2017-18Research/Epilepsy/EP

Musicogenic epilepsy (ME), a peculiar form of reflex epilepsy, represents a neurological rarity and yet another demonstration of the extraordinary power of music on the human brain. Despite the heterogeneity of the reported musical triggers, the patients’ emotional response to music is thought to play a crucial role in provoking seizures. Accordingly, the mesial temporal structures (especially of the non-dominant hemisphere) appear most involved in seizure generation, although a more complex fronto-temporal epileptogenic network was documented in some cases. Autoimmune encephalitis has been recently included among the many possible etiologies of ME thanks to few reports of music-induced seizures in patients with anti-glutamic acid decarboxylase 65 antibodies

Temporal lobe adult-onset seizures (TAOS) related to autoimmunity represent an increasingly recognized disease syndrome within the spectrum of epilepsies. In this context, certain autoantibodies (autoABs) were often associated with limbic encephalitis (LE). Here, we aimed to gain insights into (a) the distribution of ‘neurological’ autoABs (neuroABs, defined as autoABs targeting neuronal surface structures or ‘onconeuronal’ ABs or anti-glutamate acid decarboxylase 65 (GAD65) autoABs) in a large consecutive TAOS patient cohort, to characterize (b) clinical profiles of seropositive versus seronegative individuals and to find (c) potential evidence for other autoABs. Blood sera/cerebrospinal fluid (CSF) of TAOS patients (n = 800) and healthy donors (n = 27) were analyzed for neuroABs and screened for other autoABs by indirect immunofluorescence on hippocampal/cerebellar sections and immunoblots of whole brain and synaptosome lysates. Serological results were correlated with clinico-neuropsychological features. 13% of TAOS patients (n = 105) were neuroAB⁺, with anti-GAD65 and anti-N-methyl-D-aspartate receptors (NMDAR) as most frequent autoABs in this group. In our screening tests 25% of neuroAB^– patients (n = 199) were positive (screening⁺), whereas all control samples were negative (n = 27). Intriguingly, key clinico-neuropsychological characteristics including magnetic resonance imaging (MRI) findings, epileptiform electroencephalographic (EEG) activity, and inflammatory cellular infiltrates in CSF were shared to a greater extent by neuroAB⁺ with neuroAB^–/screening⁺ patients than with neuroAB^–/screening^– patients. Serological testing in a large consecutive TAOS patient series revealed seropositivity for anti-GAD65 autoABs as the most frequent neuroAB. Intriguingly, neuroAB⁺ individuals were virtually indistinguishable from neuroAB^–/screening⁺ patients in several major clinical features. In contrast, neuroAB^–/screening^– TAOS patients differed in many parameters. These data support the potential presence of so far unrecognized autoABs in patients with TAOS.

Seizures are a frequent and diagnostically relevant symptom of ab + AE. Whereas NMDAR+ patients had few localizing semiological features, semiology in LGI1+ and GAD+ patients pointed toward a predominant temporal seizure onset. FBDS are pathognomonic for LGI1 + AE. Status epilepticus seems to be more frequent in NMDAR + AE.

As our knowledge of seizures in neural antibody-associated disease advances, precise use of terminology becomes essential for this knowledge to be effectively translated to clinical research and patient care. The terms “acute symptomatic seizures secondary to autoimmune encephalitis” and “autoimmune encephalitis-associated epilepsy,” as well as “seizures with or without features suspicious for neural antibody positivity,” aid in describing the various patient disease states that may be encountered. These states are dynamic, and so the most appropriate terminology for a given patient may change as their clinical course evolves, or as breakthroughs in the field of autoimmune neurology are made (e.g., the identification of new therapeutics for cytotoxic T-cell-mediated pathology, or new features suspicious for neural antibody positivity). As scientific discoveries related to seizures in neural antibody-associated disease continue, placing emphasis on accurateness of terminology ensures that its use helps rather than hinders progress in this field.

