Toxicon xxx (2015) 1e6
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Treatment of camptocormia with botulinum toxin Kelly L. Bertram a, b, Paola Stirpe c, Carlo Colosimo c, * a
Neurosciences, Alfred Hospital, Melbourne, Victoria, Australia Faculty of Medicine Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia c Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 May 2015 Accepted 11 June 2015 Available online xxx
Camptocormia is defined as an involuntary axial postural distortion of >45 flexion which occurs in the upright position, increases whilst walking and resolves when supine (Ashour and Jankovic, 2006). Unlike orthopaedic or age related kyphosis it is not a fixed structural deformity and produces kyphosis at predominantly lumbar and thoracic rather than cervical regions. Camptocormia has been reported due to a wide range of neurologic, psychiatric, muscular and orthopaedic conditions as well as rare reports of its emergence following the initiation of a number of medications (Finsterer and Strobl, 2010). Parkinson's disease (PD) includes prominent motor features of bradykinesia, rigidity and reduced postural balance responses in all those affected with this disease, but can also cause a range of other motor and non-motor features. Camptocormia is reported in a minority of patients with PD, and it is usually associated with longer disease duration and greater disease burden (Tiple et al., 2009). The aetiology of camptocormia in PD is debated, and responses to treatment have been generally poor and variable between studies. Recent studies have suggested the use of botulinum toxin may improve posture in some affected individuals. © 2015 Published by Elsevier Ltd.
Keywords: Camptocormia Botulinum toxin Parkinson's disease
1. Historical notes
2. Presentation
The use of the term “camptocormia” to describe this postural deformity derived from the Greek “camptos” (bent) and “Kormos” (spine) has been used since 1818 (Brodie, 1818). However popular use of this term began in 1914 to describe the appearance of a marked flexion deformity seen in soldiers affected by “shell shock” (Finsterer and Strobl, 2010), or what would now likely be considered Post Traumatic Stress Disorder. This emphasised the possible psychogenic element of this physical condition. Other organic causes of axial deformity were rarely described, sometimes referred to as “Bent Spine Syndrome”, a term associated also with parkinsonism since the 19th century. However, the clinical and epidemiological features of camptocormia were not otherwise well described in PD until the end of the last century (Djaldetti et al., 1999).
Apart from that seen in PD, camptocormia has been reported as a rare presentation of many muscular disorders including muscular dystrophy (Doherty et al., 2012), primary and secondary myopathies (Finsterer and Strobl, 2010), and peripheral neuropathic disorders including chronic inflammatory demyelinating peripheral neuropathy and motor neurone disease (Terashima et al., 2009). A primary late onset myopathy presenting as camptocormia has been reported with fatty infiltration of paravertebral and gluteal muscles with lobular endomysial fibrosis seen on muscle biopsy. Patients are generally reported to have symptom onset after 60 years of age, with a female predominance, and a positive family history suggesting a genetic aetiology (Laroche and Cintas, 2010). This condition is not associated with other neurological signs on examination, in particular the weakness is localised to extensor spinal musculature only. Generalised muscle or neuromuscular disease can produce weakness of trunk extension producing camptocormia as the presenting feature in rare cases. Endocrinopathies can produce muscle weakness, including reported cases of hypothyroidism and steroid induced myopathy. Rare cases of mitochondrial myopathy
* Corresponding author. E-mail address: [email protected] (C. Colosimo). http://dx.doi.org/10.1016/j.toxicon.2015.06.004 0041-0101/© 2015 Published by Elsevier Ltd.
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presenting with camptocormia have also been reported (Lenoir et al., 2010). Determining the underlying diagnosis requires imaging, Electromyography (EMG) and biopsy of affected muscles where necessary. Treatment is then of the primary cause where possible. Camptocormia is most commonly reported in PD, where it can present as a gradual or subacute phenomenon, and can vary day to day. Some patients will experience a sense of being “pulled forwards” though many may not initially report difficulties despite obvious postural deformities. The posture will tend to worsen as they walk, particularly after prolonged activity, and may be associated with back pain. There may be functional interference with mobility due to difficulties extending their head sufficiently to see where they are going, some patients ultimately requiring a wheelchair. Often patients can consciously improve their posture for short periods of time, or may lean against a wall to improve their posture. Whether this represents a “sensory trick” such as that seen in undisputed dystonic disorders is debated. The posture improves significantly or resolves completely on lying down. A stooped posture with mild forward flexion of the thoracic spine is commonly seen in older people, likely related to osteoporosis and lumbar spine disease. More pronounced forward flexion of the spine, associated with flexion of the hips and knees, is commonly seen in moderate to advanced PD (Oeda et al., 2013), often improving with dopaminergic treatment. Camptocormia, as a more severe axial deformity, is not common, occurring in 3e7 % of those with PD in epidemiological studies (Tiple et al., 2009; Seki et al., 2011). One Japanese study showed a higher prevalence rate of 18%, whether this relates to genetic influences or other differences in recruitment between studies is unknown (Abe et al., 2010). Camptocormia in PD is associated with longer disease duration, disease severity and history of vertebral surgery (Tiple et al., 2009) as well as a higher frequency of autonomic non-motor features (Ou et al., 2014). 