7 GUIDANCE TECHNIQUES FOR BOTULINUM TOXINS AND OTHER INJECTIONS Katharine E. Alter and Kevin P. Murphy Botulinum toxins (BoNTs) are an effective therapy for a wide variety of medical problems including muscle overactivity, pain, neurosecretory, urological, and ophthalmic disorders for patients of all ages. In pediatric patients, the most common clinical problems for which BoNTs are prescribed are muscle overactivity and sialorrhea associated with upper motor neuron syndromes (UMNSs) including cerebral palsy (CP) and acquired brain injury. BoNTs may also be recommended in children for conditions unresponsive to traditional treatments including muscle imbalance in congenital torticollis or obstetrical brachial plexus palsy, detrusor overactivity or dyssynergia, and migraine headaches. To accurately select and target skeletal muscles, salivary glands, or other structures for injection with BoNT requires a fundamental knowledge of anatomy. To improve their accuracy in targeting when performing chemodenervation procedures, most physicians utilize one or more supplementary localization techniques in addition to relying on knowledge of surface anatomy, palpation and/or range of motion (ROM) (1). The goals of precisely targeting a structure for injection include optimizing the outcomes of the procedure, reducing BoNT dose required for treatment efficacy, and minimizing potential risks and/or adverse events associated with these procedures. Commonly used guidance methods include palpation, surface anatomy/reference guides, motor point/endplate targeting, electromyography (EMG), electrical stimulation (E-Stim) and image localization techniques (brightness mode [B-mode] ultrasound [US], fluoroscopy, computed tomography [CT]), and/or combinations of these techniques (2–5). To select the most appropriate guidance technique for a given patient and injection target, physicians must be familiar with the advantages and limitations of each of these targeting methods. What follows is a review of the advantages and limitations of the guidance techniques commonly used when performing BoNT injections. PATIENT EVALUATION When a patient arrives for a scheduled BoNT procedure, it is mandatory to take an interval history and examine the patient, even for a patient well known to the examiner. This is to rule out acute illness, infection, or other medical problems, which would necessitate rescheduling the procedure. Patients should also be questioned about their current medications (medications with anticholinergic effects may potentiate BoNT effects), anticoagulation levels, and whether they have received BoNT injections from another provider within the past 3 months. This last question has become of increased importance as multiple specialists who prescribe BoNT may be treating the same patient. When patients receive BoNT from more than one specialist, these procedures should be coordinated to avoid the use of an excessive number of units and/or to prevent “booster dosing.” TREATMENT PLANNING Treatment planning prior to performing BoNT injections includes a thorough history and examination of the patient, functional assessment, and a review of the relevant anatomy. This evaluation is critical prior to performing any procedure as it will guide selection of the muscle or muscle groups or other targets. This assessment requires that a physician has an extensive knowledge of surface/cross-sectional anatomy of the region of interest including relevant muscles, salivary glands, vessels, nerves, bones, and nearby organs. In addition to structural anatomy, physicians must also be familiar with functional anatomy, kinesiology, and the biomechanics of movement. This knowledge is required for evaluation of a patient’s functional limitations and muscle selection. When performing BoNT injections, this knowledge of anatomy is the foundation upon which all other guidance techniques are based. Teaching tools that are available to clinicians to improve their knowledge of anatomy include various anatomy or biomechanics texts, print and/or electronic reference guides, anatomic simulators, and/or return to the gross anatomy lab (6–10). ANATOMIC GUIDANCE METHODS Anatomic guidance techniques rely on surface anatomy, knowledge of cross-sectional anatomy, palpation, and passive or active range of motion (PROM, AROM). The majority of anatomic reference guides used by physicians when performing BoNT injections were not developed for this purpose. These atlases were written to guide needle placement for diagnostic EMG procedures (11–13). While these texts may be useful for BoNT injections, they have limitations both for their original purpose and when used to guide BoNT injections. More recently, two anatomic atlases were published specifically for BoNT and/or other chemodenervation procedures (14–16). TECHNIQUE Once a muscle or muscles have been localized using a combination of surface anatomy, palpation, and PROM