Movement Disorders
`Vol. 20, No. 10, 2005, pp. 1330 –1337
`© 2005 Movement Disorder Society
`
`A Pilot Tolerability and Efficacy Trial of Sodium Oxybate in
`Ethanol-Responsive Movement Disorders
`
`Steven J. Frucht, MD,1* Yvette Bordelon, MD, PhD,1 William H. Houghton, MD,2
`and Dayton Reardan, PhD2
`
`1Department of Neurology, Columbia University Medical Center, New York, New York, USA
`2Orphan Medical, Inc., Minnetonka, Minnesota, USA
`
`Abstract: Sodium oxybate is currently approved in the United
`States exclusively for the treatment of cataplexy in narcoleptic
`patients. In a prior article published in this journal, we reported
`a patient with severe posthypoxic myoclonus whose myoclonus
`improved with ethanol and also with treatment with sodium
`oxybate. We extend this preliminary observation to five other
`patients with ethanol-responsive movement disorders in an
`open-label, dose-titration, add-on, 8-week trial. All five patients
`(one with severe alcohol-responsive posthypoxic myoclonus,
`
`two with ⑀-sarcoglycan–linked myoclonus– dystonia, and two
`with essential tremor) experienced improvement from baseline
`of 50% or greater as measured by blinded videotape review.
`Tolerability was satisfactory, with dose-dependent sedation as
`the most common side effect. Further studies of this drug in
`hyperkinetic movement disorders are warranted. © 2005 Move-
`ment Disorder Society
`Key words: myoclonus; tremor; ␥-hydroxybutyric acid; so-
`dium oxybate; Xyrem; ethanol
`
`An unusual and intriguing feature of certain hyperki-
`netic movement disorders is their response to ingestion
`of ethanol. The two hyperkinetic movement disorders
`best known to improve with ethanol are myoclonus–
`dystonia (MD)1 and essential tremor (ET),2 although rare
`patients with progressive myoclonic epilepsy3–5 and
`posthypoxic myoclonus (PHM)6 may also respond.
`However, ethanol is a poor treatment for these disorders
`because of its short duration of action (typically less than
`2 hours), its tendency to produce a rebound of involun-
`tary movements when it wears off, and its effects on
`behavior and mood. Further, patients with hepatic or
`cardiac disease and those with esophagitis or diabetes are
`typically prohibited from drinking at all.
`␥-hydroxybutyric acid was banned in the 1990s by the
`Food and Drug Administration because of serious health
`concerns and concerns regarding its abuse potential. In
`
`*Correspondence to: Dr. Steven J. Frucht, Neurological Institute,
`Columbia University Medical Center, 710 West 168th Street, New
`York, NY 10032. E-mail: sf216@columbia.edu
`Received 7 January 2005; Revised 2 and 16 March 2005; Accepted
`8 April 2005
`Published online 28 June 2005 in Wiley InterScience (www.
`interscience.wiley.com). DOI: 10.1002/mds.20605
`
`its sodium salt form, sodium oxybate, the drug was
`approved in 2002 only for the treatment of cataplexy in
`patients with narcolepsy. Marketed as Xyrem (Orphan
`Medical, Minnetonka, MN), all persons in the United
`States who are prescribed Xyrem must be entered into a
`central registry, the Xyrem Success Program, and close
`follow-up is required. The drug is administered in di-
`vided doses, the first given at bedtime, followed several
`hours later during the night by the second dose.7 In
`Europe, it has also been used to treat ethanol withdraw-
`al8,9 and to maintain alcohol abstinence in chronic alco-
`holics.10,11
`In 2000, Priori and colleagues12 reported a patient
`with ethanol-responsive MD whose myoclonus im-
`proved with daytime treatment with sodium oxybate.
