Steroid-responsive encephalopathy subsequently associated with Alzheimer disease pathology

This art icle was downloaded by: [ 69.251.44.160] On: 18 February 2013, At : 06: 35 Publisher: Rout ledge I nform a Lt d Regist ered in England and Wales Regist ered Num ber: 1072954 Regist ered office: Mort im er House, 37- 41 Mort im er St reet , London W1T 3JH, UK Neurocase: The Neural Basis of Cognition Publicat ion det ails, including inst ruct ions for aut hors and subscript ion informat ion: ht t p:/ / www.t andfonline.com/ loi/ nncs20 Steroid-responsive encephalopathy subsequently associated with Alzheimer's disease pathology: A case series Farrah J. Mat een ab Richard J. Caselli d b , Keit h A. Josephs , Joseph E. Parisi , Kej al Kant arci e , Clifford Jack Jr e b c b , Daniel A. Drubach , & Bradley F. Boeve a Depart ment of Neurology, Johns Hopkins Universit y, Balt imore, MD, USA b Depart ment of Neurology, Mayo Clinic, Rochest er, MN, USA b c Depart ment of Laborat ory Medicine and Pat hology, Mayo Clinic, Rochest er, MN, USA d Depart ment of Neurology, Mayo Clinic, Scot t sdale, AZ, USA e Depart ment of Diagnost ic Radiology, Mayo Clinic, Rochest er, MN, USA Version of record first published: 30 Jun 2011. To cite this article: Farrah J. Mat een , Keit h A. Josephs , Joseph E. Parisi , Daniel A. Drubach , Richard J. Caselli , Kej al Kant arci , Clifford Jack Jr & Bradley F. Boeve (2012): St eroid-responsive encephalopat hy subsequent ly associat ed wit h Alzheimer's disease pat hology: A case series, Neurocase: The Neural Basis of Cognit ion, 18:1, 1-12 To link to this article: ht t p:/ / dx.doi.org/ 10.1080/ 13554794.2010.547503 PLEASE SCROLL DOWN FOR ARTI CLE Full t erm s and condit ions of use: ht t p: / / www.t andfonline.com / page/ t erm s- and- condit ions This art icle m ay be used for research, t eaching, and privat e st udy purposes. Any subst ant ial or syst em at ic reproduct ion, redist ribut ion, reselling, loan, sub- licensing, syst em at ic supply, or dist ribut ion in any form t o anyone is expressly forbidden. The publisher does not give any warrant y express or im plied or m ake any represent at ion t hat t he cont ent s will be com plet e or accurat e or up t o dat e. The accuracy of any inst ruct ions, form ulae, and drug doses should be independent ly verified wit h prim ary sources. The publisher shall not be liable for any loss, act ions, claim s, proceedings, dem and, or cost s or dam ages what soever or howsoever caused arising direct ly or indirect ly in connect ion wit h or arising out of t he use of t his m at erial. NEUROCASE 2012, 18 (1), 1–12 Steroid-responsive encephalopathy subsequently associated with Alzheimer’s disease pathology: A case series Farrah J. Mateen1,2 , Keith A. Josephs2 , Joseph E. Parisi2,3 , Daniel A. Drubach2 , Richard J. Caselli4 , Kejal Kantarci5 , Clifford Jack Jr5 , and Bradley F. Boeve2 1 Department of Neurology, Johns Hopkins University, Baltimore, MD, USA Department of Neurology, Mayo Clinic, Rochester, MN, USA 3 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA 4 Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA 5 Department of Diagnostic Radiology, Mayo Clinic, Rochester, MN, USA Downloaded by [69.251.44.160] at 06:35 18 February 2013 2 Background: Steroid-responsive encephalopathies can be considered vasculitic or non-vasculitic. Clinicopathological studies of non-vasculitic steroid-responsive encephalopathy are unusual, but can explain the range of diagnoses consistent with a steroid-responsive presentation in life. Objective: To extend the range of clinical features and pathological findings consistent with steroid-responsive encephalopathy. Design, methods, and patients: A clinicopathological case series of four patients (two women, ages 54–71 years) with steroid-responsive encephalopathy followed at this institution until the time of death. Results: Clinical features were suggestive of Creutzfeld–Jakob disease (CJD), dementia with Lewy bodies (DLB), and parkinsonism, but pathological examination revealed only Alzheimer’s disease-related findings without evidence of Lewy bodies or prion disease in all cases. All patients demonstrated marked, sustained improvement following steroid treatment, based on clinical, magnetic resonance imaging, and/or electroencephalogram studies. Alzheimer’s disease was not diagnosed in life due to the atypical clinical features, lack of hippocampal atrophy on brain imaging, and a dramatic symptomatic response to steroids. Conclusions: Steroid-responsive encephalopathy is the clinical presentation of some patients with Alzheimer’s disease-related pathology at autopsy, and can be consistent with the clinical diagnoses of parkinsonism, DLB, or CJD disease in life. Keywords: Alzheimer’s disease; Corticosteroids; Dementia; Encephalopathy; Hashimoto’s encephalopathy; Neuropathology. There is growing interest and awareness of the steroid-responsive encephalopathies and the