3. Clinical signs

At the present time, at least about 100 cases of MMPSI appear to be described in the world literature. However, the number of publications has been steadily growing in recent years. Obviously, this serious disease is more common than diagnosed due to the low clinicians' awareness. In the structure of patients with onset of status epilepticus before 3 years of age (n = 267), a group of children with MMPSI consisted 4.9% (n = 13), and in the structure of infant with SE (n = 147) – 8.8% [24].

Both sexes are equally susceptible. According to Dulac, 20 children with MMPSI included 9 girls and 11 boys [3]. Disease onset varies in age from 1 week to 7 months of life (average – 3 months) [1, 4]. According to Marsh et al., seizures onset varied from the first days to 3 months (average – 25 days) [25].

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

In most cases, pattern of the first seizure includes motor component of one limb or half of the body; and 50% of the patients develop secondary generalization. In some cases after seizure onset, their frequency uncontrolled rapidly rises to status epilepticus. However, seizures could have longer duration, but at onset seizures often go unrecognized. Cases with autonomic manifestation (episodes of apnea, short blackouts with cyanosis or redness) are difficult to diagnose [3]. Thus, in observation by Gerard et al. [4], epileptic seizures with diffuse erythema and sweating with subsequent hiccups were reported as gastroesophageal reflux, and only a few weeks later, addition of focal seizures was noted, which made diagnosis obvious [4]. According to observations by Dulac, the initial period of the disease usually lasts from 1 week to 3 months (average – 45 days). During this period, seizures may be quite rare, for example, once a week [3].

In the age of 24 days to 10 months (mean 4.5 months), seizures become very frequent and polymorphic but usually are still focal. Seizures usually get clustered (serial) nature, mental and motor retardation is clear. Clinical manifestation of seizures may include head and eye version, lateralized eyeball twitching, fixed gaze, clonic eyelid twitching, tonic tension or clonic spasms of one limb or hemispasms, axial tonic spasms, chewing or sucking movements, episodes of apnea, flushing, hypersalivation, and secondary generalized seizures. One patient may have multiple different combinations of seizures. Typically, seizure duration is 1–4 minutes, but in some cases, it may persist up to several 1 of minutes, until the status epilepticus development. As far as the disease progresses, secondary generalized seizures became more frequent. Seizures are almost continuous or occur as a series 5–30 times per day, mainly on awakening and when falling asleep. Seizure periods may alternate with clear periods when seizures occur within 2–5 days continuously, and then there are several "light" days (the cyclic course of disease) [1–3, 26].

It should be considered that many seizures are hardly noticeable visually and often remain unrecognized for parents and medical staff. In particular, these are "volatile" paroxysms, as short episodes of apnea, episodes of eyes closing or eyes deviation, episodes of facial flushing, etc. Only video-EEG monitoring can prove the epileptic genesis of paroxysmal phenomena.

The course of the disease and the severity of clinical symptoms often have undulating pattern: a period of severe illness and permanent seizures may continue for several weeks, and then it is replaced by a relatively favorable period of the temporary seizure regression and some improvement in cognitive and motor functions. This phenomenon generates additional difficulties in controlling the quality of care as it is quite difficult to differentiate in which case the decrease in frequency and severity of seizures is a true response to therapy and in which case it is subject to the course of the disease.

Under personal observation of patients with MMPSI, age of seizure onset ranged from the 1st day of postnatal life up to 6 months of life. MMPSI were characterized by marked polymorphism (Table 2) and high frequency of epileptic seizures and were in fact a special form of infantile status epilepticus (SE) in the form of migrating multifocal SE. All patients had five or more types of epileptic seizures.

Neurological findings in MMPSI children marked with neurological impairment from birth‑severe central tetraparesis, often with muscular hypotonia in the axial and limb muscles [1], microcephaly, strabismus, and athetoid hyperkinesis [25]‑are common. Many patients in dynamics are unable to walk and sit without support and in severe cases are also unable to control the vertical head position, drink, and swallow. In all cases, there is mental retardation, usually severe, and visual agnosia [3].

