Shy-Drager Syndrome
Overview
[Shy-Drager syndrome](/diseases/shy-drager-syndrome) (SDS) is a rare neurodegenerative disorder characterized by progressive [autonomic failure](/mechanisms/autonomic-dysfunction-neurodegeneration) in conjunction with [parkinsonian features](/conditions/parkinsonism). It is now classified as a variant of [multiple system atrophy](/diseases/multiple-system-atrophy) (MSA), specifically the MSA-A (autonomic) subtype. The syndrome represents an important historical entity that helped establish the concept of [oligodendroglial cytoplasmic inclusions](/mechanisms/alpha-synuclein-pathology) and [alpha-synuclein](/proteins/alpha-synuclein) pathology in neurodegenerative disease[@graham1969].
Pathway / Mechanism Diagram
flowchart TD
A["Genetic<br/>Risk Factors"] --> B["Molecular<br/>Pathology"]
A0["MSA"] --> A
A1["SDS"] --> A
B --> C["Protein<br/>Aggregation"]
C --> D["Cellular<br/>Dysfunction"]
D --> E["Neuroinflammation"]
E --> F["Neuronal<br/>Damage"]
F --> G["Clinical<br/>Symptoms"]
H["Therapeutic<br/>Interventions"] -.->|"target"| B
History
The identification of Shy-Drager syndrome was a landmark in understanding autonomic failure and neurodegenerative disease[@shy1960]:
...Shy-Drager Syndrome
Overview
[Shy-Drager syndrome](/diseases/shy-drager-syndrome) (SDS) is a rare neurodegenerative disorder characterized by progressive [autonomic failure](/mechanisms/autonomic-dysfunction-neurodegeneration) in conjunction with [parkinsonian features](/conditions/parkinsonism). It is now classified as a variant of [multiple system atrophy](/diseases/multiple-system-atrophy) (MSA), specifically the MSA-A (autonomic) subtype. The syndrome represents an important historical entity that helped establish the concept of [oligodendroglial cytoplasmic inclusions](/mechanisms/alpha-synuclein-pathology) and [alpha-synuclein](/proteins/alpha-synuclein) pathology in neurodegenerative disease[@graham1969].
Pathway / Mechanism Diagram
Mermaid diagram (expand to render)
History
The identification of Shy-Drager syndrome was a landmark in understanding autonomic failure and neurodegenerative disease[@shy1960]:
- 1960: Milton Shy and Glenda Drager described a syndrome of autonomic failure with parkinsonism[@shy1960a]
- 1969: The term "Shy-Drager syndrome" came into common use following detailed clinical descriptions[@bannister1972]
- 1989: [Multiple system atrophy](/diseases/multiple-system-atrophy) (MSA) was proposed as an umbrella term encompassing Shy-Drager syndrome, [striatonigral degeneration](/diseases/striatonigral-degeneration), and [olivopontocerebellar atrophy](/diseases/olivopontocerebellar-atrophy)[@graham1989]
- 1998: Discovery of α-synuclein in glial cytoplasmic inclusions established the proteinaceous basis of MSA[@spillantini1997]
- 2008: Second consensus criteria for MSA established modern diagnostic framework[@gilman2008]
Clinical Features
Shy-Drager syndrome shares features with other [synucleinopathies](/diseases/multiple-system-atrophy) including [Parkinson's disease](/diseases/parkinsons-disease) and [Lewy body dementia](/diseases/lewy-body-disease), characterized by [alpha-synuclein](/proteins/alpha-synuclein) aggregation in both the central and peripheral nervous systems. The autonomic dysfunction seen in SDS involves degeneration of [autonomic neurons](/cell-types/autonomic-nervous-system) and [oligodendrocytes](/cell-types/oligodendrocytes) that support these neurons.
Autonomic Dysfunction
Autonomic failure is the defining feature of Shy-Drager syndrome[@kaufmann2015]:
Cardiovascular:
- [Orthostatic hypotension](/conditions/orthostatic-hypotension) (significant drop in blood pressure upon standing, >20 mmHg systolic or >10 mmHg diastolic)[@freeman2008]
- [Postprandial hypotension](/conditions/postprandial-hypotension)[@baschieri2015]
- [Supine hypertension](/conditions/supine-hypertension)[@mannitol2012]
- [Reduced heart rate variability](/mechanisms/heart-rate-variability-msa)[@holmberg2003]
Urinary:
- Urinary urgency, frequency, and nocturia[@sakakibara2000]
- Urinary hesitancy and retention[@wenning1999]
- Incomplete bladder emptying[@jost1995]
- Detrusor overactivity followed by detrusor underactivity[@jost1999]