320 patients were analyzed for this study. Seizures are a frequent and diagnostically relevant symptom of ab + AE. Whereas NMDAR+ patients had few localizing semiological features, semiology in LGI1+ and GAD+ patients pointed toward a predominant temporal seizure onset. FBDS are pathognomonic for LGI1 + AE. Status epilepticus seems to be more frequent in NMDAR + AE.

Seizures are a frequent and important clinical symptom in the early stages of ab + AE with abs against NMDAR, LGI1, and GAD with relevant effect on diagnosis and disease severity. Patients with NMDAR + AE had only few characteristic semiological features according to the more diffuse cerebral affection, but developing seizures is associated with a more severe disease course. By contrast, semiology in LGI1+ and GAD+ patients clearly pointed to a more focal and temporal seizure onset. FBDS are pathognomonic for LGI1+AE. SE seems to be more frequent for NMDAR + AE.

In conclusion, our study shows that, despite sharing some similarities such as seizure type and onset, older patients with AE can be distinguished from those with Late-onset epilepsy of unknown origin (LOEUO) based on their electroclinical features: in particular, high-frequency focal seizures with ictal autonomic manifestations in the elderly should raise the suspicion of an underlying immune-mediated disorder. Our study also highlights the relevant contribution of AEEG, a noninvasive, economic tool, which might reduce the diagnostic delay in LOEUO, and provide useful information to recognize AE.

Conclusion: Young people hospitalized with epilepsy have higher risk of not achieving minimum standards for numeracy and reading and not completing high school compared to matched peers. There is a need for effective strategies and interventions (e.g., early seizure control and improved multidisciplinary management and care coordination) to minimize the potential adverse effect of epilepsy on education and its sequelae such as early school leaving, unemployment and poverty in adulthood

Results: Of 320 AE patients, 75.9% had acute seizures, among whom >90% of patients had their last seizure within 12 months of disease onset. During our follow-up, 21 (9.3%) patients experienced seizure recurrence. Patients with anti-GABA_B R encephalitis had a higher cumulative incidence of seizure recurrence than those with anti-NMDAR (log-rank p = .03) or anti-LGI1/Caspr2 encephalitis (log-rank p = .04). Among patients with anti-NMDAR encephalitis, women had a significantly higher cumulative incidence of seizure recurrence than men (log-rank p = .01). Interictal epileptiform discharges (IEDs) or seizures captured on continuous electroencephalogram (EEG) in the acute phase were identified as potential risk factors for seizure recurrence (p = .04, p = .007). Among 163 patients with ≥24 months of follow-up, five (3.1%) showed persistent seizures and required ongoing antiseizure medications despite aggressive immunotherapy.

Significance: Seizure recurrence occurred in a small number of patients and chronic epilepsy occurred in 3.1% of patients during prolonged follow-up. Across all types of AE, risk factors for seizure recurrence were IEDs or seizures captured on EEG in the acute phase; for anti-NMDAR encephalitis, female sex was also a risk factor.

The prevalence of IP in our LE cohort was of 13.3%, higher than expected. According to the literature review, most cases were associated with LGI1 Ab and showed a good response to immunotherapy. With the contribution of our cases, GAD65 emerged as the second most frequently detected Ab, showing a poor outcome. Our findings widen the spectrum of IP-associated Ab, with the respective prognostic implications.

Status epilepticus (SE) is a severe condition of unrelenting seizures requiring urgent identification and treatment. SE may be unprovoked, occurring in someone with epilepsy, or may be provoked by acute intracranial disease or metabolic derangement. Increasingly encephalitis, particularly autoimmune types, is reported to cause refractory seizures. Whilst convulsive SE is readily identified, non-convulsive SE (NCSE) can be difficult to identify clinically, and electroencephalography (EEG) is required. Therefore, it is critical to identify the key clinical features associated with NCSE on EEG to inform future use of EEG.

Conclusion: There is increasing evidence that previous or concomitant encephalitis, particularly of autoimmune aetiology, is a common cause of NCSE. Therefore, in patients with altered consciousness NCSE should be considered urgently, especially when encephalitis is suspected and subtle motor signs are present.

