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REVIEW ARTICLE
Year : 2018  |  Volume : 66  |  Issue : 7  |  Page : 15-25

Parkinsonian syndromes: A review


Division of Neurology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

Date of Web Publication1-Mar-2018

Correspondence Address:
Dr. Prachaya Srivanitchapoom
Division of Neurology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkok-noi, Bangkok 10700
Thailand
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.226459

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 » Abstract 

Since James Parkinson published his remarkable clinical observations in the “An Essay On The Shaking Palsy” in 1817, the number of diseases included in the spectrum of parkinsonian syndromes (a group of diseases that have some part of their clinical features resembling those seen in Parkinson's disease), are growing. Careful history taking, comprehensive neurological examination, and utilization of proper investigations will lead the physicians to make an accurate diagnosis of the specific disease entity present. In this recent review, we cover the issue of classification of parkinsonian syndromes, and comprehensively review the characteristic features of the commonly encountered diseases that present with this syndrome. The salient aspects of the epidemiology, key clinical features, proper investigations, and possible treatment options of these diseases have also been addressed.


Keywords: Normal pressure hydrocephalus, parkinsonism plus syndromes, parkinsonism, spinocerebellar ataxia, vascular parkinsonism, Wilson's disease
Key Message: Parkinsonian syndromes include the categories of idiopathic parkinsonism, secondary parkinsonism, parkinsonism plus syndromes, and heredodegenerative parkinsonism. The characteristic features of the commonly encountered diseases that manifest with features of parkinsonian syndrome are being reviewed.


How to cite this article:
Srivanitchapoom P, Pitakpatapee Y, Suengtaworn A. Parkinsonian syndromes: A review. Neurol India 2018;66, Suppl S1:15-25

How to cite this URL:
Srivanitchapoom P, Pitakpatapee Y, Suengtaworn A. Parkinsonian syndromes: A review. Neurol India [serial online] 2018 [cited 2018 Dec 16];66, Suppl S1:15-25. Available from: http://www.neurologyindia.com/text.asp?2018/66/7/15/226459




Parkinsonian syndromes or parkinsonism refer to the group of diseases that resemble Parkinson's disease in some part of their clinical features. Thus, they may have rest tremors, bradykinesia, rigidity, and/or postural instability. Since, James Parkinson published his remarkable clinical observation on “An Essay On The Shaking Palsy” in 1817, the number of clinical entities that may be associated with parkinsonian syndromes are growing. In this review, we will cover the issue of classification of parkinsonian syndromes and comprehensively review the relatively common clinical conditions associated with parkinsonian syndromes. We shall also discuss key aspects of epidemiology, key clinical features, the appropriate investigations required, and the possible treatment options.


 » Classification of Parkinsonian Syndromes Top


Parkinsonian syndromes can be classified into four categories including idiopathic parkinsonism, secondary parkinsonism, parkinsonism plus syndromes, and heredodegenerative parkinsonism.[1] [Table 1] shows the classification of parkinsonian syndromes and examples of disorders/diseases in each category.
Table 1: Classification of parkinsonian syndromes and example of disorders/diseases in each category

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 » Common Parkinsonian Syndromes in Clinical Practice Top


