What Is “Typical” Parkinson's Disease?
Parkinson's disease (PD) is a progressive brain disorder which usually produces some combination of the following symptoms:
- Tremor at rest
- Slowed movement
- Stiffness or rigidity of muscles
- Unsteadiness when standing or walking
- "Freezing" or sudden loss of ability to move (as if the feet are "glued" to the floor)
PD results from the dying off (degeneration) of certain nerve cells found in a deep part of the brain (brain stem) called the substantia nigra. The reason for the cell death is not exactly known but is thought to be due to the accumulation of a protein called alpha-synuclein – which is why PD is considered a “synucleinopathy.” These cells produce a neurotransmitter chemical called dopamine. It is the depletion of dopamine in the brain that results in the symptoms of PD. Initially, PD symptoms improve with dopamine replacement in the form of levodopa (Sinemet). Although the dopamine producing nerve cells in the substantia nigra are dying, the nerve cells in the basal ganglia (striatum) which are normally stimulated by dopamine, have well preserved dopamine receptors and continue to respond. The cornerstone of medical treatment of PD is administration of levodopa, which is taken up and converted into dopamine by the brain.
“Atypical” Parkinsonism and How It Differs from Parkinson's Disease
Parkinsonism refers to a set of symptoms typically seen in Parkinson's disease but caused by other disorders. Atypical parkinsonism includes a variety of neurological disorders in which patients have some clinical features of PD, but the symptoms are caused not only by cell loss in the substantia nigra (the brain area most affected in classic PD), but also by added degeneration of cells in the parts of the nervous system that normally contain dopamine receptors (striatum). In other words, the patients look like they have PD, but the cause of their symptoms is different from that of “classic” PD. Patients with atypical parkinsonism have symptoms like PD, including resting tremors, slowed movement, stiffness, gait difficulty and postural instability, but have additional symptoms and signs that are not typically present in PD. This has led to the commonly used term “parkinsonism plus syndrome.” A few such syndromes that are well described and, like PD, are thought to be related to the abnormal accumulation of proteins such as alpha-synuclein (“synucleinopathy”) or tau (“tauopathy”).
The additional symptoms and signs may include inability to look up and down (vertical gaze palsy) and early postural instability leading to frequent backward falls, such as seen in progressive supranuclear palsy (PSP – a tauopathy), the most common form of atypical parkinsonism. Patients with PSP often have the “procerus sign” which is a particularly “worried” facial expression. The second most common form of atypical parkinsonism is multiple system atrophy (MSA – a synucleinopathy). Patients with MSA are typically distinguished from those with PD by the presence of autonomic features such as unstable blood pressure (particularly orthostatic hypotension, which refers to drops in blood pressure when standing), early disturbance of sexual, bladder and bowel dysfunction, reddish-blue discoloration of skin (the "cold hand" sign), and marked sleep disturbance (e.g. acting out dreams and sleep apnea). Other typical features of MSA include forward head tilt (anterocollis) or a body tilt when sitting (Pisa sign), loss of coordination, and a rapidly progressive course with inability to ambulate usually within the first three to five years of onset. MSA is divided into MSA-C (cerebellar variant) which has more symptoms of ataxia (incoordination) and MSA-P (parkinsonian variant) which has more parkinsonian symptoms but is unresponsive to the usual therapy for Parkinson's disease (levodopa).
Other forms of atypical parkinsonism are dementia with Lewy bodies (DLB – a synucleinopathy) and corticobasal syndrome (CBS – a tauopathy). Patients with DLB have, in addition to the parkinsonian features, early dementia (usually preceding or co-occurring with the parkinsonian symptoms) and visual hallucinations (seeing people, small animals or objects that are not real) with their symptoms typically fluctuating leading to “good days” and “bad days.” Patients with CBS usually present with asymmetric stiffness, apraxia (inability to carry out learned purposeful movements), alien limb (the hand or the leg seem to have "a mind of their own"), and limb dystonia (abnormal sustained muscle contractions causing abnormal postures and twisting) or myoclonus (sudden jerking).
Another common cause of atypical parkinsonism is “vascular parkinsonism” caused by multiple and usually very small strokes. These patients tend to have more symptoms in the lower extremities (lower body parkinsonism) with walking difficulties, balance problems and falls.
The various atypical parkinsonian syndromes are classified according to the patterns of damage they produce in the nervous system, the constellation of clinical symptoms they cause, and their natural course (see Table 1. Parkinsonism Plus Syndromes: Differential Diagnosis.)
Poor or no response to levodopa is a common feature to all forms of atypical parkinsonism. In contrast to typical PD, in which dopamine receptors are spared, patients with atypical parkinsonian disorders have lost their dopamine receptors and therefore they do not respond to levodopa as well as those with typical PD. This can be demonstrated by special imaging such as positron emission tomography (PET) and dopamine transporter imaging (DAT-SPECT). MRI may be also helpful in differentiating PD from atypical parkinsonism.
