Sodium Oxybate in Spasmodic Dysphonia and Voice Tremor

Spasmodic dysphonia (SD), or laryngeal dystonia, is a chronic debilitating condition that
selectively affects speech production due to involuntary spasms in the laryngeal muscles. SD
often extends beyond the impairment of vocal communication causing significant occupational
disability and life-long social isolation. SD becomes even more incapacitating when it is
associated with dystonic voice tremor (VT), which is present in about 1/3 of SD patients and
is characterized by the inability to sustain a vowel for more than a few seconds. Current
treatment of these disorders is limited to the temporary management of voice symptoms with
repeated injections of botulinum toxin into the laryngeal muscles. These injections, however,
are not fully effective in all SD patients and even less so in combined SD and VT cases.
There is, therefore, a critical need to identify alternative therapeutic options that
specifically target the pathophysiology of these disorders. On the other hand, the design and
the use of such novel therapeutic approaches will be largely unattainable if their central
mechanisms of action remain unknown. The objective of this study is to elucidate the primary
determinants of clinical response to a novel oral medication, sodium oxybate (Xyrem®), in
alcohol-responsive SD and VT patients. Using a comprehensive approach of clinico-behavioral
testing, neuroimaging and pharmacogenetics, we aim to determine the clinical response of SD
and VT symptoms to sodium oxybate and identify the primary markers of its clinical benefits.
This study will use a controlled experimental design that focuses on detailed
characterization of primary effects of a novel oral medication, sodium oxybate, for treatment
of SD and VT symptoms.

Inclusion Criteria:

1. Patients with SD and combined SD and VT will have a clinically documented adductor or
abductor form of disorder, either with or without positive effects of alcohol on their
voice symptoms;

2. Patients with vocal fold nodules (VFN) will have clinically documented vocal fold
nodules;

3. Healthy controls will be healthy volunteers with a negative history of laryngeal,
neurological, or psychiatric problems (existing neuroimaging data will be used);

4. Age from 21 to 80 years.

5. Native English speakers.

6. Right-handedness (based on Edinburgh Handedness Inventory).

Exclusion Criteria:

1. Subjects who are incapable of giving an informed consent will be excluded from the
study.

2. Pregnant and breastfeeding women until a time when they are no longer pregnant or
breastfeeding will be excluded from the study. All patients of childbearing potential
will be required to agree to use a reliable method of contraception prior to and
during the study. The method of contraception will be documented in the patient's
research chart. All women of childbearing potential will undergo a urine pregnancy
test, which must be negative for study participation.

3. All patients with a past or present history of the following conditions will be
excluded from the study;

1. Except for SD and dystonic VT, any neurological disorders, such as stroke,
movement disorders, brain tumors, traumatic brain injury with loss of
consciousness, ataxias, myopathies, myasthenia gravis, demyelinating diseases,
alcoholism, drug dependence. Patients with tremor affecting other body parts will
be excluded from the study. All patients who have dystonic movements in the body
regions other than the larynx will be excluded from the study. This will allow
maintaining the homogenous patient population and evaluating central drug effects
without confounding by the presence of other neurological conditions.

2. Any psychiatric problems, such as schizophrenia, major and/or bipolar depression,
obsessive-compulsive disorder, will be excluded to maintain the homogenous
patient population and allow for the evaluation of central drug effect without
confounding by the presence of psychiatric conditions.

3. Except for VFN in the VFN group, any laryngeal problems, such as vocal fold
paralysis, paresis, carcinoma, chronic laryngitis, will be excluded from the
study.

4. Patients with a known past or present history of grade 2 or higher hepatic and
renal dysfunction according to the NCI criteria will be excluded.

5. Patients with a known past or present history of moderate to severe congestive
heart failure will be excluded.

6. Patients with a known past or present history of cognitive impairment and active
suicidal ideations will be excluded.

4. Patients who are not symptomatic due to treatment with botulinum toxin injections into
the laryngeal muscles will be excluded from the study until the time when they are
fully symptomatic. The duration of positive effects of botulinum toxin vary from
patient to patient, lasting on average 3-4 months. All patients will be evaluated to
ensure that they are fully symptomatic prior to the entering the study.

5. To avoid the possibility of confounding effects of drugs acting upon the central
nervous system, all patients will be questioned about any prescribed or
over-the-counter medications as part of their initial intake screening. Those patients
who receive medication(s) affecting the central nervous system (except for sodium
oxybate) will be excluded from the study.

6. Patients will be asked whether they have undergone any head and neck surgeries,
particularly any brain surgery and laryngeal surgeries, such as thyroplasty, laryngeal
denervation, and selective laryngeal adductor denervation-reinnervation. Because both
brain and laryngeal surgery may potentially lead to the brain structure and function
re-organization, all subjects with a history of brain and/or laryngeal surgery will be
excluded from the study.

7. Patients who have tattoos, ferromagnetic objects in their bodies (e.g., implanted
stimulators, surgical clips, prosthesis, artificial heart valve, etc.) that are not
MRI comparable and/or cannot be removed for the purpose of MRI study participation
will be excluded from the study.