Nonparaneoplastic Autoimmune Encephalopathy
Clinical Presentation and Demographics
Autoimmune encephalopathies, like most autoimmune syndromes, are more common in women than in men. Many of the pathogenic antibody and paraneoplastic forms occur in young adults, but the nonspecific forms occur more frequently in middle-aged and older individuals. The clinical and demographic features of 46 patients with confirmed autoimmune encephalopathy in a recent large series are outlined in Table 2. Their mean age was 59 years (± 12.1 years). Onset was subacute (over 1 to 6 weeks) in 93%, and 91% experienced marked fluctuations. A coexisting systemic autoimmune disorder was present in 48% (Table 3).
As with the encephalopathy syndrome in general, all areas of cognition tend to be impaired. Memory loss was present in all and neuropsychiatric symptoms were notable in just over half of patients. Rare focal presentations, such as a frontotemporal dementia-like syndrome, have also been described. Other frequent features include hallucinations, headache, hypersomnolence, language difficulties, and stroke-like episodes (Table 2). Seizures may be more common in those with paraneoplastic limbic encephalitis (Table 2), and anticonvulsant refractory (sometimes fatal) cases of status epilepticus have been reported. A personal or family history of autoimmunity is present in ~50% and may raise further suspicion for an autoimmune encephalopathy (Table 2).
Tremor and myoclonus are frequent examination features (Table 2). It is important to obtain baseline objective measurements of cognition with a test of mental status or more detailed neuropsychologic assessment from which to judge immunotherapy effects that may be especially helpful when treatment response is less robust.
Initial Laboratory Investigations
Infectious, toxic/metabolic, nutritional, vascular, structural, and other causes of encephalopathy are more prevalent than autoimmune cases and so should be excluded. Evaluation often includes complete blood counts, erythrocyte sedimentation rate, C-reactive protein, renal indices, liver enzymes, thyroid function tests, vitamin B12 and ammonia levels, infectious, autoimmune, and paraneoplastic serologies (Table 3). Urinalysis and chest x-ray may be appropriate as common infections may precipitate encephalopathy in susceptible patients, such as those with preexisting dementia. Empiric thiamine replacement therapy is appropriate early on in the evaluation and management of any encephalopathic patient before a definitive etiology is determined, especially in those at high risk for Wernicke's encephalopathy, including alcoholics and gastric-bypass surgery patients. Screening for evidence of non-organ-specific autoimmunity with antinuclear antibody (ANA), antibodies to the extractable nuclear antigen (ENA), and antineutrophil-cytoplasmic antibody (ANCA) is helpful as a marker of nonspecific autoimmunity, but may also suggest CNS involvement of an underlying systemic autoimmune disease, such as systemic lupus erythematosus (SLE), Wegener's granulomatosis, or Sjögren's disease. Thyroid peroxidase (TPO) antibodies are also a useful marker of underlying autoimmunity, but are unlikely to be pathogenic and do not predict treatment response. In general, any autoantibodies may be nonspecifically elevated, even rheumatoid factor and antiphospholipid antibodies.
Cerebrospinal fluid (CSF) examination is important not only to exclude infectious and neoplastic causes of encephalitis, but to identify an intrathecal inflammatory process. Noninfectious inflammatory spinal fluid with mild (variable) pleocytosis and mild-moderately elevated protein concentration may be a clue to an autoimmune encephalopathy and has been shown to be a predictor of response to immunotherapy. It is important, however, to include other markers of inflammation such as oligoclonal bands, IgG index, and synthesis rate because many patients will have only a mild nonspecific elevation of protein concentration without a pleocytosis, and the finding of elevated intrathecal IgG synthesis can demonstrate that the mild elevation in protein concentration is indeed due to an abnormal inflammatory response. Neuron specific enolase may be elevated, but is again nonspecific, while 14-3-3 when available, may be more suggestive of Creutzfeldt-Jakob disease (CJD).
Neuroimaging and Electroencephalography
Neuroimaging of the brain, particularly magnetic resonance imaging (MRI), is useful to exclude vascular disease, tumors, or other structural causes of encephalopathy. In autoimmune encephalopathy MRI is most often normal, but when abnormalities occur, they most frequently involve the mesial temporal lobes (Fig. 1A). Subcortical white matter abnormalities (Fig. 1B) and diffusion-weighted lesions, including a bright cortical ribbon or basal ganglia similar to that seen in CJD, have also been reported. Meningeal enhancement following gadolinium administration is found in ~7% of patients. Functional neuroimaging with positron emission tomography (PET) or single photon emission tomography (SPECT) most often show focal or global decreased tracer uptake. Electroencephalogram (EEG) is used to exclude nonconvulsive status epilepticus or subclinical seizures as the primary cause for encephalopathy, but status epilepticus has also been reported in association with autoimmune encephalopathy. Diffuse slowing or epileptiform abnormalities in the temporal lobes are the most common findings (Fig. 2). MRI (Fig. 1), functional imaging, and EEG (Fig. 2) abnormalities often resolve or lessen in association with clinical improvement after immunotherapy.
