Summary
Main problem
Spasticity is a common feature in patients with multiple sclerosis (MS). Although options have broadened over the last years, there are still patients with no response to common therapeutic agents. Intrathecal administered triamcinolone acetonide (TCA) has been tested for spasticity in patients with MS. However, the long run effects are not known so far. The aim of this study was to evaluate the effects of repeated cycles of intrathecal TCA instillations on clinical parameters.
Methods
A total of 54 patients with clinically definite MS and no response to commonly utilized antispastic drugs were enrolled. TCA was administered every 3 months for a period of 9 months. Clinical assessments including spasticity, disability (EDSS), mobility (walking distance, and timed 25‐foot walk), bladder function, and quality of life were carried out prior to and at the end of each treatment cycle.
Results
Repeated TCA treatment led to repeated effects on spasticity (P < 0.01). Bladder function improved in every 10th patient. Quality of life improved during each cycle but did not reach significance at the end of study (P = 0.09). However, long‐lasting improvement on spasticity or EDSS was not shown at end of the study. Effects diminished over 3 months.
Conclusion
Repeated TCA instillations led to replicable effects on spasticity; subgroup analyses suggest that higher spasticity, more frequent treatments, and higher EDSS may lead to pronounced effects on spasticity and EDSS. Intrathecal TCA treatment was safe and no severe side effects occurred. We hypothesize a significant time dependence of re‐administration of TCA and that an interval of 3 months between the treatments might be too long.
Keywords: Glucocortiosteroids, Intrathecal instillations, Multiple sclerosis, Spasticity, Triamcinolone acetonide
Introduction
Symptoms such as incontinence, depression, fatigue, paresis, and spasticity can be observed in patients at the later stages of multiple sclerosis (MS). Spasticity is a disagreeable sensation characterized by increased muscle tone, overactive reflexes, pain, spasms or clonus, impaired functional abilities, and mobility. Infections, depression, and dependency from caregivers are possible consequences 1, 2, 3, 4. MS is a relevant cost factor for the social systems 5. The total costs correlate with the severity of spasticity 6. Costs attributable to severe spasticity will be four times the ones in mild spasticity 7. Treatment aims to prevent disease progression and/or to mitigate symptoms related to the disease.
Several oral agents (e.g., baclofen or tizanidine) are approved for the treatment of spasticity. High doses are required in severe cases. Clinically significant side effects such as drowsiness, weakness, and dizziness are common. Moreover, recently potentially life‐threatening events like allergic and skin reactions occurred in patients treated with tetrazepam. Baclofen pumps are effective in the treatment of spasticity, but high costs and invasiveness might restrict its utilization to selected patients 8, 9, 10, 11.
Positive results of cannabinoids for spasticity in patients with MS have been published 12, 13, and they have been authorized by the European Medicines Agency (EMA) as a treatment option in patients with moderate to severe spasticity and not sufficient response to first line therapeutic agents 14. Treatment opportunities have increased over the last years, but there are still patients with no response to commonly used antispastics.
Recently, we presented the positive effects of an open‐label trial of short‐term intrathecal triamcinolone acetonide (TCA) treatment on spasticity and mobility in patients with MS 15. Effects of TCA on spasticity are not understood in detail. Immune modulation does not seem to be responsible for antispastic effects. The effect might be mediated via neuro‐ionic channels and seems to be complex. Effects on the serotonergic systems as well as on GABA and glutamate receptors with both excitatory and inhibitory effects have been described. Excitatory effects on neuronal networks have been described in vitro. Above a certain threshold, a shutdown of electrical activity was shown. Exact mechanisms have not been revealed so far 16.
The aim of this study was to evaluate the effects of repeated cycles of intrathecal TCA instillations on clinical parameters. First, we want to evaluate whether effects of TCA instillations remain constant during repeated treatment cycles and second whether there are treatment effects outlasting intervals between cycles.
Patients and Methods
This multicentre open‐label prospective study included 54 patients with clinically definite MS (CDMS) according the criteria of McDonalds 17. Inclusion criteria required for not sufficient treatment response to first line antispastic agents at the treating physicians discretion. Disease activity had to be stable based on MRI assessments and on clinical examination. Treatment with immune‐modulatory therapeutic agents was not allowed. The trial was approved by the local ethics committee (University of Rostock) and has been registered with drks.de (DRKS00005671); all patients gave their written and informed consent before study entry.
