Diagnosis of Progressive Supranuclear Palsy

Progressive supranuclear palsy (PSP), initially called Steele-Richardson-Olszewski syndrome, is a sporadic neurodegenerative disease.

Mr. D presents to a neurology clinic because of growing concern about frequent falls. He is 65 years old and was in good health until about two years ago when he began falling, often falling backwards. He now falls more frequently than a year ago. His family also noticed a lurching gait and staggering as well as trouble with turning. He also admits to an inability to pick his feet up when walking sometimes. His son says that he tends to walk with an erect posture and his neck appears stiff and extended. They have also noticed changes in his facial expression saying he often looks like he is surprised or staring. His speech becomes slow and not as clear. Sometimes he will trip on objects, as if he does not recognize that they are there. His daughter mentions that he misses food on the portion of the plate closest to him. They note that he seems more impulsive and will laugh or cry inappropriately. His short memory is also getting worse.

Upon examination, the neurologist notices severe limitation in his vertical eye movements, although his vertical oculocephalic reflex remains intact. He also notes slowness with certain tasks such as tapping fingers and toes, opening and closing his hands, and flipping his hands over repeatedly. His neck is quite stiff with limited range of motion when moved passively. When he walks, his trunk and neck are extended, he has reduced arm swing with some guarded posture, and he appears to be staring off into the distance. He nearly falls backwards and has to be caught by the examiner on one turn and has poor postural reflexes on testing.

On a short cognitive test administered, he is found to have mild cognitive impairment. An MRI of the brain is later obtained and shows the “hummingbird sign” (atrophy of the midbrain); PSP-RS (Richarson syndrome) is diagnosed.

Progressive supranuclear palsy (PSP), initially called Steele-Richardson-Olszewski syndrome, is a sporadic neurodegenerative disease. Richardson and colleagues1,2 described a clinicopathologic entity after summarizing a series of cases with vertical supranuclear ophthalmoplegia, pseudobulbar palsy, postural instability and falls, rigidity, bradykinesia, nuchal dystonia and dementia, with pathology of heterogeneous degeneration involving the brain stem, basal ganglia, and cerebellum. This prototype syndrome was later identified as PSP-RS.

Criteria for diagnosis
The National Institute of Neurological Disorders and Stroke and the Society for Progressive Supranuclear Palsy (NINDS-SPSP) diagnostic criteria established in 1996 has been the commonly used standard for the diagnosis for PSP, mainly for PSP-RS.3 A diagnosis of “probable” PSP requires vertical supranuclear gaze palsy and postural instability and falls within 1 year of disease onset.

A diagnosis of possible PSP requires either vertical supranuclear gaze palsy or a combination of slow vertical saccades and postural instability with falls within 1 year. Both diagnoses require a progressive disease course with age at onset of 40 years or older, and mandatory exclusion criteria to rule out PSP mimics such as Parkinson disease, corticobasal ganglionic degeneration, dementia with Lewy bodies, Alzheimer disease, multiple system atrophy, vascular parkinsonism, Whipple disease, postencephalitic parkinsonism, and prion disease. The criteria also indicate supportive symptoms such as symmetric akinesia, proximal more than distal rigidity, retrocollis, poor or no response of parkinsonism to levodopa, early dysphagia and dysarthria, and cognitive impairment of frontal lobe function.

A diagnosis of definite PSP requires a history of probable or possible PSP and pathologic evidence of PSP by the aggregation of the microtubule-associated protein tau (predominantly four microtubule-binding repeats) in neurofibrillary tangles and neuropil threads, astrocytic tufts and oligodendrocytic coils in the brainstem, basal ganglia, diencephalon, and cerebellum, in particular the pallidum, subthalamus, and substantia nigra, accompanied by neuronal loss and gliosis.

The NINDS-SPSP criteria have high specificity useful for research, but low sensitivity making early diagnosis difficult because typical features such as vertical gaze palsy may be absent in early or even advanced stages. In addition, non-PSP-RS forms of PSP with symptoms similar to exclusion-criteria disease mimics are often excluded.4,5

The severity of the tau pathology load and the area involved may explain a different clinical phenotype. PSP variants proposed subsequent to the 1996 criteria include PSP-P (parkinsonism), PSP-OM (oculomotor dysfunction), PSP-I (postural instability), PSP-CBS (cortical basal syndrome), PSP-PAGF (pure akinesia with gait freezing), PSP-F (behavioral variants of frontal temporal lobe dementia), PSP-LS (language and speech, including progressive primary non-fluent aphasia and apraxia of speech), PSP-C (cerebellum), and PSP-PLS (primary lateral sclerosis).2,4,5

Although some reveal themselves in advanced staged, these variants present a persistent challenge for early clinical diagnosis given the lack of unique symptoms, as in PSP-RS (eg, vertical gaze palsy). Many of the PSP variants are diagnosed based on pathology. The lack of down gaze palsy is often the main cause of misdiagnosis, as are the overlap with other forms of parkinsonism and cognitive or behavioral changes.6,7 Moreover, the percentage of PSP variants among autopsy cases may not represent a true percentage in the natural history because of selection bias, with atypical cases more likely to be sent for autopsy. The exact percentage of PSP variants remains unknown. Overall age of onset is 66 years, with disease duration from 5.9 years in PSP-RS to 9.1 years in PSP-P, and an overall average of 8 years.4,5

