Highlights
- •EPC has many possible local or systemic etiologies.
- •Motor and non-motor variants exist.
- •Four characteristic different time courses can be distinguished.
- •In EPC, seizures are replaced by frequently repeated seizure fragments.
- •EPC indicates a feedback loop of excitation and inhibition.
Abstract
Epilepsia partialis contina (EPC) in a narrow definition is a variant of simple focal motor status epilepticus in which frequent repetitive muscle jerks, usually arrhythmic, continue over prolonged periods of time. In a broader definition (used in this review) it also includes non-motor manifestations otherwise known as aura continua. EPC may occur as a single episode, repetitive episodes, it may be chronic progressive or non-progressive. It appears as an unusual manifestation of epilepsy in which more typical paroxysmal events are partly or entirely replaced by the sustained repetition of seizure fragments in rapid succession. The minimum duration is defined as one hour but EPC may continue for up to many years. There are multiple possible etiologies which can be local or systemic, including two disease entities, Rasmussen encephalitis and Russian tick-borne spring-summer encephalitis. Among systemic brain disorders, mitochondrial diseases and non-ketotic hyperglycemia are particularly likely to cause EPC whereas stroke is a frequent cause of acute EPC. The symptoms of motor EPC have been interpreted as cortical reflex myocloni but the pathophysiology is probably not uniform for all cases. In pathophysiological terms, EPC seems to represent an oscillation of excitation and inhibition in a feedback loop whose mechanisms are still poorly understood. However, EPC only seems to occur rarely in an otherwise healthy brain. Treatment has to take account of the etiology but, in general, EPC tends to be drug-resistant. Epilepsy surgery is often indicated in Rasmussen encephalitis.
Keywords
1. Introduction: definition and subcategories
Epilepsia partialis continua (EPC) was first described by Kozhevnikov in a report on four patients with “a special form of cortical epilepsy” to the Russian Society for Neuropathology and Psychiatry on January 21, 1894 [
[1]
].In the narrow definition, EPC is a variant of simple focal motor status epilepticus in which frequent repetitive muscle jerks, usually arrhythmic, continue over prolonged periods of time. The jerks tend to by stereotyped, affecting single muscles, muscle groups, an entire limb or larger parts of one hemibody. In the recent ILAE task force report on status epilepticus [
[2]
], EPC appears as a subclass of focal motor status.However, the symptoms of EPC are often not only motor but, rather, sensorimotor in nature, and individual cases may be placed on a continuum ranging from presentations with pure motor to those with predominantly or exclusively continuous somatosensory symptoms. Therefore, a broader definition of EPC includes these and other sensory variants which otherwise (and in the ILAE task force report) [
[2]
] are often referred to as aura continua (with the latter also including cognitive and emotional variants) (Table 1). Because of the continuum extending from motor and sensorimotor to sensory EPC [3
, ], in this review we will use a broader definition of this seizure disorder.Table 1Types of aura continua.
|
For references see Ref.
[6]
.For a condition to be accepted as EPC the majority of authors insist on a minimum duration of 60 min. Whereas in motor EPC single muscular twitches or jerks can still be identified and should occur at intervals not above 10 s [
[5]
], the symptoms of aura continua (AC) may be waxing and waning but are usually uninterrupted. Typically, EPC also continues during sleep. According to our earlier proposal [[6]
], EPC would be defined comprehensively as “a condition of continuously repeated fragments of epileptic seizures (motor or sensory), with preserved consciousness, lasting ≥1 h, and representing locally restricted epileptic activity”. This definition highlights the important fact that EPC deviates from the common characteristic of epileptic seizures as time-limited events lasting from seconds to a few minutes. Because of the extended course of EPC, the diagnosis is often missed. We do not include aphasic status epilepticus in this review because it appears almost impossible to distinguish ictal from postictal aphasic symptoms [[6]
].The time course of EPC is not homogeneous. Whereas in the older literature it was just noted that the duration of EPC is variable, a recent European survey of 65 cases [
[6]
] revealed the existence of various characteristic time courses. These include the following.- 1.Solitary episode
- a)in pre-existing epilepsies
- b)acute symptomatic
- a)
- 2.Chronic repetitive non-progressive
- a)with frequent brief episodes
- b)with rare long episodes
- a)
- 3.Chronic persistent non-progressive
- a)evolving from type 2
- b)primary persistent
- a)
- 4.Chronic progressive
The classes are self-explanatory and, at the time of the survey, every patient could be clearly assigned to one of them. However, the possibility of transitions should be noted as, logically, a solitary episode (type 1) could, at follow-up, turn out to have been the first episode of a type 2, and type 3 had sometimes evolved from type 2 (“type 3a”). Interestingly, there were no transitions between types 2a and 2b, and these did not appear as a continuum. In type 2a the episodes lasted no longer than 24 h and recurred more often than once per month. In type 2b the episodes lasted from days to weeks, typically recurring at intervals of several months. These patterns remained stable over up to 29 years. A transition of type 3 to type 2 was observed only once where it appeared as the consequence of partially effective treatment rather than a spontaneous development. The survey did not include Rasmussen syndrome and therefore included no type 4 cases.
