Malignant Migrating Partial Seizures of Infancy (Coppola-Dulac Syndrome) DOI: http://dx.doi.org/10.5772/intechopen.82838


### Figure 2.

activity generation, at least up to 2 months from the onset (possibly as antiepileptic drug effect) [4]. At this stage detection of early drug resistance may result to a wrong decision about surgical treatment. Extended video-EEG monitoring also has a considerable importance in this category of patients, because visualization of seizures originating from the same cortex area does not mean that all seizures

Despite the various topographies, ictal EEG patterns of all episodes are very similar and correspond to rhythmic activity of the alpha or theta range, prone to the

EEG in personal patients (n = 35) was characterized by diffuse slowing of back-

completely replaced by continuous ictal patterns. In the initial stages of the disease, interictal record revealed regional or multiregional epileptiform discharges with formation of multifocal independent spike foci (MISF) pattern. Most cases of MMPSI (20 patients, 57.1%) initially had MISF with transformation in MMPSI as frequency of epileptic seizures increased and migratory status developed. In seven cases (20%), monofocal epilepsy was initially observed, followed by addition of extra foci, new types of seizures, and increase of multifocal ictal events up to SE. At eight infants (22.9%), the first properly done EEG investigation fixed the multiregional SE pattern with its preservation in dynamic video-EEG studies and negative prognosis for live. Ictal EEG patterns in the developed stage of MMPSI involved different areas of the cerebral cortex during a series of seizures, which could overlap each other in cases when ictal pattern in one area is not yet over, but the same pattern appeared in other cortical areas. There may be a complex picture, combining postictal changes in one region of the cerebral cortex, initial ictal pattern in another area, and developed ictal pattern in the third. Typical EEG pattern of MMPSI is presented in a

ground activity, while in the developed stage, background EEG was almost

series of electroencephalograms (Figures 1–7). In general, ictal pattern

Patient G.E., 1 year old. Diagnosis: Malignant migrating partial seizures of infancy. EEG during status seizures. Emergence of regional ictal EEG pattern in the left frontal region in the form of fast epileptiform activity and transformation to regular activity of theta range with amplitude increase and sharp wave inclusion. In the left parietal, posterior temporal region is seen delta-accentuation after the previous seizure. Manifestation: Right-

originate only from this area [28].

Epilepsy - Advances in Diagnosis and Therapy

Figure 1.

118

sided tonic seizure with oro-facial and versive components.

spread and involving all large cortex areas [7].

The same patient. Continuation of ictal EEG. Ictal epileptiform activity involves neighboring regions and same areas of the right hemisphere, but with maintenance of left-sided lateralization. Manifestation: Bilateral tonic seizure.

### Figure 3.

The same patient. Continuation of ictal EEG. Ictal epileptiform activity in the frontal areas changes to the rightsided lateralization. Manifestation: Transformation to asymmetric tonic seizure with left-sided accentuation.

demonstrates migration of paroxysmal ictal characteristics from one region to another, without formation of stable interregional relations. Probably, only due to ictal pattern migration, patients are able to stay in SE of focal seizures for a long time without development of life-threatening cerebral edema.

### Figure 4.

The same patient. Continuation of ictal EEG. Diffuse spread of ictal epileptiform activity with multiple spikes. On this background, emergence of regional accentuation of ictal pattern in the left parietal-posterior temporal region. Manifestation: Transformation to generalized tonic seizure with clonic component.

### Figure 5.

The same patient. Continuation of ictal EEG. Slowing down of frequency characteristics of the diffuse ictal pattern with transformation to the delta slowing. In the opposite left parietal-posterior temporal region, activation of the regional ictal pattern with regionally accentuated polyspikes and spike-wave complexes is seen. Manifestation: Transformation to asymmetric tonic seizure with right-sided clonic component.

> runs of fast regular spike-wave complexes were also identified; and runs of slow regular spike-wave complexes (rarely), and diffuse spike- and polyspike-wave

The same patient. Continuation of ictal EEG. Ictal pattern in the right hemisphere in the form of regular alphatheta activity with frontal-central accentuation. Postictal changes in the left hemisphere in the form of depression of the bioelectric activity with delta rhythm dominance. Manifestation: Asymmetrical tonic seizure

The same patient. Continuation of ictal EEG. Shift of ictal pattern in the left parietal-posterior temporal region to the delta slowing with slow epileptiform complexes. At the same time in the right hemisphere, emergence of a new ictal pattern in the form of low-amplitude fast activity (lafa). Manifestation: Short-term decrease of

Malignant Migrating Partial Seizures of Infancy (Coppola-Dulac Syndrome)

DOI: http://dx.doi.org/10.5772/intechopen.82838

discharges.

