Voltage-gated potassium channel limbic encephalitis presenting as functional cognitive impairment

Abstract

Limbic encephalitis is often reported to present as seizures and impaired cognition with little focus on psychiatric presentations. In this case report, we present a 49-year-old man who initially presented to the Psychiatric Liaison Service with a several month history of confusion with the additional emergence of visual hallucinations and delusions. Due to the inconsistent nature of the symptoms in the context of a major financial stressor, a provisional functional cognitive impairment diagnosis was made. Investigations later revealed a positive titre of voltage-gated potassium channel (VGKC) antibodies, subtype leucine-rich glioma inactivated 1 accounting for his symptoms which dramatically resolved with steroids and immunoglobulins. This case highlighted the need for maintaining broad differential diagnoses in a patient presenting with unusual psychiatric symptoms.

Background

Limbic encephalitis has been considered to be a classical paraneoplastic syndrome, commonly associated with autoantibodies against tumour markers in malignancies such as thyroid, breast, lung and testicular.^{1 2} However, in a subset of limbic encephalitis cases mediated by antibodies against the voltage-gated potassium channel complex, mainly towards the leucine-rich glioma inactivated 1 (LGI-1) and contactin-associated protein-like 2 (CASPR2) components (which are now commonly measured instead of antibodies to the VGKC), the majority of cases are non-neoplastic with only 30% being related to underlying malignancy.³ On presentation, the commonly reported neurologic symptoms include amnesia, confusion, seizures (psychomotor, faciobrachial, generalised tonic-clonic) and hypothalamic dysfunction.^{2 4}

Less commonly referenced in the literature are the psychiatric manifestations of limbic encephalitis. Psychiatric features such as anxiety, depression, hallucinations and delusions have been described in the literature^{5 6} but have received less attention than the more well-known neurologic presentations. Recent studies have begun to expand on the variation of psychiatric manifestations,⁷ proposing ‘psychiatric symptoms’ as one of the potential requirements for diagnosis in the most recent diagnostic criteria.⁸ While there are studies that identify cases of anti-N-Methyl-D-Aspartic Acid Receptor (NMDAR) and anti-a-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor (AMPAR) encephalitis presenting primarily with psychiatric symptoms,^{9 10} there are few describing other types of autoimmune encephalitides presenting this way. As limbic encephalitis can present with negative antibody screening or require early treatment, other proposed criteria for a definite diagnosis in addition to the clinical features are MRI abnormalities in the medial temporal lobes, and cerebrospinal fluid pleocytosis or an electroencephalogram (EEG) with epileptic or slow wave activity in the temporal lobes.⁸

In the following case, we report a patient who presents to the emergency department with primary psychiatric complaints which appear to follow a traumatic life event. The combination of these findings suggested a primary psychiatric aetiology, initially masking the diagnosis of limbic encephalitis.

Case presentation

A 49-year-old man was referred to the Psychiatric Liaison Service following a 4-month history of increased intermittent confusion and amnesia which had worsened over the preceding weeks. He was unable to give much history himself and this information was obtained from his parents and workplace. He stated he was in a hospital in Thailand and could see flying ants. He scored 13/30 on a cognitive examination losing points across all domains and 6/18 on the Frontal Assessment Battery. These symptoms all started around the time that he was an alleged victim of financial fraud which had left him at least £30 000 in debt.

While under the general medical team to rule out an organic presentation, he continued to be seen by the Psychiatric Liaison Service and presented inconsistently over time. On some occasions he had a normal mental state; being able to recall details of the day with precision including which investigations he had, conducting debates on Brexit and being able to perform complex procedures such as disassembling and reassembling a syringe driver. At other times he would state that he was in the Philippines or Thailand, gave approximate answers such as the year was 1918 or the date was October 2019 (it was in fact November 2018), did not recognise his father despite speaking to him moments before and reporting delusions that he was a time traveller. He had intermittent and varying visual hallucinations such as door handles and curtain rods moving which he described in a dramatic fashion. A behaviour chart demonstrated periods of insomnia, but otherwise was functioning and self-caring on the ward. Symptoms or signs of clinical depression and anxiety were not elicited but he did report stress over his debts and work. It was noted that on occasions he would hold both his fists outstretched and breathe deeply which he reported were panic attacks occurring for several months.

His psychiatric history consisted of panic attacks and depression earlier that year, for which he was treated with an antidepressant by his general practitioner. According to collateral history, his great grandfather had experienced fugue-like states whereby he would go missing at harvest time and reappear disorientated in different towns.

Due to episodes of odd upper limb shaking, he was referred to the neurologists who started him on empirical sodium valproate and aciclovir for possible viral encephalitis while awaiting a lumbar puncture, EEG and autoantibody screening. However, the neurologists also noted inconsistent presentations with alternations between expressive dysphasia and fluent speech. The abnormal upper limb movements were not considered typical for facio-brachial or other types of seizures and were considered to be more typical of functional non-epileptic attacks. A neuropsychology report concluded that he had a pattern of overall frontal and possible temporal lobe dysfunction but that he also performed just below the cut-off on formal measures of effort test of memory malingering (TOMM).

