e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 8 7 e9 2

Official Journal of the European Paediatric Neurology Society

Case study

Gait evolution in a family with hereditary spastic paraplegia Stephane Armand a,*, Katia Turcot a, Alice Bonnefoy-Mazure a, Pierre Lascombes b, Geraldo De Coulon b a

Willy Taillard Laboratory of Kinesiology, Geneva University Hospitals, Geneva University, Geneva, Switzerland Pediatric Orthopaedic Service, Department of Child and Adolescent, Geneva University Hospitals, Geneva University, Geneva, Switzerland

b

article info

abstract

Article history:

Background: The degree of disability in patients with hereditary spastic paraplegia has been

Received 11 February 2014

reported variable even in members of the same family (same gene mutation). Moreover, it

Received in revised form

has been established that patients with hereditary spastic paraplegia should be treated

15 August 2014

differently from cerebral palsy patients due to the progressive nature of this disease.

Accepted 16 August 2014

However, the gait evolution of hereditary spastic paraplegia showing onset symptoms at an early age has been described as stable. Therefore, this study aims to evaluate the walking

Keywords:

ability and the influence of treatments on gait evolution in a family with hereditary spastic

Hereditary spastic paraplegia

paraplegia.

Gait

Methods: Clinical gait analyses were performed in six hereditary spastic paraplegia patients

Walking

from the same family with a follow-up of 4e15 years.

Longitudinal study

Results: Based on the gait deviation index, results showed a large variation of walking

Evolution

ability in these patients and no statistical difference between the first and last examination. In fact, three patients have improved their gait (from childhood to adolescence) whereas three patients worsened their gait. Conclusions: Gait alterations in a family with hereditary spastic paraplegia are heterogeneous. Gait evolution in hereditary spastic paraplegia with early symptoms had a tendency to improve gait until adolescence with adapted treatments and to decline in the adulthood. © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

1.

Introduction

Hereditary spastic paraplegia (HSP) is not a single disease entity, but rather a group of clinically and genetically diverse

disorders that share the primary feature of progressive lower extremity spasticity and mild weakness.1 The age of symptom onset, rate of progression and degree of disability are often variable between different genetic types of HSP, as well as within individual families in which they all have precisely the

* Corresponding author. Willy Taillard Laboratory of Kinesiology, University Hospitals of Geneva, 4 Rue Gabrielle-Perret-Gentil, CH-1211 Geneva 14, Switzerland. Tel.: þ41 (0)22 37 27 827; fax: þ41 (0)22 37 27 799. E-mail address: [email protected] (S. Armand). http://dx.doi.org/10.1016/j.ejpn.2014.08.001 1090-3798/© 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

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6-6-5 5-5-1 5-5-5 5-5-5 5-5-5 5-5-1 6-5-5 5-5-5 5-5-5 5-5-5 6-5-5 6-5-5 1.06 0.95 0.78 1.2 0.87 1.21 1.31 1.35 0.98 0.86 1.28 1.57 4.5 3.8 3.2 4.5 4.7 4.3 4.1 3.7 MV 3.9 MV 3.3 0.8 2.3 1.8 1 1 2.7 1.5 1.7 MV 1.3 MV 2 7-0

CGA: clinical gait analysis; GDI: gait deviation index; MV: missing value; FMS: functional mobility scale.

22-0

11-4

12 21 9 13 14 25 15-0

First Last First Last First Last First Last CGA CGA CGA CGA CGA CGA CGA CGA

Spasticity Strength Normalised (modified (MRCS) walking Ashworth speed scale) (m/s/m) Botulinum injections

12-8 11-9 to 13-0

7-6 7-4 13-6 3-3 14-8 5-8 20-0 17-0 23-5 10-2 26-8 13-1 12-6 9-8 9-11 6-11 11-11 7-6 3 2 3 3 4 2

All patients had at least three clinical gait analysis (CGA) assessments performed during routine follow-up. Their age at the first CGA ranged from 6 to 11 to 12-6 years-months and from 10-2 to 26-8 years at last CGA. The duration of the followup was between 3-3 and 14-8 years. Between 1993 and 2008, a CGA was performed using a sixcamera motion measurement system (VICON 460; ViconPeak®, Oxford, UK). After 2008, the evaluation was done with a twelve-camera motion measurement system (VICON Mx3þ; ViconPeak®, Oxford, UK). The kinematic parameters were

F M M F F F

Gait evaluation

1 2 3 4 5 6

2.2.

