Tarvez Tucker

A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection

Objective: To evaluate the safety and efficacy of recombinant human nerve growth factor (rhNGF) in HIV-associated sensory neuropathy (SN) within a multicenter, placebo-controlled, randomized trial (ACTG 291). Background: SN affects 30% of individuals with AIDS, is worsened by neurotoxic antiretrovirals, and its treatment is often ineffective. NGF is trophic for small sensory neurons and stimulates the regeneration of damaged nerve fibers. Methods: A total of 270 patients with HIV-associated SN were randomized to receive placebo, 0.1 μg/kg rhNGF, or 0.3 μg/kg rhNGF by double-blinded subcutaneous injection twice weekly for 18 weeks. The primary outcome was change in self-reported neuropathic pain intensity (Gracely Pain Scale). Secondary outcomes included an assessment of global improvement in neuropathy by patients and investigators, neurologic examination, use of prescription analgesics, and quantitative sensory testing. In a subset, epidermal nerve fiber densities were determined in punch skin biopsies. Results: Both doses of NGF produced significant improvements in average and maximum daily pain compared with placebo. Positive treatment effects were also observed for global pain assessments (p = 0.001) and for pin sensitivity (p = 0.019). No treatment differences were found with respect to mood, analgesic use, or epidermal nerve fiber densities. Injection site pain was the most frequent adverse event, and resulted in unblinding in 39% of subjects. Severe transient myalgic pain occurred in eight patients, usually from accidental overdosing. There were no changes in HIV RNA levels or other laboratory indices. Conclusions: We found a positive effect of recombinant human nerve growth factor on neuropathic pain and pin sensitivity in HIV-associated sensory neuropathy. rhNGF was safe and well tolerated, but injection site pain was frequent.

A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection

Background: Painful sensory neuropathy is a common complication of HIV infection. Based on prior uncontrolled observations, we hypothesized that amitriptyline or mexiletine would improve the pain symptoms. Method: A randomized, double-blind, 10-week trial of 145 patients assigned equally to amitriptyline, mexiletine, or matching placebo. The primary outcome measure was the change in pain intensity between baseline and the final visit. Results: The improvement in amitriptyline group (0.31 ± 0.31 units [mean ± SD]) and mexiletine group (0.23 ± 0.41) was not significantly different from placebo (0.20 ± 0.30). Both interventions were generally well tolerated. Conclusions: Neither amitriptyline nor mexiletine provide significant pain relief in patients with HIV-associated painful sensory neuropathy.

Surgical treatment of migraine headaches

The senior author (BG) introduced the modern concept of migraine surgery in 2000. Since then, over 40 articles have been published by eight centers across the US, Europe, and Asia, describing positive outcomes after surgery in 68–95% of cases. Surgeons, neurologists, and patients are increasingly interested in this new treatment method. However, the majority of publications on this topic are found in surgical literature, with few articles presented in neurology journals. This review is an introduction to migraine surgery for neurologists from a surgeons view. It discusses the surgical treatment of migraine headaches based on the discoveries made and articles published by the senior author. It outlines the current history of migraine surgery, presents evidence supporting its effectiveness, and tries to dispel claims that what we are seeing is a placebo effect. It further describes detection of trigger sites and outlines surgical techniques of peripheral nerve decompression. We hope that this review will generate a positive discussion between surgeons and neurologists and lead to more interdisciplinary collaboration for the benefit of the patients in the future.

A phase I/II trial of nimodipine for HIV-related neurologic complications

Background: Few effective treatments are available for AIDS dementia complex (ADC) and HIV-associated neuropathy. However, recent in vitro studies indicate that nimodipine, a voltage-dependent calcium channel antagonist, can prevent HIV-related neuronal injury and may provide a novel form of treatment for these disorders. Methods: To determine the safety and possible efficacy of this agent, 41 patients with mild to severe ADC, including 19 patients with neuropathy, were entered into the AIDS Clinical Trial Group multicenter, phase-I and phase-II study. Nimodipine at 60 mg po, five times daily; 30 mg po, three times daily; or placebo was administered for 16 weeks as adjuvant treatment to antiretroviral therapy. Results: Neuropsychological performance at baseline, measured by the composite neuropsychological Z score (NPZ-8), correlated significantly with the ADC stage and with CSF levels of neopterin, a marker of immune activation. No significant differences in toxicity were observed among the three arms. Intent-to-treat analysis showed no significant change in the NPZ-8, although improvement was suggested in the high-dose arm. In addition, a trend toward stabilization in peripheral neuropathy was observed in both nimodipine arms compared with placebo. Conclusions: Nimodipine and other similar nonantiretroviral agents may provide a safe and promising avenue of treatment for neurologic disorders associated with HIV infection. The results of this study indicate that further clinical trials are warranted.

Long-term treatment with recombinant nerve growth factor for HIV-associated sensory neuropathy

HIV-associated distal sensory polyneuropathy (DSP) is a common complication of AIDS. No effective treatment is available. The authors investigated the long-term effect (48 weeks) of the neurotrophin nerve growth factor (NGF) in an open-label study of 200 subjects with HIV-associated DSP. Similar to their previously reported double-blind study, the authors showed that NGF was safe and well tolerated and significantly improved pain symptoms. However, there was no improvement of neuropathy severity as assessed by neurologic examination, quantitative sensory testing, and epidermal nerve fiber density.