potential treatment benefit that can occur in some patients with these disorders. The pathological findings among patients with steroid-responsive encephalopathies are often unknown to treating clinicians because the condition improves with available treatment. The underlying causes are multiple and can include both vasculitic and nonvasculitic etiologies. In the case of non-vasculitic Conflicts of interest/financial disclosures: Drs Mateen, Drubach, Parisi, Lennon, Kentarci, Jack, Caselli, and Josephs have no conflicts of interest to report. Dr Boeve has received grant support from Myriad Pharmaceuticals and an honorarium from GE Healthcare. Dr Kantarci has received grant support from the National Institutes of Health (K23 AG030935 (NIH/NIA), R01 AG11378 (NIH/NIA) and P50 AG16574 (NIH/NIA)). Address correspondence to Bradley F. Boeve, Department of Neurology, Mayo Clinic 200 1st Street SW, Rochester, Minnesota 55905, USA. (E-mail: bboeve@mayo.edu). c 2012 Psychology Press, an imprint of the Taylor & Francis Group, an Informa business  http://www.psypress.com/neurocase http://dx.doi.org/10.1080/13554794.2010.547503 2 MATEEN ET AL. Downloaded by [69.251.44.160] at 06:35 18 February 2013 TABLE 1 Proposed classification of autoimmune encephalopathies I. NON-VASCULITIC a. Pathogenic antibody specific (e.g.,voltage-gated potassium channel antibodies) i. Paraneoplastic ii. Non-paraneoplastic b. No known pathogenic antibody (but association with seropositivity of some general autoimmune condition exists) (e.g., non-vasculitic autoimmune meningoencephalopathy (NAIM)) i. Thyroid autoimmunity ii. Other autoimmune disorders II. VASCULITIC a. Primary i. Autoimmune b. Secondary i. Autoimmune ii. Infectious III. AMYLOID ANGIOPATHY-ASSOCIATED INFLAMMATORY causes, the additional lack of a pathogen-specific antibody may raise the possibility of non-vasculitic autoimmune meningoencephalopathy or NAIM (Table 1). Clues to the diagnosis of NAIM include an acute or subacute onset, presence of headache, seizures, or status epilepticus, clinical and/or laboratory evidence of autoimmunity, evidence of inflammation on cerebrospinal fluid (CSF) examination, marked abnormalities on electroencephalography (EEG), or some combination of these (Caselli, Boeve, Scheithauer, O’Duffy, & Hunder, 1999; Castillo et al., 2006). In many instances, however, the diagnosis of NAIM is considered only after structural, infectious, paraneoplastic, toxic, and metabolic etiologies have been excluded. High dose corticosteroid treatment often results in complete or near complete resolution of all neurologic signs, symptoms, and EEG abnormalities (Schäuble, Castillo, Boeve, & Westmoreland, 2003). Diagnosis of nonvasculitic steroid-responsive encephalopathies can be particularly challenging in individuals who have a rapidly progressive course accompanied by myoclonus, therefore suggesting Creutzfeldt– Jakob disease (CJD); in older individuals with fluctuations in alertness and cognition, accompanied by visual hallucinations and/or parkinsonism, therefore suggesting dementia with Lewy bodies (DLB); and in those with a relatively young age of onset and prominent behavioral changes and psychosis, therefore suggesting schizophrenia or frontotemporal dementia (FTD). If cerebral angiography reveals findings suggestive of primary central nervous system vasculitis (PCNSV) a trial of high doses corticosteroids, and in some patients, cyclophosphamide administration is warranted. Meningeal/brain biopsy is often considered, but is only rarely performed. In the absence of tissue confirmation, another way to potentially differentiate NAIM from a neurodegenerative, prion, or psychotic disorder is to empirically treat with highdose corticosteroids, as dramatic clinical improvement would be expected with NAIM but not the other conditions. Little histopathologic data exist on the steroidresponsive encephalopathies, and the findings have been variable. Most cases associated with thyroid peroxidase (TPO) or antithyroglobulin antibodies (often termed ‘Hashimoto’s encephalopathy’) have had perivascular inflammation involving veins and venules (Doherty et al., 2002; Nolte, Unbehaun, Sieker, Kloss, & Paulus, 2000), with only a few cases showing true vasculitis involving arteries and arterioles (Duffey, Yee, Reid, & Bridges, 2003; Shibata, Yamamoto, Sunami, Suga, & Yamashita, 1992). In some instances, no distinctive abnormalities have been seen in the meninges or brain parenchyma (Oide et al., 2004; Perrot et al., 2002; Striano et al., 2006). Brain biopsies in cases with NAIM associated with Sjögren’s syndrome have shown perivascular inflammation without true vasculitis (Caselli et al., 1991, 1993, 1999), and one case of NAIM lacking autoantibodies had panencephalitis at autopsy (Josephs, Rubino, & Dickson, 2004). Neuropsychiatric lupus may also present with striking MRI findings without evidence of inflammation at autopsy (Prabhakaran et al., 2005). One of