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Epilepsia partialis continua: A review

  • Rūta Mameniškienė
    Affiliations
    Vilnius University, Department of Neurology and Neurosurgery, Center for Neurology, Vilnius, Lithuania
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  • Peter Wolf
    Correspondence
    Correspondence to: Dag Hammarskjölds Allé 5, DK-2100 Copenhagen, Denmark.
    Affiliations
    Danish Epilepsy Centre, Dianalund, Denmark

    Serviço de Neurologia, Departamento de Clínica Médica, Hospital Universitário, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil
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Open ArchivePublished:October 18, 2016DOI:https://doi.org/10.1016/j.seizure.2016.10.010

      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 [
      • Kozhevnikov A.Y.
      A special type of cortical epilepsy.
      ].
      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 [
      • Trinka E.
      • Cock H.
      • Hesdorffer D.
      • Rossetti A.O.
      • Scheffer I.E.
      • Shinnar S.
      • et al.
      A definition and classification of status epilepticus—report of the ILAE Task Force on Classification of Status Epilepticus.
      ], 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) [
      • Trinka E.
      • Cock H.
      • Hesdorffer D.
      • Rossetti A.O.
      • Scheffer I.E.
      • Shinnar S.
      • et al.
      A definition and classification of status epilepticus—report of the ILAE Task Force on Classification of Status Epilepticus.
      ] 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 [
      • Penfield W.
      • Jasper H.
      Epilepsy and the functional anatomy of the human brain.
      ,
      • Janz D.
      Die Epilepsie.
      ], in this review we will use a broader definition of this seizure disorder.
      Table 1Types of aura continua.
      • Somatosensory
      • Proprioceptive
      • Visual
      • Auditory
      • Musical
      • Olfactory
      • Gustatory
      • Epigastric/autonomic
      • Anxiety
      • Dysmnesic
      For references see Ref.
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      .
      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 [
      • Thomas J.E.
      • Reagan T.J.
      • Klass D.W.
      Epilepsia partialis continua. A review of 32 cases.
      ], 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 [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ], 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 [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ].
      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 [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ] revealed the existence of various characteristic time courses. These include the following.
      • 1.
        Solitary episode
        • a)
          in pre-existing epilepsies
        • b)
          acute symptomatic
      • 2.
        Chronic repetitive non-progressive
        • a)
          with frequent brief episodes
        • b)
          with rare long episodes
      • 3.
        Chronic persistent non-progressive
        • a)
          evolving from type 2
        • b)
          primary persistent
      • 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. [
      • Thomas J.E.
      • Reagan T.J.
      • Klass D.W.
      Epilepsia partialis continua. A review of 32 cases.
      ] 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 [
      • Cockerell O.C.
      • Rothwell J.
      • Thompson P.D.
      • Marsden C.D.
      • Shorvon S.D.
      Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK.
      ]; this seemed to indicate a prevalence under 1 per million but the reporting may have been incomplete. Gurer et al. [
      • Gurer G.
      • Saygı S.
      • Ciger A.
      Epilepsia partialis continua: clinical and electrophysiological features of adult patients.
      ] reported 21 adults referred to their department at Hacettepe University, Ankara, from 1992 to 1999. Pandian et al. [
      • Pandian J.D.
      • Thomas S.V.
      • Santoshkumar B.
      • Radhakrishnan K.
      • Sarma P.S.
      • Joseph S.
      • et al.
      Epilepsia partialis continua—a clinical and electroencephalography study.
      ] 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 [
      • Sinha S.
      • Satishchandra P.
      Epilepsia partialis continua over last 14 years: experience from a tertiary care center from south India.
      ], and a smaller series of 17 cases, but collected prospectively in only 21 months was reported from Guwahati [
      • Shrivastava V.
      • Burj N.P.
      • Basumatary L.J.
      • Das M.
      • Goswami M.
      • Kayal A.K.
      Etiological profile of epilepsia partialis continua among adults in a tertiary care hospital.
      ]. A systematic retrospective data collection from 2003 to 2010 at Songklanagarind Hospital, Thailand, identified 75 cases [
      • Phabphal K.
      • Limapichat K.
      • Sathirapanya P.
      • Setthawatcharawanich S.
      • Geater A.
      Clinical characteristics, etiology and long-term outcome of epilepsia partialis continua in adult patients in Thailand.
      ]. 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 [
      • Kravljanac R.
      • Djuric M.
      • Jovic N.
      • Djordjevic M.
      • Zamurovic D.
      • Pejmezovic T.
      Etiology, clinical features and outcome of epilepsia partialis continua in cohort of 51 children.
      ]. The incidence of epilepsia partialis continua is slightly higher in males than in females [
      • Thomas J.E.
      • Reagan T.J.
      • Klass D.W.
      Epilepsia partialis continua. A review of 32 cases.
      ,
      • Cockerell O.C.
      • Rothwell J.
      • Thompson P.D.
      • Marsden C.D.
      • Shorvon S.D.
      Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK.
      ,
      • Juul-Jensen P.
      • Denny-Brown D.
      Epilepsia partialis continua.
      ]. Sinha and Satishchandra [
      • Sinha S.
      • Satishchandra P.
      Epilepsia partialis continua over last 14 years: experience from a tertiary care center from south India.
      ] 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 [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ]. 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 [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ] whereas type 2a (non-progressive with frequent brief recurrences) appeared like an additional seizure type standing out by its unusual long duration [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ]. 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 [
      • Bien C.G.
      • Widman G.
      • Urbach H.
      • Sassen R.
      • Kuczaty S.
      • Wiestler O.D.
      • et al.
      The natural history of Rasmussen’s encephalitis.
      ]. 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 [
      • Bien C.G.
      • Tiemeier H.
      • Sassen R.
      • Kuczaty S.
      • Urbach H.
      • von Lehe M.
      • et al.
      Rasmussen encephalitis: incidence and course under randomized therapy with tacrolimus or intravenous immunoglobulins.
      ]. Similarly, researchers in the UK surveillance study [
      • Lamb K.
      • Scott W.J.
      • Mensah A.
      • Robinson R.
      • Varadkar S.
      • Cross J.H.
      Prevalence and clinical outcome of Rasmussen encephalitis in children from the United Kingdom.
      ] 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 [
      • Hart Y.
      Rasmussen’s encephalitis.
      ]. 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 [
      • Granata T.
      • Gobbi B.
      • Spreafico R.
      • Vigevano F.
      • Capovilla G.
      • Ragona F.
      • et al.
      Rasmussen’s encephalitis: early characteristics allow diagnosis.
      ]. 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%) [
      • Oguni H.
      • Andermann F.
      • Rasmussen T.
      The natural history of the syndrome of chronic encephalitis and epilepsy: a study of the MRI series of forty eight cases.
      ]. Polymorphism of seizures can be the consequence of their multifocal intrahemispheric origin and of the progressive extension of the epileptogenic area [
      • Granata T.
      • Gobbi B.
      • Spreafico R.
      • Vigevano F.
      • Capovilla G.
      • Ragona F.
      • et al.
      Rasmussen’s encephalitis: early characteristics allow diagnosis.
      ]. With the evolution of fixed neurological deficits, seizures often become less frequent and less severe [
      • Bien C.G.
      • Widman G.
      • Urbach H.
      • Sassen R.
      • Kuczaty S.
      • Wiestler O.D.
      • et al.
      The natural history of Rasmussen’s encephalitis.
      ]. 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 [
      • Villani F.
      • Pincherle A.
      • Antozzi C.
      • Chiapparini L.
      • Granata T.
      • Michelucci R.
      • et al.
      Adult-onset Rasmussen’s encephalitis: anatomical-electrographic-clinical features of 7 Italian cases.
      ]. About 50% of patients with Rasmussen’s encephalitis have epilepsia partialis continua [
      • Thomas J.E.
      • Reagan T.J.
      • Klass D.W.
      Epilepsia partialis continua. A review of 32 cases.
      ,
      • Longaretti F.
      • Dunkley C.
      • Varadkar S.
      • Vargha-Khadem F.
      • Boyd S.G.
      • Cross J.H.
      Evolution of the EEG in children with Rasmussen’s syndrome.
      ], especially at the onset [
      • Bien C.G.
      • Widman G.
      • Urbach H.
      • Sassen R.
      • Kuczaty S.
      • Wiestler O.D.
      • et al.
      The natural history of Rasmussen’s encephalitis.
      ].

