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

Background  Encephalitis associated with antibodies to voltage-gated potassium channels (VGKC-Ab) is characterized by epilepsy, behavioral changes, and anterograde memory impairment. Magnetic resonance imaging reveals abnormal signal predominantly restricted to the mediotemporal lobes.

Objective  To determine the temporal extent and potential reversibility of retrograde amnesia in 3 patients with VGKC-Ab–associated encephalitis.

Design  Case report.

Setting  Clinical.

Patients  Three patients diagnosed as having VGKC-Ab–associated encephalitis underwent cognitive testing before and after immunotherapy.

Main Outcome Measures  In addition to standard neuropsychological tests, retrograde memory was assessed using 2 novel tests. Memory for past newsworthy events was assessed using a public events test; test material was divided into epochs of 5 years and spanned approximately 25 years. This was complemented by a famous faces test in which patients were required to identify individuals from the recent and remote past.

Results  All 3 patients were found to have temporally ungraded retrograde amnesia dating back more than 20 years. Magnetic resonance imaging in all patients revealed high-signal abnormalities predominantly affecting the hippocampi. Subsequent testing performed after immunotherapy revealed subjective improvement but no evidence of a temporal gradient in the recovery of past memories.

Conclusions  Encephalitis associated with VGKC-Ab results in extensive and temporally ungraded retrograde amnesia that is partially reversible with immunotherapy. Magnetic resonance imaging high-signal abnormalities were primarily restricted to the hippocampi. These data are supportive of theories postulating a role for the hippocampus in the storage and retrieval of all past memories, irrespective of age, rather than theories of memory consolidation that propose an involvement of the hippocampus only in the temporary storage of memories.

Encephalopathy associated with antibodies to voltage-gated potassium channels (VGKC-Ab) is a recently described and potentially reversible nonparaneoplastic encephalitis.¹ Patients with VGKC-Ab–associated encephalitis typically are initially seen with subacute loss of episodic memory, usually in association with confusion, epileptic seizures, neuropsychiatric symptoms, and a syndrome of inappropriate secretion of antidiuretic hormone.² Approximately 50% of patients showed a marked response to immunotherapy with improvement in anterograde memory and cessation or reduction of seizures.

Brain magnetic resonance (MR) imaging typically reveals abnormally high signal within the mediotemporal lobes.² Follow-up imaging (after immunotherapy) reveals partial or full resolution of the signal abnormalities but a degree of mediotemporal lobe atrophy.

Although patients are initially seen primarily with impairment of anterograde memory, several patients in the 2 major case series^2,3 to date also described a loss of recent and remote memories, often dating back several years from the time of their acute illness, indicative of an additional impairment of retrograde memory. The documentation of retrograde amnesia is of major theoretical interest given the particular 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 issues concerns the involvement of the hippocampus in the storage and retrieval of remote memories. This is exemplified by the conflicting theories of hippocampal function, which differ in terms of the temporal extent of the hippocampal involvement in retrograde memory. Theories of memory consolidation^4,5 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. Given that memory for contemporary events and recall of remote events requires interaction between the 2 systems, disconnection of the 2 systems resulting from hippocampal damage would disrupt retrieval of episodic memories independent of the age of the memories. More recently, Nadel and Moscovitch⁷ developed the multiple trace theory, which posits that experiential recall of episodic memories results in the formation of a trace, or pattern, of synaptic activation within the hippocampus. Subsequent recall produces multiple traces stored within the hippocampus such that it is always involved in the storage and retrieval of memories regardless of the age of the memories. Accordingly, hippocampal damage would also be predicted to result in the loss of recent and remote memories in the form of temporally ungraded retrograde amnesia.

The issue of retrograde amnesia occurring in the context of VGKC-Ab–associated encephalitis is explored by analysis of 3 affected patients who were noted to have impaired retrograde memory in addition to the characteristic clinical features of this disorder. Two of these patients (patients KC1 and KC2) were included in the review article by Vincent et al,³ and patient KC1 was described in a separate report.⁸ Patient KC3 is 1 of several patients described in a separate study on spatial memory.⁹

Patient KC1 was a right-handed woodcarver aged 52 years at the onset of his illness. He was initially seen in January 2002 with confabulation, generalized seizures, complex visual hallucinations, and impairment of episodic memory associated with topographical disorientation. In April 2002, he was transferred to The National Hospital for Neurology and Neurosurgery, London, England. The initial VGKC-Ab titer was found to be 4005 pmol (reference range, <100 pmol).

