The practice of neurology, 2000-2010: report of the AAN Member Research Subcommittee.

OBJECTIVE: To present an analysis of American Academy of Neurology (AAN) membership demographics and practice trends over the past decade. METHODS: Data from the 2009 AAN Census and 2010 Practice Profile Form (PPF) surveys were compared to results from 2004 and 2000 surveys. The Census was sent to all AAN members, and the PPF was sent to a random sample of US practicing neurologists. RESULTS: Since 2000, AAN membership increased by 31%, and the number of US neurologist-members increased by 14%. Mean age of US neurologists increased from 48.6 to 53.3 years, and 23.9% of neurologists are women. There was a 15% increase in the proportion of neurologists relative to the US population, from 3.41 neurologists per 100,000 population in 2000 to 3.92 neurologists in 2009. In 2009, 24.1% of US neurologists were in solo practice, 27.8% were in a neurology group, and 35.6% were in multispecialty/university settings, with little change in practice arrangements over time. The top 5 practice interest areas were unchanged since 2004 as were the number of hours devoted to patient care (42.3) or total work hours per week (57.1). Little change was observed in performed procedures, except increased use of botulinum toxin and nerve blocks and a decline in lumbar punctures. Neurologists rely more on physician assistants to see follow-up and new patients independently (p < 0.001). CONCLUSION: Despite advances in neurologic diagnosis and therapy, there has been little change in practice characteristics of US neurologists.

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.

Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: A randomized controlled trial. rhNGF Clinical Investigator Group.

CONTEXT: Nerve growth factor is a neurotrophic factor that promotes the survival of small fiber sensory neurons and sympathetic neurons in the peripheral nervous system. Recombinant human nerve growth factor (rhNGF) has demonstrated efficacy as treatment for peripheral neuropathy in experimental models and phase 2 clinical trials. OBJECTIVE: To evaluate the efficacy and safety of a 12-month regimen of rhNGF in patients with diabetic polyneuropathy. DESIGN: Randomized, double-blind, placebo-controlled phase 3 trial conducted from July 1997 through May 1999. SETTING: Eighty-four outpatient centers throughout the United States. PATIENTS: A total of 1019 men and women aged 18 to 74 years with either type 1 or type 2 diabetes and a sensory polyneuropathy attributable to diabetes. INTERVENTIONS: Patients were randomly assigned to receive either rhNGF, 0.1 microg/kg (n = 504), or placebo (n = 515) by subcutaneous injection 3 times per week for 48 weeks. Patients were assessed at baseline, 12 weeks, 24 weeks, and 48 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was a change in neuropathy between baseline and week 48, demonstrated by the Neuropathy Impairment Score for the Lower Limbs, compared between the 2 groups. Secondary outcome measures included quantitative sensory tests using the CASE IV System, the Neuropathy Symptom and Change questionnaire, the Patient Benefit Questionnaire (PBQ), and a global symptom assessment, as well as nerve conduction studies and occurrence of new plantar foot ulcers. Patients also were evaluated for presence of adverse events. RESULTS: Among patients who received rhNGF, 418 (83%) completed the regimen compared with 461 (90%) who received placebo. Administration of rhNGF was safe, with few adverse events attributed to treatment apart from injection site pain/hyperalgesia and other pain syndromes. However, neither the primary end point (P =.25) nor most of the secondary end points demonstrated a significant benefit of rhNGF. Exceptions were the global symptom assessment (P =.03) and 2 of 32 comparisons within the PBQ, which showed a modest but significant benefit of rhNGF (P =.05 for severity of pain in the legs and P =.003 for 6-month symptoms in the feet and legs). CONCLUSION: Unlike previous phase 2 trials, this phase 3 clinical trial failed to demonstrate a significant beneficial effect of rhNGF on diabetic polyneuropathy. JAMA. 2000;284:2215-2221.

A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS Clinical Trials Group Team 291.

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 microg/kg rhNGF, or 0.3 microg/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.

Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF Study Group.