Administration of TCA was performed by trained neurologists. Atraumatic needles (Sprotte®, Geisingen, Germany) were used for intrathecal TCA instillation. One therapy cycle consisted of 3–5 TCA instillations depending on spasticity. Primary outcome parameter was the effect of TCA treatment on spasticity evaluated by the modified Ashworth Scale 18; effects on Expanded Disability Status Scale (EDSS) 19, the maximum walking distance, the timed 25‐foot walk (T25‐FW), bladder function on a self‐assessment scale, and on the quality of life on a semi quantitative analogue scale were secondary outcome parameters. Parameters were collected by the investigators and the physical therapists of the participating hospitals prior to the first TCA treatment and after the last TCA therapy within a treatment cycle. Therapy cycles were performed every 12 weeks. For the first aim of our study, we analyzed treatment effects for the various cycles. For long‐lasting effects, we compared baseline values prior to first treatment with baseline values prior to TCA instillation at cycle 4.
Each patient received functional physiotherapy adapted to the individual requirements (spasticity, weakness, and ataxia). In each patient, muscle stretching, standing exercises, gait training, and relaxation exercises were performed. Patients received one unit of physiotherapy a day (60 min).
Statistical Analyses
Statistical analyses were performed with software SPSS® 15.0 (Chicago, IL, U.S.A.) and IBM® SPSS® Statistics Version 20 (Armonk, NY, U.S.A.). Kolmogorov–Smirnov test was used for checking distribution in all parameters. Socio‐demographic and clinical parameters were analyzed with the Kruskal–Wallis one‐way analysis of variance and Mann–Whitney U‐test.
Results
A total of 54 patients were included in this prospective trial. A total of 30 patients were withdrawn prior the 4th treatment cycle. Main causes were a change in treatment or patients' wish. Not complete data sets were omitted from evaluation. A total of 24 patients completed the full length of the trial (9 months). Treatment cycles were performed every 3 months with a maximum of 4 treatment cycles. Table 1 gives an overview on the included patients. Baseline values for the various outcome parameters are given in Table 2.
Table 1.
Demographic data of patients
| Patients in total | Female | Male | |
|---|---|---|---|
| Number (n) | 54 | 36 | 18 |
| Age (years) | 47.9 ± 9.7 | 48.7 ± 9.7 | 46.2 ± 9.9 |
| Course of disease | |||
| RRMS | 20 | 14 | 6 |
| SPMS | 26 | 19 | 7 |
| PPMS | 8 | 3 | 5 |
| Age at onset of disease (years) | 35.1 ± 8.7 | 35.5 ± 8.8 | 34.4 ± 8.8 |
| Disease duration (years) | 12.4 ± 8.4 | 13.0 ± 8.5 | 11.3 ± 8.1 |
Motor dysfunction was the leading symptom in 48 patients, and sensory dysfunction was the leading symptom in three patients. Three patients showed a combination of motor and sensory dysfunction.
Table 2.
Baseline characteristics of clinical parameters
| Clinical parameters at baseline | Patients in total | Female | Male | Comparison between groups |
|---|---|---|---|---|
| Ashworth scale | 2.2 ± 1.3 | 2.1 ± 1.3 | 2.4 ± 1.4 | n.s. |
| EDSS | 5.8 ± 1.6 | 5.7 ± 1.7 | 6.2 ± 1.4 | n.s. |
| T25‐FW (s) | 22.7 ± 30.4 | 24.8 ± 33.8 | 18.3 ± 22.1 | n.s. |
| Walking distance (m) | 247 ± 302 | 252 ± 314 | 237 ± 285 | n.s. |
| Quality of life | 4.6 ± 1.9 | 4.8 ± 2.1 | 4.3 ± 1.6 | n.s. |
For each parameter, average and standard deviation is presented. Spasticity is measured on the modified Ashworth scale. Parameters were not normally distributed (Kolmogorov–Smirnov test). Patient groups did not differ between female and male (Mann–Whitney U‐test). SD, standard deviation. Number of patients cycle 1 = 54; Number of patients cycle 4 = 24.
TCA was administered every other day. Depending on the severity of spasticity, 40 mg to 80 mg TCA (from 3 times up to 5 times, doses were allowed to change within treatment cycles) was utilized. Table 3 gives an overview on the administered doses.