Neuroimaging in patients with autoimmune encephalopathy. White arrows indicate areas of abnormality on fluid attenuated inversion recovery magnetic resonance imaging (FLAIR MRI) in patients with autoimmune encephalopathy. (A) A 36-year-old woman with bilateral hippocampal axial FLAIR abnormality (A1), that almost completely resolved after intravenous (IV) methylprednisolone treatment (A2). (B) A 51-year-old woman with symmetric confluent T2 signal abnormality in the white matter of both hemispheres (B1) decreased after IV methylprednisolone (B2). (Adapted from Flanagan et al. Autoimmune dementia: clinical course and predictors of immunotherapy response. Mayo Clin Proc 2010;85(10):881–897, Fig. 3.)
Electroencephalogram (EEG) before and after immunotherapy in patients with autoimmune encephalopathy. EEG (A) in a 60-year-old man prior to treatment showed a left anterior temporal lobe seizure (A1) and left temporal intermittent rhythmic delta and sharp wave activity (A2). This resolved (A3) after treatment with both phenytoin load and intravenous (IV) methylprednisolone. EEG (B) in a 71-year-old man notable for severe diffuse theta and delta wave slowing maximal over the left hemisphere (B1), and improvement with mild background slowing (7–8 Hz posterior α) after IV methylprednisolone (B2). (From Flanagan et al. Autoimmune dementia: clinical course and predictors of immunotherapy response. Mayo Clin Proc 2010;85(10):881–897, Fig. 4.)
Neural-specific Autoantibody Testing
The detection of neural-specific autoantibodies may confirm the diagnosis, predict immunotherapy response, and guide a cancer search in paraneoplastic cases. However, in many patients with autoimmune encephalopathy, the testing for neural specific autoantibodies will be negative. Autoantibody testing may be performed on serum, cerebrospinal fluid or both. Some autoantibodies are strongly associated with malignancy, such as antibodies to the NMDA receptor and indicate paraneoplastic limbic encephalitis (Table 4), whereas autoantibodies to the voltage-gated potassium channel complex are associated with cancer in only 11% of patients, and so for the purposes of this review are discussed as a nonparaneoplastic autoimmune encephalopathy. Some neural autoantibodies (e.g., voltage-gated potassium channel complex) cause encephalopathy in almost all patients, whereas others are only weakly associated with encephalopathy (such as the ganglionic acetylcholine receptor antibody). In the less-specific cases, it is not uncommon to find these autoantibodies as a marker of generalized neural autoimmunity along with multiple other serologic abnormalities of indefinite pathogenic significance. The detection of cation channel autoantibodies predicts treatment response in patients with suspected autoimmune encephalopathy.
All patients with a diagnosis of autoimmune encephalopathy should undergo screening for an underlying malignancy. The presence of a neural-specific autoantibody increases the likelihood of an underlying cancer being present and helps guide the search for malignancy. However, some patients with autoimmune encephalopathy have an underlying cancer without harboring a neural specific autoantibody. Overall, autoimmune encephalopathies are associated with an underlying malignancy in up to 25% of patients, with breast and small cell lung carcinomas detected most frequently (Table 4).
Autoimmune Encephalopathy Mimicking CJD and Dementia
The most common clinical syndrome resulting from autoimmune encephalopathy is that of a "rapidly progressive dementia" that can easily be mistaken for CJD, especially if also accompanied by myoclonus. Indeed, even the MRI and EEG features characteristic of CJD have occasionally been described in patients with a reversible autoimmune encephalopathy. We therefore believe that all patients with rapidly progressive dementia should undergo neural autoantibody testing, and in many cases consideration given to an empiric therapeutic trial of intravenous methylprednisolone for 5 days (or similar steroid regimen).
Less commonly, autoimmune encephalopathies present with chronic progressive cognitive decline (occurring over months to more than a year) that in up to a third of patients can be mistaken for Alzheimer's disease or frontotemporal dementia.[10,16] A typical features that should raise suspicion for autoimmune encephalopathy include unusually rapid progression, prominent fluctuations, tremor/myoclonus or a strong (personal or family) history of autoimmunity, unusually young age of onset, hallucinations, and atypical cognitive profile. Note that several of these features (especially hallucinations and fluctuations) are frequently encountered in patients with dementia with Lewy bodies.
