Improvement following interferon-alpha 2A in chronic inflammatory demyelinating polyneuropathy

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated disorder that usually responds to plasma exchange, intravenous gammaglobulin, or corticosteroids, but occasionally the disease is refractory to these therapies and the patients have increasing disability. We recently reported a series of patients with CIDP who had spontaneous improvement after an episode of sepsis and postulated that recovery may have followed an alteration in immune function as a result of bacterial pyogens and their induction of cytokines. ^[1] One of these patients subsequently developed a progressive-relapsing illness that was unresponsive to the conventional treatments for CIDP but greatly improved after treatment with interferon-alpha 2A.

Case report.

A 51-year-old man had progressive limb weakness for years. He had an episode of weakness at 42 years from which he did not recover, requiring a cane to walk. Five years later he had generalized weakness that progressed over several weeks. He was bedbound with 3/5 strength (MRC scale) in his arms and 2/5 in his legs. There was generalized areflexia but sensation was normal. EMG showed a demyelinating polyneuropathy, and the spinal fluid protein concentration was 136 mg/dl. Immunoelectrophoresis was normal, and GM1 and MAG antibodies were absent. There was no response to intravenous gamma-globulin (400 mg/kg/d for 5 days) but moderate improvement with plasma exchange, and he could walk with canes after several weeks. He had plasma exchange every 2 to 3 months over the next year to maintain his walking and had no further improvement with trials of prednisone and azathioprine. At 49 years he had substantial improvement following an episode of Staphylococcus sepsis, as reported previously. ^[1] There was only mild weakness of hip flexors and his condition was maintained on prednisone (30 mg/d) for the next 18 months without further exchanges. During the subsequent 6 months he had progressive generalized weakness. There was no improvement after increasing the steroid dosage or plasma exchange.

Prior to initiation of therapy with interferon-alpha, grip strength was 9 lbs in the right hand and 20 lbs in the left. He had antigravity strength in his arms but could not lift his legs off the examination Table 1. Distal leg strength was 4/5 bilaterally. He was areflexic with slight loss of vibration sensation at the toes. He needed assistance to stand from a chair and required a cane to walk.

Methods.

The patient was evaluated prospectively with quantitative strength assessment, hand grip dynamometry, modified Rankin disability score, and nerve conduction studies before and after treatment with interferon-alpha 2A. Ten muscles were assessed bilaterally using the Medical Research Council (MRC) strength grading scale (0-5): first dorsal interosseus, finger extensors, wrist extensors, triceps, biceps, and deltoids in the arms; psoas, hamstrings, tibialis anterior, and extensor hallucis longus in the legs, for a possible score of 100 points. The modified Rankin disability scale was used to determine functional disability.

Nerve conduction studies were performed in a standard fashion as described elsewhere. ^[2] The median, ulnar, peroneal, and tibial motor were studied sequentially by the same examiner using identical distal electrode placement (Table 1). Temperature was maintained at 32 degrees C.

Results.

The patient was treated with interferon-alpha 2A, three million IU subcutaneously, three injections/week. The dose of prednisone was maintained at 30 mg/day. Pretreatment MRC score was 67, and the modified Rankin score was 4. After 1 week the patient noticed improved strength. At 6 weeks he could shave, walk without a cane, stand from a chair, dress without assistance, and drive a car. Grip strength was 35 lbs on the right and 46 lbs on the left, and his MRC score increased to 84 points (Figure 1). He had transient fever, chills, and myalgias after the first several injections but no other adverse effects.

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Figure 1. Clinical assessment during treatment with interferon-alpha 2A.

Interferon-alpha 2A was discontinued after 6 weeks. Weakness increased during the next 2 weeks with progressive disability, and the MRC score declined to 71. With reinstitution of interferon injections, strength and functional ability again improved. Six weeks later the MRC score increased to 87, grip strength greatly improved (see Figure 1), and he could walk independently.

Nerve conduction studies before treatment with interferon-alpha 2A showed normal median and ulnar distal compound muscle action potential (CMAP) amplitudes with prominent conduction block (see Table 1). Tibial and peroneal potentials were reduced with conduction block in the tibial nerve, and all F-responses were absent. There was moderate to severe slowing of conduction velocities, though distal latencies were normal except for slight prolongation of the ulnar nerve. Ulnar and sural sensory potentials were normal.

After 6 weeks of treatment, all distal CMAP amplitudes increased with slight reduction in the degree of conduction block in the median, ulnar, and tibial nerves. Conduction block in the peroneal nerve became apparent following a marked increase (230%) in the distal CMAP amplitude. Conduction velocities were virtually unchanged and distal latencies were modestly improved. At 8 weeks (2 weeks after discontinuing interferon-alpha 2A), distal CMAP amplitudes diminished to pretreatment levels in most nerves, while distal latencies and conduction velocities were similar to the previous study. Because of a decline in the distal amplitude of the peroneal potential, there was a corresponding drop in the degree of conduction block. After 6 weeks of re-treatment with interferon-alpha 2A, the median distal CMAP amplitude again increased, though other conductions were unchanged.

Discussion.

This patient with CIDP had no response to corticosteroids and intravenous gammaglobulin and had only a limited response to plasma exchange, but had substantial improvement following treatment with interferon-alpha 2A. Grip strength, MRC score, Rankin score, and nerve conduction studies improved after several weeks of treatment, and the degree of recovery was greater than with previous immunomodulating therapy. Furthermore, deterioration occurred after interferon was discontinued followed by improvement with reinstitution of therapy. Others have reported improvement in CIDP patients with interferon-alpha, ^[3,4] interferon-beta, ^[5] polyinosinic-polycytidylic (poly-ICLC), ^[6] and after sepsis ^[1]; poly-ICLC and sepsis are potent inducers of interferon. ^[6,7] The mechanism by which interferon induced improvement in our patient is uncertain, but is most likely related to complex immunomodulating effects, perhaps by reducing the levels of proinflammatory cytokines such as tumor necrosis factor or interferon-gamma. Tumor necrosis factor and interferon-gamma have been demonstrated to have a role in the development of inflammatory demyelination. ^[8] Moreover, oral interferon reduces the severity of experimental allergic neuritis in rats, possibly by limiting the production of interferon-gamma. ^[9]

Distal CMAP amplitudes increased in some nerves following interferon-alpha 2A, but there was little change in conduction velocities, distal latencies, and conduction block. The increase in distal amplitudes in our patient suggests that interferon-alpha may have exerted its effects on the distal axon, perhaps by reducing very distal conduction block, ^[10] rather than reducing conduction block in more proximal nerve segments.

Interferon-alpha was well tolerated. Fever, myalgias and headache occurred hours after the first several injections, though there were no other adverse effects. Interferon-alpha may be an effective alternative treatment for patients with CIDP refractory to conventional therapy. To confirm this preliminary experience, we have undertaken a prospective trial of interferon-alpha in patients with relapsing or progressive CIDP.

Addendum.

Modified Rankin Disability Scale: 0 = asymptomatic; 1 = nondisabling symptoms that do not interfere daily activities; 2 = slight disability, unable to carry out all activities but still able to look after themselves; 3 = moderate disability, requiring assistance with some activities but able to walk without assistance; 4 = moderately severe disability, unable to walk without assistance and unable to attend to own bodily needs without assistance; 5 = severe disability, totally dependent, requiring constant nursing care and attention.