An effective immunotherapy regimen for VGKC antibody-positive limbic encephalitis
- 1Department of Neurology, The Walton Centre for Neurology and Neurosurgery, Liverpool, UK
- 2Department of Neuroradiology, The Walton Centre for Neurology and Neurosurgery, Liverpool, UK
- Correspondence to Dr Sui Wong, Neurology Specialist Registrar, The Walton Centre for Neurology and Neurosurgery, Lower Lane, Liverpool L9 7LJ, UK;
Contributors All authors contributed to the writing of the manuscript. Dr Ian Hart designed this study and supervised the manuscript writting process.
- Received 17 March 2009
- Revised 29 May 2009
- Accepted 1 June 2009
- Published Online First 26 July 2010
Background Voltage-gated potassium channel antibody-positive limbic encephalitis (VGKC+LE) frequently improves with immunotherapy, although the optimum regimen is unknown. The effectiveness of a combination immunomodulatory regimen was tested in consecutive VGKC+LE patients.
Methods This was an open-label prospective study of nine VGKC+LE patients. All patients had plasma exchange (50 ml/kg), intravenous immunoglobulin (2 g/kg) and intravenous methylprednisolone (1 g×3), followed by maintenance oral prednisolone (1 mg/kg/day). Mycophenolate (2 g/day) was used in the first three patients. Assessments included serial clinical, cognitive, brain MRI and VGKC antibody testing.
Results Within 1 week, seizures and hyponatraemia remitted in all affected patients. Cognitive function improved in all patients within 3 months. MRI appearances improved substantially within 9 months, with remission of inflammation in the majority of patients. All achieved immunological remission with normal VGKC antibody titres within 1–4 months. Major adverse events of therapy included one septicaemia and one thrombosis on plasma exchange and one death from sepsis after incidental bowel surgery. One patient remains in remission after 40 months of follow up, 26 months after being off all treatment.
Conclusions Our immunotherapy regimen was effective for the treatment of the clinical, cognitive and immunological features of VGKC+LE. Radiological improvement was seen in the majority. Pending randomised controlled trials, this regimen is proposed for the treatment of VGKC+LE.
- Addenbrookes Cognitive Examination
- Addenbrookes Cognitive Examination-Revised
- intravenous immunoglobulins
- plasma exchange
- voltage-gated potassium channel antibody-positive limbic encephalitis
Voltage-gated potassium channel antibody-positive limbic encephalitis (VGKC+LE) is a recently recognised autoimmune disorder.1–3 The natural history is variable, with a substantial proportion of patients progressing to severe and irreversible disability with extensive and temporally ungraded retrograde amnesia.1–4 VGKC antibodies are thought to be pathogenic in this condition: reduction in antibody titres by immunomodulatory treatment correlates with clinical improvement,2 3 although postmortem studies also suggest T cell involvement.5 Currently, there are no definitive data on optimal dosing, timing or duration of immunomodulatory treatment in VGKC+LE. We performed a single-centre open-label prospective study using a standard immunotherapy regimen in patients with VGKC+LE.
Nine patients with clinical features of limbic encephalitis (subacute amnesia, disorientation, seizures and/or hyponatraemia)2 3 and an elevated VGKC antibody titre (cut-off >100 pM) were identified over a 3-year period (August 2005 to June 2008). All patients and/or their next-of-kin gave written consent for publication of the results.
All patients were given induction treatment with plasma exchange (five exchanges of 50 ml/kg), intravenous immunoglobulin (IVIg; 2 g/kg over 5 days) and intravenous methylprednisolone (1 g/day×3), followed by maintenance treatment with oral prednisolone (1 mg/kg). Mycophenolate (2 g/day) was used as a steroid-sparing agent in the first three patients only. This regimen, which targeted both B and T cell-mediated immunopathogenetic mechanisms, was based on previous reports2 3 and on well-established treatment approaches used in other autoantibody-mediated diseases such as myasthenia gravis6 and in Rasmussen's syndrome.7 Symptomatic treatments for seizures and psychiatric problems were given as needed.