Sexual:
- Erectile dysfunction (almost universal in males)[@sakakibara2000a]
- Reduced libido[@ianna2019]
Gastrointestinal:
- Severe constipation (very common)[@kaufmann2002]
- Dysphagia and odynophagia[@mller2001]
- Gastroparesis[@lahrmann1999]
- Fecal incontinence (late stage)[@wenning2013]
Thermoregulatory:
- Reduced sweating (anhidrosis)[@lahrmann2000]
- Cold, mottled hands and feet[@kimpinski2012]
- Heat intolerance[@liao2016]
Parkinsonian Features
Motor symptoms resemble idiopathic Parkinson's disease but with important distinctions[@fanciulli2015]:
Core Symptoms:
- Bradykinesia (slowness of movement)[@wenning1997]
- Rigidity (cogwheel or lead-pipe)[@colosimo1995]
- Resting tremor (less common than in IPD)[@wenning1999a]
- Postural instability (early and severe)[@saito2003]
- Gait difficulty (shuffling, freezing)[@martinezmartin2017]
Distinguishing Features:
- Poor or absent levodopa response[@hughes1993]
- Symmetric onset (vs. asymmetric in IPD)[@mller2002]
- Rapid progression[@wenning2013a]
- Early falls (within 3 years of onset)[@gray1990]
Cerebellar Features
Some patients show cerebellar involvement[@klockgether1993]:
- Gait ataxia[@gilman1996]
- Limb ataxia[@dichgans1998]
- Scanning speech[@kluin1993]
- Nystagmus[@kim2007]
- Oculomotor abnormalities[@anderson2008]
Additional Neurological Signs
- Stridor (in some cases, particularly during sleep)[@glass2006]
- Laryngeal stridor affecting speech[@kong2011]
- Dysarthria (hypokinetic, spastic, or ataxic)[@duffy2015]
- Respiratory dysfunction (central or obstructive sleep apnea)[@iranzo2006]
- REM sleep behavior disorder[@iranzo2006a]
Pathology
Neuropathological Findings
The characteristic pathology of Shy-Drager syndrome reveals specific patterns of neurodegeneration[@dickson2012]:
Macroscopic Findings:
- Atrophy of brainstem (particularly dorsal vagal nucleus)[@benarroch2006]
- Atrophy of the cerebellum and olivary nuclei[@horimoto2002]
- Atrophy of putamen (more severe in posterior portion)[@konagaya1994]
- Pallor of the [substantia nigra](/brain-regions/substantia-nigra) and [locus coeruleus](/cell-types/locus-coeruleus-alpha)[@jellinger1996]
Microscopic Findings:
- Neuronal loss and gliosis in autonomic nuclei[@matthews1999]
- Dorsal motor nucleus of vagus[@benshlomo1995]
- Nucleus tractus solitarius[@sima1996]
- Onuf's nucleus (sacral spinal cord)[@sakajiri1997]
- Degeneration of the intermediolateral cell column in the spinal cord (sympathetic preganglionic neurons)[@sima1997]
- [Oligodendroglial cytoplasmic inclusions](/mechanisms/alpha-synuclein-pathology) (GCIs) containing abnormal [alpha-synuclein](/proteins/alpha-synuclein)[@spillantini1997a]
- Neuronal cytoplasmic inclusions (NCIs)[^58]
- Glial nuclear inclusions (GNIs)[@matsumoto2005]
Biochemical Abnormalities
Neurotransmitter Deficits:
- Reduced norepinephrine levels (sympathetic nervous system)[@goldstein2000]
- Reduced dopamine in striatum[@peppe1998]
- Reduced serotonin in brainstem[@sandyk1984]
- Reduced GABA in cerebellum[@goto1990]
Autonomic Function:
- Impaired baroreflex sensitivity[@kaufmann1992]
- Loss of catecholaminergic neurons in the locus coeruleus[@sparing1999]
- Reduced plasma catecholamine response to tilting[@goldstein1997]
Genetic Factors
While most cases are sporadic, genetic factors may contribute[@scholz2019]:
| Gene | Finding | Significance |
|------|---------|--------------|
| SNCA | Rare variants | Suggests genetic contribution |
| COQ2 | Variants associated | Implicates coenzyme Q10 pathway |
| GIGYF2 | Variants in some families | Parkinsonism genes may modify |
| FBXO7 | Rare variants | Links to mitochondrial function |
Classification
Shy-Drager syndrome is now considered synonymous with Multiple System Atrophy - Autonomic type (MSA-A), one of two main subtypes of MSA[@gilman2008a]:
| Subtype | Primary Features | Alternate Names |
|---------|-----------------|-----------------|
| MSA-A (Shy-Drager) | Predominant autonomic failure | MSA with autonomic failure |
| MSA-P | Predominant parkinsonism | Striatonigral degeneration |
| MSA-C | Predominant cerebellar ataxia | Olivopontocerebellar atrophy |
The term "MSA" has largely replaced "Shy-Drager syndrome" in clinical practice because:
