effectiveness of multimodality treatment for autoimmune limbic epilepsy
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Clinical commentaryEpileptic Disord 2014; 16 (4): 494-9
Effectiveness of multimodalitytreatment for autoimmunelimbic epilepsy
Divyanshu Dubey, John Konikkara, Pradeep N. Modur,Mark Agostini, Puneet Gupta, Francy Shu, Steven VerninoDepartment of Neurology, University of Texas Southwestern Medical Center, Dallas,Texas, USA
Received June 19, 2014; Accepted September 03, 2014
ABSTRACT – We evaluated the outcome of multimodality treatment inautoimmune limbic epilepsy in 3 consecutive patients (2 male and 1 female;age 33-55 years) presenting with a combination of focal non-convulsivestatus epilepticus, memory impairment, and psychosis. MRI showed rightor bitemporal T2 or FLAIR hyperintensity. Video-EEG showed seizuresof right temporo-occipital or bitemporal independent onset. Extensiveworkup failed to reveal infectious aetiology or an underlying tumour.However, the autoantibody panel was positive for one or more of theseantibodies: anti-VGKC, anti-GABAB, anti-VGCC (P/Q, N types), and anti-GAD65. All patients received: (1) conventional antiepileptic drugs includinglevetiracetam, lacosamide, phenobarbital, lamotrigine, and valproate; (2)immunomodulatory therapy including methylprednisolone, plasmaphere-sis, and intravenous immunoglobulin; and (3) rituximab. After a 4-6-weekin-hospital course, the seizures resolved in all patients but 2 had persis-tent memory impairment. None had treatment-related complications. Atthe time of last follow-up, 2-3 months later, 2 patients remained seizure-free while 2 had residual memory impairment. Our findings suggestthat multimodality treatment with a combination of conventional AEDs,
ximab is effective and safe in autoim-
aneoplastic syndrome, autoimmune
and amphiphysin. However, anti-bodies directed against the cellmembrane or synaptic receptors
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immunomodulatory therapy, and ritumune limbic epilepsy.Key words: limbic encephalitis, parepilepsy, status epilepticus, rituximab
Limbic encephalitis (LE) is char-acterized by confusion, cognitivedifficulty, memory impairment, andA
ut
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94 Epileptic Disord, Vol. 16, No. 4, December 2014
orrespondence:radeep N. Modurepartment of Neurology,niversity of Texas Southwestern Medicalenter,323 Harry Hines Blvd,allas, TX 75390, [email protected]>
seizures caused by inflammation inthe limbic structures. LE is gen-erally felt to be a paraneoplasticcondition attributed to an under-lying malignancy, with antibodiesdirected against the intracellularantigens, such as Hu, Ma2, CRMP51,
(e.g. VGKC, NMDAR, LGI1, Caspr,GABAB, GAD2) have also been as-sociated with LE, with or withoutan underlying malignancy (Davisand Dalmau, 2013). Although LE canpresent with various neuropsychi-atric manifestations, seizures are
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ommon in this disorder, often leading to refractoryutoimmune limbic epilepsy (ALE). Besides optimizingntiepileptic drugs (AEDs) and treating the underly-ng tumour (if identified), no clear guidelines existor managing ALE (Ozkara and Vivegano, 2011). Wheneizures are intractable, immunomodulators (e.g.ntravenous methylprednisolone [IVMP], intravenousmmunoglobulin [IVIG], and plasmapheresis) haveeen used as first-line therapy with variable success.
mmunosuppressants (e.g. cyclophosphamide) haveeen tried as second-line agents, but are not favouredecause of serious adverse effects. In this article,e present a series of three consecutive patients
table 1) with refractory ALE who achieved successfulutcome after receiving multimodality treatment withonventional AEDs, various immunomodulators, andn immunosuppressant (rituximab). Our aim is to addo the expanding literature on ALE, and to provide prac-ical guidelines on prompt diagnosis and managementf this potentially reversible illness.
