Epilepsy is a chronic neurological disorder characterized by recurrent abnormal hypersynchronous neuronal discharges. Beyond its hallmark electroclinical manifestations, epilepsy affects multiple physiological systems, including cardiovascular, autonomic, and cerebrovascular regulation. Increasing evidence indicates that seizures, especially those involving temporal and insular regions, disrupt the central autonomic network (CAN), which plays a key role in integrating autonomic output with cerebral hemodynamic control.

Cerebral blood flow (CBF) regulation is essential for maintaining neuronal stability, metabolic homeostasis, and resistance to ischemia during and between seizures. Critical components of cerebrovascular regulation include:

• Baseline cerebral blood flow velocity (MCAv)
• CO₂-mediated vasodilatory response, measured by the breath-holding index (BHI)
• Dynamic autoregulation during abrupt BP changes, quantified as the autoregulatory slope index (ASI)
• Cerebrovascular resistance (CVR) reflecting vascular stiffness or microvascular dysfunction

Several small studies have reported altered cerebrovascular reactivity and impaired autoregulation in epilepsy patients. However, most studies have limited sample sizes, do not distinguish between TLE and IGE phenotypes, and rarely integrate cerebral hemodynamic assessment with comprehensive autonomic profiling.

Because CAN elements—including the amygdala, insula, anterior cingulate cortex, hippocampus, and brainstem nuclei—regulate both autonomic outflow and CBF, seizures originating in these areas may cause parallel disturbances in autonomic function and cerebral hemodynamics. This interplay may also contribute to SUDEP, where impaired autonomic control, arrhythmias, and peri-ictal hypoperfusion are implicated.

Objective

To comprehensively evaluate cerebral hemodynamic parameters using TCD and determine their relationship with autonomic dysfunction (mCASS scores) in adults with epilepsy, with separate analysis of TLE and IGE subtypes.

A prospective, case–control study was carried out at Index Medical College. A total of 360 subjects were included:

• Epilepsy group: 180 patients
• Control group: 180 healthy adults

Groups were matched for age, sex, and BMI.

Inclusion Criteria

• Adults aged 18–65
• Diagnosis of epilepsy per ILAE 2017
• EEG and 3-Tesla MRI confirmation
• Ability to cooperate with testing procedures

Exclusion Criteria

• Cardiovascular disease, diabetes, neuropathy
• Stroke, neurodegenerative disorders
• Use of autonomic-modifying medications
• Substance abuse, smoking within 4 hours

Patients were sub-classified into Temporal Lobe Epilepsy (TLE) and Idiopathic Generalized Epilepsy (IGE).

Cerebral Hemodynamic Assessment

TCD sonography was performed using bilateral 2-MHz probes at the MCA. Parameters evaluated:

1. Baseline MCAv (cm/s)

Mean cerebral artery velocity measured after a 5-minute resting baseline.

2. Breath-Holding Index (BHI)

BHI = [(CBFV during final 3 seconds of breath-holding – baseline CBFV) / baseline CBFV] × 100 / breath-holding duration.

3. Autoregulatory Slope Index (ASI)

ASI = (ΔCBFV/CBFV₂) – (ΔBP/BP₂) × 100%.
Measured during Valsalva Phase II.

4. Cerebrovascular Resistance (CVR)

CVR = MAP/MCAv
Measured at baseline and during tilt.

Autonomic Scoring

Autonomic function was quantified using the modified Composite Autonomic Scoring Scale (mCASS):

• Sudomotor: 0–3
• Cardiovagal: 0–3
• Adrenergic: 0–4
• Total: 0–10

Statistical Analysis

Data were analyzed using:

• Mann–Whitney U test (epilepsy vs controls)
• Kruskal–Wallis test (TLE vs IGE vs controls)
• Spearman correlation (mCASS vs hemodynamic indices)

P < 0.05 was considered statistically significant.

Table 1: Baseline Characteristics

Groups did not differ significantly in age, sex, or BMI (p > 0.05). Most epilepsy subjects were on multiple AEDs and had moderate seizure frequency.