121

with left-sided accentuation.

Figure 7.

Figure 6.

clinical ictal severity.

The following variants of ictal patterns have been identified in patients with MMPSI: regional "saw tooth" activity of alpha and theta range; "lafa" runs were obligate ictal patterns and were detected at all patients with MMPSI; frequently

Malignant Migrating Partial Seizures of Infancy (Coppola-Dulac Syndrome) DOI: http://dx.doi.org/10.5772/intechopen.82838

### Figure 6.

The same patient. Continuation of ictal EEG. Shift of ictal pattern in the left parietal-posterior temporal region to the delta slowing with slow epileptiform complexes. At the same time in the right hemisphere, emergence of a new ictal pattern in the form of low-amplitude fast activity (lafa). Manifestation: Short-term decrease of clinical ictal severity.

### Figure 7.

The same patient. Continuation of ictal EEG. Ictal pattern in the right hemisphere in the form of regular alphatheta activity with frontal-central accentuation. Postictal changes in the left hemisphere in the form of depression of the bioelectric activity with delta rhythm dominance. Manifestation: Asymmetrical tonic seizure with left-sided accentuation.

runs of fast regular spike-wave complexes were also identified; and runs of slow regular spike-wave complexes (rarely), and diffuse spike- and polyspike-wave discharges.

The following variants of ictal patterns have been identified in patients with MMPSI: regional "saw tooth" activity of alpha and theta range; "lafa" runs were obligate ictal patterns and were detected at all patients with MMPSI; frequently

The same patient. Continuation of ictal EEG. Slowing down of frequency characteristics of the diffuse ictal pattern with transformation to the delta slowing. In the opposite left parietal-posterior temporal region, activation of the regional ictal pattern with regionally accentuated polyspikes and spike-wave complexes is seen.

Manifestation: Transformation to asymmetric tonic seizure with right-sided clonic component.

The same patient. Continuation of ictal EEG. Diffuse spread of ictal epileptiform activity with multiple spikes. On this background, emergence of regional accentuation of ictal pattern in the left parietal-posterior temporal

region. Manifestation: Transformation to generalized tonic seizure with clonic component.

Epilepsy - Advances in Diagnosis and Therapy

Figure 4.

Figure 5.

120

### Figure 8.

Patient P.S., age 1 year and 1 month old. Ictal EEG. Diagnosis: Mixed form of MMPSI + EME.EEG reveals combination of suppression-burst pattern with polyspike waves and focal ictal patterns in the left frontal and right temporal areas independently.

Coppola et al. found left temporal lobe dual pathology in a child with MMRSI, including hippocampal sclerosis and cortical-subcortical blurring [23]. Caraballo et al. reported about mesial temporal lobe sclerosis in 3 of 17 patients [27]. Gross-Tsur et al. presented patients with MMPSI decreased N-acetyl aspartate in the frontal cortex and basal ganglia revealed by MR brain spectroscopy [30].

The same patient. Continuation of ictal EEG. EEG reveals combination of suppression-burst pattern and focal

In cases of cryptogenic MMPSI, minimal or moderate subatrophic changes initially were fixed, sometimes in combination with a moderate delay of myelination,

pharmacoresistant seizures. Dysgenetic brain malformations were found at neuroimaging only in two children with symptomatic analogs of MMPSI in the form of lissencephaly-pachygyria in one girl and polymicrogyria in another girl. Remaining ten patients with symptomatic analogs of MMPSI had a wide range of hypoxicischemic CNS lesions in the form of periventricular leukomalacia, parasagittal Chugani necrosis, and diffuse cortical-subcortical atrophy ("walnut" brain).

MMPSI is a drug-resistant epilepsy form with serious prognosis. Treatment approaches are still developing. Baseline, old, and new antiepileptic drugs in various combinations, as well as corticosteroids, are ineffective [1–3].

