Abstract
Introduction
Myositis of unknown aetiology might be a very rare complication of intramuscular injections of onabotulinum toxin A (Botox) for spasticity treatment.
Case presentation
We describe a case of significant myositis of unknown aetiology in a 17-year-old man, who was admitted for rehabilitation 4 months after his initial spinal cord injury (SCI) as a result of a mountain bike accident. He has an incomplete tetraplegia, C4 AIS B international Standards for Neurological Classification for Spinal Cord Injury (ISNCSCI) [1] due to C5 vertebra 3 column fracture [2]. He had severe spasticity of his lower limb muscles treated with Botox, following which, he required two acute hospital transfers for diagnosis and management of myositis.
Discussion
This is a severe unusual presentation of myositis caused by intramuscular botulinum toxin for treatment of spasticity, in the frequent setting of spasticity where intramuscular botulinum toxin injections are routinely used.
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Introduction
Spasticity is a motor disorder characterised by a velocity dependent increase in the tonic stretch reflex [3]. It is usually accompanied by increased tone, brisk reflexes and weakness, all representing the upper motor neuron syndrome, found in a number of neurological conditions [4, 5]. Spasticity becomes clinically relevant when it interferes with function or care of patients, and is commonly treated with physical modalities or oral medications.
However, it is also frequently treated with local injections of either Botulinum neurotoxin, which inhibits the release of acetylcholine at the neuromuscular junction, causing muscle weakness, or by local chemical neurolysis involving application of local anaesthetics, phenol and alcohol to a local nerve [5]. Prior to treatment by local injection, informed consent is obtained from the patient or carers, including the possible side effects of medication discussed, using the product disclosure information [6].
Myositis is the collective term for illnesses that involve muscle inflammation with elevated creatine kinase (CK) and C reactive protein (CRP) [7]. Dermatomyositis, polymyositis, necrotizing myopathy and inclusion body myositis are four distinct subtypes of idiopathic inflammatory myopathies—in short, myositis. Recent studies have shed some light on the unique pathogenesis of each entity. While some of the clinical features are distinct, muscle biopsy is indispensable for making a reliable diagnosis. The use of magnetic resonance imaging of skeletal muscles and detection of myositis‐specific autoantibodies have become useful additions to the diagnostic repertoire [7]. Only few controlled trials are available to substantiate current treatment approaches for myositis, although novel approaches such as rituximab in patients with certain myositis-specific autoantibodies, and other biologic agents are currently being investigated [8].
In order to see if there is a relationship between Botox and myositis, an electronic literature search was performed using the Allergan Product Literature database and this did not identify any peer-reviewed publications specific to this topic. Please see Appendix B for the search strategy.
The search yielded two multicentre, randomized, double-blind, placebo-controlled studies (Studies 142 and 143) which evaluated Botox (n = 921) vs placebo (n = 257) for the temporary improvement in the appearance of moderate to severe forehead lines (FHL). There were no treatment-emergent adverse events (TEAEs) of myositis reported in Study 142. In Study 143, a TEAE of myositis was reported in one patient in the Botox 40 Unit (U) group (n = 318) and one patient in the Botox 64 U group (n = 746). All TEAEs of myositis in Study 143 were considered unrelated to the treatment by the investigators [9, 10]. The other search results did not report the complication of myositis following injections of onabotulinum toxin A [11, 12].
Case presentation
Rehabilitation ward
A 17-year-old man with sensory incomplete SCI (C4 AIS B) presented on admission to rehabilitation with severe spasticity in bilateral adductors, iliopsoas, rectus femoris and the right hamstrings, with a pattern of right knee extension and plantar flexion and left knee and hip extreme flexion. However, the Tardieu scale did not truly show the severity of the patient’s spasms, which occurred throughout the day and when he slept in supine position. His spasms were aggravated by light touch, pressure and vibration, rather than physical movement of the limbs.
He was trialled on increasing doses of oral Baclofen (which was subsequently changed over to Tizanidine) and Pregabalin, without any noticeable effect on his spasticity, and with significant side effects (drowsiness and altered liver function tests). Given the extent of the patient’s spasticity, intrathecal baclofen treatment was considered, but due to the fact that this was considered to be too invasive and permanent by the patient and his parents, decision was made to inject Onabotulinum toxin A (Botox) into the most affected muscles: bilateral adductor magnus and ilio-psoas. The adductor magnus muscles were injected with 100units (u) of Botox each diluted with 2mls of sterile normal saline (in 2 different sites, 50 u = 1 ml solution each), using electro-stimulation. The next day the ilio-psoas muscles were injected by a radiologist, using sterile technique and local anaesthetic, with CT scan guidance, after injection of contrast for good localisation (100 u Botox diluted in 5mls of sterile normal saline in each muscle, in one site). All four vials of Botox were from the same batch, having an identical serial number and expiry date.
