However, not everyone in Australia knows that drugs for potency viagra australia provide not just a temporary result, but also actually help rid the body of symptoms.
Neurorehab.nl2Practice Parameter: Therapies for essential tremor: Report of the Quality
Standards Subcommittee of the American Academy of Neurology
T. A. Zesiewicz, R. Elble, E. D. Louis, R. A. Hauser, K. L. Sullivan, R. B. Dewey, Jr, W. G. Ondo, G. S. Gronseth and W. J. Weiner 2005;64;2008-2020; originally published online Jun 22, 2005; DOI: 10.1212/01.WNL.0000163769.28552.CD This information is current as of January 23, 2007
The online version of this article, along with updated information and services, is located on the World Wide Web at: Neurology is the official journal of AAN Enterprises, Inc. A bi-monthly publication, it has beenpublished continuously since 1951. Copyright 2005 by AAN Enterprises, Inc. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Therapies for essential tremor
Report of the Quality Standards Subcommittee of the
American Academy of Neurology
T.A. Zesiewicz, MD; R. Elble, MD, PhD, FAAN; E.D. Louis, MD, MS, FAAN; R.A. Hauser, MD, MBA, FAAN; K.L. Sullivan, MSPH; R.B. Dewey, Jr., MD, FAAN; W.G. Ondo, MD; G.S. Gronseth, MD; and W.J. Weiner, MD, FAAN Abstract—Background: Essential tremor (ET) is one of the most common tremor disorders in adults and is characterized
by kinetic and postural tremor. To develop this practice parameter, the authors reviewed available evidence regarding
initiation of pharmacologic and surgical therapies, duration of their effect, their relative benefits and risks, and the
strength of evidence supporting their use. Methods: A literature review using MEDLINE, EMBASE, Science Citation
Index, and CINAHL was performed to identify clinical trials in patients with ET published between 1966 and August
2004. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based on the
level of evidence. Results and Conclusions: Propranolol and primidone reduce limb tremor (Level A). Alprazolam, atenolol,
gabapentin (monotherapy), sotalol, and topiramate are probably effective in reducing limb tremor (Level B). Limited
studies suggest that propranolol reduces head tremor (Level B). Clonazepam, clozapine, nadolol, and nimodipine possibly
reduce limb tremor (Level C). Botulinum toxin A may reduce hand tremor but is associated with dose-dependent hand
weakness (Level C). Botulinum toxin A may reduce head tremor (Level C) and voice tremor (Level C), but breathiness,
hoarseness, and swallowing difficulties may occur in the treatment of voice tremor. Chronic deep brain stimulation (DBS)
(Level C) and thalamotomy (Level C) are highly efficacious in reducing tremor. Each procedure carries a small risk of
major complications. Some adverse events from DBS may resolve with time or with adjustment of stimulator settings.
There is insufficient evidence regarding the surgical treatment of head and voice tremor and the use of gamma knife
thalamotomy (Level U). Additional prospective, double-blind, placebo-controlled trials are needed to better determine the
efficacy and side effects of pharmacologic and surgical treatments of ET.
NEUROLOGY 2005;64:2008 –2020 Background and justification.
condition because of the perception that it does not (ET) is a common adult tremor disorder, with preva- reduce life expectancy or cause symptoms besides lence estimates from population studies ranging tremor and impaired tandem walking. However, ET from 0.4% to 5%.1,2 The incidence and prevalence of may cause substantial physical and psychosocial dis- ET increase with advancing age.2 ability,5 and it is unclear whether ET is associated with ET is characterized by the presence of postural additional comorbid symptoms.6 Tremor amplitude and kinetic tremor.3 In classic ET, upper limbs gradually increases over time, and patients frequently (ⵑ95% of patients) and less commonly the head experience increasing difficulty with writing, drinking, (ⵑ34%), lower limbs (ⵑ30%), voice (ⵑ12%), tongue eating, dressing, speaking, and other fine motor tasks.5 (ⵑ7%), face (ⵑ5%), and trunk (ⵑ5%) exhibit a postural ET is a clinical diagnosis. Criteria for definite and or kinetic tremor.4 ET has been referred to as a benign probable ET include abnormal bilateral postural or ki- From the Department of Neurology and Parkinson's Disease and Movement Disorders Center (Drs. Zesiewicz and Hauser, and K.L. Sullivan), University ofSouth Florida, Tampa; Department of Neurology (Dr. Elble), Southern Illinois University School of Medicine, Springfield; GH Sergievsky Center andDepartment of Neurology (Dr. Louis), College of Physicians and Surgeons, Columbia University, New York, NY; University of Texas Southwestern MedicalCenter (Dr. Dewey), Dallas; Department of Neurology (Dr. Ondo), Baylor College of Medicine, Houston, TX; Department of Neurology (Dr. Gronseth),University of Kansas Medical Center, Kansas City; and Department of Neurology (Dr. Weiner), University of Maryland School of Medicine, Baltimore.
Approved by the Quality Standards Subcommittee on July 24, 2004; by the Practice Committee on January 29, 2005; and by the AAN Board of Directors onFebruary 26, 2005.
Received October 7, 2004. Accepted in final form March 7, 2005.
Address correspondence and reprint requests to the American Academy of Neurology, 1080 Montreal Avenue, St. Paul, MN 55116.
Copyright 2005 by AAN Enterprises, Inc.
netic tremor of the hands in the absence of other neu- lol, primidone, propranolol, propranolol long-acting, rologic signs. Many clinicians accept isolated tremor of quetiapine, research design, sotalol, stereotactic sur- the head if there is no evidence of dystonia.3 gery, thalamotomy, theophylline, therapy, topira- Propranolol and primidone are commonly used to treat ET, although propranolol is the only medication stimulation. Articles dedicated to dystonia, dystonic that is approved by the Food and Drug Administration tremor, myoclonus, cerebellar tremor, "atypical (FDA) for this purpose. It is estimated that at least tremor," Parkinson disease (PD), parkinsonism, or- 30% of patients with ET will not respond to propranolol thostatic tremor, palatal tremor, primary writing or primidone.7 Alcohol reduces tremor amplitude in 50 tremor, animal models of ET, pathophysiology, ge- to 90% of cases,8-10 but tremor may temporarily worsen netics, epidemiology, cognitive dysfunction, quality after the effect of alcohol has worn off.11 Invasive ther- of life, social phobia, and neuropsychiatric testing in apies including surgical procedures may provide clini- ET were excluded from the review.
cal benefit in cases of refractory tremor.
Pharmacologic treatment for The Quality Standards Sub- What are the safety, tolerability, and efficacy committee (QSS) of the American Academy of Neu- of pharmacologic agents in treating ET? Which drug should be used for initial treatment of ET? Is com- parameters for physicians and neurologists by pro- bined treatment with primidone and propranolol bet- viding specific recommendations for clinical decisions ter than monotherapy? Is there evidence for based on analysis of evidence. The selection of topics sustained benefit of pharmacologic treatment of ET? for which practice parameters are used is based on Do patients with ET benefit from chemodenervation prevalence, frequency of use, economic impact, mem- with botulinum toxin type A or B? bership involvement, controversy, urgency, external Surgical treatment for ET. What is the efficacy of constraints, and resources required.
thalamotomy in treating contralateral limb tremorin patients with ET? What is the efficacy of deep Panel selection and literature review process.
brain stimulation (DBS) of the thalamus in treating Neurologists with expertise in ET were invited by tremor in patients with refractory ET? Should the QSS to perform the review. Computer-assisted thalamotomy or DBS of the thalamus be the proce- literature searches were conducted for relevant En- dure of choice in patients with medically refractory glish language articles pertinent to ET and for med- ET? What are the indications for bilateral versus ications that are available in the United States.
unilateral surgical procedures in ET? Databases searched include MEDLINE, EMBASE,Science Citation Index, and CINAHL between 1966 Analysis of the evidence: Pharmacologic treat-
and 2004. A total of 502 articles pertaining to treat- ment of ET.
1. What are the safety, tolerability, ment and management of ET were published be- and efficacy of pharmacologic agents in treating tween 1966 and August 2004, and all search titles 1A. Pharmacologic agents with Level A recom- and abstracts were analyzed for content and rele- vance by individual committee members. Articles a nonselective beta-adrenergic receptor antagonist.
were accepted for further review if they consisted of Twelve class I studies found that propranolol was double-blind controlled trials, open-label studies, efficacious in treating limb tremor in ET, and tremor case series, and case reports. There were 211 articles magnitude as measured by accelerometry was re- that were accepted for further review. Each of these duced by approximately 50% (see table 1). Nine of articles was classified by two panel members using a the class I studies reported a mean dose of propran- four-tiered classification scheme that was developed olol of 185.2 mg/day. Although the remaining three and approved by the QSS (Appendix 1). Analysis of studies did not report a mean dose, the dose range for evidence is summarized in tables 1 and 2.
all studies was 60 to 320 mg/day. Side effects occurred The following key words and phrases were used in in 12% to 66% of patients and included lightheaded- the initial search and were paired with the term ness, fatigue, impotence, and bradycardia.
