Postmortem Histopathologic Analysis of Neurosyphilis: A Report of 3 Cases With Clinicopathologic Correlations

Postmortem Histopathologic Analysis of Neurosyphilis: A Report of 3 Cases With Clinicopathologic... Abstract Neurosyphilis occurs in the late stage of systemic syphilis infection; early diagnosis and treatment are crucial to the prognosis. We review 3 autopsy cases with different subtypes of neurosyphilis, that is cases with meningovascular, general paresis, and a combination of the 2, respectively. We investigated the gross morphology and leptomeninges, vessels, cerebral cortex, white matter, brainstem, cerebellum, olfactory bulb and spinal cord microscopically. We found that meningovascular inflammation exists in both early and late phases of neurosyphilis, not only in the meningovascular subtype. Vertebrobasilar artery involvement is common and infarcts of the areas perfused by these arteries in young patient highly suggests neurosyphilis. Damage to the cortical architecture and neuropil is the main mechanism of dementia in general paresis and temporal lobe may not firstly be involved as many other diseases with dementia. Early involvement of olfactory bulbs may help in the early diagnosis of the disease. Our findings indicate that many specific features may help in clinical practice and that further research is needed to clarify the mechanisms. Basilar artery, General paresis, Meningovascular, Neuropil, Neurosyphilis INTRODUCTION Syphilis is an infectious disease caused by the spirochete Treponema pallidum. Approximately 4%–10% of patients in the late stage of systemic syphilis infection will have CNS involvement, that is neurosyphilis (1). The subtypes of neurosyphilis include asymptomatic, meningeal, meningovascular, general paresis, tabes dorsalis, gumma, and optic nerve atrophy (2). When there is extensive involvement of the CNS, the clinical spectrum is so complex that early diagnosis is often difficult. Serum and CSF antibody studies are essential for the clinical diagnosis. The rapid plasma reagin test is helpful for screening and therapeutic monitoring because the titer decreases after therapy (3). The T. pallidum particle agglutination and fluorescent treponemal antibody absorption tests are more specific for definitive diagnosis (3). Early diagnosis and antiluetic therapy are very important for improving prognosis. Meningovascular neurosyphilis and general paresis are representatives of early and late stage neurosyphilis, respectively, but they can overlap in many patients. Clinical manifestations of the early stage include headache, hemiplegia, cranial nerve palsy and signs of meningitis as well as cerebral infarction whereas progressive dementia with or without psychological and behavior disorders has been the key symptom of the late stage (4, 5). Microscopically, meningovascular neurosyphilis is characterized by lymphocytic infiltration of leptomeninges with fibrous organization, arteritis, and vascular occlusion as well as consequent infarcts. Cerebral cortical atrophy, disrupted neuropil, neuronal loss, astrocyte proliferation, and activated microglia are typical features of general paresis (6). Here, we describe postmortem findings in 3 patients with neurosyphilis to analyze clinicopathological relationships, and with the aim of assisting in the early diagnosis and treatment of the disease in the modern era. MATERIALS AND METHODS Postmortem examinations were performed 24 hours after death and were limited to the brain and spinal cord. Gross neuropathological examinations were performed after 1 month of 10% buffered formalin fixation on coronal sections of the cerebral hemisphere and sections of the cerebellum and brainstem cut perpendicular to the long axis. Large arteries in the circle of Willis were separated. For light microscopy, samples were embedded in paraffin and 10-μm-thick sections were stained with hematoxylin and eosin (H&E). The slices came from the optic chiasm, olfactory bulb, frontal, lateral temporal, occipital, parietal, insular cortex, hippocampus, basal ganglia, cerebellum, midbrain, pons, medulla, cervical spinal cord, and basilar artery. Additional stains used included Luxol fast blue, Weil’s, and Nissl stains; immunohistochemistry was performed in a Ventana automated stainer, using an avidin-biotin complex, peroxidase-based method with the following polyclonal antibodies: anti-CD3 (1/100, Leica, Wetzlar, Germany), and anti-CD20 (1/200, Leica), anti-CD138 (1/100, ZSGB-Bio, Beijing, China), anti-CD68 (1/50, Dako, Glostrup, Denmark). Warthin-Starry stain was used in case 3 for identification of spirochetes. RESULTS Clinical Observations Three neurosyphilis cases (all males) were admitted to the Neurological Department of Peking Union Medical College Hospital. All of them were middle aged and had had untreated syphilis for many years. All of them had unprotected sexual intercourse with prostitutes. Although they all progressed rapidly to death, disease onset was acute or subacute (Table 1). TABLE 1. Epidemiological Data and Disease Progression Case  Sex  Age at Death (years)  Onset  Course (time after onset to death)  Systemic Syphilis History (years)  1  Male  56  Acute  9 days  38  2  Male  50  Subacute  2 months  10  3  Male  42  Subacute  45 days*  10  Case  Sex  Age at Death (years)  Onset  Course (time after onset to death)  Systemic Syphilis History (years)  1  Male  56  Acute  9 days  38  2  Male  50  Subacute  2 months  10  3  Male  42  Subacute  45 days*  10  * Respiratory failure due to pneumocystis carinii infection. The clinical and laboratory results are summarized in Table 2. Case 1 had an acute progression with vertigo, dysphagia, and right hemianesthesia. Physical examination showed left central facial and tongue palsy, loss of pharyngeal reflex, right hemianesthesia, and loss of right abdominal wall and cremasteric reflexes. Case 2 had shown 2 months of psychosis and aggressive behavior. He had cognitive decline with no focal neurologic signs on physical examination. Case 3 had progressive right hemiplegia with diplopia. Physical examination showed cognitive decline with a Mini-Mental State Examination score of 25 and Montreal Cognitive Assessment score of 22. He also had a right central facial and tongue palsy, right hemiplegia and positive right Babinski and Chaddock signs. TABLE 2. Clinical Manifestations