**Neuromodulation Therapy: Nonmedical, Nonsurgical Treatment for Intractable Epilepsy**

Hyang Woon Lee

[47] De Ferrari, G. C. (2011). Chronic vagus nerve stimulation: a new and promising ther‐

[48] Stefan H, K. G. (2012). Transcutaneous vagus nerve stimulation (t-VNS) in pharma‐

[49] DeGiorgio CM, S. J.L. (2013). Randomized controlled trial of trigeminal nerve stimu‐

[50] Pack AM. (2013). Trigeminal Nerve Stimulation May Not Be Effective for the Treat‐ ment of Refractory Partial Seizures. *Epilepsy Curr*, Jul-Aug; 13(4): 164–165.

[51] Fisher R, S. V. (2010). Electrical stimulation of the anterior nucleus of thalamus for

apeutic approach for chronic heart failure. *Eur Heart J*, Apr;32(7):847-55.

coresistant epilepsies: a proof of concept trial. *Epilepsia*, Jul;53(7)e115-8.

lation for drug-resistant epilepsy. *Neurology*, Feb 26;80(9):786-91.

160 Epilepsy Topics

treatment of refractory epilepsy. *Epilepsia*, May;51(5):899-908.

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57441

#### **1. Introduction**

Neuromodulation therapy has been tried for patients with many neuropsychiatric disorders such as Parkinson's disease, tremor, obcessive-compulsive disorder, depression, intractable pain, or addiction etc [1]. In epilepsy, this kind of treatment has been applied to treat patients with intractable epilepsy for decades who are not controlled by antiepileptic drugs (AEDs) nor surgical candidates. Historically, the earliest report of the use of electrical brain stimulation to control seizures in humans showed that focal electrical cortical stimulation could stop both normal EEG rhythms and spontaneous epileptiform discharges [2].

Vagal nerve or deep brain stimulation (e.g. thalamic stimulation) is indirect neural stimulation method, which delivers high frequency electrical stimulation indirectly to the epileptic brain via vagal nerve or thalamus, regardless of seizure foci [3,4]. This kind of stimulation is called open loop system since the stimulation is delivered intermittently and regularly without external cues (e.g. seizure onset). In contrast, closed loop system has been more recently applied in which the stimulation is directly applied to the seizure focus when seizure activity actually occurs. To do this, the stimulation system is combined with early seizure detection algorithm and activated automatically to deliver the stimulation only when the seizure activity is detected [5]. Responsive neurostimulation is an example of the closed loop system, which has been tested in recent clinical trials. While these methods need surgery to implant the electrodes for stimulation, noninvasive stimulation can be tried too especially using low frequency repetitive transcranial magnetic stimulation. In this method, the stimulation has been applied directly to the seizure focus but without combining seizure detection system so far. Although the exact therapeutic mechanism is not fully understood yet, these kinds of treatments have been reported to reduce seizures in intractable epilepsy patients.

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

In this chapter, various kinds of neuromodulation methods are introduced with the results of treatment efficacy and side effects from previous clinical trials in intractable epilepsy patients. In addition, recent clinical and basic researches to investigate possible therapeutic mechanisms are summarized. Future study directions what should be solved to improve the therapeutic efficacy and/or reduce adverse effects are also discussed.

ANT is believed to desynchronize seizure discharges thus inhibit seizure spread from hippocampus or neocortex to other brain areas [11]. Animal studies have provided evidence that low frequency ANT stimulation increases synchronization of the cortical EEG by recruit‐ ing rhythmic thalamocortical activities whereas high frequency stimulation leads to de‐

Neuromodulation Therapy: Nonmedical, Nonsurgical Treatment for Intractable Epilepsy

http://dx.doi.org/10.5772/57441

163

**2.3. Closed loop direct stimulation to the seizure focus: Responsive neurostimulation**

Closed loop neurostimulation is a method that responds immediately after the seizure is detected by automated seizure detection algorithm. Early stimulation after the seizure onset is expected to stop the seizure during the early stage before the seizure propagates to remote cortical areas thus evolving to secondarily generalization. Responsive neurostimulation (RNS) is the most recently tried one, which is a combination of early seizure detection and automated neurostimulation based on detection results from real-time EEG analysis. The RNS system requires an electrode implantation to the seizure focus for both seizure detection and electrical stimulation. Once the detection algorithm detects a seizure, high frequency electrical stimu‐

The rationale for RNS is based on the study showing that cortical stimulation could terminate afterdischarges (ADs) during functional mapping [13]. ADs, unnecessary but inevitable events, are very similar to ictal EEG discharges during seizures although they are induced activities from high frequency electrical stimulation, not spontaneously occurred ones. Interestingly, brief bursts of electrical cortical stimulation that had induced ADs if delivered longer, could stop ADs immediately in many occasions. It worked better when the stimulation was applied briefly shorter than one second and more promptly with shorter stimulation latency within several seconds after ADs occurred [14]. After this, unblinded clinical studies were conducted in adults with refractory partial epilepsy mainly for safety and feasibility [15]. And then, a double-blind, multicenter, randomized controlled clinical trial of RNS was

The controlled clinical trial was performed in 191 patients from 32 epilepsy centers who were diagnosed with highly drug-resistant partial epilepsy and had one or two focal seizure foci. The stimulation parameter for RNS was the amplitude of 0.5-12 mA, the pulse width of 40-1000 µs, and the frequency of 1-333 Hz. The average seizure frequency was significantly improved with 38% of seizure reduction in the active RNS group compared to 17% in the sham control group during the initial 12 weeks of blinded phase. During the open label period, seizure frequency was reduced in the sham control group in the initial blinded phase to the level of those in the treatment group. As with ANT stimulation, there was further progressive improvement during the open label period with median seizure reduction rate up to 50% after two years [16]. Based upon these results, RNS has been approved by FDA in November 14,

Choosing the best early seizure detection algorithm is very important for successful treatment in RNS [17]. Various EEG quantification methods have been tried for seizure prediction or early seizure detection, which include correlation dimension [18-21], correlation density [22], similarity index [23-25], phase synchronization [26-28], accumulated energy [29], complexity

synchronize EEG rhythms that will be effective for reducing seizures [12].

lation is applied automatically to abort the seizure as early as possible.

conducted, and the efficacy was reported recently [16].

2013, for patients with drug-resistant epilepsy.

#### **2. Types of neurostimulation**

#### **2.1. Open loop indirect stimulation thru the peripheral nerve: Vagal nerve stimulation**

Vagal nerve stimulation (VNS) is the first and the only FDA approved neurostimulation therapy in epilepsy, which has been tried in various seizure types and epileptic syndromes [3, 4]. The most famous clinical trials using VNS are randomized controlled trials of E03 [6] and E05 [7] in 114 and 119 patients, which provided an important evidence for FDA approval of VNS therapy in 1997. The stimulation paradigm was consisted of both high and low stimula‐ tions. The high stimulation was 3.5 mA, 30 Hz, 500 µs pulsewidth, with 30 s on time and 5 min off time, whereas the low simulation was similar output currents with 1 Hz frequency rate, 130 µs pulsewidth, on time of 30 s, and off time of 180 min.

Mechanism of action has been suggested based on the animal experiments and human researches using various electrophysiological and functional brain imaging studies [8]. It is believed that VNS modulates mainly subcortical neural network that influences larger cortical areas modifying synaptic connections. However, the exact mechanism of action how VNS reduces seizures is still under investigation, which needs future studies.

#### **2.2. Open loop indirect stimulation into the brain: Deep brain stimulation**

Stimulation of anterior nucleus of thalamus (ANT) in epilepsy patients was reported to have therapeutic effects earlier [9], and the results from double blind multicenter clinical trials have been reported recently in 110 epilepsy patients from 17 epilepsy centers [10]. In this, so-called, SANTE trial (Clinical Trials. Gov. NCT00101933), the efficacy showed 40.4% of seizure reduction during the 3 months of blinded phase in the treatment group, for both complex partial and secondarily generalized tonic clonic seizures, compared with 14.5% in the control group. Thirty-three patients with temporal lobe epilepsy (TLE) showed better response (44% of seizure reduction during the blinded phase compared with 22% reduction in TLE patients with standard treatment). Interestingly, the seizure reduction rate was increased over time in the open label period, which showed 41% median seizure reduction at 13 months. After 2 years of seizure follow-up, treated patients showed median 56% reduction in seizure frequency and 54% of patients obtaining more than 50% seizure reduction. Although there was a concern about depression (14.8%) or memory impairment (13.0%), DBS was generally safe without serious side effects such as intracranial hemorrhage, infection or death.

Possible role of thalamic DBS in epilepsy is that the thalamus might be a relay station that inhibits or disrupts epileptic seizures spreading via thalamocortical neural network. Actually, ANT is believed to desynchronize seizure discharges thus inhibit seizure spread from hippocampus or neocortex to other brain areas [11]. Animal studies have provided evidence that low frequency ANT stimulation increases synchronization of the cortical EEG by recruit‐ ing rhythmic thalamocortical activities whereas high frequency stimulation leads to de‐ synchronize EEG rhythms that will be effective for reducing seizures [12].

#### **2.3. Closed loop direct stimulation to the seizure focus: Responsive neurostimulation**

In this chapter, various kinds of neuromodulation methods are introduced with the results of treatment efficacy and side effects from previous clinical trials in intractable epilepsy patients. In addition, recent clinical and basic researches to investigate possible therapeutic mechanisms are summarized. Future study directions what should be solved to improve the therapeutic

**2.1. Open loop indirect stimulation thru the peripheral nerve: Vagal nerve stimulation**

Vagal nerve stimulation (VNS) is the first and the only FDA approved neurostimulation therapy in epilepsy, which has been tried in various seizure types and epileptic syndromes [3, 4]. The most famous clinical trials using VNS are randomized controlled trials of E03 [6] and E05 [7] in 114 and 119 patients, which provided an important evidence for FDA approval of VNS therapy in 1997. The stimulation paradigm was consisted of both high and low stimula‐ tions. The high stimulation was 3.5 mA, 30 Hz, 500 µs pulsewidth, with 30 s on time and 5 min off time, whereas the low simulation was similar output currents with 1 Hz frequency rate,

Mechanism of action has been suggested based on the animal experiments and human researches using various electrophysiological and functional brain imaging studies [8]. It is believed that VNS modulates mainly subcortical neural network that influences larger cortical areas modifying synaptic connections. However, the exact mechanism of action how VNS

Stimulation of anterior nucleus of thalamus (ANT) in epilepsy patients was reported to have therapeutic effects earlier [9], and the results from double blind multicenter clinical trials have been reported recently in 110 epilepsy patients from 17 epilepsy centers [10]. In this, so-called, SANTE trial (Clinical Trials. Gov. NCT00101933), the efficacy showed 40.4% of seizure reduction during the 3 months of blinded phase in the treatment group, for both complex partial and secondarily generalized tonic clonic seizures, compared with 14.5% in the control group. Thirty-three patients with temporal lobe epilepsy (TLE) showed better response (44% of seizure reduction during the blinded phase compared with 22% reduction in TLE patients with standard treatment). Interestingly, the seizure reduction rate was increased over time in the open label period, which showed 41% median seizure reduction at 13 months. After 2 years of seizure follow-up, treated patients showed median 56% reduction in seizure frequency and 54% of patients obtaining more than 50% seizure reduction. Although there was a concern about depression (14.8%) or memory impairment (13.0%), DBS was generally safe without

Possible role of thalamic DBS in epilepsy is that the thalamus might be a relay station that inhibits or disrupts epileptic seizures spreading via thalamocortical neural network. Actually,

efficacy and/or reduce adverse effects are also discussed.

130 µs pulsewidth, on time of 30 s, and off time of 180 min.

reduces seizures is still under investigation, which needs future studies.

serious side effects such as intracranial hemorrhage, infection or death.

**2.2. Open loop indirect stimulation into the brain: Deep brain stimulation**

**2. Types of neurostimulation**

162 Epilepsy Topics

Closed loop neurostimulation is a method that responds immediately after the seizure is detected by automated seizure detection algorithm. Early stimulation after the seizure onset is expected to stop the seizure during the early stage before the seizure propagates to remote cortical areas thus evolving to secondarily generalization. Responsive neurostimulation (RNS) is the most recently tried one, which is a combination of early seizure detection and automated neurostimulation based on detection results from real-time EEG analysis. The RNS system requires an electrode implantation to the seizure focus for both seizure detection and electrical stimulation. Once the detection algorithm detects a seizure, high frequency electrical stimu‐ lation is applied automatically to abort the seizure as early as possible.

The rationale for RNS is based on the study showing that cortical stimulation could terminate afterdischarges (ADs) during functional mapping [13]. ADs, unnecessary but inevitable events, are very similar to ictal EEG discharges during seizures although they are induced activities from high frequency electrical stimulation, not spontaneously occurred ones. Interestingly, brief bursts of electrical cortical stimulation that had induced ADs if delivered longer, could stop ADs immediately in many occasions. It worked better when the stimulation was applied briefly shorter than one second and more promptly with shorter stimulation latency within several seconds after ADs occurred [14]. After this, unblinded clinical studies were conducted in adults with refractory partial epilepsy mainly for safety and feasibility [15]. And then, a double-blind, multicenter, randomized controlled clinical trial of RNS was conducted, and the efficacy was reported recently [16].

The controlled clinical trial was performed in 191 patients from 32 epilepsy centers who were diagnosed with highly drug-resistant partial epilepsy and had one or two focal seizure foci. The stimulation parameter for RNS was the amplitude of 0.5-12 mA, the pulse width of 40-1000 µs, and the frequency of 1-333 Hz. The average seizure frequency was significantly improved with 38% of seizure reduction in the active RNS group compared to 17% in the sham control group during the initial 12 weeks of blinded phase. During the open label period, seizure frequency was reduced in the sham control group in the initial blinded phase to the level of those in the treatment group. As with ANT stimulation, there was further progressive improvement during the open label period with median seizure reduction rate up to 50% after two years [16]. Based upon these results, RNS has been approved by FDA in November 14, 2013, for patients with drug-resistant epilepsy.

Choosing the best early seizure detection algorithm is very important for successful treatment in RNS [17]. Various EEG quantification methods have been tried for seizure prediction or early seizure detection, which include correlation dimension [18-21], correlation density [22], similarity index [23-25], phase synchronization [26-28], accumulated energy [29], complexity or synchrony [30]. Improvement of early detection algorithm will be one of the most important requirements to make RNS more useful therapeutic option in treatment of intractable epilepsy.

technical notes to improve accurate and prompt seizure detection. Several important issues remain to be solved, however, such as ideal targets and stimulation parameters, and the optimization in each seizure type and/or epileptic syndrome. Investigation of the underlying therapeutic mechanisms requires more translational studies in the future that link basic

Neuromodulation Therapy: Nonmedical, Nonsurgical Treatment for Intractable Epilepsy

http://dx.doi.org/10.5772/57441

165

Several targets have been tried to treat focal or generalized epilepsy patients who are refractory to medical or surgical treatment, including vagus nerve, ANT, hippocampus, and various cortical locations according to epileptic foci. Targeting the hippocampus sounds reasonable in mesial temporal lobe epilepsy, which has been tested mostly in the form of RNS [17,42].

Other brain structures have been tried as well to control seizures; for examples, the centro‐ median nucleus of thalamus, the subthalamic nucleus, the substantia nigra reticulata, the caudate nucleus, the cerebellum, the posterior hypothalamus, and the caudal zona incerta [43]. Subthalamic nucleus, cerebellum, and trigeminal nerve stimulations have been considered as possible targets for intractable epilepsy especially for generalized epilepsy patients. The subthalamic nucleus has been tested clinically mainly for movement disorders so far, but it is also known as a relay station in the nigral system for epilepsy control that involves in seizure propagation and secondary generalization in animal researches [44,45], which has been the rationale to suggest its usefulness in epilepsy. The cerebellar stimulation was tried earlier [46], and reevaluated recently in a double-blind, randomized controlled pilot study on five patients with medically refractory motor seizures, that showed its beneficial effects especially for generalized tonic-clonic seizures [47]. The trigeminal nerve is one of the cranial nerves that connects to the large subcortical brain areas. Early studies suggesting potential clinical benefits

of trigeminal nerve stimulation for epilepsy patients have been reported [48,49].

Optimization of stimulus parameters is very important to improve the efficacy of seizure control by neuromodulation. In animal experiments, low frequency electrical stimulation can decrease neural excitability and seizure activity in both in-vivo and in-vitro models of epilepsy and stimulation effects increase synaptic inhibition via long-term depression (LTD). In epilepsy patients, low frequency electrical stimulation applied to ictal onset zones reduced seizure frequency. Low frequency electrical cortical stimulation was reported to have an inhibitory effect on epileptic focus in mesial temporal lobe epilepsy [50]. However, unwanted seizures may occur as side effects of stimulation, which needs to be solved in the future studies.

High frequency electrical stimulation has been applied both indirect stimulation to the epilepsy network via both VNS and DBS, and direct stimulation to the seizure focus via RNS [4,5]. For VNS, stimulation around 30 Hz is effective to reduce seizures. For DBS, higher frequency stimulation about 120 Hz was also reported to reduce seizures. Various stimulation frequencies

researches to relevant clinical trials.

**3.1. Targets for neurostimulation**

**3.2. Stimulus parameters**

between 1 and 333 Hz have been used for RNS.

More effective stimulation parameters have been tested in animal researches. Among the stimulation parameters, the frequency has been known as the most important factor to inhibit seizure activity better [31-33]. Several types of closed-loop brain computer interface systems have been tested in epilepsy animal model with improved seizure detection and reduced false detection rates [34].

#### **2.4. Open loop direct stimulation to the seizure focus: Repetitive transcranial magnetic stimulation**

Transcranial magnetic stimulation (TMS) is well established neurophysiologic study tool that has been used in neuroscience research and various clinical fields. TMS can be used in single, paired or repetitive trains, and repetitive stimulation [35]. Repetitive TMS (rTMS) is a safe and noninvasive method to alter neuronal functions thus applying to various clinical disorders such as stroke, pain, epilepsy etc. While other neural stimulation methods listed above need surgery to implant the electrodes for stimulation, TMS is a noninvasive stimulation without surgical intervention that is one of the greatest advantages when considered as a chronic treatment method clinically. In this method, the stimulation has been applied directly to the seizure focus but without combining seizure detection system so far.

