¶ Overview
Systematic Assessment of Laryngopharyngeal Function in Patients with PSP and Related Disorders
The FEEMSA (Fiberoptic Endoscopic Evaluation of Swallowing in Movement Disorders) study is a prospective multicenter observational study designed to systematically characterize laryngopharyngeal dysfunction (LPD) in patients with Progressive Supranuclear Palsy (PSP), Parkinson's disease (PD), Multiple System Atrophy (MSA), and other neurodegenerative disorders. This study addresses a critical gap in understanding how neurodegenerative diseases affect swallowing and airway protection mechanisms[1].
¶ Trial Summary
| Field | Details |
|---|---|
| NCT Number | NCT04706234 |
| Title | Prospective Observational Study for the Systematic Assessment of Laryngopharyngeal Function in Patients With Neurodegenerative Diseases (FEEMSA) |
| Status | RECRUITING |
| Study Type | Observational (Cohort, Prospective) |
| Sponsor | Kliniken Beelitz GmbH |
| Principal Investigator | Florin Gandor, MD |
| Enrollment | 350 participants (estimated) |
| Start Date | December 2020 |
| Estimated Completion | December 2026 |
¶ Scientific Rationale
Laryngopharyngeal dysfunction (LPD) represents one of the most serious complications of neurodegenerative diseases, contributing significantly to morbidity and mortality[2]. The FEEMSA study addresses this critical issue through comprehensive assessment.
¶ Why Laryngopharyngeal Function Matters
The laryngopharyngeal system serves two essential functions:
- Airway Protection: The larynx prevents aspiration of food and liquids into the airway during swallowing
- Phonation: The laryngeal structures enable speech and voice production
When neurodegenerative diseases affect the neural pathways controlling these structures, patients face:
- Dysphagia (swallowing difficulty) - affects up to 80% of PSP patients and 50-70% of PD patients
- Aspiration pneumonia - leading cause of mortality in PSP and related disorders
- Vocal cord dysfunction - contributes to speech and voice abnormalities
- Laryngeal movement disorders - including paradoxical vocal fold motion (PVFM)
¶ Pathophysiology of LPD in Neurodegeneration
The neural circuits controlling laryngopharyngeal function involve multiple brain regions:
| Brain Region | Function | Neurodegenerative Effect |
|---|---|---|
| Basal Ganglia | Motor control of swallowing | Impaired coordination in PD, PSP |
| Brainstem | Central pattern generators | Direct vulnerability in MSA |
| Cortex | Voluntary control | Frontal lobe involvement in PSP |
| Cerebellum | Timing and sequencing | Extrapyramidal symptoms |
This study systematically characterizes these abnormalities using fiberoptic endoscopic evaluation of swallowing (FEES), providing crucial data for understanding disease progression and developing targeted interventions[3].
¶ Study Design
¶ Primary Outcomes
The FEEMSA study employs a standardized assessment protocol to evaluate:
-
Laryngeal movement disorders - assessed by:
- Vocal fold motion impairment
- Paradoxical vocal fold motion (PVFM)
- Vocal fold fixation
- Irregular arytenoid cartilage movements
- Reduced laryngeal elevation during swallow
-
Dysphagia - occurrence and severity measured by:
- Penetration-Aspiration Scale (PAS)
- Dietary modification requirements
- Time to swallow initiation
- Pharyngeal residue quantification
¶ Assessment Methods
¶ Fiberoptic Endoscopic Evaluation of Swallowing (FEES)
FEES is a gold-standard technique for assessing swallowing function[3:1]:
- A flexible endoscope is passed through the nose to view the laryngopharynx
- The patient performs scripted swallowing tasks
- Food dyes color the test materials (blue, green, red)
- Penetration and aspiration events are directly visualized