the case reports noted above involved a 77-year-old woman with hypokinesia and rigidity leading to a diagnosis of Parkinson’s disease (PD) (Nolte et al., 2000). At autopsy, leptomeningeal lymphocytic infiltrates were identified in venules with sparse senile plaques and neurofibrillary tangles. The density was too minimal to warrant the pathologic diagnosis of Alzheimer’s disease, and vascular amyloid, nigral degeneration, and Lewy bodies were all absent (Nolte et al., 2000). This is the only published case, to our knowledge, with NAIM who clearly improved with corticosteroids, had other clinical features suggesting PD, and who subsequently had Alzheimer-type changes upon histological examination. We have recently encountered four patients who experienced a steroid-responsive encephalopathy in which autopsy revealed Alzheimer’s disease-related pathology and/or Aβ-related amyloid deposition STEROID-RESPONSIVE ENCEPHALOPATHY WITH AD PATHOLOGY Downloaded by [69.251.44.160] at 06:35 18 February 2013 in the walls of the small cerebral vessels. All were followed longitudinally with a clinically typical course for steroid-responsive encephalopathy and possibly NAIM, yet autopsy revealed Alzheimer’s disease pathology. Inflammatory changes in the meninges, brain parenchyma, and intracranial vessels were absent, and three of these cases exhibited varying degrees of parkinsonism prior to death. Due to the uncertain relationship between a frank autoimmune inflammatory encephalopathy and Alzheimer’s disease (in which inflammatory mechanisms are regarded as integral to the degenerative cascade), we present these cases in the context of the available pertinent literature. CASE SERIES Case 1 A 70-year-old woman had a 5-month history of confusion, cognitive decline, hypersomnolence, new-onset bi-frontal headaches, word blocking, emotional lability, and intermittent dysnomia. She could no longer balance her checkbook or drive her car. Her family described her movements as ‘slow’. She had treated hypothyroidism. Examination revealed constructional apraxia and attentional difficulties (unable to repeat more than 5 numeric digits) with relatively preserved delayed recall. Her upgaze was diminished. There was subtle unilateral decreased arm swing and increased tone. The initial clinical impression was possible DLB. While she met criteria for clinically probable DLB (McKeith et al., 1996), a non-neurodegenerative cause was suspected based on the short course and prominent headaches. Investigations revealed a sedimentation rate of 39 mm/1 h, thyroid stimulating hormone (TSH) mildly elevated at 5.8 mIU/l, and TPO antibodies elevated at 90 IU/ml (Table 2). Lyme serology, RPR, paraneoplastic panel, and other infectious studies were negative. MRI showed parenchymal changes in the right frontal and left occipital regions (Figure 1A, B) with diffuse pial enhancement with gadolinium. Cerebral angiogram was normal. No significant hippocampal atrophy was evident on subsequent MRI scans (Figure 1C); meningeal/brain biopsy was declined. Although the abnormalities seen on neuroimaging were viewed as atypical for NAIM, a diagnosis of possible NAIM led to methylprednisolone 3 (IVMP) treatment. One week after completion, she returned to her cognitive baseline, and the headaches and hypersomnolence resolved. One month later, the MRI showed resolution of the parenchymal and meningeal abnormalities (Figure 1D, E). She was followed annually with clinical examinations, neuropsychological assessments, and MRI scans of the brain (not shown), and was functionally independent for the next 4 years, never requiring additional corticosteroids. Throughout this time, her diagnosis was mild cognitive impairment plus mild parkinsonism, not significant enough to warrant cholinesterase inhibitor or dopaminergic therapy. Multiple microhemorrhagic foci and left frontal superficial siderosis were noted in the gradient recalled echo sequence (Figure 1F). Four years after initial presentation, she experienced a subtle decline in cognition over 5 months, then several TIA-like spells over 3 days, and died suddenly due to a massive cerebral hemorrhage. Autopsy revealed diffuse amyloid angiopathy in the leptomeningeal and parenchymal arterioles, moderate neocortical neuritic plaques, and moderate neurofibrillary tangles in the temporal limbic and neocortical structures (Braak stage V), satisfying NIA-Reagan criteria for high likelihood AD. No evidence of vasculitis or inflammation was present. There were no Lewy bodies or Lewy neurites. Case 2 A 54-year-old former business executive presented with 4 years of progressive hypersomnolence, reclusiveness, and cognitive deficits, marked by prominent memory loss. Her family first noted this change following cosmetic face-lift surgery, when she became unable to recall names and lists. She was easily disoriented, forgot conversations, misplaced objects, and wrote checks for incorrect amounts. Eventually, she