However, Dulac observed seizure aggravation during treatment with carbamazepine and vigabatrin in these patients [3]. Perez et al. observed temporary seizure remission in two cases of MMPSI with combination of stiripentol (metabolic drug, inhibitor of several cytochrome P-450 enzymes) and high doses

levetiracetam in MMPSI [32]. Okuda et al. [5] reported efficacy of potassium bromide in migrating partial seizures of infancy. A 3-month-old boy and a 4-month-old girl with failure of common antiepileptic drugs reached complete remission of seizures in one case and significant decrease of seizure frequency (95%) in another case due to treatment with potassium bromide 80 mg/kg/day [5]. In all cases of seizure control, gradual improvement in psychomotor development of children was observed that also proves the leading role of epilepti-

of clonazepam [31]. Hmaimess et al. published about effectiveness of

form activity and persistent seizures in the development of epileptic

but with progressive cerebral atrophy at 11 children with persistent

Malignant Migrating Partial Seizures of Infancy (Coppola-Dulac Syndrome)

5. Treatment

Figure 10.

ictal pattern in right occipital-posterior temporal area.

DOI: http://dx.doi.org/10.5772/intechopen.82838

encephalopathy [3].

123

Along with "classical" EEG pattern of MMPSI, atypical mixed variants were observed in the manner of superposition of continuous migratory multiregional SE pattern to suppression-burst pattern with diffuse polyspike-wave discharges (Figures 8–10). Five of these infants (three boys and two girls) had a special mixed form of epilepsy in the form of MMPSI combination with early myoclonic encephalopathy (EME) with the presence of multiple fragmented "erratic" myoclonus along with migrating focal status seizures.

Such mixed form with transformation of EME into MMPSI was also described by specialists from the Department of Pediatrics of the Taipei City Hospital Zhongxing Branch (Taipei, Taiwan) in a female neonate [29].

### 4.2 Neuroimaging

According to the world literature, CT and MRI changes are absent, and the majority of MMPSI cases are regarded as cryptogenic. Atrophic changes are nonspecific and further are exacerbated by the constant epileptic seizures [1, 25].

### Figure 9.

The same patient. Continuation of ictal EEG. EEG reveals combination of suppression-burst pattern and focal ictal patterns in the left centro-parietal area with central sagittal (vertex accent).

## Malignant Migrating Partial Seizures of Infancy (Coppola-Dulac Syndrome) DOI: http://dx.doi.org/10.5772/intechopen.82838

Figure 10. The same patient. Continuation of ictal EEG. EEG reveals combination of suppression-burst pattern and focal ictal pattern in right occipital-posterior temporal area.

Coppola et al. found left temporal lobe dual pathology in a child with MMRSI, including hippocampal sclerosis and cortical-subcortical blurring [23]. Caraballo et al. reported about mesial temporal lobe sclerosis in 3 of 17 patients [27]. Gross-Tsur et al. presented patients with MMPSI decreased N-acetyl aspartate in the frontal cortex and basal ganglia revealed by MR brain spectroscopy [30].

In cases of cryptogenic MMPSI, minimal or moderate subatrophic changes initially were fixed, sometimes in combination with a moderate delay of myelination, but with progressive cerebral atrophy at 11 children with persistent pharmacoresistant seizures. Dysgenetic brain malformations were found at neuroimaging only in two children with symptomatic analogs of MMPSI in the form of lissencephaly-pachygyria in one girl and polymicrogyria in another girl. Remaining ten patients with symptomatic analogs of MMPSI had a wide range of hypoxicischemic CNS lesions in the form of periventricular leukomalacia, parasagittal Chugani necrosis, and diffuse cortical-subcortical atrophy ("walnut" brain).

### 5. Treatment

Along with "classical" EEG pattern of MMPSI, atypical mixed variants were observed in the manner of superposition of continuous migratory multiregional SE pattern to suppression-burst pattern with diffuse polyspike-wave discharges (Figures 8–10). Five of these infants (three boys and two girls) had a special mixed form of epilepsy in the form of MMPSI combination with early myoclonic encephalopathy (EME) with the presence of multiple fragmented "erratic" myoclonus

Patient P.S., age 1 year and 1 month old. Ictal EEG. Diagnosis: Mixed form of MMPSI + EME.EEG reveals combination of suppression-burst pattern with polyspike waves and focal ictal patterns in the left frontal and

Such mixed form with transformation of EME into MMPSI was also described by specialists from the Department of Pediatrics of the Taipei City Hospital Zhongxing

According to the world literature, CT and MRI changes are absent, and the majority of MMPSI cases are regarded as cryptogenic. Atrophic changes are nonspecific and further are exacerbated by the constant epileptic seizures [1, 25].

