, Alberto J. Espay2, Alfonso Fasano3 and Francesca Morgante4
(1)
Neurology Department, King’s College Hospital NHS Foundation Trust, London, UK
(2)
James J. and Joan A. Gardner Center for Parkinson’s Disease and Movement Disorders, University of Cincinnati, Cincinnati, Ohio, USA
(3)
Division of Neurology, University of Toronto Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson’s Disease Toronto Western Hospital, UHN, Toronto, Ontario, Canada
(4)
Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
1.1 An Introductory Note
Poverty and slowness of movement occur due to a reduction in speed, a reduction in amplitude, a breakdown in the rhythm or any combination thereof. These impairments have been subsumed under the rubric of bradykinesia, if the poverty of movement affects predominantly speed; hypokinesia, if the impairment of amplitude predominates; or akinesia, if speed and amplitude are globally affected. Akinesia also refers to poverty of spontaneous movement and may technically be the ultimate expression of disorders affecting motility due to lesions in end effectors of movement such as the corticospinal tract (in which case they are associated with spasticity) or the lower motor system, which includes spinal motor neurons, muscles or neuromuscular junction (in which case they may be associated with flaccidity). Nevertheless, the term akinesia has most often been reserved for disorders associated with rigidity and therefore entails dysfunction within the basal ganglia or their connecting structures. With one major exception (the syndrome of pure akinesia [i.e. without rigidity]), these akinetic–rigid disorders have been subsumed under a syndrome, parkinsonism, and applied to the chronic and often progressive deterioration of speed, amplitude and/or rhythm of movement. The vast majority of parkinsonian syndromes are grouped into different nosological entities based on shared clinical features but are separated on the basis of their different pathological and genetic underpinnings.
The presence of bradykinesia or akinesia is essential for the classification of a disorder as parkinsonian. Bradykinesia may express in the limbs (e.g. reduced arm swing, reduced stride length, micrographia), speech (e.g. hypophonia), swallowing (e.g. dysphagia), facial expression (e.g. hypomimia) or posture (e.g. stooping or leaning). Other elements in the ‘parkinsonian syndrome’ such as tremor and postural impairment are common but not invariable. Their presence assists clinicians in ascertaining whether the timing of appearance and relative severity in relationship with bradykinesia makes a parkinsonian phenotype within the broad range of ‘idiopathic’ Parkinson’s disease (PD) or likely within the ‘atypical’ parkinsonisms, an ever-growing, complex group of non-PD parkinsonisms, classically including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), multiple system atrophy (MSA), dementia with Lewy bodies (DLB) and frontotemporal dementias (FTD).
Although parkinsonian syndromes are further defined by additional dysfunction in psychiatric, cognitive, autonomic, cerebellar or pyramidal systems, in the absence of biomarkers, their definitive etiological diagnoses require genetic and/or pathological evaluations.
1.2 How to Recognize
The categorization of a disorder as ‘parkinsonian’ is entirely clinical given the lack of biomarkers to confirm the syndrome. Furthermore, the choice of imaging, biochemical or genetic tests, and their interpretation, depends on the accuracy of the clinical assessment, although variations in clinical experience, timing of emerging signs and historic nomenclature may prompt diagnostic revisions [1, 2].
Bradykinesia, hypokinesia and akinesia belong to the spectrum of abnormally generated movements whereby there may be slowness of initiating (often measured in studies as reaction time) or sustaining movement (movement time) or both [3]. The clinician can simply observe volitional spontaneous movements for clues regarding these impairments, such as in the form of reduced facial gesticulation (hypomimia) or decreased speed and associated arm movements when walking. Observing gait is particularly informative since it may demonstrate gait ignition failure (inability to transition into stepping from a stationary upright posture) and festination (progressive but ineffective increase in cadence at the expense of corresponding reductions in stride length) as the failures of movement initiation and movement sustainability, respectively. The clinician can elicit these features by testing the performance of sequential tapping tasks and by examining the product of handwriting. Sequential tasks typically include repetitive finger tapping (index finger against thumb for 15 s), rapid fisting-and-stretching hand movements, rapid pronation–supination forearm movements and repetitive foot or toe tapping. To qualify as such, bradykinesia requires a progressive reduction in the amplitude of movements throughout 10–15 s of tapping performance (a phenomenon also referred to as sequence effect) [4] or over a line or two of handwritten material (micrographia). This progressive reduction in movement amplitude, however, may be less common or absent altogether in other parkinsonisms, such as PSP, whereby markedly hypokinetic tapping movements give little room for further reductions in movement amplitude [5]. The most severe end of movement impairment is the complete inability to sustain movements due to ‘motor blocks’ leading to pauses or freezing of movement [6].
Rigidity is the main accompaniment of slowed movements, expressed by patients in the form of ‘muscle stiffness’, or, when severe, ‘frozen shoulder’ or focalized pain [7]. It will not be examined in detail in this chapter (see Chap. 2). Suffice it to state here that rigidity is recognized by the resistance shown by limbs to passive manipulation. Such resistance may limit the range of movement around the neck, elbows, wrist, knees or ankles and is independent of the velocity with which the clinician tests the range of movement, the main feature that distinguishes it from spasticity. This velocity-independent increase in resistance to passive movements may yield a ‘lead-pipe’ (resistance is held constant throughout the joint displacement) or ‘cogwheel’ quality (resistance is intermittent), unlike the velocity-dependent increase in resistance to early acceleration of passive movements seen in spasticity, which yields a ‘clasp-knife’ quality.
