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 rapidly evolving parkinsonism that has a poor or transient response to dopaminergic therapy and often associates with one or more atypical features for Parkinson’s disease.1 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 suspected to be primarily sporadic in occurrence, although genetic susceptibility is thought to play a role.2
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. MSA tends to present slightly earlier. Recently discovered genetic polymorphisms in the alpha-synuclein gene and associations with chromosome 12 loci are linked to an increased risk of MSA and PSP, respectively.2 A lack of identifiable risk factors unfortunately makes primary prevention from APDs untenable.
MSA and DLB are synucleoinpathies associated with intracytoplasmic accumulation of alpha synuclein on postmortem pathology. PSP and CBD are tauopathies, with accumulation of abnormally phosphorylated tau proteins.3,4
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 with falls within a year of onset, early frontal cognitive deficits, and development of vertical gaze limitation in the middle stage of the disease. 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 oculomotor dysfunction with blepharospasm. Disease progression of PSP is generally rapid with significant disability within 3-4 years from presentation and death often within 12 years after diagnosis.
- MSA is a group of neurodegenerative syndromes characterized by the variable severity and timing in onset of akinetic-rigid parkinsonism, dysautonomia, cerebellar dysfunction, and corticospinal tract degeneration. A classic clinical characteristic is the progressive autonomic dysfunction that often dominates the early clinical picture and precedes the motor symptoms by several years.5 Later in the disease; akinetic-rigid parkinsonism with minimal jerky postural and action tremor, cerebellar ataxia, severe dysautonomia, and upper motor neuron signs may co-exist. Progression of disease is rapid, with severe disability and death often by 8-10 years of onset.
- CBD typically develops in the fifth to seventh decade of life and may present with unilateral bradykinesia rigidity, dystonia, myoclonus, ideomotor apraxia, and alien limb phenomena. However, variable phenotypes are increasingly recognized and cognitive impairment may be the initial concern. Over time, the disease progresses to involve the contralateral side. Response to dopaminergic treatment is usually poor. Progression of disease is rapid with severe disability or death typically occurring 6-9 years after onset.
- DLB initial and main complaint is the motor system but in the later stages of the disease, visual hallucinations, and cognitive deficits are present.6 There is an association with mild parkinsonism and the cognitive impairment particularly affects attention, executive, and visuospatial function that may fluctuate throughout the day. The disease progresses steadily, with mean survival of 7-10 years from onset of cognitive symptoms.
Specific secondary or associated conditions and complications
- Major complications of all of the APDs include falls with injury and aspiration pneumonia.
- Nocturnal strider and central hypoventilation can occur in MSA. These factors are associated with an increased risk of sudden death.
- Multiple non-motor symptoms that are commonly seen with APDs include: fatigue, constipation, depression, anxiety, chronic pain, REM sleep-behavioral disorder, anosmia, and psychosis.
2. ESSENTIALS OF ASSESSMENT
The diagnosis of the APDs is based upon clinical evaluation, with supportive radiologic findings. Diagnostic criteria for each of the APDs can serve as a guide.7,8,9 Presenting complaints are quite variable, but may include the following:
- PSP: postural instability with early posteriorly directed falls, slowing of vertical saccades, supranuclear gaze palsy, and cognitive impairment.
- MSA: primary autonomic failure, early falls, ataxia and action tremor.
- CBD: cognitive impairment, behavioral change, progressive apraxia, aphasia, and alien limb phenomenon.
- DLB: change in personality, cognitive impairment, visual hallucinations, and fluctuations in the level of consciousness.
- Parkinsonism (bradykinesia, rest tremor, rigidity and postural instability) will be present to a variable extent in the APDs. PSP tends to present with a distinctly axial rigidity. CBD tends to be quite asymmetric in its motor features. Tremor is often minimal if present in the APDs.
- Gait varies by condition and may be parkinsonian in DLB and MSA-parkinsonism (MSA-P), ataxic in MSA-cerebellar (MSA-C), and stiff with a wide base and abducted arms in PSP. Festinating gait or freezing of gait typically can be seen in advanced stages of all APDs.
- Extraocular movement abnormalities can occur in all APDs. A vertical gaze impairment is suggestive of PSP.
- 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.
It is important to routinely assess fall risk, swallow safety, vision, and cognition in order to ensure proper preventive care and supervision.
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 all APDs continues to be pursued.
Neuroimaging may be normal, but particular structural findings are suggestive of certain APDs.9 Dopamine transporter scan (DaTSCAN) cannot differentiate between idiopathic Parkinson’s disease (IPD) and the APDs.
- 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 of the posterior frontoparietal cortex with associated T2 hyperintensity on MRI.
