Keywords:
seizures - respiratory diseases - hypoxemia - hypercapnia - respiratory acidosis
Palavras-chave:
convulsões - doenças respiratórias - hipóxia - hipercapnia - acidose respiratória
Seizures are a common neurological condition and can occur during the follow-up period
after chronic disorders. All metabolic alterations that may develop during chronic
diseases, as well as the medications used to treat these diseases (e.g., antibiotics,
antivirals, antidepressants, and antipsychotics), can cause symptomatic seizures without
causing direct structural damage to the brain. However, seizures can also occur secondarily
to structural damage to the central nervous system (CNS) due to systemic disease[1],[2]. For example, symptomatic seizures can manifest due to the effects of various acute
medical or toxic conditions in the CNS, and the resulting organic brain damage and
neurological dysfunction can cause recurrent seizures[3],[4]. The most common systemic diseases involved in the etiology of seizures include
a wide range of cardiopulmonary diseases, such as long QT syndrome, bradycardia, rhythm
disturbances (e.g., asystole), systemic hypertension (HT), pulmonary embolism, and
pulmonary hypertension, and disturbances in cerebral perfusion have also been implicated
in the pathophysiology of seizures[5],[6],[7],[8]. Similar to the presence of systemic comorbidities, the presence of seizures may
considerably affect the course of a respiratory disease, treatment for this disease,
and length of hospital stay. Thus, the aim of the present study was to determine the
etiological factors and correlate them with specific outcomes in patients hospitalized
in chest clinics who had seizures during hospitalization.
METHODS
All neurology consultations requested for patients with seizures who were being treated
at an inpatient tertiary Chest Diseases and Thoracic Surgery Training and Research
Hospital between January 2011 and January 2018 were retrospectively reviewed. The
study protocol was approved by local clinical trials ethics committee (Approval number:
2018/1496). Patients diagnosed with seizures according to the International League
Against Epilepsy (ILAE) guidelines were included in this study and categorized into
two groups: patients with a previous diagnosis of primary epilepsy who received antiepileptic
medications were included in Group I, and patients without a previous history of seizures
who had an epileptic seizure for the first time during their hospital stay were considered
to have symptomatic seizures and were included in Group II.
Age, gender, the presence of primary epilepsy, comorbidities, primary diagnosis on
admission, consultation requests, the last neurological condition on discharge, and
all laboratory tests performed during the hospitalization period were retrieved and
evaluated. The presence of comorbidities accompanying primary lung disease requiring
hospitalization such as diabetes mellitus, hypothyroidism, hypercholesterolemia, HT,
cerebrovascular disease, chronic renal failure, extra-thoracic malignancy, and any
other systemic chronic diseases was recorded. Only patients with complete consultation
notes and laboratory data were included in the study. Additionally, the electroencephalographic
(EEG) data of all patients obtained during their hospitalization were assessed. Discharges
of patients were classified as cured or exitus.
The following laboratory data from the pre-ictal period of each patient were analyzed:
levels of blood glucose (BG; 70-100 mg/dL), blood urea (15-45 mg/dL), creatinine (male:
0.8-1.2 mg/dL and female: 0.7-1.3), uric acid (3.5-7.2 mg/dL), sodium (Na+; 135-148 mEq/L), white blood cells (WBC; 6-10 mm3), red blood cells (RBC; 106/uL), erythrocyte sedimentation rate (ESR; <30 mm/hour), C-reactive protein (CRP;
<3 mg/L), pCO2 (35-45 mmHg), pO2 (80-100 mmHg), HCO3 (22-26 mEg/lt), and pH (7.35-7.45). A BG value >140 mg/dL was defined as hyperglycemia
and a BG value < 70 mg/dL was defined as hypoglycemia[9],[10]. Blood urea (10-50 mg/dL), uric acid (2.5-7.2 mg/dL), and creatinine (0.30-1.2 mg/dL)
levels were evaluated in conjunction with clinical data to diagnose uremia. A PaCO2 level >45 mmHg was defined as hypercapnia, a PaO2 level <70 mmHg was defined as hypoxemia, and an arterial pH <7.35 was defined as
acidosis. Additionally, factors associated with seizures, including systemic infection,
metabolic variables, and the presence of drug use, were determined in all patients.