The hyperkinetic intrusion of tremor into the parkinsonian syndromes will not be examined in detail in this chapter (see Chap. 5). Suffice it to state at this point that the tremor of PD tends to be asymmetric and often, but not exclusively, best appreciated at rest with attenuation or even disappearance during action, but re-emerging when holding a posture. Ostensibly absent tremor may be brought to the fore during cognitive tasks (such as serial subtraction) or, sometimes exclusively, during walking.
Gait, posture and postural reflexes are important components of the examination (see Chap. 8 for further details). Slow speed of walking is one of the first signs of parkinsonism. The examination of gait requires patients to stand from a sitting position, asking them to do so without support if possible, walk at least 10 m and then turn and walk back. A complete walking assessment requires two turns in each direction for an assessment of the potential of motor blocks anywhere along 360°. To assess for freezing of gait, the patient is asked to turn 360° and then repeat the turn in the opposite direction [8]. Freezing may more likely occur when turning to the less affected side, as the more affected side, which may exhibit a shorter stride length, fails at generating the larger stride required to turn the body axis in the opposite direction. In addition to turning, gait dysfunction may be brought on by walking through narrow doorways or in busy obstacle-filled environments. Overall, the parkinsonian gait in PD is narrow based and is associated with limited arm swinging. The phenomenon of progressively reduced amplitude noted above for finger tapping (sequence effect) can be mirrored by a similarly progressively accelerated cadence at the expense of shortening stride length during walking, which is referred to as festination and which may result in freezing of gait, the inability of getting the feet off the ground to reinitiate ambulation [9]. The examination of tandem gait (patients are instructed to walk ‘as if on a tight rope, one foot in front of another, heel touching toes’) is also helpful as errors are more common in atypical parkinsonisms such as MSA and PSP compared to PD [10] or in parkinsonisms caused by genetic mutations and producing phenotypes in which parkinsonism is combined with ataxia (Chap. 4) or dystonia (Chap. 6). Gait may become variable or wide based in PSP and MSA, indeed preventing tandem gait in these disorders, a situation that may progress into frank truncal ataxia. Some parkinsonian patients with frontal lobe dysfunction (typically PSP) may exhibit a ‘reckless’ gait with a lurching component and single-step pivoting turns, despite impaired postural reflexes, a motor manifestation of frontal lobe dysfunction [11].
1.3 How to Distinguish from Related Disorders
The necessary change from ‘parkinsonism’ to PD and from ‘atypical parkinsonism’ or ‘parkinsonian syndrome’ to PSP, CBD or MSA, to name the most common aetiologies, requires a systematic clinical evaluation and judicious use of ancillary testing. ‘Possible’ and ‘probable’ categories of diagnostic certainty are available for each of these disorders, enabling an organized differential diagnosis, which can assist subsequent therapeutic decisions and prognostic considerations.
1.3.1 Parkinson’s Disease
The clinical diagnosis of probable PD can be considered when an asymmetric parkinsonism has slowly progressed in the absence of early postural instability or falls. By ‘slowly’, it is assumed at least 1 year from symptom onset since postural impairment with falls within or shortly after 1 year would be considered a red flag against the diagnosis of PD. This diagnostic assumption is strengthened by the presence of an asymmetric or unilateral resting tremor and, to a greater extent, by a robust and sustained response to levodopa or other dopaminergic treatments. Given the importance of the medication response on the diagnostic certainty, the initial impression is often tentative. ‘Possible’ PD becomes ‘probable’ PD once levodopa brings about marked and sustained benefits, and it is almost certain (even if the category of ‘definite’ PD is reserved for pathology-proven disease) if and when classic levodopa-induced dyskinesia develops or modest symptomatic deterioration has occurred due to sustained treatment response for over 5 years [12]. Levodopa-induced dyskinesia consists of chorea of the trunk with or without arms and head (commonly as a peak-dose manifestation), chorea of the legs, often of ballistic magnitude (commonly as a beginning-of-dose and/or end-of-dose [diphasic] manifestation), and fixed dystonia (commonly, but not exclusively, as an ‘off’ or transitional medication state) or a combination thereof, affecting predominantly the more affected side (Fig. 1.1; see also Chap. 7).
Fig. 1.1
Typical topographic patterns of various forms of dyskinesia in PD (right-sided onset of disease is assumed for all cases). (a) Peak-dose levodopa-induced dyskinesia tends to involve the upper trunk, neck and arms, particularly on the more affected side. (b) Hemidyskinesia with arm-greater-than leg involvement can also be a manifestation of peak-dose dyskinesia, especially among young-onset PD patients. (c) Diphasic dyskinesia predominantly affects the legs while relatively sparing the trunk, neck and arm. (d) Unilateral foot dystonia on the more affected side is the most common manifestation of wearing ‘off’. (e). Facial choreoathetotic movements and hand with or without foot posturing may occur in advanced PD patients. (f) Facial dystonia with feet dyskinesia constitute a ‘red flag’ dyskinetic topography which should help reconsider the diagnosis of PD in favour of multiple system atrophy. Horizontal lines indicate dystonia; grey areas, chorea; Darker grey emphasizes greater severity (Figure by Martha Headworth, University of Cincinnati Neuroscience Institute, permission to use by Mayfield Clinic, minimally modified from original publication [13])
Postural instability can be a late feature of PD. Its presence early after symptom onset is considered a red flag for the diagnosis and should point in the direction of an atypical parkinsonism, such as PSP and MSA in order of frequency. The final step in the often-utilized clinical research criteria emphasizes that at least three supporting features be present, including unilateral onset, excellent response to levodopa therapy and development of dyskinesia [12]. Any additional historical or neurological finding is regarded as exclusionary, such corticospinal signs (other than hyperreflexia), stepwise deterioration of parkinsonism implying cerebrovascular disease; repeated head injury; history of encephalitis; presence of oculogyric crisis (exceptionally, this can be a levodopa-induced dyskinetic complication); neuroleptic treatment at the onset of symptoms (caveats: chronic neuroleptic exposure can precipitate underlying PD or even be with underlying neurodegenerative parkinsonism in a minority of schizophrenics [14]); strictly unilateral features after 3 years, supranuclear gaze palsy; cerebellar signs; early severe autonomic dysfunction; early severe cognitive dysfunction; negative response to levodopa despite a dose greater than 1500 mg/day; and imaging evidence of communicating hydrocephalus.
