J Neural Transm DOI 10.1007/s00702-014-1197-z
NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - SHORT COMMUNICATION
Botulinum toxin A in functional popliteal entrapment syndrome: a new approach to a difficult diagnosis Florin Gandor • Stephen Tisch • Anthony J. Grabs Anthony J. Delaney • Lourens Bester • Paul Darveniza
•
Received: 19 December 2013 / Accepted: 12 March 2014 Ó Springer-Verlag Wien 2014
Abstract Functional Popliteal Entrapment Syndrome (FPES) is caused by compression of neurovascular structures in the popliteal fossa by hypertrophic muscles, provoking severe leg pain with exercise. Treatment is limited to myotomy of hypertrophic musculature. 8 FPES patients underwent imaging and exercise studies, before receiving botulinum toxin A injections (BTX-A) into the gastrocnemius and plantaris muscles. 81.3 % of patients reported clinical improvement on follow-up, and pathological ankle–brachial indices were normalized. BTX-A injection may present a new, safe, effective and non-invasive approach to FPES.
Electronic supplementary material The online version of this article (doi:10.1007/s00702-014-1197-z) contains supplementary material, which is available to authorized users. F. Gandor (&) Movement Disorders Clinic, Paracelsusring 6A, 14547 Beelitz-Heilsta¨tten, Germany e-mail: [email protected] F. Gandor S. Tisch P. Darveniza Department of Neurology, St. Vincent’s Hospital, Sydney, Australia A. J. Grabs Department of Vascular Surgery, St. Vincent’s Hospital, Sydney, Australia A. J. Delaney Narrabeen Sports and Exercise Medicine Centre, Sydney Academy of Sport, Narrabeen, Australia L. Bester Department of Radiology, St. Vincent’s Hospital, Sydney, Australia
Keywords Functional Popliteal Entrapment Syndrome Botulinum toxin A Ankle–brachial index Claudication Treatment
Introduction Compression of the popliteal artery in the popliteal fossa caused by structural abnormal anatomy has first been described in 1879 (Stuart 1879). Hamming reported the first surgical intervention in 1965 (Hamming and Vink 1965). The term Popliteal Artery Entrapment Syndrome was first introduced by Love in (1965). Anatomical variants include an abnormal relationship of the popliteal vessels to the gastrocnemius muscle or, in rare cases, an additional fibrotic band or popliteus muscle. According to the course of the popliteal artery the anatomical variants were classified into types I–IV, with type V involving the popliteal vein in any of the types I–IV (Fowl and Kempczinski 2000). The term Functional Popliteal Entrapment Syndrome (FPES) was introduced in 1985. Rignault described an entrapment syndrome, in which anatomy of the popliteal fossa shows no structural abnormality as such. However, hypertrophic musculature was in close proximity to the popliteal vessels, and contraction of these muscles during forced plantar flexion caused compression or complete occlusion of the popliteal vessels (Rignault et al. 1985). Symptoms of FPES include severe pain in the calf and tibial muscles with exercise that subsides upon rest. In comparison to structural anatomical variants (types I–V), patients with FPES are younger and of athletic build (Fowl and Kempczinski 2000). The true prevalence of popliteal artery entrapment remains unclear. Bouhoutsos reported a prevalence of 0.165 % amongst army service men
123
F. Gandor et al.
(Bouhoutsos and Daskalakis 1981). Autopsy studies have shown an incidence of 3–3.5 % in the normal population (Gibson et al. 1977). On physical examination, patients with FPES show prominent calf muscles. Pulses of the dorsal pedal and/or posterior tibial arteries are usually palpable at rest and can disappear during forced plantar flexion. Doppler and duplex sonography and angiography show widely patent vessels at rest and compression of the vasculature during forced plantar flexion with lumen narrowing and increased flow velocities, or, in severe cases, complete occlusion (Fig. 1— supplementary). To date no reports of spontaneous recovery, e.g., after diminished or withdrawal from exercise, have been reported, which may leave surgical intervention with myotomy as one main therapeutic option (Turnipseed 2004). However, a review on surgery outcomes lacks sufficient quality to recommend a standard interventional treatment for popliteal entrapment (Sinha et al. 2012). We investigated whether BTX-A, injected into the medial head of the gastrocnemius muscle and the plantaris muscle, can improve clinical symptoms in FPES.
