CASE STUDY

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A case of voltage-gated potassium channel
antibody-related limbic encephalitis
Tim Harrower*, Tom Foltynie, Luke Kartsounis, Rajith N De Silva and John R Hodges

S U M M A RY This article offers the opportunity to earn one
Category 1 credit toward the AMA Physician’s
Background A 56-year-old man presented to hospital with a 6-month Recognition Award.
history of recurrent episodes of altered behavior and ‘odd’ episodes.
He had become apathetic and uninterested in his family. He had no THE CASE
relevant past medical or family history. General and physical neurological A 56-year-old man presented to hospital with
examinations were unremarkable, as was bedside cognitive testing. a 6-month history of recurrent episodes of
Investigations Brain MRI scan, 24-h electroencephalogram, serum and altered behavior that lasted for a few days at a
cerebrospinal fluid testing for voltage-gated potassium channel antibodies, time, occurring every 2–3 weeks. He also expe-
blood screening for tumors, CT scans of the chest, abdomen and pelvis, rienced ‘odd’ episodes that lasted seconds to a
whole-body PET scan, neuropsychological examination, brain few minutes, which were characterized by the
18F-fluorodeoxyglucose-PET scan.
sudden onset of disrupted speech and complex
Diagnosis Voltage-gated potassium channel antibody-related limbic quasi-purposeful stereotyped movements, with
encephalitis. a startled, vague appearance on his face. Initially,
Management Antiepileptic drugs, immunomodulatory therapy, oral these episodes occurred weekly, but they later
steroids, plasma exchange. progressed to become a daily occurrence. The
KEYWORDS hyponatremia, immunomodulatory therapy, limbic encephalitis,
patient had become apathetic and uninterested in
voltage-gated potassium channel antibodies his family, and he uncharacteristically now spent
most of his time in bed. During his episodes of
CME altered behavior, he would be unable to recall his
occupation, and would give sudden outbursts
of expletives. He had no relevant past medical
history such as risk factors for malignancy, and
no relevant family history.
General and physical neurological examina-
tions were unremarkable, as was bedside cogni-
tive testing during his normal state. Initial
investigations included a brain MRI scan with
fluid-attenuated inversion-recovery (FLAIR) and
diffusion-weighted sequences, which was found
to be normal, and a 24-h electroencephalogram
(EEG). During the EEG, the patient experi-
enced one of his odd episodes, but no associated
TP Harrower is a Neurology Registrar, T Foltynie is a Neurology Registrar, neurophysiological evidence of a seizure was
and JR Hodges is a Professor and Consultant Neurologist, all at Addenbrooke’s observed, making a diagnosis of a seizure disorder
Hospital, Cambridge, UK. L Kartsounis is a Consultant Neuropsychologist unlikely—although this possibility was not
and RN De Silva is a Consultant Neurologist, both at Oldchurch Hospital, completely excluded. He was therefore referred
Essex, UK. to the psychiatric department with a tentative
diagnosis of pseudoseizures (nonepileptic attack
Correspondence
*Department of Neuroscience, University of Cambridge, Addenbrooke’s Hospital, Hills Road,
disorder). In-patient observation over a period of
Cambridge CB2 2QQ, UK 2 months revealed that the patient was becoming
timothy.harrower@addenbrookes.nhs.uk increasingly confused, and that he confabulated
memories. For instance, he stated one day that he
Received 31 August 2005 Accepted 23 March 2006
www.nature.com/clinicalpractice
had met Richard Branson in the hospital foyer,
doi:10.1038/ncpneuro0194 and that he was being transferred to various

JUNE 2006 VOL 2 NO 6 NATURE CLINICAL PRACTICE NEUROLOGY 339

©2006 Nature Publishing Group

