Pat Robertson has dementia

Differential diagnosis and therapy of atypical Parkinson's syndromes

Background: In addition to Parkinson's disease, there are other atypical (non-diopathic) neurodegenerative Parkinson's syndromes: dementia with Lewy bodies (DLK), multiple system atropia (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). While DLK is a common disease with a prevalence of 0.4% in the elderly population, MSA and PSP have a prevalence of around 5–10 / 100,000 and CBD around 1/100,000.

Method: This work is based on a selective literature search.

Results: The atypical Parkinson's syndromes are based on synucleinopathies and tauopathies with pathological deposits of the proteins α-synuclein and tau. The location of the deposits is largely responsible for the clinical symptoms. The DLK is based on a neuronal synucleinopathy with predominantly neocortical localization, but also brain stem involvement. Clinically, dementia and a subsequent Parkinson's syndrome dominate. The MSA is based on an oligodendrocytic synucleinopathy that mainly affects the cerebellum and the brain stem and clinically causes dysautonomy with Parkinson's syndrome or cerebellar ataxia. Synucleinopathies also often interfere with rapid eye movement (REM) sleep. The PSP and CBD are primary tauopathies. PSP usually leads to vertically accentuated supranuclear palsy and early postural instability with falls, more rarely to predominant Parkinson's syndrome (PSP-P) or frontotemporal dementia (PSP-FTD). The CBD typically shows a Parkinson's syndrome with apraxia or cortical sensitivity disturbance in marked asymmetry. The therapies are currently purely symptomatic with limited efficiency and a low level of evidence.

Conclusion: Due to the current development of causal therapeutic approaches for neurodegenerative diseases, a molecular pathological diagnosis is required. This requires close cooperation between primary care and specialized centers.

A combination of the core symptom bradykinesia with rigor, tremor or postural instability defines a Parkinson's syndrome. Apart from secondary Parkinson's syndromes, for which the causes, such as drug side effects, normal pressure hydrocephalus and vascular encephalopathy, can be identified and possibly eliminated, Parkinson’s syndromes are the result of neurodegenerative diseases. The most common neurodegenerative Parkinson’s syndrome is called Parkinson’s disease (PK) or idiopathic Parkinson’s syndrome if it occurs sporadically (non-familial) and is a clinically leading movement disorder due to brainstem-predominant α-synuclein deposition. In contrast to PK, other sporadic disease entities are called atypical Parkinson's syndromes. This review article describes current standards for the diagnosis and treatment of the most important representatives of this group, dementia with Lewy bodies (DLK) (Table 1), multiple system atrophy (MSA) (Table 2), and progressive supranuclear palsy (PSP) (Table 3 ) and corticobasal degeneration (CBD) (Table 4). The differential diagnoses and therapeutic concepts of the syndromes are discussed here.

methodology

On the basis of the authors' scientific and clinical experience, a selective literature search was carried out in PubMed from 1960 onwards. Reviews, meta-analyzes, randomized, controlled studies, cohort studies, case-control studies, guidelines and case reports were included.

Neuropathology and pathophysiology

Atypical Parkinson's syndromes are neurodegenerative diseases with intracellular deposition of amyloidogenic proteins. While the protein α-synuclein characterizes DLK, MSA and PK (synucleinopathies), the tau protein occurs in PSP and CBD (tauopathies) (1–3) (Figure 1). In PK and DLK, α-synuclein aggregates are found in nerve cells, in MSA preferably in oligodendrocytes. In PSP and CBD, tau aggregates in nerve cells, but also oligodendrocytes and astrocytes. The morphology of the astrocytic tau deposits distinguishes PSP from CBD. The different disease entities typically affect characteristic brain regions. The misfolding and aggregation of these proteins can on the one hand lead to degeneration of the affected cell populations, but on the other hand also mediate the spread in anatomically connected brain regions and thus the disease progression (4). The increasingly better understanding of pathophysiology offers new starting points for a causally oriented therapy to stop the progression of these previously incurable diseases (4).

clinic

First we describe the two atypical Parkinson's syndromes with synucleinopathy and then the two tauopathies, each in the order of decreasing prevalence.

