eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases

Progressive Supranuclear Palsy: Differential Diagnoses & Workup

Author: Eric R Eggenberger, DO, MS, FAAN, Professor, Vice-Chairman, Department of Neurology and Ophthalmology, Colleges of Osteopathic Medicine and Human Medicine, Michigan State University; Director of Michigan State University Ocular Motility Laboratory; Director of National Multiple Sclerosis Society Clinic, Michigan State University
Coauthor(s): Zeba F Vanek, MD, MBBS, DCN, Associate Professor of Neurology, David Geffen School of Medicine at UCLA; Director, UCLA Spasticity Clinic
Contributor Information and Disclosures

Updated: Sep 4, 2009

Differential Diagnoses

Absence Seizures
Neuroacanthocytosis
Alzheimer Disease
Neuroacanthocytosis Syndromes
Amyotrophic Lateral Sclerosis
Normal Pressure Hydrocephalus
Apraxia and Related Syndromes
Olivopontocerebellar Atrophy
Catatonia
Parkinson Disease
Cortical Basal Ganglionic Degeneration
Parkinson Disease in Young Adults
Dementia in Motor Neuron Disease
Parkinson-Plus Syndromes
Dementia With Lewy Bodies
Pelizaeus-Merzbacher Disease
Dizziness, Vertigo, and Imbalance
Prion-Related Diseases
Hallervorden-Spatz Disease
Syringomyelia
Huntington Disease
Whipple Disease
Multi-infarct Dementia
Wilson Disease
Multiple System Atrophy
Myasthenia Gravis

Other Problems to Be Considered

The diagnosis of PSP is clinical. The key features typically develop over time; although the full-blown picture may be relatively easy to recognize, the early or restricted cases are much more challenging (see Physical).

Other diagnoses in the differential

Cortical-basal ganglionic degeneration (alien limb syndrome, cortical sensory deficits, limb apraxia, dystonia, asymmetric bradykinesia)
Parkinson disease (tremor-dominant disease, levodopa response)
Lewy body dementia (hallucinations, cortical dementia with aphasia, parkinsonism)
Multiple system atrophy (prominent cerebellar symptoms, autonomic dysfunction, parkinsonism)
Whipple disease (ocular-masticatory myorhythmia, polymerase chain reaction [PCR] confirmation)
Creutzfeldt-Jakob disease (duration <1 y with dementia, myoclonus, abnormal findings on EEG)
Multi-infarct dementia (focal features, imaging findings)
Hydrocephalus and normal pressure hydrocephalus (dementia, urinary dysfunction, gait abnormality, imaging findings)
Rigid form of Huntington disease (family history, findings on genetic test)
Machado-Joseph Azorean disease (family history, cerebellar signs, findings on genetic test)
Wilson disease (Kayser-Fleischer rings, earlier onset, copper metabolic abnormalities)
Motor neuron disease (lower motor neuron signs, abnormal electromyograph [EMG] findings)
Myasthenia gravis (episodic weakness, abnormal EMG findings)
Amblyopia

Workup

Laboratory Studies

  • Workup is directed principally at eliminating other diagnoses.
  • Borroni and colleagues have proposed evaluation of tau forms in CSF as a reliable biomarker for PSP.25 CSF contains both extended (55 kDa) and truncated (33 kDa) tau forms, and the ratio of tau 33 kDa to 55 kDa is significantly lower in PSP than in other neurodegenerative disorders. In their study, the tau form ratio was 0.504 (+/- 0.284) in patients with PSP, versus 0.899-1.215 in patients with other neurodegenerative conditions and 0.989 (+/- 0.343) in age-matched controls. In addition, decreased tau form ratio correlated significantly with brainstem atrophy, as assessed by voxel-based morphometry.
  • Whipple PCR may be helpful in eliminating the possibility of Whipple disease, a treatable infectious disorder.

Imaging Studies

  • Magnetic resonance imaging
    • Although in early stages an MRI of the brain offers little help, in some advanced cases, the following may be present26,27,28,29,30 :
      • atrophy of the mid brain with cisternal and ventricular dilatation, thinning of the quadrigeminal plate, dilation of the third ventricle, and a nonspecific finding of increase in proton density images in the periaqueductal gray matter compatible with gliotic changes