Conclusions: In patients with temporal lobe seizures and additional limbic signs, 17% had neuronal Abs affirming ALE diagnosis. Mediotemporal MRI changes were found in all Ab-positive cases and had a positive likelihood ratio of 2.11 (95% confidence interval 1.51-2.95).

In addition to its potential role in the treatment of acute refractory status epilepticus in patients with PE and AE, ketogenic diet therapies may be feasible and safe in the management of chronic post-encephalitic and autoimmune-associated epilepsy. Patients with prior history of SE might respond better to KDT. Further studies are needed to explore the efficacy of KDT in managing seizures in patients with PE and AE. Moreover, whether the early use of KDT can alter the pathophysiology, prognosis, and outcome of patients with encephalitis warrants further exploration.

n this review, we document the clinical and immunologic characteristics of autoimmune encephalitis known to date, with the goal of helping clinicians in differential diagnosis and to provide prompt and effective treatment.

Specific autoimmune encephalitis syndrome

Although clinical manifestations of autoimmune encephalitis can vary significantly, different autoantibodies can be associated with similar phenotypes, certain clinical features suggest a specific type of autoimmune encephalitis, such as facio-brachial dystonic seizures (FBDS) and memory impairment with anti-LGI1 encephalitis; encephalopathy, insomnia, ataxia, peripheral nerve hyperexcitability, and neuropathic pain with anti-Caspr2 encephalitis; refractory SE with anti-GABAA R encephalitis; and myoclonus, tremors, hyperexcitability, and severe diarrhea with anti-DPPX encephalitis (Table 1). Seizures and movement disorders along with psychosis, confusion, or additional behavioral changes are the most relevant initial manifestations in all age groups.

AE is an important etiology in late-onset seizures, and seizures may be the first symptom of AE. 

The results of our study provide clinicians with additional information verified in a great cohort of 225 patients on the prevalence and outcomes of AE as well as predictors of when to suspect AE in patients with late-onset seizures. Although characteristic signs of inflammation in AE may be lacking especially in elderly patients, the presence of CSF and MRI signs of inflammation, mesial temporal neuropsychological alterations, younger age, a known malignancy and specific semiological features (such as FBDS) should suggest AE. An epileptic seizure may be the first symptom of AE. In short, AB testing in CSF and sera, cerebral MRI, lumbar puncture, and neuropsychological testing for mesial temporal deficits should be part of the diagnostic protocol for AE following late onset seizures.

Temporal lobe adult-onset seizures (TAOS) related to autoimmunity represent an increasingly recognized disease syndrome within the spectrum of epilepsies. 

Here, we aimed to gain insights into (a) the distribution of ‘neurological’ autoABs (neuroABs, defined as autoABs targeting neuronal surface structures or ‘onconeuronal’ ABs or anti-glutamate
acid decarboxylase 65 (GAD65) autoABs) in a large consecutive TAOS patient cohort, to
characterize (b) clinical profiles of seropositive versus seronegative individuals and to find (c) potential evidence for other autoABs

The central nervous system (CNS) is considered an immune-privileged organ, but recent research revealed that it is an active environment that interacts with diverse immune cells in both the disease state and the healthy brain. Immune processes play a vital role in CNS homeostasis, resilience, and brain reserve, and highly sensitive narrow ranges of inflammatory balance seem to be required for health. Crosstalk between the immune and nervous systems has been revealed in a wide spectrum of neurological diseases. Increased levels of proinflammatory cytokines are found in patients with epilepsy, developmental disorders, neurodegenerative diseases, and psychiatric disorders. Therefore, many neurologic and neurodevelopmental disorders in children might be re-evaluated and investigated in terms of immunologic interactions including autoantibodies, cytokines, and microRNAs.

Conclusion: Our study suggested that immunotherapy delay and IEDs were associated with the development of epilepsy in patients with anti-NMDAR, anti-LGI1, and anti-GABAB R encephalitis. Early diagnosis and treatment were required, and particular consideration should be given to patients with these risk factors.