was unable to turn on her computer or recognize previously familiar people. A 3-month course of donepezil did not lead to improvement. She had flat affect, hypoproductive speech, mild left upper extremity cogwheeling, and difficulty with every basic task of mental status testing (9/38 on the Kokmen Test of Mental Status, KTMS (Kokmen, Smith, Petersen, Tangalos, & Ivnik, 1991) 5/30 on the Mini-Mental State Examination, MMSE). Autoantibodies were elevated (Table 2). Brain MRI showed moderate atrophy primarily involving the left frontal and posterior temporoparietal cortices without significant hippocampal atrophy 4 MATEEN ET AL. TABLE 2 Summary of clinical and pathological data Downloaded by [69.251.44.160] at 06:35 18 February 2013 Case 1 Case 2 Case 3 Age of onset/sex Presenting signs & symptoms 70F Cognitive impairment, hypersomnolence, bifrontal headache 54F Cognitive impairment, seclusiveness, seizures 67M Cognitive impairment, left hemineglect, left arm and leg choreoathetotic movements, hallucinations Cognitive status STMS 32/38 STMS 9/38 MMSE 5/30 Semi-comatose (mental status testing impossible) Abnormal serum laboratory findings TPO Ab 90 (N<40), TSH 5.8 (N 0.30–5.0 mIU/l) IgM phospholipid Ab 37.9 (no normal range, usually negative) Abnormal CSF findings Protein 55 mg/dL (N<45 mg/dL) EEG findings Dysrhythmia grade 1 generalized, maximal bitemporal ANA 4.1 (N<1.0) RF (25 IU/ml) Ab to ENA 137.3 (N<25 units) U1RNP 152.2 units (N<25.0) ceruloplasmin 52.7 (N 22.9–43.1 mg/dL) Normal except Neuron Specific Enolase 29.1 ng/ml (14–3–3 normal) Dysrhythmia grade 3 with right temporal sharp waves, bilateral TIRDA MRI findings Multiple cortical and subcortical enhancing lesions in the occipital, parietal, and posterior temporal lobes bilaterally, multiple micro hemorrhages and left frontal superficial siderosis 2, 3 1 g IVMP×5 days ApoE genotype Treatment Outcome Cognitive status post-treatment Relapse Case 4 71M Cognitive impairment, behavioral change with anger and emotional lability, somnolence, bowel & bladder incontinence Oriented to person and time, not place. Poor delayed recall TPO Ab 48 (N<40) Thyroxin binding globulin 11 (N 12–26 µg/mL) Protein 65 mg/dL; 7 total nucleated cells (N≤5) Protein 112 mg/dL Dysrhythmia grade 1, asymmetric and maximal over the left temporal area Moderate generalized neocortical atrophy, leukoariaosis Increased cortical T2 signal in right frontal region Dysrhythmia grade 3 with moderately severe diffuse irregularities with excess slow wave activity in the background Mild generalized neocortical atrophy 3, 4 1 g IVMP×5 days NP 1 g IVMP×5 days Complete return to neurologic baseline, mild and intermittent headache STMS 34–37/38 NP 187.5 mg IV DXMS×5 days, given twice 6 months apart Increased verbalization, improved memory and word finding, reduced abulia MMSE 20/30 Near complete return to neurologic baseline Near complete return to neurologic baseline STMS 31/38 STMS 29/38 No Yes Yes Yes STEROID-RESPONSIVE ENCEPHALOPATHY WITH AD PATHOLOGY 5 TABLE 2 (Continued) Age at death Pathologic findings Downloaded by [69.251.44.160] at 06:35 18 February 2013 Braak NFT stage/NIAReagan Case 1 Case 2 Case 3 Case 4 75 Severe diffuse amyloid angiopathy, No evidence of inflammation or vasculitis No Lewy body/Lewy neurite pathology V/high likelihood 55 Severe patchy amyloid angiopathy, No evidence of inflammation or vasculitis No Lewy body/Lewy neurite pathology VI/high likelihood 73 Moderate diffuse amyloid angiopathy, No evidence of inflammation or vasculitis No Lewy body/Lewy neurite pathology IV/intermediate likelihood 75 Mild patchy amyloid angiopathy, No evidence of inflammation or vasculitis No Lewy body/Lewy neurite pathology VI/high likelihood Abbreviations: Ab, antibody; ANA, antinuclear antigen; DXMS, dexamethazone; ENA, extractable nuclear antigens; IVMP, intravenous methylprednisolone; MMSE, Mini-Mental State Examination score; NIA-Reagan, National Institute on Aging-Reagan Institute Criteria; NFT, neurofibrillary tangle; NP, not performed; RF, Rheumatoid Factor; STMS, Short Test of Mental Status score; TIRDA, temporal intermittent rhythmic delta activity; TPO, thyroperoxidase. A B D E C F Figure 1. MRI brain of Case 1. (Figure 2). There was severely reduced uptake in the left frontal, temporal, and parietal cortices on single photon emission computed tomography (SPECT). Given her persistent symptoms, combined with a high suspicion of an autoimmune encephalopathy, she received a trial of dexamethasone. On day 5, her speech was clearer, with less word searching (MMSE 20/30). Her husband remarked on her improved memory and volition, reduced abulia, and lack of word-finding difficulties. She returned home, independent in many but not all activities of daily living (ADLs). Her neuropsychiatric features were almost nonexistent. Three months later, she had insidious cognitive decline, with need for repeat inpatient psychiatric 6 MATEEN ET AL. A B