After having the Botulinum Toxin injections, there was no significant improvement observed with this pattern of spasticity, in terms of his wheelchair positioning, lying in bed and functional training. In total, 40 days following the injections, he started to feel unwell, with episodes of autonomic dysreflexia, which were thought to be due to a urinary tract infection (UTI). The microbiology showed Klebsiella species sensitive to Gentamicin and Trimethoprim, so he was given for two consecutive days intramuscular Gentamicin 160 mg per day (in two sites on anterior aspect of the thighs), followed by oral Trimethoprim 300 mg per day. However, his white cell count (WCC) continued to rise to 12.1×10^9/L (normal value range: 4–11x^9/L), as did his C reactive protein (CRP) at 140 mg/L (normal value range: 0–5 mg/L). He had no abdominal pain, no vomiting, was afebrile, and all other observations were stable. Two days later, his CRP continued to rise, to 190 mg/L. He was still feeling unwell, and started to experience vomiting, a high-grade fever of 39 °C, regular tachycardia at 130 beats/minute, rigors and showed peritonism on clinical examination. As a consequence, he was transferred to an acute facility for investigation and management.
First acute hospital admission
The young man was consulted by different specialists, given that his creatine kinase (CK) was 3936units/L (normal value range: 45–250 u/L). A CT scan of his abdomen and pelvis was showing extensive intramuscular oedema of the bilateral adductor muscle groups and oedema tracking along the left psoas muscle. An ultrasound showed a small volume of inter-muscular fluid in the proximal medial left thigh, inflammatory thickening and oedema of the fascia next to the femoral vessels, with no drainable collection being detected. The most likely diagnosis considered was septic myositis, so he was started on intravenous broad-spectrum antibiotics. With this treatment, bed rest and intravenous fluids, after 6 days, his clinical status has significantly improved, CK was 266 u/L and CRP 68 mg/L, and was discharged back to rehabilitation.
The differential diagnoses considered were: autoimmune myositis (however, this does not cause severe pyrexia and rigors [7]), focal myositis (but this is well circumscribed and while an MRI would be of value for diagnosis [7], it was not considered as the patient would have needed sedation) or limb limited vasculitis of the leg muscles (this is usually unilateral and with lower CK). All auto-immune screening tests were negative. Muscle biopsy was not considered at this stage, as the patient improved.
Back in rehabilitation, after three days, there was worsening of his CK and CRP: CK 822 u/L and CRP 83 mg/L respectively, with normal full blood count and electrolytes.
Second acute hospital admission
The patient was transferred back for further investigations of cause and treatment of myositis. An MRI (T2 sequence below) showed extensive myofascial inflammatory changes, consistent with myositis of the left thigh adductors and pectineus (1), right anterior compartment myofascial oedema (2) and right femoral neck and lesser trochanter changes (3) suspicious of early osteomyelitis (Fig. 1).
The orthopaedic team performed a left adductor muscle biopsy which showed prominent infarcted necrotic muscle without significant inflammation, ruling out acute infective pyomyositis (Fig. 2).
The histological appearance was non-conclusive to the underlying cause, and possible considered events were: localised response to drug or toxic causes, localised trauma, thrombus/emboli, vasculitis, or vascular spasm. An arterial Doppler of the abdomen and lower extremities was normal. Auto-antibodies screen remained negative and the patient remained clinically well despite the concerning MRI and biochemical changes. Only conservative treatment was given (bed rest and intravenous fluids) and he returned to the rehabilitation ward after five days and continued inpatient therapy consisting of daily physiotherapy and occupational therapy. An occasional rise in CK and CRP was later noted, but with increase in fluid intake and limiting intensive exercises, these levels returned to normal (Fig. 3).
Applying the Tardieu scale of spasticity evaluation, the patient’s spasticity was worse at discharge than on admission, with main worsening noted in the left hamstring and bilateral adductors. Rectus femoris and iliopsoas measurements remained the same as on admission. He was successfully discharged home with the recommendation of fortnightly monitoring of CK and CRP. As the severe spasticity was affecting the patient’s function and quality of life, he was referred for consideration of intrathecal baclofen therapy.