`We subsequently performed an open-label blinded-
`rating tolerability and efficacy trial of Xyrem (hereaf-
`ter referred to as sodium oxybate) in a single patient
`afflicted with severe ethanol-responsive PHM.13 This
`patient continues to take the drug, and she and her
`family feel that it has improved her quality of life. The
`present trial was designed to address two principal
`questions: would treatment with sodium oxybate im-
`prove myoclonus and/or tremor in patients with etha-
`
`1330
`
`AMN1028
`IPR of Patent No. 8,772,306
`
`

`
`SODIUM OXYBATE
`
`1331
`
`nol-responsive movement disorders, and would pa-
`tients be able to tolerate daytime dosing?
`
`PATIENTS AND METHODS
`The senior author (S.J.F.) enrolled five patients in this
`trial from the Movement Disorders Division of Columbia
`University Medical Center during the fall of 2004. All
`patients were afflicted with hyperkinetic movement dis-
`orders that responded to ethanol (defined as a noticeable
`change to the patient), and all were refractory to treat-
`ment with conventional medications or could not tolerate
`them. The medical center’s institutional review board
`approved the trial, and written and verbal informed con-
`sent were obtained from all patients prior to enrollment.
`Salient clinical features appear below and are summa-
`rized in Table 1.
`
`Patient 1
`A 37-year-old woman with a history of asthma suf-
`fered a cardiopulmonary arrest after a drug overdose at
`age 31, emerging from coma with severe PHM. On
`initial evaluation at our center at age 33, action and
`intention myoclonus were severe, with prominent vocal
`myoclonus and disabling negative myoclonic jerks of the
`trunk and legs. Her mother noted that ingestion of two
`glasses of wine noticeably improved her myoclonus,
`allowing her to assist in daily hygiene activities. Nine
`months prior to enrollment she sustained a subcortical
`infarct during a hospitalization for pneumonia, leaving
`her with a residual left hemiparesis.
`
`Patient 2
`A 25-year-old man presented to our medical center for
`evaluation of a 7-year history of myoclonic jerks. His
`family history was notable for a paternal grandmother
`with torticollis and two paternal first cousins with my-
`
`the patient
`oclonus, all ethanol-responsive; however,
`never consumed ethanol. Genetic testing revealed a mu-
`tation in the ⑀-sarcoglycan gene,14 confirming the diag-
`nosis of MD. Prominent proximal myoclonic jerks of the
`head, neck, and arms were triggered by voluntary actions
`such as pouring or writing.
`
`Patient 3
`A 20-year-old man presented at age 11 to our center
`for initial evaluation of myoclonus that began at age
`2.5 in his right foot. Myoclonic jerks of the trunk and
`proximal arms interfered with writing, pouring, and
`using utensils. At age 17, he developed obsessive–
`compulsive symptoms that were successfully treated
`with paroxetine. Genetic testing revealed a mutation in
`the ⑀-sarcoglycan gene, confirming the diagnosis of
`MD.14 On several occasions, he consumed ethanol,
`observing a dose-dependent improvement in myoclo-
`nus (requiring 80 gm of ethanol to reach maximal
`improvement).
`
`Patient 4
`A 67-year-old man with a family history of ET devel-
`oped mild kinetic tremor of his hands in high school.
`Tremor progressively affected his ability to eat with
`utensils, hold a cup, and write. His tremor was exquis-
`itely alcohol-responsive with moderate tremor relief 15
`min after ingestion of one glass of wine and near-com-
`plete tremor relief from two glasses. He chose not to take
`daily medication for his ET. Three years prior to enroll-
`ment, he developed cervical dystonia that also responded
`to ethanol and began receiving botulinum toxin injec-
`tions. The last injection was performed 7 weeks prior to
`enrollment.
`
`TABLE 1. Clinical features of patients with ethanol-responsive movement disorders
`
`Patient no.
