Adult convulsive status epilepticus in the developing country of Honduras

Article Outline

• Abstract
• 1. Introduction
• 2. Methods
  • 2.1. Inclusion and exclusion criteria
  • 2.2. Etiology
  • 2.3. Emergency room and in-patient treatment
  • 2.4. Emergency room and in-patient outcomes
• 3. Results
• 4. Discussion
• 5. Conclusions
• Conflict of interest statement
• Acknowledgements
• References
• Copyright

Abstract 

Epidemiologic data on convulsive status epilepticus (CSE) is needed to develop preventative strategies. Epilepsy is one of the known risk factors for CSE. A systematic review of epidemiologic studies on status epilepticus (SE) completed in the United States and Europe reports that people with epilepsy account for less than 50% of cases of SE in all age groups. Less is known about the epidemiology of SE in developing countries including those in Central America.

A high incidence of epilepsy, widespread non-adherence to anti-epileptic drugs (AED), and common use of complementary and alternative medicines have been shown in all ages in the developing country of Honduras, Central America. In 2003, an epidemiologic study of CSE in Honduran children demonstrated it is common and exhibits a long duration until onset of treatment. The etiologies, treatment, and outcomes of CSE in Honduran adults have not been thoroughly studied. This study is a consecutive case series of 31 adult patients presenting with CSE to the adult medicine emergency department of the tertiary care “Hospital Escuela” in the capital city Tegucigalpa, Honduras. The majority (77.4%) of patients had a prior history of epilepsy. Non-adherence to AED was the most common etiology of CSE (75.0%). The mortality rate in this pilot CSE study was 14.8%, which is similar to studies from industrialized countries where mortality from status epilepticus ranged from 7.6 to 22% for all age groups. However, this rate is concerning given that CSE from epilepsy and AED non-adherence generally carries a good prognosis.

Improving AED adherence in this population appears to be the most effective approach in decreasing the rate, and possibly the mortality of Honduran adult CSE.

Abbreviations: CSE, Convulsive status epilepticus, SE, Status epilepticus, AED, Anti-epileptic drugs, ILAE, International League Against Epilepsy, IRB, Institutional Review Board, MUSC, Medical University of South Carolina, NAUH, National Autonomous University of Honduras, EEG, Electroencephalogram, NCSE, Non-convulsive status epilepticus

Keywords: Convulsive status epilepticus, Honduras, Seizure, Epilepsy, Developing country, Epidemiology, Adults

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1. Introduction 

Epidemiological data on convulsive status epilepticus (CSE) is needed to develop preventative strategies.¹ A systematic review of the epidemiology of status epilepticus (SE) conducted in 2004 concluded that the incidence of SE varies greatly, but falls in the range of 9.9 to 41/100 000/year for all age groups.¹ The review also reported that people of all ages with epilepsy accounted for less than 50% of cases of SE. However, only studies from the USA, Germany, England, and Switzerland met inclusion criteria.¹ Less is known about the epidemiology of SE in developing countries, including those in Central America. Reasons for this include lack of investigators and funding for these studies, difficulty in defining a population due to scarcity of medical centers, and SE reviews that exclude studies from developing countries which failed to use International League Against Epilepsy (ILAE) classifications.

A high incidence of epilepsy and a high percentage of preventable causes of epilepsy in all ages have been shown in the developing country of Honduras.², ³, ⁴ Neurocysticercosis was the most common preventable cause found.⁴ From 1999 to 2002, a survey of 135,126 Hondurans was conducted, and the mean incidence of epilepsy was found to be 104/100,000. This value ranged from 48 to 254/100,000 with regional variability.² In the rural county of Salamá, Honduras, a study demonstrated a prevalence rate of 23.3/1000 and incidence rate of 92.7/100,000.⁴ The incidence is much higher than the range of 30 to 50/100,000 reported in industrialized nations.⁵, ⁶ Complicating the treatment of these people with epilepsy is widespread non-adherence to anti-epileptic drugs (AED) due to AED unavailability, inability to pay for the AED, inadequate education, cultural beliefs, and the common use of complementary and alternative medicines.⁷

An epidemiologic study in 2003 examined CSE in children presenting to the children's tertiary care “Hospital Escuela Materno-Infantil” in Tegucigalpa, Honduras.⁸ Of the 47 patients included in the study, the median duration of CSE was 95min due primarily to long distances traveled before reaching the hospital for treatment. Morbidity and mortality were higher in children from rural locations.⁸

The etiologies, treatment, and outcomes of CSE in Honduran adults have not been thoroughly studied. In this prospective, consecutive case series, we aim to describe the etiologies, emergency department AED treatment, and short-term in-patient outcomes of adults 18 years and older from a developing country who present with CSE to a tertiary care emergency department in the capital city of Tegucigalpa, Honduras, Central America.