      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 [
      • Mukhin K.Y.
      • Mameniškienė R.
      • Mironov M.B.
      • Kvaskova N.E.
      • Bobylova M.Y.
      • Petrukhin A.S.
      • et al.
      Epilepsia partialis continua in tick-borne Russian spring-summer encephalitis.
      ]. 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 [
      • Gurer G.
      • Saygı S.
      • Ciger A.
      Epilepsia partialis continua: clinical and electrophysiological features of adult patients.
      ,
      • Kravljanac R.
      • Djuric M.
      • Jovic N.
      • Djordjevic M.
      • Zamurovic D.
      • Pejmezovic T.
      Etiology, clinical features and outcome of epilepsia partialis continua in cohort of 51 children.
      ], Creutzfeldt–Jakob disease [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ,
      • Cockerell O.C.
      • Rothwell J.
      • Thompson P.D.
      • Marsden C.D.
      • Shorvon S.D.
      Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK.
      ] HIV and AIDS [
      • Sinha S.
      • Satishchandra P.
      Epilepsia partialis continua over last 14 years: experience from a tertiary care center from south India.
      ,
      • Phabphal K.
      • Limapichat K.
      • Sathirapanya P.
      • Setthawatcharawanich S.
      • Geater A.
      Clinical characteristics, etiology and long-term outcome of epilepsia partialis continua in adult patients in Thailand.
      ], tuberculosis including tuberculoma [
      • Gurer G.
      • Saygı S.
      • Ciger A.
      Epilepsia partialis continua: clinical and electrophysiological features of adult patients.
      ,
      • Pandian J.D.
      • Thomas S.V.
      • Santoshkumar B.
      • Radhakrishnan K.
      • Sarma P.S.
      • Joseph S.
      • et al.
      Epilepsia partialis continua—a clinical and electroencephalography study.
      ,
      • Sinha S.
      • Satishchandra P.
      Epilepsia partialis continua over last 14 years: experience from a tertiary care center from south India.
      ,
      • Phabphal K.
      • Limapichat K.
      • Sathirapanya P.
      • Setthawatcharawanich S.
      • Geater A.
      Clinical characteristics, etiology and long-term outcome of epilepsia partialis continua in adult patients in Thailand.
      ,
      • Kravljanac R.
      • Djuric M.
      • Jovic N.
      • Djordjevic M.
      • Zamurovic D.
      • Pejmezovic T.
      Etiology, clinical features and outcome of epilepsia partialis continua in cohort of 51 children.
      ], herpes simplex encephalitis [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ], cat scratch disease [
      • Puligheddu M.
      • Giagheddu A.
      • Genugu F.
      • Giagheddu M.
      • Marrosu F.
      Epilepsia partialis continua in cat scratch disease.
      ], Japanese encephalitis [
      • Solomon T.
      • Kneen R.
      • Gainsborough M.
      • Vaughn D.W.
      • Khanh V.T.
      Japanese encephalitis.
      ] and neurocysticercosis [
      • Yeh S.-J.
      • Wu R.-M.
      Neurocysticercosis presenting with epilepsia partialis continua: a clinicopathologic report and literature review.
      ].

