**3.2 Material and method**

#### **3.2.1 Participants and study area**

This is an epidemiological descriptive study of patients diagnosed as NC from Umtata General Hospital and Nelson Mandela Academic Hospital (South Africa) from January 2004 to January 2010 who were selected for a case control study in the project Neurocysticercosis protocol. (Database, n=3015). All selected patients were included in group A or group B.

#### **3.2.2 Inclusion criteria:**

**Group A:** fulfilled the following selected criteria:

1.-Positive serology ELISA test for cysticercosis

2.-CT/MRI images of the brain with intravenous contrast or gadolinium enhancement, consistent with definitive evidence of active and calcified NC on the insula lobe suitable to evaluate: ictal manifestations.

3.-Positive serology ELISA test for cysticercosis

4.-ELISA test for HIV/AIDS

## **Group B:**

182 Novel Aspects on Epilepsy

partial seizures. Seizures arising from the temporal lobe always invade the insular region, but in approximately 10% of cases, the seizures originate in the insular cortex itself (Isnard, 2004; Guenot, 2008). In 2005, Isnard studied 50 patients using intrainsular electrodes and found that the clinical presentation of insular lobe seizures was a simple partial seizures occurring in full consciousness patient, beginning with a sensation of laryngeal constriction followed by paresthesiae that were often unpleasant affecting large cutaneous territories. These initial symptoms were eventually followed by dysarthric speech and/or elementary auditory hallucinations, and seizures often ended with focal dystonic postures. Four years later he studied 164 patients in whom 472 insular electrodes were implanted, he again found that clinical presentation of insular lobe seizures are that of simple partial seizures occurring in full consciousness, beginning with a sensation of laryngeal constriction followed by paresthesia that were often unpleasant on extensive cutaneous territories. These initial symptoms were eventually followed by dysarthric speech and/or elementary auditory hallucinations, and seizures often ended with focal dystonic postures. He was able to reproduce several of the spontaneous ictal symptoms in the six patients with insular seizures. (Isnard, 2009). Looking into other ways to check clinical features of IL due to focal

According to the publications made in the last decade, very little is known about NC on the IL (Foyaca-Sibat & Ibañez-Valdés, 2006). It is important to highlight that it is a dangerous location of NC because apart from epilepsy other complications such as: autonomic dysfunction (Oppenheimer et al., 2001), neurogenic heart (Tamayo & Hachinski, 2003), electrocardiographic changes (Blumhardt et al., 1986) and sudden unexpected death in

The main aim of our study was to identify ictal manifestations in patients presenting focal lesions (NC) on the IL proved by imagenology. To our knowledge, it is the first time that results from ILE secondary to focal NC in a case-control study are reported in the medical

This is an epidemiological descriptive study of patients diagnosed as NC from Umtata General Hospital and Nelson Mandela Academic Hospital (South Africa) from January 2004 to January 2010 who were selected for a case control study in the project Neurocysticercosis protocol. (Database, n=3015). All selected patients were included in group A or group B.

2.-CT/MRI images of the brain with intravenous contrast or gadolinium enhancement, consistent with definitive evidence of active and calcified NC on the insula lobe suitable

lesions, we reviewed what happen in patients presenting NC on the IL.

epilepsy [SUDEP] (Leestma, 1984; Mc Gugan, 1999; Langan Y, 2000) can occur

literature.

**3.2 Material and method**

**3.2.2 Inclusion criteria:**

**3.2.1 Participants and study area**

to evaluate: ictal manifestations.

4.-ELISA test for HIV/AIDS

**Group A:** fulfilled the following selected criteria:

1.-Positive serology ELISA test for cysticercosis

3.-Positive serology ELISA test for cysticercosis

Demographic and clinical data were obtained through interviews with the patients and their relatives.

The differences between groups A and B were evaluated for statistical significance with the use of Statistical Package for the Social Sciences version 16.0 for windows (SPSS Inc., Chicago, Ill)

All patients received 800 mg of albendazole and 40 mg of prednisone per os daily for a week as part of treatment for NC and 200mg of carbamazepine orally every 8 hour to control epileptic seizures.

All images were acquired on the same CT scan and MR images using a three-dimensional T1-fast field echo sequence providing an isotropic voxel size of 1 mm3. Images underwent correction for no uniform intensity and were linearly registered into a standardized stereotaxic space. The interval between the first and last scan was 31 ± 21 months (range = 10 to 52).

#### **3.2.3 Exclusion criteria**

Epilepsy due to other causes

Terminal diseases, serious psychological illnesses, active addictions to psychoactive substances

Patients younger than 13 years old, pregnant ladies, patients on HAART

No written consent.

#### **3.2.4 Withdrawal criteria**

Any event that may lead to a situation that discourages the intervention or that may prevent communication with the healthcare professional.

