Etiological profile of new-onset seizures among adult Egyptians

New-onset seizure (NOS) is defined as the first seizure within a 24-h period ever experienced by the patient. A first-ever seizure can be the first manifestation of epilepsy. Or it may be a symptom of a brain tumor, a systemic disorder, an infection, or a syndrome that deserves special attention and treatment. This study aims to identify the etiology of NOS among different age and sex groups of adult Egyptian patients. A hundred and twenty adult Egyptian patients (> 18 years) presented with acute NOS were enrolled in a hospital-based cross-sectional observational study from the emergency room and neurology outpatient clinics of our hospitals within a time period of 6 months from March till September 2018. All patients were subjected to neurological examination, laboratory, neuroimaging, and electroencephalogram investigations. Among 120 adult patients presented with NOS, males were prevalent (63%). Older adults (age group > 55 years) were the most prevalent cohort (60%). Cerebrovascular diseases (CVDs) were the most common identified etiology of NOS (44.17%), followed by idiopathic epilepsy syndrome (18.33%), symptomatic mainly “metabolic” (11%), brain tumors (9.17%), post-traumatic epilepsy (6.67 %), encephalitis (5.83%), and cryptogenic (5%). Idiopathic epilepsy syndrome was the most common etiology (55.56%) of new-onset seizures among the young adult age group (< 36 years), while CVDs were the most common etiology (65.28%) among older adults (> 55 years). Also, CVDs were the most common etiology among males (43.4%) as well as females (45.4%). However, male predominance was the highest among post-traumatic seizures (87.5%). And female predominance was the highest among brain tumors identified etiology of NOS (54.5%). NOS among adults are prevalent in elder males. CVDs are the most commonly identified etiology of adult NOS across males and females. Idiopathic epilepsy syndromes are the predominant etiology among younger adults.


Background
Seizures are one of the important causes of morbidity and mortality in adults. Despite many studies are based on the seizure and epilepsy classification system, however, there are only a few studies on the clinical profile and causes of new-onset seizures [1].
New-onset seizure was defined as the first seizure (or the first cluster of seizures within a 24-h period) ever experienced by the patient [2].
A first-ever seizure can be the first manifestation of epilepsy, which is characterized by recurrent unprovoked seizures (two or more). Or it may be a symptom of a brain tumor, a systemic disorder, an infection, or a syndrome that deserves special attention and treatment [3].
Seizures are common in the general population, and about 1 in 10 people will experience a seizure in their lifetime. Most of these seizures are provoked by acute events and are not related to epilepsy [4].
Epilepsy was regarded as a disease of children for many years, but as researchers gathered more data on an aging population, they found that the incidence of newonset epilepsy increased among people older than 50. They reported an incidence of 169/100,000 per year in this population, almost twice the incidence among children [5].
The incidence rate of new-onset epilepsy in older adults ranges from 1 to 3 per 1000 person per year and is estimated to be two to six times higher than in younger adults [6].
The etiology of seizures can be easily made out in most of the older patients. The causes include subdural hematoma, stroke, central nervous system (CNS) infections, degenerative disorders like Alzheimer's disease, and malignancy. They also can occur with systemic metabolic conditions like uremia, hyperglycemia, hypoglycemia, and hyponatremia [7].
An epidemiological study of the incidence, prevalence, underlying etiology of new-onset seizures, and distribution among different age and sex groups can help predict the course of treatment and prognosis of such patients.