increase in flow velocities due to muscular contraction, indicative of vessel compression by muscular proximity. One patient also underwent angiography (Fig. 1—supplementary). Angiography was performed with the intervention table at 0° for imaging at rest. To induce forced plantar flexion, the table was tilted at 30° in a semi-erect position. Treadmill exercise tests at a mean speed of 7 km per hour (5–9) set at 10° incline for a mean of 6 min (4–8) were performed with assessment of the ankle–brachial index (ABI) in seven patients (14 legs) before and after exercise. Three patients underwent exercise tests with ABI assessments bilaterally after BTX-A application (6 legs). Patient 3 had an ABI assessment at 7 weeks, patient 4 at 23 weeks and patient 5 at 53 weeks after BTX-A-injection. Botulinum toxin A injection and follow-up
This project was approved by the St. Vincent’s Hospital Human Research and Ethics Committee (SVH 10/047). During March 2008 and March 2010, eight patients with symptoms of FPES were referred to the Department of Neurology for assessment (Tbl. 1). Patients were aged 32 years on average (16–65 years, seven male patients). All patients were physically active, of athletic built and performed running or leg exercises regularly. On physical examination, all patients showed prominent calf muscles, in particular bilateral hypertrophic plantaris muscles on palpation. The neurological examination remained normal. Furthermore, nerve conduction studies (NCS) were not performed routinely, as neither age nor the neurological examination suggested peripheral nerve pathology. In one patient, NCS showed normal results.
Recommendations for the dosage of BTX-A in the spastic lower limb range at 75 MU per head for the gastrocnemius muscle (WeMove 2005). Since BTX-A was injected in non-spastic musculature, a lower dose per muscle head was chosen for this intervention. Hence, 50 MU BTX-A (Botox, botulinum toxin type A, purified neurotoxin complex, Allergan) was injected into the medial head of the gastrocnemius muscle, and 50 MU BTX-A into the plantaris muscle under EMG guidance (electromyograph Neurostar MS92B, Teca Medelec; 75 mm MyoJect Hypodermic Needle Electrode, Viasys). EMG recordings did not reveal any pathological changes. Injection was performed in a randomly chosen leg, since both legs were equally affected in all patients. The contralateral leg served as control and received no injection during the first visit. Patients were interviewed about their clinical symptoms following an adapted Patient’s Global Impression of Change scale (a scale of no, mild, moderate and marked improvement was provided), before receiving BTX-A into the control leg. Assessments followed 53 days on average (13–189) after injections. No adverse events occured after BTX-A injection. After the second BTX-A-injection, two patients were lost for the second follow-up. Hence, 14 legs (6 patients with reported results for both legs and 2 patients with reported results for one leg) were assessed.
Imaging
Statistical analysis
Patients underwent ultrasound examination to exclude differential diagnoses such as Popliteal Artery Entrapment Syndrome, in which structural abnormalities in the popliteal fossa are present (Fowl and Kempczinski 2000), or arteriosclerotic disease with increased flow velocities at rest, structurally abnormal vessel walls, or sclerotic plaques. Subsequently, duplex sonography was performed at rest and with forced plantar flexion to elucidate possible
Statistical test was performed using SPSS software. Alpha level was set at 0.05.
Methods Patients
123
Results Patients presented with FPES typical symptoms of sustained exercise-related bilateral lower limb pain.
Botulinum toxin A in FPES
Fig. 1 ABI pre-exercise (white) and post-exercise (gray) before and after BTX-A application. n.s. not significant, n = 6 limbs, M ± SD
Ultrasound examination of the popliteal vessels showed a variety of findings, from no occlusion of the popliteal artery and vein over significant compression with increased velocities, to complete occlusion of artery and vein on forced plantar flexion. Mean ABI (normal value 0.9–1.2) of 1.13 ± 0.07 preexercise decreased significantly to 0.77 ± 0.18 post-exercise (p \ 0.001). After injection of 100 MU BTX-A, equally divided between the medial head of the gastrocnemius and the plantaris muscle, clinical symptoms improved in 13/16 (81.3 %) investigations. A marked improvement was reported for ten legs (62.5 %), a moderate for two legs (12.5 %), a mild for one leg (6.3 %) and no improvement for one leg, respectively. Symptom improvement lasted 4 months on average (3–5). Three patients underwent ABI assessment of both legs again after BTX-A-application. Before BTX-A, mean ABI was 1.17 ± 0.09 before exercise and decreased to 0.76 ± 0.14 after exercise. After BTX-A, mean ABI was 1.22 ± 0.04 before and 1.10 ± 0.20 after exercise. Shapiro–Wilk test revealed normal distribution of values, and Mauchley’s test allowed for assumption of sphericity (p = 0.932). Hence, repeated measures ANOVA was performed and showed significant difference between groups (p \ 0.001). Post hoc t test revealed significant exerciserelated decrease of ABI before BTX-A (mean ABI-difference -0.41, 95 % CI -0.50/-0.31, p \ 0.001) and no significant exercise-related change of ABI after BTX-A in all six legs (mean ABI-difference -0.12, 95 % CI -0.29/ 0.05, p = 0.133, Fig. 1; Table 1).
