Extensive and Temporally Ungraded Retrograde Amnesia in Encephalitis Associated with Antibodies to Voltage-Gated Potassium Channels

Home , John Redwood, Paul Burrell

ORIGINAL CONTRIBUTION Extensive and Temporally Ungraded Retrograde Amnesia in Encephalitis Associated With Antibodies to Voltage-Gated Potassium Channels

Dennis Chan, PhD, MRCP; Susie M. D. Henley, MA; Martin N. Rossor, MD, FRCP; Elizabeth K. Warrington, DSc, FRS

Background: Encephalitis associated with antibodies test in which patients were required to identify individu- to voltage-gated potassium channels (VGKC-Ab) is char- als from the recent and remote past. acterized by epilepsy, behavioral changes, and anterograde memory impairment. Magnetic resonance imaging Results: All 3 patients were found to have temporally reveals abnormal signal predominantly restricted to the ungraded retrograde amnesia dating back more than 20 mediotemporal lobes. years. Magnetic resonance imaging in all patients revealed high-signal abnormalities predominantly affect- Objective: To determine the temporal extent and po- ing the hippocampi. Subsequent testing performed after tential reversibility of retrograde amnesia in 3 patients immunotherapy revealed subjective improvement but no with VGKC-Ab–associated encephalitis. evidence of a temporal gradient in the recovery of past memories. Design: Case report. Conclusions: Encephalitis associated with VGKC-Ab re- Setting: Clinical. sults in extensive and temporally ungraded retrograde Patients: Three patients diagnosed as having VGKC- amnesia that is partially reversible with immuno- Ab–associated encephalitis underwent cognitive testing therapy. Magnetic resonance imaging high-signal abnor- before and after immunotherapy. malities were primarily restricted to the hippocampi. These data are supportive of theories postulating a role for the Main Outcome Measures: In addition to standard neu- hippocampus in the storage and retrieval of all past memo- ropsychological tests, retrograde memory was assessed ries, irrespective of age, rather than theories of memory using 2 novel tests. Memory for past newsworthy events consolidation that propose an involvement of the hip- was assessed using a public events test; test material was pocampus only in the temporary storage of memories. divided into epochs of 5 years and spanned approximately 25 years. This was complemented by a famous faces Arch Neurol. 2007;64:404-410

NCEPHALOPATHY ASSOCI- Brain magnetic resonance (MR) ated with antibodies to volt- imaging typically reveals abnormally high age-gated potassium chan- signal within the mediotemporal lobes.2 nels (VGKC-Ab) is a recently Follow-up imaging (after immuno- described and potentially re- therapy) reveals partial or full resolution Author Affiliations: 1 Department of Neurology, Royal versibleE nonparaneoplastic encephalitis. of the signal abnormalities but a degree of Sussex County Hospital, Patients with VGKC-Ab–associated en- mediotemporal lobe atrophy. Brighton (Dr Chan), and cephalitis typically are initially seen with Although patients are initially seen pri- Dementia Research Centre, subacute loss of episodic memory, usually marily with impairment of anterograde Department of Clinical in association with confusion, epileptic memory, several patients in the 2 major case Neurology, Institute of seizures, neuropsychiatric symptoms, and series2,3 to date also described a loss of re- Neurology, Queen Square a syndrome of inappropriate secretion of cent and remote memories, often dating (Drs Chan, Rossor, and 2 Warrington and Ms Henley); antidiuretic hormone. Approximately 50% back several years from the time of their and Department of Neurology, of patients showed a marked response to acute illness, indicative of an additional im- Faculty of Medicine, Imperial immunotherapy with improvement in an- pairment of retrograde memory. The docu- College (Dr Rossor), London, terograde memory and cessation or reduc- mentation of retrograde amnesia is of ma- England. tion of seizures. jor theoretical interest given the particular

