Balance control in Sensory Neuron Disease

Clinical Neurophysiology 118 (2007) 538–550 www.elsevier.com/locate/clinph

Balance control in Sensory Neuron Disease Antonio Nardone

a,*

, Massimo Galante a, Davide Pareyson b, Marco Schieppati

c

a

c

Posture and Movement Laboratory, Division of Physical Therapy and Rehabilitation, Fondazione Salvatore Maugeri (IRCCS), Scientific Institute of Veruno, I-28010 Veruno (Novara), Italy b Biochemistry and Genetics Unit, National Neurological Institute Carlo Besta (IRCCS), 20133 Milano, Italy Department of Experimental Medicine, Section of Human Physiology, University of Pavia and Human Movement Laboratory (CSAM), Fondazione Salvatore Maugeri (IRCCS), Scientific Institute of Pavia, I-27100 Pavia, Italy Accepted 20 November 2006

Abstract Objective: Balance control under static and dynamic conditions was assessed in patients with Sensory Neuron Disease (SND) in order to shed further light on the pathophysiology of ataxia. Methods: Fourteen patients with diabetic polyneuropathy and 11 with SND underwent clinical and neurophysiological evaluation, stabilometric recording of body sway during quiet stance with and without vision, stereometric analysis of body segment displacement while riding a platform translating in anterior–posterior direction with and without vision (dynamic condition), and EMG recording of leg muscle responses to abrupt stance perturbation produced by rotation of a supporting platform. The findings were compared to those of age matched normal subjects. Results: Clinical and neurophysiological evaluation revealed a more severe motor impairment in patients with diabetes than SND, while sensory impairment was superimposable. Some patients with SND had vestibular dysfunction of diverse severity. Body sway during stance was larger in patients with SND than diabetes with and without vision. In the stance perturbation condition, the latency of the long-loop EMG response to platform rotation was disproportionately increased with respect to the spinal response in the SND but not in diabetic patients. Under dynamic condition, patients with SND oscillated more than diabetic patients and several of them easily lost balance with eyes closed. Conclusions: Patients with SND show severe unsteadiness under both static and dynamic conditions, particularly with eyes closed. The patchy sensory loss of SND, disrupting sensation from territories other than the lower limbs and possibly including the vestibular nerve, could be responsible for this instability. Ataxia is correlated to the abnormal latency of the muscle responses to stance perturbation. Since increased response latencies cannot be attributed to a vestibular deficit, the deterioration of equilibrium control would be ascribed mainly to the degeneration of the central branch of the afferent fibres. Significance: Measures of body balance under quiet stance and dynamic conditions can provide relevant diagnostic information as to the pathophysiology and severity of ataxia and viability of the central branch of the sensory fibres, and help in separating patients with peripheral neuropathy from patients with loss of sensory neurones.  2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Body sway; Sensory Neuron Disease; Stretch reflex; Long-loop reflex; Dynamic equilibrium; Postural perturbation

1. Introduction Patients with peripheral neuropathy are generally unstable when standing quietly with eyes closed. However, not all patients are impaired to the same extent. Severity of *

Corresponding author. Tel.: +39 0322 884906; fax: +39 0322 884733. E-mail address: [email protected] (A. Nardone).

unsteadiness depends not only on the degree of peripheral neuropathy but also on the type of afferent fibres involved. For example, when the peripheral neuropathy mainly hits large myelinated afferent fibres (as in Charcot-Marie-Tooth type 1A disease), minor changes are observed during stance even with eyes closed (Nardone et al., 2000b). On the contrary, when the neuropathy involves also medium-size afferent fibres (as in the diabetic neuropathy), instability

1388-2457/$32.00  2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2006.11.012

A. Nardone et al. / Clinical Neurophysiology 118 (2007) 538–550

ensues particularly with eyes closed (Nardone and Schieppati, 2004). A likely reason for the instability in patients with diabetic neuropathy is that spindle group II afferent fibres are affected in addition to group Ia fibres. The group II fibres innervate the spindle secondary terminations, sensitive to changes in muscle length, and represent a more important source of sensory input for stance control than Ia fibres (Schieppati and Nardone, 1999). In peripheral neuropathies, balance may be paradoxically better under dynamic conditions (standing and balancing on a platform continuously translating in the anterior–posterior (A–P) direction) than under quiet stance, since other inputs and pathways can play a role and provide crucial information. Further, when the A–P translating platform moves in a predictable mode, a feedforward control mode for body equilibrium is operating, based on central integration of somatosensory, vestibular and visual inputs, sufficient for an effective production of appropriate anticipatory mechanisms (Schieppati et al., 2002). Consequently, when neuropathic patients stand and balance on the A–P translating platform, limited impairments of balance occur (Nardone et al., 2006). However, the abnormal delay between the periodic movements of the upper with respect to the lower body segments during the patients’ A–P translations indicates that the residual sensation is not enough for the central nervous system to fine-tune the pattern of anticipatory adjustments necessary for body segment coordination. A particular case of neuropathy is Sensory Neuron Disease (SND) or sensory neuronopathy or ganglionopathy, a disease leading to degeneration of the dorsal root ganglion cells (Sghirlanzoni et al., 2005), hence affecting both the peripheral and central branches of their axons. Clinically, these patients show generalised tendon-tap areflexia and especially severe sensory ataxia when standing (Lauria et al., 2003). Ataxia is likely associated with degeneration of ascending pathways (chiefly dorsal columns) (Kuntzer et al., 2004; Mori et al., 2001), but the degeneration of the centripetal branches of ganglion cell can also lead to disconnection of spino-cerebellar pathways from the proprioceptive input (McLeod and Evans, 1981). There is little information as to the capacity of patients with SND to withstand a dynamic postural balancing task. One possibility is that, in spite of their instability during quiet stance, these patients show less deficits in the A–P translating platform task, much as occurs in diabetic patients, if their central nervous system is still able to be fed by and integrate the input from other non-somatosensory modalities or to produce appropriate anticipatory synergies. On the other hand, the degradation of the central pathways conveying the somatosensory input to the supraspinal centres could strongly affect equilibrium control in SND, because of malfunctioning of the long-loop responses and of the supraspinal integration of the residual sensation (Ouchi et al., 2001). We then assessed in patients with SND, in addition to body sway during quiet stance and to body displacement on the A–P translating platform, the