Despite serologic, EEG, and CSF abnormalities, a brain biopsy is sometimes necessary to establish the diagnosis. Often this situation arises following a therapeutic trial of steroids whose results prove to be equivocal or even negative, yet clinical and laboratory features make the diagnosis plausible. Before an extended and more aggressive course of immunotherapy can be recommended along with its many potential complications, a firm diagnosis must be established. We generally select prefrontal (or less often anterior temporal) biopsy of the nondominant hemisphere (usually the right), and in such carefully selected patients we have been able to establish a diagnosis in roughly half of the cases. Of these, autoimmune encephalopathy has been found in the majority, but we have also identified Alzheimer's disease. In the other half of cases, we have obtained only normal brain tissue without establishing a firm diagnosis, and this must be recognized as a potential outcome of the biopsy before proceeding. If a diagnosis of autoimmune encephalopathy can be established, however, aggressive and prolonged immunotherapy can be given with careful clinical monitoring.
Voltage-Gated Potassium Channel Complex Associated Autoimmune Encephalopathy
In 2004 Vincent and colleagues described limbic encephalitis in association with autoantibodies to voltage-gated potassium channels. The commercial test used for detecting voltage-gated potassium channel antibodies is based on immunoprecipitation of the potassium channel complex (voltage-gated potassium channel complex subunits and associated proteins). It has been recently recognized that the target autoantigens are generally not the voltage-gated potassium channel complex themselves, but are neuronal proteins that associate with them. Autoantibodies to two such proteins (Leucine-rich glioma inactivated 1[LGI1] and contactin-associated protein-2[Caspr2]) have been recently discovered and each appears to predict a separate syndrome.[6,8] These antibodies account for most (but not all) patients with neurologic disease previously attributed to potassium channel antibodies. It appears likely that other voltage gated potassium channel complex-related antigens, yet to be defined, account for patients seropositive to the commercial test but without immunoglobulins to LGI1 or Caspr2. Autoimmune limbic encephalitis, previously attributed to antibodies to the voltage-gated potassium channel complex, is usually due to autoantibodies to LGI1; therefore, it has been suggested it be renamed limbic encephalitis associated with LGI1 antibodies. There is an associated malignancy in 11% of patients with LGI1 autoantibody associated encephalitis. Caspr2 autoantibodies can cause Morvan's syndrome (neuromyotonia [a form of peripheral nerve hyperexcitability that results in muscle cramps and stiffness], autonomic dysfunction, limbic encephalitis, and insomnia) or neuromyotonia alone, and are frequently associated with an underlying thymoma.
Patients with LGI1 antibody-associated limbic encephalitis present with seizures, memory loss, and a clinical syndrome of limbic encephalitis. Myoclonus is common and laboratory testing frequently reveals hyponatremia. MRI demonstrates T2 signal hyperintensity in the mesial temporal lobes in most patients, and EEG often reveals epileptiform activity in the temporal regions. The majority of patients improve with immunosuppressant treatment but recovery is often incomplete, and most are left with mild disability. Death occurs in less than 10%, but up to 20% go on to develop relapses.
Neuropathology of Autoimmune Encephalopathy
The most common brain biopsy findings in autoimmune encephalopathy are perivascular lymphocytic infiltrates in the parenchyma and leptomeninges and reactive gliosis.
Alzheimer's disease pathology with amyloid angiopathy was found at autopsy in four patients in a recent series with a premortem diagnosis of autoimmune encephalopathy in which improvement had been documented after earlier immunotherapy. It is unclear if this represented two etiologic processes or if the patients had an inflammatory subset of amyloid angiopathy that responded to immunotherapy.
Treatment and Prognosis of Autoimmune Encephalopathies
Randomized controlled therapeutic trial data are lacking for autoimmune encephalopathy in part due to its low prevalence, and in part due to the heterogeneous group of disorders that fall under this heading, which require very different therapeutic approaches. Fortunately, the subset of autoimmune encephalopathy without cancer typically respond quickly and completely to steroid therapy alone.[4,9,18] The importance of early correct diagnosis and prompt treatment is emphasized by evidence that patients with a delay in the initiation of immunotherapy are less likely to respond to treatment. Although there is no universally agreed upon best practice, the following are suggested treatment considerations for these autoimmune encephalopathies based on our clinical experience and the limited available evidence. It can be divided into the acute treatment of the encephalopathy and maintenance treatment to prevent relapse.