and Laboratory Results Case  Symptoms  Physical Findings  Syphilis Tests (RPR and TPPA)  CSF Analysis  Neuroimaging  1  Vertigo, dysphagia, hemi-anesthesia  L central facial palsy, R hemi-anesthesia  Both serum and CSF positive  ND  ND  2  Psychosis, aggressive  Cognitive decline, no focal signs  Both serum and CSF positive  Lymphocytes: 12×106/L; protein: 0.74g/L  Normal  3  Hemiplegia, diplopia, cognition decline  Cognitive decline, R hemiplegia, R facial palsy, positive R Babinski sign  Both serum and CSF positive*  Lymphocytes: 28×106/L, protein: 0.93 g/L  L midbrain infarct, basilar artery stenosis  Case  Symptoms  Physical Findings  Syphilis Tests (RPR and TPPA)  CSF Analysis  Neuroimaging  1  Vertigo, dysphagia, hemi-anesthesia  L central facial palsy, R hemi-anesthesia  Both serum and CSF positive  ND  ND  2  Psychosis, aggressive  Cognitive decline, no focal signs  Both serum and CSF positive  Lymphocytes: 12×106/L; protein: 0.74g/L  Normal  3  Hemiplegia, diplopia, cognition decline  Cognitive decline, R hemiplegia, R facial palsy, positive R Babinski sign  Both serum and CSF positive*  Lymphocytes: 28×106/L, protein: 0.93 g/L  L midbrain infarct, basilar artery stenosis  * Serum HIV antibody positive. ND, not done; L, left; R, right. In each patient, both the serum and CSF rapid plasma reagin and T. pallidum particle agglutination tests were positive, with positive serum HIV antibody in case 3; HIV testing was negative in the other 2 patients. The CD4 count in case 3 was 68/µl. CSF lymphocytosis and elevated protein level as well as artery stenosis were also seen, but not in all of them. Neuroimaging of case 3 showed extensive basilar meningeal enhancement without ventricle enlargement. The clinical diagnoses were: brainstem infarcts caused by syphilitic arteritis, general paresis, brainstem infarction caused by syphilitic arteritis and general paresis in cases 1–3, respectively. Cases 2 and 3 were given intravenous penicillin treatment for 2 weeks whereas case 1 was not treated. Both case 1 and 2 developed aspiration pneumonia and died from respiratory failure. Case 3 also died from an acute respiratory failure with extensive interstitial involvement with suspected pneumocystis pneumonia but without evidence. Neuropathology Gross neuropathological examination results are summarized in Table 3. There was no edema, atrophy, herniation of the brain, or hemorrhage on brain surfaces. Adhesion and thickening of leptomeninges around the brainstem and the circle of Willis was found in case 3. No lesions were found on the coronal sections of cerebral hemisphere, cerebellum, and spinal cord; necrosis in the brainstem and midbrain were identified in case 1 and 3, respectively. Basilar artery stenosis of case 1 and 3 were also seen. TABLE 3. Macroscopic Neuropathology Case  Weight of Brain (g)  Atrophy or Ventricle Enlargement  Herniation  Leptomeningeal Adhesion and Thickening  Vascular Changes  Lesions on Coronal Sections  1  1100  No  No  Not obvious  Basilar artery stenosis  Necrosis in brain stem  2  1250  No  No  No  No  No  3  1360  No  No  Around brain stem  Basilar artery stenosis  Necrosis in midbrain  Case  Weight of Brain (g)  Atrophy or Ventricle Enlargement  Herniation  Leptomeningeal Adhesion and Thickening  Vascular Changes  Lesions on Coronal Sections  1  1100  No  No  Not obvious  Basilar artery stenosis  Necrosis in brain stem  2  1250  No  No  No  No  No  3  1360  No  No  Around brain stem  Basilar artery stenosis  Necrosis in midbrain  On microscopic examination, the 3 cases showed widespread leptomeningitis with lymphocytes and macrophages (Figs. 1A, 2A, 3C). Microvascular proliferation, congestion, and perivascular inflammation were present in all through the leptomeninges, cortex, and white matter; there was also perivascular hemosiderin deposition (Figs. 2B, 3D). The cortex lamination and neuropil architecture were relatively preserved in case 1 (Fig. 1B), whereas they appeared markedly disrupted in case 2 and 3, particularly in the frontal lobe cortex (Figs. 2C, 3E). Cortical architecture in temporal lobes was relatively intact (Fig. 2D). Scattered neuron loss, neuron swelling, and ghost formation were found in case 1. In cases 2 and 3, there was marked and widespread neuron loss with and apparent microvascular hyperplasia (Fig. 2E). Activated and rod-like microglia as well as astrocyte proliferation were easily seen; some of the former surrounded neurons (Fig. 1C). Scattered CD3-, CD20-, and CD138-positive cells were seen. No demyelination or axon necrosis was seen in white matter but there was some myelin swelling. Hippocampal structures were nearly normal in all cases (Figs. 1D, 2F). Other than inflammation in the leptomeninges, the cerebellum, and spinal cord were intact (Figs. 1E, 3F). The walls of the basilar artery were thickened, infiltrated by lymphocytes and showed disruption of elastin layer in cases 1 and 3 (Figs. 1F, 3G). FIGURE 1. View largeDownload slide Case 1. (A) Thickened leptomeninges infiltrated by lymphocytes and macrophages; the vessels are congested (H&E. ×40). (B) Frontal cortex lamination is intact (Nissl stain, ×40). (C) Neurons are surrounded by increased microglia (H&E, ×100). (D) The hippocampus appears normal (Nissl, ×40). (E) Normal spinal cord with leptomeningeal inflammation (H&E, ×40). (F) Basilar artery is thickened with lymphocytes infiltrating the wall (H&E, ×40). (G) Leptomeninges over the optic chiasm also show inflammatory cell infiltrates (H&E, ×40). (H, I) Small infarcts in the pons (H, H&E, ×40; I, Weil’s method, ×40). (J) Acute (estimated 1–2 weeks), infarct (right side of field) in the medulla oblongata (H&E, ×40). FIGURE 1. View largeDownload slide Case 1. (A) Thickened leptomeninges infiltrated by lymphocytes and macrophages; the vessels are congested (H&E. ×40). (B) Frontal cortex lamination is intact (Nissl stain, ×40). (C) Neurons are surrounded by increased microglia (H&E, ×100). (D) The hippocampus appears normal (Nissl, ×40). (E) Normal spinal cord with leptomeningeal inflammation (H&E, ×40). (F) Basilar artery is thickened with lymphocytes infiltrating the wall (H&E, ×40). (G) Leptomeninges over the optic chiasm also show inflammatory cell infiltrates (H&E, ×40). (H, I) Small infarcts in the pons (H, H&E, ×40; I, Weil’s method, ×40). (J) Acute (estimated 1–2 weeks), infarct (right side of