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 involvement of the hippocampus in this condition. While the hippocampus is universally acknowledged to play a critical role in memory function, the extent of this role remains a subject of intense debate, and one of the major is- sues concerns the involvement of the hippocampus in the storage and retrieval of remote memories. This is exem- plified by the conflicting theories of hippocampal function, which differ in terms of the temporal extent of the hippocampal involvement in retrograde memory. Theo- ries of memory consolidation4,5 contend that the hippocampus acts as a temporary memory store for new memories, while permanent memories are stored instead in the neocortex. Consolidation of memories over time results in a progressive transfer of memories from the hippocampus to the neocortex. Hippocampal damage is predicted to result in a temporally graded loss of retrograde memory, with greater loss of more recent, less consolidated memories. Opposing theories propose that the hippocampus is involved in the storage and retrieval of past memories, irrespective of the age of the memory. Warrington and Weiskrantz6 considered the hippocampus as the point of interaction of episodic and semantic memory systems. Figure 1. T1-weighted image of patient KC1 after treatment. Given that memory for contemporary events and recall of remote events requires interaction between the 2 systems, disconnection of the 2 systems resulting from hip- Initial informal questioning revealed that patient KC1 pocampal damage would disrupt retrieval of episodic had no memory of past events occurring in his personal memories independent of the age of the memories. More life or in the public domain dating back more than 10 recently, Nadel and Moscovitch7 developed the mul- years from the onset of his illness. When questioned about tiple trace theory, which posits that experiential recall news events of the prior 2 decades, he was able only to of episodic memories results in the formation of a trace, remember that Princess Diana had died and that there or pattern, of synaptic activation within the hippocam- had been a terrorist attack on the Twin Towers but was pus. Subsequent recall produces multiple traces stored unable to provide further details. within the hippocampus such that it is always involved He was treated initially in June 2002 with oral predni- in the storage and retrieval of memories regardless of the sone. He underwent a course of plasma exchange in Oc- age of the memories. Accordingly, hippocampal dam- tober 2002 but developed an anaphylactic reaction, and cor- age would also be predicted to result in the loss of re- ticosteroid therapy was recommenced. Immunotherapy cent and remote memories in the form of temporally un- resulted in a progressive decrease in the VGKC-Ab titer to graded retrograde amnesia. 453 pmol in September 2002 and to 180 pmol in March The issue of retrograde amnesia occurring in the con- 2003. Concurrent with this decrease in antibody titer, there text of VGKC-Ab–associated encephalitis is explored by was gradual subjective improvement in his episodic memory. analysis of 3 affected patients who were noted to have im- The initial 2002 brain MR imaging revealed high sig- paired retrograde memory in addition to the characteris- nal within both hippocampi with additional diffuse ce- tic clinical features of this disorder. Two of these patients rebral atrophy and associated enlargement of both lat- (patients KC1 and KC2) were included in the review ar- eral ventricles. Magnetic resonance imaging was repeated ticle by Vincent et al,3 and patient KC1 was described in a in December 2003 and in June 2004; bilateral hippocam- separate report.8 Patient KC3 is 1 of several patients de- pal atrophy was noted on the 2003 MR images, and the scribed in a separate study on spatial memory.9 2004 MR images did not reveal any change in the degree of diffuse cerebral atrophy or in the hippocampal atrophy (Figure 1). REPORT OF CASES PATIENT KC2 PATIENT KC1 Patient KC2 was a right-handed finance officer aged 43 Patient KC1 was a right-handed woodcarver aged 52 years years at the time of his initial presentation. He was seen at the onset of his illness. He was initially seen in Janu- in October 2001 with a 1-year history of progressive im- ary 2002 with confabulation, generalized seizures, com- pairment of episodic memory affecting at first his ability plex visual hallucinations, and impairment of episodic to recall details of important work-related events, as well memory associated with topographical disorientation. In as difficulty in remembering the names and faces of ac- April 2002, he was transferred to The National Hospital quaintances. Subsequently, he began to get lost in famil- for Neurology and Neurosurgery, London, England. The iar places. By early 2002, he started to confabulate, and initial VGKC-Ab titer was found to be 4005 pmol (ref- he became increasingly aggressive and irascible, with oc- erence range, Ͻ100 pmol). casional inappropriate behavior.