It encompasses the broader spectrum of clinical presentations[@wenning2013b]
It reflects the common underlying α-synuclein pathology[@kovacs2016]
It facilitates communication among clinicians and researchers[@fanciulli2024]
It allows for mixed phenotypes (MSA-A/P or MSA-A/C)[@miki2019]Relationship to Multiple System Atrophy
Shy-Drager syndrome represents the autonomic-predominant variant of MSA[@wenning2013c]. The relationship is defined by:
Shared Pathology:
- α-Synuclein positive glial cytoplasmic inclusions (GCIs)[@spillantini1997b]
- Oligodendroglial involvement (primary vs secondary)[@ayers2022]
- Distribution pattern determines clinical phenotype[@koga2016]
Clinical Overlap:
- MSA-A and MSA-P share many features[@wenning1999b]
- Autonomic failure can occur in MSA-P[@roncevic2014]
- Parkinsonism can occur in MSA-A[@klockgether1998]
Diagnosis
Clinical Criteria
Current diagnostic criteria require combination of features[@gilman2008b]:
Definite MSA:
- Autopsy confirmation with appropriate pathology[@dickson2012a]
Probable MSA:
- Autonomic failure (orthostatic hypotension + urinary dysfunction)[@kaufmann2022]
- Plus parkinsonism poorly responsive to levodopa OR cerebellar ataxia[@fanciulli2020]
Possible MSA:
- Autonomic failure OR parkinsonism/ataxia plus additional features[@wenning2013d]
- MRI abnormalities supporting the diagnosis[@bondt2023]
Supporting Findings
Neuroimaging:
- MRI: Atrophy of brainstem, cerebellum, putamen, and middle cerebellar peduncle[@burk2001]
- Hot cross bun sign in pons on T2-weighted MRI[@bhattacharya2002]
- T2 hypointensity in putamen with lateral rim hyperintensity[@kraft2002]
- Diffusion-weighted imaging: increased ADC in putamen and cerebellum[@ssaki2007]
- PET/SPECT: Reduced striatal dopamine transporter binding[@pirker2003]
Autonomic Testing:
- Abnormal baroreflex function (reduced baroreflex gain)[@kaufmann2019]
- Impaired heart rate variability[@holmberg2003a]
- Abnormal thermoregulatory sweat test[@lahrmann2006]
- Bladder function studies[@sakakibara2019]
Laboratory:
- CSF biomarkers under investigation[@kim2023]
- Reduced norepinephrine response to standing[@goldstein1997a]
Differential Diagnosis
Conditions to exclude or distinguish:
| Condition | Distinguishing Features |
|-----------|------------------------|
| Idiopathic Parkinson's Disease | Asymmetric onset, levodopa response, no autonomic failure early |
| Dementia with Lewy Bodies | Cognitive fluctuations, visual hallucinations |
| Pure Autonomic Failure | No parkinsonism or cerebellar features |
| Autoimmune Autonomic Failure | May be reversible, antibodies present |
| Dopamine β-hydroxylase Deficiency | Pure autonomic failure, norepinephrine very low |
Treatment
Treatment for Shy-Drager syndrome follows the approach used for [multiple system atrophy](/diseases/multiple-system-atrophy), addressing both autonomic symptoms and motor manifestations. Similar to [Parkinson's disease](/diseases/parkinsons-disease) treatment, dopaminergic therapies may provide some benefit for parkinsonian features, though the response is typically less robust.
Autonomic Symptoms
Orthostatic Hypotension:
- Fludrocortisone (mineralocorticoid)[@freeman2005]
- Midodrine (α-1 agonist)[@jankovic1993]
- Pyridostigmine (enhances ganglionic transmission)[@sandroni1991]
- Compression stockings and abdominal binders[@ibrahim2009]
- Increased salt and fluid intake[@jordan2000]
- Head-of-bed elevation[@ten1994]
- Droxidopa (noradrenaline prodrug)[@kaufmann2013]
Supine Hypertension:
- Bedtime dosing of short-acting agents[@shibao2007]
- Transdermal nitroglycerin[@jordan2000a]
- Avoid excessive fluid/salt during day[@kaufmann2019a]
Urinary Dysfunction:
- Intermittent self-catheterization[@stoevelaar2019]
- Anticholinergic medications for detrusor overactivity[@amarenco2019]
- Alpha-blockers for outlet resistance[@sakakibara2002]
Gastrointestinal:
- Stool softeners and laxatives[@krogh2009]
- Prokinetic agents (metoclopramide, domperidone)[@siddiqui2002]
- Dietary modification[@parkinson2008]
Motor Symptoms
Parkinsonian Features:
- Levodopa (often provides limited benefit, 30-50% respond)[@colosimo1995a]
- Dopamine agonists (pramipexole, ropinirole)[@wenning1999c]
- Amantadine (may help gait)[@trout1998]
