Steroid-responsive headache in scleroderma en coup de sabre. - PubMed - NCBI
Copyright American Medical Association. The most frequent laboratory abnormalities were increased liver enzyme levels in 11, increased serum sensitive thyroid-stimulating hormone levels in 11, and increased erythrocyte sedimentation rate in 5. Misdiagnosis at presentation is common. This treatable syndrome should be considered even if the serum sensitive thyroid-stimulating hormone level and erythrocyte sedimentation rate are normal, the cerebrospinal fluid profile does not suggest an inflammatory process, and neuroimaging results are normal.
Until the pathophysiologic mechanism of this and other autoimmune encephalopathies is better characterized, we believe that descriptive terms that reflect an association rather than causation are most appropriate for this syndrome. Neurologists are often consulted to evaluate patients with acute or subacute encephalopathy. The differential diagnosis for encephalopathy is wide, but the clinical features and findings on blood, cerebrospinal fluid CSF , electroencephalography EEG , and neuroimaging studies often but not always lead to an accurate diagnosis.
Once infectious causes are excluded, an autoimmune or inflammatory process may be suspected on the basis of inflammatory and autoimmune markers in the serum and CSF and meningeal and parenchymal abnormalities on magnetic resonance imaging MRI of the brain.
Autoimmune encephalopathy may take many forms, including paraneoplastic or idiopathic limbic encephalitis, that are defined by characteristic serologic and neuroimaging abnormalities. Steroid-responsive encephalopathy associated with autoimmune thyroiditis SREAT , often referred to as Hashimoto encephalopathy , was initially described by Brain et al. Nevertheless, many uncertainties regarding the condition persist, including the spectrum of clinical findings, the associated laboratory and radiologic findings, the clinical significance of the quantitative level of TPO antibody, the criteria required for diagnosis, the appropriate terms for the condition, and the typical outcome of steroid treatment.
The literature thus far has not provided sufficient data on these challenging issues to aid the diagnosis of this disorder and guide its management. This retrospective study was reviewed and approved by the Mayo Clinic institutional review board. For the purpose of this study, the diagnosis of SREAT required fulfillment of the following criteria: This last criterion was specifically required because our primary aim was to identify patients who responded to treatment and then characterize their clinical, laboratory, and radiologic features.
These criteria are similar to those previously published, 6 , 7 , 12 except that we required the absence of voltage-gated calcium and potassium channels and other paraneoplastic autoantibodies for inclusion in this analysis.
We retrospectively reviewed and analyzed all available clinical, laboratory, radiologic, and brain biopsy data to determine the spectrum of features and findings associated with SREAT. A review of patients evaluated at our institution before has been published, which includes 2 of the cases in this study. During this same approximately 8-year period, we treated additional patients who fulfilled the same criteria described in this article, except that no significant improvement occurred following high-dose corticosteroid treatment ie, steroid-unresponsive encephalopathy associated with autoimmune encephalopathy.
We present data on these patients and argue that they likely have a nonautoimmune or noninflammatory origin for their encephalopathy.
The symptoms and findings for the 20 patients are given in Table 1. All but 1 patient required hospitalization during the acute phase of illness because of the severity of their deficits. The median age at onset was 56 years range, years. The initial clinical diagnoses are given in Table 2. The most frequent misdiagnoses were viral encephalitis, Creutzfeldt-Jakob disease, and degenerative dementia.
Nine patients had a history of hypothyroidism that antedated the onset of neurologic symptoms, and 2 had euthyroid goiter. Five additional patients developed hypothroidism after the resolution of encephalopathy. Subacute combined degeneration developed in the latter case before the diagnosis of pernicious anemia was made.
Pertinent laboratory findings are given in Table 3. By definition, all patients had thyroid antibodies. The microsomal antibody titer was elevated in 7 of 7 tested median, 1: All patients experienced a marked degree of encephalopathy, and the levels of thyroid antibodies did not correlate with the severity of neurologic deficits.
Eleven patients had mild thyroid failure serum sensitive TSH, 5. The C-reactive protein level was elevated in 3 of 9 patients tested. The CSF was analyzed in all patients. No infectious origins were identified Table 4. Neuron-specific enolase and protein levels were normal in 6 patients tested.