or AROM, the skin is disinfected and cleansed as per the physician or institution’s protocol. Standard single-use hypodermic needles are used for the injection. Needle size and length are determined by the estimated depth of the muscle. For superficial muscles, a 30 g, 1-inch needle may be sufficient, for deeper muscles 26 to 27 g, 1- to 1.5-inch needles or even a 25 g, 2.5- to 5-inch spinal needle may be required. EQUIPMENT Surface anatomy and/or cross-sectional reference guides, hypodermic needles of various lengths, and other injection supplies (gloves, skin cleansers, gauze, band aids/plasters). ADVANTAGES AND LIMITATIONS OF ANATOMIC GUIDANCE FOR BoNT THERAPY Advantages • All physicians receive training in anatomy in medical school. • Most physicians have access to a variety of anatomic reference guides and are familiar with their use, and the guides are relatively inexpensive. • Anatomic simulators can provide physicians with detailed information about orientation and function of muscles. Limitations • A physician’s training in the anatomy lab and therefore his or her last review of gross anatomy may have been many years ago. • Positioning: When treating patients with spasticity, positioning the patient as described in reference guides may be challenging, at best or may be unfeasible. When the patient is not positioned as described in the reference guide, the recommended site for needle insertion into the target may be incorrect. This limits the use of reference guides when performing BoNT injections in many patients. • Even when used to guide diagnostic EMG, as they were designed to do, studies of the accuracy of surface anatomy and/or reference guides has been called into question, see Evidence discussion. • Palpation and surface anatomy: While a few muscles may be easily identified by their surface anatomy and/or by using palpation, it may be difficult or impossible to correctly identify many muscles including: Evidence supporting or refuting the use of anatomic guidance for BoNT injections: There is an increasing body of evidence that calls into question the practice of relying solely on anatomic guidance when performing BoNT injections. CADAVER STUDIES • A 2012 study evaluated the accuracy of injections into the gastrocnemius muscles of 30 cadavers using palpation and surface landmarks. 121 physicians injected ink into the gastrocnemius muscle followed by dissection to evaluate the accuracy of ink injections (17). Only 43% of the injections were successful with 57% of the injections placed outside of the gastrocnemius muscle, either in the soft tissue (19.8%) or deep to the gastrocnemius, in the adjacent soleus muscle (37.2%). • A 2011 blinded study compared “blind” (e.g., manual) versus US placement of a wire into 14 lower limb muscles in fresh cadavers. Two clinicians (a resident with 6 months’ EMG experience and an attending ≥ 10 years’ experience) performed the needle insertions and the accuracy was then verified by CT, and assessed by a third clinician (18). The overall accuracy in the 14 tested muscles with blind wire placement using anatomic guidance was 39% (range 0%–100%) whereas the accuracy for US-guided wire placement was 96% (range 50–100%). The only muscles in which blind placement was 100% accurate were the tibialis anterior and short head of the biceps femoris, whereas with US guidance the only muscle with less than 100% accuracy was the semitendinosus muscle. Unexpectedly, the accuracy of anatomic guidance/blind placement was 0% for needle insertions into semitendinosus, rectus femoris, and extensor hallucis longus. When comparing the less and more experienced clinicians, there was no significant difference in accuracy of needle placement in the target muscle. The experienced clinician was only more accurate in the trajectory of needle insertion toward the target muscle. • A 2003 study evaluated the accuracy of fine-wire insertions by three physicians (with varying degrees of EMG experience) into 36 lower limb muscles in 10 cadavers (263 muscles) using standard EMG anatomical reference guides (11,19). The accuracy of wire placement was checked by anatomical dissection by an anatomist. In this study, 57% of wire insertions penetrated the target muscle; however, the wire tip was only in the target muscle 45% of the time. As with the previously mentioned 2011 study, there was significant variability in the accuracy of targeting different muscles from 100% for vastus medialis to 0% for 12 attempts in the hip flexors. The proximity of the wire to other structures was also reported with 17% of insertions either penetrating or passing within 5 mm of an important structure. The authors concluded that the accuracy of blind wire placement using EMG reference guides was quite variable and the development of safer strategies was recommended. CLINICAL STUDIES Comparison of Anatomic Localization With Other Localization Techniques for BoNT in Limb