Correspondence *Department of Neuroscience, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK

Email timothy.harrower@addenbrookes.nhs.uk

The case

A 56-year-old man presented to hospital with a 6-month history of recurrent episodes of altered behavior that lasted for a few days at a time, occurring every 2–3 weeks. He also experienced 'odd' episodes that lasted seconds to a few minutes, which were characterized by the sudden onset of disrupted speech and complex quasi-purposeful stereotyped movements, with a startled, vague appearance on his face. Initially, these episodes occurred weekly, but they later progressed to become a daily occurrence. The patient had become apathetic and uninterested in his family, and he uncharacteristically now spent most of his time in bed. During his episodes of 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 examinations were unremarkable, as was bedside cognitive 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 experienced one of his odd episodes, but no associated neurophysiological evidence of a seizure was observed, making a diagnosis of a seizure disorder unlikely—although this possibility was not completely excluded. He was therefore referred to the psychiatric department with a tentative diagnosis of pseudoseizures (nonepileptic attack disorder). In-patient observation over a period of 2 months revealed that the patient was becoming increasingly confused, and that he confabulated memories. For instance, he stated one day that he had met Richard Branson in the hospital foyer, and that he was being transferred to various locations within the hospital. He was uncharacteristically hostile, and experienced paranoid delusions concerning staff members. He also had features of thought disorder with thought derailment, TANGENTIALITY and PRESSURE OF SPEECH. During this extensive period of observation, no abnormal sleep behavior was observed apart from insomnia. He drank water excessively (4–6 l/day) and continued to conduct his business from his hospital bed, often writing lengthy but confused letters. During a neurological consultation on the psychiatry ward, he experienced a clear-cut focal seizure (see Supplementary Video online) with flushing and altered consciousness, focal movements and postictal confusion. A repeat EEG was undertaken, during which he again experienced a more florid odd episode. This demonstrated the presence of spike and wave profiles, thus confirming the presence of seizures.

Further investigations revealed hyponatremia (serum sodium concentration 122 mmol/l; normal range 135–145 mmol/l). The patient was closely observed during a period of water deprivation lasting 12 h, during which time the URINE CONCENTRATION TEST revealed appropriate urine concentration measurements. In addition, there was a partial correction of his serum sodium concentration and serum osmolarity, with his urine osmolarity exceeding his serum osmolarity. Together, these results indicated that the hyponatremia was the result of PSYCHOGENIC POLYDIPSIA. Laboratory testing of blood serum for vasculitis was negative and cerebrospinal fluid examination was normal. Electromyography and nerve conduction studies were normal. Routine screening for malignancy that included blood testing for tumor markers and paraneoplastic antibodies, CT scans of the chest, abdomen and pelvis, and whole-body PET scanning, were all negative. A detailed neuropsychological evaluation was undertaken during a period of the patient's altered behavior, and this revealed mild impairment of his frontal executive function and episodic memory. A limited repeat head MRI scan with contrast was undertaken, but unfortunately not with FLAIR or diffusion-weighted sequences because of the patient's inability to tolerate the procedures as a result of paranoia. The scan revealed no abnormality, but a brain ¹⁸F-fluorodeoxyglucose (FDG)-PET scan revealed diffuse hypometabolism involving both hemispheres anteriorly and posteriorly. Serum testing for voltage-gated potassium channel antibodies (VGKC-Abs) detected their presence at a level of 2,317 pmol/l (normal level <100 pmol/l).¹

The patient was commenced on a course of immunoglobulin (IV Ig; 0.4 g/kg/day for 5 days), but his behavior continued to be extremely erratic, with episodes of aggression and confusion. His epileptic seizures were more frequent and difficult to control, and ultimately required treatment with phenytoin (400 mg/day), gabapentin (600 mg three times per day) and levetiracetam (1 g twice a day). In addition, the patient's serum sodium level remained low, despite attempts at strict fluid restriction; however, it became apparent that he was getting access to water by alternative means. He was therefore treated with plasma exchange and commenced on daily high-dose oral prednisolone (60 mg/day) with bone and gastrointestinal protection in the form of a proton pump inhibitor. During the next month there was a gradual but definite improvement in his clinical state, with resolution of his neuropsychiatric symptoms and cessation of his seizures. His polydipsia also resolved, and there was a return to normal serum sodium status, which was mirrored by a drop in his VGKC-Ab titer as demonstrated in Figure 1. He was diagnosed with VGKC-Ab-related limbic encephalitis (LE), and after a total of 6 months of inpatient care, he was able to be discharged on prednisolone 40 mg/day with continued bone and gastrointestinal protection, and his previously mentioned antiepileptic therapy. At an outpatient follow-up appointment 5 months after discharge, he remained on prednisolone 40 mg/day, and his antiepileptic therapy had been reduced to phenytoin monotherapy 400 mg/day. He was well, with no further seizures, and his personality had returned to normal. His prednisolone dosage is currently being reduced at monthly intervals of 5 mg/day, and his antiepileptic therapy dosage is also being reduced.

