Epileptic syndromes with onset in the neonatal period or infancy with very poor prognosis have been recognized or better defined in recent years due to developments in diagnostic techniques, including video-electroencephalography, brain imaging, and cytogenetics. Migrating partial seizures in infancy (MPSI) is a rare, newly recognized, age-specific epileptic syndrome first described in 1995 by Coppola et al.³ In the proposed revision of the International League Against Epilepsy (ILAE) diagnostic scheme for people with epileptic seizures and with epilepsy, MPSI was labeled as a syndrome in development and included among symptomatic and probably symptomatic focal epilepsies.⁷ It is characterized by onset in the first 6 months of age, after a normal early development, of nearly continuous multifocal partial seizures arising independently and sequentially from both hemispheres, progression through a period of intractable seizures, subsequent neurologic deterioration or arrest with complete loss of both cognitive and motor abilities and, in most children, progressive decline of head circumference percentile.

MPSI was first reported in 1995 by Coppola et al.,³ who described 14 infants with a severe epileptic disorder characterized by seizure onset in the first year of life; nearly continuous multifocal seizures involving both hemispheres; no identifiable immediate or remote cause; normal neuroimaging studies at onset; and intractability to conventional antiepileptic drugs (AEDs), including phenobarbital, phenytoin, carbamazepine, valproate, vigabatrin, clobazam, nitrazepam, biotin, vitamin B₆, and corticosteroids. In this first description, the outcome was very poor with regard to both the seizure disorder and psychomotor development. Only 2 of 14 patients stopped having seizures with a combination of stiripentol and clonazepam and showed some neurologic improvement. Eleven patients developed microcephaly during the first year of life, and three patients died. After this original report, additional cases from Australia, Europe, Japan, and the United States were published.^{4,10,11,13,15,17,22} Thirty-three cases have now been reported. In particular, two cases have been reported from Australia²² that fulfill the diagnostic criteria proposed by Coppola et al.³ Both infants presented with intractable partial seizures arising independently from multiple regions of both hemispheres, with interictal electroencephalograms (EEGs) revealing multifocal epileptiform activity. There was no response to AEDs, pyridoxine, and corticosteroids, and developmental arrest followed seizure onset. Extensive investigations failed to identify an underlying cause. Both infants died. One of them underwent postmortem examination, which was normal.

Veneselli et al. reported three infants in whom seizure onset occurred before 3 months of age and was characterized by focal motor manifestations with a gradually increasing frequency.¹⁷ Either hemibody was alternatively and randomly involved, and secondary generalization was evident only during the evolution of the disease. Conventional AEDs were uneffective. No etiologic factors have been identified. Neurologic status and evolution were highly unfavorable, resulting in death in one case and severe neurodevelopmental morbidities in the others. The same malignant course, with regard to both seizure disorder and ultimate outcome, was described by Gross-Tsur et al. in two additional cases.¹⁰ One infant, microcephalic at birth, developed at age 4 months clusters of nearly continuous multifocal seizures with secondary generalization, refractory to antiepileptic drugs. By the age of 4.5 years she was seizure free but remained without any cognitive or motor function. The other, born with a normal head circumference, began seizures at the age of 3 months, never became seizure free, and died at age 18 months. Neuroimaging findings showed progressive subcortical atrophy. In both cases, extensive evaluation including skin and muscle biopsy did not clarify the etiology. However, more recently, Marsh et al.¹³ reported six new patients with the same clinical and electroencephalographic characteristics as those described by Coppola et al.³ but with the prospect of a more optimistic developmental outcome, raising the difficult distinction at onset with benign infantile or neonatal-infantile seizures. Each patient underwent comprehensive brain imaging and neurometabolic evaluations, which were unrevealing. Five patients had a long-term follow-up. Whereas all had some degree of neurodevelopmental sequelae, a few of them appeared to be less severely affected: One was able to walk, one developed some degree of spoken language, two showed developmental quotients between 50% and 100%, and only one was profoundly impaired. In terms of seizure outcome, one was still having intractable seizures when lost to follow-up. For five of six patients, six or more AEDs failed. Two patients received adrenocorticotropic hormone (ACTH); two were treated with folinic acid, and two were placed on ketogenic diet. None of them was more successful than the others. In contrast, successful seizure control was obtained with potassium bromide by Okuda et al. in two patients with a diagnosis of MPSI and refractory to conventional AEDs.¹⁵ Moreover, once seizures were controlled, both patients showed some degree of neurologic recovery. A recently published case report by Hmaimess et al. in 2006 described the first neonatal case of MPSI and documented a positive response to levetiracetam.¹¹ Unfortunately, despite the dramatic decrease in seizure activity, which paralleled a positive clinical evolution in terms of psychomotor development, the child died unexpectedly at 14 months of age. The most recent three cases at the time of this review have been reported by Coppola et al., who performed a mutational scanning of potassium, sodium, and chloride ion channels (KCNQ2, KCNQ3, SCN1A, SCN2A, and MECP2) but
failed to find any mutations.⁴ Finally, it is important to consider that studies on drug-resistant seizures with early onset classified as “catastrophic infantile epilepsy” may include cases of MPSI. Ishii et al.¹² investigated clinicoelectrical and etiologic characteristics of 15 patients with catastrophic infantile epilepsy. Although some of these patients did not belong to MPSI, a number of them, mainly those without a clear etiology, clinically and electroencephalographically resemble this syndrome.