Methods
This is a hospital-based cross-sectional observational study. Patients were recruited over 6 months (from March 2018 till September 2018). A hundred and twenty patients presented by acute (within 24 h) new-onset seizure (NOS) were included in this study.
All patients were subjected to: full medical history including past history of possible risk factors for symptomatic seizures such as diabetes mellitus (DM), chronic liver disease (hepatic encephalopathy), chronic kidney disease (CKD) or first presentation of acute renal failure (uremic encephalopathy), hypertension (hypertensive encephalopathy), posterior reversible encephalopathy syndrome (PRES) in eclampsia, autoimmune diseases as (systemic lupus erythematosus), febrile seizures, cerebrovascular accidents (CVAs) including infarction and hemorrhage, head injuries such as road traffic accidents (RTA) with traumatic brain injuries (TBI), central nervous system infections (meningitis, encephalitis), drug intake and alcohol (especially drug abuse or withdrawal), brain tumors, and operative (neurosurgical) intervention.
A family history of epilepsy. A detailed history of the new-onset seizure (type of seizure was established according to the ILAE 2017 classification of seizures).
Detailed neurological examination including Mini-Mental State Examination (MMSE), speech, cranial nerves examination, motor and sensory examination, and signs denoting a cause of seizure (fever, papilledema).
Neuroimaging including cranial computed tomography (CT) "GE Healthcare Computed Tomography Optima CT660 System, USA, 2010" scanning with/or without contrast to identify stroke (ischemic or hemorrhagic) and space-occupying lesions (SOLs) and magnetic resonance imaging (MRI) of the brain "Closed Refurbished GE 1.5 T HD xt MRI Machines, USA, 2015" (if epilepsy syndrome is suspected) for better resolution of abnormal brain structure as mesial temporal sclerosis, cortical dysplasia and with contrast (when indicated) for brain tumors.

Sampling method
The sampling technique used in this study was a purposive sampling of adults with new-onset seizures with an estimated number to be at least eighty patients.

Statistical methods
IBM SPSS statistics (V. 21.0, IBM Corp., USA, 2012) was used for data analysis.
Chi-square test to study the association between every 2 variables or comparison between 2 independent groups as regards the categorized data.
The probability of error at (P value 0.05) was considered significant, while P values 0.01 and 0.001 were highly significant.

Ethical considerations
All subjects were informed of the general aim of the study and their participation was fully voluntary. Informed written consent had been obtained and approved by the ethics committee for clinical research of the faculty of medicine.

Results
One hundred and twenty (120) patients presented to ER and Neurology Clinic, at the time of the first seizure. 63.33% were males (76 patients) and 36.67% were females (44 patients). NOS were more predominant in the older adult age group (72 patients) (60%) than in young adults (27 patients) (22.5%), with fewer incidence among the middle-aged group (21 patients) (17.5%).
Males with NOS were predominant among young and older adult age groups by (66.67%), while females with NOS were predominant among middle-aged adults by (52.38%) with a statistically non-significant difference (Table 1).

Age in correlation with different etiologies of NOS
Among the young adult age group (< 36 years of age), the most common etiology was idiopathic epilepsy Metabolic and other acute symptomatic etiologies (13.89%), brain tumors (9.72%), and encephalitis (6.94%) were more prevalent in the older adults, while posttraumatic seizures were more prevalent among middleaged (14.3%) and young adults (11%) with statistically significant value (P value < 0.001) ( Table 3).
Sex is in correlation with different etiologies of NOS: among males, CVDs were the most prevalent etiology for new-onset seizures (43.4%), followed by idiopathic epilepsy syndrome (18.4%) and then an equal distribution of both symptomatic and post-traumatic seizures (9.2%).
Among females, CVDs were also the most prevalent etiology (45.4%), followed by idiopathic epilepsy syndrome (18.2%) as the same as among males. However, brain tumors were in equal distribution as metabolic and other symptomatic seizures (13.6%). (Table 4) Male predominance was the highest among posttraumatic epilepsy (87.5%), while female predominance was the highest among brain tumors identified etiology of new-onset seizures (54.5%) (Fig. 3).