Table 3.
Cumulative dose of administered TCA
| Treatment | Patients in total (values in mg, MA, SD) | 3 applications (values in mg, MA, SD) | 5 applications (values in mg, MA, SD) | Comparison between groups |
|---|---|---|---|---|
| Cycle 1 (baseline) | 157 ± 42.4 (n = 54) | 127 ± 22.3 (n = 27) | 186 ± 37.3 (n = 27) | P < 0.000a |
| Cycle 2 (3 months) | 152 ± 54.9 (n = 34) | 122 ± 9.4 (n = 18) | 185 ± 65.5 (n = 16) | P < 0.000a |
| Cycle 3 (6 months) | 144 ± 53.1 (n = 26) | 120 ± 20.2 (n = 15) | 176 ± 70.9 (n = 11) | P < 0.005a |
| Cycle 4 (9 months) | 145 ± 57.9 (n = 24) | 120 ± 40.4 (n = 14) | 180 ± 78.9 (n = 10) | P < 0.004a |
Kolmogorov–Smirnov test, Mann–Whitney U‐test. MA, mean average, SD, standard deviation; there was one patient for whom the number of instillations has changed over the study period. Whereas the patient is included at baseline, he is excluded from analyses at later time points.
Primary Outcome Parameter
Modified Ashworth Scale
A significant decrease within one cycle (P < 0.01) was shown for all patients for the first 3 treatment cycles. Spasticity was constantly lower at the end of each cycle compared to baseline (P < 0.01) with more pronounced effects in patients with 5 TCA instillations. Effects of TCA instillations on spasticity were diminished at the beginning of the next successive cycle with no permanent effects on spasticity. Subgroup analysis was performed according the number of TCA instillations. Baseline value for patients with 5 TCA administrations was higher (2.48; SD ± 1.19) than those in patients with 3 TCA treatments (1.89, SD ± 1.19). Effects were most pronounced during the first cycle in patients with 5 TCA treatments (decrease from 2.48; SD ± 1.19 to 1.81, SD ± 1.04; P < 0.001). In patients with 5 administrations, however, a decrease from 2.48 at baseline to 2.0, SD ± 1.63 prior TCA instillation at cycle 4 and to 1.7, SD ± 1.49 after TCA treatment of cycle four was shown (P = 0.32 and P = 0.045, respectively). Sex of the patient had no influence on effects (Figure 1, Table 2).
Figure 1.
Spasticity under TCA treatment over time in (A) all patients and (B) grouped for 3 and 5 administrations. *P ≤ 0.05, **P ≤ 0.01 and ***P ≤ 0.001.
Secondary Outcome Parameters
EDSS
At the end of the 1st cycle, EDSS decreased significantly from 5.8, SD ± 1.6 to 5.5, SD ± 1.7 (P ≤ 0.001). The effect was found to be strongest in male patients (baseline: 6.2, SD ± 1.4; end of cycle: 5.7, SD ± 1.6; P = 0.017), compared to females with a decrease from 5.7, SD ± 1.6 to 5.4, SD ± 1.7; P = 0.002. There were no significant effects on EDSS during the following cycles on EDSS. No long‐lasting effects were detected at baseline of cycle 4. Effects on EDSS were comparable between treatment groups (3 or 5 TCA applications). However, in males, a trend for long‐lasting effects on EDSS was detected in contrast to females. EDSS decreased in males from 6.2, SD ± 1.4 at study baseline to 5.9, SD ± 1.7 at baseline of cycle 2 (P = 0.063), to 5.8, SD ± 1.9 at baseline of cycle 3 (P = 0.041) to 5.3, SD ± 1.6 at baseline cycle 4 (P = 0.066). In females, an increase from 5.7, SD ± 1.7 to 5.9, SD ± 2.0 was observed.
Walking Distance
The walking distance improved significantly within each treatment cycle (P < 0.001 for cycle 1, P = 0.006 for cycle 2 and P = 0.023 for cycle 4) with exception for the 3rd cycle (P = 0.083). Over the complete trial period of 9 months, walking distance did not improve (baseline value beginning of study: 247 m, SD ± 302 m; baseline value cycle 4: 249 m SD ± 335 m) compared to baseline. Sex or number of TCA instillations had no significant influence on results.