Category 1: Idiopathic parkinsonism

Parkinson's disease

Parkinson's disease (PD) is recognized as the second most common neurodegenerative disorder (after Alzheimer disease [AD]). It mainly affects the dopaminergic neurons in substantia nigra pars compacta (SNc). While most of the motor symptoms are primarily modulated by dopaminergic neurons, non-motor symptoms (NMSs) are modulated by other peripheral and central non-dopaminergic neurons including the cholinergic, noradrenergic, glutamatergic, and serotoninergic neurons. The hallmark pathological feature of PD is the presence of α-synuclein containing Lewy body and Lewy neurites;[2] however, some cases of PD with a genetic association have an absence of Lewy body pathology. The mean age of onset of PD patients is approximately 60 years; however, the number of patients with young-onset PD, in the age range of 40 to 50 years and below, is increasing. The prevalence of PD is apparently related to age, which is less than 0.5% of the population in people under the age of 50 years, and increases to 4% in people over the age of 80 years.[3] Pesticide exposure, an associated melanoma, and a history of traumatic brain injury might increase the rate of developing of PD, whereas a history of smoking, caffeine consumption, high serum urate concentration, and moderate to vigorous exercise might reduce its rate of development.[4] Early PD is approached by dividing the clinical condition into three stages, including the pre-clinical, prodromal/pre-motor, and clinical/motor stage, as shown in [Table 2].[5] PD is diagnosed by using the United Kingdom Parkinson's Disease Society Brain Bank (UKPDS-BB) criteria which provides an accuracy of around 80-90% in establishing its diagnosis.[6] In 2015, the International Parkinson and Movement Disorder Society (MDS) redefined the definition of PD and proposed the new diagnostic criteria for PD (the MDS-PD criteria).[7] A couple of issues are differing in the latter criteria from the UKPDS-BB criteria. First, the MDS-PD criteria removed postural instability from the four cardinal features of parkinsonism. Second, the MDS-PD criteria also included NMSs, such as decreasing sense of smell, autonomic dysfunction, sleep disorders, neuropsychiatric disorders and cognitive impairment; and, supportive diagnostic investigations, such as presynaptic dopaminergic imaging, cardiac metaiodobenzylguanidine (MIBG) scintigraphy, and olfactory tests in their classification system. Finally, the MDS-PD criteria established the category of “absolute exclusion criteria” which unequivocally excludes the diagnosis of PD in certain situations. However, the MDS-PD criteria are mainly applied for research-related PD work. Signs/symptoms of PD usually start on one side of the body and then slowly progress to the other side in several years. The clinical presentation, however, usually still shows an asymmetrical severity of signs/symptoms even in the late stage of the disease. The typical motor symptoms in PD are rest tremors of hand, slowness of limb movements, decreased facial expression, abnormal small alphabetical handwriting, decreased arm swing, shuffling, festination, and an en-bloc turning of the patient's torso. The commonly associated NMSs in PD are constipation, hyposmia or anosmia, rapid eye movement sleep behavior disorder (RBD), depression, anxiety, and cognitive impairment. Pharmacological and non-pharmacological approaches should be considered for managing both motor and non-motor symptoms. For treating motor symptoms in patients under the age of 60 years, if the degree of severity is moderate to severe, levodopa combination is the first option to be considered. If the severity grade is mild, a levodopa sparing strategy, that includes medications such as dopamine agonists, anticholinergics, or type B-monoamine oxidase inhibitors, is considered. For patients over the age of 60 years, levodopa combination is useful in patients with all degrees of severity of the disease.[8],[9] Advanced non-oral therapies, including continuous subcutaneous infusion of apomorphine, continuous intestinal infusion of levodopa/carbidopa gel and deep brain stimulation surgery are considered in patients who have already presented with motor complications such as levodopa-induced dyskinesias or wearing off, which are hardly controlled by adjusting oral medications.[10],[11],[12] Finally, physical activities such as Tai-Chi, Qi-Gong, or Argentine tango are encouraged in all stages of PD, if the patent can tolerate the activity.[13],[14] The possible therapeutic options for NMSs are summarized in [Table 3].[15],[16],[17],[18],[19],[20],[21],[22] The factors that might predict an unfavorable prognosis are an older age-at-onset, postural instability/gait difficulty pattern, akinetic-rigid syndrome, a rapid disease progression, cognitive impairment, RBD, orthostatic hypotension, and having the alpha synuclein (SNCA)or the beta- glucocerebrosidase (GBA)mutation.[23]
Table 2: Staging in early Parkinson's disease[5]

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Table 3: Possible therapeutic options for non-motor symptoms of Parkinson's disease

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Category 2: Secondary parkinsonism

Vascular parkinsonism

Vascular parkinsonism (VaP) occurs in the patients who develop parkinsonian symptoms and have evidence of vascular lesions in the brain parenchyma based on neuroimaging or pathological study. The prevalence of VaP among all parkinsonism patients has varied from 2% in one study [24] to 29% in another study,[25] depending on the different definitions of VaP adopted. The classical clinical features of VaP are slowly progressive “lower body parkinsonism,” which refers to predominant symmetrical parkinsonian symptoms in bilateral lower extremities, including rigidity, bradykinesia, gait abnormalities and balance problems with relatively mild parkinsonian symptoms in upper extremities. There may possibly be a concomitant association with dementia.[26] Gait abnormalities in VaP are characterized by the reduction of velocity, stride length and step height, as well as the presence of a broad-based, freezing gait, with the patient having some positive response in amelioration of his gait disturbance with external cues. There are usually preserved arm swings. Vascular lesions described in the classic VaP are termed as “non-strategic vascular lesions,”[27] which mainly involve subcortical and periventricular white matter regions bilaterally [Figure 1]a. Another clinical pattern of VaP is hemiparkinsonism, which develops after the occurrence of ischemic or hemorrhagic stroke of the SNc or the nigrostriatal pathway (termed as “strategic vascular lesions”).[27] Usually, strategic vascular lesions do not immediately produce parkinsonian symptoms right after the onset of stroke. It may take weeks to months for the patients with these lesions to develop parkinsonism. However, a recent article pointed out several interesting issues related to VaP.[27] First, non-specific abnormal structural imaging may be associated with VaP. Second, previous clinicopathological studies of patients suffering from VaP have shown no correlation between the brain magnetic resonance imaging (MRI) hyperintensities, microangiopathic brain disease, andparkinsonian symptoms. Finally, patients with many parkinsonian and non-parkinsonian syndromes have clinical manifestations that are closely mimicking those of VaP. The authors used three terms to describe VaP mimickers. These include “pseudovascular parkinsonism”, including PD or other PD-plus syndromes, such as progressive supranuclear palsy or multiple system atrophy parkinsonism subtype concomitant with non-specific white matter changes in neuroimaging; “vascular pseudoparkinsonism”, including conditionssuch asakinetic mutism, apathy or abulia due to bilateral mesial frontal strokes; and, “pseudovascular pseudoparkinsonism,” seen in conditionssuch as idiopathic normal pressure hydrocephalus.[27] A good control over the cardiovascular risk factors and administering physical therapy are the primary objectives of the therapeutic interventions instituted for managing VaP. Levodopa may be effective for treating parkinsonian symptoms in some patients; however, no factors have been detected that may predict the responsiveness of levodopa in this condition.[26],[27]
Figure 1: Vascular parkinsonism and idiopathic normal pressure hydrocephalus: (a) Vascular parkinsonism: Axial brain MRI T2W sequence shows extensive subcortical and periventricular white matter hyperintensities (The Fazekas scale = 3). (b) Idiopathic normal pressure hydrocephalus (iNPH): Axial brain CT shows dilatation of lateral and third ventricle with Evan's ratio of 0.34. (c) Coronal brain CT shows pattern of “disproportionately enlarged subarachnoid space hydrocephalus (DESH)” in iNPH; the widening of Sylvian fissures (white arrow head) out of proportion to the cortical sulci at the vertex (white arrow)

