Atypical Parkinsonian Disorders (APDs) are a group of neurodegenerative disorders characterized by parkinsonism in combination with other motor and nonmotor features. Previously known as “Parkinson plus syndromes”, they are characterized by a fairly rapidly evolving parkinsonism that has a poor or transient response to dopaminergic therapy. They include progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), and dementia with lewy bodies (DLB).
The etiologies of the APDs are unknown. They are thought to be primarily sporadic in nature, although there are reports of genetic associations.
Epidemiology including risk factors and primary prevention
There are no established risk factors (e.g., race, gender, or environmental exposure) that predispose to the APDs, but a consistent risk factor for all APDs is age. PSP, DLB and CBD generally present in the sixth decade, while MSA tends to present slightly earlier. The general lack of identifiable risk factors makes primary prevention of APDs difficult.
MSA and DLB are synucleinopathies, associated with intracytoplasmic accumulation of alpha-synuclein on postmortem pathology. PSP and CBD are tauopathies, with accumulation of abnormally phosphorylated tau proteins.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
- PSP has multiple phenotypic variants. The classic and most common form is characterized by postural instability and axial rigidity with falls within a year of onset, early frontal cognitive deficits, and development of vertical gaze palsy and slowed vertical saccades. These patients may develop a hyperextended posture and retrocollis, which can lead to falling backwards. The second most common presentation is PSP-parkinsonism (PSP-P), which may appear as an asymmetric parkinsonism with a resting tremor, an initial response to levodopa that decreases with time, and later a vertical supranuclear gaze palsy. As with other APDs, there is a risk of swallowing impairment and aspiration. The average age of onset is 65 years, with 8-year average survival from time of diagnosis.
- MSA is a group of neurodegenerative syndromes characterized by akinetic-rigid parkinsonism, dysautonomia, and cerebellar dysfunction. Two major types have been identified: MSA-P, with more predominant parkinsonism, and MSA-C, which is slightly less common, with prominent ataxia and cerebellar symptoms. Autonomic dysfunction is necessary for diagnosis, and tends to present with urinary incontinence, erectile dysfunction, and orthostatic hypotension. Patients may develop autonomic symptoms before the motor symptoms of the disease. Average age at onset has been reported to be about 56, and average survival has been estimated at 6-10 years from diagnosis. Later in the disease, patients can develop dysarthria, inspiratory stridor, and dysphagia
- CBD typically involves asymmetric myoclonus, dystonia and apraxia, as well as alien limb phenomena. Cognitive and behavioral impairments may also be involved. Average age at onset has been report at 63.7 years old in a recent review, with a mean survival of 6.6 years.
- DLB typically presents with cognitive impairment early, with visual hallucinations and fluctuating level of awareness being common symptoms of the disease. These patients may also develop parkinsonism symptoms and are more likely to have symmetric bradykinesia and rigidity. Movement symptoms may develop about a year before to a year after cognitive symptoms. This syndrome is more common than the other APDs, being the second most common form of progressive cognitive decline after dementia in Alzheimer’s.
Specific secondary or associated conditions and complications
Complications of APDs include falls and associated injuries, dysphagia and aspiration pneumonia (which is a common cause of death in these patients), REM sleep behavior disorders, OSA, nocturnal stridor (especially MSA), central hypoventilation, depression, anxiety and chronic pain. Bladder and sexual dysfunction associated with dysautonomia are commonly seen in MSA.
Essentials of Assessment
Diagnosis of APDs is primarily clinical, with supportive radiologic findings. Diagnostic criteria for each of the APDs can serve as a guide. Common presenting symptoms with each type of APD are discussed above and may be reported by the patient or the family.
- Parkinsonism (resting tremor, rigidity, bradykinesia and postural instability) will be present to a variable extent in the APDs.
- PSP tends to present with axial rigidity and hyperextended posture, a characteristic facial appearance, and vertical gaze palsy. They may present with a “rocket sign,” standing suddenly to attempt walking, and/or a “applause sign,” repeated clapping after being asked to clap 3 times.
- CBD tends to be quite asymmetric in its motor features.
- DLB tends to be more symmetric in its motor features.
- Tremor is often minimal if present in the APDs.