"essential tremor." Both brand and generic names Contrary to earlier recommendations, propranolol were used in the searches (generic names are listed may be used in patients with stable heart failure due here only): acetazolamide, alprazolam, amantadine, to left ventricular systolic dysfunction, unless there are aminophylline, antiepileptics, arotinolol, atenolol, clear contraindications to its use, such as unstable atypical neuroleptics, B-adrenergic blockers, benzo- heart failure.12 It is recommended that physicians who diazepines, botulinum toxin A, botulinum toxin B, are considering treating cardiac patients with propran- calcium channel blockers, carbonic anhydrase inhib- olol follow the recommendations of the American Jour- itors, chemodenervation, clinical trials, clonazepam, nal of Cardiology consensus statement (or the clonidine, clozapine, deep brain stimulation (DBS), equivalent) for the complete indications and contrain- gabapentin, gamma knife surgery, glutethimide, dications of its use,12 or consult with a cardiologist.
hypnotics, isoniazid, management, methazolamide, Propranolol LA (Inderal LA). metoprolol, mirtazapine, nadolol, nicardipine, nifedi- available as a long-acting (LA), once daily prepara- pine, nimodipine, olanzapine, phenobarbital, pindo- tion. One class I13 and one class II14 study found that June (2 of 2) 2005
Table 1 Oral pharmacologic agents in the treatment of essential tremor
Adverse events severity* Magnitude of effect Mild-moderate (sedation, drowsiness, 50% Mean improvement by CRS and fatigue, nausea, giddiness, vomiting, ataxia, malaise,dizziness, unsteadiness, confusion,vertigo, acute toxic reaction) Propranolol (Inderal) Mild to moderate (reduced arterial 50% Mean improvement by CRS and pressure, reduced pulse rate, tachycardia, bradycardia,impotency, drowsiness, exertionaldyspnea, confusion, headache,dizziness) Mild (skin eruption, transient 30–38% Improvement by Alprazolam (Xanax) Mild (fatigue, sedation; potential for 25–34% Mean improvement in CRS compared to baseline Atenolol (Tenormin) 25% Mean improvement by CRS and nausea, cough, dry mouth, 37% Mean improvement by accelerometry compared tobaseline Mild (lethargy, fatigue, decreased 77% Improvement by accelerometry libido, dizziness, nervousness, shortness of breath) 33% Improvement by CRS compared Sotalol (Sotacor) Mild (decreased alertness) 28% Mean improvement by CRS compared to baseline Mild (appetite suppression, weight 22–37% Mean improvement in CRS loss, paresthesias, anorexia, compared to baseline Mild-moderate drowsiness 71% Mean improvement by accelerometry and 26–57%improvement in CRS compared tobaseline Clozapine (Clozaril) Mild (sedation); Severe (potential 45% Mean improvement by Nadolol (Corgard) 60 to 70% Improvement by accelerometry in patients who hadpreviously responded topropranolol Mild (headache, heartburn) 53% Improvement by accelerometry 45% Improvement in CRS compared Botulinum toxin A in the treatment of essential tremor Botulinum toxin A Moderate (hand and finger 20% Improvement in CRS for low weakness, reduced grip strength, and high-dose BTX for postural pain at injection site, stiffness, tremor at 6, 12, and 16 weeks, and cramping, hematoma, 27% improvement in kinetic tremor at 6 weeks (only significantscores listed) Botulinum toxin A Mild-moderate (neck weakness, post- 67% Improvement by accelerometry, Moderate to Marked improvement by CRS, but did not differ fromplacebo Botulinum toxin A Mild-moderate (breathiness, weak 22% Improvement with unilateral voice, swallowing difficulty) 30% with bilateral injection,67% Improvement in self-report * Adverse events severity: mild ⫽ somewhat bothersome; moderate ⫽ very bothersome; severe ⫽ potentially harmful to patients.
CRS ⫽ Clinical Rating Scale.
propranolol LA provides effective tremor suppression articles that examined the efficacy of primidone in in ET. In these studies, propranolol LA provided the treating ET (n ⫽ 218). Four class I studies found same therapeutic response as conventional propran- that primidone effectively reduced limb tremor in olol. Eighty-seven percent of patients in one study ET, using doses from 50 to 1,000 mg/day. Only three preferred propranolol LA to propranolol for ease of studies provided mean doses of primidone, which av- eraged 481.7 mg/day. The mean reduction in tremor Primidone is an anticon- magnitude by accelerometry was approximately vulsant that is metabolized to phenylethylma- 50%. Primidone was associated with a moderate to lonamide (PEMA) and phenobarbital. There were 12 high frequency of adverse events that were more se- June (2 of 2) 2005
Table 2 Nonpharmacologic agents in the treatment of essential tremor
Adverse events severity* Magnitude of effect Chronic thalamic DBS Mild to severe (dysarthria, dysequilibrium, 60% to 90% Improvement paresthesias, weakness, headache, intracranial hemorrhage, subdural hemorrhage, leaddislodgement, ischemic changes, generalizedmotor seizures, decreased verbal fluency) Mild to severe (hemiparesis, transient problems 55% to 90% Improvement with speech and motor function, dysarthria, verbal or cognitive deficit, weakness, confusion,somnolence, facial paresis) Gamma knife surgery Mild to severe (transient arm weakness, numbness 70% to 85% Improvement in the contralateral arm, dysarthria, increased action tremor, dystonia of the contralateralupper and lower limbs, choreoathetosis); casereport documented delayed side effects Chronic thalamic DBS Mild to severe (dysarthria, dysequilibrium, paresthesias, weakness, headache, weakness,intracranial hemorrhage, subdural hemorrhage,microthalamotomy effect, lead dislodgement, is-chemic changes, generalized motor seizures,decreased verbal fluency) Chronic thalamic DBS Mild to severe (dysarthria, dysequilibrium, paresthesias, weakness, headache, weakness,intracranial hemorrhage, subdural hemorrhage,microthalamotomy effect, lead dislodgement, is-chemic changes, generalized motor seizures,decreased verbal fluency) Unilateral vs bilateral More frequent side effects with bilateral surgery * Adverse events severity: mild ⫽ somewhat bothersome; moderate ⫽ very bothersome; severe ⫽ potentially harmful to patients.
DBS ⫽ deep brain stimulation; CRS ⫽ Clinical Rating Scale.
vere at treatment initiation. These included seda- ficacy of primidone and propranolol in reducing ET.
tion, drowsiness, fatigue, nausea, vomiting, ataxia, One prospective, double-blind, randomized, placebo- malaise, dizziness, unsteadiness, confusion, vertigo, controlled crossover study compared the effects of and an acute toxic reaction. One class I study (n ⫽ propranolol (maximum dose 40 mg three times a 40) found that the use of a very low initial dose of day), primidone (maximum dose 250 mg three times primidone (7.5 mg/day) and slow titration (increas- a day), and placebo in 14 patients with ET.17 Both ing by 7.5 mg/day for 20 days) did not improve primi- propranolol (p ⬍ 0.01) and primidone (p ⬍ 0.01) sig- done tolerability.15 One class III study (n ⫽ 113) nificantly reduced limb tremor from baseline and as evaluated the use of primidone at low doses (250 compared to placebo. Nine of the 14 patients pre- mg/day) compared to high doses (750 mg/day) in a ferred primidone to propranolol, but primidone double-blind study using a clinical rating scale,16 and caused more bothersome side effects including mal- there were no significant differences in tremor eval- aise, dizziness, and unsteadiness at the initial dose uations between the two groups.
of 62.5 mg/day (class II). Another 4-week prospec- Prospective, randomized clinical tive, patient-blinded, placebo-controlled study in 13 trials indicate that propranolol, propranolol LA, and patients with ET compared the effects of placebo, primidone reduce limb tremor in ET. Magnitudes of propranolol 20 mg three times a day, and primidone effect of primidone and propranolol were approxi- 250 mg three times a day.18 Both primidone and pro- mately similar. Limited data indicate that proprano- pranolol significantly reduced tremor, whereas placebo lol LA is as effective as standard propranolol for had no effect. There was equivalent reduction in reducing tremor.
tremor magnitude after 1 week of propranolol treat- Propranolol, propranolol LA, or ment and 2 weeks of primidone treatment (class III).
primidone should be offered to patients who desire treat- The acute and chronic effects of propranolol and ment for limb tremor in ET, depending on concurrent primidone for the treatment of ET were also exam- medical conditions and potential side effects (Level A).
ined in a 1-year, randomized, open label trial.7 1Ai. Which drug should be used for initial treat- Twenty-five patients received long-acting proprano- Three studies compared the initial ef- lol, starting with 80 mg/day and increasing to 160 June (2 of 2) 2005
mg/day as necessary. Twenty-five patients received up to 400 mg/day reduced tremor. One double-blind, primidone 50 mg at night, increasing to 250 mg at placebo-controlled trial28 in 62 patients with ET re- night as necessary. Patients were evaluated at ported an 18% to 23% improvement in clinical rating 3-month intervals using self-evaluation forms, writ- scales with topiramate use, compared to 0 to 1% in ing samples, a clinical tremor scale, and accelerom- patients taking placebo. The drop-out rate was ap- etry. Propranolol had no measurable benefit in 7 of proximately 40% due to appetite suppression, weight 23 patients (30%). Four additional patients discon- loss, paresthesias, anorexia, and concentration tinued the drug due to side effects including fatigue, impotence, and bradycardia. Primidone was without Propranolol (head tremor). One class I study of benefit in 7 of 22 (32%) patients. Transient acute 18 patients with ET demonstrated that propranolol side effects occurred in eight patients taking primi- reduced head tremor amplitude by about 50% as done and included nausea, ataxia, dizziness, seda- measured by accelerometry.29 Conversely, one class tion, and confusion. The investigators concluded that II (n ⫽ 9)30 and one class III study (n ⫽ 9)31 failed to propranolol and primidone are efficacious long-term find reduction in head tremor using propranolol.
treatments for some patients with ET, but acute ad- Alprazolam, atenolol, gabapentin verse reactions with primidone and chronic side ef- (monotherapy), sotalol, and topiramate probably re- fects with propranolol limit effectiveness (class III).
duce limb tremor associated with ET. Propranolol Primidone and propranolol have probably reduces head tremor in ET, but data are similar efficacy when used as initial therapy to treat limb tremor in ET.