`
`1
`
`2
`
`3
`
`4
`5
`
`M/F
`
`F
`
`Age
`
`37
`
`M
`
`M
`
`M
`M
`
`25
`
`20
`
`67
`75
`
`Diagnosis
`
`Time (yr)
`
`Current Rx
`
`Past Rx
`
`PHM
`
`MD
`
`MD
`
`ET
`ET
`
`6
`
`7
`
`17.5
`
`50
`13
`
`Levetiracetam 2,500 mg;
`clonazepam 6 mg;
`phenobarbital 60 mg;
`alprazolam 0.5 mg;
`rabeprazole 20 mg;
`baclofen 20 mg
`Levetiracetam 500 mg;
`diazepam 15 mg
`Paroxitene 20 mg;
`clonazepam 2 mg
`
`None
`Levetiracetam 1,000 mg
`
`Valproic acid; tizanidine; primidone;
`gabapentin; paroxetine; piracetam
`
`Trihexiphenidyl; clonazepam;
`primidone
`Trihexiphenidyl;
`L-5-hydroxytryptophan; valproic
`acid; baclofen; levetiracetam
`Propranolol
`Primidone
`
`Time, duration of symptoms in years on enrollment in the trial; current Rx, current medications during the trial; past Rx, past medication exposures;
`PHM, posthypoxic myoclonus; MD, myoclonus– dystonia; ET, essential tremor.
`
`Movement Disorders, Vol. 20, No. 10, 2005
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`AMN1028
`IPR of Patent No. 8,772,306
`
`

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`1332
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`S.J. FRUCHT ET AL.
`
`Patient no.
`
`Mild side effect
`
`1
`
`2
`
`3
`
`4
`
`5
`
`HA (3 gm)
`
`HA (1 gm); dizzy
`(1 gm)
`HA (1 gm); dizzy
`(2 gm)
`
`TABLE 2. Tolerability and dose regimens of Xyrem
`
`Serious side
`effect
`
`Asthma
`
`Dose-limiting side
`effect
`
`Sedation and mild
`disinhibition
`Mild sedation and
`emotional lability
`
`Slight sedation
`
`Slight sedation and
`emotional lability
`Slight sedation
`
`Dose at
`dose-limiting
`side effect
`
`3 gm
`
`3 gm
`
`4 gm
`
`2 gm
`
`2 gm
`
`Maximum
`trial dose
`
`Final regimen
`
`2.5 gm BID
`
`2 gm t.i.d.
`
`2.5 gm BID
`
`3.5 gm BID
`
`2.5 gm q AM;
`2.5 gm q PM;
`2.5 gm q.h.s.
`3.5 gm b.i.d.
`
`1.5 gm BID
`
`1.5 gm b.i.d.
`
`1.5 gm BID
`
`1.5 gm b.i.d.
`
`Serious side effect causes illness leading to hospitalization.
`
`Patient 5
`A 75-year-old retired general surgeon developed a
`kinetic tremor of his hands at age 62, forcing him to
`retire. Action tremor of the hands became progressively
`severe, causing social embarrassment when eating in
`public. Because of severe chronic obstructive pulmonary
`disease, treatment with propranolol was contraindicated,
`and primidone was too sedating. He was not currently
`taking any medications for his pulmonary disease that
`might worsen his tremor. He drank one or two glasses of
`wine on social occasions, with mild improvement in his
`tremor.
`
`Clinical Trial Design
`The dose and timing of all other drugs were kept
`constant throughout the trial, and patients were not with-
`drawn from other medications. Patients 1–3 were exam-
`ined and videotaped using the Unified Myoclonus Rating
`Scale15 (UMRS), and Patients 4 and 5 were examined
`and videotaped using the Washington Heights Inwood
`Genetic Essential Tremor Rating Scale16 (WHIGET; see
`Appendixes I and II).
`Side effects were defined as either minor or serious
`(leading to hospitalization) using good clinical prac-
`tice standards (www.who.int/medicines/library/par/ggcp/
`GCPGuidePharmatrials), and patients were asked to re-
`port side effects at each visit. After initial examination
`
`and videotaping, patients were given 1 gm of sodium
`oxybate by mouth (2 ml of the standard 0.5 gm/ml
`solution dissolved in 60 ml of water). One hour later, the
`senior author repeated the examination and videotaping.