- DLB: MRI can demonstrate putaminal atrophy with preservation of the mesial temporal structures.
Supplemental assessment tools
- 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 part III can be used to quantify motor impairments.
- 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-opthalmogical examination may detect oculomotor abnormalities that can help differentiate the APDs from one another and from IPD.
- Cardiac I 2,3,4 metaiodobenzylguanidine scintigraphy can help differentiate DLB from Alzheimer’s disease and MSA from IPD.
Early predictions of outcomes
- PSP: delayed falling and a later onset of oculomotor abnormalities suggests a better prognosis.
- MSA: older age at disease onset and early autonomic failure are predictors of shorter survival.
- DLB: fluctuation of mental status at an early stage is a predictor of poor outcome.
- CBD: there are no identified indicators of outcome.
Home safety evaluations by physical and occupational therapists are important in identifying environmental barriers and risks. Adaptive equipment needs and 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 career. Supportive counseling regarding changes in roles and the need for caretaking may be helpful in easing this transition.
- Management of dysphagia is largely dependent upon patient and family preference.
- In PD, 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 PD.
- Various treatments for dysphagia in PD 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 stimulation17.
- 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.
3. 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.13, 14
At different disease stages
- There are no curative or disease-modifying interventions for the APDs.
- Balance training and lower limb strengthening are employed to try to prevent or limit 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 is worth attempting to decrease falls and pain.
- Regulation of sleep/wake cycle may first be treated with environmental modifications.
- Anxiety and depression are common and often need to be treated with pharmacologic and/or psychotherapy treatment.
- Neurogenic bladder dysfunction should be assessed with urodynamic studies.
- Botulinum injections may treat blepharospasms and/or neurogenic detrusor overactivity.
- 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.5
- Mild to moderate dysphagia may be managed by adaptive strategies.
- 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.
- 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.15
- Other treatments:
- Parkinsonism may be partially responsive to levodopa, and a trial is recommended, barring contraindications.
- 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 or pyridostigmine, or midodrine)5.
- Siallorhea can be treated with scopolamine, glycopyrrolate or botulinum toxin injections.
- Cognitive impairment can be addressed with speech-language-pathology (SLP) therapists, 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 of 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
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Cutting edge concepts and practice
- A phase III trial investigating coenzyme Q10 for the slowing of disease progression of PSP is under way.
- Potential therapeutic targets in the tau pathway have been identified. Tau-active agents like lithium (CBD and PSP), tideglusib (PSP) and davuntide (CBD and PSP) are currently undergoing investigation.
- 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.16
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Gaps in the evidence-based knowledge
- The underlying pathogenesis of the APDs remains under investigation. When more is known, targeted therapies may emerge.
- The role of CSF biomarkers and advanced neuroimaging in diagnosis, and detection of treatment effects, has yet to be fully elucidated.
- Litvan I. What is an Atypical Parkinsonian Disorder? In: Litvan I, ed. Atypical Parkinsonian Disorders: Clinical and Research Aspects. Totowa, NJ: Humana Press; 2005:1-9.
- Wenning GK, Krismer F, Poewe W. New insights into atypical parkinsonism. Curr Opin Neurol. 2011;24(4):331-338.
- Jankovic J, Tolosa E. Parkinson’s Disease & Movement Disorders. 5th ed. Philadelphia, PA:Lippincott; 2007:161-202.
- Boeve BF, Land AE, Litvan I. Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia. Ann Neurol. 2003;54(suppl):S15-S19.
- Williams DR, Litvan I. Parkinsonian Syndromes. CONTINUUM: Lifelong Learning in Neurology. 2013;19(5, Movement Disorders):1189-1212.
- Zupancic M, Mahajan A, Handa K. Dementia with lewy bodies: diagnosis and management for primary care providers. Prim Care Companion CNS Disord. 2011;13(5).
- Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008;71:670-676.
- Litvan I, Agid Y, Calne D, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology. 1996;47(1):1-9.
- McKeith IG, Discson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005;65(12):1863-1872.
- Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013;80(5):496-503.
- 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.
Gilman S. Parkinsonian syndromes. Clinics Ger Med. 2006;22(4):827-842.
Herd CP, Tomlinson CL, Deane KH, et al. Comparison of speech and language therapy techniques for speech problems in Parkinson’s disease. Cochrane Database Syst Rev. 2012(8):Cd002814.
Original Version of the topic:
Heather R. Ene, MD, Taylor Finseth, MD. Other extrapyramidal movement disorders. Publication date: 10/22/2013.
Aiwane Iboaya, MD
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Sarah Eickmeyer, MD
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