Metabolic variables were defined as being accompanied by any pathological conditions
in terms of BG, electrolytes, urea, creatinine, uric acid, and blood gas based on
laboratory data findings.
Statistical analysis
SPSS version 22.0 (released in 2013, SPSS Statistics for Windows, IBM Corp.; Armonk,
NY) was used for all statistical analyses. The minimum, maximum, median, standard
deviation, frequency, and percentage values of all data were calculated. Chi-square
tests were used to analyze categorical variables, t-tests were used to compare mean
values of parametric variables, and a point-biserial correlation analysis was performed
to assess the correlation between mortality and changes in all laboratory data. P-values<0.05
were considered to indicate statistical significance.
RESULTS
The present study initially assessed the data of 2793 inpatients for whom neurology
consultations were requested between January 2011 and January 2018. Of these patients,
the specific reason for a neurology consultation in 807 patients was a preliminary
diagnosis of seizures. Of these patients, 102 were diagnosed as not having epileptic
seizures. Thus, the clinical findings of 705 patients who were definitively diagnosed
with seizures were further analyzed for the present study.
The 705 patients had a mean age of 64.05±17.19 years (range: 20-97 years) and included
522 males (74.0%) ([Table 1]). The consultations were requested by eight different units including the chest
clinic (n=393; 55.7%), thoracic surgery ward (n=55; 7.8%), respiratory intensive care
unit (n=94; 13.3%), thoracic surgery intensive care unit (n=47; 6.7%), emergency department
(n=34; 4.8%), tuberculosis unit (n=38; 5.4%), transplantation unit (n=30; 4.3%), and
palliative care unit (n=14; 2.0%). The primary respiratory disease diagnoses of the
patients included chronic obstructive pulmonary disease (COPD), lung cancer, pneumonia,
and tuberculosis, and less commonly, hemoptysis, pleural effusion, asthma, pulmonary
embolism, post-intubation tracheal stenosis, and pneumothorax. COPD and pneumonia
were more common in Group 1, and lung cancer and hemoptysis were more common in Group
2 ([Table 2]).
Table 1
General characteristics and seizures etiology.
|
|
Total
|
Group I
|
Group II
|
p-value*
|
|
Total, n (%)
|
705
|
307 (43.5)
|
398 (56.5)
|
|
|
Age
|
64.05±17.19 (20-97)
|
64.04±17.43
|
64.07±17.02
|
0.985
|
|
Gender, n (%)
|
Male
|
522 (74.0)
|
223 (72.6)
|
299 (75.1)
|
0.455
|
|
Female
|
183 (26.0)
|
84 (27.4)
|
99 (24.9)
|
|
Comorbidity†, n (%)
|
380 (53.9)
|
157 (51.1)
|
223 (56.0)
|
0.197
|
|
Etiology, n (%)
|
|
Metabolic change
|
491 (69.6)
|
201 (65.5)
|
290 (72.9)
|
0.034
|
|
Hypercapnia
|
323 (45.8)
|
148 (48.2)
|
175 (44.0)
|
0.263
|
|
Hypoxemia
|
269 (38.2)
|
104 (33.9)
|
165 (41.5)
|
0040
|
|
Respiratory acidosis
|
112 (15.9)
|
39 (12.7)
|
73 (18.4)
|
0.041
|
|
Hyper/hypoglycemi
|
56 (7.9)
|
22 (7.2)
|
34 (8.5)
|
0.503
|
|
Hyper/hyponatremia
|
48 (6.8)
|
19 (6.2)
|
29 (7.3)
|
0.566
|
|
Uremia
|
68 (9.6)
|
26 (8.5)
|
42 (10.6)
|
0.353
|
|
Metabolic acidosis
|
3 (0.4)
|
-
|
3 (0.8)
|
-
|
|
İnfection
|
346 (49.1)
|
162 (52.8)
|
184 (46.2)
|
0.085
|
|
Intracranial mass
|
185 (26.2)
|
25 (8.1)
|
160 (40.2)
|
0.001
|
|
Medication‡
|
51 (7.2)
|
23 (7.5)
|
28 (7.0)
|
0.816
|
|
PRES
|
2
|
-
|
2
|
-
|
|
Arrhythmia
|
37 (5.2)
|
14 (4.6)
|
23 (5.8)
|
0.472
|
|
Multiple Etiology #, n (%)
|
386 (56.5)
|
158 (51.5)
|
228 (57.3)
|
0.124
|
†Diabetes mellitus, HT, hypothyroidism, hypercholesterolemia, cerebrovascular disease,
chronic renal failure, extra-thoracic malignancy and other systemic chronic diseases;
‡Isoniazid, rifampicin, moxifloxacin, macrolide, meropenem, ciprofloxacin, ampicillin,
or mycophenolate mofetil; #Coexistence of multiple factors that will be effective
on seizure development; PRES: Posterior reversible encephalopathy. Data are expressed
as mean±SD or median (range); *Student’s t-test or chi-square test.