Single‐Site Botulinum Toxin Type A Injection for Elimination of Migraine Trigger Points

Background.—Botulinum toxin may be effective in suppressing migraine. Most injection regimens utilized have involved multiple sites.

Subacute, reversible motor neuron disease

Four patients with a clinical syndrome closely resembling amyotrophic lateral sclerosis recovered completely, without treatment, 5 to 12 months after onset. Electrodiagnostic tests revealed acute and chronic denervation, with normal motor and sensory nerve conduction studies. The CSF was normal, and tests for paraproteinemia, heavy metal intoxication, and systemic illness were negative. Although such cases are rare, the possibility of spontaneous recovery should always be considered when counseling patients with suspected ALS.

Hourglass deformity after botulinum toxin type A injection

Background.—Complications, such as eyelid ptosis, have been attributed to botulinum toxin type A. An “hourglass” deformity, which is the consequence of temporalis muscle atrophy, has not been reported previously.

Botulinum toxin A and migraine surgery.

Having observed the safe use of botulinum toxin A (Botox; Allergan, Inc., Irvine, Calif.) in craniofacial patients for correction of strabismus by ophthalmology colleagues, it seemed safe to use it in extraorbital muscles as well. Prompted by the successful use on one of our own (Guyuron) corrugator muscles, several of our staff requested that Botox be injected into their frowning muscles in the late 1980s. Synchronously, two patients who were afflicted with dysfunction of the depressor labii inferioris muscle, one iatrogenically and the other congenitally, sought the lead author’s advice. They were treated with Botox and were pleased with their outcomes. Further use of Botox culminated in a reasonable experience that included 30 muscles, of which 28 responded favorably, which was presented during the 1992 meeting of the American Society for Aesthetic Plastic Surgery.1 It would not have been fathomable then that one day injection of Botox would become the most frequently performed procedure in aesthetic surgery. Our experiences with Botox continued predominantly in the aesthetic arena. Serendipitously, two patients reported elimination of migraine headaches following forehead rejuvenation. A retrospective study was commenced that included 314 patients who had undergone forehead rejuvenation. Of those patients, 39 had been diagnosed with migraine headaches based on the criteria established by the International Headache Society, and 31 of the 39 had experienced either a complete elimination of or significant improvement in the frequency and/or severity of their headaches, with an average follow-up of 47 months.2 Concurrently, several articles were published advocating the use of Botox for treatment of migraine headaches.3–6 The only common denominator between these two modalities that could potentially affect migraine headaches was elimination of corrugator supercilii muscle function. Contrary to some beliefs, both supratrochlear and supraorbital nerves pierce the corrugator supercilii muscle. While the trunk of the former passes through the muscle, only the branches of the latter penetrate this muscle. Intrigued by these findings, we were compelled to review the literature to find a reasonable explanation as to the mechanism of migraine headaches and the role that Botox and surgery may play. Approximately 30 years ago, a neurology colleague asserted that irritation of the peripheral branches of the trigeminal nerve results in release of substance P and neurokinins which travel along the nerve and produce a localized meningitis.2 The author, however, did not cite any reason for the inflammation or irritation of the nerve branches. We postulate that this inflammation is caused by continual contraction of the muscle around the nerve. The evidence for this hypothesis was abundant. The most convincing support in favor of a peripheral mechanism role is efficacy of botulinum toxin on migraine headaches. Botox’s effect is predominantly peripheral, although it has been claimed that botulinum toxin may have some central effects as well.4 The latter, however, has not been substantiated by scientific evidence. Additionally, many of the patients with frontal migraine headaches exhibit deep frown lines with unusually bulky corrugator supercilii muscles. Our report, which was published in the August 2000 issue of Plastic and Reconstructive Surgery,2 was a retro-

Induction of Progressive Profound Hypocitraturia with Increasing Doses of Topiramate

OBJECTIVES To provide prospective, longitudinal evidence of the effects of topiramate, an antiepileptic medication prescribed for migraine headaches, on stone-risk factors, specifically as pertaining to dosing and rapidity of onset. METHODS Patients scheduled to begin topiramate therapy were recruited to participate in the study. Enrolled subjects collected a pretreatment 24-hour urine specimen with subsequent 24-hour urine specimens collected 5 days after beginning topiramate and after each dose escalation. RESULTS Six subjects enrolled in the study, 4 of whom completed two additional urine collections after initiating topiramate therapy. The pretreatment urine collections of the 4 subjects with additional samples revealed the following mean (range) values: urine volume 1550 (1300 to 1900) mL, pH 6.75 (6 to 7), creatinine 1436.3 (1196 to 1590) mg/day, calcium 305.8 (209 to 423) mg/day, and citrate 606.8 (290 to 860) mg/day. Five days after initiation of topiramate, mean calcium decreased to 211.5 mg/day (31% decrease), and mean citrate decreased to 398 (99 to 804) mg/day, an average decrease of 39.8% (6.5% to 65.9%) per patient. After a dose escalation, calcium increased to 286.8 mg/day, but citrate decreased further to 209 (119 to 353) mg/day, an average decrease of 65.1% (57.9% to 71.7%) per patient from pretreatment levels. CONCLUSIONS Topiramate therapy induces a profound decrease in urinary citrate levels, equivalent to the levels seen in distal renal tubular acidosis. Citrate levels decrease quickly after the start of topiramate therapy and continue to decrease with escalating doses.