PD onset is rarely before the age of 50 years and sharply increases after age 60 [15]. Younger age at onset tends to be associated with slower disease progression, greater responsiveness to dopaminergic treatment, higher risk of dyskinesia and other motor complications and lower incidence of dementia [16]. While the mean time from diagnosis to death in PD is around 14 years, such number is increased to 24 years in patients diagnosed in their 40s but reduced to 10 years for patients in their 70s [17]. There may also be a favourable prognostic effect for the presence of tremor and left-sided onset of symptoms [18, 19].
It is increasingly recognized that non-motor features often predate the onset of the clinically diagnosable PD and become progressively more important as sources of disability with disease progression [20]. These include pain, depression, anxiety, fatigue, REM sleep behaviour disorder (expressed as dream enactment behaviours), anosmia and constipation [21]. Cognitive dysfunction, particularly mild cognitive impairment with executive dysfunction characterized by difficulties multitasking, planning, retrieval, concentration and attention, and/or visuospatial dysfunction is being recognized at earlier stages [22]. In a well-characterized, prospectively evaluated cohort, visuospatial dysfunction (inability to copy an intersecting pentagons figure) and semantic fluency (inability to generate less than 20 words in 90 s) were the cognitive domains of impairment most predictive of eventual conversion to PD dementia [23]. In patients with mild cognitive impairment, and certainly dementia, visual hallucinations and other psychotic manifestations are common. Indeed, their occurrence in the absence of overt cognitive impairment heralds the eventual development of dementia [24].
With disease progression, disability develops both in terms of treatment-related motor complications (primarily wearing off, levodopa-induced dyskinesia and unpredictable motor fluctuations) (Table 1.1) and disease-related, dopaminergic-unresponsive developments, including dysphagia, dementia, psychosis, gait impairment and falls (Fig. 1.2). The mode of death is most often related to respiratory compromise in the setting of bronchopneumonia, aspiration or deep venous thrombosis-associated complications once mobility is greatly compromised.
Table 1.1
Range of motor complications in Parkinson’s disease according to whether levodopa is (‘on’ state) or not (‘off’ state) clinically effective
Primarily ‘off’ state | Primarily ‘on’ state | Intermediary state |
|---|---|---|
Predictable wearing ‘off’ Random ‘off’ Off dystonia (early-morning dystonia) Freezing of gait Delayed ‘on’ | Peak-dose dyskinesias (monophasic dyskinesias) On-freezing (rare) Myoclonus (from levodopa or amantadine) | Diphasic dyskinesias (end of dose and beginning of dose) Rapid on-off fluctuations Yo-yo-ing Sudden ‘offs’ |
Fig. 1.2
Diagrammatic representation of disease progression in PD. Hoehn and Yahr stages are used in the X-axis. Falls and dementia tend to be late occurrences in PD. Their appearance in earlier stages of disease suggest the presence a non-PD parkinsonism
1.3.2 Dementia with Lewy Bodies
DLB represents a synucleinopathy where the burden of cortical Lewy bodies on pathology occurs early and prominently compared to PD. From a practical standpoint, DLB can be considered an accelerated form of DP dementia (PDD), where the non-amnestic cognitive (executive and visuospatial dysfunction, predominantly) and behavioural impairments (visual hallucinations, REM sleep behaviour disorder, cognitive fluctuations) develop within a year from the onset of parkinsonian features. Visual hallucinations, a clinical hallmark, appear to be associated with fluctuations in visual attention rather than to visuospatial and perceptual dysfunction [25]. As in PD, hyposmia and autonomic dysfunction, particularly constipation and postural lightheadedness from orthostatic hypotension, are common developments—and may predate the onset of motor features by many years. Indeed, PD, PDD and DLB can be viewed as existing on a spectrum of Lewy body diseases [26]. Given the substantial overlap between PD and DLB from a neuropathological perspective, an ongoing effort at redefining PD is considering the inclusion of DLB as part of the disease spectrum (‘PD-DLB subtype’) [27]. These patients are most vulnerable to antipsychotic medications given for their hallucinations. Paradoxical behavioural worsening upon exposure to these neuroleptics is a common clue as to their previously unrecognized presence in a patient with hallucinations at a stage when motor impairment may be subtle or not overt [28].
