Holmes Tremor Research Articles

EEG Findings in a Patient with Holmes Tremor after AVM Surgery: A Case Report and Literature Review.

Background: Holmes tremor (HT) is a rare motor disorder characterized by high-amplitude and low-frequency resting, intentional, and postural tremors. HT typically arises from disruptions in neural pathways, including the dopaminergic system. Its causes include cerebrovascular incidents, neoplasms, demyelination, and infections. Diagnosis involves thorough clinical, neurophysiological, and neuroimaging assessments. Our report details the clinical profile, neuroimaging and EEG results and levodopa treatment response of an HT patient after cerebral arteriovenous malformation (AVM) surgery. Case Report: A female patient who underwent AVM surgery developed head tremor and dystonia. Neuroimaging revealed left thalamus involvement. Video electroencephalography (EEG) revealed high-amplitude, low-frequency tremors. The patient responded well to levodopa treatment. Conclusions: Involuntary rhythmic or non-rhythmic movements are a primary clinical feature of HT. A differential diagnosis of epilepsy and HT can be achieved through neurophysiological monitoring, avoiding the overuse of antiepileptic drugs. Symptoms can be alleviated with levodopa intervention.

Functional Neurological Disorders Among Patients With Tremor.

Functional neurological disorders (FNDs) are increasingly recognized in the general population and neurology clinics, and there is evidence that patients with neurological disorders are more likely to have a FND. This study was designed to identify the clinical features of FNDs among patients with movement disorders when the two disorders coexist. The clinical histories and video recordings of 150 consecutive patients with tremors were examined: the types of tremor included essential tremor; essential tremor plus; dystonic tremor; tremor associated with dystonia; and drug-induced, myoclonic, orthostatic, task-specific, parkinsonian, Holmes, and unclassified tremor. Using criteria for "possible" and "probable" coexistent FND, clinical features that helped differentiate between functional and other neurological tremors were identified. There were 27 (18%) patients with functional manifestations, and 17 (11% of full sample) of these patients had signs suggestive of comorbid functional tremor. Patients with comorbid functional manifestations were younger at presentation, and these patients had greater severity of tremor, particularly upper limb postural tremor. Functional manifestations were not more commonly observed among patients with any particular type of tremor, except for patients with Holmes tremor, who were more likely to have comorbid functional neurological manifestations. About 18% of patients with diverse types of tremors also had comorbid functional neurological manifestations. Of the coexistent FNDs, functional tremor was the most common. Patients with co-occurring functional and other neurological tremors presented for evaluation at a younger age and had greater severity of arm tremor than those without comorbid functional neurological manifestations.

Holmes Tremor in A Case of AIDS with Toxoplasma Abscess: Is A Common Result of Different Pathogenetic Mechanisms?

Holmes tremor is a low-frequency tremor clinic that predominantly affects proximal extremities during rest, posture, and action. It is generally associated with lesions located in the mesencephalon or thalamus. It is thought that the clinic is formed in similar phenomenology but as a result of different physiopathologic events. It is known that weeks, months, or even years pass from the underlying cause for the duration of symptoms. In this article, it is aimed to present a case of Holmes tremor, developing approximately nine months after HIV-related toxoplasmic abscess located in the mesencephalon and the thalamus and to discuss these rare associations with the literature.

Deep Brain Stimulation with Double Targeting of the VIM and PSA for the Treatment of Rare Tremor Syndromes

