By reviewing case series and case reports, we seek to provide a deeper understanding of this condition and shed light on its clinical characteristics.
Neurological Manifestations
Based on the reviewed cases, the neurological manifestations of COVID-19-associated AE can be categorized into seven main categories: disturbance of consciousness, seizure, psychiatric symptoms, neuromuscular symptoms, extrapyramidal movements, cerebellar syndrome, and other clinical symptoms.
The most commonly reported symptoms were seizure, disturbance of consciousness, and psychiatric symptoms. Seizures in severely ill patients were predominantly generalized tonic-clonic seizures and refractory status epilepticus. Disturbances of consciousness were characterized by confusion, unconsciousness, and delirium.
Psychiatric symptoms included cognitive deterioration, abnormal behavior, persecutory delusions, and hallucinations. Additionally, neuromuscular symptoms and extrapyramidal movements were observed as initial symptoms in some cases, presenting as myalgia, weakness, catatonia, myoclonus, and limb tremors.
Analysis of every single psychiatric manifestation
- Cognitive Deterioration: Cognitive deterioration refers to a decline in cognitive functioning, including impairments in memory, attention, executive functions, and overall cognitive abilities. In the context of COVID-19-associated AE, cognitive deterioration can manifest as a progressive or sudden decline in cognitive abilities, leading to difficulties in thinking, reasoning, problem-solving, and information processing. This symptom can significantly impact daily functioning and quality of life.
- Abnormal Behavior: Abnormal behavior in the context of COVID-19-associated AE encompasses a range of atypical or unusual behaviors that deviate from an individual’s typical patterns. This can include agitation, restlessness, aggression, disinhibition, impulsivity, or other behaviors that are out of character for the person. Abnormal behavior may disrupt social interactions, relationships, and activities of daily living, causing distress to the individual and their caregivers.
- Persecutory Delusions: Persecutory delusions are a specific type of psychotic symptom observed in some cases of COVID-19-associated AE. Individuals with persecutory delusions hold fixed, false beliefs that they are being targeted, harmed, or conspired against by others. These beliefs can be paranoid in nature and may lead to heightened anxiety, fear, and mistrust. Persecutory delusions can significantly impact an individual’s perception of reality and may contribute to social withdrawal and impaired functioning.
- Hallucinations: Hallucinations, both auditory and visual, can occur in COVID-19-associated AE. Auditory hallucinations involve perceiving sounds or voices that are not actually present, while visual hallucinations entail seeing objects, people, or events that do not exist. Hallucinations can be distressing and disorienting, causing significant confusion and fear. They can disrupt daily activities, impair communication, and contribute to overall psychological distress.
- Neuromuscular Symptoms: Neuromuscular symptoms observed in COVID-19-associated AE include myalgia (muscle pain) and weakness. Myalgia refers to generalized or localized muscle pain, which can cause discomfort, fatigue, and reduced mobility. Weakness refers to a decrease in muscle strength and can lead to difficulties in performing physical tasks, such as lifting objects or walking. These symptoms may result from the direct effects of the autoimmune response on muscle tissue or as a secondary consequence of neurological dysfunction.
- Extrapyramidal Movements: Extrapyramidal movements refer to abnormal involuntary movements that can occur in COVID-19-associated AE. These movements can include catatonia, myoclonus, and limb tremors. Catatonia involves a range of motor abnormalities, such as immobility, rigid posturing, and purposeless motor activity. Myoclonus is characterized by sudden, brief muscle jerks, which can affect various body parts. Limb tremors involve rhythmic shaking of the extremities. These movement abnormalities can significantly impact motor coordination, fine motor skills, and overall physical functioning.
Analyzing these psychiatric and neurological symptoms helps to understand the diverse and complex manifestations of COVID-19-associated AE. Each symptom contributes to the overall clinical picture and highlights the multifaceted nature of the condition. Prompt recognition, accurate diagnosis, and appropriate management of these symptoms are essential for optimizing patient outcomes and improving their overall well-being.
Types of AE
The types of COVID-19-associated AE identified in this review include anti-NMDA encephalitis, unknown AE, limbic encephalitis, anti-MOG encephalitis, anti-GABA encephalitis, anti-Caspr2 encephalitis, and combinations of different antibody types such as anti-NMDA and anti-GAD65 encephalitis and anti-AMPA and anti-CRMP-5 encephalitis.