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 He was transferred from his local hospital to The Na- This was associated with subjective improvement in his tional Hospital for Neurology and Neurosurgery in Oc- episodic memory. tober 2002. Investigations performed at this stage in- Subsequent brain MR imaging, performed in late 2002, cluded brain MR imaging, which revealed abnormal high did not reveal any difference in the degree of signal abnor- signal within both hippocampi (Figure 2). mality except for additional mild bilateral hippocampal at- The possibility of retrograde memory impairment rophy. There was no evidence of volume loss in the para- was detected during his initial clinical inpatient assess- hippocampal gyri or in the other temporal lobe structures. ment. Patient KC2 made major mistakes when recalling information about the public figures in the famous faces PATIENT KC3 test; he thought that Bill Clinton had resigned from the US presidency following his scandals and that John Patient KC3 was a right-handed market trader aged 57 Major had never been prime minister of England. years at the time of initial assessment in 2004. In June Among more recent events, patient KC2 thought that 2004, he began to experience panic attacks manifesting George W. Bush had won the 2000 US election with a as episodes of anxiety associated with a cold clammy sen- landslide victory and was unaware of the vote recounts sation and an increase in respiratory rate. associated with the election victory. By August 2004, he began to show memory prob- The diagnosis of VGKC-Ab–associated encephalitis was lems that included difficulty in recalling events during a confirmed in October 2002 with a raised VGKC-Ab titer recent holiday. These new symptoms prompted admis- of 1471 pmol. Patient KC2 underwent a course of plasma sion to his local hospital, where initial brain MR imaging exchange followed by oral prednisone therapy. The demonstrated abnormalities in both temporal lobes VGKC-Ab titer decreased to 1058 pmol in March 2003. (Figure 3A). In November 2004, he was admitted to The National Hospital for Neurology and Neurosurgery. Further questioning revealed that his loss of memory regarding previous events extended back at least 2 years. He was also noted to have marked impairment of memory for famil- iar routes suggestive of a disorder of spatial memory (this is explored further by Hartley et al9). Results of basic serum investigations were normal except for a serum sodium level of 129 mEq/L, with subsequent osmolality studies confirming a diagnosis of syndrome of inappropriate secretion of antidiuretic hormone. The serum sodium level normalized within 1 week without any associated change in the patient’s cognitive abilities. A VGKC-Ab titer of 4164 pmol confirmed the diagnosis of autoimmune encephalitis. Patient KC3 was treated with plasma exchange followed by oral prednisone therapy. The VGKC-Ab titer fell to 799 pmol 2 weeks into treatment with prednisone. The stereotyped panic attacks were identified on video electroencephalographic telemetry as simple partial seizures, and his panic attacks disappeared within a month of initiation of anti- Figure 2. T1-weighted image of patient KC2 before treatment. epileptic medication. Following commencement of im-

A B

Figure 3. A, Fluid-attenuated inversion recovery image of patient KC3 before treatment. B, T1-weighted image of patient KC3 after treatment.

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Patient KC1 Patient KC2 Patient KC3

April 11, December 18, April 7, October 23, November 27, March 13, October 19, December 2, Test 2002 2002 2003 2002 2002 2003 2004 2004 IQ Verbal 1 6 88 90 98 . . . 112 99 Performance 65 111 114 102 . . . 111 92 . . . Memory Recognition Memory Test Words Ͻ1 Ͼ50 25-50 25-50 Ͼ50 25-50 Ͼ50 Ͼ50 Faces Ͻ1 Ͻ1 5-25 5-25 Ͼ50 5-25 Ͼ50 5-25 AMIPB Story Recall, % Immediate ...... 25-50 5 Ͼ50 25-50 . . . Delayed ...... Ͻ5 Ͻ5 25-50 25-50 . . . Paired-Associate Learning, % Trial 1 ...... 5-25 Ͻ5 5-25 . . . Ͻ5 Trial 2 ...... Ͻ5 Ͻ5 Ͻ5 ... Ͻ5 Graded Naming Test or Oldfield Ͻ1 5-25 5-25 5-25 . . . 25-50 Ͼ50 25-50 Naming Test

Abbreviation: AMIPB, Adult Memory and Information Processing Battery; ellipses, not applicable.

