Editorial “Parkinsonism across the spectrum of movement disorders and beyond”

JosephJankovicaDaniel D.TruongbcMatteoBolognad

doi : 10.1016/j.jns.2021.120013

Volume 433, 15 February 2022, 120013

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The etiopathogenetic and pathophysiological spectrum of parkinsonism

MatteoBolognaabDanielTruongcdJosephJankovice

doi : 10.1016/j.jns.2021.120012

Volume 433, 15 February 2022, 120012

Parkinsonism is a syndrome characterized by bradykinesia, rigidity, and tremor. Parkinsonism is a common manifestation of Parkinson's disease and other neurodegenerative diseases referred to as atypical parkinsonism. However, a growing body of clinical and scientific evidence indicates that parkinsonism may be part of the phenomenological spectrum of various neurological conditions to a greater degree than expected by chance. These include neurodegenerative conditions not traditionally classified as movement disorders, e.g., dementia and motor neuron diseases. In addition, parkinsonism may characterize a wide range of central nervous system diseases, e.g., autoimmune diseases, infectious diseases, cerebrospinal fluid disorders (e.g., normal pressure hydrocephalus), cerebrovascular diseases, and other conditions. Several pathophysiological mechanisms have been identified in Parkinson's disease and atypical parkinsonism. Conversely, it is not entirely clear to what extent the same mechanisms and key brain areas are also involved in parkinsonism due to a broader etiopathogenetic spectrum. We aimed to provide a comprehensive and up-to-date overview of the various etiopathogenetic and pathophysiological mechanisms of parkinsonism in a wide spectrum of neurological conditions, with a particular focus on the role of the basal ganglia involvement. The paper also highlights potential implications in the diagnostic approach and therapeutic management of patients.

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Parkinsonism and tremor syndromes

StevenBellowsJosephJankovic

doi : 10.1016/j.jns.2021.120018

Volume 433, 15 February 2022, 120018

Tremor, the most common movement disorder, may occur in isolation or may co-exist with a variety of other neurologic and movement disorders including parkinsonism, dystonia, and ataxia. When associated with Parkinson's disease, tremor may be present at rest or as an action tremor overlapping in phenomenology with essential tremor. Essential tremor may be associated not only with parkinsonism but other neurological disorders, suggesting the possibility of essential tremor subtypes. Besides Parkinson's disease, tremor can be an important feature of other parkinsonian disorders, such as atypical parkinsonism and drug-induced parkinsonism. In addition, tremor can be a prominent feature in patients with other movement disorders such as fragile X-associated tremor/ataxia syndrome, and Wilson's disease in which parkinsonian features may be present.

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Parkinsonism and dystonia: Clinical spectrum and diagnostic clues

HugoMorales-BricenoabVictor S.C.FungabKailash P.BhatiacBettinaBalintd

doi : 10.1016/j.jns.2021.120016

Volume 433, 15 February 2022, 120016

The links between the two archetypical basal ganglia disorders, dystonia and parkinsonism, are manifold and stem from clinical observations, imaging studies, animal models and genetics. The combination of both, i.e. the syndrome of dystonia-parkinsonism, is not uncommonly seen in movement disorders clinics and has a myriad of different underlying aetiologies, upon which treatment and prognosis depend. Based on a comprehensive literature review, we delineate the clinical spectrum of disorders presenting with dystonia-parkinsonism. The clinical approach depends primarily on the age at onset, associated neurological or systemic symptoms and neuroimaging. The tempo of disease progression, and the response to L-dopa are further important clues to tailor diagnostic approaches that may encompass dopamine transporter imaging, CSF analysis and, last but not least, genetic testing. Later in life, sporadic neurodegenerative conditions are the most frequent cause, but the younger the patient, the more likely the cause is unravelled by the recent advances of molecular genetics that are focus of this review. Here, knowledge of the associated phenotypic spectrum is key to guide genetic testing and interpretation of test results.

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Parkinsonism and ataxia

GiuliaFrancoaGiuliaLazzeribAlessioDi Fonzoa

doi : 10.1016/j.jns.2021.120020

Volume 433, 15 February 2022, 120020

Ataxia is not a common feature in Parkinson's disease. Nevertheless, some rare forms of parkinsonism have ataxia as one of the main features in their clinical picture, especially those with juvenile or early-onset.

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Parkinsonism and dementia

ChristosKorosaLeonidasStefanisabNikolaosScarmeasac

doi : 10.1016/j.jns.2021.120015

Volume 433, 15 February 2022, 120015

The aim of the present review is to summarize literature data on dementia in parkinsonian disorders. Cognitive decline and the gradual development of dementia are considered to be key features in the majority of parkinsonian conditions. The burden of dementia in everyday life of parkinsonian patients and their caregivers is vast and can be even more challenging to handle than the motor component of the disease.

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Parkinsonism and motor neuron disorders: Lessons from Western Pacific ALS/PDC

Peter S.Spencer

doi : 10.1016/j.jns.2021.120021

Volume 433, 15 February 2022, 120021

Recognized worldwide as an unusual “overlap” syndrome, Parkinsonism and motor neuron disease, with or without dementia, is best exemplified by the former high-incidence clusters of Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC) in Guam, USA, in the Kii Peninsula of Honshu Island, Japan, and in Papua, Indonesia, on the western side of New Guinea. Western Pacific ALS/PDC is a disappearing neurodegenerative disorder with multiple and sometime overlapping phenotypes (ALS, atypical parkinsonism, dementia) that appear to constitute a single disease of environmental origin, in particular from exposure to genotoxins/neurotoxins in seed of cycad plants (Cycas spp.) formerly used as a traditional source of food (Guam) and/or medicine (Guam, Kii-Japan, Papua-Indonesia). Seed compounds include the principal cycad toxin cycasin, its active metabolite methylazoxymethanol (MAM) and a non-protein amino acid ?-N-methylamino-L-alanine (L-BMAA); each reproduces components of ALS/PDC neuropathology when individually administered to laboratory species in single doses perinatally (MAM, L-BMAA) or repeatedly for prolonged periods to young adult animals (L-BMAA). Human exposure to MAM, a potent DNA-alkylating mutagen, also has potential relevance to the high incidence of diverse mutations found among Guamanians with/without ALS/PDC. In sum, seven decades of intensive study of ALS/PDC has revealed field and laboratory approaches leading to discovery of disease etiology that are now being applied to sporadic neurodegenerative disorders such as ALS beyond the Western Pacific region.

