control. (B) The Picostim-DyNeuMo cranial mounted deep brain stimulator used in this study. For device capabilities refer to Toth et al.. Note that the research tool is upgradeable through the firmware and software versions. (C) Postsurgical imaging shows a reconstructed 3D computed tomography (CT) scan of the canine's skull with the guide tube hub fixed in the drilled hole in the left parietal bone (white arrow) and the stimulator fixed on the frontal bone (black arrow). Wires coming from both guide tubes are connected with the stimulator. (D) Implanted guide tubes and wires in a transversal CT scan in the plane of the target structures. Note that the strong hyperintense signals around the target positions represent CT metal artifacts deriving from the electrode plates (n = 4, each) at the tip region of the wires. Please see supplemental methods for more details.
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The Picostim-DyNeuMo research system (Bioinduction, Bristol, UK) was implanted with bilateral electrodes targeting the CMN, with the implantable pulse generator placed subcutaneously on the frontal cranium (Figure 1); refer to the supplemental methods for details.
Frequency and chronic/acute pharmacological treatment of seizures until seven months after implantation. (A) The seizure frequency (left y-axis) and average daily antiseizure drug (ASD) dosage in mg/kg/day (right y-axis) of phenobarbital (PB), imepitoin (IMP), potassium bromide (KBr), topiramate (TPM) and gabapentin (GBP) twice (BID) or thrice (TID) daily are shown for every month since epilepsy onset in November 2018. When stimulation was started, no further status epilepticus (SE) occurred. After implantation, high frequency (HF) stimulation was applied after seizures occurred in order to prevent SE or further cluster seizure evolution. Since HF did not bring the desired result in the first cluster seizure (November 2020), the frequency was subsequently changed to low frequency (LF) entrainment adapted to the canine's local field potentials. PB was chronically administered as monotherapy (reduction from 13.3 to 12.5 mg/kg/day in November 2020), while other chronic medical and dietary therapy with medium-chain triglycerides was stopped after surgery. With the HF bursting boost mode for the interruption of ongoing seizures four seizures out of six attempts in November 2020 were interrupted. One seizure was noticed too late. In December 2020, one seizure was interrupted while five further ones occurred without interruption attempt. In January 2021, one attempt of seizure interruption was without success, while another seizure was noticed too late. In February 2021, two out of three attempts of seizure interruption were successful. In March 2021, three seizures were interrupted while two continued after attempt. In April 2021, four seizures were interrupted, two continued and one was noticed too late. The overall success rate of interruption attempts was 64%. Electrical stimulation has the potential of reducing acute and chronic pharmacological interventions. (B) The seizure number (left y-axis) in black dots and lines and average daily ASD dosage in mg/kg/day (right y-axis) for chronic (horizontal colored lines) and emergency treatment (vertical bars) with levetiracetam (LEV) or diazepam (DZP) are shown on a day-to-day basis since begin of March 2020 until end of April 2021 (seven months pre and post implantation). Gray arrows represent successful avoidance of further seizure occurrence/evolution after a single seizure or in cluster seizures (CS) via stimulation with (+LEV) or without LEV intervention. It turned out that initially, only the combination of acute LEV treatment and LF-entrainment prevented or interrupted cluster seizure evolution. Since February 2021, however, LEV was not administered after seizure occurrence due to severe side-effects, with LF-entrainment alone achieving cluster cessation, except in two CS events which consisted of rapid successive but few seizures in April 2021. Eight seizure evolution interruptions were conducted together with LEV and seven without LEV after stimulation onset, with only seven interruptions with LEV during LF-entrainment. DBS has the potential of reducing acute pharmacological interventions.
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The carer's seizure diaries were used for comparative analysis of seizure type prevalence and frequency, seizure-free episodes and semiology of cluster seizures before and after surgery. The dog, treated as a veterinary patient, did not adequately respond to an array of antiseizure medication; treatment consisted of phenobarbital, potassium bromide, imepitoin, topiramate and gabapentin in various combinations (see Figure 4 for details).