Discussion To our knowledge, this is the first publication of a noninvasive approach to FPES with chemodenervation by BTX-A.
Previously, comparable findings with BTX-A have been described in Thoracic Outlet Syndrome (TOS) and Piriformis Syndrome. Danielson showed improvement both in pain sensation and flow velocities in a patient suffering from vascular TOS after chemodenervation of the anterior scalene muscle with BTX-A (Danielson and Odderson 2008). Reichel reported improvement of symptoms in a small patient cohort suffering from neurogenic TOS with injection of BTX-A in the anterior scalene muscle (Reichel et al. 2011). BTX-A injections into the piriformis muscle have been reported to alleviate symptoms in Piriformis Syndrome (Kirschner et al. 2009). FPES is presumably caused by a compression of the popliteal fossa by a hypertrophic medial head of the gastrocnemius muscle and plantaris muscle. Clinical symptoms are claudication during and after exercise of the lower extremities in usually young and healthy athletes. Differential diagnoses include Popliteal Artery Entrapment Syndrome with structural abnormalities in the popliteal fossa, and peripheral artery disease (PAD), which can be excluded with vascular work-up and imaging studies. However, in contrast to FPES patients, intermittent claudication due to PAD is usually found in an older patient cohort (Fowkes et al. 2013). We investigated eight patients suffering from FPES. In our study, ultrasound tests showed a broad variety of findings, from no vascular alteration in the popliteal fossa to complete occlusion of the popliteal artery and/or vein under forced plantar flexion. Alteration of the vessel lumen under forced plantar flexion has been described in up to 53 % of the normal population (Erdoes et al. 1994; Hoffmann et al. 1997). In our study, assessment of the ABI in FPES patients post-exercise decreased significantly into the pathological range. After chemical denervation of the medial head of the gastrocnemius muscle and plantaris muscle, patients described an improvement of claudication symptoms on exercise in 87.5 %. Three patients that subsequently underwent vascular studies after BTX-A-application showed significant improvement of ABI, suggesting a vascular release. Interestingly, alleviated symptoms and normalized ABI lasted up to 53 weeks in one patient, which complies with lasting morphological effects of BTX-A in muscle biopsy and on MRI (Schroeder et al. 2009). However, out of 14 legs, 5 did not show abnormal ABI after forced plantar flexion, which in our study results in a low sensitivity for pathological ABI in FPES of 64.3 % and a specificity of only 35.7 %. ABI therefore may not serve as a valuable diagnostic test for FPES, as suggested previously (Turnipseed 2009). Hypertrophic musculature in the popliteal fossa does not exclusively irritate vascular structures on forced plantar flexion, but might also or solely affect neuronal structures. Hence, symptoms can not only be caused by focal ischemia due to altered blood flow into
123
123
M65
M25
M22
M45
M29
F28
F30
2
3
4
5
6
7
8
Bilateral lower extremity pain and tightness with exercise
Severe bilateral lower leg pain after running 75 m
Bilateral pain in calves with sprinting
Bilateral lower leg pain with exercise
Bilateral lower leg pain with exercise
Severe bilateral lower leg pain on exercise
Bilateral lower leg heaviness when running up sandhills
Severe bilateral pain in calves and soles with sustained running
Complaint
PA diam 6.0 ? 1.5 mm Velocity 3.93 m/sec PV significant compression PA sign compression Velocity 2.3 m/s PV occlusion PA diam 5.0 ? 1.5 mm Velocity 4.1 m/s PV significant compression
PA diam 6.0 ? 1.5 mm Velocity 4.7 m/s PV significant compression PA diam 6.0 ? 1.0 mm Velocity 4.84 m/s PV occlusion PA diam 7.0 ? 1.0 mm Velocity 3.8 m/s PV occlusion
