Keywords
Psychogenic Nonepileptic Seizures - Epilepsy - Retirement - Electroencephalography
- Financial Stress
Palavras-chave
Convulsões Psicogênicas não Epilépticas - Epilepsia - Aposentadoria - Eletroencefalografia
- Estresse Financeiro
INTRODUCTION
Epilepsy is a chronic disorder that may result in working disability.[1] Psychogenic non-epileptic seizures (PNES) resemble epileptic seizures; however,
they lack neurobiological origin, and are not associated with the electrophysiological
alterations observed in epilepsy.[1]
[2] Video-electroencephalographic Monitoring (VEM) is the gold-standard method to differentiate
these two conditions.[3]
The estimated annual incidence of PNES was reported as 1.4 to 4.9/100 thousand people,
and its estimated prevalence in the general population is of 2–33/100 thousand.[4]
[5] A total of 5% to 10% of the patients admitted to the outpatient clinics of epilepsy
centers and 20% to 40% of the patients monitored have PNES.[4]
[6]
Epilepsy is related to high direct and indirect costs; the indirect costs are due
to unemployment and early disability.[7] The patients diagnosed with PNES are faced with a high level of unemployment and
low income.[8]
[9] On the other hand, establishing the diagnosis of PNES may take long,[4]
[10] and the patients may not be able to work or find a job until the diagnosis has been
made, which results in high indirect costs, similar to those faced by patients with
epilepsy.[8]
The patients with PNES take anti-seizure medication (ASM) and/or psychostimulant drugs
(PSSDs) unnecessarily due to misdiagnosis and inappropriate treatment of this condition,
and they are exposed to adverse effects of the redundant medications. In addition
to the adverse effects, the medications also result in high financial costs for this
group of patients. There is limited information in the literature about the economic
burden of PNES.[11]
[12]
[13]
The present study aims to analyze the frequency of PNES as well as the direct and
indirect costs of the patients who admitted to VEM for obtain a diagnosis of epilepsy
in order to apply for disability retirement.
METHODS
The present single-center retrospective cohort study was carried out in a tertiary
healthcare center in Adana, southern Türkiye, after obtaining approval from the l
Ethics Committee for Non-invasive Clinical Research of the Faculty of Medicine of
Çukurova University (decision no: 2021/109).
The study included 134 adult patients referred to the Epilepsy Unit of the Department
of Neurology of Çukurova University between January 2013 and December 2019 who undergo
VEM to confirm the diagnosis of epilepsy, determine the frequency of seizures in patients
with a history of epilepsy, and to assess their disability.
The patients were most frequently referred from other hospitals and from the Turkish
Social Security Institution (SSI). Our center is the reference institution in our
region authorized by the Ministry of Health to issue medical board reports. The patients
were referred to confirm the diagnosis of “epilepsy” and to be hospitalized for a
minimum of 2 weeks, following the criteria of the Ministry of Family and Social Policies
on “Regulation on Disability Assessment for Adults” (no. 20.02.2019/30692).[14] The SSI requests information about the follow-up of VEM patients with VEM within
the aforementioned period, including recordings of their seizures, disclosure of the
ictal and postictal findings, and an assessment of the time it takes for the patients
to return to their daily work in the postictal period.
Patient selection and VEM
The subjects who met all of the following criteria were included:
-
Age ≥ 17 years;
-
Having an SSI request for diagnosis and frequency of seizures after VEM;
-
Having undergone VEM for five days or more;
-
History of seizure determined at the outpatient clinic;
-
Admission for the diagnosis of epilepsy;
-
Patients wishing to apply for disability retirement due to the diagnosis of epilepsy;
-
History of more than four monthly episodes of seizure; and
-
Patients assessed by a psychiatrist.
All patients were monitored with a 64-channel electroencephalography (EEG) system
(EEG 1200, Nihon Kohden, Shinjuku-ku, Tokyo, Japan). Scalp electrodes were placed
according to the standard international 10–20 system and with the guidelines of the
American Clinical Neurophysiology Society.[15]
The patients presented to the outpatient clinic with the request for a medical report
and had their histories taken; then, they were hospitalized and followed-up in VEM
Unit of the Neurology Clinic with the prediagnoses of epilepsy, PNES, or epilepsy + PNES.
