Case 1: cognitive decline

A 76-year-old man, a semi-retired postal worker, had an onset of personality change and cognitive decline over several months. He had become less argumentative, a departure from his formerly strong-minded and reportedly bullish character. This was accompanied by various cognitive deficits including episodic memory (forgetting that he had taken a train journey), topographical memory (getting lost in familiar places) and anterograde memory (losing track and being repetitive in conversation). His family also described him as having ‘vague and distant’ spells up to four times a day, during which he would be less responsive but not lose consciousness, followed by momentary disorientation. Three months after symptom onset, he was admitted initially under acute medicine with delirium and hyponatraemia (126 mmol/L). Because of historic dependent alcohol use, an initial working diagnosis of Alzheimer's disease and concurrent Wernicke's encephalopathy was made, and he was treated with intravenous (IV) thiamine.

Following assessment by cognitive neurology, a collateral history emerged that he had been abstinent for 20 years. On cognitive testing, there was evidence of executive dysfunction (unable to perform the Luria 3-stage sequence and concrete interpretation of proverbs), no ideomotor apraxia or apraxia for meaningless gestures, and normal speech and verbal working memory. He was able to reason about similarities. Addenbrooke's Cognitive Examination III (ACE-III) was 83/100, with some points lost on memory (20/26), including one point on encoding. However, visuospatial function was normal with no marks lost on cube, infinities and clock components. LGI1-Ab-E was therefore deemed by the cognitive neurology consultant to be a more probable unifying diagnosis than Alzheimer's disease, given preserved parietal function but evidence of episodic memory deficit, perhaps suggestive of selective hippocampal dysfunction or dorsolateral prefrontal cortex impairment. He had a lumbar puncture which showed a normal cell count and mildly elevated protein (599 mg/L). Magnetic resonance imaging (MRI) depicted mesial temporal lobe T2/FLAIR hyperintensity with slight left-sided swelling. These changes were consistent with LGI1-Ab-E. LGI1-autoantibodies were detected in both serum and cerebrospinal fluid (CSF). After treatment with high dose steroids and plasma exchange (PLEX), he improved. Following a brief period of neurorehabilitation, he returned to employment and independent living. At last review, his cognition had improved (ACE-III 93/100).

Case 1 discussion

In this case, autoimmune encephalitis clues included hyponatraemia – present in 60–70% of LGI1-Ab-E due to autoantibody-binding to LGI1-expressing, anti-diuretic hormone (ADH)-secreting neurons^{Reference Thompson, Bi, Murchison, Makuch, Bien and Chu7} – and subtle focal seizures.^{Reference Bastiaansen, van Steenhoven, de Bruijn, Crijnen, van Sonderen and van Coevorden-Hameete12} Seizures are observed in up to 20% of people with Alzheimer's disease, but usually as a late feature.^{Reference Mendez and Lim14} As the work-up proceeded, more phenotypic features favouring autoimmune encephalitis emerged, including sub-acute (days to weeks) onset and the pattern of neuro-cognitive and -behavioural deficits. This degree of neuro-cognitive dysfunction coming on over a few months, together with a lack of constructional and ideomotor apraxia and the presence of intact visuospatial skills lowered the likelihood of Alzheimer's disease, a simple and useful clinical test.^{Reference Tabi and Husain15}

A recent study from a tertiary cognitive clinic using stringent criteria identified that 0.8% of people could be diagnosed with exclusive or concurrent autoimmune encephalitis (Table 1).^{Reference Bastiaansen, van Steenhoven, Te Vaarwerk, van der Flier, Teunissen and de Graaff16} All were stated to have clinical features inconsistent with dementia, such as subacute or fluctuating disease course. However, the same researchers have highlighted that up to 50% of patients >45 years old with LGI1-Ab-E could still fulfil dementia diagnostic criteria. These patients did not have prominent seizures, MRI or CSF abnormalities, and 71% presented with cognitive decline.^{Reference Bastiaansen, van Steenhoven, de Bruijn, Crijnen, van Sonderen and van Coevorden-Hameete12}

