This Week in the Journal August 8, 2002 Antiretroviral-Drug Resistance among Newly HIV-Infected Patients In a study of 377 patients with newly acquired human immunodefi- Patients with Resistance (%) 20 Nucleoside RT inhibitors Nonnucleoside RT inhibitors Protease inhibitors ciency virus (HIV) infection in 10 cities in North America, the prev- 15 alence of antiretroviral-drug resistance increased from 3.4 percent in 10 1995 through 1998 to 12.4 percent in 1999 through 2000. The fre- quency of multidrug resistance at presentation also increased, from 5 1.1 percent to 6.2 percent. After initial antiretroviral therapy was ad- ministered, it took longer to achieve viral suppression in those who 0 1995 1996 1997 1998 1999 2000 were infected with resistant virus, and the time to virologic failure in Year these patients was shorter. The frequency of drug-resistant virus is increasing among patients with newly diagnosed HIV infections, reflecting a higher rate of trans- mission of resistant virus. Drug-resistance testing before treatment is now indicated even for patients who are newly infected and have never received antiretroviral therapy. see page 385 (editorial, page 438) Intramuscular Injection of Botulinum Toxin for Wrist and Finger Spasticity after a Stroke “Botulinum toxin A Intramuscular injection of botulinum toxin type A has been used to treat patients with spasticity after a stroke, but its efficacy remains un- had positive effects on certain. In this randomized, double-blind, placebo-controlled trial in- volving patients with spasticity after a stroke, one-time injections of functional disability.” botulinum toxin A into wrist and finger muscles with high flexor tone reduced muscle tone and improved functional disability over a 12-week period. There were no major adverse effects of botulinum toxin in- jections. Treatment with injections of botulinum toxin A in wrist and finger muscles appears to be safe and effective in the short term, reducing disability and improving the quality of life in patients with upper- limb spasticity after a stroke. see page 395 (Perspective, page 382) Copyright © 2002 Massachusetts Medical Society. N Engl J Med, Vol. 347, No. 6 · August 8, 2002 · www.nejm.org · 381 Downloaded from www.nejm.org on August 25, 2007 . Copyright © 2002 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne 2002, the Food and Drug Admin- a double-blind, randomized, con- PERSPECTIVE istration (FDA) approved the use trolled trial, subjects picked their of botulinum toxin for the treat- own “principal target of treatment”: ment of “frown lines” at the glabel- hygiene, dressing, pain, or limb pos- Stroke, Spasticity, la, between and above the eyes. This ture. Six weeks after the injections, cosmetic use of the toxin has already 62 percent of the subjects who re- and Botulinum attracted the interest of countless ceived botulinum toxin reported Toxin people who want to look younger. improvement, as compared with 27 The toxin is also used to erase percent of those who received pla- “crow’s feet” — wrinkles at the lat- cebo. There were no serious adverse B otulinum toxin is in the news eral margin of each eye. effects. The benefits lasted for at these days. First came Sep- In this issue of the Journal, Bra- least 12 weeks. tember 11 and fears of chem- shear and colleagues (see pages Each year, approximately 750,000 ical terrorism. One gram of this 395–400) report that local intra- Americans have a stroke. Roughly “most poisonous poison” could kill muscular injections of botulinum a third die, making stroke the third a million people were it not for toxin can ameliorate disability of the leading cause of death after myo- problems of delivery. Then, in April wrist and fingers after a stroke. In cardial infarction and cancer. An- Neuromuscular Junction Axon terminal Normal Action of Botulinum Toxin A Transmitter Release Neuron Muscle cell Light chain Heavy chain Acetylcholine Synaptic vesicle Botulinum toxin cleaves SNARE proteins SNARE Botulinum proteins Synaptobrevin toxin receptor Syntaxin SNAP 25 Acetylcholine Botulinum Synaptic released toxin A cleft Acetylcholine Muscle cell receptor Acetylcholine in nerve terminals is packaged in vesicles. Normally, vesicle membranes fuse with those of the nerve terminals, releasing the transmitter into the synaptic cleft. The process is mediated by a series of pro- teins collectively called the SNARE proteins. Botulinum toxin, taken up into vesicles, cleaves the SNARE pro- teins, preventing assembly of the fusion complex and thus blocking the release of acetylcholine. 382 · N Engl J Med, Vol. 347, No. 6 · August 8, 2002 · www.nejm.org Downloaded from www.nejm.org on August 25, 2007 . Copyright © 2002 Massachusetts Medical Society. All rights reserved. T HIS WEEK IN TH E JOUR NA L other third recover, and a third are spasticity because cervical cerebro- groups of muscles, including bleph- disabled. Of the approximately spinal fluid is too close to the brain, arospasm, hemifacial spasm, cervical 4 million people who have survived which tolerates baclofen poorly. dystonia (torticollis), and writer’s a stroke, many have hemiplegia and The limitations of oral drug therapy cramp. These uses of the toxin were impairment of the hands. also apply to spasticity of the legs, welcomed as major therapeutic ad- Two questions arise. To what ex- which has been treated with intra- vances in neurology. tent is disability caused by spastic- thecal injections of phenol or surgi- In the past decade, botulinum ity? Why is botulinum toxin used cal resection of dorsal nerve roots toxin has been used to treat spas- to treat it? (rhizotomy) to diminish reflex ac- ticity caused by cerebral palsy, spi- If the corticospinal tracts on one tivity. The multiplicity of treatments nal cord injury, multiple sclerosis, side of the brain are injured, the im- is ipso facto evidence that there is and stroke. Injections in leg mus- mediate effect is contralateral hem- no optimal treatment. Moreover, al- cles are said to help relieve bother- iparesis or hemiplegia. If the injury though such treatments have led to some muscle spasms, allow a care- is mild, there may be serious loss improvements in measured joint giver to wash and dress the patient, of dexterity with only slight weak- angles or scales of limb mobility, it