Conditions: Meniere Disease
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 40
Healthy volunteers: no

Brief summary:
As of yet, the cause of Meniere's disease is uncertain and there is no cure. Given the lack of high level evidence for treatments, we seek to perform a randomized, placebo-controlled, double-blind, crossover, pilot trial of venlafaxine for treating Meniere's disease. Venlafaxine is a safe and well-tolerated medication. It has never been trialed in Meniere's disease, but there is evidence that it could be effective in helping with vertigo attacks and other aspects of the disorder.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Venlafaxine intervention 2: Placebo oral tablet
Intervention descriptions: intervention 1: Daily oral intake 37.5 mg intervention 2: Daily oral intake

Protocol document:
Prot_SAP_001.pdf: 
 Version 12/12/2019 - 1 
 
Assessing the Efficacy of a Serotonin and Norepinephrine Reuptake Inhibitor for 
1 
Improving Meniere’s Disease Outcomes 
2 
NCT04218123 
3 
Principal Investigator: Habib Georges Rizk MD 
4 
Co-Investigators: Yuan Fang Liu MD, Shaun A. Nguyen MD FAPCR 
5 
Department of Otolaryngology – Head and Neck Surgery, Medical University of South Carolina 
6 
 
7 
 
8 
135 Rutledge Avenue, MSC 550 
9 
Charleston, SC 29425 
10 
843-876-0112 
11 
rizkh@musc.edu 
12 
 
13 
Financial officer contact: 
14 
Velma Stamp 
15 
Research & Sponsored Programs 
16 
Phone: 843-792-3657 
17 
stampvg@musc.edu 
 
18 


 Version 12/12/2019 - 2 
 
SUMMARY 
19 
Meniere’s disease (MD) affects 2 to 4 people per 10,000 and represents up to 15% of new 
20 
patients with vertigo in a tertiary neurotology clinic.1 As of yet, its pathophysiology is uncertain 
21 
and there is no gold-standard treatment.2 Given the lack of level I evidence for MD therapies, we 
22 
seek to perform a randomized, placebo-controlled, double-blind, crossover, pilot trial of 
23 
venlafaxine extended-release (ER) 37.5 mg daily for the prophylactic treatment of MD. 
24 
Venlafaxine is a safe and well-tolerated medication,3-5 and it will be trialed at the lower end of 
25 
the dosage spectrum typically used for depression.6 No literature exists for the use of venlafaxine 
26 
in MD, but there is evidence that it could be effective through both central and peripheral 
27 
vestibular-modulating mechanisms. 
28 
Venlafaxine is a serotonin and norepinephrine reuptake inhibitor (SNRI) typically used in 
29 
the treatment of depression.7 There is evidence to suggest that selective serotonin reuptake 
30 
inhibitors (SSRIs) can be effective in the treatment of MD through serotonin’s ability to 
31 
modulate vestibular function in vestibular nuclei, the inferior olive, and the cerebellum.8,9 
32 
Norepinephrine has also been shown to inhibit activity in vestibular nuclei.10 Lamotrigine, a 
33 
serotonin, norepinephrine, and dopamine reuptake inhibitor, has been shown to be effective in 
34 
treating MD and is currently in a clinical trial.11 Venlafaxine can reduce vasopressin receptor 
35 
activation.12 This may reduce endolymphatic hydrops, because the endolymphatic sac expresses 
36 
vasopressin receptors which may be important in fluid and ion homeostasis in the inner ear.13-16 
37 
Venlafaxine is well-known in the treatment of anxiety and depression,17,18 which are 
38 
common comorbidities in MD19 that may ultimately contribute to a cycle of somatic and 
39 
psychological symptoms synergistically aggravating disease perception.19,20 Furthermore, 
40 
migraine is quite common in MD.21,22 Venlafaxine has been shown to be effective in the 
41 


 Version 12/12/2019 - 3 
 
treatment of migraine6 and vestibular migraine,23,24 which highlights its potential in treating MD 
42 
given that vestibular migraine may share with MD many aspects of presentation and 
43 
pathophysiology.25,26 
44 
This trial will take place in a tertiary, multidisciplinary, vestibular-focused, neurotology 
45 
clinic at the Medical University of South Carolina (MUSC), led by Dr. Habib Rizk. Dr. Yuan Liu 
46 
will assist with patient recruitment in clinic and project coordination. Dr. Shaun Nguyen will also 
47 
help with project coordination, as well as data analysis given his expertise in conducting clinical 
48 
trials. Forty subjects will be recruited to achieve 80% power in detecting at least a 30% 
49 
difference in vertigo frequency control. The study will require about 14.5 months to complete: an 
50 
8-month recruitment period to obtain 40 subjects; and for each subject a 1-month lead-in 
51 
screening period, a 2-month first treatment phase, a 1.5-month washout phase, and a 2-month 
52 
second treatment phase. The subjects will be randomized to treatment and the investigators will 
53 
be blinded to outcomes until after the data have been collected and analyzed. Using patient-
54 
reported symptoms and various validated instruments, the outcomes measured will include 
55 
change in vertiginous symptoms, functional level, cognitive function, anxiety and depression 
56 
severity, and quality of life (QOL). 
57 
If the results demonstrate that venlafaxine is effective in the prophylactic treatment of 
58 
patients with MD, the path will be paved for larger parallel-treatment design studies. Serotonin 
59 
and norepinephrine reuptake inhibitors have not been trialed in MD, but they hold promise as a 
60 
non-invasive medical treatment option. 
61 
 
 
62 


 Version 12/12/2019 - 4 
 
TABLE OF CONTENTS 
63 
Budget…………………………………………………………………..... 5 
64 
Biographical sketch………………………………………………………. 6 
65 
 
Funding………………………………………………………........ 18 
66 
 
Letters of support…………………………………………………. 19 
67 
Specific aims……………………………………………………………… 22 
68 
Background and significance…………………………………………….. 23 
69 
Subjects and methods…………………………………………………….. 28 
70 
 
Subject selection………………………………………………….. 28 
71 
 
Study protocol……………………………………………………. 29 
72 
 
Outcome measures……………………………………………….. 33 
73 
 
Data analysis……………………………………………………… 37 
74 
 
Potential limitations……………………………………………..... 38 
75 
Figures……………………………………………………………………. 39 
76 
Tables ……………………………………………………………………. 40 
77 
Appendices……………………………………………………………….. 45 
78 
Bibliography……………………………………………………………… 59 
79 
 
 
80 


 Version 12/12/2019 - 5 
 
BUDGET 
81 
- 
Number of venlafaxine ER capsules needed: 3048 
82 
o 60 capsules for 40 subject for 2 months of treatment: 2400 
83 
o 7 capsules for 20 subjects for weaning over 2 weeks after the 1st treatment phase: 
84 
140 
85 
o 20% drop-out rate (e.g., side effects, loss to follow-up): additional 508 capsules 
86 
- 
Number of placebo capsules needed: 3048 
87 
o 60 capsules for 40 subject for 2 months of treatment: 2400 
88 
o 7 capsules for 20 subjects for weaning over 2 weeks after the 1st treatment phase: 
89 
140 
90 
o 20% drop-out rate: 508 capsules 
91 
- 
Total capsules needed: 6092 
92 
- 
Items 1-5 were reviewed and approved by the Investigational Drug Services (IDS) 
93 
pharmacy at the Medical University of South Carolina (MUSC). 
94 
- 
Item 6 cost estimate was obtained from the MUSC drug distribution center. 
95 
- 
Item 7 cost estimate was obtained from the South Carolina Clinical and Translational 
96 
Research Institute for hiring trained research personnel. 
97 
- 
Item 8 cost estimate was obtained from the MUSC outpatient laboratory. 
98 
- 
This budget was approved by the MUSC Office of Research and Sponsored Programs. 
99 
Number Item 
Cost ($) 
1 
IDS pharmacy randomization fee (one time) 
50.00 
2 
IDS compounding fee ($1.25 per capsule) 
7620.00 
3 
IDS pharmacy setup and initiation cost 
3250.00 
4 
IDS pharmacy annual renewal fee 
525.00 
5 
IDS dose dispensing fee ($25 per dose, 2 dispenses per subject, 
20% drop-out rate) 
2400.00 
6 
Venlafaxine extended-release cost ($3.01 per 30 capsules, plus 
9% sales tax) 
333.34 
7 
Research coordinator ($55 per hour, estimate 1 hour per subject 
per data collection time point for 4 time points) 
8800.00 
8 
Comprehensive metabolic panel ($27.90 per subject, 20% drop-
out rate) 
1339.20 
 
Total 
$24317.54 
 
 
100 


 Version 12/12/2019 - 6 
 
BIOGRAPHICAL SKETCH 
101 
Principal Investigator 
102 
 
103 
Contact Information 
104 
- 
Address: 135 Rutledge Avenue, MSC 550, Charleston, SC 29425 
105 
- 
Email: rizkh@musc.edu 
106 
- 
Phone: 843-876-0112 
107 
- 
Fax: 843-792-0546 
108 
 
109 
NAME: Rizk, Habib Georges 
eRA COMMONS USER NAME: rizkhabib 
POSITION TITLE: Assistant Professor of Otolaryngology Head & Neck Surgery 
EDUCATION/TRAINING 
110 
INSTITUTION AND 
LOCATION 
DEGREE 
(if 
applicable) 
START 
DATE 
MM/YYYY 
END 
DATE 
MM/YYYY 
FIELD OF STUDY 
Saint-Joseph University, 
Beirut 
MD 
09/2000 
06/2007 
Medicine 
 
Saint-Joseph University, 
Beirut 
 
MS 
 
07/2007 
 
10/2010 
 
Biomedical Sciences 
 
Saint-Joseph University, 
Beirut 
 
MS 
 
09/2009 
 
06/2010 
 
Microvascular Surgery 
 
Medical University of South 
Carolina, Charleston, SC 
 
MS 
 
07/2015 
 
06/2017 
 
Master of Science in Clinical 
Research 
 
Saint-Joseph 
University/University of the 
Mediterranean-Aix Marseille 
III, Beirut/Marseille 
 
Resident 
 
07/2009 
 
06/2011 
 
Interuniversity Diploma in 
Endoscopy and Surgery in 
Otorhinolaryngology and 
Skull Base 
 
Hôtel-Dieu de France 
Hospital, Beirut 
 
Resident 
 
07/2007 
 
06/2012 
 
Otolaryngology-Head & 
Neck Surgery Resident 
 
Christiana Care Health 
System, Newark, DE 
 
Fellow 
 
07/2012 
 
06/2013 
 
Otology Medicine and 
Surgery Fellowship 
Medical University of South 
Carolina, Charleston, SC 
Fellow 
07/2013 
06/2015 
Neurotology Fellowship 
 