Rituximab is effective for antibody-associated disorders such as lupus, myasthenia gravis, and neuromyelitis optica. Here, we present three patients who were admitted with recalcitrant status epilepticus and demonstrated serum antibodies against NMDAR, LGI1, or VGCC using a cell-based assay. All patients demonstrated complete, long-term epilepsy control and improvement in symptoms with rituximab.​

​Seizures are a well-recognized and often prominent manifestation of autoimmune encephalitic syndromes. Progress in the detection of pathogenic neural autoantibodies has led to increased awareness of autoimmune causes of seizures. Clinical studies of patients with these autoantibodies have improved our understanding of the seizure characteristics, treatments, and seizure prognosis in these disorders.

This paper defines two main diagnostic entities (distinct situations): (a) acute symptomatic seizures secondary to autoimmune encephalitis, and (b) autoimmune-associated epilepsy, the latter of which suggests an enduring predisposition to seizures. Such a distinction is relevant when discussing the pathophysiology (how the disease functions), treatment, prognosis, and social consequences of these disorders.

​Intravenous immunoglobulin (IVIG) is an effective acute treatment strategy for reducing seizures in patients with seizures tied to two rare types of antibody-associated encephalitis, LGI1, and CASPR2, according to results from a small, double-blinded randomized, placebo-controlled trial featured as part of the 2020 AAN Science Advances.

Highly Recommended paper

Most autoimmune encephalitides present with seizures, but the probability of evolving to epilepsy is relatively small. The risk of epilepsy is higher for disorders in which the antigens are intracellular (often T cell-mediated) compared with disorders in which the antigens are on the cell surface (antibody-mediated).

A common feature of all types of autoimmune epileptic seizures is the refractoriness to antiepileptic drugs unless immunotherapy is concurrently used. It is currently unclear whether some antiepileptics are better than others in patients with these disorders.

The clinical presentation may be complex and testing may need to be repeated when findings are initially negative or if specific antibodies are not found.  Each antibody has its unique clinical findings, cancer association, and response to treatment. Advances in the detection and identification of causative antibodies and other biomarkers will aid in diagnosis and prompt treatment of these patients in the future.

Autoimmune Epilepsy is a rapidly expanding field. Check out this review article discussing the latest advances, diagnostics and therapeutics.

Objective: To follow prospectively a group of patients with seizures or epilepsy and suggestive clinical features of autoimmune aetiology and find out how many are finally diagnosed with acute symptomatic seizures (ASS) secondary to autoimmune encephalitis or autoimmune-related epilepsy, and how many develop epilepsy. Notably, all patients with GAD ab 17/17 (100 %) evolved to chronic disease. Four patients (29 %) with ASS secondary to autoimmune encephalitis developed epilepsy.

Significance: ASS secondary to autoimmune encephalitis or autoimmune-related epilepsy will be diagnosed in nearly half of patients who have been suspected of it. The only diagnostic clue is neuronal ab. Patients who have suffered ASS secondary to autoimmune encephalitis may develop epilepsy over time.

The incidence of SE in patients with AE in western China was 22.03%. EEG and head MRI abnormalities may be susceptibility factors for SE in patients with AE. Glasgow scores <8 when admitted to hospital, abnormal EEG, and seizure duration >30 minutes were risk factors for a poor prognosis in the status of epilepsy (modified Rankin score 3–6).

In patients with medial temporal lobe T2-hyperintensity and one of the diffusion restriction patterns described herein, the signal abnormality may be a peri-ictal phenomenon rather than indicative of LE and should prompt investigation for seizure. Even in patients with LE, these patterns should raise concern for seizure.

The prevalence of autoimmune epilepsy isn’t known. Recent research suggests that people with autoimmune disease are almost four times likelier to have epilepsy than are people without autoimmune disorders. “Autoimmune-mediated epilepsy is probably a lot more common than we think,” Dr. Britton says.

In addition to the presence of neural antibodies, clinical features suggestive of autoimmune epilepsy include:

• Acute to subacute onset, with seizures occurring every three months or less
• Multiple types of seizures or faciobrachial dystonic seizures
• Resistance to anti-seizure medication
• Personal or family history of autoimmunity
• History of recent or past neoplasia
• Viral prodrome
• Evidence of CNS inflammation