The seizures defined by the patient and their relatives were recorded in the VEM Unit,
the patient records (hospitalization period in the requested report: two to four weeks)
were video-monitored [VM]) in another room, and the follow-up was completed.
After the follow-up with VEM and VM, we categorized the patients' into three groups
according to their diagnoses: epilepsy, epilepsy + PNES, and PNES. Patients were included
in the epilepsy group when ictal EEG and associated seizure patterns were observed
on VEM; subjects were included in the PNES group when associated with a typical non-epileptic
episode without ictal EEG; and the epilepsy + PNES group was composed of patients
in whom an epileptic seizure was observed with a non-epileptic episode. However, in
addition to non-epileptic episodes, patients who did not have an ictal period during
the follow-up but had abnormal EEG, radiological, or pathological/abnormal neurological
examination findings and a history of ictal period were semiologically included in
the epilepsy + PNES group.
The clinical findings and demographic features of all patients were extracted from
their medical files and discharge summaries. Age at onset, family history of epilepsy,
risk factors for epilepsy, frequency of episodes, history of status epilepticus, kind
and duration of the use of ASMs or psychiatric drugs were recorded for every patient,
as well as the result of the neurological examination (normal or abnormal) and the
electrophysiological and brain magnetic resonance imaging (MRI) findings (normal,
abnormal). The duration of the video-EEG recording, the time of occurrence of the
epileptic seizures or PNES (day, night), the number of seizures or events and their
duration were also recorded. The costs of the medicines were calculated as the dollar
equivalent of the lowest label price of the drugs in Turkish lira determined by the
SSI.
All patients were examined throughout their hospitalization periods by two senior
epileptologists, and the VEM records were manually reviewed by two senior epileptologists.
The psychiatric assessment was performed by a trained psychiatrist who was blinded
to the epilepsy diagnosis during hospitalization. All the patients were assessed using
axes I and II of the Structured Clinical Interview for the Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition (SCID).
According to the study design, 34 patients were excluded because they had been hospitalized
for fewer than 4 days.
Statistical analysis
The statistical analyses were performed using the Statistical Package for the Social
Sciences (IBM SPSS Statistics for Windows, IBM Corp., Armonk, NY, US) software, version
20.0. The categorical variables were expressed as frequencies and percentages, and
the continuous variables, as mean and standard deviation values. The Chi-squared test
was used to compare the categorical variables, and the comparison of means was performed
with the Student t-test or the Mann-Whitney U test, where appropriate. Statistical significance was
set as p < 0.05 for all tests.
RESULTS
A total of 168 patient files were reviewed. According to the study design, 34 patients
were excluded because they had been hospitalized for fewer than 4 days. Of the 134
patients, 119 were male (88.8%), with a mean age of 39.3 ± 11.3 (range: 17–65) years.
All of the patients had been referred from another center for a diagnosis of epilepsy.
After the history was obtained in the outpatient clinic, the patients were admitted
to the VEM Unit with the prediagnoses of epilepsy (59.7%), PNES (3.7%) and PNES + epilepsy
(36.6%). The mean length of hospital stay was of 11.9 ± 4.2 (range: 5–30) days. Following
VEM and VM, 56% (n = 75) of the patients were diagnosed with epilepsy, 22.4% (n = 30),
with PNES, and 21.6% (n = 29), with PNES + epilepsy, and their disability reports
were prepared. Almost all of those patients, except for 3 (2.2%), were on antiepileptic
treatment, the mean duration of medication usage was of 18.3 ± 12.9 years, and the
mean monthly frequency of seizures was of 5.8 ± 5.5 according to the first history
obtained. The demographic characteristics of the patients are presented in [Table 1].