Introduction: In tremor syndromes, pharmacological therapy is the primary treatment, but deep brain stimulation (DBS) is used when it is insufficient. We explore the use of DBS, focusing on the globus pallidus internus for dystonia and the ventral intermediate nucleus (VIM) for tremor conditions. We introduce the posterior subthalamic area (PSA) as a potential target, suggesting its efficacy in tremor reduction, particularly in rare tremor syndromes. We aim to evaluate the efficacy and safety of double targeting the VIM and PSA in rare tremor conditions, highlighting the limited existing data on this. Methods: Between 2019 and 2023, 22 patients with rare tremor syndromes were treated with bilateral DBS of the VIM and PSA. This case series consisted of 7 isolated head tremor, 1 hepatic encephalopathic tremor due to Abernethy syndrome, 2 voice tremor, 4 dystonic tremor, and 8 Holmes tremor (2 multiple sclerosis, 2 cerebellar insult, and 4 posttraumatic) patients. Patients’ preoperative and 12-month postoperative tremor scores were compared, and the optimum VIM and PSA stimulation areas were investigated. Results: There was a significant reduction in the mean TRS score from 3.70 (±0.57) to 0.45 (±0.68) after 12 months of surgery. Specific outcomes for different indications were observed: for head tremor, 6 of 7 patients showed a reduction in TRS scores to 0 points; the vocal tremor patients demonstrated improvement; this change was not statistically significant, which is likely to be due to the low number of patients in this subgroup; the dystonic tremor patients showed either complete tremor abolition or a reduction in TRS scores; the Holmes tremor patients showed an 80% reduction in TRS scores; and the hepatic encephalopathy tremor and Abernethy syndrome patients showed a 75% improvement in TRS scores. The stimulation parameters converged on the VIM and dorsal PSA. Complications included the need for electrode repositioning, infections requiring electrode removal and re-implantation, dysarthria, and stimulation-induced ataxia, which was resolved by adjusting the stimulation parameters. Discussion: The literature on DBS for rare tremors is limited. Double targeting of the VIM and PSA appears to produce promising improvements on the outcomes reported in the existing literature on VIM-only DBS. The proximity of the VIM and PSA allows for flexible electrode placement, contributing to the potential success of the dual-target approach. We also discuss the theoretical advantages of targeting the PSA based on the distribution of tremor circuits, emphasizing the need for further research and electrophysiological studies.

Movement Disorders in Brain Sagging Syndrome Due To Spontaneous Intracranial Hypotension: A Review.

Spontaneous intracranial hypotension (SIH), a treatable condition that stems from spinal leakage of cerebrospinal fluid, usually presents with orthostatic headache, nausea, vomiting, dizziness, and tinnitus. A subset of patients, especially those with sagging of brain structures ("brain sagging syndrome"), develop several movement abnormalities. As SIH is treatable with epidural blood patch (EBP), movement disorders neurologists should be familiar with this syndrome. The authors performed a literature search in PubMed in July 2024 using the Boolean phrase- (("Brain sagging")OR("Intracranial hypotension"))AND(((((((((("Movement disorders")OR("Involuntary movements"))OR("Tremor"))OR("Dystonia"))OR("Chorea"))OR("Ballismus"))OR("Myorhythmia"))OR ("Tic"))OR("Ataxia"))OR("Parkinsonism")). We tabulated 21 case reports/series that highlighted the presence of movement disorders. The most reported phenomenology is gait unsteadiness. While it usually emerges in the background of the classic SIH symptoms, rarely, patients may present with isolated gait dysfunction. Tremor is the second most reported phenomenology with postural and kinetic tremor being the common subtypes. Holmes tremor has also been reported in SIH. Other reported phenomenologies are parkinsonism, chorea, and dystonia. One study reported a unique phenomenology i.e. compulsive repetitive flexion and breath holding in 35.3% of the patients. In majority of the patients, EBP resulted in substantial clinical and radiological improvement. Brain sagging syndrome due to SIH may present with a wide range of movement disorders. Mechanical distortion of the posterior fossa and subcortical structures result in the emergence of such movement abnormality. SIH adds to the list of conditions that result in "treatable movement disorders." Therefore, movement disorders neurologists should be versed with the diagnosis and clinical features of this condition.

Repetitive transcranial magnetic stimulation (RTMS) as a modality of Holmes tremor therapy: Case report

Repetitive transcranial magnetic stimulation (RTMS) as a modality of Holmes tremor therapy: Case report