Initial informal questioning revealed that patient KC1 had no memory of past events occurring in his personal life or in the public domain dating back more than 10 years from the onset of his illness. When questioned about news events of the prior 2 decades, he was able only to remember that Princess Diana had died and that there had been a terrorist attack on the Twin Towers but was unable to provide further details.

He was treated initially in June 2002 with oral prednisone. He underwent a course of plasma exchange in October 2002 but developed an anaphylactic reaction, and corticosteroid therapy was recommenced. Immunotherapy resulted in a progressive decrease in the VGKC-Ab titer to 453 pmol in September 2002 and to 180 pmol in March 2003. Concurrent with this decrease in antibody titer, there was gradual subjective improvement in his episodic memory.

The initial 2002 brain MR imaging revealed high signal within both hippocampi with additional diffuse cerebral atrophy and associated enlargement of both lateral ventricles. Magnetic resonance imaging was repeated in December 2003 and in June 2004; bilateral hippocampal atrophy was noted on the 2003 MR images, and the 2004 MR images did not reveal any change in the degree of diffuse cerebral atrophy or in the hippocampal atrophy (Figure 1).

Patient KC2 was a right-handed finance officer aged 43 years at the time of his initial presentation. He was seen in October 2001 with a 1-year history of progressive impairment of episodic memory affecting at first his ability to recall details of important work-related events, as well as difficulty in remembering the names and faces of acquaintances. Subsequently, he began to get lost in familiar places. By early 2002, he started to confabulate, and he became increasingly aggressive and irascible, with occasional inappropriate behavior.

He was transferred from his local hospital to The National Hospital for Neurology and Neurosurgery in October 2002. Investigations performed at this stage included brain MR imaging, which revealed abnormal high signal within both hippocampi (Figure 2).

The possibility of retrograde memory impairment was detected during his initial clinical inpatient assessment. Patient KC2 made major mistakes when recalling information about the public figures in the famous faces test; he thought that Bill Clinton had resigned from the US presidency following his scandals and that John Major had never been prime minister of England. Among more recent events, patient KC2 thought that George W. Bush had won the 2000 US election with a landslide victory and was unaware of the vote recounts associated with the election victory.

The diagnosis of VGKC-Ab–associated encephalitis was confirmed in October 2002 with a raised VGKC-Ab titer of 1471 pmol. Patient KC2 underwent a course of plasma exchange followed by oral prednisone therapy. The VGKC-Ab titer decreased to 1058 pmol in March 2003. This was associated with subjective improvement in his episodic memory.

Subsequent brain MR imaging, performed in late 2002, did not reveal any difference in the degree of signal abnormality except for additional mild bilateral hippocampal atrophy. There was no evidence of volume loss in the parahippocampal gyri or in the other temporal lobe structures.

Patient KC3 was a right-handed market trader aged 57 years at the time of initial assessment in 2004. In June 2004, he began to experience panic attacks manifesting as episodes of anxiety associated with a cold clammy sensation and an increase in respiratory rate.

By August 2004, he began to show memory problems that included difficulty in recalling events during a recent holiday. These new symptoms prompted admission to his local hospital, where initial brain MR imaging demonstrated abnormalities in both temporal lobes (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 familiar 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 antiepileptic medication. Following commencement of immunotherapy, there was subjective improvement in anterograde memory but no improvement in retrograde memory.

Initial volumetric brain MR imaging revealed abnormal high signal restricted to the hippocampi and amygdalae bilaterally with no evidence of abnormal signal within the parahippocampal gyri or the remainder of the temporal lobes. Subsequent MR imaging performed 8 weeks after the initial imaging revealed mild volume loss affecting the right hippocampus only, with no other detectable abnormalities (Figure 3B).

The results of general neuropsychological testing for all 3 patients are summarized in Table 1. Although some tests, such as the Recognition Memory Test,¹⁰ were applied to all 3 patients, there were some differences in other tests applied, reflecting the fact that patients were assessed initially in different hospitals for clinical purposes.

The 3 patients had been assessed using the Wechsler Adult Intelligence Scale–Revised¹¹ before treatment or after treatment (Table 1). Except for patient KC1, who was very impaired at his first assessment, scores within the average range were recorded for all 3 patients. Patient KC1 was anomic at the first 2 assessments but had improved by the third assessment. There was no evidence of anomia in patient KC2 or in patient KC3.