MPSI is a severe, probably symptomatic, age-dependent focal epilepsy defined by the following diagnostic criteria: (a) normal development before seizure onset; (b) seizures beginning before age 6 months; (c) migrating focal motor seizures at onset; (d) multifocal seizures becoming nearly continuous; (f) intractability to conventional AEDs; (e) lack of demonstrable etiology; and (g) severe psychomotor delay on follow-up. The clinical features and EEG pattern suggest that MPSI may rank among the catastrophic epilepsies of infancy. Moreover, due to the high frequency of seizures and the intense epileptiform activity that contribute to the progressive disturbance of cerebral function, MPSI could also be included in the epileptic encephalopathies.

Its prevalence is unknown because only small series of patients have been published.^{4,10,11,13,15,17,22} Both sexes are equally affected.

The etiology is not known, but a functional or metabolic disorder is suspected. All reported patients had normal magnetic resonance imaging (MRI) and computed tomography (CT) scans at the onset of seizures. There is no evidence of familiarity because no familial recurrence of migrating seizures has been reported, and there is no consanguinity. In the series reported by Coppola et al., three patients had family history of febrile seizures and four of epilepsy.³ Veneselli et al. reported one patient with a family history of first-degree seizures.¹⁷ Neurometabolic evaluations performed in all cases have excluded inborn errors of metabolism. In those cases that were examined with postmortem, neuropathology failed to demonstrate cortical dysplasia, neuronal migration defects, or cortical vacuolation.^3,22 Preliminary genetic studies excluded any abnormality in the coding region of several relevant sodium, potassium, and chloride ion channel gene involved in other epileptic syndromes of the first year of life, suggesting lack of any molecular link between benign familial neonatal or neonatal-infantile seizures or Dravet syndrome and MPSI.⁴

The first seizure occurs before 6 months of age (1 day to 6 months; mean 25 days) in normal infants, who have no antecedent risk factors. Seizures begins with focal motor movements that can alternate from one side of the body to another with lateral deviation of the head and eyes and eye jerks, twitching of the eyelids, limb myoclonic jerks, and increased tone of one or both limbs.^{3,4,10,11,13,15,17,22} At the beginning, many of the motor manifestations are relatively subtle and easily overlooked both by parents and the nursing staff, such as fixed sight, psychomotor arrest, lateral deviation of the eyes, and chewing-like movements. Sometimes, electrical seizures are not associated with any clinical manifestations, although they may spread and involve both hemispheres.^13,22 It is also worth mentioning that in very young patients motor and autonomic signs are often the only clinically relevant symptoms of seizures. Focal motor components are often accompanied by autonomic signs including flushing of the face, salivation, and apnea.^3,13,15,17 Epileptic spasms have been described in only one patient, appearing during the course of the disease and associated with a focal discharge.³ Truly generalized tonic–clonic seizures are very rare.²² The combination of these various manifestations produces a wide range of ictal semiology that may vary in a given infant from one seizure to another, although there are predominant focal motor components. Prolonged observation soon shows that both sides are alternatively affected, which demonstrates the involvement of the whole brain cortex. Seizures are relatively brief, but often last several minutes, and thus are longer than observed in patients with benign seizures in infancy. In addition, they tend to recur in series of 5 to 30 seizures during drowsiness and/or at awakening, several times a day. Such clusters may last up to 2 to 5 days. Initially seizures are rare, occurring roughly once a week. Nevertheless, two patients presented with status epilepticus.³ Soon after, seizure frequency tend to increase and, at an age ranging from 24 days to 10 months, become almost continuous in most of the reported cases. These consecutive seizures can overlap, with one seizure beginning before the end of the previous one (Fig. 1).^3,11 At this stage, seizures tend to cluster, and clusters of seizures may last up to 2 to 5 days. Between seizures during these clusters, infants are floppy, drooling, often somnolent, and unable to drink and swallow. Between clusters, the infant may recover partially. As patients recover slightly, however, the next cluster occurs and patients regress. Moreover, with time, seizures tend to generalize more frequently.