Holmes tremor in progressive multifocal leukoencephalopathy: A video case report

AbstractBackgroundProgressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system caused by the John Cunningham virus. Various brain regions are affected by PML. Therefore, patients with PML show various neurological symptoms. However, tremors are rare neurological symptoms of PML.Case PresentationA 49‐year‐old man developed intermittent slow tremor in the left hand, bilateral dysesthesia and gait disturbance. Brain magnetic resonance imaging showed hyperintense lesions in the right parietofrontal lobe, right thalamus, left middle cerebellar peduncle, left dentate nucleus, pons and medulla oblongata on fluid‐attenuated inversion recovery images. The patient was positive for HIV antibodies. In addition, HIV‐1 RNA was increased. Quantitative real‐time polymerase chain reaction identified John Cunningham virus DNA in the cerebrospinal fluid; HIV‐associated PML was diagnosed. Surface electromyography showed 3‐Hz grouped discharges in the left flexor carpi ulnaris and extensor carpi radialis, which were consistent with Holmes tremor (HT). Although we administered antiretroviral therapy and mirtazapine, the neurological and radiological findings progressively worsened, and the patient died on day 90. Including the present case, there have been 10 reported cases of PML with HT.ConclusionsAlthough tremors are rarely observed in PML, HT might be a common tremor phenotype in patients with PML. If the neurologist observes HT in patients with multiple brain lesions, PML should be considered.

Abstract 103: Acute Onset Rhythmic Tremor In Acute Frontal Cortical Infarction: A Case Report

Introduction Acute ischemic stroke varies in presentation, and it is crucial to quickly identify patients presenting with stroke for timely intervention. Secondary movement disorders occurring after a delayed period following ischemic stroke have been well‐documented, though rare. Holmes tremor specifically has been described as a delayed result of ischemic infarction involving subcortical structures such as mollaret triangle, thalamus, and basal ganglia. However, it is novel for frontal cortical infarcts to present with acute‐onset contralateral limb tremor, especially as an isolated symptom. Our case suggests a “secondary insult” involving the frontal cortex can disinhibit the motor pathway that leads to tremor in preexisting midbrain and thalamic lesions. We present a 67‐year‐old male with acute onset, constant, rhythmic tremor in the setting of acute ischemic frontal cortical infarction. Methods n/a, case report Results A 67‐year‐old male with medical history of pineal gland cyst status‐post shunt placement and hypertension who presented for evaluation of acute onset right upper extremity rhythmic tremor that started 24 hours prior. He did not have any associated weakness, numbness, vision changes, nausea, or vomiting. He had never had this tremor before. Neurologic examination was significant for a 4.0 Hz rhythmic resting tremor that was present throughout exam and was non‐distractible. This tremor remained consistent even with kinetic movements and postures. Electroencephalogram (EEG) was performed STAT during this tremor and was not based in seizure. Non‐contrast head computerized tomography (CT) was negative for any acute hemorrhage or intracranial pathology. CT angiogram head and neck showed left internal carotid artery (ICA) long segment tapered occlusion from the proximal cervical ICA to the distal petrous segment, likely dissection of undetermined chronicity. Magnetic resonance imaging (MRI) Brain with and without contrast was significant for acute punctate foci involving the precentral cortex of the left frontal lobe consistent with acute ischemic infarction. Encephalomalacia was also present involving the bilateral posterior thalami and left midbrain chronic ischemic infarctions. This suggests the tremor was caused by disinhibition of the motor pathway from the ischemic insult to the frontal cortex, as he had pre‐existing asymptomatic ischemic insult to the typical structures known to cause this tremor. He was outside of the Tenecteplase window and was given a load of Aspirin followed by aspirin 81 mg daily. He was trialed on propranolol for treatment of symptomatic tremor however this was discontinued before discharge as it was ineffective and patient preferred to hold off on other treatments. He is now awaiting outpatient Neurology follow up. Conclusion This case suggests that acute onset Holmes tremor can be the sole presenting sign in acute ischemic frontal cortical infarction. The pre‐existing asymptomatic infarctions in the midbrain and thalamus also support that a “second hit” located in the frontal cortex can disinhibit the motor pathway between the cortex and rubral tract. This is important as Holmes tremor is more commonly known to be from a mechanism of damage to the red nucleus or thalamic structures in a delayed manner, typically at least two weeks after stroke. This knowledge will help identify rare strokes in a timely manner.

Analysis of Semiology, Lesion Topography and Treatment Outcomes: A Prospective Study on Post Thalamic Stroke Holmes Tremor.