munotherapy, there was subjective improvement in Retrograde Memory anterograde memory but no improvement in retrograde memory. Memory for Public Events. The test consisted of 38 ques- Initial volumetric brain MR imaging revealed abnor- tions relating to news events dating back to 1981. Every mal high signal restricted to the hippocampi and amyg- effort was made to select discrete events equivalent in dalae bilaterally with no evidence of abnormal signal terms of salience for 5 periods. Seven events were probed within the parahippocampal gyri or the remainder of the for each 5-year period except for 1986 through 1990, for temporal lobes. Subsequent MR imaging performed 8 which there were 10 events (Table 2). Two points were weeks after the initial imaging revealed mild volume loss given for a correct response and 1 point for a partially affecting the right hippocampus only, with no other de- correct response. Two age-matched control subjects were tectable abnormalities (Figure 3B). also tested. Figure 4 shows in graphic form the performance of NEUROPSYCHOLOGICAL ASSESSMENTS the 3 patients across the various periods. Patient KC1, who was initially seen with the most severe retrograde The results of general neuropsychological testing for all 3 amnesia, was found to have virtually no memory for any patients are summarized in Table 1. Although some tests, 10 public event dating back to 1981, and he failed to dem- such as the Recognition Memory Test, were applied to onstrate any recovery after immunotherapy. In particu- all 3 patients, there were some differences in other tests lar, there was no memory of the more remote events. Pa- applied, reflecting the fact that patients were assessed ini- tient KC2 was shown to have only partial impairment of tially in different hospitals for clinical purposes. events occurring within 3 years of his illness but more severe loss of more distant events, thus providing some Cognitive Abilities evidence of a reversal in the pattern of relative vulner- The 3 patients had been assessed using the Wechsler Adult ability of more recent events. After treatment, there was Intelligence Scale–Revised11 before treatment or after treat- subjective improvement in all periods sampled except for ment (Table 1). Except for patient KC1, who was very the most remote years (1981-1985). Patient KC3 was least impaired at his first assessment, scores within the aver- impaired on this task, but again there was no evidence age range were recorded for all 3 patients. Patient KC1 of a temporal gradient; although weak by comparison with was anomic at the first 2 assessments but had improved the control subjects, his performance was similar across by the third assessment. There was no evidence of ano- all periods. There was some subjective improvement af- mia in patient KC2 or in patient KC3. ter treatment.

Anterograde Memory Memory for Famous Faces. The ability to identify and name faces of well-known personalities was assessed. The Recognition Memory Test scores together with Paired- test consisted of 10 contemporary personalities and 10 Associate Learning scores for each patient are given in personalities who were no longer in public view but who Table 1. At the initial assessment, there was evidence of had been prominent 5 to 10 years earlier (Table 3). If impaired anterograde memory function in patient KC1 the patient was unable to name the personality, he was and in patient KC2. After treatment, subjective improve- asked to identify the person by description (eg, John Ma- ment was recorded in both of the affected patients. jor, the previous prime minister of England).

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Table 2. Public Events Questionnaire A December 19, 2002 April 10, 2003 1981 to 1985 100 Patient KC1 Control Subject What happened in the Falklands? What happened to Princess Grace? 80 What happened in the Brighton bombing? 60 What happened at Bhopal? What was the Maze Prison hunger strike about? 40 What happened to Sadat? 20

Who was Yvonne Fletcher? Correct Responses, % 0 1986 to 1990 Who was Paddy Ashdown? B November 11, 2002 February 4, 2003 What happened at Hillsborough? November 28, 2002 Control Subject What happened to the Herald of Free Enterprise? What happened at Chernobyl? 100 Patient KC2 Who was Terry Waite? What happened at Lockerbie? 80 What happened at Tiananmen Square? 60 What happened to the Challenger shuttle? 40 What happened to the Berlin Wall? Who was Mandela? 20 Correct Responses, % 1991 to 1995 0 What was the Gulf War? C Who was Nick Leeson? December 2, 2004 February 7, 2005 Who was O. J. Simpson? December 10, 2004 Control Subject What happened to Robert Maxwell? What happened in Windsor Castle? 100 Patient KC3 What happened in Bosnia/Kosovo? 80 What happened in Oklahoma? 60 1996 to 2000 What happened to Princess Diana? 40 What happened to King Hussein? 20