Investigations

All blood tests including an immunology and initial autoantibody screen were normal apart from a fall in serum sodium (130 mmol/L from 139 mmol/L 9 days prior). CT and MRI scans were normal.

Lumbar puncture was also normal but a week after initially presenting an EEG showed marked excess slow activity in the background bilaterally in keeping with cerebral dysfunction such as encephalopathy. This and the hyponatraemia were initially attributed to sodium valproate which was therefore discontinued in favour of levetiracetam.

A month after his presentation, his anti-VGKC titre results returned positive at 1756 pmol/L (0–59 pmol/L) with positive subtype LGI-1 antibody. CASPR2, Gamma Aminobutyric Acid (GABA), glycine, NMDA and Glutamic Acid Decarboxylase (GAD) antibodies were negative. A repeat EEG demonstrated excess abnormal slow activity bilaterally suggestive of encephalopathy and a possible seizure focus located in the right anterior temporal region. At this point the diagnosis of limbic encephalitis was made.

Differential diagnosis

Provisional diagnoses of functional cognitive impairment (or ‘hysterical pseudodementia’) with functional non-epileptic attacks were made by the teams involved. It was considered that his psychiatric symptoms and cognitive impairment were too inconsistent and dramatically described to be compatible with organic causes and that they were out of keeping with his general functioning on the ward. Additionally, he scored below cut-off on a TOMM indicating suboptimal effort. Finally, the initial normal investigations and recent financial stressors lent more weight to a psychiatric aetiology.

Once the first EEG report was obtained, it was considered that given his continued apparent functional symptoms, the encephalopathy was likely due to valproate encephalopathy. Sodium valproate was discontinued, and a repeat EEG was considered later to review whether the encephalopathy had resolved.

Although the ongoing impression was of a functional disorder, he would have met criteria for possible dementia with Lewy bodies in view of the subacute onset, clinical fluctuations, well-formed visual hallucinations and an abnormal EEG.

However, the positive VGKC, specifically LGI-1 antibody titre resulted in a revision of the diagnosis. In hindsight, the initial EEG was likely reflective of limbic dysfunction and the arm movements and apparent panic attacks were likely manifestations of seizures. This, along with the normal MRI brain result, indicates he would have met the proposed criteria for ‘possible’ but not ‘definite’ autoimmune encephalitis.⁸ Additionally hyponatraemia is associated with VGKC limbic encephalitis.¹¹

Treatment

He was treated with 5 days of intravenous methylprednisolone and immunoglobulins and started on lamotrigine with tapering down of levetiracetam due to the potential for neuropsychiatric side effects. Psychotropic medications were not considered necessary but the Psychiatric Liaison Service raised a safeguarding alert for financial abuse and provided supporting letters regarding his lack of capacity to deal with his finances which resulted in the relevant banks taking action to prevent fraud. The remainder of his inpatient stay was focused on occupational therapy and he had several periods of day leave to ensure he was safe to be discharged back home fully.

Outcome and follow-up

His symptoms resolved rapidly with the introduction of steroids and immunoglobulins. His abbreviated mental test score improved from 1/10 to 9/10 by the time of discharge. He declined psychiatric follow-up in clinic, however, a telephone consultation 1 month later revealed he felt nearly back to baseline and was no longer experiencing any visual hallucinations, delusions and his confusion had markedly improved.

He continued to be followed up by specialist neurology services while on lamotrigine and a tapering dose of oral prednisolone.

Discussion

While the clear majority of anti-VGKC encephalitis cases present with primarily neurological symptoms such as seizures and cognitive impairment, recent literature has begun to report more cases presenting primarily with psychiatric symptoms including hallucinations and delusions^{5 6} as well as personality change, insomnia, anxiety, panic attacks and depression.^{5 6 11} Some reports suggest the presence of psychosis in as many as 30% of cases.¹² Even among the recent increase in the focus on psychiatric symptoms, few report psychiatric symptoms as the primary presentation.

Our case shows how difficult it can be to distinguish between organic and psychiatric disease on clinical findings alone and how distractors in the history or presentation can lead to a conclusion of a psychiatric causation. The initial presentation of variable confusion on a background of depression and panic attacks, dramatic delusions and hallucinations, apparent functional epileptic attacks in the context of the acute, severe financial stressor was potentially indicative of a primary psychiatric diagnosis.

However, this case demonstrates that in the face of a new onset of psychiatric symptoms, maintaining broad differential diagnoses and working closely with different specialties can uncover other treatable conditions.

Patient’s perspective.

I thought it was lucky that someone thought hang on a minute, maybe this is something else even though I was out of sorts, otherwise I could have ended up in a psychiatry unit. I am better now and intending to go back to work in a few months time. I am truly grateful to everyone in the hospital.

Learning points.

• Neuropsychiatric presentations of anti-leucine-rich glioma inactivated 1 encephalitis are not confined to cognitive problems.

• Other psychiatric symptoms may be predominant such as in this case hallucinations, delusions and anxiety.

• Distractors in a patient’s presentation, such as the financial stressors and apparent functional presentation can lead to diagnostic overshadowing.