      2.1.4 Stroke

      Stroke is generally recognized as a typical cause of EPC [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ] 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. [
      • Thomas J.E.
      • Reagan T.J.
      • Klass D.W.
      Epilepsia partialis continua. A review of 32 cases.
      ], 6/21 by Gurer et al. [
      • Gurer G.
      • Saygı S.
      • Ciger A.
      Epilepsia partialis continua: clinical and electrophysiological features of adult patients.
      ], 2/20 by Pandian et al. [
      • Pandian J.D.
      • Thomas S.V.
      • Santoshkumar B.
      • Radhakrishnan K.
      • Sarma P.S.
      • Joseph S.
      • et al.
      Epilepsia partialis continua—a clinical and electroencephalography study.
      ], 15/76 by Sinha and Satishchandra [
      • Sinha S.
      • Satishchandra P.
      Epilepsia partialis continua over last 14 years: experience from a tertiary care center from south India.
      ] and 11/75 by Phabphal et al. [
      • Phabphal K.
      • Limapichat K.
      • Sathirapanya P.
      • Setthawatcharawanich S.
      • Geater A.
      Clinical characteristics, etiology and long-term outcome of epilepsia partialis continua in adult patients in Thailand.
      ]. In the only prospective case collection [
      • Shrivastava V.
      • Burj N.P.
      • Basumatary L.J.
      • Das M.
      • Goswami M.
      • Kayal A.K.
      Etiological profile of epilepsia partialis continua among adults in a tertiary care hospital.
      ] 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 [
      • Gurer G.
      • Saygı S.
      • Ciger A.
      Epilepsia partialis continua: clinical and electrophysiological features of adult patients.
      ,
      • Kravljanac R.
      • Djuric M.
      • Jovic N.
      • Djordjevic M.
      • Zamurovic D.
      • Pejmezovic T.
      Etiology, clinical features and outcome of epilepsia partialis continua in cohort of 51 children.
      ]. It was the cause in 13.8% of the cases in a European EPC survey [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ]. Other malformations include Sturge–Weber syndrome [
      • Joe B.
      • Goldsmith I.
      • Yoshor D.
      • Verma A.
      Successful treatment of epilepsia partialis continua by partial focal resection in a patient with Sturge-Weber syndrome.
      ], hemimegalencephaly [
      • Kravljanac R.
      • Djuric M.
      • Jovic N.
      • Djordjevic M.
      • Zamurovic D.
      • Pejmezovic T.
      Etiology, clinical features and outcome of epilepsia partialis continua in cohort of 51 children.
      ] and lobar holoprosencephalia [
      • Kravljanac R.
      • Djuric M.
      • Jovic N.
      • Djordjevic M.
      • Zamurovic D.
      • Pejmezovic T.
      Etiology, clinical features and outcome of epilepsia partialis continua in cohort of 51 children.
      ].

      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 [
      • Thomas J.E.
      • Reagan T.J.
      • Klass D.W.
      Epilepsia partialis continua. A review of 32 cases.
      ,
      • Cockerell O.C.
      • Rothwell J.
      • Thompson P.D.
      • Marsden C.D.
      • Shorvon S.D.
      Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK.
      ], dysembryoplastic neuroepithelial tumours [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ], meningioma [
      • Cockerell O.C.
      • Rothwell J.
      • Thompson P.D.
      • Marsden C.D.
      • Shorvon S.D.
      Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK.
      ], haemangioma and haemangioblastoma [
      • Thomas J.E.
      • Reagan T.J.
      • Klass D.W.
      Epilepsia partialis continua. A review of 32 cases.
      ,
      • Cockerell O.C.
      • Rothwell J.
      • Thompson P.D.
      • Marsden C.D.
      • Shorvon S.D.
      Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK.
      ], cavernoma [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ] and metastases [
      • Gurer G.
      • Saygı S.
      • Ciger A.
      Epilepsia partialis continua: clinical and electrophysiological features of adult patients.
      ]. Some neoplastic etiologies like lymphoma [
      • Thomas J.E.
      • Reagan T.J.
      • Klass D.W.
      Epilepsia partialis continua. A review of 32 cases.
      ] and gliomatosis cerebri [
      • Shahar Y.B.
      • Kramer U.
      • Nass D.
      • Savitzki D.
      Epilepsia partialis continua associated with widespread gliomatosis cerebri.
      ] are not strictly local.

      2.1.7 Other causes

      Brain trauma (including subdural hematoma [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ]) is a less common cause of EPC but has been reported in several series [
      • Thomas J.E.
      • Reagan T.J.
      • Klass D.W.
      Epilepsia partialis continua. A review of 32 cases.
      ,
      • Cockerell O.C.
      • Rothwell J.
      • Thompson P.D.
      • Marsden C.D.
      • Shorvon S.D.
      Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK.
      ], and EPC has occasionally been reported as a symptom of perinatal birth injury [
      • Cockerell O.C.
      • Rothwell J.
      • Thompson P.D.
      • Marsden C.D.
      • Shorvon S.D.
      Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK.
      ] and of multiple sclerosis [
      • Spatt J.
      • Goldenberg G.
      • Mamoli B.
      Epilepsia partialis continua in multiple sclerosis.
      ].