Downloaded by [69.251.44.160] at 06:35 18 February 2013 Figure 2. MRI brain of Case 2. hospitalization by 6 months. She was nearly dependent for all ADLs due to profound memory loss and disorganization. She became seclusive, tearful, agitated, depressed, and expressed suicidal plans. Clonazepam and escitalopram were tried without noticeable benefit. ANA, ENA, and U1RNP remained elevated. Cerebral angiogram and CSF analysis was normal. Dexamethasone for 5 days and then oral prednisone was given. She became more calm and cooperative, but required quetiapine thrice daily and lorazepam, each evening, for agitation. She was dismissed on oral prednisone 60 mg daily. Three months later, she rapidly declined, experiencing medication-refractory seizures, and died despite treatment. Autopsy revealed frequent neocortical neuritic plaques and diffuse neocortical neurofibrillary tangles (Braak stage VI) characteristic of high-likelihood AD. There was no evidence of vasculitis or inflammation and no Lewy bodies or Lewy neurites. Case 3 A 67-year-old male farmer presented with recurrent episodes of encephalopathy associated with subjective fever, frontal headaches, neck stiffness, anorexia, nausea, incontinence, lethargy, and visual hallucinations. He was unable to care for himself. His first two episodes were similar and each lasted less than 1 week. Symptoms spontaneously resolved. The third episode was more severe with subjective left-sided weakness and hemineglect. He was obtunded upon presentation, with eye opening to speech or sternal rub only. He had inappropriate speech and was completely disoriented. (More detailed mental status testing was not possible due to his disorientation and obtundation.) Bizarre, choreoathetotic movements were observed in his left upper extremity with left plantar drift. There was diffuse hyporeflexia with bilateral plantar flexor responses. Extensive work up was unrevealing, including autoimmune panel with TPO antibody titre, HSVPCR, and two cerebral angiograms. MRI showed increased T2 signal on fluid-attenuated inversion recovery (FLAIR) along the right frontoparietal cortical ribbon suggestive of CJD, as well as hazy increased T2 signal in much of the supratentorial white matter (Figure 3A). Right frontal meningeal and brain biopsy was normal. IVMP was given with markedly improved alertness and orientation to month and year, by day 1. He was able to make jokes with his relatives, and continued to slowly improve after 5 days, with resolved hallucinations, choreoathetoid movements, and incontinence. MRI performed 2 weeks after completion of the methylprednisolone trial showed resolution in the T2 signal abnormality, although the hazy white matter signal changes persisted (Figure 3B). He was fully independent by hospital dismissal, and returned to managing his finances again and performing occupational tasks. The MRI changes resolved completely (KTMS 31/28 at 9 months). Over the following 5 years, he experienced less dramatic periods of encephalopathy, reasonably well-managed with oral prednisone. After experiencing a lacunar caudate infarct, with a negative work-up for cardioembolism, he was treated with cyclophosphamide with excellent symptomatic control. Five years after initial presentation, he experienced cognitive decline, visual hallucinations, delusions, and parkinsonism, and was diagnosed with probable DLB. MRI of the brain again showed the hazy increased signal in the cerebral white matter (not shown), and only mild hippocampal atrophy (Figure 3C). He did not benefit from donepezil. His progression continued until death, 1 year later, whereupon neuropathologic examination showed moderate neocortical neuritic plaques and sparse neocortical neurofibrillary tangles (Braak stage IV) characteristic of intermediate likelihood AD, and moderate diffuse amyloid angiopathy. No histopathologic evidence of vasculitis or inflammation was present. There were no Lewy bodies or Lewy neurites. Case 4 A 71-year-old man with a 2-year history of angiogenic myeloid metaplasia had a 6-month STEROID-RESPONSIVE ENCEPHALOPATHY WITH AD PATHOLOGY 7 Downloaded by [69.251.44.160] at 06:35 18 February 2013 A B C Figure 3. MRI brain of Case 3. course of rapidly progressive forgetfulness, behavioral change, agitation, and low-grade headaches following laparoscopic cholecystectomy. He had experienced post-operative delirium, but this had resolved in hospital. After returning home, he slept up to 18 hours daily and had episodes of erratic driving, incoherent babbling, and emotional lability. There was new episodic bowel and bladder incontinence and unstable gait. He was brought to medical attention after he was unable to bathe himself. He was oriented to time and person. He could not remember where he lived, and recalled zero of four objects after one and 5 minutes. There was mild dysmetria. Negative studies included protein 14–3–3, neuron specific enolase, paraneoplastic panel, and