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Idiopathic normal pressure hydrocephalus

Idiopathic normal pressure hydrocephalus (iNPH) is the most common cause of hydrocephalus in adult patients. The prevalence of iNPH increases with age. A population-based study in Sweden showed that the prevalence was 0.2% in people in the age range of 70 to 79 years and increased to 5% in people over the age of 80 years.[28] The diagnosis of iNPH requires a focus on the clinical signs/symptoms, neuroimaging, and exclusion of other possible etiologies. The clinical triad of iNPH is composed of gait abnormality, urinary incontinence, and dementia. However, the presence of the complete clinical triad is not necessary for diagnosing iNPH in a patient. The characteristic symptoms are often bilateral, gradual in onset and slowly progressive, without the presence of other neurological deficits such as spasticity, hyperreflexia, and motor weakness. Gait abnormality in iNPH is described as a higher-level gait disorder, which has a characteristic abnormality of sensorimotor integration as well as execution of motor functions, in the presence of normal primary sensory and primary motor systems as well as cerebellar functions.[29] Many manifestations of gait abnormality in iNPH including gait ignition failure; a broad-based, shuffling, festination, and magnetic gait; turning the torso en-bloc; and, frequent falls, are seen. These are compatible with the manifestations of “lower body parkinsonism”. Cognitive impairment and/or dementia in iNPH is mainly caused by frontal lobe dysfunction. Executive dysfunction with relatively preserved memory, point against the diagnosis of iNPH; while, hallucination, aphasia, agnosia, and delirium indicate the presence of other dementia syndromes.[30] Typical urinary symptoms in iNPH are composed of urge to void and inability to control the micturition.[31] However, urinary incontinence is quite common in the elderly patients so physicians should first eliminate the presence of other possible etiologies. Neuroimaging is a useful tool for diagnosing iNPH. Computer tomography (CT) or MRI can reveal the shape of ventricles, especially the third and lateral ventricles, identify the site of obstruction in the cerebrospinal fluid (CSF) pathway, and the status of the surrounding brain parenchyma. To confirm ventriculomegaly, Evan's ratio should be assessed by dividing the measured maximum width of bilateral frontal horns of the lateral ventricles by the greatest distance of the brain in the same axial section.[32] If the Evan's ratio is greater than 0.3, it confirms the presence of ventriculomegaly [Figure 1]b; however, it is not specific for hydrocephalus. To differentiate ventriculomegaly in cerebral atrophy from iNPH, physicians should look for the pattern of “disproportionately enlarged subarachnoid space hydrocephalus (DESH),”[33] and widening of the Sylvian fissures out of proportion to the cortical sulci at the level of cerebral convexity [Figure 1]c. In addition, patients with iNPH usually present with bilateral periventricular white matter lesions, which are in close proximity to the ventricular wall. This finding represents transependymal leakage of CSF into the adjacent white matter. Lumbar tap test is the investigation of choice for confirming the normal CSF opening pressure as well as for the exclusion of other possible etiologies that may lead to hydrocephalus, and for assessing the clinical improvement, especially in gait abnormality, after a large-volume CSF drainage. The volume of CSF that is considered to be adequate to drain, to unequivocally establish the clinical improvement, ranges from 30-50 mL.[34] Gait assessment should be done before the CSF tap test and immediately after performing this test. Significant gait improvement after performing the CSF tap test is a good predictor for performing either a ventriculoperitoneal or lumboperitoneal shunt surgery. However, absence of benefit from a CSF tap test does not prevent a patient from clinical responding to a CSF diversion procedure because the sensitivity of this test is only in the range of 50%-80%, while its specificity is in the range of 60%-100%.[34] Other CSF hydrodynamic tests include institution of an external lumbar drainage, the CSF infusion test, and an intracranial pressure monitoring; however, these tests are sophisticated and their conduction is limited to a few tertiary or large referral hospitals. All symptoms may improve after surgery; however, improvement in cognitive impairment is usually less appreciated.