2. Epidemiological and nosological aspects
No formal epidemiological data seem to exist, but EPC is not rare. In several centres it was possible to collect substantial series in limited periods of time: Thomas et al. [
[5]
] identified 32 cases in the records of patients examined at the Mayo Clinic between 1950 and 1973 with the caveat that this was not likely to reflect the true incidence as especially EPC of short duration may not have been listed in the diagnosis summary which was their basis for identification.36 cases were identified in one year (1993), 10 of the cases being new, in the British Neurological Surveillance Unit where all neurologists participated [
[7]
]; this seemed to indicate a prevalence under 1 per million but the reporting may have been incomplete. Gurer et al. [[8]
] reported 21 adults referred to their department at Hacettepe University, Ankara, from 1992 to 1999. Pandian et al. [[9]
] ascertained 20 cases from the medical records of 1985–1999 of a tertiary referral centre in Trivandrum (India). Two more reports exist from Indian tertiary Centres. Sinha and Satishchandra of Bangalore identified retrospectively 76 patients from 14 years [[10]
], and a smaller series of 17 cases, but collected prospectively in only 21 months was reported from Guwahati [[11]
]. A systematic retrospective data collection from 2003 to 2010 at Songklanagarind Hospital, Thailand, identified 75 cases [[12]
]. This study excluded patients with EPC in established epilepsy. The only pediatric cohort includes 51 cases collected retrospectively in the period 1993–2009 in two pediatric tertiary clinical centres of Belgrade, Serbia [[13]
]. The incidence of epilepsia partialis continua is slightly higher in males than in females [5
, 7
, 14
]. Sinha and Satishchandra [[10]
] found a male-to-female ratio of 46:30, a mean age of 30.2 ± 23.4 years, and a median age of 26 years. EPC is not always an obvious diagnosis, and the highly variable figures reported could reflect different diagnosticians’ awareness and attention rather than true differences in occurrence.EPC may be an acute symptomatic event caused by stroke or trauma. Other causes of a single EPC episode in previously healthy people (type 1b) in the European survey included Creutzfeldt–Jacob disease, systemic infection, local postbioptic encephalitis, and HHE syndrome in the stage of hemiconvulsions but remained unclarified in two cases [
[6]
]. Otherwise, EPC is rarely the only manifestation of epilepsy.In preexisting epilepsy, an episode of EPC (type 1a) could be provoked by sleep withdrawal, changes of antiepileptic drug (AED) therapy or intercurrent disease [
[6]
] whereas type 2a (non-progressive with frequent brief recurrences) appeared like an additional seizure type standing out by its unusual long duration [[6]
]. In fact, this type of EPC could be considered a variant of seizure clustering which is well known from temporal lobe epilepsies and, in a different way, from frontal lobe epilepsies.As EPC is mostly considered a motor type of epilepsy, the literature gives the impression that it is a condition of the frontal or the perirolandic cortex. But even if non-motor variants of EPC are included, it remains primarily a neocortical phenomenon. Aura continua may occasionally occur in mesiotemporal lobe epilepsy (see Table 1) but only as an exception.
EPC has many possible causes comprising both local and systemic etiologies.
2.1 Local etiologies
Local etiologies of a condition with narrowly localized seizure activity are immediately logical and need no further explanation. Some typical etiologies are discussed here.