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extent to which leg muscle EMG responses presumably mediated by long-loop supraspinal pathways are affected. Indeed, impulsive postural perturbations consisting in rotations of the supporting platform evoke responses that can be divided into spinal and supraspinal reflexes according to their latency of onset (Ackermann et al., 1987; Horak and Diener, 1994; Schieppati and Nardone, 1999; Nardone et al., 2006). Therefore, aim of this study was both to compare the balance performance of patients with SND to that of normal subjects and patients affected by diabetic polyneuropathy and to obtain an estimate of the impairment of peripheral and supraspinal long-loop reflex pathways in patients with SND. Preliminary data have been presented in abstract form (Nardone et al., 2005). 2. Methods 2.1. Subjects The mean age of the 11 patients with Sensory Neuron Disease (SND) was 62.8 ± 9.3 years (SD). The control and the reference group consisted in 21 normal subjects (61.6 ± 10.3 years) and 14 patients with diabetic polyneuropathy (63.9 ± 10.4 years), respectively. The findings from the normal subjects belonged to the laboratory database. The diabetic patients had previously been evaluated clinically and electrophysiologically and their balance assessed by means of the same tests used in the present investigation (Nardone et al., 2006). All patients gave informed consent to participate in the study; the experiments were conducted according to the Declaration of Helsinki and were approved by the local Ethics Committee. 2.2. Clinical data Patients with SND (see Table 1) were diagnosed according to the presence of a pattern of non-length-dependent sensory impairment, in a patchy fashion including head and trunk, and of distinct clinical and neurophysiological abnormalities. MRI findings of degeneration of dorsal columns at the cervical level are a hallmark of the disease (Lauria et al., 2000; Mori et al., 2001; Sghirlanzoni et al., 2005): these were searched in 10 out of the 11 patients and found in all of them. The aetiology of SND was idiopathic (6), hereditary (2), immune-mediated (3). No SND patient had paraneoplastic sensory neuronopathy, a disease with a different pathophysiology (Ogawa et al., 2004). Caloric examination was done in eight SND patients to assess vestibular function. All SND patients complained of positive sensory symptoms, such as burning-pain paraesthesia at some stage of the disease. The following neurological signs were bilaterally quantified in diabetic and SND patients, by means of the Neurological Impairment Score (NIS) (Dyck et al., 1995), based on lower limb muscle strength (distal and proximal muscle groups), sensation at the level of the great toe (touch-pressure, vibration with

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Table 1 Clinical findings in the sensory neuronopathy patients Patient

Sex, age

Total NIS

Muscle weakness

Tendon reflexes

Sensory examination

I-P

Glutei

Ham

Quad

D-F

P-F

Ach

Pat

T-P

P-P

Vib

J-P

Distribution Patchy at trunk and limbs Stocking-glove Stocking-glove, BVA Stocking-glove, BVA Stocking-glove Patchy at trunk and limbs, UVH Stocking-glove, UVH Stocking-glove, UVH Stocking-glove Patchy, stockingglove, BVA Stocking-glove and trunk

1

F 67

9

44

4

0

0

0

0

0

2

2

1

0

2

2

2 3

F 42 F 70

10 4

27 24

0 0

0 0

0 0

0 0

0 0

0.5 0

2 2

2 2

0 1

0 0

2 0

2 0

4

F 56

9

11

1

0

0

0

0

0

0

0

0

2

1.5

1

5 6

M 61 M 67

9 19

17 77

0 2

0 0

0 2

0 2

0 1

0 1

2 2

2 2

2 1

0 2

1.5 2

2 1

7

F 63

7

49

0

0

0

0

0

0

2

2

1

1

2

2

8

F 56

10

10

0

0

0

0

0

0

2

0

0

0

2

1

9 10

F 62 F 76

47 25

53 8

0 0

0 0

0 0

0 0

0 0

0 0

2 1.5

2 0

0 1

1.5 1

2 1

1 1

11

F 71

1

38

0

0

0

0

0

0

2

2

1

1

2

2

Lab findings

Cerebrospinal fluid

Cervical MRI T2

Aetiology

fl c-Globulin › a2-globulin Normal aFP, ANA, ANCA Normal

Not tested

Entire

Idiopathic

Not tested Normal

Gracilis Not tested Entire Gracilis Entire

Normal

Oligoclonal bands Not tested Protein 67 mg% Normal

Genetic Immunemediated Immunemediated Idiopathic Idiopathic

Entire

Idiopathic

Normal

Normal

Entire

Idiopathic

Normal Normal

Not tested Not tested

Entire Entire

Genetic Idiopathic

Normal

Normal

Entire

Immunemediated

Normal Normal

NIS: neuropathy impairment score (Dyck et al., 1995). Force: 0 normal, 4 severely reduced. Sensation (scored at great toe) and reflexes: 0 normal, 2 absent. I-P: iliopsoas; Ham: hamstrings; Quad: quadriceps; D-F and P-F: ankle dorsal and plantar flexors. Ach: Achilles; Pat: patellar. T-P: touch-pressure; P-P: pricking pain; Vib: vibration; J-P: joint position. T2: hyperintensity in axial T2weighted gradient echo images. Entire: both dorsal columns; Gracilis: hyperintensity only in fasciculus gracilis. BVA: bilateral vestibular areflexia; UVH: unilateral vestibular hyporeflexia. aFP: afetoprotein; ANA: anti-nuclear antibodies; ANCA: anti-neutrophilic cytoplasmic antibodies.