#### **3.2.5 Ethical aspects**

Written informed consent was obtained in the first assessment of eligible patients for participation. All patients received information on the study's objective and procedures in addition to ethical considerations, including and the participant's right to intimacy, anonymity, confidentiality, withdrawal, and information. Both investigators completed CITI training-course on the Protection of Human Research and sworn to the Hippocratic Oath and committed to respecting the norms of good clinical practice, as well as the requirements of the Helsinki Declaration.

Clinical Features of Epilepsy Secondary to Neurocysticercosis at the Insular Lobe 185

18.4% (n=3) *P***< 0.0001**

(n=9) 4.54% (n=1) *P***< 0.0001**

(n=8) 9.09% (n=2) *P=* 0.0281

(n=5) 4.54% (n=1) *P=* 0.0918

Patients with NC on the temporal lobe presented TLE or partial secondary to generalized motor seizures except one who complained of a sensation of laryngeal constriction, perioral parentheses and sense of levitation and later loss of consciousness and tonic-clonic

We tried to correlate the location of the lesion and ictal manifestation considering NC lesion small enough to produce non additional damage on surrounding tissue avoiding situations reported by Roper et al. in 1993 and Duffau in 2003. They described insular epilepsy in patients presenting seizures involved visceral sensory hallucinations followed by motor automatism and motor seizures with somatic sensory hallucinations and then produced visceral motor effects. Unfortunately, they studied patients with mass lesion (low-grade astrocytoma) big enough to involve the temporal lobe region. In our series, lesions of NC active or calcified measured less than 15 mm in both groups to assure that no surrounding tissue was affected. Fortunately, we also had previous information about insular NC from a

X2 OR (CI=95.0 %)

21.390 **20.26**(Wolf=4.18)

8.836 **15.75**(Wolf=1.77)

5.064 6.15 (Wolf=1.12)

3.321 6.25 (Wolf=0.61)

Group A B Fisher test

**76%** (n=16)

**42.8%**

Table 2. Clinical features commonest found

Graphic 1. Clinical features of insula lobe epilepsy

Laryngeal constriction

Unpleasant paresthesia

**Source:** Table 2

Dysphagia 38.09%

Levitation 23.80%

secondary generalized seizures.

Methods for patient selection and information processing was accepted by clinical governance at Mthatha General Complex, and approval From the University of Transkei, and Walter Sisulu University IRB and the respective Ethical Committees (UNITRA:0018/05, and WSU:0068/009) were obtained.

#### **3.3 Results and comments**

The total number of patients with ILE due to unilateral calcified and active NC on the IL in our database is 21 and its prevalence is 0.69%. Four patients (19%) from this group presented an associated ischemic stroke due to infectious vasculitis. Three of them were HIV-positive (See figure 5)

Fig. 5. CT scan of the brain shows calcified and active NC, some ring enhancing lesion is seen. Hypodensity lesion secondary to ischemic stroke on the right frontal and insular lobes with partial compression of the right lateral ventricle is also observed.

Demographic features are summarized in Table 1 and no remarkable differences among both groups including HIV status were found.

Table 1. Demographics characteristics

Commonest ictal manifestations with statistical significance (*p*>0.0001) were: sensation of laryngeal constriction (n=16) and unpleasant paresthesia (n=9) in fully conscious patients. See Table 2 and Graphic 1.

Less common problems without statistical value were: dysphagia, levitation and mild chest oppression.

Table 2. Clinical features commonest found

Patients with NC on the temporal lobe presented TLE or partial secondary to generalized motor seizures except one who complained of a sensation of laryngeal constriction, perioral parentheses and sense of levitation and later loss of consciousness and tonic-clonic secondary generalized seizures.

**Source:** Table 2

184 Novel Aspects on Epilepsy

Methods for patient selection and information processing was accepted by clinical governance at Mthatha General Complex, and approval From the University of Transkei, and Walter Sisulu University IRB and the respective Ethical Committees (UNITRA:0018/05,

The total number of patients with ILE due to unilateral calcified and active NC on the IL in our database is 21 and its prevalence is 0.69%. Four patients (19%) from this group presented an associated ischemic stroke due to infectious vasculitis. Three of them were

Fig. 5. CT scan of the brain shows calcified and active NC, some ring enhancing lesion is seen. Hypodensity lesion secondary to ischemic stroke on the right frontal and insular lobes

Groups Age Gender (%) HIV (%)

Demographic features are summarized in Table 1 and no remarkable differences among

A (n=21) 32.2 (16.9) 49.1 50.9 13.9 31.2 54.9 B (n=22) 31.9 (15.3) 47.9 52.1 15.7 28.8 55.6

Commonest ictal manifestations with statistical significance (*p*>0.0001) were: sensation of laryngeal constriction (n=16) and unpleasant paresthesia (n=9) in fully conscious patients.