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 line and vertical axis on the right) over time (in weeks) and treatment courses.

IV Ig, intravenous immunoglobulin.

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Discussion of diagnosis

LE is one of a number of autoimmune encephalitides including Hashimoto's encephalitis and lupus encephalitis that have been recognized in recent years.² These conditions are important because they are potentially reversible, and they have associated antibodies that can serve as diagnostic and treatment markers. LE has typically been regarded as a paraneoplastic disorder, and is associated with malignancies of the lung (most commonly small-cell lung carcinoma), testis, thymus, and breast. LE is usually associated with anti-Hu antibodies (antineuronal nuclear antibody 1 [ANNA-1]), Ma2, amphiphysin, anti-CV2 (collapsin response-mediator protein-5 [CRMP5]), P/Q-type calcium channel, and Purkinje cell cytoplasmic autoantibody type 2 (PCA-2).^{2, 3, 4, 5}

In recent years, however, a different form of LE has been identified that is associated with VGKC-Abs.^{1, 6, 7, 8, 9} This type can respond to immunotherapy, and does not seem to be linked to the remote effects of a neoplastic process,¹ although the presence of VGKC-Ab-related LE does not automatically exclude the possibility of the patient possessing a malignancy. The condition was first described only as recently as 2001 by Buckley et al.⁶ Subsequent reports of the condition have highlighted the acute or subacute presentation, and the symptoms of amnesia, confusion and seizures, which are typically accompanied by hyponatremia.^{1, 6, 10} Rapid eye movement (REM) behavior disorder has also recently been reported in VGKC-Ab-related LE.¹¹ Neuroradiological evidence of either unilateral or bilateral medial temporal lobe signal change is usually observed on MRI scan in such cases,¹² and patients normally respond well to immunomodulatory therapy, although this is not universally the case.^{1, 6, 10}

The present case demonstrates some of the classic features of VGKC-Ab-related LE: the patient's symptoms were responsive to aggressive immunomodulation (although plasma exchange and oral steroids were necessary to achieve this response), and as is typical—but not always the case—he had no evidence of a malignancy despite an active search that included whole-body PET studies. He had the well-recognized characteristics of seizures and hyponatremia, but he also had a predominantly neuropsychiatric phenotype at presentation.¹³ Although neuropsychiatric features such as paranoia with thought disorders have been described in paraneoplastic LE,¹⁴ they do not appear as yet to have been fully appreciated in VGKC-Ab-related LE, but neuropsychological features such as general intellectual decline, frontal lobe dysfunction and mild memory impairment have been described in the latter.^{1, 8, 15} It is unclear how common VGKC-Ab-related LE is in the general psychiatric population, but this case does indicate that testing for the VGKC-Abs might be of benefit in patients with acute atypical psychotic illnesses, especially in the presence of seizures.

In previously described cases of VGKC-Ab-related LE, hyponatremia has been reported to be secondary to the syndrome of inappropriate antidiuretic hormone secretion (SIADH).^{1, 10} In the present case, however, the hyponatremia appeared to be caused by psychogenic polydipsia. As the encephalitis improved with immunomodulatory therapy, so the hyponatremia also improved. This improvement in the patient's hyponatremia might, therefore, have reflected the resolution of his psychogenic polydipsia as his psychiatric condition improved.

A second patient with fluctuating relatively mild amnesia and personality change was also evaluated. The patient was a 67-year-old male, who presented with a 12-month history of memory decline accompanied by personality change—his family reported that he had become passive, apologetic and overly obliging. He had no features of REM behavior disorder. General and physical neurological examinations were unremarkable. Bedside cognitive testing revealed correct orientation for place, but when asked the date, he reported the incorrect month and year. His recall of current heads of state was about 10 years out of date.