Low frequency rTMS (less than 1 Hz) is known to inhibit cortical excitability [36,37] while high frequency rTMS (5-20 Hz) increases cortical excitability [38]. Low frequency rTMS, especially using 1 Hz stimulation, has been tried for refractory epilepsy. In a randomized clinical trial in 21 epilepsy patients with cortical developmental malformation, 1 Hz rTMS significantly reduced the number of seizures in the active group compared to the sham control group for at least 2 months [39]. A meta-analysis showed that low frequency rTMS has favorable antiepileptic effects, especially in patients with cortical dysplasia or neocortical epilepsy, with an effect size of 0.71 and 95% confidence interval at 0.30-1.12 [40]. Another established form of rTMS protocol is theta-burst stimulation (TBS), a burst of three 50-Hz pulses in trains repeated at 200-ms intervals. Continuous TBS (cTBS) consists of burst trains for 20-40 s that has an inhibitory effect on corticospinal excitability. On the other hand, intermittent TBS (iTBS), burst trains with a duration for 20-40 s for about 190 s, repeated in every 10 s, has a facilitating effect on corticospinal tract [41]. TBS is known to have longer effects than conventional rTMS paradigms that can be useful for clinical application, possibly including epilepsy, that will need further verification in controlled clinical trials.

#### **3. Unsolved questions and future direction**

In this chapter, various kinds of neuromodulation methods are introduced with a review of previous clinical trials and basic researches. We have reviewed important findings from previous clinical trials and other basic researches that contribute to our understanding of possible therapeutic mechanisms of neuromodulation for epilepsy treatment, as well as recent technical notes to improve accurate and prompt seizure detection. Several important issues remain to be solved, however, such as ideal targets and stimulation parameters, and the optimization in each seizure type and/or epileptic syndrome. Investigation of the underlying therapeutic mechanisms requires more translational studies in the future that link basic researches to relevant clinical trials.

#### **3.1. Targets for neurostimulation**

or synchrony [30]. Improvement of early detection algorithm will be one of the most important requirements to make RNS more useful therapeutic option in treatment of intractable epilepsy. More effective stimulation parameters have been tested in animal researches. Among the stimulation parameters, the frequency has been known as the most important factor to inhibit seizure activity better [31-33]. Several types of closed-loop brain computer interface systems have been tested in epilepsy animal model with improved seizure detection and reduced false

**2.4. Open loop direct stimulation to the seizure focus: Repetitive transcranial magnetic**

seizure focus but without combining seizure detection system so far.

need further verification in controlled clinical trials.

**3. Unsolved questions and future direction**

Transcranial magnetic stimulation (TMS) is well established neurophysiologic study tool that has been used in neuroscience research and various clinical fields. TMS can be used in single, paired or repetitive trains, and repetitive stimulation [35]. Repetitive TMS (rTMS) is a safe and noninvasive method to alter neuronal functions thus applying to various clinical disorders such as stroke, pain, epilepsy etc. While other neural stimulation methods listed above need surgery to implant the electrodes for stimulation, TMS is a noninvasive stimulation without surgical intervention that is one of the greatest advantages when considered as a chronic treatment method clinically. In this method, the stimulation has been applied directly to the

Low frequency rTMS (less than 1 Hz) is known to inhibit cortical excitability [36,37] while high frequency rTMS (5-20 Hz) increases cortical excitability [38]. Low frequency rTMS, especially using 1 Hz stimulation, has been tried for refractory epilepsy. In a randomized clinical trial in 21 epilepsy patients with cortical developmental malformation, 1 Hz rTMS significantly reduced the number of seizures in the active group compared to the sham control group for at least 2 months [39]. A meta-analysis showed that low frequency rTMS has favorable antiepileptic effects, especially in patients with cortical dysplasia or neocortical epilepsy, with an effect size of 0.71 and 95% confidence interval at 0.30-1.12 [40]. Another established form of rTMS protocol is theta-burst stimulation (TBS), a burst of three 50-Hz pulses in trains repeated at 200-ms intervals. Continuous TBS (cTBS) consists of burst trains for 20-40 s that has an inhibitory effect on corticospinal excitability. On the other hand, intermittent TBS (iTBS), burst trains with a duration for 20-40 s for about 190 s, repeated in every 10 s, has a facilitating effect on corticospinal tract [41]. TBS is known to have longer effects than conventional rTMS paradigms that can be useful for clinical application, possibly including epilepsy, that will

In this chapter, various kinds of neuromodulation methods are introduced with a review of previous clinical trials and basic researches. We have reviewed important findings from previous clinical trials and other basic researches that contribute to our understanding of possible therapeutic mechanisms of neuromodulation for epilepsy treatment, as well as recent

detection rates [34].

**stimulation**

164 Epilepsy Topics

Several targets have been tried to treat focal or generalized epilepsy patients who are refractory to medical or surgical treatment, including vagus nerve, ANT, hippocampus, and various cortical locations according to epileptic foci. Targeting the hippocampus sounds reasonable in mesial temporal lobe epilepsy, which has been tested mostly in the form of RNS [17,42].

Other brain structures have been tried as well to control seizures; for examples, the centro‐ median nucleus of thalamus, the subthalamic nucleus, the substantia nigra reticulata, the caudate nucleus, the cerebellum, the posterior hypothalamus, and the caudal zona incerta [43]. Subthalamic nucleus, cerebellum, and trigeminal nerve stimulations have been considered as possible targets for intractable epilepsy especially for generalized epilepsy patients. The subthalamic nucleus has been tested clinically mainly for movement disorders so far, but it is also known as a relay station in the nigral system for epilepsy control that involves in seizure propagation and secondary generalization in animal researches [44,45], which has been the rationale to suggest its usefulness in epilepsy. The cerebellar stimulation was tried earlier [46], and reevaluated recently in a double-blind, randomized controlled pilot study on five patients with medically refractory motor seizures, that showed its beneficial effects especially for generalized tonic-clonic seizures [47]. The trigeminal nerve is one of the cranial nerves that connects to the large subcortical brain areas. Early studies suggesting potential clinical benefits of trigeminal nerve stimulation for epilepsy patients have been reported [48,49].

#### **3.2. Stimulus parameters**

Optimization of stimulus parameters is very important to improve the efficacy of seizure control by neuromodulation. In animal experiments, low frequency electrical stimulation can decrease neural excitability and seizure activity in both in-vivo and in-vitro models of epilepsy and stimulation effects increase synaptic inhibition via long-term depression (LTD). In epilepsy patients, low frequency electrical stimulation applied to ictal onset zones reduced seizure frequency. Low frequency electrical cortical stimulation was reported to have an inhibitory effect on epileptic focus in mesial temporal lobe epilepsy [50]. However, unwanted seizures may occur as side effects of stimulation, which needs to be solved in the future studies.

High frequency electrical stimulation has been applied both indirect stimulation to the epilepsy network via both VNS and DBS, and direct stimulation to the seizure focus via RNS [4,5]. For VNS, stimulation around 30 Hz is effective to reduce seizures. For DBS, higher frequency stimulation about 120 Hz was also reported to reduce seizures. Various stimulation frequencies between 1 and 333 Hz have been used for RNS.

Intermittent versus continuous stimulation also has been discussed. Interestingly, intermittent stimulation around 1.68% of the time was reported to be effective although less than when the device was activated 50% of the time [51].

**4. Conclusion**

**Acknowledgements**

**Author details**

Hyang Woon Lee\*

**References**

Research Institute, Seoul, South Korea

Recent progress of technological and methodological advances in neuromodulation leads to high possibilities for using these methods more widely to treat intractable epilepsy. These technological advances have been introduced to generate more practical ways of neuromo‐ dulation methods for chronic use in clinical fields. One of the remarkable advances is the combination of neuromodulation with early seizure detection algorithm. Along with results from basic researches in animals and humans, the underlying therapeutic mechanisms have been investigated as well. In addition, studies have been performed to improve the therapeutic efficacy by optimizing stimulation parameters, and accuracy of early seizure detection.

Neuromodulation Therapy: Nonmedical, Nonsurgical Treatment for Intractable Epilepsy

http://dx.doi.org/10.5772/57441

167

Advances in the field of neuromodulation reviewed here, as well as general advances in neuroscience, would provide us a new insight in the treatment of intractable epilepsy. Furthermore, advances in neuromodulation in epilepsy therapy could allow us progress in related neuroscience and clinical fields, especially to investigate and modulate complex neural

This work was supported by the Ewha Global Top 5 Grant 2011 of Ewha Womans University and by the Korean Science and Engineering Foundation (KOSEF) Grant funded by the South Korean government (MOST) (R01-2007-000-11080-0), and by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry

Department of Neurology, Ewha Womans University School of Medicine and Ewha Medical

[1] Krack P, Hariz MI, Baunez C, Guridi J, Obeso JA. Deep brain stimulation: from neu‐

[2] Penfield W, Jasper H. Electrocorticography. In: Epilepsy and the functional anatomy

rology to psychiatry? Trends Neurosci 2010;33(10):474-484.

of the human brain. Little, Brown, Boston, pp 692-738, 1954.

of Education, Science and Technology [R01-2011-0015788 and KRF-2009-006-5721].

network based on normal and abnormal brain functions.

Standardization of stimulation parameters is also needed for individual seizure types and/or specific epileptic syndromes. Future studies in both basic and human researches to improve treatment efficacy based on therapeutic mechanisms will be mandatory for practical use of neuromodulation therapy in intractable epilepsy patients.

#### **3.3. Unveiling therapeutic mechanism**

Epileptic seizure is characterized by a brief, transient increase of abnormally excitable and synchronized activities in neural network. Interestingly, and somewhat paradoxically, the activity can be eliminated by neurostimulation, often using very high frequency especially in the VNS, DBS, and RNS.

From the observation that electrical stimulation suppressed ADs and seizures throughout the course of kindling, that indicates a strong antiepileptogenic effect. While the kindling seems very similar to long-term potentiation (LTP), electrical stimulation acts like LTD or depotentiation, which might explain how neuromodulation controls epilepsy in terms of the mechanism of action. Interestingly, LTP and kindling have many similarities although cellular mechanisms are different in many respects. On the other hand, prolonged electri‐ cal stimulation can elicit LTD that can be opposite phenomenon to LTP where the synap‐ tic transmission is reduced. That is, electrical stimulation can depotentiate synapses that underwent LTP already. However, electrical stimulation can induce enhancement of synaptic strength like LTP, which needs further studies to verify stimulation parameters based on the therapeutic mechanisms [52].

Long lasting hyperpolarization was also suggested as a possible mechanism to reduce seizures in low frequency deep brain electrical stimulation, mediated via GABAB inhibitory postsy‐ naptic potentials and/or slow after-hyperpolarization [53]. High frequency sinusoidal fields were reported to suppress epileptiform activity in rat hippocampal slices, which was associ‐ ated with potassium efflux and following depolarization block [54].

The rationale behind chronic intermittent stimulation is to modulate the background brain activity so that epileptic seizures are less likely to occur. This could be either reducing network hypersynchronization or modulating specific pathways involving epileptic network [5]. The mechanisms are expected to be distinct from those of antiepileptic drugs in which the antie‐ pileptic effects are mediated by alterations of cellular and/or synaptic functions. Interestingly, many clinical studies using VNS, DBS, and RNS showed that the stimulation effects were improved over time for up to two years. These observations suggest the possibility that acute seizure inhibition mechanism might be different from chronic prevention or antiepileptogenic mechanism, which is actually an ideal goal of any antiepileptic treatments.

#### **4. Conclusion**

Intermittent versus continuous stimulation also has been discussed. Interestingly, intermittent stimulation around 1.68% of the time was reported to be effective although less than when the

Standardization of stimulation parameters is also needed for individual seizure types and/or specific epileptic syndromes. Future studies in both basic and human researches to improve treatment efficacy based on therapeutic mechanisms will be mandatory for practical use of

Epileptic seizure is characterized by a brief, transient increase of abnormally excitable and synchronized activities in neural network. Interestingly, and somewhat paradoxically, the activity can be eliminated by neurostimulation, often using very high frequency especially in

From the observation that electrical stimulation suppressed ADs and seizures throughout the course of kindling, that indicates a strong antiepileptogenic effect. While the kindling seems very similar to long-term potentiation (LTP), electrical stimulation acts like LTD or depotentiation, which might explain how neuromodulation controls epilepsy in terms of the mechanism of action. Interestingly, LTP and kindling have many similarities although cellular mechanisms are different in many respects. On the other hand, prolonged electri‐ cal stimulation can elicit LTD that can be opposite phenomenon to LTP where the synap‐ tic transmission is reduced. That is, electrical stimulation can depotentiate synapses that underwent LTP already. However, electrical stimulation can induce enhancement of synaptic strength like LTP, which needs further studies to verify stimulation parameters

Long lasting hyperpolarization was also suggested as a possible mechanism to reduce seizures in low frequency deep brain electrical stimulation, mediated via GABAB inhibitory postsy‐ naptic potentials and/or slow after-hyperpolarization [53]. High frequency sinusoidal fields were reported to suppress epileptiform activity in rat hippocampal slices, which was associ‐

The rationale behind chronic intermittent stimulation is to modulate the background brain activity so that epileptic seizures are less likely to occur. This could be either reducing network hypersynchronization or modulating specific pathways involving epileptic network [5]. The mechanisms are expected to be distinct from those of antiepileptic drugs in which the antie‐ pileptic effects are mediated by alterations of cellular and/or synaptic functions. Interestingly, many clinical studies using VNS, DBS, and RNS showed that the stimulation effects were improved over time for up to two years. These observations suggest the possibility that acute seizure inhibition mechanism might be different from chronic prevention or antiepileptogenic

ated with potassium efflux and following depolarization block [54].

mechanism, which is actually an ideal goal of any antiepileptic treatments.

device was activated 50% of the time [51].

**3.3. Unveiling therapeutic mechanism**

based on the therapeutic mechanisms [52].

the VNS, DBS, and RNS.

166 Epilepsy Topics

neuromodulation therapy in intractable epilepsy patients.

Recent progress of technological and methodological advances in neuromodulation leads to high possibilities for using these methods more widely to treat intractable epilepsy. These technological advances have been introduced to generate more practical ways of neuromo‐ dulation methods for chronic use in clinical fields. One of the remarkable advances is the combination of neuromodulation with early seizure detection algorithm. Along with results from basic researches in animals and humans, the underlying therapeutic mechanisms have been investigated as well. In addition, studies have been performed to improve the therapeutic efficacy by optimizing stimulation parameters, and accuracy of early seizure detection.

Advances in the field of neuromodulation reviewed here, as well as general advances in neuroscience, would provide us a new insight in the treatment of intractable epilepsy. Furthermore, advances in neuromodulation in epilepsy therapy could allow us progress in related neuroscience and clinical fields, especially to investigate and modulate complex neural network based on normal and abnormal brain functions.

#### **Acknowledgements**

This work was supported by the Ewha Global Top 5 Grant 2011 of Ewha Womans University and by the Korean Science and Engineering Foundation (KOSEF) Grant funded by the South Korean government (MOST) (R01-2007-000-11080-0), and by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology [R01-2011-0015788 and KRF-2009-006-5721].

#### **Author details**

#### Hyang Woon Lee\*

Department of Neurology, Ewha Womans University School of Medicine and Ewha Medical Research Institute, Seoul, South Korea

#### **References**


[3] Ben-Menachem E. Vagus-nerve stimulation for the treatment of epilepsy. Lancet Neurology 2002;1:477-482.

[13] Lesser RP, Kim SH, Beyderman L, Miglioretti DL, Webber WR, Bare M, Cysyk B, Krauss G, Gordon B. Brief bursts of pulse stimulation terminate afterdischarges

Neuromodulation Therapy: Nonmedical, Nonsurgical Treatment for Intractable Epilepsy

http://dx.doi.org/10.5772/57441

169

[14] Motamedi GK, Lesser RP, Miglioretti DL, Mizuno-Matsumoto Y, Gordon B, Webber WR, Jackson DC, Sepkuty JP, Crone NE. Optimizing parameters for terminating cort‐

[15] Fountas KN, Smith JR, Murro AM, Politsky J, Park YD, Jenkins PD. Implantation of a closed-loop stimulation in the management of medically refractory focal epilepsy: a

[16] Morrell MJ, RNS System in Epilepsy Study Group. Responsive cortical stimulation for the treatment of medically intractable partial seizures. Neurology

[17] Liu C, Wen XW, Ge Y, Chen N, Hu WH, Zhang T, Zhang JG, Meng FG. Responsive neurostimulation for the treatment of medically intractable epilepsy. Brain Research

[18] Lehnertz K, Elger CE. Can epileptic seizures be predicted? Evidence from nonlinear time series analysis of brain electrical activity. Physical Review Letters 1998;80: 5019–

[19] Lehnertz K, Andrzejak RG, Arnhold J, Kreuz T, Mormann F, Rieke C. Nonlinear EEG analysis in epilepsy: its possible use for interictal focus localization, seizure anticipa‐

[20] Tito M, Cabrerizo M, Ayala M, Barreto A, Miller I, Jayakar P, Adjouadi, M. Classifi‐ cation of electroencephalographic seizure recordings into ictal and interictal files us‐

[21] Rabbi, A.F., Aarabi, A., Fazel-Rezai, R., 2010. Fuzzy rule-based seizure prediction based on correlation dimension changes in intracranial EEG. Conference Proceed‐ ings: Annual International Conference of the IEEE Engineering in Medicine and Biol‐

[22] Martinerie J, Adam C, Le Van Quyen M, Baulac M, Clemenceau S, Renault B, Varela FJ. Epileptic seizures can be anticipated by non-linear analysis. Nature Medicine

[23] Le Van Quyen M, Adam C, Martinerie J, Baulac M, Clemenceau S, Varela F. Spatiotemporal characterization of non-linear changes in intracranial activities prior to hu‐ man temporal lobe seizures. European Journal of Neuroscience 2000;12: 2124–2134.