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Duration (years)

A. Nardone et al. / Clinical Neurophysiology 118 (2007) 538–550

a 128-Hz tuning fork, joint position, pricking pain), patellar and Achilles tendon reflexes. 2.3. Electrophysiological study Table 2 shows a summary of the data. M waves evoked by electrical stimulation of the parent nerves were recorded from the flexor digitorum brevis (FDB) and extensor digitorum brevis (EDB) muscles of one side in each patient in order to assess axonal damage (Asbury, 1988). Conduction velocity (CV) and amplitude of the sensory action potential (SAP) of the sural nerve, and CV of motor fibres of the tibial and deep peroneal nerves were measured. To grade the electrophysiological severity, a ‘composite neuropathy score’ (NS) for the lower limb was calculated (Bergin et al., 1995). This was obtained by adding together the scores based on M wave amplitudes of EDB and FDB, amplitude of sural SAP, and CV scores for deep peroneal, tibial and sural nerves. Electrophysiological sensory and motor scores have also been reported separately. 2.4. Stabilometry Subjects were required to stand still for 51 s on a dynamometric platform (Kistler, type 9281B, Switzerland) with feet spaced 10 cm apart. Each trial within a series was repeated twice, alternately with eyes open (EO), when subjects gazed at a target placed at 50 cm at eye height, and eyes closed (EC). The three components of the force acting on the platform (Fx, Fy, Fz) were sampled at 10 Hz, and from these variables a program calculated the centre of foot pressure (CFP). Sway area (SA) was the surface swept by the shifts of the line joining the position of the average CFP to the successive positions of the instantaneous CFP. 2.5. Balance under predictable dynamic condition Subjects and patients stood with feet spaced 10 cm apart on a platform (Lomazzi & Co. and e-TT, Italy) that pro-

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duced a horizontal sinusoidal (0.2 Hz) translation (peakto-peak 60 mm) in the A–P direction. Each trial within a series lasted 30 s; the first 10 s of adaptation time was not recorded. Each trial was repeated twice, alternately with EO and EC. Reflective markers were fixed on one side of the body at the lateral malleolus (invariable with respect to the moving platform), the greater trochanter (hip) and on the earphone (head) that reduced the faint sound produced by the platform. Displacement of the markers was recorded by means of a stereometric device (Vicon 460, Oxford Metrics, UK). The SD of the markers’ trace in the sagittal plane of the entire recorded epoch was computed (Corna et al., 1999), on the assumption that this was a comprehensive index of the A–P oscillations of the head in space (Nardone et al., 2000a; Schieppati et al., 2002). The cross-correlation (CC) between the traces of the head and malleolus markers was calculated. This produced a correlation coefficient (R) that gave a measure of the strength of the association between the periodic movements of the upper body and those of the support base. The time lag between the periodic displacements of head and malleolus markers within each trial was also computed. A time lag equal to 0 indicates in-phase displacement of two markers; a positive time lag indicates a delay of the head displacement with respect to the sinusoidal movement of the malleolus. The time lags were not entered into the analysis when they derived from correlations with R-values lower than 0.6 (Vincent, 1995; Corna et al., 1999). The accuracy of the time lag calculation was 8.33 ms, due to the sampling frequency of 120 Hz.

2.6. Reflex responses to impulsive stance perturbation Subjects stood with EO and feet spaced 10 cm apart on a tilting platform (Lomazzi & Co., Italy). Perturbations consisted of 20–30 toe-up and toe-down rotations (depending on patients’ compliance) of 3 amplitude at 50/s. The interval between trials varied between 8 and 10 s. Toe-up and toe-down rotations were presented in pseudo-random

Table 2 Electrophysiological findings in the sensory neuronopathy patients Patient

1 2 3 4 5 6 7 8 9 10 11

M wave (mV)

SAP (lV)

Motor CV (m/s)

FDB

EDB

Sol

Sural

Tibial nerve

Deep peroneal nerve

Lower limb

NS

9.6 5.2 2.8 16 6.9 5 3.8 16 16 8.5 6

4.2 1.4 2.8 11 3 2.2 4.7 5.3 7.9 9 6.4

n.t. 3.4 15 10 n.t. 6.1 5.6 n.t. 16 7.4 16

0 0 0 0 2.5 0 1.5 1.6 0 0 0

48.7 42 43.6 43 40.2 31 38 44.1 44 42 36

49.1 42 43.5 45 43.7 35 40 42.6 45.1 43 36

2 10 3 3 3 7 4 2 2 3 3

FDB: flexor digitorum brevis; EDB: extensor digitorum brevis; Sol: soleus; SAP: sensory action potential; CV: conduction velocity; NS: neuropathy score (Bergin et al., 1995; 0 = normal). n.t.: not tested.