3. Other axial deformities in Parkinson's disease In addition to camptocormia, other axial abnormalities occur in PD, including anterocollis, Pisa syndrome and scoliosis (Ashour and Jankovic, 2006). Anterocollis in PD is usually a form of cervical dystonia, producing forward flexion of the neck at the cervical spine. This can occur as a separate disease entity, presenting with neck pain and stiffness, abnormal movements and postures of the head and neck, and patients may display a “sensory trick”. Anterocollis occurs in 5e6% of those with PD (Revuelta, 2012), and is more commonly reported in another neurodegenerative disorder, Multiple System Atrophy (MSA). Anterocollis is differentiated from camptocormia by the location of the flexion deformity in the neck only. Marked neck flexion can be seen in situations which produce weakness of neck extension, referred to as “dropped head syndrome”. This generally implies a concurrent muscular or neuromuscular disorder. Pisa syndrome implies a marked lateral flexion of the trunk, which can be mobile, and like camptocormia can resolve on lying down (Doherty et al., 2011). Pisa syndrome is much less common, seen in 2% of those with PD (Bonanni et al., 2007). Scoliosis is a lateral curvature of the spine which includes axial vertebral rotation and is a fixed deformity visible on x-ray. It is postulated that prolonged Pisa syndrome can produce scoliosis (Doherty et al., 2011) but this may also be pre-existing, becoming more notable as the patient develops a typical stooped posture of PD. Fixed spinal deformities can be produced by vertebral fractures, spondylitis and focal disease of the spine such as ankylosing spondylitis. These produce postural abnormalities which do not alter significantly when recumbent, and can occur in those with PD
especially in older patients. 4. Pathophysiology Initial reports of camptocormia stressed the likelihood of a psychiatric aetiology. This is no longer considered the case, particularly with camptocormia associated with PD, however the pathogenesis remains unknown. Competing hypotheses have been proposed, with incongruous evidence from small studies. Although some authors postulate it is related to excessive axial rigidity, the poor response in camptocormia to dopaminergic therapies and deep brain stimulation surgery, which are highly effective for other motor components of PD, suggests that an alternate mechanism is likely (Margraf et al., 2010). The dominant theory is that of focal dystonia producing an imbalance in activity in the muscles of flexion and extension of the spine, resulting in the abnormal posture (Jankovic, 2010). Dystonia is a movement disorder defined as intermittent or sustained muscle contractions causing abnormal, often repetitive movements, postures or both which may be instigated or worsened by voluntary action (Albanese et al., 2013). Dystonia is postulated to occur due to abnormal sensorimotor processing, abnormal plasticity and reduction of surround inhibition in susceptible individuals (Breakefield et al., 2008). This is likely to involve various levels of cortical, basal ganglia and spinal motor neuron integration, explaining the similarities in clinical phenomenology which can occur due to various genetic, metabolic and structural pathologies. Axial predominant dystonia is an uncommon presentation, which can be primary or occur following injury or surgery to the spine. Axial dystonia responds poorly to oral medications though some response to anticholinergics can be seen (Bhatia et al., 1997). The potential for correction of the posture voluntarily, albeit briefly, and when leaning against a support such as a wall has suggested to some that a sensory trick may be present, implicating a focal dystonia affecting axial musculature. Reported improvement in camptocormia following pallidotomy or deep brain stimulation surgery for the treatment of motor dysfunction in PD has also been postulated to suggest a dystonic aetiology (Slawek et al., 2003; Hellmann et al., 2006). Based on the presentation of camptocormia in primary myopathy, and the suggestion of “dropped head” syndrome in PD as a neck extensor myopathy with myopathic changes rather than dystonic anterocollis (Lava and Factor, 2001; Katz et al., 1996) some authors have suggested a primary, focal myopathy may account for camptocormia in PD (Laroche et al., 1995). Evidence for a focal myopathic cause of camptocormia in PD has been demonstrated in some cases, with myopathic changes on EMG (Schabitz et al., 2003) and biopsy of paravertebral muscles (Spuler et al., 2010). Increased spontaneous activity and small polyphasic potentials on EMG, and increased variability in fibre size and internal nuclei compared to age matched control subjects has been reported (Margraf et al., 2010), however these findings are not seen in all affected patients (Djaldetti et al., 1999). A recent case-controlled study of muscular MRI in PD with camptocormia of variable duration showed early paravertebral muscle oedema and swelling, with later fatty degeneration (Margraf et al., 2015). The most convincing study compared paraspinal muscle biopsies of 14 patients with camptocormia to post-mortem muscle specimens of control subjects without PD (Wrede et al., 2012). Consistent patterns of myopathic change including myofibrillar disorganisation, loss of type 2 fibres and hypertrophy of type 1 fibres were seen. In addition, endomysial fibrosis in affected muscles correlated with the severity of clinical impairment due to camptocormia. Although generally described as separate disorders, camptocormia and Pisa syndrome share many features, in particular the
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resolution when supine, suggesting a common aetiology. Pisa syndrome and camptocormia may often coexist in the same patient. Pisa syndrome has also been reported as a tardive phenomenon following neuroleptic or antidopaminergic use in addition to that seen in PD. Rarely, it has been seen after the introduction of cholinesterase inhibitors to treat Alzheimer's disease (Suzuki and Matsuzaka, 2002). Pisa syndrome can occur following pallidotomy, a severe disruption to unilateral basal ganglia function which may be responsible for lateralised muscle responses producing the postural distortion (van de Warrenburg et al., 2007). PD pathology is uniquely asymmetrical within the basal ganglia, yet in camptocormia the postural distortion is in the sagittal plane. In addition, poor responses to treatment implicate a pathophysiological mechanism other than progressive dopaminergic dysfunction. The association of camptocormia with non-motor features including sleep disruption, perceptual problems and hallucinations is intriguing for the possible involvement of brainstem structures. Various brainstem structures are known to be involved in regulation of sleep (Boeve et al., 2007), and disruption to serotonergic and cholinergic outputs from the brainstem to