Atenolol, gabapentin (mono- Either primidone or propran- therapy), sotalol, and topiramate should be consid- olol may be used as initial therapy to treat limb ered as treatment of limb tremor associated with ET tremor in ET (Level B).
(Level B). Alprazolam is recommended with caution 1B. Pharmacologic agents with Level B recom- due to its abuse potential (Level B). Propranolol should be considered as treatment of head tremor in short-acting benzodiazepine. One class I study19 and patients with ET (Level B).
one class II study20 that used clinical rating scales 1C. Pharmacologic agents with Level C recom- found that alprazolam reduced limb tremor (25% to 34% improvement in clinical ratings compared to a benzodiazepine, significantly reduced kinetic placebo) in doses of 0.125 to 3 mg/day. Side effects tremor in 14 patients in one class II study using ranged from none to 50% in these studies and in- doses ranging from 0.5 to 6 mg/day.32 Clonazepam cluded mild sedation and fatigue. Alprazolam is had little efficacy in a class III study of 15 patients probably efficacious in treating ET, but its use is taking 0.5 to 4 mg/day, and there was a 40% comple- tion rate due to drowsiness.33 The use of clonazepam is recommended with caution due to its abuse poten- Atenolol is a selective beta- tial and possible withdrawal symptoms following 1-adrenoreceptor antagonist with low lipid solubility.
abrupt discontinuance.34 Limited data indicate that atenolol has anti-tremor Clozapine is an atypical efficacy in patients with ET. However, in one study, neuroleptic with minimal extrapyramidal side ef- atenolol had a lower magnitude of effect than sotalol fects. Two studies found that clozapine reduced ET and propranolol.22 Doses of atenolol ranged from 50 in doses of 6 to 75 mg/day.35,36 In one class II study, to 150 mg/day. Adverse events were mild and con- 87% of patients had at least a 50% reduction in sisted of lightheadedness, nausea, cough, dry mouth, tremor as measured by clinical tremor rating scales,35 and sleepiness.
and there was approximately a 45% reduction in Gabapentin (Neurontin) (monotherapy). tremor amplitude as measured by accelerometry acute- pentin is an anticonvulsant with a structure similar ly.36 Sedation decreased "markedly" after 6 to 7 weeks to gamma-aminobutyric acid (GABA) and is ap- in 12 of 13 patients in this study. None of the patients proved as adjunctive therapy for partial seizures.
in either study experienced agranulocytosis.
One class I study found that gabapentin reduced Nadolol is a beta-adrenergic tremor when used as monotherapy in doses of 1,200 receptor blocking agent and an antihypertensive mg/day (n ⫽ 16), with a 77% improvement in tremor agent. One class II study in 10 patients with ET as measured by accelerometry at day 15.23 found that nadolol, in doses of 120 or 240 mg/day, Sotalol is a nonselective beta- reduced tremor in a double-blind, placebo-controlled adrenergic receptor antagonist. In one study, sotalol trial using accelerometry.37 However, only patients effectively reduced tremor compared to placebo as who had previously responded to propranolol experi- measured by both subjective and objective assess- enced significant tremor reduction from nadolol.
ments24 (class I).
There were no statistical differences between the Topiramate is an anti- groups taking either dose, and no adverse reactions convulsant that blocks sodium channels and potenti- were reported.
ates GABA activity. Three class II studies25-27 and Nimodipine, a calcium one class IV study28 found that topiramate in doses channel blocker, at a dose of 30 mg four times daily June (2 of 2) 2005
reduced tremor amplitude by 53% as measured by Mirtazapine is an anti- accelerometry in one class I study (n ⫽ 16).38 Fifteen depressant that acts as an ␣-2-receptor antagonist of 16 patients completed the study, and eight pa- and selective blocker of postsynaptic 5HT2 and 5HT3 tients improved.
receptors.46 One class II study evaluated the safety Clonazepam, clozapine, nadolol, and tolerability of mirtazapine in 17 patients with and nimodipine possibly reduce limb tremor associ- ET and found no significant improvement with mir- ated with ET.
Nadolol and nimodipine may Nifedipine (Adalat, Procardia). be considered when treating limb tremor in patients calcium channel blocker and an antihypertensive.
with ET (Level C). Clonazepam should be used with One class II study found that nifedipine 10 mg/day caution due to its abuse potential and possible with- as a single dose increased tremor by 71% as mea- drawal symptoms (Level C). Clozapine is recom- sured by accelerometry.48 mended only for refractory cases of limb tremor in Verapamil is an antihyper- ET due to the risk of agranulocytosis (Level C).
tensive agent that acts as a calcium ion influx inhib- 1D. Pharmacologic agents with recommendations itor. One class II study found that a single 80 mg against use (Level A).
dose of verapamil taken orally did not alter tremor class I studies (n ⫽ 24) found that trazodone, a sero- activity in patients with ET.48 toninergic agonist, did not significantly alter pos- Methazolamide, mirtazapine, nifed- tural or kinetic tremor as measured by clinical ipine, and verapamil probably do not reduce limb tremor in ET.
Trazodone is ineffective in reducing limb tremor associated with ET.
nifedipine, and verapamil are not recommended for treatment of limb tremor in ET (Level C).
mended for treatment of limb tremor in ET (Level A).
1G. Pharmacologic agents with level U recommen- 1E. Pharmacologic agents with recommendations There are several additional drugs listed in against use (Level B).
table 1 that may reduce tremor. However, the stud- Acetazolamide is a carbonic anhydrase inhibitor.
ies were too small to make a recommendation, or the One class I study evaluated the efficacy of acetazol- results were conflicting, resulting in a Level U amide in reducing ET compared to placebo (n ⫽ 19).19 Acetazolamide in doses ranging from 62.5 to Amantadine is an an- 750 mg/day use did not result in significant tremor tiviral and antiparkinsonian agent. One class III reduction. Another class IV, open-label study found study found that amantadine 100 mg twice daily that acetazolamide (in doses up to 500 mg/day) re- given to six patients with ET for a 1-month period duced tremor severity, but did not improve patient did not reduce tremor amplitude or frequency.49 self-assessment or motor task scale.41 Isoniazid (Laniazid, Nydrazid). antibacterial agent that is used to treat tuberculosis.
adrenergic agonist that is used as an antihyperten- One class II study randomized 11 patients with ET sive agent. Two class II studies50,51 found that to isoniazid (doses up to 1,200 mg/day) or placebo clonidine effectively reduced tremor magnitude in over a 4-week period.42 Only 2 of 11 patients had patients with ET, although one class II study found objective or subjective response to isoniazid.
that tremor was not significantly altered by Pindolol is a beta-blocker and clonidine therapy.52 an antihypertensive agent. One class I study found Gabapentin (Neurontin) (adjunct therapy). that pindolol 15 mg/day (n ⫽ 24) did not reduce class II studies (n ⫽ 45)53,54 reported little or modest tremor amplitude or frequency compared to baseline benefit when gabapentin was used as adjunctive as measured by accelerometry.43 therapy in doses of 1,800 and 3,600 mg/day. One Acetazolamide, isoniazid, and pin- study found no significant changes in clinical rating dolol probably do not reduce limb tremor associated scale scores,54 while the other study found a 42% improvement from gabapentin and a 28% improve- Acetazolamide, isoniazid, and ment from placebo.53 There was a 12% reduction in pindolol are not recommended for treatment of limb tremor with gabapentin by accelerometry, but this tremor in ET (Level B).
was not significant.53 1F. Pharmacologic agents with recommendations Glutethimide is a non- against use (Level C).
barbiturate sedative agent that reduced ET by class Methazolamide is a carbonic anhydrase inhibitor that is used to treat ocular conditions such as glauco- ma.44 One class II study evaluating the use of metha- amino acid precursor of tryptamine and serotonin, zolamide in doses of 50 to 300 mg/day did not find a and pyridoxine is a coenzyme for dopa decarboxylase.
reduction in tremor compared to placebo using pa- One case series demonstrated that l-tryptophan/ tient self-assessment, tremor severity scales, and pyridoxine failed to improve tremor in 2 patients June (2 of 2) 2005
Metoprolol (Lopressor, Toprol). There is insufficient evidence beta-1-adrenoreceptor antagonist, and the evidence to make recommendations regarding the use of regarding its anti-tremor efficacy is conflicting. One amantadine, clonidine, gabapentin (adjunct ther- class I study showed that a single dose of 150 mg apy), glutethimide, L-tryptophan/pyridoxine, meto- metoprolol improved tremor.57 However, one class I study found that metoprolol was ineffective for the quetiapine, and theophylline in the treatment of management of limb tremor in ET when used in limb tremor in ET (Level U).
doses of 150 and 300 mg/day for 2 to 4 weeks.58 2. In patients with ET, is combined treatment with Nicardipine is a calcium primidone and propranolol superior to monotherapy? channel blocker and an antihypertensive agent. One Several studies have addressed this question, but class II study found that nicardipine over a 4-week none employed double-blind, randomized methodol- period did not reduce tremor significantly, while a sin- ogy. One study (class II) found that the addition of gle 30 mg dose produced significant reductions in primidone 50 to 1,000 mg/day to propranolol reduced tremor amplitude compared to baseline and placebo.59 tremor amplitude more than when propranolol was The atypical antipsychotic used alone.68 Propranolol monotherapy at the maxi- medication olanzapine reduced tremor in a class IV mum effective dose (average dose 260 mg/day) re- study using a mean dose of 14.87 mg/day.60 Twenty duced tremor amplitude a mean of 35%, while the percent of patients reported sedation, and several addition of primidone (50 to 1,000 mg/day) decreased patients reported weight gain.