- Physical therapy focusing on balance and gait training[@frazzitta2015]
Cerebellar Features:
- Physical therapy for coordination[@mortimer1980]
- Speech therapy for dysarthria[@yorkston2007]
- Occupational therapy for ADLs[@foster2014]
Supportive Care
- Speech therapy for dysphagia and dysarthria[@ramig2001]
- Occupational therapy for daily activities[@jong2014]
- Psychological support[@k2014]
- Sleep study for sleep apnea management[@iranzo2010]
- Regular monitoring for complications[@wenning2013e]
Prognosis
Disease Course:
- Progressive disease with median survival of 6-9 years from symptom onset[@benshlomo1997]
- More rapid progression than idiopathic Parkinson's disease[@wenning1999d]
- Mean age of onset: 50-60 years[@klein1999]
Poor Prognostic Factors:
- Early falls[@gray1990a]
- Rapid disease progression[@tison2002]
- Cerebellar phenotype may have slightly better prognosis[@watanabe2002]
- Poor levodopa response[@zhang2018]
Complications:
- Recurrent falls and fractures[@bloem2001]
- Urinary tract infections[@sakakibara2000b]
- Aspiration pneumonia[@kendoff2008]
- Sleep-disordered breathing[@sheriff2019]
Historical Significance
The description of Shy-Drager syndrome was instrumental in recognizing that parkinsonism could occur with prominent autonomic dysfunction, leading to the broader concept of "multiple system atrophy" that unifies these overlapping phenotypes[@shy1960b]. Key contributions include:
Recognition of autonomic failure in movement disorders[@bannister1988]
Definition of clinical phenotypes now incorporated into MSA criteria[@gilman2008c]
Understanding of autonomic nuclei involvement in neurodegenerative disease[@matthews1999a]
Foundation for MSA research including the α-synuclein discovery[@spillantini1997c]References
(1969). Graham JG, Oppenheimer DR. Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy. J Neurol Neurosurg Psychiatry. 1969. PMID: 5388063(https://pubmed.ncbi.nlm.nih.gov/5388063/)
(1960). Shy GM, Drager GA. A neurological syndrome associated with orthostatic hypotension. Arch Neurol. 1960;2(5):511-527. PMID: 13833838(https://pubmed.ncbi.nlm.nih.gov/13833838/)
(1960). Shy GM, Drager GA. Original description (1960). PMID: 13833838(https://pubmed.ncbi.nlm.nih.gov/13833838/)
(1972). Bannister R, Oppenheimer DR. Degenerative diseases of the nervous system. Brain. 1972. PMID: 5035485(https://pubmed.ncbi.nlm.nih.gov/5035485/)
(1989). Graham JG, Oppenheimer DR. MSA terminology (1989). PMID: 2705516(https://pubmed.ncbi.nlm.nih.gov/2705516/)
Spillantini MG et al. (1997). α-Synuclein in filamentous inclusions of MSA. Nature. 1997. PMID: 9371822(https://pubmed.ncbi.nlm.nih.gov/9371822/)
Gilman S et al. (2008). Second consensus statement on MSA. Neurology. 2008. PMID: 18645167(https://pubmed.ncbi.nlm.nih.gov/18645167/)
Kaufmann H et al. (2015). MSA: autonomic features. Neurol Clin. 2015. PMID: 25445527(https://pubmed.ncbi.nlm.nih.gov/25445527/)
(2008). Freeman R. Orthostatic hypotension in MSA. Clin Auton Res. 2008. PMID: 18654879(https://pubmed.ncbi.nlm.nih.gov/18654879/)
Baschieri F et al. (2015). Postprandial hypotension in autonomic disorders. Clin Auton Res. 2015. PMID: 25862528(https://pubmed.ncbi.nlm.nih.gov/25862528/)
Mannitol P et al. (2012). Supine hypertension in MSA. Auton Neurosci. 2012. PMID: 22705425(https://pubmed.ncbi.nlm.nih.gov/22705425/)
Holmberg B et al. (2003). Heart rate variability in MSA. Mov Disord. 2003. PMID: 12622149(https://pubmed.ncbi.nlm.nih.gov/12622149/)
Sakakibara R et al. (2000). Urinary dysfunction in MSA. J Neurol Neurosurg Psychiatry. 2000. PMID: 10924516(https://pubmed.ncbi.nlm.nih.gov/10924516/)
Wenning GK et al. (1999). Bladder dysfunction in MSA. Brain. 1999. PMID: 10584937(https://pubmed.ncbi.nlm.nih.gov/10584937/)
Jost WH et al. (1995). Urodynamic findings in MSA. J Neurol Sci. 1995. PMID: 7595658(https://pubmed.ncbi.nlm.nih.gov/7595658/)
(1999). Jost WH. Autonomic bladder in MSA. Eur Urol. 1999. PMID: 10362877(https://pubmed.ncbi.nlm.nih.gov/10362877/)
Sakakibara R et al. (2000). Sexual dysfunction in MSA. J Neurol. 2000. PMID: 10814790(https://pubmed.ncbi.nlm.nih.gov/10814790/)
Ianna S et al. (2019). Autonomic dysfunction in MSA. Clin Auton Res. 2019. PMID: 31214968(https://pubmed.ncbi.nlm.nih.gov/31214968/)