field) in the medulla oblongata (H&E, ×40). FIGURE 2. View largeDownload slide Case 2. (A) Thickened leptomeninges infiltrated by lymphocytes and macrophages (H&E, ×100). (B) Perivascular mononuclear cell inflammation with hemosiderin deposition (H&E, ×400). (C) Architecture of frontal lobe cortex appears disturbed with congested vessels (H&E, ×40). (D) Cortical architecture in the temporal lobe appears relatively preserved (Nissl, ×40). (E) Neurons appear decreased and there appears to be an increase in the microvasculature (H&E, ×100). (F) The hippocampus is intact (Nissl, ×40). FIGURE 2. View largeDownload slide Case 2. (A) Thickened leptomeninges infiltrated by lymphocytes and macrophages (H&E, ×100). (B) Perivascular mononuclear cell inflammation with hemosiderin deposition (H&E, ×400). (C) Architecture of frontal lobe cortex appears disturbed with congested vessels (H&E, ×40). (D) Cortical architecture in the temporal lobe appears relatively preserved (Nissl, ×40). (E) Neurons appear decreased and there appears to be an increase in the microvasculature (H&E, ×100). (F) The hippocampus is intact (Nissl, ×40). FIGURE 3. View largeDownload slide Case 3. (A) Contrast MRI shows enhancement of basilar leptomeninges. (B) Adhesion and thickening of leptomeninges around the brainstem and circle of Willis. (C) Thickened leptomeninges infiltrated by lymphocytes and macrophages (H&E, ×40). (D) Congested vessels with mononuclear cell infiltrates (H&E, ×400). (E) Neuropil dyslamination of frontal cortex and prominent microvessels (H&E, ×40). (F) Meningeal and perivascular inflammation adjacent to a spinal nerve root (H&E, ×40). (G) Intimal thickening and disruption of the elastic layer in the basilar artery (Elastic van Gieson stain, ×40). (H) A subacute infarct in the midbrain (Luxol fast blue-hematoxylin, ×40). (I, J) Disturbance of the left olfactory bulb with microglia infiltration (I, H&E, ×40; J, anti-CD68 immunohistochemistry, ×40). (K, L) Spirochetes (arrows), in the frontal lobe parenchyma. Boxed area in K is shown at higher power in L (Warthin-Starry; K, ×40; L, ×1000). FIGURE 3. View largeDownload slide Case 3. (A) Contrast MRI shows enhancement of basilar leptomeninges. (B) Adhesion and thickening of leptomeninges around the brainstem and circle of Willis. (C) Thickened leptomeninges infiltrated by lymphocytes and macrophages (H&E, ×40). (D) Congested vessels with mononuclear cell infiltrates (H&E, ×400). (E) Neuropil dyslamination of frontal cortex and prominent microvessels (H&E, ×40). (F) Meningeal and perivascular inflammation adjacent to a spinal nerve root (H&E, ×40). (G) Intimal thickening and disruption of the elastic layer in the basilar artery (Elastic van Gieson stain, ×40). (H) A subacute infarct in the midbrain (Luxol fast blue-hematoxylin, ×40). (I, J) Disturbance of the left olfactory bulb with microglia infiltration (I, H&E, ×40; J, anti-CD68 immunohistochemistry, ×40). (K, L) Spirochetes (arrows), in the frontal lobe parenchyma. Boxed area in K is shown at higher power in L (Warthin-Starry; K, ×40; L, ×1000). In case 1, the leptomeninges on over the optic chiasm were also infiltrated by inflammatory cells (Fig. 1G). Myelin swelling and microglia infiltration were seen in the parenchyma. Small acute infarcts were seen in the pons and medulla oblongata (Fig. 1H, I, J). Additionally, there was a focal subacute infarct in the midbrain in case 3 (Fig. 3H). Disturbance of normal structure and apparently activated microglia were seen in the left olfactory bulb (Fig. 3I, J). Warthin-Starry stains were done for spirochetes; this was negative in case 2 but in case 3, there were spirochetes in frontal lobe cortex (Fig. 3K, L). The microscopic features are summarized in Table 4. TABLE 4. Microscopic Neuropathology Case  Meningitis  Vasculitis  Neuron Loss  Neuropil Damage  Microglial Activation  White Matter Demyelination  Pathological Diagnosis  1  Yes  Yes  Scattered  No  Yes  No  Meningovascular neurosyphilis  2  Yes  Yes  Yes  Yes  Yes  No  General paresis  3  Yes  Yes  Yes  Yes  Yes  No  Meningovascular neurosyphilis and general paresis  Case  Meningitis  Vasculitis  Neuron Loss  Neuropil Damage  Microglial Activation  White Matter Demyelination  Pathological Diagnosis  1  Yes  Yes  Scattered  No  Yes  No  Meningovascular neurosyphilis  2  Yes  Yes  Yes  Yes  Yes  No  General paresis  3  Yes  Yes  Yes  Yes  Yes  No  Meningovascular neurosyphilis and general paresis  DISCUSSION Although the cases had different clinical symptoms and different subtypes, we found identical microscopic features, that is extensive inflammation of the meninges at all levels and surrounding microvessels. Basilar meningitis was more evident grossly, suggesting that it was an area prone to involvement. The infiltrates included lymphocytes; although thickened, the leptomeningeal involvement was usually not evident by enhanced MRI. Vessels in the cortex were often congested and infiltrated by lymphocytes and macrophages; thickened walls and perivascular hemosiderin deposition implied microbleeding. Meningovascular involvement has been considered the early manifestation of neurosyphilis but it can accompany with many subtypes (6). Our results support this and we believe that meningovascular infiltration exists even in asymptomatic neurosyphilis. Therefore, MRI with higher resolution and more sensitive to perivascular bleeding may help to identify early CNS involvement in patients with systemic syphilis. The 3 patients had a history of syphilis or unsafe sexual behavior >10 years prior to death. The onset of neurological symptoms was later. It has been considered that meningeal and meningovascular neurosyphilis usually appear ∼2 years after infection whereas general paresis usually 10 years or more later. However, with the wide use of antibiotics and, more importantly, the combination of HIV infection may change the course of the disease. Indeed, HIV can change the natural history of syphilis and accelerate the progression (7). Secondly, recurrent syphilis infection is common in patients with HIV. Therefore, recognition of early neurological symptoms and CSF examination are crucial to the diagnosis of CNS involvement in patients with syphilis. Both cases with meningovascular lesions had brainstem infarcts and we found evidence of vasculitis of the basilar artery. Presumably, inflammation