Category 3: Parkinsonism plus syndromes

Multiple system atrophy

Multiple system atrophy (MSA) is a rare neurodegenerative disorder which affects various neuronal systems including the basal ganglia, cerebellar, and autonomic nervous systems. Its pathological hallmark is α-synuclein-containing inclusions accumulated in the cytoplasm of oligodendrocytes, which are named the “glial cytoplasmic inclusion” bodies (GCIs).”[35] The prevalence of MSA is approximately 3-5%,[36] and its incidence ranges from 0.1-2.4 cases per 100,000 person-years in people over the age of 50 years.[37] The mean age of onset of MSA is about 60 years and the mean survival of patients ranges between 6-9 years. MSA is divided into three subtypes, a classification that follows the occurrence of a predominant clinical abnormality. Thus, MSA may be of the autonomic (MSA), the cerebellar (MSA-C), or the parkinsonian (MSA-P) subtypes. MSA-P is more frequently found in the Western countries [38] whereas MSA-C is more often found in Japan.[39] Patients with MSA may present with both motor symptoms and NMSs. Parkinsonism in MSA is predominantly an akinetic-rigid syndrome with rapid progression, and majority of cases have a bilateral involvement. The classical rest tremors present only in 33% of patients, but postural and kinetic tremors with polymini myoclonus present in approximately 50% patients. Gait ataxia (86%), limbs ataxia (78%), and scanning speech (69%) are the top three clinical presentations of cerebellar dysfunctions in MSA.[40] However, gaze-evoked nystagmus, square wave jerk, or hypometric saccades may also be present. Early MSA-C is sometimes hard to differentiate from other conditions causing chronic progressive acquired cerebellar ataxia, such as chronic alcohol consumption, drug- or toxin-induced cerebellar ataxia; or, from sporadic cases of inherited adult-onset cerebellar ataxia, such as spinocerebellar ataxia or fragile-X tremor/ataxia syndrome. Other symptoms that might be present are axial deformities such as camptocormia, Pisa syndrome or dropped head syndrome; craniocervical dystonia such as oromandibular dystonia associated with levodopa treatment or anterocollis; pyramidal dysfunctions such as hyperreflexia or positive Babinski sign; and, high-pitch dysarthria, dysphagia, and inspiratory stridor associated with vocal cord paralysis or laryngeal dystonia. Common NMSs presenting in MSA are orthostatic hypotension, urinary incontinence, erectile dysfunction, rapid eye movement sleep behaviour disorder (RBD), and chronic constipation. Cold hand phenomenon and hypo- or anhidrosis may also occur. The diagnosis of MSA requires a combination of the following items that include evidence of genuine stress incontinence, autonomic dysfunction, parkinsonism, and cerebellar dysfunction. MSA is further classified into its three levels; definite, probable, and possible MSA.[41] Besides the clinical diagnosis, ancillary investigations may help to confirm the diagnosis and exclude other etiologies. In MSA-P, the structural brain MRI may show a combination of hyperintense signals on T2W sequences on the dorsolateral border of putamen [the putaminal rim sign; [Figure 2]a as well as the presence of putaminal hypointensities on T2W sequences, and putaminal atrophy. In MSA-C, the brain MRI may show cruciform hyperintense signal in the pons [the hot-cross-bun sign; [Figure 2]b and atrophy of the middle cerebellar peduncle and/or pons on T2W sequences. However, both the putaminal rim and the hot-cross-bun signs have a high degree of specificity but a low sensitivity in establishing the diagnosis of MSA. Fluorodeoxyglucose positron emission tomography (FDG-PET) may help to differentiate MSA from either PD and from other atypical forms of parkinsonism. It may show hypometabolism in the brainstem, cerebellum, and putamen.[42] Autonomic tests such as the passive head-up tilt test, the Valsalva maneuver, or the 24-hour ambulatory blood pressure monitoring may help to confirm the diagnosis of autonomic dysfunction in MSA. Cardiac 123 I-MIBG labelled scintigraphy helps in differentiating between MSA-P and PD, which shows a normal cardiac radiotracer uptake in MSA-P but a reduced radiotracer uptake in PD.[43] Management in MSA patients is challenging. In general, management in MSA focuses on the control of symptoms for improving the quality of life. Levodopa may be useful for controlling parkinsonism. Usually, the response is poor and some patients may develop levodopa-associated oromandibular dystonia. Occupational therapy and physical therapy, especially gait and balance training, are also important in the patients who have bulbar involvement, cerebellar ataxia, and postural deformities. Treatment strategies for NMSs resemble those ones conducted for PD [Table 3]. Many diseases modifying agents such as riluzole, minocycline, rifampicin, and rasagiline failed to show their neuroprotective property in MSA. Also, the result of the mesenchymal stem cell therapy in MSA is still inconclusive.[44]
Figure 2: Parkinsonism plus syndromes: (a) Multiple system atrophy (MSA): Axial brain MRI T2W sequence shows the “putaminal rim sign” (white arrow) in MSA-parkinsonism subtype; and, (b) the “hot-cross-bun sign” (black arrow) with middle cerebellar peduncle atrophy (black arrow head) in MSA-cerebellar subtype. (c) Progressive supranuclear palsy (PSP): Sagittal brain MRI T1W sequence shows the “hummingbird sign”, a sign of midbrain atrophy (white arrow head) without pontine atrophy. (d) Corticobasal syndrome (CBS): Axial brain MRI T1W sequence shows an asymmetrical frontoparietal atrophy which is greater in the left hemisphere

