Frequency and Pathophysiology of Post-Seizure Todd’s Paralysis

Xu, Sui-Yi; Li, Ze-Xing; Wu, Xiaowei; Li, Ling; Li, Changxin

doi:10.12659/msm.920751

Cited by 13 publications

(14 citation statements)

References 34 publications

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“… 8 , 16 , 25 Spreading depolarization arising secondary to a seizure may contribute to postictal complications such as migraine and hemiplegia (e.g. Todd’s paralysis 26 ) whereas spreading depolarization preceding a seizure may underlie migraine-related seizures. However, not all seizures are associated with spreading depolarization, and epilepsy patients do not always display peri-ictal spreading depolarization-related deficits.…”

Section: Introductionmentioning

confidence: 99%

Kcnq2/Kv7.2 controls the threshold and bi-hemispheric symmetry of cortical spreading depolarization

Aiba

Noebels

2021

Brain

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Spreading depolarization (SD) is a slowly propagating wave of massive cellular depolarization associated with acute brain injury and migraine aura. Genetic studies link depolarizing molecular defects in Ca2+ flux, Na+ current in interneurons, and glial Na+-K+ ATPase with SD susceptibility, emphasizing the important roles of synaptic activity and extracellular ionic homeostasis in determining SD threshold. In contrast, although gene mutations in voltage-gated potassium ion channels that shape intrinsic membrane excitability are frequently associated with epilepsy susceptibility, it is not known whether epileptogenic mutations that regulate membrane repolarization also modify SD threshold and propagation. Here we report that the Kcnq2/Kv7.2 potassium channel subunit, frequently mutated in developmental epilepsy, is an SD modulatory gene with significant control over the seizure-SD transition threshold, bihemispheric cortical expression, and diurnal temporal susceptibility. Chronic DC-band cortical EEG recording from behaving conditional Kcnq2 deletion mice (Emx1cre/+::Kcnq2flox/flox) revealed spontaneous cortical seizures and SD. In contrast to the related potassium channel deficient model, Kv1.1-KO mice, spontaneous cortical SDs in Kcnq2 cKO mice are tightly coupled to the terminal phase of seizures, arise bilaterally, and are observed predominantly during the dark phase. Administration of the nonselective Kv7.2 inhibitor XE991 to Kv1.1-KO mice reproduced the Kcnq2 cKO-like SD phenotype (tight seizure coupling and bilateral symmetry) in these mice, indicating that Kv7.2 currents directly and actively modulate SD properties. In vitro brain slice studies confirmed that Kcnq2/Kv7.2 depletion or pharmacological inhibition intrinsically lowers the cortical SD threshold, whereas pharmacological Kv7.2 activators elevate the threshold to multiple depolarizing and hypometabolic SD triggers. Together these results identify Kcnq2/Kv7.2 as a distinctive SD regulatory gene, and point to SD as a potentially significant pathophysiological component of KCNQ2-linked epileptic encephalopathy syndromes. Our results also implicate KCNQ2/Kv7.2 channel activation as a potential adjunctive therapeutic target to inhibit SD incidence.

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Section: Introductionmentioning

confidence: 99%

Kcnq2/Kv7.2 controls the threshold and bi-hemispheric symmetry of cortical spreading depolarization

Aiba

Noebels

2021

Brain

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“…In a recent work, NfL detected drug‐induced neurotoxicity and decreased following cessation of treatment 50 . Of note, epileptic seizures can cause a temporary paralysis of one side of the body that mimics the clinical presentation of a stroke, so‐called Todd's paralysis 51 . A Todd's paralysis usually resolves within few days and NfL could help in excluding a stroke as etiology of such a paralysis, that is , low NfL could support a different etiology than stroke.…”