brain MRI. Atypical CJD was suspected, but considering an elevation in TPO antibodies (Table 2), he was started on IVMP. There was no change by day 5. He was dismissed to a nursing home on 100 mg daily oral prednisone. Over the following week, he experienced marked cognitive and functional improvements. He was able to feed and bathe himself and the incontinence ceased. He returned home and performed household and farm chores with little difficulty. He began using the microwave, shower, and television remote control properly. Although he reported persistent forgetfulness by 3 weeks post-hospitalization (29/38 KTMS), his overt confusion and headaches resolved. At 9 months, he performed all ADLs, maintained his own finances, and drove a car. Months afterwards, he developed asymmetric parkinsonism, and then increased encephalopathy thought to be associated with progression of his myeloid metaplasia. He died at 30 months after his initial neurologic presentation. Neuropathologic examination showed moderate patchy amyloid angiopathy, frequent neocortical neuritic plaques and diffuse neocortical neurofibrillary tangles (Braak stage VI), all consistent with high likelihood AD, but no evidence of vasculitis, inflammation, or Lewy body pathology. DISCUSSION Herein, we present four cases with the following shared key features: (1) steroid-responsive encephalopathy, (2) unrevealing investigation for rheumatological and paraneoplastic disorders, (3) Alzheimer’s disease-related pathology on brain tissue examination, (4) prominent behavioral change as a key feature in symptomatic improvement and decline, and (5) absence of typical symptoms and imaging features of Alzheimer’s disease. Encephalopathy with steroid responsivity subsequently associated with AD pathology has not been reported to our knowledge. In 1966, Downloaded by [69.251.44.160] at 06:35 18 February 2013 8 MATEEN ET AL. Brain et al. described a case of encephalopathy that ‘waxed and waned for over a year’ in a 48-year-old man who also had Hashimoto’s disease of the thyroid (Brain, Jellinek, & Ball, 1966). Brain tissue was never examined in the originally described patient and his condition did not respond to steroids. Nonetheless, more than 100 subsequent cases of presumed ‘Hashimoto’s encephalopathy’ have been reported in which steroid-responsivity has been considered a defining feature. This has included less than 10 autopsy-based cases. Isolated pathological reports reveal perivascular lymphocytic infiltration, particularly in the walls of small vessels (Castillo et al., 2006; Chong, Rowland, & Utiger, 2003; Duffey et al., 2003; Nolte et al., 2000) without vasculitis, but not in all cases (Striano et al., 2006). Other nonspecific markers than thyroid antibodies occur in a minority of patients including elevated sedimentation rate (Castillo et al., 2006; Chong et al., 2003) C-reactive protein, and ANA (Chong et al., 2003). In 1999, the terms ‘steroid-responsive encephalopathy associated with autoimmune thyroiditis’ (SREAT) and ‘nonvasculitic autoimmune inflammatory meningoencephalitis’ (NAIM) were coined to describe five encephalopathic patients with clinical steroid responsivity (Caselli et al., 1999). The intent of the new terminology was to encompass a wider group of diseases that were ultimately steroid-responsive but could be related to a variety of possible diseases including systemic lupus erythematosus, Sjögren’s syndrome, and eosinophilic syndrome, as well as Hashimoto’s encephalopathy. Other diseases within this categorization could include vasculitis without vasculitic changes on brain biopsy (potentially due to mild or early disease) or autoimmune encephalopathies due to recognized autoantibodies such as voltage-gated potassium-channel antibodies. Response in the five patients initially reported as ‘NAIM’ ranged from modest improvement and gradual resolution over months to complete remittance of symptoms. Four had elevated concentrations of serum autoantibodies, and all had histological evidence of inflammation on biopsy (brain, leptomeningeal, or salivary gland). Later, autopsy of a single case of NAIM revealed panencephalitis without vasculitis (Josephs et al., 2004). A subsequent case of probable NAIM (without autopsy) was reported to mimic CJD (Chong et al., 2003) with steroid-responsive parkinsonian features of rest tremor, shuffling gait, and cogwheel rigidity. However, a pathological case series of NAIM included a majority of steroid-‘nonresponders’ making steroid-responsivity an uncertain defining criterion for NAIM; rather, NAIM is best considered a clinicopathological diagnosis marked quite literally by non-vasculitic meningoencephalitis on tissue examination and/or imaging preceded by a presumed autoimmune encephalopathy in life. It has been proposed that Hashimoto’s encephalopathy represents just one form of NAIM (Caselli et al., 1999). In fact, multiple disease entities show a tendency towards steroid