      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 [
      • Cockerell O.C.
      • Rothwell J.
      • Thompson P.D.
      • Marsden C.D.
      • Shorvon S.D.
      Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK.
      ,
      • Pandian J.D.
      • Thomas S.V.
      • Santoshkumar B.
      • Radhakrishnan K.
      • Sarma P.S.
      • Joseph S.
      • et al.
      Epilepsia partialis continua—a clinical and electroencephalography study.
      ,
      • Kravljanac R.
      • Djuric M.
      • Jovic N.
      • Djordjevic M.
      • Zamurovic D.
      • Pejmezovic T.
      Etiology, clinical features and outcome of epilepsia partialis continua in cohort of 51 children.
      ] and there are several additional reports. The following disorders are included:
      • Alpers disease [
        • Mameniškienė R.
        • Bast T.
        • Bentes C.
        • Canevini M.P.
        • Dimova P.
        • Granata T.
        • et al.
        Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
        ,
        • Cockerell O.C.
        • Rothwell J.
        • Thompson P.D.
        • Marsden C.D.
        • Shorvon S.D.
        Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK.
        ].
      • Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) [
        • Mameniškienė R.
        • Bast T.
        • Bentes C.
        • Canevini M.P.
        • Dimova P.
        • Granata T.
        • et al.
        Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
        ,
        • Cockerell O.C.
        • Rothwell J.
        • Thompson P.D.
        • Marsden C.D.
        • Shorvon S.D.
        Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK.
        ].
      • ADCK3 mutations [
        • Hikmat O.
        • Tzoulis C.
        • Knappskog P.M.
        • Johansson S.
        • Boman H.
        • Sztromwasser P.
        • et al.
        ADCK3 mutations with epilepsy, stroke-like episodes and a POLG mimic?.
        ].
      • NADH-coenzyme Q reductase deficiency [
        • Antozzi C.
        • Franceschetti S.
        • Filippini G.
        • Barbiroli B.
        • Savoiardo M.
        • Fiacchino F.
        • et al.
        Epilepsia partialis continua associated with NADH-coenzyme Q reductase deficiency.
        ].
      • MERRF [
        • Sinha S.
        • Satishchandra P.
        Epilepsia partialis continua over last 14 years: experience from a tertiary care center from south India.
        ].
      • Leigh syndrome [
        • Elia M.
        • Musumeci S.A.
        • Ferri R.
        • Colamaria V.
        • Azan G.
        • Greco D.
        • et al.
        Leigh syndrome and partial deficit of cytochrome c oxidase associated with epilepsia partialis continua.
        ].

      2.2.2 Metabolic disorders

      Metabolic disorders seem to be a possible cause of EPC especially in elderly patients [
      • Çokar Ö.
      • Aydιn B.
      • Özer F.
      Non-ketotic hyperglycaemia presenting as epilepsia partialis continua.
      ].

      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 [
      • Phabphal K.
      • Limapichat K.
      • Sathirapanya P.
      • Setthawatcharawanich S.
      • Geater A.
      Clinical characteristics, etiology and long-term outcome of epilepsia partialis continua in adult patients in Thailand.
      ], and 14 of 21 patients with this condition presented with EPC [
      • Tiamkao S.
      • Tiamkao S.
      • Nitinavakarn B.
      • Chotmongkol V.
      • Jitpimolmard S.
      Seizures in nonketotic hyperglycemia.
      ]. In the Guwahati series NKH was the cause of EPC in 59% of the cases [
      • Shrivastava V.
      • Burj N.P.
      • Basumatary L.J.
      • Das M.
      • Goswami M.
      • Kayal A.K.
      Etiological profile of epilepsia partialis continua among adults in a tertiary care hospital.
      ]. Singh and Strobos [
      • Singh B.M.
      • Strobos R.J.
      Epilepsia partialis continua associated with nonketotic hyperglycemia: clinical and biochemical profile of 21 patients.
      ] 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 [
      • Sinha S.
      • Satishchandra P.
      Epilepsia partialis continua over last 14 years: experience from a tertiary care center from south India.
      ]. The pathogenesis of EPC in NKH has not been sufficiently clarified (as discussed in detail by Çokar et al.) [
      • Çokar Ö.
      • Aydιn B.
      • Özer F.
      Non-ketotic hyperglycaemia presenting as epilepsia partialis continua.
      ].
      Other reported metabolic causes include hypocalcemia [
      • Belluzzo M.
      • Monti F.
      • Pizzolato G.
      A case of hypocalcemia-related epilepsia partialis continua.
      ], hepatic encephalopathy [
      • Thomas J.E.
      • Reagan T.J.
      • Klass D.W.
      Epilepsia partialis continua. A review of 32 cases.
      ,
      • Parker T.
      • Freilich S.
      • Tidswell T.
      • Angus-Leppan H.
      Hepatic encephalopathy with epilepsia partialis continua: a case report.
      ], toxemia graviditatis [
      • Sinha S.
      • Satishchandra P.
      Epilepsia partialis continua over last 14 years: experience from a tertiary care center from south India.
      ] and renal failure [
      • Phabphal K.
      • Limapichat K.
      • Sathirapanya P.
      • Setthawatcharawanich S.
      • Geater A.
      Clinical characteristics, etiology and long-term outcome of epilepsia partialis continua in adult patients in Thailand.
      ].