111 
 
112 


 Version 12/12/2019 - 7 
 
A. Personal Statement 
113 
I am a neurotologist committed to a research career aiming to develop a better understanding of 
114 
undertreated/underdiagnosed or poorly investigated vestibular disorders such as vestibular 
115 
migraine, Meniere’s disease and superior semicircular canal dehiscence, their impact on patients, 
116 
as well as determining the best treatment course for these entities. My long-term goal is to 
117 
develop metrics that would allow us to improve patients’ quality of life, reduce their fall risk, and 
118 
minimize their loss of productivity. I am a fellowship-trained neurotologist and have participated 
119 
in multiple clinical outcomes-related research trials for various neurotologic pathologies during 
120 
my postdoctoral training, resulting in 30 publications. Upon completing my clinical training, I 
121 
was recruited to establish and direct a multidisciplinary vestibular program at the Medical 
122 
University of South Carolina. Our team is comprised of neurologists, physical therapists, 
123 
dieticians, and audiologists who collaborate to provide the best care for patients with vestibular 
124 
disorders. We see approximately 2000 patients a year with various causes of dizziness and gait 
125 
disturbances. Since 2015, I have served on educational panels in the American Academy of 
126 
Otolaryngology, notably the Equilibrium Committee, as well as the joint task force with the 
127 
American Academy of Neurology to develop measures aiming to improve the clinical evaluation 
128 
of vestibular patients. I have also served as a physician expert on the American Balance Society 
129 
(ABS) multidisciplinary meetings. I am also an ABS board member and I chair the program and 
130 
the nomination committees. I am the co-director of the biennial Charleston Vestibular Update 
131 
Course. I have completed a Master of Science in Clinical Research to get more formal training in 
132 
epidemiology, study design and analysis, biostatistics and regression analysis, community 
133 
engagement research, grant application development, and team science, in order to 
134 
better accomplish my research goals. To date, we have quantified the impact of vestibular 
135 
disorders on cognitive function (a). We have also defined the skull base thickness in patients 
136 
with superior semicircular canal dehiscence (b). These works led to a collaboration with the 
137 
Otolaryngology and Neurosurgery departments of the University of Cincinnati on a 
138 
contemporary review on idiopathic intracranial hypertension (c), as well as to a collaboration 
139 
with the Neurotology Division at the University of California San Francisco on the epidemiology 
140 
of vestibular migraine (d). I currently have an intramural grant to foster 
141 
interprofessional/interdisciplinary training in the clinical care setting at the Medical University of 
142 
South Carolina. I am currently mentoring two vestibular audiologists (Christine Strange and 
143 
Cortney Van Ausdal) as well as one of our vestibular therapists (Rebecca English) to help with 
144 
their career development. They have presented data from our vestibular clinic in national 
145 
meetings over the past three years as well as participated in expert panels at the American 
146 
Academy of Otolaryngology National Meeting. I have mentored a predoctoral student (Taylor 
147 
Locklear) funded by a T32 institutional grant for the summer of 2018. In the past 9 months, he 
148 
has already had two oral presentations at national meetings, one manuscript published, and one 
149 
manuscript submitted and undergoing the peer-review process at the Journal of Vestibular 
150 
Research concerning the association of vitamin D and BPPV. 
151 
a. Liu YF, Locklear TD, Sharon JD, Lacroix E, Nguyen SA, Rizk HG. Quantification of 
152 
Cognitive Dysfunction in Dizzy Patients Using the Neuropsychological Vertigo 
153 
Inventory. Otol Neurotol, 2019;40(7):e723-e731. PMID: 31295206 
154 


 Version 12/12/2019 - 8 
 
b. Rizk HG, Hatch J, Stevens SM, Lambert PR and Meyer TA, Lateral Skull Base 
155 
Attenuation in Patients with Superior Semicircular Canal Dehiscence, Otolaryngol H 
156 
Neck Surg, 2016, 155:641-648. PMID: 27221578 
157 
c. Stevens SM, Rizk HG, Golnik K, Andaluz N, Samy RN, Meyer TA, Lambert PR, 
158 
Idiopathic intracranial Hypertension: Contemporary review and implications for the 
159 
Otolaryngologist, Laryngoscope. 2018, 128: 248-256, doi:10.1002/lary26581. PMID: 
160 
28349571. 
161 
d. Formeister EJ, Rizk HG, Kohn MA and Sharon JD, The Epidemiology of Vestibular 
162 
Migraine: A Population-based Survey Study, Otol Neurotol, 2018, 39:1037-1044. 
163 
doi:10.1097/MAO0000000000001900. PMID 30020261 
164 
B. Positions and Honors 
165 
Positions and Employment 
166 
2015 -  
Assistant Professor of Otolaryngology Head & Neck Surgery, Medical 
University of South Carolina, Charleston, SC 
2015 -  
Director Vestibular Program, Medical University of South Carolina, Charleston, 
SC 
 
167 
Other Experience and Professional Memberships 
168 
2008 -  
Member, Lebanese Order of Physicians 
2012 -  
Member, American Academy of Otolaryngology- Head & Neck Surgery 
2015 -  
Member, Vestibular Disorders Association 
2016 -  
Member, Equilibrium Committee-American Academy of Otolaryngology-Head 
&Neck Surgery 
2016 -  
Member, History and Archives Committee-American Academy of 
Otolaryngology-Head &Neck Surgery 
2017 -  
Programs Committee Member, American Balance Society 
2017 -  
American Academy of Otolaryngology-Head &Neck Surgery and American 
Academy of Neurology, Neurotology Measures workgroup 
2017 -  
Editorial Board, Frontiers in Neurology-Neurotology Subsection 
2018 - 2020 
Board of Directors, American Balance Society 
 
169 
Honors 
170 
2000 
Summa Cum Laude, French Baccalaureate-Academie d'Aix-Marseille 
2000 
Cum Laude, Lebanese Baccalaureate 
2000 
USJ's 125th Anniversary Academic Achievement Award, Saint Joseph 
University 
2010 
Resident Research Award (3rd prize of the jury), International Francophone 
Society of Otolaryngology 
2016 
Board of Directors Nominee, American Balance Society 


 Version 12/12/2019 - 9 
 
2017 
Board of Directors Nominee, American Balance Society 
2017 
 
2018-2020 
2018-2020 
AAOHNS representative for Neurotology Measures Group, American Academy 
of Otolaryngology-Head & Neck Surgery 
Board of Directors, American Balance Society 
Chairman, Program Committee American Balance Society (2019). Member, 
Program Committee (2018,2020) 
 
171 
C. Contribution to Science 
172 
1. Quality of life measures and cognitive dysfunction in vestibular pathologies: 
173 
This project started with the advent of our multidisciplinary vestibular clinic. A large portion 
174 
of our patients with dizziness complained of cognitive difficulties. Our current dizziness-
175 
related QOL questionnaires usually assess the physical, functional and emotional dimensions 
176 
of a pathology’s impact, with few or non-existent inquiries into the cognitive dysfunction of 
177 
those patients. It is the latter that usually affects QOL and productivity the most. With the 
178 
lack of a standardized tool to measure this impairment, we administered the well-established 
179 
general Cognitive Failure Questionnaire (CFQ) on all our dizzy patients to quantify that 
180 
dimension of the QOL that is affected. We found major disparities of cognitive dysfunction 
181 
that are driven by the etiology, in conjunction with other factors. Vestibular migraine and 
182 
Meniere’s disease drove the CFQ scale very high (a). We then proceeded to test the English 
183 
version of the newly-developed Neuropsychological Vertigo Inventory (NVI). We have 
184 
started the project and are collaborating with the Neurotology Division at UCSF. We will be 
185 
studying the NVI as well to assess its usability in clinic as an outcome tool and clinical tool 
186 
and have already obtained pilot results (b).  In collaboration with UCSF we have also 
187 
participated in a project to describe the epidemiology of vestibular migraine (c). During the 
188 
course of these projects, we collected a vast amount of information about vestibular function 
189 
tests, in patients with various diagnoses, especially in regard to vestibular evoked myogenic 
190 
potentials, to look at their role in non-traditional indications such as Meniere’s disease and 
191 
vestibular migraine (d). This is the subject of a submitted manuscript to Audiology and 
192 
Neurotology that is currently under peer-review. 
193 
a. Rizk HG, Thomas C and Meyer TA, Self-Perceived cognitive dysfunction in patients 
194 
with various diagnoses of dizziness, AAO-HNS Meeting, Chicago, IL, September 2017 
195 
b. Liu YF, Locklear TD, Sharon JD, Lacroix E, Nguyen SA, Rizk HG. Quantification of 
196 
Cognitive Dysfunction in Dizzy Patients Using the Neuropsychological Vertigo 
197 
Inventory. Otol Neurotol, 2019;40(7):e723-e731. PMID: 31295206 
198 
c. Formeister EJ, Rizk HG, Kohn MA and Sharon JD, The Epidemiology of Vestibular 
199 
Migraine: A Population-based Survey Study, Otol Neurotol, 2018, 39:1037-1044. 
200 
doi:10.1097/MAO0000000000001900 PubMed PMID 30020261 
201 
d. Rizk H, Strange C, Van Ausdal C, English R, McRackan TM and Meyer TA, Are 
202 
VEMPs useful for the differential diagnosis of Ménière’s Disease and Vestibular 
203 
Migraine, American Academy Otolaryngology-Head&Neck Surgery, Atlanta, October 
204 
2018 
205 


 Version 12/12/2019 - 10 
 
2. Radiographic characteristics and clinical outcomes in patients with vestibular and 
206 
neurotological pathologies: 
207 
My neurotology fellowship was focused on chronic ear disease, cochlear implantation, and 
208 
spontaneous cerebrospinal fluid leaks research. Over the course of two years, I was involved 
209 
in a protocol for measuring skull base thickness in our CSF leak patients, providing 
210 
quantifying metrics about the pathology. This initial project was expanded to look at 
211 
outcomes of surgery correlated to the skull base thickness and body mass index (BMI). Once 
212 
our vestibular clinic was established, I translated this protocol into our superior semicircular 
213 
canal dehiscence (SSCD) patients. We found, interestingly, that despite having on average a 
214 
lower BMI than our spontaneous leak patients, the SSCD subjects had a generalized thinner 
215 
skull base. This reinforces the possibility of multiple mechanisms, probably autocrine, 
216 
independent of increased intracranial pressure, which participate in some of those 
217 
neurotologic pathologies. Other teams corroborated these findings in subsequent studies. 
218 
a. Stevens SM, Rizk HG, Golnik K, Andaluz N, Samy RN, Meyer TA, Lambert PR, 
219 
Idiopathic intracranial Hypertension: Contemporary review and implications for the 
220 
Otolaryngologist, Laryngoscope. 2018, 128: 248-256, doi:10.1002/lary2658. PubMed 
221 
PMID: 28349571. 
222 
b. Rizk HG, Hatch JL, Stevens SM, Lambert PR, Meyer TA. Lateral Skull Base Attenuation 
223 
in Superior Semicircular Canal Dehiscence and Spontaneous Cerebrospinal Fluid 
224 
Otorrhea. Otolaryngol Head Neck Surg. 2016 Oct;155(4):641-8. PubMed PMID: 
225 
27221578. 
226 
c. Stevens SM, Rizk HG, McIlwain WR, Lambert PR, Meyer TA. Association between 
227 
Lateral Skull Base Thickness and Surgical Outcomes in Spontaneous CSF Otorrhea. 
228 
Otolaryngol Head Neck Surg. 2016 Apr;154(4):707-14. PubMed PMID: 26908549. 
229 
d. Hatch JL, Schopper H, Boersma IM, Rizk HG, Nguyen SA et al, The Bone Mineral 
230 
Density of the Lateral Skull Base and its Relation to Obesity and Spontaneous 
231 
Cerebrospinal Fluid Leaks, Otol Neurotol, 2018, doi: 10.1097/MAO.0000000000001969 
232 
PubMed PMID: 30124620 
233 
 
234 
Complete List of Published Work in MyBibliography 
235 
https://www.ncbi.nlm.nih.gov/myncbi/1VM4mAsHw2qQq/bibliography/public/ 
236 
 
237 
D. Additional Information: Research Support and/or Scholastic Performance 
238 
• MUSC 2018-2020 Interprofessional Team-Based Clinical Experience Development 
239 
Grant program: Development of new Interprofessional, Team-Based, Patient-Care 
240 
Experiences for MUSC Interdisciplinary/Interprofessional Management of Patients at the 
241 
MUSC Dizziness and Vestibular Disorders Clinic 
242 
 
 
243 


 Version 12/12/2019 - 11 
 
Co-Investigator 
244 
Contact Information 
245 
- 
Address: 135 Rutledge Avenue, MSC 550, Charleston, SC 29425 
246 
- 
Email: liuyua@musc.edu 
247 
- 
Phone: 843-876-0112 
248 
- 
Fax: 843-792-0546 
249 
 