Muscles The results from anatomic/cadaver studies are supported by clinical studies evaluating the accuracy of needle placement using anatomic techniques in upper and lower limb muscles. • Manual placement versus EMG: A 2013 prospective study describes the development of a structured protocol using surface anatomy and PROM to localize lower limb muscle injection sites for BoNT injections. The described manual localization protocol details the origin, insertion, innervation, and function of the muscles; how to position the patient, localize the muscle belly, and support the limb, the site, and direction for needle insertions; and the PROM procedure to verify needle location. The authors report that the accuracy of needle insertion using this protocol will be verified using E-Stim. All patients were sedated for the BoNT procedure. While this study provides a description of the protocol, it provides no results from data collection. Therefore the accuracy of this manual/PROM localization protocol is unknown (20). • Manual placement versus EMG: A randomized controlled trial (RCT) in 27 adult patients with spasticity from UMNS (brain injury, spinal cord injury) compared the effectiveness of BoNT injections in upper and lower limb muscles guided by EMG versus injections guided by landmark-based systems. Outcome measures included evaluation of the reduction of spasticity using the Modified Ashworth Scale (MAS) and the functional outcome using the Modified Barthel Index. While a reduction in MAS score and improved Barthel Index score was noted in all subjects, the degree of improvement in spasticity and function was greater in patients where BoNT injections were guided by EMG. The authors concluded that when performing BoNT injections for the treatment of spasticity, the use of EMG to guide injections was superior to injections guided by anatomic/landmark-based reference guides (21). • Manual versus EMG: A 2003 study of the efficacy of BoNT injections in adult patients with focal hand dystonia reported superiority of EMG compared to anatomic guidance (22). • Manual placement versus E-Stim: A 2009 study in children with CP (hemiplegia or diplegia) compared the efficacy of BoNT injections guided either by palpation or E-Stim. At 3 months, patients who had injections guided by E-Stim had a statistically greater reduction in MAS scores, PROM, Composite Spasticity Scale scores, and Gross Motor Function Measure scores than those patients injected using manual guidance alone (23). • Manual placement checked by E-Stim: A 2005 study in 226 children with CP investigated the accuracy of manual needle for BoNT injections checked with E-Stim to confirm needle position in upper and lower limb muscles (1,376 needle insertions) (24). The needle insertion site was determined by surface anatomy/manual placement and depth estimated by limb size and using PROM. Once the clinician was satisfied with the position of the needle, the accuracy was checked by using E-Stim. During stimulation, the clinician observed the pattern of muscle twitch and whether the twitch response was in the target muscle, or other muscles. The reported accuracy of manual placement was as follows: gastrocsoleus 78%, hip adductors 67%, medial hamstrings 46%, tibialis posterior 11%, biceps brachii 62%, pronator teres 22%, flexor carpi radialis (FCR) 13%, flexor carpi ulnaris (FCU) 16%, and adductor pollicis 35%. The authors concluded for the muscles tested that manual placement was adequate only in the gastrocnemius. They also postulated that inaccurate muscle targeting could be responsible, at least in part, for a lack of response or insufficient clinical response following BoNT injections in children with CP. • Manual placement, E-Stim and US: A 2012 RCT of 49 adult patients evaluated the efficacy of BoNT injections in the gastrocnemius muscle of 49 adult patients with poststroke spasticity (PSS) (25). The study compared the efficacy of three localization techniques (manual, E-Stim, US) using a fixed dose and dilution protocol (onabotulinumtoxinA 100 units medial head, 100 units lateral, dilution 100 units reconstituted with 2 mL preservative free normal saline). At 4 weeks, the patients injected with US guidance had a greater reduction in MAS score than in patients injected with manual needle placement. The US injection group also had a greater increase in PROM compared with the E-Stim and manual injection groups. There was no difference in the Tardieu Scale score between the 3 groups. The authors concluded that when performing BoNT in the gastrocnemius muscle of adult patients with PSS, US guidance provided a greater reduction in MAS and clinical benefit than injections guided with manual needle placement or E-Stim. • Manual placement checked by US: In a 2009 study of 39 children with CP, the accuracy of blind needle placement in the gastrocnemius muscles was checked using US by a blinded clinician (26). The authors