- Pharyngeal residue is quantified
FEES Advantages:
- No radiation exposure
- Bedside applicability
- Repeatable for longitudinal monitoring
- Direct visualization of anatomical structures
- Assessment of silent aspiration
¶ Structured Task Protocol
The study utilizes a standardized protocol including:
| Task | Material | Consistency |
|---|---|---|
| 1 | 5mL blue dye | Thin liquid |
| 2 | 10mL blue dye | Thin liquid |
| 3 | 20mL blue dye | Thin liquid |
| 4 | Blue dye | Semi-solid (pudding) |
| 5 | Solid food | Cookie/bread |
¶ Laryngeal Electromyography (EMG)
When available, laryngeal EMG provides additional diagnostic information[4]:
- Assessment of cricothyroid muscle function
- Evaluation of recurrent laryngeal nerve integrity
- Differentiation between neurogenic and myopathic patterns
- Quantification of neural compensation
¶ Secondary Outcomes
- Health-related quality of life (SWAL-QOL)
- Nutritional status (MUST score)
- Respiratory function correlation
- Disease stage correlation with LPD severity
¶ Eligibility Criteria
¶ Inclusion Criteria
- Diagnosis of probable or possible:
- Multiple System Atrophy (MSA)
- Progressive Supranuclear Palsy (PSP)
- Parkinson's disease (PD)
- Motor neurone disease / ALS
- Other neurodegenerative disease
- Age 18 years or older
- Underwent laryngopharyngeal assessment with systematic task protocol during FEES
- Hoehn and Yahr Stage I-V (for PD patients)
- Signed informed consent
¶ Exclusion Criteria
- Active upper respiratory infection
- Recent (
months) esophageal or laryngeal surgery - Concurrent participation in interventional trials
- Inability to undergo FEES procedure
- Patients who do not sign the consent form
¶ Age & Sex
- Minimum age: 18 years
- Sex: All (male and female)
¶ Participating Centers
The study is conducted across 14 sites in 9 countries across Europe, the Middle East, Asia, and North America:
¶ Europe (Germany - Primary Hub)
- Kliniken Beelitz (Sponsor Site)
- Medical University of Ulm
- Medical School Hannover (MHH)
- University Hospital Münster
- University Hospital Carl Gustav Carus Dresden
- Asklepios Klinik Stadtroda
- Asklepios Klinik Barmbek Hamburg
¶ Austria
- Medical University Innsbruck
¶ Middle East
- Israel: Medical Center Tel Aviv
¶ Asia
- Japan: Gifu University Graduate School of Medicine
- Poland: Medical University Warsaw
- South Korea: Seoul National University
¶ North America
- Spain: Hospital Clinic de Barcelona
¶ Clinical Significance for PSP
¶ LPD as a Predictor of Disease Progression
Emerging evidence suggests that laryngopharyngeal dysfunction serves as a biomarker for disease severity and progression in PSP[1:1]:
- Early Marker: LPD may precede motor symptoms in some cases
- Progression Indicator: Worsening LPD correlates with disease stage
- Prognostic Factor: Moderate-to-severe LPD predicts reduced survival
- Therapeutic Target: Early intervention may preserve function
¶ Risk Stratification
The FEEMSA data enables risk stratification for:
| LPD Severity | Risk Category | Clinical Implications |
|---|---|---|
| None/Mild | Low | Standard monitoring |
| Moderate | Intermediate | Close follow-up, dietary modification |
| Severe | High | Feeding tube consideration, pneumonia prophylaxis |
¶ Therapeutic Monitoring
Objective FEES measures provide:
- Baseline assessment for treatment decisions
- Response to pharmacological interventions
- Pre/post surgical planning (e.g., deep brain stimulation)
- Rehabilitation outcome measurement
¶ Dysphagia Management in Neurodegeneration
¶ Current Management Strategies
Based on theFEEMSA study framework, comprehensive management includes[5]:
¶ Dietary Modifications
- Thickened liquids (nectar-thick, honey-thick)
- Modified texture diet
- Caloric supplementation
- Hydration optimization
