Clinical manifestations

Presentation and course

The first sign of the syndrome is a sudden, prolonged hemiconvulsion in the form of status epilepticus. It occurs in a child without antecedents, between 5 months and 4 years old, with a peak incidence during the first two years of life. A febrile episode is almost always associated, but in many cases, no cause is obvious (05). The onset of convulsions may pass unnoticed, the child being discovered convulsing in bed. They present as predominantly unilateral clonic jerks. The rhythm is variable, and the jerks can be asynchronous. Impairment of consciousness is not a permanent or even constant feature. In long-lasting convulsions, jerks may diffuse to the opposite side or change sides. Aversion of head and eyes may be observed, sometimes even before the occurrence of jerks. Autonomic symptoms (hypersalivation, cyanosis, etc.) may be associated.

If untreated, hemiconvulsions may last for several hours.

Massive flaccid hemiplegia immediately follows the unilateral seizure. When jerks change sides, it is usually the side involved last that remains hemiplegic. Evolution of hemiplegia is variable. It can either remain as a permanent neurologic deficit with signs of spasticity or decrease progressively, leaving behind a slight hemiparesis. To differentiate hemiplegia from Todd paresis, a minimum duration of seven days is arbitrarily set. In more than 80% of the cases, the hemiplegia is permanent (25). Rarely, it may disappear completely, although some degree of spasticity and pyramidal signs usually persist. In contrast with congenital hemiplegia, the face is constantly involved, and aphasia is present in left-sided cases.

Focal seizures of temporal, extratemporal, or multifocal origin appear within 1 to 5 years in 80% of patients. Most of the patients also have secondarily generalized tonic-clonic convulsions and often convulsive status epilepticus. An unusual case of a child with typical hemiconvulsion-hemiplegia epilepsy later developed "hemi-Lennox-Gastaut-like phenotype" from the unaffected brain hemisphere (45).

Seizures are usually resistant to antiseizure medication. Intellectual disabilities are common.

Prognosis and complications

Prognosis clearly depends on prompt treatment of the initial prolonged episodes. Following the initial febrile episode, prophylactic treatment of febrile convulsions is indicated. This may prevent recurrence of febrile convulsions, but it doesn't seem to prevent the later development of focal epilepsy. The long-term outcome for patients with hemiconvulsion-hemiplegia-epilepsy syndrome is, so far, unclear. In a case study, a favorable seizure-free outcome over 10 years was reported in a 24-year-old patient taking antiseizure medications (37). In a study of five patients, hemiconvulsion-hemiplegia-epilepsy syndrome was associated with language reorganization, but poor cognitive outcome (43). In cases of delayed epilepsy, surgical outcome may be good, especially when the mesial temporal lobe appears to be the only epileptogenic area (38).

In an attempt to further characterize the types of epilepsy within the setting of hemiconvulsion-hemiplegia-epilepsy syndrome, Chauvel and Dravet analyzed a series of 37 adult patients at Sainte-Anne Hospital in Paris for surgical therapy (17). The age of HH syndrome ranged from 1 month to 9 years. Only 19% presented the initial episode after the age of three years. By definition, and on the basis of the inclusion criteria used, all patients presented with drug-resistant focal epilepsy, and they all had a hemicorporeal motor deficit of variable degree. The majority of the patients had several seizure types, whereas only nine patients (24%) had one type of seizures. The epileptogenic zone was considered unifocal in 29 patients and multifocal in eight patients. In the unifocal group, a striking predominance of suprasylvian localizations was found, as compared to the pure temporal lobe epilepsies in five patients. In 14 patients of the 29 patients (nearly 50%), the epileptogenic zone included the frontocentral and parietocentral regions; prefrontal epilepsies were rare, and no pure occipital epilepsy was reported. In the multifocal group, a predominant involvement of the parietal lobe was noticed in seven of eight patients.

Clinical vignette

At the age of 23 months while on holiday in a Third World country, a 19-month-old girl had experienced a status epilepticus, comprising predominantly a left-sided seizure during an acute febrile attack. The seizures lasted 90 minutes. No cause was found. This episode of focal status was followed initially by a flaccid left hemiplegia, which gave way to a permanent and severe spastic hemiparesis not affecting the face. During the next 3 years, she received treatment with phenobarbital and physiotherapy. Her motor disability concerned mainly the left hand. She initially went to normal school but always had some difficulties. EEGs showed clear-cut asymmetry, and CT scan evidenced hemispherical atrophy.