Recognition Memory Test scores together with Paired-Associate Learning scores for each patient are given in Table 1. At the initial assessment, there was evidence of impaired anterograde memory function in patient KC1 and in patient KC2. After treatment, subjective improvement was recorded in both of the affected patients.

Memory for Public Events. The test consisted of 38 questions relating to news events dating back to 1981. Every effort was made to select discrete events equivalent in terms of salience for 5 periods. Seven events were probed for each 5-year period except for 1986 through 1990, for which there were 10 events (Table 2). Two points were given for a correct response and 1 point for a partially correct response. Two age-matched control subjects were also tested.

Figure 4 shows in graphic form the performance of the 3 patients across the various periods. Patient KC1, who was initially seen with the most severe retrograde amnesia, was found to have virtually no memory for any public event dating back to 1981, and he failed to demonstrate any recovery after immunotherapy. In particular, there was no memory of the more remote events. Patient KC2 was shown to have only partial impairment of events occurring within 3 years of his illness but more severe loss of more distant events, thus providing some evidence of a reversal in the pattern of relative vulnerability of more recent events. After treatment, there was subjective improvement in all periods sampled except for the most remote years (1981-1985). Patient KC3 was least impaired on this task, but again there was no evidence of a temporal gradient; although weak by comparison with the control subjects, his performance was similar across all periods. There was some subjective improvement after treatment.

Memory for Famous Faces. The ability to identify and name faces of well-known personalities was assessed. The test consisted of 10 contemporary personalities and 10 personalities who were no longer in public view but who had been prominent 5 to 10 years earlier (Table 3). If the patient was unable to name the personality, he was asked to identify the person by description (eg, John Major, the previous prime minister of England).

The number of personalities correctly named and identified by each patient for each period is given in Table 4. Patient KC1 and patient KC3 found the contemporary and the more temporally remote individuals difficult not only to name but also to identify. Patient KC2 was somewhat less impaired. These data are limited by the lack of control subjects; however, we would have anticipated satisfactory identification scores at the least.

The 3 patients in this study were observed to have impairment of retrograde memories when assessed around the time of diagnosis of VGKC-Ab–associated encephalitis. Formal testing of remote memories revealed in all patients temporally ungraded retrograde amnesia extending back more than 20 years. All 3 patients were administered immunotherapy, with treatment resulting in a decrease in VGKC-Ab titers. Subsequent testing of retrograde memory function performed after immunotherapy revealed subjective improvement that varied across individuals. Using public events questionnaire, there was no evidence of improvement on subsequent testing of patient KC1, who had the most severe memory loss. After treatment, patient KC2 was able to recall more information relating to all but the most remote periods. By contrast, patient KC3 exhibited improved ability to recall information from all but the most recent periods. The absence of any temporal gradient to the retrograde memory impairment was also noted on the famous faces test. The test failed to reveal any difference in the ability of the 3 patients to identify famous individuals from the contemporary period and from a period dating 5 to 10 years back from the date of testing.

The loss of recent and remote memories documented in this study expands the range of clinical features of VGKC-Ab–associated encephalitis and provides evidence that the memory deficit in this disorder is more extensive than previously acknowledged and incorporates anterograde and retrograde amnesia. As with the loss of anterograde memories, immunotherapy resulted in partial recovery of retrograde memory function, indicating a degree of reversibility in this acquired cognitive deficit.

Magnetic resonance imaging in all 3 patients revealed abnormal high signal predominantly affecting the hippocampi. Subsequent imaging revealed resolution of the abnormal high-signal changes and development of mild hippocampal atrophy. These findings are similar to those documented in previous studies^2,3 of VGKC-Ab–associated encephalitis in which the initial signal change on MR imaging is noted primarily within the mediotemporal lobes. Similarly, the evolution of MR imaging changes is consistent with that noted in a serial MR imaging study¹² of limbic encephalitis in which patients with VGKC-Ab were noted to have unilateral or bilateral mediotemporal lobe swelling at the time of the initial imaging, with resolution of swelling and hippocampal atrophy observed on subsequent imaging.

