Other Extrapyramidal Movement Disorders

Disease/Disorder

Definition^1-5

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. This syndrome is usually the result of a dysfunctional nigrostriatal pallidal pathway. They include progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), and dementia with Lewy bodies (DLB).⁵

Etiology

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. From case-controlled studies of MSA, occupational exposure to plastic monomers and additives, pesticides, metallic dusts and organic solvents may be risk factors. 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.⁵

Patho-anatomy/physiology

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)

• Progressive supranuclear palsy: 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. There can also be behavioral changes seen such as apathy and disinhibition. 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.⁶
• Multiple system atrophy: 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
• Corticobasal degeneration: CBD typically involves asymmetric myoclonus, dystonia and apraxia, as well as alien limb phenomena. Cognitive and behavioral impairments may also be involved. CBD patients can also present with a non-fluent agrammatic variant of primary progressive aphasia. Average age at onset has been reported at 63.7 years old in a recent review, with a mean survival of 6.6 years.³
• Dementia with Lewy bodies: 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
• Chronic pain
• Bladder and sexual dysfunction associated with dysautonomia are commonly seen in MSA.

Essentials of Assessment

History^1-3,5,7,8

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.

Physical examination

• Parkinsonism (resting tremor, rigidity, bradykinesia and postural instability) will be present to a variable extent in the APDs. Tremor is often minimal if present in the APDs.
• Extraocular movement abnormalities can occur in all APDs.
• 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.
• 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.
• 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.  Limb or orobuccal apraxia, limb dystonia, alien limb syndrome, aphasia, cortical sensory loss and/or limb myoclonus are suggestive of CBD.
• DLB tends to be more symmetric in its motor features.

Functional assessment: From a functional standpoint, important considerations in the APDs include assessment of fall risk, cognition, vision, and swallow safety.

Laboratory studies

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.

Imaging⁹

Neuroimaging can be normal, or can show characteristics findings as described below:

• Lewy Body Spectrum Disorders: Atrophy in the occipital lobe, temporoparietal cortex, and occipital cortex with preservation of the hippocampus (distinguishing it from Alzheimer’s disease). Lewy body also has the most accumulation of Amyloidopathy on PET scan.
• Multiple System Atrophy (MSA): Thin band of high signal around the putamen (Putaminal rim sign), cruciform T2-weighted hyperintensity within the Pons (hot cross buns sign), and an abnormal T2-weighted hyperintensity in the middle cerebellar peduncle (middle cerebellar peduncle sign).
• Progressive Supranuclear Palsy:  Atrophy of the midbrain as it runs to the optic chiasm while looking in the sagittal plain (hummingbird sign), and concavity of the of the dorsal lateral portions of the midbrain bilaterally in axial imaging (morning glory sign).
• Corticobasal Degenerative Syndromes: asymmetric cortical atrophy of the frontoparietal lobe contralaterally to the more affected side.
• Several types of specialized CTs and SPECT scans may be used to provide more detail about which neurological structures are involved.

Supplemental assessment tools^1,3,18

• Disease-specific rating scales exist for PSP (Progressive Supranuclear Palsy Rating Scale) and MSA (Unified Multisystem Atrophy Rating Scale).
• The Disease specific rating scales above have additional quality of life scales that can help predict mortality and morbidity (PSPRS-Qol and MSARS-QoL).  
• 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.

Early predictions of outcomes^{1,2,3,4,5,6,19}

• Better prognosis for PSP: delayed falling, a later onset of oculomotor abnormalities, and patients with the subcortical phenotype
• 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.

Environmental

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

Acute/subacute

• There are no curative or disease-modifying interventions for the APDs.
• European guidelines for physiotherapy in PD are three times per week with a duration of 45 mins for 12 weeks.¹⁰
• It is important that each physiotherapy treatment is personalized to each patient, keeping feasibility, individual goals, capacity and preference in mind.¹¹
• 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. Medications include melatonin and in some cases clonazepam.¹¹
• Anxiety and depression are common. Psychotherapy as well as pharmacological treatment should be considered.
• Neurogenic bladder dysfunction should be assessed with urodynamic studies. Handheld urinals can be used to reduce falls when patients have nocturia.¹¹
• 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.⁷

Chronic

• Strategy training or cueing based rehabilitation is a form of therapy where visual or auditory cues are provided to the patient to provoke movement. For example, the use of rhythmic auditory stimulation has shown to significantly improve stride length and speed after one week of use.¹²
• 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.⁴
• 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.¹³
• 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.⁷
• 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.⁷

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.⁵
• Orthostatic hypotension is a debilitating symptom of these disorders. Treatments begin with removal of offending agents such as B-Blockers, antihypertensives, diuretics, or alpha blockers. Patients may also use blood volume expansion by increasing dietary salt and fluids. Physical measures such as abdominal binder, and waist high compression stockings can also be useful. Pharmacologically, midodrine is a good choice for these patients as it lasts roughly 4 hours and is tolerated well with little side-effects.¹⁴
• Supine hypertension can be treated with short acting antihypertensives (losartan), or transdermal clonidine. Transdermal clonidine can keep patients from becoming syncopal, as they are able to simply remove the patch before standing.
• 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

• Aerobic exercise has shown significant improvement in UPDRS scores as well as VO2 max when compared to stretching exercises alone.¹⁵
• Trans magnetic stimulation and Transcranial direct current stimulation has been shown to significantly improve motor symptoms and cerebellar activation in MSA patients.¹⁶
• A dynamic antigravity postural system along with a vibration sound system used in 3 sessions/week for 2 months showed improvement of PSP rating scale and PD36 QOL scale scores at the end of the treatment.¹⁷
• Intrathecal autologous mesenchymal stem cells may slow motor progression in MSA with adverse events included low back pain associated with thickening nerve roots.¹⁸
• Antisense oligonucleotides and small interfering RNA have shown mixed results in animal trials and will likely be the next frontier for PSP care.¹⁹

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.²⁰
• The role of CSF biomarkers and advanced neuroimaging in diagnosis, and detection of treatment effects, has yet to be fully elucidated.