PV partial compression
PV partial compression
PV occlusion PA no compression
PV occlusion PA no compression
PA occlusion
PA occlusion
PV occlusion
compression
PV occlusion
PV occlusion
PV occlusion
PV occlusion PA occlusion
PV occlusion PA occlusion
PA significant
Velocity 5.44 m/s
Velocity 6.2 m/s
PA near occlusion
PA diam 6.0 ? 1.5 mm
PA diam 6.0 ? 1.5 mm
1.14/0.93
Not assessed
1.08/0.94
1.23/0.86
1.00/0.63
1.14/0.59
1.15/0.81
1.05/0.40
Right
Left
Right
1.14/0.93
Not assessed
1.08/0.91
1.27/0.91
1.17/0.86
1.18/0.69
1.15/0.81
1.09/0.51
Left
ABI pre-BTX pre-/post-exercise
Doppler/duplex study at rest and on forced plantar flexion
PA popliteal artery, PV popliteal vein, diam diameter
M16
1
Sex/age
Table 1 Detailed patient list
Moderate
Marked
Lost for follow-up
Marked
Marked
Mild
Marked
Marked
Right
Lost for follow-up
Marked
Marked
No
Marked
Marked
Mild
Marked
Left
Improvement after BTXA
1.23/1.30
1.23/1.18
1.17/0.82
Right
1.27/1.30
1.23/1.05
1.17/0.93
Left
ABI post-BTX pre-/postexercise
F. Gandor et al.
Botulinum toxin A in FPES
the lower limb, but also can be provoked by irritation of the tibial nerve (Turnipseed and Pozniak 1992). Therefore, a negative vascular work-up with normal duplex and Doppler studies and normal findings on ABI does not exclude FPES. However, since symptoms only appear intermittently, NCS might not show pathological results, as shown in one patient. In conclusion, we suggest the use of BTX-A-injection as a non-invasive alternative to surgery or restraint from physical exercise in the treatment of FPES and suggest the following treatment algorithm: In young patients with severe exercise-induced pain of the lower limb that subsides upon rest, clinical and ultrasound examination of the lower limb should exclude structural changes in the popliteal fossa. Hypertrophic musculature, especially plantaris and gastrocnemius muscles can then indicate muscular entrapment. BTX-A-induced improvement after injection of plantaris and gastrocnemius muscle may be helpful to establish the diagnosis of FPES and is an attractive hypothesis for future studies. Independently repeated injections of BTX-A may be considered to achieve long-term improvement. Further studies in a larger cohort of patients via a double-blind, randomized, controlled design should be performed to enforce these findings. Acknowledgments We thank Georg Ebersbach and Doreen Gruber for discussion of results and assistance in statistical analysis. Conflict of interest
No conflicts of interest to disclose.
References Bouhoutsos J, Daskalakis E (1981) Muscular abnormalities affecting the popliteal vessels. Br J Surg 68:501–506 Danielson K, Odderson IR (2008) Botulinum toxin type A improves blood flow in vascular thoracic outlet syndrome. Am J Phys Med Rehabil 87:956–959. doi:10.1097/PHM.0b013e31818a51c3 Erdoes LS, Devine JJ, Bernhard VM, Baker MR, Berman SS, Hunter GC (1994) Popliteal vascular compression in a normal population. J Vasc Surg 20:978–986
Fowkes F, Rudan D, Rudan I, Aboyans V, Denenberg J, McDermott M, Norman P, Sampson U, Williams L, Mensah G, Criqui M (2013) Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 382:1329–1340 Fowl R, Kempczinski R (2000) Popliteal artery entrapment. In: Rutherford RB (ed) Vascular surgery, 5th edn. Pa Saunders, Philadelphia, pp 1087–1093 Gibson MH, Mills JG, Johnson GE, Downs AR (1977) Popliteal entrapment syndrome. Ann Surg 185:341–348 Hamming JJ, Vink M (1965) Obstruction of the popliteal artery at an early age. J Cardiovasc Surg (Torino) 6:516–524 Hoffmann U, Vetter J, Rainoni L, Leu AJ, Bollinger A (1997) Popliteal artery compression and force of active plantar flexion in young healthy volunteers. J Vasc Surg 26:281–287 Kirschner JS, Foye PM, Cole JL (2009) Piriformis syndrome, diagnosis and treatment. Muscle Nerve 40:10–18. doi:10.1002/ mus.21318 Love JW, Whelan TJ (1965) Popliteal artery entrapment syndrome. Am J Surg 109:620–624 Reichel G, Hartmann R, Stenner A (2011) Poster: Botulinumtoxin A beim neurogenen Thoracic Outlet Syndrom—ein Erfahrungsbericht u¨ber 16 behandelte Patienten. German BotulinumtoxinCongress Rignault DP, Pailler JL, Lunel F (1985) The ‘‘functional’’ popliteal entrapment syndrome. Int Angiol 4:341–343 Schroeder AS, Ertl-Wagner B, Britsch S, Schro¨der JM, Nikolin S, Weis J, Mu¨ller-Felber W, Koerte I, Stehr M, Berweck S, Borggraefe I, Heinen F (2009) Muscle biopsy substantiates longterm MRI alterations one year after a