the thalamus may play a role in the development of visual hallucinations (Bertram and Williams, 2012). Sleep studies in PD camptocormia show an increased rate of periodic leg movements of sleep (Lavault et al., 2009) and one study suggested reduced midbrain and pontine size may explain this correlation (Bonneville et al., 2008). MSA is a rare sporadic disorder of the presenile age, causing autonomic failure, parkinsonism and cerebellar dysfunction. Anterocollis, Pisa syndrome and camptocormia occur far more frequently in this condition than in PD (Stefanova et al., 2009). Postural balance control requires integration of visual, vestibular and proprioceptive inputs with a motor output response to prevent falling. Vestibular hypofunction has been reported in PD and correlated with lateral flexion deformity when unilateral, but not with falls (Pollak et al., 2009; Vitale et al., 2011). Visual disturbance and visual processing deficiencies occur at multiple sites in PD, including delays in visual evoked responses and disturbances of visuospatial processing (Gawel et al., 1981). Proprioception has also been shown to be abnormal in PD (Vaugoyeau et al., 2007; Zia et al., 2000)and impaired axial proprioception correlates with motor severity (Wright et al., 2010). Proprioceptive dysregulation has been postulated to contribute to the development of postural abnormalities including camptocormia. 5. Management options No specific treatment has been shown to ameliorate the flexion deformity in all cases. Physical therapies including the use of a gait aid to encourage a more upright posture, physical rehabilitation, and the use of restraints have been used with variable outcome in individual cases, but are not routinely successful and management is often unsatisfactory (Melamed and Djaldetti, 2006). Although physical therapies such as bracing and back extension exercises have been advocated (Ye et al., 2015; de Seze et al., 2008), the response rate is poor and they are often poorly tolerated. There are reports of non-formal bracing techniques such as “backpack” therapy to be beneficial in a small number of patients (Gerton et al., 2010). Dopaminergic therapy improves rigidity and the stooped posture commonly seen in PD, but effects on camptocormia are limited. Individual patients may benefit from increased levodopa (Finsterer and Strobl, 2011) or apomorphine (Katerina et al., 2014), an infusional dopamine agonist medication. Other medications which have been trialled for PD, such as anticholinergics, have not shown beneficial effect (Finsterer and Strobl, 2010). Spinal surgery including laminectomy and fusion have been
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proposed as management options in severe cases, however the response is often disappointing, and the recovery may be fraught with complications (Babat et al., 2004). Deep Brain Stimulation (DBS) surgery is beneficial for motor improvement in PD, whether placed in the subthalamic nucleus (STN) or globus pallidus. The effect on camptocormia is variable, it may significantly improve, even if previously severe, or may not change despite an overall successful surgical outcome (Umemura et al., 2010; Capelle et al., 2011). One study suggested DBS to the STN for PD improved camptocormia only in those who had reported this axial deformity within 18 months prior to the operation (Schulz-Schaeffer et al., 2015). In addition to attempts to improve the posture, attention should be paid to management of pain, protection of bone integrity and falls prevention with the use of gait aids as required. 6. The role of botulinum toxin Botulinum toxin serotype A is highly effective in reducing muscle overactivity in focal dystonia for which it is the recommended treatment (Albanese et al., 2006). Anterocollis in PD may respond to botulinum toxin injections as used for other patterns of cervical dystonia (Jankovic, 2009). Botulinum toxin for camptocormia has been trialled in only a few studies, with variable results (see Table 1). It is as yet uncertain which muscles should be primarily targeted, given the location of flexion is predominantly in the lumbar region and may therefore involve overactivity of hip or spinal flexors or weakness of the extensor muscles of the back. Azher and Jankovic described 16 patients with camptocormia who failed to respond to a number of oral agents. Six of the 11 PD patients were treated with botulinum toxin to either rectus abdominis, paraspinal muscles, or both. Three patients were reported to have a good response to this treatment lasting at least 8 weeks, though the extent of the postural change or response to repeated injections was not documented (Azher and Jankovic, 2005). Ultrasound guided injection of iliopsoas or rectus abdominis with 100e300 incobotulinum toxin A in one study of 10 patients was ineffective (Fietzek et al., 2009). Injections of 500e1500 units of abobotulinum toxin A to the deep portion of iliopsoas of 3 PD and one MSA patient in another study resulted in some weakness of hip flexion and questionable efficacy (von Coelln et al., 2008). CT guidance to more accurately target the iliopsoas in a separate study of two patients, with rectus abdominis also treated, was also ineffective (Colosimo and Salvatori, 2009). Furusawa and colleagues injected lidocaine into the abdominal muscles of 5 patients with improved posture following injection of the external oblique but not rectus abdominis or internal oblique, and postulated the involvement of this muscle in production of camptocormia (Furusawa et al., 2012). In a follow-up study, repeated injection of lidocaine to the external oblique muscles bilaterally was provided to 12 patients with PD related camptocormia over 5 days. In association with a rehabilitation program, 9 patients showed some improvement in posture which was maintained in 8 patients for up to 90 days (Furusawa et al., 2013). A single case of response to botulinum toxin injection to the external oblique for camptocormia associated with PD has been reported (Wijemanne and Jimenez-Shahed, 2014). Camptocormia had been present for 2 years, and the patient had partial resection of the rectus abdominis for a breast reconstruction surgery unilaterally. Injections of botulinum toxin to rectus abdominis bilaterally reduced painful abdominal contractions but had little effect on her posture. EMG of the external oblique revealed marked activity, and treating this muscle with 200 units of onabotulinum toxin A in