Ten years later, she started having focal seizures. They usually began with elementary visual hallucinations followed by automatisms mainly of the right arm. Secondary generalization was rare. She also described a feeling of contraction of the left arm. Frequency was rather variable, but she could experience up to six episodes in a day. A few years later, she was obliged to abandon normal school; her IQ was evaluated at 59. Several antiepileptic drugs, at optimal doses, failed to control her seizures. Last year, she took gabapentin and topiramate and experienced a considerable reduction in seizure frequency and intensity. Regular injection of botulin toxin allowed her to partially use her left hand.

Biological basis

Etiology and pathogenesis

Prolonged clonic convulsions with a marked unilateral predominance usually occur in the course of a febrile disease. Causes of the initial convulsions are multiple. A number of acute cerebral disorders have been occasionally related to the occurrence of the syndrome (meningitis, subdural effusions, head trauma, etc.). In many cases, no cause is obvious (idiopathic hemiconvulsion-hemiplegia-episode syndrome), and such cases may represent only prolonged febrile convulsions that do not otherwise differ from common febrile convulsions. In such cases, the seizure activity itself could be responsible for the appearance of new lesions occurring in a previously normal brain. Alternatively, the presence of a preexisting asymptomatic lesion of perinatal or prenatal origin may be responsible in a number of cases (hemiconvulsion-hemiplegia-episode syndrome of structural etiology) for the initiation or localization of the seizure. The prolonged seizure would then produce or contribute to the development of irreversible brain damage with resultant focal epilepsy (06; 42; 54; 53; 03; 09).

The role of long-lasting febrile convulsions, as part of a hemiconvulsion-hemiplegia-episode, in the genesis of hippocampal sclerosis and consequent mesial temporal lobe epilepsy remains disputed. A statistical association is well demonstrated (51), and there are strong arguments in favor of an etiologic relationship (33); however, the presence or absence of other contributing factors is not clearly established (58; 57; 09; 12; 34). Furthermore, focal epilepsy in hemiconvulsion-hemiplegia-episode syndrome can be temporal, extratemporal, or multifocal.

Hirayama and colleagues reviewed 55 children with acute encephalopathy participating in a Status Epilepticus Study Group from 1988 to 2013 (31). Acute encephalopathy was classified into eight subtypes: acute encephalopathy with biphasic seizures and late reduced diffusion; hemiconvulsion-hemiplegia syndrome; acute necrotizing encephalopathy; hemorrhagic shock and encephalopathy syndrome; clinically mild encephalitis/encephalopathy with a reversible splenial lesion; acute encephalitis with refractory, repetitive partial seizures; Reye-like syndrome; and unclassified. Of the 55 cases, 14 (25.4%) had underlying neurologic disorders, including perinatal insults (n=6) and genetic syndrome and/or brain malformations (n=8). These preceding morbidities were relatively common in hemiconvulsion-hemiplegia syndrome (3 out of 9, 33.3%). Also, a history of epilepsy or febrile seizures were frequent in hemiconvulsion-hemiplegia syndrome (4 out of 9, 44.4%), whereas they were rare in other acute encephalopathy subtypes (31).

The existence of predisposing genetic factors has been discussed (48; 12). A high incidence of family history of febrile convulsions is frequently present (19; 02). In a report by Yamazaki and colleagues, a mutation (S218L) in the gene for calcium channel voltage-dependent P/Q-type alpha 1A subunit (CACNA1A), associated with familial hemiplegic migraine, was identified in a 5-year-old girl presenting with hemiconvulsion-hemiplegia-epilepsy syndrome (66). A number of different mutations in CACNA1A have been identified in patients with familial hemiplegic migraine, and of these, severe attacks with unilateral cerebral edema after trivial head trauma are associated with the mutation S218L. This genetic association may, therefore, reveal shared pathologic mechanisms associated with hemiconvulsion-hemiplegia-epilepsy syndrome and familial hemiplegic migraine.

In two cases, the clinical similarity with Dravet syndrome led to the identification of a mutation in SCN1A, although no such mutations were revealed in a series of 10 patients with hemiconvulsion-hemiplegia-epilepsy syndrome (55; 39). Robinson and colleagues reported a 3-year-old boy with a 1;3 translocation leading to a terminal 1q43q44 deletion and a terminal 3p26.1p26.3 duplication who developed hemiconvulsion-hemiplegia-epilepsy syndrome after a prolonged febrile seizure (50). The authors discuss the pathogenesis of this condition in the context of the patient's complex genetic background.