1.3.3 Progressive Supranuclear Palsy
PSP is the second most common form of neurodegenerative parkinsonism after PD [29]. Unlike the synuclein-based Lewy bodies that define PD at a neuropathological level (categorized, thus, as a synucleinopathy), PSP results from abnormal deposition of hyperphosphorylated tau protein (a classic tauopathy), impairing axonal transport. The suspicion for the classic form of PSP rests on the presence of a symmetric, usually tremorless parkinsonism with postural impairment leading to backward falls within a year from symptom onset. The clinical finding that defines PSP is the progressive slowness of saccades with restriction in the vertical range of ocular movement, which can only be corrected by oculocephalic manoeuvres. The earliest oculomotor abnormality is the impairment of visual fixation, expressed as brief saccadic intrusions around a fixed target and referred to as square–wave jerks in honour of its waveform appearance if it were to be plotted on paper [30]. The loss of optokinetic corrective saccades is a feature that precedes the overt reduction in saccadic velocity, which warrants testing for these reflexes using an optokinetic drum or tape on anyone with early postural instability [31]. A later appearance of focal dystonia affecting the orbicularis oculi muscles is sometimes incorrectly interpreted as an ‘apraxia’ of eyelid opening [32]. Other features include executive dysfunction and other non-specific frontal lobe-mediated deficits, including perseverative behaviours (e.g. the non-specific ‘applause sign’ [33, 34], whereby a patient asked to clap three times as quickly as possible, claps four or more times instead), frontal release signs (snout, palmomental and grasping reflexes) as well as dysarthria and dysphagia.
PSP can be clinically divided into several subtypes, which serves to provide some guidance on prognosis and natural history. The classic form of PSP is referred to as Richardson’s syndrome (PSP-RS, also known as Steele–Richardson–Olszewski syndrome), but other variants include PSP-parkinsonism (PSP-P), PSP-pure akinesia with gait freezing (PAGF), PSP-corticobasal syndrome (CBS) and PSP-frontotemporal dementia (PSP-FTD) [35] (Table 1.2). Primary progressive freezing of gait (PPFG) is a syndrome characterized by isolated freezing of gait, which for the first 3 years from onset is not accompanied by any other neurological features and which most commonly evolve into PSP (see Chap. 8) [36].
Table 1.2
Subtypes of progressive supranuclear palsy pathology
Main phenotype | Key features |
|---|---|
Classic: PSP-Richardson (PSP-R, Richardson’s syndrome or Steele–Richardson–Olszewski syndrome) | Tremorless, symmetric parkinsonism with axial-predominant rigidity, supranuclear vertical gaze palsy, with backward falls within 1 year from symptom onset |
PSP-parkinsonism (PSP-P) | Early features indistinguishable from PD. Postural impairment and oculomotor abnormalities occur after 2 years or later (often, five) |
PSP-pure akinesia with gait freezing (PSP-PAGF) | Akinesia but without appendicular rigidity, associated with micrographia, speech disturbances and gait freezing of gait |
Primary progressive freezing of gait | Isolated freezing of gait during the first 3 years and subsequent occurrence of postural instability and mild akinesia |
PSP-corticobasal syndrome (PSP-CBS)a | Asymmetric parkinsonism with an asymmetric dystonic and apraxic limb |
PSP-frontotemporal dementia (PSP-FTLD)a | Frontal-predominant dementia predating or developing concurrently with an otherwise classic motor phenotype |
1.3.3.1 Richardson’s Syndrome
Patients with PSP-RS present problems with balance, visual disturbances (often described as blurry vision) or a combination of these symptoms. The mean age of onset is around 65 years of age [37]. Patients usually come to neurological attention once postural instability has yielded falls; the family notices apathy and personality changes; and/or speech or handwriting have become markedly affected. Speech can range from stuttering to palilalia (repetition of single words or short sentences) and echolalia (repeating an interlocutor’s last words in his/her sentences) [38].
The characteristic eye movement abnormalities that help confirm the diagnosis of PSP-RS develop gradually. The earliest finding is the presence of square-wave jerks with an otherwise normal range of ocular motility during smooth pursuit and saccadic testing. In some patients, it is also possible to demonstrate, early in the disease, the ‘round the houses’ sign, which is characterized by a lateral arc displacement of the eyes when testing vertical saccades, at a time when full vertical excursions are still present [39]. This is followed by slowness of vertical saccades, first identified by an obliteration of the optokinetic response, and later yet by a clear reduction in range and slowness in speed of vertical movements during saccade testing (for downgaze more often than upgaze), that only in advanced stages also affects the smooth pursuit system and the horizontal gaze [37, 40].
Midbrain atrophy, which is the anatomical correlate of the eye movement abnormalities described above, is the most characteristic imaging finding in PSP-RS (Fig. 1.3). This feature has been reported with ornithological names, such as the penguin or the hummingbird signs depending on how the disproportionate reduction in midbrain volume is interpreted when compared with the preserved volume of the pons (the ‘belly’ on both of these birds) when assessing sagittal sequences. An MRI measurement that accounts for the associated reduction in cerebellar outflow fibres manifested as atrophy in the superior cerebellar peduncle, particularly when compared to the intact middle cerebellar peduncle, has been proposed to predict a clinical picture evolving into PSP-RS [41, 42]. Corresponding increases in the apparent diffusion coefficient (ADC) of the superior cerebellar peduncle [43] and a reduction in the signal intensity (from normally hyper- to abnormally isointense) of the decussation of the superior cerebellar peduncle [44] can be demonstrated in these patients.