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Parkinsonism and cerebrospinal fluid disorders

JinyoungYounabcMassimilianoTodiscodeMarioZappiafClaudioPacchettidAlfonsoFasanocg

doi : 10.1016/j.jns.2021.120019

Volume 433, 15 February 2022, 120019

Although various motor manifestations can be seen in patients with cerebrospinal fluid (CSF) disorders, such as hydrocephalus or intracranial hypotension, the clinical presentation with parkinsonism is not clearly elucidated.

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Parkinsonism and cerebrovascular disease

ManishaNarasimhanRaymondSchwartzGlendaHalliday

doi : 10.1016/j.jns.2021.120011

Volume 433, 15 February 2022, 120011

The relationship between cerebrovascular disease and parkinsonism is commonly seen in everyday clinical practice but remains ill-defined and under-recognised with little guidance for the practising neurologist. We attempt to define this association and to illustrate key clinical, radiological and pathological features of the syndrome of Vascular Parkinsonism (VaP). VaP is a major cause of morbidity in the elderly associated with falls, hip fractures and cognitive impairment. Although acute parkinsonism is reported in the context of an acute cerebrovascular event, the vast majority of VaP presents as an insidious syndrome usually in the context of vascular risk factors and radiological evidence of small vessel disease. There may be an anatomic impact on basal ganglia neuronal networks, however the effect of small vessel disease (SVD) on these pathways is not clear. There are now established reporting standards for radiological features of SVD on MRI. White matter hyperintensities and lacunes have been thought to be the representative radiological features of SVD but other features such as the perivascular space are gaining more importance, especially in context of the glymphatic system. It is important to consider VaP in the differential diagnosis of Parkinson disease (PD) and in these situations, neuroimaging may offer diagnostic benefit especially in those patients with atypical presentations or refractoriness to levodopa. Proactive management of vascular risk factors, monitoring of bone density and an exercise program may offer easily attainable therapeutic targets in PD and VaP. Levodopa therapy should be considered in patients with VaP, however the dose and effect may be different from use in PD.

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Parkinsonism in viral, paraneoplastic, and autoimmune diseases

FrankXingaLucaMarsilibDaniel D.Truongac

doi : 10.1016/j.jns.2021.120014

Volume 433, 15 February 2022, 120014

Secondary parkinsonism, namely parkinsonism due to causes other than idiopathic neurodegeneration, may have multiple etiologies. Common secondary etiologies of parkinsonism such as drug-induced or vascular etiologies are well documented. Other secondary causes of parkinsonism such as infectious (mainly viral and prion-like diseases), autoimmune (systemic/drug-induced) and paraneoplastic etiologies are rare but are a topic of increasing interest. Older examples from the existing literature demonstrate the intricacies of viral infection from the last pandemic of the 20th century on the development of hypokinetic symptoms experienced in post-encephalitic patients. Viral and prion-like infections are only part of a complex interplay between the body's immune response and aberrant cell cycle perturbations leading to malignancy. In addition to the classic systemic autoimmune diseases (mainly systemic lupus erythematosus – SLE, and Sjögren syndrome), there have been new developments in the context of the current COVID-19 pandemic as well as more prominent use of immunotherapies such as immune checkpoint inhibitors in the treatment of solid tumors. Both of these developments have deepened our understanding of the underlying pathophysiologic process. Increased awareness and understanding of these rarer etiologies of parkinsonism is crucial to the modern diagnostic evaluation of a patient with parkinsonian symptoms as the potential treatment options may differ from the conventional levodopa-based therapeutic regimen of idiopathic Parkinson's disease. This review article aims to give an up-to-date review of the current literature on parkinsonian symptoms, their pathogenesis, diagnostic methods, and available treatment options. Many potential future directions in the field of parkinsonian conditions remain to be explored.

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Functional neurological disorder and somatic symptom disorder in Parkinson's disease

MarcoOnofrjaMirellaRussoaClaudiaCarrariniaStefanoDelli PizziabAstridThomasabLauraBonanniaAlberto J.EspaycStefano L.Sensiabd

doi : 10.1016/j.jns.2021.120017

Volume 433, 15 February 2022, 120017

The occurrence of Functional Neurological Disorder (FND) and Somatic Symptom Disorder (SSD) in PD was not commonly accepted until recently, despite some evidence that emerged in the pre and early L-Dopa era. More recently, the recognition of FND and SSD were noted to be relevant for the management of PD. FND and SSD appear early in the course of PD, often preceding motor symptoms, may interfere with treatment outcomes, often acquire psychotic features during progression, and are mixed with and often concealed by the progressive cognitive decline. We review the related features from the range of the available reports and discuss theoretical models conceived to explain the potential pathophysiological background of these disorders. Finally, we suggest that FND and SSD should be included among the non-motor symptoms of PD and be considered a prodromal feature in a subset of patients.

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