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2. Methods 

Adult patients with CSE were consecutively enrolled from November 2008 to May 2009. Institutional Review Board (IRB) approval of the study was obtained at the Medical University of South Carolina (MUSC) in Charleston, SC, USA, and the National Autonomous University of Honduras (NAUH) in Tegucigalpa, Honduras. Informed consent of each enrollee was signed before study participation.

2.1. Inclusion and exclusion criteria 

All patients 18 years and older presenting to the NAUH Hospital Escuela adult medical emergency room during the defined study period during an on-going convulsive seizure equal to or greater than 5min were included.⁹, ¹⁰, ¹¹ Patients who presented to the emergency department with seizures which were self-limited, and did not require emergent AED were excluded. The investigators did not seek IRB approval for the inclusion of pregnant women, prisoners, or institutionalized patients; therefore, these vulnerable populations were excluded.

2.2. Etiology 

CSE etiologies were determined by history, laboratory testing, neuroimaging, and electroencephalogram (EEG). All CSE events were classified according to International League Against Epilepsy (ILAE) guidelines based on semiologic description.¹²

2.3. Emergency room and in-patient treatment 

The 1st and 2nd line AED used to treat the CSE, and the time between CSE patient arrival to the emergency department and administration of the 1st AED were the primary treatment aims.

2.4. Emergency room and in-patient outcomes 

The primary outcome measure was mortality. In-patient recurrence of seizures and CSE were also evaluated.

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3. Results 

Of the 36 patients evaluated, 31 CSE patients met inclusion criteria and were enrolled. There were 18 females (58.1%) and 13 males (41.9%) (Table 1). CSE was most common in the 18–30-year age range, and percentages decreased as age increased (Fig. 1). Tonic–clonic semiology was seen in 25 cases (80.6%) (Table 1). Four cases were described as tonic status epilepticus (12.9%). One patient presented to the emergency department in subtle CSE, while another patient was initially in tonic–clonic status epilepticus and progressed to subtle CSE. There was one case of clonic status epilepticus (Table 1).

Table 1. Patient characteristics in 31 consecutive adults with convulsive status epilepticus when initially seen at Hospital Escuela adult medical emergency department in Tegucigalpa, Honduras.

Age in years	Gender	History of epilepsy	ILAE class	1st AED for CSE	2nd AED for CSE	Time from ED arrival to 1st AED	Recurrent in-patient Seizure	Recurrent inpatient CSE	Mortality
18	F	Yes	TC→SCSE	PHT	CLZ	420	No	No	No
20	F	Yes	C	DZP	CLZ	15	Yes	Yes	No
34	F	Yes	TC	DZP	PHT	5	No	No	No
31	M	No	TC	MDZ	MDZ	15	Yes	Yes	No
19	M	Yes	TC	PHT	DZP	20	NR	NR	NR
21	F	Yes	T	DZP	PHT	5	No	No	No
43	F	Yes	TC	DZP	PHT	30	Yes	No	No
52	F	Yes	TC	DZP	PHT	10	NR	NR	No
33	M	No	SCSE	DZP	PHT	10	NR	NR	Yes
39	F	Yes	TC	DZP	PHT	10	No	No	No
41	F	Yes	T	DZP	PHT	10	No	No	No
37	F	No	TC	DZP	PHT	10	NR	NR	No
22	M	Yes	T	DZP	PHT	5	No	No	No
20	F	No	TC	DZP	PHT	20	No	No	Yes
26	F	Yes	TC	DZP	PHT	10	NR	NR	NR
48	F	Yes	TC	PHT	PHT	30	No	No	No
28	M	No	TC	DZP	PHT	40	NR	NR	NR
42	F	Yes	T	DZP	PHT	5	Yes	Yes	Yes
71	M	No	TC	DZP	PHT	15	No	No	No
48	M	Yes	TC	DZP	DZP	5	Yes	Yes	Yes
23	M	Yes	TC	DZP	PHT	5	No	No	No
46	F	Yes	TC	PHT	PHT	30	No	No	No
28	F	Yes	TC	MDZ	DZP	10	No	No	No
28	M	Yes	TC	DZP	PHT	5	No	No	No
38	F	Yes	TC	PHT	PHT	NR	No	No	No
39	M	Yes	TC	PHT	None	10	No	No	No
43	M	Yes	TC	DZP	PHT	10	NR	NR	NR
64	M	No	TC	DZP	PHT	10	No	No	No
42	F	Yes	TC	DZP	PHT	5	No	No	No
20	M	Yes	TC	DZP	DZP	10	Yes	No	No
23	F	Yes	TC	DZP	PHT	10	Yes	No	No

ILAE, international league against epilepsy classification; AED, anti-epileptic drugs; CSE, convulsive status epilepticus; ED, emergency department; F, female; M, male; NR, not recorded; TC, tonic–clonic; SCSE, subtle convulsive status epilepticus; C, clonic; T, tonic; PHT, phenytoin; DZP, diazepam; MDZ, midazolam; CLZ, clonazepam.