ase studies
atient 1 was a 53-year-old Caucasian male with aistory of hypertension, hyperlipidaemia, and coro-ary artery disease, who presented with new-onseteizures of eight weeks duration. His seizures wereharacterized by staring, left head deviation, leftacial twitching, and generalized tonic-clonic acti-ity. Seizures remained intractable to multiple AEDs,nd he developed anterograde memory loss, agita-ion, visual and auditory hallucinations, and worseningonfusion leading to persistently altered mental status.pon transfer to our facility, the patient was severelyisoriented and confused without focal neurologicaleficits. Video-EEG monitoring (VEM) showed focalon-convulsive status epilepticus (FNCSE) with clini-al and electrographic seizures originating from theight temporo-parietal region (figure 1A). InterictalEG showed periodic lateralized epileptiform dis-harges (PLEDs) in the right temporo-parieto-occipitalegion. Brain MRI showed FLAIR hyperintensity inhe medial right temporal lobe (figure 2A). CSFtudies showed normal glucose, mildly elevated pro-ut
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© John Libbey Eupileptic Disord, Vol. 16, No. 4, December 2014
ein (55 mg/dL), normal nucleated cell count, negativeSV PCR, and negative West Nile virus (WNV) anti-odies. Although FNCSE eventually resolved on aombination of levetiracetam, lacosamide, and phe-obarbital, he remained amnestic and confused, withubsequent VEM showing electrographic seizures of
CRMP: collapsin response mediator protein.Caspr: contactin-associated proteinlike; GABAB: gamma
minobutyric acid type B; GAD: glutamic acid decarboxy-ase; LGI: leucine-rich glioma inactivated; NMDAR: N-methyl
-aspartate receptor; VGKC: voltage-gated potassium channel.
scoscia5
3
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Treatment of autoimmune limbic epilepsyeft temporal onset. He was treated empirically with 5 gVMP over 5 days. Because of only minimal improve-
ent in mental status, he received five cycles oflasmapheresis. Paraneoplastic panel showed anti-GCC3 (P/Q and N type) and anti-GABAB antibodies.T of chest and abdomen was negative for tumour.ervical lymph node biopsy showed no evidence ofalignancy. Despite improvement in the mental state,
e continued to have short-term memory impairmentnd developed visual hallucinations. This promptedcourse of 2 g/kg IVIG over 5 days, followed by 1 g
V rituximab to achieve long-term immunosuppres-ion. At the time of discharge from the acute careetting to a rehabilitation facility, the seizures wereontrolled but mild disorientation and short-termemory impairment persisted. At the last follow-up
isit, 91 days after inpatient discharge, the patient hadne witnessed complex partial seizure; he had resi-ual memory impairment and behavioural problems,espite significant improvement.atient 2 was a 33-year-old African-American femaleith a history of glutamic acid decarboxylase 65
GAD65) antibody-positive stiff person syndrome andeizures, who presented with progressively wors-ning memory impairment and intractable seizures.he also reported a one-year history of fatigue, gaittaxia, rigidity, and myoclonus triggered by loud noisehyperekplexia). Upon admission, she was noted toave dysconjugate gaze, increased tone, bilateral dys-etria, and wide-based ataxic gait. VEM showed brief
ut frequent electrographic seizures of independentight and left temporal onset (figure 1B). InterictalEG showed frequent right temporal sharp waves.rain MRI showed bilateral FLAIR hyperintensities
nvolving the parahippocampal gyri (figure 2B), raisinghe possibility of ALE as a new diagnosis despite prioristory of epilepsy. CSF studies were unremarkable.eizures improved with IV fosphenytoin, lacosamide,nd lamotrigine. Given the history of GAD65-positiveyndrome, she was empirically treated with IVIG, at
g/kg over five days. Serum paraneoplastic panelhowed anti-GAD65 (4,531 nmol/L) and anti-VGKC0.04 nmol/L) antibodies. CT chest and abdomen didot show underlying malignancy. Because of persis-
ent left posterior temporal electrographic seizures,he was treated with 500 mg IV rituximab withoutomplications. Subsequent monitoring showed res-
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lution of electrographic seizures. Two months later,he was readmitted with increased frequency oflinical and electrographic seizures of bitemporalndependent onset (left greater than right), promptingn increase in baseline AEDs and a second dose of00 mg IV rituximab. At the time of discharge, CD19
VGCC: voltage-gated calcium channel.