      2.2.3 Idiopathic epilepsies

      EPC has been reported occasionally in Benign Childhood Epilepsy with Centro-Temporal Spikes (“Benign Rolandic Epilepsy”) [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ,
      • Kravljanac R.
      • Djuric M.
      • Jovic N.
      • Djordjevic M.
      • Zamurovic D.
      • Pejmezovic T.
      Etiology, clinical features and outcome of epilepsia partialis continua in cohort of 51 children.
      ].

      2.2.4 Autoimmune disorders

      EPC has been reported in autoimmune disorders including Sjögren syndrome [
      • Bansai S.K.
      • Sawhney I.M.S.
      • Chopra J.S.
      Epilepsia partialis continua in Sjögren’s syndrome.
      ] and recurrent paraneoplastic encephalitis [
      • Mut M.
      • Schiff D.
      • Dalmau J.
      Paraneoplastic recurrent multifocal encephalitis presenting with epilepsia partialis continua.
      ]. Limbic encephalitis was a reported cause in one series [
      • Kravljanac R.
      • Djuric M.
      • Jovic N.
      • Djordjevic M.
      • Zamurovic D.
      • Pejmezovic T.
      Etiology, clinical features and outcome of epilepsia partialis continua in cohort of 51 children.
      ] 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 [
      • Kravljanac R.
      • Djuric M.
      • Jovic N.
      • Djordjevic M.
      • Zamurovic D.
      • Pejmezovic T.
      Etiology, clinical features and outcome of epilepsia partialis continua in cohort of 51 children.
      ]. 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 [
      • Wiser H.G.
      • Graf H.P.
      • Bernoulli C.
      • Siegfried J.
      Quantitative analysis of intracerebral recordings in epilepsia partialis continua.
      ,
      • Chauvel P.
      • Liegeois-Chauvel C.
      • Marquis P.
      • Bancaud J.
      Distinction between the myoclonus-related potential and the epileptic spike in epilepsia partialis continua.
      ] that commonly consist of discrete spikes, sharp waves or slow wave activity and periodic lateralized epileptiform discharges [
      • Pandian J.D.
      • Thomas S.V.
      • Santoshkumar B.
      • Radhakrishnan K.
      • Sarma P.S.
      • Joseph S.
      • et al.
      Epilepsia partialis continua—a clinical and electroencephalography study.
      ]. 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 [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ]. 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 [
      • Dulac O.
      • Dravet C.
      • Plouin P.
      • Bureau M.
      • Ponsot G.
      • Gerbaut L.
      • et al.
      Nosological aspects of epilepsia partialis continua in children.
      ]. 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 [
      • Thomas J.E.
      • Reagan T.J.
      • Klass D.W.
      Epilepsia partialis continua. A review of 32 cases.
      ,
      • Cockerell O.C.
      • Rothwell J.
      • Thompson P.D.
      • Marsden C.D.
      • Shorvon S.D.
      Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK.
      ,
      • Dulac O.
      • Dravet C.
      • Plouin P.
      • Bureau M.
      • Ponsot G.
      • Gerbaut L.
      • et al.
      Nosological aspects of epilepsia partialis continua in children.
      ].
      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) [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ]. 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 [
      • Pandian J.D.
      • Thomas S.V.
      • Santoshkumar B.
      • Radhakrishnan K.
      • Sarma P.S.
      • Joseph S.
      • et al.
      Epilepsia partialis continua—a clinical and electroencephalography study.
      ]. In electrocorticography, interictal epileptiform activity is widespread and the onset of seizures occurs in multiple independent sites [
      • So N.K.
      • Gloor P.
      Electroencephalographic and electrocorticographic findings in chronic encephalitis of Rasmussen type.
      ]. Stereo-EEG correctly identifies the origin of the discharge and the clinico-EEG sequence [
      • Chauvel P.
      • Liegeois-Chauvel C.
      • Marquis P.
      • Bancaud J.
      Distinction between the myoclonus-related potential and the epileptic spike in epilepsia partialis continua.
      ].
      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 [
      • Granata T.
      • Gobbi B.
      • Spreafico R.
      • Vigevano F.
      • Capovilla G.
      • Ragona F.
      • et al.
      Rasmussen’s encephalitis: early characteristics allow diagnosis.
      ]. 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) [
      • Granata T.
      • Gobbi B.
      • Spreafico R.
      • Vigevano F.
      • Capovilla G.
      • Ragona F.
      • et al.
      Rasmussen’s encephalitis: early characteristics allow diagnosis.
      ]. 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 [
      • So N.K.
      • Gloor P.
      Electroencephalographic and electrocorticographic findings in chronic encephalitis of Rasmussen type.
      ]. Andrews described contralateral epileptiform discharges in 2 patients and these became even more frequent than the ipsilateral ones [
      • Andrews P.I.
      • McNamara J.O.
      • Lewis D.V.
      Clinical and electroencephalographic correlates in Rasmussen encephalitis.
      ]. As in other conditions, EPC in RE is not always accompanied by rhythmic EEG discharges on surface EEG [
      • Bien C.G.
      • Granata T.
      • Antozzi C.
      • Cross J.H.
      • Dulac O.
      • Kurthen M.
      • et al.
      Pathogenesis diagnosis and treatment of Rasmussen encephalitis: a European consensus statement.
      ].