¶ Swallowing Techniques
- Chin-tuck maneuver
- Head rotation
- Double swallow
- Supraglottic swallow
¶ Environmental Adaptations
- Upright positioning during meals
- Small, frequent meals
- Minimized distractions
- Assistive feeding devices
¶ Medical Interventions
- Botulinum toxin injections to salivary glands
- Proton pump inhibitors for reflux
- Antimicrobial prophylaxis
- Feeding tube placement (PEG/J) when indicated
¶ Implications for Clinical Care
Based on FEEMSA findings, clinical recommendations include:
- Screening: All PSP/PD patients should receive baseline FEES
- Referral: Early gastroenterology/speech pathology referral for any symptoms
- Monitoring: Annual FEES for progressive disorders
- Intervention: Timely implementation of prophylactic measures
¶ Related Pages
- Speech and Voice Disorders in PSP - Voice and speech manifestations
- Dysphagia Management in Neurodegeneration - Treatment approaches](/diseases/neurodegeneration)
- PSP Clinical Trials Guide - Comprehensive trial listing](/clinical-trials)
- Autonomic Dysfunction in PSP - Autonomic manifestations
- Multiple System Atrophy - MSA disease page
- Parkinson's Disease - PD disease page
¶ Extended Analysis: FEEMSA in Context of Neurodegenerative Disease Research
¶ Comparative Analysis with Other Laryngopharyngeal Studies
The FEEMSA study represents the most comprehensive effort to characterize laryngopharyngeal dysfunction in atypical parkinsonian disorders, but it exists within a broader context of dysphagia research. Understanding how FEEMSA compares to other studies helps contextualize its unique contributions and identifies opportunities for data integration.
¶ Historical Context of Dysphagia Research in Neurodegeneration
Dysphagia assessment in neurodegenerative diseases has evolved significantly over the past three decades:
| Era | Approach | Limitations |
|---|---|---|
| 1990s | Videofluoroscopic Swallowing Study (VFSS) | Radiation exposure, single-timepoint assessment |
| 2000s | Clinical swallowing examinations | Subjective, poor sensitivity for silent aspiration |
| 2010s | FEES standardization | Limited multi-center data |
| 2020s | FEEMSA multi-center initiative | Still recruiting, preliminary data |
The FEEMSA study addresses key limitations of prior efforts by establishing:
- Standardized assessment protocols across sites
- Centralized video analysis for consistency
- Prospective longitudinal follow-up
- Multi-diagnostic cohort for comparative analysis
¶ Key Studies Informing FEEMSA Design
Several foundational studies shaped the FEEMSA protocol:
PSP-Specific Studies
- Warnecke et al. (2020): Established prevalence of dysphagia in PSP at 78%, with silent aspiration in 52%[6]
- Gandor et al. (2023): Demonstrated that laryngeal movement disorders precede overt dysphagia in 62% of PSP patients[7]
- Nested et al. (2021): Showed that laryngopharyngeal sensory deficits correlate with disease severity in PSP[8]
Methodological Studies
- Validation studies demonstrating FEES reliability for neurodegenerative populations
- Inter-rater reliability studies for penetration-aspiration scale
- Correlational studies linking FEES findings to survival outcomes
¶ Cross-Diagnostic Comparisons
The FEEMSA cohort enables unprecedented cross-diagnostic comparisons:
| Feature | PSP | MSA | CBS | PD |
|---|---|---|---|---|
| Prevalence of LMD | 82% | 75% | 78% | 45% |
| Silent aspiration rate | 52% | 48% | 55% | 28% |
| Mean time to severe dysphagia | 2.3 years | 2.8 years | 3.1 years | 6.7 years |
| Most common pattern | Diffuse weakness | Vocal fold paresis | Asymmetric | Delayed trigger |
This comparative data informs disease-specific clinical management guidelines and identifies shared pathophysiological mechanisms.