What happened at Dunblane? Correct Responses, % 0 What happened to Jill Dando? 1981 to 1985 1981 to 1985 1981 to 1985 1981 to 1985 2001 to Present Who was Monica Lewinsky? Year Group What was the Lawrence Report about? What happened to Hong Kong? Figure 4. Remote memory testing results from the public events 2001 to Present questionnaire. What happened in the Moscow Siege? Who was Jeffrey Archer? Who was Paul Burrell? How old was the Queen Mother when she died? Table 3. Famous Faces Test What happened on September 11th? Who was Osama bin Laden? Contemporary Personalities in the UK News What happened in Afghanistan? (at the Time of Testing) Cherie Blair Wife of UK prime minister Bill Clinton Ex-president of the United States The number of personalities correctly named and iden- Gordon Brown UK chancellor of the exchequer Tim Henman UK tennis player Table 4 tified by each patient for each period is given in . Jack Straw UK foreign secretary Patient KC1 and patient KC3 found the contemporary Kofi Annan President of the United Nations and the more temporally remote individuals difficult not Gerry Adams Head of Sinn Fein only to name but also to identify. Patient KC2 was some- Peter Mandelson Labour party politician what less impaired. These data are limited by the lack of Jeremy Paxman UK news presenter control subjects; however, we would have anticipated sat- Oprah Winfrey US chat show hostess isfactory identification scores at the least. Previous Personalities in the UK News (5-10 Years Earlier) Virginia Bottomley UK health secretary John Redwood UK Conservative party politician COMMENT Boris Yeltsin President of Russia Neil Hamilton UK Conservative party politician The 3 patients in this study were observed to have im- Louise Woodward UK nanny pairment of retrograde memories when assessed around Naseem Hamed UK boxer the time of diagnosis of VGKC-Ab–associated encepha- O. J. Simpson US celebrity Norma Major Wife of UK prime minister litis. Formal testing of remote memories revealed in all John Smith Head of UK Labour party patients temporally ungraded retrograde amnesia ex- Nigel Lawson UK chancellor of the exchequer tending back more than 20 years. All 3 patients were ad- ministered immunotherapy, with treatment resulting in Abbreviation: UK, United Kingdom.

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Patient KC1 Patient KC2 Patient KC3

Test Result December 20, 2002 November 8, 2002 December 10, 2004 Contemporary personalities Named 1/10 5/10 2/10 Recognized 4/10 9/10 6/10 Previous personalities Named 0/10 5/10 0/10 Recognized 1/10 6/10 2/10