Surgical GDI interventions modification between first and last GCA (%) Years Years-months Years-months Years-months Age Age Age (years-months) (years-months) (years-months)

Six patients (4 females and 2 males) with autosomal dominant HSP and from the same family (blood relative with the same grand-father) were included in this study. The criteria proposed by McDermott et al.1 were used for the selection of patients. The diagnosis was confirmed by a genetic test (mutations in SPG3A). All patients have presented their first symptoms before the age of 4 years. Patient's characteristics are reported in Table 1. This retrospective study was approved by the local Ethics Committee.

Baclofen pump

Patients

Time between CGA

2.1.

Age at last CGA

Materials and methods

Age at first CGA

2.

Table 1 e Characteristics of HSP patients, treatments, clinical gait analysis times, function and physical evaluation.

1) The walking ability is variable within individuals of the same family with the same HSP gene mutation. 2) The gait evolution of HSP autosomal dominant inheritance pattern with symptoms onset in early is stable with adapted treatments.

Patients Sex Age at onset

same HSP gene mutation.2,3 Moreover, HSP symptoms that begin after adolescence typically worsen insidiously. In contrast, HSP symptoms that begin in early childhood may not show significant worsening over many years.2 Gait disturbances are the earliest clinical finding and the main clinical feature in HSP patients. Two studies have characterized the HSP gait.3,4 They reported gait alterations associated with spasticity and weakness of the lower limb. These gait alterations are very similar to those observed in patients with spastic diplegia (cerebral palsy e CP).5e7 Nowadays, even if HSP patients have similar symptoms and gait alterations to CP patients, they are treated differently due to the progression of the HSP disease.7 Compared with CP, orthopaedic corrections (i.e., soft tissues and bones surgery) are often discarded of the therapeutic plane in HSP patients. However, some reviews reported a clinical impression of stable disease progression in HSP patients having an onset of the symptoms in the first years of life.2,8 To the best of our knowledge, the stability of the disease has not been objectivised with an instrumented gait analysis. Knowing the middle (5 years) gait evolution of HSP could change the therapeutic options for these patients. Therefore, the purpose of this study is to evaluate the walking ability and the influence of treatments on gait evolution in a family with HSP. The following hypotheses were tested:

FMS

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e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 8 7 e9 2

computed according to the Plug-in-Gait model (ViconPeak®, Oxford, UK). All patients were asked to walk at their selfselected speed along a 10-m walkway. The primary outcome was the gait deviation index (GDI).9 This index is a multivariate measure of overall gait pathology. Five gait cycles by session and patient was used to compute the GDI excepted for one session for which only one gait cycle was used (Patient 5 e First evaluation). The gait variable scores (GVS) for each of the nine Movement Analysis Profile (MAP) components were used to quantify local kinematic gait deviations at first and last CGA.10

2.3.

2.4.

89

Data analysis

Considering the small sample, the non-parametric Wilcoxon matched paired test, was used to evaluate the evolution between the first and the last CGA. Spearman's correlation was performed to investigate the relationship between the duration of the follow-up and the gait evolution. A significant Pvalue was set at 0.05.

3.

Results

3.1.

Gait evolution

Function and physical evaluation

Walking speed, functional mobility scale (FMS)11 and the Gross Motor Function Classification System (GMFCS)12 were used to measure functional mobility at each session. Video recordings were used to estimate FMS and GMFCS when these scores were not available. For each CGA, a standardized physical examination was performed to assess the range of motion, the muscle strength (Medical Research Council Scale) and the muscle spasticity (modified Ashworth scale) of the lower limb. As performed by Klebe et al., the severity of spasticity was calculated as the mean value of both lower limbs on a scale 0e5.3 In the same manner the strength was evaluated as the mean value of flexion/extension on a scale of 0e5. Spasticity and strength were missing for the first assessment of the patients 3 and 5.

