Is Pallido‐Pyramidal Syndrome Still a Useful Concept? No

A syndrome is a characteristic collection of symptoms and signs that tend to cluster together. It is sometimes unique to a single disease but more commonly has multiple potential aetiologies. However, the identification of a syndrome limits the list of etiological differential diagnoses and guides diagnostic investigations and/or management.1

The term pallido‐pyramidal disease, revised to pallido‐pyramidal syndrome (PPS) by subsequent authors and used hereafter to denote either, was coined by Davison in 1954 to denote the combination of parkinsonism and bilateral pyramidal signs.2 His report was based on clinical findings observed in 5 patients, and a genetic aetiology was presumed as a result of the familial occurrence of the syndrome in 4 patients. Postmortem examination of the fifth, sporadic case, originally regarded by Ramsay Hunt as having dyssynergia cerebellaris progressiva but who then evolved into a parkinsonism syndrome with bilateral Babinski and pyramidal signs, showed pallor and bluish pigmentation of the globus pallidus, mild shrinkage with neuronal loss and depigmentation in the substantia nigra, and signs of demyelination of the corticospinal tract. Occasional reports subsequently appeared of other patients with PPS but use of the term has increased particularly in the past decade, mostly in the context of describing the phenotype of patients with genetically determined, young‐onset or juvenile‐onset parkinsonism.

Here we argue that the term PPS is not useful in clinical practice and should be abandoned for several reasons. First, the clinicopathological concept of PPS is misleading as evidence suggests that pallidal pathology of itself does not cause the tremulous parkinsonism that is integral to the syndrome. Second, PPS is not a valid pathological entity as there are no known diseases that affect only the pallidum and pyramidal system without affecting other structures. Third, although various genetically determined movement disorders have been reported as being causes of PPS because parkinsonism and pyramidal signs are frequently part of their phenotype, their relationship to the underlying etiology in the originally reported patients is unknown. Therefore, in agreement with and as similarly argued by others,3 we propose that the term PPS be abandoned and be replaced by the more valid formulations of parkinsonism–pyramidal3, 4 and dystonia–pyramidal1 syndromes. In contrast to PPS, these alternative syndromic formulations do have diagnostic value as they have been proven to be associated with specific etiologies, especially genetic movement disorders.

Is PPS a Valid Clinicopathological Entity?

Clinico‐radiological correlation studies of patients with pallidal lesions have shown that there are 2 major associated syndromes: dystonia and parkinsonism. Neuropsychiatric disorders such as abulia or akinetic mutism have also been reported with bilateral pallidal lesions.5

Hemidystonia and generalized dystonia can develop after contralateral or bilateral lesions of the globus pallidus, respectively.6 According to Davison's clinical description, only 1 of the patients had abnormal postures suggestive of lower limb dystonia. Rather than dystonia, all 5 of Davison's patients had tremor (3 with typical rest tremor, including the autopsied case), bradykinesia, and gait abnormalities.2 His suggested nosology of PPS assumed that the pallidal pathology was responsible for parkinsonism with tremor. However, according to contemporary series, rest tremor has not been reported with isolated pallidal lesions.7 Bilateral lesions of the pallidum cause atypical rather than typical parkinsonism, manifest as predominant akinesia and freezing of gait.8 As hinted by the pathological findings of Davison, it could be argued that substantia nigra pathology could have been the main pathophysiological mechanism of parkinsonism and not the changes in the pallidum. At present, a well‐established concept is that all tremors involve a cerebellar–thalamic network and that nigrostriatal denervation is a prerequisite for the development of rest tremor.9 In support of this view, patients diagnosed as PPS with levodopa responsiveness have been shown to have nigrostriatal denervation in [18F] fluorodopa positron emission tomography studies, suggesting that the pathophysiology of that parkinsonism is mainly from the nigral pathology.10 In terms of the specificity of pallidal lesions causing dystonia, freezing of gait, and parkinsonism, lesion‐mapping studies in patients with these disorders suggest that damage to a functional brain network rather than a specific brain location can cause any of these manifestations.7