of the vascular wall caused disruption of intima, necrosis, and fibrosis of adventitia and stenosis of the lumen, which resulted in thrombosis and cerebral infarction. It has been reported that medium-sized and large arteries are more commonly involved in neurosyphilis and that infarcts of the middle cerebral and vertebrobasilar artery distributions result (8, 9). In addition to the size of these arteries, we think basilar meningitis also may predispose to basilar artery involvement. Thus, neurosyphilis must be emphasized as a cause of vertebrobasilar infarcts in young patients without other risk factors in clinical practice (9, 10). Two of our cases had cognitive decline with or without behavioral or psychological symptoms. Microscopically, we observed damage of cortical architecture, neuron loss, infiltration of lymphocytes and activated microglia, and gliosis, which support the diagnosis of general paresis (6). However, cerebral atrophy was not obvious macroscopically, probably due to the short courses of CNS involvement. The patient without dementia had relatively normal cortical structures, which further supported the opinion that neuronal loss and neuropil damage were the mechanism of cognitive decline in the others. We also suggest the disturbance of connections between neurons, or neuropil by activated microglia and gliosis participates in the pathogenesis. Lymphocytosis was not as obvious as microglial activation, indicating that the latter is an important feature of neurosyphilis, although it is more often identified only by postmortem examination. Neuronal loss and neurofibrillary tangles in limbic area and temporal lobe are early neuropathologic changes of Alzheimer disease (AD) (11). Hippocampal sclerosis may coexist with AD pathology, and was the main pathologic changes in the oldest old, which was defined as pure hippocampus sclerosis dementia (12, 13). Neurosyphilis is a great mimicker and it has been reported that neurosyphilis can mimic early onset AD with bilateral hippocampal atrophy (14). However, in our cases, the neuropil of the cortex and morphology of neurons in temporal lobe were relatively preserved, that is better than in the frontal lobes. Moreover, the hippocampi were normal, that is without atrophy, hippocampal sclerosis, or gliosis. On the other hand, personality changes and depression, which were typical symptoms of frontal lobe damage, were obvious in our cases. Therefore, we think that although temporal lobe involvement is apparent in neurosyphilis and that later spread to the whole brain is inevitable, symptoms of frontal lobe involvement may appear earlier. Further understanding of the disease progression is necessary for early diagnosis. Olfactory loss and hyposmia accompany aging and neurodegenerative diseases. Microscopically, mitral cell loss and ectopic glomeruli formation alter the normal synaptic organization of olfactory bulb in aging, as well as early amyloid deposition in AD (15). A MRI study also found early involvement of olfactory bulb and tract in AD, suggesting a method of early diagnosis and recognition of the disease (16). In case 3, we also found structural damage and microglial infiltration of the olfactory bulb. Thus, olfactory involvement may be an early manifestation of neurosyphilis in systemic syphilis patients. In conclusion, our autopsy findings further confirm the neuropathologic features of neurosyphilis. We verified the wide distribution of meningovascular inflammation in different subtypes of neurosyphilis and the common involvement of vertebrobasilar arteries. We also tried to identify some early manifestations of the disease based on the neuropathologic changes that would assist early diagnosis; however, we only raised hypotheses based on the morphologic analysis. Large scale studies and animal research is needed for further verification and exploration of mechanisms. In any case, clinicians should be aware of the pathological spectrum of neurosyphilis and attempt early diagnosis of the treatable disease in clinical practice. REFERENCES 1 Conde-Sendín MA, Amela-Peris R, Aladro-Benito Yet al.  , Current clinical spectrum of neurosyphilis in immunocompetent patients. Eur Neurol  2004; 52: 29– 35 Google Scholar CrossRef Search ADS PubMed  2 Conde-Sendín MA, Hernández-Fleta JL, Cárdenes-Santana MAet al.  , Neurosyphilis: Forms of presentation and clinical management. Rev Neurol  2002; 35: 380– 6 Google Scholar PubMed  3 Larsen SA, Steiner BM, Rudolph AH. Laboratory diagnosis and interpretation of tests for syphilis. Clin Microbiol Rev  1995; 8: 1– 21 Google Scholar PubMed  4 Zhang HL, Lin LR, Liu GLet al.  , Clinical spectrum of neurosyphilis among HIV-negative patients in the modern era. Dermatology  2013; 226: 148– 56 http://dx.doi.org/10.1159/000347109 Google Scholar CrossRef Search ADS PubMed  5 Yu Y, Wei M, Huang Yet al.  , Clinical presentation and imaging of general paresis due to neurosyphilis in patients negative for human immunodeficiency virus. J Clin Neurosci  2010; 17: 308– 10 http://dx.doi.org/10.1016/j.jocn.2009.07.092 Google Scholar CrossRef Search ADS PubMed  6 Scaravilli F, Esiri M, Sharer Let al.  , Infections of the central nervous system. In: Gray F, De Girolami U, Poirier J, eds. Escourolle & Poirier Manual of Basic Neuropathology.  Chapter 5. Philadelphia: Butterworth-Heinemann 2004; 120– 22 7 Lynn WA, Lightman S. Syphilis and HIV: A dangerous combination. Lancet Infect Dis  2004; 4: 456– 66 http://dx.doi.org/10.1016/S1473-3099(04)01061-8 Google Scholar CrossRef Search ADS PubMed  8 Holmes MD, Brant-Zawadzki MM, Simon RP. Clinical features of meningovascular syphilis. Neurology  1984; 34: 553– 6 http://dx.doi.org/10.1212/WNL.34.4.553 Google Scholar CrossRef Search ADS PubMed  9 Feng W, Caplan M, Matheus MGet al.  , Meningovascular syphilis with fatal vertebrobasilar occlusion. Am J Med Sci  2009; 338: 169– 71 http://dx.doi.org/10.1097/MAJ.0b013e3181a40b81 Google Scholar CrossRef Search ADS PubMed  10 Morgello S, Laufer H. Quaternary neurosyphilis in a Haitian man with human immunodeficiency virus infection. Hum Pathol  1989; 20: 808– 11 http://dx.doi.org/10.1016/0046-8177(89)90078-6 Google Scholar CrossRef Search ADS PubMed  11 Hyman BT, Phelps CH, Beach TGet al.  , National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement  2012; 8: 1– 13 Google Scholar CrossRef Search ADS PubMed  12 Zarow C, Weiner MW, Ellis WGet al.  , Prevalence, laterality, and comorbidity of hippocampal sclerosis in an autopsy sample. Brain Behav  2012; 2: 435– 42 http://dx.doi.org/10.1002/brb3.66 Google Scholar CrossRef Search ADS PubMed  13 Nelson PT, Schmitt FA, Lin Yet al.  , Hippocampal sclerosis in advanced age: Clinical and pathological features. Brain  2011; 134: 1506– 18 http://dx.doi.org/10.1093/brain/awr053 Google Scholar CrossRef Search ADS PubMed  14 Mehrabian S, Raycheva M, Traykova Met al.  , Neurosyphilis with dementia and bilateral hippocampal atrophy on brain magnetic resonance imaging. BMC Neurol  2012; 12: 96 http://dx.doi.org/10.1186/1471-2377-12-96 Google Scholar CrossRef Search ADS PubMed  15 Kovács T. Mechanisms of olfactory dysfunction in aging and neurodegenerative disorders. Ageing Res Rev  2004; 3: 215– 32 Google Scholar CrossRef Search ADS PubMed  16 Thomann PA, Dos Santos V, Toro Pet al.  , Reduced olfactory bulb and tract volume in early Alzheimer’s disease–a MRI study. Neurobiol Aging  2009; 30: 838– 41 Google Scholar CrossRef Search ADS PubMed  © 2018 American Association of Neuropathologists, Inc. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Neuropathology & Experimental Neurology Oxford University Press

Postmortem Histopathologic Analysis of Neurosyphilis: A Report of 3 Cases With Clinicopathologic Correlations

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Abstract

Abstract Neurosyphilis occurs in the late stage of systemic syphilis infection; early diagnosis and treatment are crucial to the prognosis. We review 3 autopsy cases with different subtypes of neurosyphilis, that is cases with meningovascular, general paresis, and a combination of the 2, respectively. We investigated the gross morphology and leptomeninges, vessels, cerebral cortex, white matter, brainstem, cerebellum, olfactory bulb and spinal cord microscopically. We found that meningovascular inflammation exists in both early and late phases of neurosyphilis, not only in the meningovascular subtype. Vertebrobasilar artery involvement is common and infarcts of the areas perfused by these arteries in young patient highly suggests neurosyphilis. Damage to the cortical architecture and neuropil is the main mechanism of dementia in general paresis and temporal lobe may not firstly be involved as many other diseases with dementia. Early involvement of olfactory bulbs may help in the early diagnosis of the disease. Our findings indicate that many specific features may help in clinical practice and that further research is needed to clarify the mechanisms. Basilar artery, General paresis, Meningovascular, Neuropil, Neurosyphilis INTRODUCTION Syphilis is an infectious disease caused by the spirochete Treponema pallidum. Approximately 4%–10% of patients in the late stage of systemic syphilis infection will have CNS involvement, that is neurosyphilis (1). The subtypes of neurosyphilis include asymptomatic, meningeal, meningovascular, general paresis, tabes dorsalis, gumma, and optic nerve atrophy (2). When there is extensive involvement of the CNS, the clinical spectrum is so complex that early diagnosis is often difficult. Serum and CSF antibody studies are essential for the clinical diagnosis. The rapid plasma reagin test is helpful for screening and therapeutic monitoring because the titer decreases after therapy (3). The T. pallidum particle agglutination and fluorescent treponemal antibody absorption tests are more specific for definitive diagnosis (3). Early diagnosis and antiluetic therapy are very important for improving prognosis. Meningovascular neurosyphilis and general paresis are representatives of early and late stage neurosyphilis, respectively, but they can overlap in many patients. Clinical manifestations of the early stage include headache, hemiplegia, cranial nerve palsy and signs of meningitis as well as cerebral infarction whereas progressive dementia with or without psychological and behavior disorders has been the key symptom of the late stage (4, 5). Microscopically, meningovascular neurosyphilis is characterized by lymphocytic infiltration of leptomeninges with fibrous organization, arteritis, and vascular occlusion as well as consequent infarcts. Cerebral cortical atrophy, disrupted neuropil, neuronal loss, astrocyte proliferation, and activated microglia are typical features of general paresis (6). Here, we describe postmortem findings in 3 patients with neurosyphilis to analyze clinicopathological relationships, and with the aim of assisting in the early diagnosis and treatment of the disease in the modern era. MATERIALS AND METHODS Postmortem examinations were performed 24 hours after death and were limited to the brain and spinal cord. Gross neuropathological examinations were performed after 1 month of 10% buffered formalin fixation on coronal sections of the cerebral hemisphere and sections of the cerebellum and brainstem cut perpendicular to the long axis. Large arteries in the circle of Willis were separated. For light microscopy, samples were embedded in paraffin and 10-μm-thick sections were stained with hematoxylin and eosin (H&E). The slices came from the optic chiasm, olfactory bulb, frontal, lateral temporal, occipital, parietal, insular cortex, hippocampus, basal ganglia, cerebellum, midbrain, pons, medulla, cervical spinal cord, and basilar artery. Additional stains used included Luxol fast blue, Weil’s, and Nissl stains; immunohistochemistry was performed in a Ventana automated stainer, using an avidin-biotin complex, peroxidase-based method with the following polyclonal antibodies: anti-CD3 (1/100, Leica, Wetzlar, Germany), and anti-CD20 (1/200, Leica), anti-CD138 (1/100, ZSGB-Bio, Beijing, China), anti-CD68 (1/50, Dako, Glostrup, Denmark). Warthin-Starry stain was used in case 3 for identification of spirochetes. RESULTS Clinical Observations Three neurosyphilis cases (all males) were admitted to the Neurological Department of Peking Union Medical College Hospital. All of them were middle aged and had had untreated syphilis for many years. All of them had unprotected sexual intercourse with prostitutes. Although they all progressed rapidly to death, disease onset was acute or subacute (Table 1). TABLE 1. Epidemiological Data and Disease Progression Case  Sex  Age at Death (years)  Onset  Course (time after onset to death)  