A novel case of a patient withanti-LGI1 encephalitis with a predominant long-term psychiatric presentation. An atypical presentation (such as atypical psychiatric symptoms, neurocognitive disorder, and hyponatremia) should prompt further investigations such as CSF analysis, considering that MRI and EEG may be normal. FDG-PET might be of interest but few data are available in the literature. Early treatment of anti-LGI1 encephalitis is crucial for overall prognosis and may delay the development of dementia in some cases.

A case of anti-LGI1 encephalitis with concomitant IgLON5 antibodies. Co-occurring IgLON5 antibodies in anti-LGI1 encephalitis are exceptional, but may appear in genetically predisposed individuals.

Highlights

Autoimmune limbic encephalitis (ALE) shows a wide spectrum of neuropsychological impairments, which might exceed the limbic system, with no evidence of differences between AAB groups. Neuropsychological assessment for diagnosing ALE should include long-term memory, memory recognition, autobiographical-episodic memory, emotion recognition, and a detailed investigation of depression.

Findings illustrate specific clinical features of anti-LGI1 encephalitis and provided preliminary evidences of gut dysbiosis. This may help distinguish the disorder from other AEs. Moreover, gut microbiota are expected to be potential therapeutic targets of anti-LGI1 encephalitis.

Forty-eight patients were included (98% males; median age 64 years), and 35 participated in telephone interviews (73%). 

Discussion: CASPR2-encephalitis has a progressive course and is highly heterogeneous at the early stage. In men older than 50 years, otherwise unexplained seizures, cerebellar ataxia, and/or neuropathic pain are suggestive of early-stage CASPR2-encephalitis, especially if they coincide with recent asthenia, mood disorders, or insomnia.

A case report of a 62-year-old man with anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis, an autoimmune disorder, characterized by faciobrachial dystonic seizures, epilepsy, memory deficits and altered mental status. While hiccup is not commonly found in patients, clinicians should be aware that persistent hiccups might be one of the initial manifestations of LGI1 subtype of voltage-gated potassium channel complex antibody associated autoimmune encephalitis.

In this patient, it is difficult to determine whether the hiccups arise from hyponatremia or temporal, basal ganglia, insula, hypothalamus involvement in this disease. However, hiccups appear with other symptoms and disappear after immunotherapy. It can be therefore concluded that persistent hiccups may behave as one of the atypical symptoms of LGI1-antibody encephalitis.

This study provides a detailed clinical neuropsychological presentation of autoimmune limbic encephalitis (ALE) in immunotherapy-naïve patients. It confirms that memory impairments and symptoms of depression form hallmarks of ALE. It also provides further and new insights: (i) Memory impairment predominantly pertains to a consolidation impairment for new information resulting in long-term memory and recognition deficits. (ii) Short-term and working memory can be impaired, but usually only at a subclinical level. (iii) Recall of retrograde autobiographical episodes can be affected and (iv) ALE-patients suffer from deficits in emotion recognition especially regarding fear. In addition, we found (v) apraxia in pantomimes and imitation of gestures, which has not yet been described in ALE-patients. Further deficits may include impaired visuo-construction, processing speed, and flexibility. However, the performances between patients vary considerably.

Taken together, neuropsychological deficits presented in our cohort indicate possible involvement of brain networks outside the limbic system in ALE.

Neuropsychological assessment for diagnosing ALE should include long-term memory, memory recognition, autobiographical-episodic memory, emotion recognition, and a detailed investigation of symptoms of depression.

This international, retrospective cohort study included patients with CASPR2 autoimmunity from participating expert centers in Europe. Patients with ataxia and/or movement disorders were analyzed in detail using questionnaires and video recordings. 

We observed distinct movement disorders in CASPR2 autoimmunity (14.6%): episodic ataxia (6.7%), paroxysmal orthostatic segmental myoclonus of the legs (3.7%) and continuous segmental spinal myoclonus (4.3%). These occurred together with further associated symptoms or signs suggestive of CASPR2 autoimmunity. However, 2/164 patients (1.2%) had isolated segmental spinal myoclonus. Movement disorders and ataxia are highly prevalent in CASPR2 autoimmunity. Paroxysmal orthostatic segmental myoclonus of the legs is a novel albeit rare manifestation. Further distinct movement disorders include isolated and combined segmental spinal myoclonus and autoimmune episodic ataxia.