Table 1
Demographic and clinical characteristics of the study sample
|
Epilepsy: n (%)
|
PNES: n (%)
|
PNES + epilepsy: n (%)
|
Total: n (%)
|
p
|
|
Patients: n (%)
|
75 (56%)
|
30 (22.4%)
|
29 (21.6%)
|
134
|
|
|
Gender: male/female
|
66/9
|
27/3
|
26/3
|
119 (88.8)/15 (11.2)
|
0.94
|
|
Age in years (mean ± SD)
|
39.7 ± 11.2
|
35.5 ± 11.8
|
42.2 ± 10.2
|
39.31 ± 11.3 (17-65)
|
0.06
|
|
Age at seizure onset (mean ± SD)
|
18.7 ± 12.1
|
24.4 ± 14.7
|
23.5 ± 14.8
|
21.1 ± 13.5
|
0.03
|
|
Risk factors for epilepsy
|
Febrile convulsion
|
18 (54.5)
|
9 (27.3)
|
6 (18.2)
|
33 (24.6)
|
0.6
|
|
Head trauma
|
29 (51.8)
|
17 (30.4)
|
10 (17.9)
|
56 (41.8)
|
0.2
|
|
Difficult delivery
|
3 (4)
|
2 (6.7)
|
3 (10.3)
|
8 (6)
|
0.4
|
|
CNS infection
|
2 (2.7)
|
0
|
2 (6.9)
|
4 (3)
|
0.3
|
|
CVD
|
4 (5.3)
|
0
|
5 (55.6)
|
9 (6.7)
|
0.02
|
|
Space-occupying lesion (benign/malignant)
|
7 (9.3)
|
2 (6.7)
|
0
|
9 (6.7)
|
0.2
|
|
Family history of epilepsy (%)
|
14.7
|
13.3
|
13.8
|
|
0.9
|
|
Prediagnosis in outpatient clinic: n (%)
|
Epilepsy
|
64 (80)
|
9 (11.3)
|
7 (8.8)
|
80 (59.7)
|
< 0.001
|
|
PNES
|
1 (20)
|
4 (80)
|
0
|
5 (3.7)
|
|
PNES + epilepsy
|
10 (20.4)
|
17 (34.7)
|
22 (44.9)
|
49 (36.6)
|
|
ASMs taken: n (%)
|
None
|
|
3 (10)
|
|
3 (2.3)
|
< 0.001
|
|
1
|
24 (32)
|
17 (56.7)
|
11 (37.9)
|
52 (38.8)
|
|
≥2
|
51 (68)
|
10 (33.3)
|
18 (62.1)
|
79 (58.9)
|
|
Monthly frequency of seizures: mean ± SD
|
Before monitoring
|
5.01 ± 4.8
|
5.1 ± 7.2
|
6.9 ± 6.5
|
5.5 ± 5.8
|
0.3
|
|
During monitoring
|
|
|
|
|
|
|
Seizure frequency/month mean ± SD (min.–max.)
|
1.83 ± 2.8 (0–15)
|
|
0.9 ± 1.6 (0–7)
|
1.2 ± 2.3 (0–15)
|
0.001
|
|
PNES frequency/month mean ± SD (min.–max.)
|
|
1.4 ± 1.9 (0–8)
|
3.3 ± 6.1 (0–30)
|
1.04 ± 3.2 (0–30)
|
|
Time of event: n (%)
|
Daytime
|
35 (46.7)
|
21 (70)
|
16 (55.1)
|
72 (53.7)
|
0.01
|
|
Night
|
0 (0)
|
2 (6.7)
|
2 (6.9)
|
4 (2.9)
|
|
Asleep + awake
|
40 (53.3)
|
7 (23.3)
|
11 (37.9)
|
58 (43.3)
|
|
Years of ASM use (mean ± SD)
|
20.1 ± 11.7
|
8.7 ± 9.6
|
19.1 ± 11.9
|
17.5 ± 12.2
|
< 0.001
|
|
Abnormal neurological examination: n (%)
|
22 (29.3)
|
5 (13.3)
|
8 (27.6)
|
35 (26.1)
|
0.18
|
|
Abnormal EEG: n (%)
|
63 (84)
|
11 (36.7)
|
24 (75.9)
|
94 (73.1)
|
< 0.001
|
|
Abnormal MRI: n (%)
|
59 (78.7)
|
5 (16.7)
|
18 (58.6)
|
82 (61.2)
|
< 0.001
|
Abbreviations: ASM, anti-seizure medication; CNS, central nervous system; CVD, cerebrovascular
disease; EEG, electroencephalography; MRI, magnetic resonance imaging; PNES, psychogenic
non-epileptic seizure; SD, standard deviation;.
