Contributed by Marcelo Merello, MD
Director, Neuroscience Department
Head Movement Disorders Section
Institute for Neurological Research Raul Carrea (FLENI)
Buenos Aires, Argentina
2019 Updates contributed by Angelo Antonini, MD, PhD
Professor, Department of Neuroscience
University of Padua, Italy
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Parkinson’s disease (PD) is a neurodegenerative disorder characterized primarily by loss of dopamine neurons in the substantia nigra. Symptoms generally develop on one body side slowly over years but the progression may differ from one person to another due to the diversity of the disease. People with PD may experience tremor, mainly at rest (described as pill rolling tremor in hands), bradykinesia, limb rigidity, gait and balance problems. Prevalence is approximately 200 cases per 100,000 population, and the incidence is about 25 cases per 100,000 population, but these figures might show differences from one region of the world to another.
When motor manifestations appear, people with PD have lost more than 50% of nigral dopamine cells suggesting that pathological changes may begin many decades before the appearance of clinical signs. The premotor phase is characterized in many cases by non-motor manifestations such as REM-sleep behavior disorder, apathy, mood changes, anxiety, constipation and loss of olfaction.
The cause of PD is probably multifactorial, with contributions from hereditary predisposition, environmental toxins, and aging. In recent years it has become evident that there is also a genetic contribution to PD and several mutations have been identified (GBA, LRRK2, PRKN, SNCA), although in most world regions only a minority cases are explained by genetics.
Diagnosis remains clinical and is based on motor manifestations. Brain MRI or CT and molecular imaging (ie of the dopamine transporter in the striatum) of the striatum may be performed to support clinical evaluation. The clinical features of PD include both the motor symptoms (described above), as well as non-motor issues. These non-motor symptoms include neuropsychiatric symptoms including mood disturbances and cognitive changes; autonomic dysfunction, pain and sleep issues.
Levodopa has remained the cornerstone of PD treatment for more than 50 years. However, after a few years of treatment and mainly due to the progression of the disease, the benefit of levodopa shortens and motor complications appear in many patients. This had led to the introduction of many other medications including inhibitors of catechol-O-methyltransferase (COMT), monoamine oxidase type B (MAO-B) inhibitors and dopamine agonists. Enzyme blockers act by either extending levodopa or dopamine half-life while dopamine agonists mimic the action of dopamine on brain dopamine receptors.
More recently, surgical and infusion therapies have become available to improve management in selective patients with motor complications. Surgery includes the use of deep brain stimulation of the subthalamic nucleus and globus pallidus internus. The use of drug infusions is based on the possibility to deliver continuously either levodopa or apomorphine (a dopamine agonist with high affinity to dopamine receptors), mimicking the natural tonic receptor stimulation in the basal ganglia.
Parkinsonism
Contributed by David John Burn, MD, FRCP
Professor, Clinical Ageing Reserach Unit
Campus for Ageing and Vitality, Newcastle University
Newcastle Upon Tyne, UK
The defining feature of parkinsonism is bradykinesia, or slowness with decrement and degradation of repetitive movements (“fatigue”). Subtle “bradykinesia” has been reported to occur in the “normal elderly” population, but this may reflect a non-specific slowness rather than bradykinesia as defined above. Parkinson’s disease is the most common neurodegenerative cause of parkinsonism. Other causes include multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration.
These other neurodegenerative conditions are sometimes grouped together under term of “atypical parkinsonism” or “parkinson-plus syndromes”. They do not respond as well to dopaminergic treatments and generally have a worse prognosis compared to typical Parkinson’s disease. Degenerative causes of parkinsonism may be difficult to diagnose in the earliest stages and ancillary investigations may be of limited value in this instance.
