Researchers say serotonin may play in breathing problems associated with epileptic seizures

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Could a chemical produced by the brain that regulates mood, sleep and breathing also be protective in people with epilepsy?

New research has found that higher levels of serotonin in the blood after a seizure are linked to a lower incidence of seizure-related breathing problems called apneas, when a person temporarily stops breathing. T

he study is published in the September 4, 2019, online issue of Neurology.

Serotonin, a hormone that transmits signals between nerve cells in the brain, is known to regulate breathing and waking from sleep, but what is unknown is how it may influence breathing before, during and after seizures,” said study author Samden D. Lhatoo, MD, FRCP, of McGovern Medical School at University of Texas Health Science Center in Houston, Texas, who conducted the research at Case Western Reserve University in Cleveland, Ohio.

“Our findings show that higher levels of serotonin after a seizure are associated with less breathing dysfunction, and while we cannot make any links between serotonin levels and a risk of sudden unexplained death in epilepsy (SUDEP), our research may provide some important clues, since SUDEP has been linked in previous research to profound breathing dysfunction after generalized convulsive seizures.”

The study involved 49 people with difficult-to-treat epilepsy with an average age of 42. Participants, who had been diagnosed with epilepsy for an average of 17 years, spent time in an epilepsy monitoring unit, where researchers examined one seizure for each participant, evaluating the electrical activity in the brain and the heart, oxygen levels in the blood, as well as changes in blood flow.

Blood samples were collected within about 10 minutes after the seizure and again at least 12 hours later to measure serotonin levels.

A total of 35 percent of the people had apnea during their seizures, and 30 percent had apnea after their seizures.

Researchers found that serotonin levels after a seizure were higher than before a seizure in people who did not temporarily stop breathing during a seizure.

For 32 people who did not temporarily stop breathing during a seizure, serotonin levels were an average of 140 nanograms per milliliter (ng/ml) higher than an average of 110 ng/ml before seizure. For 17 people who did temporarily stop breathing, their serotonin levels were not significantly higher compared to before seizure.

In 19 people with generalized convulsive seizures who did not temporarily stop breathing after a seizure, serotonin levels were higher after seizure, an average of 190 ng/ml, than before the seizure, an average of 120 ng/ml.

But serotonin levels were not significantly higher compared to before seizure in eight people with generalized convulsive seizures who temporarily stopped breathing after seizure.

This shows a stick and ball model of serotonin

Researchers found that serotonin levels after a seizure were higher than before a seizure in people who did not temporarily stop breathing during a seizure. The image is in the public domain.

Researchers also found that a higher heart rate was accompanied by higher serotonin levels after seizure in people who did not temporarily stop breathing after a seizure compared to those who did.

“Our results give new insight into a possible link between serotonin levels and breathing during and after seizure,” said Lhatoo.

“This may give hope that perhaps someday new therapies could be developed that may help prevent SUDEP.

However, our study was small and much more research is needed to confirm our findings in larger groups before any treatment decisions can be made. It is also important to note that excess serotonin can be harmful, so we strongly recommend against anyone trying to find ways to increase their serotonin levels in response to our study findings.”

In addition to the small study size, a limitation of the study was that the timing of blood draws was not consistent.

Funding: The study was supported by the National Institutes of Health and the National Institute of Neurological Disorders and Stroke.


Sudden Unexpected Death in Epilepsy (SUDEP) is the second leading neurological cause of total years of potential life lost after stroke in the United States.1 

The occurrence of SUDEP is usually seizure-related, and SUDEP risk factors include frequent generalized seizures and long-standing epilepsy.2 

The precise pathophysiological mechanisms of death are unclear, but ictal, post-ictal or interictal cardiorespiratory dysfunction, with arousal failure, are thought to account for most deaths that have been monitored.3

Serotonin (5-HT, 5-hydroxytryptamine) is a major neurotransmitter that is produced by serotonergic raphe neurons in the brainstem, which project throughout the central nervous system.4 

These serotonergic neurons play an important role in cardiovascular control, breathing, arousal mechanisms, and a “serotonin axis” may comprise the common link between these mechanisms, seizures and SUDEP.5 

The majority of serotonin (>95%) in the body is found outside the nervous system.6 Peripheral serotonin is synthesized by enterochromaffin cells in the gut, which release some of it to be taken up by platelets that express serotonin transporter (SERT), but not serotonin synthesizing proteins. The pool of serotonin in the periphery is largely separate from that in the brain, because serotonin does not easily cross the blood brain barrier (BBB).7 

However, during intense seizure activity, such as status epilepticus, the permeability of the BBB increases,8 potentially allowing exchange of 5-HT between peripheral circulation and the central nervous system. We set out to examine if seizures induced changes in peripheral serotonin levels, which have hitherto not been systematically studied in humans.