single dose of botulinum toxin injected into the lateral gastrocnemius muscle of healthy volunteers. Mov Disord 24:1494–1503. doi:10.1002/mds.22661 Sinha S, Houghton J, Holt PJ, Thompson MM, Loftus IM, Hinchliffe RJ (2012) Popliteal entrapment syndrome. J Vasc Surg 55(252–262):e30. doi:10.1016/j.jvs.2011.08.050 Stuart TP (1879) Note on a variation in the course of the popliteal artery. J Anat Physiol 13:162 Turnipseed WD (2004) Clinical review of patients treated for atypical claudication: a 28-year experience. J Vasc Surg 40:79–85. doi:10.1016/j.jvs.2004.02.034 Turnipseed WD (2009) Functional popliteal artery entrapment syndrome: a poorly understood and often missed diagnosis that is frequently mistreated. J Vasc Surg 49:1189–1195. doi:10. 1016/j.jvs.2008.12.005 Turnipseed WD, Pozniak M (1992) Popliteal entrapment as a result of neurovascular compression by the soleus and plantaris muscles. J Vasc Surg 15:285–293 (discussion 293–4) WeMove (2005) Management of spasticity with Botulinum toxin type A (Botox)—suggested adult Botox dosing, 3rd edn. WeMove; 2005. Available at http://www.mdvu.org
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NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - SHORT COMMUNICATION
Botulinum toxin A in functional popliteal entrapment syndrome: a new approach to a difficult diagnosis Florin Gandor • Stephen Tisch • Anthony J. Grabs Anthony J. Delaney • Lourens Bester • Paul Darveniza
•
Received: 19 December 2013 / Accepted: 12 March 2014 Ó Springer-Verlag Wien 2014
Abstract Functional Popliteal Entrapment Syndrome (FPES) is caused by compression of neurovascular structures in the popliteal fossa by hypertrophic muscles, provoking severe leg pain with exercise. Treatment is limited to myotomy of hypertrophic musculature. 8 FPES patients underwent imaging and exercise studies, before receiving botulinum toxin A injections (BTX-A) into the gastrocnemius and plantaris muscles. 81.3 % of patients reported clinical improvement on follow-up, and pathological ankle–brachial indices were normalized. BTX-A injection may present a new, safe, effective and non-invasive approach to FPES.
Electronic supplementary material The online version of this article (doi:10.1007/s00702-014-1197-z) contains supplementary material, which is available to authorized users. F. Gandor (&) Movement Disorders Clinic, Paracelsusring 6A, 14547 Beelitz-Heilsta¨tten, Germany e-mail: [email protected] F. Gandor S. Tisch P. Darveniza Department of Neurology, St. Vincent’s Hospital, Sydney, Australia A. J. Grabs Department of Vascular Surgery, St. Vincent’s Hospital, Sydney, Australia A. J. Delaney Narrabeen Sports and Exercise Medicine Centre, Sydney Academy of Sport, Narrabeen, Australia L. Bester Department of Radiology, St. Vincent’s Hospital, Sydney, Australia
Keywords Functional Popliteal Entrapment Syndrome Botulinum toxin A Ankle–brachial index Claudication Treatment
Introduction Compression of the popliteal artery in the popliteal fossa caused by structural abnormal anatomy has first been described in 1879 (Stuart 1879). Hamming reported the first surgical intervention in 1965 (Hamming and Vink 1965). The term Popliteal Artery Entrapment Syndrome was first introduced by Love in (1965). Anatomical variants include an abnormal relationship of the popliteal vessels to the gastrocnemius muscle or, in rare cases, an additional fibrotic band or popliteus muscle. According to the course of the popliteal artery the anatomical variants were classified into types I–IV, with type V involving the popliteal vein in any of the types I–IV (Fowl and Kempczinski 2000). The term Functional Popliteal Entrapment Syndrome (FPES) was introduced in 1985. Rignault described an entrapment syndrome, in which anatomy of the popliteal fossa shows no structural abnormality as such. However, hypertrophic musculature was in close proximity to the popliteal vessels, and contraction of these muscles during forced plantar flexion caused compression or complete occlusion of the popliteal vessels (Rignault et al. 1985). Symptoms of FPES include severe pain in the calf and tibial muscles with exercise that subsides upon rest. In comparison to structural anatomical variants (types I–V), patients with FPES are younger and of athletic build (Fowl and Kempczinski 2000). The true prevalence of popliteal artery entrapment remains unclear. Bouhoutsos reported a prevalence of 0.165 % amongst army service men