2.1.1 Rasmussen encephalitis
Rasmussen’s encephalitis (RE), sometimes referred to as Rasmussen syndrome, is a rare and severe chronic progressive inflammatory disease, usually affecting one brain hemisphere, leading to hemispheric atrophy. Typically it affects children, although late-onset cases have been described. A bimodal distribution has been reported (median ages 5.3 and 18.9 years), and as many as 10% of cases first manifest in early adulthood [
[15]
]. Investigators in a German study estimated a countrywide incidence of diagnosed RE as 2.4 per 10 million people under age 18 years per year [[16]
]. Similarly, researchers in the UK surveillance study [[17]
] estimated an incidence of 1.7 per 10 million people aged 16 years and younger per year (a prevalence of 0.18 per 100,000 people).The clinical presentation of RE is characterized by intractable focal, multifocal and unilateral (rarely bilateral) seizures. Usually, there is progression of the disease over months or years, with cognitive and speech deterioration, hemiparesis, visual field deficits, and possible cortical sensory loss []. In the early phases seizures are frequently polymorphic with constant presence of motor involvement and possible association with somatosensory, visual or autonomic symptoms and loss of contact [
[19]
]. Simple focalmotor seizures are the most common (77% of cases), followed by secondarily generalized tonic-clonic seizures (42%), complex focal (19% with automatisms and 31% with subsequent unilateral motor involvement), postural seizures probably originating in the supplementary motor region (24%) and somatosensory seizures (21%) [[20]
]. Polymorphism of seizures can be the consequence of their multifocal intrahemispheric origin and of the progressive extension of the epileptogenic area [[19]
]. With the evolution of fixed neurological deficits, seizures often become less frequent and less severe [[15]
]. Adult-onset RE is characterized by a slower and less severe clinical course and neurologic impairment than the childhood form. Two different patterns of adult-onset RE clinical presentation can be defined: the first characterized by prominent focal epileptic seizures and the other by focal cortical myoclonus [[21]
]. About 50% of patients with Rasmussen’s encephalitis have epilepsia partialis continua [5
, 22
], especially at the onset [[15]
].2.1.2 Tick-borne encephalitis (TBE)
Tick-borne Russian spring-summer encephalitis, in brief TBE, is an arbovirus or flavivirus infection well-known to cause EPC in Siberia. Over several decades, this encephalitis has been migrating westward and now reached Central and Northern Europe. However, West of the Urals TBE has not been known to produce EPC. A recent paper reviewed the Russian literature including two large case series, and reported ten new cases, delineating the specific features of this type of EPC [
[23]
]. Unlike Rasmussen, it is never progressive, and the hypothesis that Kozhevnikov’s original report referred to cases of TBE was rejected.2.1.3 Other inflammatory causes
Whereas several series include cases of unspecified encephalitis, distinct inflammatory causes include such diverse diseases as subacute sclerosing panencephalitis [
8
, 13
], Creutzfeldt–Jakob disease [6
, 7
] HIV and AIDS [10
, 12
], tuberculosis including tuberculoma [8
, 9
, 10
, 12
, 13
], herpes simplex encephalitis [[6]
], cat scratch disease [[24]
], Japanese encephalitis [[25]
] and neurocysticercosis [[26]
].2.1.4 Stroke
Stroke is generally recognized as a typical cause of EPC [
[6]
] but there does not seem to be any publications specifically focusing on this topic. In major EPC case series, stroke was identified as the cause in 8/32 cases reported by Thomas et al. [[5]
], 6/21 by Gurer et al. [[8]
], 2/20 by Pandian et al. [[9]
], 15/76 by Sinha and Satishchandra [[10]
] and 11/75 by Phabphal et al. [[12]
]. In the only prospective case collection [[11]
] stroke was considered the cause of EPC in one case of 17.2.1.5 Focal cortical dysplasia (FCD) and other brain malformations
FCD is an etiology which is more frequently reported in the newer series involving access to MRI as a standard investigation [
8
, 13
]. It was the cause in 13.8% of the cases in a European EPC survey [[6]
]. Other malformations include Sturge–Weber syndrome [[27]
], hemimegalencephaly [[13]