`Patients were maintained on a dose of 1 gm twice per day
`(taken 4 –5 hr apart, typically after breakfast and lunch)
`until their next office visit 2 weeks later, when the
`examination and videotaping were repeated 1 hr after
`receiving 2 gm of sodium oxybate by mouth (4 ml of 0.5
`gm/ml solution dissolved in 60 ml of water). After 2
`weeks taking 2 gm twice daily, the procedure was re-
`peated after a 3 gm office dose; finally, 2 weeks after
`receiving 3 gm twice daily, the procedure was repeated
`after a 4 gm office dose. The maximum dose allowed in
`the trial was 4 gm twice daily. Patients and the senior
`author determined at each visit whether or not to proceed
`to the next dose level, based principally on their ability to
`tolerate the most recent dose regimen. After deciding on
`a maximum tolerated dose, patients received a dose in
`the office 0.5 gm less and the examination was video-
`taped.
`
`Methods and Data Analysis
`The senior author copied the entire videotape seg-
`ments and patient writing samples from each visit,
`blinded them to trial order and identifying features, and
`randomly ordered them for review using a random-num-
`
`TABLE 3. UMRS subscores for Patient 1
`
`UMRS section
`
`Score range
`
`0 gm
`
`1
`2
`3
`4
`5
`6
`
`NM, not measured.
`
`0–44
`0–128
`0–17
`0–160
`0–20
`0–4
`
`33
`3
`8
`108
`20
`4
`
`Movement Disorders, Vol. 20, No. 10, 2005
`
`1 gm
`
`NM
`3
`3
`96
`20
`3
`
`2 gm
`
`NM
`0
`1
`64
`13
`3
`
`3 gm
`
`2.5 gm
`
`Drug effect
`
`31
`3
`3
`86
`15
`3
`
`NM
`0
`2
`54
`12
`2
`
`50%
`40%
`
`AMN1028
`IPR of Patent No. 8,772,306
`
`

`
`SODIUM OXYBATE
`
`1333
`
`TABLE 4. UMRS subscores for Patient 2
`
`UMRS section
`
`Score range
`
`0 gm
`
`1
`2
`3
`4
`5
`6
`
`0–44
`0–128
`0–17
`0–160
`0–28
`0–4
`
`5
`4
`4
`25
`10
`1
`
`1 gm
`
`NM
`2
`2
`29
`8
`1
`
`2 gm
`
`NM
`3
`2
`9
`4
`1
`
`3 gm
`
`NM
`0
`0
`11
`5
`1
`
`2.5 gm
`
`Drug effect
`
`0
`0
`0
`3
`4
`1
`
`88%
`60%
`
`ber table. A movement disorder expert (Y.B.) blinded to
`trial design and dose schedule scored each videotape.
`Subscores for each visit were calculated as described
`previously.15 We modified section 5 of the UMRS in
`which functional performance (pouring water, using a
`soup spoon) is performed only with the dominant arm
`(section 5). In this modification, these tasks were video-
`taped while being performed with both arms, because
`myoclonic jerks were significantly worse in the non-
`dominant left arm in Patients 2 and 3. This increased the
`maximum score of section 5 of the UMRS from 20 to 28.
`
`RESULTS
`
`Tolerability
`Transient headache and dizziness were common and
`did not require dose reduction (Table 2). All patients
`experienced dose-limiting sedation or emotional lability;
`however, the dose at which this occurred varied from 2 to
`4 gm between patients. These side effects resolved for
`each patient when the individual dose was reduced by 0.5
`gm.
`One serious adverse event occurred during the trial.