250 
NAME: Liu, Yuan Fang 
eRA COMMONS USER NAME: liuyua 
POSITION TITLE: Neurotology and Skull Base Surgery Fellow 
EDUCATION/TRAINING 
251 
INSTITUTION AND LOCATION DEGREE 
(if 
applicable) 
START 
DATE 
MM/YYYY 
END 
DATE 
MM/YYYY 
FIELD OF STUDY 
David Geffen School of Medicine 
at University of California, Los 
Angeles; Los Angeles, CA 
MD 
08/2009 
06/2013 
Medicine 
 
Loma Linda University Health, 
Department of Otolaryngology – 
Head and Neck Surgery; Loma 
Linda, CA 
 
 
 
07/2013 
 
06/2018 
 
Otolaryngology 
(Residency) 
 
Medical University of South 
Carolina, Department of 
Otolaryngology – Head and Neck 
Surgery; Charleston, SC 
 
 
 
07/2018 
 
06/2020 
 
Neurotology and skull 
base surgery 
(Fellowship) 
 
252 
A. Personal Statement 
253 
I am in my final year of training in neurotology and skull base surgery. I have been developing 
254 
over these past years the foundational knowledge in medicine and medical research needed to 
255 
successfully complete this prospective study. I have broad training in otolaryngology, but 
256 
throughout my residency and into fellowship, I have delved deeper into the study of neurotologic 
257 
diseases, especially vestibular disorders such as Meniere’s disease and vestibular migraine. I 
258 
have won awards from the American Otological Society and Triological Society for quality of 
259 
research submitted to national meetings as a resident. I have also won the Research Resident 
260 
Award repeatedly during residency. In my final year of residency, I served on the Otology and 
261 
Neurotology Education Committee of the American Academy of Otolaryngology – Head and 
262 
Neck Surgery. I also co-authored a chapter on dizziness in the book ENT Essentials. As a fellow, 
263 
I have increased my research workload due to a growing interest in many fields of otology and 
264 
neurotology, and in anticipation of a future as an academic neurotologist, with the career goal of 
265 
advancing knowledge in hearing and vestibular sciences. I have successfully collaborated with 
266 


 Version 12/12/2019 - 12 
 
colleagues, residents, and medical students on numerous publications, and I am currently 
267 
mentoring several residents and medical students in otologic research. I have worked closely 
268 
with Dr. Rizk, who is one of my current mentors, since the start of fellowship. I hope to build the 
269 
neurotology and skull base program at Loma Linda University, where I will likely return to work 
270 
after completing fellowship; and I will strive to establish a partnership with the Medical 
271 
University of South Carolina to tackle challenges in research which require a multi-institutional 
272 
approach. This current proposal builds on my previous work in Meniere’s disease and vestibular 
273 
migraine. If successful, it will be a significant advance in the study of Meniere’s disease 
274 
treatment and has the potential to spur on new investigative pathways in understanding the 
275 
disorder. 
276 
a. Liu YF, Locklear TD, Sharon JD, Lacroix E, Nguyen SA, Rizk HG. Quantification of 
277 
Cognitive Dysfunction in Dizzy Patients Using the Neuropsychological Vertigo 
278 
Inventory. Otol Neurotol, 2019;40(7):e723-e731. 
279 
b. Liu YF, Renk E, Rauch SD, Xu HX. Efficacy of intratympanic gentamicin in Menière's 
280 
disease with and without migraine. Otol Neurotol. 2017 Aug;38(7):1005-1009. 
281 
c. Liu YF, Xu H. The intimate relationship between vestibular migraine and Meniere’s 
282 
disease: a review of pathogenesis and presentation. Behav Neurol. 2016;2016:3182735. 
283 
d. Liu YF, Hu J, Streelman M. The Epworth Sleepiness Scale in the assessment of sleep 
284 
disturbance in veterans with tinnitus. Int J Otolaryngol. 2015;2015:429469. 
285 
 
286 
B. Positions and Honors 
287 
Positions and Employment 
288 
2018 -  
Clinical Instructor of Otolaryngology – Head and Neck Surgery, Medical 
University of South Carolina; Charleston, SC 
 
289 
Other Experience and Professional Memberships 
290 
2013 -  
American Academy of Otolaryngology – Head and Neck Surgery 
2017 - 2018 
Member, Otology and Neurotology Education Committee, American Academy 
of Otolaryngology- Head & Neck Surgery 
 
291 
Honors 
292 
2006, 2007 
Harvard College Research Grant 
2007 
Harvard College Scholar 
2009 
Cum laude in biochemical sciences, Harvard University 
2009 
California Regents Scholarship 
2009 
Donald, Jason, and Stefan Wong Memorial Scholarship, David Geffen School of 
Medicine at UCLA 
2000 
Chief’s Research Fellowship, UCLA Department of Internal Medicine 


 Version 12/12/2019 - 13 
 
2011 
Subspecialty Award, 39th Annual Western Student Medical Research Forum 
Regional Meeting 
2011 
Community Service Award, David Geffen School of Medicine at UCLA 
2016 
Travel Award, Triological Society 
2016, 2018 
 
2017 
2017 
 
2017 
 
2018 
Resident Research Award, Loma Linda University Department of 
Otolarygnology – Head and Neck Surgery 
Resident Research Travel Award, American Otological Society 
Resident In-Service Exam Award, Loma Linda University Department of 
Otolarygnology – Head and Neck Surgery 
Dr. George Chonkich Resident of the Year Award, Loma Linda University 
Department of Otolarygnology – Head and Neck Surgery 
Chief Resident of the Year Award, Loma Linda University Department of 
Otolarygnology – Head and Neck Surgery 
 
293 
C. Contribution to Science 
294 
1. My initial research interests were broadly distributed in various disciplines of 
295 
otolaryngology. Specially pertaining to head and neck surgery, I uncovered the benefits of 
296 
early swallowing exercises for patients undergoing chemoradiation, performed a pilot study 
297 
of a novel free flap monitoring system, revealed mechanical properties of the nasal septal 
298 
cartilage and the effects of surgery on its integrity, explored the efficacy of various 
299 
maxillomandibular procedures in improving sleep apnea, reported on the efficacy of a 
300 
treatment protocol for burning mouth syndrome, systematically reviewed the utility of 
301 
preoperative imaging for parathyroid disease in patients with concurrent thyroid disease, and 
302 
discovered the need for reduced prescription of postoperative opioids in a prospective, 
303 
randomized trial. 
304 
a. Liu YF, Vuong C, Walker PC, Peterson NR, Inman JC, Andrade Filho PA, Lee SC. 
305 
Noninvasive free flap monitoring using Eulerian video magnification. Case Rep 
306 
Otolaryngol. 2016;2016:9471696. 
307 
b. Liu YF, Messinger K, Inman JC. Yield strength testing in human cadaver nasal septal 
308 
cartilage and L-strut constructs. JAMA Facial Plast Surg. 2017;19(1):40-45. 
309 
c. Han P, Liu YF, Messinger K, Ardeshirpour F, Inman J. Redefining the nasal septal L-
310 
strut: a quantitative analysis of septal arcs and angles. Laryngoscope. 2018;128(8):1806-
311 
1810. 
312 
d. Nguyen KS, Liu YF, Chang C, Park J, Kim C, Hondorp B, Vuong C, Xu H, Crawley B, 
313 
Simental A, Church C, Inman J. A randomized single-blinded trial of ibuprofen versus 
314 
opioid-based primary analgesic therapy in outpatient otolaryngology surgery. 
315 
Otolaryngol Head Neck Surg. 2019 Mar 5:194599819832528. 
316 
2. When I decided on a career in otology and neurotology, I began to focus my research efforts 
317 
in hearing and vestibular sciences. I revealed that intratympanic gentamicin was less 
318 
effective in treating functional deficit of those suffering from Meniere’s disease when 
319 
vestibular migraine was a comorbidity. In recent collaborations with Dr. Rizk, I described 
320 


 Version 12/12/2019 - 14 
 
ways that different characteristics of vestibular evoked myogenic potentials can be useful in 
321 
differentiating Meniere’s disease and vestibular migraine (submitted for publication). 
322 
Concurrently, I worked with Dr. Rizk to describe cognitive function in patients with various 
323 
vestibular diseases, such as Meniere’s disease, vestibular migraine, and benign paroxysmal 
324 
positional vertigo (BPPV). We used a novel instrument developed specifically for patients 
325 
with dizziness, and found that Meniere’s disease had similar cognitive impairment to 
326 
vestibular migraine, both worse than BPPV. We are starting a new prospective phase of the 
327 
study to recruit healthy subjects in order to compare cognitive function among those with 
328 
dizziness with those without. 
329 
a. Liu YF, Renk E, Rauch SD, Xu HX. Efficacy of intratympanic gentamicin in Meniere's 
330 
disease with and without migraine. Otol Neurotol. 2017;38(7):1005-1009. 
331 
b. Liu YF, Locklear TD, Sharon JD, Lacroix E, Nguyen SA, Rizk HG. Quantification of 
332 
Cognitive Dysfunction in Dizzy Patients Using the Neuropsychological Vertigo 
333 
Inventory. Otol Neurotol, 2019;40(7):e723-e731.  
334 
 
335 
Complete List of Published Work in MyBibliography 
336 
https://www.ncbi.nlm.nih.gov/myncbi/1NU3b9rUboo5a/bibliography/public/ 
337 
 
338 
D. Additional Information: Research Support and/or Scholastic Performance 
339 
None 
340 
 
 
341 


 Version 12/12/2019 - 15 
 
Co-Investigator 
342 
Contact Information 
343 
- 
Address: 135 Rutledge Avenue, MSC 550, Charleston, SC 29425 
344 
- 
Email: nguyensh@musc.edu 
345 
- 
Phone: 843-876-0112 
346 
- 
Fax: 843-792-0546 
347 
 
348 
NAME: Nguyen, Shaun A. 
eRA COMMONS USER NAME: nguyensa 
POSITION TITLE: Professor and Director of Clinical Research 
EDUCATION/TRAINING 
349 
INSTITUTION AND 
LOCATION 
DEGREE 
(if 
applicable) 
START 
DATE 
MM/YYYY 
END 
DATE 
MM/YYYY 
FIELD OF STUDY 
University of South Carolina; 
Columbia, SC 
 
East Carolina University; 
Greenville, NC 
 
 
SHSU with University College 
London; London, 
United Kingdom 
 
North Middlesex Hospital, 
University College 
London; London, United 
Kingdom 
 
North Middlesex Hospital, 
University College 
London; London, United 
Kingdom 
 
Medical University of South 
Carolina; Charleston, 
SC 
 
 
Medical University of South 
Carolina; Charleston, 
SC 
BS 
 
 
MA 
 
 
 
MD 
08/1985 
 
 
07/1989 
 
 
 
06/1993 
 
 
 
07/1999 
 
 
 
 
07/2000 
 
 
 
 
07/2001 
 
 
 
 
01/2005 
05/1989 
 
 
05/1993 
 
 
 
06/1999 
 
 
 
06/2000 
 
 
 
 
06/2001 
 
 
 
 
12/2005 
 
 
 
 
12/2006 
Biology 
 
 
Applied Sociology and 
Biostatistics 
Radiological Science 
 
Medicine 
 
 
 
House Officer 
Medicine/Surgery 
 
 
 
Senior House Officer in 
Surgery 
 
 
 