All patients underwent EEG studies, of which 19 results were abnormal. Generalized slowing was seen in 19 patients. Other findings included focal slowing, triphasic waves, epileptiform abnormalities, and photomyogenic response. One patient had a normal routine EEG result. Steroid therapy was associated with improvement or resolution of EEG abnormalities in all 17 patients who had EEG follow-up.
Cranial MRI was performed in 19 patients 1 patient had a permanent pacemaker. Four patients had a diffuse increased signal on T2-weighted and fluid-attenuated inversion recovery FLAIR images in the cerebral white matter, and 1 MRI showed extensive dural enhancement.
Following corticosteroid therapy, the MRI findings normalized in the 4 cases with white matter signal changes as exemplified in the study by Bohnen et al 13 ; meningeal enhancement has persisted for throughout 5 years in the other patient. Cerebral angiography was performed in 5 patients to look for evidence of vasculitis. Findings were normal in each case except for 1, which showed a nonspecific slow transit time in the distribution of the anterior cerebral artery.
Meningeal or brain biopsy was performed in 2 cases. Histologic findings were entirely normal in the 1 patient with striking meningeal thickening and dural enhancement on MRI. In another patient with diffuse white matter signal changes on imaging, histologic findings included patchy myelin pallor, scant perivascular chronic inflammation, mild gliosis, and microglial activation. By definition, marked clinical improvement was seen in all patients following high-dose corticosteroid therapy, in which 15 returned to their normal neurologic baseline status and 5 had mild residual symptoms, which included tremor in 1, gait impairment in 1, mild forgetfulness in 1, mild forgetfulness and tremor in 1, and mild forgetfulness and gait impairment in 1.
Three required treatment of relapses with additional short courses of intravenous methylprednisolone, and 9 patients required continuous treatment with oral steroids or with other immunomodulatory therapy to maintain remission. Thyroid hormone therapy was initiated in patients with laboratory evidence of hypothyroidism, but neurologic improvement did not correlate with thyroid hormone therapy.
Data on 12 patients with a subacute encephalopathy associated with autoimmune thyroiditis who failed to improve with high-dose corticosteroids are given in Table 5. The 2 patients with autopsy-proven Creutzfeldt-Jakob disease cases 1 and 2 and case 5 had an increased signal in the cerebral cortical ribbon on FLAIR-positive and FLAIR-negative diffusion-weighted images and increased neuron-specific enolase or protein levels; thus, these patients were suspected to have Creutzfeldt-Jakob disease ante mortem.
However, because of our experience with another patient with an increased signal in the cortical ribbon on FLAIR images who responded to corticosteroids B. The patient with autopsy-proven Lewy body disease had a history of dream enactment behavior that was highly suggestive of rapid eye movement REM sleep behavior disorder and thus of underlying Lewy body disease, 15 but the markedly elevated thyroid microsomal antibody titer led the physicians involved in his care to diagnose him as having probable Hashimoto encephalopathy and to treat him with steroids.
The patient with neurofilament inclusion body disease had clinical and radiologic features typical of frontotemporal dementia, 16 but the markedly elevated thyroid microsomal antibody titer led to her treatment with corticosteroids also; this patient is case US1 in the study by Josephs et al. This large series of patients provides an additional characterization of SREAT and should aid in improving recognition of patients in whom to consider instituting therapy.
The clinical findings are varied but consistent with those reported previously. Other features that characterize SREAT include fluctuating symptoms, tremor, myoclonus, transient aphasia, sleep abnormalities, seizures, and gait difficulties. Headache, neuropsychiatric features, and lateralized motor or sensory deficits were present in a few cases.
Given the nonspecific nature of the neurologic and laboratory findings, and the age at onset spanning several decades, it is not surprising that alternative initial diagnoses were considered in all of our patients. Notably, disorders such as Creutzfeldt-Jakob disease, Alzheimer disease, and dementia with Lewy bodies were suspected in many cases, underscoring the need to consider autoimmune encephalopathy even in those with features that suggest irreversible prion and degenerative disorders.
The levels of thyroid antibodies were variable. All patients were encephalopathic, but antibody levels did not correspond to the severity of the clinical deficits. The presence of thyroid antibodies in serum, not the level, was the clinically relevant issue, indicating that SREAT should be considered in patients with encephalopathy even if thyroid antibody levels are only mildly elevated.