Please cite this article in press as: Bertram, K.L., et al., Treatment of camptocormia with botulinum toxin, Toxicon (2015), http://dx.doi.org/ 10.1016/j.toxicon.2015.06.004
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Table 1 Synopsis of reports on the use of Botulinum toxin A in camptocormia. Author
Patients
Duration of camptocormia
Total toxin dose per injection cycle
Location of injection
Response
Von Coelln
4: e 3 PD 1 MSA
1e3 years
1000e3000 Mu Abobotulinum toxin A
2 Unilateral IL 2 Bilateral IL
Wijemanne
1-PD
2 years
400 Mu Onabotulinum toxin A
Colosimo
2 ePD
Not stated
800 Mu Onabotulinum toxin A
Fietzek
10 e PD
1.9 ± 0.2(IL) 3.0 ± 1.4(RA)
100e300 Mu Incobotulinum toxin A
Bilateral RA; Unilateral RA, contralateral EO Bilateral IL CT guided Bilateral RA 5 Bilateral IL 5 Bilateral RA
1 improved upright posture for 2 weeks 1 improved upright posture for 6 weeks 1 no improvement 1 worsening of MSA, no improvement in posture RA-Improved pain, minimal postural change: RA þ EO-Improved from 45 to 15e20 forward flexion in the “on” motor state No response over 2 weeks
Azher
16 described (9 injected): 11 PD 5 other MD
4.5 ± 3.9 yrs
PD group 350e600 Mu Onabotulinum toxin A NON PD group 300e800 Mu Onabotulinum toxin A
RA ± PS
No improvement in goal attainment scales incorporating pain relief, postural improvement, f unctional goals at 3 weeks PD group- 3 no response; 3 good response; 5 not injected Other group- 2 no response; 1 partial response; 2 not injected
Abbreviations: PD- Parkinson's Disease; MSA- Multiple System Atrophy; MD-movement disorders; RA- Rectus Abdominis; IL- iliopsoas; EO- External Oblique; PS- paraspinal; Mu- Mouse units.
addition to 200 units to the intact rectus resulted in significant improvement in posture lasting three months, which was maintained with repeated injections. A single case of injection to rectus abdominis also failed to improve the posture, despite a possible sensory trick apparent in the patient (Gerton et al., 2010). Based on the small studies and variable responses, recent guidelines for the use of botulinum toxin A in management of PD have ascribed a level “U” recommendation (i.e. insufficient data) for the use of toxin in camptocormia (Mills et al., 2015). Two small randomised studies have shown mild improvements may be achieved in Pisa syndrome in PD with botulinum toxin injections (Table 2). A placebo controlled study of 26 patients showed an unsustained improvement in axial posture when associated with physical therapy (Tassorelli et al., 2014). All patients in this study had a degree of camptocormia in addition to lateral trunk flexion, and location of injections was determined by EMG patterns of prolonged tonic activity. At the end of four week rehabilitation program all participants reported improvement in back pain; however, those who received botulinum toxin injections prior to the rehabilitation program had a greater pain response than those given placebo. An objective functional scale of activity also showed a greater and more prolonged response which was sustained out to 6 months. Kinematic analysis showed improvement in both anterior flexion and lateral inclination with botulinum toxin for 3 months after the injection. A crossover design smaller study reduced pain and improved disability in 6 of 9 patients with improvement of objective postural measurement in 6 patients (Bonanni et al., 2007). Using goniometric measurements during the
defined “on” state 1 h after morning levodopa medications, these 6 patients showed improvement in axial posture of between 15 and 30 . Four patients in this study elected to continue treatment with botulinum toxin after the completion of the study. 7. Conclusion Camptocormia is an uncommon and complex symptom, occurring as part of PD or due to another disorder. Fundamental to developing a reliable treatment for this disabling condition is a thorough understanding of its pathophysiology. Although some evidence exists for both the dystonia and myopathy theories, findings are not consistent across studies. The response of a few patients to botulinum toxin suggests a dystonic aetiology may be relevant in some patients. Interestingly, evidence for efficacy of botulinum toxin in the treatment of axial postural abnormalities in PD is greater for Pisa syndrome than camptocormia. Whether this is due to different pathophysiological mechanisms, or simply to better trial design in the two controlled trials in Pisa syndrome, remains a matter of debate. It is possible that a combination of peripheral and central mechanisms can produce a common phenotype, that is, camptocormia, in different individuals, resulting in the variability seen in treatment response. Whilst the pathophysiology of camptocormia and related syndromes remains uncertain, adequate treatment is likely to remain elusive. In this regard, the evidence supporting the use of botulinum toxin injection in paravertebral and abdominal muscles remains lacking, and well-designed, large multicentre studies are necessary before
Table 2 Synopsis of reports on the use of Botulinum toxin A in Pisa syndrome. Author
Patients
Duration of Pisa syndrome Total toxin dose per injection cycle
Location of injection
3.1 ± 1.9 yrs Tassorelli 26 PD randomised 13 injected with toxin (13 placebo)
50e175 Mu Incobotulinum Up to 4 muscles per person (RA,IL, PS) based on EMG toxin A AND 4 week rehabilitation findings program
Bonanni
500 Mu Abobotulinum toxin A
9 PD
1e4 years
Bilateral PS
Response Improved pain, camptocormia and lateral trunk flexion compared with baseline and placebo at end of rehabilitation; improvement in lateral flexion apparent at 3 but not 6 months 6 improved pain and objective measurement of lateral flexion 1 improved pain only 2 no response
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Disord. 20 (11), 1140e1144. Terashima, M., Kataoka, H., Sugie, K., Horikawa, H., Ueno, S., 2009. Coexistence of chronic inflammatory demyelinating polyneuropathy and camptocormia. J. Neurol. Neurosurg. Psychiatry 80 (11), 1296e1297. Tiple, D., Fabbrini, G., Colosimo, C., et al., 2009. Camptocormia in Parkinson disease: an epidemiological and clinical study. J. Neurol. Neurosurg. Psychiatry 80 (2), 145e148. Umemura, A., Oka, Y., Ohkita, K., Yamawaki, T., Yamada, K., 2010. Effect of subthalamic deep brain stimulation on postural abnormality in Parkinson disease. J. Neurosurg. 112 (6), 1283e1288. van de Warrenburg, B.P., Bhatia, K.P., Quinn, N.P., 2007. Pisa syndrome after unilateral pallidotomy in Parkinson's disease: an unrecognised, delayed adverse event? J. Neurol. Neurosurg. Psychiatry 78 (3), 329e330.