`Patient 1 developed an upper respiratory infection that
`triggered an asthma exacerbation, requiring treatment
`with oral antibiotics, prednisone, and frequent broncho-
`dilator inhalers. As similar events had occurred in the
`past, the senior author judged that this event was not
`likely related to the study drug and she was continued in
`the trial. Myoclonus visibly worsened during her asthma
`exacerbation (her third office visit, at which time she
`received 3 gm of sodium oxybate), but by the next visit
`the respiratory infection had resolved, steroids and anti-
`
`biotics had been discontinued, and myoclonus had im-
`proved.
`
`Clinical Course
`Improvement in involuntary movements was dose-
`dependent and could be observed in the office by the
`patient and senior author within 30 to 45 min after
`receiving each dose. The duration of benefit was 3.5 to 4
`hr; as patients titrated to higher doses, they became
`aware when the dose would wear off. Patients described
`the benefit of treatment as similar to the effect of ethanol.
`Dose-limiting sedation roughly correlated with the max-
`imum amount of ethanol that patients could tolerate. We
`did not observe a waning of effectiveness of the drug
`during the course of the trial. All five patients decided to
`continue taking the drug after completing the trial; due to
`the 4-hr duration of action, dosing schedules were ad-
`justed for Patients 1 and 2.
`
`Blinded Rating of Efficacy
`
`Myoclonus Patients 1–3.
`In the three myoclonus patients, myoclonus at rest
`(section 2 of the UMRS) and stimulus-sensitive myo-
`clonus (section 3) improved in dose-dependent fashion
`(Tables 3–5). Action myoclonus (section 4) improved by
`50%, 57%, and 88%, respectively, while functional per-
`formance (section 5) improved by 40%, 60%, and 25%
`(see Video, Segments 1–3). Patient self-assessment
`scores improved for Patients 2 and 3 and were un-
`changed for Patient 1. Physician global assessment
`scores (UMRS part 6) were mild (1 out of 4) for Patients
`2 and 3 and remained unchanged throughout the trial,
`
`TABLE 5. UMRS subscores for Patient 3
`
`UMRS section
`
`Score range
`
`0 gm
`
`1
`2
`3
`4
`5
`6
`
`0–44
`0–128
`0–17
`0–160
`0–28
`0–4
`
`10
`15
`6
`35
`12
`1
`
`1 gm
`
`NM
`13
`2
`25
`13
`1
`
`2 gm
`
`4 gm
`
`Drug effect
`
`7
`15
`3
`26
`9
`1
`
`5
`10
`1
`15
`12
`1
`
`57%
`25%
`
`Movement Disorders, Vol. 20, No. 10, 2005
`
`AMN1028
`IPR of Patent No. 8,772,306
`
`

`
`1334
`
`S.J. FRUCHT ET AL.
`
`TABLE 6. WHIGET subscores for Patient 4
`
`WHIGET section
`
`Score range
`
`Total sustention
`Total action
`
`0–6
`0–40
`
`0 gm
`
`2.5
`19.5
`
`1 gm
`
`0.5
`10
`
`2 gm
`
`0
`5
`
`1.5 gm
`
`0.5
`4
`
`Drug effect
`
`79%
`
`while scores decreased from severe disability (4) to mod-
`erate impairment (2) in Patient 1.
`
`Essential Tremor Scores (Patients 4 and 5).
`Blinded videotape review revealed dose-dependent
`improvement in sustention tremor and action tremor (Ta-
`bles 6 and 7) of 79% in Patient 4 and 48% in Patient 5
`(see Video, Segments 4 and 5). Scores for rest tremor
`were not calculated, as rest tremor was absent in one
`patient and mild in the other. Blinded rating of the
`severity of torticollis in Patient 4 decreased from mod-
`erate to mild at the 1 gm twice-daily dose.