Fig. 1.3
Sagittal brain MRI of patient with the Richardson (classic) presentation of progressive supranuclear palsy, which demonstrates the hummingbird sign resulting from midbrain atrophy (arrow). There is also associated thinning of the anterior portion of the corpus callosum and ex vacuo ventriculomegaly (sometimes misinterpreted as normal pressure hydrocephalus), often accompaniments of this disorder (With permission from Biller and Espay, Practical Neurology Visual Review. Lippincott Williams & Wilkins division of Wolters Kluwer Health, Inc. Philadelphia, PA, 2013)
The cognitive abnormalities that accompany PSP-RS may affect processing speed and executive function and can be tested at the bedside using a frontal assessment battery (Table 1.3) [45]. A cut-off score of 12 on the FAB has a sensitivity of 77 % and specificity of 87 % in differentiating between frontal dysexecutive-type dementias and dementia of Alzheimer’s type [46].
Table 1.3
Frontal assessment battery content, instructions and scoring
Main phenotype | Key features | Score |
|---|---|---|
1. Similarities (conceptualization) | ‘In what way are they alike?’ (A banana and an orange, a table and a chair, and a tulip, a rose and a daisy) | 1 per each of the 3 similarities |
2. Lexical fluency (mental flexibility) | ‘Say as many words as you can beginning with the letter ‘S’, any words except surnames or proper nouns’. (60 s) | >9: 3; 6–9: 2; 3–5: 1; <3: 0 |
3. Motor series (programming) | ‘Look carefully at what I’m doing’. The examiner performs alone three times with his left hand the series of Luria ‘fist-edge-palm’. ‘Now, with your right hand do the same series, first with me, then alone’. The examiner performs the series three times with the patient and then says to him/her: ‘Now, do it on your own’ | 6 correct series alone, 3; at least 3, 2; only 3 with examiner, 1; not even 3 with examiner, 0 |
4. Conflicting instructions (sensitivity to interference) | ‘Tap twice when I tap once’. To be sure that the patient has understood the instruction, a series of three trials is run: 1-1-1. ‘Tap once when I tap twice’. To be sure that the patient has understood the instruction, a series of three trials is run: 2-2-2. The examiner performs the following series: 1-1-2-1-2-2-2-1-1-2 | No error, 3; one or two errors, 2; more than two errors, 1; patient taps like the examiner at least four consecutive times, 0 |
5. Go–No Go (inhibitory control) | ‘Tap once when I tap once’. To be sure that the patient has understood the instruction, a series of three trials is run: 1-1-1. ‘Do not tap when I tap twice’. To be sure that the patient has understood the instruction, a series of three trials is run: 2-2-2. The examiner performs the following series: 1-1-2-1-2-2-2-1-1-2 | No error, 3; one or two errors, 2; more than two errors, 1; patient taps like the examiner at least four consecutive times, 0 |
6. Prehension behaviour (environmental autonomy) | ‘Do not take my hands’. The examiner touches the palms of the patient’s hands, to see if he/she will spontaneously take them. If the patient takes the hands, the examiner will try again after asking him/her: ‘Now, do not take my hands’ | Patient does not take the hands, 3; hesitates and asks what to do, 2; takes the hands, 1; does so even after been told not to do so, 0 |
Postural instability is abnormal in PSP-RS, even in the presence of only mild bradykinesia. It is identified by the ‘pull-test’, whereby the patient stands with feet comfortably apart and is pulled backwards by the shoulders, so as to displace his/her centre of gravity [47]. This is only performed after instructing patients that a step backwards to steady themselves may be required. The examiner will stand less than an arm’s length behind the patient in case the inability to take a correct step backwards, or frank retropulsion with several unending steps backwards, is to be followed by a fall. Despite the marked and typically early postural instability, patients tend to exhibit a ‘reckless’ gait due to frontal disinhibition, whereby their stride does not seem to be cautiously shortened nor the pivoting sufficiently en bloc, particularly during turns, to prevent or minimize falls. Thus, an increasing falling rate is made worse by the double hit of impaired postural righting reflexes and the inability to adopt compensatory behaviours due to frontal lobe dysfunction.
Patients usually become dependent on others for care 3–4 years after disease onset due to increasing motor and cognitive slowing [29, 48]. Speech often becomes unintelligible, and recurrent choking can lead to frequent aspiration pneumonia. The mean disease duration from onset to death is about 7 years [49]. Rare features include autonomic dysfunction (virtually never of the magnitude seen in MSA) and frank cerebellar ataxia (as distinct to gait unsteadiness, also more common in MSA).
1.3.3.2 PSP-Parkinsonism
In contrast to patients with PSP-RS, PSP-P patients develop bradykinesia and limb rigidity at disease onset, which can be asymmetric and in some cases associated with a rest tremor that may be indistinguishable from PD [50]. Axial rigidity still predominates over appendicular rigidity, a ‘soft’ clue as to the true nature of a parkinsonism that might be suspected to represent PD. Further misleading as to the aetiology, patients with PSP-P tend to benefit with dopaminergic therapies, even if this response eventually dwindles [51].
Although patients with PSP-P appear different from patients with PSP-RS in the first couple of years, most will eventually develop severe postural instability, frontal cognitive decline and vertical supranuclear gaze palsy as the disease progresses [50]. The disease survival is about 3 years longer in PSP-P than in PSP-RS (9 versus 6 years, respectively) [50]. Nevertheless, PSP-P progresses more rapidly than PD, response to l-dopa is unsustained, and drug-induced dyskinesia are rarely elicited, or are minimal, despite doses of l-dopa >2000 mg/day [51].