Parkinsonism can also be symptomatic, as a result of various vascular, drug-related, infectious, toxic, structural and other known secondary causes. Of these, drug-induced parkinsonism is probably the most common and includes agents that block post-synaptic dopamine D2 receptors with high affinity (such as antipsychotic and anti-emetic medications) and sodium valproate. Vascular parkinsonism (“arteriosclerotic pseudoparkinsonism”) tends to have a lower body emphasis with gait disturbance and concomitant cognitive impairment.
Multiple System Atrophy (MSA)
July 2019
Authored by Gregor Wenning, MD, PhD, Professor of Clinical Neurbiology, Medical University of Innsbruck, Austria
Multiple system atrophy (MSA) is a rare and progressive α-synucleinopathy associated with oligodendroglial inclusions and neuronal loss affecting the striatum, substantia nigra, pons, and cerebellum among other brain areas. Clinically, symptoms may include severe parkinsonism unresponsive to levodopa, cerebellar ataxia, autonomic or pyramidal dysfunction in variable combination. According to predominance of parkinsonian or cerebellar symptoms patients are classified into subtype MSA-P or MSA-C, respectively. Mean age at motor symptom onset is 56.2 ± 8.4 years with no difference in sex distribution, and median survival is 6 to 10 years (9.8 years). Prior to motor symptom onset 20-75% of patients experience a prodromal phase which lasts from several months to years and is characterized by autonomic failure affecting cardiovascular, respiratory, urogenital, gastrointestinal, and sudomotor functions. In addition, rapid eye movement sleep behavior disorder (RBD) is frequently observed in the premotor stage of α-synucleinopathies with more than half of patients reporting RBD prior to motor onset and is present in up to 88% of patients diagnosed with probable MSA. To date, the etiology of MSA is still elusive, yet a complex interaction incorporating genetic predisposition and environmental factors is suggested to drive disease initiation and progression, as familial aggregation following an autosomal dominant or recessive inheritance pattern has been reported in several European and Japanese families. Nevertheless, MSA is largely considered to occur sporadically.
Currently, treatment options focus on specific signs and symptoms, and include medications to raise blood pressure or to reduce signs of Parkinsonism (transient response rate for 1-3 years in 38%), impotence drugs, bladder care, physiotherapy and speech therapy.
Progressive Supranuclear Palsy (PSP)
July 2019
Authored by Günter Höglinger, MD, Chair, Dept. of Neurology, Hannover Medical School, Hannover, Germany
Progressive Supranuclear Palsy (PSP) is an adult-onset neurodegenerative disorder with cerebral four-repeat (4R-) tau pathology in neurons, oligodendrocytes and astrocytes. Neurofibrillary tangles in PSP predominate in the brain stem and basal ganglia and to lesser degree in frontal and temporal cortices and cerebellum. Oligodendroglial coiled bodies are variably present. Tau-positive tufted astrocytes confirm the diagnosis. The differential anatomical distribution of tau pathology appears to determine the highly variable clinical manifestations of PSP.
The predominant clinical manifestation of PSP is called Richardson’s syndrome, i.e. a combination of postural instability with slowing of vertical saccades and supranuclear vertical gaze palsy in the early clinical course. The second most common manifestation is PSP with predominant Parkinsonism, i.e. an akinetic-rigid syndrome developing supranuclear ocular motor dysfunction at a later disease stage. Other clinical manifestations of PSP include progressive gait freezing, predominant frontal presentation, predominant speech/language disorder, and corticobasal syndrome, among others.
PSP is a sporadic disease, with common variants in MAPT being the most important risk factor. PSP typically shows its first clinical signs and symptoms after the age of 40, with 66 years on average. Average survival time from disease onset to death is 7.9 yrs., with aspiration pneumonia due to bulbar dysphagia being the most common cause. There is no approved drug available for PSP. Recommended off-label medications, physiotherapy and speech therapy provide utmost limited and temporal improvement in motor functions.
Most important unmet needs in PSP research are the characterization of prodromal conditions suggestive of PSP, imaging or fluid biomarkers to objectively diagnose and track the disease, and the development of clinically meaningful disease-modifying therapies.