Anti-NMDA encephalitis
Anti-NMDA encephalitis was first described in 2007 and has since gained recognition as a distinct clinical entity. It primarily affects the central nervous system (CNS), leading to a wide range of neurological and psychiatric symptoms. The presence of autoantibodies targeting the NMDA receptors plays a crucial role in the pathogenesis of this condition. The aim of this review is to consolidate the current knowledge and provide insights into the various aspects of anti-NMDA encephalitis.
Clinical Presentation: Anti-NMDA encephalitis presents with a diverse array of symptoms, including psychiatric manifestations, seizures, movement disorders, autonomic dysfunction, and cognitive impairments. Psychiatric symptoms often precede the neurological symptoms and may include psychosis, behavioral changes, mood disturbances, and hallucinations. Recognition of these symptoms is crucial for early diagnosis and intervention.
- Pathophysiology: The underlying pathophysiology of anti-NMDA encephalitis involves an autoimmune response targeting the NMDA receptors in the brain. Autoantibodies, primarily of IgG class, bind to the NR1 subunit of the NMDA receptor, leading to internalization and subsequent functional impairment of the receptor. The exact trigger for the autoimmune response is not fully understood, but viral infections, tumors, and other factors have been implicated.
- Diagnostic Approach: Diagnosing anti-NMDA encephalitis requires a multidisciplinary approach, involving clinical evaluation, laboratory tests, neuroimaging, electroencephalography (EEG), and the detection of NMDA receptor antibodies in cerebrospinal fluid (CSF) or serum. Various diagnostic criteria and scoring systems have been proposed to aid in the accurate and timely diagnosis of this condition.
- Treatment Strategies: Early initiation of treatment is crucial for better outcomes in anti-NMDA encephalitis. Immunosuppressive therapies, such as corticosteroids, intravenous immunoglobulin (IVIG), and plasma exchange, are commonly employed to suppress the autoimmune response. Additionally, tumor removal and immunotherapy may be necessary in cases associated with underlying neoplasms. Supportive care, including seizure management, psychiatric interventions, and rehabilitation, is also essential for optimal recovery.
Anti-MOG encephalitis
Anti-MOG encephalitis is an emerging autoimmune disorder that primarily affects the CNS. It is characterized by the presence of autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG), a protein expressed on the surface of myelin-producing cells. This article provides a comprehensive review of the current knowledge regarding anti-MOG encephalitis, highlighting its clinical features, underlying pathophysiology, diagnostic challenges, and therapeutic options.
- Clinical Presentation: Anti-MOG encephalitis can manifest with a wide spectrum of clinical features, ranging from isolated optic neuritis and myelitis to more extensive CNS involvement, including encephalopathy, seizures, and movement disorders. The clinical presentation can vary across different age groups, with distinct patterns observed in pediatric and adult patients. Understanding the diverse clinical manifestations is crucial for early recognition and accurate diagnosis.
- Pathophysiology: The exact pathogenic mechanism of anti-MOG encephalitis is not fully understood. However, it is believed to involve both cellular and humoral immune responses targeting MOG in the CNS. The binding of anti-MOG antibodies to MOG-expressing cells triggers inflammation, demyelination, and damage to the myelin sheath. Several factors, including genetic predisposition and environmental triggers, may contribute to the development of the autoimmune response.
- Diagnostic Approach: Diagnosing anti-MOG encephalitis requires a comprehensive approach that integrates clinical evaluation, neuroimaging, cerebrospinal fluid (CSF) analysis, and detection of anti-MOG antibodies. Differentiating anti-MOG encephalitis from other demyelinating disorders, such as multiple sclerosis and aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder, is essential for tailored treatment strategies. Various diagnostic criteria and laboratory techniques, including cell-based assays and enzyme-linked immunosorbent assays (ELISAs), have been developed to aid in the accurate diagnosis of anti-MOG encephalitis.
- Treatment Strategies: The optimal treatment approach for anti-MOG encephalitis is still being defined. High-dose corticosteroids are commonly used as first-line therapy to reduce inflammation and stabilize symptoms. However, immunomodulatory treatments, such as intravenous immunoglobulin (IVIG), plasma exchange, and immunosuppressive agents, may be necessary in refractory or severe cases. Additionally, symptomatic management, including seizure control and rehabilitation, plays a crucial role in optimizing patient outcomes.
