The Action of Botulinum Toxin A on the Sternocleidomastoid Muscle: An Experimental Study on Rats.

In this study, we aim to investigate the effective dose of botulinum neurotoxin A that results in paralysis of the sternocleidomastoid muscle for a minimum duration of 28 days in Wistar rats. This research is the first in a series of studies to investigate the value of botulinum toxin A in the healing of clavicle fractures through the temporary paralysis of the sternocleidomastoid. A surgical incision was made under general anaesthesia, and botulinum neurotoxin A in respective doses of 4 and 6 international units (IU) or normal saline in equivalent volumes were injected directly into the exposed muscle. Electromyography was conducted on days 0, 7, and 28 following substance administration to determine the extent of muscle paralysis. Electromyography on day 0 showed no paralysis in either group. Animals injected with neurotoxin all exhibited paralysis on days 7 and 28 that was weaker in the group injected with the smaller dose of 4 IU. One death occurred in the group injected with the higher dose (6 IU), whereas in the control group, no paralysis was seen. Botulinum neurotoxin A in a dose of 6 IU resulted in complete paralysis of the sternocleidomastoid in rats for a minimum of 28 days. A dose of 4 IU resulted in less potent paralysis but was safer in our research. Botulinum neurotoxin is a substance utilised in cosmetics and therapeutics for many years, yet research shows that its use can be expanded to target a wider range of pathologies. In this series of studies, we aim to explore the neurotoxin's applications on the treatment of clavicle fractures. To investigate this, we need to first establish the duration of its action on the sternocleidomastoid muscle.

Botulinum toxin treatment of dystonic anterocollis: What to inject.

BACKGROUND: Anterocollis (AC) is a rare form of cervical dystonia, which responds poorly to botulinum toxin treatment. OBJECTIVES: To recognise the different clinical phenotypes of AC and to detail the selection of muscles from the results of treating a cohort of 15 AC patients with Botulinum Toxin. METHODS: The study was performed using prospectively collected data. We included 15 patients with cervical dystonia and AC posture, treated between 2016 and 2019 in our joint Neuro-ENT clinic. We excluded patients with posterior cervical muscle weakness and patients with Parkinsonism. We characterised the primary dystonic posture of every AC patient as posterior sagittal shift, head flexion or neck flexion, or a combination of the three. RESULTS: All AC patients had a more widespread dystonic picture with a majority having Meige syndrome, but AC was the most problematic feature. Treatment with botulinum toxin required the injection not only of the deep cervical flexor (DCF), but also the sterno-cleido-mastoid (SCM) and moreover the supra-hyoid (SH) muscles. The choice between the longus capiti and the longus colli depended on the AC posture. Half of the patients had a dramatic improvement with 90% satisfaction or above. CONCLUSION: AC posture is a complex but treatable type of CD. A joint Neuro-ENT clinic is an ideal setting in which to target all the dystonic muscles. This allows the injection of the longus capiti (under nasal endoscopic approach) as well as the supra-hyoid and SCM muscles in the same session.

Anatomo-sonographic identification of the longissimus capitis and splenius cervicis muscles: principles for possible application to ultrasound-guided botulinum toxin injections in cervical dystonia.

OBJECTIVE: The main objective of this study was to define and verify anatomo-sonographic landmarks for ultrasound-guided injection of botulinum toxin into the longissimus capitis (LC) and splenius cervicis (SC) muscles. METHODS AND RESULTS: After a preliminary work of anatomical description of the LC and SC muscles, we identified these muscles on two cadavers and then on a healthy volunteer using ultrasound and magnetic resonance imaging (MRI) to establish a radio-anatomical correlation. We defined an anatomo-sonographic landmark for the injection of each of these muscles. The correct positioning of vascular glue into the LC muscle and a metal clip into the SC muscle of a fresh cadaver as verified by dissection confirmed the utility of the selected landmarks. DISCUSSION: For the LC muscle, the intramuscular tendon of the cranial part of the muscle appears to be a reliable anatomical landmark. The ultrasound-guided injection can be performed within the cranial portion of the muscle, between the intra-muscular tendon and insertion into the mastoid process at dens of the axis level. For the SC muscle, the surface topographic landmarks of the spinous processes of the C4-C5 vertebrae and the muscle body of the levator scapulae muscle seem to be reliable landmarks. From these, the ultrasound-guided injection can be carried out laterally by transfixing the body of the levator scapulae. CONCLUSION: The study defined two cervical anatomo-sonographic landmarks for injecting the LC and SC muscles.