Systemic Syphilis History (years)  1  Male  56  Acute  9 days  38  2  Male  50  Subacute  2 months  10  3  Male  42  Subacute  45 days*  10  Case  Sex  Age at Death (years)  Onset  Course (time after onset to death)  Systemic Syphilis History (years)  1  Male  56  Acute  9 days  38  2  Male  50  Subacute  2 months  10  3  Male  42  Subacute  45 days*  10  * Respiratory failure due to pneumocystis carinii infection. The clinical and laboratory results are summarized in Table 2. Case 1 had an acute progression with vertigo, dysphagia, and right hemianesthesia. Physical examination showed left central facial and tongue palsy, loss of pharyngeal reflex, right hemianesthesia, and loss of right abdominal wall and cremasteric reflexes. Case 2 had shown 2 months of psychosis and aggressive behavior. He had cognitive decline with no focal neurologic signs on physical examination. Case 3 had progressive right hemiplegia with diplopia. Physical examination showed cognitive decline with a Mini-Mental State Examination score of 25 and Montreal Cognitive Assessment score of 22. He also had a right central facial and tongue palsy, right hemiplegia and positive right Babinski and Chaddock signs. TABLE 2. Clinical Manifestations and Laboratory Results Case  Symptoms  Physical Findings  Syphilis Tests (RPR and TPPA)  CSF Analysis  Neuroimaging  1  Vertigo, dysphagia, hemi-anesthesia  L central facial palsy, R hemi-anesthesia  Both serum and CSF positive  ND  ND  2  Psychosis, aggressive  Cognitive decline, no focal signs  Both serum and CSF positive  Lymphocytes: 12×106/L; protein: 0.74g/L  Normal  3  Hemiplegia, diplopia, cognition decline  Cognitive decline, R hemiplegia, R facial palsy, positive R Babinski sign  Both serum and CSF positive*  Lymphocytes: 28×106/L, protein: 0.93 g/L  L midbrain infarct, basilar artery stenosis  Case  Symptoms  Physical Findings  Syphilis Tests (RPR and TPPA)  CSF Analysis  Neuroimaging  1  Vertigo, dysphagia, hemi-anesthesia  L central facial palsy, R hemi-anesthesia  Both serum and CSF positive  ND  ND  2  Psychosis, aggressive  Cognitive decline, no focal signs  Both serum and CSF positive  Lymphocytes: 12×106/L; protein: 0.74g/L  Normal  3  Hemiplegia, diplopia, cognition decline  Cognitive decline, R hemiplegia, R facial palsy, positive R Babinski sign  Both serum and CSF positive*  Lymphocytes: 28×106/L, protein: 0.93 g/L  L midbrain infarct, basilar artery stenosis  * Serum HIV antibody positive. ND, not done; L, left; R, right. In each patient, both the serum and CSF rapid plasma reagin and T. pallidum particle agglutination tests were positive, with positive serum HIV antibody in case 3; HIV testing was negative in the other 2 patients. The CD4 count in case 3 was 68/µl. CSF lymphocytosis and elevated protein level as well as artery stenosis were also seen, but not in all of them. Neuroimaging of case 3 showed extensive basilar meningeal enhancement without ventricle enlargement. The clinical diagnoses were: brainstem infarcts caused by syphilitic arteritis, general paresis, brainstem infarction caused by syphilitic arteritis and general paresis in cases 1–3, respectively. Cases 2 and 3 were given intravenous penicillin treatment for 2 weeks whereas case 1 was not treated. Both case 1 and 2 developed aspiration pneumonia and died from respiratory failure. Case 3 also died from an acute respiratory failure with extensive interstitial involvement with suspected pneumocystis pneumonia but without evidence. Neuropathology Gross neuropathological examination results are summarized in Table 3. There was no edema, atrophy, herniation of the brain, or hemorrhage on brain surfaces. Adhesion and thickening of leptomeninges around the brainstem and the circle of Willis was found in case 3. No lesions were found on the coronal sections of cerebral hemisphere, cerebellum, and spinal cord; necrosis in the brainstem and midbrain were identified in case 1 and 3, respectively. Basilar artery stenosis of case 1 and 3 were also seen. TABLE 3. Macroscopic Neuropathology Case  Weight of Brain (g)  Atrophy or Ventricle Enlargement  Herniation  Leptomeningeal Adhesion and Thickening  Vascular Changes  Lesions on Coronal Sections  1  1100  No  No  Not obvious  Basilar artery stenosis  Necrosis in brain stem  2  1250  No  No  No  No  No  3  1360  No  No  Around brain stem  Basilar artery stenosis  Necrosis in midbrain  Case  Weight of Brain (g)  Atrophy or Ventricle Enlargement  Herniation  Leptomeningeal Adhesion and Thickening  Vascular Changes  Lesions on Coronal Sections  1  1100  No  No  Not obvious  Basilar artery stenosis  Necrosis in brain stem  2  1250  No  No  No  No  No  3  1360  No  No  Around brain stem  Basilar artery stenosis  Necrosis in midbrain  On microscopic examination, the 3 cases showed widespread leptomeningitis with lymphocytes and macrophages (Figs. 1A, 2A, 3C). Microvascular proliferation, congestion, and perivascular inflammation were present in all through the leptomeninges, cortex, and white matter; there was also perivascular hemosiderin deposition (Figs. 2B, 3D). The cortex lamination and neuropil architecture were relatively preserved in case 1 (Fig. 1B), whereas they appeared markedly disrupted in case 2 and 3, particularly in the frontal lobe cortex (Figs. 2C, 3E). Cortical architecture in temporal lobes was relatively intact (Fig. 2D). Scattered neuron loss, neuron swelling, and ghost formation were found in case 1. In cases 2 and 3, there was marked and widespread neuron loss with and apparent microvascular hyperplasia (Fig. 2E). Activated and rod-like microglia as well as astrocyte proliferation were easily seen; some of the former surrounded neurons (Fig. 1C). Scattered CD3-, CD20-, and CD138-positive cells were seen. No demyelination or axon necrosis was seen in white matter but there was some myelin swelling. Hippocampal structures were nearly normal in all cases (Figs. 1D, 2F). Other than inflammation in the leptomeninges, the cerebellum, and spinal cord were intact (Figs. 1E, 3F). The walls of the basilar artery were thickened, infiltrated by lymphocytes and showed disruption of elastin layer in cases 1 and 3 (Figs. 1F, 3G). FIGURE 1. View largeDownload slide Case 1. (A) Thickened leptomeninges infiltrated by lymphocytes and macrophages; the vessels are congested (H&E. ×40). (B) Frontal cortex lamination is intact (Nissl