Timed 25‐Foot Walk
The T25‐FW did not improve during the treatment with TCA in none of the various subgroups; not within a cycle, nor over the complete trial period.
Bladder Function
Patients were asked to assess their urinary function as continent, incontinent, feeling of residual urine at baseline, and the beginning of each cycle and at the end of each cycle (with possible improvement in bladder function). At baseline, 31 patients (59.6%) reported continent function, whereas 21 patients (40.4%) reported incontinence or feeling of residual urine. After the 1st TCA treatment, 18 patients (34.6%) reported incontinence or feeling of residual urine, whereas 32 patients (61.5%) reported continence, and 2 patients (3.8%) reported an improvement of their complaints. At the end of the trial, 9 patients (37.5%) reported urinary complaints (incontinence or feeling of residual urine). Within each cycle, bladder function improved in about 10 percent of the treated patients; this effect was most prominent during the 2nd cycle, when improvement was registered in almost 17%. Effects have almost diminished at the beginning of the successive cycle.
Quality of Life
Quality of life (QoL) improved after TCA instillation during each treatment cycle (cycle 1 P < 0.001 for cycle 1; P = 0.02 for cycle 3 and P = 0.01 for cycle 4, respectively) with exception of cycle 2 (P = 0.08). The increase in quality of life was most prominent during the 1st cycle (increase from 4.6, SD = 1.9 to 5.7, SD = 1.7; P < 0.001). The effect of TCA treatment lasted for 3 months. At baseline of cycle 4, QoL was tendentiously higher (5.4, SD = 1.7) compared to baseline (P = 0.09).
However, there was steady but not significant increase in QoL at beginning of each cycle compared to baseline. This effect was pronounced in patients with 5 TCA instillations. Effects were comparable between the sexes.
MRI
In all patients, MRIs were carried out before each cycle. During the 9 months in none of the patients, gadolinium enhancing lesions or new/enlarging T1 or T2 lesions were detected. Furthermore, neither arachnoiditis nor cerebral or spinal cord atrophy was observed.
Side Effects
No severe side effects such as meningitis, arachnoiditis, or other infections were observed. Back pain and postpuncture headache were treated with analgesics. All patients were able to participate in physiotherapy after TCA instillations. Most common side effects were headache in up to every tenth patient. Cell count in the CSF was 10.8 cells/μL (SD = 18.9) on average at baseline prior to 1st instillation, and 2.5 cells/μL (SD ± 2.8) at month 9 after last instillation. The small number of side effects may be drawn back to the use of atraumatic needles and were in the range of published trials 20, 21.
Discussion
Here we present the results of intrathecal administered TCA as symptomatic treatment option in patients with MS over a trial period of 9 months. TCA was administered in patients with severe spasticity with no response to first line antispastic agents.
The effects of intrathecal TCA may be explained by anti‐inflammatory properties on the one hand 22, as even in the later stages of MS inflammatory processes are at least partly responsible for progression 23, 24. In our patients, cell count in CSF decreased from slightly more than 10 cells/μL to 2.5 cells/μL after last instillation. On the other hand, neurophysiological processes may lead to decreased muscle tone as shown in vitro 16.
Our primary outcome parameter spasticity did not reach significant improvement at month 9 (prior to instillation of TCA). However, at the end of study, a significant decrease in spasticity at the end of each cycle was seen compared to baseline and within various cycles (with exception of cycle 4). The effect was stronger in patients with five TCA treatments. Those patients had higher spasticity. The effect on spasticity was not feasible at the beginning of the following treatment cycle 3 months later. Subgroups analysis showed that patients with 5 instillations benefited more from treatment.
EDSS was not improved significantly over the trial period. Within the 1st cycle, EDSS decreased significantly. Thereafter, no significant improvement was reported during treatment cycles. Although improved spasticity seems to influence mobility, we could not find a significant improvement in walking distance. Subgroup analyses showed that male patients showed better outcome in EDSS with a trend for long‐lasting effects. Male patients had a higher average EDSS at baseline than women (Table 2).
Results for the T25‐FW did not show an improvement. We conclude that TCA treatment might have more pronounced effects on endurance (walking distance) than on speed (T25‐FW). Bladder function improved in every 10 person within a treatment cycle. The treatment effect diminished over the interval period of 3 months.
