Secondary and Primary Dystonia

Pathophysiological Differences

Maja Kojovic; Isabel Pareés; Panagiotis Kassavetis; Francisco J. Palomar; Pablo Mir; James T. Teo; Carla Cordivari; John C. Rothwell; Kailash P. Bhatia; Mark J. Edwards

Disclosures

Brain. 2013;136(7):2038-2049. 

In This Article

Results

Transcranial Magnetic Stimulation

There was no difference in age between patients with secondary and primary dystonia and healthy participants. As expected, the Burke-Fahn-Marsden score was higher in patients with secondary compared to primary dystonia (z = −2.9; P = 0.004) and the disease duration was longer (z = −3.14; P = 0.002). No difference was found in the duration of botulinum toxin treatments between dystonia groups (z = −0.72; P = 0.93).

Corticospinal Excitability

At baseline, no significant difference was found in resting motor threshold, active motor threshold, 1 mV MEPs TMS intensity or EMG root mean square amplitude between patients with secondary and primary dystonia and healthy participants or between affected and non-affected sides in patients with secondary dystonia (Table 3).

As expected, a repeated measures ANOVA showed a significant effect of Stimulus intensity [F(9, 207) = 28.9; P < 0.001] on the input-output relationship, due to an increase of MEP size with increasing intensity, whereas there was no effect of the factor Group and no Group × Stimulus intensity interaction. The side comparison in secondary dystonia, also revealed a significant effect of Stimulus intensity [F(9, 36) = 13.6; P < 0.001], whereas the main factor Side and the interaction Side × Stimulus intensity were both non-significant. These results indicate that there was no difference in baseline corticopinal excitability between patients with secondary dystonia and primary dystonia and healthy participants or between the affected and non-affected side in patients with secondary dystonia (Fig. 1A and B).

Figure 1.

Input/output curves. The mean MEP amplitude (±SEM) is given on the y-axis against the stimulus intensity given on the x-axis (as a percentage of resting motor threshold stimulus intensity). (A) The input-output curves in patients with secondary dystonia, patients with primary dystonia and healthy participants are not significantly different. (B) There is no difference in input-output curves between the affected and non-affected side in patients with secondary dystonia. RMT = resting motor threshold.

Short-interval Intracortical Inhibition

ANOVA revealed a significant effect of the factor Group [F(2, 27) = 5.11; P = 0.01], due to less SICI in patients with secondary dystonia compared with healthy participants (P = 0.01), whereas there was no difference between primary and secondary dystonia or between primary dystonia and healthy participants. When the affected side was compared with the non-affected side in secondary dystonia, a paired-sample t-test revealed that there was less SICI (P = 0.02) on the more affected side (Fig. 2A).

Figure 2.

Intracortical excitability: SICI and cortical silent period. (A) In patients with secondary dystonia, SICI is reduced on the affected side, compared with the non-affected side and with healthy participants. Data are plotted as a ratio to the unconditioned MEP amplitude (**P ≤ 0.01; *P < 0.05); (B) there is no difference in cortical silent period (CSP) duration between patients with secondary dystonia, patients with primary dystonia and healthy participants.

Cortical Silent Period

ANOVA revealed no difference in cortical silent period between patients with secondary dystonia, primary dystonia and healthy participants. A paired-sample t-test showed no difference in cortical silent period between the affected and non-affected side in secondary dystonia (Fig. 2B).

Paired Associative Stimulation

An ANOVA revealed a significant effect of Group [F(2, 28) = 12; P < 0.001], due to a larger response to PAS in patients with primary dystonia compared to both patients with secondary dystonia (P < 0.001) and healthy participants (P < 0.001), whereas there was no difference between patients with secondary dystonia and healthy participants. Factors Muscle and Time point were not significant as were all two-way and three-way interactions, indicating that the PAS response was higher in primary dystonia at all three time points after PAS in both abductor pollicis brevis and adductor digiti minimi muscles (Figs 3A and B and 4). When the affected side was compared to the non-affected side in secondary dystonia, an ANOVA revealed a significant effect of the factor Muscle [F(1, 9) = 8.7; P = 0.02], due to a larger response to PAS in abductor pollicis brevis compared with adductor digiti minimi. Factors Side and Time point were not significant, as were the interactions between main factors, indicating that there was no difference in the PAS response between the affected and non-affected side in secondary dystonia and that there was no spread of the PAS effect to the adductor digiti minimi muscle on either side (Fig. 3C).

Figure 3.

PAS effect on corticospinal excitability, as measured by change in 1 mV MEP amplitude in abductor pollicis brevis and adductor digiti minimi muscle. (A) In the abductor pollicis brevis (APB) muscle, patients with primary dystonia have a higher response to PAS at all three time points (i.e. 0 min, 15 min and 30 min after PAS) compared with patients with secondary dystonia and healthy participants (**P ≤ 0.01). There is no difference in PAS response between patients with secondary dystonia and healthy participants. Averaged MEP amplitudes at each time point afer PAS is normalized to baseline avaraged MEP (before PAS) and given on the y-axis; time is given on the x-axis. (B) Patients with primary dystonia have a spread of PAS effect in non-median innervated adductor digiti minimi (ADM) muscle (**P ≤ 0.01), that is not present in patients with secondary dystonia or healthy participants. (C) There is no difference in PAS response between the affected and non-affected side in patients with secondary dystonia. On both the affected and non-affected side, PAS response is larger in abductor pollicis brevis compared to adductor digiti minimi muscle (*P ≤ 0.05). PAS response is expressed as an avareged response for three time points after PAS (0, 15, 30 min) and normalized to baseline MEPs.

Figure 4.

Averaged PAS response in individual participants. For each participant, PAS response is expressed as an avaraged MEP amplitude for three time points after PAS (i.e. 0 min, 15 min and 30 min after PAS) and plotted on the y-axis. For secondary dystonia, data refer to the affected side. APB = abductor pollicis brevis; ADM = adductor digiti minimi.

There was no difference in of the effect of PAS on resting motor threshold or active motor threshold or cortical silent period in patients with secondary dystonia (both sides), patients with primary dystonia or healthy participants.

Eye Blink Classical Conditioning

ANOVA revealed a significant difference in age between the groups [F(2, 32) = 5.9; P = 0.006], because our patients with secondary dystonia were younger than the primary dystonia control subjects (P = 0.007) and healthy participants (P = 0.03).

For the eye blink classical conditioning data, a Kruskal-Wallis ANOVA revealed a significant effect of the factor Group [χ2 = 10.2; P = 0.006]. Post hoc Mann-Whitney-U tests showed that that this was due to more conditioned responses in secondary compared to primary dystonia in Blocks 2–6 and more conditioned responses in healthy participants compared to patients with primary dystonia (Blocks 4–6) (see Table 4 for statistics). There was however no difference between patients with secondary dystonia and healthy participants. We further confirmed with Friedman ANOVA that the number of conditioned responses increased over blocks in both patients with secondary dystonia [χ2 = 22.4; P < 0.001] and healthy participants [χ2 = 22.9; P < 0.001], but not in patients with primary dystonia [χ2 = 3.53; P = 0.6] (Fig. 5).

Figure 5.

Eye blink classical conditioning. Patients with seconary dystonia have significantly more conditioned eyeblink responses compared to patients with primary dystonia. Note that data from patients with secondary dystonia in the present study are compared to historical data from patients with primary dystonia and healthy participants obtained in our laboratory using the same experimental protocol. Data are presented as a mean ± SEM.

We found no significant correlation between clinical and demographic data and TMS or eye blink classical conditioning measures in our patients.

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