Enhanced spasticity in primary progressive MS patients treated with interferon beta-1b

Interferon beta-1b (IFNβ-1b) is the first approved therapy proven in large multicenter trials to alter the natural course of MS. These trials defined the efficacy and toxicity of interferon treatment in relapsing-remitting MS patients, but further studies are needed to define the usefulness of interferons in other forms of MS. Anecdotal reports of increased spasticity in some MS patients on interferon treatment were given at a recent consensus conference,¹ and the observation prompted us to examine spasticity in 19 consecutive primary progressive MS patients who were beginning interferon therapy.

Patients and methods. We collected data from the first 19 consecutive primary progressive MS patients whom we observed and who had obtained IFNβ-1b for compassionate use. For this evaluation they signed an informed consent form that included the information that IFNβ-1b has been tested successfully only in relapsing-remitting MS and that there are no clinical data on the use of this drug in primary progressive MS. The patients (aged 26 to 62 years) had an average duration of disease of 10.84 years, with an Expanded Disability Status Scale (EDSS) score ranging from 2.5 to 7.5.

Patients were treated with IFNβ-1b (8 mIU SC every other day) over a period of 1 year and monitored by clinical examination before treatment and every 2 months after initiation of treatment. Evaluations included the EDSS score,² the Ashworth Scale (figure), and a six-point scale for spastic reflexes (1 = reflexia, 2 = hyporeflexia, 3 = normoreflexia, 4 = hyperreflexia, 5 = unsustained clonus, 6 = sustained clonus). Increase in muscle tone and reflexes by one point was considered sufficient to establish an increase in spasticity (table). Changes in spasticity and in the EDSS score were used as an end point. Brain and spinal MRIs were performed at baseline and after 6 and 12 months, and laboratory testing (hemogram and liver function, glucose, and thyroid function tests) was performed monthly.

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Figure. Ashworth Scale. ▪ = Primary progressive MS patients treated with interferon beta-1b (IFNβ-1b); ▴ = primary progressive MS patients not treated with IFNβ-1b; ★ = relapsing-remitting MS patients treated with IFNβ-1b.

Only two patients were on medications for spasticity before interferon therapy. They received intrathecal baclofen. They were allowed to modify their doses after the increase in spasticity. Only seven patients required initiation of oral baclofen. All patients followed IFN therapy for 6 months, after which seven discontinued. Concomitant fever was not measured; however, antipyretic medication was used to suppress fever caused by interferon in all patients after the first appearance of temperature elevation.

The comparison group consisted of 19 patients with primary progressive MS followed in the same way but without IFNβ-1b treatment. A statistical comparison of the two groups showed that they did not differ significantly in age (40 ± 11 versus 42 ± 4.7 years). Using the data to calculate the t-test, we obtained the following values: duration of therapy, t = 0.996; Ashworth Scale, t = 1.997; reflex scale, t = 0.589; and EDSS, t = 1.339. All values confirm that these two groups are perfectly homogeneous. Following the same criteria, a group of 10 patients with clinically defined relapsing-remitting MS^3,4 were also treated with IFNβ-1b (EDSS score 1.5 to 3.5) to complete the study.

Results. Some of the 19 patients with primary progressive MS treated with IFNβ-1b manifested a significant change in clinical spasticity after an average time of 2 months (see table) that was also documented in the spasticity and reflex scales (see figure). A detailed examination of the data related to nontreated patients showed that of a total of 19 patients, 17 (89%) maintained constant values, whereas only 2 (11%) had an increase in the two value scales (Ashworth and reflex scales). In the treated patients, however, 13 (68%) had an increase in values, whereas only 6 (32%) were constant. According to the Ashworth Scale, 10 of 13 patients (77%) had an increase of one point, whereas the remaining 3 patients (23%) had a twofold increase. On the reflex scale, however, 6 of 13 patients (46%) had an increase of one point, whereas the remaining 7 patients (54%) had a twofold increase. As a result, the EDSS score increased in all these patients. However, the brain and spinal MRIs performed at 6 and 12 months showed no evidence of new demyelinating lesions, which could explain the worsening of the EDSS score.

Patient 12 serves as a typical example for the clinical situation; 3 months after starting IFNβ-1b he had a relevant increase in spasticity (from 3 to 4 on the Ashworth Scale, and from 4 to 6 on the reflex scale), and a spastic bladder paresis also appeared. This patient, who had an intrathecal infusion system⁵ implanted 2 years earlier for spasticity, increased the daily dose of infused baclofen by 15 µg/d after 3 months on IFNβ-1b. He then returned to a pretreatment baclofen dosage 2 months after cessation of IFNβ-1b therapy.

All patients continued therapy for 6 months, whereas seven primary progressive patients decided to discontinue IFNβ-1b treatment within 6 months after initiation of therapy (see table). One patient, to control spasticity, was taking 35 µg/d of intrathecal baclofen before IFNβ-1b treatment. During IFNβ-1b treatment baclofen was increased to 55 µg/d but was decreased to 35 µg/d after therapy suspension. Among 13 patients with an increase in spasticity during IFNβ-1b treatment, 7 required initiation of oral baclofen (dosages from 20 to 60 mg daily). In these subjects spasticity was observed even if the fever vanished. We did not note any relation between the changes in spasticity and antipyretic treatment.

A similar increase in spasticity was not observed in the 10 patients with relapsing-remitting MS treated under the same conditions. In the 19 patients with primary progressive MS not treated with IFNβ-1b, an increase in spasticity appeared in only 2 (11%) during the study period.

Discussion. We observed a frequent and clinically relevant increase in spasticity in patients with primary progressive MS that could not be correlated with any new pathology on MRI. This phenomenon usually appeared approximately 2 months after initiation of therapy and, in some patients, caused an increased need for baclofen. Symptoms of spasticity improved several months after interruption of treatment. This time lag differs from other clinical effects of beta-interferons. Thus this is probably a reversible functional side effect of interferon whose mechanism is not entirely understood. It is probably linked to a direct effect on the motor neurons or to a release of spasticity from previous central control. The symptom lasted throughout the entire treatment period and probably did not result from body temperature elevation (as part of a flu-like syndrome) because it vanished after the first month in most subjects. Further studies are needed to better understand the mechanism of this side effect. The design for further clinical trials on primary progressive MS should consider the possibility of this phenomenon because increased reversible spasticity could mask positive clinical effects on the EDSS score or other effects of IFNβ-1b on, for example, fatigue, mood, or cognition (B.G.W. Arnason, personal communication, 1996).

The smaller percentage of the 19 patients with primary progressive MS who experienced an increase in spasticity but were not being treated with IFNβ-1b minimizes the possibility that this increase was due to disease progression and new small lesions that could not be discerned on spinal MRI. Ongoing controlled clinical studies on interferons in primary progressive MS should help to clarify the issue of a causal relation. Both groups present a normal probability distribution because more than 95% of the subjects can be retained homogeneous among themselves (median ± 2 SD).

Acknowledgment

The authors thank Dr. Maurizio Petix for statistical analysis and Ms. Antonina Donato editing the manuscript.