Association of hemiconvulsion-hemiplegia-epilepsy syndrome with microdeletion of 1q44 (case report) has also been published, although it is not clear whether this was causal or coincidental association (30). Furthermore, microdeletion (9.1 Mb) in 5q33.3q34 has been reported in a patient with hemiconvulsion-hemiplegia-epilepsy syndrome and global developmental impairment (65).

A report of a 9-month-old girl with L-2 hydroxyglutaric aciduria who presented with hemiconvulsion-hemiplegia-epilepsy syndrome has also been published (41). The patient had homozygosity for the p.Lys81Glu (c.241A> G) missense mutation of the L-2-hydroxyglutarate dehydrogenase gene.

Hemiconvulsion-hemiplegia-epilepsy syndrome has also been described in a few cases with influenza-associated encephalitis/encephalopathy in Australia (16) and in a girl with genetic cobalamin C deficiency (44). In a retrospective review of 37 children with influenza virus infection, only one was diagnosed with hemiconvulsion-hemiplegia-epilepsy syndrome (28). Neurologic outcomes were usually favorable, except in cases with pre-existing neurologic or metabolic disorders (28). A report of hemiconvulsion-hemiplegia-epilepsy syndrome in a 2-year-old boy, in the setting of SARS-CoV2 infection and multisystem inflammatory syndrome in children, was published (29).

The pathophysiological mechanisms involved are not elucidated. In a case report by Yamazaki and colleagues, a mechanism responsible for hemiconvulsions and hemiplegia was proposed to derive from vasospasms of cerebral vascular smooth muscle with possible cortical spreading depression associated with CACNA1A mutation (66).

Focal cortical dysplasias type III were reported in three cases of hemiconvulsion-hemiplegia-epilepsy syndrome (36).

Tanaka and colleagues reported ictal and postictal SPECT findings in a 5-month-old boy (61). When the SPECT was performed during left-sided hemiconvulsions and during the third day after focal status epilepticus, diffuse hyperperfusion was revealed in the right hemisphere. On the seventh and tenth day after status, diffuse hypoperfusion was exhibited in the right hemisphere. Striking neuroimaging findings suggestive of diffuse cytotoxic edema confined to one hemisphere, including extensive diffusion-weighted imaging abnormalities, were reported by Freeman and colleagues following early MRI screening (24).

The explanation for involvement of one hemisphere is not clear, but may involve maturation of brain structures such as the corpus callosum or genetic factors (12).

Epidemiology

The exact incidence and prevalence of the syndrome is unknown. However, the incidence of hemiconvulsion-hemiplegia-epilepsy syndrome has declined considerably during the past years in countries where emergency care is highly developed (53). There was only one (0.06%) equivocal case in the National Institute of Neurological and Communicative Disorders and Stroke Collaborative Perinatal Project reports from the U.S. (46; 47).

In one of his first papers on the syndrome, Gastaut reported on 150 cases (25). In 1972, Roger and colleagues reported 59 cases (52). Four years later, Vivaldi in his PhD thesis analyzed 45 cases, 25 that occurred between 1955 and 1965 and only 10 thereafter (64). In the epidemiological study of Beaumanoir in the district of Geneva, the number of cases of hemiconvulsion-hemiplegia-epilepsy syndrome reported between 1967 and 1978 decreased from 7.77 to 1.64 (of 10,000 children under 5 years of age) (18). The incidence has declined considerably during the past 10 years in countries where emergency care is highly developed and prompt use of intravenous or rectal benzodiazepines for the treatment of febrile convulsions has become common practice. The mean age at onset in the six patients described by Salih and colleagues corresponds to the start of the rapid development in social welfare and health care in Saudi Arabia (56).

However, hemiconvulsion-hemiplegia-epilepsy syndrome is still a problem in developing countries (63; 07; 10). In a study from Morocco, 35 patients followed up for this syndrome from January 2005 to December 2015, with an age of onset ranged from 1 to 10 years (07). In another study from Niger, this syndrome was found to have a hospital prevalence 2.5% (10).

Prevention

Because hemiconvulsions are the first symptom in previously asymptomatic patients, prophylactic treatment is not feasible. Postconvulsive hemiplegia may be prevented with appropriate vigorous and early management of acute episodes. Thus, the most important factor is the prompt recognition and treatment of the hemiclonic seizure.

Differential diagnosis

The hemiconvulsion-hemiplegia-epilepsy syndrome constitutes a unique sequence of events. Differential diagnosis aims to identify the causative factors of the initial episode of prolonged partial status. Workup primarily includes elimination of infections of the CNS (eg, meningitis and encephalitis). Lumbar puncture is advised in children younger than 18 months old and especially younger than six months of age. Herpes encephalitis often manifests initially in infants with febrile focal seizures and may pose a real problem (02).