NIAAA Fellow in 
Addiction and 
Substance Abuse 
Psychiatry 
 
Radiology Fellowship 


 Version 12/12/2019 - 16 
 
A. Personal Statement 
350 
I have the expertise, leadership, and motivation necessary to successfully carry out the proposed 
351 
work in Meniere’s disease research. I have a broad background in otolaryngology, radiology, and 
352 
clinical trials research, with specific training and expertise in key research areas (research 
353 
methodology, biostatistics, outcomes research, cost-effective analysis, and clinical trials) for this 
354 
application. As a resident/fellow, I carried out translational research in alcohol addiction models, 
355 
clinical research involving investigational new drugs, and outcomes research in substance abuse 
356 
where I won seven national/international research awards. As one of the first certified principal 
357 
investigators (CPI) by the American Academy of Physician Investigators, I am directing one of 
358 
the most robust clinical trials programs in otolaryngology – head and neck surgery in the world, 
359 
where I have served as principal investigator/co-investigator on over 200 clinical trials (Phases 1, 
360 
2, and 3) investigating the treatment of hearing loss, Meniere’s disease, tinnitus, chronic 
361 
sinusitis, obstructive sleep apnea, and head and neck cancer. I will work with Dr. Rizk and Dr. 
362 
Liu in identifying and enrolling potential patients with Meniere’s disease. In summary, I have a 
363 
demonstrated record of accomplished and productive research projects with over 165 
364 
publications in an area of high relevance in otolaryngology, and my expertise and experience 
365 
have prepared me to become an important member in the proposed project. 
366 
 
367 
B. Positions and Honors 
368 
Positions and Employment 
369 
2005 - 2008 
 
2006 - 2008 
2008 - 2009 
2008 - 2011 
 
2008 -  
 
 
2009 - 2010 
 
 
2010 - 
2011 - 2012 
 
2012 - 2015 
 
2015 - 
Assistant Professor, Department of Radiology and Radiological Science, 
Medical University of South Carolina (MUSC), Charleston, SC 
Assistant Professor, Clinical Services, MUSC 
Assistant Professor, College of Health Professions, MUSC 
Assistant Professor, Department of Otolaryngology - Head and Neck Surgery, 
MUSC 
Director of Clinical Research Fellowship Program, Department of 
Otolaryngology- Head and Neck Surgery, MUSC. 
Assistant Professor, Division of Physician Assistant Studies, College of Health 
Professions, MUSC 
Associate Member, College of Graduate Studies, MUSC 
Assistant Professor, Department of Otolaryngology - Head and Neck Surgery, 
MUSC 
Associate Professor, Department of Otolaryngology - Head and Neck Surgery, 
MUSC 
Professor, Department of Otolaryngology – Head and Neck Surgery, MUSC 
 
370 
Other Experience and Professional Memberships 
371 
2005 
Judge- Medical University of South Carolina Student Research Day 
2006 - 2018 
Judge- Perry Halushka Student Research Day at MUSC. 


 Version 12/12/2019 - 17 
 
2019 
Chair Judge- Perry Halushka Student Research Day at MUSC. 
 
372 
Academic Committee Activities (past 5 years): 
373 
University 
374 
Year 
Name of Committee 
Role 
Institution 
2008 - 
Faculty Senate 
Senator 
MUSC 
2008 - 
Institutional Advancement 
Committee 
Member 
MUSC 
College of Medicine 
Year 
Name of Committee 
Role 
Institution 
2013 - 
Admissions Committee 
Interviewer 
MUSC 
2013 - 
Diversity Committee 
Member 
MUSC 
College of Health Professions 
Year 
Name of Committee 
Role 
Program 
2007 – 2010 
Thesis Committee 
Director 
M.S. in Nurse Anesthesia 
2007 – 2010 
Thesis Committee 
Director 
M.S. in Physician Assistant Studies 
 
375 
College of Graduate Studies 
376 
Year 
Name of Committee 
Role 
Program 
2009 - 
Thesis Committee 
Mentor 
M.S. in Clinical Research 
 
377 
Honors 
378 
1989 
Phi Delta Kappa National Honor Society 
1989 
Gamma Beta Phi National Honor Society 
1989 
Golden Key National Honor Society 
1992 
Eta Sigma Gamma National Honor Society 
1992 
Kappa Delta Pi National Honor Society 
2002 
Junior Investigator Award- Research Society on Alcoholism 
2002 
Resident/Fellow Research Award- MUSC Annual Research Day 
2003 
Junior Investigator Award- Research Society on Alcoholism 
2003 
2004 
2004 
2004 
2006 
Enoch Gordis Award Finalist- Research Society on Alcoholism 
Resident/Fellow Research Award- MUSC Annual Research Day 
Junior Investigator Award- Research Society on Alcoholism 
Junior Investigator Award- Guze Symposium on Alcoholism 
Cum Laude Award- Outstanding Scientific Paper- Society of Computed Body 
Tomography and Magnetic Resonance. 
 
379 
C. Contribution to Science 
380 
My bibliography on NCBI: https://www.ncbi.nlm.nih.gov/pubmed/?term=nguyen+sa  
381 


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Funding 
382 
- 
Current funding: none 
383 
- 
Overlapping funding: none 
384 
- 
Pending funding: none 
385 
 
 
386 


 Version 12/12/2019 - 19 
 
 
387 


 Version 12/12/2019 - 20 
 
 
388 


 Version 12/12/2019 - 21 
 
 
389 


 Version 12/12/2019 - 22 
 
SPECIFIC AIMS 
390 
MD is a frequent cause of episodic vertigo, but evidence-based therapies for MD are limited. The 
391 
goal of the proposed project is to identify evidence-based treatments for MD that will improve 
392 
disease-specific outcomes as well as cognitive, psychological, and quality of life outcomes. Our 
393 
overall objective for this proposal is to determine the efficacy of venlafaxine ER at a dose of 37.5 
394 
mg per day in the treatment of MD, with specific attention to change in dizziness episode 
395 
frequency and severity, along with the other above mentioned outcomes. Our central hypothesis 
396 
is that venlafaxine in the prophylactic treatment of MD reduces the severity and the frequency of 
397 
the vertigo spells and improves functional, cognitive, psychological, and quality of life outcomes 
398 
in these patients. 
399 
The specific aims of this project are the following: 
400 
- 
Aim 1 is to compare the efficacy of venlafaxine to placebo in decreasing the number and 
401 
severity of dizziness episodes, and in improving functional outcomes in patients with 
402 
definite MD. 
403 
- 
Aim 2 is to compare the efficacy of venlafaxine to placebo in improving self-perceived 
404 
cognitive, psychological, and QOL outcomes in definite MD. 
405 
- 
Our exploratory aim is to validate the English version of the newly developed 
406 
Neuropsychological Vertigo Inventory as an appropriate tool to measure cognitive 
407 
dysfunction in patients with MD and to measure response to treatment. 
408 
 
 
409 


 Version 12/12/2019 - 23 
 
BACKGROUND AND SIGNIFICANCE 
410 
Meniere’s disease (MD) is a major cause of episodic vertigo, affecting around 190 people per 
411 
100,000 in the US.27 It represents up to 15% of new patient consultations for vertigo in a tertiary 
412 
neurotology clinic.1 MD was first described in the 19th century and is one of the most studied 
413 
topics in otology.28 But despite its prominent historical role in research, its etiology is uncertain 
414 
and a cure remains absent.29,30 
415 
Many therapies have been tried to curtail the symptoms of MD, including lifestyle 
416 
modifications with reduction of salt intake and increase in water intake; medications such as 
417 
diuretics, betahistine, transtympanic steroids, transtympanic gentamicin; and surgical treatments 
418 
such as endolymphatic sac decompression, vestibular neurectomy, and labyrinthectomy.2 
419 
However, no gold-standard treatment or treatment protocol exists, and existing therapies for MD 
420 
rely heavily on lower levels of evidence.2,31 Furthermore, although some therapies have proven 
421 
to reduce episodic vertigo, such as transtympanic gentamicin, they carry significant side effects 
422 
including hearing loss and tinnitus, which are already consequences of the disease itself.32 
423 
Venlafaxine is a serotonin and norepinephrine reuptake inhibitor (SNRI) typically used in 
424 
the treatment of depression.7 It has been shown to be effective for depression at doses between 
425 
75 mg and 375 mg, 2 to 3 times daily.7 We aim to use a 37.5 mg daily dose, as has been used in 
426 
successful treatment of vestibular migraine.23,24 There are several reasons why we seek to 
427 
conduct a trial to evaluate the efficacy of venlafaxine in the treatment of MD, as detailed below. 
428 
There is evidence to suggest that selective serotonin reuptake inhibitors (SSRIs) can be 
429 
effective in the treatment of MD through central mechanisms.33-35 It has been shown in rats that 
430 
serotonin can modify responsiveness to glutamate and N-methyl-d-aspartate (NMDA) in 
431 


 Version 12/12/2019 - 24 
 
vestibular nuclei, leading to depression of excitatory activity.8 In addition, microinjection of 
432 
serotonin into the rat inferior olive has been shown to increase firing rate of neurons while 
433 
slowing oscillation frequency and increasing oscillation coherence, suggesting a role for 
434 
serotonin in enhancing motor timing in the olivocerebellar system.9 These studies suggest that 
435 
serotonin plays an important role in regulating vestibular function, as SSRIs have been shown to 
436 
be effective in treating vertigo, and SSRI withdrawal has been associated with acute dizziness, 
437 
vertigo, and incoordination.36-39 Norepinephrine has been shown to have inhibitory activity in the 
438 
medial vestibular nuclei and excitatory activity in the lateral vestibular nuclei of rats.10 In one 
439 
study, 85% of neurons in all vestibular nuclei experienced change in basal firing rate with 
440 
norepinephrine application, with inhibition in 86% of those tested, acting mainly through alpha2-
441 
adrenergic receptors.40 Lamotrigine, a serotonin, norepinephrine, and dopamine reuptake 
442 
inhibitor, has been shown to be effective in treating MD and is currently in a clinical trial.11 
443 
Venlafaxine, through its activity in increasing serotonin and norepinephrine concentrations, 
444 
could therefore mitigate the vestibular symptoms of MD through central mechanisms. 
445 
Venlafaxine has been shown to reduce vasopressin receptor activation in mice.12 This 
446 
potential action of venlafaxine is important in that plasma vasopressin has been found to be 
447 
increased in MD and implicated in endolymphatic hydrops.41,42 The endolymphatic sac is 
448 
important in regulating ion and fluid homeostasis in the inner ear,43,44 and is therefore important 
449 
to consider in the development of MD, as MD has been shown to be a disease of endolymphatic 
450 
hydrops.45 Notably, vasopressin type 2 receptors have been found to be expressed in the luminal 
451 
epithelium of the endolymphatic sac,13 and vasopressin is thought to be a potential regulator of 
452 
endolymphatic ion and fluid homeostasis.14,15 It has been proposed that similar to how 
453 
vasopressin induces translocation of aquaporins into luminal cell membranes in the kidney, it 
454 