- Gait may be parkinsonian in DLB and MSA-parkinsonism (MSA-P), ataxic in MSA-cerebellar (MSA-C), and stiff, wide-based, with abducted arms in PSP. Festinating gait or freezing of gait are seen more in advanced stages of these disorders.
- Extraocular movement abnormalities can occur in all APDs.
- Limb or orobuccal apraxia, limb dystonia, alien limb syndrome, aphasia, cortical sensory loss and/or limb myoclonus are suggestive of CBD.
- Severe orthostasis, poor limb vascularity, ataxia, upper motor neuron signs and anterocollis are suggestive of MSA. The “cold hands sign” can be seen in MSA, where patients have a dusky and violaceous appearance of their hands. Functional assessment
From a functional standpoint, important considerations in the APDs include assessment of fall risk, cognition, vision, and swallow safety.
No laboratory studies can confirm or differentiate between the APDs. However, laboratory investigation may be performed to exclude other disorders. Orthostatic blood pressure and pulse should be measured in all patients. The search for reliable biological markers for the APDs is ongoing.
Neuroimaging may be normal or may show characteristic findings as described below.
- PSP: cortical and brainstem atrophy most pronounced in the midbrain (i.e., “hummingbird” or “penguin” sign).
- MSA: may show atrophy of the putamen, pons, and middle cerebellar peduncles on MRI. Hyperintensities in the pons from degeneration of the ponto-cerebellar fibers may be seen (i.e., “hot cross bun sign”), but is neither sensitive nor highly specific for MSA.
- CBD: possible focal asymmetric atrophy may be seen in the parietal lobes.
- DLB: MRI can demonstrate putaminal atrophy, with preservation of the mesial temporal structures (a distinguishing feature from Alzheimer’s disease).
Supplemental assessment tools1,3
- Disease-specific rating scales exist for PSP (Progressive Supranuclear Palsy Rating Scale) and MSA (Unified Multisystem Atrophy Rating Scale).
- The Movement Disorders Society Unified Parkinson’s Disease Rating Scale can be used to quantify motor impairments and other impairments in idiopathic Parkinson’s disease (IPD) as well as APD.
- Neuropsychological evaluation can identify the pattern and severity of cognitive impairment for diagnostic, treatment and life planning purposes.
- The Berg Balance Scale is often used to evaluate postural stability and balance.
- Polysomnography can be useful in evaluating sleep complaints.
- Neuro-ophthalmologic examination may be helpful to detect oculomotor abnormalities, and may help to differentiate the APDs from one another and from IPD.
- Several types of specialized CTs and SPECT scans may be used to provide more detail about which neurological structures are involved.
Early predictions of outcomes1,2,3,4,5,6
- Better prognosis for PSP: delayed falling and a later onset of oculomotor abnormalities.
- Poor prognosis/decreased survival for MSA: older age at disease onset and early autonomic failure.
- Poor prognosis for DLB: fluctuation of mental status at an early stage.
Home safety evaluations by physical and occupational therapists are important for identifying environmental barriers and risks. Adaptive equipment needs, as well as caregiver education, should be addressed.
Social role and social support system
Onset of the APDs generally occurs after an individual has established a family and a career. Assessing the patient’s social support system, work and home life is a key component of the initial physiatric assessment of these patients. Supportive counseling regarding changes in both the patient’s ability to work, and family roles with regard to caretaking may be helpful in easing this transition.
Rehabilitation Management and Treatments
Available or current treatment guidelines
- There are no published guidelines for the rehabilitation of the APDs. However, guidelines for the management of IPD can be adapted for this purpose.10,11
At different disease stages
- There are no curative or disease-modifying interventions for the APDs.
- Balance training and lower limb strengthening may help prevent or decrease falls.
- Bradykinesia and hypokinesia can be addressed with Lee Silverman Voice Treatment (LSVT) BIG treatment.
- Hypophonia can be addressed with LSVT LOUD treatment.
- Postural correction treatments can decrease fall risk and pain.
- Regulation of sleep/wake cycle can be addressed with consideration of sleep hygiene and environment modifications, as well as medication.
- Anxiety and depression are common. Psychotherapy as well as pharmacological treatment should be considered.
