Clinical Review & Education
JAMA Neurology Clinical Challenge
Personality Change and Gait Dysfunction Lawrence S. Honig, MD, PhD
A
B
C
Figure 1. A, Patient testing. Constructional apraxia is seen in her copying of the top row template figures, with preserved writing in script. B, Brain magnetic resonance imaging at the time of presentation. The top panel shows selected sagittal T1-weighted images, and the bottom panel shows selected axial
T1-weighted images. C, Brain positron emission tomography using fluorodeoxyglucose F 18 tracer in the axial plane. Frontal and temporal hypometabolism is seen, more marked on the right, with some apparent sensorimotor sparing bilaterally.
A woman in her 50s was referred to a neurologist for a history of gait, balance, personality, and judgment changes over 4 years. Her family noted that her first symptoms appeared at age 55, with subtle gait dysfunction and then evident imbalance. By age 57, there was concern over progressive withdrawal from social interchange, personality changes, and impairment of judgment. By age 59, she was experiencing bouts of inappropriate out-ofcontext laughter and tears, inattention, daytime fatigue, and frank memory impairment. She developed visuoperceptive changes and difficulties using the television remote control device. She developed obsessive checking behaviors. She started having swallowing difficulties but nonetheless had unexpected weight gain. She developed progressively worse motoric problems, with stiffness, abnormal posturing, a left toe pointing upward, and falls. Her medical history was significant only for restless legs syndrome, hypertension, hyperlipidemia, myopia, and a deviated nasal septum. Her family history revealed that her father was alive and well at approximately age 90 years, and her mother had died at approximately age 80 years with a history of neuropsychiatric disease and gait change. There was no history of tobacco, excess alcohol, or recreational drug use. General examination findings were noncontributory. Neurological examination revealed abnormal mental status, with full orientation and good registration, concentration, digit span, and language function but with poor calculations and constructions (Figure 1A) and decreased short-term memory. Nonetheless, her Mini-Mental State Examination score was 28 of 30. Cranial nerve examination revealed some decreased upgaze and mild facial masking. Motor examination revealed rigidity and dystonic posturing in the left arm and leg, imbalance on gait, decreased arm swing, and retropulsion but no significant tremor. Sensory examination findings were normal. Reflex examination showed mild left hyperreflexia with an upgoing left toe. Blood and urine laboratory study results were within normal limits. Cerebrospinal fluid was unremarkable except for biomarkers that showed a mid-range β-amyloid 42 level of 530 pg/mL and normal total tau and phosphotau levels of 182 and 25 pg/mL, respectively. Magnetic resonance imaging of the brain was reported as unremarkable (Figure 1B). Positron emission tomography (PET) imaging of the brain revealed right frontotemporoparietal hypometabolism with some sensorimotor sparing (Figure 1C), which was neither typical nor atypical of Alzheimer disease. Electroencephalography showed left frontotemporal sharp waves and slowing. She had continued progressive decline in cognition and motor function and died almost mute and bedridden in her early 60s after a 9-year course of illness. jamaneurology.com
WHAT IS YOUR DIAGNOSIS?