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order. The perturbation types were balanced within each patient. The surface EMG was bilaterally recorded from soleus and tibialis anterior (TA) muscles (Schieppati and Nardone, 1999). Electrodes were fixed at an inter-electrode distance of about 3 cm on the muscle belly. EMG was amplified (·10,000), band-pass filtered (100 Hz–3 kHz, 6 dB/octave) and converted analog-to-digital at a sampling rate of 1 kHz. Signals were full-wave rectified and averaged. Responses to toe-up rotations consisted of two successive EMG bursts (the short-latency, SLR, and the medium-latency response, MLR) in the stretched soleus muscle. A late response in the TA muscle occurring after about 140 ms in normal subjects was termed antagonist reaction (AR) (Nardone et al., 1990). Responses to toedown rotations consisted of a MLR in the stretched TA and an AR in the soleus. The responses were identified on the superimposed traces of the rectified and averaged signals recorded from the muscles of the two legs. Only the MLR and AR of the TA muscle were subjected to further analysis, because they were consistent among subjects and patients and were characterised by the largest burst of activity. The onset of the responses was set at the time when the rectified and averaged EMG burst increased beyond two SDs of the mean value of the background prestimulus EMG activity (Schieppati et al., 1995; Schieppati and Nardone, 1997).

even when a successful eyes-open performance was obtained. For the EMG responses to perturbation, we averaged the mean latency values from both legs. A oneway ANOVA between three subject groups was then performed for each response. Paired comparisons were made by using the Newman-Keuls post-hoc test. 3. Results 3.1. Comparison of the clinical characteristics in the SND and diabetic patients, and the neuropathy impairment score (NIS) Table 1 summarises the clinical data of the patients with SND. Mean values of NIS strength of triceps surae and tibialis anterior (TA) muscle are compared in the SND and diabetic patient groups in Fig. 1A. The largest loss of force was found in the TA of diabetic patients (sum of scores, s.s. 209), though the difference with SND patients (s.s. 116) was only marginally significant (U-test, z = 1.9, P = 0.06). Most patients had absent knee and ankle jerks in response to tendon percussion and decreased vibration sense. These

2.7. Statistical analysis When not differently stated, values are expressed as means ± SD for each group. Although all patients participated in all types of protocols, the number of the normal subjects’ sample varied depending on the protocol; this number is indicated in the relevant paragraphs. For all subjects, in both stabilometric and dynamic tests, we averaged the values from the two trials recorded for each visual condition. Since sway values were not normally distributed, logarithmic transformation was made. For the analysis of the CC between head and malleolus traces, in order to statistically assess R-values, these were transformed into z-scores as follows: z = 1/2 ln (1 + R)/(1 R) (Corna et al., 1999). z-Scores ranged from about 0 to about 3, corresponding to R-values of 0 and 0.99, respectively. For clinical and electrophysiological scores, the Mann– Whitney U-test between diabetic patients and patients with SND was performed. For both stabilometric (sway area and position of CFP) and dynamic variables (A–P translation of head and hip), a two-way (visual condition: EO and EC; three subject groups: normal, diabetic, SND) analysis of variance (ANOVA) was performed. With EC, several patients with SND did not successfully complete the required postural tasks (five patients for static conditions, six for dynamic conditions). Visual conditions were treated as repeated measures to check the possibility that differences between groups were dependent on visual information. This reduced the number of patients entering the ANOVA

Fig. 1. Clinical findings and electrophysiological data in diabetic and Sensory Neuron Disease (SND) patients. (A) Neuropathy impairment score relative to force of muscles about the ankles. (B) Tibial nerve motor conduction velocity. (C) Neuropathy score relative to lower limb electrophysiological findings. Means + standard deviation (SD). *P = 0.06; **P < 0.01; ***P < 0.001.

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findings are in keeping with involvement of large peripheral nerve fibres in both patient groups. Interestingly, however, joint position sense was slightly but significantly more impaired in SND (s.s. 184) than in the diabetic patients (s.s. 141) (U-test, z = 2.1, P < 0.05). The vibration sense score was not significantly different between SND (s.s. 173) and diabetic patients (s.s. 152) (U-test, z = 1.6, P = 0.10). Pricking pain sense was also similarly affected in diabetic (s.s. 168) and SND patients (s.s. 157), in keeping with involvement of the small afferent fibres in both patient groups. Vestibular function was tested in eight of the SND patients. At the caloric examination, three patients had bilateral vestibular areflexia and three patients unilateral hyporeflexia; two showed no deficits. 3.2. Assessment of peripheral nerve fibre impairment: electrophysiological tests, and the composite Neuropathy Score (NS) Table 2 summarises the electrophysiological data of the patients with SND. Sural nerve sensory action potential (SAP) was absent in all except three SND patients. Motor CV of the tibial and deep peronal nerves (Fig. 1B) was significantly decreased in diabetic with respect to SND patients (t-test, P < 0.001 for both nerves). The composite NS for the lower limb accounts for the overall axonal and demyelinating involvement of the motor and sensory fibres and is shown in Fig. 1C. Patients with SND were less affected than diabetic patients (U-test, z = 3.1, P < 0.002). These findings are in keeping with the signs of motor and sensory impairment reported in Table 1 and with the damage of large peripheral nerve fibres in both patient groups. The NS was calculated separately for the motor and the sensory side (sural action potential, SAP) of the score. It turned out that patients with SND (s.s. 84) were much less impaired than diabetic patients (s.s. 241) on the motor side (U-test, z = 3.2, P < 0.001), but similarly so on the sensory side (diabetic, s.s. 189.5; SND, s.s. 139.5; U-test, z = 0.2, P = 0.8). The mean SAP amplitude was 0.81 lV and 0.37 lV in patients with diabetes and SND, respectively (t-test, P = 0.51). 3.3. Body balance during quiet stance on the stable platform Fig. 2A shows examples of body sway area (SA) in a normal subject and in a patient with SND during stance under eyes-open (EO) and eyes-closed (EC) conditions. The mean SA values of the normal subject (n = 17) and patient groups are reported in Fig. 2B. Two-way analysis of variance (ANOVA) showed that SA was different between the three groups (F = 27.7, df = 2.34, P < 0.0001) and between visual conditions (F = 163.2, df = 1.34, P < 0.0001). The interaction was significant (F = 13.1, df = 2.34, P < 0.0001). The post hoc test showed differences between normal subjects and diabetic (EO: P < 0.001; EC: P < 0.001) and SND patients (EO and