`
`DISCUSSION
`In this open-label
`trial, sodium oxybate produced
`dose-dependent improvements in blinded ratings of eth-
`anol-responsive myoclonus and tremor. The drug was
`tolerated at doses that produced clinical benefit. The
`most common side effect was sedation, which was also
`dose-dependent; however, the dose that produced clinical
`benefit was lower than the sedation-limiting dose.
`While these results are promising, we urge movement
`disorder specialists who might read this report and want
`to use the drug in their patients to exercise extreme
`caution. Xyrem (Orphan Medical) is currently approved
`in the United States only for treatment of cataplexy in
`narcoleptic patients. All patients who receive Xyrem
`must be enrolled in the Xyrem Success Program, a cen-
`tral registry that monitors and distributes the drug.17 The
`Xyrem Success Program has ensured appropriate and
`safe use of the drug with no incidents of diversion or
`inappropriate use.18 Sodium oxybate should not be used
`in patients with movement disorders outside of a proto-
`col approved by a medical center’s institutional review
`board. These protocols should include videotaped exam-
`inations or placebo-controlled designs using validated
`clinical rating scales. Patient selection is critical, and
`patients with a history of active substance abuse, poor
`compliance, or major depression should be excluded
`from participation. This is of particular concern in MD
`
`patients, in whom there is an increased risk of ethanol
`abuse, and also in patients with intractable hyperkinetic
`movement disorders, who might adjust their dosing reg-
`imens in a search for therapeutic benefit.
`The mechanism of sodium oxybate’s antimyoclonic
`and antitremor activity remains unknown. ␥-hydroxybu-
`tyric acid (GHB) occurs naturally in the brain and is
`formed through metabolism of its precursor, ␥-aminobu-
`tyric acid (GABA).19 The GHB receptor is distinct from
`the GABA-B receptor20; when given as a drug, it is likely
`that some GHB is converted to GABA.19 Sodium oxy-
`bate may act via the GABA-B receptor either directly or
`via conversion to GABA.21 However, GABA-B agonists
`such as baclofen do not improve ET or myoclonus, and
`clonazepam has minimal effect on ET, suggesting that
`other mechanisms may be involved.
`Because our trial was open-label, placebo effect limits
`broader application of the data to other patients and also
`likely contributed to the perception of benefit by Patients
`1–3 (section 1 of the UMRS). However, some lessons
`may be learned from our experience. Patient 1 is similar
`to our prior patient with ethanol-responsive PHM.13
`Prominent stimulus-sensitive proximal jerks and postural
`negative myoclonus suggests a pattern consistent with
`reticular reflex myoclonus in both cases.22 Reticular re-
`flex PHM is sufficiently rare that a double-blind placebo-
`controlled trial of sodium oxybate in this patient popu-
`lation may not be feasible. It therefore seems reasonable
`to consider a test dose of ethanol in these patients if
`standard antimyoclonic drugs fail. Patients who respond
`to ethanol might also benefit from treatment with sodium
`oxybate. Myoclonus also improved in our two patients
`with MD, a finding similar to the observation of Priori
`and colleagues.12 However, given the risk of ethanol
`abuse in the MD population, the long-term tolerability of
`sodium oxybate must be established before it can be
`recommended as a treatment for MD patients.
`Present treatments for ET include primidone,23 pro-
`pranolol,24 gabapentin,25 levetiracetam,26 topiramate,27
`
`TABLE 7. WHIGET subscores for Patient 5
`
`WHIGET section
`
`Score range
`
`Total sustention
`Total action
`
`0–6
`0–11
`
`0 gm
`
`4
`23
`
`1 gm
`
`3
`19
`
`2 gm
`
`3
`12
`
`1.5 gm
`
`2.5
`13.5
`
`Drug effect
`
`48%
`
`Movement Disorders, Vol. 20, No. 10, 2005
`
`AMN1028
`IPR of Patent No. 8,772,306
`
`

`
`SODIUM OXYBATE
`
`1335
`
`and 1-octanol.28 Deep brain stimulation (DBS) of the
`ventrointermediate thalamus is currently the most reli-
`able technique for producing immediate relief of appen-
`dicular tremor.29 Bilateral stimulation is typically re-
`quired for head tremor30 and voice tremor,31 and the
`unavoidable but small operative risks of DBS32 and the
`possibility of delayed lead failure or infection33 are a
`concern. It remains to be seen whether other ET patients
`will respond to sodium oxybate.