Less common problems without statistical value were: dysphagia, levitation and mild chest

Mean (Std) Male Female + - Unknown

with partial compression of the right lateral ventricle is also observed.

both groups including HIV status were found.

Table 1. Demographics characteristics

See Table 2 and Graphic 1.

oppression.

and WSU:0068/009) were obtained.

**3.3 Results and comments**

HIV-positive (See figure 5)

Graphic 1. Clinical features of insula lobe epilepsy

We tried to correlate the location of the lesion and ictal manifestation considering NC lesion small enough to produce non additional damage on surrounding tissue avoiding situations reported by Roper et al. in 1993 and Duffau in 2003. They described insular epilepsy in patients presenting seizures involved visceral sensory hallucinations followed by motor automatism and motor seizures with somatic sensory hallucinations and then produced visceral motor effects. Unfortunately, they studied patients with mass lesion (low-grade astrocytoma) big enough to involve the temporal lobe region. In our series, lesions of NC active or calcified measured less than 15 mm in both groups to assure that no surrounding tissue was affected. Fortunately, we also had previous information about insular NC from a

Clinical Features of Epilepsy Secondary to Neurocysticercosis at the Insular Lobe 187

By definition, the cause of death in SUDEP is currently unknown, but it is very probable that cardiac arrhythmia during and between seizures plays a potential role. It has been suggested on postmortem studies and interictal cardiac abnormalities observed (Falconer & Rajs, 1976; Leestma, 1989; Ryvlin et al., 2006; Stollberger & Finsterer, 2004). Several suggestions have been made concerning the mechanisms behind SUDEP, most involving speculations on the possible role of autonomic effects such as cardiorespiratory disturbances. Clinical and experimental studies have shown that physical activity can decrease seizure frequency, as well as lead to improved cardiovascular and psychological health in patients with epilepsy (Arida et al., 2007). Information concerning risk factors for SUDEP is conflicting, but potential risk factors include: cold temperatures (Scorza et al., 2007), certain seizure types (Foyaca-Sibat &Ibañez-Valdés, 2006; Kloster & Engelskojon,1999), early adulthood (Lesstma,1997) early onset of epilepsy (Nilsson, 1999), long duration of epilepsy (Walczak et al., 2001), uncontrolled TLE (Walczak et al., 2001; Speling et al.,1999), high seizure frequency(Lagan & Nashef, 2005), and higher numbers of AED (Nilsson et al.,2001) and. Additionally, potential pathomechanisms for SUDEP are unknown, but it is very probable that cardiac arrhythmias during and between seizures, electrolyte disturbances, arrhythmogenic drugs or transmission of epileptic activity to the heart via the autonomic nervous system potentially play a role (Stollberger & Finsterer, 2004). An increasing number of reports about SUDEP secondary to NC are seen on the medical literature gradually (Holmes, 2010) more details about SUDEP can be found in the

Mortality due to epilepsy is a significant concern. Patients with epilepsy have a mortality rate significantly higher compared with the general population. The standardized mortality rate (SMR) is shown to be 1.6-9.3 times higher in this group (Nouri, 2011). Based on our observations we consider that ILE can be differentiated from TLE if patients remain fully conscious during the attack. When epileptic activity spread from IL to temporal lobe or vice

If the above-cited features are not keeping in mind, diagnosis of ILE never going to be

We have hypothesized that NC on the temporal lobe can cause ictal manifestations which can be spread to the IL leading to a combination of TLE and ILE but most symptoms from IL are masked by those from TLE even before patients become unconscious. Further investigation should be made to reach final conclusions. In our experience, this sequence of ictal symptoms: laryngeal constriction, perioral paresthesia, dysphagia, and sense of levitation look reliable enough to characterize insular lobe epileptic seizures secondary to NC. To our knowledge, it is the first time that results from ILE secondary to focal NC in a

We like to express our gratitude to all veterinarian doctors working in this field particularly: Professors Rosina Tammi Krecek, Albert Lee Willingham, Linda Cowan, Samson Mukaratiwua and other members of the Cysticercosis Working Group for Eastern and

Special thanks to Professor Helen Carabin from the Department of Biostatistics and Epidemiology College of Public Health University of Oklahoma Health Sciences Center for

versa then clinical differentiation can be almost impossible to perform.

Southern Africa (CWGESA) for their dedications and commitment.

her invaluable enthusiasm, persistence, and leadership in our research team.

made and cardiac complications or SUDEP may happen.

other chapters of this book.

case-control studies are reported.

**4. Acknowledgment**

pilot study made five years back (Foyaca-Sibat & Ibañez-Valdés, 2006) and based on those results we refined our selecting criteria. Our prevalence of ILE is low because it is an uncommon epileptic disorder.

