Residual Fatigue and Cognitive Deficits in Patients After LGI1-Antibody Encephalitis (2023)

Leucine-rich glioma-inactivated 1 antibody encephalitis (LGI1-Ab-E) typically affects older men who present with prominent amnesia and frequent seizures1-3 and often shows a marked short-term improvement with immunotherapies.4 In particular, seizure cessation occurs within just a few weeks. However, only traditional cognitive domains have been investigated as longer-term outcomes, with improvements in cognition described as “not good enough.”5 Here, motivated by patient feedback and our clinical observations, we aimed to quantify the residual deficits observed after LGI1-Ab-E across several functional domains.


Participants were recruited to this cross-sectional study from previous cohorts,4 author clinics, or via the Encephalitis Society and assessed by neurologist interview and a battery of tests measuring:

  1. Cognition: Addenbrooke’s Cognitive Examination (ACE), Mini-Mental State Examination (MMSE), and Frontal Assessment Battery (FAB)

  2. Affective symptoms: Hospital Anxiety and Depression Scale (HADS)

  3. Clinician-rated disability: modified Rankin Scale (mRS) and the Clinical Assessment Scale in Autoimmune Encephalitis (CASE)

  4. Fatigue: Fatigue Scale for Motor and Cognitive Function (FSMC) and Modified Fatigue Impact Scale (MFIS).

All patients gave written informed consent (Research Ethics Committee approval 16/YH/0013).


(Video) What is LGI1 Antibody Encephalitis?

Clinical data were gathered from 60 patients with LGI1-Ab-E, assessed at a median of 41 months (range, 4-179 months) after symptom onset (Table). From peak illness to post illness, a marked fall in disability was noted using both the CASE (median [SD] score of 6 [3.4] to 2 [1.7]) and mRS (median [SD] score of 3 [1.1] to 2 [1.1]; Figure, A; both P < .001), with 81% (n = 48 of 59) showing a “good” functional outcome (mRS ≤2). However, only 4 of 27 (15%) of those in employment at diagnosis returned to their premorbid role (Table). The median age of those medically retired or transitioning to a less demanding role was 56 years (range, 46-70 years), representing a reduction of 10 years’ fully productive working life in the United Kingdom. Consistent with this vocational effect, more detailed clinical testing captured widespread deficits.

By comparison with age-appropriate cutoffs derived from manuals or publications, 63% of the LGI1-Ab-E cohort (n = 38 of 60) were impaired on at least 1 of cognition, mood, and fatigue (Figure, B). Cognitive testing revealed total ACE was impaired in 32% (n = 18 of 56; score <88 of 100); 16% (n = 9 of 56) attained scores less than that of healthy elderly individuals in memory, fluency, and visuospatial capabilities, whereas attention (9% impaired [n = 5 of 56]) and language abilities (5% impaired [n = 3 of 56]) were relatively spared. Of affective features, both depression (HADS-D >7) and anxiety (HADS-A >7) were present in 19% (n = 11 of 58) and 33% (n = 19 of 58), respectively. However, overall fatigue was the most common long-term deficit, detected in 52% with the FSMC (n = 16 of 31), rated as severe in 56% of these patients (n = 9 of 16) (Figure, B).

The interrelationships between these deficits revealed the strongest correlations between fatigue and both anxiety and depression (ρ = 0.78 and ρ = 0.77, respectively; P < .001, after Holm-Bonferroni multiple comparison corrections; Figure, C and D). In addition, extent of fatigue correlated with both the greater disability (from mRS) and poorer cognition by ACE (Figure, D).


Although mRS represents the most widely used outcome measure in studies of autoimmune encephalopathies, the data here indicate that despite a “good” mRS, several long-term residual deficits remain: across domains of cognition, mood, and fatigue, with a significant effect on employment status. Our cohort’s mean mRS was comparable with other LGI1-Ab-E studies,2-4 suggesting this traditional outcome measure captures only limited long-term morbidity in multiple studies. Fatigue was the most commonly impaired domain in our cohort, a novel finding in LGI1-Ab-E. This observation is closely reflected by the many patients in our clinic who volunteer fatigue as a major residual symptom. Also, it parallels findings in pediatric N-methyl-d-aspartate receptor antibody encephalitis, where fatigue is associated with quality of life.6

Overall, we continue to advocate early immunotherapy to achieve optimal clinical outcomes in patients with LGI1-Ab-E. Future studies can now also ask whether this approach mitigates the appearance of fatigue, in addition to amelioration of the other expanded long-term cognitive deficits highlighted within our study.

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Article Information

Corresponding Author: Sarosh R. Irani, DPhil, Oxford Autoimmune Neurology Group, Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Level 3, West Wing, Oxford, Oxfordshire OX3 9DS, England (

Accepted for Publication: February 5, 2021.