] and lobar holoprosencephalia [[13]
].2.1.6 Neoplastic disease
Brain tumours have been described as causes of EPC in several series and in separate reports. The tumours include glioma [
5
, 7
], dysembryoplastic neuroepithelial tumours [[6]
], meningioma [[7]
], haemangioma and haemangioblastoma [5
, 7
], cavernoma [[6]
] and metastases [[8]
]. Some neoplastic etiologies like lymphoma [[5]
] and gliomatosis cerebri [[28]
] are not strictly local.2.1.7 Other causes
Brain trauma (including subdural hematoma [
[6]
]) is a less common cause of EPC but has been reported in several series [5
, 7
], and EPC has occasionally been reported as a symptom of perinatal birth injury [[7]
] and of multiple sclerosis [[29]
].2.2 EPC with systemic etiologies
EPC has not only been reported in relation to local pathologies but also in some systemic disorders, particularly the following:
2.2.1 Mitochondrial diseases
Interestingly, mitochondrial diseases seem to be particularly likely to cause EPC. Examples appear in most of the reported series [
7
, 9
, 13
] and there are several additional reports. The following disorders are included:2.2.2 Metabolic disorders
Metabolic disorders seem to be a possible cause of EPC especially in elderly patients [
[33]
].2.2.2.1 Non-ketotic hyperglycemia (NKH)
This etiology was highly prevalent in Thailand where it was identified in 34 of 75 patients with EPC [
[12]
], and 14 of 21 patients with this condition presented with EPC [[34]
]. In the Guwahati series NKH was the cause of EPC in 59% of the cases [[11]
]. Singh and Strobos [[35]
] collected 21 patients with NKH and EPC and highlighted the fact that EPC was the presenting symptom leading to the diagnosis of diabetes mellitus in nine of them. It was the cause in 7.9% of the cases from Bangalore [[10]
]. The pathogenesis of EPC in NKH has not been sufficiently clarified (as discussed in detail by Çokar et al.) [[33]
].Other reported metabolic causes include hypocalcemia [
[36]
], hepatic encephalopathy [5
, 37
], toxemia graviditatis [[10]
] and renal failure [[12]
].2.2.3 Idiopathic epilepsies
EPC has been reported occasionally in Benign Childhood Epilepsy with Centro-Temporal Spikes (“Benign Rolandic Epilepsy”) [
6
, 13
].2.2.4 Autoimmune disorders
EPC has been reported in autoimmune disorders including Sjögren syndrome [
[38]
] and recurrent paraneoplastic encephalitis [[39]
]. Limbic encephalitis was a reported cause in one series [[13]
] but may become a more frequent diagnosis in the future as awareness of this diagnosis is increasing.2.2.5 Other
Other systemic etiologies include infantile ceroid lipofuscinosis and Menkes disease [
[13]
]. Finally, in all larger series the etiology remains uncertain in some cases.3. EEG
EPC is reported to present irregularly occurring focal discharges of cortical origin [
40
, 41
] that commonly consist of discrete spikes, sharp waves or slow wave activity and periodic lateralized epileptiform discharges [[9]
]. In the 2011 European survey epileptiform activity was found in 42 cases of 65 (64.6% of all cases, 8 in type 1, 13 in type 2, and 21 in type 3), slow waves in 11 cases (two each in types 1 and 2, and seven in type 3), and local flattening in one case of type 3 [[6]
]. Long term video-EEG recordings show that EPC persists during sleep and that there is no major modification of seizure frequency by the sleep and wake cycle [[42]
]. However, a normal EEG does not refute the diagnosis of epilepsy or a cortical origin of the disorder as it can be normal in about one-fifth of patients with EPC [5
, 7
, 42
].EEG may fail to show epileptiform activity because the cortical activity is too small to show up over prominent background activity or because the dipole of the discharge is oriented at an unfavourable angle with respect to the recording electrodes on the scalp. Of 65 cases in the European survey, the EEG was unrevealing in 11 (17%) patients (two of type 1, three of type 2, six of type 3) [
[6]
]. Of 20 patients who fulfilled the criteria for EPC between 1985 and 1999, EEG was normal in three patients even in the presence of EPC [[9]
]. In electrocorticography, interictal epileptiform activity is widespread and the onset of seizures occurs in multiple independent sites [[43]
]. Stereo-EEG correctly identifies the origin of the discharge and the clinico-EEG sequence [[41]