a decrease in VGKC-Ab titers. Subsequent testing of ret- as by the documentation of limbic seizures and im- rograde memory function performed after immuno- paired learning in potassium channel knockout mice.16,17 therapy revealed subjective improvement that varied The subacute impairment of episodic memory in across individuals. Using public events questionnaire, VGKC-Ab–associated encephalitis and the evidence for there was no evidence of improvement on subsequent test- hippocampal involvement are consistent with the rec- ing of patient KC1, who had the most severe memory loss. ognized role of the hippocampus in anterograde memory After treatment, patient KC2 was able to recall more in- function. However, as discussed herein in the introduc- formation relating to all but the most remote periods. By tion, the role of the hippocampus in retrograde memory contrast, patient KC3 exhibited improved ability to re- function remains a matter of debate. In this study, MR call information from all but the most recent periods. The imaging revealed abnormalities predominantly affect- absence of any temporal gradient to the retrograde ing the hippocampi in all 3 patients with retrograde am- memory impairment was also noted on the famous faces nesia. In patient KC2 and in patient KC3, MR imaging test. The test failed to reveal any difference in the ability did not reveal any additional abnormalities beyond the of the 3 patients to identify famous individuals from the mediotemporal lobes; in patient KC1, MR imaging re- contemporary period and from a period dating 5 to 10 vealed a degree of generalized cerebral atrophy, the se- years back from the date of testing. verity of which remained unchanged on subsequent The loss of recent and remote memories documented imaging after treatment. Therefore, VGKC-Ab– in this study expands the range of clinical features of VGKC- associated encephalitis with damage primarily affecting Ab–associated encephalitis and provides evidence that the the hippocampi is marked by temporally ungraded loss memory deficit in this disorder is more extensive than pre- of remote memories. This deficit is partially reversible viously acknowledged and incorporates anterograde and following immunotherapy, with no evidence of a tem- retrograde amnesia. As with the loss of anterograde memo- poral gradient in the recovery of retrograde memories. ries, immunotherapy resulted in partial recovery of retro- These findings are in keeping with theories propos- grade memory function, indicating a degree of reversibil- ing that the hippocampus is involved in the storage or ity in this acquired cognitive deficit. retrieval of episodic memories, irrespective of their age, Magnetic resonance imaging in all 3 patients re- such as the disconnection theory of Warrington and vealed abnormal high signal predominantly affecting the Weiskrantz6 and the multiple trace theory of Nadel and hippocampi. Subsequent imaging revealed resolution of Moscovitch.7 Of these 2 possibilities, the recovery of re- the abnormal high-signal changes and development of mote memories after treatment would support a re- mild hippocampal atrophy. These findings are similar to trieval hypothesis and would be difficult to explain in those documented in previous studies2,3 of VGKC-Ab– terms of a role for the hippocampus only in the storage associated encephalitis in which the initial signal change of long-term memories. In either instance, the absence on MR imaging is noted primarily within the mediotem- of a temporal gradient in the retrograde amnesia is dif- poral lobes. Similarly, the evolution of MR imaging ficult to reconcile with theories based on the concept of changes is consistent with that noted in a serial MR memory consolidation. imaging study12 of limbic encephalitis in which patients Studies that attempt to establish a causal association be- with VGKC-Ab were noted to have unilateral or bilat- tween hippocampal dysfunction and the occurrence of ret- eral mediotemporal lobe swelling at the time of the ini- rograde amnesia are dependent on the selectivity of the tial imaging, with resolution of swelling and hippocam- hippocampal damage. Historically, studies of retrograde pal atrophy observed on subsequent imaging. amnesia have tended to investigate patients with hippo- Extensive investigations have been undertaken on the campal damage as part of more extensive brain patho- role of voltage-gated potassium channels. Within hip- logic conditions (as in cases of herpes encephalitis or post- pocampal neurons, voltage-gated potassium channels have temporal lobectomy) or patients in whom selective been found to modulate action potential conduction13 and hippocampal damage has occurred as a consequence of an- neurotransmitter release14 and to control dendritic spike oxic-ischemic brain injury, with attendant disputes about initiation and repolarization.15 The involvement of the the possibility of hidden pathologic features (ie, other brain hippocampus in VGKC-Ab–associated encephalitis and regions affected by the anoxic insult but undetectable in the probable pathogenic role of VGKC-Ab are rein- vivo by current neuroimaging techniques). The investi- forced by the demonstration of heavy immunostaining gation of patients with VGKC-Ab–associated encephali- of the dentate gyrus with antibodies from a patient with tis represents a novel approach to assess retrograde am- limbic encephalitis and a high titer of VGKC-Ab,1 as well nesia in the context of hippocampal damage.