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Published Online: March 29, 2021. doi:10.1001/jamaneurol.2021.0477

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Binks SNM et al. JAMA Neurology.

Author Contributions: Dr Irani had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. These authors contributed equally to the manuscript: Drs Binks and Veldsman. Joint senior authors: Drs Husain and Irani.

Concept and design: Binks, Veldsman, Easton, Okai, Irani.

Acquisition, analysis, or interpretation of data: Binks, Veldsman, Leite, Okai, Husain, Irani.

Drafting of the manuscript: Binks, Veldsman, Easton, Okai, Irani.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Binks, Veldsman, Okai, Irani.

Obtained funding: Binks, Husain, Irani.

Administrative, technical, or material support: Easton, Irani.

Supervision: Leite, Okai, Husain, Irani.

Conflict of Interest Disclosures: Dr Binks reported grants from Wellcome Trust and grants from the National Institute for Health Research during the conduct of the study; in addition, Dr Binks had a patent for PCT/GB2019/051257 pending University of Oxford. Dr Husain reported personal fees from Otsuka Consulting, Biogen, Excemed, and Lilly outside the submitted work. Dr Irani reported grants and personal fees from UCB Pharma and grants from CSL outside the submitted work; in addition, Dr Irani had a patent for LGI1/Caspr2 antibody detection with royalties paid from euroImmun AG and a patent for antibody diagnostics issued. No other disclosures were reported.

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Funding/Support: Dr Irani is supported by the Wellcome Trust (104079/Z/14/Z), BMA Research Grants–Vera Down grant (2013), Margaret Temple (2017), Epilepsy Research UK (P1201), the Fulbright UK-US commission (MS Society research award), and by the NIHR Oxford Biomedical Research Centre. Dr Husain is supported by the Wellcome Trust (206330/Z/17/Z) and the National Institute for Health Research Oxford Biomedical Research Centre during the conduct of the study. Dr Binks has received salary support from the National Institute for Health Research and is currently supported by the Wellcome Trust. his research was funded in whole, or in part, by the Wellcome Trust (104079/Z/14/Z).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The views expressed are those of the author(s) and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health).



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Ariño H, Armangué T, Petit-Pedrol M, et al. Anti-LGI1-associated cognitive impairment: presentation and long-term outcome. Neurology. 2016;87(8):759-765. doi:10.1212/WNL.0000000000003009PubMedGoogle ScholarCrossref

(Video) Dr. Ming Lim ~ Treatment and Best Outcomes for Pediatric Autoimmune Encephalitis


Finke C, Prüss H, Heine J, et al. Evaluation of cognitive deficits and structural hippocampal damage in encephalitis with leucine-rich, glioma-inactivated 1 antibodies. JAMA Neurol. 2017;74(1):50-59. doi:10.1001/jamaneurol.2016.4226PubMedGoogle ScholarCrossref


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(Video) Autoimmune Encephalitis: What Psychiatrists Need to Know


What is the prognosis for LGI1 autoimmune encephalitis? ›

Also, there is a risk that the disease may flare up again in approximately 25% of patients. This is usually seen within the first few months, often with treatment withdrawal. LGI1-antibody encephalitis has a very low mortality rate, in the order of <1%.

What are the long term effects of limbic encephalitis? ›

Following encephalitis, some people may experience emotional and behavioural changes including low mood, increased anxiety, depression, mood swings, frustration, aggression, impulsivity, disinhibition, and/or poor emotional regulation.

What are the symptoms of LGI1 autoimmune encephalitis? ›

Leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis is an autoimmune encephalitis which frequently manifests as an autoimmune limbic encephalitis. Patients may present with subacute onset of memory loss, behavioural disturbances and seizures.

What is the life expectancy of someone with autoimmune encephalitis? ›

"An individual with autoimmune encephalitis might have 40 to 50 more years to live.

Can you fully recover from autoimmune encephalitis? ›

Some people with AE will recover fully, others will have mild ongoing problems, and some will be left with marked, ongoing, life-changing problems. Recovery involves both physical and mental rehabilitation. Rehabilitation may start in the hospital, but often requires ongoing therapy over months to years.

What are the long term effects of autoimmune encephalitis? ›

Highlights. Most autoimmune encephalitis symptoms improve fully or partially after treatment. The most common residual symptoms are cognitive and mood dysfunctions. Impaired alertness and psychosis have the highest improvement rates.

How do you treat LGI1 autoimmune encephalitis? ›

The treatment of LGI1 antibody encephalitis is largely patterned after treatment to NMDA receptor encephalitis. First-line treatment consists of steroids followed by or in conjunction with plasma exchange/intravenous immunoglobulin. First-line treatment has been found to be effective in 80%.