 Version 12/12/2019 - 25 
 
may play a role in fluid dysregulation in the endolymphatic sac in MD.13,46 Specifically, Claudin 
455 
4, a tight junction molecule expressed in the endolymphatic duct and sac, was recently shown to 
456 
be a target of vasopressin.47 Systemic administration of vasopressin in guinea pigs has been 
457 
demonstrated to cause bilateral inner ear hydrops with hearing loss.16 Furthermore, interventions 
458 
aimed to decrease systemic vasopressin such as stress reduction have been shown to be better 
459 
than traditional medications alone in controlling vertigo in MD after a 2-year follow up.41 One 
460 
study found that long term decreased vasopressin after endolymphatic sac surgery was associated 
461 
with better vertigo control.48 These data suggest that venlafaxine may be useful in treating MD 
462 
through its vasopressin modulating activity. 
463 
A large number of patients with MD suffer from comorbid anxiety and depression.19 One 
464 
study found that 70-80% of patients with active MD could be diagnosed with depression while 
465 
the same was true in 32-39% of those with inactive MD.49 It is unclear whether psychological 
466 
factors such as anxiety and depression could take part in causing MD, but it is feasible that once 
467 
these factors are present, a positive feedback loop may set in where the somatic symptoms of 
468 
MD could worsen the psychological symptoms, which could then in turn worsen the perception 
469 
of somatic symptoms, and so on.19,20 This is the basis for the potential development of persistent 
470 
postural-perceptual dizziness, a disease that is exceptionally difficult to manage, in patients with 
471 
MD.50 Furthermore, vasopressin, as a stress hormone related to anxiety and depression,51 could 
472 
alter inner ear fluid mechanics as earlier mentioned.14 We have found through a prospective 
473 
study of cognitive function in dizzy patients that MD presents with cognitive dysfunction greater 
474 
than that of benign paroxysmal positional vertigo, and comparable to that of vestibular migraine; 
475 
and a great deal of this cognitive decline was mediated through depression.52 Venlafaxine is a 
476 


 Version 12/12/2019 - 26 
 
well-known and effective treatment for anxiety and depression,17,18 and as such, may prove 
477 
useful in treating both the psychological and somatic repercussions of MD. 
478 
Migraine is comorbid in 22-56% of MD patients, twice as high as the general 
479 
population.21,22 It has come to be increasingly recognized that MD and vestibular migraine are 
480 
closely related in that they have great overlap in presentation,53 diagnostic criteria,54,55 and 
481 
potentially pathophysiology.25,26 For instance, the trigeminovascular system, which is widely 
482 
thought to be the pathway for activation of migraine,25 can directly affect inner ear blood flow 
483 
through the trigeminal nerve.56 It has been hypothesized that chronic under-perfusion may lead to 
484 
ischemic injury and incite MD.57 Venlafaxine has shown efficacy in the treatment of 
485 
migraineError! Bookmark not defined. and vestibular migraine,23,24 but it has never been trialed for MD. 
486 
Venlafaxine has a well-established safety profile.3 It is well-tolerated in the treatment of 
487 
depression.4,5 In addition, it will be used in the proposed trial at the lower end of the depression 
488 
treatment dosage spectrum (typically >75 mg daily). In a trial of venlafaxine 75 mg daily vs. 
489 
placebo for migraine prophylaxis, excellent or good tolerance was reported in 86.7% of patients, 
490 
with common side effects of nausea, vomiting, drowsiness, fatigue, and insomnia.6 It does not 
491 
bind significantly to adrenergic, muscarinic cholinergic, or histamine H1 receptors.7 Thus, it has 
492 
a low risk of causing significant anticholinergic side effects.4 
493 
High quality evidence is needed when examining MD treatments, especially when 
494 
introducing a potential new class of therapy. A 2018 international consensus article provided an 
495 
algorithm for MD treatment, which found a lack of level I evidence for any specific modality.30 
496 
Thus, given the evidence discussed suggesting the potential of venlafaxine as a non-invasive 
497 
therapy to alter the natural course of MD through both central and peripheral vestibular 
498 
mechanisms, we believe a high-quality pilot study seeking to examine changes to multiple 
499 


 Version 12/12/2019 - 27 
 
aspects of disease burden (i.e., vestibular, functional, psychiatric, cognitive, quality of life) 
500 
would be worthwhile to prove or disprove the efficacy of this class of medication. 
 
501 


 Version 12/12/2019 - 28 
 
SUBJECTS AND METHODS 
502 
Institutional Review Board (IRB) approval for this prospective study will be requested prior to 
503 
enrollment of subjects. 
504 
 
505 
Subject Selection 
506 
Study subjects will be prospectively recruited from patients presenting with dizziness to our 
507 
tertiary, multidisciplinary, vestibular-focused, neurotology clinic. Subjects must meet the 
508 
following inclusion criteria: be 18 years of age or older; have definite MD as defined by the 
509 
Barany Society 2015 international consensus statement54 (Table 1); have active MD with at least 
510 
2 vertigo episodes in the month prior to enrollment; and score at least 36 on the Dizziness 
511 
Handicap Inventory (DHI),58 representing at least moderate handicap. Patients with the following 
512 
will be excluded: other concurrent vestibular or balance disorder (especially those with vestibular 
513 
migraine-related vertigo episodes despite not meeting diagnostic criteria for vestibular migraine); 
514 
prior treatment with venlafaxine; history of medical (e.g., gentamicin) or surgical (e.g., 
515 
labyrinthectomy) vestibular ablative treatment; history of otologic, lateral skull base, or brain 
516 
surgery; history of radiation to the head or neck; known neurologic disorder affecting cognition; 
517 
currently taking another serotonin modulating medication; seizures; stroke; myocardial 
518 
infarction; hepatic or renal impairment; hyperlipidemia; coagulopathy; psychiatric disorder other 
519 
than anxiety or depression; glaucoma; uncontrolled hypertension; and pregnancy or intention of 
520 
pregnancy. 
521 
 
522 
Sample Size 
523 


 Version 12/12/2019 - 29 
 
This is a randomized, double-blind, crossover trial which will required a treatment group and a 
524 
placebo group. Based on a power of 80%, we calculated possible sample sizes using: 1) expected 
525 
proportion of subjects achieving treatment success, and 2) difference in DHI score needed for 
526 
clinical significance. 
527 
We estimate 20% of the placebo group will develop a good response to treatment (>50% 
528 
reduction in vertigo frequency).59-62 To detect a difference of 30% in success rate, such that at 
529 
least 50% of patients in the venlafaxine arm will develop a similar response, 36 subjects would 
530 
be needed per treatment arm. Given the crossover design this would results in 18 subjects per 
531 
treatment arm before crossing over, and 36 total subjects. 
532 
The original publication detailing the development of the DHI found a standard deviation 
533 
in score of 21.9 among dizzy patients, and a minimum difference of 18 points after treatment to 
534 
signify a significant change in self-perceived dizziness handicap.58 Using these values, we 
535 
calculate a per treatment arm sample size of 24, which results in 24 total patients needed for the 
536 
crossover design. 
537 
Using the proportions sample size calculation (because it has a greater number of 
538 
subjects), and factoring in a 10% drop-out rate (e.g., improper medication use, inadequate data), 
539 
a total of 40 patients would need to be enrolled. 
540 
 
541 
Study Protocol 
542 
A timeline summary of the study protocol is presented in Figure 1 and Table 2. Based on our 
543 
high clinical volume of new dizzy patients (around 80 per month), and that approximately 10% 
544 
of patients will have a diagnosis of definite MD, we estimate that 8 patients can be screened per 
545 


 Version 12/12/2019 - 30 
 
month. Because around 40% of our referrals are outside the Tri-county area of Charleston, which 
546 
may present a problem for follow-up, a conservative estimate of enrollment is 5 subjects per 
547 
month. In order to enroll 40 patients, our total study period will be approximately 14.5 months 
548 
(last patient screened will require 6.5 months to provide all data). 
549 
 
550 
Screening Period 
551 
New patients diagnosed with definite MD will undergo a 1-month screening period during which 
552 
they will keep a diary of each vertigo episode, including duration, severity on a visual-analog 
553 
scale of 1 to 10 from least to most severe, and associated symptoms (aural fullness/pressure, 
554 
hearing loss, tinnitus, and/or headache). They will receive an audiogram from our clinic 
555 
audiologist at their initial visit to make the diagnosis of definite MD, which will be staged based 
556 
on hearing loss according to the 1995 American Academy of Otolaryngology Head and Neck 
557 
Surgery (AAOHNS) guidelines63 (Table 3). The frequency of their vertigo episodes in the 2 
558 
months prior will be documented, along with all prior medical treatments for MD. 
559 
Before the end of their initial clinic visit, they will receive conservative treatment 
560 
typically recommended for patients diagnosed with MD in our clinic. This treatment will consist 
561 
of dietary and lifestyle modifications, including salt restriction to 1500 mg a day; increased water 
562 
intake to a minimum of 35 ml/kg per day; and caffeine, alcohol, tobacco, and stress 
563 
avoidance.30,64-66 Subjects who are considering enrollment in the trial will be instructed to stop 
564 
all medications used for MD, such as diuretics and betahistine. Patients who require oral or 
565 
transtympanic steroids for acute hearing loss will not be eligible for enrollment. 
566 
We suspect many patients will have comorbid migraine as has been seen in our clinic. 
567 


 Version 12/12/2019 - 31 
 
These patients will be counseled about trigger identification (e.g., dietary, environments, 
568 
workplace, lifestyle). Our migraine treatment strategies are outlined in Appendix A. 
569 
 
570 
Enrollment and Randomization 
571 
Patients who document 2 or more MD-related vertigo episodes in their diary during the screening 
572 
period will be offered enrollment in the study. Patients who document fewer episodes will 
573 
continue to receive standard of care treatment in clinic. If a patient is interested in participating, 
574 
the study coordinator will describe the study protocol, assess the patient’s eligibility based on the 
575 
inclusion and exclusion criteria, and have the patient sign necessary paperwork per standard IRB 
576 
procedures. Patients will be required to receive comprehensive metabolic panel testing to rule out 
577 
metabolic disturbances and renal and liver dysfunction. Vitals will also be screened for 
578 
uncontrolled hypertension. Female patients who have not undergone menopause will be given 
579 
urine pregnancy tests and advised against pregnancy during the trial period. Once enrolled, the 
580 
patient will complete the following surveys: 1) Dizziness Handicap Inventory (DHI),58 2) 
581 
Neuropsychological Vertigo Inventory (NVI),67 3) Cognitive Failure Questionnaire (CFQ),68 4) 
582 
Patient Health Questionnaire-9 (PHQ9),69 5) Penn State Worry Questionnaire (PSWQ),70 6) 
583 
Meniere’s Disease Patient-Oriented Symptom Index (MDPOSI),71 and 7) 20-Item Short Form 
584 
Health Survey (SF20).72 Descriptions of these tools are provided below in the Outcome 
585 
Measures section. 
586 
Enrolled subjects will be randomly assigned to 2 groups, one taking a daily venlafaxine 
587 
ER 37.5 mg tablet, and the other taking a daily placebo replica of venlafaxine manufactured by 
588 
our university investigational drug services pharmacy. Randomization of subjects will take place 
589 


 Version 12/12/2019 - 32 
 
before enrollment of any subjects. The pharmacy staff will not have access to patient data beside 
590 
patient identifiers. The pharmacy will be instructed to use the Excel random number generator 
591 
function to generate a list of 40 numbers between 1 and 1000, representing patients 1 through 40, 
592 
in order of enrollment. The 20 lowest numbers will be assigned to the venlafaxine group, and the 
593 
rest to the placebo group. The pharmacy staff will then distribute the medication or placebo 
594 
accordingly to the blinded clinicians to give to subjects in order of enrollment. When the groups 
595 
cross over, the pharmacy staff will perform a switch in the medication without revealing subject 
596 
group identities to the clinician. For patients who drop out, the subsequent enrolled patients will 
597 
take on their treatment group assignment. After all data have been collected, the pharmacy staff 
598 
will reveal to the statistician whether a patient belongs in group “1” or “2”, without revealing 
599 
which group received the placebo first. After all data have been analyzed, the pharmacy staff will 
600 
give the identifier key (revealing identity of groups 1 and 2) to the investigators to interpret the 
601 
results. 
602 
Subjects will be given a 2-month supply of medication or placebo plus 7 capsules for the 
603 
2-week weaning period by the pharmacy. They will be advised on how to take the medication 
604 
and the side effects of venlafaxine by the investigator. They will be instructed to call the 
605 
principal (HR) or co-investigator (YL) at the clinic number or page either of them (instructions 
606 
will be provided) afterhours, if any side effects are affecting their ability to take the medication. 
607 
Subjects will again be instructed to keep a diary of every vertigo episode. 
608 
 