The same patient. Continuation of ictal EEG. EEG reveals combination of suppression-burst pattern and focal

ictal patterns in the left centro-parietal area with central sagittal (vertex accent).

along with migrating focal status seizures.

Epilepsy - Advances in Diagnosis and Therapy

4.2 Neuroimaging

Figure 9.

122

Figure 8.

right temporal areas independently.

Branch (Taipei, Taiwan) in a female neonate [29].

MMPSI is a drug-resistant epilepsy form with serious prognosis. Treatment approaches are still developing. Baseline, old, and new antiepileptic drugs in various combinations, as well as corticosteroids, are ineffective [1–3]. However, Dulac observed seizure aggravation during treatment with carbamazepine and vigabatrin in these patients [3]. Perez et al. observed temporary seizure remission in two cases of MMPSI with combination of stiripentol (metabolic drug, inhibitor of several cytochrome P-450 enzymes) and high doses of clonazepam [31]. Hmaimess et al. published about effectiveness of levetiracetam in MMPSI [32]. Okuda et al. [5] reported efficacy of potassium bromide in migrating partial seizures of infancy. A 3-month-old boy and a 4-month-old girl with failure of common antiepileptic drugs reached complete remission of seizures in one case and significant decrease of seizure frequency (95%) in another case due to treatment with potassium bromide 80 mg/kg/day [5]. In all cases of seizure control, gradual improvement in psychomotor development of children was observed that also proves the leading role of epileptiform activity and persistent seizures in the development of epileptic encephalopathy [3].

Chien et al. have stopped erratic myoclonus and suppressive-burst pattern on EEG in a mixed form of EME + MMPSI using dextromethorphan 20 mg/kg [29].

6. Prognosis

populations:

MMPSI is a form of epilepsy with poor prognosis. Within a few months after disease onset, frequency and duration of seizures increase up to the serial seizures and status epilepticus. A number of patients die in the first year of life due to multiple prolonged epileptic seizures, development of respiratory distress syndrome, and decorticate rigidity [30]. Based on the generalized clinical observations, mortality in this syndrome is 28% [3]. The results obtained by Marsh et al. are prognostically more favorable: during the 7-year follow-up, all six patients survived; however, psychomotor retardation with severe muscular hypotonia persisted in three of them, and only one patient reached seizure control for a long time [25]. Mortality at personal observed cases was 25.7% (n = 9); however, the expected

Malignant Migrating Partial Seizures of Infancy (Coppola-Dulac Syndrome)

mortality is higher due to short follow-up (1 year) in more than half of these patients. The oldest of the survived patients with MMPSI is 9 years old; there is gross delay of psychomotor development with unformed verticalization skills, absence of voice activity, spastic tetraparesis, and multiple focal asymmetric tonic,

Follow-up of patients with MMPSI allowed distinguishing the following sub-

• "Classical" form in the form of marked SE of migrating multifocal seizures is pharmacoresistant with a poor prognosis for psychomotor development,

• Mixed form (MMPSI + EME) with a combination of electro-clinical MMPSI characteristics but also with the presence of fragmented "erratic" myoclonus and suppression-burst pattern with polyspike-wave discharges on EEG (five cases, 14.3%) with also poor prognosis for mental and motor functions,

• "Moderate" or "mild" form with a consistent evolution from unifocal form to multifocal form with EEG pattern MISF, and then developed expressed MMPSI electro-clinical characteristics, but with a possible regression and decrease in frequency of seizures during combined antiepileptic therapy (six cases, 17.1%).

• "Subtle" form, in the form of only "subtle" minimal motor seizures, inhibitory seizures, multiple ictal patterns during sleep, and leading to awakening (five cases, 14.3%). This form causes a rough developmental delay in infants, but

without video-EEG monitoring, it remains unrecognized [20].