Holmes tremor (HT) comprises rest, postural and intention tremor subtypes, usually involving both proximal and distal musculature. Perturbations of nigro-striatal pathways might be fundamental in the pathogenesis of HT along with cerebello-thalamic connections. Nine patients with an HT phenotype secondary to thalamic stroke were included. Epidemiological and clinical records were obtained. Structural and functional brain imaging were performed with magnetic resonance imaging (MRI) or computed tomography (CT) and positron emission tomography (PET), respectively. Levodopa was administered in sequentially increasing dosage, with various other drugs in case of inadequate response. Longitudinal follow-up was performed for at least three months. The essential tremor rating assessment scale (TETRAS) was used for assessment. The mean latency from stroke to tremor onset was 50.4 ± 30.60 days (range 21-90 days). Dystonia was the most frequently associated hyperkinetic movement (88.8%). Tremor was bilateral in 22.2% of participants. Clinical response was judged based on a reduction in the TETRAS score by a prefixed value (≥ 30%), pertaining to which 55.5% (n = 5) of subjects were classified as responders and the rest as non-responders. The responders showed improvement with significantly lower doses of levodopa than the remaining nonresponders (240 ± 54.7 mg vs. 400 ± 40.8 mg; p = 0.012). Although levodopa is useful in HT, augmenting the dosage of levodopa beyond a certain point might not benefit patients clinically. Topography of vascular lesions within the thalamus might additionally influence the phenomenology of HT.

The Relevance of Intraoperative Clinical and Accelerometric Measurements for Thalamotomy Outcome.

Thalamotomy alleviates medication-refractory tremors in patients with movement disorders such as Parkinson's Disease (PD), Essential tremor (ET), and Holmes tremor (HT). However, limited data are available on tremor intensity during different thalamotomy stages. Also, the predictive value of the intraoperative tremor status for treatment outcomes remains unclear. Therefore, we aimed to quantify tremor status during thalamotomy and postoperatively. Data were gathered between January 2020 and June 2023 during consecutive unilateral thalamotomy procedures in patients with PD (n = 13), ET (n = 8), and HT (n = 3). MDS-UPDRS scores and tri-axial accelerometry data were obtained during rest, postural, and intention tremor tests. Measurements were performed intraoperatively (1) before lesioning-probe insertion, (2) directly after lesioning-probe insertion, (3) during coagulation, (4) directly after coagulation, and (5) 4-6 months post-surgery. Accelerometric data were recorded continuously during the coagulation process. Outcome measures included MDS-UPDRS tremor scores and accelerometric parameters (peak frequency, tremor amplitude, and area under the curve of power (AUCP)). Tremor intensity was assessed for the insertion effect (1-2), during coagulation (3), post-coagulation effect (1-4), and postoperative effect (1-5). Following insertion and coagulation, tremor intensity improved significantly compared to baseline (p < 0.001). The insertion effect clearly correlated with the postoperative effect (ρ = 0.863, p < 0.001). Both tremor amplitude and AUCP declined gradually during coagulation. Peak frequency did not change significantly intraoperatively. In conclusion, the study data show that both the intraoperative insertion effect and the post-coagulation effect are good predictors for thalamotomy outcomes.

Giant Tumefactive Perivascular Spaces: An Unusual Cause of Holmes Tremor

A 34-year-old man presented with a 2-year history of medically refractory Holmes tremor in the right upper limb. Magnetic resonance imaging revealed a large, nonenhancing, multiseptate cystic lesion of cerebrospinal fluid intensity in the left thalamopeduncular region causing brainstem compression and hydrocephalus. A diagnosis of giant tumefactive perivascular spaces was made after a biopsy ruled out an infectious or neoplastic etiology. Significant clinicoradiologic improvement was noted following a ventriculoperitoneal shunt. Giant tumefactive perivascular spaces should be included as one of the rare differentials of a large, nonenhancing cystic lesion situated along the course of perforator vessels. Treatment options include cerebrospinal fluid diversion with or without cyst fenestration.

Levodopa-responsive Holmes Tremor in a Young Patient with Hypertrophic Olivary Degeneration

Levodopa-responsive Holmes Tremor in a Young Patient with Hypertrophic Olivary Degeneration

Functional and structural lesion network mapping in neurological and psychiatric disorders: a systematic review.

