What’s next for atypical Parkinsonian syndromes?
With improved modern diagnostics, the frequency and distribution of atypical parkinsonisms are yet to be clarified.
Improvement and completion of the groups of criteria, allowing the establishment of a possible, probable, and certain diagnosis, is pending.
Improvement, implementation in practice, the discovery of new laboratories and imaging, and possibly genetic tests are ahead.
The main efforts in the field of treatment are related to the search for neuroprotectors such as inhibitors of tau protein or ±-synuclein aggregation.
What are the laboratory methods for diagnosis?
Appropriate laboratory methods for the diagnosis of atypical parkinsonism are in the process of development and implementation in practice. Looking for suitable cerebrospinal fluid markers. Auditory and somatosensory evoked potentials are investigated. In patients with multisystem atrophy, electromyography of the external anal sphincter helps to differentiate from idiopathic Parkinsonian syndrome but not from progressive supranuclear palsy.
Polysomnography helps differentiate ±-synucleinopathies from tauopathies. Auditory startle reflex is normal in multisystem atrophy, absent in progressive supranuclear palsy, and delayed in dementia with Lewy bodies. In the tauopathies, genetic tests can detect an H1/H1 haplotype, but since H1/H1 is also found in the main population (60%), these tests are of no diagnostic value.
- autonomic tests – an abnormal cardiovascular reflex has been described in multisystem atrophy. Skin temperature was examined before and after cooling in an attempt to aid in the diagnosis of multisystem atrophy. Orthostatism is possible in all atypical parkinsonisms, but is more common in multisystem atrophy and dementia with Lewy bodies; it is characteristic that in multisystem atrophy it develops faster than in idiopathic parkinsonism.
- nuclear magnetic resonance – in patients with Parkinson’s syndromes, narrowing of the substantia nigra, pars compacta can be detected on MRI. MRI signs of multisystem atrophy for hypointensity of the putamen and cleft-like hyperintensity of the outer edge of the putamen, the latter sign perhaps being specific. In progressive supranuclear palsy, there is also hypointensity of the putamen. Atrophy of the tectum and tegmentum (and dilatation of the aqueductus cerebri at the level of the midbrain) is found. In corticobasal dystrophy, asymmetric frontal and parietal atrophy and dilatation of the cerebral ventricles are found.
- magnetic resonance spectroscopy shows a difference in atypical Parkinsonian syndromes, but its usefulness, especially in the early stages of the disease, remains to be clarified.
- positron emission tomography studies are being developed but are not yet widely available and their applicability in questionable cases has not been proven. 4. A new ultrasound method is also being developed – brain parenchymal sonography.
What is the clinical picture and treatment of atypical Parkinsonian syndromes?
To differentiate between the various atypical Parkinson’s syndromes, as well as to distinguish them from Parkinson’s disease, it is important not only to know the clinic of the disease, but also to follow the development of the symptoms, especially during the first 4 years, since a large part of the symptoms or close to them may occur in varying percentages in several diseases.
dementia with Lewy bodies – clinically the disease overlaps with Alzheimer’s disease and Parkinson’s disease. In half of the cases, cognitive disorders are the beginning of the disease, and in the rest, to be diagnosed with dementia with Lewy bodies, dementia must develop within 1-3 years. Parkinsonism develops in 80% of patients. Cognitive impairments fluctuate, encompassing changes in attention and alertness. Fluctuations may be accompanied by somnolence and last minutes to months.
Psychiatric symptoms such as delusions, and recurrent visual hallucinations unrelated to the medication taken are characteristic. Parkinsonism is symmetrical, akinetic, and rigid, and tremors are less prevalent. (Resting tremor 27-55%). Dysarthria, dysphagia, and falls are more common than in Parkinson’s disease. Additional symptoms are apraxia, aphasia, disorders of visual-spatial orientation, acalculia, agnosia, syncope, transient loss of consciousness, and non-visual hallucinations. Up to 87% of patients with dementia with Lewy bodies have a good response to dopaminergic treatment.