Dementia with Lewy Bodies

Epidemiology: Dementia with Lewy bodies (DLK) is the second most common form of neurodegenerative brain dysfunction in old age, after dementia in Alzheimer's disease. The prevalence in the population over 65 years of age is around 0.4%. The disease begins between the ages of 50 and 80. Men are affected slightly more often than women (5, 6).

Clinical features: The initial symptoms consist of a reduction in cognitive performance with noticeable fluctuations in episodes of poor and better cognitive performance (Table 1). Deficits relate to the naming of objects, verbal fluency, optical-spatial disturbances (for example in the clock-sign test) and executive functions. The latter can be seen when tasks have to be planned and changed in a situation. In contrast to Alzheimer's dementia, memory disorders usually do not appear in DLK at the onset of the disease (7).

Vivid, recurring, or persistent visual hallucinations, delusional beliefs, listlessness, depression, and anxiety are common (8). An akinetic-rigid movement disorder is often present at the time of diagnosis, but it almost always develops over time.

Diagnosis: The clinical signs are progressive dementia, fluctuations in cognitive performance, vivid optical hallucinations and Parkinson's syndrome (5).

Magnetic resonance imaging (MRI) can reveal atrophy in the caudate, putamen, and thalamus. In contrast to Alzheimer's disease, the cortex is not atrophied very much and the medial temporal lobe in particular is not atrophied (eFigure) (9).

In order to improve the diagnostic reliability of the DLK, the dopamine transporter can be used in specialized centers with the 123I-FP-CIT single-photon emission computed tomography (SPECT) is shown (10), the cerebral glucose metabolism can be measured with the 18F-FDG positron emission tomography (PET) (11) and the β-amyloid deposition can be measured with the corresponding PET imaging (12). In addition to the dopaminergic deficit, there is a characteristic hypometabolism, especially in the occipital regions of the primary visual cortex and in the visual association cortex. However, the medial temporal lobe and posterior cingulate are not affected. Deposition of β-amyloid is present, but less pronounced than in Alzheimer's dementia (10–12).

Differential diagnosis: There are two important differential diagnoses: Alzheimer's dementia and PK with dementia. The DLK differs markedly from Alzheimer's dementia in that it has fewer and later memory disorders (mini-mental status examination), greater visual and spatial deficits (clock-sign test), the typical fluctuations in cognitive performance, the existing Parkinson's disease Syndrome, the often existing "rapid eye movement" (REM) sleep behavior disorder and a slight atrophy of the medial temporal lobe / hippocampus (eFigure). The DLK and the PK with dementia form a spectrum without clear clinical or neuropathological boundaries. The sequence of symptoms is usually used to differentiate. If the cognitive impairments are present at least one year before the motor symptoms, a DLK is present. If movement disorders occur before or at the same time as cognitive disorders, the clinical picture is usually classified as Parkinson's disease with dementia (5).

Therapy: The treatment of DLK must take into account cognitive disorders, neuropsychiatric symptoms, and motor deficits in equal measure (13). One particular difficulty is that levodopa medication can improve Parkinson's symptoms, but worsen neuropsychiatric symptoms. Dopamine agonists are prohibited because of these side effects. Patients are particularly sensitive to the side effects of neuroleptics. The main features of symptomatic therapy are explained in Table 1. The level of evidence reported there for the individual therapy methods is divided according to the templates of the Scottish Intercollegiate Guidelines Network (SIGN) 2008. The recommendation grades are according to the specification of the working group of the scientific medical professional societies e. V. (AWMF) 2012 reproduced. The same applies to the other diseases described below.

Multiple system atrophy

Epidemiology: Multiple system atrophy (MSA) has a prevalence of around 5/100 000. The mean age of onset is in the sixth decade of life and the gender distribution is balanced. After an average of six to ten years, the patients usually die from aspiration or nocturnal cardio-respiratory arrest (14).

Clinical features: MSA shows two different types of predominance - either Parkinson’s syndrome (MSA-P, around 60% of cases in Europe) or cerebellar symptoms (MSA-C, around 40%). In addition to the movement disorder, vegetative symptoms, in particular urinary incontinence, erectile dysfunction or orthostatic hypotension, are obligatory in MSA (Table 2). An isolated autonomic malfunction ("pure autonomic failure", PAF) can precede the motor disorders of an MSA.