MMPSI is an independent epileptic syndrome with special clinical-

neurophysiological characteristics, distinct from other forms of epilepsy. Diagnosis can be established if there are different types of focal seizures, involving multiple extended EEG and electro-clinical ictal EEG patterns with involvement of several independent areas in both hemispheres. All the patients need complex investigations including dynamic video-EEG monitoring, neuroimaging, and genetic tests

MMPSI should also be differentiated from the syndrome described by Ohtahara – "severe epilepsy with multiple independent spike foci" (SE-MISF). In

versive, pharyngo-oral, and dialeptic seizures.

DOI: http://dx.doi.org/10.5772/intechopen.82838

seizures, and life (19 cases, 54.3%).

(whole-exome sequencing is more preferable).

seizures, and life.

7. Conclusions

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There are different opinions about usefulness of ketogenic diet in MMPSI. So, François et al. proclaimed that seizures in MMPSI are also resistant to ketogenic diet [33]. But specialists from Children's Neuroscience Centre of Royal Children's Hospital (Parkville, Victoria, Australia) published data about efficacy of the ketogenic diet in children with this pharmacoresistant form of epilepsy [34].

Surgical treatment of MMPSI is unreasonable because of diffuse nature of brain damage and lack of clear local structural defect [3]. Theoretically, anterior callosotomy may be offered as a palliative intervention; however, there is no such experience in this form of epilepsy.

A group of scientists from the Pediatric Neurology Department of Azienda Ospedaliera Universitaria (Ancona, Italy) have published about positive experience of vagus nerve stimulation (VNS therapy) in three infants with pharmacoresistant MMPSI [35].

Our cases confirmed that MMPSI are resistant to antiepileptic therapy. Monotherapy had no significant effect in all patients. All patients with MMPSI failed to relieve from epileptic seizures. In 14 MMPSI cases, antiepileptic therapy was completely ineffective (56%), reduction of seizures >50% was observed in seven patients (28%), and only in six patients decrease of seizures was >75% (17.16%). Relatively effective combinations of antiepileptic drugs included valproates with barbiturates (phenobarbital and hexamidine) and benzodiazepines. Clobazam 1 mg/kg was most effective among benzodiazepine groups. In two patients positive effect was observed with combination of levetiracetam, and in one case – with combination of benzodiazepine and topiramate. Phenytoin in two cases caused moderate positive effect with "escape effect." In one patient, frequency of seizures decreased during treatment with potassium bromide (50 mg/kg) but with side effects in the form of hypersomnia. High doses of vitamin B6 in two cases were moderately positive.

Ethosuximide, rufinamide, carbamazepine, and oxcarbazepine have no substantial positive effect. In one case, carbamazepine in cryptogenic focal frontal epilepsy with temporary positive effect caused subsequent aggravation of seizures with appearance of additional foci with clinical and electroencephalographic transformation into MMPSI.

Hormone therapy caused only a temporary moderate positive effect in eight cases and was completely ineffective at other cases.

For emergent relief of SE of hemiconvulsive and secondary generalized tonic-clonic seizures in 15 cases of MMPSI, benzodiazepines (relanium and midazolam) had only a temporary effect in eight or were completely ineffective in seven cases.

Positive effect in SE in MMPSI was observed with sodium oxybate administration at a dose of 100–150 mg/kg, 400 mg/min. This was done in seven cases of hemiconvulsive (n = 3) and secondary generalized tonic-clonic SE (n = 4) resistant to benzodiazepines with a temporary regression (six cases) or a decrease of clinical-EEG paroxysmal events (one case).

In three patients with MMPSI, intravenous valproates caused significant positive effect in relieving SE, especially in cases of tonic-autonomic seizures with episodes of apnea, with aggravation during treatment with benzodiazepines [36]. The recommended dose was 25 mg/kg intravenous over 5 min with the following maintenance infusion – 2 mg/kg/h.

Sodium thiopental (4 mg/kg for 2 min and then infusion of 0.2 mg/kg per minute) is the last chance to stop drug-resistant SE but caused death in one girl due to central inhibition of cardiac activity.

Malignant Migrating Partial Seizures of Infancy (Coppola-Dulac Syndrome) DOI: http://dx.doi.org/10.5772/intechopen.82838