Biomarkers
The difficulty in clinical diagnosis of PSP variants has motivated a search for biomarkers, which so far are lacking, although several findings are supportive of the diagnosis.8,9 Atrophy of the midbrain on mid-sagittal brain MRI, referred to as the “hummingbird” sign, has been reported to have 100% specificity for PSP-RS but only moderate sensitivity. Midbrain atrophy has been found to correlate with disease progression.10

Quantitative approaches such as the midbrain to pons area ratio and the ratio of middle and superior cerebellar peduncles to the midbrain – pons ratio are also promising. Striatal presynaptic dopamine transporter loss in DaTscanTM does not distinguish PSP from other presynaptic neurodegenerative disorders, such as Parkinson disease, multiple system atrophy, or dementia with Lewy bodies. Functional imaging targeting tau pathology holds promise but is still in the research phase. Genetic biomarkers such as the H1 haplotype of microtubule-associated protein tau or polymorphisms in several other genes are thought to be risk factors, but PSP remains largely a sporadic disease. Cerebrospinal fluid concentrations of total and phosphorylated tau are not increased in PSP patients, unlike Alzheimer disease.

Updated criteria
Given the diagnostic challenges, the movement disorder society recently proposed updated diagnostic criteria.11 Mandatory criteria include age 40 years or older with a gradually progressive course. Exclusion criteria for other diseases include AD, multiple system atrophy, dementia with Lewy bodies, amyotrophic lateral sclerosis (but not primary lateral sclerosis), vascular parkinsonism, encephalitis, encephalopathy, prion disease, ataxia, and identifiable causes of postural instability. In addition, there are context dependent exclusion criteria based on abnormal imaging, lab tests, and genetic findings for PSP mimics.

The core clinical features are classified into 4 domains: oculomotor dysfunction, postural instability, akinesia, and cognitive dysfunction; and 3 levels of certainty in each domain. There are also clinical clues (levodopa resistance, dysarthria, dysphagia, and photophobia) and imaging findings (midbrain atrophy or hypometabolism, and postsynaptic striatal dopaminergic degeneration). The combination of these then forms diagnostic certainty (probable, possible, and suggestive) and predominance type. Definitive PSP remains a pathological diagnosis regardless of clinical presentation. The new criteria cover all PSP variants except PSP-C and PSP-PLS, which are viewed as rare forms. The newly added suggestive form allows a neurologist to have a high suspicion for PSP, which warrants close follow up.

Conclusion
Overall, the diagnosis of PSP remains a challenge, given the nonspecific symptoms among the variants seen in other neurodegenerative diseases, and the late appearance or absence of vertical gaze palsy in some patients. The combination of PSP with other concomitant degenerative disease (such as Alzheimer disease and amyloid disease) makes the diagnosis even more challenging.

The latency of downgaze palsy was seen to have a strong prognostic value in PSP progression in a clinicopathological study, and baseline cognitive function and mood have also been reported to be associated with the progression.6,12

Raising awareness of PSP and close follow-up remain essential for early and accurate diagnosis. Treatment options remain limited. Carbidopa/levodopa and amantadine can be tried in PSP patients, with resting tremor reported to be responsive in some cases, but postural instability and gaze palsy remains refractory to available medications.6 Pedunculopontine nucleus deep brain stimulation remains an inconclusive treatment for axial symptoms. Physical, occupational, speech, and swallow therapy remain mainstays of treatment along with that for cognitive and mood symptoms. Immunotherapy that targets tau pathology is undergoing clinical trials.

References:

1. Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. a heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch Neurology. 1964;10:333-359.
2. Williams DR, Lees AJ, Wherrett JR, Steele JJ. Clifford Richardson and 50 years of progressive supranuclear palsy. Neurology. 2008;70:566-573.
3. Litvan I, Agid Y, Calne D, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology. 1996;47:1-9.
4. Williams DR, di Silva R, Paviour DC, et al. Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson’s syndrome and PSP-parkinsonism. Brain. 2005;128:1247-1258.
5. Respondek G, Stamelou M, Kurz C, et al. The phenotypic spectrum of progressive supranuclear palsy: a retrospective multicenter study of 100 definite cases. Mov Disord. 2014;29:1758-1766.
6. Xie T, Kang UJ, Kuo SH, et al. Comparison of clinical features in pathologically confirmed PSP and MSA patients followed at a tertiary center. NPJ Parkinsons Dis. 2015. https://www.nature.com/articles/npjparkd20157.pdf. Accessed February 5, 2018.
7. Birdi S, Rajput AH, Frenton M, et al. Progressive supranuclear palsy diagnosis and confounding features: report on 16 autopsied cases. Mov Disord. 2002;17:1255-1264.
8. Whitwell J, Hoglinger GU, Antonini A, et al. Radiological biomarkers for diagnosis in PSP: where are we and where do we need to be? Mov Disord. 2017;32:955-971.
9. Boxer AL, Yu JT, Golbe LI, et al. Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches. Lancet Neurol. 2017;16:552-563.
10. Dutt S, Binney R, Heuer HW, et al. Progreesuib of brian atrophy in PSP and CBS over 6 months and 1 year. Neurology. 2016;87:2016-2025.
11. Hoglinger GU, Respondek G, Stamelou M, et al. Clinical diagnosis of progressive supranuclear palsy: the movement disorder society criteria. Mov Disord. 2017;32:853-864.
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