reported an overall accuracy of blind placement in the gastrocnemius of 78.7%. The accuracy of needle placement in the thinner lateral gastrocnemius was 64% overall (46% in younger patients), whereas accuracy of needle placement in the medial gastrocnemius was 93% overall (87% in younger patients). The authors concluded that supplementary localization should be considered for the medial gastrocnemius muscle in younger patients and for the lateral gastrocnemius for all patients. • Manual placement checked by US: In a second 2009 study of 54 children with CP, the authors evaluated the effect of a number of variables on the effectiveness of lower limb BoNT injections (27). Variables included patient age, BoNT dose, BoNT dilution, muscles injected, and guidance method for injections. BoNT injections were guided by manual needle placement in 44% of patients and by US in 56% of patients. The authors reported a greater efficacy of injections guided by US, in patients less than 6 or greater than 12 years of age, when the muscles injected were hamstrings or gastrocnemii and when the dose/muscle was greater than 0.8 units/kg of onabotulinumtoxinA. Dilution had no effect on efficacy. The authors concluded that this study confirmed the usefulness of US guidance for BoNT injections in lower limb muscles. • Location of muscle/muscle fascicles using recommendations from reference guides checked by US: In a 2010 study of forearm flexor muscles in patients with spasticity, the location of the muscle or muscle fascicles using anatomic reference guides was compared to the position of the muscle/muscle fascicle using US. There were significant differences between the estimated position of the muscle or muscle fascicles compared to US for the FCR, flexor policis longus (FPL), and for the fascicles of the flexor digitorum superficialis (FDS) (28). CONCLUSIONS Although a thorough knowledge of surface and functional anatomy is a requirement when performing BoNT injections and critical for muscle selection, the use of this knowledge alone may not be the optimal method to guide BoNT injections. While many clinicians report a good effect with BoNT using blind needle placement, no study to date has shown this technique to be superior to using a supplemental guidance method. Due to the limitations of anatomic guidance techniques, many if not most clinicians choose to use one or more supplementary localization techniques when performing BoNT injections. MOTOR ENDPLATE TARGETING OR LOCALIZATION TECHNIQUE It is well established that to exert its action BoNT avidly binds to and is internalized at cholinergic nerve terminals including at the neuromuscular junction. Knowing this, clinicians and researchers have suggested (or investigated) that targeting the endplate zones or motor points may enhance the uptake of the toxin (29–32). The technique of motor point or endplate targeting requires knowledge of the location and distribution of motor endplates (MoEPs) in human skeletal muscle. The location of motor points or endplate zones in mammalian muscles has been studied in animal models and in humans using histochemical staining and electrophysiologic methods (32–35). STUDIES ON THE LOCATION OF MOTOR ENDPLATE LOCATION AND DISTRIBUTION In the 1950s, two researchers published data on the location and distribution of MoEP in human skeletal muscles. Coers described three types or arrangements of MoEP in human muscle: (a) muscles having a single innervation band, (b) muscles with multiple innervation bands, and (c) muscles where the innervation bands were scattered throughout (35). Christensson published data on the distribution and pattern of MoEP in stillborn infants. She reported that MoEPs were distributed in a single transverse band at the midpoint of unipennate muscles and in a concave band in bipennate muscles (gastrocnemius) (34). In the last decade, additional anatomical studies detailing the location of MoEP have been published (29,36,37). Kim et al. reported that the MoEPs in gastrocnemius and soleus muscles were distributed along the length of the muscle. They reported the location of the most proximal of MoEPs in the medial gastrocnemius, lateral gastrocnemius, and soleus at 9.6% (+/- 3.5%), 12.0% (+/- 3.4%), and 20.5% (+/- 3.9%, of the lower leg length. The most distal MoEPs were reportedly located at 37.5% (+/- 5.5%), 37.9% (+/-2.3%), and 46.7% (+/- 3.6%) of lower limb length, respectively (36). In the biceps brachii muscle, an inverted V arrangement of MoEP has been reported (37). The authors reported the MoEP zone to be 1 cm in width, laterally located 7 cm superior to the olecranon, in the midline located 11 cm superior to the olecranon, and medially 8 cm proximal to the olecranon. The authors also reported the ratio of MoEP location to total olecranon–acromion length: 0.25 at the lateral edge, 0.39 at midline, and 0.28 medially. The location and distribution of MoEP in the psoas muscle