].In Rasmussen’s encephalitis, EEG shows polymorphic delta waves over the affected hemisphere, mainly in temporal and central location, as early as 4 months after disease onset [
[19]
]. This may be accompanied by epileptiform abnormalities (in 9 out of 12 patients), which may evolve into (subclinical) ictal EEG patterns (in 5 from those 9) [[19]
]. During the disease course, in most cases, contralateral asynchronous slow waves and epileptiform discharges occur. However, ictal patterns are rarely recorded from contralateral electrodes. So and Gloor found bilaterally independent ictal onsets in 3 out of 32 patients [[43]
]. Andrews described contralateral epileptiform discharges in 2 patients and these became even more frequent than the ipsilateral ones [[44]
]. As in other conditions, EPC in RE is not always accompanied by rhythmic EEG discharges on surface EEG [[45]
].4. Clinical relations
Unless EPC occurs as an acute symptomatic event it is typically not a patient’s only seizure type but manifests together with other types of seizures. Of 32 cases of Thomas et al. [
[5]
] EPC was preceded by “generalized epileptic seizures” in five, and by focal seizures in the same body part that later became involved in EPC in ten. In the European survey of Mameniškienė et al. [[6]
] EPC was the only manifestation in only eight of 65 patients and the concomitant seizure types were simple focal (SF) in 45, complex focal (CF) in 15, and secondarily generalized tonic-clonic (SGTC) in 30. In Cockerell et al. [[7]
] 11% of patients had SF, 17% CF, and 32% SGTC seizures. All 20 patients of Pandian et al. [[9]
] also had other seizures including SF in 17, CF in two and SGTC in seven. Of the 76 patients of Sinha and Satishchandra [[10]
] 53 (69.3%) manifested as de novo EPC whereas 23 (30.3%) had a preceding history of recurrent seizures.Thus, whereas concomitant seizures in adult patients invariably seem to be focal and represent the “full edition” of which fragments appear in the EPC, the situation in children seems to be slightly different. In Kravljanac et al. [
[13]
] all children also had other seizures which included “generalized tonic-clonic” (primary? secondary? both?) in 74.5%, CF in 88%, SF in 49%, “polymorphic” seizures in 84.3%, myoclonic in 7.8% and infantile spasms in one patient (3%). 39 children (76.5%) also had other types of status epilepticus indicating that EPC more often occurred in children with rather serious conditions.This aspect has received relatively little attention but seems not to be restricted to children. Patients who develop EPC are often seriously ill. In most series, the majority of patients have neurological deficits as can be seen in Table 2. This is not common in unselected series of epilepsy.
Table 2Rate of patients with neurological signs.
| Authors | No. of patients | Neurological signs |
|---|---|---|
| Bien et al. [16] | 32 | 90.6% |
| Lamb et al. [17] | 65 | 69.2% |
| Hart | 36 | 44.0% |
| Granata et al. [19] | 21 | 95.2% |
| Oguni et al. [20] | 20 | 80.0% |
| Puligheddu et al. [24] | 51 | 72.5% |
One of the peculiarities of EPC is the sensitivity of the symptoms to external input, both sensory stimulation and movement, as was noted by several authors. Several patients of Thomas et al. [
[5]
] reported that “loud noise, nervous tension and certain postures or volitional activity of the affected limb served as aggravating factors.” 36.9% of the patients of Mameniškienė et al. [[6]
] reported trigger mechanisms, and in this study also the contrary effect, i.e. inhibition or reduction of seizure activity by relaxation or strong innervation was reported. Cockerell et al. [[7]
] found stimulus sensitivity in 28%, and movement sensitivity in 22% of their patients. 40% of the patients of Pandian et al. [[9]
] were stimulus sensitive and 30% movement sensitive. In the cohort of Phabphal et al. [[12]
] 36% were stimulus sensitive. In one exceptional case report [[46]
] proprioceptive stimulation due to a peripheral trauma seemed even to be the initial trigger of sensorimotor EPC in a patient with rolandic FCD type 1A.5. Pathophysiology
It is unlikely that all types of EPC have the same pathophysiology. EPC as an acute symptomatic event caused by stroke is different from EPC as the presenting symptom of a chronic encephalitis. Some conditions are better understood than others.