123
F. Gandor et al.
(Bouhoutsos and Daskalakis 1981). Autopsy studies have shown an incidence of 3–3.5 % in the normal population (Gibson et al. 1977). On physical examination, patients with FPES show prominent calf muscles. Pulses of the dorsal pedal and/or posterior tibial arteries are usually palpable at rest and can disappear during forced plantar flexion. Doppler and duplex sonography and angiography show widely patent vessels at rest and compression of the vasculature during forced plantar flexion with lumen narrowing and increased flow velocities, or, in severe cases, complete occlusion (Fig. 1— supplementary). To date no reports of spontaneous recovery, e.g., after diminished or withdrawal from exercise, have been reported, which may leave surgical intervention with myotomy as one main therapeutic option (Turnipseed 2004). However, a review on surgery outcomes lacks sufficient quality to recommend a standard interventional treatment for popliteal entrapment (Sinha et al. 2012). We investigated whether BTX-A, injected into the medial head of the gastrocnemius muscle and the plantaris muscle, can improve clinical symptoms in FPES.
increase in flow velocities due to muscular contraction, indicative of vessel compression by muscular proximity. One patient also underwent angiography (Fig. 1—supplementary). Angiography was performed with the intervention table at 0° for imaging at rest. To induce forced plantar flexion, the table was tilted at 30° in a semi-erect position. Treadmill exercise tests at a mean speed of 7 km per hour (5–9) set at 10° incline for a mean of 6 min (4–8) were performed with assessment of the ankle–brachial index (ABI) in seven patients (14 legs) before and after exercise. Three patients underwent exercise tests with ABI assessments bilaterally after BTX-A application (6 legs). Patient 3 had an ABI assessment at 7 weeks, patient 4 at 23 weeks and patient 5 at 53 weeks after BTX-A-injection. Botulinum toxin A injection and follow-up
This project was approved by the St. Vincent’s Hospital Human Research and Ethics Committee (SVH 10/047). During March 2008 and March 2010, eight patients with symptoms of FPES were referred to the Department of Neurology for assessment (Tbl. 1). Patients were aged 32 years on average (16–65 years, seven male patients). All patients were physically active, of athletic built and performed running or leg exercises regularly. On physical examination, all patients showed prominent calf muscles, in particular bilateral hypertrophic plantaris muscles on palpation. The neurological examination remained normal. Furthermore, nerve conduction studies (NCS) were not performed routinely, as neither age nor the neurological examination suggested peripheral nerve pathology. In one patient, NCS showed normal results.
Recommendations for the dosage of BTX-A in the spastic lower limb range at 75 MU per head for the gastrocnemius muscle (WeMove 2005). Since BTX-A was injected in non-spastic musculature, a lower dose per muscle head was chosen for this intervention. Hence, 50 MU BTX-A (Botox, botulinum toxin type A, purified neurotoxin complex, Allergan) was injected into the medial head of the gastrocnemius muscle, and 50 MU BTX-A into the plantaris muscle under EMG guidance (electromyograph Neurostar MS92B, Teca Medelec; 75 mm MyoJect Hypodermic Needle Electrode, Viasys). EMG recordings did not reveal any pathological changes. Injection was performed in a randomly chosen leg, since both legs were equally affected in all patients. The contralateral leg served as control and received no injection during the first visit. Patients were interviewed about their clinical symptoms following an adapted Patient’s Global Impression of Change scale (a scale of no, mild, moderate and marked improvement was provided), before receiving BTX-A into the control leg. Assessments followed 53 days on average (13–189) after injections. No adverse events occured after BTX-A injection. After the second BTX-A-injection, two patients were lost for the second follow-up. Hence, 14 legs (6 patients with reported results for both legs and 2 patients with reported results for one leg) were assessed.