Fig. 2. (A) Stabilometric recordings during quiet stance with eyes open (EO) and eyes closed (EC) in a normal subject and a SND patient. (B) Means + SD of body sway area under EO and EC in the groups of normal subjects, diabetic and SND patients (five SND patients were not taken into account, and did not enter the statistical analysis, because they were unable to stand EC). *P < 0.05; **P < 0.01; ***P < 0.001.

EC, P < 0.001) under both visual conditions. Further, regardless of visual conditions, patients with SND showed a larger sway area than diabetic patients (EO and EC, P < 0.001). Note that the impairment of balance control with EC in SND patients was certainly underestimated by the statistical analysis since five of them were not able to maintain quiet stance with EC in spite of being able to do so with EO. The mean position of the CFP in percent of foot length in the A–P axis was also analysed but is not illustrated. The two-way repeated-measures ANOVA (3 groups · 2 visual conditions) showed that CFP position was different across groups (F = 6.2, df = 2.35, P < 0.01). There was no interaction between vision and groups (two-way repeated-measures ANOVA, 3 groups · 2 visual conditions, F = 1.3, df = 2.35, P = 0.28), indicating that body orientation was not differently affected by vision in these patient groups. The post hoc test showed that the differences in CFP position between SND (EO: 47.3 ± 8.3%, n = 11; EC: 45.2 ± 5.3%, n = 6) and diabetic patients (EO: 40.0 ± 9.7%, n = 14; EC: 40.0 ± 10.5%, n = 14) and between diabetic patients and normal subjects (EO: 34.1 ± 6.0%; EC: 34.2 ± 6.2%) were significant (P < 0.001 for all comparisons).

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3.4. Body balance under dynamic conditions on the translating platform As shown in the example of Fig. 3A, the SND patient showed increased and irregular A–P oscillations with respect to the normal subject. Two-way repeated-measures ANOVA (group, visual condition) was separately made on the mean head and hip marker standard deviations (SDs) of normal subjects (n = 12), diabetic patients (n = 14) and patients with SND (n = 5, five patients were unable to balance EC and one both EO and EC). As shown in Fig. 3B and C (filled bars), head SD was different within the three groups (F = 8.9, df = 2.28, P < 0.001) and between visual conditions (F = 506.6, df = 1.28, P < 0.0001). The interaction was significant (F = 8.1, df = 2.28, P < 0.01). The post hoc test showed no difference between normal subjects and diabetic patients (EO: P = 0.38; EC: P = 0.14). With EC, patients with SND oscillated significantly more than normal subjects (EO: P = 0.31; EC: P < 0.001) and diabetic patients (EO: P = 0.77; EC: P < 0.001). Hip SD (open

bars) was not different within the three groups (F = 1.9, df = 2.28, P = 0.17) but between visual conditions (F = 309.1, df = 1.28, P < 0.0001). The interaction between vision and groups was significant (F = 7.9, df = 2.28, P < 0.01). The post-hoc test showed no difference between normal subjects and diabetic patients (EO: P = 0.55; EC: P = 0.28); however, the hip oscillated more in patients with SND than in normal subjects and diabetic patients, but significantly so only with EC (normal subjects EO: P = 0.16; EC: P < 0.001; diabetic patients EO: P = 0.12; EC: P < 0.01). On average, the percent ratio of head to hip displacement with EC was 126.5 ± 6.7%, 130.3 ± 10.4% and 143.6 ± 19.1%, respectively, in normal subjects, diabetic and SND patients. One-way ANOVA showed that these ratios were different between subject groups (F = 4.4, df = 2.28, P < 0.05). In particular, SND patients showed a larger ratio than both normal subjects (P < 0.005) and diabetic patients (P < 0.05). This instability with EC in patients with SND was demonstrated also by the fact that

Fig. 3. (A) Anterior–posterior (A–P) displacement of head, greater trochanter (hip) and malleolus in a normal subject and a SND patient while standing on a movable platform with EC. (B,C) Means + SD of A–P displacement of hip and head with EO and EC, respectively. The horizontal dashed line in each graph indicates the SD of A–P displacement of malleolus (invariable with respect to the translating platform). (C) Mean time delay (lag) ± standard error (SE) between the displacement of head and of malleolus in normal subjects, diabetic and SND patients with EO and EC (six SND patients did not enter the statistical analysis, because they were unable to balance EC). *P < 0.05; **P < 0.01; ***P < 0.001.