The patient's screening for underlying malignancy again included tumor markers, paraneoplastic antibodies, whole-body CT scanning and whole-body FDG-PET scanning—all of which were normal. The VGKC-Ab was elevated in the serum (1,157 pmol/l; see Figure 2) and was also positive in the cerebrospinal fluid (15 pmol/l; normally the antibody is undetectable). An MRI scan (see Figure 3) revealed bilateral hyperintensity in the medial aspect of the temporal lobes characteristic of LE. Electromyography and nerve conduction studies were found to be normal. Treatment with nine courses of IV Ig (each course consisting of 0.4 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). A follow-up appointment with the patient 18 months after presentation, on a maintenance dose of prednisolone 20 mg/day, showed no evidence of neoplasia, deterioration in memory, or neuroradiological changes. This patient had an unusually long history, with relatively mild and variable memory impairment. He also had no evidence of seizures, which have been present in the majority of previously reported cases.^{1, 8, 10, 16}

Figure 2 A comparison of voltage-gated potassium channel antibody titer (red line with axis on the right) and memory (blue line; delayed verbal memory recall expressed in percentage of expected recall; vertical axis on the left) over time in weeks for second patient seen.

Vertical arrows indicate the nine intravenous immunoglobulin treatment courses (0.4 g/kg/day for 5 days). Steroids were instituted at diagnosis starting at 60 mg/day reducing over 3 months to 40 mg/day.

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Figure 3 MRI images of brain of second patient.

(A) Coronal view T2-weighted image. (B) T1-weighted image at same position. (C) and (D) Fluid-attenuated inversion-recovery (FLAIR) images of the brain demonstrating high signal in the medial temporal lobe bilaterally.

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In both patients described here, there were no symptoms, signs or neurophysiological evidence of peripheral VGKC-Ab-related pathology such as Morvan's syndrome or neuromyotonia. In cases such as these, there is growing evidence of a direct pathological role for the VGKC-Ab.^{16, 17} Although no evidence of malignancy was found in the two cases described, it may be too early to be certain of the benign nature of their condition.

Treatment and management

Testing for the presence of VGKC-Abs in the serum is mandatory in all suspected cases of VGKC-Ab-related LE, and it appears to be a sensitive and reliable test for the condition.¹ Immunomodulatory therapy represents first-line treatment, and the serum VGKC-Ab level can be used as a therapeutic marker that allows adjustments to be made to the treatment with a view to lowering, and preferably eradicating, the serum VGKC-Ab level. In the first case described here, IV Ig failed to produce any significant VGKC-Ab titer change or clinical improvement, and it was therefore supplemented with the use of plasma exchange, followed by long-term oral steroids.⁷ In the second case described, however, a clinical improvement and significant reduction in the VGKC-Ab titer was achieved with the use of IV Ig and oral steroids. It appears, therefore, that in the initial phase of VGKC-Ab-related LE, a treatment response can be achieved with either IV Ig and oral steroids, or Ig in combination with plasma exchange. Maintenance of immunosuppression with the use of steroids is also usually required, although as it is unclear for how long this maintenance treatment should be given, treatment duration should be titrated with the clinical condition of the patient, and if possible with serial VGKC-Ab titers.

Conclusion

These cases demonstrate the expanding clinical phenotype of VGKC-Ab-related LE and the need to investigate for the condition in those patients presenting with neuropsychiatric features and more chronic memory loss, in addition to the more typical features of seizures, confabulation, amnesia, confusion and hyponatremia. The physician's clinical goals for such patients remain to identify the syndrome early, investigate the patient appropriately and institute immunomodulatory therapy as soon as possible. Clinical identification and supply of serum samples to relevant laboratories will undoubtedly contribute to research—and ultimately understanding—of this condition, which is probably currently under-recognized.

Acknowledgments

The patients and their families are thanked for their full co-operation at all stages of the assessment and treatment. The primary patient described is also thanked for allowing publication of the supplementary online material, for which his written consent was obtained. The radiological expertise of Drs Chawda, Antoun and Balaam is greatly appreciated. Professor Angela Vincent (Department of Clinical Neurology, University of Oxford, UK) is acknowledged for determining the VGKC-Ab titers in the serum and cerebrospinal fluid.

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Supplementary information

Supplementary Video (wmv 14 MB)

Video clip of patient experiencing focal seizure

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Subject areas under which this article appears: Neuroimmunology and neuroinflammation | Neuropsychiatric disorders