A further challenge to defining PPS is the absence of criteria for the diagnosis of the pyramidal component. Although Davison described hyperreflexia, spasticity, a Babinski sign, and absent abdominal reflexes as part of the pyramidal syndrome, there was no mention of weakness in his patients. The problem of a syndrome with a lack of well‐defined criteria is that the inclusion or exclusion of certain features (weakness in this case) can modify the diagnostic sensitivity and specificity. Increased tendon jerks can occur in Parkinson's disease11 and, when tested objectively, spasticity and rigidity cannot be reliably differentiated.12 A striatal toe mimicking a Babinski response can be observed in dystonia13 and parkinsonism.14 Patients with Parkinson's disease are weaker than controls, including in leg muscles.15 Therefore all of the features of the upper neuron syndrome that are used to determine the presence of spasticity or pyramidal dysfunction16 can be observed in parkinsonism or dystonia. Interestingly, in the pathologically examined case in the original report, the extensor plantar response was interpreted as a dystonic toe by Ramsay Hunt and as a Babinski sign by Davison.2, 3

The core clinical features of PPS have also been expanded and therefore become less specific over time. Dystonia is now regarded as part of the syndrome even though none of Davison's patients had this feature.17 This reduces its usefulness in clinical practice as the syndromic diagnoses of parkinsonism with pyramidal signs versus dystonia with pyramidal signs have different, albeit overlapping, etiological differential diagnoses, including different appropriate pathways for genetic investigations (Parkinson's panel vs. dystonia panel). Perhaps because of the ambiguities and uncertainties in how to define PPS, it has even been suggested that the syndrome of dystonia–parkinsonism that most commonly characterises diseases that cause neurodegeneration with brain iron accumulation (NBIA) should be replaced with the label of PPS.18 Genes that cause neurodegeneration with brain iron accumulation syndromes can manifest a wide phenotypic spectrum that includes dystonia, parkinsonism, and pyramidal involvement,19 and neither term alone reflects this complexity.

Is PPS a Valid Pathological Concept?

In Davison's original series, pathology was available for 1 of his 5 patients, the only sporadic case. Further characterization of the histopathology with protein staining and molecular studies were not available at that time. Therefore, the precise pathological diagnosis that would be applied in the modern era, and whether his case represents a known or novel entity, remain unknown.

Although a number of genetic and neurodegenerative diseases in which the pallidum and corticospinal tracts are prominently affected are known, in these conditions other brain regions are also involved, and most are phenotypically different from PPS. For example, probably one of the more frequent conditions that leads to childhood‐onset progressive combined dystonia with pyramidal signs is the syndrome of hypomyelination with atrophy of the basal ganglia and cerebellum syndrome, most commonly caused by TUBB4A mutations. Pathologically, there is degeneration of the pallidum and atrophy of the internal capsule with hypomyelination of the white matter tracts, but also the involvement of many other structures including the putamen and cerebellum,20 and parkinsonism has not been reported.

Another example of a disease that can show both pallidal and pyramidal involvement pathologically, among other findings, is PANK2‐associated neurodegeneration. The neuropathology is characterized by prominent selective involvement of the globous pallidus with neuroaxonal spheroids, a nonspecific marker of axonal degeneration, whereas the substantia nigra shows only mild atrophy.21 The dominant phenotype of PANK2‐associated neurodegeneration is childhood‐onset progressive combined dystonia, and much more rarely, adult‐onset akinetic‐rigid parkinsonism with freezing of gait, although pyramidal signs can be seen in some patients. Other well‐defined clinicopathological entities such as multiple system atrophy can also show atrophy of the pallidum and corticospinal tracts in addition to the substantia nigra and putamen.21

Despite these examples, given that there is no clinicopathological entity that solely affects the globus pallidus and pyramidal system, it becomes difficult to attribute a particular clinical presentation to pallido‐pyramidal as opposed to more widespread basal ganglia pathology, casting further doubt about the meaningfulness of the clinico‐pathological term PPS.