but unfortunately not with FLAIR or diffusion- Figure 1 A comparison of serum sodium concentration (blue line and vertical axis on the left) and serum voltage-gated potassium channel antibody titer (red weighted sequences because of the patient’s line and vertical axis on the right) over time (in weeks) and treatment courses. and URINE CONCENTRATION TEST revealed appro. focal movements and at strict fluid restriction. (600 mg three times per day) and levetiracetam content is difficult to follow he experienced a clear-cut focal seizure (see (1 g twice a day). Electromyography and nerve conduc- 132 – – 1. During this extensive period of observa. Together. A repeat EEG was under. but a brain 18F-fluorodeoxyglucose (FDG)-PET scan revealed diffuse hypometabolism involving both hemispheres anteriorly and posteriorly. no abnormal sleep behavior was observed but his behavior continued to be extremely erratic. He was uncharacter. In status. CT scans of the chest. JUNE 2006 VOL 2 NO 6 ©2006 Nature Publishing Group . CASE STUDY www. with plasma exchange and commenced on daily PSYCHOGENIC ence of spike and wave profiles. PRESSURE OF SPEECH tion. GLOSSARY locations within the hospital. His polydipsia also resolved. and this revealed 118 – –0 mild impairment of his frontal executive func- 1 5 10 15 20 24 tion and episodic memory. were 124 – – 500 all negative. often writing cult to control. gabapentin rapidly. so that not only is the patient speaking lengthy but confused letters. His ideas appear to occur to the patient faster than (4–6 l/day) and continued to conduct his epileptic seizures were more frequent and diffi- the patient can properly business from his hospital bed. of paranoia. which was mirrored by a drop in his addition. with his urine osmolarity exceeding his serum osmolarity. during which time the his seizures. inability to tolerate the procedures as a result IV Ig.000 tive and cerebrospinal fluid examination was 134 – antibody titer (pmol/l) normal. The patient ment in his clinical state. During the next excessive water drinking in (serum sodium concentration 122 mmol/l. but their speech logical consultation on the psychiatry ward. during which he again experienced a more by alternative means. and whole-body PET scanning. the responses never approach derailment. ment with phenytoin (400 mg/day). with resolution of his stimulus to drink was closely observed during a period of water neuropsychiatric symptoms and cessation of deprivation lasting 12 h. He was therefore treated appropriately. TANGENTIALITY and PRESSURE OF The patient was commenced on a course of the point of the questions SPEECH. these results indi- 140 – – 2. He drank water excessively with episodes of aggression and confusion. the patient’s serum URINE CONCENTRATION Supplementary Video online) with flushing sodium level remained low. He also their presence at a level of 2. 0. intravenous immunoglobulin. it became ability of the kidneys to postictal confusion. thus confirming high-dose oral prednisolone (60 mg/day) with POLYDIPSIA the presence of seizures.317 pmol/l (normal digressive.000 bodies. and experienced paranoid channel antibodies (VGKC-Abs) detected A pattern of speech characterized by oblique.500 cated that the hyponatremia was the result of PSYCHOGENIC POLYDIPSIA. A detailed neuropsychological 122 – evaluation was undertaken during a period of 120 – the patient’s altered behavior.500 tion studies were normal. abdomen and pelvis. and ultimately required treat- verbalize them. despite attempts TEST A test that measures the and altered consciousness. During a neuro. or irrelevant had features of thought disorder with thought level <100 pmol/l). month there was a gradual but definite improve- the absence of a physiologic normal range 135–145 mmol/l). however. Serum testing for voltage-gated potassium TANGENTIALITY istically hostile.1 replies to questions. bone and gastrointestinal protection in the form An uncommon clinical syndrome characterized by Further investigations revealed hyponatremia of a proton pump inhibitor. there was a return to normal serum sodium priate urine concentration measurements. The scan revealed no abnormality. Laboratory 138 – testing of blood serum for vasculitis was nega- Serum Na+ concentration (mmol/l) Voltage-gated potassium channel 136 – – 2. Routine screening 130 – for malignancy that included blood testing 128 – for tumor markers and paraneoplastic anti- 126 – – 1. In addition. A subjective sign whereby apart from insomnia. This demonstrated the pres. delusions concerning staff members. also known as the water deprivation test florid odd episode.com/clinicalpractice/neuro Steroids Plasma serum sodium concentration and serum osmo- IV lg instituted exchange larity. A limited repeat Weeks from presentation head MRI scan with contrast was undertaken. immunoglobulin (IV Ig.4 g/kg/day for 5 days). He 340 NATURE CLINICAL PRACTICE NEUROLOGY HARROWER ET AL. apparent that he was getting access to water conserve or excrete water taken. there was a partial correction of his VGKC-Ab titer as demonstrated in Figure 1.nature.

