Steroids for Neuromuscular Disease: What’s Proven, What’s Not?

Abstract & Commentary

Synopsis: Absence of evidence-based medicine is both humbling, as well as a reminder of how substantial a role the art and oral tradition of medicine plays in the care of neurologic patients.

Source: Bromberg MB, et al. Corticosteroid Use in the Treatment of Neuromuscular Disorders: Empirical and Evidence-Based Data. Muscle Nerve. 2004:30:20-37.

Chronic inflammatory demyelinating polyradiculoneuropathy: Even prior to its complete clinical explication, steroids were assessed, and found to be beneficial in inflammatory neuropathy. Initially, adrenocorticotrophic hormone (ACTH) was administered. Early reports remain unclear as to whether the patients suffered from acute or chronic polyneuropathy. Eventually, positive responses were associated with administration of ACTH or cortisone in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Only 1 randomized placebo-controlled trial of prednisone in CIDP involving 28 patients is reported, claiming a small, but significant, benefit in the treated group. Post hoc analysis of the data found no convincing evidence of benefit. Group studies, however, do support a role for prednisone, with up to 95% of patients doing well at 2 years. Initial dosing and tapering schedules vary between reports, and daily vs alternate-day dosing comparisons are not available. Pulsed high-dose dexamethasone has been tried, reportedly with benefit, but 50% of patients experience side effects including nausea, vomiting, weight-gain, hypertension, and altered mood. Too few patients were studied to recommend dexamethasone.

Myasthenia Gravis: Historically, adrenal and anterior pituitary extracts, implanted desoxycorticosterone pellets, ACTH, and cortisone had all been administered to myasthenic patients with varying degrees of success. In 1966, prednisone emerged as a treatment modality, when mentioned during discussion at a meeting of the New York Academy of Sciences. Both initial daily and alternate-day regimens have since been reported, either as an initial high-dose followed by a taper, or as a low-dose followed by a gradual increase. Early, transient worsening of weakness is known to occur with initiation of treatment. Its pathoetiology remains uncertain, and the alternate-day, low-dose paradigm, with subsequent dose escalation, does not guarantee its prevention. Randomized controlled trials, with prednisone in myasthenia, do not exist, and will never be done, as the collective clinical experience unequivocally supports its long-term efficacy. With up to 17 years follow-up, 80% of patients achieve remission or moderate-to-marked improvement. Controlled, tapering-scheduled trials similarly have never been performed, and hence, medical care is more art than science at this juncture. Slow and steady is the rule, but more than 80% remain on some prednisone, averaging 35 mg on alternate days. Pulsed, high-dose intravenous methylprednisolone, 2000 mg, given q 5 days for up to 3 doses, was beneficial in rapidly reversing myasthenic crisis with respiratory failure in 12 of 15 patients in a single report.

Inflammatory Muscle Disease: Adrenal extract was initially thought to be of questionable benefit in dermatomyositis or polymyositis, but, by the mid-20th century, ACTH and cortisone reportedly, and strikingly, improved both forms of acute myositis. Again, controlled randomized trials of corticosteroids are lacking. Experience attests to a 50% recovery or improvement rate with less aggressive disease, 80% in children, with a 25% mortality rate when myositis is associated with collagen vascular or neoplastic disease. Initiation of therapy usually begins at 1 mg/kg/d for several months, followed by a tapering over 2-5 years, to a maintenance dose of 10-20 mg, required for up to 15 years. Relapse during taper occurs in 40%, and requires increased prednisone dosage followed by a, yet, slower taper. Alternate day therapy, 100 m q.o.d. vs 50 mg q.d., may be equally efficacious with fewer side-effects, but has been reported in few patients.

Duchenne Muscular Dystrophy: Exactly 30 years ago, 14 Duchenne muscular dystrophy patients were given prednisone, and followed for up to 28 months in an open trial. Modest improvement was appreciated. In a second trial, patients treated in a 3-year, alternate-day, randomized, placebo-controlled manner, using prednisolone, showed no significant benefit. Further open-label and randomized trials followed, with some benefit in end-point measures being noted, including muscle strength, forced vital capacity, and timed, functional tasks. Benefits appeared to stabilize by 3 months, and remained to trial-end in daily, but not alternate-day, dosage-treatment studies. Using historical controls, prolonged treatment (3 years) slowed decline, compared to untreated patients. Weight gain was the most prominent side-effect (average gain, 17%), with 10% developing cataracts and glucosuria in long-term treatment groups. Blinded, placebo-controlled treatment with deflazacort, a weaker steroid with a more advantageous side-effect profile, resulted in improved leg-strength and timed Gowers’ maneuver, but time of wheelchair confinement was not different in the treated group.

Commentary

Absence of evidence-based medicine is both humbling, as well as a reminder of how substantial a role the art, and oral tradition, of medicine plays in the care of neurologic patients. Other manner of therapy for 1 or more of the above mentioned neuromuscular disorders, equally experiential and non-evidenced based, include immunosuppression using azathioprine 2-3 mg/kg/d, cyclosporine up to 5 mg/lkg/d, or cyclophosphamide, as intravenous pulse therapy up to 1 gm/m2 body surface area, or up to 2 mg/kg/d orally (J Neurol Neurosurg Psychiatry. 2003;74(Suppl II):ii25-ii31). Mycophenolate mofetil (CellCept), 1 gm b.i.d., is gaining increasing popularity, given its ease of use and relatively favorable side-effect profile. Intravenous immunoglobulin has a definite role in several areas, some indications based on rigorous, randomized controlled study. Timing of introduction of these agents remains the subject of debate. Michael Rubin

Dr. Rubin, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.