tremor by a mean of 60 to 70%. Twelve percent of Phenobarbital is an patients had acute reactions to primidone adminis- anticonvulsant and a sedative. One class II study tration including ataxia and confusion. Titration was (n ⫽ 17) that evaluated the anti-tremor effect of phe- limited in nine patients due to sedation and vertigo.
nobarbital compared to propranolol and placebo In another study, 18 patients received in random found that while phenobarbital was better than pla- order placebo, primidone (250 mg/day), propranolol cebo when tremor was measured with accelerometry (240 mg/day), both drugs, or no drugs (class II). Ac- but not with a clinical rating scale.61 Another class I celerometric recordings were made of both postural study (n ⫽ 16) found that phenobarbital (mean dose and kinetic tremor. Primidone and propranolol alone 136 ⫾ 25 mg/day) was no better than placebo.62 were equally efficacious in treating both postural Quetiapine is an atypical and kinetic tremor. The combined use of primidone antipsychotic agent. One class IV study (n ⫽ 10) and propranolol was more effective than either drug evaluated the safety and tolerability of quetiapine alone for both types of tremor (p ⬍ 0.05), although (up to 75 mg/day) as monotherapy in ET over a 6-week the magnitude of this effect was small.5 period.63 Patients were evaluated with a clinical rating The combined use of primidone and scale. Six patients completed the study, and the mean propranolol possibly reduces limb tremor in ET more tolerated dose of quetiapine was 60 mg ⫾ 21.08 (range than either drug alone. There was no worsening of 25 to 75 mg). The most common side effect was somno- adverse events when primidone and propranolol lence. No statistical differences were noted pre- and were used in combination.
Primidone and propranolol Theophylline is a xan- may be used in combination to treat limb tremor thine derivative bronchodilator that can induce when monotherapy does not sufficiently reduce tremor.64,65 However, several studies have demon- tremor (Level B).
strated that theophylline in low doses may improve 3. In patients with ET, is there evidence for sus- ET.66,67 In one double-blind, crossover study, patients tained benefit of pharmacologic treatment? who were given a single oral dose of theophylline had trial found that primidone (doses 375 to 750 mg/day) no significant change in tremor for the following 24 was effective for up to 1 year69 (class III). In another hours.66 However, tremor was significantly improved open label extension study, 18 patients with ET took after 4 weeks of treatment with theophylline 300 mg/ propranolol for 12 months.70 Propranolol continued day as measured by clinical rating scales. In another to provide benefit although 5 of 12 patients (42%) double-blind trial, patients were given placebo, pro- required an increased dose at 12 months compared pranolol 80 mg/day, or theophylline 150 mg/day for 4 to 3 to 6 months. Eighty-three percent of patients weeks.67 No reduction in tremor was noted in patients experienced greater than 20% reduction in tremor taking theophylline until the end of the second week of after 3 to 6 months (using clinical tests such as treatment. Both propranolol and theophylline reduced handwriting and drawing, self-rating of functional tremor at study endpoint compared to baseline. No ad- disability, and accelerometry) while 66% of patients verse events were reported with theophylline use.
had their tremor magnitude reduced by more than There are insufficient or conflicting 20% of their baseline values after 12 months (class data regarding the use of amantadine, clonidine, III). A third open-label study examined the acute gabapentin (adjunct therapy), glutethimide, L-trypto- and chronic effects of propranolol and primidone in phan/pyridoxine, metoprolol, nicardipine, olanzap- 50 patients with ET who were randomly assigned to ine, phenobarbital, quetiapine, and theophylline to receive either long-acting propranolol (80 to 160 mg/ treat limb tremor associated with ET.
day) or primidone (50 to 250 mg/day).7 Patients were June (2 of 2) 2005
evaluated at 1, 3, 6, 9, and 12 months of treatment, One class II study that evaluated the use of BTX and tremor was assessed by rating scales and accel- A to treat head tremor in 10 patients with ET found erometry. Ten of 25 patients (40%) treated with pro- that there was moderate to marked improvement in pranolol continued to benefit after 1 year of clinical rating scales in five patients with BTX injec- treatment. In four patients, the dose of propranolol tions and in one patient with placebo injections.72 remained the same, while in the other six patients, Forty units of BTX were injected into each sterno- the dose was increased. At the end of 1 year, pro- cleidomastoid muscle, and 60 U were injected into pranolol controlled symptoms in 40% of patients each splenius capitis muscle using EMG guidance.
with the majority requiring an increase in dosage.
Five patients had moderate to marked improvements Over 50% of patients who were treated with primi- in subjective ratings scales, compared to three pa- done maintained benefit at 1 year. Reduction in clin- tients who received placebo. However, subjective and ical benefit occurred in 12.5% of patients treated clinical rating scale evaluations did not differ signif- with propranolol and 13.0% of those taking primi- icantly between those who received BTX and those done (class III). Another double-blind study found who received placebo. Side effects consisted of neck that both low doses of primidone (250 mg/day) and weakness and post-injection pain in most patients. An- high doses of primidone (750 mg/day) improved ET other open-label study using clinical rating scales and for 12 months (class II).16 accelerometry found that tremor amplitude changed Primidone and propranolol main- significantly after BTX injections compared to baseline tain anti-tremor efficacy in the majority of patients (baseline 0.079, post-treatment 0.0255, p ⬍ 0.05), and for at least 1 year.
all patients reported subjective improvement.73 The dosages of propranolol Two class III studies using blinded voice analysis and primidone may need to be increased by 12 evaluated the effects of BTX A on voice tremor.74,75 In months of therapy when treating limb tremor in ET one study, 30% of patients (3 of 10) demonstrated an objective reduction in tremor severity with bilateral 4. Do patients with ET benefit from chemodenerva- injection into the vocal cords, compared to 22% of those tion with botulinum toxin type A or B? who received unilateral injection.74 Another study (n ⫽ toxin (BTX) A has been used to treat hand, head, and 15) found a 67% self-report of benefit following BTX voice tremor in ET. Twelve studies evaluated the injections.75 Eighty percent of patients reported bre- safety and effectiveness of BTX A in treating ET (6 athy, weak voices for 1 to 2 weeks, while 20% had for limb tremor [n ⫽ 210], 3 for head tremor [n ⫽ 62], hoarseness and swallowing difficulties for 4 weeks.
and 3 for voice tremor [n ⫽ 25]), while there are no The effect of BTX A on limb tremor studies that evaluated the use of BTX B to treat ET.
in ET is modest and is associated with dose- One class I study randomized 133 patients with ET dependent hand weakness. BTX A may reduce head to receive injections of 50 U or 100 U of BTX into tremor and voice tremor associated with ET, but their limbs and demonstrated modest benefit.71 For data are limited. When used to treat voice tremor, those patients who received a total of 50 U of BTX, BTX A may cause breathiness, hoarseness, and swal- 15 U were injected into each of the flexor carpi radi- alis and ulnaris and 10 U into each of the extensor BTX A injections for limb, carpi radialis and ulnaris. For those patients who head, and voice tremor associated with ET may be received a total of 100 U of BTX, 30 U were injected considered in medically refractory cases (Level C for into each of the flexor carpi radialis and ulnaris and limb, head, and voice tremor).
20 U into each of the extensor carpi radialis andulnaris. Clinical tremor rating scale scores signifi- Analysis of the evidence: Surgical treatment of
cantly improved from baseline for the low- and high- 5. What is the efficacy of thalamotomy in treat- dose groups for postural tremor at 6, 12, and 16 ing contralateral limb tremor in patients with ET? weeks and for kinetic tremor at the 6-week evalua- Thalamotomy involves creating a lesion in the ven- tion. Subjective assessments indicated mild improve- tral intermediate nucleus (VIM) of the thalamus. The ment for low and high dose groups at 6 weeks, but no area is localized using stereotactic techniques, and the change at 12 and 16 weeks. The magnitude of the location can be confirmed by macro-stimulation (as- change in postural tremor was on average less than sessing the clinical effects of high frequency stimula- one point on the rating scale, and kinetic tremor was tion to see if the tremor will improve without only reduced at the 6-week evaluation. There was unwanted effects) and micro-electrode recording tech- minimal functional improvement, and neither physi- niques (measuring the electrical activity of individual cian nor patient reported any benefit at 12- and 16- neurons to ensure that their discharge pattern is typi- week follow-up. Hand weakness was reported in 30% cal for the desired target).
of patients in the low-dose group and in 70% of pa- Open label trials (n ⫽ 181) indicate that thalamo- tients in the high-dose group. Additional side effects tomy reduces limb tremor in 80 to 90% of patients included pain at the injection site, stiffness, cramp- with ET. One class I study found that tremor was ing, hematoma, and paresthesias. These side effects abolished "completely" or "almost completely" in 79% made blinded treatment and evaluation difficult, if of patients.76 A class III study found that tremor was not impossible.
abolished in 90% of patients who received thalamot- June (2 of 2) 2005
omies,77 while another class III study reported that pared to thalamotomy. Potential disadvantages include there was an 83% improvement in action tremor, a the greater cost and effort in programming and main- 77% improvement in postural tremor, and a 56% taining the device.