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D. Dubey, et al.
Table 1. Clinical characteristics of three patients.
Patient 1 Patient 2 Patient 3
Age (years) 53 33 55
Gender M F M
Race Caucasian African-American Caucasian
Time fromsymptom onsetto duration
8 weeks 4 weeks 12 weeks
Prodromal syndrome Yes Yes Yes
Presenting symptom Behavioural changes Memory loss Seizure
Seizures Clinical and electrographic Clinical and electrographic Clinical
Behavioural changes Yes No Yes
Memory impairment Yes Yes Yes
Autonomic dysfunction Yes Yes Yes
CSF pleocytosis No No No
Elevated CSF Protein Yes No Yes
Autoantibodies Anti-GABAB,anti-VGCC (P/Qand N type)
Anti-GAD65,anti-VGKC
Anti-VGKC
EEG findings Righttemporo-parietalfocalnon-convulsivestatus epilepticus
Bitemporalindependent focalnon-convulsivestatus epilepticus
Right temporalfocalnon-convulsivestatus epilepticus
MRI Findings FLAIRhyperintensityinvolving rightmedial temporallobe
FLAIRhyperintensityinvolving bilateralhippocampii andfornices (rightgreater than left)
FLAIRhyperintensityinvolving righthippocampus anduncus
Malignancy workup Negative Negative Negative
Antiepileptic drugs Levetiracetam,lacosamide,phenobarbital
Fosphenytoin,lacosamide,lamotrigine
Levetiracetam,valproate,lamotrigine,phenobarbital
IV steroids Yes Yes Yes
Plasmapheresis Yes No Yes
IV immunoglobulins Yes Yes Yes
Rituximab Yes Yes Yes
Last follow-up visit 91 days; rare seizure;residual memory andbehavioural problems
63 days; seizure free;intermittent musclespasm and back pain
68 days; seizurefree; residualmemory problem
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igure 1. EEG findings: (A) right temporo-parietal ictal dischnd (C) right posterior temporal-occipital interictal epileptiform
ount was 0.1%, and the electrographic seizures hadesolved, but she continued to have spasms that wereon-epileptic, felt to be related to the underlying stiff-erson syndrome. At the last follow-up visit, 63 daysA
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© John Libbey Eupileptic Disord, Vol. 16, No. 4, December 2014
fter inpatient discharge, she had remained seizure-ree, however, she continued to have intermittent
uscle spasm and back pain.atient 3 was a healthy 55-year-old Caucasian maleho presented to the outside facility with worseningemory impairment, behavioural problems, agitation,
nd FNCSE with clinical seizures of right temporal
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nset. Brain MRI showed T2 hyperintensity involv-ng the right medial temporal lobe (figure 2C). CSFtudies showed elevated protein (77 mg/dL), normallucose, and normal cell count. Studies for infec-
rotext, 2014497
ious aetiology were unremarkable. Biopsy of the rightemporal lobe was non-diagnostic, consistent withon-specific inflammation. Upon transfer to our faci-
ity, the seizures were controlled by a combination ofevetiracetam, valproate, lamotrigine, and phenobar-ital, but he remained confused and agitated without
ocal neurological deficits. VEM showed no clinical or
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igure 2. MRI findings: (A) FLAIR hyperintensity in the medial rihe parahippocampal gyri in Patient 2; and (C) T2 hyperintensity
lectrographic seizure activity, but showed frequentight posterior temporal-occipital interictal epilepti-orm discharges (figure 1C). He received 5 g IVMP overdays. Levetiracetam was discontinued due to concernf behavioural problems, but the other AEDs were con-
inued. Quetiapine was started for agitation and visualallucinations. Lack of improvement in mental statusrompted five cycles of plasmapheresis followed by
VIG, at 2 g/kg over 5 days. Quetiapine was stoppednd haloperidol was started. Paraneoplastic panel wasositive for anti-VGKC antibodies (0.13 nmol/L). CThest and abdomen did not show underlying mali-nancy. Because of persistently altered mental status,e was treated with rituximab 500 mg IV. At the time ofischarge to an inpatient rehabilitation facility, CD19ount was 0.2%, and the seizures were completely con-rolled and the agitation was markedly improved. Atast follow-up visit, 68 days after inpatient discharge,he patient had remained seizure-free, and had no
ore behavioural outbursts or agitation, however, heontinued to have residual memory impairment.