with no further seizures.4 g/kg/day for 5 days). P/Q-type modulation (although plasma exchange and oral calcium channel. delayed verbal memory lupus encephalitis that have been recognized recall expressed in percentage of expected recall. tant because they are potentially reversible. features of VGKC-Ab-related LE: the patient’s amphiphysin.1 although predominantly neuropsychiatric phenotype the presence of VGKC-Ab-related LE does not at presentation. 0 10 20 30 40 50 60 DISCUSSION OF DIAGNOSIS Weeks from presentation LE is one of a number of autoimmune encepha. anti-CV2 (collapsin response.1. serve as diagnostic and treatment markers. He was well.1.nature.10 Rapid eye movement (REM) It is unclear how common VGKC-Ab-related behavior disorder has also recently been reported LE is in the general psychiatric population. and after a total of 6 months of inpatient care. and his antiepileptic therapy had been reduced to phenytoin monotherapy – 1. At antibody titer (pmol/l) an outpatient follow-up appointment 5 months (delayed recall) after discharge. over time in weeks for second patient seen.13 Although neuropsychiatric automatically exclude the possibility of the patient features such as paranoia with thought disorders possessing a malignancy. but he also had a remote effects of a neoplastic process. His prednisolone dosage is currently 10 – – 500 being reduced at monthly intervals of 5 mg/day.000 previously mentioned antiepileptic therapy. he remained on prednisolone 50 – – 1. LE has typically been regarded as a paraneoplastic disorder. vertical axis on the left) in recent years. The condition was first have been described in paraneoplastic LE. Abs. testis. Figure 2 A comparison of voltage-gated potassium channel antibody titer litides including Hashimoto’s encephalitis and (red line with axis on the right) and memory (blue line. autoantibody type 2 (PCA-2). and Purkinje cell cytoplasmic steroids were necessary to achieve this response). he was able to be discharged 100 – – 2.15 hyponatremia.2 These conditions are impor. which are typically accompanied by impairment have been described in the latter. LE is although this is not universally the case.14 they described only as recently as 2001 by Buckley et al.6–9 This type can respond to immuno.2–5 and as is typical—but not always the case—he In recent years. carcinoma). confusion and frontal lobe dysfunction and mild memory seizures. and his personality had returned to normal. especially in the MRI scan in such cases. and his Voltage-gated potassium channel 75 – – 2. in VGKC-Ab-related LE. thymus. Steroids were instituted at diagnosis starting at 60 mg/day reducing over and they have associated antibodies that can 3 months to 40 mg/day.8.6. JUNE 2006 VOL 2 NO 6 HARROWER ET AL. and his antiepileptic therapy dosage is also –0 0– being reduced. and breast. and the symptoms of amnesia.1.000 25 – 400 mg/day.500 40 mg/day. CASE STUDY www. a different form of LE had no evidence of a malignancy despite an active has been identified that is associated with VGKC. however. He had the well-recognized characteristics of therapy. search that included whole-body PET studies. and does not seem to be linked to the seizures and hyponatremia. and is associated with malignancies of the lung (most commonly small-cell lung respond well to immunomodulatory therapy. in VGKC-Ab-related LE.6 do not appear as yet to have been fully appreciated Subsequent reports of the condition have high. but neuropsychological lighted the acute or subacute presentation.6.500 on prednisolone 40 mg/day with continued Centile of expected memory fuction bone and gastrointestinal protection.com/clinicalpractice/neuro was diagnosed with VGKC-Ab-related limbic encephalitis (LE). The present case demonstrates some of the classic neuronal nuclear antibody 1 [ANNA-1]).12 and patients normally presence of seizures.10 usually associated with anti-Hu antibodies (anti.11 Neuroradiological but this case does indicate that testing for the evidence of either unilateral or bilateral medial VGKC-Abs might be of benefit in patients with temporal lobe signal change is usually observed on acute atypical psychotic illnesses. features such as general intellectual decline. Ma2. Vertical arrows indicate the nine intravenous immunoglobulin treatment courses (0.1. NATURE CLINICAL PRACTICE NEUROLOGY 341 ©2006 Nature Publishing Group . symptoms were responsive to aggressive immuno- mediator protein-5 [CRMP5]).