Table 1 Autoantibodies either detected as dementia mimics in a Dutch memory clinic cohort, or which can present with psychiatric-predominant syndromes. Reproduced with adaptations from Table 1 of Uy et al ^a

AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CASPR2, contactin-associated protein-like 2; DPPX, dipeptidyl peptidase-like protein 6; F, female; FBDS, faciobrachial dystonic seizures; FLAIR, fluid-attenuated inverted recovery; GABA_A/BR, Gamma aminobutyric acid A/B receptors; IgLON5, immunoglobulin-like cell-adhesion molecule 5; LE, limbic encephalitis; LGI1, Leucine-rich glioma-inactivated 1; M, male; MRI, magnetic resonance imaging; NMDAR, N-Methyl-D-aspartic acid receptor; PSP, progressive supranuclear palsy; REM/NREM, rapid eye movement/non-rapid eye movement.

a. This is an open access article distributed under the terms of the Creative Commons CC BY 4.0 licence, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. Additional references used in this version and not in the main reference list are included in supplementary information.

b. Data from retrospective Dutch cohort of Bastiaansen et al (2021).^{Reference Bastiaansen, van Steenhoven, de Bruijn, Crijnen, van Sonderen and van Coevorden-Hameete12} Table replicated with additions from Uy et al (2021).^{Reference Uy, Binks and Irani1}

Unlike NMDAR-Ab-E, in which definitive diagnosis relies upon the detection of NMDAR-autoantibodies in CSF,^{Reference Graus, Titulaer, Balu, Benseler, Bien and Cellucci2} LGI1-antibodies are not always found in CSF with usual testing methods.^{Reference Gadoth, Pittock, Dubey, McKeon, Britton and Schmeling8} The rate of serum LGI1-antibodies of uncertain clinical significance in healthy and disease control populations is low (<0.1%).^{Reference Dahm, Ott, Steiner, Stepniak, Teegen and Saschenbrecker17} Serum LGI1-antibody testing should be considered with an atypical case such as this one.

Case 2: rapidly progressive dementia mimicking CJD

A 90-year-old male retired scientist deteriorated over a few months. He developed a prominent movement disorder, frequent falls, cognitive decline and incontinence. He could no longer drive or live independently, and required a Zimmer frame and daily help. The illness began with abnormal jerking movements of his right side, spreading to bilateral involvement, and he then developed orofacial dyskinesias. There were no hallucinations. His personality changed, becoming prone to aggressive outbursts.

On examination, he was disinhibited and had word-finding difficulties, answering questions with repetitive and circumlocutory speech, and full neurological examination was impossible. A rapidly progressive dementia (RPD) was considered, including sporadic CJD. Dementia screening bloods were unremarkable. CT head was within normal limits for age, and MRI brain showed severe bilateral hippocampal atrophy, with no medial temporal lobe high signal and was reported as consistent with Alzheimer's disease. LGI1-antibodies were strongly positive in serum but negative in the CSF. Montreal Cognitive Assessment (MoCA) improved from 22/30 (with points lost in trail making, indicative of executive dysfunction, attention, and all five marks for delayed recall) to 30/30 with immunotherapy. However, ongoing psychiatric input, including aripiprazole, was needed for residual persistent behavioural challenges. Continued challenging behaviour led to a residential care placement.

Case 2 discussion

Autoimmune encephalitis is an important differential diagnosis of RPD, a small (3–4%) and clinically challenging type of dementia.^{Reference Day13} As noted above, FBDS (often described by individuals as jerks, jolts or spasms) may be confused with the myoclonus of CJD, most typical in the sporadic form. One study found that ~20% of people with LGI1-Ab-E and FBDS were suspected of having CJD during their disease course.^{Reference Flanagan, Kotsenas, Britton, McKeon, Watson and Klein18} Features favouring FBDS over myoclonus include stereotypy, and recurrence up to hundreds of times a day;^{Reference Uy, Binks and Irani1} also in LGI1-Ab-E, as this case illustrates, FBDS frequently precede cognitive impairment.^{Reference Thompson, Bi, Murchison, Makuch, Bien and Chu7} This is unlikely with myoclonus and CJD, where it is a late feature.