A prolonged hemiconvulsion in the course of a febrile episode may be the first manifestation of Dravet syndrome. In contrast to hemiconvulsion-hemiplegia-epilepsy syndrome, Dravet syndrome is characterized, at this stage of the disease, by multiple recurrences of hemiconvulsions in the months following the initial episode. Changes in the side of hemiconvulsions are a frequent feature. Furthermore, in Dravet syndrome, postconvulsive hemiplegia, when present, is always of short duration and corresponds to Todd paresis (22; 09).

When the context of the hemiconvulsion-hemiplegia episode and the sequence of events are not well established, other causes of acquired hemiplegia, particularly of vascular origin such as arterial thrombosis or embolism, should be eliminated. Typically, the MRI findings after a hemiconvulsion-hemiplegia episode are not confined to vascular territories. Sturge-Weber syndrome can manifest with focal status epilepticus, but it has distinct skin and MRI correlates that establish diagnosis. Epilepsia partialis continua, especially when related to Rasmussen encephalitis, only superficially resembles hemiconvulsion-hemiplegia-epilepsy syndrome. Infectious causes (meningitis and encephalitis) or metabolic etiologies (eg, mitochondrial disorders) also may need to be excluded.

Acquired postconvulsive hemiplegia may be difficult to distinguish from congenital hemiplegia when it occurs in infants, especially as seizures may reveal a previously unrecognized deficit. Flaccidity and facial involvement are strong arguments in favor of an acquired hemiplegia (03).

Diagnosis of hemiconvulsion-hemiplegia-epilepsy syndrome has also been done in a 30-year-old man who had episodes of hemiconvulsions and ipsilateral weakness since childhood but was undiagnosed and managed for his epilepsy (11).

Diagnostic workup

EEG. The EEG discharge associated with the initial hemiconvulsion is characterized by high-voltage, rhythmic (2 to 3 Hz) slow waves, which may be unilateral but usually involve both hemispheres, more or less asymmetrically. Amplitude is higher on the hemisphere contralateral to the clinical seizure. High-amplitude spikes or sharp waves and recruiting rhythms (10 Hz) mainly concerning the posterior regions intermingle with slow waves only on the side contralateral to the clinical jerks. Occasionally, especially toward the end of a seizure, the spikes and slow waves may alternate as in true spike-wave complexes. Onset of the ictal discharge is generally recorded over the central-posterior part of the hemisphere but diffusion is rapid. Polygraphic recordings do not demonstrate any consistent relationship between muscle jerks and EEG discharges.

Postictal patterns. Spontaneous termination of the seizure is generally brisk. Slow waves and spikes are followed by a brief extinction of all rhythms, then by delta slowing, with higher amplitude on the hemisphere ictally engaged, alternating with short periods of suppression of activity. Contralaterally, physiological rhythms intermingled with slow waves reappear (26).

When the seizure stops following IV injection of a benzodiazepine, the ictal discharge progressively vanishes. Anomalies persist longer in the ictally engaged hemisphere. Postictal asymmetry is obvious, with abundant fast rhythms invading the opposite hemisphere.

Neuroradiological findings. In the acute stage, immediately after the initial convulsive episode, CT scan may show swelling and edema of the hemisphere involved in the epileptic discharge. Later, a rather characteristic, uniform hemiatrophy follows prolonged episodes (26; 04; 35; 18). In a report by Toldo and colleagues, MRI-identified abnormalities in the white matter seven days following the initial prolonged hemiconvulsion (62). Severe gliosis and unilateral brain atrophy were evident a month later.

In a clinico-MRI study of 10 children with hemiconvulsion-hemiplegia-epilepsy syndrome, Barcia and colleagues defined MRI features as “typical,” ie, strictly unilateral involvement, and “atypical,” ie, bilateral, and compared clinical data from both groups (13). Hemiconvulsion-hemiplegia-epilepsy syndrome occurred at a mean age of 20.5 months (range 8 to 48 months). In all cases, status epilepticus lasted for more than one hour and was characterized by unilateral clonic seizures followed by ipsilateral hemiplegia (persistent in five patients). Two patients in this series died--the first from multiorgan failure two weeks after the status epilepticus and the other from a second episode of ipsilateral intractable febrile status epilepticus three years after the first episode. Early MRI (days 1 to 7 from status epilepticus) showed hemispheric cytotoxic edema in all patients, extending to the contralateral side for one patient. T2 hyperintensity in the basal ganglia was disclosed in 70% of patients and in the hippocampus in 60% of patients. After one month (in intermediate and chronic phases), all surviving patients but one showed hemispheric cortical atrophy corresponding to the regions involved during the early stage. Comparing clinical features of patients presenting with “typical” features to those with “atypical” findings, the second group presented psychomotor delay before status epilepticus. The authors concluded that early MRI is important for the prompt diagnosis of hemiconvulsion-hemiplegia-epilepsy syndrome and showed that involvement of subcortical structures has been underestimated. Hippocampal involvement is not constant.

