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30 Atypical Parkinsonism Andrew Lees

Diagnosis is a system of more or less accurate guessing in which the end point achieved is a name. These names applied to disease come to assume the importance of specific entities, whereas they are for the most part no more than insecure and temporary conceptions. —Sir Thomas Lewis (1931)

Despite its imprecision, atypical parkinsonism is a useful clinical term. It unites a group of disorders linked by the predominant presence of bradykinesia, but where additional clinical features exclude Parkinson’s disease (PD; hence the analogous but currently less-favored term Parkinson’s plus). In most cases, disease progression is rapid and relentless and the response to dopaminergic drugs minimal or temporary. Multiple system atrophy (MSA) is the most common example among the primary neurodegenerations, but a substantial number of cases are found at autopsy to have neurofibrillary tangle degeneration, or a combination of neocortical and subcortical Lewy bodies. Extensive subcortical cerebrovascular disease without additional neurodegenerative pathological change is another relatively common cause, but one that presents considerable diagnostic difficulties in clinical practice. Because so many of these pathologies carry a grim and hopeless prognosis, the delicate nuance of uncertainty implicit within the term atypical parkinsonism may be preferable to a more precise alternative clinical label. Nonetheless, names given to neurological disorders assume great importance, both within the medical profession and for those individuals who acquire them: “giving a name to the enemy,” however baleful, is often greeted, at least initially, with a sense of relief— “better the devil you know!” Division into more precise nosological entities is also essential for research. MSA is a synucleinopathy whereas progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are four-repeat primary tauopathies. Erroneous inclusion of cases of vascular Parkinson’s syndrome could invalidate a genetic study on MSA or an epidemiological study of PSP. Recent clinico-pathological studies of Parkinson’s syndromes have led to an increased awareness among neurologists of MSA of the parkinsonism type (MSA-P, striatonigral degeneration, Shy– Drager syndrome), vascular Parkinson’s syndrome, and a motley collection of conditions united by the abnormal accumulation of hyperphosphorylated tau protein in the brain and subcortical neurofibrillary degeneration. The best-recognized conditions in this group are PSP, CBD, and frontotemporal dementia with parkinsonism (FTDP). Much rarer, but of great contemporary interest, are the inherited heavy-metal storage disorders including Hallervorden–Spatz disease and HARP syndrome (recessively inherited and caused by mutations in pantothenate kinase 2 [PANK 2] on chromosome 20), neuroferritinopathy (dominantly inherited and caused by a light ferritin chain mutation on

From: Current Clinical Neurology: Atypical Parkinsonian Disorders Edited by: I. Litvan © Humana Press Inc., Totowa, NJ