609 
Treatment and Washout Phases 
610 


 Version 12/12/2019 - 33 
 
Each treatment phase will last 2 months. Details of patient diaries will also be documented and 
611 
patients will be instructed to maintain their diaries. Diaries will also be checked for adequacy to 
612 
make sure subjects are documenting their symptoms appropriately. Between the first and second 
613 
2-month treatment phases there will be a 1.5-month washout period, during the first 2 weeks of 
614 
which, subjects will wean off the first medication by taking the capsules every other day, and 
615 
during the last 4 weeks of which, no trial medication or any other new medication will be taken 
616 
but diaries will be maintained. If at any point in the trial acute hearing loss develops, a new 
617 
audiogram will be obtained and transtympanic and oral steroid treatments will be offered. If a 
618 
patient chooses to receive steroid treatment after being counseled about the risks and benefits, he 
619 
or she will be disqualified from the trial. 
620 
 
621 
Outcome Measures 
622 
Symptoms and Functional Level 
623 
The main symptoms of MD to be examined are number of vertigo episodes and severity of 
624 
episodes. Symptom reduction will be calculated based on the 1995 AAOHNS guidelines63 for 
625 
assessing MD improvement after treatment (Table 4) and previous studies on treatment 
626 
outcomes of episodic vestibular disorders such as vestibular migraines.73,74 We will use a 
627 
modified version of vertigo control classification because our treatment phases are 2 months long 
628 
and we will not be able to wait 18-24 months after treatment to assess efficacy per AAOHNS 
629 
guidelines.63 Previous studies have defined four categories of response to treatment: 1) very good 
630 
response if more than 75% reduction in vertigo spells frequency and/or intensity, 2) good 
631 
response if 50-75% reduction, 3) fair response if 25-50% reduction, and 4) poor response if less 
632 


 Version 12/12/2019 - 34 
 
than 25% reduction. Combining the 2 approaches, our numerical value calculation (Table 4) will 
633 
be the mean number of vertigo episodes in the 2 months after starting a treatment (either 1st or 
634 
2nd treatment phase) divided by the mean number of vertigo episodes in the 3 months prior to the 
635 
1st treatment phase multiplied by 100 and round to the nearest whole number. Our vertigo control 
636 
classes will be defined as follows: 
637 
- 
Class A: numerical value 0 (complete control of vertigo) 
638 
- 
Class B: numerical value 0-40 or >60% reduction in mean vertigo episode severity (good 
639 
control of vertigo) 
640 
- 
Class C: numerical value 41-80 or 20-60% reduction in severity (fair control of vertigo) 
641 
- 
Class D: numerical value 81-120 or -20-20% reduction in severity (no change in vertigo) 
642 
- 
Class E: numerical value >120 or >20% worsening in severity (worse vertigo) 
643 
- 
Class F: secondary treatment initiated due to disability from vertigo (e.g. steroid 
644 
injection, gentamicin injection, endolymphatic sac decompression, labyrinthectomy) 
645 
We will document duration of episodes and associated symptoms (aural fullness/pressure, 
646 
hearing loss, tinnitus, and/or headache) as well, but will simply conduct direct numerical 
647 
comparisons or provide descriptive analyses given their likely subjectivity and variability. 
648 
Functional level will be assessed according to the 1995 AAOHNS guidelines63 (Table 5) at 
649 
every visit. 
650 
 
651 
Questionnaires 
652 
The Dizziness Handicap Inventory (DHI, Appendix B) is a 25-item questionnaire of self-
653 
perceived handicap from dizziness.58 There are 7 questions in the physical domain, 9 in the 
654 


 Version 12/12/2019 - 35 
 
emotional domain, and 8 in the functional domain. The DHI has been shown to be valid and 
655 
reliable, has been translated into 14 languages, and is the most widely-used survey of self-
656 
reported impairment from dizziness.58,75 It has also been shown to correlate well with balance 
657 
testing.76 The DHI will be used to assess the overall severity of vestibular symptoms in our MD 
658 
subjects. 
659 
The English version of the Neuropsychological Vertigo Inventory (NVI, Appendix C) 
660 
consists of 28-items with a 5-point Likert scale for each question.67Error! Bookmark not defined. It was 
661 
recently developed as a cognitive assessment specific to patients with dizziness. The NVI 
662 
assesses 7 domains of cognition: space perception, attention, time perception, memory, 
663 
emotional, visual/oculomotor, and motor. We recently conducted a prospective study showing 
664 
that the NVI can detect a difference in cognitive dysfunction among different vestibular 
665 
disorders; including MD, vestibular migraine, and benign paroxysmal positional vertigo; and that 
666 
it is more sensitive than the DHI in revealing these differences.52 We will use the NVI to gauge 
667 
vestibular-specific changes in cognitive impairment after treatment. 
668 
The Cognitive Failure Questionnaire (CFQ, Appendix D) is a 25-item survey which 
669 
assesses cognitive and executive function not tied to any specific disease state.68 It aims to assess 
670 
perception, memory, and motor function in everyday tasks. The CFQ is valid and well-
671 
established,77,78 and will be used as a reference for cognitive dysfunction to gauge the results of 
672 
the NVI, since the NVI is a newer survey. 
673 
The Patient Health Questionnaire (PHQ9, Appendix E) is a 9-item survey that assesses 
674 
the severity of depression.69 It is a validated tool that has been shown to be reliable in assessing 
675 
outcomes of depression treatment.79 The Penn State Worry Questionnaire (PSWQ, Appendix F) 
676 
is a 16-item survey for assessment of anxiety which has been used to identify generalized anxiety 
677 


 Version 12/12/2019 - 36 
 
disorder.70,80 Psychological disturbances have been recognized in MD and it is important to 
678 
assess their severity along with that of vestibular symptoms.19,81 Therefore, the PHQ9 and PSWQ 
679 
will be used to assess the extent of depression and anxiety effects on quality of life in MD 
680 
subjects. 
681 
The Meniere’s Disease Patient-Oriented Symptom Index (MDPOSI, Appendix G) is a 
682 
23-item survey developed as a MD-specific tool to assess the impact of MD symptoms on 
683 
patients’ lives.82 It is valid and reliable, and we aim to use it as a more specific measure of 
684 
disease-related quality of life than the DHI.71 
685 
The Medical Outcomes Study 20-item Short Form Health Survey (SF20, available at 
686 
https://www.rand.org/health-care/surveys_tools/mos/20-item-short-form/survey-instrument.html) 
687 
is a 20-item general health questionnaire originally developed for the Medical Outcomes Study 
688 
to assess quality of life in chronic diseases.72 It assesses 6 areas of health: physical functioning, 
689 
role functioning, social functioning, mental health, health perceptions, and pain. We will use this 
690 
survey to gauge in a broad sense the general quality of life of MD patients given MD is a chronic 
691 
disease. 
692 
 
693 
Adverse Effects 
694 
Side effects experienced by subjects at any point, whether it affects their ability to continue 
695 
treatment or not, will be tabulated during visits and from patient phone calls. Specifically, we 
696 
will monitor for minor side effects of nausea, insomnia, somnolence, constipation, sweating, dry 
697 
mouth, nervousness and asthenia; and major side effects of rash, increase in blood pressure, 
698 
weight change, seizures, and serotonin syndrome.4 A comprehensive metabolic panel will be 
699 


 Version 12/12/2019 - 37 
 
required prior to taking any medication to rule out any gross renal or hepatic abnormalities. 
700 
Urine pregnancy tests will be administered for female patients who have not undergone 
701 
menopause. No other laboratory tests will be performed unless other abnormalities are suspected. 
702 
 
703 
Data Analysis 
704 
The benefit of a crossover study over a traditional clinical trial design is that it relies on 
705 
elimination of carryover effects after the 1st treatment phase.83 A confirmatory pre-test to check 
706 
the adequacy of the washout period and the assumption of negligible carryover effects will be 
707 
performed by using unpaired Student t-tests comparing all outcome measure means at the end of 
708 
the 2nd treatment phase with that of the end of the 1st treatment phase for both the venlafaxine 
709 
and placebo groups. For outcome measures that pass the confirmatory test, paired t-tests will be 
710 
used to gauge within-subject differences per the crossover study design. For outcome measures 
711 
that do not pass the confirmatory test, only the 1st treatment phase data will be used for analysis 
712 
as if it were a parallel-treatment clinical trial. 
713 
Descriptive statistics will be performed on demographics and all other variables. In 
714 
general, Student t-tests will be used to compare means of 2 groups and Pearson chi-square tests 
715 
will be used to compare proportions where appropriate. The Kolmogorov-Smirnov test will be 
716 
used to assess normality of variables and the Mann-Whitney U test will be used in lieu of the 
717 
Student t- test for variables with non-normal distributions. Pearson correlations will be calculated 
718 
to assess associations among questionnaire results. Linear regression will be performed to weigh 
719 
the effect of venlafaxine or placebo against that of other variables such as depression and 
720 
anxiety, which may confound results. P<0.05 will be used to establish statistical significance. 
721 


 Version 12/12/2019 - 38 
 
 
722 
Potential Limitations 
723 
Vestibular symptoms may wax and wane over time in MD, potentially biasing results of the 
724 
treatment phases due to underlying natural progression of the disease. However, this difference 
725 
should be minimal given the short interval of 3 months between start of the first and second 
726 
treatment. Another problem may be inadequate washout time for the effects of the 1st treatment 
727 
phase to wear off. We will assess for significant carryover effects as described above. There 
728 
may, however, be permanent carryover effects after 1 course of treatment which we cannot 
729 
control. 
 
730 


 Version 12/12/2019 - 39 
 
Figure 1. Study timeline summary. During the 1st and 2nd treatment phases, patients could 
731 
receive either venlafaxine or placebo according to randomization performed by the pharmacy to 
732 
ensure that the physician and patient are blinded. Asterisks indicate data collection time points 
733 
by study coordinator. 
734 
 
735 
 
736 
 
737 
 
738 
 
739 
 
740 
 
741 
 
 
742 
*
*
*
*
Screening: 
1 month 
1st treatment: 
2 months 
2nd treatment: 
2 months 
Washout: 
1.5 months 


 Version 12/12/2019 - 40 
 
Table 1. Definite Meniere’s disease diagnostic criteria from Barany Society international 
743 
consensus statement.54 
744 
A 
Two or more spontaneous episodes of vertigo, each lasting 20 minutes to 12 hours. 
B 
Audiometrically documented low- to medium-frequency sensorineural hearing loss in 
one ear, defining the affected ear on at least one occasion before, during or after one of 
the episodes of vertigo. 
C 
Fluctuating aural symptoms (hearing, tinnitus or fullness) in the affected ear. 
D 
Not better accounted for by another vestibular diagnosis. 
 