iscussion
or patients with new-onset seizures in the setting ofcute or subacute neurocognitive manifestations, aiagnosis of autoimmune limbic epilepsy (ALE) shoulde entertained. However, no definitive guidelinesxist for treating ALE (Ozkara and Vivegano, 2011). Ourtudy demonstrates that if seizures remain refractoryo conventional AEDs, immunomodulation can be
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© John Libbey Eu98
eneficial while the diagnostic workup is pursued. Ifn underlying malignancy is discovered, the treatmentf the tumour seems to be most effective. However,hen the malignancy workup is negative, rituximab
ppears to be an effective and safe option as ourtudy demonstrates. Our series is along the lines ofrecent study which reported success with various
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mporal lobe in Patient 1; (B) bilateral FLAIR hyperintensities inright medial temporal lobe in Patient 3.
ombinations of IVMP, IVIG, plasmapheresis, andyclophosphamide in 12 patients with autoimmunepilepsy (Quek et al., 2012). Our series expands the
iterature and highlights the effectiveness of ritux-mab in a heterogeneous group of ALE patients withifferent types of antibodies.he rationale for immunotherapy in ALE is based onultiple lines of evidence. It has been shown that the
ntibodies from patients bind to the GABAB receptorsn rat neurons, and disruptions of the rodent GABAB
eceptors result in clinical phenotypes similar to lim-ic encephalitis and epilepsy (Lancaster et al., 2010).
mmunoglobulins from patients with anti-NMDARntibodies have been shown to cause neuronal dys-unction in cultured hippocampal neurons, whilenfusion of CSF from these patients resulted in a reduc-ion of hippocampal NMDAR immunostaining in ratsHughes et al., 2010). Brain biopsies of patients with LEave revealed inflammatory changes, such as extensiveeuronal loss, gliosis, microglial nodules, perivascular
ymphocytic cuffing, and leptomeningeal mononu-lear cell infiltrates (Graus et al., 2008). Thus, these find-ngs point towards immune-mediated neuronal da-
age which can be curbed by immunosuppressants.esides the conventional AEDs to control the seizures,e hypothesize that multimodality immunotherapy
s effective in ALE because of different mechanismsf action on the immune system. First, glucocorti-oids reduce inflammation by modulating chemokinend cytokine production, adhesion molecule expres-ion, and white blood cell production (Rhen andidlowski, 2005). Second, plasmapheresis, an extra-
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orporeal blood purification technique, removes largeolecular-weight molecules, such as immunoglobu-
ins, and filters out plasma membrane proteins suchs VGKC complexes from the blood (Winters, 2012).hird, IVIG, a sterile, purified IgG product fromooled human plasma, helps modulate complementctivation, suppress idiotypic antibodies, saturate Fc
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eceptors on macrophages, and suppress cytokines,hemokines, and metalloproteinases (Boros et al.,005). Finally, rituximab, a humanized monoclonal IgG,argets CD20, the surface antigen of B lymphocytes,hereby eliminating the latter prior to their differen-iation into plasma cells (Dropcho, 2013).one of our patients underwent PET, thus there
emained a small possibility that an underlying mali-nancy could still exist. We could also not deter-ine which therapy may have provided the greatest
mpact on outcome, since all of the therapies weredministered over a short period of time. Neverthe-ess, our series demonstrates successful treatment ofntractable non-paraneoplastic ALE using conventionalEDs, empiric immunomodulation, and rituximab, the
atter being a potentially less toxic alternative toyclophosphamide. Further studies are needed to sup-ort our findings and determine the optimum durationf immunotherapy to prevent relapse. �
isclosures.
© John Libbey Eupileptic Disord, Vol. 16, No. 4, December 2014
one of the authors have any conflict of interest to disclose.
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