Ultrasound Study to Validate the Anterior Cervical Approach to the Longus Colli Muscle Using Electromyography Control Alone.

Background: One of the main difficulties in the treatment of dystonic anterocollis is the injection of the deep flexor muscles of the neck such as Longus Colli (LCo). The injection of the LCo has been regarded as difficult and potentially dangerous; since we published our anterior median approach, a number of questions about the precision and the safety of our technique have been raised by colleagues. Methods: 7 patients with anterocollis were injected, using our injection technique and when the needle was deemed to be in place, we used the ultrasound probe to determine what the needle had passed through, the depth of the tip of the needle and if the identified muscle was indeed LCo. Results: On the ultrasound section the LCo muscle is between 24 and 28 mm deep in the patients examined in this study. The location of the needle was confirmed by ultrasound and in most cases the needle was placed in the right axis but sometimes not deep enough. The EMG control made it possible to correct the depth in all cases. In most of the injections the needle traversed the thyroid. No acute incident occurred by this route of injection. Injections were performed between 22 and 28 mm deep. Discussion: From this study and based on a review of complications over 9 years experience with injecting LCo under EMG control using an anterior approach, we conclude that this technique is precise, safe and well tolerated. Summary Highlights: The injection of the Longus Coli muscle for anterocollis has been regarded as difficult and potentially dangerous. This study showed, using ultrasound to determine the needle trajectory, that the anterior approach using EMG control is a precise, safe and well tolerated technique.

A methodological approach for botulinum neurotoxin injections to the longus colli muscle in dystonic anterocollis: A case series of 4 patients and a literature review.

We review the current approaches and their feasibility to treat dystonic anterocollis by injecting longus colli muscle (LCo) with botulinum neurotoxin (BoNT) as well as present our personal experiences in this field compared with the findings from previously published studies. First, we searched the PubMed database for the publications reporting patients who received LCo injections for anterocollis; we also thoroughly examined the references included in each of the found publications. Second, we present and analyze our own experiences in injecting LCo under EMG guidance in patients with dystonic anterocollis due to heredodegenerative disorders. We found 11 publications describing administration of LCo injections for the treatment of dystonic anterocollis in a total of 28 patients with primary dystonia aged between 21 and 80 years. The mean age of our patients was 44.8 years with the mean anterocollis duration being 15 months. OnabotulinumtoxinA in a dose of up to 35 U per LCo muscle was not associated with the development of transient dysphagia. The mean percentage of patient satisfaction was 36.3%, and the mean duration of the beneficial effect was 2.5 months. All patients agreed to receive a repeat injection. We provide a set of empirically based suggestions on the current use of BoNT injections to LCo for managing anterocollis in outpatient clinics, including pretreatment work-up, injection technique, and dose range.

Injection into the Longus Colli Muscle via the Thyroid Gland.

Background: Anterior forms of cervical dystonia are considered to be the most difficult to treat because of the deep cervical muscles that can be involved. Case Report: We report the case of a woman with cervical dystonia who presented with anterior sagittal shift, which required injections through the longus colli muscle to obtain a satisfactory outcome. The approach via the thyroid gland was chosen. Discussion: The longus colli muscle can be injected under electromyography (EMG), computed tomography (CT), ultrasonography (US), or endoscopy guidance. We recommend using both ultrasonography and electromyography guidance as excellent complementary techniques for injection at the C5-C6 level.

Evaluation of the efficacy of ropivacaine injection in the anterior and middle scalene muscles guided by ultrasonography in the treatment of Thoracic Outlet Syndrome.

