Parkinson-Plus Syndrome

Etiology

The vast majority of Parkinson-plus syndrome cases occur sporadically, and the precise etiology remains unknown. A few examples of familial cases suggest that genetics may play a role in the pathogenesis of PPS.[7] Environmental factors additionally contribute to the evolution of these diseases.[8]

Epidemiology

Lewy Body Dementia 

LBD is one of the most common causes of neurodegenerative dementia, accounting for up to 30 percent of all dementia cases. The only forms of dementia more common are Alzheimer disease (AD) and vascular dementia. The prevalence is estimated to be 5 percent of the general population, and the incidence is approximately 0.1 percent annually.[9][10]

Multiple System Atrophy 

The approximate prevalence of MSA ranges from 2 to 5 cases per 100,000, and the incidence is 3 per 100,000. The mean age of onset is estimated to be 54 years. Men and women are affected equally.[11]

Corticobasal Degeneration

The approximate annual incidence of CBD ranges between 0.62 to 0.92 per 100,000, and the prevalence ranges from 5 to 7 per 100,000.[12] The disease typically presents at a mean age of 61 to 64 years. There is a suggested predominance of females.

Progressive Supranuclear Palsy 

The approximate prevalence of PSP is 3 to 7 per 100,000. The approximate incidence is 1.1 per 100,000 person-years.[12]

Pathophysiology

The pathophysiology of PPS can be divided into two groups, alpha-synucleinopathies and tauopathies. These groups allude to the type of protein (alpha-synuclein and tau proteins) which folds into a toxic and cell-damaging form.[1][2] It is proposed that the misfolded, toxic proteins cause cell death and induce improper folding of other proteins as the disease spreads throughout the brain.[2] 

In tauopathies such as PSP and CBD, cytoskeleton proteins become abnormally phosphorylated, leading to the development of tau inclusions in neurons and glial cells.[4] A similar process occurs in the alpha-synucleinopathies PD, LBD, and MSA.[6] The specific inclusions formed by alpha-synuclein are referred to as Lewy bodies in PD and LBD.[6] It is unknown why tau and alpha-synuclein proteins originally misfold, but it is postulated that it is due to sporadic mutations and environmental factors.[1][2]

The specific PPS condition is related to the type of neurons targeted and the location of these toxic proteins in the brain. 

Lewy Body Dementia (LBD)

In LBD, alpha-synuclein dysfunction and associated Lewy body deposits contribute to the impairment of particularly susceptible dopaminergic and cholinergic neurons.[13] Neurodegeneration begins in the brainstem and progresses to the olfactory bulb, substantia nigra, limbic areas, and the neocortex.[14][13]

Multiple System Atrophy (MSA)

MSA is suggested to be due to the prion-like spreading of alpha-synuclein proteins primarily, as well as glial cytoplasmic inclusions of tau and ubiquitin proteins.[15] Locations of pathology include the substantia nigra, Purkinje cells of the cerebellum, caudate nucleus, putamen, locus ceruleus, pontine nuclei, and inferior olivary nucleus.[16][17]

Progressive Supranuclear Palsy (PSP)

PSP involves tau cytoplasmic inclusions within neurons, referred to as neurofibrillary tangles.[14] These inclusions lead to neuronal loss, gliosis, and damage to astrocytes and oligodendrocytes. Areas targeted include the basal ganglia (substantia nigra, subthalamic nucleus, internal globus pallidus), oculomotor complex, cerebral cortex periaqueductal gray matter, superior colliculi, basis pontis, and dentate nucleus.[18]

Corticobasal Degeneration (CBD)

CBD is associated with tau astrocytic plaques and inclusions in the glia. These tau proteins lead to severe gliosis, neuronal loss, and ballooned achromatic neurons.[19] In CBD, there is prominent asymmetric frontoparietal atrophy.[19]

History and Physical

Parkinson-plus syndrome presents with parkinsonism as well as a variety of other clinical features that can be elicited by obtaining a focused history and physical along with close neurological monitoring. As in classical PD, there is apraxia, rigidity, bradykinesia, tremor, and postural instability.[1] 