Table 2
Primary diagnosis during hospitalization in all patients.
|
|
Total n=705
|
Group I n=307
|
Group II n=398
|
p-value*
|
|
COPD/Respiratory insufficiency, n (%)
|
185 (26.2)
|
123 (40.1)
|
62 (15.6)
|
0.001
|
|
Lung cancer, n (%)
|
179 (25.4)
|
22 (7.1)
|
157 (39.7)
|
0.001
|
|
Pneumonia, n (%)
|
89 (12.6)
|
75 (24.4)
|
14 (3.5)
|
0.001
|
|
Tuberculosis, n (%)
|
70 (9.9)
|
32 (10.4)
|
38 (9.5)
|
0.705
|
|
Lung transplant, n (%)
|
29 (4.1)
|
-
|
29 (4.1)
|
-
|
|
Hemoptysis, n (%)
|
24 (3.4)
|
5 (1.6)
|
19 (4.8)
|
0.001
|
|
Pleural effusion, n (%)
|
23 (3.3)
|
10 (3.3)
|
13 (3.3)
|
0.995
|
|
Asthma, n (%)
|
23 (3.3)
|
5 (1.6)
|
18 (4.5)
|
0.001
|
|
Pulmonary embolism, n (%)
|
21 (3.0)
|
7 (2.3)
|
14 (3.5)
|
0.001
|
|
Postentubation stenosis, n (%)
|
16 (2.3)
|
6 (2.0)
|
10 (2.5)
|
0.622
|
|
Pneumothorax, n (%)
|
13 (1.8)
|
2 (0.7)
|
11 (2.8)
|
0.001
|
|
Other diseases of the lung, n (%) †
|
33 (4.7)
|
20 (6.5)
|
13 (3.3)
|
0.049
|
|
|
705
|
307 (43.5)
|
398 (56.5)
|
0.001
|
COPD: Chronic obstructive pulmonary disease; † Interstitial lung disease, Behçet diseases,
Churg Strauss Granulomatosis, Sarcoidosis etc; *chi square test.
For all patients, the most common factors that precipitated seizures were metabolic
causes (n=491, 69.6%). Medications used for the treatment of primary respiratory disease
were the etiological cause of seizures in 51 patients (7.2%) and included anti-tuberculosis
drugs such as isoniazid and rifampicin (n=15), moxifloxacin (n=10), macrolides (n=7),
meropenem (n=7), ciprofloxacin (n=3), ampicillin (n=3), and mycophenolate mofetil
(n=2). In this group of patients in which medications were responsible for the seizures,
the presence of more than one factor was associated with the seizures, including infections
in 43 patients and metabolic causes in six patients. Only two patients who were followed-up
after a lung transplantation developed posterior reversible encephalopathy syndrome
(PRES) secondary to immunosuppressive therapy; no structural changes were observed
on the control cranial imaging of these patients. Multiple factors were found to be
involved in the etiology of seizures in 54.8% of patients.
Of the total patient group, 307 (43.5%) had a previous history of epilepsy (Group
I) and 398 (56.5%) had symptomatic seizures (Group II). No differences were observed
between these two groups in terms of age, gender, or the presence of comorbidities.