Note: Values of p ≤ 0.05 were considered statistically significant and marked in bold in the table.
Although there was a predominance of male patients in all three groups, neither gender
distribution (p = 0.94), mean age (p = 0.2), age at seizure onset (p = 0.08), family history of epilepsy (p = 0.9), monthly frequency of seizures (p = 0.3), nor the findings of the neurological examination (p = 0.18) were statistically different among them. However, the duration of ASM usage
was longer in the epilepsy and epilepsy + PNES groups (p < 0.001), and abnormal EEG and MRI findings were also significantly different in
these two groups (p < 0.001 for both).
The seizures were recorded during the day or had a diurnal pattern in the epilepsy
group. In the PNES and epilepsy + PNES groups, since some attacks were recorded after
VEM was completed and only when VM recording was available, the attacks that occurred
in the evening were recorded as nightly or attacks, since the wake pattern could not
be determined. Thus, it was also determined that the episodes in patients with PNES
could occur at night. Seizures were frequently asleep + awake in patients with epilepsy
and were also frequently recorded during the day in patients with PNES (p = 0.01).
A total of 18.6% (n = 25) of the patients were using antidepressants, and 11.2% (n = 15),
antipsychotic drugs. The use of PSSDs was significantly higher in the PNES group compared
to the other two groups (p = 0.05).
The SCID I and II showed that 15.9% of the patients had conversion disorder, 4.5%,
psychosis, 4.5%, mental retardation (3 in group 1, and 1 in group 3), 3.4%, depressive
disorder, 2.3%, epileptic personality disorder, 1.1%, antisocial personality disorder
(in group 3), 1.1%, obsessive personality disorder, and 1.1%, panic disorder.
We found that the longest duration of ASM use in the PNES group was of 38 (mean: 8.7 ± 9.65)
years (p < 0.001); however the duration ASM use was longer among the epilepsy and epilepsy + PNES
groups (p = 0.05) ([Table 3]), and the cost of drug usage was statistically significantly higher in the epilepsy
group (p < 0.001; [Table 3]). Long-term PSSD use was evident in all t groups (p = 0.390). We observed that PSSD was started approximately 10 years after the diagnosis
of epilepsy; however, in PNES patients, they were started at the onset of symptoms
or around that time. In PNES patients, the mean annual cost of ASM use was of 160.67 ± 94.04
dollars, and the mean cost of PSSD use was of 148.3 ± 72.48 dollars. The mean cost
of all diagnostic procedures and follow-up during the hospital stay was of 582.9 ± 330.0
(range: 103.52–1601.3) dollars. The cost of the hospital stay comprised laboratory
examinations (complete blood count, serum drug levels, routine blood biochemistry),
VEM, radiological imaging, consultations, hospitalization, and patient care parameters.
Table 2
Psychiatric comorbidities and type of psychostimulant drug used among the study sample
|
|
Epilepsy (n = 75; 56%)
|
PNES (n = 30; 22.4%)
|
PNES + epilepsy (n = 29; 21.6%)
|
p
|
|
Psychiatric comorbidity
|
No: n (%)
|
60 (80)
|
16 (53.3)
|
19 (65.5)
|
0.04
|
|
Yes: n (%)
|
15 (20)
|
14 (46.7)
|
10 (34.5)
|
|
Psychostimulant drug
|
Antidepressants: n (%)
|
7 (9.3)
|
10 (33.3)
|
8 (27.5)
|
0. 05
|
|
Antipsychotics: n (%)
|
9 (12)
|
4 (13.3)
|
2 (6.9)
|
0.7
|
Note: Value of p ≤ 0.05 were considered statistically significant and marked in bold in the table.