BACKGROUND: Preclinical studies have demonstrated that nerve growth factor may prevent or reverse peripheral neuropathy. We have therefore tested the effects of recombinant human nerve growth factor in patients with diabetic polyneuropathy. METHODS: A total of 250 patients with symptomatic diabetic polyneuropathy randomly received either placebo or one of two doses of recombinant human nerve growth factor for 6 months. Patients were assessed for symptoms and signs of polyneuropathy before and after treatment. RESULTS: Compared with placebo, recombinant human nerve growth factor led to significant improvement after 6 months of treatment, as measured by the sensory component of the neurologic examination, two quantitative sensory tests, and the impression of most subjects that their neuropathy had improved. Three prospectively identified multiple endpoint analyses indicated improvements in the nerve growth factor treatment groups over the placebo group in all three analyses (p = 0.032; p = 0.008; p = 0.005). Recombinant human nerve growth factor was well tolerated, with injection site discomfort reported as the most frequent adverse event. CONCLUSIONS: Recombinant human nerve growth factor appears to be safe and shows preliminary evidence of efficacy in patients with symptomatic diabetic polyneuropathy.

Botulinum toxin type B: a double-blind, placebo-controlled, safety and efficacy study in cervical dystonia.

We enrolled and treated 122 patients with idiopathic cervical dystonia in a double-blind, placebo-controlled safety and efficacy study of botulinum toxin type B (BotB). Both A-responsive and A-resistant patients were enrolled. Patients received intramuscular injections of either BotB (2,500 U, 5,000 U, or 10,000 U) or placebo. The primary outcome measure of efficacy was the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at 4 weeks following study drug administration. Secondary measures of efficacy were TWSTRS-Severity, -Disability, and -Pain subscale scores, and Analog Pain Assessment, Investigator Global Assessment, Patient Global Assessment, and Sickness Impact Profile scores. Duration of effect was estimated with an intent-to-treat analysis of responders. Safety measures included clinical parameters, laboratory tests, and adverse events. The primary and most of the secondary analyses indicated a statistically significant treatment effect and a dose response. BotB is safe, well tolerated, and efficacious in the treatment of cervical dystonia at the doses tested.

The effect of systemically administered recombinant human nerve growth factor in healthy human subjects.

This phase I double-masked, randomized, placebo-controlled study evaluated the safety of single intravenous or subcutaneous doses of recombinant human nerve growth factor (rhNGF) in healthy human volunteers at doses ranging from 0.03 to 1 micrograms/kg. No life-threatening adverse events were seen at any dose. At doses above 0.1 microgram/kg, subjects reported mild to moderate muscle pain, primarily in the bulbar and truncal musculature. The duration and severity of these myalgias varied in a dose-dependent manner, and women appeared to be more susceptible than men. Intravenous rhNGF produced earlier and more pronounced systemic effects than did identical subcutaneous doses. Subjects receiving subcutaneous rhNGF noted hyperalgesia at the injection site, a local effect persisting up to 7 weeks, that also varied in a dose-dependent manner. Antibodies to NGF were not detected in any subject. These results indicate that systemically administered rhNGF exerts a characteristic and reproducible biological effect in healthy subjects at very low doses and in a dose-dependent manner.

Intracranial myxopapillary ependymoma: case report.

The authors report an unusual case of a myxopapillary ependymoma arising from the lateral ventricle. The patient, a 37-year-old woman, developed recurrent symptoms including scotomata, disorientation, and headache during two successive pregnancies before the definitive diagnosis. The causes of this ependymoma variant and its relationship to pregnancy are discussed.

L-tryptophan and the eosinophilia-myalgia syndrome: pathologic findings in eight patients.

Pathologic findings in eight patients with the eosinophilia-myalgia syndrome, secondary to L-tryptophan ingestion, are reported. Tissue was obtained by biopsy alone in six patients, by biopsy and autopsy in the seventh patient, and by autopsy alone in the eighth patient. Muscle biopsies in five patients demonstrated an inflammatory infiltrate composed predominantly of lymphocytes, histiocytes, plasma cells, and a few eosinophils. The inflammation involved the perimysial and epimysial connective tissue, the walls of some small blood vessels, the perineurium of small nerve twigs, muscle spindles, and fibrous septae of subcutaneous adipose tissue. In two patients with peripheral neuropathy and one patient without overt neuropathy, denervation atrophy of muscle and perimysial and epimysial fibrosis were present. Sural nerve biopsy tissue taken from two patients displayed prominent axonopathy in one, and minimal changes in the second. Pulmonary changes in the two autopsied patients included endothelial cell damage, endovasculitis and fibromyxoid intimal change im arteries and veins, and interstitial pneumonitis with fibrosis.