Serial assessments of response to treatment were made over follow-up periods of 4–40 months, including clinical examination, cognitive testing with the Addenbrooke's Cognitive Examination (ACE) or its revised version (ACE-R),8 brain MRI using standard T1- and T2-weighted sequences and VGKC antibody titres.
The nine patients (male to female ratio 8:1, mean age at onset 63 years, range 46–75) had symptoms from 1.5 to 24 months (mean 11 months) before diagnosis of VGKC+LE, specifically memory problems (9/9), seizures (8/9), fluctuating confusion (5/9) and behavioural change (5/9). One patient had cerebellar ataxia 1 year after the first symptoms of seizures and memory difficulties. All patients were VGKC antibody positive, with presenting titres ranging from 210 to 4102 pM (mean 1630±1370 pM) (table 1). Cognitive testing (ACE) before treatment showed greatest impairment in memory subscores (see online table 1). MRIs were abnormal at presentation in 7/9 patients (see online table 2), with T2 hyperintensity or oedema affecting the hippocampi with or without changes in the amygdalae, predominantly on the left.
All patients showed a rapid decline in VGKC antibody titre following initiation of the immunomodulatory regimen (figure 1). Within 1–4 months of treatment, all patients achieved immunological remission (VGKC antibody titre <100 pM). All but two patients remained in immunological remission thereafter. The exceptions had a slight increase in VGKC antibody titre associated with tapering of steroids, resolving with increased immunosuppression.
All patients improved rapidly following treatment. Both seizures (8/8) and hyponatraemia (3/3) remitted within 1 week, without alteration in antiepileptic drug therapy. Only two patients had seizure recurrence during follow-up, associated with raised VGKC antibody titre: patient 1 had three complex partial seizures when steroids were tapered at 7 months and patient 2 had a single complex partial seizure at 26 months when on a tapering dose of prednisolone (5 mg). Patient 1 had her prednisolone increased to 30 mg and a further course of IVIg (2 g/kg). Patient 2 had prednisolone increased to 20 mg. Thereafter, both patients were seizure free.
Cognitive function improved in all patients by self- and informant report and was confirmed by clinical opinion. All but one returned to functioning in the community (patient 8, treatment started May 2008, receiving inpatient neurorehabilitation). ACE and ACE-R scores (see online table 1) showed improvement in 4/5 patients tested (range 7–20 points/100) both pretreatment and post-treatment, with the greatest improvement in the memory subscores (range 3–11 points/26). Ongoing improvements were seen even several months after VGKC antibodies became negative, as illustrated by patient 5 who showed improvement up to 11 months following treatment although VGKC antibodies were negative within 2 months of starting treatment.
All patients with abnormal brain MRI showed improvement of T2 hyperintensity and oedema within 6–9 months of starting immunomodulatory treatment (see online table 2). There was a time lag in the resolution of MRI abnormalities in relation to clinical and immunological remission; these occurred within 1–4 months in all patients, whereas full radiological remission occurred within 6–9 months in 5/7 patients. Two patients had ongoing swelling or signal change when last assessed. Atrophy of hippocampi and amygdala was seen in two patients 2–6 months after treatment started (7–8 months after symptom onset, respectively). These two patients had the highest VGKC antibody titres at presentation (4102 and 4064 pM).
Major adverse events thought to be related to the treatment regimen occurred in three patients. Two developed complications related to the femoral line required for plasma exchange: one developed methicillin-resistant Staphylococcus aureus septicaemia and a vertebral discitis; the other developed a haematoma at the femoral line site, deep vein thrombosis of the affected leg and pulmonary embolism. Both patients were successfully treated. One patient who was in remission on mycophenolate and prednisolone 4 months after commencement of immunomodulatory treatment underwent an elective haemorrhoidectomy, which was complicated by Listeria septicaemia from which he died.