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Contents lists available at ScienceDirect
Toxicon journal homepage: www.elsevier.com/locate/toxicon
Treatment of camptocormia with botulinum toxin Kelly L. Bertram a, b, Paola Stirpe c, Carlo Colosimo c, * a
Neurosciences, Alfred Hospital, Melbourne, Victoria, Australia Faculty of Medicine Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia c Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 May 2015 Accepted 11 June 2015 Available online xxx
Camptocormia is defined as an involuntary axial postural distortion of >45 flexion which occurs in the upright position, increases whilst walking and resolves when supine (Ashour and Jankovic, 2006). Unlike orthopaedic or age related kyphosis it is not a fixed structural deformity and produces kyphosis at predominantly lumbar and thoracic rather than cervical regions. Camptocormia has been reported due to a wide range of neurologic, psychiatric, muscular and orthopaedic conditions as well as rare reports of its emergence following the initiation of a number of medications (Finsterer and Strobl, 2010). Parkinson's disease (PD) includes prominent motor features of bradykinesia, rigidity and reduced postural balance responses in all those affected with this disease, but can also cause a range of other motor and non-motor features. Camptocormia is reported in a minority of patients with PD, and it is usually associated with longer disease duration and greater disease burden (Tiple et al., 2009). The aetiology of camptocormia in PD is debated, and responses to treatment have been generally poor and variable between studies. Recent studies have suggested the use of botulinum toxin may improve posture in some affected individuals. © 2015 Published by Elsevier Ltd.
Keywords: Camptocormia Botulinum toxin Parkinson's disease
1. Historical notes
2. Presentation
The use of the term “camptocormia” to describe this postural deformity derived from the Greek “camptos” (bent) and “Kormos” (spine) has been used since 1818 (Brodie, 1818). However popular use of this term began in 1914 to describe the appearance of a marked flexion deformity seen in soldiers affected by “shell shock” (Finsterer and Strobl, 2010), or what would now likely be considered Post Traumatic Stress Disorder. This emphasised the possible psychogenic element of this physical condition. Other organic causes of axial deformity were rarely described, sometimes referred to as “Bent Spine Syndrome”, a term associated also with parkinsonism since the 19th century. However, the clinical and epidemiological features of camptocormia were not otherwise well described in PD until the end of the last century (Djaldetti et al., 1999).
Apart from that seen in PD, camptocormia has been reported as a rare presentation of many muscular disorders including muscular dystrophy (Doherty et al., 2012), primary and secondary myopathies (Finsterer and Strobl, 2010), and peripheral neuropathic disorders including chronic inflammatory demyelinating peripheral neuropathy and motor neurone disease (Terashima et al., 2009). A primary late onset myopathy presenting as camptocormia has been reported with fatty infiltration of paravertebral and gluteal muscles with lobular endomysial fibrosis seen on muscle biopsy. Patients are generally reported to have symptom onset after 60 years of age, with a female predominance, and a positive family history suggesting a genetic aetiology (Laroche and Cintas, 2010). This condition is not associated with other neurological signs on examination, in particular the weakness is localised to extensor spinal musculature only. Generalised muscle or neuromuscular disease can produce weakness of trunk extension producing camptocormia as the presenting feature in rare cases. Endocrinopathies can produce muscle weakness, including reported cases of hypothyroidism and steroid induced myopathy. Rare cases of mitochondrial myopathy
* Corresponding author. E-mail address: [email protected] (C. Colosimo). http://dx.doi.org/10.1016/j.toxicon.2015.06.004 0041-0101/© 2015 Published by Elsevier Ltd.