and the serum VGKC-Ab level and physical neurological examinations were can be used as a therapeutic marker that allows unremarkable. An MRI scan (see Figure 3) revealed bilateral hyper- intensity in the medial aspect of the temporal lobes characteristic of LE.16 be secondary to the syndrome of inappropriate In both patients described here. however. as Morvan’s syndrome or neuromyotonia. A follow-up appointment with Figure 3 MRI images of brain of second patient. (B) T1-weighted image at same position. on a image. have been present in the majority of previously related LE. This patient had an unusually long history.com/clinicalpractice/neuro A B date. The patient was a 67-year-old male. or neuroradiological changes. (C) and (D) Fluid-attenuated maintenance dose of prednisolone 20 mg/day. A second patient with fluctuating relatively mild amnesia and personality change was also TREATMENT AND MANAGEMENT evaluated. so the hyponatremia also of a direct pathological role for the VGKC- improved. He also had no evidence of seizures. normally the antibody is undetectable). The patient’s screening for under- lying malignancy again included tumor markers. This improvement in the patient’s Ab. apologetic and overly obliging. with rela- tively mild and variable memory impairment.16. His recall of current heads of state was about 10 years out of date. inversion-recovery (FLAIR) images of the brain demonstrating high signal in the showed no evidence of neoplasia. which In previously described cases of VGKC-Ab. see Figure 2) and was also posi- C D tive in the cerebrospinal fluid (15 pmol/l. General line treatment. Treatment with nine courses of IV Ig (each course consisting of 0. (A) Coronal view T2-weighted the patient 18 months after presentation. he reported the incorrect month and year. whole- body CT scanning and whole-body FDG- PET scanning—all of which were normal. Testing for the presence of VGKC-Abs in the who presented with a 12-month history of serum is mandatory in all suspected cases of memory decline accompanied by personality VGKC-Ab-related LE. have reflected was found in the two cases described. their condition. Bedside cognitive testing revealed adjustments to be made to the treatment with a correct orientation for place.CASE STUDY www.4 g/kg/day for 5 days) and oral steroids commencing at 60 mg/day and reducing to 40 mg/day over a period of 3 months resulted in a marked improvement in his episodic memory with an eventual return to predicted above-average levels (see Figure 2).10 symptoms. there is growing evidence modulatory therapy. the hyponatremia of peripheral VGKC-Ab-related pathology such appeared to be caused by psychogenic polydipsia. signs or neurophysiological evidence In the present case.157 pmol/l.17 Although no evidence of malignancy hyponatremia might. deterioration medial temporal lobe bilaterally. but when asked the view to lowering. He had Immunomodulatory therapy represents first- no features of REM behavior disorder.nature. therefore. there were no antidiuretic hormone secretion (SIADH). hyponatremia has been reported to reported cases.1. Electromyography and nerve conduction studies were found to be normal. In As the encephalitis improved with immuno. and it appears to be a change—his family reported that he had become sensitive and reliable test for the condition.8. and preferably eradicating. paraneoplastic antibodies. cases such as these.1 passive. in memory.10.1. it may be the resolution of his psychogenic polydipsia as too early to be certain of the benign nature of his psychiatric condition improved. JUNE 2006 VOL 2 NO 6 ©2006 Nature Publishing Group . The VGKC-Ab was elevated in the serum (1. the 342 NATURE CLINICAL PRACTICE NEUROLOGY HARROWER ET AL.