Another patient died with a bowel perforation 9 months after commencement of treatment, thought unrelated to his immunomodulatory treatment.
VGKC+LE is a relatively rare condition, and reports to date have been retrospective series of patients treated with different immunomodulatory regimens.1–4 Therefore, the optimum treatment for VGKC+LE is not known.
All nine patients in this study received a uniform immunomodulatory regimen and were prospectively monitored at a single centre. All had typical clinical, cognitive, neuroradiological and immunological features of VGKC+LE, although several (4/9) had rather long disease courses (of more than a year). Response to treatment, with remission of seizures and resolution of hyponatraemia, was seen within 1 week. Within 1–4 months, VGKC antibody titre normalised. Within 1–3 months, patients and their relatives reported improvement in memory problems, which was supported by clinical observation and, in some cases, by cognitive testing. Within 6–9 months, brain MRI hippocampal swelling and signal change improved, although two patients had ongoing signal change and two had developed focal atrophy. All patients responded to treatment, even when symptoms had been present for up to 2 years. All surviving patients remain in immunological remission following this treatment regimen over 4–40-month periods of follow-up. Our first patient was on prednisolone for a total of 14 months and has remained well for a further 26 months off both steroids and antiepileptic medications.
The rationale for combined plasma exchange and intravenous immunoglobulins at the induction phase of treatment was to rapidly clear VGKC antibodies believed to be pathogenic in VGKC+LE, to halt the destructive process of ongoing and irreversible damage to the limbic system. The titre of VGKC antibodies present before treatment may be crucial: the two patients who developed hippocampal atrophy had the highest VGKC titres (>4000 pM). The chosen treatment approach was based in part on prior experience with difficult cases of autoimmune neurological disorders such as Rasmussen's encephalitis7 and myasthenia crises refractory to IVIG alone, and previous experience in this condition.2 3 However, limited resources for both IVIg and plasma exchange and the risks of adverse events do raise the question of whether both are required and highlight the need for randomised trials.
The benefits of oral steroids in achieving faster falls in antibody titres and improved cognitive function was suggested by Vincent et al2 Our aim was to keep patients on high-dose steroids for a minimum of 6 months to achieve sustained clinical stability and persisting low VGKC antibody titre before dose tapering. Experience suggests that tapering of steroids should be done gradually with close monitoring for signs of clinical and immunological deterioration. Steroid taper was interrupted in two patients because of recurrence of seizures, prompting an increase in steroid dose and slowing of subsequent taper.
The use of mycophenolate was discontinued after the first three patients, as it was felt not to be required and as recent trials of mycophenolate in myasthenia gravis have not shown strong supportive evidence for its use.9
In summary, our findings support the use of this immunotherapy regimen, which proved to be effective, rapidly acting and to induce sustained immunological remission. In all patients, clinical improvement and evidence of suppression of central nervous system inflammation occurred even though treatment was started after up to 24 months of clinical symptoms. It is, however, likely that intensive treatment started early in VGKC+LE could ameliorate or prevent hippocampal atrophy-associated cell death and clinical disability, highlighting the importance of timely diagnosis and treatment. There is a need for pragmatic multicentre randomised controlled trials to determine the optimum treatment regimen for VGKC+LE using appropriate outcome measures and, particularly given the high rate of complications seen in this study, for safety monitoring. In the absence of such trials, we believe that our study shows promising results sufficient to propose this treatment protocol for VGKC+LE.
We thank Dr Kieran O'Driscoll for clinical advice and our colleagues (Drs M. Doran, N.A. Fletcher, P.R.D. Humphrey, B.R.F. Lecky, A.G. Marson, A. Nicolson, M. Wilson) who referred the patients. Preliminary data from this study were presented at the Association of British Neurology March 2008 meeting.
↵* Dr Ian Hart died on 10 November 2008
Competing interests None.
Patient consent Obtained.
provenance and peer review Not commissioned; externally peer reviewed.