    • Righini and colleagues reported the usefulness of midsagittal T1-weighted MRI appearance of the superior profile of the midbrain; the appearance of a flat or concave profile (as opposed to the normal convex profile) was associated with a 68% sensitivity and an 89% specificity for the diagnosis of PSP compared with patients with Parkinson disease.31
    • These findings are not pathognomonic of PSP, and components of these imaging findings may be observed in several other diseases in the differential diagnosis.
  • Neuroimaging: Neuroimaging is often performed to eliminate other entities in the differential diagnosis. The presence of significant abnormalities (eg, large vessel ischemic disease, hydrocephalus) casts doubt on the diagnosis of PSP. Functional neuroimaging includes positron emission tomography (PET) and single-photon emission computed tomography (SPECT).
    • PET: These studies may help reveal physiopathologic aspects of the disease. PET studies have shown a global cerebral hypometabolism with relative selectivity in the frontal cortex.32,33,34 Regional cerebral blood flow and oxygen metabolism are decreased in the caudate and putamen and impaired in the thalamus and the brain stem. PET studies have also documented significantly lowered glucose metabolism in the midbrain compared with controls.35  Fluorodopa (F-dopa) PET has shown a reduction in the F-dopa influx in the caudate and putamen. In idiopathic Parkinson disease, the caudate is affected less severely; therefore, this finding can help in distinguishing these conditions.36 The costs of PET studies and their limited availability restrict this technique to experimental trials.
    • SPECT: Striatal dopamine receptor binding is reduced in some patients with PSP with I iodobenzamide SPECT. This can be used to distinguish vascular white matter lesions from PSP.37

Other Tests

  • Sleep studies
    • Sleep patterns are often abnormal in individuals with PSP. Polysomnograms show diminished total sleep time, increased awakenings, progressive loss of rapid eye movement (REM) sleep,38,39 and decreased REM–to–non-REM (NREM) quotient.40,41
    • REM sleep behavior disorder, consisting of motor activity associated with vivid dreams during REM sleep, also occurs in individuals with PSP.
    • These abnormalities are not specific for PSP. For example, Sixel-Döring et al found that although polysomnographically recorded sleep is more severely impaired in PSP than in Parkinson disease, patients with PSPS and those with Parkinson disease showed no difference in Parkinson Disease Sleep Scale scores.42

Histologic Findings

The histopathology of PSP involves diffuse brainstem disease. Neuronal loss, NFTs, and gliosis affect the reticular formation and ocular motor nuclei. Early pathology is evident primarily in the mid brain, perhaps explaining the early vertical eye movement characteristics. The pontine nucleus raphe interpositus and pedunculopontine and deep pontine nuclei are also affected.

  • The distribution and ultrastructure of NFTs in PSP is distinct from those found in Alzheimer disease. PSP is associated with more subcortical involvement, with 15- to 20-nm wide single tubules, compared to the cortically based paired helicoidal filaments of Alzheimer disease.
  • In one series, examination of PSP cases revealed the uniform presence of t -positive cortical lesions. These were found in highest concentration in the precentral and angular gyrus, primarily affecting the deep cortical layers, and involved both small and large neurons. These characteristics are distinct from the NFT pattern observed in Alzheimer disease. NFT concentration analysis appeared to implicate the pedunculopontine nucleus in lesion spread.

Although NFTs are the histologic hallmarks of PSP, neuropil threads have also been found extensively.

Besides the brainstem structures, the striatum, medial pallidum, subthalamic nucleus, and the substantia nigra are also affected.

Many questions are unanswered about the pathologic features linking PSP, Alzheimer disease, idiopathic Parkinson disease, and, in particular, corticobasal degeneration. Further ultrastructural and genetic studies are needed to reveal the cause and the pathogenesis of the disease.

More on Progressive Supranuclear Palsy

Overview: Progressive Supranuclear Palsy
Differential Diagnoses & Workup: Progressive Supranuclear Palsy
Treatment & Medication: Progressive Supranuclear Palsy
Follow-up: Progressive Supranuclear Palsy
References
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Further Reading

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Keywords

Steele-Richardson-Olszewski syndrome, PSP, parkinsonism, neurodegenerative disease, imbalance, immobility, dementia, visual symptoms, dysphagia, dysarthria, vertical gaze palsy

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Contributor Information and Disclosures

Author

Eric R Eggenberger, DO, MS, FAAN, Professor, Vice-Chairman, Department of Neurology and Ophthalmology, Colleges of Osteopathic Medicine and Human Medicine, Michigan State University; Director of Michigan State University Ocular Motility Laboratory; Director of National Multiple Sclerosis Society Clinic, Michigan State University
Eric R Eggenberger, DO, MS, FAAN is a member of the following medical societies: American Academy of Neurology, American Academy of Ophthalmology, American Osteopathic Association, and North American Neuro-Ophthalmology Society
Disclosure: Nothing to disclose.

Coauthor(s)

Zeba F Vanek, MD, MBBS, DCN, Associate Professor of Neurology, David Geffen School of Medicine at UCLA; Director, UCLA Spasticity Clinic
Zeba F Vanek, MD, MBBS, DCN is a member of the following medical societies: Movement Disorders Society
Disclosure: Nothing to disclose.

Medical Editor

Joseph Quinn, MD, Assistant Professor, Department of Neurology, Portland VA Medical Center, Oregon Health Sciences University
Joseph Quinn, MD is a member of the following medical societies: American Academy of Neurology, Society for Neuroscience, and Society for Pediatric Radiology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Nestor Galvez-Jimenez, MD, MSc, MHA, Chairman, Department of Neurology, Program Director, Movement Disorders, Department of Neurology, Division of Medicine, Cleveland Clinic Florida
Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical societies: American Academy of Neurology, American College of Physicians, and Movement Disorders Society
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

 
 
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