A. Alzheimer disease, frontal variant B. Frontotemporal dementia C. Progressive supranuclear palsy D. Corticobasal degeneration E. Spinocerebellar ataxia
(Reprinted) JAMA Neurology May 2015 Volume 72, Number 5
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Yale University User on 05/16/2015
597
Clinical Review & Education JAMA Neurology Clinical Challenge
Diagnosis C. Progressive supranuclear palsy
Discussion During her life, the patient’s diagnoses included frontotemporal dementia (because of her behavioral changes, with relative preservation of cognition early on), progressive supranuclear palsy (because of her motor changes, including falls), and corticobasal syndrome (because of her markedly asymmetric dystonia). However, progressive supranuclear palsy was the most likely diagnosis because of the early features of imbalance and falls, parkinsonism without tremor, and marked midbrain atrophy visible on magnetic resonance (MR) imaging (hummingbird sign is seen in the sagittal midline slice [top right of Figure 2]).1-5 Alzheimer disease was unlikely because of the lack of early memory change, the MR imaging and PET results, and the normal tau and phosphotau levels in cerebrospinal fluid. While there was considerable imbalance and cerebellar atrophy, the asymmetric examination findings, prominent brainstem atrophy, cognitive changes,3 and lack of dysmetria, nystagmus, or other classic cerebellar signs all militated against spinocerebellar degeneration. Although the asymmetric motor examination results could be indicative of corticobasal ganglionic degeneration (corticobasal degeneration), these findings can also be seen in progressive supranuclear palsy. The lack of a classic pattern of bicentral hypometabolism on PET, the presence of marked midbrain tectal atrophy2 and dysphagia, and the absence of alien limb or dysgraphesthesia all make corticobasal syndrome less likely. Finally, while several features were suggestive of behavioral variant frontotemporal degeneration, the presence of such prominent motor signs and symptoms early in the disease course, as well as the MR imaging and PET results, makes such a diagnosis less likely. The diagnosis of progressive supranuclear palsy
Figure 2. Brain magnetic resonance imaging (same as Figure 1B) was interpreted as “normal” but in fact shows marked midbrain atrophy, most prominent in the tectum (yellow arrowhead), and also evident in the “hummingbird” sign seen on sagittal image (white arrowhead).
(Steele-Richardson-Olszewski syndrome) was confirmed at autopsy.1,5 Throughout the cortex and subcortical gray nuclei, a diffuse and severe burden of glial phosphorylated tau pathology was observed, evidenced through immunohistochemical staining with antibody AT8. There were frequent tufted astrocytes, scattered neuronal and glial tangles, marked gliosis, and glial cytoplasmic inclusions in the white matter. Neuronal losses in the substantia nigra, pars compacta, and pars reticulata were severe. There were few neuronal tangles and no evident plaques using immunohistochemical stains for β-amyloid. Finally, there was no evidence of α-synuclein aggregates (as seen in Lewy body disease) or transactive response DNA-binding protein 32 (TDP-43) abnormalities (as seen in some frontotemporal dementia disorders).
Conflict of Interest Disclosures: None reported.
ARTICLE INFORMATION Author Affiliation: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Gertrude H. Sergievsky Center, and Department of Neurology, Columbia University Medical Center, New York, New York. Corresponding Author: Lawrence S. Honig, MD, PhD, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Gertrude H. Sergievsky Center, and Department of Neurology, Columbia University Medical Center, 630 W 168th St (Physicians and Surgeons Unit 16), New York, NY 10032 ([email protected]).
REFERENCES 1. Litvan I, Hauw JJ, Bartko JJ, et al. Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders. J Neuropathol Exp Neurol. 1996; 55(1):97-105. 2. Rolland Y, Vérin M, Payan CA, et al; NNIPPS Study Group. A new MRI rating scale for progressive supranuclear palsy and multiple system atrophy: validity and reliability. J Neurol Neurosurg Psychiatry. 2011;82(9):1025-1032.
3. Burrell JR, Hodges JR, Rowe JB. Cognition in corticobasal syndrome and progressive supranuclear palsy: a review. Mov Disord. 2014;29 (5):684-693. 4. Magdalinou N, Lees AJ, Zetterberg H. Cerebrospinal fluid biomarkers in parkinsonian conditions: an update and future directions. J Neurol Neurosurg Psychiatry. 2014;85(10):10651075. 5. Murray ME, Kouri N, Lin WL, Jack CR Jr, Dickson DW, Vemuri P. Clinicopathologic assessment and imaging of tauopathies in neurodegenerative dementias. Alzheimers Res Ther. 2014;6(1):1.
Published Online: March 30, 2015. doi:10.1001/jamaneurol.2014.3668.
