Autoimmune Encephalopathy

Eoin P. Flanagan, M.B.B.Ch.; Richard J. Caselli, M.D.

Disclosures

Semin Neurol. 2011;31(2):144-157. 

In This Article

Other Autoimmune and Related Causes of Encephalopathy

Systemic Autoimmune Diseases

Systemic autoimmune diseases may cause an encephalopathy and it is usually due to an inflammatory meningoencephalitis. This may be seen with a variety of autoimmune diseases including Sjögren's, systemic lupus erythematosus, hypereosinophilic syndrome, and Behçet's disease. Although such diseases may have associated vasculitis, more often the pathology shows perivascular nonvasculitic inflammation similar to that described with nonparaneoplastic autoimmune encephalopathy above.

Whether Sjögren's syndrome specifically causes a multiple sclerosis-like syndrome (in addition to its nonspecific association with autoimmune encephalopathy) is controversial, but in such purported cases there is usually an inflammatory spinal fluid and subcortical/periventricular T2 signal changes on MRI brain.[32] Central nervous system lupus may cause encephalopathy, often in the setting of disseminated intravascular coagulation and associated nonbacterial thrombotic endocarditis with cerebral embolization.[32] Behçet's syndrome is a disease characterized by recurrent oral and genital ulceration and uveitis, and is most prevalent in Mediterranean countries and the Middle East. Encephalopathy or a meningoencephalitis with brainstem involvement has been reported with Behçet's.[33] Elevated CSF protein concentration or CSF pleocytosis (lymphocytic or neutrophilic) is common, and MRI typically reveals lesions in the brainstem, but cerebral venous thrombosis may also be seen.[33] Most patients have a monophasic course. The clinical features and suggested diagnostic tests for systemic autoimmune diseases causing encephalopathy are outlined in Table 5. A similar treatment approach is used for encephalopathy with SLE, Sjögren's syndrome, and Behçet's. High-dose corticosteroids represent the mainstay of therapy, whereas cyclophosphamide is usually reserved for refractory cases. Steroid-sparing agents, including azathioprine and mycophenolate, are used in selected patients at risk for relapse. Associated thromboses, usually related to antiphospholipid antibody syndrome, should be treated with anticoagulation.

Other Immunotherapy Responsive Encephalopathies of Uncertain Etiology

Encephalopathy that is responsive to immunotherapy may occur in some inflammatory neurologic diseases of uncertain etiology. In multiple sclerosis, cognitive impairment is common but usually mild with information processing and attention most severely affected. Large acute lesions in multiple sclerosis, such as tumefactive multiple sclerosis,[34] may cause encephalopathy and often responds to high-dose steroids. Primarily gray matter demyelination is a rare variant of multiple sclerosis that may cause progressive dementia.[35,36] Neurosarcoidosis is another inflammatory disorder that may cause encephalopathy. It has a predilection for the base of the brain; other features such as lupus pernio, erythema nodosum, hilar adenopathy, or uveitis may be suggestive. Leptomeningeal involvement is common and pathologic findings revealing noncaseating granuloma is diagnostic. Extra-CNS biopsy is preferable and transbronchial, mediastinal biopsy as well as conjunctival biopsy may reveal the diagnosis and obviate the need for CNS biopsy.[37] Neurosarcoidosis is frequently steroid responsive, but there have also been reports of treatment success with tumor necrosis factor inhibitors, e.g., infliximab in refractory cases.[38] Hypereosinophilic syndromes are multisystem disorders of uncertain etiology that may cause encephalopathy in some cases. Skin manifestations of eczema and lichenification with pulmonary eosinophilia (cough or asthma) are common with gastrointestinal and cardiac involvement often seen. Peripheral eosinophilia (> 1500/μL) on two occasions without another cause is suggestive of the diagnosis. Microemboli in the cerebral circulation may also occur. Testing for tyrosine kinase-associated mutations is important as it dictates treatment. Those with genetic mutations detected are treated with imatinib[39]; those without are treated with steroids.[40]

Other Causes of Encephalopathy in Patients with Autoimmune Disease

Patients with autoimmune disorders are at risk of developing encephalopathy for reasons other than extension of the underlying disease process to the brain. Distinguishing an underlying infection as a cause of encephalopathy from cognitive dysfunction caused by autoimmune disease affecting the brain is critical, as potentially severe complications or death may result if a patient with an underlying infection is given immunosuppressants. Patients taking chronic immunosuppressants represent immunocompromised hosts and therefore extensive testing may be necessary to exclude infection as a possible cause of their encephalopathy. Medications used to treat autoimmune disorders may affect the nervous system and result in encephalopathy. Possible side effects include steroid psychosis, steroid-associated hyperglycemia, or metabolic encephalopathy due to liver or renal failure associated with steroid-sparing immunosuppressants, such as azathioprine, IVIg, or mycophenolate. Lymphoma causing encephalopathy may occur due to chronic activation of the immune system in systemic autoimmune disorders or secondary to chronic use of immunosuppressants such as mycophenolate, azathioprine, or rituximab. Posterior reversible encephalopathy has been reported with immunosuppressants (most often those used in posttransplant patients), including tacrolimus and cyclosporine, but may also occur with Wegener's, SLE, systemic sclerosis, or polyarteritis nodosa.[41]

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