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chromosome 19),Wilson’s disease (recessively inherited and caused by mutations of copper-transporting P-type ATPase on chromosome 13), and acaeruloplasminaemia (recessively inherited and caused by mutations of the caeruloplasmin gene on chromosome 3). As concepts of what constitutes the clinical picture of PD continue to evolve, our definition of atypical Parkinsonism will also be modified. For example, early autonomic failure, early severe dementia, a negative response to 1000 mg per day of L-dopa for at least 6 wk, and more than one affected firstdegree relative have been considered “red flags” for atypical parkinsonism, and yet all of these have been linked with Lewy body pathology in clinico-pathological studies (1). On the other hand, “minimal change” MSA with an excellent sustained response to L-dopa may be indistinguishable from PD throughout the whole course of the illness (2). A 4–6 Hz “pill-rolling rest tremor” remains the single best clinical marker for PD (3) but a few patients never notice one; in others it may be slight and unobtrusive, and some lose their rest tremor completely as the clinical picture evolves (4) Greater attention to olfaction in the clinical examination may become important as preliminary data indicate that the majority of patients with PD and dementia with Lewy bodies (DLB) have hyposmia, whereas olfactory discrimination in vascular Parkinson’s, PSP, CBD, and parkin mutations is usually normal (5). Formed visual hallucinations, which occur commonly in PD and DLB, are extremely rare in MSA, PSP, and CBD and may be another rather neglected red flag for PD especially in the absence of any associated dementia. PSP (Steele–Richardson–Olszewski disease) is usually included as an important cause of atypical parkinsonism, but Richardson in his seminal descriptions emphasized the marked clinical differences between PSP and PD, although he later conceded that the phenomenology of PSP was likely to broaden with greater clinical awareness and further pathological study (6). L-Dopa-unresponsive symmetrical bradykinesia with prominent axial involvement, preserved downgaze, and extensive subcortical neurofibrillary tangle formation is now recognized as one of the more common causes of atypical parkinsonism, but it is questionable whether this should be included as a clinical variant of Steele– Richardson–Olszewski disease (7,8). CBD, a much rarer clinico-pathological entity, is also included in the list of neurodegenerative disorders presenting with parkinsonism. Despite this, a presentation with predominant parkinsonism must be extraordinarily rare as unilateral myoclonus, jerky tremor, rigidity, cortical sensory loss, dyspraxia, and dystonia usually dominate the clinical picture. Much interest is at present focused on the parkinsonian signs seen in DLB. This clinical syndrome first described by Kosaka and other Japanese colleagues presents with prominent cognitive decline, delirium, and visual hallucinations, usually in the seventh and eighth decades of life, but the histopathological findings cannot be reliably distinguished in an individual case from those found in PD. Many of these cases also have extensive additional neocortical neurofibrillary tangles, hence the alternative name “Lewy body variant of Alzheimer’s disease.” However, there is a very interesting group of young patients with pure diffuse cortical and subcortical Lewy body pathology who present with rapidly progressive dementia, behavioral disturbance, and atypical parkinsonism (9). Parkinsonism is seen at some stage in most cases of DLB and it has been reported that the therapeutic response to L-dopa is poorer and rest tremor less frequent and intrusive than in PD (10). However, it is my clinical impression that the L-dopa response is also less striking in many elderly PD patients— especially when there is associated cognitive impairment (11)—and it is now accepted that rest tremor may disappear in the later stages of PD. It seems justified on clinical grounds to distinguish PD and DLB, but from a molecular biological perspective both are likely to share very similar if not identical pathological processes. In comparison with PD the atypical Parkinson’s syndromes are all uncommon, at least in Caucasians. There are some very preliminary data to suggest that atypical features, including a poorer response to L-dopa, may be more common in Africans and Indians with presumed PD, and that an increased frequency of comorbid cerebrovascular disease or associated diabetes mellitus does not account for this difference (12,13). In one South London movement disorder clinic survey, the percentage of atypical parkinsonism was found to be 22% in black African and African/Caribbean

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patients and 20% in South Asian patients compared to 7% in whites (14) This raises the interesting possibility that the phenotype of PD may vary somewhat from race to race, but pathological diagnosis is needed to take this interesting possibility further. A higher incidence of atypical parkinsonism has also been reported among the Chamorros of the Mariana Islands (bodig) (15), the Afro-Caribbean population of the French Antilles (16) and the indigenous population of New Caledonia. For example in Guadeloupe, of 220 consecutive patients examined at the CHU Pointe a Pitre, 26.5% fulfilled National Institute of Neurological Disorders and Stroke (NINDS) criteria for PSP and 43.8% were unclassifiable using available published clinical criteria for the recognized parkinsonian syndromes (17). The possibility that cycad or annonacae toxicity may explain these geographic clusters of atypical parkinsonism has been proposed: however, genetic factors may also be important and it is now recognized that spinocerebellar ataxia (SCA) 2 and SCA 3 may present with atypical parkinsonism particularly in Afro-Caribbean and Oriental populations (18–20). Huntington’s disease is another autosomal dominantly inherited disorder that occasionally presents with atypical parkinsonism in middle age (21). Neuroleptic-provoked Parkinson’s syndrome, which is often clinically indistinguishable from PD in the elderly, remains a much more common condition than MSA, PSP, or DLB, although it seems likely that more judicious use of the older antipsychotic drugs and employment of the newer drugs with reputedly fewer extrapyramidal side effects may have reduced its frequency a little. There is a poor or negligible response to L-dopa (22), so if the history of neuroleptic intake is overlooked these cases may be misdiagnosed as MSA or PSP (23). A proportion of elderly-onset cases do not improve even a year after neuroleptic withdrawal, indicating that the drug has probably unmasked latent PD. The clinical diagnosis of vascular Parkinson’s syndrome remains at best an insecure one. Most neurologists now recognize the syndrome of “lower half parkinsonism” with a broad-based, shuffling gait and freezing, with only minimal hand bradykinesia, hypomimia, and often normal speech. Diffuse cerebrovascular disease, especially if there is a history of hypertension, is the most common pathological finding. Striatal cerebrovascular disease is, however, a relatively common associated pathological finding in the elderly parkinsonian patient (1) and it is probable that in some patients this modifies the clinical picture. Parkinsonism following a stroke is less well accepted, but there are a number of reported cases in the literature with supportive neuroimaging or pathological confirmation (24,25). In the absence of specific biological or genetic markers for any of the neurodegenerative processes associated with atypical Parkinson’s syndromes, their diagnosis and differentiation depend primarily on scrupulous history taking and a full clinical examination. Diagnosis of the established classical presentation of MSA or PSP is straightforward but “overlap syndromes,” “atypical presentations,” and early incomplete clinical pictures are frequent, and pose formidable challenges. A recent crosssectional survey in two tertiary university hospital referral centers for movement disorders in Western Europe revealed that at any one time there were about 5% of atypical parkinsonian patients who could not be more precisely categorized using currently available clinical diagnostic criteria (26). A clinico-pathological study of the first 100 patients diagnosed as PD by UK neurologists 20 yr ago coming to autopsy at the Queen Square Brain Bank for Neurological Disorders (QSBB) in London revealed that 24% did not have severe nigral and locus coeruleus neuronal loss with Lewy bodies in surviving neurones. However, retrospective application of the QSBB criteria for the clinical diagnosis of PD by a movement disorder specialist blinded to the pathological diagnosis improved the accuracy of clinical diagnosis retrospectively to 86%. The most common pathology in the misdiagnosed cases was extensive subcortical neurofibrillary tangles (27). Conversely 12% of 100 cases fulfilling operational criteria for the pathological diagnosis of PD were found to have clinical signs that would have excluded a diagnosis of PD using QSBB operational criteria (1). Ten years later, using identical ascertainment and methodology, diagnostic accuracy had risen to 90% and did not improve further with retrospective application of the QSBB criteria; on this second review MSA-P had taken over as the commonest cause for misdiagnosis. This improvement is likely to reflect a greater clinical aware-