      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. [
      • Thomas J.E.
      • Reagan T.J.
      • Klass D.W.
      Epilepsia partialis continua. A review of 32 cases.
      ] 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. [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ] 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. [
      • Cockerell O.C.
      • Rothwell J.
      • Thompson P.D.
      • Marsden C.D.
      • Shorvon S.D.
      Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK.
      ] 11% of patients had SF, 17% CF, and 32% SGTC seizures. All 20 patients of Pandian et al. [
      • Pandian J.D.
      • Thomas S.V.
      • Santoshkumar B.
      • Radhakrishnan K.
      • Sarma P.S.
      • Joseph S.
      • et al.
      Epilepsia partialis continua—a clinical and electroencephalography study.
      ] also had other seizures including SF in 17, CF in two and SGTC in seven. Of the 76 patients of Sinha and Satishchandra [
      • Sinha S.
      • Satishchandra P.
      Epilepsia partialis continua over last 14 years: experience from a tertiary care center from south India.
      ] 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. [
      • Kravljanac R.
      • Djuric M.
      • Jovic N.
      • Djordjevic M.
      • Zamurovic D.
      • Pejmezovic T.
      Etiology, clinical features and outcome of epilepsia partialis continua in cohort of 51 children.
      ] 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.
      AuthorsNo. of patientsNeurological signs
      Bien et al.
      • Bien C.G.
      • Tiemeier H.
      • Sassen R.
      • Kuczaty S.
      • Urbach H.
      • von Lehe M.
      • et al.
      Rasmussen encephalitis: incidence and course under randomized therapy with tacrolimus or intravenous immunoglobulins.
      3290.6%
      Lamb et al.
      • Lamb K.
      • Scott W.J.
      • Mensah A.
      • Robinson R.
      • Varadkar S.
      • Cross J.H.
      Prevalence and clinical outcome of Rasmussen encephalitis in children from the United Kingdom.
      6569.2%
      Hart
      • Hart Y.
      Rasmussen’s encephalitis.
      3644.0%
      Granata et al.
      • Granata T.
      • Gobbi B.
      • Spreafico R.
      • Vigevano F.
      • Capovilla G.
      • Ragona F.
      • et al.
      Rasmussen’s encephalitis: early characteristics allow diagnosis.
      2195.2%
      Oguni et al.
      • Oguni H.
      • Andermann F.
      • Rasmussen T.
      The natural history of the syndrome of chronic encephalitis and epilepsy: a study of the MRI series of forty eight cases.
      2080.0%
      Puligheddu et al.
      • Puligheddu M.
      • Giagheddu A.
      • Genugu F.
      • Giagheddu M.
      • Marrosu F.
      Epilepsia partialis continua in cat scratch disease.
      5172.5%
      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. [
      • Thomas J.E.
      • Reagan T.J.
      • Klass D.W.
      Epilepsia partialis continua. A review of 32 cases.
      ] 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. [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ] 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. [
      • Cockerell O.C.
      • Rothwell J.
      • Thompson P.D.
      • Marsden C.D.
      • Shorvon S.D.
      Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK.
      ] found stimulus sensitivity in 28%, and movement sensitivity in 22% of their patients. 40% of the patients of Pandian et al. [
      • Pandian J.D.
      • Thomas S.V.
      • Santoshkumar B.
      • Radhakrishnan K.
      • Sarma P.S.
      • Joseph S.
      • et al.
      Epilepsia partialis continua—a clinical and electroencephalography study.
      ] were stimulus sensitive and 30% movement sensitive. In the cohort of Phabphal et al. [
      • Phabphal K.
      • Limapichat K.
      • Sathirapanya P.
      • Setthawatcharawanich S.
      • Geater A.
      Clinical characteristics, etiology and long-term outcome of epilepsia partialis continua in adult patients in Thailand.
      ] 36% were stimulus sensitive. In one exceptional case report [
      • Paglioli E.
      • Martins W.A.
      • De la Cruz W.
      • Andrade V.
      • Duval da Silva V.
      • Nunes R.M.
      • et al.
      Epilepsia partialis continua triggered by traumatic hand injury: a peripheral tuning of brain excitability.
      ] 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 [
      • Rasmussen T.
      • Olszewski J.
      • Lloyd-Smith D.
      Focal seizures due to chronic localized encephalitis.
      ]. Similarities of RE and TBE further supported this hypothesis [
      • Asher D.M.
      • Gajdusek D.C.
      Virologic studies in chronic encephalitis.
      ]. However, attempts to identify a pathogenic viral agent have yielded contradictory findings and have remained inconclusive [
      • McLachlan R.S.
      • Girvin J.P.
      • Blume W.T.
      • Reichman H.
      Rasmussen’s chronic encephalitis in adults.
      ,
      • Atkins M.R.
      • Terrell W.
      • Hulette C.M.
      Rasmussen’s syndrome: a study of potential viral etiology.
      ,
      • Jay V.
      • Becker L.E.
      • Otsubo H.
      • Cortez M.
      • Hwang P.
      • Hoffman H.J.
      • et al.
      Chronic encephalitis and epilepsy (Rasmussen’s encephalitis): detection of cytomegalovirus and herpes simplex virus 1 by the polymerase chain reaction and in situ hybridization.
      ]. Later, the condition was linked to an autoimmune process triggered by circulating auto-antibodies activating the subunit 3 of the ionotropic glutamate receptor (GluR3Ab) [
      • Rogers S.W.
      • Andrews P.I.
      • Gahring L.C.
      • Whisenand T.
      • Cauley K.
      • Crain B.
      • et al.
      Autoantibodies to glutamate receptors GluR3 in Rasmussen’s encephalitis.
      ,
      • Levite M.
      • Fleidervish I.A.
      • Schwarz A.
      • Pelled D.
      • Futerman A.H.
      Autoantibodies to the glutamate receptor kill neurons via activation of the receptor ion channel.
      ]. More recently, a cytotoxic T lymphocytes reaction against neurons was demonstrated to play a causative role in RE [
      • Bien C.G.
      • Widman G.
      • Urbach H.
      • Sassen R.
      • Kuczaty S.
      • Wiestler O.D.
      • et al.
      The natural history of Rasmussen’s encephalitis.
      ]. Identification of antibodies to α-7-acetylcholine receptor in patients with biopsy proven RE [
      • Watson R.
      • Jiang Y.
      • Bermudez I.
      • Houlihan L.
      • Clover L.
      • McKnight K.
      • et al.
      Absence of antibodies to glutamate receptor type 3 (GluR3) in Rasmussen encephalitis.
      ] suggests that the syndrome of RE may encompass several different autoimmune entities [
      • Mantegazza R.
      • Bernasconi P.
      • Baggi F.
      • Spreafico R.
      • Ragona F.
      • Antozzi C.
      • et al.
      Antibodies against GluR3 peptides are not specific for Rasmussen’s encephalitis but are also present in epilepsy patients with severe, early onset disease qand intractable seizures.
      ].
      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 [
      • Bien C.G.
      • Granata T.
      • Antozzi C.
      • Cross J.H.
      • Dulac O.
      • Kurthen M.
      • et al.
      Pathogenesis diagnosis and treatment of Rasmussen encephalitis: a European consensus statement.
      ,
      • Rasmussen T.
      • Olszewski J.
      • Lloyd-Smith D.
      Focal seizures due to chronic localized encephalitis.
      ].