There are probably many causes of atypical parkinsonism, but no one specific cause has been identified. Usually only one member of a family is affected and, therefore, these disorders are thought to be sporadic and not inherited. There is much active research into the causes of these disorders.
How to Support Research
Because the various atypical parkinsonism diseases are relatively uncommon, it is difficult to obtain public funding for research. Therefore, research into these disorders largely depends upon private contributions, particularly from patients and families affected with the diseases. Besides financial support and willingness to participate in clinical research projects, scientists are interested in examining postmortem brains of patients who were afflicted with these disorders. To arrange for a brain donation to a qualified “brain bank” you should contact your neurologist or the National Parkinson's Foundation for further information.
Support Groups for Patients and Their Families
Patients affected with atypical parkinsonism and their families should consider joining national or local support groups. Membership in these organizations facilitates exchange of information that may be useful in coping with the physical and mental disabilities associated with these disorders. Also, many local support groups offer exercise therapy which may be helpful to some patients. With the emotional support of family members and expert medical management guided by knowledgeable and compassionate physicians, many patients with atypical parkinsonism can lead enjoyable and productive lives.
Baizabal-Carvallo JF, Jankovic J. Parkinsonism, movement disorders and genetics in frontotemporal dementia. Nat Rev Neurol. 2016 Mar;12(3):175-85.
Bhatia KP, Stamelou M. Nonmotor Features in Atypical Parkinsonism. Int Rev Neurobiol. 2017;134:1285-1301.
Boxer AL, Yu JT, Golbe LI, Litvan I, Lang AE, Höglinger GU. Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches. Lancet Neurol. 2017 Jul;16(7):552-63.
Brooks DJ, Seppi K; Neuroimaging Working Group on MSA. Proposed neuroimaging criteria for the diagnosis of multiple system atrophy. Mov Disord. 2009;24:949-64.
Cardoso F. Botulinum toxin in parkinsonism: The when, how, and which for botulinum toxin injections. Toxicon. 2017 Aug 23.
Deutschländer AB, Ross OA, Dickson DW, Wszolek ZK. Atypical Parkinsonian syndromes: a general neurologist's perspective. Eur J Neurol. 2017 Aug 12.
Dubois B, Slachevsky A, Pillon B, et al. "Applause sign" helps to discriminate PSP from FTD and PD. Neurology. 2005 Jun 28;64(12):2132-3.
Fahn S, Jankovic J. Principles and Practice of Movement Disorders, Churchill Livingstone, Elsevier, Philadelphia, PA, 2007:1-652. (Accompanied by a DVD of movement disorders.)
Ha AD, Brown CH, York MK, Jankovic J. The prevalence of symptomatic orthostatic hypotension in patients with Parkinson's disease and atypical parkinsonism. Parkinsonism Relat Disord. 2011 Sep;17(8):625-8.
Hirschbichler ST, Erro R, Ganos C, Stamelou M, Batla A, Balint B, Bhatia KP. "Atypical" atypical parkinsonism: Critical appraisal of a cohort. Parkinsonism Relat Disord. 2017 Apr;37:36-42.
Hoglinger GU, Melhem NM, Dickson DW, et al. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Gene. 2011;43:699-705.
Jankovic J, eds. Neurology in Clinical Practice, 5th ed., Butterworth-Heinemann (Elsevier), Philadelphia, PA, Chapter 75, 2008:2081-122.
Jankovic J, Lang AE. Movement disorders: Diagnosis and Assessment. In: Bradley WG, Daroff RB, Fenichel GM, Jankovic J, eds. Neurology in Clinical Practice, 5th ed., Butterworth-Heinemann (Elsevier), Philadelphia, PA, Chapter 23, 2008:293-325.
Jankovic J, Shannon KM. Movement disorders. In: Bradley WG, Daroff RB, Fenichel GM, Jankovic J, Tintner R. Dystonia and parkinsonism. Parkinsonism Relat Disord. 2001;8:109-21.
Jankovic J. Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 2008;79:368-76.
Jankovic J. Parkinsonism. In: Goldman L and Ausiello D, eds. Cecil Textbook of Medicine, 22nd ed., Harcourt Health Sciences (W.B. Saunders), Philadelphia, 2004:2306-10.
Jankovic J. Pathophysiology and clinical assessment of parkinsonian symptoms and signs. In: Pahwa R, Lyons K, Koller WC, ed.: Handbook of Parkinson's Disease, Marcel Dekker, Inc., New York, NY, 2003:71-107.
Jankovic J. Searching for a relationship between manganese, welding, and Parkinson's disease. Neurology. 2005;64(12):2021-8.
Kagi G, Bhatia KP, Tolosa E. The role of DAT-SPECT in movement disorders. J Neurol Neurosurg Psychiatry. 2011;81:5-12.