However, although there were no significant improvements in mobility as measured by EDSS and walking distance, the minored spasticity and the improved bladder function led to a significant improve in quality of life. Moreover, we hypothesize a significant time dependence of re‐administration of TCA. After 3 months, various parameters worsened significantly (spasticity, bladder function, and quality of life).
Our results are consistent with findings of Hoffmann et al. who showed a short‐term and a less strong long‐lasting effect on EDSS and walking distance 20. Subgroup analyses in our cohort showed that patients with higher spasticity got more TCA treatments and profited more from treatment. EDSS improvement was shown in male patients. Males had higher EDSS than females. In conclusion, the more severe the symptoms are, the better the outcome will be. Effects on QoL were more prominent in patients with lower EDSS (<5) with an increase from 5.44, SD ± 1.6 at baseline to 6.67, SD ± 1.21 at baseline of cycle 4; P = 0.0241 ) compared to patients with higher EDSS (increase from 4.41, SD ± 1.95 to 4.94, SD ± 1.60; P = 0.141 (Friedman Test)). Patients with lower EDSS benefited more from treatment (P = 0.002 [Mann–Whitney U‐test]). The effects on outcome parameters were not influenced by diseases activity as measured on MRI, as no Gd‐enhancing, or new or enlarging T1 or T2 lesions were detected. Repeated TCA administration was safe, and no severe side effects were reported. No unexpected side effects occurred in our study and were comparable to former studies.
However, possible side effects should be taken into account. They may be caused either by the lumbar puncture itself or by the administered therapeutic agent. Postlumbar puncture complications include postlumbar puncture headache, hygromas, infections and tentorial herniation 25. Intrathecal corticosteroid administrations have been performed since the 1950s. Initially, methylprednisolone acetate (MPA) has been utilized. Aseptic meningitis, constrictive or adhesive arachnoiditis, cauda equine syndrome, prolonged postlumbar puncture headache, bacterial meningitis, abscesses, and seizures were associated with the treatment 26. The complications seemed to be related to the composition of MPA. An animal study did not reveal neurotoxic effects when triamcinolone diacetate—a depot corticosteroid—was used 27. Steroid crystal suspensions leading to a sustained release were administered intrathecal, and no clear neurotoxic effects were seen in a pilot study utilizing TCA in MS 28. So far, no neurotoxic effects were seen for TCA administration in MRI assessments and biomarker studies 15, 20, 21, 29. Nevertheless, physicians should be aware of possible side effects. Recently, a case of herpes infection after epidural steroid injections was reported 30. Potential risks and benefits have to be balanced. Experience on opportunistic infections in the long‐term intrathecal treatment is pending.
About half of the enrolled patients withdrew prematurely from the study. This high dropout rate may be explained by the invasive treatment and by the need for hospitalization. In addition, the response rate to TCA treatment was about 50–75% in former published trials 20, and thus, the withdrawal of the patients may in part be explained by the expectable therapeutic effects.
Five key messages may be derived from those results. First, repeated TCA instillations show replicable short‐term effects on spasticity. Second, repeated TCA administrations do not lead to increased or sustained effects on spasticity. Third, intervals of 3 months might be too long as effects are diminished after 3 months. Fourth, subgroup analyses suggest that higher spasticity, more frequent treatments, and higher EDSS may lead to pronounced effects on spasticity and EDSS. Fifth, even after repeated TCA treatments (up to 20 TCA instillations), no worsening was observed in any of the clinical parameters. This is of great importance as neurotoxic effects have been discussed to be associated with TCA treatment 26, 27, 29.
The high rate of premature termination on the trial highlights that repeated TCA administration is an invasive treatment option and should be restricted to highly selected patients.
We are of limitations of our trial. A placebo controlled is not possible due to ethical concerns. Moreover, interpretation may be influenced by the multicenter design with TCA dosages adapted for the individual subject needs regimens based on the treating physicians' assessment.
In conclusion, the interval of 3 months between the cycles can be optimized and shorter intervals should be introduced. TCA instillations may be a treatment option in patients with bladder dysfunction (about every tenth patient reported improved bladder functions). Our subgroup analyses show that TCA administration might a treatment option in highly selected patients (particular with spasticity in the lower limbs who will most probably benefit from treatment).
Conflict of Interest
The authors declare no conflict of interest.
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