improvement in handwriting and drawing 3 months Ethical and cost considerations are often stated to after surgery.78 In all studies, most patients experi- preclude ideal controlled study designs that would enced either complete abolition of tremor or marked necessarily include "sham" surgeries, or in the case to moderate improvement, and studies indicate that of DBS, implanting nonfunctioning devices. How- there is long-term benefit from the procedure. Pro- ever, DBS is uniquely suited to single blind evalua- spective comparisons against best medical manage- tions since it can be easily activated and inactivated ment are lacking, although thalamotomy is reserved prior to assessment by a blinded investigator. Elec- for medically refractory patients. Adverse events as- trophysiologic measures including accelerometry sociated with thalamotomy occurred in 14 to 47% of have also been used in several studies for tremor patients. Twenty-nine patients in all of the examined studies had adverse effects that did not resolve with Studies indicate that contralateral limb tremor is time (16%). In one study (n ⫽ 37), 16% of patients consistently improved by DBS, as determined by ob- who underwent a unilateral thalamotomy had per- servation, writing tests, pouring tests, and activities manent hemiparesis and speech difficulty.79 Other of daily living questionnaires (n ⫽ 82 patients). Two adverse events include transient problems with prospective, blinded trials have examined the effects speech and motor function, dysarthria, verbal or cog- of DBS in patients with ET (n ⫽ 23)88,89 (class III).
nitive deficit, weakness, confusion, somnolence, and Although the treatment of patients was not random- facial paresis.
ized, evaluation was conducted in a blinded, random Limited data indicate that bilateral thalamotomy manner. Following unilateral DBS, there was a is associated with a high frequency of side effects, mean tremor improvement of 60% to 90% on clinical although most of these studies focused on bilateral rating scales. Results of the few trials with both thalamotomy in PD rather than in ET.80-84 Dysar- blinded (to activation status) and unblinded postsur- thria, dysphonia, and voice reduction has been re- gical evaluations on the same patients demonstrate ported in 28 to 88% of patients with PD who received there was negligible "placebo response" and signifi- bilateral thalamotomies80,84 and the condition was cant tremor reduction.
marked in 67% of patients.84 Additionally, 64% of Bilateral thalamic stimulation was evaluated in patients with PD in one study reported transient nine medically refractory patients with ET at base- mental confusion,80 and 54% of patients with PD in line before the first implant, before the second im- another study84 reported mental changes. Bilateral plant, and at 6 and 12 months following surgeries.89 thalamotomy is no longer performed to treat ET.
Motor scores when the implant was "off" did not Unilateral thalamotomy effectively differ between baseline evaluations and those per- treats contralateral limb tremor in ET. Bilateral formed 6 and 12 months after surgery. However, thalamotomy is associated with more frequent andoften severe side effects.
there were significant improvements in motor scores Unilateral thalamotomy may when the implant was activated at both the 6- and be used to treat limb tremor in ET that is refractory 12-month evaluations (class III). For postural and to medical management (Level C), but bilateral kinetic tremor, there was a 67% improvement in hand thalamotomy is not recommended due to adverse tremor on the first side and a 64% improvement on the side effects (Level C).
second side following surgery. The mean total tremor 6. What is the efficacy of deep brain stimulation of score improved from 66.1 ⫾ 11.6 to 28.4 ⫾ 12.8 12 the thalamus in treating tremor in patients with re- months after the second surgery (p ⬍ 0.05).
fractory ET? 6A. Deep brain stimulation (unilateral In all studies, a total of 37 patients experienced and bilateral) and limb tremor.
Deep brain stimu- adverse effects resulting from DBS (18%). Of these, lation (DBS) uses high frequency electrical stimula- 28 were related to equipment malfunction or lead tion from an implanted electrode to modify the displacement. One study reported a death associated activity of the target area. The exact mechanisms by with the procedure due to a perioperative intracere- which DBS suppresses tremor are unknown, and bral hemorrhage.76 Other side effects associated with postmortem examinations have not shown any per- DBS were dysarthria, dysequilibrium, paresthesias, manent anatomic changes other than the electrode weakness, headache, intracranial hemorrhage, sub- tract.85,86 Placement strategies are similar to those dural hemorrhage, lead dislodgement, ischemic for thalamotomy. For ET, the electrode is inserted changes, generalized motor seizures, and decreased into the VIM thalamus. It is connected to a pulse verbal fluency. Many of these side effects resolved generator that is placed in the chest wall. Electrode with time or with adjustment of stimulator settings.
montage (four electrodes placed 1.5 mm apart and DBS of the VIM thalamic nucleus the electrode case), voltage, pulse frequency, and effectively reduces contralateral limb tremor in med- pulse width can be adjusted to optimize tremor con- ically refractory ET.
trol.87 This flexibility in placing and adjusting the DBS of the VIM thalamic nu- "functional lesion" is the main advantage of DBS com- cleus may be used to treat medically refractory limb June (2 of 2) 2005
tremor in ET (Level C).6B. DBS and head and voice the patients who received thalamotomy compared to Data on the reduction of voice tremor after DBS. Five patients who received thalamotomy had DBS is limited. One class III study found that DBS asymptomatic intracranial hemorrhages, and one pa- effectively reduced voice tremor in seven patients tient had a symptomatic hemorrhage. Five patients with ET (five unilateral, two bilateral).90 All patients reported cognitive abnormalities, two patients expe- had undergone DBS for management of upper limb rienced hemiparesis, and two patients had aphasia.
tremor. Four of seven patients had voice tremor re- All complications resolved within 1 month. Compli- duction as measured by objective tests. The patient cations of DBS included seizures in one patient, al- who had the greatest improvement in voice tremor though four patients eventually had a lead replaced, had received bilateral implantation, although an- one had IPG malfunction, and one had surgery for a other patient who received bilateral stimulation had dead battery. The authors concluded that DBS no appreciable reduction in voice tremor. Another should be the procedure of choice due to fewer seri- open-label study of patients with PD, ET, and MS ous adverse events (class IV). A similar class IV ret- who received bilateral thalamic stimulation found rospective study of six patients with ET found no that six of seven patients with voice tremor improved difference in the clinical benefit achieved by either one grade on a clinical rating scale.91 However, an procedure.96 However, ataxia, dysarthria, and gait open-label trial failed to find any significant change disturbance were more common after thalamotomy in voice tremor with unilateral or bilateral thalamic (42%) than DBS (26%). Both PD and ET patients were included in this study (class IV).
Studies of DBS and head tremor have produced Both DBS and thalamotomy effec- conflicting results. One class III study that evaluated tively suppress tremor in ET.
the effect of unilateral thalamic DBS on head tremor failed to find an improvement.93 Another class III events than thalamotomy (Level B). However, the study of 38 patients found that unilateral DBS of the decision to use either procedure depends on each thalamus improved head tremor in 71% of patients patient's circumstances and risk for intraoperative at 3-month postoperative evaluation, while 26% of pa- complications compared to feasibility of stimulator tients were unchanged and 3% worsened.94 An open- monitoring and adjustments.
label study (class IV, n ⫽ 15) also reported that 90% of 8. What are the indications for bilateral vs unilat- patients with ET experienced improvement in head eral surgical procedures in ET? One class III study tremor after bilateral DBS.91 In all studies, adverse comparatively examined the effects of unilateral vs events were similar to those of DBS for limb tremor.
bilateral DBS.97 This study of 13 patients with ET There are conflicting data regard- found that bilateral thalamic DBS was more effec- ing the use of DBS for head and voice tremor in ET.
tive than unilateral DBS at controlling appendicular There is insufficient evidence and midline tremors. Using the Unified Tremor Rat- to make recommendations regarding the use of tha- ing Scale, hand tremor scores in patients with ET lamic DBS for head or voice tremor (Level U).
7. Should thalamotomy or DBS of the thalamus be randomized to "on" stimulation improved from 6.7 ⫾ the procedure of choice in patients with medically 0.9 to 1.3 ⫾ 1.2 (p ⬍ 0.005) at the 3-month, second refractory ET? In a class I study, 13 patients with side assessment, and legs improved from 2.3 ⫾ 1.1 to ET were randomly assigned to undergo either 0.5 ⫾ 0.5 (p ⬍ 0.005). Side effects, including dysar- thalamotomy or DBS, and functional abilities were thria, tended to occur more frequently in patients compared preoperatively and 6 months postopera- who underwent bilateral DBS.
tively using the Frenchay Activities Index (FAI).76 In another study, bilateral thalamic stimulation Functional ratings improved more in patients who was performed in nine medically refractory patients received thalamic stimulation than in those who re- with ET.89 Patients received evaluations at baseline, ceived thalamotomy. Side effects were present in before the first implant, before the second implant, 50% of thalamotomy patients and included cognitive and at 6 and 12 months following surgeries. Tremor deterioration, mild dysarthria, and mild gait or bal- scores tended to be better following the second proce- ance disturbance. In the DBS group, one patient dure than after the first procedure (class III). Speech (14% of treated patients) had mild gait and balance evaluations were available for six of the nine pa- disturbance. The authors concluded that while both tients, and three of the six patients had worsening of DBS and thalamotomy effectively reduced tremor, dysarthria with both stimulators on.