stain, ×40). (C) Neurons are surrounded by increased microglia (H&E, ×100). (D) The hippocampus appears normal (Nissl, ×40). (E) Normal spinal cord with leptomeningeal inflammation (H&E, ×40). (F) Basilar artery is thickened with lymphocytes infiltrating the wall (H&E, ×40). (G) Leptomeninges over the optic chiasm also show inflammatory cell infiltrates (H&E, ×40). (H, I) Small infarcts in the pons (H, H&E, ×40; I, Weil’s method, ×40). (J) Acute (estimated 1–2 weeks), infarct (right side of field) in the medulla oblongata (H&E, ×40). FIGURE 1. View largeDownload slide Case 1. (A) Thickened leptomeninges infiltrated by lymphocytes and macrophages; the vessels are congested (H&E. ×40). (B) Frontal cortex lamination is intact (Nissl stain, ×40). (C) Neurons are surrounded by increased microglia (H&E, ×100). (D) The hippocampus appears normal (Nissl, ×40). (E) Normal spinal cord with leptomeningeal inflammation (H&E, ×40). (F) Basilar artery is thickened with lymphocytes infiltrating the wall (H&E, ×40). (G) Leptomeninges over the optic chiasm also show inflammatory cell infiltrates (H&E, ×40). (H, I) Small infarcts in the pons (H, H&E, ×40; I, Weil’s method, ×40). (J) Acute (estimated 1–2 weeks), infarct (right side of field) in the medulla oblongata (H&E, ×40). FIGURE 2. View largeDownload slide Case 2. (A) Thickened leptomeninges infiltrated by lymphocytes and macrophages (H&E, ×100). (B) Perivascular mononuclear cell inflammation with hemosiderin deposition (H&E, ×400). (C) Architecture of frontal lobe cortex appears disturbed with congested vessels (H&E, ×40). (D) Cortical architecture in the temporal lobe appears relatively preserved (Nissl, ×40). (E) Neurons appear decreased and there appears to be an increase in the microvasculature (H&E, ×100). (F) The hippocampus is intact (Nissl, ×40). FIGURE 2. View largeDownload slide Case 2. (A) Thickened leptomeninges infiltrated by lymphocytes and macrophages (H&E, ×100). (B) Perivascular mononuclear cell inflammation with hemosiderin deposition (H&E, ×400). (C) Architecture of frontal lobe cortex appears disturbed with congested vessels (H&E, ×40). (D) Cortical architecture in the temporal lobe appears relatively preserved (Nissl, ×40). (E) Neurons appear decreased and there appears to be an increase in the microvasculature (H&E, ×100). (F) The hippocampus is intact (Nissl, ×40). FIGURE 3. View largeDownload slide Case 3. (A) Contrast MRI shows enhancement of basilar leptomeninges. (B) Adhesion and thickening of leptomeninges around the brainstem and circle of Willis. (C) Thickened leptomeninges infiltrated by lymphocytes and macrophages (H&E, ×40). (D) Congested vessels with mononuclear cell infiltrates (H&E, ×400). (E) Neuropil dyslamination of frontal cortex and prominent microvessels (H&E, ×40). (F) Meningeal and perivascular inflammation adjacent to a spinal nerve root (H&E, ×40). (G) Intimal thickening and disruption of the elastic layer in the basilar artery (Elastic van Gieson stain, ×40). (H) A subacute infarct in the midbrain (Luxol fast blue-hematoxylin, ×40). (I, J) Disturbance of the left olfactory bulb with microglia infiltration (I, H&E, ×40; J, anti-CD68 immunohistochemistry, ×40). (K, L) Spirochetes (arrows), in the frontal lobe parenchyma. Boxed area in K is shown at higher power in L (Warthin-Starry; K, ×40; L, ×1000). FIGURE 3. View largeDownload slide Case 3. (A) Contrast MRI shows enhancement of basilar leptomeninges. (B) Adhesion and thickening of leptomeninges around the brainstem and circle of Willis. (C) Thickened leptomeninges infiltrated by lymphocytes and macrophages (H&E, ×40). (D) Congested vessels with mononuclear cell infiltrates (H&E, ×400). (E) Neuropil dyslamination of frontal cortex and prominent microvessels (H&E, ×40). (F) Meningeal and perivascular inflammation adjacent to a spinal nerve root (H&E, ×40). (G) Intimal thickening and disruption of the elastic layer in the basilar artery (Elastic van Gieson stain, ×40). (H) A subacute infarct in the midbrain (Luxol fast blue-hematoxylin, ×40). (I, J) Disturbance of the left olfactory bulb with microglia infiltration (I, H&E, ×40; J, anti-CD68 immunohistochemistry, ×40). (K, L) Spirochetes (arrows), in the frontal lobe parenchyma. Boxed area in K is shown at higher power in L (Warthin-Starry; K, ×40; L, ×1000). In case 1, the leptomeninges on over the optic chiasm were also infiltrated by inflammatory cells (Fig. 1G). Myelin swelling and microglia infiltration were seen in the parenchyma. Small acute infarcts were seen in the pons and medulla oblongata (Fig. 1H, I, J). Additionally, there was a focal subacute infarct in the midbrain in case 3 (Fig. 3H). Disturbance of normal structure and apparently activated microglia were seen in the left olfactory bulb (Fig. 3I, J). Warthin-Starry stains were done for spirochetes; this was negative in case 2 but in case 3, there were spirochetes in frontal lobe cortex (Fig. 3K, L). The microscopic features are summarized in Table 4. TABLE 4. Microscopic Neuropathology Case  Meningitis  Vasculitis  Neuron Loss  Neuropil Damage  Microglial Activation  White Matter Demyelination  Pathological Diagnosis  1  Yes  Yes  Scattered  No  Yes  No  Meningovascular neurosyphilis  2  Yes  Yes  Yes  Yes  Yes  No  General paresis  3  Yes  Yes  Yes  Yes  Yes  No  Meningovascular neurosyphilis and general paresis  Case  Meningitis  Vasculitis  Neuron Loss  Neuropil Damage  Microglial Activation  White Matter Demyelination  Pathological Diagnosis  1  Yes  Yes  Scattered  No  Yes  No  Meningovascular neurosyphilis  2  Yes  Yes  Yes  Yes  Yes  No  General paresis  3  Yes  Yes  Yes  Yes  Yes  No  Meningovascular neurosyphilis and general paresis  DISCUSSION Although the cases had different clinical symptoms and different subtypes, we found identical microscopic features, that is extensive inflammation of the meninges at all levels and surrounding microvessels. Basilar meningitis was more evident grossly, suggesting that it was an area prone to involvement. The infiltrates included lymphocytes; although thickened, the leptomeningeal involvement was usually not evident by enhanced MRI. Vessels in the cortex were often congested and infiltrated by lymphocytes and macrophages; thickened walls and perivascular hemosiderin deposition implied microbleeding. Meningovascular involvement has been considered the early manifestation of neurosyphilis but it can accompany with many subtypes (6). Our results support this and we believe that meningovascular infiltration exists even in asymptomatic neurosyphilis. Therefore, MRI with higher resolution and more sensitive to perivascular bleeding may help to identify early CNS involvement in patients with systemic syphilis. The 3 patients had a history of syphilis or unsafe sexual behavior >10 years prior to death. The onset of neurological symptoms was later. It has been considered that meningeal and meningovascular neurosyphilis usually appear ∼2 years after infection whereas general paresis usually 10 years or more later. However, with the wide use of antibiotics and, more importantly, the combination of HIV infection may change the course of the disease. Indeed, HIV can change the natural history of syphilis and accelerate the progression (7). Secondly, recurrent syphilis infection is common in patients with HIV. Therefore, recognition of early neurological symptoms and CSF examination are crucial to the diagnosis of CNS involvement in patients with syphilis. Both cases with meningovascular lesions had brainstem infarcts and we found evidence of vasculitis of the basilar artery. Presumably, inflammation of the vascular wall caused disruption of intima, necrosis, and fibrosis of adventitia and stenosis of the lumen, which resulted in thrombosis and cerebral infarction. It has been reported that medium-sized and large arteries are more commonly involved in neurosyphilis and that infarcts of the middle cerebral and vertebrobasilar artery distributions result (8, 9). In addition to the size of these arteries, we think basilar meningitis also may predispose to basilar artery involvement. Thus, neurosyphilis must be emphasized as a cause of vertebrobasilar infarcts in young patients without other risk factors in clinical practice (9, 10). Two of our cases had cognitive decline with or without behavioral or psychological symptoms. Microscopically, we observed damage of cortical architecture, neuron loss, infiltration of lymphocytes and activated microglia, and gliosis, which support the diagnosis of general paresis (6). However, cerebral atrophy was not obvious macroscopically, probably due to the short courses of CNS involvement. The patient without dementia had relatively normal cortical structures, which further supported the opinion that neuronal loss and neuropil damage were the mechanism of cognitive decline in the others. We also suggest the disturbance of connections between neurons, or neuropil by activated microglia and gliosis participates in the pathogenesis. Lymphocytosis was not as obvious as microglial activation, indicating that the latter is an important feature of neurosyphilis, although it is more often identified only by postmortem examination. Neuronal loss and neurofibrillary tangles in limbic area and temporal lobe are early neuropathologic changes of Alzheimer disease (AD) (11). Hippocampal sclerosis may coexist with AD pathology, and was the main pathologic changes in the oldest old, which was defined as pure hippocampus sclerosis dementia (12, 13). Neurosyphilis is a great mimicker and it has been reported that neurosyphilis can mimic early onset AD with bilateral hippocampal atrophy (14). However, in our cases, the neuropil of the cortex and morphology of neurons in temporal lobe were relatively preserved, that is better than in the frontal lobes. Moreover, the hippocampi were normal, that is without atrophy, hippocampal sclerosis, or gliosis. On the other hand, personality changes and depression, which were typical symptoms of frontal lobe damage, were obvious in our cases. Therefore, we think that although temporal lobe involvement is apparent in neurosyphilis and that later spread to the whole brain is inevitable, symptoms of frontal lobe involvement may appear earlier. Further understanding of the disease progression is necessary for early diagnosis. Olfactory loss and hyposmia accompany aging and neurodegenerative diseases. Microscopically, mitral cell loss and ectopic glomeruli formation alter the normal synaptic organization of olfactory bulb in aging, as well as early amyloid deposition in AD (15). A MRI study also found early involvement of olfactory bulb and tract in AD, suggesting a method of early diagnosis and recognition of the disease (16). In case 3, we also found structural damage and microglial infiltration of the olfactory bulb. Thus, olfactory involvement may be an early manifestation of neurosyphilis in systemic syphilis patients. In conclusion, our autopsy findings further confirm the neuropathologic features of neurosyphilis. We verified the wide distribution of meningovascular inflammation in different subtypes of neurosyphilis and the common involvement of vertebrobasilar arteries. We also tried to identify some early manifestations of the disease based on the neuropathologic changes that would assist early diagnosis; however, we only raised hypotheses based on the morphologic analysis. Large scale studies and animal research is needed for further verification and exploration of mechanisms. In any case, clinicians should be aware of the pathological spectrum of neurosyphilis and attempt early diagnosis of the treatable disease in clinical practice. REFERENCES 1 Conde-Sendín MA, Amela-Peris R, Aladro-Benito Yet al.  , Current clinical spectrum of neurosyphilis in immunocompetent patients. Eur Neurol  2004; 52: 29– 35 Google Scholar CrossRef Search ADS PubMed  2 Conde-Sendín MA, Hernández-Fleta JL, Cárdenes-Santana MAet al.  , Neurosyphilis: Forms of presentation and clinical management. Rev Neurol  2002; 35: 380– 6 Google Scholar PubMed  3 Larsen SA, Steiner BM, Rudolph AH. Laboratory diagnosis and interpretation of tests for syphilis. 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Ageing Res Rev  2004; 3: 215– 32 Google Scholar CrossRef Search ADS PubMed  16 Thomann PA, Dos Santos V, Toro Pet al.  , Reduced olfactory bulb and tract volume in early Alzheimer’s disease–a MRI study. Neurobiol Aging  2009; 30: 838– 41 Google Scholar CrossRef Search ADS PubMed  © 2018 American Association of Neuropathologists, Inc. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Journal of Neuropathology & Experimental NeurologyOxford University Press

Published: Apr 1, 2018

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