Does autoimmune encephalitis cause brain damage? ›

Left untreated, autoimmune encephalitis can quickly become serious. It may lead to coma or permanent brain injury. In rare cases, it can be fatal.

Does autoimmune encephalitis relapse? ›

Anti-NMDAR encephalitis can recur in around one out of every six cases, and symptoms are generally milder than when it first appears. Recurrence is not related to the severity in the acute phase or the prognosis at follow-up.

Is brain damage from encephalitis permanent? ›

Summary. Viral encephalitis is an inflammation of the brain caused by a virus. The most serious potential complication is permanent brain damage.

Can encephalitis cause problems later in life? ›

Survivors of severe cases of encephalitis can be left with permanent problems such as fatigue, irritability, impaired concentration, seizures, hearing loss, memory loss and blindness. The recovery process may take months to even years.

How long does it take for the brain to heal from encephalitis? ›

Encephalitis can cause short-term after effects and those that will accompany you for the rest of your life. On average, in the mild form, the body recovers in 1-2 months, in the moderate form in 3-4 months, and in the severe condition in several years.

What are the behavioral changes after encephalitis? ›

For example, following encephalitis a person may have a shorter fuse or/and say/do things without thinking due to changes in frontal brain systems. It can be more difficult to control emotional reactions with an increase in anger outbursts. At the extreme, this may include acting with verbal or physical aggression.

Can brain damage from encephalitis be reversed? ›

Treating the underlying cause of the disorder may improve symptoms. However, the encephalopathy may cause permanent structural changes and irreversible damage to the brain.

Can you go back to normal after encephalitis? ›

Recovery from encephalitis may take time. Initial recovery may be rapid but usually falls short of complete. Further recovery takes place more slowly over a period of months, even years.

What are the disabilities of autoimmune encephalitis? ›

Drs. Yeshokumar and Probasco concluded that patients with autoimmune encephalitis frequently suffer from persistent impairment in neurologic disability, neurocognitive symptoms, and adaptive function. Many of these impairments are not captured adequately by the Modified Rankin Scale.

Does autoimmune encephalitis show up on MRI? ›

According to a recent review of 42 patients with VGKC encephalitis, most (69%) demonstrated MR imaging findings classic for autoimmune encephalitis in the acute setting (T2-FLAIR hyperintense lesions in 1 or both medial temporal lobes) and had an increased propensity to develop chronic findings of mesial temporal ...

How is life after encephalitis? ›

Following encephalitis, some people may experience emotional and behavioural changes including low mood, increased anxiety, depression, mood swings, frustration, aggression, impulsivity, disinhibition, and/or poor emotional regulation.

Can autoimmune encephalitis cause dementia? ›

Abstract. Autoimmune dementia and encephalopathies (ADE) are complex disorders that can cause immune-mediated cognitive deficits and have confusing nomenclature. Presentation varies from acute limbic encephalitis to subacute or chronic disorders of cognition mimicking neurodegenerative dementia.

Can autoimmune encephalitis cause memory loss? ›

Anti-NMDAR encephalitis is usually a multistage illness that progresses from psychosis, memory deficits, seizures, and speech dysfunction to movement disorders, coma, and central hypoventilation.

What part of the brain does autoimmune encephalitis affect? ›

Autoimmune encephalitis (AE) is a type of brain inflammation where the body's immune system attacks healthy cells and tissues in the brain or spinal cord. It is a rare, complex disease that can cause rapid changes in both physical and mental health.

Can LGI1 encephalitis be treated with rituximab? ›

LGI1 encephalitis is an autoimmune disorder characterized by cognitive symptoms and seizures, which rarely respond to common antiepileptic drugs (AEDs). Rituximab (RTX) is a CD-20-depleting monoclonal antibody which has been used for the treatment of LGI1 encephalitis, however, its efficacy remains controversial.

How quickly does IVIG work for autoimmune encephalitis? ›

Some people with AE improve within days of receiving their first line treatments and don't need additional medications that act on the immune system. Steroids and/or IVIG may be continued for several weeks to months, slowly decreasing the dose, to ensure that the brain inflammation stops.

Is LGI1 IGG autoimmune encephalitis? ›

Anti- leucine-rich-glioma-inactivated 1(LGI1) antibody autoimmune encephalitis is a rare type of encephalitis. It is the most common autoimmune limbic encephalitis and the second most common after Anti-NMDAR encephalitis [1]. The most prominent clinical features are epilepsy and cognitive decline [2].