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• Fig. 1. 

  Convulsive status epilepticus (CSE) patients’ age in years. This graph demonstrates that the majority of patients presenting with CSE were between the ages of 18 and 30 years. As age increased, the percentage of patients decreased. This is consistent with Honduran vital statistic data showing that 54% of the population in between 15 and 64 years of age.

Evaluation of the AED treatment of CSE used in the emergency department (Fig. 2, Fig. 3) revealed that Diazepam was used as the first-line AED in 23 cases (74.2%). Phenytoin was used in 23 (76.7%) of the 30 patients who required second-line therapy. Time from emergency room arrival until 1st AED treatment of CSE ranged from 5 to 420min (mean=26.7min, median=10min, and mode=10min) (Table 1). Use of a third-line AED in the emergency department was reported in 17 patients. Phenytoin was most commonly used (n=9). In five of nine patients, phenytoin was re-loaded to achieve a higher level. Phenytoin administration after failure of two doses of benzodiazepines was reported in four patients. Two of the three patients treated with Midazolam received an intravenous drip. Three patients also received single doses of diazepam as third-line treatment. Fourth-line AED treatment was reported in seven patients. Phenytoin re-load was the most common fourth-line AED (n=4) used. Two patients received Midazolam, and an intravenous drip was recorded for one of these patients. No other anesthetic agents were used.

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• Fig. 2. 

  First-line anti-epileptic drugs (AED) used as treatment for convulsive status epilepticus in the Hospital Escuela adult medical emergency department. Twenty-three of 31 patients (74.2%) received diazepam as their first-line AED.

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• Fig. 3. 

  Second-line anti-epileptic drugs (AED) used as treatment of convulsive status epilepticus in the Hospital Escuela adult medical emergency department. Twenty-three out of 30 patients (76.7%) requiring second-line AED received phenytoin as their second-line AED.

Etiologic risk factors identified in our patient population included a history of epilepsy, AED non-adherence, alcohol abuse, metabolic abnormalities, central nervous system infection, intracranial hemorrhage, and post-partum eclampsia (Fig. 4). Each patient had at least one etiologic risk factor. A high percentage of patients had a previous history of epilepsy n=24 (77.4%) (Table 1). AED non-adherence was confirmed in 18 of 24 patients (75.0%) with epilepsy. Alcohol abuse was confirmed in 6 of 26 patients (23.1%). Twenty-four of 30 patients underwent neuroimaging. One computed tomography scan showed multiple calcifications consistent with neurocysticerosis. Two neuroimaging studies were consistent with viral encephalitis. One patient had diffuse cerebral edema consistent with their history of post-partum eclampsia. Left sided subdural hemorrhage was found in two patients, and one of those also had a subarachnoid hemorrhage. One patient had a cavernous angioma, and another patient's study was remarkable only for small vessel disease.

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• Fig. 4. 

  Etiologies of convulsive status epilepticus. A high percentage of patients had a previous history of epilepsy n=24 (77.4%). Anti-epileptic drug non-adherence was confirmed in 18 of 24 patients (75.0%) with epilepsy.

Short term in-patient mortality data revealed 4 deaths among the 27 reported mortality outcomes (14.8%) (Table 1). Of those patients with confirmed in-patient outcome data, 7 of 24 (29.2%) in-patients experienced additional isolated seizures, and 4 of 24 (16.7%) in-patients had a recurrence of CSE.

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4. Discussion 

The vast majority of patients (n=28; 90.3%) presenting with CSE were under 51 years of age. Honduran vital statistics data in 2009 showed that 54% of Hondurans are between 15 and 64 years, and only 3.6% are over age 65 years.¹³ The majority (77.4%) of patients presenting to Hospital Escuela with CSE had a prior history of epilepsy. This percentage is higher than has been documented in epidemiologic reviews of status epilepticus from industrialized countries. In that setting, fewer than 50% of status epilepticus patients of all ages had a prior history of epilepsy.¹ However, values may differ, in part, due to inclusion of CSE and non-convulsive status epilepticus (NCSE) in reviews from industrialized countries. Inclusion of NCSE in our study was impractical because emergent EEG services, which are necessary to diagnosis NCSE, are not always available at this institution. Long-term EEG monitoring also is not available.