Discussion
Given the severity of the patient’s symptoms, Allergan Medical Section was contacted and a severe adverse reaction report was completed. This service provided advice regarding a vast literature search looking for myositis following Botox injections. Only one study showed myositis in two patients who received Botox in facial muscles, but both cases were subsequently not thought to be related to Botox [9, 10]. In addition, there are a number of studies that indicate successful treatment of myositis with Botulinum Toxin [7, 13]. Mancini et al. [14] describes a subset of patients who experienced flu-like syndrome and oedema of the Botox injected leg, which some patients endured for more than 4 weeks, within a group of patients who had a higher dose (i.e., 100 u into soleus or 200 u into the gastrocnemius muscles).
The potentiating effects in our presented case might include the use of intramuscular Gentamicin also into the anterior thigh compartment, after the onset of symptoms, as well as influenza vaccination 10 days prior to onset of symptoms. The inability of our patient to localise his symptoms added to the severity and complexity of his presentation, and possibly delayed his diagnosis.
In summary, a dose-related effect (2 successive days of 200 units) of the onabotulinum A cannot be ruled out. This case remains open for discussion and no conclusions can be drawn, except perhaps to include myositis in the possible side-effects following injections of Botox for spasticity, when asking the patient for informed consent. Another potential consideration would be avoiding intramuscular aminoglycosides around sites of potential botulinum diffusion. There will be further scope to explore if point of care ultrasound may be of value for routine post botulinum toxin surveillance in the setting of treating patients with severe spasticity and concomitant sensory loss.
References
American Spinal Injury Association. International Standards for Neurological Classification of Spinal Cord Injury. Richmond, VA: American Spinal Injury Association; 2019.
Bono CM, Vives MJ, Kauffman CP Cervical Injuries: Indications and Options for Surgery. In: Lin V, editor. Spinal Cord Medicine Principles and Practice: Demos Medical Publishing; 2003. p. 132.
Lance JW. What is spasticity? Lancet. 1990;335:606 https://doi.org/10.1016/0140-6736(90)90389-m.
Trompetto C, Marinelli L, Mori L, Pelosin E, Currà A, Molfetta L, et al. Pathophysiology of spasticity: implications for neurorehabilitation. Biomed Res Int. 2014;2014:354906 https://doi.org/10.1155/2014/354906.
Horn LJ, Singh G, Dabrowski E Chemoneurolysis With Phenol and Alcohol: A Dying Art That Merits Revival. In: Brashear A, Elovic E, editors. Spasticity Diagnosis and Management: Demos Medical Publishing; 2011. p. 101-19.
Therapeutic Goods Administration. AusPAR Botox Botulinum toxin, type A Allergan Australia Pty Ltd PM-2012-01467-3-3. Australian Government Department of Health; 2013.
Carstens PO, Schmidt J. Diagnosis, pathogenesis and treatment of myositis: recent advances. Clin Exp Immunol. 2014;175:349–58. https://doi.org/10.1111/cei.12194.
Barsotti S, Lundberg IE. Current treatment for myositis. Curr Treatm Opt Rheumatol 2018;4:299–315. https://doi.org/10.1007/s40674-018-0106-2.
Fagien S, Cohen JL, Coleman W, Monheit G, Carruthers J, Street J, et al. Forehead line treatment with OnabotulinumtoxinA in subjects with forehead and glabellar facial rhytids: a phase 3 study. Dermatol Surg. 2017;43:S274–s84. https://doi.org/10.1097/dss.0000000000001414. Suppl 3.
De Boulle K, Werschler WP, Gold MH, Bruce S, Sattler G, Ogilvie P, et al. Phase 3 study of OnabotulinumtoxinA distributed between frontalis, glabellar complex, and lateral canthal areas for treatment of upper facial lines. Dermatol Surg. 2018;44:1437–48. https://doi.org/10.1097/dss.0000000000001612.
Kaji R, Osako Y, Suyama K, Maeda T, Uechi Y, Iwasaki M. Botulinum toxin type A in post-stroke lower limb spasticity: a multicenter, double-blind, placebo-controlled trial. J Neurol. 2010;257:1330–7. https://doi.org/10.1007/s00415-010-5526-3.
Wein T, Esquenazi A, Jost WH, Ward AB, Pan G, Dimitrova R. OnabotulinumtoxinA for the treatment of poststroke distal lower limb spasticity: a randomized. Trial PM R 2018;10:693–703. https://doi.org/10.1016/j.pmrj.2017.12.006.
Schrey A, Airas L, Jokela M, Pulkkinen J. Botulinum toxin alleviates dysphagia of patients with inclusion body myositis. J Neurol Sci. 2017;380:142–7. https://doi.org/10.1016/j.jns.2017.07.031.