The use of L-dopa with a COMT inhibitor is recommended. Cognitive disorders are treated with cholinesterase inhibitors, visual hallucinations with 50 mg clozapine, and orthostatic hypotension – with sympathomimetics. Because of the risk of hallucinations, low doses of L-dopa are sought and dopamine agonists are not used.
multisystem atrophy – the disease is characterized by parkinsonism, accompanied by cerebellum, autonomic, and other atypical features. Two forms of the disease are described: MSA-P – in 80% of patients with dominant parkinsonism and MSA-C with dominant cerebellar ataxia. Men and women from 33 to 78 years old are affected, with the average age being 54 years.
Life expectancy is 6-9 years. Parkinsonian manifestations are mainly bradykinesia, rigidity, postural tremor, resting tremor (34%), loss of balance, and unsteady gait. They are found in 90% of patients. In 27-56% the onset is asymmetric. Cerebral manifestations are ataxia, dysarthria, and oculomotor disturbances. They are found in 50% of patients. Autonomic and pyramidal disorders develop in almost all patients. Autonomic disorders are mainly orthostatic hypotension, erectile dysfunction, decreased genital sensitivity in women, constipation, hypo to anhidrosis, urinary incontinence, or retention.
Pyramidal signs are weakly expressed – Babinski’s reflex, pseudobulbar paresis, and hyperreflexia. In addition, sleep, cognitive disorders, depression, and others can be observed. Response to L-dopa treatment is 69-75%, but rapidly declines, with up to 35% remaining partially responsive. There is no effective medical treatment. Hypotension can be affected by fluid intake NaCl, and more frequent meals.
progressive supranuclear palsy – the disease presents with early postural instability and falls, vertical supranuclear palsy, frontal subcortical dementia, and parkinsonism with bradykinesia and marked axial rigidity, responding to L-dopa treatment. Patients with progressive supranuclear palsy are homozygous for the H1 tau haplotype. The disease affects men twice as often.
The relationship between progressive supranuclear palsy and neurotoxic substances is described. Smoking and coffee consumption are protective factors. Progressive supranuclear palsy develops in the sixth or seventh decade, never before 40 years, with an average age of 58 years. Patients live 2 to 12 years, usually up to 24 years, with death occurring in an average of 5 years and caused by hypostatic pneumonia. Gaze paresis usually develops after 3 years, and is most often preceded by a delay in vertical saccades.
Characteristic clinical syndromes are also pseudobulbar palsy, staring, lack of blinking, and sitting “en block”. Rarer are pyramidal and cerebellar syndromes. Static tremor occurs in 17%. Dementia is characterized by memory impairment, difficulty planning, apathy, or irritability.
corticobasal dystrophy – this is a slowly progressive disease with onset in adulthood, characterized by degeneration of the basal ganglia and cerebral cortex. The disease does not begin before the age of 45 and affects both sexes equally. Median survival is 7-8 years, with death occurring from aspiration pneumonia or sepsis. There are two phenotypes with different anatomical involvement.
The disease is associated with an H1/H1 tau phenotype. The combination of motor and perceptual disturbances is characteristic. In about 50% of cases, the disease is presented with asymmetric parkinsonism, dystonia, apraxia of the limbs, myoclonus, neglect, and possibly “alienated” limb syndrome. Early speech is possible, but no swallowing disorders.
In other patients, aphasia, attention deficits, frontal-type behavioral disturbances, and other cognitive symptoms are possible. Incontinence, bilateral pyramidal, or Parkinsonian disturbances are possible. Parkinsonism is not affected by L-dopa and in 95% of cases, it starts asymmetrically.
What is the epidemiology of atypical Parkinsonian syndromes?
Despite the increasingly better diagnosis of atypical Parkinson’s syndromes, the data on the incidence of this group vary between researchers and in different years.
This may also be related to differences in geographic distribution, as well as to an increase in disease incidence as a consequence of factors such as environmental hazards and increased life expectancy.
