A novel neural computational model of generalized periodic discharges in acute hepatic encephalopathy

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Purpose: Triphasic waves arising in patients with toxic metabolic encephalopathy (TME) are often considered different from generalized periodic discharges (GPDs) in patients with generalized nonconvulsive status epilepticus (GNCSE). The primary objective of this study was to investigate whether a common mechanism can explain key aspects of both triphasic waves in TME and GPDs in GNCSE.Method: A neural mass model was used for the simulation of EEG patterns in patients with acute hepatic encephalopathy, a common etiology of TME. Increased neuronal excitability and impaired synaptic transmission because of elevated ammonia levels in acute hepatic encephalopathy patients were used to explain how triphasic waves and GNCSE arise. The effect of gamma-aminobutyric acidergic drugs on epileptiform activity, simulated with a prolonged duration of the inhibitory postsynaptic potential, was also studied. Results:The simulations show that a model that includes increased neuronal excitability and impaired synaptic transmission can account for both the emergence of GPDs and GNCSE and their suppression by gamma-aminobutyric acid-ergic drugs. Conclusions:The results of this study add to evidence from other studies calling into question the dichotomy between triphasic waves in TME and GPDs in GNCSE and support the hypothesis that all GPDs, including those arising in TME patients, occur via a common mechanism.

Section: Background Of Neural Mass Modelmentioning

confidence: 99%

“…Nevertheless, the underlying mechanisms generating epileptiform activity in our model (increased neuronal excitability and impaired synaptic transmission) are quite general and seem likely to be common to many or all forms of TME. 15,16…”

Section: Limitationsmentioning

confidence: 99%

Do Triphasic Waves and Nonconvulsive Status Epilepticus Arise From Similar Mechanisms? A Computational Model

Ligtenstein

Song

Jin

et al. 2021

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“…29 Elevated neuronal excitability, impaired synaptic transmission, and enhanced postsynaptic inhibition have been hypothesized as a mechanism for the generation of TWs in a recent computational model. 46 Because cefepime was shown to have a dose-dependent modulation of γ-aminobutyric acid-A receptors in animal models, 47 it is possible that cefepime causes a preferential inhibition of γ-aminobutyric acid-A receptors in the inhibitory neurons, leading to a release phenomenon and generation of TWs.…”

Section: Discussionmentioning

confidence: 99%

Acute Toxicity and Triphasic Waves—The Example of Cefepime

Husari¹,

Ritzl

Kaplan

2020

Purpose: Triphasic waves (TWs) have been associated with a host of medication toxicities, and cefepime has emerged recently as a frequently encountered offending agent. This investigation aims to evaluate cefepime-induced encephalopathy and to report the associated clinical, EEG expression with TWs, and the radiologic findings.Methods: A retrospective multicenter observational study examining adult patients with cefepime-induced encephalopathy with generalized periodic discharges on either routine or continuous EEG between January 2014 and January 2020. Clinical, electrographic, and radiologic data were collected. Patients in whom cefepime was not the sole causative factor for their encephalopathy were excluded.Results: Twenty-seven patients with cefepime-induced encephalopathy marked by generalized periodic discharges with triphasic morphology were identified at both centers, whereas no patients were presenting with generalized periodic discharges without TWs. Patients had a median age of 63 years (interquartile range, 56-73). Fifty-six percent of the cohort (15 patients) were ,65 years of age. Eighteen patients (67%) had either acute or chronic kidney impairment (either acute kidney injury or chronic kidney disease or both), whereas 81% had preexisting white matter disease on brain imaging. Of these, 14 patients (51%) were classified as either moderate or severe. In the majority of the patients, TWs were either state-dependent or stimulus-sensitive, and in one third of them presented only as stimulus-induced pattern. All patients improved with discontinuation of cefepime.Conclusions: Cefepime toxicity should be considered in the differential diagnosis in encephalopathic patients with TWs. The presence of preexisting white matter disease in these patients should heighten the degree of suspicion, especially in younger patients and patients without renal dysfunction.

“…10 But seizures and periodic discharges both seem to be associated with the degree of primary brain injury 11 and the inflammation 12 that occurs as a result. Modeling studies that replicate the morphology of GPDs in particular have highlighted that brain injuriesdeither from anoxia or from hepatic failuredcreate an imbalance between neuronal excitability and impaired synaptic transmission [13][14][15] that lead to the development of periodic patterns that at times can reach the frequency thresholds used clinically to define seizures. 16 Therefore, periodic discharges should not be thought of as "ictal" nor "nonictal" but rather a distinct (albeit nonspecific) pathologic entity somewhere betweenda more accurate reflection of the original concept of the ictal-interictal continuum.…”

Section: Ictal-interictal Patternsmentioning

confidence: 99%

Can We Distinguish Triphasic Waves From Other Generalized Periodic Discharges? Do We Need to?

Foreman¹

2021

Triphasic waves are intuitively distinctive waveforms that fall under the umbrella of generalized periodic discharges. The ability to distinguish these waveforms consistently could be helpful if a specific underlying pathophysiology could be identified. However, scalp EEG and clinical observation have been limited in their ability to elucidate the underlying cortical physiology that leads to triphasic waves. Evidence from intracranial physiologic data and computational modeling suggest that these and other periodic discharges should be viewed not as strictly ictal nor non-ictal but rather on the spectrum between these two. Triphasic waves in particular appear to result from an abnormal balance between cortical excitation and synaptic transmission with input from functionally connected brain networks, such as the thalamocortical pathways involved in arousal. The practical implication of triphasic waves begins with acknowledgement of uncertainty and a rational approach should ask whether the patterndor its treatmentmight be creating harm.