Discussion
As far as we know, there were no major hospital-based studies which evaluated new-onset seizures in adults especially from Egypt.
Most epidemiologic studies of seizure disorders are studies of the prevalence of epilepsy and only a few prospective incidence studies of cases with a first seizure in the adult population exist [8].
The importance of adult-onset seizures stems from their frequent association with secondary causes. If proper analysis of etiology is made with history taking, clinical examination, and appropriate investigations, the presenting seizures can be treated accordingly, thus reducing associated morbidity and mortality [2].
In 2010, the International League against Epilepsy (ILAE) Commission for Classification of Epilepsy divided epilepsies into three main categories (idiopathic mainly "genetic", structural or/metabolic, unknown cause "cryptogenic") according to the etiologies of epilepsy [9].
In the present study, we evaluated the data of 120 patients presented to ER and Neurology Clinics, who aged (≥ 18 years old) at the time of first seizure. Males represented (63.33%) of our cohort, while females represented (36.67%) with male to female ratio (1.7:1).
Another study group reported that the rate of newonset seizures was considerably higher in men than in women. The same study group reported that acute symptomatic seizure is also common in older patients.  The incidence of acute seizures in patients over age 60 was estimated at 50 to 100 per 100,000 per year [10].
In the current study, we reported that new-onset seizures (NOS) were more common in the older age group (> 55 years), accounting for 60% of total cases.
Another community-based epidemiological study showed that the average annual incidence of epilepsy in the elderly aged 65 years and older is up to 240 per 100, 000 [11].
In concomitant to our study, a study group reported that the number of patients with first seizure is more in the age group > 60 years [12].
It is in contrary to other studies done in India, where the majority of cases were the young and middle-aged groups < 40 years, with a higher prevalence of CNS infections in these age groups provoking symptomatic NOS [2,8,13].
Past medical illnesses usually give a clue to the possible etiology. History of hypertension was significantly associated with unprovoked seizures, whether associated or not with stroke [14].
In the current study, 61 patients (50.83%) had PH of systemic HTN and 42 patients had PH of CVA (35%).
Subjects with a history of both had a fourfold increase in seizure risk compared with subjects with neither, probably due to the synergism between PH of CVA and PH of HTN [14].
Another study group found that hypertension was present in 16% of their cohort with NOS and PH of CVA among 8% [12].
Alterations of metabolic homeostasis are associated with seizures in many situations and may be the only symptom of electrolyte imbalances. These are commonly seen in people with hyponatremia, hypocalcemia, hypoglycemia, and hyperglycemia. The more rapid the disturbance develops the more likely it is to induce seizures [15,16].
In the present study, 10 patients had acute symptomatic metabolic seizures. Five patients were diagnosed with hypocalcemia-induced NOS, 3 patients had NOS out of hyperglycemia, 1 patient had NOS secondary to uremia, and 1 patient had hyponatremia-induced NOS.  Regarding neuroimaging investigations, in patients in whom lesions could not be picked up by CT brain in spite of clinical evidence of structural lesion, MRI brain (with or/without contrast) was done.
Two studies revealed that CT failed to detect the abnormality in MRI-positive cases 26% and 57% of the time [17].
In the current study, neuroimaging abnormal findings were detected among (75%) of the participants. A recent study recruited 416 adult patients with NOS, detected neuroimaging abnormalities among 53% of its cohort [17].
These findings are in concomitant to other studies which recruited 100 cases presented with adult newonset seizures. The most common abnormal CT findings were ischemic infarcts (18%), followed by brain tumors (either primary or secondary) (8%) [2].
However, different study results were influenced by endemic infectious diseases. One group study concluded that the most common abnormality in CT scan was a ring-enhancing lesion (mostly tuberculoma) (12%) as well as cerebral infarcts (12%), followed by generalized cerebral atrophy (4%) and meningioma, gliosis, and calcification (2%) for each [13].
The above findings highlighted the importance of neuroimaging among adult-onset seizures patients for appropriate etiological diagnosis of seizures.