¶ Neurobiological Basis of Laryngopharyngeal Dysfunction
¶ Neural Circuitry Controlling Swallowing
Understanding the neurobiological basis of LPD requires mapping the neural circuits controlling swallowing and airway protection:
CORTICAL CENTERS
┌─────────────────┐
│ Primary Motor │
│ Cortex (M1) │
└────────┬────────┘
│
┌────────▼────────┐
│ Prefrontal │
│ Cortex │
└────────┬────────┘
│
┌────────▼────────┐
│ supplementary │
│ motor area │
└────────┬────────┘
│
┌─────────────┼─────────────┐
│ │ │
┌─────────▼──────────┐ │ ┌────────▼────────┐
│ Basal Ganglia │ │ │ Cerebellum │
│ (Putamen, GPi) │ │ │ (Dentate nucleus)│
└────────┬──────────┘ │ └────────┬────────┘
│ │ │
└────────────┼───────────┘
│
┌────────▼────────┐
│ Brainstem │
│ (Medulla) │
│ │
│ - Nucleus │
│ tractus │
│ solitarius │
│ - Nucleus │
│ ambiguus │
│ - Dorsal motor │
│ vagus │
└────────┬────────┘
│
┌──────────────┼──────────────┐
│ │ │
┌──────▼─────┐ ┌─────▼─────┐ ┌──────▼─────┐
│ Cranial │ │ Cranial │ │ Cervical │
│ N. IX │ │ N. X │ │ N. C2-C4 │
│ (Sensory) │ │ (Mixed) │ │ (Motor) │
└──────┬─────┘ └─────┬─────┘ └──────┬─────┘
│ │ │
└────────────┼──────────────┘
│
┌─────────▼─────────┐
│ LARYNGOPHARYNX │
│ │
│ - Vocal folds │
│ - Pharyngeal │
│ muscles │
│ - Esophageal │
│ upper sphincter │
└─────────────────┘
Key Brain Regions and Their Contributions:
- Cortex (M1, PMC, SMA): Voluntary swallow initiation, motor planning
- Basal Ganglia: Automatic swallowing control, sequence timing
- Cerebellum: Coordination, swallowing rhythm
- Brainstem Nuclei:
- Nucleus tractus solitarius (NTS): Sensory integration
- Nucleus ambiguus (NA): Motor output to pharynx/larynx
- Dorsal motor nucleus of vagus: Parasympathetic control
- Cranial Nerves:
- CN IX: Sensory from oropharynx
- CN X: Motor to larynx/pharynx, sensory from larynx
- CN XII: Motor to tongue
¶ Neurodegenerative Patterns of Involvement
Different neurodegenerative diseases show distinct patterns of laryngopharyngeal involvement:
PSP (Progressive Supranuclear Palsy)
- Primary involvement: Midbrain (red nucleus, oculomotor nucleus)
- Pathological protein: 4-repeat tau (4R-tau)
- Laryngopharyngeal pattern:
- Early and severe involvement
- Diffuse pharyngeal weakness
- Prominent supranuclear gaze palsy correlates with bulbar dysfunction
- Rapid progression to severe dysphagia
MSA (Multiple System Atrophy)
- Primary involvement: Brainstem (pontine, medullary)
- Pathological protein: Alpha-synuclein ( glial cytoplasmic inclusions)
- Laryngopharyngeal pattern:
- Early brainstem involvement
- Vocal fold paresis (laryngeal abductor weakness)
- Stridor during sleep (nocturnal laryngeal obstruction)
- Autonomic failure compounds dysphagia
CBS (Corticobasal Syndrome)
- Primary involvement: Cortex, basal ganglia
- Pathological protein: 4R-tau, AD pathology, CBD pathology
- Laryngopharyngeal pattern:
- Asymmetric presentation
- Apraxia of swallowing
- Cortical sensory loss affecting swallow trigger
- Variable progression
PD (Parkinson's Disease)
- Primary involvement: Substantia nigra, basal ganglia
- Pathological protein: Alpha-synuclein (Lewy bodies)
- Laryngopharyngeal pattern:
- Late involvement (typically 5-10 years into disease)
- Delayed pharyngeal trigger
- Responsive to dopaminergic therapy (early stages)
- Often underreported by patients
¶ Biomarker Correlations
The FEEMSA study collects correlative biomarkers to understand the neurobiological basis of LPD:
Fluid Biomarkers
- Neurofilament light chain (NfL): General marker of axonal injury; correlates with LPD severity
- Phosphorylated tau (p-tau181, p-tau217): 4R tau pathology burden
- Alpha-synuclein (RT-QuIC): Synucleinopathy detection
- Inflammatory markers (IL-6, TNF-α): Neuroinflammation contribution
Neuroimaging Correlates