Laurens B, Vergnet S, Lopez MC, Foubert-Samier A, Tison F, Fernagut PO, Meissner WG. Multiple System Atrophy - State of the Art. Curr Neurol Neurosci Rep. 2017 May;17(5):41.
Lipp A, Sandroni P, Ahlskog JE, et al. Prospective differentiation of multiple system atrophy from Parkinson disease, with and without autonomic failure. Arch Neurol. 2009;66:742-50.
Mahapatra RK, Edwards MJ, Schott JM, Bhatia KP. Corticobasal degeneration. Lancet Neurol. 2004;3:736-43.
Munoz DG, Dickson DW, Bergeron C, et al. The neuropathology and biochemistry of frontotemporal dementia. Ann Neurol. 2003;54:S24-S28.
Murman DL, Kuo SB, Powell MC, Colenda CC. The impact of parkinsonism on costs of care in patients with AD and dementia with Lewy bodies. Neurology. 2003;61:944-9.
Nath U, Ben-Shlomo Y, Thomson RG, Lees AJ, Burn DJ. Clinical features and natural history of progressive supranuclear palsy: A clinical cohort study. Neurology. 2003;60:910-6.
Osaki Y, Ben-Shlomo Y, Lees AJ, et al. Accuracy of clinical diagnosis of progressive supranuclear palsy. Mov Disord. 2004;19:181-9.
Ozawa T, Paviour D, Quinn NP, et al. The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain. 2004;127:2657-71.
Puschmann A. New Genes Causing Hereditary Parkinson's Disease or Parkinsonism. Curr Neurol Neurosci Rep. 2017 Sep;17(9):66.
Racette BA, Esper GJ, Antenor J, et al. Pathophysiology of parkinsonism due to hydrocephalus. J Neurol Neurosurg Psychiatry. 2004;75:1617-9.
Schreglmann SR, Bhatia KP, Stamelou M. Advances in the Clinical Differential Diagnosis of Parkinson's Disease. Int Rev Neurobiol. 2017;132:79-127.
Seppi K, Schocke MF, Donnemiller E, et al. Comparison of diffusion-weighted imaging and [123I]IBZM-SPECT for the differentiation of patients with the Parkinson variant of multiple system atrophy from those with Parkinson's disease. Mov Disord. 2004;19:1438-45.
Seppi K, Schocke MF, Esterhammer R, et al. Diffusion-weighted imaging discriminates progressive supranuclear palsy from PD, but not from the Parkinson variant of multiple system atrophy. Neurology. 2003;60:922-7.
Seppi K, Yekhlef F, Diem A, et al. Progression of parkinsonism in multiple system atrophy. J Neurol. 2005;252:91-6.
Sleegers K, Brouwers N, Van Damme P, et al. Serum biomarker for progranulin-associated frontotemporal lobar degeneration. Ann Neurol. 2009;65:603-9.
Soliveri P, Piacentini S, Girotti F. Limb apraxia in corticobasal degeneration and progressive supranuclear palsy. Neurology. 2005;64:448-53.
Thaisetthawatkul P, Boeve BF, Benarroch EE, et al. Autonomic dysfunction in dementia with Lewy bodies. Neurology. 2004;62:1804-9.
Thomas M, Jankovic J. Clinical diagnosis of vascular parkinsonism and non-degenerative atypical parkinsonian disorders. In: Litvan I, 1st ed. Atypical Parkinsonian Disorders: Clinical and Research Aspects (Current Clinical Neurology), Humana Press, Totowa, New Jersey, 2005.
Thomas M, Jankovic J. Clinical diagnosis of vascular parkinsonism and nondegenerative atypical parkinsonian disorders. In: Litvan I, ed. Atypical Parkinsonism, Humana Press, Totowa, New Jersey, 2008:393-408.
Thomas M, Jankovic J. Neurodegeneration and iron storage in the brain. Curr Opin Neurol. 2004;17:437-42.
Thomas M, Jankovic J. Parkinson-plus syndromes. In: Noseworthy J, editor-in-chief, Neurological Therapeutics: Principles and Practice, Martin Dunitz LTD, London, UK, 2003:2483-504.
Wenning GK, Colosimo C, Geser F, Poewe W. Multiple system atrophy. Lancet Neurol. 2004;3:93-103.
Wenning GK, Litvan I, Tolosa E. Milestones in atypical and secondary Parkinsonisms. Mov Disord. 2011;26:1083-95.
Williams DR, Lees AJ. Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol. 2009;8:270-9.
Zijlmans JC, Katzenschlager R, Daniel SE, Lees AJ. The L-dopa response in vascular parkinsonism. J Neurol Neurosurg Psychiatry. 2004;75:545-7.
Zwergal A, la Fougere C, Lorenzl S, et al. Postural imbalance and falls in PSP correlate with functional pathology of the thalamus. Neurology. 2011;77:101-9.
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