[24] Le Van Quyen M, Martinerie J, Navarro V, Boon PD, Have M, Adam C, Renault B, Varela F, Baulac M. Anticipation of epileptic seizures from standard EEG recordings.

tion, and prevention. Journal of Clinical Neurophysiology 2001;18:209–222.

ing correlation sum. Computers in Biology and Medicine 2009;39:604–614.

ical afterdischarges with pulse stimulation. Epilepsia. 2002;43(8):836-46.

caused by cortical stimulation. Neurology 1999;53:2073-2081.

technical note. Stereotact Funct Neurosurg. 2005;83(4):153-158.

2011;77:1295-1304.

Bulletin 2013;97:39-47.

ogy Society 2010;2010:3301–3304.

1998;4:1173–1176.

Lancet 2001;357:183–188.

5023.


[13] Lesser RP, Kim SH, Beyderman L, Miglioretti DL, Webber WR, Bare M, Cysyk B, Krauss G, Gordon B. Brief bursts of pulse stimulation terminate afterdischarges caused by cortical stimulation. Neurology 1999;53:2073-2081.

[3] Ben-Menachem E. Vagus-nerve stimulation for the treatment of epilepsy. Lancet

[4] Ben-Menachem E. Neurostimulation – past, present, and beyond. Epilepsy Currents

[5] Bergey GK. Neurostimulation in the treatment of epilepsy. Experimental Neurology

[6] The Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus nerve stimulation for the treatment of medically intractable seizures. Neurolo‐

[7] Handforth A, Degiorgio CM, Schachter SC, Uthman BM, Naritoku DK, Tecoma ES, Henry TR, Collins SD, Vaughn BV, Gilmartin RC, Labar DR, Morris GL 3rd, Salinsky MC, Osorio I, Ristanovic RK, Labiner DM, Jones JC, Murphy JV, Ney GC, Wheless JW. Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-

[8] Groves DA, Brown VJ. Vagal nerve stimulation: a review of its applications and po‐ tential mechanisms that mediate its clinical effects. Neurosci Biobehav Rev

[9] Kerrigan JF, Litt B, Fisher RS, Cranstoun S, French JA, Blum DE, Dichter M, Shetter A, Baltuch G, Jaggi J, Krone S, Brodie M, Rise M, Graves N. Electrical stimulation of the anterior nucleus of the thalamus for the treatment of intractable epilepsy. Epilep‐

[10] Fisher R, Salanova V, Witt T, Worth R, Henry T, Gross R, Oommen K, Osorio I, Naz‐ zaro J, Labar D, Kaplitt M, Sperling M, Sandok E, Neal J, Handforth A, Stern J, DeSal‐ les A, Chung S, Shetter A, Bergen D, Bakay R, Henderson J, French J, Baltuch G, Rosenfeld W, Youkilis A, Marks W, Garcia P, Barbaro N, Fountain N, Bazil C, Good‐ man R, McKhann G, Babu Krishnamurthy K, Papavassiliou S, Epstein C, Pollard J, Tonder L, Grebin J, Coffey R, Graves N; SANTE Study Group. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia

[11] Graber KD, Fisher FS. Deep brain stimulation for epilepsy: animal models. In: Noe‐ bels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National

[12] Mirski MA, Tsai YC, Rossell LA, Thakor NV, Sherman DL. Anterior thalamic medi‐ cation of experimental seizures: selective EEG spectral coherence. Epilepsia

Neurology 2002;1:477-482.

2012;12:188-191.

168 Epilepsy Topics

2013;244:87-95.

gy 1995;45:224-230.

2005;29:493-500.

sia 2004;45(5):346-354.

2010;51:899–908.

2003;44:355-365.

control trial. Neurology. 1998 Jul;51(1):48-55.

Center for Biotechnology Information (US); 2012.


[25] Navarro V, Martinerie J, Le Van Quyen M, Baulac M, Dubeau, F, Gotman J. Seizure anticipation: do mathematical measures correlate with video-EEG evaluation? Epi‐ lepsia 2005;46:385–396.

[38] Pascual-Leone A, Grafman J, Hallett M. Modulation of cortical motor output maps during development of implicit and explicit knowledge. Science 1994;263:1287-1289.

Neuromodulation Therapy: Nonmedical, Nonsurgical Treatment for Intractable Epilepsy

http://dx.doi.org/10.5772/57441

171

[39] Fregni F, Otachi PTM, do Valle A, Boggio PS, Thut G, Rigonatti SP, Pascual-Leone A, Kette D. Valente KD. A randomized clinical trial of repetitive transcranial magnetic

[40] Hsu WY, Cheng CH, Lin MW, Shih YH, Liao KK, Lin YY. Antiepileptic effects of low frequency repetitive transcranial magnetic stimulation: a meta-analysis. Epi Res

[41] Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation

[42] Osorio I, Overman J, Giftakis J, Wilkinson SB. High frequency thalamic stimulation

[43] Tykocki T, Mandat T, Kornakiewicz A, Koziara H, Nauman P. Deep brain stimula‐

[44] Gale K. Subcortical structures and pathways involved in convulsive seizure genera‐

[45] Deransart C, LePham BT, Marescaux C, Depaulis A. Role of the subthalamo-nigral input in the control of amygdale-kindled seizures in the rat. Brain Res 1998;807:78-83.

[46] Krauss GL, Fisher RS. Cerebellar and thalamic stimulation for epilepsy. Adv Neurol

[47] Velasco F, Carrillo-Ruiz JD, Brito F, Velasco M, Velasco AL, Marquez I, Davis R. Double-blind, randomized controlled pilot study of bilateral cerebellar stimulation

[48] DeGiorgio CM, Soss J, Cook IA, Markovic D, Gornbein J, Murray D, Oviedo S, Gor‐ don S, Corralle-Leyva G, Kealey CP, Heck CN. Randomized controlled trial of trige‐ minal nerve stimulation for drug-resistant epilepsy. Neurology. 2013;80(9):786-791.

[49] Pop J, Murray D, Markovic D, Degiorgio CM. Acute and long-term safety of external trigeminal nerve stimulation for drug-resistant epilepsy. Epilepsy Behav

[50] Yamamoto J, Ikeda A, Satow T, Takeshita K, Takayama M, Matsuhashi M, Matsumo‐ to R, Ohara S, Mikuni N, Takahashi J, Miyamoto S, Taki W, Hashimoto N, Rothwell JC, Shibasaki H. Low-frequency electric cortical stimulation has an inhibitory effect on epileptic focus in mesial temporal lobe epilepsy. Epilepsia 2002; 43(5): 491-495.

[51] Lian J, Bikson M, Sciortino C, Stacey WC, Durand DM. Local suppression of epilepti‐ form activity by electrical stimulation on rat hippocampus in vitro. J Physiol

for treatment of intractable motor seizures. Epilepsia. 2005 ;46(7):1071-1081.

for inoperable mesial temporal epilepsy. Epilepsia 2007;48(8):1561-1571.

of the human motor cortex. Neuron 2005;45:201-206.

tion. J Clin Neurophysiol 1992;9(2):264-277.

tion for refractory epilepsy. Arch Med Sci 2012;8(5):805-816.

stimulation in patients with refractory epilepsy. Ann Neurol 2006;60:447-455.

2011;96:231-240.

1993;63:231-245.

2011;57:574-576.

2003;547(Pt 2): 427-434.


[38] Pascual-Leone A, Grafman J, Hallett M. Modulation of cortical motor output maps during development of implicit and explicit knowledge. Science 1994;263:1287-1289.

[25] Navarro V, Martinerie J, Le Van Quyen M, Baulac M, Dubeau, F, Gotman J. Seizure anticipation: do mathematical measures correlate with video-EEG evaluation? Epi‐

[26] Mormann F, Lehnertz K, David P, Elger CE. Mean phase coherence as a measure for phase synchronization and its application to the EEG of epilepsy patients. Physica D

[27] Wang L, Wang C, Fu F, Yu X, Guo H, Xu C, Jing X, Zhang H, Dong X. Temporal lobe seizure prediction based on a complex Gaussian wavelet. Clinical Neurophysiology

[28] Le Van Quyen M., Soss, J., Navarro, V., Robertson, R., Chavez, M., Baulac, M., Mar‐ tinerie, J. Preictal state identification by synchronization changes in long-term intra‐

[29] Litt, B., Esteller, R., Echauz, J., D'Alessandro, M., Shor, R., Henry, T., Pennell, P., Ep‐ stein, C., Bakay, R., Dichter, M., Vachtsevanos, G., 2001. Epileptic seizures may begin hours in advance of clinical onset: a report of five patients. Neuron 2001;30:51–64.

[30] Jouny CC, Franaszczuk PJ, Bergey GK. Signal complexity and synchrony of epileptic seizures: is there an identifiable preictal period? Clinical Neurophysiology

[31] Durand DM. Control of seizure activity by electrical stimulation: effect of frequency.

[32] Nelson TS, Suhr CL, Freestone DR, Lai A, Halliday AJ, McLean KJ, Burkitt AN, Cook MJ. Closed-loop seizure control with very high frequency electrical stimulation at seizure onset in the GAERS model of absence epilepsy. Int J Neural Syst 2011;21(2):

[33] Rajdev P, Ward M, Irazoqui P. Effect of stimulus parameters in the treatment of seiz‐ ures by electrical stimulation in the kainate animal model. Int J Neural Syst

[34] Liang SF, Liao TC, Shaw FZ, Chang DW, Young CP, Chiueh H. Closed-loop seizure

[35] Dayan E, Censor N, Buch ER, Sandrini M, Cohen LG. Noninvasive brain stimulation: from physiology to network dynamics and back. Nature Neuroscience 2013;16(7):

[36] Censor N, Cohen LG. Using repetitive transcranial magnetic stimulation to study the underlying neural mechanisms of human motor learning and memory. J Physiol

[37] Muellbacher W, et al. Early consolidation in human primary motor cortex. Nature

control on epileptic rat models. J Neural Eng 2011;8(4):045001.

cranial EEG recordings. Clinical Neurophysiology 2005;116:559–568.

lepsia 2005;46:385–396.

2000;144:358–369.

170 Epilepsy Topics

2011;122:656–663.

2005;116:552–558.

2011;21(2):151-162.

163-173.

838-844.

2011;589:21-28.

2002;415:640-644.

Conf Proc IEEE Eng Med Biol Soc 2009;2375.


[52] Li H, Chen A, Xing G, Wei M-L, Rogawski MA. Kainate receptor-mediated heterosy‐ naptic facilitation in the amygdala. Nat Neurosci 2001;4:612-620.

**Chapter 9**

**Psychogenic Non-Epileptic Spells**

Batool F. Kirmani, Diana Mungall Robinson, Jose Aceves, David Gavito, Richard Phenis and

Additional information is available at the end of the chapter

The psychogenic non-epileptic spells are the most frequent referrals to the specialized epilepsy center because of the intractable nature of the spells. Psychogenic non-epileptic spells (PNES) are also referred to as "pseudoseizures", psychogenic seizures, non-epileptic seizures or stressrelated spells [1]. PNES is a form of conversion disorder but misdiagnosis and delay in diagnosis is common [2,3,4]. The reason for misdiagnosis is overinterpretation of the EEG and lack of data regarding the semiology of the spells. The gold standard is to capture these spells for definitive diagnosis under medical withdrawal in an epilepsy monitoring unit by video-EEG. The PNES are not epileptic seizures but they are extremely disabling and adversely affect

The prevalence of PNES was reported by Benabadis and colleagues in a retrospective review. Benbadis et al conducted a retrospective review of available prevalence, incidence, and hospital-based data to estimate the prevalence of PNES. The prevalence was based on the following generally accepted data: prevalence of epilepsy is 0.5-1%, and proportion of intractable epilepsy is 20-55%, and 10-20% of patients referred to epilepsy centers are found to have PNES. From these data, using a prevalence of epilepsy of 0.5% to 1%, a low estimate was determined to be 1/50,000 and a high estimate was determined to be 1/3,000. The conclu‐ sion of this retrospective review was that there was a prevalence of 2 to 33 people per 100,000 [7]. The only population based study which estimated the incidence of PNES was conducted

> © 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**2. Epidemiology of psychogenic non-epileptic seizures**

Daniel Cruz

**1. Introduction**

quality of life [5,6].

http://dx.doi.org/10.5772/57440


**Chapter 9**

## **Psychogenic Non-Epileptic Spells**

Batool F. Kirmani, Diana Mungall Robinson, Jose Aceves, David Gavito, Richard Phenis and Daniel Cruz

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57440

#### **1. Introduction**

[52] Li H, Chen A, Xing G, Wei M-L, Rogawski MA. Kainate receptor-mediated heterosy‐

[53] Toprani S, Durand DM. Long-lasting hyperpolarization underlies seizure reduction by low frequency deep brain electrical stimulation. J Physiol 2013; Epub in advance.

[54] Bikson M, Lian J, Hahn PJ, Stacey WC, Sciortino C, Durand DM. Suppression of epi‐ leptiform activity by high frequency sinusoidal fields in rat hippocampal slices. J

naptic facilitation in the amygdala. Nat Neurosci 2001;4:612-620.

Physiol 2001;531(1):181-191.

172 Epilepsy Topics

The psychogenic non-epileptic spells are the most frequent referrals to the specialized epilepsy center because of the intractable nature of the spells. Psychogenic non-epileptic spells (PNES) are also referred to as "pseudoseizures", psychogenic seizures, non-epileptic seizures or stressrelated spells [1]. PNES is a form of conversion disorder but misdiagnosis and delay in diagnosis is common [2,3,4]. The reason for misdiagnosis is overinterpretation of the EEG and lack of data regarding the semiology of the spells. The gold standard is to capture these spells for definitive diagnosis under medical withdrawal in an epilepsy monitoring unit by video-EEG. The PNES are not epileptic seizures but they are extremely disabling and adversely affect quality of life [5,6].

#### **2. Epidemiology of psychogenic non-epileptic seizures**

The prevalence of PNES was reported by Benabadis and colleagues in a retrospective review. Benbadis et al conducted a retrospective review of available prevalence, incidence, and hospital-based data to estimate the prevalence of PNES. The prevalence was based on the following generally accepted data: prevalence of epilepsy is 0.5-1%, and proportion of intractable epilepsy is 20-55%, and 10-20% of patients referred to epilepsy centers are found to have PNES. From these data, using a prevalence of epilepsy of 0.5% to 1%, a low estimate was determined to be 1/50,000 and a high estimate was determined to be 1/3,000. The conclu‐ sion of this retrospective review was that there was a prevalence of 2 to 33 people per 100,000 [7]. The only population based study which estimated the incidence of PNES was conducted

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

by Sigurdardottir et al. Sigurdardottir and colleagues conducted a retrospective chart review of all long-term video EEG studies made in Iceland from January 1992 to December 1996 in order to determine the incidence of PNES. All patients were aged 15 or greater and had been diagnosed with PNES at National University Hospital (Landspitalinn), Iceland. The diagnosis of PNES was determined by clinical observation and EEG, and all of these patients underwent long-term video-EEG monitoring (LVEM). A total of 14 patients met the inclusion criteria and were aged 16-54 years (mean 27.6). There were 11 female patients (78.6%). There was an average annual population of 200,191 persons aged 15 years or greater for a total of 1,000,955 persons over the entire study period. The incidence of PNES was 1.4 in a 100,000 population. The 15-24 year old age group had the highest age-specific incidence. The incidence decreased in subsequent older age groups. Half of the patients (N=7) also had epilepsy, with the majority having generalized tonic-clonic seizures only (N=3), followed by Generalized tonic clonic seizures (GTC )and myoclonus (N=2), tonic seizures (N=1), and absences (N=1). 2 of 7 patients with PNES and without epilepsy were on antiepileptic drug (AED) treatment prior to PNES diagnosis. The researchers concluded that the incidence in people aged 15-24 years was ~5% of the incidence of epilepsy and 4% of reported epilepsy from Iceland for persons aged ≥15 years [8]. Szaflarski and colleagues conducted the retrospective study which determined the incidence of PNES in a medium-sized urban community. Adult patients who underwent prolonged video and EEG monitoring (PVEM) were identified between January 1, 1995 and December 30, 1998 at the University Hospital or Veteran Administration Medical Center in Cincinnati, OH. Patients were classified into four groups: definite PNES, possible PNES, possible epilepsy, and definite epilepsy. A board-certified electroencephalographer reviewed all tracings and videos. Population characteristics were examined with univariate analysis and comparison of similar features between patients with PNES and those with epilepsy were analyzed with bivariate analysis. During the study period, 600 patients were monitored with 3 patients at the Veteran Affairs Medical Center and 174 at the University of Ohio fulfilling the residence criteria. Definite PNES was diagnosed in 77 patients and definite epilepsy was diagnosed in 85 patients. Also, there was an increase in the incidence of PNES over the study from 1.88/100,000 in 1995 to 4.6/100,000 in 1998 (mean incidence 3.03/100,000). Patients aged 25-45 years had the highest incidence of PNES (4.38/100,000). Groups of patients with PNES had a shorter average duration of illness before diagnosis and were more likely to have a history of psychiatric disorders (48.6% versus 30.4%; p=0.023) than definite epilepsy patients. Epilepsy patients were more likely to be treated with more antiepileptic drugs before admis‐ sion than PNES (4.85 versus 2.53; p <0.001). No significant differences were found in the PNES compared with epilepsy groups in gender (women 73% versus 60%), age (37.2 versus 37 years), or history of febrile seizures, head trauma, or family history of epilepsy. The authors conclude that improved access to PVEM and higher clinician awareness may be related to the increasing incidence of PNES over the study period [9].

**2.1. Psychogenic non-epileptic seizures in different population subgroups**

of sexual abuse in approximately 25% of the patients with PNES [12].