Anti-gamma-aminobutyric acid (GABA)
Anti-GABA encephalitis is a recently recognized autoimmune disorder that affects the CNS. It is characterized by the presence of autoantibodies directed against GABA receptors, resulting in neurological and psychiatric manifestations. This article aims to provide a comprehensive review of the current knowledge regarding anti-GABA encephalitis, including its clinical spectrum, underlying mechanisms, diagnostic challenges, and therapeutic options.
- Clinical Presentation: Anti-GABA encephalitis presents with a diverse array of neurological and psychiatric symptoms. Neurological manifestations may include seizures, movement disorders, encephalopathy, and limbic encephalitis. Psychiatric symptoms often coexist and can include mood disturbances, psychosis, and cognitive impairments. Recognizing the wide range of clinical presentations is crucial for early diagnosis and appropriate management.
- Pathophysiology: The pathophysiological mechanisms underlying anti-GABA encephalitis are not yet fully elucidated. It is believed that autoantibodies against GABA receptors disrupt the inhibitory function of GABAergic neurotransmission, leading to neuronal hyperexcitability and dysfunction. The exact trigger for the autoimmune response is still under investigation, and potential associations with infections and genetic predisposition have been proposed.
- Diagnostic Approach: Diagnosing anti-GABA encephalitis requires a comprehensive approach involving clinical evaluation, neuroimaging, electroencephalography (EEG), cerebrospinal fluid (CSF) analysis, and the detection of anti-GABA receptor antibodies in serum or CSF. Differentiating anti-GABA encephalitis from other autoimmune encephalitides and related disorders is crucial for tailored treatment strategies. Various diagnostic criteria and laboratory techniques, including cell-based assays and immunohistochemistry, have been utilized to aid in the accurate diagnosis of anti-GABA encephalitis.
- Treatment Strategies: The treatment of anti-GABA encephalitis mainly focuses on immunotherapy to suppress the autoimmune response and manage symptoms. First-line treatments typically include corticosteroids and intravenous immunoglobulin (IVIG). In refractory cases or severe presentations, additional immunomodulatory therapies such as plasma exchange, rituximab, or cyclophosphamide may be considered. Symptomatic management, including antiepileptic drugs and psychiatric interventions, is also essential for comprehensive care.
- Prognosis: The prognosis of anti-GABA encephalitis varies among individuals and is influenced by factors such as the severity of the disease, response to treatment, and the presence of underlying tumors. Early recognition and initiation of appropriate therapies are associated with better outcomes. However, some patients may experience persistent neurological deficits or relapses, highlighting the importance of long-term follow-up care.
Anti-Caspr2 encephalitis
Anti-Caspr2 encephalitis is a recently recognized autoimmune disorder primarily affecting the CNS. It is characterized by the presence of autoantibodies directed against Caspr2, a protein involved in the organization of the nodes of Ranvier. This article aims to provide a comprehensive review of the current knowledge regarding anti-Caspr2 encephalitis, including its clinical features, underlying mechanisms, diagnostic challenges, and therapeutic options.
- Clinical Presentation: Anti-Caspr2 encephalitis presents with a diverse range of neurological and psychiatric symptoms. Neurological manifestations may include limbic encephalitis, seizures, movement disorders, peripheral nerve hyperexcitability, and autonomic dysfunction. Psychiatric symptoms such as psychosis, cognitive impairments, and behavioral changes are also commonly observed. Recognizing the varied clinical presentations is essential for early diagnosis and appropriate management.
- Pathophysiology: The pathophysiological mechanisms underlying anti-Caspr2 encephalitis involve the disruption of the Caspr2-mediated signaling pathway. Autoantibodies targeting Caspr2 lead to internalization and subsequent downregulation of Caspr2, disrupting the normal functioning of the nodes of Ranvier and impairing neuronal signaling. The trigger for the autoimmune response is not fully understood, and genetic and environmental factors may play a role.
- Diagnostic Approach: Diagnosing anti-Caspr2 encephalitis requires a comprehensive approach involving clinical evaluation, neuroimaging, electroencephalography (EEG), cerebrospinal fluid (CSF) analysis, and the detection of anti-Caspr2 antibodies in serum or CSF. Differentiating anti-Caspr2 encephalitis from other autoimmune encephalitides and related conditions is crucial for tailored treatment strategies. Various diagnostic criteria and laboratory techniques, including cell-based assays and immunohistochemistry, have been employed to aid in the accurate diagnosis of anti-Caspr2 encephalitis.