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Dementia with Lewy bodies

Lewy body dementias refer to the dementia syndromes that have Lewy bodies and Lewy neurites as the main diagnostic features on a neuropathological examination of the brain tissue. Lewy body dementias are composed of Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). DLB ranks as the second most common etiology responsible for the dementia syndrome after AD. The prevalence of DLB among patients with dementia ranges from 0-23%.[45] While disease progression in PD follows the pattern of spread of the Lewy bodies (that is assessed by the Braak staging), DLB behaves differently. The temporal relationship between the motor symptoms of parkinsonism and the development of dementia is the crucial point for differentiating between DLB and PDD. Dementia in PDD usually occurs in the advanced stage of PD, whereas dementia in DLB typically occurs earlier (especially in the first year after the onset of motor symptoms).[44] The core clinical features of DLB are dementia, visual hallucinations, fluctuation of sensorium along with motor symptoms of parkinsonism, and RBD.[46] The patterns of cognitive impairment in DLB and PDD are similar. Attention deficit, executive dysfunction, visuospatial abnormalities and difficulty in performing multiple tasks are the major cognitive problems in DLB as well as PDD. Short-term memory deficit can also occur, but it is less pronounced compared to that seen in AD.[47] Visual hallucinations have been reported in up to 80% patients with DLB.[48] These hallucinations are typically well-formed, unimodal, and with clear details of the objects visualized. They are usually described as hallucinations in which animals or persons including human adults, children, or deceased family members appear. The patients usually respond to these hallucinations, depending upon their degree of insight and emotional status. Fluctuations of sensorium are basically similar to that seen in patients with delirium. The latter symptom is hard to detect by obtaining a single “yes-no” response to pointed questioning of the patient. Therefore, the Dementia Cognitive Fluctuation Scale has been developed for screening this symptom. It provides a sensitivity of 80% and a specificity of 76% in differentiating the clinical syndromes of DLB and PDD from AD.[49] The other supportive features for diagnosing DLB [47] are the presence of severe neuroleptic sensitivity including the presence of the neuroleptic malignant syndrome, severe autonomic dysfunction, and frequent falls; evidence of reduced dopamine transporter concentration, as detectable by the dopamine transporter scan (single-photon emission computed tomogrpahy [SPECT], or positron emission tomography [PET] scan); evidence of reduced cardiac sympathetic innervation [detected by the 123 I-MIBG scintigraphy]; relative preservation of medial temporal lobe structures on structural brain imaging; generalized low uptake on SPECT/PET perfusion/metabolism scan with reduced occipital activity with or without the cingulate island sign on fluorodeoxyglucose (FDG)-PET scan; and, prominent posterior slow-wave activity on electroencephalogram with periodic fluctuations in the pre-alpha/theta range. Treatment of DLB requires a multidisciplinary approach and should focus on both motor symptoms and NMSs. Till date, no evidence has confirmed the role of non-pharmacological approaches for treating DLB. However, the current consensus report of the DLB consortium [47] mentions that researches related to physical exercise, cognitive training, and caregiver-oriented education and training to manage the psychiatric symptoms have shown some promising outcome. Pharmacological approaches for both motor symptoms and NMSs are usually recommended.[50] Cholinesterase inhibitors (ChEIs) such as rivastigmine and donepezil have been shown to effectively manage the cognitive impairment, apathy as well as anxiety in DLB patients; however, the data on the usefulness of memantine is limited. Evidence of the treatment options for the associated manifestations of psychosis and depression in the presence of DLB is scant. A low-dose quetiapine for treating psychosis, and selective serotonin reuptake inhibitors (SSRIs) or selective serotonin-norepinephrine reuptake inhibitors (SNRIs) for treating depression in DLB patients may be considered. Motor symptoms can be controlled with levodopa; however, its low dose administration and slow titration are preferred to minimize the risk of hallucination and psychosis. Clonazepam may reduce the symptoms of RBD and minimize the risk of sleep-related injury.

Progressive supranuclear palsy (PSP)