Previous studies based on video ictal recordings, and direct electric insular stimulation of the insular cortex for presurgical evaluation of temporal lobe epilepsy described clinical features of ictal manifestation on IL eventually followed by dysarthric speech and focal motor convulsive symptoms no present in our series. Other clinical manifestation in our series including speech problems, neurogenic heart and sudden unexpected death were not included for statistical analysis at this time because were not considered in our objectives.

Some patients became a little bit surprised when we asked for some symptoms that they did not expressed before because these symptoms did not recall attention from patients and relatives which may contribute to an underestimate prevalence of this type of seizures mainly in patients presenting it sporadically . A fully conscious patient with laryngeal discomfort, dyspnea, unpleasant perioral or somatic paresthesia, and dysarthric speech, followed by somatomotor symptoms, implies an insular onset and a good respond to antiepileptic treatment can help to confirm it.

Antiparasitic treatment for NC at the IL should be prescribed with caution because the risk of developing complications such as: the neurogenic heart and/or SUDEP. One patient from this series died because subendocardic hemorrhage probable due to active and calcified NC on the right insula cortex documented by postmortem examination (See figure 6)

Fig. 6. Lateral view of the right insular lobe fixed in formalin. One cyst with the scolex inside (in vesicualr stage) on anterior insula is seen, another cyst without scolex with turbid fluidfilled oval cysts and local inflammatory reaction on the middle-anterior (agranular) insula is observed. Left insula was normal and no other cysts were found all over the brain. Cause of death: SUDEP/Neurogenic heart (subendocardial hemorrhage)

#### **3.3.1 Sudden unexpected death in epilepsy secondary to neurocysticercosis**

Although largely neglected in earlier literature, sudden unexpected death in epilepsy (SUDEP) is the most important epilepsy-related mode of death, and is the leading cause of death in people with chronic uncontrolled epilepsy. Research during the past two to three decades has shown that incidence varies substantially depending on the epilepsy population studied, ranging from 0—09 per 1000 patients-years in newly diagnosed patients to 9 per 1000 patient-years in candidates for epilepsy surgery.(Tomson et al., 2008)

By definition, the cause of death in SUDEP is currently unknown, but it is very probable that cardiac arrhythmia during and between seizures plays a potential role. It has been suggested on postmortem studies and interictal cardiac abnormalities observed (Falconer & Rajs, 1976; Leestma, 1989; Ryvlin et al., 2006; Stollberger & Finsterer, 2004). Several suggestions have been made concerning the mechanisms behind SUDEP, most involving speculations on the possible role of autonomic effects such as cardiorespiratory disturbances. Clinical and experimental studies have shown that physical activity can decrease seizure frequency, as well as lead to improved cardiovascular and psychological health in patients with epilepsy (Arida et al., 2007). Information concerning risk factors for SUDEP is conflicting, but potential risk factors include: cold temperatures (Scorza et al., 2007), certain seizure types (Foyaca-Sibat &Ibañez-Valdés, 2006; Kloster & Engelskojon,1999), early adulthood (Lesstma,1997) early onset of epilepsy (Nilsson, 1999), long duration of epilepsy (Walczak et al., 2001), uncontrolled TLE (Walczak et al., 2001; Speling et al.,1999), high seizure frequency(Lagan & Nashef, 2005), and higher numbers of AED (Nilsson et al.,2001) and. Additionally, potential pathomechanisms for SUDEP are unknown, but it is very probable that cardiac arrhythmias during and between seizures, electrolyte disturbances, arrhythmogenic drugs or transmission of epileptic activity to the heart via the autonomic nervous system potentially play a role (Stollberger & Finsterer, 2004). An increasing number of reports about SUDEP secondary to NC are seen on the medical literature gradually (Holmes, 2010) more details about SUDEP can be found in the other chapters of this book.

Mortality due to epilepsy is a significant concern. Patients with epilepsy have a mortality rate significantly higher compared with the general population. The standardized mortality rate (SMR) is shown to be 1.6-9.3 times higher in this group (Nouri, 2011). Based on our observations we consider that ILE can be differentiated from TLE if patients remain fully conscious during the attack. When epileptic activity spread from IL to temporal lobe or vice versa then clinical differentiation can be almost impossible to perform.

If the above-cited features are not keeping in mind, diagnosis of ILE never going to be made and cardiac complications or SUDEP may happen.

We have hypothesized that NC on the temporal lobe can cause ictal manifestations which can be spread to the IL leading to a combination of TLE and ILE but most symptoms from IL are masked by those from TLE even before patients become unconscious. Further investigation should be made to reach final conclusions. In our experience, this sequence of ictal symptoms: laryngeal constriction, perioral paresthesia, dysphagia, and sense of levitation look reliable enough to characterize insular lobe epileptic seizures secondary to NC. To our knowledge, it is the first time that results from ILE secondary to focal NC in a case-control studies are reported.