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presenting with camptocormia have also been reported (Lenoir et al., 2010). Determining the underlying diagnosis requires imaging, Electromyography (EMG) and biopsy of affected muscles where necessary. Treatment is then of the primary cause where possible. Camptocormia is most commonly reported in PD, where it can present as a gradual or subacute phenomenon, and can vary day to day. Some patients will experience a sense of being “pulled forwards” though many may not initially report difficulties despite obvious postural deformities. The posture will tend to worsen as they walk, particularly after prolonged activity, and may be associated with back pain. There may be functional interference with mobility due to difficulties extending their head sufficiently to see where they are going, some patients ultimately requiring a wheelchair. Often patients can consciously improve their posture for short periods of time, or may lean against a wall to improve their posture. Whether this represents a “sensory trick” such as that seen in undisputed dystonic disorders is debated. The posture improves significantly or resolves completely on lying down. A stooped posture with mild forward flexion of the thoracic spine is commonly seen in older people, likely related to osteoporosis and lumbar spine disease. More pronounced forward flexion of the spine, associated with flexion of the hips and knees, is commonly seen in moderate to advanced PD (Oeda et al., 2013), often improving with dopaminergic treatment. Camptocormia, as a more severe axial deformity, is not common, occurring in 3e7 % of those with PD in epidemiological studies (Tiple et al., 2009; Seki et al., 2011). One Japanese study showed a higher prevalence rate of 18%, whether this relates to genetic influences or other differences in recruitment between studies is unknown (Abe et al., 2010). Camptocormia in PD is associated with longer disease duration, disease severity and history of vertebral surgery (Tiple et al., 2009) as well as a higher frequency of autonomic non-motor features (Ou et al., 2014). 3. Other axial deformities in Parkinson's disease In addition to camptocormia, other axial abnormalities occur in PD, including anterocollis, Pisa syndrome and scoliosis (Ashour and Jankovic, 2006). Anterocollis in PD is usually a form of cervical dystonia, producing forward flexion of the neck at the cervical spine. This can occur as a separate disease entity, presenting with neck pain and stiffness, abnormal movements and postures of the head and neck, and patients may display a “sensory trick”. Anterocollis occurs in 5e6% of those with PD (Revuelta, 2012), and is more commonly reported in another neurodegenerative disorder, Multiple System Atrophy (MSA). Anterocollis is differentiated from camptocormia by the location of the flexion deformity in the neck only. Marked neck flexion can be seen in situations which produce weakness of neck extension, referred to as “dropped head syndrome”. This generally implies a concurrent muscular or neuromuscular disorder. Pisa syndrome implies a marked lateral flexion of the trunk, which can be mobile, and like camptocormia can resolve on lying down (Doherty et al., 2011). Pisa syndrome is much less common, seen in 2% of those with PD (Bonanni et al., 2007). Scoliosis is a lateral curvature of the spine which includes axial vertebral rotation and is a fixed deformity visible on x-ray. It is postulated that prolonged Pisa syndrome can produce scoliosis (Doherty et al., 2011) but this may also be pre-existing, becoming more notable as the patient develops a typical stooped posture of PD. Fixed spinal deformities can be produced by vertebral fractures, spondylitis and focal disease of the spine such as ankylosing spondylitis. These produce postural abnormalities which do not alter significantly when recumbent, and can occur in those with PD
especially in older patients. 4. Pathophysiology Initial reports of camptocormia stressed the likelihood of a psychiatric aetiology. This is no longer considered the case, particularly with camptocormia associated with PD, however the pathogenesis remains unknown. Competing hypotheses have been proposed, with incongruous evidence from small studies. Although some authors postulate it is related to excessive axial rigidity, the poor response in camptocormia to dopaminergic therapies and deep brain stimulation surgery, which are highly effective for other motor components of PD, suggests that an alternate mechanism is likely (Margraf et al., 2010). The dominant theory is that of focal dystonia producing an imbalance in activity in the muscles of flexion and extension of the spine, resulting in the abnormal posture (Jankovic, 2010). Dystonia is a movement disorder defined as intermittent or sustained muscle contractions causing abnormal, often repetitive movements, postures or both which may be instigated or worsened by voluntary action (Albanese et al., 2013). Dystonia is postulated to occur due to abnormal sensorimotor processing, abnormal plasticity and reduction of surround inhibition in susceptible individuals (Breakefield et al., 2008). This is likely to involve various levels of cortical, basal ganglia and spinal motor neuron integration, explaining the similarities in clinical phenomenology which can occur due to various genetic, metabolic and structural pathologies. Axial predominant dystonia is an uncommon presentation, which can be primary or occur following injury or surgery to the spine. Axial dystonia responds poorly to oral medications though some response to anticholinergics can be seen (Bhatia et al., 1997). The potential for correction of the posture voluntarily, albeit briefly, and when leaning against a support such as a wall has suggested to some that a sensory trick may be present, implicating a focal dystonia affecting axial musculature. Reported improvement in camptocormia following pallidotomy or deep brain stimulation surgery for the treatment of motor dysfunction in PD has also been postulated to suggest a dystonic aetiology (Slawek et al., 2003; Hellmann et al., 2006). Based on the presentation of camptocormia in primary myopathy, and the suggestion of “dropped head” syndrome in PD as a neck extensor myopathy with myopathic changes rather than dystonic anterocollis (Lava and Factor, 2001; Katz et al., 1996) some authors have suggested a primary, focal myopathy may account for camptocormia in PD (Laroche et al., 1995). Evidence for a focal myopathic cause of camptocormia in PD has been demonstrated in some cases, with myopathic changes on EMG (Schabitz et al., 2003) and biopsy of paravertebral muscles (Spuler et al., 2010). Increased spontaneous activity and small polyphasic potentials on EMG, and increased variability in fibre size and internal nuclei compared to age matched control subjects has been reported (Margraf et al., 2010), however these findings are not seen in all affected patients (Djaldetti et al., 1999). A recent case-controlled study of muscular MRI in PD with camptocormia of variable duration showed early paravertebral muscle oedema and swelling, with later fatty degeneration (Margraf et al., 2015). The most convincing study compared paraspinal muscle biopsies of 14 patients with camptocormia to post-mortem muscle specimens of control subjects without PD (Wrede et al., 2012). Consistent patterns of myopathic change including myofibrillar disorganisation, loss of type 2 fibres and hypertrophy of type 1 fibres were seen. In addition, endomysial fibrosis in affected muscles correlated with the severity of clinical impairment due to camptocormia. Although generally described as separate disorders, camptocormia and Pisa syndrome share many features, in particular the