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6 patients with SND were not able to perform the postural task EC. On the contrary, all patients with SND but one were able to balance on the platform with EO. The coupling between upper and lower body parts during balancing on the movable platform was estimated through the calculation of the cross-correlation (CC) function. On average, the CC coefficients (z-scores) between head and malleolus were 1.2, 1.1, 0.9 and 1.7, 1.7, 1.5, with EO and EC, respectively, for normal subjects, diabetic and SND patients. The changes in the z-scores were tested by a 2-way ANOVA for repeated measures (3 groups · 2 visual conditions). There was no difference across groups (F = 1.4, df = 2.28, P = 0.27). However, within each group there was a significant effect of vision on the CC values (F = 29.7, df = 1.28, P < 0.001). The interaction was not significant (F = 0.41, df = 2.28, P = 0.67). The time lags between head and malleolus were also measured. Two-way ANOVA showed significant differences across groups (F = 4.6, df = 2.27, P < 0.05) and visual conditions (F = 6.4, df = 1.27, P < 0.05). The interaction was significant (F = 4.9, df = 2.27, P < 0.05). The posthoc test showed differences between normal subjects and patients with SND (EO: P < 0.01), but not between normal subjects and diabetic patients (P = 0.39) (Fig. 3D). Further, the time lag was different between the two patient groups (P < 0.05). In patients with SND, time lag was significantly longer with EO than EC (P < 0.01). We hypothesised that abnormal balance under dynamic condition and body sway during quiet stance were two aspects of the same equilibrium disorder. Therefore, we correlated the head or hip SDs with sway area, under each visual condition. However, no relationship reached a significant value for any regression made within each subject group. 3.5. Reflex responses to impulsive stance perturbation (platform rotation) Typical averaged EMG responses of Sol and TA muscles to toe-down and toe-up perturbation, obtained from a normal subject and a patient with SND, are reported in Fig. 4A. In the normal subject, toe-down evoked a MLR in TA, followed by an AR in Sol; toe-up evoked SLR and MLR in Sol, followed by AR in TA. In this SND patient, toe-down rotation elicited a similar pattern of responses but the response bursts had a longer latency than in this normal subjects; toe-up failed to evoke full-blown SLR and MLR in Sol, and the occurrence of AR in TA was delayed. All responses were present in all normal subjects, while Sol SLRs and Sol MLRs appeared in 11 and 13 diabetic patients and in 6 and 10 patients with SND. The MLRs and ARs of the TA were recorded in all patients and were characterised by the largest bursts of activity. One-way ANOVA showed that the latencies of the TA responses were significantly different between groups (MLR, F = 16.8, df = 2.34, P < 0.001; AR, F = 8.9, df = 2.34, P < 0.001). The post-hoc test showed that the

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latency of TA MLR was slightly longer in diabetic patients than in normal subjects (P = 0.07). As shown in Fig. 4B, the latency of TA MLR of the patients with SND (n = 13) was much longer than in both normal subjects (n = 11) and diabetic patients (n = 13) (P < 0.01, for both comparisons). By and large, the latency of AR behaved similarly to that of MLR, being significantly longer in SND with respect to both normal subjects (P < 0.001) and diabetic patients (P < 0.05). We compared the latencies of TA MLR with those of TA AR across SND patients. The graph in Fig. 4C shows the relationship between the latencies of these two responses in normal subjects, diabetic and SND patients. The regression line fitting the data points of the patients with SND shows a significant positive slope (y = 1.67x + 2.52, R2 = 0.60, P < 0.01). The slope was largely greater than 1, implying a disproportionately longer delay of TA AR with respect to MLR. This is in keeping with the degeneration of the central branch of the sensory fibres. As shown in the graph, the patients with SND unable to stand on the oscillating platform with EC (filled triangles) had the longest latencies for both MLRs and ARs. 3.6. Relationship between clinical or neurophysiological findings and balance control variables in SND patients Since the static and dynamic balance performances of patients with SND showed a wide variation, we looked for possible correspondences between the recorded variables and the clinical state or neurophysiological findings. In spite of the diversity of patients’ characteristics (see Tables 1 and 2), no obvious relationship was found between balance scores and clinical features. In particular, the patients with severe patchy hypoesthesia involving the trunk did not have the worst balance performances, either EO or EC. The three patients with bilateral vestibular areflexia were not similarly impaired with EC (one patient of this subgroup could stand quietly and counteract the platform A–P displacement). Of the three patients with unilateral vestibular hyporeflexia, one was able and two were unable to stand quietly and ride the platform under both visual conditions. No correlations were found, either, between balance performances and sensory detection thresholds, nerve conduction studies, or latencies of MLR or AR of the TA muscle. 4. Discussion 4.1. Balance in static and dynamic tasks In patients with SND, leg muscle strength and motor CV are largely normal, while changes in sensory neuropathy scores and perception threshold in the lower limbs are similar to those of the diabetic patients. However, balance control during quiet stance is far more severely deranged in SND. Also, patients with SND tend to stand more forward-inclined than diabetic patients. It had been

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Fig. 4. (A) EMG traces of soleus and tibialis anterior (TA) muscle during toe-down and toe-up rotation of the supporting platform in a normal subject (upper panel) and a SND patient (lower panel). The vertical dashed line indicates the onset of platform movement. SLR, short-latency response; MLR, medium-latency response; AR, antagonist reaction. (B) Means ± SD of onset latency of TA MLR to toe-down and TA AR to toe-up rotations. *P < 0.05; ***P < 0.001. (C) Relationship between latency of onset of TA AR and TA MLR in normal subjects, diabetic and SND patients. The regression line fitted through all data points of SND patients (continuous line) is steeper than the identity (dotted line).