Psychogenic seizures are more common in women. Women account for approximately 70 to 80% incidence of PNES, but the incidence varies depending on the etiology [6,10, 11,12]. There are certain factors that contribute to the increase risk of PNES. The most important factor is the history of sexual abuse seen more commonly in women. This issue has also been addressed historically by Freud based on his observations. Freud's earlier observations describe Hysteria which is now the basis of the concept of psychogenic non-epileptic seizures. Hysteria is a Greek word which means "wandering uterus" and is related to history of sexual abuse in women and repressed sexual drives [13,14]. Alper and colleagues in a case series described the history

Psychogenic Non-Epileptic Spells http://dx.doi.org/10.5772/57440 175

There are several studies which show the prevalence of pseudoseizures in the elderly. McBride et al performed a retrospective chart review in elderly patients in order to determine the utility and results of video-EEG monitoring. All patients admitted to the epilepsy monitoring unit at Columbia-Presbyterian Medical Center from January 21, 1991 to April 12, 1999 aged 60 years and older were reviewed. Reasons for admission included diagnosis of paroxysmal events, further characterization of known seizure, pre-surgical evaluation, medication adjustment or toxicity, and evaluation to rule out non-convulsive status epilepticus or subclinical seizures. Ninety-four patients were identified with 99 admissions, with five patients having two separate admissions, comprising 8% of all admissions. There were 62 females and 37 males. On average, patients were 70 years old and ranged from 60-94. The mean length of the stay was 3.8 days and ranged from 1-14 days. The most common reason for admission was to diagnose the nature of paroxysmal events (56%). A total of 118 epileptic seizures were recorded in 46 patients. Ninety-eight non-epileptic events were recorded in 27 patients. Both epileptic seizures and non-epileptic events were found in four patients. Of those with non-epileptic events, 13 patients had psychogenic seizures. There were epileptiform discharges in 26% of patients with non-epileptic events and 76% of patients with epileptic events had interictal epileptiform discharges. The authors concluded that in the majority of patients, video-EEG monitoring in elderly patients led to a definitive diagnosis. Also, they concluded that nonepileptic events are common in the elderly, including PNES, and are often misdiagnosed and mistreated as epileptic seizures [15]. Abubakr et al performed a retrospective chart review study to report the results of video/EEG recordings in patients aged 60 and older at the new Jersey Neuroscience Institute. An electronic medical record search between December 1999 and December 2001 was reviewed for all elderly patients admitted to the epilepsy monitoring unit (EMU) found 58 patients who underwent video/EEG. The elderly population accounted for 17% of EMU admissions. The reasons for video/EEG monitoring for study patients were diagnosis of events (33 patients, 57%), characterization and localization of seizure (21 patients, 36%), adjustment of medication (2 patients, 3%), and non-convulsive status epilepticus (2 patients, 3%). Study subjects were ranged between 60-91 years old and 45% were females. Six

*2.1.1. Psychogenic non-epileptic seizures in women*

*2.1.2. Pseudoseizures in the elderly*

#### **2.1. Psychogenic non-epileptic seizures in different population subgroups**

#### *2.1.1. Psychogenic non-epileptic seizures in women*

by Sigurdardottir et al. Sigurdardottir and colleagues conducted a retrospective chart review of all long-term video EEG studies made in Iceland from January 1992 to December 1996 in order to determine the incidence of PNES. All patients were aged 15 or greater and had been diagnosed with PNES at National University Hospital (Landspitalinn), Iceland. The diagnosis of PNES was determined by clinical observation and EEG, and all of these patients underwent long-term video-EEG monitoring (LVEM). A total of 14 patients met the inclusion criteria and were aged 16-54 years (mean 27.6). There were 11 female patients (78.6%). There was an average annual population of 200,191 persons aged 15 years or greater for a total of 1,000,955 persons over the entire study period. The incidence of PNES was 1.4 in a 100,000 population. The 15-24 year old age group had the highest age-specific incidence. The incidence decreased in subsequent older age groups. Half of the patients (N=7) also had epilepsy, with the majority having generalized tonic-clonic seizures only (N=3), followed by Generalized tonic clonic seizures (GTC )and myoclonus (N=2), tonic seizures (N=1), and absences (N=1). 2 of 7 patients with PNES and without epilepsy were on antiepileptic drug (AED) treatment prior to PNES diagnosis. The researchers concluded that the incidence in people aged 15-24 years was ~5% of the incidence of epilepsy and 4% of reported epilepsy from Iceland for persons aged ≥15 years [8]. Szaflarski and colleagues conducted the retrospective study which determined the incidence of PNES in a medium-sized urban community. Adult patients who underwent prolonged video and EEG monitoring (PVEM) were identified between January 1, 1995 and December 30, 1998 at the University Hospital or Veteran Administration Medical Center in Cincinnati, OH. Patients were classified into four groups: definite PNES, possible PNES, possible epilepsy, and definite epilepsy. A board-certified electroencephalographer reviewed all tracings and videos. Population characteristics were examined with univariate analysis and comparison of similar features between patients with PNES and those with epilepsy were analyzed with bivariate analysis. During the study period, 600 patients were monitored with 3 patients at the Veteran Affairs Medical Center and 174 at the University of Ohio fulfilling the residence criteria. Definite PNES was diagnosed in 77 patients and definite epilepsy was diagnosed in 85 patients. Also, there was an increase in the incidence of PNES over the study from 1.88/100,000 in 1995 to 4.6/100,000 in 1998 (mean incidence 3.03/100,000). Patients aged 25-45 years had the highest incidence of PNES (4.38/100,000). Groups of patients with PNES had a shorter average duration of illness before diagnosis and were more likely to have a history of psychiatric disorders (48.6% versus 30.4%; p=0.023) than definite epilepsy patients. Epilepsy patients were more likely to be treated with more antiepileptic drugs before admis‐ sion than PNES (4.85 versus 2.53; p <0.001). No significant differences were found in the PNES compared with epilepsy groups in gender (women 73% versus 60%), age (37.2 versus 37 years), or history of febrile seizures, head trauma, or family history of epilepsy. The authors conclude that improved access to PVEM and higher clinician awareness may be related to the increasing

174 Epilepsy Topics

incidence of PNES over the study period [9].

Psychogenic seizures are more common in women. Women account for approximately 70 to 80% incidence of PNES, but the incidence varies depending on the etiology [6,10, 11,12]. There are certain factors that contribute to the increase risk of PNES. The most important factor is the history of sexual abuse seen more commonly in women. This issue has also been addressed historically by Freud based on his observations. Freud's earlier observations describe Hysteria which is now the basis of the concept of psychogenic non-epileptic seizures. Hysteria is a Greek word which means "wandering uterus" and is related to history of sexual abuse in women and repressed sexual drives [13,14]. Alper and colleagues in a case series described the history of sexual abuse in approximately 25% of the patients with PNES [12].

#### *2.1.2. Pseudoseizures in the elderly*

There are several studies which show the prevalence of pseudoseizures in the elderly. McBride et al performed a retrospective chart review in elderly patients in order to determine the utility and results of video-EEG monitoring. All patients admitted to the epilepsy monitoring unit at Columbia-Presbyterian Medical Center from January 21, 1991 to April 12, 1999 aged 60 years and older were reviewed. Reasons for admission included diagnosis of paroxysmal events, further characterization of known seizure, pre-surgical evaluation, medication adjustment or toxicity, and evaluation to rule out non-convulsive status epilepticus or subclinical seizures. Ninety-four patients were identified with 99 admissions, with five patients having two separate admissions, comprising 8% of all admissions. There were 62 females and 37 males. On average, patients were 70 years old and ranged from 60-94. The mean length of the stay was 3.8 days and ranged from 1-14 days. The most common reason for admission was to diagnose the nature of paroxysmal events (56%). A total of 118 epileptic seizures were recorded in 46 patients. Ninety-eight non-epileptic events were recorded in 27 patients. Both epileptic seizures and non-epileptic events were found in four patients. Of those with non-epileptic events, 13 patients had psychogenic seizures. There were epileptiform discharges in 26% of patients with non-epileptic events and 76% of patients with epileptic events had interictal epileptiform discharges. The authors concluded that in the majority of patients, video-EEG monitoring in elderly patients led to a definitive diagnosis. Also, they concluded that nonepileptic events are common in the elderly, including PNES, and are often misdiagnosed and mistreated as epileptic seizures [15]. Abubakr et al performed a retrospective chart review study to report the results of video/EEG recordings in patients aged 60 and older at the new Jersey Neuroscience Institute. An electronic medical record search between December 1999 and December 2001 was reviewed for all elderly patients admitted to the epilepsy monitoring unit (EMU) found 58 patients who underwent video/EEG. The elderly population accounted for 17% of EMU admissions. The reasons for video/EEG monitoring for study patients were diagnosis of events (33 patients, 57%), characterization and localization of seizure (21 patients, 36%), adjustment of medication (2 patients, 3%), and non-convulsive status epilepticus (2 patients, 3%). Study subjects were ranged between 60-91 years old and 45% were females. Six patients had psychogenic non-epileptic seizures (PNES), with five of them being women and 4 of them being greater than 70 years old. One patient presented with abdominal spasms and the others with motor symptoms. Two of six patients had a suspected diagnosis of PNES on admission. Physiologic non-epileptic seizure was the most common diagnosis and occurred in 26 patients (45%). The diagnosis of non-epileptic seizures in 27% of these patients resulted in AED discontinuation. The most common seizure type was complex partial seizures and occurred in 23 patients (40%). Six of these patients had both complex partial seizures and secondary generalization. The authors concluded that in the majority of cases, video/EEG monitoring in the elderly results in a definitive diagnosis and assists physicians with antiepi‐ leptic drug therapy management decisions [16]. Kawai et al conducted a retrospective review of video-EEG monitoring in geriatric veterans from 1999 to 2006. All patients admitted to the epilepsy monitoring unit at Michael E. DeBakey Veterans Affairs Medical Center of Houston, Texas were reviewed. Of the 440 admissions during this time, 71 of these patients were aged 60 and older, which included multiple admissions. Ninety-four percent of these were males, and the average age was 68 years. The mean duration of monitoring studies was 73.7 hours (range 2-96 hrs). Thirty-four of 71 patients (48%) had typical events, including 12 with epileptic events (35%). Nine patients (75%) had temporal lobe seizures, 2 patients (17%) had extratem‐ poral seizures, and 1 patient (8.3%) had poorly localized seizures. The most common etiology was not identifiable (7 patients), and intracranial hemorrhage and history of tumor resection (2 patients). Non-epileptic events were seen in 22 of 71 patients (65%). Ten patients (45%) had PNES and 12 patients (55%) had physiologic non-epileptic seizures. Of the patients with nonepileptic seizures, 14 of 22 (65%) were on AEDs before video-EEG monitoring with 6 having PNES and 8 having physiologic non-epileptic seizures. The authors concluded that video-EEG monitoring in elderly patients was useful to guide physicians to the appropriate diagnosis and treatment of paroxysmal seizure-like symptoms [17].

anxiety disorders and mood disorders [19,21]. The differential diagnosis of PNES is broad and includes frontal lobe seizures, vasovagal syncope with anoxic seizures, breath- holding spells, self-stimulatory behavior, gastroesophageal reflux, stereotypes, complex motor tics, parasom‐

Psychogenic Non-Epileptic Spells http://dx.doi.org/10.5772/57440 177

PNES should be strongly suspected when there are atypical clinical features, poor response to medications in spite of adequate trials and when several routine electroencephalograms have been reported within normal limits [22]. Metrick et al conducted a retrospective chart review and analyzed the records of children referred for the treatment of intractable epilepsy. A total of 222 records were found for children aged <16 years admitted to the MINCEP Epilepsy Program for Children in St. Paul, Minnesota for evaluation and treatment of refractory seizures between August 1986 and August 1988. Children with normal and abnormal intelligence were included. All children had at least 24 hours of video-EEG monitoring. Of the 222 children admitted, 27 patients (12%) had non-epileptic events on video-EEG monitoring. Study subjects were aged 7 months to 16 years (median 8.4 years) with 18 females. The study called these 4 different group pure psychogenic events (5 patients), psychogenic events plus epileptic seizures (3 patients), pure non-epileptic physiologic events (5 patients), and non-epileptic physiologic events plus seizures (14 patients). Parents or caretakers identified a history of multiple seizure types in all groups except the children with pure psychogenic seizures. Twenty-two patients (64%) had a history of status epilepticus. Twenty-five of 27 patients had a history of interictal epileptiform abnormalities on previous routine EEGs. Eight patients (30%) had their AEDs completely discontinued after the non-epileptic events were identified. Nine other patients (33%) were able to reduce the number of AEDs in the treatment regimen. The researchers concluded that in all children with refractory seizures or multiple seizure types a diagnosis of non-epileptic events should be considered [23]. Prolonged video electroence‐ phalogram is the gold standard for diagnosis and an effort should be made to capture the typical spells that may occur spontaneously or induced by provocative measures. Definite diagnosis is made when several episodes are captured which are not associated with abnormal EEG changes. Careful consideration must be given to the fact that lack of epileptic changes in the electroencephalogram does not conclusively indicate that the episode is PNES. Frontal lobe seizures and some complex motor seizures originating from deep seated focus may manifest motor activity and normal electroencephalograms resembling PNES. Prolonged video electroencephalograms capturing several typical events may be required to make the correct diagnosis. Measuring serum prolactin levels to distinguish PNES from epileptic seizures is not routinely used in children and may have several limitations. Once the diagnosis is established, information needs to be conveyed to the family and patient in a non-judgmental tactful manner and patient needs to be referred to a mental health specialist to determine appropriate therapy which include counseling and if required psychotropic medication to treat co-morbid condi‐ tions. Prognosis in children is much better than in adults and a significant percentage were

nias, paroxysmal kinesigenic and non-kinesigenic dyskinesias.

PNES free several years after the diagnosis was made [22,24].

#### *2.1.3. Psychogenic Non-Epileptic Seizures (PNES) in children*

Psychogenic non epileptic seizures (PNES) in children are transient, episodic alterations in behavior that mimic true epileptic seizures but without abnormal electrical discharges. PNES was found in 3.5 % [18] in one study and 7% [19] in another study in children that were evaluated in neurology clinics for persistent seizures. There is a paucity of literature regarding this entity in children and adolescents. In most cases, there is delay in the diagnosis of months [11,18,20]. During the delay, patients are labeled as being epileptic and are usually started on antiepileptic medication. Poor response to the medication and frequent visits to the emergency room are common. The cost of misdiagnosing PNES as epileptic seizures is very high from economic and psychosocial aspects. The distinction of PNES from epileptic seizures is difficult to be made solely on clinical grounds. The clinical manifestations of PNES vary according to age as reported by some investigators. Younger children tend to manifest more subtle motor activity which includes eye fluttering, head shaking, staring, unresponsiveness and limpness. In contrast, adolescents tend to manifest prominent motor activity which includes side to side head movements, thrashing or flailing movements of the extremities, generalized arrhythmical jerking and pelvic thrusting [11]. Triggering factors include school phobia, familial problems, social difficulties with peers or friends and sexual abuse [18,20]. Comorbid conditions include anxiety disorders and mood disorders [19,21]. The differential diagnosis of PNES is broad and includes frontal lobe seizures, vasovagal syncope with anoxic seizures, breath- holding spells, self-stimulatory behavior, gastroesophageal reflux, stereotypes, complex motor tics, parasom‐ nias, paroxysmal kinesigenic and non-kinesigenic dyskinesias.

patients had psychogenic non-epileptic seizures (PNES), with five of them being women and 4 of them being greater than 70 years old. One patient presented with abdominal spasms and the others with motor symptoms. Two of six patients had a suspected diagnosis of PNES on admission. Physiologic non-epileptic seizure was the most common diagnosis and occurred in 26 patients (45%). The diagnosis of non-epileptic seizures in 27% of these patients resulted in AED discontinuation. The most common seizure type was complex partial seizures and occurred in 23 patients (40%). Six of these patients had both complex partial seizures and secondary generalization. The authors concluded that in the majority of cases, video/EEG monitoring in the elderly results in a definitive diagnosis and assists physicians with antiepi‐ leptic drug therapy management decisions [16]. Kawai et al conducted a retrospective review of video-EEG monitoring in geriatric veterans from 1999 to 2006. All patients admitted to the epilepsy monitoring unit at Michael E. DeBakey Veterans Affairs Medical Center of Houston, Texas were reviewed. Of the 440 admissions during this time, 71 of these patients were aged 60 and older, which included multiple admissions. Ninety-four percent of these were males, and the average age was 68 years. The mean duration of monitoring studies was 73.7 hours (range 2-96 hrs). Thirty-four of 71 patients (48%) had typical events, including 12 with epileptic events (35%). Nine patients (75%) had temporal lobe seizures, 2 patients (17%) had extratem‐ poral seizures, and 1 patient (8.3%) had poorly localized seizures. The most common etiology was not identifiable (7 patients), and intracranial hemorrhage and history of tumor resection (2 patients). Non-epileptic events were seen in 22 of 71 patients (65%). Ten patients (45%) had PNES and 12 patients (55%) had physiologic non-epileptic seizures. Of the patients with nonepileptic seizures, 14 of 22 (65%) were on AEDs before video-EEG monitoring with 6 having PNES and 8 having physiologic non-epileptic seizures. The authors concluded that video-EEG monitoring in elderly patients was useful to guide physicians to the appropriate diagnosis and

Psychogenic non epileptic seizures (PNES) in children are transient, episodic alterations in behavior that mimic true epileptic seizures but without abnormal electrical discharges. PNES was found in 3.5 % [18] in one study and 7% [19] in another study in children that were evaluated in neurology clinics for persistent seizures. There is a paucity of literature regarding this entity in children and adolescents. In most cases, there is delay in the diagnosis of months [11,18,20]. During the delay, patients are labeled as being epileptic and are usually started on antiepileptic medication. Poor response to the medication and frequent visits to the emergency room are common. The cost of misdiagnosing PNES as epileptic seizures is very high from economic and psychosocial aspects. The distinction of PNES from epileptic seizures is difficult to be made solely on clinical grounds. The clinical manifestations of PNES vary according to age as reported by some investigators. Younger children tend to manifest more subtle motor activity which includes eye fluttering, head shaking, staring, unresponsiveness and limpness. In contrast, adolescents tend to manifest prominent motor activity which includes side to side head movements, thrashing or flailing movements of the extremities, generalized arrhythmical jerking and pelvic thrusting [11]. Triggering factors include school phobia, familial problems, social difficulties with peers or friends and sexual abuse [18,20]. Comorbid conditions include

treatment of paroxysmal seizure-like symptoms [17].