Table 3
Annual cost in US dollars and years of drug use per diagnosis
|
Epilepsy
|
PNES
|
PNES + epilepsy
|
p
|
|
Years of ASM use: mean ± SD (min.–max.)
|
20.16 ± 11.75 (1–58)
|
8.7 ± 9.65 (1–38)
|
19.14 ± 11.9 (1–51)
|
< 0.001
|
|
Years of PSSD use: mean ± SD (min.–max.)
|
10.16 ± 8.65 (1–30)
|
6.25 ± 6.13 (1–20)
|
7.37 ± 5.28 (1–15)
|
0.390
|
|
Annual cost of ASM use: mean ± SD (min.–max.)
|
224.33 ± 112.47 (19.44–618.48)
|
160.67 ± 94.04 (24.24–423.6)
|
198.99 ± 110.92 (24.24–495.96)
|
0.027
|
|
Annual cost of PSSD use: mean ± SD (min.–max.)
|
352.66 ± 380.59 (27.84–965.28)
|
148.3 ± 72.48 (57.96–274.8)
|
92.88 ± 23.77 (77.76–129.6)
|
0.096
|
Abbreviations: ASM, anti-seizure medication; PSSD, psychostimulant drug; SD, standard
deviation.
Note: Value of p ≤ 0.05 were considered statistically significant and marked in bold in the table.
DISCUSSION
The present study, based on diagnoses confirmed through VEM and psychiatric evaluations,
showed the prevalence of PNES (22.4%), epilepsy (56%), and epilepsy + PNES (21.6%);
the overall frequency of PNES was of 44%.
Studies[4]
[6] have reported that 5% to 10% of the outpatients in epilepsy clinics and 20% to 40%
of inpatients in epilepsy monitoring units have PNES. Yon et al.[6] stated that 10.2% out of 1,983 patients who underwent VEM had PNES; moreover, 44.8%
of these patients had definite PNES, 32.5% had definite PNES + epilepsy, and the remaining
patients had disorders of other subgroups.[6] Benbadis et al.[16] reported that, during the follow-up of patients diagnosed with PNES, 9.4% were found
to have concomitant epilepsy. In the present study, we found a higher prevalence (44%)
of PNES and epilepsy + PNES and previous studies[4] reported a ratio ranging from 10% to 20%. In the present study and in the one by
Yon et al.,[6] the patients had similar sociocultural characteristics, and both studies found that
the frequency of PNES was higher in patients followed up with VEM; we suppose that
the rate of PNES was higher in the present study because the patients who requested
disability reports were included, and they had ulterior motives. However, Asadi-Pooya
et al.,[17] in a multicenter, international, and cross-cultural study, reported that PNES patients
share more similarities than differences.
As shown in the present study, a significant difference was found between the frequency
of seizures reported by the patient and their relatives and the frequency of seizures
observed during the clinical follow-up. Although there was no significant difference
in the epilepsy group, the frequency of seizures reported in the history was higher
in the epilepsy + PNES and PNES groups than in the clinical follow-ups. We evaluated
that this may be explained by the ulterior motives of the patients when requesting
the disability reports.
According to the historical features, 55% of all the patients were defined generalized
seizures. It is noteworthy that 83.3% of the patients in the PNES group were defined
as generalized seizures according to the semiological features reported by the patients
or their relatives. Most of the attacks in patients with PNES were indicated as generalized
seizures.
Although it is hard to distinguish between PNES and epileptic seizures, it has been
estimated that the delay in the diagnosis of PNES can range from 3 to 8.4 years.[4]
[10]
[18]
[19] Delay in diagnosis causes unnecessary use of antiepileptics, resulting in both adverse
effects and a socioeconomic burden.[17] In the present study, PNES patients started to use PSSDs in the year of symptom
onset[, but epilepsy patients started using PSSDs long after the diagnosis of epilepsy
([Table 3]). It seems that patients with epilepsy needed psychiatric support due to the clinical
conditions created by the unresolved disease, stigmatization, poor quality of life,
unemployment, and low income.
Patients with PNES are common in epilepsy centers, filling almost 40% of VEM Units
and costing an estimated 650 million dollars annually.[8] Studies conducted in Ireland[12] and in the United States[20] have shown that the annual cost for PNES patients is similar to that of chronic
epilepsy patients until they are diagnosed. However, both studies are from high-income
countries, and there are no data on the economic burden of PNES in developing countries
such as Türkiye. For PNES, the estimated yearly total cost of direct medical expenses
per person was calculated as €5,429.30 in Ireland[12] and as US$8,156 in the United States.[11] In the present study, we calculated an average cost of US$582.9 ± 330.0 (range:
103.52–1,601.3) per person for direct medical expenses during the period of hospitalization
and follow-up for the disability assessment. On the other hand, we determined the
annual cost per person as US$308.97 due to the use of ASM + PSSD in the PNES patients.