responsivity, but the core features, age predilection, test results, and/or autopsy features have important differences (Table 3). In this series, although all cases would fall under the broad categorization of steroid-responsive encephalopathy, cases 1 and 4 could be considered examples of ‘Hashimoto’s encephalopathy’. These cases revealed a combination of clouded consciousness, cognitive dysfunction, headaches, and high serum concentrations of TPO antibodies (Chong et al., 2003). These same patients (1,4) were once thought to have CJD. Three cases (1,3,4) had clinical features suggesting Lewy body disease, but Lewy bodies were absent. None had sufficient hippocampal atrophy to strongly suspect evolving Alzheimer’s disease, and two had MRI abnormalities that resolved following steroid treatment. There was no evidence of vasculitis or inflammation of any kind on brain biopsy (n = 1), cerebral angiography (n = 2), or autopsy (all 4). The present cases are unique in the existing literature because they document a coincidence of Alzheimer’s disease-related pathology with a clinical condition that is steroid responsive. The number of people with Alzheimer’s disease and amnestic mild cognitive impairment who experience benefit from steroids is unknown to the authors, but we postulate that β-amyloid deposition in the brain can rarely be responsible for an inflammatory encephalopathic condition. Alternatively, an inflammatory condition in the brain may prompt the deposition of Aβ. Both theories remain somewhat speculative. Therefore, steroid responsivity of the symptoms in these patients may be either coincidental or related to the inflammation-neurodegeneration cascade that has been postulated to exist for β-amyloid deposition in the brain (Esiri & Wilcock, 1986; Ginsberg, Geddes, & Valentine, 1988; Mandybur & Balko, 1992; Sarazin et al., 2002; Sudo & Tashiro, 1998). In 2005, Scolding et al. introduced the term ‘Aβrelated angiopathy’ (ABRA) for the rare condition Downloaded by [69.251.44.160] at 06:35 18 February 2013 TABLE 3 Comparisons between steroid-responsive encephalopathies and the four cases in this report SREAT1 PACNS2 Varies – mostly in middle-aged to elderly adults Core features Encephalopathy often accompanied by stroke-like episodes, psychosis, myoclonus, seizures PLUS Elevated thyroid antibodies (see below) Antibody associations None Antithyroid microsomal, Antithyroid peroxidase Antithyroglobulin Usually normal, or Usually abnormal, with elevated only mildly protein and elevated protein lymphocytic pleocytosis Usually normal, or Confluent and multifocal white only nonspecific matter lesions, age-related CSF findings MRI findings Mostly in middle-aged to elderly adults Acute demyelinating Encephalomyelitis5 Neuropsychiatric lupus4 Varies – Both adults and children Encephalopathy often Encephalopathy accompanied by stroke-like often episodes, psychosis, movement accompanied by disorder, headache PLUS multifocal Elevated ANA May have frank neurologic signs vasculitis, microangiopathy, and symptoms ± arterial thrombosis and infarcts headache PLUS Amyloid angiopathy PLUS Patchy inflammation of the small and medium-sized cerebral and leptomeningeal arteries None Anti-neuronal Anti-phospholipid Antiribosomal-P Most common in children & adolescents, F>M Our cases 54–71 years Encephalopathy Encephalopathy accompanied by accompanied by florid white matter changes on varying degrees of MRI Usually monophasic behavioral changes, inflammatory demyelinating somnolence, headache, disease (can be recurrent); often movement disorder w/ antecedent febrile prodrome, viral infection, or vaccination None No consistent profile Normal to mildly elevated Usually abnormal with elevated Variably abnormal, Often but not always abnormal, protein protein, lymphocytic pleocytosis, with elevated protein and with elevated and increased oligoclonal bands lymphocytic pleocytosis protein and lymphocytic pleocytosis Focal parenchymal Variable, but usually Patchy gray matter hyperintensities Variable lesions, small or large, changes (n = 2). multifocal and asymmetric not localized to a major abnormal with Resolving white matter distribution, predominantly cerebrovascular territory. confluent and STEROID-RESPONSIVE ENCEPHALOPATHY WITH AD PATHOLOGY Varies – mostly in middle-aged adults but can occur in children Encephalopathy often accompanied by multifocal neurologic signs and symptoms, and headache PLUS Patchy inflammation of the small and medium-sized cerebral and leptomeningeal arteries Age Mixed amyloid angiopathy with angiitis3 9 Downloaded by [69.251.44.160] at 06:35 18 February 2013 changes Diffuse increased signal in white matter is seen rarely EEG Steroid responsivity? Biopsy/Autopsy findings Almost always abnormal, with slowing ± epileptiform activity Yes (by definition) IVIG or PLEX sometimes needed Often normal Lymphocytic infiltration of small vessels, perivascular cuffs of lymphocytic cells