`Many other questions remain unanswered as well. Will
`patients with other ethanol-responsive movement disorders
`also improve with treatment? Will movement disorders that
`do not benefit from ethanol (for example, half of all patients
`with ET) benefit from treatment? If not, might response to
`the drug reveal potential differences in pathogenesis be-
`tween responsive and nonresponsive patients? Double-
`blind placebo-controlled multicenter trials are currently
`planned to help address these issues.
`
`Conclusion
`In an open-label pilot tolerability and efficacy study of
`five patients with ethanol-responsive movement disorders,
`we have shown that sodium oxybate improved myoclonus
`and tremor and that patients were able to tolerate daytime
`dosing of the drug. Further studies of this agent in patients
`with hyperkinetic movement disorders are warranted.
`
`LEGENDS TO THE VIDEO
`Segments from videos before and during treatment
`have been edited from complete examinations in order to
`illustrate the change with treatment.
`Segment 1. Severe action myoclonus prevents Patient
`1 from putting pen to paper or targeting a spoon to a cup.
`One hour after receiving 2.5 gm of sodium oxybate, she
`can write (although slowly) and her control of the spoon
`is improved.
`Segment 2. Writing, pouring, or using a spoon in
`Patient 2 triggers proximal and axial flurries of myoclo-
`nus. After receiving 3 gm of sodium oxybate, the ampli-
`tude and frequency of the jerks are diminished and the
`movements are more fluid.
`Segment 3. Walking triggers myoclonic jerks of the
`right leg in Patient 3, and violent proximal and truncal
`myoclonus activate with writing and pouring. After re-
`ceiving 4 gm of sodium oxybate, his walking is modestly
`improved. Although his functional performance scores
`(section 5 of the UMRS) were unchanged by blinded
`review, writing and pouring appear modestly improved.
`Segment 4. Patient 4⬘s examination before treatment
`reveals a classic kinetic tremor with writing, using a
`spoon, and drinking. After 2 gm of sodium oxybate,
`tremor amplitude is markedly diminished.
`
`Segment 5. Patient 5⬘s kinetic tremor on pouring,
`using a spoon, and drinking was more severe. Although
`still present after receiving 2 gm of sodium oxybate, the
`amplitude has diminished and voluntary movements are
`more fluid.
`
`Acknowledgments: We thank the patients and their families
`for their participation, the manuscript reviewers for their care-
`ful critique, and Drs. Elan Louis and William Riggs for their
`comments. Drs. Paul E Greene and Pietro Mazzoni helped care
`for the patients, and Dr. Laurie Ozelius performed the genetic
`testing for ⑀-sarcoglycan mutations. Dr. Frucht also expresses
`his gratitude to Norman and Barbara Seiden, Theodora Mason,
`and the Myoclonus Research Foundation for their generous
`support.
`
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`APPENDIX I: MODIFIED UMRS SCORE SHEET
`
`Sections 1– 6 of the UMRS are shown. Full details regarding the scale can be found in Louis and colleagues.16 Higher scores indicate more severe
`involuntary movements. The range for each section appears in braces.
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`APPENDIX II: MODIFIED WHIGET SCORE SHEET
`
`Higher scores indicate more severe tremor. The range for total sustention scores is 0 – 6; for total action tremor, 0 – 40. (Full details of the WHIGET
`can be found online at http://www.who.int/medicines/library/par/ggcp/GCPGuidePharmatrials).
`
`Movement Disorders, Vol. 20, No. 10, 2005
`
`AMN1028
`IPR of Patent No. 8,772,306