176 Epilepsy Topics

*2.1.3. Psychogenic Non-Epileptic Seizures (PNES) in children*

PNES should be strongly suspected when there are atypical clinical features, poor response to medications in spite of adequate trials and when several routine electroencephalograms have been reported within normal limits [22]. Metrick et al conducted a retrospective chart review and analyzed the records of children referred for the treatment of intractable epilepsy. A total of 222 records were found for children aged <16 years admitted to the MINCEP Epilepsy Program for Children in St. Paul, Minnesota for evaluation and treatment of refractory seizures between August 1986 and August 1988. Children with normal and abnormal intelligence were included. All children had at least 24 hours of video-EEG monitoring. Of the 222 children admitted, 27 patients (12%) had non-epileptic events on video-EEG monitoring. Study subjects were aged 7 months to 16 years (median 8.4 years) with 18 females. The study called these 4 different group pure psychogenic events (5 patients), psychogenic events plus epileptic seizures (3 patients), pure non-epileptic physiologic events (5 patients), and non-epileptic physiologic events plus seizures (14 patients). Parents or caretakers identified a history of multiple seizure types in all groups except the children with pure psychogenic seizures. Twenty-two patients (64%) had a history of status epilepticus. Twenty-five of 27 patients had a history of interictal epileptiform abnormalities on previous routine EEGs. Eight patients (30%) had their AEDs completely discontinued after the non-epileptic events were identified. Nine other patients (33%) were able to reduce the number of AEDs in the treatment regimen. The researchers concluded that in all children with refractory seizures or multiple seizure types a diagnosis of non-epileptic events should be considered [23]. Prolonged video electroence‐ phalogram is the gold standard for diagnosis and an effort should be made to capture the typical spells that may occur spontaneously or induced by provocative measures. Definite diagnosis is made when several episodes are captured which are not associated with abnormal EEG changes. Careful consideration must be given to the fact that lack of epileptic changes in the electroencephalogram does not conclusively indicate that the episode is PNES. Frontal lobe seizures and some complex motor seizures originating from deep seated focus may manifest motor activity and normal electroencephalograms resembling PNES. Prolonged video electroencephalograms capturing several typical events may be required to make the correct diagnosis. Measuring serum prolactin levels to distinguish PNES from epileptic seizures is not routinely used in children and may have several limitations. Once the diagnosis is established, information needs to be conveyed to the family and patient in a non-judgmental tactful manner and patient needs to be referred to a mental health specialist to determine appropriate therapy which include counseling and if required psychotropic medication to treat co-morbid condi‐ tions. Prognosis in children is much better than in adults and a significant percentage were PNES free several years after the diagnosis was made [22,24].

#### *2.1.4. Patients with dual diagnosis of both seizures and Psychogenic Non-Epileptic Seizures*

The most complicated patients are those who have both epilepsy and Psychogenic nonepileptic seizures. The gold standard remains prolonged video–EEG monitoring in an epilepsy monitoring unit to characterize all events for definite diagnosis. Ten to 40 % patients with PNES also have true epilepsy as reported in the literature [25-29]. Interictal EEG abnormalities have also been reported in patients with PNES but they should not be interpreted as evidence of epilepsy [30].

(N=3, 28.4%). Concurrent psychological disorders were seen in 12 of 14 patients, including depression (64%), anxiety (50%), and physical/sexual abuse (29%). On average, study patients were on 2.6 AEDs (range 1-5) and had failed 2.1 AEDs (range 0-9). Eleven patients (78.6%) improved with regular counseling. Three patients (21.4%) with mental retardation did not show improvement with regular counseling. The authors concluded that video-EEG moni‐ toring is helpful to characterize increased frequency and new episode characterizations as well as the need for a multidisciplinary team approach between neurologists, epileptologists, psychiatrists, and psychologists to best manage these patients [33]. The reason for dual diagnosis is the development of psychiatric problems in patients with chronic long standing epilepsy or the presence of concomitant psychiatric disorders [34]. Most of the patients generally have fairly well controlled epilepsy when they develop PNES but still represent a

Psychogenic Non-Epileptic Spells http://dx.doi.org/10.5772/57440 179

difficult group of patients regarding management [35,36].

daily spells to several times a week [39].

**3. Clinical semiology of Psychogenic Non-Epileptic Seizures**

eye opening and closure as these will all help in establishing the correct diagnosis.

Careful history plays a key role in the diagnosis of non-epileptic events. The history should include the seizure triggers and careful history of the semiology of the seizures from the witness. The history should also include the duration, alteration of consciousness, type of convulsive movements experienced during a seizure, presence or absence of tongue bite, urinary incontinence, autonomic symptoms, emotional symptoms like weeping or crying and

The PNES usually occur in front of the witness or in a clinical setting [37]. The PNES occur during daytime but not during sleep. Presence of nocturnal events raise suspicion for epileptic rather than nonepileptic seizures [38]. The other finding is the frequency of seizures. Nonepileptic seizures are more common than epileptic seizures and frequency may range from

Ictal features of PNES include purposeful or semipurposeful movements, thrashing, writhing, side-to-side head jerking and pelvic thrusting which are different from synchronized tonic – clonic activity in true epileptic seizures [38-40]. Leis and colleagues conducted a retrospective chart review study to analyze ictal features in patients with psychogenic seizures undergoing video-EEG monitoring. At the Epilepsy Unit of University of Iowa, 254 patients were moni‐ tored, and 47 (18%) had psychogenic seizures and videotaped recordings to analyze their typical events. Twenty-seven patients were female (57%) and 20 were men (43%). There was a mixed seizure disorder in 11 of 47 patients (23%). The most common ictal presentation was unresponsiveness without predominant motor manifestations. The motor characteristics of out-of-phase limb movements, side-to-side head movements, and pelvic thrusting had been previously considered to distinguish psychogenic seizures, they were observed infrequently (19%, 15%, and 8% respectively). Antiepileptic drug therapy was administered to 35 patients (74%) for their spells. Of these 35 patients, 25 (69%) had pure psychogenic seizures. Six of these 25 patients (4 women, mean age 27 years) with pure psychogenic seizures were treated pharmacologically for status epilepticus entirely due to observation without even a cursory

Benbadis and colleagues performed a retrospective chart review study to determine the proportion of patients with psychogenic non-epileptic seizures (PNES) who also have evidence of epilepsy. The authors reviewed all adult patients with PNES who underwent EEG-video monitoring from January 1 to December 31, 1999. Patients were excluded if their episodes mimicked simple partial seizures or if they had a loss of consciousness. One or both boardcertified electroencephalographers determined if there was evidence for epilepsy defined by epileptiform discharges, including sharp waves or spikes, spike-wave complexes, polyspikes, or any ictal pattern. Over this one-year period, 211 patients were monitored and 32 patients (15%) were diagnosed with PNES. Study patients mean age was 33.8 (range 19-72) and 20 (62%) were females. Three patients (9.4%) of the 32 patients with PNES had interictal epileptiform discharges, 20 (62%) had completely normal EEG, 6 (19%) had normal variants (three wicket spikes, three small sharp spikes), and 3 (9.4%) had mild nonspecific abnormalities (mild slowing or asymmetry). The three patients were on lower doses or no antiepileptic drugs. The authors concluded that epilepsy coexists with PNES in a small portion of patients [31]. Martin et al conducted a retrospective study to examine the frequency of epilepsy in patients with a definitive diagnosis of PNES by video-EEG monitoring from July 1, 1998 to December 31, 2002. All patients consecutively admitted to the video-EEG monitoring unit at the University of Alabama at Birmingham Hospital were reviewed. Patients were referred for characterization of paroxysmal events for undiagnosed events with uncertainty of epileptic seizures versus psychogenic evens, probable epileptic seizures with classification of seizure type, or probable epileptic seizures with localization of seizures for possible surgery. This was the first video-EEG monitoring for all patients with the average duration of 3 days (range 1-7 days). A total of 1,590 patients received a definitive diagnosis and were included in the study of 2,007 patients receiving video-EEG monitoring. PNES was diagnosed in 514 patients (32.3%) with 29 of these patients (5.3%) having both PNES and epilepsy. Other than PNES, non-epileptic diagnoses occurred in 65 patients (3.2%), including sleep disorders, migraine, panic attacks, dysautono‐ mia, movement disorders, TIA, cough syncope, and vestibular symptoms. The authors concluded that in patients referred for video-EEG monitoring there is little overlap between epileptic seizures and PNES when strict diagnostic criteria are applied [32]. Kirmani et al conducted a retrospective chart review of all patients with epilepsy admitted to the Scott and White Hospital epilepsy monitoring unit in Temple, TX from 2008-2011. Fourteen patients who were admitted to the EMU due to increased frequency of seizures or for characterization of new kinds of spells were found to have epilepsy and concomitant PNES. The mean age of study patients was 43 years (range 21-67 years) with 10 females (71.5%) and four males (28.5%). The majority of patients had partial epilepsy (N=11, 78.6%) followed by generalized epilepsy (N=3, 28.4%). Concurrent psychological disorders were seen in 12 of 14 patients, including depression (64%), anxiety (50%), and physical/sexual abuse (29%). On average, study patients were on 2.6 AEDs (range 1-5) and had failed 2.1 AEDs (range 0-9). Eleven patients (78.6%) improved with regular counseling. Three patients (21.4%) with mental retardation did not show improvement with regular counseling. The authors concluded that video-EEG moni‐ toring is helpful to characterize increased frequency and new episode characterizations as well as the need for a multidisciplinary team approach between neurologists, epileptologists, psychiatrists, and psychologists to best manage these patients [33]. The reason for dual diagnosis is the development of psychiatric problems in patients with chronic long standing epilepsy or the presence of concomitant psychiatric disorders [34]. Most of the patients generally have fairly well controlled epilepsy when they develop PNES but still represent a difficult group of patients regarding management [35,36].

#### **3. Clinical semiology of Psychogenic Non-Epileptic Seizures**

*2.1.4. Patients with dual diagnosis of both seizures and Psychogenic Non-Epileptic Seizures*

epilepsy [30].

178 Epilepsy Topics

The most complicated patients are those who have both epilepsy and Psychogenic nonepileptic seizures. The gold standard remains prolonged video–EEG monitoring in an epilepsy monitoring unit to characterize all events for definite diagnosis. Ten to 40 % patients with PNES also have true epilepsy as reported in the literature [25-29]. Interictal EEG abnormalities have also been reported in patients with PNES but they should not be interpreted as evidence of

Benbadis and colleagues performed a retrospective chart review study to determine the proportion of patients with psychogenic non-epileptic seizures (PNES) who also have evidence of epilepsy. The authors reviewed all adult patients with PNES who underwent EEG-video monitoring from January 1 to December 31, 1999. Patients were excluded if their episodes mimicked simple partial seizures or if they had a loss of consciousness. One or both boardcertified electroencephalographers determined if there was evidence for epilepsy defined by epileptiform discharges, including sharp waves or spikes, spike-wave complexes, polyspikes, or any ictal pattern. Over this one-year period, 211 patients were monitored and 32 patients (15%) were diagnosed with PNES. Study patients mean age was 33.8 (range 19-72) and 20 (62%) were females. Three patients (9.4%) of the 32 patients with PNES had interictal epileptiform discharges, 20 (62%) had completely normal EEG, 6 (19%) had normal variants (three wicket spikes, three small sharp spikes), and 3 (9.4%) had mild nonspecific abnormalities (mild slowing or asymmetry). The three patients were on lower doses or no antiepileptic drugs. The authors concluded that epilepsy coexists with PNES in a small portion of patients [31]. Martin et al conducted a retrospective study to examine the frequency of epilepsy in patients with a definitive diagnosis of PNES by video-EEG monitoring from July 1, 1998 to December 31, 2002. All patients consecutively admitted to the video-EEG monitoring unit at the University of Alabama at Birmingham Hospital were reviewed. Patients were referred for characterization of paroxysmal events for undiagnosed events with uncertainty of epileptic seizures versus psychogenic evens, probable epileptic seizures with classification of seizure type, or probable epileptic seizures with localization of seizures for possible surgery. This was the first video-EEG monitoring for all patients with the average duration of 3 days (range 1-7 days). A total of 1,590 patients received a definitive diagnosis and were included in the study of 2,007 patients receiving video-EEG monitoring. PNES was diagnosed in 514 patients (32.3%) with 29 of these patients (5.3%) having both PNES and epilepsy. Other than PNES, non-epileptic diagnoses occurred in 65 patients (3.2%), including sleep disorders, migraine, panic attacks, dysautono‐ mia, movement disorders, TIA, cough syncope, and vestibular symptoms. The authors concluded that in patients referred for video-EEG monitoring there is little overlap between epileptic seizures and PNES when strict diagnostic criteria are applied [32]. Kirmani et al conducted a retrospective chart review of all patients with epilepsy admitted to the Scott and White Hospital epilepsy monitoring unit in Temple, TX from 2008-2011. Fourteen patients who were admitted to the EMU due to increased frequency of seizures or for characterization of new kinds of spells were found to have epilepsy and concomitant PNES. The mean age of study patients was 43 years (range 21-67 years) with 10 females (71.5%) and four males (28.5%). The majority of patients had partial epilepsy (N=11, 78.6%) followed by generalized epilepsy

Careful history plays a key role in the diagnosis of non-epileptic events. The history should include the seizure triggers and careful history of the semiology of the seizures from the witness. The history should also include the duration, alteration of consciousness, type of convulsive movements experienced during a seizure, presence or absence of tongue bite, urinary incontinence, autonomic symptoms, emotional symptoms like weeping or crying and eye opening and closure as these will all help in establishing the correct diagnosis.

The PNES usually occur in front of the witness or in a clinical setting [37]. The PNES occur during daytime but not during sleep. Presence of nocturnal events raise suspicion for epileptic rather than nonepileptic seizures [38]. The other finding is the frequency of seizures. Nonepileptic seizures are more common than epileptic seizures and frequency may range from daily spells to several times a week [39].

Ictal features of PNES include purposeful or semipurposeful movements, thrashing, writhing, side-to-side head jerking and pelvic thrusting which are different from synchronized tonic – clonic activity in true epileptic seizures [38-40]. Leis and colleagues conducted a retrospective chart review study to analyze ictal features in patients with psychogenic seizures undergoing video-EEG monitoring. At the Epilepsy Unit of University of Iowa, 254 patients were moni‐ tored, and 47 (18%) had psychogenic seizures and videotaped recordings to analyze their typical events. Twenty-seven patients were female (57%) and 20 were men (43%). There was a mixed seizure disorder in 11 of 47 patients (23%). The most common ictal presentation was unresponsiveness without predominant motor manifestations. The motor characteristics of out-of-phase limb movements, side-to-side head movements, and pelvic thrusting had been previously considered to distinguish psychogenic seizures, they were observed infrequently (19%, 15%, and 8% respectively). Antiepileptic drug therapy was administered to 35 patients (74%) for their spells. Of these 35 patients, 25 (69%) had pure psychogenic seizures. Six of these 25 patients (4 women, mean age 27 years) with pure psychogenic seizures were treated pharmacologically for status epilepticus entirely due to observation without even a cursory neurologic exam or chart review. Aggressive treatment of status epilepticus in 1 patient escalated to the point of respiratory arrest in 1 woman who was 2 months pregnant. A psychogenic cause to these spells was not considered in the differential diagnosis until all the patients failed to respond to pharmacologic treatment. The authors concluded that in treatment of seizures, even in the acute care of presumed status epilepticus, the diagnosis must not be based solely on inspection and should be supported by the history and physical examination findings [41]. The other study which provided detailed semiology of PNES was conducted by Seneviratne and colleagues. Seneviratne et al conducted a retrospective study of the semiology of PNES captured by video-EEG monitoring and categorize the observed patterns. From January 2002 to June 2007 the medical records were reviewed of all adult patients who underwent monitoring (mean 3, range 1-8 days) at two tertiary care epilepsy centers. Patients with PNES and no background of epilepsy were selected for the study. Sixty-one patients were identified with 330 PNES events with a mean number of 5 events recorded per patient. There were 45 females and 16 males with a mean age of 38 years (range: 16-83 years). Three types of motor manifestations were detailed on visual analysis of PNES events. 1) Rhythmic Motor PNES: 47.6% of all PNES events, rhythmic tremor, trembling, or rigor like movements of the upper limbs more commonly than the lower limbs. 2) Hypermotor PNES: 3.3 % of all PNES events had hyperkinetic or hypermotor movements with violent thrashing, punching or kicking involving the extremities or trunk. 3) Complex Motor PNES: 10% of all PNES events had complex motor movements with complex and multifocal asymmetrical movements of both proximal and distal extremities with flexion, extension, and ab/adduction. 4) Dialeptic PNES: 11.2% of all PNES events had prolonged, motionless, unresponsive patients with no motor manifestations who appeared to be in a coma-like state unresponsive to external stimuli. 5) Nonepileptic auras: 23.6% of all PNES events had various subjective sensations without any external manifestations described by the patients as "I feel weird", "zoning out", and "I am going through a trance". 6) Mixed PNES: 5.2% of all PNES events had a combination of types 1-5. Eighty-two percent of cases had the same semiologic type in a given patient. The authors concluded that the PNES patients they studied had highly stereotypic events within and across individual patients [42].

ty of 98.1%) of ictal eye closure indicating a high likelihood of PNES. Conversely, true epileptic seizures had an ictal eye opening and had a high positive predictive value of 0.987 (sensitivity 98.1% and specificity 96.2%). Thus the authors concluded that careful history taking of seizure semiology may help discern between ES and PNES and home video clips of a seizure may help to make the diagnosis without long-term monitoring [44]. Autonom‐ ic symptoms are absent in PNES but weeping, ictal stuttering, partial preservation of

Psychogenic Non-Epileptic Spells http://dx.doi.org/10.5772/57440 181

The evaluation and diagnosis of PNES requires careful history and diagnostic testing. Ali et al conducted a literature review of PNES to make suggestions for treatment and to aid clinicians in identifying PNES episodes. The mean time between developing clinical symptoms and establishing a correct diagnosis of PNES is 7.2 years. Physicians can facilitate early diagnosis by referring patients with atypical features for video-EEG monitoring. General features that can raise a physician's suspicions include high seizure frequency with multiple emergency room visits, association with multiple other psychiatric disorders, comorbid personality disorders, abuse history, lack of response with treatment, and lack of loss of control over bladder or bowl during episodes. PNES pre-ictal features include pseudo sleep, which shows a sensitivity of 56% and specificity of 100% for pseudoseizure. PNES events typically are witnessed and begin gradually at time of stress or visual/auditory stimuli. Ictal features of PNES include asynchronous contractions, non-stereotypic movements that change during the episode, and a lack of rapid contractions with slow relaxation pattern seen in true epileptic clonic seizures. Patients may exhibit side-to-side head movements, forceful eye closure, and ictal vocalizations. Post-ictal features are easy to recognize, and physicians should watch for a short duration (~1 minute) shallow, irregular, and quiet breathing pattern, as well as the absence of confusion, headache, and fatigue. Lab findings that are not present after PNES episodes but are present after epileptic seizures are elevated serum prolactin, creatine kinase, ammonia, and white blood cell count. Video-EEG is highly recommended for patients with atypical features and in one study found that 24 percent of subjects had been misdiagnosed with epilepsy that had an accurate diagnosis of PNES. When a patient is informed of their diagnosis, the should be referred to a psychiatrist for treatment and neurologists remove AEDs, but the complete care away from neurology until the spells have decreased. The authors believe this is due to the disruption of the rapport that neurologists have with the patient, negatively affects the outcome of PNES, and premature discharge to psychiatry may increase patient resistance to accept the diagnosis. Predictors of good outcome include shorter duration of spells, presentation in children and adolescents, mild psychiatric history, identifiable acute psychological trauma, and independent living. The authors conclude that skilled clinicians can make a diagnosis based on clinical findings and their guidance can be used to help clinicians

consciousness and later recall of the ictal event also suggest PNES [38,45,46]).