DBS has fewer adverse effects and resulted in Thalamic DBS suppresses con- greater functional improvement.
tralateral limb tremor, so bilateral DBS is necessary In another open-label study, 17 patients with ET to suppress tremor in both upper limbs. However, received thalamotomy and were matched to 17 pa- there is no evidence of a synergistic effect on limb tients with ET who had previously received DBS.95 tremor with bilateral DBS, and there are insufficient There were no significant differences between any data regarding the risk:benefit ratios of unilateral vs efficacy outcome variables comparing thalamotomy bilateral DBS. Similarly, there are insufficient data to DBS of the thalamus at baseline or follow-up vis- regarding the use of bilateral DBS for head and voice its. However, surgical complications were higher for June (2 of 2) 2005
Bilateral DBS is necessary to Future research recommendations.
suppress tremor in both upper limbs, but there are ing one of the most common adult movement disor- insufficient data regarding the risk:benefit ratio of ders, research on treatment of ET is limited. Future bilateral vs unilateral DBS in the treatment of limb research considerations include the following: tremor (Level U). Similarly, there are insufficientdata to recommend bilateral or unilateral DBS for 1. There should be a concerted effort to standardize head and voice tremors. Side effects are more fre- outcome measures to assess tremor and to corre- quent with bilateral DBS, and bilateral thalamotomy late accelerometry with clinical rating scales. This is not recommended.
is important in determining the magnitude of ef- 9. Does gamma knife thalamotomy effectively re- fect of pharmacologic or surgical treatments.
Gamma knife surgery is performed by 2. Knowledge of clinical and pathologic heterogene- delivering radiation to an intracranial target based ity of ET and how these relate to profiles of phar- on anatomic imaging. Electrophysiologic guidance is macologic responsiveness should be determined to not possible. Several studies (n ⫽ 61) have reported help guide clinicians in selecting appropriate favorable results with gamma knife thalamot- medications for their patients.
omy,98,99 although one case report documented de- 3. Studies are needed to determine the cost vs bene- layed side effects from the procedure including fit profile for treatments of ET.
contralateral arm numbness and dysarthria.100 In 4. Additional clinical trials should be conducted to one retrospective study (class IV), gamma knife assess the pharmacologic and surgical treatment treatment resulted in complete tremor arrest in 75% of head and voice tremor.
of patients (n ⫽ 9), and all patients benefited subjec- 5. Additional randomized, prospective, double-blind, tively from the procedure.98 There were significant placebo-controlled trials are needed to better de- improvements in drawing capability at follow-up termine the efficacy and side effect profiles of (median of 6 months). The onset of improvement oc- pharmacologic and surgical therapies for ET.
curred at a median of 6 weeks following the proce-dure, and additional improvements continued for thenext 6 months. One patient developed transient arm This statement is provided as an edu- weakness. In a class III study, 52 patients with ET cational service of the American Academy of Neurol- received unilateral gamma knife thalamotomy and ogy. It is based on an assessment of current scientific were followed for a median of 26 months.99 Patients and clinical information. It is not intended to include were assessed using the Fahn-Tolosa-Marin rating all possible proper methods of care for a particular scale with blinded assessments. At 1 year after sur- neurologic problem or all legitimate criteria for gery, 92% of patients were completely or nearly com- choosing to use a specific procedure. Neither is it pletely free of tremor; at 4-year follow-up, this intended to exclude any reasonable alternative percentage decreased to 88%. One patient experi- methodologies. The AAN recognizes that specific pa- enced mild contralateral arm and leg weakness, tient care decisions are the prerogative of the patient while another patient developed transient paresthe- and the physician caring for the patient, based on all sias. However, one case report (class IV) described of the circumstances involved.
severe complications that occurred approximately 7months after gamma knife thalamotomy.100 Thesecomplications were progressive and included numb- Appendix 1
ness in the contralateral arm, dysarthria, increased Classification of evidence action tremor, dystonia of the contralateral upper Class I: Prospective, randomized, controlled clinical trial with masked out-come assessment, in a representative population. The following are re- and lower limbs, and choreoathetosis. The depen- dence on anatomic imaging, the typical delay of a) Primary outcome(s) clearly defined.
weeks to months for clinical results to occur, and the b) Exclusion/inclusion criteria clearly defined.
c) Adequate accounting for drop-outs and cross-overs with numbers suffi- risks of delayed progressive neurologic deficits are ciently low to have minimal potential for bias.
disadvantages of gamma knife thalamotomy, com- d) Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical pared to thalamic DBS. Long-term follow-up studies adjustment for differences.
are needed to assess the risk:benefit ratio of gamma Class II: Prospective matched group cohort study in a representative popu- knife thalamotomy.
lation with masked outcome assessment that meets a– d above OR a RCT in Several studies have found favor- a representative population that lacks one criteria a– d.
able results with gamma knife thalamotomy, but de- Class III: All other controlled trials including well-defined natural historycontrols or patients serving as own controls in a representative population, layed complications have been reported, and clinical where outcome is independently assessed or independently derived by ob- improvement may take weeks to months to occur.
jective outcome measurement.* There is insufficient evidence Class IV: Evidence from uncontrolled studies, case series, case reports, or to make recommendations regarding the use of expert opinion.
gamma knife thalamotomy in the treatment of ET *Objective outcome measurement: an outcome measure that is unlikely tobe affected by an observer's (patient, treating physician, investigator) ex- pectation or bias (e.g., blood tests, administrative outcome data).
June (2 of 2) 2005
20. Huber SJ, Paulson GW. Efficacy of alprazolam for essential tremor.
Neurology 1988;38:241–243. Class II.
Classification of recommendations 21. Ananth J. Benzodiazepines: selective use to avoid addiction. Postgrad A ⫽ Established as effective, ineffective, or harmful for the given condition in the specified population. (Level A rating requires at least two con- 22. Jefferson D, Jenner P, Marsden CD. beta-Adrenoreceptor antagonists sistent Class I studies.) in essential tremor. J Neurol Neurosurg Psychiatry 1979;42:904 –909.
B ⫽ Probably effective, ineffective, or harmful for the given condition in the specified population. (Level B rating requires at least one Class I study 23. Gironell A, Kulisevsky J, Barbonoj M, et al. A randomized placebo- or at least two consistent Class II studies.) controlled comparative trial of gabapentin and propranolol in essential C ⫽ Possibly effective, ineffective, or harmful for the given condition in the tremor. Arch Neurol 1999;56:475– 80. Class I.
specified population. (Level C rating requires at least one Class II 24. Leigh PN, Jefferson D, Twomey A, et al. Beta-adrenoreceptor mecha- study or two consistent Class III studies.) nisms in essential tremor; a double-blind placebo controlled trial of U ⫽ Data inadequate or conflicting given current knowledge, treatment is metoprolol, sotalol and atenolol. J Neurol Neurosurg Psychiatry 1983; 46:710 –715. Class I.
25. Connor GS. A double-blind placebo-controlled trial of topiramate treat- ment for essential tremor. Neurology 2002;59:132–134. Class II.
26. Hulihan J, Connor GS, Shu-Chen W, et al. Topiramate in essential tremor: pooled data from a double-blind, placebo-controlled, crossover Adverse events severity trial. American Academy of Neurology 2003. Abstracts: P04.068. Class II.
Mild: Somewhat bothersome but not clinically harmful 27. Ondo WG, Jankovic J, Stacy MA, et al. Topiramate for essential tremor.
Moderate: Very bothersome but not clinically harmful Neurology 2004;62:LBS.004. Class II.
Severe: Pose/potentially pose harm to patients 28. Galvez-Jimenez N, Hargreave M. Topiramate and essential tremor.
Ann Neurol 2000;47:837– 838. Class IV.
29. Koller WC. Propranolol therapy for essential tremor of the head. J Neu- Appendix 4
rol 1984;34:1077–1079. Class I.
Quality Standards Subcommittee members Gary Franklin, MD, MPH (Co- 30. Sweet RD, Blumberg J, Lee JE, et al. Propranolol treatment of essen- Chair); Gary Gronseth, MD (Co-Chair); Charles E. Argoff, MD; Stephen tial tremor. Neurology 1974;24:64 – 67. Class II.
Ashwal, MD (ex-officio); Christopher Bever, Jr., MD; Jody Corey-Bloom, 31. Calzetti S, Sasso E, Negrotti A, et al. Effect of propranolol in head MD, PhD; John D. England, MD; Jacqueline French, MD (ex-officio); Gary tremor: quantitative study following single-dose and sustained drug H. Friday, MD; Michael Glantz, MD; Deborah Hirtz, MD; Donald J. Iver- administration. Clin Neuropharmacol 1992;15:470 – 476. Class III.
son, MD; David J. Thurman, MD; Samuel Wiebe, MD; William J. Weiner, 32. Biary N, Koller W. Kinetic predominant essential tremor: successful MD; and Catherine Zahn, MD (ex-officio).
treatment with clonazepam. Neurology 1987;37:471– 474. Class II.
33. Thompson C, Lang A, Parkes JD, et al. A double-blind trial of clonaz- epam in benign essential tremor. Clin Neuropharmacol 1984;7:83– 88.
34. American Psychiatric Association Task Force. Benzodiazepines: depen- 1. Louis ED, Ottman R, Hauser WA. How common is the most common dence, toxicity, and abuse. Washington, DC: American Psychiatric adult movement disorder: estimates of the prevalence of essential Press, 1990.
tremor throughout the world. Mov Disord 1998;13:5–10.
35. Ceravolo R, Salvetti S, Piccini P, et al. Acute and chronic effects of 2. Benito-Leon J, Bermejo-Pareja F, Morales JM, et al. Prevalence of clozapine in essential tremor. Mov Disord 1999;14:468 – 472. Class II.
essential tremor in three elderly populations of central Spain. Mov 36. Pakkenberg H, Pakkenberg B. Clozapine in the treatment of tremor.