5.1 Pathophysiology related to etiologies
5.1.1 Rasmussen encephalitis
In his initial description of RE, Rasmussen hypothesized a chronic viral infection based on findings indicating an immune reaction in the brain such as lymphocyte infiltration and microglial nodules [
[47]
]. Similarities of RE and TBE further supported this hypothesis [[48]
]. However, attempts to identify a pathogenic viral agent have yielded contradictory findings and have remained inconclusive [49
, 50
, 51
]. Later, the condition was linked to an autoimmune process triggered by circulating auto-antibodies activating the subunit 3 of the ionotropic glutamate receptor (GluR3Ab) [52
, 53
]. More recently, a cytotoxic T lymphocytes reaction against neurons was demonstrated to play a causative role in RE [[15]
]. Identification of antibodies to α-7-acetylcholine receptor in patients with biopsy proven RE [[54]
] suggests that the syndrome of RE may encompass several different autoimmune entities [[55]
].The pathological changes usually consist of reactive astrocytosis, neuronal loss, abundant foci of perivascular mononuclear cells, thickened meninges with lymphocytic infiltration and microglial nodules. During the residual stage, the illness is presented as a diffuse gliosis and spongy degeneration of the cortex [
45
, 47
].5.1.2 TBE
EPC in TBE is caused by a neurotropic virus, but it is not yet known in sufficient detail how the virus changes neuronal function to produce the peculiar type of ictal activity of EPC. In particular it is not known what is different about the changes the Siberian mutant of the virus produces from those produced by Western mutants to cause EPC. This will be difficult to study as there is usually no indication for surgical intervention or biopsy in these cases.
5.1.3 EPC in systemic diseases
The mechanisms are still unknown which result in the occurrence of EPC in some systemic diseases affecting the brain. Fundamentally, the pathological conditions seem to establish some cortical dysequilibrium that facilitates the oscillatory epileptic activity characterizing EPC, perhaps in interplay with some non-specific local trigger mechanism. Why this should happen particularly in mitochondrial diseases and non-ketotic hyperglycemia remains to be clarified.
5.2 EPC as an acute symptomatic event (type 1b)
Typically in these cases the limb affected by EPC is paretic. However, we are not aware of any analysis of temporal or quantitative relations between EPC as repetitive seizure fragments, fully developed focal seizures, paresis caused by the primary etiology, possible Todd’s paresis, temporary versus permanent paresis. All these relations would be important to understand the pathology.
5.3 Frequently recurrent brief episodes (type 2a)
As mentioned above, the episodes of this type appear as an additional seizure type along with others, longer but still self-limited and not outlasting 24 h. They may only differ in degree from the more common seizure clusters of frontal lobe and temporal lobe epilepsies, mainly by the increased fragmentation and density of seizure activity. The awareness of this type of EPC is new [
[6]
], and comparative studies, e.g. with seizure clusters in frontal lobe epilepsies have not yet been undertaken.5.4 Chronic non-progressive EPC (types 2b and 3)
In the European survey [
[6]
] this was the largest group, comprising 43 of 65 cases (66%) and presumably most representative of non-Rasmussen, non-stroke EPC. It is a rather inhomogeneous group, spanning from cases with visual aura continua as the first symptom of an occipital arteriovenous malformation and persisting after its successful obliteration; over cases with recurrent rare episodes of EPC lasting several days (type 2b) but evolving into a persistent type 3a; to cases of primary persistent EPC in TBE (type 3b). The pathophysiology is probably inhomogeneous and, in general, not well-known.Cockerell et al. [
[7]