Progressive supranuclear palsy (PSP) was first described by Steele, Richardson, and Olszewski in 1964.[51] The pathological hallmark of this disease are tau-containing star-shaped astrocytic tufts and neurofibrillary tangles.[52] Areas of distribution of the pathology determines the different phenotypes of PSP. In the classic Richardson's syndromes (PSP-RS), the pathology is mainly found in the frontal lobe, corpus striatum, pallidum, subthalamic nucleus, SNc, pons, ventrotegmental area, and dentate nuclei.[53] The estimated prevalence of PSP is approximately 5-7 per 100,000 individuals.[54],[55] The average age of onset of PSP-RS is around the mid-sixties with the peak prevalence being around 70-74 years.[55] However, the study conducted in Japan, that also included other phenotypes of PSP, revealed the prevalence of 17.9 per 100,000 individuals.[56] PSP-RS is the most common subtype. Gait difficulty, frequent falls, vertical supranuclear gaze palsy (especially downgaze palsy), and progressive cognitive decline are the common presenting symptoms of PSP-RS. Characteristics of gait abnormality in PSP-RS are the presence of a board-based gait, with stiffness of legs, and a pivotal turn. The contributing factors of frequent falls are the loss of postural reflexes, prominent axial rigidity, freezing of gait, and retropulsion of the body. Gait difficulty and frequent falls usually occur within the first two years.[57] Slow vertical saccades and limitation of downgaze are the more sensitive signs in PSP-RS. Dementia usually presents in the advanced stage of the disease. A frontal subcortical dementia is typical. Executive dysfunction, reduced verbal fluency, perseveration (e.g. the presence of the “applause sign”), grasping, and pseudobulbar laughing/crying are also observed in PSP patients. Apraxia of eyelid opening, retrocollis, astonished face, and procerus sign raise suspicion regarding the diagnosis of PSP. To effectively diagnose PSP, National Institute of Neurological Disorders and Stroke (NINDS) proposed the clinicopathological diagnostic criteria in 1996.[58] The criteria divided the diagnosis into three levels including the definite, probable, and possible diagnosis with a high degree of specificity (85-100%) but a low sensitivity (approximately 50%). The new MDS criteria for the diagnosis of PSP (MDS-PSP), has been recently published.[59] The criteria are composed of the basic, core, and supportive features which divide the diagnosis into four levels including definite, probable, possible and suggestive. The difference between the NINDS and the MDS-PSP criteria is that the latter included four domains to establish the core features for diagnosis, namely, ocular motor dysfunction, postural instability, akinesia and cognitive dysfunction, whereas the former included only ocular movement abnormalities and postural instability with falls. The MDS-PSP criteria also mentioned the situation in which the patients present with some subtle signs and symptoms of PSP but do not fulfill the criteria for the diagnosis of possible or probable PSP. It refers to the term “suggestive of PSP” which is beneficial for the early recognition of the disease, and for conducting further longitudinal studies. Furthermore, the MDS-PSP criteria established the elements for proving the diagnosis of non-Richardson's PSP phenotypes. The clinical characteristics of PSP-RS and non-Richardson's PSP phenotypes are summarized in [Table 4].[60],[61],[62],[63] In PSP-RS, the structural brain MRI showed marked midbrain atrophy (e.g. the hummingbird sign [Figure 2]c or the morning glory sign;[64] however, the most reliable biomarkers to differentiate PSP-RS from other parkinsonian syndromes are the midbrain-pons ratio and the MR Parkinsonism Index (MRPI).[63] In addition, the MDS-PSP criteria suggested that image findings of significant midbrain atrophy or hypometabolism and/or postsynaptic-striatal dopaminergic degeneration are considered as the “supportive imaging findings.”[63]
Table 4: Clinical characteristics of the variants of progressive supranuclear palsy

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Currently, there is no specific treatment for PSP. A multidisciplinary approach that includes a neurologist, psychiatrist, physical therapist, occupational therapist, nutritionist, and social workers is important. Non-pharmacological approaches include physical and speech therapy, swallowing evaluation and nutritional assessment. Pharmacological approaches involve the use of levodopa, dopamine agonists, and amantadine to control parkinsonian symptoms. SSRIs may be beneficial for controlling depression, while SNRIs may be beneficial for treating apathy. Choline esterase inhibitors, such as rivastigmine, might be used to treat cognitive impairment but the effect is modest. Other symptoms such as apraxia of eyelids opening, blepharospasm, and drooling can be treated with botulinum toxin (BoNT) injection.[65],[66]

Corticobasal syndrome

Corticobasal degeneration (CBD) was first mentioned by Rebeiz and colleague in 1967.[67],[68] They described a series of three similar patients who presented with progressive symptoms of asymmetric, akinetic-rigid syndrome, and higher cortical dysfunctions of unknown etiology. Their neuropathological findings showed corticodentatonigral degeneration with neuronal achromasia. However, in the past decades, numerous evidences have shown that CBD is not a single clinicopathological disease.[69] Various neurodegenerative syndromes including PSP, primary progressive non-fluent aphasia (PNFA), and behavioral variant of frontotemporal dementia (bvFTD) can present with the pathological hallmark of CBD (this includes 4-repeat-hyperphosphorylated tau-containing astrocytic plaques and thread-like processes in the gray and white matter as well as in neurons and glial cells in the cortical and striatal regions). Conversely, the classic phenotype of CBD can be influenced by a variety of neuropathologies, including the tau (e.g. PSP) and the non-tau pathology (e.g. TDP-43 in FTD-TDP). Therefore, the term “corticobasal syndromes (CBS)” is proposed for describing these complex entities. The exact incidence and prevalence of CBS are hard to evaluate due to the term “CBS” encompassing various clinical phenotypes. However, one study showed that the prevalence was approximately 0.9% in cases of parkinsonism.[70] The incidence was less than one per 100,000 patient-years.[71] Usually, the mean onset of CBS patients is around the age of 60 years.[72] The key features of CBS are asymmetrical parkinsonism, dystonia, myoclonus, ideomotor apraxia, alien limb syndrome, and cortical sensory loss. Additional features including aphasia, cognitive impairment, postural instability, gait abnormality, pyramidal dysfunctions (e.g. positive Babinski sign and hyperreflexia), and bulbar dysfunction may also be observed. Recently, the clinical diagnostic criteria for diagnosing four different syndromes including the classic CBD, bvFTD, PNFA, and progressive supranuclear palsy with corticobasal syndrome presentation (PSP-CBS) were proposed.[69] Neuroimaging such as CT, MRI, or FDG-PET may help the physicians to diagnose CBS or to sometimes differentiate CBS from other parkinsonian syndromes.[42] Asymmetric frontoparietal atrophy seen on structural brain imaging [Figure 2]d or an asymmetric cortical hypometabolism visualized on a FDG-PET scan is a typical finding in the classic CBD.[42] Proteinopathic scan for assessing tau and β-amyloid ligands is under investigation to differentiate various neurodegenerative syndromes based on their underlying proteinopathy.