Out of 32 patients with LGI1 (n = 24) and CASPR2 (n = 8) encephalitis, 20 (15 LGI1, 5 CASPR2) fulfilled the inclusion criteria. Twelve patients were excluded because of ongoing seizures (n = 3) or lack of video-EEG in the follow-up (n = 9). The average age was 62.5 ± 11.04 years (mean ± SD; range = 41–82 years) at disease onset, and 13 of the 20 patients were male (Table 1). The average reported seizure-free interval at the last follow-up was 24.2 ± 20.91 months (mean ± SD) and ranged from 3 to 76 months (Figure 1). Seizures persisted for an average of 21.3 ± 22.39 months (±SD; range = 1–96 months) before seizure freedom was achieved. All patients were taking ASM at the time of video-EEG and received first-line immunosuppressive therapy. We recorded seizures in four of 20 eligible patients (20%) during 24–48 h of video-EEG, although they previously reported seizure freedom. The reported seizure-free interval (before the recorded seizure) in these patients ranged between 3 and 27 months. In two patients focal impaired awareness seizures (after 18 and 27 months of patient-reported seizure freedom) were recorded, and in two other patients focal aware seizures (after 3 and 4 months of patient-reported seizure freedom) were recorded. The two patients who had suffered focal impaired awareness seizures had not noticed their seizures. In one of these patients, the seizure was recorded out of sleep. One of the patients with focal aware seizures did not interpret the seizure as such, and the other patient with the focal aware seizure had a habitual aura. The four patients with seizure relapse did not show other clinical signs of relapse of the autoimmune encephalitis, such as decline in the neuropsychological performance, behavior changes, new seizure semiology, or new findings in the cerebral magnetic resonance imaging.

We describe the case of a 7-year-old girl with anti-leucine-rich glioma-inactivated 1 (anti-LGI1) antibodies (Abs) who presented with isolated epileptic seizures. Her refractory focal seizures did not respond to anti-seizure medicines but responded rapidly to immunotherapy. She remained seizure-free at 2 years follow-up. Reviewing the literature, isolated epileptic seizures have not been reported as the phenotype of anti-LGI1 autoimmunity in children. Our study indicated that screening for anti-LGI1 Abs is necessary for children with severe and/or drug-resistant new-onset focal epileptic seizures.

Significance: In patients with LGI1 encephalitis, rapid initiation of immunomodulatory treatment favors long-term epilepsy remission. Evolution to drug-resistant epilepsy drug-resistant epilepsy (DRE). DRE might primarily reflect the anatomical lesion of limbic structures. Determining what modalities of immune treatment may alter these outcomes requires prospective studies with long-term follow-up. 

LGI1-antibody encephalitis is rare in children. To the best of our knowledge, we describe the first pediatric case with FBDS and highlight the importance of early recognition. Like in adults, relapse can occur in children, but is very rare. Prompt treatment with rituximab can accelerate recovery and prevent relapse. Larger studies are needed in children to better define the clinical spectrum of this condition.

Anti-LGI1-, and anti-CASPR2 Ab-mediated encephalitis have benefited from a surge in knowledge with respect to pathobiology, diagnosis and management. Incipient characterisation of disease molecular and neuropathology, and genetic underpinnings represent recent advances in the field. Questions remain however, such as the respective role of T-cells, given the varying HLA class-II associations, and the significance thereof in light of clinical similarities. Both diseases are commonly characterised

IgG from patients with anti-CASPR2 encephalitis causes reversible memory impairment, inhibits the interaction of CASPR2/TAG1, and decreases the levels of CASPR2 and related proteins (VGKC, AMPAR). These findings fulfill the postulates of antibody-mediated disease and provide a biological basis for antibody-removing treatment approaches.

Retrospective case series of 118 patients with LGI1 antibody encephalitis evaluated at Mayo Clinic across all US sites from 1 May 2008 to 31 March 2019. Corticosteroids appeared more effective acutely than IVIg in improving LGI1 antibody encephalitis in this retrospective comparison of immunotherapies. While improvement with immunotherapy is typical and long-term outcome is favourable, short-term memory deficits are noted in approximately a third of the patients.

Comprehensive presentation of neuropsychological performance of Autoimmune limbic encephalitis (ALE) in an immune therapy-naïve sample. 

ALE shows a wide spectrum of neuropsychological impairments, which might exceed the limbic system, with no evidence of differences between autoantibodies (AABs) groups. Neuropsychological assessment for diagnosing ALE should include long-term memory, memory recognition, autobiographical-episodic memory, emotion recognition, and a detailed investigation of depression.

This current case report describes a patient with seronegative LE that presented 2 months after the onset of the disease with symptoms of severe autobiographical amnesia and a deficit in emotional face recognition.

In conclusion, the seronegative variant of LE still represents a significant challenge for achieving a correct diagnosis. New and more sensitive techniques to find antibodies other than the ones previously described could improve the knowledge and prognosis of this clinical condition. In addition, early treatment of symptoms could minimize cognitive dysfunction in the long term.