The GDI was between 55 and 99 at the first CGA, and between 66 and 85 at the last GGA (Fig. 1). The comparison between the first and the last gait assessment did not show a significant difference (P ¼ 0.75). The GDI was improved in three patients (12%, 13%, and 25%) and was worse in three patients (9%, 14% and 21%). The kinematic gait patterns in the sagittal plane of each CGA and each patient is presented in Fig. 2 and the MAP GVS components are presented in Table 2. In the improving group, the first patient (Patient 1) had a bilateral botulinum toxin in the triceps surae at the age of 12-8 years and a surgical intervention at the age of 15-0 years (bilateral muscle lengthening of the gastrocnemius and a hemi-transposition of the tibialis anterior). Gait patterns

Fig. 1 e Illustration of the evolution of the gait deviation index (GDI) related to age and treatments for each HSP patient. For a same patient, each evaluation is indicated with the corresponding marker. A treatment corresponding to an injection of botulinum toxin is indicated with a T, to a surgery with a S and to a baclofen pump with a B. All treatments are described below: T1: bilateral injection of botulinum toxin in the gastrocnemius and the soleus. S1: bilateral muscle lengthening (gastronemius), hemi-transposition of the tibialis anterior. S2: muscle lengthening (gastronemius, soleus) on the right side and bilateral tenotomy (hamstring). B0eB1: period during which the patient had the baclofen pump.

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e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 8 7 e9 2

showed an increased ankle dorsiflexion and an increased knee flexion during swing. The second patient (Patient 4) has benefited from a bilateral botulinum toxin in the triceps surae at the age of 7-0 years. This patient improved considerably the first year after the injection (20%) and remained relatively stable during the following three years (4%). Knee recurvatum was considerably reduced at the last assessment. The third patient (Patient 6) has benefited from a surgical intervention consisting of bilateral muscle lengthening of the gastrocnemius and a hemi-transposition of the tibialis anterior at the age of 11-4 years. The presence of equinus during gait has decreased, however an increased knee flexion appeared during stance. In the worsening group, the first patient (Patient 2) had a baclofen pump during 1e4 years. The GDI was worsening during this period (20%). Once the pump was stopped, the gait remained stable (0%). The gait patterns evolution showed an increased of ankle dorsiflexion and knee flexion and a reduced pelvis tilt. The second patient (Patient 3) had no treatment between the two first CGA (9-11 and 21-4 years). At the age of 22-0 years, the patient had a surgical procedure with unilateral triceps muscle lengthening and a bilateral hamstring tenotomy. The GDI decreased of 9% during 13-6

years of follow-up. Gait patterns showed an increased ankle dorsiflexion, a decreased knee flexion in stance, an increased hip flexion associated with an increased pelvic tilt. The third patient (Patient 5) presented a 14-8 years follow-up. This patient had no treatment between 11-11 and 26-8 years and had the least altered gait among all patients (GDI of 99 at the first CGA). The kinematics showed a reduced hip extension at the last evaluations. The Spearman's correlation between the duration of follow-up and the difference in GDI was not statistically significant (r ¼ 0.77, P ¼ 0.07). However, there is a tendency to have a gait improvement on middle-term follow-up and a gait decline for long-term follow-up.

3.2.

Functional and physical evaluation

All the patients were scored GMFCS 2 at the first and last assessment. The normalised walking speed was decreased (not significantly) in 5 patients (P ¼ 0.11) and the FMS was decreased in 4 patients (Table 1). For the strength and spasticity, there were no statistical differences between the first and the last assessment (P ¼ 0.25).

Fig. 2 e Kinematic gait patterns in the sagittal plane for each patient and each session for the right side. More the colour is dark more the assessment is recent.

10.5/9.7 7.7/7.6 5.5/8.5 6.7/5 5/17.2 39.8/8.2 9/17.2 2.2/2.8 8.5/10 9.9/10.2 CGA: clinical gait analysis; MAP: motion analysis profile; GVS: gait variable score.