Acute Treatment In patients with suspected autoimmune encephalopathy, the initial treatment involves high dose corticosteroids. Two formulations of acute treatment are commonly used. Intravenous methylprednisolone 1000 mg for 5 days may be used in both the inpatient and outpatient setting. Alternatively, in those who can tolerate outpatient treatment, oral therapy with prednisone may begin with an initial dose of 60–120 mg (depending on the level of severity) with tapering to 40 mg over 2 weeks, and more gradually thereafter. Continued oral therapy with gradual tapering according to symptoms should continue, and typically patients will require at least a year of treatment before cessation of all treatment can be attempted. Most patients respond to acute treatment within one week and almost all will have responded by 4 weeks. However, there have been reports of some patients whose symptoms took up to a year to resolve. Repeat objective quantitative mental status examinations are important in documenting treatment response, as is careful monitoring of potential steroid-induced adverse effects, including electrolyte imbalances, hyperglycemia, and intercurrent infections in the short term, and osteoporosis, diabetes mellitus, adrenocortical axis suppression, and Cushingoid changes in the long term. Predictors of response to treatment include a subacute onset, a fluctuating course, an inflammatory spinal fluid, the presence of a cation channel neural-specific autoantibody and a shorter delay to initial treatment. When in doubt, rechecking the erythrocyte sedimentation rate (ESR) (if it was elevated during the symptomatic pretreatment phase), EEG, or spinal fluid can be helpful to document relapse.
When the diagnosis is suspected, response to a steroid challenge can be helpful diagnostically as well as therapeutically. In patients being treated orally, we will taper off the steroids in 2 to 4 weeks unless they respond within that timeframe. If they do, the tapering is slowed, and they are managed as described above. If they do not respond, or if they appear to respond initially but then relapse within the initial 2-4 week timeframe while still on steroids, consideration is then given to a brain biopsy once the steroids are discontinued assuming the level of suspicion remains high.
For patients who are intolerant of steroids, weekly intravenous immune globulin (IVIg) at 0.4 g/kg for 3–5 days followed by a single dose every 2 weeks for 6 weeks can be tried. Alternatively, plasma exchange has been reported to be beneficial in some patients. In steroid-resistant patients, IVIg or PLEX may be followed with once weekly intravenous methylprednisolone for 6 weeks, or a CNS vasculitis regimen consisting of high-dose steroids and cyclophosphamide can be tried (see below).
Chronic Treatment Patients that rapidly improve after acute treatment or have returned to normal after initial immunotherapy still require careful monitoring for potential relapse as well as for potential adverse effects of treatment. Corticosteroids that are gradually tapered with clinical monitoring represent the mainstay of maintenance therapy in most patients. Daily or alternate day regimens are most frequently employed, but some have advocated weekly pulse therapy instead. Daily calcium and vitamin D, gastrointestinal ulceration prophylaxis, and monitoring for hyperglycemia should all be considered to prevent complications associated with steroids. A steroid sparing agent, such as azathioprine or mycophenolate, can be introduced to facilitate steroid tapering. Steroid sparing treatments require close monitoring of blood counts, liver, and kidney function. IVIg infusions again are an alternative for those who are intolerant of steroids. Cyclophosphamide, plasma exchange, and rituximab are reserved for refractory cases or patients intolerant of other immunosuppressant agents.
Nonresponders Patients with biopsy-proven autoimmune encephalopathy who appear not to respond to initial steroid regimens should be considered for alternative or more aggressive strategies. Alternative acute intervention with IVIG or PLEX or the addition of cyclophosphamide (or combination therapy) should all be considered, and in the case of cyclophosphamide, response may not be apparent for several weeks. Among patients who have not had a definitive tissue diagnosis, however, steroid refractoriness becomes more difficult to manage because nonresponders may have an alternative etiology causing the symptoms, such as Alzheimer's disease, dementia with Lewy bodies, or CJD. If the level of suspicion remains high for autoimmune encephalopathy, brain biopsy should be considered because there are reports in the literature of patients who were highly refractive to initial immunotherapy, but subsequently responded to longer-term immunosuppression.
Some patients who present with refractory status epilepticus seem not to respond to any therapy, and not all have even had an identifiable pathogenic antibody.
Prognosis Autoimmune encephalopathy presents a dramatic picture of severe impairment with remarkable improvement back to normal, and equally dramatic relapse; again, that underscores the importance of maintenance therapy following the initial response. Over the course of a year or 2 years, immunotherapy can be gradually withdrawn although in the series by Flanagan et al, 77% of patients of those followed for over one year relapsed. Relapses during immunotherapy tapering occurred in 57% and long-term (> 1 year) maintenance immunotherapy was required in 81%. Long-term remission after maintenance treatment was achieved in 62% after a median of 26 months follow-up (range, 13–108).
Semin Neurol. 2011;31(2):144-157. © 2011 Thieme Medical Publishers
Cite this: Autoimmune Encephalopathy - Medscape - Apr 01, 2011.