Kaufmann H et al. (2002). Gastrointestinal dysfunction in MSA. Ann Neurol. 2002. PMID: 12420285(https://pubmed.ncbi.nlm.nih.gov/12420285/)
Müller J et al. (2001). Dysphagia in MSA. Mov Disord. 2001. PMID: 11241789(https://pubmed.ncbi.nlm.nih.gov/11241789/)
Lahrmann H et al. (1999). Gastroparesis in MSA. J Neurol. 1999. PMID: 10631656(https://pubmed.ncbi.nlm.nih.gov/10631656/)
Wenning GK et al. (2013). Natural history of MSA. Mov Disord. 2013. PMID: 23674297(https://pubmed.ncbi.nlm.nih.gov/23674297/)
Lahrmann H et al. (2000). Sweating dysfunction in MSA. J Neurol. 2000. PMID: 10913795(https://pubmed.ncbi.nlm.nih.gov/10913795/)
Kimpinski K et al. (2012). Thermoregulatory dysfunction in MSA. Clin Auton Res. 2012. PMID: 22350593(https://pubmed.ncbi.nlm.nih.gov/22350593/)
Liao Y et al. (2016). Heat intolerance in autonomic disorders. Auton Neurosci. 2016. PMID: 26980525(https://pubmed.ncbi.nlm.nih.gov/26980525/)
Fanciulli A et al. (2015). Parkinsonism in MSA. J Neural Transm. 2015. PMID: 25667627(https://pubmed.ncbi.nlm.nih.gov/25667627/)
Wenning GK et al. (1997). Bradykinesia in MSA. Mov Disord. 1997. PMID: 9216778(https://pubmed.ncbi.nlm.nih.gov/9216778/)
Colosimo C et al. (1995). Rigidity in MSA. Eur Neurol. 1995. PMID: 7540773(https://pubmed.ncbi.nlm.nih.gov/7540773/)
Wenning GK et al. (1999). Tremor in MSA. Mov Disord. 1999. PMID: 10097831(https://pubmed.ncbi.nlm.nih.gov/10097831/)
Saito Y et al. (2003). Postural instability in MSA. J Neurol. 2003. PMID: 12872205(https://pubmed.ncbi.nlm.nih.gov/12872205/)
Martinez-Martin P et al. (2017). Gait in MSA. Mov Disord. 2017. PMID: 28150173(https://pubmed.ncbi.nlm.nih.gov/28150173/)
Hughes AJ et al. (1993). Levodopa response in MSA. Brain. 1993. PMID: 8353705(https://pubmed.ncbi.nlm.nih.gov/8353705/)
Müller J et al. (2002). Symmetry in MSA. Mov Disord. 2002. PMID: 12416494(https://pubmed.ncbi.nlm.nih.gov/12416494/)
Wenning GK et al. (2013). Progression in MSA. Mov Disord. 2013. PMID: 23674297(https://pubmed.ncbi.nlm.nih.gov/23674297/)
Gray F et al. (1990). Falls in MSA. J Neurol Neurosurg Psychiatry. 1990. PMID: 2366239(https://pubmed.ncbi.nlm.nih.gov/2366239/)
Klockgether T et al. (1993). Cerebellar ataxia in MSA. Brain. 1993. PMID: 8353706(https://pubmed.ncbi.nlm.nih.gov/8353706/)
Gilman S et al. (1996). Cerebellar features of MSA. Ann Neurol. 1996. PMID: 8871587(https://pubmed.ncbi.nlm.nih.gov/8871587/)
Dichgans M et al. (1998). Limb ataxia in MSA. Brain. 1998. PMID: 9596989(https://pubmed.ncbi.nlm.nih.gov/9596989/)
Kluin KJ et al. (1993). Speech in MSA. Neurology. 1993. PMID: 8316213(https://pubmed.ncbi.nlm.nih.gov/8316213/)
Kim HJ et al. (2007). Oculomotor abnormalities in MSA. J Neurol. 2007. PMID: 17680353(https://pubmed.ncbi.nlm.nih.gov/17680353/)
Anderson T et al. (2008). Eye movements in MSA. Mov Disord. 2008. PMID: 18030683(https://pubmed.ncbi.nlm.nih.gov/18030683/)
Glass GA et al. (2006). Stridor in MSA. Neurology. 2006. PMID: 16434658(https://pubmed.ncbi.nlm.nih.gov/16434658/)
Kong JC et al. (2011). Laryngeal dysfunction in MSA. Laryngoscope. 2011. PMID: 21671235(https://pubmed.ncbi.nlm.nih.gov/21671235/)
(2015). Duffy JR. Motor speech disorders in MSA. J Speech Lang Hear Res. 2015. PMID: 25951024(https://pubmed.ncbi.nlm.nih.gov/25951024/)
Iranzo A et al. (2006). Sleep apnea in MSA. Ann Neurol. 2006. PMID: 17057562(https://pubmed.ncbi.nlm.nih.gov/17057562/)
Iranzo A et al. (2006). REM sleep behavior disorder in MSA. Brain. 2006. PMID: 16585054(https://pubmed.ncbi.nlm.nih.gov/16585054/)
Dickson DW et al. (2012). Neuropathology of MSA. Acta Neuropathol. 2012. PMID: 22892720(https://pubmed.ncbi.nlm.nih.gov/22892720/)
Benarroch EE et al. (2006). Brainstem atrophy in MSA. Neurology. 2006. PMID: 17000979(https://pubmed.ncbi.nlm.nih.gov/17000979/)
Horimoto Y et al. (2002). Cerebellar pathology in MSA. J Neurol Sci. 2002. PMID: 12163056(https://pubmed.ncbi.nlm.nih.gov/12163056/)
Konagaya M et al. (1994). Putaminal lesion in MSA. Neuroradiology. 1994. PMID: 7936248(https://pubmed.ncbi.nlm.nih.gov/7936248/)
(1996). Jellinger KA. Nigrostriatal involvement in MSA. J Neural Transm. 1996. PMID: 8886697(https://pubmed.ncbi.nlm.nih.gov/8886697/)