The traditional approach to studying the neurobiological mechanisms of brain disorders and localizing brain function involves identifying brain abnormalities and comparing them to matched controls. This method has been instrumental in clinical neurology, providing insight into the functional roles of different brain regions. However, it becomes challenging when lesions in diverse regions produce similar symptoms. To address this, researchers have begun mapping brain lesions to functional or structural networks, a process known as lesion network mapping (LNM). This approach seeks to identify common brain circuits associated with lesions in various areas. In this review, we focus on recent studies that have utilized LNM to map neurological and psychiatric symptoms, shedding light on how this method enhances our understanding of brain network functions. We conducted a systematic search of four databases: PubMed, Scopus, and Web of Science, using the term "Lesion network mapping." Our focus was on observational studies that applied lesion network mapping in the context of neurological and psychiatric disorders. Following our screening process, we included 52 studies, comprising a total of 6,814 subjects, in our systematic review. These studies, which utilized functional connectivity, revealed several regions and network overlaps across various movement and psychiatric disorders. For instance, the cerebellum was found to be part of a common network for conditions such as essential tremor relief, parkinsonism, Holmes tremor, freezing of gait, cervical dystonia, infantile spasms, and tics. Additionally, the thalamus was identified as part of a common network for essential tremor relief, Holmes tremor, and executive function deficits. The dorsal attention network was significantly associated with fall risk in elderly individuals and parkinsonism. LNM has proven to be a powerful tool in localizing a broad range of neuropsychiatric, behavioral, and movement disorders. It holds promise in identifying new treatment targets through symptom mapping. Nonetheless, the validity of these approaches should be confirmed by more comprehensive prospective studies.

Novel Mutation In The APT13A2 Gene Associated With Ataxia, Cerebellar Tremor, Bipolar Disease and Epilepsy (P9-11.010)

<h3>Objective:</h3> To Report a Novel Mutation In The ATP13A2 Gene Causing Cerebellar Ataxia With Bipolar Disorder And Epilepsy Without Parkinsonism. <h3>Background:</h3> ATP13A2 gene mutations are rare and initially were identified in patients with autosomal recessive (AR) juvenile onset of parkinsonism with supranuclear gaze palsy, and dementia, also known as Kufer-Rakeb disease. Subsequently, recognized phenotypic variability of biallelic mutations in this gene widened and include AR hereditary spastic paraplegia or spastic ataxia. Pure cerebellar ataxia is rarely caused by mutations in this gene. <h3>Design/Methods:</h3> Case report and genetic analysis of the ATP13A2 gene in affected proband and both parents. <h3>Results:</h3> The proband is a 40-year-old male of Iranian descent who developed difficulties walking with multiple falls as a teenager. He transitioned from a walker to a wheelchair dependency in his 20s. He was diagnosed with spinocerebellar ataxia with Holmes tremor in both arms. His examination showed vertical ophthalmoplegia without any signs of Parkinsonism or spasticity. The patient had signs of a mild developmental delay and in his 20s he was also diagnosed with bipolar disorder. He developed seizures in his 40s and they were well-controlled on levetiracetam. Brain MRI showed cerebellar atrophy with no iron deposits in basal ganglia. His parents were first cousins. Family history was noticeable for similar problems in two deceased cousins who were also from consanguineous marriages. Genetic testing showed a novel homozygous mutation in exon 26 of ATP13A2, c.2899G&gt;C (p.Asp967His). We did not find this in 100 controls. Both parents were heterozygous at the same codon. We also confirmed the mutation in the CLIA certified laboratory, which is cataloged as rs772870846. In vitro analysis showed this variant being deleterious. <h3>Conclusions:</h3> We report a novel mutation in the ATP13A2 gene with unique constellation of clinical features, further expanding the phenotypic spectrum of movement disorders associated with this genetic condition. <b>Disclosure:</b> Dr. Yousaf has nothing to disclose. Dr. D’Aguiar Rosa has nothing to disclose. Dr. Ghani has nothing to disclose. Dr. Hedera has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Hedera has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Abbvie. Dr. Hedera has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for University of Louisville.