The clinical characteristics such as age, gender, and tumor occurrence rates of anti-LGI1 encephalitis and anti-Caspr2 encephalitis in western China are different from those in the Western countries. Most patients in our study had favorable long-term functional outcomes. The relapse rates are still high in both types of encephalitis, which warrants caution.

Results: The main clinical manifestations included epilepsy (100%), faciobrachial dystonic seizures (FBDS; 44.2%), cognitive dysfunction (95.3%), neuropsychiatric disturbances (76.7%), sleep disorders (58.1%), and disturbance of consciousness (48.8%). Twenty-two patients (51.2%) had hyponatremia, 31 (72.1%) had abnormal EEG results, and 30 (69.8%) had abnormal brain MRI scans, mainly involving the hippocampus (76.7%) or temporal lobe (40%). Twenty of 34 patients (58.8%) in a follow-up MRI examination exhibited hippocampal atrophy. Twenty-five patients (58.2%) were administered corticosteroids and intravenous immunoglobulin, whereas 17 patients were treated only with corticosteroids. Forty-one patients (95.3%) had favorable outcomes after a median of 21.5 months (IQR: 7-43) of follow-up. Serum sodium level was a factor associated with a disabled status (odds ratio=0.81, 95% CI=0.66, 0.98, p=0.03). Anti-LGI1 encephalitis patients were characterized by seizures, FBDS, cognitive deficits, neuropsychiatric disturbances, and hyponatremia.

Conclusions: Most patients with anti-LGI1 encephalitis are nonparaneoplastic, have low recurrence rates, and have favorable prognostic outcomes. Rapid evaluation, prompt immunotherapy, and long-term follow-up are essential in the care of anti-LGI1 encephalitis patients.

In this review, we will focus on LGI1 binding partners, “A Disintegrin And Metalloprotease (ADAM) 22 and 23”, the complex they form at the synapse, and will discuss the effects of LGI1 on neuronal excitability and synaptic transmission in physiological and pathological conditions. Finally, we will highlight new insights regarding N-terminal Leucine-Rich Repeat (LRR) domain and C-terminal Epitempin repeat (EPTP) domain and their potentially distinct role in LGI1 function.

Brain 18F-fluorodeoxyglucose positron emission tomography (FDG PET) is a sensitive technique for assisting in the diagnosis of patients with anti-leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis. The purpose of this study aimed to explore the glucose metabolic patterns of this disorder based on PET voxel analysis.This retrospective study enrolled 25 patients with anti-LGI1 encephalitis.

Conclusion

Subcortical hypermetabolism associated with cortical hypometabolism presented with a common metabolic pattern in patients with anti-LGI1 encephalitis in the present study. The resolution of the metabolic gradient of the hippocampal hypermetabolism and neocortical hypometabolism may bring about improved clinical neurologic disability.

Autoimmune limbic encephalitis is a challenging diagnosis for several reasons. The clinical presentation can mimic various other diseases and, therefore, the differential diagnosis is large. Additionally, radiological features are frequently absent or non-specific in the more common subtypes. Being aware of the ways in which LE can present allows it to be considered as a diagnostic possibility in undifferentiated neuro-psychiatric presentations, which in turn improves treatment outcomes. Ongoing research into the pathogenesis and application of novel radiological techniques will assist in further characterizing these conditions in the future.

Autoimmune limbic encephalitis is a challenging diagnosis for several reasons. The clinical presentation can mimic various other diseases and, therefore, the differential diagnosis is large. Additionally, radiological features are frequently absent or non-specific in the more common subtypes. Being aware of the ways in which LE can present allows it to be considered as a diagnostic possibility in undifferentiated neuro-psychiatric presentations, which in turn improves treatment outcomes. Ongoing research into the pathogenesis and application of novel radiological techniques will assist in further characterizing these conditions in the future.

Pain is a recognized association with LGI1-/ CASPR2-antibodies. Of 147 patients, pain was experienced by 17/33 (52%) CASPR2- versus 20/108 (19%) LGI1-antibody patients (p=0.0005), and identified as neuropathic in 89% versus 58% of these, respectively. Typically, normal nerve conduction studies and reduced intraepidermal nerve fibre densities were observed in subsets of both cohorts. In LGI1-antibody patients, pain responded to immunotherapy (p=0.008), often rapidly, with greater residual patient-rated impairment observed in CASPR2-antibody patients (p=0.019). Serum CASPR2-antibodies, but not LGI1-antibodies, bound in vitro to unmyelinated human sensory neurons and rodent dorsal root ganglia, suggesting pathophysiological differences which may underlie clinical observations.