8 Schott JM et al. The radiological that in the initial phase of VGKC-Ab-related LE. and ANNA-2 autoantibodies. and electroencephalographic findings in Vincent (Department of Clinical Neurology.com/clinicalpractice/neuro serum VGKC-Ab level. associated with malignant thymoma. Neurology 62: 1177–1182 11 Iranzo A et al. Maintenance of immuno. however. investigate the patient 13 Parthasarathi UD et al. in addition to the associated limbic encephalitis. cerebral atrophy. 16 Pozo-Rosich P et al.nature. (2000) Paraneoplastic limbic assessment and treatment. Ann Neurol 54: 530–533 17 Ances BM et al. in press therapy as soon as possible. pathogenesis. (2003) Clinical. Ann Neurol 59: 178–181 more typical features of seizures. The physi. confusion and hyponatremia. 12 Fauser S et al. immunological The primary patient steroids. of plasma exchange. 7 Buckley C and Vincent A (2005) Autoimmune with the clinical condition of the patient.7 In the second case described. suppression with the use of steroids is also paraneoplastic limbic encephalitis. IV Ig and oral steroids. These cases demonstrate the expanding clinical 202–210 10 Thieben MJ et al. online material. limbic encephalitis: correlation with clinical course and cian’s clinical goals for such patients remain to neuropsychology. (2004) Potassium channel The patients and their here. (2003) Voltage-gated potassium channel antibodies in limbic encephalitis. or Ig in combination 5 Lawn ND et al. Lancet Neurol 1: 294–305 his written consent was 4 Lennon VA (1994) The case for a descriptive generic obtained. imaging. nomenclature: clarification of immunostaining criteria expertise of Drs Chawda. and therapy. (2004) Potentially reversible phenotype of VGKC-Ab-related LE and the need autoimmune limbic encephalitis with neuronal to investigate for the condition in those patients potassium channel antibody. It appears. Lancet 361: 1266 The authors declared 9 Newsom-Davis J et al. therefore. NATURE CLINICAL PRACTICE NEUROLOGY 343 ©2006 Nature Publishing Group . immunotherapy-responsive form of limbic their full co-operation and it was therefore supplemented with the use encephalitis. Brain 127: 701–712 at all stages of the 2 Gultekin SH et al. confabulation. treatment duration should be titrated Neurol 50: 73–78 cerebrospinal fluid. (2003) Neuropsychiatric findings in anti-Ma2-positive paraneoplastic limbic encephalitis. Clinical identification 14 Scheid R et al. Antoun and Balaam is Neurology 44: 2412–2415 greatly appreciated. and if channelopathies. Mayo Clin Proc 78: University of Oxford. Brain described is also thanked 123: 1481–1494 for allowing publication a clinical improvement and significant reduction 3 Voltz R (2002) Paraneoplastic neurological syndromes: of the supplementary in the VGKC-Ab titer was achieved with the use an update on diagnosis. Neurology 61: 1159–1161 tories will undoubtedly contribute to research— 15 McArdle JP and Millingen KS (1988) Limbic encephalitis and ultimately understanding—of this condition. (2005) FDG-PET and MRI in potassium channel antibody-associated non-paraneoplastic amnesia. and Competing interests autoimmunity. followed by long-term oral encephalitis: neurological symptoms. Ann determining the VGKC-Ab titers in the serum and be given. PET correlates. Brain 128: 1764–1777 JUNE 2006 VOL 2 NO 6 HARROWER ET AL. CASE STUDY www. IV Ig failed to produce any significant antibody-associated encephalopathy: a potentially families are thanked for VGKC-Ab titer change or clinical improvement. (2005) Treatment-responsive limbic Supplementary information is available on the encephalitis identified by neuropil antibodies: MRI and Nature Clinical Practice Neurology website. magnetic resonance Professor Angela with plasma exchange. (2003) Amnesia. Ann NY Acad Sci 998: interests. 1363–1368 usually required. (2006) Rapid eye movement sleep presenting with neuropsychiatric features and behavior disorder and potassium channel antibody- more chronic memory loss. (2003) Autoimmune disorders of they have no competing CONCLUSION neuronal potassium channels. Acta Neurol Scand 111: 338–343 identify the syndrome early. In the first case described References Acknowledgments 1 Vincent A et al. ANNA-1. a treatment response can be achieved with either for PCA-1. Nat Clin Pract Neurol 1: 22–33 possible with serial VGKC-Ab titers. (2001) Potassium channel antibodies UK) is acknowledged for how long this maintenance treatment should in two patients with reversible limbic encephalitis. for which of IV Ig and oral steroids. Pathology 20: 292–295 which is probably currently under-recognized. findings and tumour association in 50 patients. and supply of serum samples to relevant labora.: Psychiatric presentation of voltage-gated potassium channel antibody associated appropriately and institute immunomodulatory encephalopathy: case report. Br J Psychiatry. although as it is unclear for 6 Buckley C et al.