Till date, specific treatments and disease-modifying agents have not been available for effectively treating this disease. Levodopa is used to control parkinsonian symptoms; however, the outcome is poor. Clonazepam, levetiracetam, and valproic acid have been tried and have shown some benefit in controlling myoclonus. BoNT injection is used to minimize dystonic symptoms; however, if the patients develop limbs apraxia or alien hand, BoNT may be insufficient to improve the limb functions and the patients' quality of life.[65] The prognosis of CBS is poor especially in patients presenting with dementia. The mean survival ranges from 7 to 9 years from the time of diagnosis of CBS.[73]

Category 4: Heredodegenerative parkinsonism

Wilson disease

Wilson disease (WD) is an autosomal recessive inherited disease. WD occurs due to the abnormal incorporation of copper into apoceruloplasmin to form ceruloplasmin; and, the abnormal excretion of copper from the hepatocytes into the biliary canaliculi due to mutation of the ATP7B gene, located on chromosome 13, causing abnormality of the ATP7B protein encoding. Excessive copper spills out of the liver into the systemic circulation resulting in deposition of copper in multiple organs such as the brain and cornea, thus causing various clinical syndromes.[74] The prevalence of WD varies from one per 2,600 to one per 10,000 individuals,[75],[76] based upon the different regions evaluated; however, its worldwide incidence is estimated at approximately one per 30,000 individuals.[77] Hepatic, neurologic, and psychiatric manifestations are the top three presentations of WD.[74] Hepatic manifestations, presenting in 40-50% of cases,[78] range from asymptomatic elevation of liver enzymes to acute fulminant liver failure; however, the most frequent hepatic manifestation in WD is chronic liver cirrhosis with complications such as esophageal varices, splenomegaly, and ascites. Psychiatric manifestations are noted in approximately 30-40% of the cases.[79] Depression, anxiety, and psychosis frequently occur while cognitive impairment and dementia are rarely reported. Neurologic signs are present in 40-60% of the patients.[78] Usually, these neurological symptoms occur later than hepatic manifestations do (approximately 30 months later).[78] Movement disorders are the primary neurological manifestations in WD.[80] Tremors, parkinsonism, dystonia, and cerebellar dysfunctions are frequently observed in patients with WD. The classic wing-beating tremor, a proximal, wide amplitude tremor presenting in the arms, is well characterized in these patients with WD. Focal dystonia, especially risus sardonicus, the fixed facial dystonic contraction resulting in elevation of the eyebrows and a facial appearance of grinning, is frequently observed. Generalized and segmental dystonia are also reported. Parkinsonian symptoms including bradykinesia, drooling, hypomimia, and micrographia occur in approximately 40% of patients of WD presenting with neurological symptoms.[81] Dysarthria is also commonly observed in WD patients. Cerebellar dysfunctions, dystonia, pyramidal dysfunctions, or parkinsonism may contribute to the pathogenesis of dysarthria. Chorea, ballism, tics, and autonomic dysfunctions are infrequent manifestations.[78] The various organs involved in WD are summarized in [Table 5].[80],[81] The diagnosis of WD may be established by detecting the presence of the characteristic clinical manifestations, by identifying Kayser-Fleischer rings (K-F rings), by measuring the levels of serum ceruloplasmin and the 24-hour urinary copper, by performing the liver biopsy, and by the genetic testing. The diagnosis of neuropsychiatric manifestations in WD [75] generally requires the following features to be present in a patient: (1) The presentation of K-F rings, which may be observed in greater than 90% of patients with WD with neuropsychiatric manifestations, while it may be observed in less than 50% of the patients with WD with hepatic manifestations; (2) low serum level of ceruloplasmin (<20 mg/dl), which is a highly sensitive but less specific marker for diagnosing WD; and, (3) elevated level of 24-hours urine copper (>40 mcg/24-hours), which is highly suggestive WD if the level is greater than 100 mcg/24-hours. The absence of positivity of one of these tests is an indication for the performance of liver biopsy for measuring hepatic copper concentration, and for genetic testing for evaluating the presence of ATP7B mutation. These features can help to confirm the diagnosis of WD with neuropsychiatric manifestations. Once WD is diagnosed, the first-degree relatives of the patient must be screened for detecting the presence of subclinical WD in them.[75] Brain imaging is also useful for the diagnosis and follow-up of patients with WD with neurologic manifestations. The typical brain MRI features in WD are the presence of T2W hyperintensities in bilateral basal ganglia and thalamus [Figure 3]a with or without subcortical white matter or/and brainstem involvement. Some brain MRI findings suggest the diagnosis of WD, such as the face of the giant or/and miniature panda.[78] However, these findings are also revealed in other conditions such as Leigh disease or extrapontine myelolysis. Management of patients with WD includes the administration of symptomatic and specific treatment.[74],[75],[76],[81] Symptomatic treatment is aimed at relieving specific symptoms of the patients such as tremor, dystonia, parkinsonism, depression, hallucination, or anxiety. For example, anticholinergic medication may be used to control dystonia while levodopa may be used to control parkinsonism. The specific treatment is aimed at promoting the excretion of excessive copper out of the various organs. The main chelating drugs for this treatment include D-penicillamine and trientine that increase renal copper excretion. Trientine has a minimal risk of causing worsening of neurological symptoms during the initial phase of therapy. In the pre-symptomatic or maintenance phase, zinc or tetratiomolybdate in combination with a diminished copper-rich diet can be used instead of chelating drugs. Liver transplantation is an effective therapeutic option in WD presenting with acute liver failure or decompensated liver cirrhosis; however, the role of transplantation in treating neuropsychiatric symptoms of WD is controversial. The treatment should ideally be administered throughout the life of the patient, and therefore, these patients needed a regular and prolonged follow-up. Indeed, an early diagnosis and institution of prompt treatment leads to a good outcome.
Table 5: System involvement in Wilson's disease