Table 2: Cerebral Hemodynamic Impairment

Epilepsy vs Controls

Patients exhibited significantly:

• Lower basal cerebral perfusion
• Reduced CO₂-reactive vasodilatation
• Poorer autoregulation
• Increased vascular resistance

Table 3: Subtype Analysis: TLE vs IGE vs Controls

TLE exhibited the most severe abnormalities

• Lowest MCAv (47.1 cm/s)
• Lowest BHI (0.74)
• Most negative ASI (–20.1)
• Highest CVR (2.22)

IGE showed intermediate abnormalities.

All measures differed significantly across groups (p < 0.001).

Table 4: Correlation between Autonomic and Cerebrovascular Dysfunction

All correlations were statistically significant (p < 0.001).

Interpretation

• Worse autonomic dysfunction → poorer cerebrovascular reactivity
• Higher vascular resistance accompanies higher mCASS scores
• Suggests shared CAN–vascular regulatory disruption

The findings of the present study provide strong and comprehensive evidence that patients with epilepsy exhibit significant autonomic nervous system (ANS) dysfunction along with marked impairment in cerebral hemodynamics, and that these disturbances are intricately correlated, pointing to a common pathophysiological substrate linking autonomic failure and neurovascular dysregulation in chronic epilepsy. In this large, prospective, case–control analysis involving 180 epilepsy patients and 180 age- and sex-matched controls, we observed that all three fundamental autonomic domains—cardiovagal, adrenergic, and sudomotor—were impaired among patients, with a severity gradient most pronounced in temporal lobe epilepsy (TLE), followed by idiopathic generalized epilepsy (IGE), and least evident among controls.

Consistent with this autonomic derangement, multiple indices of cerebral blood flow regulation, measured through transcranial Doppler sonography (TCD), were significantly altered, including lower mean cerebral artery velocity (MCAv), reduced breath-holding index (BHI), impaired autoregulatory slope index (ASI), and elevated cerebrovascular resistance (CVR). The correlation matrix further revealed robust associations between autonomic deficits, as measured by modified composite autonomic scoring scale (mCASS) and its subscores, and the hemodynamic indices, highlighting that greater autonomic dysfunction was consistently associated with poorer cerebrovascular reactivity and autoregulation. These findings not only corroborate but significantly extend existing literature, situating our results within a robust scientific framework that emphasizes epilepsy as a disorder of broad neurophysiological networks extending far beyond the cortical seizure focus.

It has long been recognized that epilepsy disrupts the central autonomic network (CAN), a highly integrated set of brain regions including the amygdala, hippocampus, insula, cingulate cortex, hypothalamus, periaqueductal gray, nucleus tractus solitarius, and rostral ventrolateral medulla; these structures collectively orchestrate cardiovascular, respiratory, thermoregulatory, and sudomotor processes. Seizures that originate from or propagate through these structures, particularly in TLE where the amygdala and hippocampus are primary foci, exert profound and cumulative effects on autonomic output, likely contributing to the chronic autonomic dysfunction observed in this study.

Previous work by Hilz et al. demonstrated vagal impairment in temporal lobe epilepsy, and our finding of significantly reduced heart rate (HR) variability during deep breathing (11.4 ± 4.2 vs. 17.9 ± 5.4 bpm) aligns with these early observations, as does the decreased E:I ratio (1.18 vs. 1.32), indicating reduced parasympathetic control over cardiac function. Similar patterns have been described by Lotufo et al., who reported reduced HRV in epilepsy patients and emphasized the role of left temporal structures in modulating vagal output. The present study adds to this evidence with a large dataset and rigorous methodology, showing clearly that cardiovagal impairment is widespread even during interictal periods.

Further supporting parasympathetic impairment is the significantly lower Valsalva ratio (1.32 vs. 1.56) observed in epilepsy patients, which reflects attenuated baroreflex-mediated HR recovery and diminished vagal responsiveness. Nagai et al. reported similar findings in patients with hippocampal sclerosis, reinforcing that chronic temporal lobe epileptogenicity impairs vagal reflex arcs. This pattern of reduced cardiovagal output is particularly relevant because diminished baroreflex sensitivity has been identified as one of the key risk markers for sudden unexpected death in epilepsy (SUDEP).

Epilepsy is associated with significant and widespread autonomic dysfunction involving cardiovagal, adrenergic, and sudomotor domains. These findings underscore epilepsy as a systemic disorder with important autonomic implications extending beyond seizure activity. Routine autonomic assessment may help identify high-risk patients, including those susceptible to SUDEP, and guide personalized therapy and monitoring strategies.

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