The hypokinetic-rigid Parkinson’s syndrome, which is in the foreground in MSA-P, is usually less asymmetrical on the sides and less levodopa-responsive than in PK. The classic slow pill-rolling resting tremor of PK is rare in MSA. Instead, there is usually an irregular, higher-frequency holding tremor.

The most common symptom of MSA-C is gait ataxia with a broad-based gait pattern. In addition, there is often ataxia of the extremities, cerebellar oculomotor disorders, scanting dysarthria and intention tremor.

Further symptoms typical of MSA, but not present in all patients, can occur in both types of predominance (15). For example, patients in advanced stages of the disease often suffer from dysarthria, inspiratory stridor and dysphagia. Pyramidal orbital signs show up in 30–50% of patients with MSA, but not in PK patients. In addition, focal dystonias and poor posture (antecollis, Pisa syndrome, contractures of the hands / feet) are not uncommon (14). Many MSA patients have an incidental REM sleep behavior disorder (14).

Diagnosis: The diagnostic criteria of the MSA were last revised in 2008 (16). The diagnosis requires at least one symptom of vegetative dysfunction (orthostatic hypotension, urinary incontinence, erectile dysfunction) with the exclusion of symptomatic causes. Furthermore, sporadic, progressive Parkinson's symptoms (MSA-P) or ataxia (MSA-C) as well as at least one other symptom typical of MSA or a characteristic imaging finding are required. Atrophy in putamen, middle cerebellar stalk, pons and cerebellum shows on MRI (Figure 2), hypometabolism in putamen, brain stem or cerebellum on FDG-PET. Signal anomalies in T2-weighted MRI images with 1.5 Tesla (eFigure) are not included in the diagnostic criteria, but still suggest an MSA: a cross-shaped hypointensity in pons (“hot cross bun” symbol) and a hypointense putamen with hyperintense marginal border (putamen marginal sign) (17).

Therapy: Levodopa therapy can improve the hypokinetically rigid symptoms of MSA-P in around a third of patients (18). So far there is no effective treatment for ataxia. Symptomatic treatment of the vegetative symptoms is recommended (13) (Table 2), as this significantly reduces the quality of life (19). In addition, logo, occupational and physiotherapeutic measures are indicated to maintain independence.

Progressive supranuclear palsy

Epidemiology: Progressive supranuclear palsy (PSP) has a prevalence of around 5–10 / 100,000 people. The mean age of onset is around 65 years. After an average of eight years, the patients die, often from aspiration in dysphagia. The gender ratio is largely balanced (20).

Clinical features: The clinical manifestations of PSP are diverse (Table 3). The most common (around 40%) is the classic Richardson syndrome with levodopa-resistant akinetic-rigid syndrome of the axial muscles, a tendency to fall backwards early in the course of the disease and vertically pronounced supranuclear palsy (21). While the patient cannot move the eyes up or down at will, the vertical eye movements can still be triggered by the vestibulo-ocular reflex (passive head movement by the examiner). Frontal brain syndrome with reduced drive (apathy) and disruption of executive functions, for example positive applause, which describes the inability to stop after clapping three times, is also typical. In addition, there is a pathological Luria sequence, which means that the patient is unable to correctly execute the hand-edge-fist-palm sequence at least six times. The verbal fluency is also included < 9="" s-wörtern="" in="" 60="" sekunden="" reduziert.="" charakteristisch="" ist="" weiterhin="" eine="" spastische="" (pseudobulbäre)="" sprech-="" und="" schluckstörung.="" nicht="" selten="" zeigt="" sich="" eine="" psp-pathologie="" mit="" zunächst="" im="" vordergrund="" stehendem,="" asymmetrischem="" levodopa-responsivem="" parkinson-syndrom="" (psp-p,="" circa="" 20 %),="" das="" klinisch="" nicht="" von="" einer="" pk="" unterschieden="" werden="" kann,="" bis="" später="" eine="" vertikale="" supranukleäre="" blickparese="" auftritt.="" ein="" seltenes="" syndrom="" mit="" plötzlichen="" und="" vorübergehenden="" gang-blockaden="" ohne="" begleitenden="" rigor="" oder="" tremor="" wird="" als="" pure="" akinese="" mit="" gang-freezing="" (pagf,="">< 5 %) bezeichnet="" und="" ist="" sehr="" typisch="" für="" eine="" zugrundeliegende="" psp-neuropathologie.="" mitunter="" kann="" zu="" beginn="" der="" krankheit="" ein="" klinisches="" bild="" entsprechend="" der="" verhaltensbetonten="" (behavioralen)="" variante="" der="" frontotemporalen="" demenz="" (bvftd,="" circa="" 15 %)="" oder="" einer="" progressiven="" nichtflüssigen="" aphasie="" (pnfa,="" circa="" 5 %)="" im="" vordergrund="" stehen,="" die="" sich="" klinisch="" erst="" von="" anderen="" formen="" einer="" frontotemporalen="" demenz="" unterscheiden="" lassen,="" wenn="" okulomotorische="" probleme="" erscheinen.="" ebenfalls="" kann="" eine="" psp-pathologie="" klinisch="" ein="" kortikobasales="" syndrom="" (cbs,="" circa="" 10 %)="" hervorrufen,="" das="" im="" kapitel="" zur="" cbd="" beschrieben="" wird="">