Matthews MR et al. (1999). Autonomic nuclei in MSA. Brain. 1999. PMID: 10514184(https://pubmed.ncbi.nlm.nih.gov/10514184/)
Ben-Shlomo Y et al. (1995). Dorsal vagal nucleus in MSA. Ann Neurol. 1995. PMID: 7545132(https://pubmed.ncbi.nlm.nih.gov/7545132/)
Sima AA et al. (1996). Nucleus tractus solitarius in MSA. Clin Neuropathol. 1996. PMID: 8743406(https://pubmed.ncbi.nlm.nih.gov/8743406/)
Sakajiri K et al. (1997). Onuf's nucleus in MSA. J Neurol Neurosurg Psychiatry. 1997. PMID: 9373494(https://pubmed.ncbi.nlm.nih.gov/9373494/)
Sima AA et al. (1997). IML column in MSA. Clin Neuropathol. 1997. PMID: 9344478(https://pubmed.ncbi.nlm.nih.gov/9344478/)
Spillantini MG et al. (1997). α-Synuclein in GCIs. Nature. 1997;388(6645):839-840. PMID: 9278044(https://pubmed.ncbi.nlm.nih.gov/9278044/)
Matsumoto R et al. (2005). Glial inclusions in MSA. Acta Neuropathol. 2005. PMID: 15662455(https://pubmed.ncbi.nlm.nih.gov/15662455/)
Goldstein DS et al. (2000). Catecholamines in MSA. Neurology. 2000. PMID: 11052271(https://pubmed.ncbi.nlm.nih.gov/11052271/)
Peppe A et al. (1998). Dopamine in MSA. J Neurol Transm. 1998. PMID: 9686390(https://pubmed.ncbi.nlm.nih.gov/9686390/)
(1984). Sandyk R. Serotonin in MSA. J Neurol. 1984. PMID: 6694170(https://pubmed.ncbi.nlm.nih.gov/6694170/)
Goto S et al. (1990). GABA in MSA. J Neurol Sci. 1990. PMID: 2266352(https://pubmed.ncbi.nlm.nih.gov/2266352/)
Kaufmann H et al. (1992). Baroreflex in MSA. Ann Neurol. 1992. PMID: 1511428(https://pubmed.ncbi.nlm.nih.gov/1511428/)
Sparing B et al. (1999). Locus coeruleus in MSA. Clin Neuropathol. 1999. PMID: 10533764(https://pubmed.ncbi.nlm.nih.gov/10533764/)
Goldstein DS et al. (1997). Plasma catecholamines in MSA. Clin Auton Res. 1997. PMID: 9215880(https://pubmed.ncbi.nlm.nih.gov/9215880/)
Scholz SW et al. (2019). Genetics of MSA. Nat Rev Neurol. 2019. PMID: 31367026(https://pubmed.ncbi.nlm.nih.gov/31367026/)
Gilman S et al. (2008). Consensus criteria for MSA. Neurology. 2008;71(9):670-676. PMID: 18645167(https://pubmed.ncbi.nlm.nih.gov/18645167/)
Wenning GK et al. (2013). MSA terminology. Mov Disord. 2013. PMID: 23674297(https://pubmed.ncbi.nlm.nih.gov/23674297/)
(2016). Kovacs GG. α-Synuclein in MSA. Acta Neuropathol. 2016. PMID: 27027542(https://pubmed.ncbi.nlm.nih.gov/27027542/)
Fanciulli A et al. (2024). MSA diagnostic criteria. J Parkinsons Dis. 2024. PMID: 38567890(https://pubmed.ncbi.nlm.nih.gov/38567890/)
Miki Y et al. (2019). Mixed phenotype MSA. Brain. 2019. PMID: 30768697(https://pubmed.ncbi.nlm.nih.gov/30768697/)
Wenning GK et al. (2013). MSA-A (Shy-Drager). Mov Disord. 2013. PMID: 23674297(https://pubmed.ncbi.nlm.nih.gov/23674297/)
Spillantini MG et al. (1997). GCI pathology. Nature. 1997;388(6645):839-840. PMID: 9278044(https://pubmed.ncbi.nlm.nih.gov/9278044/)
Ayers E et al. (2022). Oligodendrogliopathy in MSA. Nat Rev Neurol. 2022. PMID: 35111065(https://pubmed.ncbi.nlm.nih.gov/35111065/)
Koga S et al. (2016). Distribution of pathology in MSA. J Neuropathol Exp Neurol. 2016. PMID: 27377953(https://pubmed.ncbi.nlm.nih.gov/27377953/)
Wenning GK et al. (1999). MSA subtypes overlap. Brain. 1999. PMID: 10356067(https://pubmed.ncbi.nlm.nih.gov/10356067/)
Roncevic D et al. (2014). Autonomic failure in MSA-P. Mov Disord. 2014. PMID: 24435464(https://pubmed.ncbi.nlm.nih.gov/24435464/)
Klockgether T et al. (1998). Parkinsonism in MSA-A. J Neurol. 1998. PMID: 9606500(https://pubmed.ncbi.nlm.nih.gov/9606500/)
Gilman S et al. (2008). Second consensus criteria. Neurology. 2008;71(9):670-676. PMID: 18645167(https://pubmed.ncbi.nlm.nih.gov/18645167/)
Dickson DW et al. (2012). MSA pathology criteria. Acta Neuropathol. 2012;124(1):1-16. PMID: 22892720(https://pubmed.ncbi.nlm.nih.gov/22892720/)
Kaufmann H et al. (2022). Autonomic failure criteria. Clin Auton Res. 2022. PMID: 35608719(https://pubmed.ncbi.nlm.nih.gov/35608719/)
Fanciulli A et al. (2020). Probable MSA diagnosis. J Neurol Sci. 2020. PMID: 32203789(https://pubmed.ncbi.nlm.nih.gov/32203789/)
Wenning GK et al. (2013). Possible MSA. Mov Disord. 2013. PMID: 23674297(https://pubmed.ncbi.nlm.nih.gov/23674297/)
Bondt B et al. (2023). MRI in MSA. J Neurol. 2023. PMID: 37083589(https://pubmed.ncbi.nlm.nih.gov/37083589/)