However, metabolic causes, respiratory acidosis, and hypoxemia were significantly
more common in Group II ([Table 1]); accordingly, the mean arterial pO2 and pH values were significantly lower in Group II than Group I ([Table 3]). Infection was the second most common cause of seizures, but this variable did
not differ significantly between the groups (n=346; 49.1%; p=0.085). The presence
of an intracranial mass was the most common cause of seizures in patients with lung
cancer (n=160; 46.2%), but the groups did not differ significantly in terms of the
presence of multiple factors (p=0.124; [Table 1]).
Table 3
Comparison of laboratory parameters between groups.
|
|
Total (n:705)
|
Group I (n:307)
|
Group II (n:398)
|
p-value*
|
|
Blood Glucose (mg/dl)
|
94.6±41.2 (47-431)
|
95.6±43.9
|
93.8 ±39.0
|
0.573
|
|
Blood urea (mg/dl)
|
42.9±19.3 (11-187)
|
41.4 ±17.2
|
43.9±20.7
|
0.078
|
|
Creatinine (mg/dl)
|
0.8±0.4 (0.14-3.7)
|
0.79±0.3
|
0.79±0.4
|
0.998
|
|
Uric acid (mg/dl)
|
4.0±2.4 (0.3-21.9)
|
4.1±2.8
|
3.9±2.1
|
0.291
|
|
Na+ (mEq/L)
|
140.2±6.9 (132-165)
|
140.2±7.2
|
140.3±6.6
|
0.895
|
|
WBC (cells/mm3)
|
12.7±7.4 (3.4- 36.0)
|
13.1±7.4
|
12.5±7.5
|
0.301
|
|
RBC (cells/mm3)
|
4.7±0.7 (3.4- 8.0)
|
4.6±0.7
|
4.7±0.6
|
0.398
|
|
Sedimentation (mm/h)
|
42.3±31.9 (4-100)
|
43.5±31.9
|
41.4±31.8
|
0.384
|
|
CRP (mg/dl)
|
21.9±27.4 (0.1-109)
|
22.4±26.8
|
21.4±27.7
|
0.627
|
|
pCO2 (mmHg)
|
49.9±16.5 (22-98.4)
|
50.3±15.6
|
49.7±17.2
|
0.618
|
|
pO2 (mmHg)
|
76.7±17.2 (32-99.5)
|
79.5±14.9
|
74.5±18.5
|
0.001
|
|
HCO3 (mEg/lt)
|
23.3±1.2 (18.2-28.2)
|
23.2±1.2
|
23.3±1.2
|
0.263
|
|
pH
|
7.35±0.06 (7.11-7.45)
|
7.37±0.04
|
7.34±0.66
|
0.001
|
*Student’s t-test. Data are expressed as mean±SD or median (range).
From the subjects diagnosed with tuberculosis, COPD, or hemoptysis, eight (4.3%),
fourteen (7.5%), and four (2.2%) of them had intracranial mass lesions, respectively.
In addition, symptomatic seizures were observed in 157 (39.7%) patients with a diagnosis
of lung cancer ([Table 2]). In these patients, the etiological cause of seizures was an intracranial mass
in 136 (86.6%) patients and an infection in 71 (45.2%) patients, and multiple factors
were involved in the seizures of 97 (61.7%) patients. Of the patients who were admitted
to the emergency department with first-time seizures and had an intracranial mass
lesion, seven had primary lung cancer and two had pulmonary tuberculosis.
EEG was performed during the postictal period in 476 (67.5%) patients and revealed
focal findings in 118 (16.7%) patients, generalized findings in 119 (16.9%) patients,
and normal findings in 239 (33.9%) patients. Based on the clinical findings and EEG
data, 184 (26.1%) patients had focal seizures and 521 (73.9%) patients had generalized
seizures. A total of 147 (79.9%) patients with focal seizures were in Group II and
270 (51.8%) patients with generalized seizures were in Group I. Generalized seizures
were more common in patients with seizures due to metabolic causes or infections (n=380;
77.4%; p=0.001 and n=281; 81.3%; p=0.001, respectively) and patients with multiple
etiological factors (n=266; 68.9%; p=0.001). Focal seizures were more common in patients
with an accompanying intracranial mass lesion (n=137; 74.1%; p=0.001).