      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 [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ], 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 [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ] 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. [
      • Cockerell O.C.
      • Rothwell J.
      • Thompson P.D.
      • Marsden C.D.
      • Shorvon S.D.
      Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK.
      ] 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 [
      • Guerrini R.
      Physiology of epilepsia partialis continua and subcortical mechanisms of status epilepticus.
      ] 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. [
      • Vaudano A.E.
      • Di Bonaventura C.
      • Carni M.
      • Rodionov R.
      • Lapenta L.
      • Casciato S.
      • et al.
      Ictal haemodynamic changes in a patient affected by subtle Epilepsia Partialis Continua.
      ] 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 [
      • Vaudano A.E.
      • Di Bonaventura C.
      • Carni M.
      • Rodionov R.
      • Lapenta L.
      • Casciato S.
      • et al.
      Ictal haemodynamic changes in a patient affected by subtle Epilepsia Partialis Continua.
      ]. Likewise, Espay et al. [
      • Espay A.J.
      • Schmithorst V.J.
      • Szaflarski J.P.
      Chronic isolated hemifacial spasm as a manifestation of epilepsia partialis continua.
      ] 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 [
      • Mameniškienė R.
      • Bast T.
      • Bentes C.
      • Canevini M.P.
      • Dimova P.
      • Granata T.
      • et al.
      Clinical course and variability of non-Rasmussen, non-stroke motor and sensory epilepsia partialis continua. A European survey and analysis of 65 cases.
      ].
      Various stimulation methods have been applied in individuals or small groups of patients: vagus nerve stimulation [
      • De Benedictis A.
      • Freri E.
      • Rizzi M.
      • Franzini A.
      • Ragona F.
      • Specchio N.
      • et al.
      Vagus nerve stimulation for drug-resistant epilepsia partialis continua: report of four cases.
      ], transcranial magnetic stimulation [
      • Rotenberg A.
      • Bae E.H.
      • Takeoka M.
      • Tormos J.M.
      • Schachter S.C.
      • Pascual-Leone A.
      Repetitive transcranial magnetic stimulation in the treatment of epilepsia partialis continua.
      ] and neocortical stimulation [
      • Valentin A.
      • Ughratdar I.
      • Cheserem B.
      • Morris R.
      • Selway R.
      • Alarcon G.
      Epilepsia partialis continua responsive to neocortical electrical stimulation.
      ]. 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 [
      • Bien C.G.
      • Granata T.
      • Antozzi C.
      • Cross J.H.
      • Dulac O.
      • Kurthen M.
      • et al.
      Pathogenesis diagnosis and treatment of Rasmussen encephalitis: a European consensus statement.
      ]. The surgical isolation of the affected hemisphere is the only treatment that halts disease progression [
      • Tubbs R.S.
      • Nimjee S.M.
      • Oakes W.J.
      Long-term follow-up in children with functional hemispherectomy for Rasmussen's encephalitis.
      ,
      • Devlin M.
      • Cross J.H.
      • Harkness W.
      • Chong W.K.
      • Harding B.
      • Vargha-Khadem F.
      • et al.
      Clinical outcomes of hemispherectomy for epilepsy in childhood and adolescence.
      ] 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 [
      • Honavar M.
      • Janota I.
      • Polkey C.E.
      Rasmussen’s encephalitis in surgery for epilepsy.
      ]. Thus, selective resection of the epileptogenic zone is likely to be a good choice for adolescent and adult patients who cannot undergo a hemispherectomy [
      • Guan Y.
      • Zhou J.
      • Luan G.
      • Liu X.
      Surgical treatment of patients with Rasmussen encephalitis.
      ]. Hemispherectomy and hemispherotomy are useful methods to control seizures and improve the functional state of the patients [
      • Jonas R.
      • Nguyen S.
      • Hu B.
      • Asarnow R.F.
      • LoPresti C.
      • Curtiss S.
      • et al.
      Cerebral hemispherectomy: hospital course, seizure, developmental, language, and motor outcomes.
      ,
      • Marras C.E.
      • Granata T.
      • Franzini A.
      • Freri E.
      • Villani F.
      • Casazza M.
      • et al.
      Hemispherotomy and functional hemispherectomy: indications and outcome.
      ,
      • Van Schooneveld M.M.
      • Jennekens-Schinkel A.
      • van Rijen P.C.