rarely reported Very few case reports PACNS2 Neuropsychiatric lupus4 Punctate, T2-high signal, transient periventricular and subcortical white matter changes May show accompanying venous sinus thrombosis, brain atrophy, infarction, myelopathy. May be normal. Almost always abnormal, with slowing ± epileptiform activity sometimes with space occupying lesions mimicking tumor multifocal white matter lesions, sometimes with space occupying lesions mimicking tumor Often abnormal, with slowing Often abnormal, with slowing Usually Usually Usually Cyclophosphamide often needed Cyclophosphamide often needed Cyclophosphamide sometimes needed Mixed inflammatory cell infiltrate in the small and medium sized vessels with fibrinoid necrosis in the leptomeninges and/or cerebral cortex Amyloid angiopathy PLUS Mixed inflammatory cell infiltrate in the small and medium sized vessels with fibrinoid necrosis in the leptomeninges and/or cerebral cortex Variable – normal to lymphocytic infiltration or pervascular cuffing to frank vasculitis and necrosis Acute demyelinating Encephalomyelitis5 affecting white matter, many variations exist including periventricular lesions (in 60%) and initially N scans Our cases changes on T2 FLAIR (n = 1). Pial enhancement (n = 1) Atrophy No specific findings reported Moderate slowing Usually Yes – in all 4 cases Cyclophosphamide needed in 1 case Sleeve-like demyelination in hypercellular areas of lymphocytic perivenous inflammation Note: 1 See Duffey et al. (2006), Brain et al. (1966), and Paulus and Nolte (2003). 2 See Scolding et al. (2005), Kadkhodayan et al. (2004), Kumar, Wijdicks, Brown, Parisi, and Hammond (1997), and Riemer et al. (1997). 3 See Ginsberg et al. (1988), Mandybur and Balko (1992), Sudo and Tashiro (1998), and Scolding et al. (2005). 4 See Graham and Jan (2003), Hanley (2005), Trysberg and Tarkowski (2004), and West (2003). 5 See Schwarz, Mohr, Knauth, Wildemann, and Storch-Hagenlocher (2001), Tan et al. (2004), Wingerchuk (2006), and Wingerchuk (2003). Amyloid angiopathy PLUS Neuritic plaques and neurofibrillary tangles characteristic of Alzheimer’s disease NO evidence of inflammation or vasculitis MATEEN ET AL. SREAT1 Mixed amyloid angiopathy with angiitis3 10 TABLE 3 (Continued) Downloaded by [69.251.44.160] at 06:35 18 February 2013 STEROID-RESPONSIVE ENCEPHALOPATHY WITH AD PATHOLOGY in which (Aβ) is deposited in the small cerebral vessels (Scolding, Joseph, Kirby, Mazanti, & Gray, 2005). Nine histology-positive cases of ABRA were reported (median age 72 years) and three showed improvement following immunosuppression. The pathological findings in our cases fit most closely with ABRA in three of the presented cases. ABRA is consistent with a normal cerebral angiogram (Kadkhodayan, Alreshaid, Moran, Cross III, & Powers, 2004) as occurred in two of our cases and does not imply the presence of a larger vessel vasculitis. In vitro Aβ is known to induce an inflammatory response in endothelial cells (Furlan, Brambilla, Sanvito, Roccatagliata, & Olivieri, 2003; Weiner & Selkoe, 2002) and can induce an interferongamma dependent meningoencephalitis in a mouse model of AD. Therefore, Aβ may induce an innate inflammatory response once it is deposited in the vasculature of the small vessels with consequent activation of astrocytes, microglia and complement, cyotokine release, and free radical formation (Weiner & Selkoe, 2002). Conversely, an inflammatory reaction may be responsible for the deposition of Aβ, and anitflammatory treatment may hypothetically quell such deposition (Hoffman Snyder, Mishark, Caviness, Drazkowski, & Caselli, 2006; Weiner & Selkoe, 2002). Identification of the subset of patients with AD who harbour a vigorous inflammatory response to Aβ may soon prove crucial. Approximately 6% of participants developed meningoencephalitis in the clinical trial of AN-1792 -parenteral Aβ synthetic peptide ‘vaccination’ for AD (Furlan et al., 2003), necessitating discontinuation of the phase II trial. Attempts to link the presence or titer of Aβ antibodies were unhelpful in identifying the few patients who developed a self-limited inflammatory reaction (Scolding et al., 2005). Thus, an indeterminate factor(s) might be responsible in some individuals who would presumably not be well-suited for Aβ-vaccination. Gathering characteristics of these patients could be a first step in identifying this important subgroup. Finally, it is possible that there is an altogether different cause of the encephalopathies reported above. We cannot rule out that the AD-pathology is coincidental given its high prevalence in the aging population. Our cases differ from previously reported ABRA in that all of the patients in the present series had evidence of elevated autoantibodies. It was precisely these antibodies, of otherwise dubious significance, that led to steroid 11 therapy and eventual improvement of symptoms. 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