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ness among UK neurologists of the wide spectrum of atypical parkinsonian disorders and the publication of sets of consensus criteria to aid clinical diagnosis (28). A recent review of 60 cases diagnosed clinically with PSP who came to autopsy at the QSBB showed that the clinical diagnosis was accurate in 47 (78%). Sources of diagnostic error included DLB, MSA, tauopathies, and motor neuron disease (MND)-ubiquitin inclusion dementia. Retrospective application of the NINDS and Society for PSP Consensus criteria marginally improved the accuracy of initial clinical diagnosis, but none of the existing diagnostic criteria for PSP could significantly improve accuracy of the final clinical diagnosis (29). A similar methodological study with MSA revealed that 51 of 59 clinically suspected cases were confirmed pathologically in the QSBB, with PD as the most common false positive; this study showed a high diagnostic accuracy for the clinical diagnosis of MSA. Retrospective application of either the Quinn or Consensus criteria for MSA further improved clinical diagnosis in the early stages, but not at the time of the last hospital visit before death (30). In an earlier study from the QSBB, Wenning et al. found that one-third of pathologically confirmed cases carried an alternative clinical diagnosis at death—usually PD (31). Litvan and colleagues (32) using material derived from a number of brain banks, found that only 50% of cases with pathologically proven MSA had been accurately diagnosed by their primary neurologist, whereas retrospective analysis by movement disorder specialists improved the accuracy to around 70%. Several studies have compared the clinical features of pathologically proven MSA with idiopathic PD and developed scoring systems weighted for different clinical features (33). These have produced sensitivities of 90%. However, application of these scoring systems in prospective clinical series is likely to be less impressive, as they are internally derived and may overestimate their true performance. In an attempt to see whether greater accuracy of clinical diagnosis could be achieved by movement disorder specialists working in a university hospital setting, the detailed case notes of 143 pathological cases of parkinsonism thoroughly investigated at the National Hospital for Neurology, Queen Square, by at least one staff movement disorder expert between 1990 and 1999 were scrutinized. The positive predictive value of a clinical diagnosis of MSA was 85.7 (30 out of 35), and the sensitivity was 88.2% (30 out of 34). For PSP, comparable figures were positive predictive value 80% (16 out of 20) and sensitivity 84.2% (16 out of 19). The positive predictive value for PD in this study was extremely high at 98.6% (72 out of 73) with a sensitivity of 91.1%, owing to seven false-negative cases. This suggests that neurologists with special training in movement disorders can expect to achieve around a 90% overall diagnostic accuracy rate for Parkinson’s syndromes in the late stages of disease (34). For more than a century the semiology of the Parkinson’s syndromes has been based on a combination of the clinical picture and the neuropathological findings. Even with this traditional twodimensional classification, new nosological entities continue to be described. Recent advances in genetics and molecular pathology have led to reappraisal of what constitutes a disease: disorders with very different clinical features are linked through identical histopathological changes and patients carrying the same genetic mutation may have very different physical signs. Further confusion stems from the finding that patients fulfilling operational clinical diagnostic criteria for a particular Parkinson’s syndrome are sometimes found to have incompatible pathological lesions, and that dual or even multiple pathologies are commonly found at postmortem examination of the elderly. Our conception of PD has been under modification ever since James Parkinson’s seminal description of the shaking palsy: his original description was embellished by the 19th-century neurologists, particularly Charcot and Gowers, and the pathological discoveries of Lewy and Tretiakoff provided substance for the notion that it was a distinct entity. However, not long after, following the pandemic of von Economo’s disease and the realization that syphilis, head trauma, and cerebrovascular disease could additionally produce parkinsonism, the very existence of the shaking palsy (PD) was called into question. In the 1960s a cluster of previously unrecognized clinico-pathological entities with