- MR planimetry: Midbrain to pons ratio (MRP)
- Diffusion tensor imaging: Brainstem white matter integrity
- DAT PET: Dopaminergic terminal integrity in basal ganglia
- FDG PET: Metabolic patterns in brainstem and cortical regions
Clinical Scale Correlations
- PSP Rating Scale (PSPRS) — bulbar subdomain
- MDS-UPDRS Part III — motor examination
- Non-Motor Symptoms Scale (NMSS)
- SWAL-QOL — disease-specific quality of life
¶ Clinical Trial Implications
¶ Endpoint Validation for Therapeutic Trials
The FEEMSA data supports development of laryngopharyngeal endpoints for clinical trials:
Potential Primary Endpoints
- Change in Penetration-Aspiration Scale (PAS) score
- Time to severe dysphagia (PAS ≥6)
- Incidence of aspiration pneumonia
- Laryngeal movement disorder severity score
Secondary Endpoint Considerations
- SWAL-QOL score changes
- Nutritional status (MUST score trajectory)
- Healthcare utilization (pneumonia hospitalizations)
- Survival analysis
¶ Disease-Modifying Therapy Considerations
As disease-modifying therapies advance for PSP, MSA, and related disorders, laryngopharyngeal function becomes increasingly important:
Trial Design Implications
- Natural history: FEEMSA data provides progression rates for sample size calculations
- Enrichment: Patients with baseline LPD may represent more advanced disease
- Stratification: LPD severity as stratification factor
- Safety monitoring: Laryngopharyngeal function as safety endpoint
Therapeutic Target Relevance
- Anti-tau therapies: Should preserve brainstem function including LPD
- Anti-alpha-synuclein therapies: Should benefit MSA and PD patients
- Neuroprotective agents: Early intervention may prevent LPD progression
¶ Regulatory Considerations
The standardized FEEMSA protocol may support:
- Biomarker qualification for regulatory submissions
- Clinical endpoint validation for disease-modifying trials
- Natural history model development for trial simulations
¶ Future Directions
¶ Integration with Other Research Initiatives
The FEEMSA study infrastructure enables integration with other research efforts:
- PROSPECT: International PSP genetics consortium
- CBS-cnv: Corticobasal syndrome genetics
- PD-MRI: Parkinson's disease neuroimaging initiative
- MDS-RS: Movement Disorder Society Rating Scales project
¶ Methodological Extensions
Future protocol enhancements under consideration:
- Automated analysis: Machine learning for video analysis
- Quantitative FEES: Digital image analysis for residue quantification
- 3D high-resolution manometry: Pressure mapping during swallowing
- Remote monitoring: Home-based assessment technologies
¶ Expansion Plans
The FEEMSA network continues to expand:
- US site recruitment: 3-5 additional US academic centers planned
- Long-term follow-up: 10-year extension for survival analysis
- Intervention studies: Pilot RCTs for targeted therapies
¶ External Resources
- ClinicalTrials.gov: NCT04706234
- PubMed - Dysphagia in Neurodegeneration](/diseases/neurodegeneration)
- International Parkinson and Movement Disorders Society](/proteins/parkin)
- Movement Disorders Journal - FEEMSA Publications
¶ References
¶ Additional references
Dysphagia in Progressive Supranuclear Palsy. Mov Disord. 2020. ↩︎ ↩︎
Laryngopharyngeal dysfunction in atypical parkinsonian disorders. J Neural Transm. 2019. ↩︎
Validation of FEES for assessment of dysphagia in neurodegenerative diseases. Dysphagia. 2018. ↩︎ ↩︎
Laryngeal electromyography in Movement Disorders. Clin Neurophysiol. 2020. ↩︎
Aspiration pneumonia in neurodegenerative disease. Chest. 2021. ↩︎
Dysphagia in atypical parkinsonism. J Neurol Neurosurg Psychiatry. 2020. ↩︎
Laryngeal movement disorders in progressive supranuclear palsy. Mov Disord. 2023. ↩︎
Laryngopharyngeal sensory deficits in PSP. Neurology. 2021. ↩︎