Diagnosis: The currently valid criteria of the National Institute of Neurological Disorders and Stroke (NINDS) and Society for Progressive Supranuclear Palsy (SPSP) for the diagnosis of PSP (22) are based on clinical evidence of the tendency to fall and eye movement disorders. They are therefore very sensitive to Richardson syndrome, but less suitable for recognizing the other clinical forms of PSP (21). Midbrain and frontal lobe atrophy can be detected on MRI (Figure 2) (23). Parkinson's symptoms usually improve only slightly in the levodopa test. In case of doubt, nuclear medicine methods can be used to detect symmetrical presynaptic nigrostriatal dopaminergic denervation (e.g. FP-CIT-SPECT), postsynaptic striatal degeneration (e.g. IBZM-SPECT), or hypometabolism in the frontal and midbrain (FDG-PET), so that the diagnosis can be clarified.

Therapy: The treatment of PSP is currently purely symptom-oriented (Table 3) (13, 20). Therapeutic target symptoms are the akinetic-rigid symptoms, the oculomotor disorders, neuropsychological deficits and an occasional dystonia as well as sleep disorders. The main features of pharmacological therapy are summarized in Table 3. In addition, speech therapy and physiotherapy measures to prevent aspiration and falls are indicated.

Corticobasal degeneration

The term corticobasal degeneration (CBD) is reserved for neuropathological diagnosis. Clinically, CBD usually manifests itself with a corticobasal syndrome (CBS) (24). However, patients with CBD pathology can also have clinical syndromes other than CBS (24) (Table 4). Likewise, patients with clinical CBS can also have an underlying PSP, Alzheimer's, or other pathology neuropathologically (25). The clinical-pathological assignment is therefore only possible to a very limited extent, which makes it necessary to strictly separate the neuropathological diagnosis CBD from the clinical picture CBS.

Epidemiology: The prevalence of CBD is around 1/100 000. CBD usually occurs equally frequently in both sexes in the sixth and seventh decades of life. Patients die after an average of eight years - most often from aspiration in dysphagia (26).

Clinical features: The concept of the CBS describes a progressive constellation of symptoms that include functional disorders of the basal ganglia and the cerebral cortex, usually with a markedly asymmetrical expression (27).

Basal ganglia symptoms include akinesia, rigor, dystonia, and myoclonus. The hypokinetic-rigid Parkinson's syndrome is typically levodopa-resistant. A tremor, which is often irregular and jerky due to the superimposition of myoclonus, can also occur. As the disease progresses, many patients show a characteristic, fixed dystonic posture of the affected arm, which usually consists of flexion of the hand and forearm and adduction of the upper arm in the shoulder joint (28). In the course of the disease, most patients develop rigid immobility within a few years and require care.

The following cortical symptoms are possible:

  • Apraxia (disruption of voluntary movements while motor function is intact)
  • cortical loss of sensitivity (despite intact primary sensation, disruption of the topographical assignment in 2-point discrimination, graphesthesia, stereognosia)
  • Alien limb phenomenon (experiencing an extremity as not belonging to one's own body)
  • Pyramid orbit sign
  • Behavioral disorders
  • Aphasia (24).

Diagnosis: The current consensus criteria (24) describe the different clinical phenotypes that can be associated with a CBD pathology (Table 4). The CBS is defined as already described.Asymmetric parietal atrophy (eFigure) and hypometabolism as well as pre- and postsynaptic nigrostriatal degeneration can be shown by imaging methods.