Disord. 2003;18:389 –394.
Acta Neurol Scand 1986;73:295–297. Class III.
3. Deuschl G, Bain P, Brin M. Consensus statement of the Movement 37. Koller WC. Nadolol in essential tremor. Neurology 1983;33:1076 –1077.
Disorder Society on tremor. Ad Hoc Scientific Committee. Mov Disord 38. Biary N, Bahou Y, Sofi MA, et al. The effect of nimodipine on essential 4. Hsu YD, Chang MK, Sung SC, et al. Essential tremor: clinical, electro- tremor. Neurology 1995;45:1523–1525. Class I.
myographical and pharmacological studies in 146 Chinese patients.
39. Koller WC. Tradozone in essential tremor. Clin Neuropharmacol 1989; Zhonghua Yi Xue Za Zhi (Taipei) 1990;45:93–99.
12:134 –137. Class I.
5. Koller WC, Biary N, Cone S. Disability in essential tremor: effect of 40. Cleeves J, Findley LJ. Trazodone is ineffective in essential tremor.
treatment. Neurology 1986;36:1001–1004. Class III.
J Neurol Neurosurg Psychiatry 1990;53:268 –269. Class I.
6. Lacritz LH, Dewey R Jr., Giller C, et al. Cognitive functioning in indi- 41. Busenbark K, Parwa R, Hubble J, et al. The effect of acetazolamide on viduals with "benign" essential tremor. J Int Neuropsychol Soc 2002;8: essential tremor: an open-label trial. Neurology 1992;42:1394 –1395.
7. Koller WC, Vetere-Overfield B. Acute and chronic effects of propranolol and 42. Hallett M, Ravits J, Dubinsky RM, et al. A double-blind trial of isonia- primidone in essential tremor. Neurology 1989;39:1587–1588. Class III.
zid for essential tremor and other action tremors. Mov Disord 1991;6: 8. Lou JS, Jankovic J. Essential tremor: clinical correlates in 350 patients.
253–256. Class II.
Neurology 1991;41:234 –238.
43. Teravainen H, Larsen A, Fogelholm R. Comparison between the effects 9. Koller W, Busenbark K, Miner K. The relationship of essential tremor of pindolol and propranolol on essential tremor. Neurology 1977;27: to other movement disorders: report on 678 patients. Essential Tremor 439 – 442. Class I.
Study Group. Ann Neurol 1994;35:717–723.
44. Epstein DL, Grant WM. Carbonic anhydrase inhibitor side effects. Se- 10. Rajput AH, Jamieson H, Hirsh S, Quraishi A. Relative efficacy of alco- rum chemical analysis. Arch Ophthalmol 1977;95:1378 –1382.
hol and propranolol in action tremor. Can J Neurol Sci 1975;2:31–35.
45. Busenbark K, Pahwa R, Hubble J, et al. Double-blind controlled study 11. Koller WC, Biary N. Effect of alcohol on tremors: comparison with of methazolamide in the treatment of essential tremor. Neurology 1993; propranolol. Neurology 1984;34:221–222.
12. Packer M, Cohn JN, Abraham WT, et al. Consensus recommendations for 43:1045–1047. Class II.
the management of chronic heart failure. Am J Cardiol 1999;83:1A–38A.
46. de Boer TH, Maura G, Raiteri M, et al. Neurochemical and autonomic 13. Cleeves L, Findley LJ. Propranolol and propranolol-LA in essential pharmacological profiles of the 6-aza-analogue of mianserin, Org 3770 tremor: a double blind comparative study. J Neurol Neurosurg Psychi- and its enantiomers. Neuropharmacology 1988;27:399 – 408.
atry 1988;51:379 –384. Class I.
47. Pahwa R, Lyons KE. Mirtazapine in essential tremor: a double-blind, 14. Koller WC. Long-acting propranolol in essential tremor. Neurology placebo-controlled pilot study. Mov Disord 2004;18:584 –587. Class II.
1985;35:108 –110. Class II.
48. Topaktas S, Onur R, Dalkara T. Calcium channel blockers and essen- 15. O'Suilleabhain P, Dewey RB. Randomized trial comparing primidone tial tremor. Eur Neurol 1987;27:114 –119. Class II.
initiation schedules for treating essential tremor. Mov Disord 2002;17: 49. Koller WC. Amantadine in essential tremor. Ann Neurol 1984;16:621– 383–386. Class I.
622. Class III.
16. Serrano-Duenas M. Use of primidone in low doses (250 mg/day) versus 50. Serrano-Duenas M. Clonidine versus propranolol in the treatment of high doses (750 mg/day) in the management of essential tremor.
essential tremor. A double-blind trial with a one-year follow-up. Neuro- Double-blind comparative study with one-year follow-up. Parkinsonism logia 2003;18:248 –254.
Relat Disord 2003;10:29 –33. Class III.
51. Caccia MR, Osio M, Galimberti V, et al. Propranolol, clonidine, urapidil, 17. Gorman WP, Cooper R, Pocock P, et al. A comparison of primidone, and trazodone infusion in essential tremor: a double-blind crossover propranolol, and placebo in essential tremor, using quantitative analy- trial. Acta Neurol Scand 1989;79:379 –383.
sis. J Neurol Neurosurg Psychiatry 1986;49:64 – 68. Class II.
52. Koller W, Herbster G, Cone S. Clonidine in the treatment of essential 18. Dietrichson P, Epsen E. Primidone and propranolol in essential tremor: tremor. Mov Disord 1986;1:235–237.
a study based on quantitative tremor recording and plasma anticonvul- 53. Ondo W, Hunter C, Vuong KD, et al. Gabapentin for essential tremor: a sant levels. Acta Neurol Scand 1987;75:332–340. Class III.
multiple-dose, double-blind, placebo-controlled trial. Mov Disord 2000; 19. Gunal DI, Afsar N, Bekiroglu N, et al. New alternative agents in essen- 15:678 – 682. Class II.
tial tremor therapy: double-blind placebo-controlled study of alprazolam 54. Pahwa R, Lyons K, Hubble JP, et al. Double-blind, controlled trial of and acetazolamide. Neurol Sci 2000;21:315–317. Class I.
gabapentin in essential tremor. Mov Disord 1998;13:465– 467. Class II.
June (2 of 2) 2005
55. McDowell FH. The use of glutethimide for treatment of essential 79. Akbostanci MC, Slavin KV, Burchiel KJ. Stereotactic ventral interme- tremor. Mov Disord 1989;4:75– 80. Class IV.
dial thalamotomy for the treatment of essential tremor: results of a 56. Mozzis CE, Prange AJ, Hall CD, et al. Inefficacy of tryptophan/ series of 37 patients. Stereotact Funct Neurosurg 1999;72:174 –177.
pyridoxine in essential tremor. Lancet 1971;2:165–166.
57. Calzetti S, Findley LJ, Gresty MA, et al. Metoprolol and propranolol in 80. Selby G. Stereotactic surgery for the relief of Parkinson's disease. 2.
essential tremor: a double-blind, controlled study. J Neurol Neurosurg An analysis of the results in a series of 303 patients (413 operations).
Psychiatry 1981;44:814 – 819. Class I.
J Neurol Sci 1967;5:343–375.
58. Calzetti S, Findley LJ, Perucca E, et al. Controlled study of metoprolol 81. Matsumoto K, Shichijo F, Fukami T. Long-term follow-up review of and propranolol during prolonged administration in patients with essen- cases of Parkinson's disease after unilateral or bilateral thalamotomy.
tial tremor. J Neurol Neurosurg Psychiatry 1982;45:893– 897. Class I.
J Neurosurg 1984;60:1033–1044.
59. Garcia Ruiz PJ, Garcia de Yebenes Prous J, Jimenez Jimenez J. Effect 82. Miyamoto T, Bekku H, Moriyama E, et al. Present role of stereotactic of nicardipine on essential tremor: brief report. Clin Neuropharmacol thalamotomy for parkinsonism. Retrospective analysis of operative re- 1993;16:456 – 459. Class II.
sults and thalamic lesions in computed tomograms. Appl Neuro- 60. Yetimalar Y, Irtman G, Gurgor N, et al. Olanzapine efficacy in the physiol 1985;48:294 –304.
treatment of essential tremor. Eur J Neurol 2003;10:79 – 82. Class IV.
83. Kelly PJ, Gillingham FJ. The long-term results of stereotaxic surgery 61. Baruzzi A, Procaccianti G, Martinelli P, et al. Phenobarbital and pro- and L-dopa therapy in patients with Parkinson's disease. A 10-year pranolol in essential tremor: a double-blind controlled clinical trial.
follow-up study. J Neurosurg 1980;53:332–337.
Neurology 1983;33:296 –300. Class II.
84. Giuffre R, Gambacorta D. The therapeutic possibilities of L-dopa and 62. Sasso E, Perucca E, Calzetti S. Double-blind comparison of primidone amantadine in Parkinsonian patients who have undergone bilateral and phenobarbital in essential tremor. Neurology 1988;38:808 – 810.
thalamotomy. Eur Neurol 1971;5:311–316.
85. Caparros-Lefebvre D, Ruchoux MM, Blond S, et al. Long-term tha- 63. Micheli F, Cersosimo MG, Raina G, et al. Quetiapine and essential lamic stimulation in Parkinson's disease: postmortem anatomoclinical tremor. Clin Neuropharmacol 2002;25:303–306. Class IV.
study. Neurology 1994;44:1856 –1860.