of adult cadavers were reported in a 2010 study. The authors reported an average of 3.7 (range 2–7) nerve branches from the lumbar plexus innervating the long pennate psoas muscle, which was made up of converging fibers of variable length. The area of the MoEP zone was reported to correlate with a zone between 30.83% and 70.25% of the distance from T12 to the inguinal ligament. Therefore the majority of the MoEPs were proximal to the sacral promontory (29). MoEP TARGETING FOR BoNT INJECTIONS Clinicians have suggested or recommended targeting MoEP for BoNT injections, for decades (30,31,38). There is limited data from trials comparing MoEP targeting to other techniques. LOWER LIMB In a 2014 double-blind randomized controlled trial (DB-RCT), Im et al. compared the efficacy of a fixed dose of BoNT with injections placed within the MoEP zone suggested by anatomical studies (2/10 and 3/10 of calf length) to injections below the mid-belly of the muscle. Both groups improved and there were no statistical differences between the two groups in either clinical or electrophysiologic measures (39). In a 2011 review, Van Campenhout et al. published the location of MoEPs in lower limb muscles and anatomical guidelines for the use of MoEP targeting for BoNT injections. Based on the location of MoEP, the authors recommended an optimal injection zone for the gastrocnemius, soleus, tibialis posterior, semitendinosus, semimembranosus, biceps femoris, gracilis, rectus femoris, adductors longus, brevis, magus, and psoas muscles. UPPER LIMB In a 2009 DB-RCT, Gracies et al. used published information on the location of the MoEP in the biceps brachii to compare the effectiveness of a fixed dose of onabotulinumtoxinA using MoEP targeting, standard dilution (100 units in 1 ml), and high volume dilution (100 units in 5 ml). The authors reported a greater benefit with injections using MoEP targeting and those with high volume dilution of onabotulinumtoxinA (40). MoEP TARGETING TECHNIQUES The use of MoEP targeting can be incorporated into conventional targeting techniques used to guide BoNT injections. When using manual or blind needle guidance for BoNT injections, physicians can make use of published motor point maps or the information (where available) as to the location of MoEPs or MoEP zones (29,36,37). When using EMG, physicians can target MoEP by listening for endplate noise and injecting toxin in this zone/location (30). If using E-Stim, MoEPs are targeted by repositioning the needle within the muscle and maintaining a maximal or visible twitch while reducing the stimulation intensity (40). While MoEP cannot be visualized with US or other imaging-based guidance techniques, the published information on the location of MoEPs in muscles can be used when using US to guide BoNT injections. ADVANTAGES AND LIMITATIONS OF MoEP TARGETING FOR BoNT THERAPY Advantages of MoEP Targeting Targeting of MoEP when performing BoNT chemodenervation procedures has at least a theoretical advantage over injections placed in areas away from the MoEP. The data on the superiority of MoEP targeting is limited and additional controlled trials are needed to determine whether all BoNT injections should be performed using this technique. Disadvantages of MoEP Targeting A potential disadvantage of MoEP targeting is that it may increase the time required to perform a BoNT procedure. Using this technique requires measuring the limb and marking MoEP zones. However, this information is memorized or can be transcribed to a template or form, which can be used in clinical practice to speed up this process. If MoEP targeting is not superior, then the extra time and effort required for this method is unnecessary. MoEP targeting, as currently described, is not useful for nonmuscle targets. Studies of the location of other cholinergic nerve terminals in organs targeted for BoNT injections may become available in the future. CONCLUSIONS While there is limited data on the superiority of MoEP targeting over injection at other sites in skeletal muscles, this practice requires minimal time or effort. Therefore, clinicians should consider incorporating this technique into whatever guidance technique or techniques that they currently use to guide BoNT injections into muscles.
Muscles of the neck or forearm where complex overlapping may make it difficult to correctly identify a target muscle
Deeply situated muscles in the limb or neck; where it may be impossible to palpate the target muscle and/or estimate muscle depth
Obesity obscures surface landmarks or palpation of the target muscle and limiting depth/location estimation
Disuse atrophy or atrophy caused by repeated BoNT injections may limit estimation of muscle depth
Patients in whom spasticity has caused anatomic rearrangements or deformities
Postoperative muscle changes following lengthening or transfers
Patient cooperation
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