OBJECTIVE: A clinical, placebo-controlled, randomized, double-blind trial with two parallel groups. OBJECTIVE: to evaluate the efficacy of ropivacaine injection in each belly of the anterior and middle scalene muscles, guided by ultrasonography, in the treatment of Nonspecific Thoracic Outlet Syndrome (TOS) compared to cutaneous pressure. METHODS: 38 patients, 19 in the control group (skin pressure in each belly of the anterior and middle scalene muscles) and 19 in the intervention group (ropivacaine). Subjects with a diagnosis of Nonspecific Thoracic Outlet Syndrome, pain in upper limbs and/or neck, with no radiculopathy or neurological involvement of the limb affected due to compressive or encephalic root causes were included. The primary endpoint was functionality, evaluated by the Disabilities of the Arm, Shoulder, and Hand - DASH scale validated for use in Brasil. The time of the evaluations were T0 = before the intervention; T1 = immediately after; T2 = 1 week; T3 = 4 weeks; T4 = 12 weeks; for T1, the DASH scale was not applied. RESULTS: Concerning the DASH scale, it is possible to affirm with statistical significance (p> 0.05) that the intervention group presented an improvement of functionality at four weeks, which was maintained by the 12th week. CONCLUSION: In practical terms, we concluded that a 0.375% injection of ropivacaine at doses of 2.5 ml in each belly of the anterior and middle scalene muscles, guided by ultrasonography, in the treatment of Nonspecific Thoracic Outlet Syndrome helps to improve function.

Evaluation of the efficacy of ropivacaine injection in the anterior and middle scalene muscles guided by ultrasonography in the treatment of Thoracic Outlet Syndrome

SUMMARY A clinical, placebo-controlled, randomized, double-blind trial with two parallel groups. OBJECTIVE to evaluate the efficacy of ropivacaine injection in each belly of the anterior and middle scalene muscles, guided by ultrasonography, in the treatment of Nonspecific Thoracic Outlet Syndrome (TOS) compared to cutaneous pressure. METHODS 38 patients, 19 in the control group (skin pressure in each belly of the anterior and middle scalene muscles) and 19 in the intervention group (ropivacaine). Subjects with a diagnosis of Nonspecific Thoracic Outlet Syndrome, pain in upper limbs and/or neck, with no radiculopathy or neurological involvement of the limb affected due to compressive or encephalic root causes were included. The primary endpoint was functionality, evaluated by the Disabilities of the Arm, Shoulder, and Hand - DASH scale validated for use in Brasil. The time of the evaluations were T0 = before the intervention; T1 = immediately after; T2 = 1 week; T3 = 4 weeks; T4 = 12 weeks; for T1, the DASH scale was not applied. RESULTS Concerning the DASH scale, it is possible to affirm with statistical significance (p> 0.05) that the intervention group presented an improvement of functionality at four weeks, which was maintained by the 12th week. CONCLUSION In practical terms, we concluded that a 0.375% injection of ropivacaine at doses of 2.5 ml in each belly of the anterior and middle scalene muscles, guided by ultrasonography, in the treatment of Nonspecific Thoracic Outlet Syndrome helps to improve function.

RESUMO Ensaio clínico, controlado por placebo, aleatorizado, duplo-cego, com dois braços paralelos. OBJETIVO Avaliar a eficácia da injeção de ropivacaína em cada ventre dos músculos escalenos anterior e médio, guiada por ultrassonografia, no tratamento da Síndrome do Desfiladeiro Torácico Neurogênico inespecífico comparado com o toque cutâneo. MÉTODOS Trinta e oito pacientes, sendo 19 no grupo controle (toque cutâneo em cada ventre dos músculos escalenos anterior e médio) e 19 no grupo intervenção (ropivacaína). Foram incluídos sujeitos com diagnóstico de Síndrome do Desfiladeiro Torácico Neurogênico inespecífico com dor em membros superiores e/ou cervicalgia sem radiculopatia ou comprometimento neurológico do membro em questão por causas radiculares compressivas ou encefálicas. O desfecho primário foi a funcionalidade avaliada pela escala Disabilitie of the Arm, Shoulder and Hand - Dash, validada no Brasil. O tempo das avaliações foram T0 = antes da intervenção; T1 = imediatamente após, T2 = 1 semana, T3 = 4 semanas e T4 = 12 semanas, sendo que para o T1 não foi aplicado o Dash. RESULTADOS Com relação ao Dash, de forma estatisticamente significante (p>0,05), é possível afirmar que o grupo intervenção apresentou melhora da funcionalidade a partir de quatro semanas, e essa melhora se manteve até a 12a semana. CONCLUSÃO Em termos práticos, conclui-se que a injeção de ropivacaína 0,375% nas doses de 2,5 ml em cada ventre dos músculos escalenos anterior e médio, guiada por ultrassonografia, no tratamento da Síndrome do Desfiladeiro Torácico Neurogênico inespecífico auxilia na melhora da função.