Teaching Neuro Images : Holmes tremor after midbrain stroke

A 69-year-old man presented with a continuous right upper extremity resting tremor with a 3-Hz frequency ([video 1][1]). The tremor developed gradually, 4 months after a left midbrain stroke. MRI showed an infarct in the left medioventral midbrain ([figure 1][2]). [123I]-2β-carbomethoxy-3β-(4-

153 Utilizing a 32-Channel System for Treatment of Complex Movement Disorders: Initial Case Series

INTRODUCTION: Complex, mixed movement disorders affecting multiple pathways (e.g., Holme’s Tremor (HT) or comorbid essential tremor (ET) with dystonia, among others) represent significant challenges for surgical treatment. These disease states are likely the result of combined or complex network pathologies, requiring multi-nodal targeting for DBS. METHODS: Multiple simultaneous deep targets were implanted using four 8-contact, directional leads placed through 2 burr-holes, which were connected to a 32-channel pulse generator. Targets were chosen based on disorders and comorbidities. RESULTS: Seven complex movement disorder patients were operated on at Stanford University using the approach described above. All seven patients in the series reported significant improvement in symptoms, and four patients also had objective metrics recorded demonstrating significant improvements. In these four patients, patient A presented with DBS-refractory Parkinsonian tremor and showed additional 17% reduction in UPDRS after addition of a third lead from an existing burr hole, utilizing the 32-channel system. Similarly patient C with HT and patients D and E with ET/dystonia all demonstrated significant improvement in TRS (p &lt; 0.01) and dystonic symptoms after bilateral dual targeting of VIM and GPi through two burr-holes. Programming utilized tailored fractionation and stimulation parameters to achieve optimal results. CONCLUSIONS: We present the largest initial case series demonstrating the feasibility of a 32-channel multi-target DBS strategy for treating complex movement disorders. This approach warrants further investigation for treating complex, multi-circuit neuropsychiatric disorders.

Wernekink Commissure Syndrome With Bilateral Cerebellar Signs and Holmes Tremor in a Patient With a Preexisting Movement Disorder

Wernekink commissure syndrome (WCS) is an extremely rare midbrain syndrome, in which there is the selective destruction of the decussation of the superior cerebellar peduncle, which commonly presents with bilateral cerebellar signs. We describe a case of WCS with Holmes tremorin a patient having an undiagnosed involuntary movement disorder since childhood following an undocumented case of meningitis. The patient presented with sudden onset gait instability with bilateral cerebellar signs (more prominent on the left side), Holmes tremorin bilateral limbs, slurred speech, and marked dysarthria. No ophthalmoplegia or palatal tremors were noted. The patient was conservatively managed along the lines of a stroke, and there was a marked improvement in cerebellar signs and Holmes tremorwith time but no evolution (improvement or worsening) was observed in the involuntary movements of limbs and face that were present before the onset of WCS.

Deep Brain Stimulation for Holmes Tremors and Literature Review.

Deep Brain Stimulation for Holmes Tremors and Literature Review.

Optimal deep brain stimulation connectivity to treat Holmes tremor

Optimal deep brain stimulation connectivity to treat Holmes tremor

Presynaptic Hemiparkinsonism Following Cerebral Toxoplasmosis: Case Report and Literature Review.

Cerebral toxoplasmosis (CTx) is a central nervous system opportunistic infection with variable neurological manifestations. Although tropism of Toxoplasma gondii for the basal ganglia is well known, movement disorders (MDs) represent only a small percentage of CTx-related neurological complications. CTx-associated MDs are usually hyperkinetic, whereas parkinsonism associated with evidence of presynaptic dopaminergic deficit has never been described. We report a human immunodeficiency virus-positive patient who developed a complex MD featuring unilateral tremor combined with parkinsonism and dystonia following an acute episode of disseminated CTx. Her dopamine transporter scan (DaTscan) documented contralateral presynaptic dopaminergic deficit. Levodopa initiation improved both tremor and parkinsonism after ineffective trials of several other medications over the years. A total of 64 patients presenting with CTx-related MDs have been described. The most common MD was chorea (44%), followed by ataxia (20%), parkinsonism (16%), tremor (14%), dystonia (14%), myoclonus (3%), and akathisia (2%). DaTscan was performed only in 1 case, of Holmes tremor, that demonstrated reduced presynaptic dopaminergic uptake. Positive response to dopaminergic treatment was reported in 3 cases of Holmes tremor and 2 cases of parkinsonism. Presynaptic dopaminergic deficit may occur in CTx-related tremor combined with parkinsonism. Its identification should prompt initiation of levodopa, thus avoiding unnecessary trials of other drugs.