previously shown that various patients and elderly subjects stand more forwards inclined than normal subjects, probably in search of a safer posture and a stronger afferent input from the calf muscles and feet (Schieppati et al., 1994). Besides, compared to diabetic patients with peripheral neuropathy, in whom equilibrium during the continuous and predictable perturbations delivered by the movable platform is little affected (Nardone and Schieppati, 2004; Nardone et al., 2006), patients with SND could hardly withstand the dynamic perturbations with eyes closed. These findings therefore show, first, that patients with SND do worse, under both static and dynamic equilibrium conditions, than polyneuropathic patients having similar lower limb sensory deficits and an even more severe motor deficit. Second, that vision is far more important in SND than in other neuropathies with loss of myelinated fibres in the peripheral nerve, like CMT1A disease (Nardone et al., 2000b) or diabetes (Nardone and Schieppati, 2004). Third, that the balance problem under static and dynamic conditions in patients with SND may be the expression of failure of one common control mechanism, as indicated by their inability to stand quietly or ride the platform with eyes closed. However, their balance performance under

dynamic conditions was not simply predictable from the quality of their static performances, due to the poor correlation between the two variables across the SND population. The larger instability during the dynamic task in patients with SND than in other peripheral neuropathy patients was not expected. Experiments with muscle vibration affecting Ia spindle discharge in normal subjects (De Nunzio et al., 2005) and with peripheral neuropathy patients (Nardone et al., 2006), showed that deranged or absent somatosensory input only produced delayed generation of anticipatory synergies without inducing major instability. The much larger increase in body oscillation on the movable platform and the inability of some patients with SND to cope with this task eyes closed imply that the added loss of ascending spinal pathways can even prevent production of effective balancing synergies. 4.2. Medium-latency and long-loop muscle responses to impulsive stance perturbations When the rotating platform imposed rapid ankle plantar- or dorsiflexions, the latency of the tibialis anterior

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medium-latency response to stretch (MLR) and of the antagonist reaction (AR) was increased in the patients with SND to a larger extent than in the diabetic patients. However, at variance with diabetic patients, the AR latency was disproportionately increased with respect to MLR. The increased MLR latency, likely dependent on defective group II spindle afferent fibres feeding spinal reflex circuits (Nardone and Schieppati, 1998; Schieppati and Nardone, 1999), may be part of the balance problems in the patients with SND. On the other hand the much delayed AR, consistent with the abnormal transmission of this proprioceptive input to supraspinal centres (Mu¨ller et al., 1991), may be responsible for the major worsening in body sway control compared to other neuropathic patients. Also in other diseases these responses are delayed: for instance, they become very late in cerebellar patients suffering from Friedreich’s ataxia, which also affects dorsal root ganglia and their ascending projections including the spinocerebellar pathways (Hughes et al., 1968; Diener et al., 1984). The longer latencies of the responses to perturbation in the patients with SND compared to diabetic patients might be at least in part connected to their slightly more forward leant posture, as measured during the stabilometric trials, leading to reduced tibialis anterior length. However, forward inclined postures have been previously shown to increase TA MLR latency in normal subjects of less than 6 ms (Schieppati et al., 1995) or of about 1 ms (Diener et al., 1983). These changes have to be compared to the present increase of about 27 ms in the patients with SND. Conversely, the forward inclined posture produced a decrease of the TA AR of about 20 ms (Schieppati et al., 1995) or an increase of 16 ms (Diener et al., 1983) in normal subjects, that have to be compared to the present much larger increase of about 36 ms in the patients with SND. Unfortunately, a measure of the CFP immediately before the platform rotation is not currently available for either diabetic or SND patients. This is a potential limitation, since factors such as anxiety, expectancy or attentional demand associated with the upcoming postural disturbance may have influenced differently the stance attitude of the patient groups. The absence of a significant correlation between the AR latency in the TA and measures of imbalance (under both static and dynamic conditions) across the individual SND patients does not automatically rule out a potential cause-effect relationship between AR latency and imbalance. We do not know whether sensory input from other muscles is used in the balancing tasks and whether such information is also not properly conveyed to the supraspinal centres because of similarly degenerated spinal pathways. Long-loop responses in other non-recorded muscles could be abnormal and contribute to instability. Moreover, the delay in the TA AR might be partly due to abnormal input from more proximal body segments, also a source of input for balance corrections to postural perturbation (Bloem et al., 2000).

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4.3. Why is equilibrium poorer in Sensory Neuron Disease than in other polyneuropathies? No unequivocal information as to the functional consequences of the loss of central pathways damaged by the pathological process in SND is available in the literature. This information could help answer the simple question of why sensory loss in the lower limbs, apparently similar to those of other peripheral neuropathies, produces larger instability in SND. Recent clinical and magnetic resonance imaging studies (Lauria et al., 2000; Mori et al., 2001) showed changes extending throughout the length of the posterior columns. These reports confirm that patients with SND do not have the length-dependent fibre degeneration seen in ‘dying-back’ disorders, but have dorsal ganglion cell degeneration. Therefore, given that the sensory message does not reach the spinal cord, as much as it occurs in peripheral sensory neuropathies, it appears that the added degeneration of the central branch of the sensory neuron can produce further worsening of balance control. In fact, it has been known for a long time that degeneration of the dorsal columns produces disturbance in knowledge of movement and position and ataxia, in spite of negligible effect on primary sensibility for light touch and pressure (Nathan et al., 1986). The segmental and supraspinal circuits normally fed by the central axon of the sensory neurons would suffer anterograde trans-synaptic degeneration in SND. In fact, both gracilis and cuneatus cells of the medulla oblongata have been shown to be slightly decreased in number due to this phenomenon (Satake et al., 1998). Further, the dorsal root ganglion cells innervating muscle and joint receptors also feed postsynaptic neurons in the ipsilateral spinal cord grey matter projecting to supraspinal nuclei such as the nucleus Z and x in primates (Nijensohn and Kerr, 1975; Rustioni et al., 1979) and cats (Schieppati and Ducati, 1981; Mackel and Miyashita, 1993), a relay to the motor thalamus, onto which also cerebellar output converges. There are cells in nucleus Z and in the dorsal column nuclei that project to the cerebellar cortex (Cheek et al., 1975, in cats; Saigal et al., 1982 in sheep). This degeneration would possibly change the excitability of these circuits and the way they process the remaining sensory input. MRI in these patients does not show clear degeneration of non-dorsal column pathways, in spite of SND being shown to be associated with spino-cerebellar degeneration (McLeod and Evans, 1981). In pure SND, the neurons of origin of the dorsal spino-cerebellar tracts are possibly not affected, because they are not located in the dorsal root ganglia but in the spinal grey matter. But the peripheral input to these neurones and the functional traffic in this tract may be abnormal and produce impaired cerebellar action. Also note that the presence of serum antibodies to Purkinje cells and dorsal root ganglia neurons has been reported in SND without malignancy (Nemni et al., 1993). This could explain why similar equilibrium recordings are common in spino-cerebellar ataxias (Diener et al., 1984).