64. Buss DC, Phillis IW, Littley MD, et al. The effect of theophylline on 86. Boockvar JA, Telfeian A, Baltuch GH, et al. Long-term deep brain thyrotoxic tremor. Br J Clin Pharmacol 1989;28:103–107.
stimulation in a patient with essential tremor: clinical response and 65. Van Der Vet APH, Kreukniet J, Drost RH, et al. Lung function im- postmortem correlation with stimulator termination sites in ventral provement, tremor measurements and c-AMP determinations in a thalamus. Case report. J Neurosurg 2000;93:140 –144.
group of ten patients with asthmatic bronchitis after one week sus- 87. Hubble JP, Busenbark KL, Wilkinson S, et al. Deep brain stimulation tained release theophylline medications compared to one week placebo.
for essential tremor. Neurology 1996;46:1150 –1153.
Int J Clin Pharmacol Ther Toxicol 1986;24:638 – 642.
88. Koller W, Pahwa R, Busenbark K, et al. High-frequency unilateral 66. Mally J, Stone TW. The effect of theophylline on essential tremor: the thalamic stimulation in the treatment of essential and parkinsonian possible role of GABA. Pharmacol Biochem Behav 1991;39:345–349.
tremor. Ann Neurol 1997;42:292–299. Class III.
67. Mally J, Stone TW. Efficacy of an adenosine antagonist, theophylline, 89. Pahwa R, Lyons KL, Wilkinson SB, et al. Bilateral thalamic stimula- in essential tremor: comparison with placebo and propranolol. J Neurol tion for the treatment of essential tremor. Neurology 1999;53:1447– Sci 1995;132:129 –132.
1450. Class III.
68. Koller WC, Royse VL. Efficacy of primidone in essential tremor. Neurol- 90. Carpenter MA, Pahwa R, Miyawaki KL, et al. Reduction in voice tremor ogy 1986;36:121–124. Class II.
under thalamic stimulation. Neurology 1998;50:796 –798. Class III.
69. Sasso E, Perucca E, Fava R, et al. Primidone in the long-term treat- 91. Taha JM, Janszen MA, Favre J. Thalamic deep brain stimulation for ment of essential tremor: a prospective study with computerized quan- the treatment of head, voice, and bilateral limb tremor. J Neurosurg titative analysis. Clin Neuropharmacol 1990;13:67–76. Class III.
70. Calzetti S, Sasso E, Baratti M, et al. Clinical and computer-based 92. Limousin P, Speelman JD, Gielen F, et al. Multicentre European assessment of long-term therapeutic efficacy of propranolol in essential study of thalamic stimulation in parkinsonian and essential tremor.
tremor. Acta Neurol Scand 1990;81:392–396. Class III.
J Neurol Neurosurg Psychiatry 1999;66:296 –298.
71. Brin MF, Lyons KE, Doucette J, et al. A randomized, double masked, 93. Ondo W, Jankovic J, Schwartz K, et al. Unilateral thalamic deep brain controlled trial of botulinum toxin type A in essential hand tremor.
stimulation for refractory essential tremor and Parkinson's disease Neurology 2001;56:1523–1528. Class I.
tremor. Neurology 1998;51:1063–1069. Class III.
72. Pahwa R, Busenbark K, Swanson-Hyland EF, et al. Botulinum toxin treat- 94. Koller WC, Lyons KE, Wilkinson SB, Pahwa R. Efficacy of unilateral ment of essential head tremor. Neurology 1995;45:822– 824. Class II.
deep brain stimulation of the VIM nucleus of the thalamus for essen- 73. Wissel J, Masuhr F, Schelosky L. Quantitative assessment of botuli- tial head tremor. Mov Disord 1999;14:847– 850.
num toxin treatment in 43 patients with head tremor. Mov Disord 95. Pahwa R, Lyons KE, Wilkinson SB, et al. Comparison of thalamotomy to deep brain stimulation of the thalamus in essential tremor. Mov 74. Warrick P, Dromey C, Irish JC, et al. Botulinum toxin for essential Disord 2001;16:140 –143. Class IV.
tremor of the voice with multiple anatomical sites of tremor: a crossover 96. Tasker RR. Deep brain stimulation is preferable to thalamotomy for design study of unilateral versus bilateral injection. Laryngoscope 2000; tremor suppression. Surg Neurol 1998;49:145–153; discussion 153– 110:1366 –1374. Class III.
154. Class IV.
75. Hertegard S, Granqvist S, Lindestad PA. Botulinum toxin injections for 97. Ondo W, Almaguer M, Jankovic J, et al. Thalamic deep brain stimula- essential voice tremor. Ann Otol Rhinol Larnygol 2000;109:204 –209.
tion: comparison between unilateral and bilateral placement. Arch Neurol 2001;58:218 –222. Class III.
76. Schuurman PR, Bosch DA, Bossuyt PM, et al. A comparison of continu- 98. Niranjan A, Kondziolka D, Baser S, et al. Functional outcomes after ous thalamic stimulation and thalamotomy for suppression of severe gamma knife thalamotomy for essential tremor and MS-related tremor. N Engl J Med 2000;342:461– 468. Class I.
tremor. Neurology 2000;55:443– 446. Class IV.
77. Nagaseki Y, Shibazaki T, Hirai T, et al. Long-term follow-up results of 99. Young RF, Jacques S, Mark R, et al. Gamma knife thalamotomy for selective VIM-thalamotomy. J Neurosurg 1986;65:296 –302. Class III.
treatment of tremor: long-term results. J Neurosurg 2000;93:128 –135.
78. Zirh A, Reich SG, Dougherty PM, et al. Stereotactic thalamotomy in the treatment of essential tremor of the upper extremity: reassessment 100. Siderowf A, Gollump SM, Stern MB, et al. Emergence of complex, including a blinded measure of outcome. J Neurol Neurosurg Psychia- involuntary movements after gamma knife radiosurgery for essential try 1999;66:772–775. Class III.
tremor. Mov Disord 2001;16:965–967. Class IV.
June (2 of 2) 2005
Practice Parameter: Therapies for essential tremor: Report of the Quality
Standards Subcommittee of the American Academy of Neurology
T. A. Zesiewicz, R. Elble, E. D. Louis, R. A. Hauser, K. L. Sullivan, R. B. Dewey, Jr, W. G. Ondo, G. S. Gronseth and W. J. Weiner 2005;64;2008-2020; originally published online Jun 22, 2005; DOI: 10.1212/01.WNL.0000163769.28552.CD This information is current as of January 23, 2007
including high-resolution figures, can be found at: & Services
A related article has been published: Supplementary material can be found at: http://www.neurology.org/cgi/content/full/01.WNL.0000163769.2 This article, along with others on similar topics, appears in thefollowing collection(s): Tremor
All Clinical trials
Permissions & Licensing
Information about reproducing this article in parts (figures, tables)or in its entirety can be found online at: Information about ordering reprints can be found online:
A Case Report on Recovery of Nephrotic Syndrome via Fradarmani Nephrotic Syndrome with minimal or are steroid dependent, generally undergo change (MCNS) is also known as Nil disease 8 weeks treatment with an Alkylating agent or Lipoid Nephrosis. It accounts for 85-90 such as Chlorambucil (0.1 - 0.2 mg/kg/day) percent of nephrotic syndrome in children or Cyclophosphamide (2mg/Kg/day). Re-
Lithium Insertion in Nanostructured TiO2(B) ANTHONY G. DYLLA, GRAEME HENKELMAN, AND KEITH J. STEVENSON* Department of Chemistry & Biochemistry, The University of Texas at Austin, Austin, Texas 78712, United States RECEIVED ON JUNE 12, 2012 to become feasible alternatives to current technology, but only if scientists can develop energy storage materialsthat offer high capacity and high rate capabilities. Chemists havestudied anatase, rutile, brookite and TiO2(B) (bronze) in bothbulk and nanostructured forms as potential Li-ion batteryanodes. In most cases, the specific capacity and rate of lithiationand delithiation increases as the materials are nanostructured.Scientists have explained these enhancements in terms of highersurface areas, shorter Liþ diffusion paths and different surfaceenergies for nanostructured materials allowing for more facilelithiation and delithiation. Of the most studied polymorphs,nanostructured TiO2(B) has the highest capacity with promising high rate capabilities. TiO2(B) is able to accommodate 1 Liþ per Ti,giving a capacity of 335 mAh/g for nanotubular and nanoparticulate TiO2(B). The TiO2(B) polymorph, discovered in 1980 by Marchand andco-workers, has been the focus of many recent studies regarding high power and high capacity anode materials with potential applicationsfor electric vehicles and grid storage. This is due to the material's stability over multiple cycles, safer lithiation potential relative to graphite,reasonable capacity, high rate capability, nontoxicity, and low cost (Bruce, P. G.; Scrosati, B.; Tarascon, J.-M. Nanomaterials for RechargeableLithium Batteries. Angew. Chem., Int. Ed. 2008, 47, 2930"2946). One of the most interesting properties of TiO2(B) is that both bulk andnanostructured forms lithiate and delithiate through a surface redox or pseudocapacitive charging mechanism, giving rise to stable high ratecharge/discharge capabilities in the case of nanostructured TiO2(B). When other polymorphs of TiO2 are nanostructured, they still mainlyintercalate lithium through a bulk diffusion-controlled mechanism. TiO2(B) has a unique open crystal structure and low energy Liþ pathwaysfrom surface to subsurface sites, which many chemists believe to contribute to the pseudocapacitive charging.