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resolution when supine, suggesting a common aetiology. Pisa syndrome and camptocormia may often coexist in the same patient. Pisa syndrome has also been reported as a tardive phenomenon following neuroleptic or antidopaminergic use in addition to that seen in PD. Rarely, it has been seen after the introduction of cholinesterase inhibitors to treat Alzheimer's disease (Suzuki and Matsuzaka, 2002). Pisa syndrome can occur following pallidotomy, a severe disruption to unilateral basal ganglia function which may be responsible for lateralised muscle responses producing the postural distortion (van de Warrenburg et al., 2007). PD pathology is uniquely asymmetrical within the basal ganglia, yet in camptocormia the postural distortion is in the sagittal plane. In addition, poor responses to treatment implicate a pathophysiological mechanism other than progressive dopaminergic dysfunction. The association of camptocormia with non-motor features including sleep disruption, perceptual problems and hallucinations is intriguing for the possible involvement of brainstem structures. Various brainstem structures are known to be involved in regulation of sleep (Boeve et al., 2007), and disruption to serotonergic and cholinergic outputs from the brainstem to the thalamus may play a role in the development of visual hallucinations (Bertram and Williams, 2012). Sleep studies in PD camptocormia show an increased rate of periodic leg movements of sleep (Lavault et al., 2009) and one study suggested reduced midbrain and pontine size may explain this correlation (Bonneville et al., 2008). MSA is a rare sporadic disorder of the presenile age, causing autonomic failure, parkinsonism and cerebellar dysfunction. Anterocollis, Pisa syndrome and camptocormia occur far more frequently in this condition than in PD (Stefanova et al., 2009). Postural balance control requires integration of visual, vestibular and proprioceptive inputs with a motor output response to prevent falling. Vestibular hypofunction has been reported in PD and correlated with lateral flexion deformity when unilateral, but not with falls (Pollak et al., 2009; Vitale et al., 2011). Visual disturbance and visual processing deficiencies occur at multiple sites in PD, including delays in visual evoked responses and disturbances of visuospatial processing (Gawel et al., 1981). Proprioception has also been shown to be abnormal in PD (Vaugoyeau et al., 2007; Zia et al., 2000)and impaired axial proprioception correlates with motor severity (Wright et al., 2010). Proprioceptive dysregulation has been postulated to contribute to the development of postural abnormalities including camptocormia. 5. Management options No specific treatment has been shown to ameliorate the flexion deformity in all cases. Physical therapies including the use of a gait aid to encourage a more upright posture, physical rehabilitation, and the use of restraints have been used with variable outcome in individual cases, but are not routinely successful and management is often unsatisfactory (Melamed and Djaldetti, 2006). Although physical therapies such as bracing and back extension exercises have been advocated (Ye et al., 2015; de Seze et al., 2008), the response rate is poor and they are often poorly tolerated. There are reports of non-formal bracing techniques such as “backpack” therapy to be beneficial in a small number of patients (Gerton et al., 2010). Dopaminergic therapy improves rigidity and the stooped posture commonly seen in PD, but effects on camptocormia are limited. Individual patients may benefit from increased levodopa (Finsterer and Strobl, 2011) or apomorphine (Katerina et al., 2014), an infusional dopamine agonist medication. Other medications which have been trialled for PD, such as anticholinergics, have not shown beneficial effect (Finsterer and Strobl, 2010). Spinal surgery including laminectomy and fusion have been
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proposed as management options in severe cases, however the response is often disappointing, and the recovery may be fraught with complications (Babat et al., 2004). Deep Brain Stimulation (DBS) surgery is beneficial for motor improvement in PD, whether placed in the subthalamic nucleus (STN) or globus pallidus. The effect on camptocormia is variable, it may significantly improve, even if previously severe, or may not change despite an overall successful surgical outcome (Umemura et al., 2010; Capelle et al., 2011). One study suggested DBS to the STN for PD improved camptocormia only in those who had reported this axial deformity within 18 months prior to the operation (Schulz-Schaeffer et al., 2015). In addition to attempts to improve the posture, attention should be paid to management of pain, protection of bone integrity and falls prevention with the use of gait aids as required. 6. The role of botulinum toxin Botulinum toxin serotype A is highly effective in reducing muscle overactivity in focal dystonia for which it is the recommended treatment (Albanese et al., 2006). Anterocollis in PD may respond to botulinum toxin injections as used for other patterns of cervical dystonia (Jankovic, 2009). Botulinum toxin for camptocormia has been trialled in only a few studies, with variable results (see Table 1). It is as yet uncertain which muscles should be primarily targeted, given the location of flexion is predominantly in the lumbar region and may therefore involve overactivity of hip or spinal flexors or weakness of the extensor muscles of the back. Azher and Jankovic described 16 patients with camptocormia who failed to respond to a number of oral agents. Six of the 11 PD patients were treated with botulinum toxin to either rectus abdominis, paraspinal muscles, or both. Three patients were reported to have a good response to this treatment lasting at least 8 weeks, though the extent of the postural change or response to repeated injections was not documented (Azher and Jankovic, 2005). Ultrasound guided injection of iliopsoas or rectus abdominis with 100e300 incobotulinum toxin A in one study of 10 patients was ineffective (Fietzek et al., 2009). Injections of 500e1500 units of abobotulinum toxin A to the deep portion of iliopsoas of 3 PD and one MSA patient in another study resulted in some weakness of hip flexion and