Imaging
Statistical analysis
Patients underwent ultrasound examination to exclude differential diagnoses such as Popliteal Artery Entrapment Syndrome, in which structural abnormalities in the popliteal fossa are present (Fowl and Kempczinski 2000), or arteriosclerotic disease with increased flow velocities at rest, structurally abnormal vessel walls, or sclerotic plaques. Subsequently, duplex sonography was performed at rest and with forced plantar flexion to elucidate possible
Statistical test was performed using SPSS software. Alpha level was set at 0.05.
Methods Patients
123
Results Patients presented with FPES typical symptoms of sustained exercise-related bilateral lower limb pain.
Botulinum toxin A in FPES
Fig. 1 ABI pre-exercise (white) and post-exercise (gray) before and after BTX-A application. n.s. not significant, n = 6 limbs, M ± SD
Ultrasound examination of the popliteal vessels showed a variety of findings, from no occlusion of the popliteal artery and vein over significant compression with increased velocities, to complete occlusion of artery and vein on forced plantar flexion. Mean ABI (normal value 0.9–1.2) of 1.13 ± 0.07 preexercise decreased significantly to 0.77 ± 0.18 post-exercise (p \ 0.001). After injection of 100 MU BTX-A, equally divided between the medial head of the gastrocnemius and the plantaris muscle, clinical symptoms improved in 13/16 (81.3 %) investigations. A marked improvement was reported for ten legs (62.5 %), a moderate for two legs (12.5 %), a mild for one leg (6.3 %) and no improvement for one leg, respectively. Symptom improvement lasted 4 months on average (3–5). Three patients underwent ABI assessment of both legs again after BTX-A-application. Before BTX-A, mean ABI was 1.17 ± 0.09 before exercise and decreased to 0.76 ± 0.14 after exercise. After BTX-A, mean ABI was 1.22 ± 0.04 before and 1.10 ± 0.20 after exercise. Shapiro–Wilk test revealed normal distribution of values, and Mauchley’s test allowed for assumption of sphericity (p = 0.932). Hence, repeated measures ANOVA was performed and showed significant difference between groups (p \ 0.001). Post hoc t test revealed significant exerciserelated decrease of ABI before BTX-A (mean ABI-difference -0.41, 95 % CI -0.50/-0.31, p \ 0.001) and no significant exercise-related change of ABI after BTX-A in all six legs (mean ABI-difference -0.12, 95 % CI -0.29/ 0.05, p = 0.133, Fig. 1; Table 1).
Discussion To our knowledge, this is the first publication of a noninvasive approach to FPES with chemodenervation by BTX-A.
Previously, comparable findings with BTX-A have been described in Thoracic Outlet Syndrome (TOS) and Piriformis Syndrome. Danielson showed improvement both in pain sensation and flow velocities in a patient suffering from vascular TOS after chemodenervation of the anterior scalene muscle with BTX-A (Danielson and Odderson 2008). Reichel reported improvement of symptoms in a small patient cohort suffering from neurogenic TOS with injection of BTX-A in the anterior scalene muscle (Reichel et al. 2011). BTX-A injections into the piriformis muscle have been reported to alleviate symptoms in Piriformis Syndrome (Kirschner et al. 2009). FPES is presumably caused by a compression of the popliteal fossa by a hypertrophic medial head of the gastrocnemius muscle and plantaris muscle. Clinical symptoms are claudication during and after exercise of the lower extremities in usually young and healthy athletes. Differential diagnoses include Popliteal Artery Entrapment Syndrome with structural abnormalities in the popliteal fossa, and peripheral artery disease (PAD), which can be excluded with vascular work-up and imaging studies. However, in contrast to FPES patients, intermittent claudication due to PAD is usually found in an older patient cohort (Fowkes et al. 2013). We investigated eight patients suffering from FPES. In our study, ultrasound tests showed a broad variety of findings, from no vascular alteration in the popliteal fossa to complete occlusion of the popliteal artery and/or vein under forced plantar flexion. Alteration of the vessel lumen under forced plantar flexion has been described in up to 53 % of the normal population (Erdoes et al. 1994; Hoffmann et al. 1997). In our study, assessment of the ABI in FPES patients post-exercise decreased significantly into the pathological range. After chemical denervation of the medial head of the gastrocnemius