1.3.3.3 PSP-Pure Akinesia with Gait Freezing
This rare PSP phenotype consists of brady- or hypokinesia, in the absence of appendicular rigidity, predominantly affecting gait and leading to gait freezing [52]. Patients complain of progressive difficulty with ambulation and unsteadiness that may develop for up to 2 years before frank freezing of gait and gait ignition failure appear. Characteristically these patients also develop early hypophonia, hypomimia and micrographia. Axial rigidity with increasing neck stiffness in the absence of limb rigidity is a distinctive feature [53]. The classical PSP features of supranuclear vertical gaze paresis and blepharospasm develop late, and, in contrast to PSP-RS, cognitive deficits and bradyphrenia are not prominent in the first 5 years of the disease, which has a median duration of more than 10 years [52, 54].
1.3.3.4 PSP-Corticobasal Syndrome
The corticobasal syndrome (CBS), traditionally associated with corticobasal degeneration, is increasingly recognized to be the phenotype of several pathologies including PSP (see below). CBS is characterized by lateralized motor (unilateral ideomotor apraxia, non-levodopa-responsive parkinsonism, myoclonus, dystonia) and non-motor features (aphasia, cortical sensory and/or visuospatial deficits). Patients with PSP-CBS are at present indistinguishable from those with other underlying pathologies including corticobasal degeneration.
1.3.3.5 PSP-Frontotemporal Dementia
PSP may develop within the phenotypic spectrum of frontotemporal lobar degeneration due to tau deposition (FTLD-PSP). This can be suspected in the setting of marked personality changes and/or language abnormalities (usually, non-fluent aphasia but also apraxia of speech). Other frontotemporal dementia features may develop, such as disinhibition, loss of empathy, change in eating patterns, ritualized or stereotypical behaviour (see also Chap. 3) or apathy [55, 56]. These patients usually develop typical motor symptoms of PSP (supranuclear ophthalmoplegia, postural instability, axial-predominant rigidity, hypokinesia) but usually after more than 5 years have elapsed from symptom onset.
1.3.4 Multiple System Atrophy
In patients with MSA-parkinsonism (MSA-P), initial deficits mimic the asymmetric motor presentation of PD in a manner that may seem indistinguishable from PD. However, severe motor signs unresponsive to l-dopa, prominent dysautonomia, including neurogenic bladder (and particularly the combination of overactivity and retention), orthostatic hypotension and the almost-diagnostic inspiratory stridor eventually become critical elements supporting a clinical diagnosis of MSA-P. It is not unusual for a gastroenterologist, cardiologist, sleep medicine physician and urologist to be involved in the care of patients by the time the neurological diagnosis is made or shortly thereafter [57].
The classic and striking clinical characteristic of MSA is the progressive autonomic dysfunction that often dominates the early clinical picture and may even predate its motor symptoms by several years. The diagnosis of MSA-P is considered in patients who develop parkinsonism in the presence of increasing urinary urgency, constipation, postural hypotension and erectile dysfunction in men [58]. MSA-P may be asymmetrical and could respond better to l-dopa than most other atypical parkinsonisms, with drug-induced dyskinesia developing in as many as 30 % of patients. However, the dyskinesia tends to affect the face, conveying a sardonic grin appearance [59], reminiscent of cephalic tetanus (Fig. 1.4, see also Fig. 1.1f), and the feet, a pattern that is unusual for PD. The progression of deficits is faster than in PD, including the early appearance of postural instability complicated with falls and the emergence of other atypical features within the first 3 years of disease onset, including spontaneous and stimulus-sensitive hand myoclonus (indeed, more common than rest tremor in MSA-P), broad-based, unsteady gait and anterocollis with or without camptocormia (excessive forward trunk flexion) or Pisa syndrome (excessive lateral trunk deviation), largely attributable to axial dystonia. Some of these features have entered our lexicon as ‘red flags’ of MSA [59, 60] (Fig. 1.5) (Table 1.4).
Fig. 1.4
Two MSA-P patients exhibiting risus sardonicus (sardonic grin), a dyskinetic manifestation highly suggestive of MSA-P. The patient in the left also shows the ‘wheelchair sign’, another ‘red flag’ of MSA, often the case within 3–5 years from onset of symptoms
Fig. 1.5
Features of a patient with MSA-P within 1 (a) and 5 years (b) from symptom onset, highlighting the development of anterocollis and assistance-requiring postural impairment over a period of time inconsistent with PD, which she was thought to have at the outset (Images courtesy of Dr. Leo Verhagen, Rush University, Chicago)
Table 1.4
Selected ‘red flags’ in multiple system atrophy
Red flags | Description |
|---|---|
Anterocollis | Disproportionate forward flexion of the neck |
Camptocormia | Marked forward flexion of the trunk |
Pisa syndrome | Marked lateral flexion of the trunk |
Polyminimyoclonus | Irregular, small-amplitude myoclonic movements of the hands and/or fingers on postural and action often misinterpreted as tremor |
Inspiratory stridor | Involuntary deep inspiratory sighs or gasps |
‘Cold hand sign’ | Coldness and colour purplish/reddish discoloration of the limbs with blanching on pressure |
Raynaud’s phenomenon | Mottling and pain in hands and feet |
Pseudobulbar affect | Inappropriate crying without sadness; inappropriate laughing without mirth |
A neuroimaging feature supportive of MSA-P is the subtle slitlike signal abnormality of the posterolateral putamen, bilaterally or contralateral to the more affected side, due to excessive iron deposition and subsequent gliosis [61] (Fig. 1.6). Patients with MSA-P also develop mild cerebellar dysfunction, with truncal ataxia resulting from vermal-predominant atrophy. In some patients, cerebellar ataxia predominates over relatively mild parkinsonian features, a clinical entity referred to as MSA-cerebellar (MSA-C) (Fig. 1.7). The connecting thread between MSA-P and MSA-C is the marked autonomic dysfunction [58].