Objective: To evaluate the cognitive and neurofunctional outcomes in patients with (LGI1) encephalitis.

Results: The results showed that 81 of 86 (94.2%) patients with anti-LGI1 encephalitis were successfully followed up, while eight (9.9%) died after discharge. Among the 73 survivors, clinical relapses occurred in 18 (24.7%) patients, and those with relapses were at a higher risk of developing remote symptomatic seizure (p = .019). Although 85.2% of the patients became functionally independent (mRS ≤2), the sequelae of symptomatic seizure, neuropsychiatric symptoms, and cognitive deficits were found in 11.0%, 21.9%, and 39.7% of the patients, respectively. Residual cognitive deficits primarily occurred in the elderly subjects as well as those with symptoms of memory deficit, psychiatric disorders, sleep disturbance, disturbance of consciousness at diagnosis, and higher CSF protein levels.

Conclusions: Although most patients survived and became functionally independent, a subset of patients could not return to all premorbid activities. They may have clinical relapses or suffer from remote symptomatic seizure, neuropsychiatric symptoms, and cognitive impairment.

Clinical, radiological, electrophysiological, treatment, follow-up, and outcome data were collected by retrospective chart review.

Increased [¹⁸F]flortaucipir PET retention was observed in the two LGI1 antibody encephalitis patients with hippocampal atrophy and persistent cognitive impairment, including one patient with autopsy‐proven AD and moderate‐stage neurofibrillary pathology. Inflammation associated with autoimmune encephalitis may accelerate the accrual of tau neuropathology in susceptible individuals and may associate with hippocampal atrophy and persistent cognitive complaints.

Corticosteroids appeared to be more effective acutely than IVIG in improving LGI1 antibody encephalitis in this retrospective comparison of immunotherapies. While improvement with immunotherapy is frequent, most patients have residual long-term memory deficits.

Conclusion: Our results indicate a link between T- and B-cell activity and cognition in epilepsy patients with suspected limbic encephalitis, thus suggesting that flow cytometry results can provide an understanding of cognitive impairment in LE patients with autoantibodies against intracellular antigens.

Methods: Twenty-seven patients with leucine-rich glioma-inactivated protein 1 antibody (LGI1-Ab) encephalitis, seven patients with contactin protein-like 2 antibody (Caspr2-Ab)-associated diseases, and 14 healthy controls.

Conclusion: Sleep disorders in patients with VGKC-Ab-associated diseases include decreased total sleep time (TST)and poor sleep efficiency. Our studies provide evidence of status dissociatus (SD) in patients with LGI1-Ab encephalitis.

Relapse involving need for re-admission to an acute setting occurred in four cases and medication side effects (sedation) in three. As a whole, these cases highlight the complex and potentially unusual course of recovery in individuals with LE.

Double-negative VGKC antibodies usually target intracellular epitopes and lack pathogenic potential. The VGKC antibody titre is not a clinically reliable measure. The concept of a ‘clinically relevant’ VGKC antibody titre has created many misdiagnoses, often where finding the antibody has overruled the clinical diagnosis. The evidence from multiple international groups suggests there are no longer clinical reasons to test for VGKC antibodies. Stopping this test will reduce clinically irrelevant results, improve diagnostic accuracy and limit the use of unnecessary, potentially toxic, immunotherapies in patients.

Regarding the abnormal metabolic pattern in LGI1 AE subjects exhibiting hypermetabolism was specifically located in the basal ganglia (BG) and medial temporal lobe (MTL). BG hypermetabolism was observed in 28 subjects (82%), and 68% of patients showed MTL hypermetabolism. A total of 17 patients (50%) exhibited faciobrachial dystonic seizures (FBDS), and the remaining subjects showed non-FBDS symptoms (50 and 50%). BG-only hypermetabolism was detected in seven subjects in the FBDS subgroup (7/16) but in only one subject in the non-FBDS subgroup

Autoimmune limbic encephalitis is part of CASPR 2 antibody-associated disease. A man with this rare disorder and a very high antibody titre had a unique history of laboratory exposure to the antigen. Together with earlier observations this case calls for caution in laboratory handling of nerve tissue.

First report of CASPR2 associated psychosis related to an ovarian teratoma. Prompt reduction of psychotic symptoms after excision of teratoma. The diagnosis of autoimmune psychosis can be made in the presence of autoantibodies in the serum while CSF is unremarkable.

Patients with depressive and psychotic symptoms non-responding to antidepressant and antipsychotic treatment should be screened for neuronal autoantibodies including CASPR2.