Unlike the aforementioned Irish study,[12] the present study was not based on pre-VEM health expenses, and we only calculated
the cost of hospitalization for diagnosis and the cost of use of ASM +PSSD before
the diagnosis was made. Therefore, we determined that if a person is hospitalized
once a year, there is an annual cost of US$891.87 (minimum amount: US$582.9 + US$308.97)
for their diagnosis and the medical treatment.
In 1994, Begley et al.[21] calculated the cost per patient after the diagnosis of epilepsy as US$4,272 for
patients in remission and as US$138,602 for those with resistant epilepsy; an approximate
cost was calculated, and, in a study published 21 years later, in 2015, Begley and
Durgin[22] emphasized that these costs were mostly related to the use of ASMs. In a study conducted
in China,[13] the authors emphasized that the annual direct cost per patient was of US$372, the
costs due to loss of productivity were of US$289, and a large part of the direct cost
was also due to the use of ASMs. In the present study, since the patients themselves
requested disability reports with the diagnosis of resistant epilepsy, it would be
inevitable that the annual costs per PNES patient would be as high as the costs for
those with resistant epilepsy had the correct diagnosis not been made.
In the present study, compared to epileptic patients, PNES patients had more psychiatric
comorbidities (p = 0.04; [Table 2]), which included conversion disorder, psychosis, depressive disorder, personality
disorders, panic disorder, and intellectual disability. Our results are in agreement
with those of the literature; PNES patients have a higher risk of developing posttraumatic
stress disorder, personality disorder, and anxiety, but not depression.[23] Scévola et al.[23] showed that 100% of PNES patients had psychiatric comorbidities, and the analysis
of 32 studies by Diprose et al.[2] revealed that this rate ranged from 53% to 100% in PNES patient. In the present
study, the rate of psychiatric comorbidities was higher in PNES patients (46.7%) than
in the epilepsy group.
In the present study, we observed that PNES patients started using PSSDs earlier than
those with epilepsy and almost at the same time they started using ASMs ([Table 3]). Consistent with the findings of the study conducted by Hantke et al.,[24] we determined that PNES patients frequently used benzodiazepines and antipsychotic
drugs and were followed up with at least two or more drug combinations. For ASM, in
the study by Zanzmera et al.,[25] 28.1% of the PNES patients were using ASMs, whereas, in the present study, only
2.2% of patients were not using ASMs.
In previous studies,[26]
[27] there was a predominance of the female gender among PNES patients, but, in the study,
most of the patients were male. The fact that active workers in Turkish society are
predominantly male and that men have to have a regular income to provide for their
household was believed to be the reason for the high number of requests for disability
reports by male patients.
We found that the comorbid PNES rate was high in chronic epileptic patients. This
may be related to the ulterior motive of these patients, who want a disability report
to get disability retirement. That is why the VEM in such patients is significant
to confirm the diagnosis of epilepsy and comorbid conditions.
In conclusion, all patients included in the present study were diagnosed with epilepsy
before their admission to our VEM Unit, and most of them were diagnosed with PNES
or comorbid PNES after monitoring. Physicians should definitely consider PNES in patients
with resistant epilepsy and comorbid psychiatric diseases. Therefore, it would be
suitable to refer the patients who are not clinically in remission and who meet the
criteria for the use of PSSDs to tertiary centers for VEM as soon as possible. Thus,
unnecessary use of medications, associated high costs, and adverse effects may be
prevented.
In addition, long-term follow-up and psychosocial support to patients diagnosed with
PNES will provide crucial information concerning their prognosis, their tendency to
quit or continue using ASMs, as well as support for employment and the possibility
for resolving the disease.
Limitation of the study
Due to the retrospective nature of the present study, the expenses incurred in the
last year before VEM could not be determined. Since the active substance of the drugs
used by the patients was recorded in their medical files, the cost of that drug was
calculated based on the preparation with the lowest market value. However, we know
that preparations containing the same active substance may have different prices in
our country. Therefore, we supposed that the annual cost for each patient in terms
of drugs could be higher.