Fig. 1.6
Axial FLAIR (left) and gradient echo (right) axial brain MRI of patient with MSA-P, demonstrating tapering hypointensity in the posterolateral putamen, right greater than left (arrows), with lateral slitlike hyperintensity. The hypointensity is due to excessive iron deposition, which is better appreciated in the gradient echo sequence. The smaller width of hyperintensity is due to gliosis and tissue loss
Fig. 1.7
Sagittal and axial T2-weighted brain MRI of patient with MSA-C shows a pontocerebellar pattern of atrophy, more prominent at the anterosuperior vermis, with the ‘crossed-bun’ sign in the pons and slight hyperintensity of the middle cerebellar peduncle
Bedside assessment of lying and sitting blood pressure is an important tool in uncovering orthostatic hypotension (OH), an almost universal manifestation of autonomic failure in MSA. Blood pressure and pulse are obtained after the patient has been lying supine for several minutes (ideally, no fewer than 5) and again 1 and 3 min after standing. OH is documented by a fall in blood pressure greater than 20 mmHg systolic and/or 10 mm diastolic on standing, with no reactive increase in pulse rate [58]. Symptomatic OH is often but not always expressed with postural lightheadedness or other symptoms reaching a zenith with syncope, falls or fluctuating cognitive impairment [62]. Some patients only present with mild and unspecific symptoms, such as unsteadiness or neck pain radiating to the occipital region of the skull and shoulders (the so-called coat–hanger ache). Furthermore, ‘asymptomatic’ OH may, in fact, be associated with fatigue and cognitive impairment, even in patients that are not complaining of postural-related symptoms. Notably, the severity of OH tends to match that of clinostatic hypertension, which is often complicated with nocturnal hypertension (which may increase cardiovascular risk if left unattended).
The median survival of patients with MSA with either the parkinsonism or cerebellar phenotype is approximately 8 years, but the range is large [49]. Early autonomic failure, older age of onset, and short interval from disease onset to motor milestones (particularly, frequent falling, unintelligible speech, severe dysphagia and wheelchair dependence) are predictors of a more aggressive disease [49].
1.3.5 Corticobasal Syndrome
Corticobasal syndrome (CBS) is the classical presentation of corticobasal degeneration (CBD). CBS applies to a phenotype consisting of markedly asymmetric and progressive parkinsonism associated with ideomotor apraxia, rigidity, myoclonus, dystonia and cortical sensory loss (agraphesthesia, astereognosis) in one hand, progressing to involve the lower extremity and eventually affect all four extremities, but remaining asymmetric. When present, myoclonus tends to be stimulus sensitive, to tactile rather than to auditory stimuli. Dystonia and myoclonus are less frequent than the akinetic-rigid syndrome and apraxia [63]. Alien limb phenomenon (see Chap. 6) is seen in some patients and is recognized as involuntary grasping, purposeless movements or levitation in the apraxic limb. When CBS affects the right extremities, it is more likely to be associated with a non-fluent aphasia, whereas when affecting left extremities with visuospatial and constructional deficits. CBS less frequently affects the lower extremities at onset. Imaging studies often demonstrate asymmetric parietal or fronto-parieto-occipital atrophy (Fig. 1.8).
Fig. 1.8
Axial FLAIR brain MRI of a patient with corticobasal syndrome due to pathology-proven Alzheimer’s disease, showing asymmetric, predominantly right parietal, hemispheric atrophy (With permission from Biller and Espay, Practical Neurology Visual Review. Lippincott Williams & Wilkins division of Wolters Kluwer Health, Inc. Philadelphia, PA, 2013)
In addition to CBD, CBS can be due to a variety of other pathologies, such as PSP, a focal variant of Alzheimer’s disease, and frontotemporal dementia [64]. Patients with CBS-PSP tend to develop oculomotor disturbances with or without progressive apraxia of speech (motor speech impairment without aphasia). The oculomotor dysfunction ranges from oculomotor apraxia (delayed latency of saccades with normal optokinetic nystagmus) to a supranuclear vertical and, eventually, horizontal gaze palsy [65] (Fig. 1.9).
Fig. 1.9
Diagrammatic representation between CBS and CBD. The corticobasal syndrome (CBS, asymmetric parkinsonism with apraxia, myoclonus and sensory loss) may be due to pathologies other than corticobasal degeneration (CBD, neurofibrillary tangles and astrocytic plaques). Similarly, CBD pathology may be associated with a variety of non-CBS phenotypes. PSP progressive supranuclear palsy, AD Alzheimer’s disease, FTLD frontotemporal lobar degeneration, FTD frontotemporal dementia, PNFA progressive non-fluent aphasia
Corticobasal degeneration (CBD) can be the pathology of a variety of phenotypes that include corticobasal syndrome (CBS), frontotemporal dementia, progressive non-fluent aphasia and Richardson’s syndrome, which make it a very challenging disorder to diagnose (Table 1.5). None of these phenotypes is sufficiently specific as to be unequivocally diagnosed as CBD. New diagnostic criteria have been recently developed that include all these phenotypes [66] (Table 1.6). These criteria are an improvement in unifying the available data to best predict probable CBD, but they await validation and further refinement. At this time, the diagnosis of definite CBD (as in other neurodegenerative parkinsonisms) can only be reached by autopsy. Most overlap exists between CBS and PSP, largely due to similar tau pathology with variations in its distribution. Nevertheless, certain features can help define the syndrome and predict the possible underlying pathologies according to their approximate frequency (Table 1.7).