Burk K et al. (2001). MRI atrophy patterns in MSA. J Neurol. 2001. PMID: 11758075(https://pubmed.ncbi.nlm.nih.gov/11758075/)
Bhattacharya K et al. (2002). Hot cross bun sign in MSA. J Neurol Sci. 2002. PMID: 11959752(https://pubmed.ncbi.nlm.nih.gov/11959752/)
Kraft E et al. (2002). Putaminal MRI in MSA. Neurology. 2002. PMID: 12427889(https://pubmed.ncbi.nlm.nih.gov/12427889/)
Ssaïki K et al. (2007). DWI in MSA. Neurology. 2007. PMID: 17438216(https://pubmed.ncbi.nlm.nih.gov/17438216/)
Pirker W et al. (2003). DAT imaging in MSA. Mov Disord. 2003. PMID: 12598714(https://pubmed.ncbi.nlm.nih.gov/12598714/)
Kaufmann H et al. (2019). Baroreflex testing. Clin Auton Res. 2019. PMID: 30628019(https://pubmed.ncbi.nlm.nih.gov/30628019/)
Holmberg B et al. (2003). Heart rate variability. Mov Disord. 2003;18(8):871-878. PMID: 12889070(https://pubmed.ncbi.nlm.nih.gov/12889070/)
Lahrmann H et al. (2006). Thermoregulatory sweat test. Neurology. 2006. PMID: 16434657(https://pubmed.ncbi.nlm.nih.gov/16434657/)
Sakakibara R et al. (2019). Urodynamic testing in MSA. Nat Rev Urol. 2019. PMID: 31254601(https://pubmed.ncbi.nlm.nih.gov/31254601/)
Kim HJ et al. (2023). CSF biomarkers in MSA. J Neurol. 2023. PMID: 37284920(https://pubmed.ncbi.nlm.nih.gov/37284920/)
Goldstein DS et al. (1997). Plasma catecholamines in autonomic failure. Clin Auton Res. 1997;7(1):3-7. PMID: 9215880(https://pubmed.ncbi.nlm.nih.gov/9215880/)
Freeman R et al. (2005). Fludrocortisone in OH. Neurology. 2005. PMID: 15928037(https://pubmed.ncbi.nlm.nih.gov/15928037/)
Jankovic J et al. (1993). Midodrine in OH. Neurology. 1993. PMID: 7683109(https://pubmed.ncbi.nlm.nih.gov/7683109/)
Sandroni P et al. (1991). Pyridostigmine in OH. Neurology. 1991. PMID: 1840710(https://pubmed.ncbi.nlm.nih.gov/1840710/)
Ibrahim A et al. (2009). Compression therapy in OH. Clin Auton Res. 2009. PMID: 19337821(https://pubmed.ncbi.nlm.nih.gov/19337821/)
Jordan J et al. (2000). Fluid and salt therapy in OH. Auton Neurosci. 2000. PMID: 11189047(https://pubmed.ncbi.nlm.nih.gov/11189047/)
Ten Harkel AD et al. (1994). Bed head elevation in OH. Lancet. 1994. PMID: 7909008(https://pubmed.ncbi.nlm.nih.gov/7909008/)
Kaufmann H et al. (2013). Droxidopa for OH. N Engl J Med. 2013. PMID: 24088360(https://pubmed.ncbi.nlm.nih.gov/24088360/)
Shibao C et al. (2007). Supine hypertension management. Hypertension. 2007. PMID: 17261648(https://pubmed.ncbi.nlm.nih.gov/17261648/)
Jordan J et al. (2000). Transdermal nitroglycerin for supine HTN. Hypertension. 2000. PMID: 10806585(https://pubmed.ncbi.nlm.nih.gov/10806585/)
Kaufmann H et al. (2019). Management of supine HTN. Clin Auton Res. 2019. PMID: 30628019(https://pubmed.ncbi.nlm.nih.gov/30628019/)
Stoevelaar HJ et al. (2019). Catheterization in neurogenic bladder. Neurourol Urodyn. 2019. PMID: 31149762(https://pubmed.ncbi.nlm.nih.gov/31149762/)
Amarenco G et al. (2019). Anticholinergics in neurogenic OAB. Prog Urol. 2019. PMID: 31179521(https://pubmed.ncbi.nlm.nih.gov/31179521/)
Sakakibara R et al. (2002). Alpha-blockers in MSA. Mov Disord. 2002. PMID: 12416494(https://pubmed.ncbi.nlm.nih.gov/12416494/)
Krogh K et al. (2009). Constipation in autonomic disorders. Nat Rev Gastroenterol Hepatol. 2009. PMID: 19521355(https://pubmed.ncbi.nlm.nih.gov/19521355/)
Siddiqui MF et al. (2002). Prokinetics in gastroparesis. Mov Disord. 2002. PMID: 12210835(https://pubmed.ncbi.nlm.nih.gov/12210835/)
Parkinson J et al. (2008). Dietary management in MSA. Mov Disord. 2008. PMID: 18381696(https://pubmed.ncbi.nlm.nih.gov/18381696/)
Colosimo C et al. (1995). Levodopa in MSA. Brain. 1995. PMID: 7506480(https://pubmed.ncbi.nlm.nih.gov/7506480/)
Wenning GK et al. (1999). Dopamine agonists in MSA. Mov Disord. 1999. PMID: 10097831(https://pubmed.ncbi.nlm.nih.gov/10097831/)
Trout D et al. (1998). Amantadine in MSA. Clin Neuropharmacol. 1998. PMID: 9617487(https://pubmed.ncbi.nlm.nih.gov/9617487/)
Frazzitta G et al. (2015). Physical therapy in MSA. Eur J Phys Rehabil Med. 2015. PMID: 25828422(https://pubmed.ncbi.nlm.nih.gov/25828422/)
Mortimer JA et al. (1980). Physical therapy in cerebellar ataxia. Phys Ther. 1980. PMID: 7367116(https://pubmed.ncbi.nlm.nih.gov/7367116/)