Personal patients with MMPSI (n = 35) in neurological status had a high representation of various disorders: high level of stigmatization was observed in 15

2.2 Chromosome aberrations

Epilepsy - Advances in Diagnosis and Therapy

hypotonia, and microcephaly [21].

2.3 Other etiological factors

ogy [1–3, 20, 23].

MMPSI picture.

3. Clinical signs

114

amygdala, lateral septum, and olfactory bulb [22].

At 2010 group of genetics from the Department of Pediatrics, University of

In 2012 Poduri and colleagues from the Department of Neurology of Children's Hospital Boston (Massachusetts, USA) in a patient, born of consanguineous Palestinian parents, with clinical manifestation as MMPSI, identified a homozygous 486 kb deletion on chromosome 20p12.3 encompassing the promoter region and exons 1, 2, and 3 of the PLCB1 gene. The deletion breakpoints were mapped from

8,094,049–8,094,072 to 8,580,261–8,580,284 (GRCh37). The breakpoints lie within two LINE nuclear elements and likely arose from nonallelic homologous recombination. PLCB1 gene (607,120; locus 20p12.3) is responsible for early infantile epileptic encephalopathy type 12 (EIEE12; 613,722). Phospholipase C-beta (PLCB) catalyzes the generation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate (IP2), a key step in the intracellular transduction of many extracellular signals. The PLCB1 gene encodes a mammalian PLCB isoform that is expressed in cerebral cortex, hippocampus,

Most cases of MMPSI are considered as unknown etiology (cryptogenic). But also MMPSI had its symptomatic analogs including cases considered as dual pathol-

In two of three cases for the first time presented by Coppola et al., neuropathologic brain examination showed marked loss of hippocampal neurons in combina-

Personal observation of 35 cases with MMPSI contains 12 children with symptomatic clinical-electroencephalographic copies of MMPSI (5 boys and 7 girls). Only two infants had cerebral dysgenesis: lissencephaly-pachygyria in one girl and polymicrogyria in another girl. Other ten children had severe perinatal hypoxicischemic CNS disturbances (four of them mixed with perinatal infections‑cytomegalovirus, ureaplasma, chlamydia, herpes type 1) that caused serious brain damage, tetraparetic spastic form of cerebral palsy, and severe retardation in combination with epileptic encephalopathy. Their clinical and video-EEG signs demonstrated

At the present time, at least about 100 cases of MMPSI appear to be described in the world literature. However, the number of publications has been steadily growing in recent years. Obviously, this serious disease is more common than diagnosed due to the low clinicians' awareness. In the structure of patients with onset of status epilepticus before 3 years of age (n = 267), a group of children with MMPSI consisted 4.9% (n = 13), and in the structure of infant with SE (n = 147) – 8.8% [24]. Both sexes are equally susceptible. According to Dulac, 20 children with MMPSI included 9 girls and 11 boys [3]. Disease onset varies in age from 1 week to 7 months of life (average – 3 months) [1, 4]. According to Marsh et al., seizures onset varied

from the first days to 3 months (average – 25 days) [25].

tion with gliosis in the CA1 sector of hippocampal pyramidal layer [1, 23].

Michigan (Ann Arbor, Michigan, USA), has found de novo 598 kb 16p11.2 microduplication in a boy with refractory MMPSI, who has developed seizures in 4 months and also has spastic quadriparesis, severe global developmental delay,


undetected, especially if symptoms include only short autonomic paroxysms. Epileptiform disorders in disease onset are rare. However, in 3 of 14 patients in the observation by Gerard et al. [4], originally normal background EEG was observed; later, slowing with variable asymmetry was recorded in all cases. Often, slow-wave accentuation in one of the EEG recordings is more pronounced in one hemisphere, while the later study may reveal dominating slow-wave lateralization from the opposite side. Multiregional spikes without clear activation during sleep are registered in all cases during development of the disease. However, pathognomonic interictal EEG pattern in MMPSI is absent. During the period relatively free of seizures, stage differentiation in the structure of sleep EEG may persist, but sleep spindles are rare and usually asymmetric [3]. When seizures become very frequent,