598
JAMA Neurology May 2015 Volume 72, Number 5 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Yale University User on 05/16/2015
jamaneurology.com
JAMA Neurology Clinical Challenge
Personality Change and Gait Dysfunction Lawrence S. Honig, MD, PhD
A
B
C
Figure 1. A, Patient testing. Constructional apraxia is seen in her copying of the top row template figures, with preserved writing in script. B, Brain magnetic resonance imaging at the time of presentation. The top panel shows selected sagittal T1-weighted images, and the bottom panel shows selected axial
T1-weighted images. C, Brain positron emission tomography using fluorodeoxyglucose F 18 tracer in the axial plane. Frontal and temporal hypometabolism is seen, more marked on the right, with some apparent sensorimotor sparing bilaterally.
A woman in her 50s was referred to a neurologist for a history of gait, balance, personality, and judgment changes over 4 years. Her family noted that her first symptoms appeared at age 55, with subtle gait dysfunction and then evident imbalance. By age 57, there was concern over progressive withdrawal from social interchange, personality changes, and impairment of judgment. By age 59, she was experiencing bouts of inappropriate out-ofcontext laughter and tears, inattention, daytime fatigue, and frank memory impairment. She developed visuoperceptive changes and difficulties using the television remote control device. She developed obsessive checking behaviors. She started having swallowing difficulties but nonetheless had unexpected weight gain. She developed progressively worse motoric problems, with stiffness, abnormal posturing, a left toe pointing upward, and falls. Her medical history was significant only for restless legs syndrome, hypertension, hyperlipidemia, myopia, and a deviated nasal septum. Her family history revealed that her father was alive and well at approximately age 90 years, and her mother had died at approximately age 80 years with a history of neuropsychiatric disease and gait change. There was no history of tobacco, excess alcohol, or recreational drug use. General examination findings were noncontributory. Neurological examination revealed abnormal mental status, with full orientation and good registration, concentration, digit span, and language function but with poor calculations and constructions (Figure 1A) and decreased short-term memory. Nonetheless, her Mini-Mental State Examination score was 28 of 30. Cranial nerve examination revealed some decreased upgaze and mild facial masking. Motor examination revealed rigidity and dystonic posturing in the left arm and leg, imbalance on gait, decreased arm swing, and retropulsion but no significant tremor. Sensory examination findings were normal. Reflex examination showed mild left hyperreflexia with an upgoing left toe. Blood and urine laboratory study results were within normal limits. Cerebrospinal fluid was unremarkable except for biomarkers that showed a mid-range β-amyloid 42 level of 530 pg/mL and normal total tau and phosphotau levels of 182 and 25 pg/mL, respectively. Magnetic resonance imaging of the brain was reported as unremarkable (Figure 1B). Positron emission tomography (PET) imaging of the brain revealed right frontotemporoparietal hypometabolism with some sensorimotor sparing (Figure 1C), which was neither typical nor atypical of Alzheimer disease. Electroencephalography showed left frontotemporal sharp waves and slowing. She had continued progressive decline in cognition and motor function and died almost mute and bedridden in her early 60s after a 9-year course of illness. jamaneurology.com
WHAT IS YOUR DIAGNOSIS?