An autoimmune cause may underlie up to 13% of non-CJD RPD seen in specialist clinics.^{Reference Geschwind19} This and other early studies examined antibodies directed against the voltage-gated potassium channel (VGKC) complex. This test has since been superseded by more specific cell-based assays for LGI1, the predominant antigenic target in central nervous system presentations, and also contactin-associated protein 2 (CASPR2) antibodies.^{Reference Irani, Alexander, Waters, Kleopa, Pettingill and Zuliani5,Reference Michael, Waters and Irani20} These antibodies can also cause encephalitis but commonly drive peripheral nerve disease. A variety of surface autoantibodies, including to LGI1, have been found in up to ~6% of post-mortem RPD patients, further accentuating the importance of excluding a reversible pathology in these people.^{Reference Chitravas, Jung, Kofskey, Blevins, Gambetti and Leigh21}

Brain atrophy was found in both people with LGI1-Ab-E initially thought to have dementia in Bastiaansen et al.^{Reference Bastiaansen, van Steenhoven, Te Vaarwerk, van der Flier, Teunissen and de Graaff16} The patient described in case 2 had bilateral hippocampal atrophy which could be consistent with Alzheimer's disease or with limbic encephalitis (LE) in its later stages. However, despite its possibility, the question of concurrent Alzheimer's disease was not explored further, so it is possible he had both conditions. Although he did improve from a cognitive perspective, which would be less consistent with Alzheimer's disease, he remained neurobehaviourally disturbed and did not return to independent living.

In the Oxford Autoimmune Neurology Service, out of 60 LGI1-Ab-E patients, nearly 20% had moderate to moderately severe disability and loss of functional independence. Also, few working-aged individuals (4/27, 15%) were able to return to their previous employment.^{Reference Binks, Veldsman, Easton, Leite, Okai and Husain9} Thus the outcomes in LGI1-Ab-E, while generally good, remain not ‘good enough’ with both delayed recognition and treatment, and unmet need for more effective therapeutics, likely to contribute.^{Reference Day22}

Case 3: cognitive decline and psychosis

A 67-year-old retired male gardener, living alone with no prior psychiatric or forensic history, was witnessed by friends to have an aggressive verbal outburst. Over the next 4 months, this was followed by becoming quieter, withdrawn and forgetful. He developed frequent short-lived moments of reduced responsiveness lasting 3–5 s. He was also reported to have filled his house with cardboard boxes, was restless, spent excessively, and repetitively counted paper clips (most likely punding – a problem with impulse control in keeping with the overall neurobehavioural presentation). He had less need for sleep, his self-care deteriorated and he became unconcerned about not eating. Acquaintances observed episodes of left-hand jerking movements and facial contortion lasting up to 10 s. During these, there was clouding of consciousness. His GP organised routine blood tests, including electrolytes, and MRI brain, which were unremarkable. The community psychiatry team diagnosed mania and prescribed olanzapine, but he was non-compliant with treatment. He then began conversing with unseen individuals he believed to be living in his house, reporting people were holding parties with cats coming out of the walls and believed that pictures were talking to him. He continued to be disinhibited including leaving the house dressed as a pirate or even naked, and he was found trying to stop traffic. This led to a compulsory in-patient psychiatric admission 14 months after the start of symptoms.

On the ward, he continued to have the same left-sided jerks every few hours as well as frequent falls. Based on the presence of visual hallucinations and falls, dementia with Lewy bodies (DLB) was considered. However, symptomatic treatments were of little help. Around 3 months into the admission, the prominent ongoing left-sided jerks prompted the in-patient team to test serum for LGI1-antibodies. After a positive result, and liaison with the medical team, he was admitted to the local general hospital for high dose IV steroids. A repeat MRI brain now demonstrated bilateral T2 high signal in the medial temporal lobes, consistent with LE. Routine CSF examination, not including neurodegeneration markers, was unremarkable. After 5 days of IV steroids, there was notable improvement. On day 6, his friends were able to hold a normal conversation with him, and he had no further seizures.