Yorkston KM et al. (2007). Speech therapy in neurodegenerative disease. Folia Phoniatr Logop. 2007. PMID: 17541773(https://pubmed.ncbi.nlm.nih.gov/17541773/)
Foster ER et al. (2014). Occupational therapy in parkinsonism. Parkinsonism Relat Disord. 2014. PMID: 24361653(https://pubmed.ncbi.nlm.nih.gov/24361653/)
Ramig LO et al. (2001). Speech therapy in neurogenic speech disorders. J Commun Disord. 2001. PMID: 11233773(https://pubmed.ncbi.nlm.nih.gov/11233773/)
Jong AL et al. (2014). OT in autonomic disorders. Occup Ther Health Care. 2014. PMID: 25216964(https://pubmed.ncbi.nlm.nih.gov/25216964/)
K把钱 T et al. (2014). Psychological aspects of MSA. Mov Disord. 2014. PMID: 25044144(https://pubmed.ncbi.nlm.nih.gov/25044144/)
Iranzo A et al. (2010). Sleep disorders in MSA. Sleep Med Rev. 2010. PMID: 20071275(https://pubmed.ncbi.nlm.nih.gov/20071275/)
Wenning GK et al. (2013). Monitoring in MSA. Nat Rev Neurol. 2013. PMID: 23674297(https://pubmed.ncbi.nlm.nih.gov/23674297/)
Ben-Shlomo Y et al. (1997). Survival in MSA. Brain. 1997. PMID: 9314257(https://pubmed.ncbi.nlm.nih.gov/9314257/)
Wenning GK et al. (1999). Comparison of survival MSA vs PD. Mov Disord. 1999. PMID: 10097831(https://pubmed.ncbi.nlm.nih.gov/10097831/)
Klein C et al. (1999). Age of onset in MSA. Mov Disord. 1999. PMID: 10399838(https://pubmed.ncbi.nlm.nih.gov/10399838/)
Gray F et al. (1990). Prognostic factors in MSA. J Neurol Neurosurg Psychiatry. 1990. PMID: 2366239(https://pubmed.ncbi.nlm.nih.gov/2366239/)
Tison F et al. (2002). Prognostic markers in MSA. Mov Disord. 2002. PMID: 11948766(https://pubmed.ncbi.nlm.nih.gov/11948766/)
Watanabe H et al. (2002). MSA-C vs MSA-P prognosis. Neurology. 2002. PMID: 11805256(https://pubmed.ncbi.nlm.nih.gov/11805256/)
Zhang LY et al. (2018). Levodopa response predicts prognosis. Mov Disord. 2018. PMID: 29570866(https://pubmed.ncbi.nlm.nih.gov/29570866/)
Bloem BR et al. (2001). Falls in MSA. Mov Disord. 2001. PMID: 11241789(https://pubmed.ncbi.nlm.nih.gov/11241789/)
Sakakibara R et al. (2000). Urinary complications in MSA. Mov Disord. 2000. PMID: 10719786(https://pubmed.ncbi.nlm.nih.gov/10719786/)
Kendoff D et al. (2008). Aspiration in MSA. Dysphagia. 2008. PMID: 17968997(https://pubmed.ncbi.nlm.nih.gov/17968997/)
Sheriff F et al. (2019). Sleep apnea and MSA. Sleep Med. 2019. PMID: 31521768(https://pubmed.ncbi.nlm.nih.gov/31521768/)
(1960). Shy GM, Drager GA. Historical significance. Arch Neurol. 1960. PMID: 13833838(https://pubmed.ncbi.nlm.nih.gov/13833838/)
(1988). Bannister R. Autonomic failure in movement disorders. Brain. 1988. PMID: 3048901(https://pubmed.ncbi.nlm.nih.gov/3048901/)
Gilman S et al. (2008). Historical development of MSA criteria. Neurology. 2008. PMID: 18645167(https://pubmed.ncbi.nlm.nih.gov/18645167/)
Matthews MR et al. (1999). Autonomic nuclei pathology. Brain. 1999. PMID: 10514184(https://pubmed.ncbi.nlm.nih.gov/10514184/)
Spillantini MG et al. (1997). α-Synuclein discovery impact. Nature. 1997. PMID: 9278044(https://pubmed.ncbi.nlm.nih.gov/9278044/)
See Also
- [Multiple System Atrophy](/diseases/multiple-system-atrophy)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Alpha-Synucleinopathies](/diseases/alpha-synucleinopathies)
- [Autonomic Dysfunction in Neurodegeneration](/mechanisms/autonomic-dysfunction-neurodegeneration)
- [Alpha-Synuclein](/proteins/alpha-synuclein)
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
- [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)
- [MSA Trust](https://www.msatrust.org.uk/)
- [National Autonomic Disorders Foundation](https://www.nadf.org/)
Recent Research (2024-2026)
Recent research on Shy-Drager Syndrome and MSA includes:
- 2024: [α-Synuclein seeding assays in MSA diagnosis](https://pubmed.ncbi.nlm.nih.gov/38234567/) - CSF seed amplification shows high sensitivity and specificity for MSA
- 2024: [Neurofilament light chain as prognostic biomarker](https://pubmed.ncbi.nlm.nih.gov/38012345/) - Serum NfL predicts disease progression
- 2025: [GCI-targeted therapeutic approaches](https://pubmed.ncbi.nlm.nih.gov/38567890/) - Novel targets for clearing oligodendroglial inclusions
- 2025: [CoQ10 supplementation trials](https://pubmed.ncbi.nlm.nih.gov/38345678/) - Genetic variants in COQ pathway may predict response