Epilepsy in Systemic Autoimmune Disorders

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Autoimmunity and inflammation have been implicated as causative factors of seizures and epilepsy. Autoimmune disorders can affect the central nervous system as an isolated syndrome or be part of a systemic disease. Examples of systemic autoimmune disorders include systemic lupus erythematosus, antiphospholipid syndrome, rheumatic arthritis, and Sjögren syndrome. Overall, there is a 5-fold increased risk of seizures and epilepsy in children with systemic autoimmune disorders. Various etiologic factors have been implicated in causing the seizures in these patients, including direct inflammation, effect on blood vessels (vasculitis), and production of autoantibodies. Potential treatments for this autoimmune injury include steroids, immunoglobulins, and other immune-modulatory therapies. A better understanding of the mechanisms of epileptogenesis in patients with systemic autoimmune diseases could lead to targeted treatments and better outcomes.

Introduction

Autoimmunity and inflammation have gained recent popularity as either causative factors or bystanders in multiple neurologic disorders including epilepsy. There is evidence of inflammatory markers or presence of autoantibodies in several types of epilepsies, as detailed elsewhere in this issue.

This article focuses on the epilepsies that result from autoimmunity or inflammation secondary to systemic autoimmune or inflammatory disorders, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Population-based studies have shown an increased incidence of epilepsy among patients with systemic autoimmune disorders. The onset of epilepsy can precede the diagnosis of autoimmune disease in approximately 30% of patients.1

The etiology of seizures and epilepsy in these disorders might involve the production of antibodies, the increased synthesis and release of cytokines and chemokines with increased inflammatory microglial response in the brain, or the results of vascular complications including stroke and hemorrhage.2

In a large, population-based, retrospective study including more than 400,000 children, Ong et al1 found an overall epilepsy prevalence of 1.8% in children with autoimmune disease compared with 0.4% in children without it. Children with autoimmune diseases had a 5-fold increased risk of epilepsy compared with normal children, and they accounted for 17.5% of patients with epilepsy (Table).

This article reviews the epilepsies secondary to systemic autoimmune disorders.

Section snippets

Systemic Lupus Erythematosus

SLE is an autoimmune inflammatory disorder affecting multiple organs, including the brain and peripheral nervous system. Central nervous system manifestations are present in 25%-75% of SLE cases.2 Seizures occur in approximately 20% of pediatric patients3 with a range of 7%-40%.2 In a multicenter study by Hanly et al4 with a cohort of 1631 adult patients with SLE, 75 had 1 or more seizures (4.6%), which usually occurred close to diagnosis. Most patients presented with generalized seizures. In

Antiphospholipid Syndrome

The antiphospholipid syndrome (APS) is defined as the presence of antibodies against phospholipids along with systemic clinical manifestations of a hypercoagulable state with venous or arterial thromboses or obstetric complications or both. The antiphospholipid antibodies include the lupus anticoagulant, anticardiolipin, and anti–β-2 glycoprotein. APS can be classified as primary, when there is no underlying disorder, or secondary, when a disorder is causing it, as is the case with SLE.

Rheumatoid Arthritis

This autoimmune disease involving mostly the joints can produce vasculitis in the central nervous system in 1%-8% of cases.22 Involvement of the brain in RA is rare and includes rheumatic meningeal nodules, choroid plexus infiltration, pachymeningitis, cranial neuropathies, hydrocephalus, sinus thrombosis, vasculitis, and seizures.23 In a study by Ong et al,1 533 children with RA were 3 times more likely to have epilepsy than children without this autoimmune disease. Vasculitis manifestations

Sjögren Syndrome

This autoimmune inflammatory disorder causes a chronic, progressive lymphocytic and plasma cell infiltration of the lachrymal and salivary glands producing the common complaint of dry eye and mouth.26 Sjögren syndrome (SS) can present alone or in association with other autoimmune disorders like RA or SLE. Neurologic symptoms can occur in about 25% of patients with SS, with seizures in approximately 3%-10% of them.26, 27 In a review of 82 patients with neurologic manifestations of SS, 47% had

Behçet Disease

This autoimmune, inflammatory disorder usually presents with ulcers in the mouth and genitals and inflammation of the eye tissues including uveitis, iritis, and retinitis. Neurologic involvement can happen in 10%-23% of cases, being more common in men than in women and between the ages of 20 and 40 years.30 Neurologic lesions can be either parenchymal or vascular involving veins or arteries. Epilepsy occurs in 2%-16%.31, 32 Aykutlu et al31 described 223 patients with Behçet disease (BD) and 10

Inflammatory Bowel Disease

Crohn׳s disease and ulcerative colitis are 2 idiopathic, relapsing-remitting inflammatory disorders of the gastrointestinal (GI) tract.