Six months later, during oral steroids taper, overspending and impulsive decision-making returned. He improved with an increase of steroids alongside aripiprazole. Four years post-onset, his ACE score is 94/100, and all anti-seizure and anti-psychotic medications have been successfully withdrawn.

Case 3 discussion

This case presented with many LGI1-Ab-E hallmark features: a man in his mid-60s with a prominent neurobehavioural syndrome encompassing relatively rapid onset of personality and behavioural change, cognitive decline and seizures. However, the presence and relevance of temporal lobe seizures (brief moments of behavioural arrest) and FBDS (left hand jerks and facial contortion lasting seconds) was initially overshadowed by the prominent behavioural changes and major risks to himself and others. Subtle seizures are overlooked in a quarter of people, as reported in in a cohort of 48 patients with LGI1-Ab-E.^{Reference Bastiaansen, van Steenhoven, de Bruijn, Crijnen, van Sonderen and van Coevorden-Hameete12} Frequent falls are another clue.^{Reference Uy, Binks and Irani1} A further flag to an autoimmune case is the fast progression; only CJD approaches the tempo seen in patients with autoimmune encephalitis.^{Reference Day13} Psychotic symptoms occur in about a fifth of people with LGI1-Ab-E.^{Reference Gadoth, Pittock, Dubey, McKeon, Britton and Schmeling8} Psychotic features are well known in DLB, but here the speed of onset, lack of fluctuations and absence of Parkinsonian features pointed away from this.^{Reference Day13} Lack of response to antipsychotic medication has also been suggested as a trigger to consider an autoimmune cause.^{Reference Herken and Prüss23} In contrast to NMDAR-Ab-E, there is no reported increased sensitivity or antipsychotic malignant-like syndrome in LGI1-Ab-E. Initial MRI brain imaging was normal, but this may be the case in up to 30–40% LGI1-Ab-E, especially if performed early.^{Reference Gadoth, Pittock, Dubey, McKeon, Britton and Schmeling8}

This individual's illness was responsive to first-line immunotherapy, in LGI1-Ab-E high dose steroids often with PLEX or IV immunoglobulins. Observational evidence shows adding immunotherapy to anti-seizure medications brings about rapid seizure cessation and halts progression to cognitive decline.^{Reference Thompson, Bi, Murchison, Makuch, Bien and Chu7} Rituximab, a CD20 monoclonal antibody which depletes B cells, is gaining traction for LGI1-Ab-E relapse,^{Reference Thaler, Zimmermann, Kammermeier, Strippel, Ringelstein and Kraft24} having observational support for this in NMDAR-Ab-E.^{Reference Nosadini, Eyre, Molteni, Thomas, Irani and Dalmau25}

Four years post-onset, his ACE score is 94/100, and all anti-seizure and anti-psychotic medications have been successfully withdrawn, but he reports ongoing significant and functionally limiting fatigue. In a published cohort of 60 LGI1-Ab-E patients, fatigue was the most common chronic problem in >50%,^{Reference Binks, Veldsman, Easton, Leite, Okai and Husain9} and the most important determinant of quality of life.^{Reference Binks, Veldsman, Handel, Jacob, Maddison and Coebergh26} Alongside this, widespread neuropsychiatric difficulties were found. This included cognitive difficulties in a third of patients surveyed, as well as increased anxiety in a third and depressive symptoms in a fifth.^{Reference Binks, Veldsman, Easton, Leite, Okai and Husain9} These findings highlight the need for multidisciplinary rehabilitation beyond the acute illness phase, with psychiatric alongside neurology input together with other therapies.

Continuing professional development – suggested further reading

A new research paper using stringent criteria to identify patients with autoimmune encephalitis from a tertiary memory clinic can be found in a work by Bastiaansen et al. (2023).¹⁶

A case-based focus on causes of rapidly progressive dementia, including LGI1-Ab-E can be found in a work by Day (2022).¹³

Practical tips on readily executable bedside assessment of parietal lobe function, including of apraxia can be found in a work by Tabi & Husain (2023).¹⁵

A recent review of a broad range of autoimmune encephalitides in a clinically-oriented journal can be found in a work by Uy, Binks and Irani (2021).¹