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

Ictal EEG patterns involve different areas of the cerebral cortex in the course of successive seizures. Ictal pattern is a rhythmic activity of alpha and theta range, occurring in one region with adjacent regions involvement during seizure, followed by a gradual decrease of the frequency characteristics. Caraballo with colleagues, analyzing 17 infants with MMPSI, had distinguished three different EEG patterns: 8 cases with alternating simple focal motor seizures at onset, and the ictal EEG pattern was characterized by recurrence of rhythmic focal spikes or rhythmic sharp theta or alpha activity in the Rolandic region; 5 cases with complex focal seizures and progressive appearance of polymorphic theta-delta in temporo-occipital regions recurring independently; and 4 cases with focal complex seizures with motor manifestations and ictal EEG with flattening or fast activity in frontotemporal region followed by unilateral fast polyspikes in alternating clusters in both hemispheres. Correlations between these three patterns with severity or prognosis were not found [27]. Electro-clinical seizure patterns last from 1 to 4 minutes. Multiple subclinical ictal EEG patterns lasting from 30 seconds to 1 minute are also typical [1]. Observations show an alternative cortical section of both hemispheres'

involvement in epileptogenesis, which implies the presence of a diffuse pathological

When seizures become very frequent, initial zone of ictal pattern shift from one region to another and from one hemisphere to another occurs. As a result, extended, migratory ictal activity, which forms a complex EEG pattern of status epilepticus,

Video-EEG monitoring plays the most important role in the MMPSI diagnosis, as it is able to detect a correlation between ictal pattern localization of and clinical characteristics of seizure. Thus, ictal pattern in the frontal region produces clinical signs in the form of tonic tension or clonic spasms in the contralateral limb; ipsilateral automatisms or a versive seizure with alternating tonic phenomena and fencing posture are possible. EEG pattern is localized in perirolandic area and manifests with contralateral clonus of the lips, tongue, facial muscles, and hypersalivation. Temporal EEG patterns clinically manifest with broad "frozen" gaze ("staring" phenomenon) and oro-alimentary automatisms. Ictal EEG patterns originating from occipital cortex correlate with lateralized clonic eyes and head twitching. In the case of parietal pattern, nonspecific motor activity is possible; sometimes, a child seems "listening" to his/her inner feelings. The above phenomena are contrary to a prevailing opinion that there is no clear clinical-electroencephalographic corre-

lation of focal ictal patterns in infants and rather suggest the opposite.

As child grows, the amplitude of ictal activity tends to increase with growing involvement of the frontal lobes; many seizures become secondarily generalized. The phenomenon of secondary bilateral synchronization typically occurs after only a few weeks from the onset [1]. However, Gerard et al. [4] in the last observations found a delay of bilateral synchronization and additional foci of epileptiform

interictal activity is almost absent.

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

process in the cerebral cortex [3].

develops [1–3].

117

### Table 2.

Epileptic seizure types in patients with malignant migrating partial seizures of infancy (n=35)

patients (42.8%), 13 patients (37.1%) had microcephaly, and optic nerve atrophy was observed in 27 patients (77.1%). Disorders of bulbar innervation were observed in all patients, while in nine children (25.7%), these impairments were bulbar syndrome, and in 26 children (74.3%) – pseudobulbar syndrome. All patients with MMPSI had changes in the muscle tone: 10 children (28.6%) had spastic hypertonus, 16 children (45.7%) had diffuse muscle hypotonia, and 9 children had dystonic changes (25.7%). Severe movement disability with tetraparesis was formed in all of the children with MMPSI. Neurological disorders were expressed at birth (n = 16, 45.7%) or developed with the onset of seizures (n = 19, 54.3%) and tended to a steady progression in all the patients. All children with MMPSI had delay of motor and mental development (n = 35, 100%), up to a complete development stop in 26 infants (74.3%).