745 
 
 
746 


 Version 12/12/2019 - 41 
 
Table 2. Study protocol summary. Bolded actions signify data collection time points. 
747 
Phase 
Timing 
Actions 
Screening 
1 month before 
enrollment (1st 
clinic visit) 
Diagnose definite MD 
Audiogram 
Document vertigo frequency during prior 2 months 
Assess symptoms and function 
Recommend dietary and lifestyle modifications 
Instruct patient to keep diary of vertigo episodes and 
associated symptoms 
1 month period 
Patient keeps diary 
Round 1 
Enrollment and 
treatment round 1 
begins (2nd visit) 
Assess symptoms and function 
Patient completes DHI, NVI, CFQ, PHQ9, PSWQ, 
MDPOSI, and SF20 
Patient starts venlafaxine or placebo based on 
randomized, blind assignment prior to enrollment, 
comprehensive metabolic panel prior to starting 
medication, urine pregnancy test if appropriate 
Instruct patient to keep diary of vertigo episodes and 
associated symptoms 
2 month period 
Patient takes medication and keeps diary 
Treatment round 1 
ends (3rd visit) 
Assess symptoms and function 
Repeat same questionnaires from enrollment 
Washout 
1.5 month period 
Wean off 1st medication by taking it every other day for 2 
weeks, then no medications for 4 weeks 
Patient keeps diary 
Round 2 
Treatment round 2 
begins (4th visit) 
Assess symptoms and function 
Repeat same questionnaires from enrollment 
Patient crosses over to venlafaxine or placebo with 
clinician still blinded 
2 month period 
Patient takes medication and keeps diary 
Treatment round 2 
ends (5th visit) 
Assess symptoms and function 
Repeat same questionnaires from enrollment 
 
 
748 


 Version 12/12/2019 - 42 
 
Table 3. Meniere’s disease staging. The table and footnotes below are from the guideline 
749 
publication verbatim.63 
750 
Stage Four-tone average (dB) 
1 
<25 
2 
26-40 
3 
41-70 
4 
>70 
“Staging is based on the four-tone average (arithmetic mean rounded to the nearest whole 
751 
number) of the pure-tone thresholds at 0.5, 1,2, and 3 kHz of the worst audiogram during the 
752 
interval 6 months before treatment. This is the same audiogram that is used as the baseline 
753 
evaluation to determine hearing outcome from treatment. Staging should be applied only to cases 
754 
of definite or certain Meniere's disease.” 
755 
 
 
756 


 Version 12/12/2019 - 43 
 
Table 4. Vertigo control classification. The table and footnotes below are from the guideline 
757 
publication verbatim.63 
758 
Quantifying control of vertigo spells in response to treatment 
Numerical Value 
Class 
0 
A (complete control of definitive spells) 
1-40 
B 
41-80 
C 
81-120 
D 
>120 
E 
Secondary treatment initiated due to 
disability from vertigo 
F 
“Numerical Value=(X/Y)x100, rounded to the nearest whole number, where X is the 
759 
average number of definitive spells per months for one year after initiating therapy and 
760 
Y is the average number of definitive spells in the 6 months preceding therapy 
761 
(including the lead-in screening month).” 
762 
 
 
763 


 Version 12/12/2019 - 44 
 
Table 5. Functional level assessment. The table below is from the guideline publication 
764 
verbatim.63 
765 
Regarding your current state of overall functioning, not just during 
attacks, check the ONE that best applies: 
1. My dizziness has no effect on my activities at all. 
2. When I am dizzy, I have to stop what I am doing for a while, but it soon 
passes and I can resume activities. I continue to work, drive and engage 
in any activity I choose without restriction. I have not changed any plans 
or activities to accommodate my dizziness. 
3. When I am dizzy, I have to stop what I am doing for a while, but it does 
pass and I can resume activities. I continue to work, drive and engage in 
most activities I choose, but I have had to change some plans and make 
some allowance for my dizziness. 
4. 
 I am able to work, drive, travel, take care of a family or engage in most 
essential activities, but I must exert a great deal of effort to do so. I must 
constantly make adjustments in my activities and budget my energies. I am 
barely making it. 
5. 
 I am unable to work, drive or take care of a family. I am unable to do 
most of the active things that I used to. Even essential activities must be 
limited. I am disabled. 
6. I have been disabled for one year or longer and/or I receive compensation 
(money) because of my dizziness or balance problem. 
 
 
766 


 Version 12/12/2019 - 45 
 
Appendix A. Outline of headache treatment protocol. Adapted from Robbins et al.84 
767 
 
768 
Education 
769 
- 
Diary 
770 
- 
Trigger identification and avoidance 
771 
- 
Lifestyle hygiene- sleep, diet, exercise 
772 
First-line migraine abortive medications 
773 
- 
Sumatriptan (Imitrex): gold standard; given as 50 mg x 2, 100 mg x 1, 20 mg nasal spray, 
774 
6 mg IM, or Treximet (sumatriptan and naproxen) x1 
775 
- 
Rizatriptan (Maxalt): fast (oral disintegrating tablets: Maxalt MLT); given as 5 mg or 10 
776 
mg, max 20 mg/day 
777 
- 
Naratriptan (Amerge): longer duration, lower side effects, decreased efficacy, can be used 
778 
for menstrual migraine; given as 1 mg or 2.5 mg 
779 
- 
Zolmitriptan (Zolmig): fastest, long half-life; given as 2.5 mg or 5 mg tab, or 5 mg nasal 
780 
spray 
781 
- 
Eletriptan (Relpax): given as 40 mg or 80 mg 
782 
- 
Almotriptan (Axert): low adverse effects; given as 6.25 mg or 12.5 mg 
783 
- 
Aspirin, caffeine, and acetaminophen (Excedrin Migraine): can have rebound headache; 
784 
max 2 cap/day 
785 
- 
Naproxen (Aleve): good for young patients, can cause GI upset; given at onset with food, 
786 
repeat in 2 hours, max 6 tab/day 
787 
- 
Ibuprofen: 400 mg to 800 mg Q3H, maximum 2,400 mg/day 
788 
- 
Isometheptene mucate, dichloralphenazone, and acetaminophen (Amidrine): safe in 
789 
children 
790 
- 
Dihydroergotamine (Migranal): good for morning headaches, menstrual migraine; do not 
791 
use with antifungals, protease inhibitors, triptans, in cardiovascular disease, uncontrolled 
792 
hypertension; max 8 nasal sprays/day 
793 
Second-line abortive medications 
794 
- 
Ergotamine (Ergomar) 
795 
- 
Caffeine and ergotamine (Cafergot) 
796 
- 
Dihydroergotamine 
797 
- 
Ketorolac (Toradol) 
798 
- 
Compounded suppositories: see Robbins 
799 
- 
Compounded lozenges: see Robbins 
800 
First-line preventive medications 
801 
- 
Amitriptyline (Elavil): best efficacy, more side effects than nortriptyline; 10 mg QHS and 
802 
titrate up 
803 
- 
Nortriptyline (Pamelor): 10 mg QHS and titrate up; EKG if 50 mg reached, (20 mg often 
804 
sufficient) 
805 
- 
Propranolol (Inderal): 60 mg slow release to start, can increase to 120 mg 
806 
- 
Naproxen: 500 mg daily, can be BID 
807 


 Version 12/12/2019 - 46 
 
- 
Verapamil: 120 mg to start then double 
808 
- 
Clonazepam (Klonopin): 0.25 mg or 0.5mg, titrate up to 0.5 mg BID 
809 
- 
Sodium valproate (Depakote): 250 mg, titrate up to 500 mg BID 
810 
- 
Topiramate (Topamax): 25 mg BID, increase 25 mg/week up to 50 mg BID 
811 
- 
Magnesium gluconate: safe except in renal failure, good add-on; 1000 mg TID 
812 
Second-line preventive medications 
813 
- 
Combination therapy: 
814 
o Amitriptyline and propranolol 
815 
o First-line preventative and Mg gluconate 
816 
o First-line preventative and NSAID 
817 
- 
Gabapentin (Neurontin): 300 mg BID 
818 
- 
Pregabalin (Lyrica): 50 mg or 100 mg, titrate up to 200 mg BID 
819 
- 
Tanacetum parthenium (Feverfew): 2-4 tabs/day 
820 
Third-line preventive medications 
821 
- 
Phenelzine (Nardil): 
822 
- 
Repetitive dihydroergotamine cycle breaking 
823 
Menstrual migraines preventive medications 
824 
- 
NSAID 
825 
- 
Ergotamine 
826 
- 
Triptans (naratriptan 2.5 mg daily or BID for 3 days) 
827 
- 
Hormonal therapy (estrogen patch, long cycle contraceptives) 
828 
- 
Tamoxifen – see Robbins 
829 
Alternative medications 
830 
- 
Butterbur extract (Petadolex) 
831 
- 
Vitamin B2: 400 mg/day 
832 
- 
CoEnzyme Q: 100 mg TID 
833 
Migraine hypothesis testing 
834 
- 
Steroids (prednisone): 50 mg, repeat x3 days 
835 
Antiemetic 
836 
- 
Promethazine (Phenergan): very effective; given as 25 mg or 50 mg pill or suppositories 
837 
Q6H as needed 
838 
Notes on medications we rarely use 
839 
- 
Isometheptene mucate, dichloralphenazone, and acetaminophen 
840 
- 
Caffeine only if too much sedation 
841 
- 
Butalbital (Fiorinal) 
842 
- 
Butalbital, caffeine, and acetaminophen (Esgic, Fioricet) 
843 
- 
Narcotics 
844 
 
 
845 


 Version 12/12/2019 - 47 
 
Appendix B. Dizziness Handicap Inventory (DHI). Used with permission from GP Jacobson.58 
846 
 
847 
The patient is asked to answer each question as it pertains to dizziness or unsteadiness problems, 
848 
specifically considering their condition during the last month. Questions are designed to 
849 
incorporate functional (F), physical (P), and emotional (E) impacts on disability. 
850 
To each item, the following scores can be assigned: No=0 Sometimes=2 Yes=4 
851 
Scoring: 
852 
- 
Scores greater than 10 points should be referred to balance specialists for further 
853 
evaluation. 
854 
- 
16-34 Points (mild handicap) 
855 
- 
36-52 Points (moderate handicap) 
856 
- 
54+ Points (severe handicap) 
857 
P1. Does looking up increase your problem? 
o Yes 
o Sometimes 
o No 
E2. Because of your problem, do you feel frustrated? 
o Yes 
o Sometimes 
o No 
F3. Because of your problem, do you restrict your travel for business or 
recreation? 
o Yes 
o Sometimes 
o No 
P4. Does walking down the aisle of a supermarket increase your problems? 
o Yes 
o Sometimes 
o No 
F5. Because of your problem, do you have difficulty getting into or out of 
bed? 
o Yes 
o Sometimes 
o No 
F6. Does your problem significantly restrict your participation in social 
activities, such as going out to dinner, going to the movies, dancing, or 
going to parties? 
o Yes 
o Sometimes 
o No 
F7. Because of your problem, do you have difficulty reading? 
o Yes 
o Sometimes 
o No 
P8. Does performing more ambitious activities such as sports, dancing, 
household chores (sweeping or putting dishes away) increase your 
problems? 
o Yes 
o Sometimes 
o No 
E9. Because of your problem, are you afraid to leave your home 
without having someone accompany you? 
o Yes 
o Sometimes 
o No 
E10. Because of your problem have you been embarrassed in front of 
others? 
o Yes 
o Sometimes 
o No 
P11. Do quick movements of your head increase your problem? 
o Yes 
o Sometimes 
o No 
F12. Because of your problem, do you avoid heights? 
o Yes 
o Sometimes 
o No 
P13. Does turning over in bed increase your problem? 
o Yes 
o Sometimes 
o No 


 Version 12/12/2019 - 48 
 
F14. Because of your problem, is it difficult for you to do strenuous 
homework or yard work? 
o Yes 
o Sometimes 
o No 
E15. Because of your problem, are you afraid people may think you are 
intoxicated? 
o Yes 
o Sometimes 
o No 
F16. Because of your problem, is it difficult for you to go for a walk by 
yourself? 
o Yes 
o Sometimes 
o No 
P17. Does walking down a sidewalk increase your problem? 
o Yes 
o Sometimes 
o No 
E18.Because of your problem, is it difficult for you to concentrate 
o Yes 
o Sometimes 
o No 
F19. Because of your problem, is it difficult for you to walk around your 
house in the dark? 
o Yes 
o Sometimes 
o No 
E20. Because of your problem, are you afraid to stay home alone? 
o Yes 
o Sometimes 
o No 
E21. Because of your problem, do you feel handicapped? 
o Yes 
o Sometimes 
o No 
E22. Has the problem placed stress on your relationships with members of 
your family 
or friends? 
o Yes 
o Sometimes 
o No 
E23. Because of your problem, are you depressed? 
o Yes 
o Sometimes 
o No 
F24. Does your problem interfere with your job or household 
responsibilities? 
o Yes 
o Sometimes 
o No 
P25. Does bending over increase your problem? 
o Yes 
o Sometimes 
o No 
858 