Section: Upper and Lower Extremitiesmentioning

confidence: 99%

“…50 Of note, epileptic seizures can cause a temporary paralysis of one side of the body that mimics the clinical presentation of a stroke, so-called Todd's paralysis 51. A Todd's paralysis usually resolves within few days and NfL could help in excluding a stroke as etiology of such a paralysis, that is,…”

mentioning

confidence: 99%

Neurological symptoms and blood neurofilament light levels

Barro

Zetterberg

2021

Acta Neurol Scand

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Neurofilament light chain (NfL), a component of the neuronal cytoskeleton, is increasingly recognized as promising biomarker in the clinical evaluation of neurological patients. 1,2 NfL is released from the neurons to the cerebrospinal fluid (CSF) and blood upon damage. Damage of the peripheral nervous system will also result in a release of NfL primarily into the blood. 3 The concentration in blood is approximately 50 times lower than in CSF, due to the proximity of CSF to the neuronal tissue. 4 Lately, highly sensitive assays enabled a reliable quantification of NfL in blood. 5 In our experience, the sensitivity and automation implemented with this technology enable the prospective and reliable evaluation of NfL levels in the blood of patients. 1 There is a high correlation between NfL levels measured in plasma and serum 6,7 and the evidence collected by plasma or serum measurements resulted to be consistent; thus, we refer in this review to blood NfL. Of note, the absolute NfL concentration is about 15% lower in EDTA plasma than serum; therefore, longitudinal comparisons of absolute values or with a reference range

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“…Todd's paralysis 17 ). However, not all seizures are associated with SD, and epilepsy patients do not always display postictal SD-related deficits.…”

Section: Introductionmentioning

confidence: 99%

“…SD arising secondary to a seizure may contribute to postictal complications such as migraine and hemiplegia (e.g. Todd’s paralysis 17 ). However, not all seizures are associated with SD, and epilepsy patients do not always display postictal SD-related deficits.…”

Section: Introductionmentioning

confidence: 99%

Kcnq2/Kv7.2 controls the threshold and bihemispheric symmetry of cortical spreading depolarization

Aiba

Noebels

2020

Preprint

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Spreading depolarization (SD) is a slowly propagating wave of massive cellular depolarization associated with acute brain injury and migraine aura. Genetic studies link molecular defects in enhanced cytoplasmic Ca2+ flux, glial Na+-K+ ATPase, and interneuronal Na+ current with SD susceptibility, emphasizing the important roles of synaptic activity and extracellular ionic homeostasis in determining SD threshold. In contrast, gene mutations in ion channels that shape intrinsic membrane excitability are frequently associated with epilepsy susceptibility. It is not well known whether epileptogenic mutations in voltage-gated potassium channels that regulate membrane repolarization also modify SD threshold and generation pattern. Here we report that the Kcnq2/Kv7.2 potassium channel subunit, frequently mutated in developmental epilepsy, is an SD modulatory gene with significant control over seizure-SD transition threshold, bilateral cortical expression, and temporal susceptibility. Chronic DC-band cortical EEG recording from awake conditional Kcnq2 deletion mice (Emx2cre/+::Kcnq2flox/flox) revealed spontaneous cortical seizures and SD. In contrast to a related potassium channel deficient model, Kv1.1 KO mice, spontaneous cortical SDs in Kcnq2 cKO mice are tightly coupled to the terminal phase of seizures, arise bilaterally, and are observed predominantly during the dark phase. Administration of the nonselective Kv7.2 inhibitor XE991 to Kv1.1 KO mice reproduced the Kcnq2 cKO-like SD phenotype (tight seizure coupling and bilateral symmetry) in these mice, indicating that Kv7.2 currents directly and actively modulate SD properties. In vitro brain slice studies confirmed that Kcnq2/Kv7.2 depletion or pharmacological inhibition intrinsically lowers the cortical SD threshold, whereas pharmacological activators elevate the threshold to multiple depolarizing and hypometabolic SD triggers. Together these results identify Kcnq2/Kv7.2 as a distinctive SD regulatory gene, and point to SD as a potentially significant pathophysiological component of KCNQ2-linked epileptic encephalopathy syndromes. Our results also implicate KCNQ2/Kv7.2 channel activation as an adjunctive therapeutic target to inhibit SD incidence.

show abstract

Frequency and Pathophysiology of Post-Seizure Todd’s Paralysis

Cited by 13 publications

References 34 publications

Kcnq2/Kv7.2 controls the threshold and bi-hemispheric symmetry of cortical spreading depolarization

Kcnq2/Kv7.2 controls the threshold and bi-hemispheric symmetry of cortical spreading depolarization

Neurological symptoms and blood neurofilament light levels

Kcnq2/Kv7.2 controls the threshold and bihemispheric symmetry of cortical spreading depolarization

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