Another common etiologic risk factor in this adult CSE population was non-adherence to AED, which was confirmed in 75.0% of the patients with a history of epilepsy. This is not surprising given the high rates of non-adherence to AED reported in this population.⁷ A previous study has shown that up to 48% of status epilepticus cases in the setting of known epilepsy occurred despite optimal AED levels.¹⁴ Therefore, the importance care beyond therapeutic AED levels, such as neurologic specialty care and out-patient diagnostic tests to improve accuracy of diagnosis and treatment should not be ignored.

The 2005 Salamá study reported neurocysticercosis was the main etiology of symptomatic epilepsy in this rural Honduran county.⁴ Though we would have expected neurocysticercosis to be present in a high percentage of our patients, we were surprised to find only one case of CSE was due to neurocysticercosis. Reasons for this are unclear, and further epidemiologic data is warranted.

Similar to well-known treatment algorithms used throughout the United States and Europe, a benzodiazepine was most commonly used as first-line treatment followed by phenytoin.¹⁵, ¹⁶ Due to limited medication availability, diazepam was used instead of lorazepam, and phenytoin instead of fosphenytoin (Fig. 2, Fig. 3). Third-line anesthetic agents commonly used in industrialized countries were only occasionally used.¹³ Likely limiting the use of these agents is the fact that critical care medical equipment, such as ventilators and intubation kits, was not as readily available as in industrialized countries.

We found that, similar to experiences of Murthy et al.¹⁷ who studied CSE in India, reported times from seizure onset to emergency room arrival were quite variable and prolonged due to transportation issues, including limited availability of emergency response services. Our data for times of CSE length prior to emergency room arrival varied so much (30min to 5 days), that reliable estimates on total duration of CSE could not be determined in our study. Therefore, for the purposes of our study, patients met criteria if they had on-going convulsive seizures for 5 or more minutes in the emergency room, even though all of our study patients had variable lengths of CSE by history prior to arrival in the emergency room. This criteria was selected in agreement with the “operational definition” of status epilepticus originally proposed by Lowenstein, and carried forth by others including Alledredge, and Starreveld.⁹, ¹⁰, ¹¹ Although the time from patients’ arrival to the emergency department until treatment with a first-line AED ranged from 5 to 420min, the most prolonged delay (420min) was in a case of tonic–clonic CSE that appeared to resolve. However, on neurologic reevaluation the patient had continued seizing as subtle CSE. This case demonstrates how limited emergent EEG capabilities may hinder care in this population. In general, when the diagnosis of CSE could be made easily on clinical grounds, antiepileptic medications were quickly administered.

The mortality rate in this pilot CSE study from Honduras was 14.8% (n=4). Two of the four patients that died had a prior history of epilepsy. One of these patients was non-adherent with AED. The other patient reported AED adherence, but unfortunately the AED serum level was not recorded. Both mortalities in the setting of epilepsy were surrounded by additional complicating factors. One patient had Down's syndrome and a hospital course complicated by pneumonia. The second person with epilepsy and CSE was reportedly abusing alcohol, and the hospital course was complicated by electrolyte abnormalities and pneumonia. Two additional deaths occurred in CSE patients with chronic renal failure requiring hemodialysis. The mortality rate in our study is similar to studies from industrialized countries where mortality from status epilepticus ranges from 7.6 to 22% for all age groups.¹ However, our reported mortality rate may be concerning given that previous data has shown that mortality in CSE is predicted by CSE etiology, and status epilepticus in the setting of epilepsy with or without AED non-adherence generally carries a low risk of death and morbidity.¹⁸, ¹⁹ If CSE caused by AED non-adherence is responsible for a large percentage of the CSE associated deaths in this population, then improvement of AED adherence would be not only good strategy for prevention of CSE, but would also reduce mortality. Likewise, the potentially higher mortality rate suggests a need for improved access to timely acute care as well as in-patient measures such as long-term monitoring EEG, ventilators, and an increased number ICU beds.

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5. Conclusions 

Although etiologies of CSE varied in this study, the majority (77.4%) of adult patients presenting to Hospital Escuela with CSE had a prior history of epilepsy. Of those with epilepsy, a large percentage (75.0%) was non-adherent to AED. Improving AED adherence among epilepsy patients appears to be the most effective approach to decrease the rate of CSE and possibly mortality in this adult population.

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Conflict of interest statement 

The authors have no conflicts of interest to report.

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Acknowledgements 

The authors of this project would like to thank the patients in this study and their families. We also thank the Neurology residents and medical students at Hospital Escuela for their care of the patients. We are grateful to the Neurosciences Department at the Medical University of South Carolina, including Research Chair, Peter Kalivas PhD, Residency Program Director, Paul Pritchard MD, and Neurology Chairman, David Bachman MD for their support and for travel funds (HJS) which made this study possible. Also, we would like to thank Anthony Coombs BS for his editorial assistance.

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