Extensive investigations have been undertaken on the role of voltage-gated potassium channels. Within hippocampal neurons, voltage-gated potassium channels have been found to modulate action potential conduction¹³ and neurotransmitter release¹⁴ and to control dendritic spike initiation and repolarization.¹⁵ The involvement of the hippocampus in VGKC-Ab–associated encephalitis and the probable pathogenic role of VGKC-Ab are reinforced by the demonstration of heavy immunostaining of the dentate gyrus with antibodies from a patient with limbic encephalitis and a high titer of VGKC-Ab,¹ as well as by the documentation of limbic seizures and impaired learning in potassium channel knockout mice.^16,17

The subacute impairment of episodic memory in VGKC-Ab–associated encephalitis and the evidence for hippocampal involvement are consistent with the recognized role of the hippocampus in anterograde memory function. However, as discussed herein in the introduction, the role of the hippocampus in retrograde memory function remains a matter of debate. In this study, MR imaging revealed abnormalities predominantly affecting the hippocampi in all 3 patients with retrograde amnesia. In patient KC2 and in patient KC3, MR imaging did not reveal any additional abnormalities beyond the mediotemporal lobes; in patient KC1, MR imaging revealed a degree of generalized cerebral atrophy, the severity of which remained unchanged on subsequent imaging after treatment. Therefore, VGKC-Ab–associated encephalitis with damage primarily affecting the hippocampi is marked by temporally ungraded loss of remote memories. This deficit is partially reversible following immunotherapy, with no evidence of a temporal gradient in the recovery of retrograde memories.

These findings are in keeping with theories proposing that the hippocampus is involved in the storage or retrieval of episodic memories, irrespective of their age, such as the disconnection theory of Warrington and Weiskrantz⁶ and the multiple trace theory of Nadel and Moscovitch.⁷ Of these 2 possibilities, the recovery of remote memories after treatment would support a retrieval hypothesis and would be difficult to explain in terms of a role for the hippocampus only in the storage of long-term memories. In either instance, the absence of a temporal gradient in the retrograde amnesia is difficult to reconcile with theories based on the concept of memory consolidation.

Studies that attempt to establish a causal association between hippocampal dysfunction and the occurrence of retrograde amnesia are dependent on the selectivity of the hippocampal damage. Historically, studies of retrograde amnesia have tended to investigate patients with hippocampal damage as part of more extensive brain pathologic conditions (as in cases of herpes encephalitis or posttemporal lobectomy) or patients in whom selective hippocampal damage has occurred as a consequence of anoxic-ischemic brain injury, with attendant disputes about the possibility of hidden pathologic features (ie, other brain regions affected by the anoxic insult but undetectable in vivo by current neuroimaging techniques). The investigation of patients with VGKC-Ab–associated encephalitis represents a novel approach to assess retrograde amnesia in the context of hippocampal damage.

In summary, the demonstration of extensive retrograde amnesia in 3 patients with VGKC-Ab–associated encephalitis expands the range of cognitive deficits identified with this condition. Considered in light of the evidence of damage predominantly affecting the hippocampi, the lack of any temporal gradient in the retrograde memory loss or in the pattern of recovery after immunotherapy is supportive of the notion that the hippocampus is critically involved in the storage and retrieval of remote and recent memories. Further studies of the selectivity of hippocampal involvement in VGKC-Ab–associated limbic encephalitis may provide additional insights into the neuroanatomical locus of remote memory.

Correspondence: Dennis Chan, PhD, MRCP, Department of Neurology, Royal Sussex County Hospital, Eastern Road, Brighton BN2 5BE, United Kingdom (dennis.chan@bsuh.nhs.uk).

Accepted for Publication: November 1, 2006.

Author Contributions:

Study concept and design: Chan, Rossor, and Warrington. Acquisition of data: Chan, Henley, and Warrington. Analysis and interpretation of data: Chan, Rossor, and Warrington. Drafting of the manuscript: Chan, Henley, and Warrington. Critical revision of the manuscript for important intellectual content: Chan and Rossor. Administrative, technical, and material support: Chan, Henley, and Rossor. Study supervision: Chan and Warrington.

Financial Disclosure: None reported.

Funding/Support: This study was supported by the Medical Research Council of Great Britain.

Acknowledgment: We thank Jonathan Stewart, FRCP, Tom Hughes, MD, and James Rakshi, MD, for their referral of the patients in this study. We also thank John Stevens, FRCR, for his review of the MR images and Angela Vincent, FRCPath, FMedSci, for performing the VGKC-Ab assays.