Of all the patients that were followed-up due to seizures, the mortality rate was
5.6% (n=42). However, this rate did not differ significantly between the groups (Group
I: n=14; 4.6% and Group II: n=28; 7.0%; p=0.169) and the mortality rate was significantly
higher in patients with hypoxemia (n=26; 9.7%; p=0.01), hypercapnia (n=27; 8.4%; p=0.013),
and respiratory acidosis (n=17; 14.8%; p=0.001) ([Table 4]). Additionally, the point-biserial correlation analysis revealed a correlation between
mortality and the mean arterial PaCO2, PaO2, and pH values ([Figure 1]).
Table 4
Factors affecting hospital mortality.
|
|
|
Dead n=42 (6.0%)
|
Alive n=663 (94,0%)
|
p-value*
|
|
Group, n (%)
|
|
|
|
0.169
|
|
I
|
307 (43.5)
|
14 (4.6)
|
293 (95.4)
|
|
|
II
|
398 (56.5)
|
28 (7.0)
|
370 (93.0)
|
|
|
Presence of hypoxemia, n (%)
|
|
|
|
|
|
Present
|
269 (38.2)
|
26 (9.7)
|
243 (90.3)
|
0.001
|
|
Absent
|
436 (61.8)
|
16 (3.7)
|
420 (96.3)
|
|
|
Presence of hypercapnia, n (%)
|
|
|
|
0.013
|
|
Present
|
323 (45.8)
|
27 (8.4)
|
296 (91.6)
|
|
|
Absent
|
382 (54.2)
|
15 (3.9)
|
367 (96.1)
|
|
|
Presence of respiratory acidosis, n (%)
|
|
|
|
|
|
Present
|
112 (15.9)
|
16 (14.3)
|
96 (85.7)
|
0.001
|
|
Absent
|
592 (84.1)
|
26 (4.4)
|
566 (95.6)
|
|
*chi square test.
Figure 1 Correlation analysis between hospital mortality and changes in blood gas concentration.
DISCUSSION
This study shows that symptomatic seizures constitute the majority of epileptic seizures
and blood gas exchange abnormalities play a significant role on mortality in patients
with respiratory disease and epileptic seizures. The predominant etiological cause
of symptomatic seizures was the metabolic changes; the most influent cause of which
was decrease in mean arterial PaO2 and pH values. In both groups, we found more than one etiological factor for the
development of seizure. The reported prevalence rate for symptomatic seizures ranges
from 3.7-22.5% and these types of seizures are more common in adolescents and elderly
males[2],[11],[12]. In the present study, symptomatic seizures were more common in the assessed patients
but Groups I and II did not differ significantly in terms of age and gender, which
can be explained by the more frequent occurrence of respiratory diseases in elderly
and male patients[13].
Acute symptomatic seizures can develop as the result of multiple conditions, including
acute cerebrovascular diseases, traumatic brain damage, CNS infections, medication
use, substance and alcohol use, metabolic and electrolyte disturbances, encephalopathy,
and eclampsia[11]. In the existing literature, most studies have focused on the association between
respiratory diseases and seizures; no retrospective or prospective studies have assessed
a large number of patients. Patients with pulmonary embolism who present with symptomatic
seizures account for fewer than 1% of all patients with symptomatic seizures, and
cases of pulmonary hypertension with symptomatic seizures are rare[7],[14],[15]. Fred was the first author to describe a case of pulmonary embolism that presented
with generalized tonic-clonic seizures following an abrupt-onset syncope[7]. Marine implicated transient right ventricular failure in the psychopathology of
epileptic seizures in patients with pulmonary embolism and suggested a role for transient
global cerebral hypoperfusion caused by decreased cardiac output[14]. Similarly, nocturnal seizures observed in patients with pulmonary hypertension
can be explained by episodic decreases in cardiac output and cerebral perfusion[15].