- Neurogenic bladder dysfunction should be assessed with urodynamic studies.
- Botulinum injections may treat blepharospasms and/or neurogenic detrusor overactivity.
- Discussion of expected disease progression and end-of-life decisions should occur early in the course of treatment while cognition is less affected. Medical Power of Attorney (POA) and living wills should be discussed during this time frame.12
- Freezing of gait may improve with the use of laser canes, laser walkers, or other sensory cues.
- Limb dystonia can be addressed with range-of-motion exercises, stretching, orthotics, oral medications and botulinum toxin injections.
- Myoclonus may be treated with valproic acid, clonazepam, levetiracetam, and piracetam.2
- Mild to moderate dysphagia may be managed by adaptive strategies. In IPD, disturbances may manifest in any stage of the swallowing process (oral preparatory, oral, pharyngeal, and esophageal stage). Abnormal bolus formation due to impaired lingual movements, aspiration due to delayed laryngeal movements, and impaired upper esophageal sphincter movements are common findings in IPD. Various treatments for dysphagia in IPD have been described including surgical interventions, bolus modification, neuromuscular electrical stimulation, postural and airway protective maneuvers, pharmacological interventions, deep brain stimulation (DBS), and repetitive transcranial magnetic stimulation.14
- Prism usage in reading glasses may be used to correct convergence in PSP.
- Pre-terminal or end of life care:
- Gastrostomy may be required for severe dysphagia. Management of swallowing dysfunction, especially as it becomes more severe, should include a discussion of patient and family wishes. Some individuals may choose to forgo gastrostomy and may choose to continue to eat what they enjoy despite aspiration risk, especially at later stages of these diseases.12
- Wheelchair mobility may be necessary when there is a high fall risk.
- Non-Invasive Positive Pressure Ventilation (NIPPV) or tracheostomy with assisted ventilation may be integral in treating respiratory failure due to cervical, laryngeal, and/or pharyngeal dystonia.12
- Other treatments:
- Parkinsonism may be partially responsive to levodopa, and a trial is recommended, barring contraindications. Other dopaminergic agents such as amantadine may be trialed as well.1
- Orthostasis can be addressed by increasing dietary salt and non-caffeinated fluids, physical measures (e.g., support stockings or an abdominal binder), and/or pharmacologically (e.g., fludrocortisone, indomethacin, pyridostigmine, midodrine).2
- Sialorrhea can be treated with scopolamine, glycopyrrolate or botulinum toxin injections.
- Cognitive impairment can be addressed with speech-language-pathology (SLP), behavioral interventions, anticholinesterase inhibitors, and memantine.
Coordination of care
An interdisciplinary team including physiatrists, neurologists, speech therapists, physical therapists, occupational therapists, nurses, and social workers can collaborate to most effectively address the complex and multifaceted issues that occur over the disease course.
Patient & family education
Patient and family education is an ongoing process as the disease progresses. In addition, local support groups and online information sources are available, including:
- Worldwide Education and Awareness for Movement Disorders (WeMove)
- Foundation for PSP, CBD and Related Brain Disease (CurePSP)
- The Multiple System Atrophy Coalition
- Lewy Body Dementia Association
Cutting Edge/ Emerging and Unique Concepts and Practice
- A multicenter, randomized, placebo-controlled, double-blind clinical trial to determine whether coenzyme Q10 (CoQ10) is safe, well tolerated, and effective in slowing functional decline in PSP was completed. Though it was well tolerated, high doses of CoQ10 did not significantly improve PSP symptoms or disease progression.15
- Four large randomized, placebo-controlled, double-blind disease-modification trials were completed using rasagiline (MSA), rifampicin (MSA), tideglusib (PSP), or davunetide (PSP). All failed to demonstrate signal efficacy with regard to the primary outcome measures.16
- Two randomized, placebo-controlled, double-blind trials studied the efficacy of droxidopa in the symptomatic treatment of neurogenic orthostatic hypotension, including patients with MSA, with positive results in one trial.16
- Autologous mesenchymal stem cells and small molecular agents are under investigation in phase II trials for the treatment of MSA.