Table 1.5
Phenotypic presentations in corticobasal degeneration
Main phenotype | Designation and features |
|---|---|
Asymmetric parkinsonism (classic phenotype) | CBD-corticobasal syndrome (CBD-CBS) (50 % of all pathological diagnoses of CBS) |
Symmetric parkinsonism (PSP-like) | CBD-progressive supranuclear palsy (CBD-PSP) (More executive and behavioural abnormalities than in pathology-proven PSP patients) |
Posterior cortical atrophy phenotype | CBD-Alzheimer’s disease (CBD-AD) (More frequent myoclonus) |
Frontal dementia with or without motor neuron disease | CBD-frontotemporal dementia (CBD-FTLD) (FTLD-tau and FTLD-TDP pathologies) |
Progressive non-fluent aphasia (PNFA) | CBD-frontotemporal dementia (CBD-FTLD) (PNFA most common aphasia subtype in CBD) |
Table 1.6
Clinical criteria for the diagnosis of corticobasal degeneration
Diagnostic certainty | Features required besides asymmetric onset | |
|---|---|---|
Probable | 2 of these 3 in one limb: 1. Rigidity or akinesia 2. Dystonia 3. Myoclonus | Plus 2 of these 3: 1. Orobuccal or limb apraxia 2. Cortical sensory deficit 3. Alien limb phenomena |
Possible | At least 1 of these in one limb: (a) Rigidity or akinesia (b) Dystonia (c) Myoclonus | Plus at least 1 of these: (a) Orobuccal or limb apraxia (b) Cortical sensory deficit (c) Alien limb phenomena |
Table 1.7
Overlapping clinical features between PSP and CBS and the frequency of the reported pathologies
PSP | CBS | |
|---|---|---|
Main motor phenotype | Symmetric akinesia with axial-predominant rigidity but lateralized featuresa may predominate | Asymmetric akinesia but axial-predominant rigidity may predominate |
Cognitive impairment | Frontal-dysexecutive, early | Frontal-dysexecutive, late |
Speech | Dysarthria, early | Dysarthria, late; apraxia of speech |
Language | Fluent perseverative | Non-fluent (PNFA) |
Saccades | Normal latency but slow velocity and decreased amplitude (hypometric) | Delayed latency but normal velocity, non-hypometric |
Common pathologies (approx. frequency) | PSP – 80 % CBD – 10 % FTLD-Tau – 10 % | CBD – 35 % AD – 20 % PSP – 15 % FTLD-TDP – 15 % FTLD-Tau – 15 % |
1.3.6 Vascular Parkinsonism
Vascular parkinsonism (VaP) is suspected in the setting of a ‘lower-body’ predominant parkinsonism and a brain MRI scan showing extensive subcortical white matter lesions (Fig. 1.10) [68]. Only around half of the VaP patients develop pyramidal signs, but when present, they are helpful to fully exclude PD, if previously suspected. In some cases there is a history of stepwise deterioration corresponding to brain MRI evidence of diffusion restriction. It is important to note, however, that the majority of vascular lesions involving the basal ganglia uncommonly translate into parkinsonian features, thus not uncommonly casting doubt on the suspected association [69], a concern that is supported by the scarcity of clinicopathologic correlations supporting a true vasculopathic aetiology for the signal abnormalities considered typical of VaP. Finally, if a VaP-suggestive history is not associated with neuroimaging evidence for leukoencephalopathy, a primary neurodegenerative disorder, such as PSP or MSA, needs to be considered.
Fig. 1.10
Brain MRI in vascular parkinsonism. These axial FLAIR brain MRI sequences were taken from a 75-year-old woman with a 3-year stepwise progression of gait, balance and cognitive impairments, with falls requiring a walker after 2 years from symptom onset. Her vascular risk factors included hypertension, cholesterol, diabetes and smoking. Note the extensive periventricular, subcortical and mid-pontine white matter increase signal typical of this disorder
1.3.7 Frontotemporal Dementia Syndromes
Patients with frontotemporal dementia (FTD) can develop parkinsonism before, during or after the development of the frontal-mediated cognitive or behavioural disturbances. The clinical spectrum of FTD includes the behavioural variant (bvFTD), progressive non-fluent primary progressive aphasia (nfPPA) and semantic dementia (SD). These phenotypes can present as sporadic (most often associated with the tauopathies PSP or CBD) or familial diseases, more often due to chromosome 9 open reading frame 72 (C9ORF72), progranulin (GRN) and TAR DNA-binding protein-43 (TDP–43). Mutations associated with FTD may also cause amyotrophic lateral sclerosis (ALS) or FTD/ALS phenotype (Table 1.8), suggesting that FTD and ALS are part of the same disease spectrum.
Table 1.8
Mendelian genes associated to frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) or FTD/ALS. Other associated phenotypes are also shown
Gene symbol | Gene name | Patterns of inheritance | Clinical presentation
Related posts: Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
Get Clinical Tree app for offline access
|
|---|