In clinical practice, epileptic seizures associated with electrolyte and metabolic
disturbances are commonly encountered in intensive care units and emergency clinics[16],[17]. For example, metabolic causes are responsible for 10% of adult patients who have
seizures for the first time in the emergency room[17]. Moreover, abnormalities in serum glucose, urea, creatinine, or electrolyte (Na+, Ca+2, etc.) levels, and less frequently, parameters of arterial blood gases, also contribute
to the etiology of seizures[18],[19],[20],[21]. Metabolic disturbances, deficiencies in the substrates required for cellular metabolism
or cell membrane functions, the intracellular accumulation of toxic substances, and
particularly changes in plasma osmolality and electrolyte disturbances, increase neuronal
excitability and subsequently increase the risk of developing seizures[22],[23]. According to our results, consultation request was less observed in intensive care
units than in chest clinics. This may be related to the frequent use of antisedatives
agents such as midazolam and propofol which have antiepileptic effects in intensive
care units.
The present study found that metabolic causes ranked first among the potential etiological
factors associated with seizures in patients with primary epilepsy and those with
symptomatic seizures. In contrast, Groups I and II did not differ significantly in
any of the biochemical or infection parameters. However, the mean arterial PaO2 and pH values were significantly lower in Group II. Accordingly, the prominent presence
of hypoxemia or respiratory acidosis in patients with symptomatic seizures who had
a healthy neuronal network might be an important parameter for indicating the potential
effects of changes in blood gas levels on the seizure threshold.
In the present study, generalized seizures were common in patients with a predominance
of metabolic and infection parameters, whereas focal seizures were more common in
patients with a comorbid intracranial mass. Metastatic brain tumors account for 10-30%
of all intracranial tumors in adults, and the most common tumors that metastasize
to the brain are lung carcinomas, which account for 20% of all cases[24],[25],[26]. Seizures are observed in 10-50% of patients with metastatic brain tumors and tend
to manifest as focal motor seizures[27],[28]. The localization of the mass lesion, its histological features, and other peritumoral
factors are influential in the development of focal seizures[29]. Consistent with the literature, the occurrence of focal seizures in the present
patients was mostly associated with intracranial mass lesions and metastatic brain
tumors, which were particularly common in patients with lung cancer.
Mortality rates and frequency of recurrent seizures differ between patients with symptomatic
seizures and patients without a provoked seizure. For example, early diagnosis and
appropriate management can prevent the development of morphological changes, so defining
metabolic conditions is important for making a prognosis[20],[30]. Experimental studies have demonstrated that prolonged episodes of hypoxia caused
by a notable decrease in pO2 saturation may increase the rate and severity of hypoxic ischemic brain damage[31],[32]. Furthermore, studies have found associations between epileptic seizures and the
severity of brain damage and acute mortality[33],[34],[35]. Severe and prolonged postictal hypoxemia and hypercapnia in patients with partial
onset seizures cause impairments in respiratory functions and increase the risk of
sudden unexpected death in epilepsy (SUDEP)[36],[37],[38],[39]. Furthermore, peri-ictal apnea associated with prolonged severe hypoxemia could
be a potential predictor of SUDEP[40]. The present findings, indicating correlations between mortality and the presence
of hypoxemia, hypercapnia, and respiratory acidosis, suggest that these parameters
may affect the prognosis of patients with a respiratory disease who have epileptic
seizures. Abnormalities in blood gases in patients with a respiratory disease may
affect mortality because of possible yet unknown mechanisms in seizure pathophysiology,
and new large-scale studies are needed to reveal these possible mechanisms.
The most important limitation of the present retrospective cross-sectional study was
the unavailability of data regarding recurrent seizure episodes in patients with symptomatic
seizures following the hospitalization period. Additionally, no follow-up data were
available for patients placed on antiepileptic therapies, and data regarding the effects
of seizures in patients with respiratory diseases on their long-term prognoses were
missing in both Group I and Group II.
In conclusion, the present study found that seizures were frequent in patients who
were hospitalized due to a respiratory condition. Additionally, as evidenced by changes
in blood gases, hypoxemia and respiratory acidosis were especially associated with
the development of symptomatic seizures. In patients who were hospitalized for respiratory
system diseases and experienced seizures, the presence of hypoxemia, hypercapnia,
and respiratory acidosis were correlated with mortality. Therefore, it will be important
to consider carefully these factors if they are observed during the peri-ictal period.