Methods

We studied patients with intractable epilepsy who were admitted to the Epilepsy Monitoring Unit and consented to participate in a multi-institution, IRB approved, prospective, multicenter SUDEP study as part of the NINDS Center for SUDEP Research’s Autonomic and Imaging Biomarkers project.

Seizures of 41 epileptic patients were monitored by standard surface video-EEG methods using the Nihon-Kohden system (Tokyo, Japan).

Peripheral capillary oxygen saturation (SpO2) was measured using pulse oximetry (Nellcor OxiMax N-600x Convidien). Epilepsy phenotypic and electroclinical data were collected, including age, gender, body mass index, epilepsy syndrome, seizure types, etiology, seizure frequency, seizure duration, seizure phase (tonic, clonic, jittery), duration of PGES,9 and medications.

Post-ictal and interictal venous blood samples were collected in serum separator tubes, spun down, and serum was frozen and sent to a reference lab (LabCorp, Burlington, NC) for measurement of serotonin levels using high-pressure liquid chromatography (HPLC) with electrochemical detection.

Since seizure occurrence during admission was not guaranteed, interictal sampling was only carried out if post-ictal samples were successfully obtained. Interictal samples were obtained at rest and always at least 12 hours after the last recorded clinical seizure. The normal lab reference values for serum serotonin are 21–321 ng/mL. Seizures were classified according to the ILAE 2017 seizure classification. Statistical analysis was done using SPSS software version 24.0 (IBM Corp, NY). A bivariate Spearman correlation coefficient was used for comparing interictal serum serotonin levels and PGES or duration of the tonic phase. P<0.05 was considered to be statistically significant.

Results

Patient characteristics are shown in Table 1. A total of 41 patients were enrolled in the study (18 males and 23 females) with an average age of 40.6±14 (range 20–77) years and mean body mass index (BMI) of 29.3±7.6 (range 19–53). Patients were pooled into two groups based on the type of seizures recorded, with 19 seizures in the group with generalized seizures (GTCS of genetic generalized epilepsy and FBTCS) and 26 seizures in the group with focal seizures without secondary generalization.

The distribution of gender and race was similar in both groups. No significant differences were seen in age, BMI or number of anti-epileptic drugs (AEDs) used (Table 1). Patients with generalized seizures had a history of epilepsy for a mean duration of 20.5±13.3 years, whereas patients with focal seizures had a mean duration of epilepsy of 16.2±16.3 years (p=0.33).

Pre-existing health issues associated with cardiac, pulmonary, sleep or psychiatric disorder was similar in both groups.

The psychiatric disorders were mainly anxiety, depression or bipolar disorder. However, none of the patients were on selective serotonin re-uptake inhibitors (SSRIs). The epileptogenic zone was mainly temporal for focal seizures. Seizure semiologies for both groups are shown in Table 1. No differences were seen for EEG seizure duration and clinical seizure duration (Table 1).

SpO2 nadir (%) significantly differed (p<0.001) between the two seizure groups, with a more pronounced decline in oxygen levels in the generalized seizure group when compared to the focal seizure group. Of the 19 generalized seizure patients, the seizure during which the serotonin samples were taken was the first during the admission in 14/19 (74%), second seizure in 4/19 (21%), and third seizure in 1/19 (5%).

Table 1.

Clinical characteristics of the patients.