Depending on the specific PPS, other possible clinical features include dementia, hallucinations, dysautonomia, symmetrical onset, myoclonus, pyramidal tract signs, supranuclear gaze palsy, and alien limb phenomenon.[5] PPS is also notable for its rapid progression and reduced response to classical PD medications. As the disease progresses, patients experience difficulty with ambulation and activities of daily living, as well as an overall decline in function.[4][5]

Lewy Body Dementia

LBD consists of dementia characterized by deficits in attention, cognition, and visuospatial function. Other notable features include visual hallucinations, rapid eye movement sleep behavior disorder (RBD), repeated falls, autonomic dysfunction, antipsychotic drug sensitivity, delusions, and depression. LBD consists of two clinical entities: dementia with Lewy bodies and PD dementia. Dementia with Lewy bodies is classified as dementia occurring first or within one year of the movement disorder. PD dementia occurs in a patient first receiving the diagnosis of PD and then developing dementia symptoms after one year or more of the diagnosis.[20]

Multiple System Atrophy 

The cardinal features of MSA are akinetic-rigid parkinsonism, cerebellar ataxia, autonomic failure, urogenital dysfunction, and pyramidal signs. There are two clinical subtypes of MSA based on motor presentation: MSA with predominant parkinsonism (MSA-P) and MSA with predominant cerebellar ataxia (MSA-C).[5]

The predominant motor feature may also change as the disease progresses. MSA-P is associated with bradykinesia, postural instability, rigidity, and a jerky postural and action tremor. MSA-C is characterized by gait and limb ataxia, dysarthria, and eye movement disturbances. Dysautonomia in both motor subtypes is standard and includes early-onset erectile dysfunction, urinary frequency, incontinence, and late-appearing orthostatic hypotension.[21] Cognitive function in MSA is usually well preserved.

Corticobasal Degeneration

CBD presents as an asymmetric movement disorder, with symptoms affecting one limb initially. Akinesia features include extreme rigidity, focal myoclonus, dystonia, alien limb phenomenon, and apraxia.[5] Cognitive impairment is common and may be the presenting feature. The cognitive decline includes aphasia, executive dysfunction, visuospatial deficits, and behavioral change. Episodic memory is often preserved.[22] 

Progressive Supranuclear Palsy 

PSP presents a variety of unique phenotypes. The most common and classic form of PSP is known as Richardson syndrome (PSP-RS). PSP-RS initially presents with gait dysfunction that leads to frequent falls. Supranuclear palsy is the hallmark of PSP, as patients cannot move the eyes vertically, focus on objects, or control eyelid movements. Ophthalmoparesis usually appears within four years but may take up to 10 years to develop.[23]

PSP patients are described as having axial rigidity and standing with an extended posture as opposed to the flexed posture in PD. Patients tend to pivot quickly and often fall backward. Other common symptoms include dysphagia, dysarthria, rigidity, frontal cognitive dysfunction, and sleep abnormalities.[24]

Phenotypes of PSP include PSP with predominant oculomotor dysfunction (PSP-OM), postural instability (PSP-PI), frontal presentation (PSP-F), speech/language disorder (PSP-SL), corticobasal syndrome (PSP-CBS), and progressive gait freezing (PSP-PGF).

Evaluation

Although Parkinson-plus syndrome is a clinical diagnosis, a full medical workup consists of detailed laboratory testing and imaging studies to help rule out other common diagnoses. Unfortunately, in most PPS conditions, laboratory and imaging findings are non-diagnostic.[1][2][4]

Lewy Dody Dementia

The evaluation of LBD begins as an analysis of dementia. This consists of a cognitive assessment with a Mini-Mental State Examination (MMSE) or Montreal Cognitive Assessment (MoCA). Laboratory testing includes a basic workup with a chemistry panel, complete blood count (CBC), thyroid function test, and vitamin B12 levels. Neuroimaging is performed with computed tomography (CT) or magnetic resonance imaging (MRI). Imaging findings in LBD include generalized brain atrophy and white matter lesions, pronounced cortical atrophy, degeneration of the putamen, and reduced perfusion, most marked in the occipital areas.[20]