Local Anesthetic Block of the Anterior Scalene Muscle Increases Muscle Height in Patients With Neurogenic Thoracic Outlet Syndrome.

BACKGROUND: Local anesthetic (LA) blocks of the anterior scalene muscle are used to predict which patients with neurogenic thoracic outlet syndrome (TOS) may benefit from surgical decompression. The block is thought to work through both analgesic and muscle relaxation effects, but evidence of the latter is lacking. The aim of our study was to assess the effects of LA blocks on anterior scalene muscle anatomy as captured by magnetic resonance imaging (MRI). METHODS: Over a two-year period, a series of patients with neurogenic TOS underwent MRI-guided anterior scalene blocks with an LA. Patients underwent MRI both before injection and 30 minutes after injection. Anterior scalene muscle heights (measured from the superior border of the first rib to the top of C3 vertebrae) before and after injection were compared for the injected side and the noninjected (control) side, both overall and stratified by subjective patient response to injection. RESULTS: A total of 54 patients with neurogenic TOS were included. The median age was 39 years (interquartile range, 27-45), 61% were women, and 46% had a history of neck trauma. Forty-five patients (83%) had a favorable response to injection. Overall, there was no significant change in scalene muscle height for either the injected side (preinjection: 90.0 ± 1.2 mm vs. postinjection: 90.7 ± 1.2; P = 0.12) or the control side (preinjection: 89.3 ± 1.4 mm vs. postinjection: 88.9 ± 1.3 mm; P = 0.83). However, when stratified by patient response, those with a positive response had a larger increase in muscle height for the injected side than for the control side (change in baseline: 0.65 ± 0.58 mm vs. -0.53 ± 0.48 mm; P = 0.05). In contrast, nonresponders had no significant change in scalene height for either the injected or control side (change in baseline: 0.59 ± 1.30 mm vs. 0.37 ± 1.07; P = 1.00). Notably, responders had significantly longer anterior scalene muscles at baseline than nonresponders (92.2 ± 1.1 mm vs. 79.5 ± 2.5; P < 0.001). CONCLUSIONS: LA blocks of the anterior scalene muscle may provide symptomatic relief in patients with neurogenic TOS by increasing muscle height, although the clinical significance of this small change is unclear. Patients who do not have a response to the block tend to have significantly shorter anterior scalene muscle heights than patients who respond, suggesting an anatomic difference in responders versus nonresponders.

Thoracic Outlet Syndrome Treated With Injecting Botulinum Toxin Into Middle Scalene Muscle and Pectoral Muscle Interfascial Planes: A Case Report.

Thoracic outlet compression syndrome is a complex syndrome of neurovascular compression at the superior thoracic aperture, thought to occur at 1 of 3 anatomical compartments: the interscalene triangle, the costoclavicular space, and the retropectoralis minor space. Injection into the middle interscalene muscle (ISM) and/or pectoralis muscle plane (PECS I and II) is gaining popularity because it provides significant symptomatic relief. A 44-year-old woman was diagnosed with thoracic outlet compression syndrome, with failed conservative therapy, including physical therapy. She refused surgical intervention. ISM and PECS I and II blocks with botulinum toxin type A were successful. In combination, PECS I/II and ISM injections can provide excellent symptomatic relief.

Anatomical Look Into OnabotulinumtoxinA Injection for Chronic Migraine Headache.

BACKGROUND AND OBJECTIVES: While existing studies about onabotulinumtoxinA for chronic migraines have focused on injection location and appropriate dosing, little consideration has been given to patient body habitus and its potential impact on efficacy. We hypothesized that with increasing patient body mass index (BMI) there would be more subcutaneous fat separating targeted muscle groups from the skin surface, such that standard 0.5-inch needles used in existing protocols may not allow intramuscular injection. This may have implications for treatment planning. METHODS: Anatomically normal computed tomography scans of the head, neck, and face were randomly selected. Subjects were stratified into 4 groups based on BMI, with 30 patients in each group. Four standardized locations were chosen to obtain measurements from the skin surface to the underlying muscle fascia, including (1) frontalis, (2) temporalis, (3) semispinalis capitis, and (4) trapezius. RESULTS: Median depth for the temporalis was 12.65 mm (Q1 = 9.32 mm, Q3 = 15.08 mm) for the BMI greater than 35 kg/m group. Median depth for the semispinalis capitis was 13.77 mm (Q1 = 10.3 mm, Q3 = 15.7 mm) for the BMI 30 to 35 kg/m group, and 14.75 mm (Q1 = 11.00, Q3 = 17.00 mm) for the BMI greater than 35 kg/m group. Median depth for the trapezius was 13.95 mm (Q1 = 10.18 mm, Q3 = 19.00 mm) for the BMI greater than 35 kg/m group. These medians exceeded the length of the standard 0.5-inch (12.-mm) needle used in existing protocols. CONCLUSIONS: Our study demonstrates that with increasing BMI there is a greater distance between the skin surface and the muscle fascia of muscles that are targeted for injection in standard chronic migraine botulinum toxin injection protocols. Because of this, patient body habitus may be an important factor in injection technique.