and relieve pain. ness. These are the “negative” ef- has been difficult to demonstrate The findings reported by Bra- fects of upper-motor-neuron le- functional improvement in walking shear et al. warrant further study sions. Immediately or within days, or use of the hands. because questions remain. Which the “positive” signs appear: over- Therapeutic use of botulinum patients are the best candidates for active tendon reflexes, Hoffmann toxin bypasses some of these prob- botulinum toxin? Can functional and Babinski signs, clonus, and hy- lems. The toxin prevents acetylcho- improvement be expected? Will this pertonia, or increased resistance of line vesicles from binding with pro- treatment help patients regain in- muscle to passive movement. Over teins needed for fusion to surface dependence in activities of daily time, the spasticity may worsen, membranes and exocytosis. This in- living? Why did so many patients causing fixed flexion contractures hibitory effect reduces the number have a response to placebo? The at the elbows, wrists, and fingers. of presynaptic transmitter vesicles, appropriate role of botulinum tox- These complications are the target impeding neuromuscular transmis- in in the management of spasticity of therapy. Spasticity is attribut- sion and weakening the muscle (see after stroke will surely be tested in able to overactivity of monosynap- Figure). In contrast to treatment more trials to come. tic muscle-stretch reflexes, hyperto- with phenol and rhizotomy, the nia, or both. effects of botulinum toxin are not LEWIS P. ROWLAND, M.D. William Landau, in Clinical Neu- permanent, persisting only until Columbia–Presbyterian Medical Center romythology and Other Arguments new neuromuscular junctions are New York, NY 10032 and Essays, Pertinent and Imperti- formed in weeks or months. And nent (Armonk, N.Y.: Futura, 2001), in contrast to drug therapy, which argues that disability in these cir- may induce sedation or somno- cumstances arises from the negative lence, injections of toxin have only symptoms, not from spasticity. It local effects. is fruitless, he concludes, to expect The use of botulinum toxin to functional improvement from the treat neurologic disease dates back treatment of spasticity. Yet there is to around 1970, when the toxin was a huge literature on anti-spasticity used to reduce the overactivity of treatments. Physical therapy is one extraocular muscles in patients with approach. Another is the adminis- strabismus. This approach was ap- tration of baclofen or tizanidine to proved by the FDA in 1989 and reduce spinal cord reflex activity. rapidly replaced muscle surgery, Taken by mouth, however, baclofen which had previously been the has limited effectiveness. Therefore, standard treatment. By 1990, bot- implanted pumps have been used ulinum toxin had also been used — to deliver baclofen directly to the successfully and safely — to treat cerebrospinal fluid. This approach involuntary-movement disorders at- is not an option for treating hand tributable to overactivity of local N Engl J Med, Vol. 347, No. 6 · August 8, 2002 · www.nejm.org · 383 Downloaded from www.nejm.org on August 25, 2007 . Copyright © 2002 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne “Factors other than Variant Cystic Fibrosis Phenotypes in the Absence of CFTR Mutations mutations in the CFTR Classic cystic fibrosis is an autosomal recessive disorder that is caused gene can produce by loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Clinical manifestations in the phenotypes clinically airways, pancreas, male reproductive tract, and sweat glands that re- semble those occurring in classic cystic fibrosis have been observed indistinguishable from in patients with mutations that reduce, but do not eliminate, the func- tion of CFTR protein. This study included 30 patients who had no nonclassic cystic fibrosis identifiable CFTR mutations and who had some features of cystic fibrosis but did not meet a clinical definition of classic cystic fibrosis. caused by CFTR The authors conclude that this variant phenotype derives from factors dysfunction.” other than mutations in the CFTR gene. If reproducible, these findings suggest that a syndrome with many aspects of cystic fibrosis can arise from mutations in genes other than CFTR. see page 401 (editorial, page 439) Voriconazole for Invasive Aspergillosis 100 Invasive aspergillosis is a major infectious complication in patients with Patients Surviving (%) 80 Voriconazole group prolonged neutropenia and in transplant recipients, and for decades, amphotericin has been the standard treatment. This randomized, un- 60 Amphotericin B group blinded trial involving 391 patients compared voriconazole with am- 40 photericin as the initial treatment for invasive aspergillosis. Those 20 treated with voriconazole had a significantly better response rate and P=0.02 improved survival at 12 weeks (70.8 percent vs. 57.9 percent, 0 0 2 4 6 8 10 12 P=0.02). Weeks Voriconazole represents a major advance in the treatment of invasive aspergillosis. In this randomized trial, treatment with voriconazole, a broad-spectrum triazole, led to improved survival and was better tolerated than amphotericin, with fewer severe adverse reactions. see page 408 Medical Progress: Inflammatory Bowel Disease Clinical experience has suggested that Crohn’s disease and ulcerative Type 1 helper colitis constitute distinct, if not discrete, entities. However, whether T cell these conditions are fundamentally different or are part of a mechanis- tic continuum is a question with both conceptual and practical impli- cations for management. This review summarizes current understand- ing of the mechanisms underlying the major forms of inflammatory bowel disease and discusses approaches to therapy. Inflammatory bowel disease is the result of inappropriate and ongo- ing activation of the mucosal immune system fueled by the presence Antigen-presenting of normal luminal flora. This aberrant response appears to be facil- cell itated by defects in both the barrier function of the intestinal epithe- lium and the mucosal immune system. see page 417 384 · N Engl J Med, Vol. 347, No. 6 · August 8, 2002 · www.nejm.org Downloaded from www.nejm.org on August 25, 2007 . Copyright © 2002 Massachusetts Medical Society. All rights reserved.