- Deep brain stimulation surgery targeting the pedunculopontine nucleus has shown promise in reducing both motor and nonmotor symptoms of PSP in a small case series.12
Gaps in the Evidence-Based Knowledge
- The underlying pathogenesis of the APDs remains under investigation. When more is known, targeted therapies may emerge.
- Larger cohorts are required to validate genetic associations and biological pathways particularly when genetics possibly plays a role in the susceptibility and/or mutations of certain genes that directly lead to tauopathies such as PSP.17
- The role of CSF biomarkers and advanced neuroimaging in diagnosis, and detection of treatment effects, has yet to be fully elucidated.
- Levin, J. Kurz, A., Arzberger, T., Giese, A., and G.U. Hoglinger. The differential diagnosis and treatment of atypical Parkinsonism. Dtsch Arzetebl Intl. 2016; 113: 61-69.
- Keener, A. M., MD, and Y. M. Bordelon, MD, PhD. Parkinsonism. Semin Neurol. 2016; 36: 330-334.
- Wenning, G.K., et al. The natural history of multiple system atrophy: a prospective European cohort study. Lancet Neurol. 2013; 12: 264-274.
- Cykowski, M. D., et al. Expanding the spectrum of neuronal pathology in multiple system atrophy. Brain. 2015; 138: 2293-2309.
- Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013;80(5):496-503.
- Coyle-Gilchrist, I. T.S., et al. Prevalence, characteristics and survival of frontotemporal lobar degeneration syndromes. Neurology. 2016; 86: 1736-1743.
- Goetz et al. MDS-Unified Parkinson’s Disease Rating Scale. International Parkinson and Movement Disorder Society. Scale last updated 8/13/2019.
- Macijauskiene J, Lesauskaite V. Dementia with Lewy bodies: the principles of diagnostics, treatment and management. Medicina (Kaunas). 2010;48(1):1-8.
- Berardeli A, Wenning GK, Antonini A, et al. EFNS/MDS-ES recommendations for the diagnosis of Parkinson’s disease. Eur J Neurol. 2013;20:16-34.
- Tominson CL, Patel S, Meek C, et al. Physiotherapy intervention in Parkinson’s disease: systematic review and meta-analysis. Brit Med J. 2012;345:p.e5004.
- Fox C, Ebersbach G, Ramig L, Sapir S. LSVT LOUD and LSVT BIG: Behavioral Treatment Programs for Speech and Body Movement in Parkinson Disease. Parkinson’s Disease. 2012;2012:12.
- Lokk J, Delbari A. Clinical aspects of palliative care in advanced Parkinson’s disease. BMC Palliat Care. 2012;11(1):20.
- Hazrati LN. Clinicopathological study in progressive supranuclear palsy with pedunculopontine stimulation. Movement Disord. 2012;27(10):1304-1307.
- Van Hooren MRA, Baijens LWJ, Voskuilen S, Oosterloo M, Kremer B. Treatment effects for dysphagia in Parkinson’s disease: A systematic review. Parkinsonism Relat Disord. 2014;20(8):800-807.
- Apetauerova D, Scala SA, Hamill RW, Simon DK, Pathak S, Ruthazer R, Standaert DG, Yacoubian TA. CoQ10 in progressive supranuclear palsy: A randomized, placebo-controlled, double-blind trial. Neurol Neuroimmunol Neuroinflamm. 2016 Aug 2;3(5):e266.
- Poewe, W., Mahlknecht, P. and Krismer, F. (2015), Therapeutic advances in multiple system atrophy and progressive supranuclear palsy. Mov Disord., 30: 1528-1538.
- Wen, Y., Zhou, Y., Jiao, B., & Shen, L. (2021). Genetics of Progressive Supranuclear Palsy: A Review. Journal of Parkinson’s disease, 11(1), 93–105. https://doi.org/10.3233/JPD-202302
Original Version of the topic
Heather R. Ene, MD, Taylor Finseth, MD. Other extrapyramidal movement disorders. 10/22/2013
Previous Revision(s) of the topic
Aiwane Iboaya, MD, Sarah Eickmeyer, MD. Other extrapyramidal movement disorders. 9/5/2018
Sarah Eickmeyer, MD
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Aimee Lambeth, DO
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Aiwane Iboaya, MD
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