A simplified ultrasonography-guided approach for neurotoxin injection into the obliquus capitis inferior muscle in spasmodic torticollis.

The obliquus capitis inferior (OCI) muscle may be crucially involved in generating the tremulous component of spasmodic torticollis. This study was undertaken to evaluate the efficacy of a simplified ultrasonography-guided approach of botulinum neurotoxin injection into the OCI in the management of spasmodic torticollis. Here, a novel off-plane technique of ultrasonography-guided botulinum neurotoxin injection into the OCI is demonstrated on video. We investigated its effect in five patients with tremulous torticollis with only partial response to conventional injection technique not injecting OCI. On ultrasonography the OCI and its neighboring structures (greater occipital nerve, vertebrae C1 and C2) were clearly displayed. Unlike the previously proposed approach with axial OCI imaging and in-plane medio-lateral needle insertion, we applied here an off-plane needle insertion technique. With this, the ultrasonography guidance of needle insertion was easier using the sagittal imaging plane rather than the axial plane. Compared to botulinum neurotoxin injection into more superficial neck muscles only, additional ultrasonography-guided botulinum neurotoxin injection into the OCI led to a higher benefit (self-rated improvement of cervical dystonia, p = 0.026, Mann-Whitney test), especially of the tremulous component (p = 0.007), even though the total botulinum neurotoxin dose was not changed. We conclude that selected patients with tremulous torticollis may benefit from botulinum neurotoxin injection into the OCI.

Local anesthetic effect of docosahexaenoic acid on the nociceptive jaw-opening reflex in rats.

Although docosahexaenoic acid (DHA) administration suppresses sodium channels in primary afferent sensory neurons, the acute local effect of DHA on the trigeminal nociceptive reflex remains to be elucidated, in vivo. Therefore, the aim of the present study was to investigate whether local administration of DHA attenuates the nociceptive jaw-opening reflex (JOR) in vivo in the rat. The JOR evoked by electrical stimulation of the tongue was recorded by a digastric muscle electromyogram (dEMG) in pentobarbital-anesthetized rats. The amplitude of the dEMG response was significantly increased in proportion to the electrical stimulation intensity (1-5 x threshold). At 3 x threshold, local administration of DHA (0.1, 10 and 25 mM) dose-dependently inhibited the dEMG response, and lasted 40 min. Maximum inhibition of the dEMG signal amplitude was seen within approximately 10 min. The mean magnitude of inhibition of the dEMG signal amplitude by DHA (25 mM) was almost equal to the local anesthetic, 1% lidocaine (37 mM), a sodium channel blocker. These findings suggest that DHA attenuates the nociceptive JOR via possibly blocking sodium channels, and strongly support the idea that DHA is a potential therapeutic agent and complementary alternative medicine for the prevention of acute trigeminal nociception.

Botulinum toxin type A relieves sternocleidomastoid muscle fibrosis in congenital muscular torticollis.