**4. Diagnosis of Psychogenic Non-Epileptic Seizures**

make the diagnosis of PNES [47].

The other features including clenched mouth during a tonic seizure and injuries on the tip of the tongue rather than the sides points towards the diagnosis of PNES [43]. Ictal eye closure is also considered a sign of a psychogenic event [43,44]. Chung et al conducted a retrospective study of video-EEG monitoring data to study whether persistent ictal eye opening and closure was reliable to differentiate between ES and PNES. From July 2003 to June 2004, 234 consecutive patients (age 6-65 years) underwent long-term video-scalp EEG monitoring at the Barrow Neurologic Institute. 221 patients had a total of 938 ictal events (median number of seizures per patient=4). Fifty-two of 221 patients (23.5%) had PNES and 156 (70.6%) had ES. Seventy-five percent of patients with PNES were female. During habitual seizures, 50 of 52 PNES patients consistently closed their eyes for the entire duration of the seizure and a few who closed their eyes forcefully with facial frowning. However, 152 of 156 patients with ES had their eyes deviated to one side or were open. Rhythmic eye blinking was seen during tonic-clonic activity, followed be postictal confusion with eye closure. There was a positive predictive value of 0.943 (sensitivity of 96.2% and specifici‐ ty of 98.1%) of ictal eye closure indicating a high likelihood of PNES. Conversely, true epileptic seizures had an ictal eye opening and had a high positive predictive value of 0.987 (sensitivity 98.1% and specificity 96.2%). Thus the authors concluded that careful history taking of seizure semiology may help discern between ES and PNES and home video clips of a seizure may help to make the diagnosis without long-term monitoring [44]. Autonom‐ ic symptoms are absent in PNES but weeping, ictal stuttering, partial preservation of consciousness and later recall of the ictal event also suggest PNES [38,45,46]).

#### **4. Diagnosis of Psychogenic Non-Epileptic Seizures**

neurologic exam or chart review. Aggressive treatment of status epilepticus in 1 patient escalated to the point of respiratory arrest in 1 woman who was 2 months pregnant. A psychogenic cause to these spells was not considered in the differential diagnosis until all the patients failed to respond to pharmacologic treatment. The authors concluded that in treatment of seizures, even in the acute care of presumed status epilepticus, the diagnosis must not be based solely on inspection and should be supported by the history and physical examination findings [41]. The other study which provided detailed semiology of PNES was conducted by Seneviratne and colleagues. Seneviratne et al conducted a retrospective study of the semiology of PNES captured by video-EEG monitoring and categorize the observed patterns. From January 2002 to June 2007 the medical records were reviewed of all adult patients who underwent monitoring (mean 3, range 1-8 days) at two tertiary care epilepsy centers. Patients with PNES and no background of epilepsy were selected for the study. Sixty-one patients were identified with 330 PNES events with a mean number of 5 events recorded per patient. There were 45 females and 16 males with a mean age of 38 years (range: 16-83 years). Three types of motor manifestations were detailed on visual analysis of PNES events. 1) Rhythmic Motor PNES: 47.6% of all PNES events, rhythmic tremor, trembling, or rigor like movements of the upper limbs more commonly than the lower limbs. 2) Hypermotor PNES: 3.3 % of all PNES events had hyperkinetic or hypermotor movements with violent thrashing, punching or kicking involving the extremities or trunk. 3) Complex Motor PNES: 10% of all PNES events had complex motor movements with complex and multifocal asymmetrical movements of both proximal and distal extremities with flexion, extension, and ab/adduction. 4) Dialeptic PNES: 11.2% of all PNES events had prolonged, motionless, unresponsive patients with no motor manifestations who appeared to be in a coma-like state unresponsive to external stimuli. 5) Nonepileptic auras: 23.6% of all PNES events had various subjective sensations without any external manifestations described by the patients as "I feel weird", "zoning out", and "I am going through a trance". 6) Mixed PNES: 5.2% of all PNES events had a combination of types 1-5. Eighty-two percent of cases had the same semiologic type in a given patient. The authors concluded that the PNES patients they studied had highly stereotypic events within and across

The other features including clenched mouth during a tonic seizure and injuries on the tip of the tongue rather than the sides points towards the diagnosis of PNES [43]. Ictal eye closure is also considered a sign of a psychogenic event [43,44]. Chung et al conducted a retrospective study of video-EEG monitoring data to study whether persistent ictal eye opening and closure was reliable to differentiate between ES and PNES. From July 2003 to June 2004, 234 consecutive patients (age 6-65 years) underwent long-term video-scalp EEG monitoring at the Barrow Neurologic Institute. 221 patients had a total of 938 ictal events (median number of seizures per patient=4). Fifty-two of 221 patients (23.5%) had PNES and 156 (70.6%) had ES. Seventy-five percent of patients with PNES were female. During habitual seizures, 50 of 52 PNES patients consistently closed their eyes for the entire duration of the seizure and a few who closed their eyes forcefully with facial frowning. However, 152 of 156 patients with ES had their eyes deviated to one side or were open. Rhythmic eye blinking was seen during tonic-clonic activity, followed be postictal confusion with eye closure. There was a positive predictive value of 0.943 (sensitivity of 96.2% and specifici‐

individual patients [42].

180 Epilepsy Topics

The evaluation and diagnosis of PNES requires careful history and diagnostic testing. Ali et al conducted a literature review of PNES to make suggestions for treatment and to aid clinicians in identifying PNES episodes. The mean time between developing clinical symptoms and establishing a correct diagnosis of PNES is 7.2 years. Physicians can facilitate early diagnosis by referring patients with atypical features for video-EEG monitoring. General features that can raise a physician's suspicions include high seizure frequency with multiple emergency room visits, association with multiple other psychiatric disorders, comorbid personality disorders, abuse history, lack of response with treatment, and lack of loss of control over bladder or bowl during episodes. PNES pre-ictal features include pseudo sleep, which shows a sensitivity of 56% and specificity of 100% for pseudoseizure. PNES events typically are witnessed and begin gradually at time of stress or visual/auditory stimuli. Ictal features of PNES include asynchronous contractions, non-stereotypic movements that change during the episode, and a lack of rapid contractions with slow relaxation pattern seen in true epileptic clonic seizures. Patients may exhibit side-to-side head movements, forceful eye closure, and ictal vocalizations. Post-ictal features are easy to recognize, and physicians should watch for a short duration (~1 minute) shallow, irregular, and quiet breathing pattern, as well as the absence of confusion, headache, and fatigue. Lab findings that are not present after PNES episodes but are present after epileptic seizures are elevated serum prolactin, creatine kinase, ammonia, and white blood cell count. Video-EEG is highly recommended for patients with atypical features and in one study found that 24 percent of subjects had been misdiagnosed with epilepsy that had an accurate diagnosis of PNES. When a patient is informed of their diagnosis, the should be referred to a psychiatrist for treatment and neurologists remove AEDs, but the complete care away from neurology until the spells have decreased. The authors believe this is due to the disruption of the rapport that neurologists have with the patient, negatively affects the outcome of PNES, and premature discharge to psychiatry may increase patient resistance to accept the diagnosis. Predictors of good outcome include shorter duration of spells, presentation in children and adolescents, mild psychiatric history, identifiable acute psychological trauma, and independent living. The authors conclude that skilled clinicians can make a diagnosis based on clinical findings and their guidance can be used to help clinicians make the diagnosis of PNES [47].

Prolonged video–EEG monitoring is now considered the gold standard. Additional studies include Single positron emission computed tomography (SPECT), saline provocation during video-EEG monitoring, serum prolactin levels, and neuropsychological testing.

**4.2. Role of additional diagnostic techniques in the evaluation of Psychogenic Non-Epileptic**

Psychogenic Non-Epileptic Spells http://dx.doi.org/10.5772/57440 183

Cragar et al conducted a literature review to analyze the possible alternatives to video-EEG for diagnosis of PNES. The literature was searched from 1967 through November 2001 using keywords in the PsychINFO database and were divided into 7 categories of alternative PNES diagnostic techniques: demographic/medical history variables, seizure semiology, provoca‐ tive testing, prolactin levels, single photon emission computed tomography (SPECT), psycho‐ logical testing, and neuropsychological testing. Medical history variables included history of abuse, psychiatric treatment history, frequency of seizures (not shown in four studies to have a significant difference between epilepsy an PNES groups), epileptic spells are more likely to occur during sleep and are more stereotyped, older age of onset and duration of seizure disorder, variable semiology, and length of spells (six studies all concluded that PNES spells last longer than all types of epilepsy spells). A saline induction provocation test has a 74% sensitivity, but does not always induce spells. Prolactin levels estimate the average sensitivity to be 89% and are suggestive of epilepsy, but a negative outcome is not highly predictive of PNES. The use of SPECT data to differentiate PNES from epilepsy is not recommended as a first choice due to expense, radioactive materials, and difficulty of interpretation due to muscle and movement artifact. Review of SPECT studies suggests an average sensitivity of 72% across different types of scans and is 59% specific to epilepsy when there is a presence of SPECT abnormalities. The use of the MMPI to diagnose PNES patients is 70% of epilepsy and PNES patients may be correctly diagnosed by using the Wilkus et al (1984) classification rules. The MMPI-2 may add diagnostic utility above other variables such as the medical history, but this utility was not elaborated on. Neuropsychological testing does not adequately differentiate PNES from patients with epilepsy, or both, and all 3 groups test results' suggest cognitive impairment compared to the normal population. The authors concluded that it is unlikely that the gold standard, video-EEG monitoring, will be replaced by any of the alternative techniques they reviewed, yet may be more helpful as complementary diagnostic tools [51]. Devinsky et al conducted a retrospective chart review in order to compare the clinical features of patients with epileptic seizures (ES) and nonepileptic seizures (NES) to only ES or only NES. A total of 387 consecutive admissions for video-EEG monitoring yielded 248 patients with ES (64%), 40 patients (10%) with other physiologic disorders, 99 patients (25%) with NES, and 20 patients (20%) with ES+NES. These were matched to 20 ES and 20 NES patients. These patients were 70% female with a mean age of 32 (19-57 years old). All patients underwent a saline provocation test and all ES/NES patients developed NES after ES. In patients with ES/NES, there ES seizures were similar to ES only seizures and NES were similar to NES only spells. The electrodiagnostic and neuroimaging studies in ES/NES patients were similar to ES patients, but their psychiatric interview and inventories were similar to NES patients. In ES/NES patients, the ES and NES events were different from each other, but may be stereotypic and differentiated during video-EEG recording. Once the different events are characterized, the more prevalent or disturbing types can be identified and referred for the appropriate psychiatric or AED treatment [52].

Studies of patients undergoing video-electroencephalogram (vEEG) reveal that the majority of patients with NES meet criteria for a diagnosis of conversion disorder [53,54]. The most

**Seizures**

#### **4.1. Role of video-EEG monitoring in the diagnosis of PNES**

Benbadis et al conducted a retrospective chart review study of patients who underwent video-EEG monitoring at an epilepsy center in order to investigate the disposition outcomes from January to December 2012. The charts of all adults and children sent for inpatient video-EEG monitoring (>24 hours) were reviewed at University of South Florida-Tampa General Hospital. During that period of time, there were 251 patients monitored for 1-7 days (mean=2.8 days). Non-epileptic events were found in 30% of patients (N=75). Six of the 75 patients had evidence of coexisting epilepsy. Of the 69 patients with non-epileptic events without coexisting epilepsy (pure non-epileptic events), psychogenic non-epileptic seizures (PNES) were found in 61. Patients diagnosed with PNES had their AEDs gradually discontinued and were referred for mental health treatment. Fifty-eight patients with epileptic events were candidates for resective surgery, 47 with epileptic events were non-surgical candidates, and in 57 patients no events were recorded. The authors concluded that there are many possible outcomes of video-EEG monitoring, and in their case the two largest groups were PNES (30%) and surgical candidates (23%) [48].

Zhang et al conducted a retrospective study to compare the clinical outcomes after video-EEG monitoring of patients diagnosed with PNES and epileptic seizures (ES). From November 2006 and January 2008, patients were followed after admission for elective video-EEG monitoring. Sixty-two of an eligible 103 patients agreed to follow up via telephone or mail questionnaires after discharge from monitoring. Follow up occurred for 6-16 months. ES without PNES was identified in 66% of patients (N=41), followed by PNES without ES in 18% of patients (N=11), 10% (N=6) had both ES and PNES, and 6% (N=4) with indeterminate diagnoses. Improvement of overall condition was reported in ~50% of patients in each group. Both groups showed a decrease in seizure frequency and had a significant decrease in AED use at follow up. The PNES group showed a greater more sustained decrease in AED use at follow up than the ES group. The ES group reported a statistically significant improvement in Seizure Worry (P=0.003), Medication Side Effects (P<0.001), and Social Function (P<0.001) [49]. Benbadis and colleagues conducted a retrospective review to analyze the yield of short-term outpatient EEG monitoring for suspected PNES. Seventy-four adult cases of short-term outpatient EEG video monitoring were found from October 2000 to January 2003 at University of South Florida-Tampa General Hospital. Each short-term monitoring session lasted between 1-2 hours. The suspected diagnosis of PNES was confirmed in 66% of cases (N=49). No event was induced in 23 patients and 2 patients had an induced event that was not habitual type. The authors concluded that for confirmation of a suspected diagnosis of PNES, short-term outpatient video EEG monitoring obviated the need for long-term inpatient video EEG monitoring [50].

#### **4.2. Role of additional diagnostic techniques in the evaluation of Psychogenic Non-Epileptic Seizures**

Prolonged video–EEG monitoring is now considered the gold standard. Additional studies include Single positron emission computed tomography (SPECT), saline provocation during

Benbadis et al conducted a retrospective chart review study of patients who underwent video-EEG monitoring at an epilepsy center in order to investigate the disposition outcomes from January to December 2012. The charts of all adults and children sent for inpatient video-EEG monitoring (>24 hours) were reviewed at University of South Florida-Tampa General Hospital. During that period of time, there were 251 patients monitored for 1-7 days (mean=2.8 days). Non-epileptic events were found in 30% of patients (N=75). Six of the 75 patients had evidence of coexisting epilepsy. Of the 69 patients with non-epileptic events without coexisting epilepsy (pure non-epileptic events), psychogenic non-epileptic seizures (PNES) were found in 61. Patients diagnosed with PNES had their AEDs gradually discontinued and were referred for mental health treatment. Fifty-eight patients with epileptic events were candidates for resective surgery, 47 with epileptic events were non-surgical candidates, and in 57 patients no events were recorded. The authors concluded that there are many possible outcomes of video-EEG monitoring, and in their case the two largest groups were PNES (30%) and surgical

Zhang et al conducted a retrospective study to compare the clinical outcomes after video-EEG monitoring of patients diagnosed with PNES and epileptic seizures (ES). From November 2006 and January 2008, patients were followed after admission for elective video-EEG monitoring. Sixty-two of an eligible 103 patients agreed to follow up via telephone or mail questionnaires after discharge from monitoring. Follow up occurred for 6-16 months. ES without PNES was identified in 66% of patients (N=41), followed by PNES without ES in 18% of patients (N=11), 10% (N=6) had both ES and PNES, and 6% (N=4) with indeterminate diagnoses. Improvement of overall condition was reported in ~50% of patients in each group. Both groups showed a decrease in seizure frequency and had a significant decrease in AED use at follow up. The PNES group showed a greater more sustained decrease in AED use at follow up than the ES group. The ES group reported a statistically significant improvement in Seizure Worry (P=0.003), Medication Side Effects (P<0.001), and Social Function (P<0.001) [49]. Benbadis and colleagues conducted a retrospective review to analyze the yield of short-term outpatient EEG monitoring for suspected PNES. Seventy-four adult cases of short-term outpatient EEG video monitoring were found from October 2000 to January 2003 at University of South Florida-Tampa General Hospital. Each short-term monitoring session lasted between 1-2 hours. The suspected diagnosis of PNES was confirmed in 66% of cases (N=49). No event was induced in 23 patients and 2 patients had an induced event that was not habitual type. The authors concluded that for confirmation of a suspected diagnosis of PNES, short-term outpatient video EEG monitoring obviated the need for long-term inpatient video EEG monitoring [50].

video-EEG monitoring, serum prolactin levels, and neuropsychological testing.

**4.1. Role of video-EEG monitoring in the diagnosis of PNES**

candidates (23%) [48].