 Version 12/12/2019 - 49 
 
Appendix C. Neuropsychological Vertigo Inventory (NVI).67 Used with permission from 
859 
authors of the original study and use of the English version with permission from Dr. R. 
860 
Srinivasa Raghavan of The Royal Surrey County Hospital. 
861 
 
862 
Please choose an appropriate response to the statements based on your most recent experience of 
863 
everyday life: 
864 
1. Never  2. Rarely  3. Sometimes  4. Very often  5. All the time 
(or) 
865 
1. Strongly disagree 2. Disagree 3. Not sure / Not applicable 4. Agree 5. Strongly agree 
866 
 
867 
Q1 I have a poor sense of direction 
Q2 I find it difficult to locate myself on a map 
Q3 I tend to go the wrong way when I set off to go somewhere 
Q4 When I go out I have trouble finding my way back 
Q5 I can’t place major historical events in the right chronological order 
Q6 I get confused about what day of the week it is 
Q7 I don’t always know what year we are in 
Q8 I don’t know which season we are in 
Q9 I find it difficult to concentrate 
Q10 I am absent minded 
Q11 I find it difficult to organize myself 
Q12 I am easily distracted 
Q13 I forget my appointments 
Q14 I have problems with my memory 
Q15 I find it hard to remember names of people 
Q16 I forget birthdays and anniversaries 
Q17 My mood changes each day 
Q18 I find it hard to get up in the morning 
Q19 I feel depressed 


 Version 12/12/2019 - 50 
 
Q20 I feel tired 
Q21 My eyes feel tired when I use the computer or watch television 
Q22 I tend to lose track of what I am reading and have to start all over again 
Q23 I am a slow reader 
Q24 For me table entries and newspaper columns appear jumbled 
Q25 I am clumsy 
Q26 I don’t think my handwriting is neat 
Q27 
I am not very good using my hands when it comes to DIY, drawing or 
sculpture 
Q28 My balance is poor 
Total score 
 
 
868 


 Version 12/12/2019 - 51 
 
Appendix D. Cognitive Failure Questionnaire (CFQ).68 
869 
 
870 
The following questions are about minor mistakes which everyone makes from time to time, but 
871 
some of which happen more often than others. We want to know how often these things have 
872 
happened to you in the past 6 months. Please circle the appropriate number. 
873 
 
874 
Very 
often 
Quite 
often 
Occasion- 
ally 
Very 
rarely 
Never 
1. 
Do you read something and find 
you haven’t been thinking about 
it and must read it again? 
2. 
Do you find you forget why you 
4 
4 
3 
3 
2 
2 
1 
1 
0 
0 
went from one part of the house 
to the other? 
3. 
Do you fail to notice signposts on 
4 
3 
2 
1 
0 
the road? 
4. 
Do you find you confuse right 
4 
3 
2 
1 
0 
and left when giving directions? 
5. 
Do you bump into people? 
4 
3 
2 
1 
0 
6. 
Do you find you forget whether 
you’ve turned off a light or a fire 
or locked the door? 
7. 
Do you fail to listen to people’s 
4 
4 
3 
3 
2 
2 
1 
1 
0 
0 
names when you are meeting 
them? 
8. 
Do you say something and realize 
4 
3 
2 
1 
0 
afterwards that it might be taken 
as insulting? 
9. 
Do you fail to hear people 
4 
3 
2 
1 
0 
speaking to you when you are 
doing something else? 
10. 
Do you lose your temper and 
4 
3 
2 
1 
0 
regret it? 
11. 
Do you leave important letters 
4 
3 
2 
1 
0 
unanswered for days? 
12. 
Do you find you forget which 
4 
3 
2 
1 
0 
way to turn on a road you know 
well but rarely use? 
13. 
Do you fail to see what you want 
4 
3 
2 
1 
0 
in a supermarket (although it’s 
there)? 
14. 
Do you find yourself suddenly 
4 
3 
2 
1 
0 
wondering whether you’ve used a 
word correctly? 


 Version 12/12/2019 - 52 
 
15. 
Do you have trouble making up 
4 
3 
2 
1 
0 
your mind? 
16. 
Do you find you forget 
4 
3 
2 
1 
0 
appointments? 
17. 
Do you forget where you put 
4 
3 
2 
1 
0 
something like a newspaper or a 
book? 
18. 
Do you find you accidentally 
4 
3 
2 
1 
0 
throw away the thing you want 
and keep what you meant to 
throw away – as in the example 
of throwing away the matchbox 
and putting the used match in 
your pocket? 
19. 
Do you daydream when you 
4 
3 
2 
1 
0 
ought to be listening to 
something? 
20. 
Do you find you forget people’s 
4 
3 
2 
1 
0 
names? 
21. 
Do you start doing one thing at 
4 
3 
2 
1 
0 
home and get distracted into 
doing something else 
(unintentionally)? 
22. 
Do you find you can’t quite 
4 
3 
2 
1 
0 
remember something although 
it’s “on the tip of your tongue”? 
23. 
Do you find you forget what you 
4 
3 
2 
1 
0 
came to the shops to buy? 
24. 
Do you drop things? 
4 
3 
2 
1 
0 
25. 
Do you find you can’t think of 
anything to say? 
4 
3 
2 
1 
0 
 
875 
 
 
876 


 Version 12/12/2019 - 53 
 
Appendix E. Patient Health Questionnaire (PHQ9).69 
877 
Use of the PHQ-9 to Make a Tentative Depression Diagnosis: 
878 
The clinician should rule out physical causes of depression, normal bereavement and a history 
879 
of a manic/hypomanic episode 
880 
 
881 
Step 1: Questions 1 and 2 
882 
Need one or both of the first two questions endorsed as a “2” or a “3” 
883 
(2 = “More than half the days” or 3 = “Nearly every day”) 
884 
Step 2: Questions 1 through 9 
885 
Need a total of five or more boxes endorsed within the shaded area of the form to arrive at the 
886 
total symptom count. (Questions 1-8 must be endorsed as a “2” or a “3”; Question 9 must be 
887 
endorsed as “1” a “2’ or a “3”) 
888 
Step 3:  Question 10 
889 
This question must be endorsed as “Somewhat difficult” or “Very difficult” or 
890 
“Extremely difficult” 
891 
 
892 
Use of the PHQ-9 for Treatment Selection and Monitoring 
893 
Step 1 
894 
A depression diagnosis that warrants treatment or a treatment change, needs at least one of the first 
895 
two questions endorsed as positive (“more than half the days” or “nearly every day”) in the past 
896 
two weeks. In addition, the tenth question, about difficulty at work or home or getting along with 
897 
others should be answered at least “somewhat difficult” 
898 
Step 2 
899 
Add the total points for each of the columns 2-4 separately 
900 
(Column 1 = Several days; Column 2 = More than half the days; Column 3 = Nearly every day. Add 
901 
the totals for each of the three columns together. This is the Total Score 
902 
The Total Score = the Severity Score 
903 
Step 3 
904 
Review the Severity Score using the following TABLE. 
905 
 
906 
PHQ9 Score Provisional Diagnosis 
Treatment Recommendation 
Patient Preferences should be 


 Version 12/12/2019 - 54 
 
considered 
5-9 
Minimal Symptoms* 
Support, educate to call if 
worse, return in one month 
10-14 
Minor depression 
++ Dysthymia* 
Major Depression, mild 
Support, watchful waiting 
Antidepressant or psychotherapy 
Antidepressant or psychotherapy 
15-19 
Major depression, moderately 
severe 
Antidepressant or psychotherapy 
>20 
Major Depression, severe 
Antidepressant and psychotherapy 
(especially if not improved on 
monotherapy) 
 
907 
* If symptoms present ≥ two years, then probable chronic depression which warrants 
908 
antidepressants or psychotherapy (ask “In the past 2 years have you felt depressed or sad 
909 
most days, even if you felt okay sometimes?”) 
910 
++ If symptoms present ≥ one month or severe functional impairment, consider active treatment 
911 
 
912 
Over the past 2 weeks, how often have 
Not 
Several More Nearly 
you been bothered by any of the 
At all 
Days 
Than 
Half 
Every 
following problems? 
 
 
the 
Days 
Day 
 
913 
1. Little interest or pleasure in doing things 
0 
1 
2 
3 
2. Feeling down, depressed or hopeless 
0 
1 
2 
3 
Trouble falling asleep, staying asleep, or 
sleeping too much 
0 
1 
2 
3 
4. Feeling tired or having little energy 
0 
1 
2 
3 
5. Poor appetite or overeating 
0 
1 
2 
3 
Feeling bad about yourself - or that you’re a 
failure or have let yourself or your family down 
0 
1 
2 
3 
Trouble concentrating on things, such as reading 
the newspaper or watching television 
0 
1 
2 
3 


 Version 12/12/2019 - 55 
 
Moving or speaking so slowly that other people 
could have noticed. Or, the opposite - being so 
fidgety or restless that you have been moving 
around a lot more than usual 
0 
1 
2 
3 
Thoughts that you would be better off dead or 
of hurting yourself in some way 
0 
1 
2 
3 
 
914 
10. If you checked off any problems, how difficult have those problems made it for you to Do 
915 
your work, take care of things at home, or get along with other people? 
916 
Not difficult at all 
917 
Somewhat difficult 
918 
Very difficult 
919 
Extremely difficult 
920 
 
 
921 


 Version 12/12/2019 - 56 
 
Appendix F. Penn State Worry Questionnaire (PSWQ).70 
922 
Each item is scored 1-5, as indicated below. Items 1, 3, 8, 10, and 11 are reversed scored. Total is 
923 
sum of all 16 items. Possible range of scores is 16-80. 
924 
Algorithm 
925 
Total = 16-39 Low Worry 
926 
Total = 40-59 Moderate Worry 
927 
Total = 60-80 High Worry 
928 
 
929 
Instructions: Rate each of the following statements on a scale of 1 (“not at all typical of me”) to 5 
930 
(“very typical of me”). Please do not leave any items blank. 
931 
1 
2 
3 
4 
5 
932 
Not at all typical of me 
Very typical of me 
933 
 
934 
1. 
If I do not have enough time to do everything, I do not worry about it. 
  
 
935 
2. 
My worries overwhelm me. 
936 
3. 
I do not tend to worry about things. 
937 
4. 
Many situations make me worry. 
938 
5. 
I know I should not worry about things, but I just cannot help it. 
  
 
939 
6. 
When I am under pressure I worry a lot. 
  
 
940 
7. 
I am always worrying about something. 
941 
8. 
I find it easy to dismiss worrisome thoughts.   
 
942 
9. 
As soon as I finish one task, I start to worry about everything else I have to do. 
  
 
943 
10. 
I never worry about anything. 
944 
11. 
When there is nothing more I can do about a concern, I do not worry about it anymore. 
  
945 
12. 
I have been a worrier all my life. 
946 
13. 
I notice that I have been worrying about things. 
  
 
947 
14. 
Once I start worrying, I cannot stop. 
948 
15. 
I worry all the time. 
949 
 
 
950 


 Version 12/12/2019 - 57 
 
Appendix G. Meniere’s Disease Patient-Oriented Symptom Index (MDPOSI).71,82 
951 
 
952 
 
953 
 
954 


 Version 12/12/2019 - 58 
 
 
955 


 Version 12/12/2019 - 59 
 
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956 
 
957 
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