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bradykinesia as a prominent feature were delineated and neuroleptic drugs started to replace postencephalitic parkinsonism as the most common cause of secondary parkinsonism. Attempts to distinguish these atypical cases from PD have led to the development of operational exclusion criteria and supportive red flags to aid diagnostic accuracy of brainstem Lewy body PD. It has always been recognized that PD is protean in its clinical manifestations and natural history which has led to proposals for tremulous, akinetic-rigid, young-onset, senile, and benign and malignant subtypes. Widespread acknowledgement of the malady’s clinical heterogeneity has also led to calls for abolition of the term PD in favor of idiopathic Parkinsonism. The cloning of at least four gene mutations in familial Parkinson’s syndrome—in which the clinical picture closely resembles classical sporadic PD—has further led to a reconsideration of clinical terminology. Some molecular pathologists link PD, DLB, and MSA because all three are associated with the abnormal misfolding and aggregation of alpha-synuclein. PSP, corticobasal ganglionic degeneration, and some rare familial cases of frontotemporal degeneration, on the other hand, have been embraced under the rubric of primary tauopathy. The paradigm for treatment of neurodegenerative disease has largely hinged on the success of Ldopa in PD and the clinico-biochemical/pathological correlate linking bradykinesia with dopaminergic lesions in the pars compacta of the substantia nigra. However, the success of this approach has served to hide its shortcomings: as neurologists record the constellation of symptoms and signs in a patient with atypical parkinsonism and speculate on why specific brain regions appear selectively vulnerable at postmortem examination, they should not forget Sir Thomas Lewis’s cautionary words to his cardiological colleagues 70 yr ago, that what were then considered discrete entities would in time prove to be no more than ephemeral conceptions. In fact what we often perceive as entities are really processes, each made up of a finite number of specific events. Neurodegeneration results from a limited number of pathological events each of which engenders biochemical consequences at cellular level. These are modified by genetic and environmental factors and may result in nerve cell death by apoptosis or necrosis. What determines—in an atypical parkinson’s case—why a particular neurone takes the tau/tangle or synuclein/Lewy body/glial cytoplasmic inclusion route to cell death may depend on many factors, including the particular chemistry of that neuron, the timing of the event, and the influence of supporting glia. Greater understanding of the mechanisms that cause these destructive biochemical cascades will shed light on the causes of the atypical Parkinson syndromes and, with luck, lead to effective new disease-modifying treatments. The words of L’Hermitte and Cornil from 1921 remain as relevant today as then: We must either admit that there exists in addition to multiple Parkinsonian syndromes, an authentic Parkinson’s disease with particular lesions and a characteristic evolution and symptomatology or we must say that there is no Parkinson’s disease just as there is no hemiplegic disease or pseudobulbar disease.

As we evolve from the traditional clinico-pathological concept of disease entities to a more dynamic consideration of pathological processes, it may be more useful for neurologists in future to describe patients who fulfill a definition of parkinsonism (bradykinesia plus rigidity and/or rest tremor) in terms of their associated physical signs (e.g., dementia, autonomic failure, supranuclear downgaze palsy), functional and physical disability (as quantified by rating scales), disease duration, response to dopaminergic therapy, and genetic profile, rather than attempting to guess the associated histopathological findings on the basis of pattern recognition. In the meantime, however, we must use the crumbs of knowledge we have gathered by clinical observation and research about these brutal clinical syndromes to inform and relieve suffering in our patients.

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