Is PPS a Valid Genetic Entity?

As a result of the limitations in knowledge of the science of molecular genetics at the time of the original report, a genetic basis of PPS in Davison's familial cases, although highly likely, was never proven. Nonetheless, neurologists have continued to use the term PPS, especially in association with both sporadic cases and affected sibships where a hereditary condition is suspected. Since the introduction of molecular genetics to the field of movement disorders, several genes have been described as having a PPS phenotype, including in initial reports Parkin, FBXO7, ATP13A2, C19orf12, and alpha‐synuclein mutations. However, the large number of different gene mutations that have been subsequently reported as causing parkinsonism with pyramidal signs makes this syndromic diagnosis nonspecific.4 Furthermore, in many of these genetic disorders, these signs are only part of the phenotypic spectrum, leading to poor specificity for a given molecular abnormality. Conversely, conditions classically considered as PPS can present as isolated parkinsonism without pyramidal signs, including FBXO7 22 and ATP13A2 mutations.23

Should the Concept of PPS Be Abandoned?

We have provided evidence that the clinical findings of tremulous parkinsonism in the original and many subsequently reported patients with PPS are unlikely to actually arise from pallidal pathology. We are also unaware of any pathological or genetic entities that solely affect the pallidum and pyramidal systems. There is evidence that dopamine deficiency as a result of nigral pathology is the most likely pathophysiological underpinning of parkinsonism in PPS. Although bilateral pallidal lesions can cause atypical parkinsonism, often with neuropsychiatric manifestations, isolated unilateral or bilateral pallidal lesions most typically produce dystonia. Therefore, we agree with others who have also suggested that the term PPS is both inaccurate and ambiguous and should be abandoned.3, 4

Davison's observation of a distinct syndrome of parkinsonism and pyramidal impairment, however, remains clinically useful despite being inaccurately named and should be revised simply to the concept and terminology of parkinsonism–pyramidal syndromes. Where dystonia, with or without parkinsonism, is the dominant movement disorder occurring with pyramidal signs, the syndromic term dystonia with spasticity (with or without parkinsonism) has previously been suggested,1 although to align the two, dystonia–pyramidal syndrome could easily be substituted. These suggested terms also have the advantage of, in the individual patient, avoiding the assumption that the specific pathology of a specific anatomical site is responsible for what is often complex movement disorder phenomenology. This usually cannot be assumed in the setting of neurodegenerative or genetically determined diseases, as opposed to a patient with distinct structural lesions. Specifying parkinsonism versus dystonia as the dominant movement disorder associated with pyramidal signs will also allow more accurate diagnostic testing, including with next‐generation genetic testing pathways.

Author Roles

1) Research project: A. Conception, B. Organization, C. Execution; 2) Statistical Analysis: A. Design, B. Execution, C. Review, and Critique; 3) Manuscript: A. Writing of the first draft, B. Review, and Critique.

H.M.‐B.: 1A, 1B, 1C, 3A

V.S.C.F.: 1A, 1B, 1C, 3A, 3B

Disclosures

Ethical Compliance Statement: The authors confirm that they have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Informed patient consent was not necessary for this work.

Funding Sources and Conflicts of Interest: The authors have nothing to report.

Financial Disclosures from the Previous 12 Months: H.M.‐B. has nothing to disclose. Dr Fung receives a salary from NSW Health, has received unrestricted research grants from the Michael J Fox Foundation, Abbvie and Merz, is on Advisory Boards and/or has received travel grants from Abbvie, Allergan, Cavion, Ipsen, Merz, Praxis, Seqirus, Stada, Teva and UCB, and receives royalties from Health Press Ltd.