      • Braun K.P.
      • van Nieuwenhuizen O.
      Hemispherectomy: a basis for mental development in children with epilepsy.
      ,
      • Pulsifer M.B.
      • Brandt J.
      • Salorio C.F.
      • Vining E.P.
      • Carson B.S.
      • Freeman J.M.
      The cognitive outcome of hemispherectomy in 71 children.
      ]. 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 [
      • Jonas R.
      • Nguyen S.
      • Hu B.
      • Asarnow R.F.
      • LoPresti C.
      • Curtiss S.
      • et al.
      Cerebral hemispherectomy: hospital course, seizure, developmental, language, and motor outcomes.
      ]. 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 [
      • Vadera S.
      • Moosa A.N.
      • Jehi L.
      • Gupta A.
      • Kotagal P.
      • Lachhwani D.
      • et al.
      Re-operative hemispherectomy for intractable epilepsy: a report of 36 patients.
      ]. Following surgical procedures, seizure freedom rates between 62.5 and 90% have been reported [
      • Guan Y.
      • Zhou J.
      • Luan G.
      • Liu X.
      Surgical treatment of patients with Rasmussen encephalitis.
      ,
      • Jonas R.
      • Nguyen S.
      • Hu B.
      • Asarnow R.F.
      • LoPresti C.
      • Curtiss S.
      • et al.
      Cerebral hemispherectomy: hospital course, seizure, developmental, language, and motor outcomes.
      ,
      • Villemure J.G.
      • Daniel R.T.
      Peri-insular hemispherotomy in paediatric epilepsy.
      ,
      • Delalande O.
      • Bulteau C.
      • Dellatolas G.
      • Fohlen M.
      • Jalin C.
      • Buret V.
      • et al.
      Vertical parasagittal hemispherotomy: surgical procedures and clinical long-term outcomes in a population of 83 children.
      ]. 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 [
      • Vining E.P.
      • Freeman J.M.
      • Pillas D.J.
      • Uematsu S.
      • Carson B.S.
      • Brandt J.
      • et al.
      Why would you remove half a brain? The outcome of 58 children after hemispherectomy—the Johns Hopkins experience: 1968 to 1996.
      ,
      • Wiebe S.
      • Berg A.T.
      Big epilepsy surgery for little people: what’s the full story on hemispherectomy?.
      ]. Moreover, a shorter duration of frequent seizures before surgery may lead to a better long-term cognitive outcome [
      • Guan Y.
      • Zhou J.
      • Luan G.
      • Liu X.
      Surgical treatment of patients with Rasmussen encephalitis.
      ].
      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 [
      • Granata T.
      • Fusco L.
      • Gobbi G.
      • Freri E.
      • Ragona F.
      • Broggi G.
      • et al.
      Experience with immunomodulatory treatments in Rasmussen’s encephalitis.
      ]. 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 [
      • Bahi-Buisson N.
      • Villanueva V.
      • Bulteau C.
      • Delalande O.
      • Dulac O.
      • Chiron C.
      • et al.
      Long term response to steroid therapy in Rasmussen encephalitis.
      ]. Intravenous immunoglobulines provide clinical improvement in long-term administration in adult-onset RS while they are generally less encouraging in children for unclear reasons [
      • Leach J.P.
      • Chadwich D.W.
      • Miles J.B.
      • Hart I.K.
      Improvement in adult-onset Rasmussen’s encephalitis with long-term immunomodulatory therapy.
      ]. 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 [
      • Bien C.G.
      • Tiemeier H.
      • Sassen R.
      • Kuczaty S.
      • Urbach H.
      • von Lehe M.
      • et al.
      Rasmussen encephalitis: incidence and course under randomized therapy with tacrolimus or intravenous immunoglobulins.
      ]. Plasma exchange and protein A immunoadsorption can be useful in refractory status epilepticus because of removing of circulating autoantibodies [
      • Lousa M.
      • Sanchez-Alonso S.
      • Rodriguez-Diaz R.
      • Dalmau J.
      Status epilepticus with neuron-reactive serum antibodies: response to plasma exchange.
      ]. Anecdotal attempts with intraventricular alpha-interferon and rituximab are described [
      • Dabbagh O.
      • Gascon G.
      • Crowell J.
      • Bamoggadam F.
      Intraventricular interferon-alpha stops seizures in Rasmussen’s encephalitis: a case report.
      ,
      • Thilo B.
      • Stingele R.
      • Knudsen K.
      • Boor R.
      • Bien C.G.
      • Deuschl G.
      • et al.
      A case of Rasmussen encephalitis treated with rituximab.
      ].

      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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