] investigated 16 patients with a view to clarify the pathophysiology. Although the clinical appearance of the muscle jerks was similar in all patients, six of them had EEG and EMG evidence for a cortical origin, some but not all with giant sensory evoked potentials suggestive of cortical reflex myoclonus; five had indirect evidence for a cortical origin, from EMG, magnetic stimulation and other investigations; two had myoclonus which arose not of cortical but subcortical sources (brainstem and basal ganglia). In three patients the origin remained unclarified. The hypothesis of EPC being related to cortical reflex myoclonus may also be supported by the frequently made observation of activation of EPC by exteroceptive and proprioceptive stimulation. The literature supporting the cortical reflex myoclonus concept including involvement of the thalamus was reviewed by Guerrini [[56]
] who also highlighted the possible key role of cortical myoclonus in the transition from cortical seizure fragments to full seizures. He further discussed other subcortical mechanisms as well as the possibility of a relation of EPC to cortical tremor which seems to form a continuum with cortical myoclonus, however, with a frequency of 7–15 Hz, rather different from EPC.Clinical, neurophysiological and experimental evidence thus seems to indicate that cortical reflex myoclonus may be involved in a subgroup of the cases of EPC but not all. It does not sufficiently explain the sustained activity in what appears like a closed circuit, especially as EPC is usually not rhythmic (as would be expected if every jerk, in a simple mechanism following its proprioception, triggered the next). It also does not explain non-motor types of EPC where there is no muscular activity whose proprioception could precipitate the next reflex event, whereas the continuum existing from purely motor via sensorimotor to purely somatosensory EPC makes differences in pathophysiology unlikely.
In addition, although little attention has been paid in literature on the type of motor phenomena in EPC, these do not always seem to be myoclonic but may also include brief tonic movements.
The fundamental question is why the epileptic mechanisms in these cases change from generating occasional paroxysmal events to entertaining long-lasting oscillations. If paroxysmal events intercur, they usually start at the site of EPC and often (but not always) interrupt the oscillations for shorter or longer intervals. What is unusual in EPC is not that some focal seizures stop rapidly after onset. This happens all the time as focal seizures are very variable in their extension. What is unusual is that the seizures habitually stop very rapidly after onset, roughly at the same stage, and recommence quasi-immediately, like in a feed-back loop, and that this can continue over years. Highly efficient inhibitory mechanisms seem to be at play which could be local or network mechanisms or both.
In an EEG-fMRI study of a patient with a perirolandic FCD and EPC type 3 Vaudano et al. [
[57]
] demonstrated event-related BOLD signal increases indicating a network maintaining epileptic activity and including the ipsilateral anterior cingulate and occipital cortex, the bilateral prefrontal cortex and the contralateral cerebellum but not the thalamus. The possibility was discussed that the role of the cerebellum could be inhibitory [[57]
]. Likewise, Espay et al. [[58]
] in their case described a widespread bilateral network problem using EEG-fMRI, but they did not discuss the relation of excitation and inhibition.It could be a consequence of the constant arrest of seizure spread preventing the development of a full seizure that the ictogenic system never enters a postictal refractory state with the consequence that no truly interictal state is ever reached. However, it is known from numerous intracerebral recordings during long-term monitoring that vivid subclinical local seizure activity may exist in the clinically interictal state. The possibility cannot be excluded that EPC only differs in degree from the interictal state in many other focal epilepsies, the difference being that inhibition in EPC is efficient enough to prevent full seizures but not efficient enough to prevent fragments of incipient seizures.
The frequent anatomically related neurological deficits indicate that, in a non-specific way, EPC rarely develops in an otherwise intact brain.