References

1. Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology 2013;80(5):496-503 doi: 10.1212/WNL.0b013e31827f0fd1.
2. DeRosier F, Hibbs C, Alessi K, et al. Progressive supranuclear palsy: Neuropathology, clinical presentation, diagnostic challenges, management, and emerging therapies. Dis Mon 2024;70(8):101753 doi: 10.1016/j.disamonth.2024.101753 [published Online First: 20240621].
3. International Association of P, Related D. Clinical parkinsonism & related disorders. Oxford: Elsevier Ltd, 2019.
4. Keener AM, Bordelon YM. Parkinsonism. Semin Neurol 2016;36(4):330-4 doi: 10.1055/s-0036-1585097 [published Online First: 20160919].
5. Atypical Parkinsonian Disorders : Clinical and Research Aspects [program]. 1st 2005. version. Totowa, NJ: Humana Press : Imprint: Humana, 2005.
6. International Brain Research O. IBRO neuroscience reports. Amsterdam: Elsevier B.V, 2021.
7. Lokk J, Delbari A. Clinical aspects of palliative care in advanced Parkinson’s disease. BMC Palliat Care 2012;11:20 doi: 10.1186/1472-684X-11-20 [published Online First: 20121025].
8. Street D, Jabbari E, Costantini A, et al. Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials. Brain 2023;146(8):3232-42 doi: 10.1093/brain/awad105.
9. Saeed U, Lang AE, Masellis M. Neuroimaging Advances in Parkinson’s Disease and Atypical Parkinsonian Syndromes. Front Neurol 2020;11:572976 doi: 10.3389/fneur.2020.572976 [published Online First: 20201015].
10. Domingos J, Keus SHJ, Dean J, de Vries NM, Ferreira JJ, Bloem BR. The European Physiotherapy Guideline for Parkinson’s Disease: Implications for Neurologists. J Parkinsons Dis 2018;8(4):499-502 doi: 10.3233/JPD-181383.
11. Saluja A, Goyal V, Dhamija RK. Multi-Modal Rehabilitation Therapy in Parkinson’s Disease and Related Disorders. Ann Indian Acad Neurol 2023;26(Suppl 1):S15-S25 doi: 10.4103/aian.aian_164_22 [published Online First: 20221121].
12. Bryant MS, Rintala DH, Lai EC, Protas EJ. An evaluation of self-administration of auditory cueing to improve gait in people with Parkinson’s disease. Clin Rehabil 2009;23(12):1078-85 doi: 10.1177/0269215509337465.
13. van Hooren MR, Baijens LW, Voskuilen S, Oosterloo M, Kremer B. Treatment effects for dysphagia in Parkinson’s disease: a systematic review. Parkinsonism Relat Disord 2014;20(8):800-7 doi: 10.1016/j.parkreldis.2014.03.026 [published Online First: 20140408].
14. Coon EA, Ahlskog JE. My Treatment Approach to Multiple System Atrophy. Mayo Clin Proc 2021;96(3):708-19 doi: 10.1016/j.mayocp.2020.10.005.
15. van der Kolk NM, de Vries NM, Kessels RPC, et al. Effectiveness of home-based and remotely supervised aerobic exercise in Parkinson’s disease: a double-blind, randomised controlled trial. Lancet Neurol 2019;18(11):998-1008 doi: 10.1016/S1474-4422(19)30285-6 [published Online First: 20190911].
16. Zhang M, He T, Wang Q. Effects of Non-invasive Brain Stimulation on Multiple System Atrophy: A Systematic Review. Front Neurosci 2021;15:771090 doi: 10.3389/fnins.2021.771090 [published Online First: 20211213].
17. Di Pancrazio L, Bellomo RG, Franciotti R, et al. Combined rehabilitation program for postural instability in progressive supranuclear palsy. NeuroRehabilitation 2013;32(4):855-60 doi: 10.3233/NRE-130909.
18. Singer W, Dietz AB, Zeller AD, et al. Intrathecal administration of autologous mesenchymal stem cells in multiple system atrophy. Neurology 2019;93(1):e77-e87 doi: 10.1212/WNL.0000000000007720 [published Online First: 20190531].
19. Sidoroff V, Bower P, Stefanova N, et al. Disease-Modifying Therapies for Multiple System Atrophy: Where Are We in 2022? J Parkinsons Dis 2022;12(5):1369-87 doi: 10.3233/JPD-223183.
20. Wen Y, Zhou Y, Jiao B, Shen L. Genetics of Progressive Supranuclear Palsy: A Review. J Parkinsons Dis 2021;11(1):93-105 doi: 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, Aimee Lambeth, DO, Aiwane Iboaya, MD. Other Extrapyramidal Movement Disorders. 4/14/2022.

Author Disclosure

Ann Wingard, DO
Nothing to Disclose

Laura Allen-Matlock, MD
Nothing to Disclose

Sarah Eickmeyer, MD
Nothing to Disclose