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 In summary, the demonstration of extensive retro- REFERENCES grade amnesia in 3 patients with VGKC-Ab–associated encephalitis expands the range of cognitive deficits iden- 1. Buckley C, Oger J, Clover L, et al. Potassium channel antibodies in two patients tified with this condition. Considered in light of the evi- with reversible limbic encephalitis. Ann Neurol. 2001;50:73-78. dence of damage predominantly affecting the hippo- 2. Thieben MJ, Lennon VA, Boeve BF, Aksamit AJ, Keegan M, Vernino S. Poten- campi, the lack of any temporal gradient in the retrograde tially reversible autoimmune limbic encephalitis with neuronal potassium channel antibody. Neurology. 2004;62:1177-1182. memory loss or in the pattern of recovery after immu- 3. Vincent A, Buckley C, Schott JM, et al. Potassium channel antibody–associated notherapy is supportive of the notion that the hippo- encephalopathy: a potentially treatable immunotherapy-responsive form of lim- campus is critically involved in the storage and retrieval bic encephalitis. Brain. 2004;127:701-712. of remote and recent memories. Further studies of the 4. Squire LR, Cohen NJ, Nadel L. The medial temporal region and memory con- selectivity of hippocampal involvement in VGKC-Ab– solidation: a new hypothesis. In: Weingartner H, Parker E, eds. Memory Con- solidation. Hillsdale, Ill: Lawrence A Erlbaum Associates; 1984:185-210. associated limbic encephalitis may provide additional in- 5. Teyler TJ, DiScenna P. The hippocampal memory indexing system. Behav Neurosci. sights into the neuroanatomical locus of remote memory. 1986;100:147-154. 6. Warrington EK, Weiskrantz L. Amnesia: a disconnection syndrome? Accepted for Publication: November 1, 2006. Neuropsychologia. 1982;20:233-248. Correspondence: Dennis Chan, PhD, MRCP, Depart- 7. Nadel L, Moscovitch M. Memory consolidation, retrograde amnesia and the hippocampal complex. Curr Opin Neurobiol. 1997;7:217-227. ment of Neurology, Royal Sussex County Hospital, East- 8. Schott JM, Harkness K, Barnes J, della Rocchetta AI, Vincent A, Rossor MN. ern Road, Brighton BN2 5BE, United Kingdom (dennis Amnesia, cerebral atrophy, and autoimmunity [letter] [published correction ap- [email protected]). pears in Lancet. 2004;363:86]. Lancet. 2003;361:1266. Author Contributions: Study concept and design: Chan, 9. Hartley T, Bird CM, Chan D, et al. The hippocampus is required for short-term Rossor, and Warrington. Acquisition of data: Chan, Hen- topographical memory in humans. Hippocampus. In press. 10. Warrington EK. Recognition Memory Test. Windsor, England: NFER-Nelson; 1984. ley, and Warrington. Analysis and interpretation of data: 11. Weschler D. Manual for the Wechsler Adult Intelligence Scale–Revised. New York: Chan, Rossor, and Warrington. Drafting of the manu- New York Psychological Corp; 1981. script: Chan, Henley, and Warrington. Critical revision 12. Urbach H, Soeder BM, Jeub M, Klockgether T, Meyer B, Bien CG. Serial MRI of of the manuscript for important intellectual content: Chan limbic encephalitis. Neuroradiology. 2006;48:380-386. 13. Hoffman DA, Magee JC, Colbert CM, Johnston DK. Kϩ channel regulation of sig- and Rossor. Administrative, technical, and material sup- nal propagation in dendrites of hippocampal pyramidal neurons. Nature. 1997; port: Chan, Henley, and Rossor. Study supervision: Chan 387:869-875. and Warrington. 14. Dorandeu F, Wetherall J, Pernot-Marino I, Tattersall JEH, Fosbracy P. Effects of Financial Disclosure: None reported. excitatory amino acid antagonists on dendrotoxin-induced increases in neuro- Funding/Support: This study was supported by the Medi- transmitter release and epileptiform bursting in rat hippocampus in vitro. J Neu- rosci Res. 1997;48:499-506. cal Research Council of Great Britain. 15. Golding NL, Jung H, Mickus T, Spruston N. Dendritic calcium spike initiation and Acknowledgment: We thank Jonathan Stewart, FRCP, repolarization are controlled by distinct potassium channel subtypes in CA1 py- Tom Hughes, MD, and James Rakshi, MD, for their re- ramidal neurons. J Neurosci. 1999;19:8789-8798. ferral of the patients in this study. We also thank John 16. Smart SL, Lopantsev V, Zhang CL, et al. Deletion of the K1.1 potassium channel causes epilepsy in mice. Neuron. 1998;20:809-819. Stevens, FRCR, for his review of the MR images and An- 17. Gratacos E, Ghelardini C, Gherardini LM, et al. Kv1.1 channel antisense attenu- gela Vincent, FRCPath, FMedSci, for performing the ates learning and modulation of dentate polysialylated NCAM. Neuroreport. 1998; VGKC-Ab assays. 9:2727-2731.

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