Does encephalitis lower IQ? ›

In the short-term, they also showed executive, IQ, and naming deficits, which resolved in the long-term. Patients with Other or Unknown causes of encephalitis showed moderate memory impairments, but no significant impairment on executive tests.

What mental illness can you get after encephalitis? ›

Patients with anti-AMPA-receptor encephalitis mainly present with short-term memory loss, confusion, mood disturbances, sleep disorders, seizures, and psychosis (13, 14).

What is the most serious symptom of encephalitis? ›

Get immediate care if you are experiencing any of the more-severe symptoms associated with encephalitis. A severe headache, fever and change in consciousness require urgent care.

What are the stages of autoimmune encephalitis? ›

Anti-NMDA receptor encephalitis is divided into stages: prodrome, early, middle, and late.

Can encephalitis cause dementia later in life? ›

Most cases of encephalitis in adults are related to viral infection by HSV-1. This scenario enables the clinical evolution to neuroinflammatory and glial damage processes, 10 mostly threatening immunocompromised or immunosuppressed patients, whose possible unfavorable prognosis are cognitive impairment and dementia.

Is encephalitis considered a disability? ›

Encephalitis can be described as an invisible disability which affects not only one person, but the whole family. Emotional support for the whole family may be needed.

What is the prognosis for hsv1 encephalitis? ›

With treatment, most people with this disease start to improve within a day or two and tend to recover fully within about a month. But without treatment, very serious complications can set in, including death. Even with treatment, some people with severe cases may have long-term brain damage.

What is post encephalitis syndrome? ›

Post-encephalitic parkinsonism is a disease believed to be caused by a viral illness that triggers degeneration of the nerve cells in the substantia nigra. Overall, this degeneration leads to clinical parkinsonism. Post-encephalitic parkinsonism. Specialty.

Can you get encephalitis twice? ›

HSE tends to occur only once. It is rare to relapse later in life. However, in the cases where there is worsening despite on-going treatment (Aciclovir), it may be due to insufficient doses (often based on the patient's body weight) or other complications of encephalitis may have developed, such as seizures.

What is supportive therapy for encephalitis? ›

Supportive care

Intravenous fluids to ensure proper hydration and levels of essential minerals. Anti-inflammatory medicines, such as corticosteroids, to reduce swelling and pressure within the skull. Anticonvulsant medicines, such as phenytoin (Dilantin), to stop or prevent seizures.

What drugs treat neuroinflammation? ›

Currently, no drugs are approved to treat neuroinflammation, but there are several in development and undergoing clinical trials.

How serious is autoimmune encephalitis? ›

Left untreated, autoimmune encephalitis can quickly become serious. It may lead to coma or permanent brain injury. In rare cases, it can be fatal.

How fast does autoimmune encephalitis progress? ›

The symptoms typically develop quickly over weeks to a few months. Long-standing psychiatric issues (for many months or years) are not a sign of autoimmune encephalitis.

What is a neuropsychiatric manifestation of autoimmune encephalitis? ›

In the existing literature, the most common psychiatric symptoms in AE are behavioral problems, followed by hallucinations, memory deficits, confusion, paranoia, depression, and catatonia.

Is encephalitis damage reversible? ›

Long-term outlook for viral encephalitis

In many cases, the person makes a full recovery. In other cases, the person can be left with varying degrees of brain damage, which may require long-term supportive care and therapy.

Can encephalitis cause permanent damage? ›

Treating encephalitis

The disease can progress quickly and has the potential to cause severe, irreversible neurological damage. Antiviral drugs used to treat viral encephalitis include acyclovir and ganciclovir. For most encephalitis-causing viruses, no specific treatment is available.

What are the chances of a full recovery from encephalitis? ›

Mild cases of encephalitis are usually short and result in a full recovery. However, despite improvements in diagnosis and treatment, encephalitis still leads to death in about 10% of patients.

What kind of doctor treats autoimmune encephalitis? ›

What Kind of Doctors Can Diagnose Autoimmune Encephalitis? in diagnosing and autoimmune encephalitis are neurologists.


1. Eoin P. Flanagan, MBBCh. Diagnostic Approach to Autoimmune Encephalitis.
(Downstate Neurology)
2. Auto Immune Encephalitis Brain On Fire
(Yashoda Hospitals - Hyderabad)
3. EUROIMMUN US -Webinar 1 Autoimmune Encephalitis
4. Dr. Silky Pahlajani speaker "Autoimmune Encephalitis: The Bridge Between Neurology and Psychiatry"
(HESA Online Info)
5. Autoimmune encephalitis - Neurology march weekly webinar 2023
(college physicians malaysia)
6. Dr. Maarten Titulaer speaker "Autoimmune Encephalitis: The Bridge Between Neurology and Psychiatry"
(HESA Online Info)


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