Indicative biomarkers that contribute to the diagnosis of LBD include reduced dopamine transporter uptake in the basal ganglia evident on positron emission tomography (PET) or single-photon emission computerized tomography (SPECT), low uptake of 123-iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy, and confirmation of REM sleep without atonia on polysomnography. Supportive biomarkers for diagnosis include relative preservation of medial temporal lobe structures on CT or MRI, low uptake on PET perfusion scans with reduced occipital activity, and posterior slow-wave activity on electroencephalogram (EEG) with periodic fluctuations in the pre-alpha and theta range.[20]

Multiple System Atrophy 

As in other PPS diseases, laboratory and imaging studies are non-specific, and diagnosis is based on clinical features. Neuroimaging is used to rule out other diseases but may also show atrophy of the putamen, pons, or middle cerebellar peduncle, along with signal changes in the putamen. A definite diagnosis of MSA is based on post-mortem neurodegenerative changes in the striatonigral or olivopontocerebellar structures, with pathology showing alpha-synuclein inclusions in glial cells.[25] Other useful tests include autonomic function testing and bladder function analysis with sphincter electromyography (EMG).[26][27]

Corticobasal Degeneration

No established biological markers exist for CBD. Routine blood, urine, and cerebrospinal fluid (CSF) analyses are all non-diagnostic, while neuroimaging studies are non-specific. Workup includes laboratory tests such as CBC, electrolytes, vitamin B12, thyroid function tests, syphilis testing (to investigate for causes of cognitive deficits), and copper and ceruloplasmin levels to rule out Wilson's disease. Workup includes erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), and liver function tests to investigate rheumatologic disease; CSF testing for biomarkers of neurodegeneration can be performed, such as analysis for 14-3-3 protein, neuron-specific enolase, and CSF real-time quaking-induced conversion (CSF RT-QuIC) to test for prionopathies such as Creutzfeldt-Jakob disease (CJD). 

Evaluation for AD can be performed by testing for Amyloid beta-42, phosphorylated tau, and total tau. Regarding neuroimaging, CBD has been shown to have more asymmetric atrophy of the frontal and parietal lobes.[28] Cortical atrophy is observed mainly in the central sulci, supplementary motor area, and superior frontal gyrus. PET and SPECT imaging demonstrate asymmetric activity in the subcortical basal ganglia and cortical frontal-parietal regions.[28]

Progressive Supranuclear Palsy 

In PSP, a medical workup is based upon eliminating other diagnoses. Although not diagnostic, neuroimaging is notable for the hummingbird sign (or penguin silhouette sign) on MRI, a name derived from predominant midbrain atrophy with preserved pons resembling a hummingbird or penguin in silhouette. PET studies have shown hypometabolism in the frontal cortex, putamen, caudate, thalamus, and brainstem. Fluorodopa (F-dopa) PET study demonstrates a lower influx of F-dopa in the caudate and putamen compared to PD. 

Furthermore, sleep studies are often abnormal in PSP patients with lower total sleep time, loss of REM sleep, and increased awakenings. Histologic findings in PSP show prominent involvement in the basal ganglia (specifically the internal globus pallidus, subthalamic nucleus, and substantia nigra), oculomotor complex, superior colliculi, dentate nucleus, periaqueductal gray matter, and basis pontis.

Treatment / Management

In general, there are no disease-modifying treatments for PPS conditions. Treatment is focused on symptom management and improving quality of life. A minority of patients may show some relief of parkinsonism symptoms with levodopa. Alternative agents with limited benefit for parkinsonism include monoamine oxidase type B (MAO-B) inhibitor selegiline, the dopamine-releasing agent amantadine, and dopamine receptor agonists. 

Managing tremors includes using propranolol, clonazepam, topiramate, and gabapentin. Anticholinergics and baclofen may be helpful. Physical therapy helps prevent falls, reduces contractures, and promotes mobility. Physical therapists can also help with movement problems through cardiovascular, strengthening, flexibility exercises, gait training, and general fitness programs. 