Management

Most cases of fever and prolonged convulsions occur during the first 18 months of life. Early and vigorous treatment of prolonged infantile seizures of whatever origin, especially of febrile convulsions, seems to be the only way to reduce the incidence of postconvulsive hemiplegia and late-onset partial epilepsy.

Symptomatic therapy of the acute convulsive episode involves mainly benzodiazepines, particularly diazepam, lorazepam, or midazolam (67; 49; 27; 68). Diazepam can be administered easily by either venous or rectal route. The usual dosage is 0.5 to 1 mg/kg given as a single dose. The dose may be repeated after 10 to 20 minutes. Buccal midazolam is now becoming an easy-to-use alternative to rectal diazepam (60). Antipyretic drugs are used in combination. According to the eventual causal agent, additional anti-infectious therapy is required. Decompressive craniectomy has been described as a lifesaving measure in the rare incidence of herniation due to diffuse cerebral edema from hemiconvulsion-hemiplegia-epilepsy syndrome (14).

In the complete form of the syndrome, focal seizures of temporal or extratemporal origin should be treated as any other type of focal epilepsy using antiepileptic drugs such as carbamazepine, levetiracetam, oxcarbazepine, sodium valproate, gabapentin, lamotrigine, lacosamide, clobazam, or topiramate.

Surgical treatment is an alternative. However, epilepsies due to extended brain damage may prove difficult to handle surgically. The decision for a limited cortical resection will usually require an invasive presurgical evaluation to be performed by a group specialized in epilepsy surgery. Of the 37 patients explored in Sainte-Anne (17), surgery was estimated to be possible in only 20 patients. Following surgery, nine patients (45%) became seizure free or experienced less than one seizure per year; three patients (15%) showed a significant reduction (by 40%) in seizure frequency, and no change was obtained in seven patients (35%). One patient deceased during a postoperative status.

Hemispherectomy (total, subtotal, or “functional”) may be another surgical alternative, particularly when limited cortical resection is not feasible. Delalande included seven children with hemiconvulsion-hemiplegia-epilepsy syndrome in a series of 53 patients referred for hemispherectomy (20). Indications and clinical outcomes of hemispherectomy for epilepsy of various etiologies have been reviewed (21).

Kwan and colleagues reported on four years follow-up in three children who underwent callosotomy (40). All patients experienced a significant reduction of “generalized tonic seizures,” but focal seizures of the sensory type remained unchanged.

Kim and associates evaluated the role and prognosis of surgical treatment in patients with delayed epilepsy in 26 consecutive patients with hemiconvulsion-hemiplegia-epilepsy syndrome who underwent surgical treatment for delayed epilepsy (38). The multidisciplinary presurgical evaluations included brain MRI, video-EEG monitoring, FDG-PET, and ictal SPECT. Anterior temporal lobectomy, cortical resection, functional hemispherectomy, and callosotomy were performed according to the results of presurgical evaluations. Patients were grouped into either the temporal lobe epilepsy group (n = 12) or the neocortical/multifocal epilepsy group (n = 14) according to the results of presurgical evaluations. There were no significant differences in demographic characteristics between the two groups. All patients in the temporal lobe epilepsy group became seizure-free after anterior temporal lobectomy, but only four patients became seizure-free, and an additional two patients showed improvement, after various surgical procedures in the neocortical/multifocal group (p = 0.002).

Outcomes

The long-term outcome is typically permanent focal motor deficits and drug-resistant epilepsy (59). Hemi-Lennox-Gastaut-like syndrome has been reported in a boy with hemiconvulsion hemiplegia epilepsy syndrome (45).

Among 44 patients who underwent hemispherotomy and had long-term follow up data, most of whom had hemiconvulsion hemiplegia epilepsy syndrome, seizure freedom was attained in 93.2%, and antiseizure medications were reduced or stopped in 82% (01).