Electrophysiological data were useful; it detected abnormality among 37.5% of our cohort. EEG epileptiform activity (spikes and sharp waves) was detected in 19.1% of the patients, while non-epileptiform activity (cerebral slowing) was detected in 18.3%.  In the current study, out of 30 patients with normal neuroimaging studies, 24 patients underwent DEEG study; of those, 15 patients had abnormal DEEG findings, revealing the yield of post-ictal DEEG in NOS.
Our results were in concomitant with other studies. One study reported that out of 100 patients with newonset seizures, 44% had abnormal DEEG records suggestive of seizure activity where as the remaining 56% had normal DEEG records [2].
The same results were reported in another study with DEEG abnormalities among 40% of their patient and normal DEEG among 20% [12].
In contrast to another group who studied NOS among the older age cohort only (> 65 years old), they reported abnormal EEG in 18.8% of their cohort and normal EEG in (49.3%) [18].
Younger patients with epilepsy often show a genetic cause. However, new-onset epilepsy in the elderly is mainly the consequence of accumulated injuries to the brain and other secondary factors [19].
New-onset epilepsy in elderly people often has underlying etiology including cerebrovascular diseases, brain tumors, and traumatic head injury. Post-stroke seizure is likely to increase because of the increasing aging population, and age itself is an independent risk factor for stroke [20].
The present study revealed that CVDs are the most common etiology for adult new-onset seizures by poststroke seizure/epilepsy (44.17%). CVDs had the highest prevalence in the older adult (> 55 years) age group (65.28%).
Therefore, a close follow-up of stroke patients is needed for early detection of subtle fits which are hardly identified by the patients themselves or their caregivers, as well as understanding the characteristics of post-stroke seizures, etiological causes, and drug-drug interactions while treating those patients is necessary for effective patient management.
Among identified etiologies of new-onset seizures in relation to age, idiopathic seizures were more common in younger adults (55.56%) followed by cryptogenic (14.8%) and post-traumatic epilepsy (11%) with P value (< 0.001).
Encephalitis-related seizures were common in the older age group (6.94%) in comparison to young adults (3.7%) and middle-aged adults (4.7%); post-traumatic seizures were more common among middle-aged (14.29%) and young adult (11.11%) groups in comparison to older age group (2.78%).
The mentioned results were in concomitant with other study groups' results. One study found that stroke was the most common etiology of adult new-onset seizures (23%), followed by idiopathic (22%) [2].
Another group studied 50 cases of adult new-onset seizures and found that CVDs were the most common etiology (34%) followed by idiopathic (22%) being the second most common etiology [12].
The same results were revealed by a study group that recruited 100 cases presented with new-onset seizures in adults and found that stroke was the leading cause of seizures accounting for 21%; infection was the next leading cause of seizures accounting for 17% and metabolic causes account for 15% [1].
However, endemic CNS infections in some areas dramatically changed the results of a study done in India, which enrolled 98 cases presented with new-onset seizures after age 20 years. They reported that CNS infections mainly "neurocystecercosis" were the leading cause of first seizure in adults accounting for 39.7%, followed by CVDs (26.5%) [8].
The present study revealed that CVDs were the most prevalent etiology of new-onset seizures among males (43.4%), as well as females (45.4%). However, male predominance was the highest among post-traumatic epilepsy (87.5%), while female predominance was the highest among brain tumors identified etiology of newonset seizures (54.5%).
The different heterogeneity of etiologies, i.e. CVDs, idiopathic, post-traumatic, SOLs, metabolic, and CNS infections among adult patients with new-onset seizures and their relative contributions, depend on the age composition of the study population, sample size, and endemicity of CNS infections.
One of our study limitations is the narrow window for post ictal EEG 48-72 h that resulted into 34% dropping and missing of this pivotal investigation in our epileptic patients. Future research direction for recruitment of more patients through multicenter contribution can aid in making a national registry system and database for NOS patients across the country.

Conclusion
New-onset seizures among adults are prevalent in elder males. CVDs are the most common identified etiology of adult new-onset seizures across males and females. However, idiopathic epilepsy syndromes are the predominant etiology of NOS among younger adults.