6. Treatment
The treatment of EPC will in many instances be decided by the underlying etiology. Otherwise, the condition is rather resistant to pharmacotherapy. Benzodiazepines can interrupt EPC and serve as a diagnostic aid in aura continua if there are doubts, but they are not a good longer term treatment. A rapidly acting benzodiazepine with a short half-life like midazolam could be used as an intermittent drug in cases of repetitive EPC type 2a but to our knowledge this has not yet been tried. In the European survey, the relatively best results for continuous treatment were obtained with topiramate and levetiracetam [
[6]
].Various stimulation methods have been applied in individuals or small groups of patients: vagus nerve stimulation [
[59]
], transcranial magnetic stimulation [[60]
] and neocortical stimulation [[61]
]. There are too few cases to reach any definite conclusions about these treatments.6.1 Rasmussen encephalitis
Various medical options are available to stop the epileptic manifestations and slow neurologic regression. Common antiepileptic drugs and antiviral treatments are generally not effective and are usually only temporizing measures [
[45]
]. The surgical isolation of the affected hemisphere is the only treatment that halts disease progression [62
, 63
] and has played a major role in seizure treatment of RE since the 1950s. Focal excision and callosotomy are unsatisfactory in many cases. Multiple subpial transections also fail to control seizures [[64]
]. Thus, selective resection of the epileptogenic zone is likely to be a good choice for adolescent and adult patients who cannot undergo a hemispherectomy [[65]
]. Hemispherectomy and hemispherotomy are useful methods to control seizures and improve the functional state of the patients [66
, 67
, 68
, 69
]. Disconnection can be achieved by different techniques and there are no convincing data that one approach is better than the others in the elimination of seizures and the prevention of both perioperative and long-term complications [[66]
]. However, a possible disadvantage of these techniques compared with anatomical hemispherectomy is that incomplete disconnections may give rise to residual seizures. Nevertheless, some data in the literature also indicate that some patients have become seizure free after a second operation [[70]
]. Following surgical procedures, seizure freedom rates between 62.5 and 90% have been reported [65
, 66
, 71
, 72
]. There is a certain reluctance to perform surgery in the early phases although the best clinical outcome is achieved only when it is done as soon as possible after the diagnosis and surgery performed earlier may result in a higher quality of life than later surgery [73
, 74
]. Moreover, a shorter duration of frequent seizures before surgery may lead to a better long-term cognitive outcome [[65]
].Immunomodulation therapy can be considered when early surgery is not feasible—when the dominant hemisphere is involved and there is a slow disease progression (in such cases surgery would worsen motor and language functions); when RE is suspected but confirmatory neurologic deterioration and hemispheric atrophy have not yet occurred and in the cases of bilateral disease [
[75]
]. Cycles of high doses of intravenous bolus of methylprednisolone followed by oral prednisone are effective in children with a status epilepticus and in the early stages of the disease while they are unable to prevent relapses [[76]
]. Intravenous immunoglobulines provide clinical improvement in long-term administration in adult-onset RS while they are generally less encouraging in children for unclear reasons [[77]
]. Use of tacrolimus, an inhibitor of cytokine synthesis, allowed to preserve neurologic function and to delay the progression of cerebral hemiatrophy in RS while no significant improvement was observed in seizure outcome [[16]
]. Plasma exchange and protein A immunoadsorption can be useful in refractory status epilepticus because of removing of circulating autoantibodies [[78]
]. Anecdotal attempts with intraventricular alpha-interferon and rituximab are described [79
, 80
].7. Conclusions
EPC is an unusual manifestation of epilepsy in which the common paroxysmal events are partly or entirely replaced by sustained repetition of seizure fragments in rapid succession. The minimum duration is defined as one hour but EPC may continue for many years. EPC may occur as a single episode, repetitive episodes, as a chronic progressive or non-progressive disorder. In some cases, EPC appears as an analogy to seizure clusters.
There are multiple possible etiologies which can be local or systemic, including two disease entities, Rasmussen encephalitis and Russian tick-borne spring–summer encephalitis. Among systemic brain disorders, mitochondrial diseases and non-ketotic hyperglycemia seem to be particularly likely to cause EPC whereas stroke is a frequent cause of acute EPC. The diagnostic work-up comprises magnetic resonance imaging to clarify the etiology and EEG which typically shows focal epileptiform or slow wave activity corresponding anatomically to the semiology. But the EEG may also be unrevealing.
The symptoms of motor EPC have been interpreted as cortical reflex myocloni but the pathophysiology is probably not the same in all cases. In general terms, EPC seems to represent an oscillation of excitation and inhibition in a feedback loop whose mechanisms are still poorly understood. However, EPC seems only rarely to occur in an otherwise healthy brain.
Treatment has to consider the etiology but in general EPC is rather drug resistant. Epilepsy surgery is frequently the treatment of choice in Rasmussen encephalitis.
Conflict of interest statement
The authors have no conflicts of interest to reveal
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Article info
Publication history
Published online: October 18, 2016
Accepted:
October 13,
2016
Received in revised form:
October 12,
2016
Received:
August 30,
2016
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