Furthermore, SREAT should be considered in patients with encephalopathy regardless of whether they are euthyroid or mildly hypothyroid. As has long been recognized for patients with autoimmune thyroid disease, multiple other autoimmune disorders commonly coexist. Whether the elevated liver enzyme levels represent a forme fruste of autoimmune hepatitis or some other process is not clear, but this finding warrants further investigation.
The finding of elevated CSF protein levels in most of our patients is consistent with prior reports. The MRI abnormalities found in some of our patients were consistent with an active encephalopathic process, including diffuse white matter signal abnormalities and meningeal enhancement. In several patients these abnormalities resolved following steroid therapy, a phenomenon that has been reported previously. These imaging characteristics are different from the striking mesial temporal lobe abnormalities encountered in subacute inflammatory autoimmune or paraneoplastic limbic encephalitis.
Although the data in this study may improve the recognition of potential patients with SREAT, the underlying pathogenesis remains unclear. We consider TPO antibody 1 of several related thyroid and gastric autoantibody markers of neurologic autoimmunity.
Several other etiologies have been proposed, including hypothyroidism itself, humoral factors, antigen-antibody complexes, overt vasculitis, intrathecal thyroid antibodies, and global cerebral hypoperfusion. Systematic studies of patients with encephalopathy, which could include a battery of serum and CSF autoimmune markers or other radiologic studies, may offer insights into the pathogenetic mechanisms.
The nomenclature in the autoimmune encephalopathies remains confusing. We therefore view nonvasculitic autoimmune inflammatory meningoencephalitis as the most appropriate term for encompassing all subtypes of steroid-responsive encephalopathies of nonvasculitic origin and favor the terms steroid-responsive encephalopathy associated with autoimmune thyroiditis 6 or steroid-responsive encephalopathy associated with Hashimoto thyroiditis 31 for the subtype of nonvasculitic autoimmune inflammatory meningoencephalitis described in this report.
Debate over the nomenclature will likely continue until the precise autoimmune or inflammatory processes are identified and proved to be pathogenic. Some may argue with our use of the term steroid-responsive in describing this entity, in which the response to a treatment defines the entity of interest.
Although we recognize the inherent circularity of defining a syndrome based on response to treatment as could also be argued regarding the utility of levodopa responsiveness in diagnosing Parkinson disease , we conceded to the considerable practical utility of emphasizing steroid responsiveness that we hope will improve the diagnosis and therapy of encephalopathic patients.
We hypothesize that patients with an encephalopathy associated with thyroid antibodies who do not markedly improve with corticosteroids represent those with a nonautoimmune or noninflammatory disorder, and our 4 patients who underwent autopsy and who did not respond to high-dose corticosteroids support this contention. We suspect that most of the other nonresponders in Table 5 , and most others who do not respond to corticosteroids, have an underlying neurodegenerative or prion disorder.
The issue for physicians who evaluate patients with a subacute encephalopathy associated with autoimmune thyroiditis is whether corticosteroid therapy is justified. Given the fact that the alternative diagnoses, such as Creutzfeldt-Jakob disease or a neurodegenerative disorder, can be incurable, a corticosteroid trial may be warranted in appropriate patients.
Perhaps certain features or findings may predict which patients will and will not respond to corticosteroids, and this important issue is certainly worthy of further study. We acknowledge several limitations of this study.
Because of the retrospective nature of this clinical series, not all patients underwent the same tests and evaluations. Our data should not be viewed as inclusive of all patients with SREAT at our institution during an 8-year period. In addition, the data should not be viewed as showing the entire spectrum of neurologic and laboratory findings associated with SREAT. In this period of study, numerous patients seen at our institution with a steroid-responsive encephalopathy were not tested for thyroid autoimmunity and therefore would not have been identified for inclusion in our analysis.
However, we hope that our findings improve the recognition of patients who may have an autoimmune or inflammatory mechanism underlying their encephalopathy, as well as stimulate further research into SREAT and other forms of nonvasculitic autoimmune inflammatory meningoencephalitis.
Study concept and design: Castillo, Mokri, and Boeve. Analysis and interpretation of data: Drafting of the manuscript: Critical revision of the manuscript for important intellectual content: