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Clinically Undetected Motor Neuron Disease in Pathologically Proven Frontotemporal Lobar Degeneration with Motor Neuron Disease

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Clinically Undetected Motor Neuron Disease in Pathologically Proven Frontotemporal Lobar Degeneration with Motor Neuron Disease ORIGINAL CONTRIBUTION Clinically Undetected Motor Neuron Disease in Pathologically Proven Frontotemporal Lobar Degeneration With Motor Neuron Disease Keith A. Josephs, MST, MD; Joseph E. Parisi, MD; David S. Knopman, MD; Bradley F. Boeve, MD; Ronald C. Petersen, MD, PhD; Dennis W. Dickson, MD Background: Frontotemporal lobar degeneration with evidence of motor neuron disease. Semiquantitative motor neuron disease (FTLD-MND) is a pathological analysis of motor and extramotor pathological findings entity characterized by motor neuron degeneration and revealed a spectrum of pathological changes underlying frontotemporal lobar degeneration. The ability to detect FTLD-MND. Hippocampal sclerosis, predominantly of the clinical signs of dementia and motor neuron disease the subiculum, was a significantly more frequent occur- in pathologically confirmed FTLD-MND has not been rence in the cases without clinical evidence of motor assessed. neuron disease (PϽ.01). In addition, neuronal loss, gliosis, and corticospinal tract degeneration were less Objectives: To determine if all cases of pathologically severe in the other 3 cases without clinical evidence of confirmed FTLD-MND have clinical evidence of fronto- motor neuron disease. temporal dementia and motor neuron disease, and to de- termine the possible reasons for misdiagnosis. Conclusions: Clinical diagnostic sensitivity for the el- ements of FTLD-MND is modest and may be affected by Method: Review of historical records and semiquantita- the fact that FTLD-MND represents a spectrum of patho- tive analysis of the motor and extramotor pathological find- logical findings, rather than a single homogeneous en- ings of all cases of pathologically confirmed FTLD-MND. tity. Detection of signs of clinical motor neuron disease is also difficult when motor neuron degeneration is mild Results: From a total of 17 cases of pathologically con- and in patients with hippocampal sclerosis. firmed FTLD-MND, all had clinical evidence of fronto- temporal dementia, while only 10 (59%) had clinical Arch Neurol. 2006;63:506-512 RONTOTEMPORAL DEMENTIA MND).4 Therefore, FTLD-MND currently (FTD) is a clinical term ap- represents a distinct pathological entity. plied to patients who pre- During the last decade, we and others sent with progressive demen- have observed cases that at autopsy have tia with an insidious onset, had histologic evidence of mixed fea- Fprominent behavioral or language dysfunc- tures of FTLD and MND. Furthermore, tion, or both. Motor neuron disease (MND) clinical studies have revealed an in- is also a clinical term, but it is applied to creased frequency of MND in cases of patients with clinical evidence of cortico- FTD,3 and an increased frequency of FTD spinal tract involvement, evidence of brain- in cases of MND.2 Unfortunately, studies stem or spinal cord anterior horn cell in- correlating the clinical signs of FTD- volvement, or both. Recent studies have MND with the pathologic diagnosis of revealed that clinical features of FTD and FTLD-MND are limited.5 We therefore set MND (FTD-MND) can occur in the same out to assess the association of clinical fea- patient and not infrequently.1-3 tures of FTD-MND and pathologically con- firmed FTLD-MND. Author Affiliations: Departments of Neurology For editorial comment METHODS (Drs Josephs, Knopman, Boeve, see page 489 and Petersen) and Laboratory Medicine and Pathology CASE ASCERTAINMENT As with the clinical syndrome of FTD- (Dr Parisi), Mayo Clinic, Rochester, Minn; Department of MND, pathologic studies have indepen- The Mayo Clinic (Rochester, Minn) pathologi- Pathology and Neuroscience dently identified cases with frontotempo- cal database was searched to identify all cases (Dr Dickson), Mayo Clinic, ral lobar degeneration and features of typical that were autopsied with a pathological diag- Jacksonville, Fla. motor neuron degeneration (FTLD- nosis of Pick disease, FTLD-MND, or demen- (REPRINTED) ARCH NEUROL / VOL 63, APR 2006 WWW.ARCHNEUROL.COM 506 ©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 tia lacking distinctive histopathologic features. We also re- rons plus (1) shrunken residual motor neurons, (2) evidence viewed our cases of FTLD, but none had pathologic evidence of neuronophagia, (3) Bunina bodies, or (4) ubiquitin- of motor neuron degeneration.6 All identified cases were then immunoreactive intraneuronal inclusions, including Lewy body– reexamined pathologically with modern neuropathologic stains. like hyaline inclusions, skeinlike inclusions, or pleomorphic Only cases with a final diagnosis of FTLD-MND were retained cytoplasmic inclusions, which were grouped with skeinlike in- for this study. clusions for the purpose of analysis. Evidence of frontotempo- A retrospective review of the historical records of all cases ral lobar degeneration included the presence of superficial spon- with final pathological diagnosis of FTLD-MND was under- giosis, neuronal loss, and astrogliosis affecting predominantly taken. Special attention was paid to any sign or symptom sug- layer II of the cortex, with or without the presence of ubiquitin- gestive of bulbar dysfunction, upper or lower motor neuron dis- immunoreactive neuronal cytoplasmic inclusions. Neuronal in- ease (or both), and the treating physician’s diagnoses at onset tranuclear inclusions were not detected. and throughout the disease course. STATISTICAL ANALYSIS PATHOLOGICAL ANALYSIS Statistical analyses were performed with SigmaStat software (Sy- stat Software Inc, Point Richmond, Calif). Univariate correla- In all cases identified from the previously described electronic tions for analysis of clinical and pathologic factors used Spear- search, slides of frontal, temporal, and parietal neocortex, hip- man rank order correlation analysis. A P value of less than .05 pocampus, basal ganglia, thalamus, midbrain, pons, medulla, was considered significant. and cerebellum were reviewed. In all cases, sections were stud- ied with hematoxylin-eosin (HE) and modified Bielschowsky staining, as well as other stains needed for routine evaluation, RESULTS including immunohistochemistry for markers of glial pathol- ogy. Those stains include glial fibrillary acid protein for astro- We identified 18 cases that fulfilled pathological criteria cytes and either CD68 or HLA-DR antigens for microglia. Neu- for FTLD-MND, including presence of ubiquitin- ronal pathology was studied with antibodies to neurofilament immunoreactive neuronal inclusions in motor or extra- ␣ protein, ubiquitin, -synuclein, and phospho-tau. motor neuronal populations or both in all cases. The In all cases, the hypoglossal nucleus and/or cervical spinal ubiquitin-positive inclusions were negative for tau, anterior horn cells were reviewed for evidence of motor neu- ␣-synuclein, and neurofilament. ron degeneration with HE and ubiquitin. In many cases, stains for glial fibrillary acidic protein and macrophages were also avail- One case was removed from further analysis because able. Neuronal loss and gliosis were assessed semiquantita- of a clinical diagnosis of multiple sclerosis 20 years prior tively in the hypoglossal nucleus and the anterior horn cells of to death. The demographics of the other 17 cases are pre- the spinal cord with a 4-point scale (0=none; 1ϩ=focal neu- sented in Table 1. Of these, 13 (76%) were male. The ronal loss and focal microgliosis; 2ϩ=extensive neuronal loss mean age at onset and disease duration were 52 years and with microgliosis and empty cell beds containing macro- 2.3 years, respectively. phages; 3ϩ=almost complete loss of motor neurons with at- rophy and astrocytic fibrillar gliosis). The presence of Bunina CLINICAL FEATURES bodies was assessed on HE staining in motor neurons of the hypoglossal nucleus and spinal anterior horn cells. Lewy body– All patients had clinical features suggestive of fronto- like hyaline inclusions were assessed on HE staining and ubiq- uitin stains. Skeinlike and pleomorphic cytoplasmic inclu- temporal dysfunction; however, only 10 cases carried a sions were assessed on ubiquitin immunostains. The diagnosis of FTD-MND or a comparable diagnostic term corticospinal tract was assessed for wallerian degeneration us- (such as amyotrophic lateral sclerosis–dementia or de- ing HE (presence of atrophy with vacuolation and lipid-laden mentia with MND) prior to death. Of the other 7 cases, macrophages), myelin stains (pallor on Luxol fast blue), or mac- 4 were diagnosed as FTD, 2 with a rapidly progressive rophage stains (increased ameboid microglia) paying special dementing illness, and 1 as FTD vs Alzheimer disease. attention to the pyramids in the medulla and the lateral fu- All 10 cases with a clinical diagnosis of FTD-MND had niculi in the spinal cord. The severity of corticospinal tract de- evidence of motor neuron disease on clinical examina- generation was assessed semiquantitatively on a 5-point scale ϩ tion, while the other 7 did not. (0=none, 1 =very mild vacuolation and sparse macro- Two cases were initially diagnosed as FTD only (data phages; 2ϩ =vacuolation with many lipid-laden macro- phages; 3ϩ=many lipid-laden macrophages with myelin loss; not shown); however, they later developed signs of MND 4ϩ=myelinated fiber loss, tract atrophy and astrocytic glio- and were subsequently diagnosed as FTD-MND. One of sis). Extramotor inclusions were assessed semiquantitatively these 2 cases (case 13) developed signs of MND approxi- with ubiquitin immunostains with a 5-point grading scale mately 45 months
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