Therapy: The symptomatic treatment (13) (Table 4) of the akinetic-rigid syndrome with levodopa leads to a slight temporary improvement in about 30% of the CBD patients. A myoclonus responds to clonazepam, among other things. In the case of focal dystonia, the local injection of botulinum toxin can be useful (28). Anticholinergics are used for tremors. Physiotherapy, occupational therapy and speech therapy should also be prescribed.

outlook

For a long time, attempts have been made in atypical Parkinson's syndromes to diagnose a molecular-neuropathologically defined disease entity on the basis of neurological-psychiatric symptom constellations and MRI findings. The clinical syndromes and patterns of regional brain atrophies (Figure 2) as well as functional disorders that can be demonstrated by nuclear medicine correlate well (eFigure). However, it has been shown that different molecular pathologies can cause overlapping syndromes and imaging findings (Figure 1). For example, a CBS can be based on a CBD, a PSP, or other pathologies (24). Conversely, for example, PSP pathology can manifest itself with a variety of syndromes (21). Therefore, syndromes often do not allow a sufficient assignment to a disease entity. Since the established therapies aim to relieve symptoms through neurotransmitter modulation, a syndromic classification was sufficient for everyday clinical practice. The previous treatment approaches remain unsatisfactory in terms of symptom control and do not delay the progression of the disease. Fortunately, the last few years have provided spectacular insights into the mechanisms of the disease, so that causal therapeutic approaches can be clinically tested. These include modulators of pathological protein misfolding such as the substance Anle138b and antibodies against α-synuclein or tau (29, 30). However, interventions against defined molecular target structures require a diagnosis based on the molecular pathology in order to prove the existence of the molecular target structures for a causal therapy in the individual patient. Therefore, we are currently facing the challenge of defining and diagnosing neurodegenerative diseases as entities on the basis of their molecular pathology and non-clinical syndromes. Against this background, it is very gratifying that new diagnostic tools have been developed in the field of molecular imaging, for example Tau-PET (eFigure). In this way, molecular processes that were previously only visible in neuropathological examinations can be used diagnostically - such as the deposits of the tau protein. We can therefore be optimistic that in the coming years we will get clinically relevant innovations in the field of these rapidly progressing, fatal diseases.

thanksgiving

Günter Höglinger was supported by the German Research Foundation (DFG, HO2402 / 6–2). We thank Dr. Maximilian Patzig, Department of Neuroradiology at the LMU Munich for providing the MRI images. We thank Prof. Dr. Alexander Drzezga, Clinic and Polyclinic for Nuclear Medicine at the University Hospital Cologne, for providing the Tau-PET images.

Conflict of interest
PD Dr. Levin received study support (third-party funding) from Parkinson Fonds Deutschland gGmbH and lecture fees from Bayer Healthcare and MSD.

Prof. Dr. Giese holds shares and has personal relationships with MODAG. He also holds shares in the patent "EP2307381 - New drugs for inhibiting ..." and various national follow-up patents.

Prof. Dr. Höglinger is a member of the advisory boards of Asceneuron, Bristol-Myers Squibb, Roche and UCB Pharma. He has received lecture fees from Abbvie, Bristol-Myers Squibb, Elan, Noscira, Roche, Sellas, Teva, and UCB Pharma.

The other authors declare that they have no conflict of interest.

Manuscript dates
submitted: June 11, 2015, revised version accepted: October 20, 2015

Address for the authors
Prof. Dr. med. Günter U. Höglinger
Technical University of Munich (TUM) and
German Center for Neurodegenerative Diseases e. V. (DZNE)
Clinic for Neurology and Chair for Translational Neurodegeneration
Feodor-Lynen Strasse 17
81377 Munich
[email protected]

Citation style
Levin J, Kurz A, Arzberger T, Giese A, Höglinger GU: The differential diagnosis and treatment of atypical Parkinsonism. Dtsch Arztebl Int 2016; 113: 61-9.
DOI: 10.3238 / arztebl.2016.0061

@ The German version of this article is available online:
www.aerzteblatt-international.de

Additional material
eFigure:
www.aerzteblatt.de/16m0061 or via QR code

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