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Figure 3: Wilson disease and spinocerebellar ataxia. (a) Wilson disease: Axial brain MRI T2W sequence shows symmetrical hyperintensities of lentiform nuclei (black arrow), caudate nuclei (white arrow), and thalami (black arrow head). (b) Spinocerebellar ataxia (SCA): Axial brain MRI T2W sequence shows significant atrophy of cerebellar hemispheres (white arrow head) and the pons

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Spinocerebellar ataxia (SCA)

Spinocerebellar ataxia (SCA) refers to a group of autosomal dominant disorders presenting with slowly progressive pan-cerebellar dysfunctions, generalized hyperreflexia, and lower limbs spasticity without obvious motor weakness. Recently, the newest subtype, SCA38, caused by mutations within the ELOVL5 (fatty acid elongase subtype 5) gene, has been reported.[82] Besides the characteristic presence of ataxia, other non-ataxic features such as motor neuron disease, parkinsonism, dystonia, chorea, myoclonus, essential tremor-like movement, slow saccadic eye movement, retinopathy, cognitive impairment, and seizure may also be associated with this disease and may help to differentiate between various subtypes of SCA. In general, brain imaging of SCA shows marked cerebellar and brainstem atrophy [Figure 3]b. The PD-like phenotype is described in SCA2, SCA3, and SCA17.[83] Non-ataxic features of SCA2[84] and SCA3[85] are peripheral neuropathy, motor neuron disease, and a combination of various movement disorders including myoclonus, chorea, parkinsonism, and dystonia. SCA2 usually presents with slow saccades while SCA3 may present with staring eyes, ophthalmoparesis, and action-induced myoclonus of facial muscles. Non-ataxic features of SCA17[86] are characterized by dementia, psychiatric symptoms, chorea, dystonia, and parkinsonism. SCA2 and SCA3 are the top two subtypes that frequently present with PD-like phenotype worldwide.[87] PD-like phenotype in SCA2 is rather common in the Asian populations, while this phenotype is often reported in populations of African origin in SCA3.[83] Patients with SCA2 and SCA3 with a PD-like phenotype are more likely to have a later age of onset of the disease, and a shorter CAG repeat expansion; while patients with SCA2 and SCA17 with the PD-like phenotype are more likely have a shorter CAG repeat expansion as well as a combined CAG/CAA expansion.[83] Based on the short CAG repeat expansion, a reduced penetrance occurs, which results in a sporadic occurrence of progressive cerebellar ataxia that mimics the presence of an acquired neurodegenerative cerebellar ataxia such as MSA-C. The presence of SCA with the PD-like phenotype is supported by radiological evidence of an abnormal dopamine transporter imaging as well as pathological evidence of neurodegeneration in the SNc. These findings may explain why patients manifesting with the PD-like phenotype in SCA2, SCA3, and SCA17 respond to levodopa treatment. Furthermore, there has been some evidence to suggest that motor complications could occur in SCA2[88] and SCA3[89] with PD-like phenotype after receiving levodopa.


 » Conclusion Top


The number of disease entities manifesting as parkinsonian syndrome is growing by the day. A careful history taking and a comprehensive neurological examination will often enable physicians to arrive at a proper provisional diagnosis; it will also lead them to select a reasonable set of investigations for establishing the exact diagnosis. In addition, newer imaging modalities, genetic studies, and clinicopathological studies will reveal the underlying pathophysiology and pathogenesis of the individual diseases that manifest with parkinsonian features. Future research in the field of parkinsonism is mandated to fill the current knowledge gap.

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Conflicts of interest

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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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