Left/right Left/right

13.1/14.3 23.1/24.8 24.4/25.2 10.1/9.7 4/15.4 7.4/3.9 17.1/17.1 7/7 9.7/10.5 15/15.1 5.8/7.6 8.8/7.8 9.6/17.1 2.8/6.3 3/3.5 8.7/16.2 10.4/8.4 1.8/1.6 3/3 4.4/4.5

Left/right Left/right

5.1/4.8 7.1/8.7 4.7/3.6 4.7/3.3 3/2.7 5.2/7.3 10/7.7 2.7/2.3 4.1/3.2 4.3/4.6 8.8/11.1 8.7/10.1 17.5/27.3 2.5/6.5 11.4/12.2 6.8/10.8 16.7/17.7 3.5/3.4 8.3/7.8 4.3/4.2

Left/right Left/right

12.3/13.4 6.4/9.7 11.5/21.2 4.3/8.2 7.9/7.7 21.6/8.6 28.1/33 5.3/4.1 11.8/12 13.7/16.3 10.4/11.3 6.1/12 5.4/8.9 2.8/5.8 21.3/18.3 18.3/15.2 14.5/15.6 3.4/3.3 6.7/6.7 15.4/15.5

Left/right Left/right

4.

8.5/8 9.8/6.2 14.8/6.5 4.5/4.7 7.1/8.5 4.8/4.6 17.2/23.7 3.2/3.2 8.8/8.7 6.2/6.3 11.7/9.2 9.3/8.3 30.1/25.9 4.6/4 7/5.9 19.4/7.7 21.2/17.5 3/3.1 5.3/5.3 5.3/5.4

Left/right

8.2/9 4.1/6.2 12.8/4.7 3.9/5.9 14.7/15.2 11.5/19.1 7.1/9.8 1.8/1.9 2.6/3 15.4/15.3

6.9/6.2 4.5/4.8 13.1/11.8 7.1/4 3.7/3.7 3.4/3.5 13.6/11.9 2.8/2.9 7.8/7.6 5.7/5.9

Left/right

10.4/10.5 5.1/6.3 20.2/14.5 3.4/9 16.8/18.8 9.7/5.6 12.2/14 1.9/2 4.8/4.9 19.3/19.3 GPS ( ) Ankle flexion/extension ( ) Foot progression angle ( ) Knee flexion/extension ( ) Hip flexion/extension ( ) Hip abduction/adduction ( ) Hip rotation ( ) Pelvis tilt ( ) Pelvis obliquity ( ) Pelvis rotation ( )

Left/right

Left/right

Last CGA First CGA Last CGA

Patient 5

First CGA Last CGA

Patient 4

First CGA Last CGA

Patient 3

First CGA Last CGA

Patient 2

First CGA Last CGA

Patient 1

Table 2 e MAP GVS components for each HSP patient for the first and last clinical gait analysis.

First CGA

Patient 6

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91

Discussion

The gait alterations estimated with the GDI (from 99 to 55) differed between each individual from the same family. The results confirmed the first hypothesis that the severity of symptoms varies even among members of the same family.2,3 At the best of our knowledge, this is the first study to investigate the evolution of walking in patients with HSP. GMFCS, walking speed and FMS showed a relatively stable gait evolution even during a long-term follow-up in the 6 HSP patients. However, the GDI showed a more variable evolution of gait with a tendency of amelioration from childhood to adolescence and deterioration from adolescence to adulthood. Gait scores (Gait Profile Score or GDI) have been already shown more sensible to GMFCS to detect modifications after treatments in cerebral palsy.13 So, the results confirmed partially the second hypothesis that the gait evolution of HSP autosomal dominant inheritance pattern with symptoms onset in early childhood is stable with adapted treatments. On the three patients that have a decline of gait, two had more than 20 years old at the last assessment. Flink et al. reported a very little worsening through the first two decades and slow decline thereafter linked to advancing spasticity and general muscular deconditioning.2 As for CP patients, our results showed that gait at middle-term improved with adapted treatments14e16 and declined at long-term.17 Based on these results, we believe that the gait of HSP with symptoms onset in early childhood could be improved with treatments similar to those used in cerebral palsy (e.g., botulinum injections, surgical interventions). This finding is contrary to the generally accepted ideas that HSP should be treated differently from CP patients due the progression of the disease.3,7 This is, however, in agreement with the clinical impression reported in reviews that HSP with onset in early childhood is essentially nonprogressive during the first two decades.2,8 The limitations of this study are the small sample size and the variety of treatments; as a result, it is difficult to draw clear conclusions based on statistics. However, this is the first study that objectively describes the gait pattern evolution in HSP. Even if further studies are still needed to corroborate present results, we can conclude that gait alterations of HSP patients of a same family are variable and that gait evolution in HSP patients with early symptoms had a tendency to improve until adolescence with adapted therapeutic strategies and to decline in the adulthood.