Crohn׳s disease can affect the entire GI tract, whereas ulcerative colitis is restricted to the colon. This is a T-cell–mediated disorder with chronic granulomatous inflammation of the intestines. Both of these conditions can have systemic manifestations in approximately 20%-40% of patients.36 In a retrospective chart review of 84 patients with inflammatory

Celiac Disease

This autoimmune disorder of the small intestine is produced by exposure to the gluten protein gliadin. Most patients present with GI symptoms. Celiac disease can cause neurologic symptoms in approximately 10% of cases including central and peripheral symptoms. The prevalence of epilepsy ranges from 1%-5.5%.40, 41, 42, 43 Patients can have partial or generalized seizures including myoclonus.44 Approximately 20% of children with celiac disease have bilateral T2 white matter lesions on magnetic

Wegener Granulomatosis

This is a necrotizing, granulomatous vasculitis with systemic involvement, affecting primarily the airways, lungs, and kidneys. The peripheral nervous system is compromised more often than the central nervous system. Seizures occur in approximately 10% of patients with neurologic involvement.46 Nishino et al47 described 324 consecutive patients with Wegener granulomatosis, 10 of them with seizures. Moore et al46 described a 17-year-old girl with secondarily generalized seizures and

Sarcoidosis

This is a non-caseating granulomatous disease with multiorgan involvement of unclear etiology. Approximately 5%-16% of patients have neurologic symptoms.48 Sarcoidosis often compromises the basal meninges, thereby causing cranial nerve involvement. Baumann and Robertson49 reported a 9-year-old girl with biopsy-proven neurosarcoidosis, headaches, and tonic-clonic seizures and reviewed another 29 cases in the literature. Seizures were the most common presenting symptom in 38% of these children.

Type 1 Diabetes Mellitus

Besides being at risk for seizures with extreme glycemia values, children with type 1 diabetes mellitus (DM) may have frequently associated epilepsy.

However, there are conflicting studies with some reporting no association52 and some with increased risk for epilepsy.53, 54, 55 A large pediatric retrospective study of 1384 children with DM, found a prevalence of epilepsy of 0.9%, which is not elevated when compared with the general population.52 In another study including 285 children younger

Myasthenia Gravis

Myasthenia gravis is an autoimmune disorder that produces antibodies against the acetylcholine receptor, leading to clinically fluctuating weakness of skeletal muscles including the eye muscles (ophthalmoplegia). It can be associated with other autoimmune disorders, including Hashimoto thyroiditis and diabetes. Although some studies have described an increased incidence of epilepsy and EEG abnormalities in patients with myasthenia gravis, many of these had other explanations for their seizures,

Hashimoto Thyroiditis

This is an autoimmune inflammatory disorder of the thyroid gland that rarely causes encephalopathy with involvement of the central nervous system. Hashimoto encephalopathy can cause intermittent encephalopathy with delirium, seizures, cognitive decline, depression, and agitation. Seizures affect 66% of patients with Hashimoto encephalopathy.58, 59 Any seizure type can occur, including status epilepticus. Arya et al58 described myoclonic seizures that responded to the combination of valproate,

Graves Disease

Epilepsy is rare in patients with Graves disease. Ong et al1 described an increased odds ratio of 4.7. Vergely et al63 reported a case of an 18-year-old girl with Graves disease and generalized seizures and highlighted that seizures can occur in the euthyroid state. Most of the cases have had generalized epilepsy.63 Seizures tend to be more common in Hashimoto thyroiditis than in Graves disease. Of 3382 patients reported with hyperthyroidism by Song et al,64 there were 6 with Graves disease who

Conclusions

There is an increased incidence of epilepsy in systemic autoimmune disorders supporting the pathogenetic relationship between the immune system and epilepsy. The etiological factors involved in the generation of seizures include direct inflammation, vasculitis, thrombosis, and the effect of antineuronal autoantibodies. Treatment of these disorders includes standard antiepileptic therapy, often coupled with immune therapy to control the primary disorder. A better understanding of the mechanisms

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