Occupational therapy can assist in promoting independence for activities of daily living. Speech therapy is important in evaluating dysphagia, while dieticians can assist in proper nutrition planning. Palliative and safety measures are important for end-of-life care and limiting stress for the patient and caregivers.[5] 

Music or expressive arts therapists may provide meaningful activities that can reduce anxiety and improve well-being. There are also various other treatments and therapies which are specific for individual PPS diseases.

Lewy Body Dementia 

In LBD, cholinesterase inhibitors or memantine can be used to treat cognitive or behavioral symptoms. Antipsychotic medications are used when behavioral symptoms are severe. Disabling parkinsonism can be treated with levodopa, although effects are limited.[20] REM sleep behavior disorder is treated with melatonin or clonazepam. Mental health counselors can help LBD patients manage difficult emotions and behaviors. 

Multiple System Atrophy 

Botulinum toxin injections may alleviate focal dystonias in MSA. Chronic orthostatic hypotension resulting from autonomic dysfunction can be improved with fludrocortisone acetate or midodrine. REM sleep behavior disorder can be treated with melatonin or clonazepam if necessary.[29](B3)

Corticobasal Degeneration 

In CBD, dystonia can be treated with botulinum toxin to improve function in the affected limb.[29] Clonazepam is the agent of choice for treating myoclonus. Acetylcholinesterase inhibitors such as donepezil or rivastigmine can be attempted to treat cognitive deficits.[30](B3)

Progressive Supranuclear Palsy

There are a variety of therapeutic options to address the ophthalmological symptoms of PSP. Patients with limited extraocular movements can use mirror-prism lenses to read and perform activities of daily living with more independence. Eyelid opening apraxia and blepharospasm can be relieved with eyelid crutches and botulinum toxin.[29] Artificial tears should be used for treating a decreased blink rate, and dark glasses can reduce photophobia.(B3)

Differential Diagnosis

Each Parkinson-plus syndrome disease and classical PD must be considered when forming a differential diagnosis. Other similar diagnoses include AD, vascular dementia, normal pressure hydrocephalus, CJD, and certain psychiatric diseases.[1][2] Extrapyramidal side effects of medications can also be a cause of parkinsonism.[4]

Prognosis

Compared to idiopathic PD, PPS conditions progress more rapidly and culminate in death earlier.[1][2][4]

Lewy Body Disease 

In LBD, symptoms progress rapidly, with an estimated survival of 1.8 to 9.5 years. Studies show that survival for LBD is shorter compared to AD. Cognitive decline is progressive, and the median time to severe dementia is approximately five years. Parkinsonism and non-motor symptoms, including autonomic dysfunction and neuropsychiatric deficits, worsen over time.[20] Behavioral symptoms such as hallucinations, delusions, depression, and anxiety may require nursing home admission.

Multiple System Atrophy

Compared to idiopathic PD, the disease progression of MSA is much quicker. From symptom onset, autonomic dysfunction begins in 2.5 years, wheelchair confinement occurs in 3.5 to 5 years, and patients are bedridden for 5 to 8 years. Following diagnosis, death occurs after 6 to 10 years in most patients.[29]

Corticobasal Degeneration

CBD progresses rapidly to death, with the most common cause of mortality being complications from immobility or dysphagia (pneumonia and sepsis).[31] From the onset of symptoms, the median survival time is approximately 6 to 8 years but ranges from 2 to 13 years.[32]

Progressive Supranuclear Palsy

The progression of PSP is rapid, and patients usually become dependent on care within three to four years from symptom onset. Death occurs approximately six to nine years after the diagnosis.[18] Shorter survival is seen more in the PSP-RS phenotype compared to the other variants.[29]

Complications

There are various complications in PPS. These are often related to aspects of dementia and parkinsonism. Complications of parkinsonism include immobility and falls. Dysphagia can result in aspiration pneumonia and sepsis in many of these diseases. Urinary tract abnormalities may lead to complications like urinary tract infections.[6] 

Frequently, medications present many unwanted side effects. Furthermore, autonomic dysfunction can present with cardiac complications.[7] Often overlooked, behavioral symptoms such as anxiety and depression lead to suicidal ideation.[8]