Conflict of interests None.

references

1. McDermott C, White K, Bushby K, Shaw P. Hereditary spastic paraparesis: a review of new developments. J Neurol Neurosurg Psychiatry 2000;69:150e60. 2. Fink JK. Hereditary spastic paraplegia. Curr Neurol Neurosci Rep 2006;6:65e76.

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3. Klebe S, Stolze H, Kopper F, et al. Gait analysis of sporadic and hereditary spastic paraplegia. J Neurol 2004;251:571e8. 4. Nichols M, Dorociak R, Aiona M. Sagittal plane lower extremity kinematics in children with hereditary spastic paraplegia. Gait Posture 2006;24:S66e8. 5. Cimolin V, Piccinini L, D'Angelo MG, et al. Are patients with hereditary spastic paraplegia different from patients with spastic diplegia during walking? Gait evaluation using 3D gait analysis. Funct Neurol 2007;22:23e8. 6. Piccinini L, Cimolin V, D'Angelo MG, et al. 3D gait analysis in patients with hereditary spastic paraparesis and spastic diplegia: a kinematic, kinetic and EMG comparison. Eur J Paediatr Neurol 2011;15:138e45. 7. Wolf SI, Braatz F, Metaxiotis D, et al. Gait analysis may help to distinguish hereditary spastic paraplegia from cerebral palsy. Gait Posture 2011;33:556e61. 8. Salinas S, Proukakis C, Crosby A, Warner TT. Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms. Lancet Neurol 2008;7:1127e38. 9. Schwartz MH, Rozumalski A. The gait deviation index: a new comprehensive index of gait pathology. Gait Posture 2008;28:351e7. 10. Baker R, McGinley JL, Schwartz MH, et al. The gait profile score and movement analysis profile. Gait Posture 2009;30:265e9.

11. Graham HK, Harvey A, Rodda J, Nattrass GR, Pirpiris M. The functional mobility scale (FMS). J Pediatr Orthop 2004;24:514e20. 12. Palisano R, Rosenbaum P, Walter S, et al. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol 1997;39:214e23. 13. Rutz E, Tirosh O, Thomason P, Barg A, Graham HK. Stability of the gross motor function classification system after singleevent multilevel surgery in children with cerebral palsy. Dev Med Child Neurol 2012;54:1109e13. 14. Nordmark E, Lundkvist Josenby A, Lagergren J, et al. Longterm outcomes five years after selective dorsal rhizotomy. BMC Pediatr 2008;8:54. 15. Eames NW, Baker R, Hill N, et al. The effect of botulinum toxin A on gastrocnemius length: magnitude and duration of response. Dev Med Child Neurol 1999;41:226e32. 16. Gough M, Eve LC, Robinson RO, Shortland AP. Short-term outcome of multilevel surgical intervention in spastic diplegic cerebral palsy compared with the natural history. Dev Med Child Neurol 2004;46:91e7. 17. Andersson C, Mattsson E. Adults with cerebral palsy: a survey describing problems, needs, and resources, with special emphasis on locomotion. Dev Med Child Neurol 2001;43:76e82.

Gait evolution in a family with hereditary spastic paraplegia.

The degree of disability in patients with hereditary spastic paraplegia has been reported variable even in members of the same family (same gene mutat...
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