Congenital muscular torticollis (CMT) is a neck deformity that involves shortening of sternocleidomastoid muscle (SCM) characterized by muscle atrophy and interstitial fibrosis. To investigate wheatear Botulinum toxin type A (BTA) has anti-fibrotic effects in CMT, we established acquired muscular torticollis that mimetics CMT in rabbit by intra-SCM injection of anhydrous alcohol. The treatment groups received BTA (2.5units or 5units) injection into the fibrotic SCM. The shortening and thickening of SCM were recorded by B-mode ultrasound. Changes in Col1A1, Fn, α-SMA expression were determined by immunohistochemistry. In vitro studies, TGF-ß induced NIH3T3 fibroblasts were used to evaluate anti-fibrosis effect of BTA. Expression of the myofibroblast marker α-SMA and fibrosis markers Col1A1 and Fn were detected by Western blotting and quantitative RT-PCR. Our results showed that BTA injection attenuated shortening and thickening of fibrotic SCM. Elevated expression of Col1A1, Fn, α-SMA were confirmed in this fibrotic muscle model but reversed after BTA injection. Similar results observed in TGF-ß induced NIH3T3 fibroblasts in both mRNA and protein levels. In conclusion, our results suggested that BTA could be a promising agent against SCM fibrosis in CMT through regulating fibroblast and inhibiting myofibroblast differentiation.

Sonographic Guide for Botulinum Toxin Injections of the Neck Muscles in Cervical Dystonia.

Intramuscular botulinum toxin (BoTX) injection is the first-line treatment of cervical dystonia. Poor treatment outcomes and some side effects, however, have been reported after BoTX applications. One of the most important reasons is incorrect localization of the needle during toxin injections. Without imaging, it is impossible to verify precise needle positioning in the proper muscle. Ultrasound has been recommended because of its high capability in illustrating most of the neck muscles. This review article discusses how ultrasound imaging can be used to scan/access neck muscles, mainly from the perspective of BoTX injections.

Spectral EMG Changes in Cervical Dystonia Patients and the Influence of Botulinum Toxin Treatment.

Botulinum toxin (BoNT) injections in the dystonic muscles is the preferred treatment for Cervical Dystonia (CD), but the proper identification of the dystonic muscles remains a challenge. Previous studies showed decreased 8-14 Hz autospectral power in the electromyography (EMG) of splenius muscles in CD patients. Cumulative distribution functions (CDF's) of dystonic muscles showed increased CDF10 values, representing increased autospectral powers between 3 and 10 Hz, relative to power between 3 and 32 Hz. In this study, we evaluated both methods and investigated the effects of botulinum toxin. Intramuscular EMG recordings were obtained from the splenius, semispinalis, and sternocleidomastoid muscles during standardized isometric tasks in 4 BoNT-naïve CD patients, 12 BoNT-treated patients, and 8 healthy controls. BoNT-treated patients were measured 4-7 weeks after their last BoNT injections and again after 11-15 weeks. We found significantly decreased 8-14 Hz autospectral power in splenius muscles, but not in the semispinalis and sternocleidomastoid muscles of CD patients when compared to healthy controls. CDF10 analysis was superior in demonstrating subtle autospectral changes, and showed increased CDF10 values in all studied muscles of CD patients. These results did not change significantly after BoNT injections. Further studies are needed to investigate the origin of these autospectral changes in dystonia patients, and to assess their potential in muscle selection for BoNT treatment.

Insights into the Functional Anatomy Behind the PREEMPT Injection Paradigm: Guidance on Achieving Optimal Outcomes.

OBJECTIVE: To provide clinically relevant insights on the identification of the muscles and techniques involved in the safe and effective use of onabotulinumtoxinA for chronic migraine prophylaxis. BACKGROUND: Although guidance on the use of onabotulinumtoxinA for chronic migraine is available, based on the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program, clinical experience has shown that insufficient understanding of the anatomy and function of the head and neck muscles may lead to undesirable outcomes and suboptimal efficacy. DESIGN/METHODS: Each muscle involved in the standardized PREEMPT injection paradigm is reviewed with a thorough description of each muscle's anatomy (ie, muscle description and location, innervation, vascular supply) and function. Key insights based on clinical experience are also provided to help improve outcomes. RESULTS: The identification of the muscles in the PREEMPT injection paradigm should be based on each patient's unique anatomy and injections should be administered using the advised techniques. A thorough examination of the patient prior to treatment is also critical to determine if any preexisting conditions may increase the risk for unwanted outcomes and appropriate expectations should be communicated. CONCLUSIONS: Thorough knowledge of the functional anatomy of the muscles involved in the standardized PREEMPT injection paradigm is critical to achieve the efficacy and safety observed in clinical trials. In addition, it is important to assess a patient's baseline condition to anticipate the risk for unwanted outcomes that may result from treatment.