- Treatment Strategies: The treatment of anti-Caspr2 encephalitis primarily involves immunotherapy to suppress the autoimmune response and manage symptoms. First-line therapies typically include corticosteroids, intravenous immunoglobulin (IVIG), or plasma exchange. In refractory or severe cases, additional immunomodulatory agents such as rituximab or cyclophosphamide may be considered. Symptomatic management, including antiepileptic drugs and psychiatric interventions, is also important for comprehensive care.
- Prognosis: The prognosis of anti-Caspr2 encephalitis varies among individuals and is influenced by factors such as disease severity, prompt initiation of treatment, and the presence of underlying tumors. Early recognition and intervention are associated with better outcomes. However, some patients may experience persistent neurological deficits or relapses, highlighting the importance of long-term follow-up and individualized care.
Unknown AE accounted for the highest proportion (46%), followed by anti-NMDA encephalitis (26%), limbic encephalitis (10%), and anti-MOG encephalitis (8%). Rare cases of AE, such as anti-Caspr2 encephalitis, anti-NMDA and anti-GAD65 encephalitis, and anti-AMPA and anti-CRMP-5 encephalitis, were also reported.
Mechanisms of COVID-19-Associated AE
The mechanisms underlying COVID-19-associated AE are complex and not yet fully understood. Possible mechanisms include viral invasion mediated by angiotensin-converting enzyme-2 (ACE-2) receptors, invasion of the central nervous system through peripheral nerves, and virus-triggered inflammatory storms involving the central nervous system.
ACE-2 receptors, widely distributed in various tissues and organs, including vascular endothelial cells, neuronal cells, glial cells, and the brainstem, may facilitate viral invasion. Peripheral nervous system involvement may occur through the olfactory nerve, leading to olfactory bulb invasion and subsequent spread to the brainstem.
The immune response triggered by SARS-CoV-2 infection results in the release of inflammatory factors, which can damage the blood-brain barrier, leading to brain tissue edema, necrosis, and potential direct invasion by the virus.
Diagnosis, Treatment, and Outcomes
Diagnosis of AE typically involves a combination of clinical presentation, imaging analysis, cerebrospinal fluid (CSF) analysis, and electroencephalogram (EEG) findings. MRI scans can detect abnormalities in approximately 60% of AE cases, with most showing T2 and Flair high signal shadows in the medial temporal lobe, insular lobe, and amygdala.
However, around 40% of MRI scans may not exhibit significant changes. CSF analysis, while lacking specificity, is still an important diagnostic tool, although approximately 30% of results may appear normal.
It is crucial to differentiate COVID-19-associated AE from false positives. A multicenter study revealed that 72% of patients did not meet the diagnostic criteria for AE, indicating a high rate of misdiagnosis.
Factors contributing to misdiagnosis may include the overinterpretation of positive serum antibodies and misinterpretation of functional/psychiatric or nonspecific cognitive dysfunctions such as encephalopathy.
Treatment strategies for COVID-19-associated AE generally involve the administration of methylprednisolone, intravenous immunoglobulin, plasmapheresis, and oral prednisone. Prompt initiation of treatment has shown positive outcomes, with most patients achieving complete recovery. However, a small percentage of patients may experience residual cognitive impairment.
Limitations
This review has several limitations. Firstly, the inclusion of only case reports and case series may introduce publication bias. Secondly, the restriction to articles published in English may have resulted in the omission of relevant studies published in other languages. Thirdly, the availability of data varied among studies, leading to potential gaps in information.
Conclusion
COVID-19-associated AE represents a specific neurological manifestation of the disease, with potentially severe consequences for affected individuals. This comprehensive review highlights the diverse neurological manifestations, types of AE, potential mechanisms, diagnostic challenges, and treatment approaches associated with COVID-19-related AE.
Although further research is needed to fully elucidate the underlying mechanisms and improve diagnostic accuracy, prompt initiation of appropriate treatment holds promise for favorable patient outcomes. Enhancing our understanding of COVID-19-associated AE is essential for guiding clinical management and optimizing patient care in the context of this ongoing global pandemic.