- for multisystem atrophy, the data varies around 4.4-4.5/100,000
- for progressive supranuclear palsy – 1.5 to 6.4/100,000
- for cortico-basal dystrophy 1.7-4.9/100,000
What is the pathology in atypical Parkinsonian syndromes?
Intraneuronal cytoplasmic filamentous protein inclusions are characteristic of atypical Parkinsonian syndromes.
In dementia with Lewy bodies and multisystem atrophy, the main constituent is the presynaptic protein ± synuclein with a gene located on chromosome four. In dementia with Lewy bodies, Lewy bodies are formed in the neurons, which are also found in Parkinson’s disease. There are three types of Lewy bodies – stem, core, and intermediate type. In multisystemic atrophy, inclusions are also found in oligodendrocytes. Soluble ± synuclein is found in the cytoplasm of healthy people. Phosphorylation of ± synuclein is increased in patients, which is associated with the formation of insoluble fibrils.
In progressive supranuclear palsy and corticobasal dystrophy, the inclusions contain 4-repeat tau protein and are found in neurons and glia. Tau protein in the inclusions is abnormally hyperphosphorylated. The gene for the tau protein is located on the long arm of chromosome 17. Tau protein is associated with microtubules involved in intracellular transport. It accumulates in oligodendrocytes, forming “spiral bodies ” and around axons as “threads”. A marker for progressive supranuclear palsy is the ” astrocytic tuft “, and corticobasal dystrophy – the astrocytic plaque.
What is the pathogenesis of atypical Parkinsonian syndromes?
The causes of atypical Parkinsonian syndromes are unknown. Genetic and environmental factors are believed to play a role in development. With age, various damaged molecules accumulate in brain cells. Lipids, DNA, and proteins are damaged by different mechanisms.
Oxidation, peroxidation, modification, aggregation, and infections contribute to the development of the disease. Also, the deficiency of some of the adaptation mechanisms – such as nerve growth factors, antioxidant enzymes, and antiapoptotic proteins is also important in the pathogenesis of diseases. Accumulation of damaged molecules leads to synaptic disruption, dendritic regression, and apoptosis. In varying degrees, depending on the disease, in addition to neurons, glia are also affected.
In atypical Parkinson’s syndromes, the dopaminergic cells of the substantia nigra are affected, which degenerate.
How are atypical Parkinsonian syndromes classified?
Parkinson’s syndromes cover 5 main groups:
- idiopathic Parkinson syndrome
- monogenetic forms of Parkinsonism
- symptomatic parkinsonism
- pseudo parkinsonism
- atypical parkinsonian syndromes
The group of atypical Parkinsonian syndromes includes:
- dementia with Lewy bodies
- multisystem atrophy
- progressive supranuclear palsy
- corticobasal dystrophy
The classification is not universally accepted and some authors give other schemes.
What is the definition of atypical Parkinsonian syndrome?
Atypical parkinsonian syndromes are characterized by rapidly developing parkinsonism, often with postural instability.
For 3 years from the beginning, transient or poor response to dopaminergic therapy, associated symptoms such as supranuclear palsy paresis, early autonomic involvement, apraxia, “alienation” of limbs, pyramidal or cerebellar dysfunction.
Introduction
The diagnosis of one of the major neurological diseases, Parkinson’s disease, is difficult. In more than 50% of patients with a primary diagnosis of Parkinson’s disease, there is no Parkinsonian syndrome.
It is even more difficult to differentiate between idiopathic parkinsonism and other true parkinsonism, especially when the disease is discovered. According to some authors, the term idiopathic parkinsonism may even cease to exist in the future.
The main atypical parkinsonian syndromes at that time were described in the second half of the last century – dementia with Lewy bodies – 1984, multisystem atrophy – 1969, progressive supranuclear palsy – 1964 and corticobasal dystrophy – 1967.
Good knowledge of these diseases is related to selecting appropriate laboratory tests, making an accurate diagnosis, giving a prognosis for the development of the disease, selecting appropriate therapy given the clinical effect, and avoiding the side effects of inappropriate medications, as well as adequate genetic counseling.