Mancini F, Sandrini G, Moglia A, Nappi G, Pacchetti C. A randomised, double-blind, dose-ranging study to evaluate efficacy and safety of three doses of botulinum toxin type A (Botox) for the treatment of spastic foot. Neurol Sci. 2005;26:26–31. https://doi.org/10.1007/s10072-005-0378-9.
Haugh AB, Pandyan AD, Johnson GR. A systematic review of the Tardieu Scale for the measurement of spasticity. Disabil Rehabil. 2006;28:899–907. https://doi.org/10.1080/09638280500404305.
Acknowledgements
Ms Nicole Whitehead, Physiotherapist at Spinal Injuries Unit, Royal Rehab, Ryde, NSW 2112, Australia for assessing the patient before and after injections and offering ongoing advice regarding spasticity management. Dr Hwei Choo Soh, Senior Staff Specialist, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards NSW 2065, Australia, for the provision and interpretation of the histopathological slides. Royal North Shore Hospital Consulting specialists: Dr David Hunter, Consulting Rheumatologist, Dr Dimitri Papadimitriou, Consulting Orthopaedic Surgeon and Dr Melanie Figtree, Consulting Infectious Diseases Specialist. Dr Andreea Heriseanu, DClinPsych/PhD, who assisted in the proofreading of the manuscript. No financial assistance was received in support of the study.
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REH was responsible for extracting and analysing the clinical information, writing the report, interpreting results, and updating reference lists. PC was responsible for providing the histopathology slides and MRI findings, liaising with all treating specialists, conducting the literature search and contributing to the writing of the report and the reference list.
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Appendices
Appendix A
Tardieu Scale [15]
This scale quantifies muscle spasticity by assessing the response of the muscle to stretch applied at specified velocities. Grading is always performed at the same time of day, in a constant position of the body for a given limb. For each muscle group, reaction to stretch is rated at a specified stretch velocity with 2 parameters x and v. Measurements take place at 3 velocities to stretch (V1, V2, and V3). Responses are recorded at each velocity as X/Y, with X indicating the quality of muscle reaction from 0 to 5 rating, and Y indicating the degree of angle at which the muscle reaction occurs.
By moving the limb at different velocities, the response to stretch can be more easily gauged since the stretch reflex responds differently to velocity.
Velocities:
V1: As slow as possible, slower than the natural drop of the limb segment under gravity.
V2: Speed of limb segment falling under gravity.
V3: As fast as possible, faster than the rate of the natural drop of the limb segment under gravity.
Scoring:
0 No resistance throughout the course of the passive movement.
1 Slight resistance throughout the course of passive movement, no clear catch at a precise angle.
2 Clear catch at a precise angle, interrupting the passive movement, followed by release.
3 Fatigable clonus with less than 10 s when maintaining the pressure and appearing at the precise angle.
4 Unfatigable clonus with more than 10 s when maintaining the pressure and appearing at a precise angle.
5 Joint is immovable.
Example:
When testing spasticity of the hamstring at the speed V1, place the patient in the supine position. Flex the hip to 90 degrees, with the opposite hip extended (as for popliteal angle test). Beginning with the knee flexed, extend the knee as slowly as possible. If a clear catch interrupts the passive movement at −70 degrees of extension, followed by a release facilitating further extension to −50 degrees of extension, then the Tardieu V1 score would be 2/−70. The rating would be repeated for V2 and V3 velocities. Evaluating movement of a part at different velocities may help distinguish passive stiffness from spasticity.
Appendix B
Literature search:
Search Databases: Allergan Product Literature Database Search Date: 14-MAY-2020
Search Parameters: (BOTOX OR BOTOX VISTA OR BOTOX Cosmetic OR VISTABEL OR VISTABEX) AND (myositis OR inflammatory myopathy).
Search Limits: Meta-Analyses, Systematic Reviews, Clinical Trials, Observational Studies, Case Reports, English, Humans Allergan’s Product Literature Database contains publications compiled from publicly accessible literature databases (i.e., MEDLINE®, EMBASE.com®, etc.).
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Heriseanu, R.E., Chari, P. A severe case of non-infective myositis six weeks post intramuscular injections of Onabotulinum toxin A (Botox) in a young man with tetraplegia: case report. Spinal Cord Ser Cases 7, 76 (2021). https://doi.org/10.1038/s41394-021-00442-1
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DOI: https://doi.org/10.1038/s41394-021-00442-1
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