182 Epilepsy Topics

Cragar et al conducted a literature review to analyze the possible alternatives to video-EEG for diagnosis of PNES. The literature was searched from 1967 through November 2001 using keywords in the PsychINFO database and were divided into 7 categories of alternative PNES diagnostic techniques: demographic/medical history variables, seizure semiology, provoca‐ tive testing, prolactin levels, single photon emission computed tomography (SPECT), psycho‐ logical testing, and neuropsychological testing. Medical history variables included history of abuse, psychiatric treatment history, frequency of seizures (not shown in four studies to have a significant difference between epilepsy an PNES groups), epileptic spells are more likely to occur during sleep and are more stereotyped, older age of onset and duration of seizure disorder, variable semiology, and length of spells (six studies all concluded that PNES spells last longer than all types of epilepsy spells). A saline induction provocation test has a 74% sensitivity, but does not always induce spells. Prolactin levels estimate the average sensitivity to be 89% and are suggestive of epilepsy, but a negative outcome is not highly predictive of PNES. The use of SPECT data to differentiate PNES from epilepsy is not recommended as a first choice due to expense, radioactive materials, and difficulty of interpretation due to muscle and movement artifact. Review of SPECT studies suggests an average sensitivity of 72% across different types of scans and is 59% specific to epilepsy when there is a presence of SPECT abnormalities. The use of the MMPI to diagnose PNES patients is 70% of epilepsy and PNES patients may be correctly diagnosed by using the Wilkus et al (1984) classification rules. The MMPI-2 may add diagnostic utility above other variables such as the medical history, but this utility was not elaborated on. Neuropsychological testing does not adequately differentiate PNES from patients with epilepsy, or both, and all 3 groups test results' suggest cognitive impairment compared to the normal population. The authors concluded that it is unlikely that the gold standard, video-EEG monitoring, will be replaced by any of the alternative techniques they reviewed, yet may be more helpful as complementary diagnostic tools [51]. Devinsky et al conducted a retrospective chart review in order to compare the clinical features of patients with epileptic seizures (ES) and nonepileptic seizures (NES) to only ES or only NES. A total of 387 consecutive admissions for video-EEG monitoring yielded 248 patients with ES (64%), 40 patients (10%) with other physiologic disorders, 99 patients (25%) with NES, and 20 patients (20%) with ES+NES. These were matched to 20 ES and 20 NES patients. These patients were 70% female with a mean age of 32 (19-57 years old). All patients underwent a saline provocation test and all ES/NES patients developed NES after ES. In patients with ES/NES, there ES seizures were similar to ES only seizures and NES were similar to NES only spells. The electrodiagnostic and neuroimaging studies in ES/NES patients were similar to ES patients, but their psychiatric interview and inventories were similar to NES patients. In ES/NES patients, the ES and NES events were different from each other, but may be stereotypic and differentiated during video-EEG recording. Once the different events are characterized, the more prevalent or disturbing types can be identified and referred for the appropriate psychiatric or AED treatment [52].

Studies of patients undergoing video-electroencephalogram (vEEG) reveal that the majority of patients with NES meet criteria for a diagnosis of conversion disorder [53,54]. The most recent version of the Diagnostic and Statistical Manual of Mental Disorders (DSM), the DSM – Fifth Edition (DSM-5), lists conversion disorder in the somatic symptom and related disorders category (American Psychiatric Association [APA], 2013) [55]. A diagnosis of conversion disorder requires a minimum of one symptom involving a change in voluntary motor or sensory function, along with evidence of "incompatibility" between known medical conditions and the symptom (e.g., vEEG capturing a paroxysmal episode). The symptom cannot be better accounted for by other medical or mental disorders, and psychosocial functioning is significantly impacted. Stress or trauma correlating with the time of symptom onset is supportive evidence for a diagnosis but, in contrast to the prior DSM, is not required [55]. Another change with the DSM-5 is that a clinician does not have to judge whether the presenting symptom is unintentionally manifested for diagnosis of conversion disorder. However, if there is clear evidence that the symptom is deliberately produced, a diagnosis of factitious disorder or malingering is more appropriate [55].

PNES (mean age: 30; 75% female) with 233 episodes recorded. At the time of monitoring, 56.7% were taking antidepressant medication and 100% were taking AEDs, most patients were on multiple AEDs. Six patients (9%) had concurrent epilepsy, with complex partial epilepsy being the most common (N=4). Both the neurologist and psychiatrist diagnosed all of the PNES patients with conversion disorder. Twenty-one percent of patients (N=13) were diagnosed with only a conversion disorder, while most were diagnosed with another axis I or axis II diagnosis, most commonly major depression (31%, N=19), followed by generalized anxiety disorder (15%, N=9). The authors concluded that ongoing education and cooperation between neurologists and psychiatrists are critical to properly diagnose and manage patients with PNES [62]. Drake et al conducted a retrospective review of patients with severe PNES with frequent and prolonged spells that mimicked status epilepticus in order to identify clinical and psychomet‐ ric features to assist diagnosis. Twenty patients were admitted to the Epilepsy Unit of The Ohio State University Hospitals from July 1982 to July 1989. The mean age was 27.9 years old and 19 of 20 were female (95%). The clinical seizures averaged more than 2 minutes in length and were atypical with common back arching and pelvic thrusting. For the spells that continued patients received IV diazepam, phenytoin, and phenobarbital. Sixteen of the 20 patients had been previously diagnosed as epileptic due to observed seizures or abnormal EEG findings both with and without additional seizures. Five patients' PNES spells stopped spontaneously, 4 ceased with the suggestion that improvement was forthcoming, and 11 required intubation due to respiratory arrest. Four patients were cognitively impaired, 10 patients had conversion or somatization disorders, and 10 received psychiatric diagnoses of personality disorders (5 borderline and 5 mixed borderline-histrionic types). At a later date, 14 patients (70%) were found to have experienced a recent acute situational stress prior to their spell. The patients with conversion disorder had their AEDs discontinued and gradually improved, while cognitively impaired individuals were helped by situational changes, behavior modifications, or neuroleptics. Patients with personality disorders continued having attacks and eventually

Psychogenic Non-Epileptic Spells http://dx.doi.org/10.5772/57440 185

Pharmacological treatment of NES consists of the use of antidepressants, particularly SSRIs [64]. In a prospective study, venlafaxine reduced the frequency of NES as well as symptoms of depression and anxiety [65]. A pilot study comparing sertraline to placebo demonstrated a lower frequency of paroxysmal events associated with sertraline but no differences were

A literature review of psychological treatments of NES found that various psychological interventions are beneficial with no particular treatment being superior [67]. In a review of eye movement desensitization and reprocessing (EMDR) therapy for medically unexplained symptoms, which included a small group of NES patients in the sample, findings indicated that EMDR may be an effective treatment, especially when there is an identifiable trauma [64]. A study examining brief augmented psychodynamic interpersonal therapy for the treatment of NES indicated a significant reduction in paroxysmal event frequency, with 25% of the participants being event free for an average of 3.5 years following therapy, as well as reduced reliance on healthcare services [68]. A randomized control trial (RCT) found that the addition of cognitive-behavioral therapy (CBT) for treatment of NES resulted in a significantly greater reduction in the frequency of paroxysmal events than standard medical care alone [69]. Similarly, another study utilizing CBT demonstrated that 11 of 17 patients who completed 12

observed for quality of life and psychosocial functioning between the groups [66].

ceased following up [63].

Although the majority of patients with NES are diagnosed with conversion disorder, NES may also be diagnosed as somatization disorder, dissociative disorder NOS, post-traumatic stress disorder, and undifferentiated somatoform disorder [54].Comorbid psychiatric diagnoses are common for patients with NES and, in addition to frequently diagnosed conversion disorder, consist of other somatoform disorders, posttraumatic stress disorder (PTSD), dissociative disorder, psychotic disorders, anxiety, and depression, along with the majority of patients endorsing a history of abuse [54,56,57]. It is clear that patients with NES are a heterogeneous group and pharmacological and psychological treatment should be determined by the underlying cause and psychiatric disorder [56,58,59].

#### **5. Treatment**

The correct diagnosis plays an important role in the management of PNES -- the earlier the diagnosis, the better the outcome [60].

Reuber and House conducted a literature review of treatment options for psychogenic nonepileptic seizures. After the diagnosis of PNES is made and communicated to the patient, they should be referred to a mental health practitioner. There is no specific treatment for PNES, but most brief psychological therapies are based on cognitive-behavioral therapy (CBT) most commonly used in patients with normal intellectual functioning. CBT tends to be less effective in patients with a history of more severe and chronic somatization and benefit from longer term contact with a clinician focusing on stress management and living with symptoms. Family therapy is also recommended but no specific recommendations were made for families of a patient with PNES. Treatment of co-existing psychiatric or neurologic disorders is recom‐ mended. The authors conclude that PNES should be diagnosed early with prompt referral for psychiatric assessment [61]. Bora et al conducted a retrospective review of the sociodemo‐ graphics, clinical characteristics, and psychiatric diagnoses of patients with PNES. Data from 2000-2008 from long-term video EEG monitoring (LVEM, lasting ~5 days) from a specialized epilepsy center in Turkey was analyzed. During this period of time, 440 patients with refractory epilepsy or indeterminate diagnoses underwent LVEM and 67 patients had a diagnosis of PNES (mean age: 30; 75% female) with 233 episodes recorded. At the time of monitoring, 56.7% were taking antidepressant medication and 100% were taking AEDs, most patients were on multiple AEDs. Six patients (9%) had concurrent epilepsy, with complex partial epilepsy being the most common (N=4). Both the neurologist and psychiatrist diagnosed all of the PNES patients with conversion disorder. Twenty-one percent of patients (N=13) were diagnosed with only a conversion disorder, while most were diagnosed with another axis I or axis II diagnosis, most commonly major depression (31%, N=19), followed by generalized anxiety disorder (15%, N=9). The authors concluded that ongoing education and cooperation between neurologists and psychiatrists are critical to properly diagnose and manage patients with PNES [62]. Drake et al conducted a retrospective review of patients with severe PNES with frequent and prolonged spells that mimicked status epilepticus in order to identify clinical and psychomet‐ ric features to assist diagnosis. Twenty patients were admitted to the Epilepsy Unit of The Ohio State University Hospitals from July 1982 to July 1989. The mean age was 27.9 years old and 19 of 20 were female (95%). The clinical seizures averaged more than 2 minutes in length and were atypical with common back arching and pelvic thrusting. For the spells that continued patients received IV diazepam, phenytoin, and phenobarbital. Sixteen of the 20 patients had been previously diagnosed as epileptic due to observed seizures or abnormal EEG findings both with and without additional seizures. Five patients' PNES spells stopped spontaneously, 4 ceased with the suggestion that improvement was forthcoming, and 11 required intubation due to respiratory arrest. Four patients were cognitively impaired, 10 patients had conversion or somatization disorders, and 10 received psychiatric diagnoses of personality disorders (5 borderline and 5 mixed borderline-histrionic types). At a later date, 14 patients (70%) were found to have experienced a recent acute situational stress prior to their spell. The patients with conversion disorder had their AEDs discontinued and gradually improved, while cognitively impaired individuals were helped by situational changes, behavior modifications, or neuroleptics. Patients with personality disorders continued having attacks and eventually ceased following up [63].

recent version of the Diagnostic and Statistical Manual of Mental Disorders (DSM), the DSM – Fifth Edition (DSM-5), lists conversion disorder in the somatic symptom and related disorders category (American Psychiatric Association [APA], 2013) [55]. A diagnosis of conversion disorder requires a minimum of one symptom involving a change in voluntary motor or sensory function, along with evidence of "incompatibility" between known medical conditions and the symptom (e.g., vEEG capturing a paroxysmal episode). The symptom cannot be better accounted for by other medical or mental disorders, and psychosocial functioning is significantly impacted. Stress or trauma correlating with the time of symptom onset is supportive evidence for a diagnosis but, in contrast to the prior DSM, is not required [55]. Another change with the DSM-5 is that a clinician does not have to judge whether the presenting symptom is unintentionally manifested for diagnosis of conversion disorder. However, if there is clear evidence that the symptom is deliberately produced, a diagnosis of

Although the majority of patients with NES are diagnosed with conversion disorder, NES may also be diagnosed as somatization disorder, dissociative disorder NOS, post-traumatic stress disorder, and undifferentiated somatoform disorder [54].Comorbid psychiatric diagnoses are common for patients with NES and, in addition to frequently diagnosed conversion disorder, consist of other somatoform disorders, posttraumatic stress disorder (PTSD), dissociative disorder, psychotic disorders, anxiety, and depression, along with the majority of patients endorsing a history of abuse [54,56,57]. It is clear that patients with NES are a heterogeneous group and pharmacological and psychological treatment should be determined by the

The correct diagnosis plays an important role in the management of PNES -- the earlier the

Reuber and House conducted a literature review of treatment options for psychogenic nonepileptic seizures. After the diagnosis of PNES is made and communicated to the patient, they should be referred to a mental health practitioner. There is no specific treatment for PNES, but most brief psychological therapies are based on cognitive-behavioral therapy (CBT) most commonly used in patients with normal intellectual functioning. CBT tends to be less effective in patients with a history of more severe and chronic somatization and benefit from longer term contact with a clinician focusing on stress management and living with symptoms. Family therapy is also recommended but no specific recommendations were made for families of a patient with PNES. Treatment of co-existing psychiatric or neurologic disorders is recom‐ mended. The authors conclude that PNES should be diagnosed early with prompt referral for psychiatric assessment [61]. Bora et al conducted a retrospective review of the sociodemo‐ graphics, clinical characteristics, and psychiatric diagnoses of patients with PNES. Data from 2000-2008 from long-term video EEG monitoring (LVEM, lasting ~5 days) from a specialized epilepsy center in Turkey was analyzed. During this period of time, 440 patients with refractory epilepsy or indeterminate diagnoses underwent LVEM and 67 patients had a diagnosis of

factitious disorder or malingering is more appropriate [55].

underlying cause and psychiatric disorder [56,58,59].

diagnosis, the better the outcome [60].

**5. Treatment**

184 Epilepsy Topics

Pharmacological treatment of NES consists of the use of antidepressants, particularly SSRIs [64]. In a prospective study, venlafaxine reduced the frequency of NES as well as symptoms of depression and anxiety [65]. A pilot study comparing sertraline to placebo demonstrated a lower frequency of paroxysmal events associated with sertraline but no differences were observed for quality of life and psychosocial functioning between the groups [66].

A literature review of psychological treatments of NES found that various psychological interventions are beneficial with no particular treatment being superior [67]. In a review of eye movement desensitization and reprocessing (EMDR) therapy for medically unexplained symptoms, which included a small group of NES patients in the sample, findings indicated that EMDR may be an effective treatment, especially when there is an identifiable trauma [64]. A study examining brief augmented psychodynamic interpersonal therapy for the treatment of NES indicated a significant reduction in paroxysmal event frequency, with 25% of the participants being event free for an average of 3.5 years following therapy, as well as reduced reliance on healthcare services [68]. A randomized control trial (RCT) found that the addition of cognitive-behavioral therapy (CBT) for treatment of NES resulted in a significantly greater reduction in the frequency of paroxysmal events than standard medical care alone [69]. Similarly, another study utilizing CBT demonstrated that 11 of 17 patients who completed 12 CBT sessions were episode-free by the final session and experienced improved functioning and quality of life as well as decreased psychiatric symptoms [70]. In addition, group psycho‐ therapy for treatment of NES has demonstrated effectiveness for reducing the frequency of paroxysmal events [71,72]. Research has provided some evidence that various psychological interventions are effective for the treatment of NES, however, most studies were not well conducted and there needs to be more research conducted that utilizes RCT [68,70].

[3] Benbadis SR.,Psychogenic non-epileptic seizures. In Wyllie E, editor. The treatment of epilepsy: principles and practice. 4th edition: Lippincott and Williams 2006 ;

Psychogenic Non-Epileptic Spells http://dx.doi.org/10.5772/57440 187

[4] Reuber M, Fernández G, Bauer J, Helmstaedter C, Elger CE. Diagnostic delay in psy‐

[5] Szaflarski JP, Szaflarski M, Hughes C, Ficker DM, Cahill WT, Privitera MD. Psycho‐ pathology and quality of life: psychogenic non-epileptic seizures versus epilepsy.

[6] Barry E, Krumholz A, Bergey C, Alemyehu S, Grattan L. Non-epileptic posttraumatic

[7] Benbadis SR, Hauser WA. An estimate of the prevalence of psychogenic non-epilep‐

[8] Sigurdardottir KR, Olafsson E. Incidence of psychogenic seizures in adults: a popula‐

[9] Szaflarski JP, Ficker DM, Cahill WT, et al. Four-year incidence of psychogenic none‐ pileptic seizures in adults in Hamilton county, OH. Neurology. 2000; 55(10):1561–

[10] Meierkord H, Will B, Fish D, Shorvon S. The clinical features and prognosis of pseu‐ doseizures diagnosed using video-EEG telemetry. Neurology 1991;41:1643-1646.

[11] Lancman ME, Brotherton TA, AsconapéJJ, Penry JK. Psychogenic seizures in adults:

[12] Alper K, Devinsky O, Perrine K, Vazquez B, Luciano D. Nonepileptic seizures and

[13] Slavney PR. Perspectives on Hysteria. Baltimore: The Johns Hopkins University

[14] Veith I. Hysteria : The history of a disease. Chicago: University of ChicagoPress;1965.

[15] McBride AE, Shih TT, Hirsch LJ. Video-EEG monitoring in the elderly: a review of 94

[16] Abubakr A, Wambacq I. Seizures in the elderly: Video/EEG monitoring analysis. Epi‐

[17] Kawai M, Hrachovy RA, Franklin PJ, et al. Video-EEG monitoring in a geriatric vet‐

[18] Patel H, Scott E, Dunn D, Garg BP. Non-epileptic seizures in children. Epilepsia

childhood sexual and physical abuse. Neurology. 1993;43(10):1950

eran population. J Clin Neurophysiol. 2007;24(6):429–432.

chogenic nonepileptic seizures. Neurology. 2002 Feb 12;58(3):493-5.

Med Sci Monitor 2003; CR113-CR118.

seizures. Epilepsia 1991;32:322-328.

tic seizures. Seizure. 2000;9(4):280–281.

a longitudinal analysis. Seizure. 1993;2(4):281

patients. Epilepsia. 2002;43(2):165–169.

lepsy Behav. 2005;7(3):447–450

2007;48: 2086-2092.

tion-based study in Iceland. Epilepsia. 1998;39(7):749–752.