A. Alzheimer disease, frontal variant B. Frontotemporal dementia C. Progressive supranuclear palsy D. Corticobasal degeneration E. Spinocerebellar ataxia
(Reprinted) JAMA Neurology May 2015 Volume 72, Number 5
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Yale University User on 05/16/2015
597
Clinical Review & Education JAMA Neurology Clinical Challenge
Diagnosis C. Progressive supranuclear palsy
Discussion During her life, the patient’s diagnoses included frontotemporal dementia (because of her behavioral changes, with relative preservation of cognition early on), progressive supranuclear palsy (because of her motor changes, including falls), and corticobasal syndrome (because of her markedly asymmetric dystonia). However, progressive supranuclear palsy was the most likely diagnosis because of the early features of imbalance and falls, parkinsonism without tremor, and marked midbrain atrophy visible on magnetic resonance (MR) imaging (hummingbird sign is seen in the sagittal midline slice [top right of Figure 2]).1-5 Alzheimer disease was unlikely because of the lack of early memory change, the MR imaging and PET results, and the normal tau and phosphotau levels in cerebrospinal fluid. While there was considerable imbalance and cerebellar atrophy, the asymmetric examination findings, prominent brainstem atrophy, cognitive changes,3 and lack of dysmetria, nystagmus, or other classic cerebellar signs all militated against spinocerebellar degeneration. Although the asymmetric motor examination results could be indicative of corticobasal ganglionic degeneration (corticobasal degeneration), these findings can also be seen in progressive supranuclear palsy. The lack of a classic pattern of bicentral hypometabolism on PET, the presence of marked midbrain tectal atrophy2 and dysphagia, and the absence of alien limb or dysgraphesthesia all make corticobasal syndrome less likely. Finally, while several features were suggestive of behavioral variant frontotemporal degeneration, the presence of such prominent motor signs and symptoms early in the disease course, as well as the MR imaging and PET results, makes such a diagnosis less likely. The diagnosis of progressive supranuclear palsy
Figure 2. Brain magnetic resonance imaging (same as Figure 1B) was interpreted as “normal” but in fact shows marked midbrain atrophy, most prominent in the tectum (yellow arrowhead), and also evident in the “hummingbird” sign seen on sagittal image (white arrowhead).
(Steele-Richardson-Olszewski syndrome) was confirmed at autopsy.1,5 Throughout the cortex and subcortical gray nuclei, a diffuse and severe burden of glial phosphorylated tau pathology was observed, evidenced through immunohistochemical staining with antibody AT8. There were frequent tufted astrocytes, scattered neuronal and glial tangles, marked gliosis, and glial cytoplasmic inclusions in the white matter. Neuronal losses in the substantia nigra, pars compacta, and pars reticulata were severe. There were few neuronal tangles and no evident plaques using immunohistochemical stains for β-amyloid. Finally, there was no evidence of α-synuclein aggregates (as seen in Lewy body disease) or transactive response DNA-binding protein 32 (TDP-43) abnormalities (as seen in some frontotemporal dementia disorders).
Conflict of Interest Disclosures: None reported.
ARTICLE INFORMATION Author Affiliation: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Gertrude H. Sergievsky Center, and Department of Neurology, Columbia University Medical Center, New York, New York. Corresponding Author: Lawrence S. Honig, MD, PhD, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Gertrude H. Sergievsky Center, and Department of Neurology, Columbia University Medical Center, 630 W 168th St (Physicians and Surgeons Unit 16), New York, NY 10032 ([email protected]).
REFERENCES 1. Litvan I, Hauw JJ, Bartko JJ, et al. Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders. J Neuropathol Exp Neurol. 1996; 55(1):97-105. 2. Rolland Y, Vérin M, Payan CA, et al; NNIPPS Study Group. A new MRI rating scale for progressive supranuclear palsy and multiple system atrophy: validity and reliability. J Neurol Neurosurg Psychiatry. 2011;82(9):1025-1032.
3. Burrell JR, Hodges JR, Rowe JB. Cognition in corticobasal syndrome and progressive supranuclear palsy: a review. Mov Disord. 2014;29 (5):684-693. 4. Magdalinou N, Lees AJ, Zetterberg H. Cerebrospinal fluid biomarkers in parkinsonian conditions: an update and future directions. J Neurol Neurosurg Psychiatry. 2014;85(10):10651075. 5. Murray ME, Kouri N, Lin WL, Jack CR Jr, Dickson DW, Vemuri P. Clinicopathologic assessment and imaging of tauopathies in neurodegenerative dementias. Alzheimers Res Ther. 2014;6(1):1.
Published Online: March 30, 2015. doi:10.1001/jamaneurol.2014.3668.
598
JAMA Neurology May 2015 Volume 72, Number 5 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Yale University User on 05/16/2015
jamaneurology.com