Generalized
Convulsive Seizures1
(n=19)
Focal Seizures
(n=26)
P value
Demographics:
Gender – Male
   Female
10 (58%)
9 (42%)
8 (36%)
14 (64%)
0.68
Age, y41.6 ± 15.539.9 ± 13.00.70
Body mass index, BMI30.1 ± 7.528.6 ± 7.80.53
History:
Anti-epileptic medications, n2.7 ± 1.12.5 ± 1.20.49
Epilepsy duration, y20.5 ± 13.316.2 ± 16.30.33
Cardiac disorder5 (26.3%)8 (30.8%)
Pulmonary disorder1 (5.3%)4 (15.4%)
Sleep disorder2 (7.7%)
Psychiatric disorder26 (31.6%)6 (23.1%)
Type of Epilepsy:
Generalized
Focal

4 (21.0%)
15 (79.0%)


26 (100.0%)
Epileptogenic zone:
Generalized
Temporal
Frontal
Parietal
Unknown

4 (21.0%)
3 (15.8%)
4 (21.0%)
1 (5.3%)
7 (33.3%)


15 (57.7%)
4 (15.3%)
3 (11.5%)
4 (15.3%)
Seizure semiology3:
Generalized onset motor tonic-clonic4 (21.1%)
FOIA clonic2 (7.7%)
FOIA non-motor onset8 (30.8%)
FOA motor onset automatisms3 (11.5%)
FOIA motor onset hyperkinetic13 (50%)
Focal to bilateral tonic-clonic15 (78.9%)
Seizure parameters:
EEG Sz. duration (sec)94.8 ± 52.2166.6 ± 451.60.43
Clinical Sz. duration (sec)87.0 ± 51.9167.0 ± 471.0 (n=24)0.42
No. of Sz. with Apnea5 (26.3 %)
No. of Sz. with Hypoxemia5 (26.3%)
SpO2 Nadir (%)63.6 ± 16.3 (n=14)92.8 ± 3.6 (n=18)<0.001
Tonic phase duration (sec)6.0 ± 2.7 (n=12)
Jittery phase duration (sec)12.9 ± 10.6 (n=13)
Clonic phase duration (sec)27.3 ± 15.5 (n=18)
PGES duration (sec)28.0 ± 19.2 (n=11)
Post-ictal EEG Burst suppression (sec)99.8 ± 142.8 (n=4)
Post-ictal EEG Continuous slow (sec)723.3 ± 519.9 (n=8)
EEG Return to Baseline duration (sec)1363.3 ± 1374.5 (n=7)
EEG Seizure End to Blood draw (min)11.2 ± 12.17.2 ± 7.60.21

Open in a separate window1

Generalized tonic-clonic seizures and focal to bilateral tonic-clonic seizures2None of the patients were on SSRIs3ILAE classification of seizures; FOIA-focal onset impaired awareness; FOA-focal onset aware

Post-ictal serotonin levels in serum were increased after generalized seizures compared to interictal levels but not after focal seizures.

The average time elapsed between post-ictal blood draw and end of seizure for generalized seizures was 11.2±12.1 minutes and 7.2±7.6 minutes for focal seizures; there was no significant difference between these two groups (Table 1).

Interictal blood samples were drawn after a 12h seizure-free period. Mean post-ictal serotonin levels after generalized seizure, were 173.1±91.8 ng/ml (range 30–386), and in the interictal state were 119.4±63.3 ng/ml (range 26–227) (Figure 1a).

For focal seizures, mean post-ictal and interictal serotonin levels were similar, at 130.9±95.9 ng/ml (range 25–353), and 132.2±79.6 ng/ml (range 31–416) (Figure 1a).

Increase in post-ictal serotonin levels compared to interictal levels using a paired sample T-test was statistically significant for the generalized seizure group (p=0.002), but not for the focal seizure group (p=0.941, Figure 1a).

The change in serum serotonin levels (post-ictal – interictal) was also statistically significant (p=0.027) between the generalized and focal seizure groups.

The difference in serotonin level (post-ictal to interictal) was associated with reduced duration of tonic phase during generalized seizures (p=0.03, Figure 1b). Higher levels of interictal serotonin were significantly associated with shorter duration of PGES (p=0.04, Figure 1c).

In the generalized seizure group, comparison of patients who had PGES (n=11) with patients who did not have PGES (n=8), revealed no significant difference in post-ictal serotonin levels between the two groups. No other associations were observed between serotonin levels and other clinical features of the seizure.


Source:
AAN
Media Contacts:
Renee Tessman – AAN
Image Source:
The image is in the public domain.

Original Research: Closed access
“Postictal serotonin levels are associated with peri-ictal apnea”. Samden D. Lhatoo et al.
Neurology doi:10.1212/WNL.0000000000008244

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