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Moreover, recent reports describe consistent anatomic and metabolic cerebellar damage in gluten-associated sensory neuronopathies (Hadjivassiliou et al., 2003; Wilkinson et al., 2005). 4.4. Is there a role for vestibular dysfunction in SND ataxia? When somatosensory information is degraded, the vestibular input may become particularly relevant (Day and Cole, 2002; Horak and Hlavacˇka, 2001). The upper body instability of the patients with SND on the moving platform, computed on the head marker trace, might depend on a poor control of head on trunk, as occurs in patients with vestibular dysfunction (Bronstein, 1988; Kanaya et al., 1995; Buchanan and Horak, 2001–2002). Unfortunately, our recording procedure did not allow distinguishing head from upper trunk displacements. Of note, however, the large head oscillations were not isolated, but accompanied by large oscillations of the hip, again significantly larger in SND than in diabetic patients. Buchanan and Horak (2001–2002) have shown that vestibular patients rather tend to move head and trunk as a single unit when balancing on the A–P translating platform. Of the eight patients with SND who underwent vestibular examination, three had bilateral vestibular areflexia and three unilateral hyporeflexia, as tested with caloric stimulation. This is not surprising, since the vestibular nerve has a similar histological structure to the peripheral sensory nerves, and vestibular impairment has been documented in 53% of peripheral sensory neuropathies (Samaha and Katsarkas, 2000). Conceivably, since absent caloric response is not a very sensitive test, an even larger proportion of the patients suffered some degree of vestibular dysfunction, which may have contributed to their balance problem. A degree of uncertainty also depends on the caloric test only assessing the presence of horizontal semicircular canal paresis, whereas vestibular responses to perturbation arise from stimulation of not only the semicircular canals but also the otoliths (Guerraz and Day, 2005; Day and Reynolds, 2005). Two patients with bilateral vestibular areflexia could not stand or ride the platform with eyes closed, while the other (patient #4) did so and his head-oscillation data were within the range of the other patients able to stand and ride the platform eyes closed. Remarkably, proprioception was spared in this last patient, based on her normal Achilles and patellar reflexes. Two of the three patients with unilateral hyporeflexia were unable as well to ride the platform eyes closed. On the other hand, there was one patient, in whom no labyrinth dysfunction was found, unable to do the static and dynamic tasks eyes-closed. In addition, our patients unable to ride the translating platform showed the largest delay in the latency of the long-loop TA response, but this excessive latency cannot be attributable to the vestibular areflexia (Allum and Pfaltz, 1985; Allum et al., 1994). Further, in a previous investigation of patients affected by unilateral vestibular deficit without peripheral

neuropathy, we found that all were able to cope with the 0.2-Hz translation frequency, both with eyes open and closed (Corna et al., 2003). These findings would suggest that a vestibular deficit per se could not explain the major upper body instability of SND patients under these balancing conditions. 4.5. The effect of vision The visual input minimises the upper body A–P oscillation, since vision provides critical cognitive information about the environment that is used for reference for movement and posture, and helps maintaining head and trunk in space, thereby reducing the oscillation of the visual scene (Dijkstra et al., 1994). Vision is much more important in SND than diabetic patients for both static and dynamic balance control. This can be an aspecific effect, in that significantly increased dependence upon visual information both perceptually and motorically would occur in SND (Day et al., 2002), much as it happens in other diseases implying altered peripheral (Nardone et al., 2006) or central (Azulay et al., 2002) equilibrium control. Interestingly, however, in addition to reducing the A–P body oscillation on the movable platform, vision produced an increase in the delay between upper body and platform oscillation in SND. It was unexpected that the anticipatory adjustments stabilising the head in response to predictable support surface perturbation were less efficient in spite of visual information. A possibility is that the balancing performance depends on the integration of sensory input from both vision and somatosensation. If the latter is impaired, reliance on vision alone could imply a shift to a different strategy of anticipation. It is not unlikely that proprioceptive sensory information, normally carried by spino-cerebellar tracts, provides a key input for the coordination of motor output for equilibrium control. This information represents global kinematic parameters of the hindlimb (Bosco and Poppele, 2001) and may be necessary for the correct timing between the A–P translation of the platform and of the upper body. 5. Conclusion Patients with SND, although clinically presenting with lower limb sensory impairment comparable to that of other peripheral neuropathies, show severe ataxia under both static and dynamic conditions, contrary to other neuropathies. Ataxia depends on abnormal central integration of multiple sensory input, since balance control does not only rely on segmental reflex circuits fed by peripheral afferents but also on supraspinal processing of proprioceptive input and feed-forward mechanisms. The patchy sensory loss involving distal and proximal somatosensory nerves and the vestibulum may contribute to the instability of these patients. The major delay of the long latency balance-cor-

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