muscle and plantaris muscle, patients described an improvement of claudication symptoms on exercise in 87.5 %. Three patients that subsequently underwent vascular studies after BTX-A-application showed significant improvement of ABI, suggesting a vascular release. Interestingly, alleviated symptoms and normalized ABI lasted up to 53 weeks in one patient, which complies with lasting morphological effects of BTX-A in muscle biopsy and on MRI (Schroeder et al. 2009). However, out of 14 legs, 5 did not show abnormal ABI after forced plantar flexion, which in our study results in a low sensitivity for pathological ABI in FPES of 64.3 % and a specificity of only 35.7 %. ABI therefore may not serve as a valuable diagnostic test for FPES, as suggested previously (Turnipseed 2009). Hypertrophic musculature in the popliteal fossa does not exclusively irritate vascular structures on forced plantar flexion, but might also or solely affect neuronal structures. Hence, symptoms can not only be caused by focal ischemia due to altered blood flow into
123
123
M65
M25
M22
M45
M29
F28
F30
2
3
4
5
6
7
8
Bilateral lower extremity pain and tightness with exercise
Severe bilateral lower leg pain after running 75 m
Bilateral pain in calves with sprinting
Bilateral lower leg pain with exercise
Bilateral lower leg pain with exercise
Severe bilateral lower leg pain on exercise
Bilateral lower leg heaviness when running up sandhills
Severe bilateral pain in calves and soles with sustained running
Complaint
PA diam 6.0 ? 1.5 mm Velocity 3.93 m/sec PV significant compression PA sign compression Velocity 2.3 m/s PV occlusion PA diam 5.0 ? 1.5 mm Velocity 4.1 m/s PV significant compression
PA diam 6.0 ? 1.5 mm Velocity 4.7 m/s PV significant compression PA diam 6.0 ? 1.0 mm Velocity 4.84 m/s PV occlusion PA diam 7.0 ? 1.0 mm Velocity 3.8 m/s PV occlusion
PV partial compression
PV partial compression
PV occlusion PA no compression
PV occlusion PA no compression
PA occlusion
PA occlusion
PV occlusion
compression
PV occlusion
PV occlusion
PV occlusion
PV occlusion PA occlusion
PV occlusion PA occlusion
PA significant
Velocity 5.44 m/s
Velocity 6.2 m/s
PA near occlusion
PA diam 6.0 ? 1.5 mm
PA diam 6.0 ? 1.5 mm
1.14/0.93
Not assessed
1.08/0.94
1.23/0.86
1.00/0.63
1.14/0.59
1.15/0.81
1.05/0.40
Right
Left
Right
1.14/0.93
Not assessed
1.08/0.91
1.27/0.91
1.17/0.86
1.18/0.69
1.15/0.81
1.09/0.51
Left
ABI pre-BTX pre-/post-exercise
Doppler/duplex study at rest and on forced plantar flexion
PA popliteal artery, PV popliteal vein, diam diameter
M16
1
Sex/age
Table 1 Detailed patient list
Moderate
Marked
Lost for follow-up
Marked
Marked
Mild
Marked
Marked
Right
Lost for follow-up
Marked
Marked
No
Marked
Marked
Mild
Marked
Left
Improvement after BTXA
1.23/1.30
1.23/1.18
1.17/0.82
Right
1.27/1.30
1.23/1.05
1.17/0.93
Left
ABI post-BTX pre-/postexercise
F. Gandor et al.
Botulinum toxin A in FPES
the lower limb, but also can be provoked by irritation of the tibial nerve (Turnipseed and Pozniak 1992). Therefore, a negative vascular work-up with normal duplex and Doppler studies and normal findings on ABI does not exclude FPES. However, since symptoms only appear intermittently, NCS might not show pathological results, as shown in one patient. In conclusion, we suggest the use of BTX-A-injection as a non-invasive alternative to surgery or restraint from physical exercise in the treatment of FPES and suggest the following treatment algorithm: In young patients with severe exercise-induced pain of the lower limb that subsides upon rest, clinical and ultrasound examination of the lower limb should exclude structural changes in the popliteal fossa. Hypertrophic musculature, especially plantaris and gastrocnemius muscles can then indicate muscular entrapment. BTX-A-induced improvement after injection of plantaris and gastrocnemius muscle may be helpful to establish the diagnosis of FPES and is an attractive hypothesis for future studies. Independently repeated injections of BTX-A may be considered to achieve long-term improvement. Further studies in a larger cohort of patients via a double-blind, randomized, controlled design should be performed to enforce these findings. Acknowledgments We thank Georg Ebersbach and Doreen Gruber for discussion of results and assistance in statistical analysis. Conflict of interest
No conflicts of interest to disclose.
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