623-630.

1563.

Press;1990.

#### **6. Prognosis**

Most studies that have assessed the prognosis in patients after PNES diagnosis suggest that only 25 to 38 percent of patients achieve complete seizure freedom [73-77]. Children have been reported to have better prognosis than adults [60].

#### **Author details**

Batool F. Kirmani1,2, Diana Mungall Robinson2 , Jose Aceves2,3, David Gavito2,5, Richard Phenis2,4 and Daniel Cruz2,4

\*Address all correspondence to: bkirmani@sw.org

1 Epilepsy Center, Department of Neurology, Scott & White Neuroscience Institute, Temple, TX, USA

2 Texas A&M Health Science Center College of Medicine, Temple, TX, USA

3 Division of Pediatric Neurology, Department of Pediatrics, Scott & White Healthcare, Temple, TX, USA

4 Division of Neuropsychology, Department of Surgery, Scott & White Healthcare, Temple, TX, USA

5 Department of Psychiatry, Scott & White Neuroscience Institute, Temple, TX, USA

#### **References**


[3] Benbadis SR.,Psychogenic non-epileptic seizures. In Wyllie E, editor. The treatment of epilepsy: principles and practice. 4th edition: Lippincott and Williams 2006 ; 623-630.

CBT sessions were episode-free by the final session and experienced improved functioning and quality of life as well as decreased psychiatric symptoms [70]. In addition, group psycho‐ therapy for treatment of NES has demonstrated effectiveness for reducing the frequency of paroxysmal events [71,72]. Research has provided some evidence that various psychological interventions are effective for the treatment of NES, however, most studies were not well

Most studies that have assessed the prognosis in patients after PNES diagnosis suggest that only 25 to 38 percent of patients achieve complete seizure freedom [73-77]. Children have been

1 Epilepsy Center, Department of Neurology, Scott & White Neuroscience Institute, Temple,

3 Division of Pediatric Neurology, Department of Pediatrics, Scott & White Healthcare,

4 Division of Neuropsychology, Department of Surgery, Scott & White Healthcare, Temple,

[2] Overintepretation of EEGs and misdiagnosis of epilepsy. Benbadis SR, Tatum WO. J

5 Department of Psychiatry, Scott & White Neuroscience Institute, Temple, TX, USA

[1] Lesser RP. Psychogenic seizures. Neurology 1996;46:1499-1507.

Clin Neurophysiol. 2003 Feb;20(1):42-4.

2 Texas A&M Health Science Center College of Medicine, Temple, TX, USA

, Jose Aceves2,3, David Gavito2,5,

conducted and there needs to be more research conducted that utilizes RCT [68,70].

**6. Prognosis**

186 Epilepsy Topics

**Author details**

TX, USA

TX, USA

**References**

Temple, TX, USA

reported to have better prognosis than adults [60].

Batool F. Kirmani1,2, Diana Mungall Robinson2

\*Address all correspondence to: bkirmani@sw.org

Richard Phenis2,4 and Daniel Cruz2,4


[19] Wyllie E., Glazer JP, Benbadis S, Kotagal P, Wolmuth B. Psychiatric features of chil‐ dren and adolescents with pseudoseizures. Arch Pediatr Adolesc Med. 1999; 153: 244-248.

[33] Kirmani B, Mungall D. Epilepsy and Concomittant Pseudoseizures: The Diagnostic

Psychogenic Non-Epileptic Spells http://dx.doi.org/10.5772/57440 189

[34] Psychological characteristics of patients with newly developed psychogenic seizures. van Merode T, Twellaar M, Kotsopoulos IA, Kessels AG, Merckelbach H, de Krom

[35] Nonepileptic seizures after resective epilepsy surgery. Glosser G, Roberts D, Glosser

[36] New-onset psychogenic seizures after intracranial neurosurgery. Reuber M, Kral T, Kurthen M, Elger CE. Acta Neurochir (Wien). 2002 Sep;144(9):901-7; discussion 907

[37] A spell in the epilepsy clinic and a history of "chronic pain" or "fibromyalgia" inde‐ pendently predict a diagnosis of psychogenic seizures. Benbadis SR Epilepsy Behav.

[38] Does the primary literature provide support for clinical signs used to distinguish psychogenic nonepileptic seizures from epileptic seizures? Avbersek A, Sisodiya S J

[39] Psychogenic nonepileptic seizures: review and update. Reuber M, Elger CE Epilepsy

[40] Ictal characteristics of pseudoseizures. Gates JR, Ramani V, Whalen S, Loewenson R

[41] Leis AA, Ross MA, Summers AK. Psychogenic seizures: ictal characteristics and di‐

[42] Seneviratne U, Reutens D, D'Souza W. Stereotypy of psychogenic seizures: insights

[43] Patterns of involvement of facial muscles during epileptic and nonepileptic events: review of 654 events. DeToledo JC, Ramsay RE Neurology. 1996;47(3):621.

[44] Chung SS, Gerber P, Kirlin KA. Ictal eye closure is a reliable indicator for psychogen‐

[45] Weeping as a common element of pseudoseizures. Bergen D, Ristanovic R Arch Neu‐

[46] Ictal stuttering: a sign suggestive of psychogenic nonepileptic seizures. Vossler DG, Haltiner AM, Schepp SK, Friel PA, Caylor LM, Morgan JD, Doherty MJ Neurology.

[47] Ali S, Jabeen S, Arain A, Wassef T, Ibrahim A. How to Use Your Clinical Judgment to Screen for and Diagnose Psychogenic Nonepileptic Seizures without Video Electro‐

Dilemma. The Internet Journal of Neurology. Jan 2013; 15(1).

DS. Epilepsia. 1999 Dec;40(12):1750-4.

Neurol Neurosurg Psychiatry. 2010;81(7):719.

agnostic pitfalls. Neurology. 1992;42(1):95–99.

from video-EEG monitoring. Epilepsia. 2010;51(7):1159–1168.

ic nonepileptic seizures. Neurology. 2006;66(11):1730–1731.

encephalogram. Innov Clin Neurosci. 2011 Jan;8(1):36-42.

2005;6(2):264.

Behav. 2003;4(3):205

rol. 1993;50(10):1059.

2004;63(3):516.

Arch Neurol. 1985;42(12):1183

MC, Knottnerus JA. J Neurol Neurosurg Psychiatry. 2004;75(8):1175.


[33] Kirmani B, Mungall D. Epilepsy and Concomittant Pseudoseizures: The Diagnostic Dilemma. The Internet Journal of Neurology. Jan 2013; 15(1).

[19] Wyllie E., Glazer JP, Benbadis S, Kotagal P, Wolmuth B. Psychiatric features of chil‐ dren and adolescents with pseudoseizures. Arch Pediatr Adolesc Med. 1999; 153:

[21] Vincentiis, Valente KD, Thome-Souza S, Kuczinsky E, Fiore LA. Negrao N. Risk fac‐ tors for psychogenic seizures in children and adolescents with epilepsy. Epilepsy Be‐

[22] Wyllie E, Fridman D, Rothner AD, Luders H, Dudley D, Morris III H, Cruse R, Eren‐ berg G, Kotagal P. Psychogenic seizures in children and adolescents: outcome after diagnosis by ictal video and electroencephalographic recording. Pediatrics 1990; 85:

[23] Metrick ME, Ritter FJ, Gates JR, et al. Nonepileptic events in childhood. Epilepsia.

[24] Gudmundsson O, Prendergast M, Foreman D, Crowley S. Outcome of pseudosei‐ zures in children and adolescents: a 6 year symptom survival analysis. Dev Med

[25] Krumholz A, Niedermeyer E. Psychogenic seizures: a clinical study with follow-up

[26] Krumholz A, Hopp J. Psychogenic (nonepileptic) seizures. Semin Neurol. 2006 Jul;

[27] Nonepileptic seizures: diagnosis and management. Krumholz A. Neurology.

[28] Evidence for epilepsy is rare in patients with psychogenic seizures. Lesser RP, Lued‐

[29] Ramsay RE, Cohen A, Brown MC. Coexisting epilepsy and non-epileptic seizures. In Rowan AJ, Gates JR, eds. Non-epileptic Seizures. Boston : Butterworth-Heinemann;

[30] Interictal EEG abnormalities in patients with psychogenic nonepileptic seizures. Reuber M, Fernández G, Bauer J, Singh DD, Elger CE. Epilepsia. 2002 Sep;43(9):

[31] Benbadis SR, Agrawal V, Tatum WO. IV. How many patients with psychogenic non‐

[32] Martin R, Burneo JG, Prasad A, Powell T, Faught E, Knowlton R, Mendez M, Kuz‐ niecky R. Frequency of epilepsy in patients with psychogenic seizures monitored by

epileptic seizures also have epilepsy? Neurology. 2001;57(5):915–917.

[20] Bathia MS, Sapra SS. Clin Pediatr 2005; 44: 617-621.

244-248.

188 Epilepsy Topics

480-484.

hav. 2006;8: 294-298.

1991;32(3):322–328

26(3):341-50.

1993:47-54

1013-20.

Child Neurol. 2001; 43: 547-551

data. Neurology. 1983 Apr;33(4):498-502.

ers H, Dinner DS. Neurology. 1983 Apr;33(4):502-4.

video-EEG. Neurology. 2003; 61(12):1791–1792.

1999;53(5 Suppl 2):S76-83. Review.


[48] Benbadis SR, O'Neill E, Tatum WO, Heriaud L. Outcome of prolonged video-EEG monitoring at a typical referral epilepsy center. Epilepsia. 2004;45(9):1150–1153.

key. Seizure. 2011 Jul;20(6):458-61. doi: 10.1016/j.seizure.2011.02.007. Epub 2011 Mar

Psychogenic Non-Epileptic Spells http://dx.doi.org/10.5772/57440 191

[63] Drake ME Jr, Pakalnis A, Phillips BB. Neuropsychological and psychiatric correlates

[64] van Rood,Y. & de Roos, C. (2009). EMDR in the treatment of medically unexplained symptoms: a systematic review. Journal of EMDR Practice and Research, 3(4),

[65] Pintor, L., Bailles, E., Matrai, S., Carreno, M., Donaire, A., Boget, T., Setoain, X., Ru‐ mia, J., & Bargallo, N. (2010). Efficiency of Venlafaxine in patients with psychogenic nonepileptic seizures and anxiety and/or depressive disorders. Journal of Neuropsy‐

[66] Bravo, T. P., Hoffman-Snyder, C. R., Wellik, K. E., Martin, K. A., Hoerth, M. T., De‐ maerschalk, B. M., & Wingerchuk, D. M. (2013). The effect of selective serotonin re‐ uptake inhibitors on the frequency of psychogenic nonepileptic seizures: a critically

[67] Gaynor, D., Cock, H., & Agrawal, N. (2009). Psychological treatments for functional non-epileptic attacks: a systematic review. Acta Neuropsychiatrica, 21, 158-168.

[68] Mayor, R., Howlett, S., Grunewald, R., & Reuber, M. (2010). Long-term outcome of brief augmented psychodynamic therapy for psychogenic nonepileptic seizures: seiz‐

[69] Goldstein, L. H., Chalder, T., Chigwedere, C., Khondoker, M. R., Moriarty, J., Toone, B. K., Mellers, J. D. C. (2010). Cognitive-behavioral therapy for psychogenic nonepi‐

[70] LaFrance, Jr., C. & Devinsky, O. (2004). The treatment of nonepileptic seizures: his‐

[71] Barry, J. J., Wittenberg, D., Bullock, K. D., Michaels, J. B., Classen, C. C., & Fisher, R. S. (2008). Group therapy for patients with psychogenic nonepileptic seizures: a pilot

[72] Metin, S. Z., Ozmen, M., Metin, B., Talasman, S., Yeni, S. N., & Ozkara, C. (2013). Treatment with group psychotherapy for chronic psychogenic nonepileptic seizures.

[73] Outcome in psychogenic nonepileptic seizures: 1 to 10-year follow-up in 164 patients. Reuber M, Pukrop R, Bauer J, Helmstaedter C, Tessendorf N, Elger CE Ann Neurol.

[74] Measuring outcome in psychogenic nonepileptic seizures: how relevant is seizure re‐ mission? Reuber M, Mitchell AJ, Howlett S, Elger CESOEpilepsia. 2005;46(11):1788.

torical perspectives and future directions. Epilepsia, 45(suppl. 2), 15-21.

ure control and health care utilization. Epilepsia, 51, 1162-1176.

leptic seizures: a pilot RCT. Neurology, 74, 1986-1994.

study. Epilepsy & Behavior, 13(4), 624-629.

Epilepsy & Behavior, 28(1), 91-94.

2003;53(3):305.

of intractable pseudoseizures. Seizure. 1992 Mar;1(1):11-3.

chiatry and Clinical Neurosciences, 22(4), 401-408.

appraised topic. Neurologist, 19(1), 30-33.

23.

248-263.


key. Seizure. 2011 Jul;20(6):458-61. doi: 10.1016/j.seizure.2011.02.007. Epub 2011 Mar 23.

[63] Drake ME Jr, Pakalnis A, Phillips BB. Neuropsychological and psychiatric correlates of intractable pseudoseizures. Seizure. 1992 Mar;1(1):11-3.

[48] Benbadis SR, O'Neill E, Tatum WO, Heriaud L. Outcome of prolonged video-EEG monitoring at a typical referral epilepsy center. Epilepsia. 2004;45(9):1150–1153.

[49] Zhang YC, Bromfield EB, Hurwitz S, Nelson A, Sylvia K, Dworetzky B. Comparison of outcomes of video/EEG monitoring between patients with epileptic seizures and those with psychogenic nonepileptic seizures. Epilepsy Behav. 2009;15(3):303–307.

[50] Benbadis SR, Siegrist K, Tatum WO, Heriaud L, Anthony K. Short-term outpatient EEG video with induction in the diagnosis of psychogenic seizures. Neurology.

[51] Cragar DE, Berry DT, Fakhoury TA, Cibula J, Schmitt F. A review of diagnostic tech‐ niques in the differential diagnosis of epileptic and nonepileptic seizures. Neuropsy‐

[52] Devinsky O, Sanchez-Villaseñor F, Vasquez B, et al. Clinical profile of patients with

[53] Devinsky, O. (1998). Nonepileptic Psychogenic Seizures: Quagmires of Pathophysiol‐

[54] Marchetti, R., Kurcgant, D., Neto, J., von Vismark, M., Marchetti, L., & Fiore, L. (2008). Psychiatric diagnoses of patients with psychogenic non-epileptic seizures.

[55] American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental

[56] Bowman, E. S. & Markand, O. N. (1996). Psychodynamics and psychiatric diagnoses of pseudoseizure subjects. The American Journal of Psychitary, 153(1), 57-63.

[57] Reuber, M., Howlett, S., & Kemp, S. (2005). Psychologic treatment of patients with psychogenic nonepileptic seizures. Expert Review Neurotherapeutics, 5(6), 737-752.

[58] Walzak TS, Papacostas S, Williams DT, et al. Outcome after the diagnosis of psycho‐

[59] Lesser, R. (2003). Treatment and outcome of psychogenic nonepileptic seizures. Epi‐

[60] Wyllie E, Freidman D, Luders H, et al. Outcome of psychogenic seizures in children

[61] Reuber M, House AO. Treating patients with psychogenic non-epileptic seizures.

[62] Bora IH, Taskapilioglu O, Seferoglu M, Kotan OV, Bican A, Ozkaya G, Akkaya C. So‐ ciodemographics, clinical features, and psychiatric comorbidities of patients with psychogenic nonepileptic seizures: experience at a specialized epilepsy center in Tur‐

epileptic and nonepileptic seizures. Neurology. 1996;46(6):1530–1533

ogy, Diagnosis, and Treatment. Epilepsia, 39(5), 458-462.

genic non-epiletic seizures. Epilepsia 1995;36:1131-1137.

and adolescents compared to adults. Neurology 1991;41:742-744.

2004;63(9):1728–1730.

190 Epilepsy Topics

Seizure, 17, 247-253.

Disorders (5th ed.).

lepsy Currents, 3(6), 198-200.

Curr Opin Neurol. 2002;15(2):207–211.

chol Rev. 2002;12(1):31–64.


[75] Non-epileptic seizures: patients' understanding and reaction to the diagnosis and im‐ pact on outcome. Carton S, Thompson PJ, Duncan JS Seizure. 2003;12(5):287.

**Chapter 10**

**Psychogenic Non-Epileptic Seizures in a Surgical**

Lorena Vega-Zelaya, Marta Alvarez, Elena Ezquiaga, Jaime Nogeiras, María Toledo, Rafael G. Sola and

Additional information is available at the end of the chapter

Jesús Pastor

**1. Introduction**

psychological origin [1, 2].

therapeutic difficulties.

http://dx.doi.org/10.5772/57439

**Epilepsy Unit: Experience and a Comprehensive Review**

Psychogenic non-epileptic seizures (PNES) are paroxysmal involuntary changes in behaviour, sensation, motor activity, cognitive processing or autonomic function that resemble epileptic seizures (ES). However, they have no electrophysiological correlate but instead possess a

Historically known as hysteria seizures by Hippocrates and Aristotle, the French neurologist Jean-Martin Charcot recognised hysteria as a neurologically diagnosable condition. Many years after this recognition, Sigmund Freud reclassified hysteria as a psychiatric disorder.

Previously, PNES has been given various names, such as pseudoseizures, non-epileptic spells or psychogenic seizures. In general, this terminology involving the prefix 'pseudo-' has become

PNES have been commonly classified as dissociative or conversion disorders. However, PNES have also been considered to be very similar to other functional somatic symptoms and syndromes [3]. In the current and recently published DSM-V, PNES are classified as a "func‐ tional neurological symptom disorder". It appears that PNES are not a single entity and that a variety of clinical manifestations can occur. Furthermore, comorbid psychiatric disorders are common; thus, it is not surprising that a PNES diagnosis is difficult to achieve. PNES exist at the interface of neurology and psychiatry and as discussed below, constitute an important challenge in the practice of both medical specialties, because of their inherent diagnostic and

> © 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

out-dated as it implies that the seizures are not real and may suggest 'malingering'.