questionable efficacy (von Coelln et al., 2008). CT guidance to more accurately target the iliopsoas in a separate study of two patients, with rectus abdominis also treated, was also ineffective (Colosimo and Salvatori, 2009). Furusawa and colleagues injected lidocaine into the abdominal muscles of 5 patients with improved posture following injection of the external oblique but not rectus abdominis or internal oblique, and postulated the involvement of this muscle in production of camptocormia (Furusawa et al., 2012). In a follow-up study, repeated injection of lidocaine to the external oblique muscles bilaterally was provided to 12 patients with PD related camptocormia over 5 days. In association with a rehabilitation program, 9 patients showed some improvement in posture which was maintained in 8 patients for up to 90 days (Furusawa et al., 2013). A single case of response to botulinum toxin injection to the external oblique for camptocormia associated with PD has been reported (Wijemanne and Jimenez-Shahed, 2014). Camptocormia had been present for 2 years, and the patient had partial resection of the rectus abdominis for a breast reconstruction surgery unilaterally. Injections of botulinum toxin to rectus abdominis bilaterally reduced painful abdominal contractions but had little effect on her posture. EMG of the external oblique revealed marked activity, and treating this muscle with 200 units of onabotulinum toxin A in
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Table 1 Synopsis of reports on the use of Botulinum toxin A in camptocormia. Author
Patients
Duration of camptocormia
Total toxin dose per injection cycle
Location of injection
Response
Von Coelln
4: e 3 PD 1 MSA
1e3 years
1000e3000 Mu Abobotulinum toxin A
2 Unilateral IL 2 Bilateral IL
Wijemanne
1-PD
2 years
400 Mu Onabotulinum toxin A
Colosimo
2 ePD
Not stated
800 Mu Onabotulinum toxin A
Fietzek
10 e PD
1.9 ± 0.2(IL) 3.0 ± 1.4(RA)
100e300 Mu Incobotulinum toxin A
Bilateral RA; Unilateral RA, contralateral EO Bilateral IL CT guided Bilateral RA 5 Bilateral IL 5 Bilateral RA
1 improved upright posture for 2 weeks 1 improved upright posture for 6 weeks 1 no improvement 1 worsening of MSA, no improvement in posture RA-Improved pain, minimal postural change: RA þ EO-Improved from 45 to 15e20 forward flexion in the “on” motor state No response over 2 weeks
Azher
16 described (9 injected): 11 PD 5 other MD
4.5 ± 3.9 yrs
PD group 350e600 Mu Onabotulinum toxin A NON PD group 300e800 Mu Onabotulinum toxin A
RA ± PS
No improvement in goal attainment scales incorporating pain relief, postural improvement, f unctional goals at 3 weeks PD group- 3 no response; 3 good response; 5 not injected Other group- 2 no response; 1 partial response; 2 not injected
Abbreviations: PD- Parkinson's Disease; MSA- Multiple System Atrophy; MD-movement disorders; RA- Rectus Abdominis; IL- iliopsoas; EO- External Oblique; PS- paraspinal; Mu- Mouse units.
addition to 200 units to the intact rectus resulted in significant improvement in posture lasting three months, which was maintained with repeated injections. A single case of injection to rectus abdominis also failed to improve the posture, despite a possible sensory trick apparent in the patient (Gerton et al., 2010). Based on the small studies and variable responses, recent guidelines for the use of botulinum toxin A in management of PD have ascribed a level “U” recommendation (i.e. insufficient data) for the use of toxin in camptocormia (Mills et al., 2015). Two small randomised studies have shown mild improvements may be achieved in Pisa syndrome in PD with botulinum toxin injections (Table 2). A placebo controlled study of 26 patients showed an unsustained improvement in axial posture when associated with physical therapy (Tassorelli et al., 2014). All patients in this study had a degree of camptocormia in addition to lateral trunk flexion, and location of injections was determined by EMG patterns of prolonged tonic activity. At the end of four week rehabilitation program all participants reported improvement in back pain; however, those who received botulinum toxin injections prior to the rehabilitation program had a greater pain response than those given placebo. An objective functional scale of activity also showed a greater and more prolonged response which was sustained out to 6 months. Kinematic analysis showed improvement in both anterior flexion and lateral inclination with botulinum toxin for 3 months after the injection. A crossover design smaller study reduced pain and improved disability in 6 of 9 patients with improvement of objective postural measurement in 6 patients (Bonanni et al., 2007). Using goniometric measurements during the
defined “on” state 1 h after morning levodopa medications, these 6 patients showed improvement in axial posture of between 15 and 30 . Four patients in this study elected to continue treatment with botulinum toxin after the completion of the study. 7. Conclusion Camptocormia is an uncommon and complex symptom, occurring as part of PD or due to another disorder. Fundamental to developing a reliable treatment for this disabling condition is a thorough understanding of its pathophysiology. Although some evidence exists for both the dystonia and myopathy theories, findings are not consistent across studies. The response of a few patients to botulinum toxin suggests a dystonic aetiology may be relevant in some patients. Interestingly, evidence for efficacy of botulinum toxin in the treatment of axial postural abnormalities in PD is greater for Pisa syndrome than camptocormia. Whether this is due to different pathophysiological mechanisms, or simply to better trial design in the two controlled trials in Pisa syndrome, remains a matter of debate. It is possible that a combination of peripheral and central mechanisms can produce a common phenotype, that is, camptocormia, in different individuals, resulting in the variability seen in treatment response. Whilst the pathophysiology of camptocormia and related syndromes remains uncertain, adequate treatment is likely to remain elusive. In this regard, the evidence supporting the use of botulinum toxin injection in paravertebral and abdominal muscles remains lacking, and well-designed, large multicentre studies are necessary before
Table 2 Synopsis of reports on the use of Botulinum toxin A in Pisa syndrome. Author
Patients
Duration of Pisa syndrome Total toxin dose per injection cycle
Location of injection
3.1 ± 1.9 yrs Tassorelli 26 PD randomised 13 injected with toxin (13 placebo)
50e175 Mu Incobotulinum Up to 4 muscles per person (RA,IL, PS) based on EMG toxin A AND 4 week rehabilitation findings program
Bonanni
500 Mu Abobotulinum toxin A
9 PD
1e4 years
Bilateral PS
Response Improved pain, camptocormia and lateral trunk flexion compared with baseline and placebo at end of rehabilitation; improvement in lateral flexion apparent at 3 but not 6 months 6 improved pain and objective measurement of lateral flexion 1 improved pain only 2 no response
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