The complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is the current consensus-derived name for a syndrome usually triggered by limb trauma. Required elements include prolonged, disproportionate distal-limb pain and microvascular dysregulation (e.g., edema or color changes) or altered sweating. CRPS-II (formerly "causalgia") describes patients with identified nerve injuries. CRPS-I (formerly "reflex sympathetic dystrophy") describes most patients who lack evidence of specific nerve injuries. Diagnosis is clinical and the pathophysiology involves combinations of small-fiber axonopathy, microvasculopathy, inflammation, and brain plasticity/sensitization. Females have much higher risk and workplace accidents are a well-recognized cause. Inflammation and dysimmunity, perhaps facilitated by injury to the blood-nerve barrier, may contribute. Most patients, particularly the young, recover gradually, but treatment can speed healing. Evidence of efficacy is strongest for rehabilitation therapies (e.g., graded-motor imagery), neuropathic pain medications, and electric stimulation of the spinal cord, injured nerve, or motor cortex. Investigational treatments include ketamine, botulinum toxin, immunoglobulins, and transcranial neuromodulation. Nonrecovering patients should be re-evaluated for neurosurgically treatable causal lesions (nerve entrapment, impingement, infections, or tumors) and treatable potentiating medical conditions, including polyneuropathy and circulatory insufficiency. Earlier impressions that CRPS represents malingering or psychosomatic illness have been replaced by evidence that CRPS is a rare complication of limb injury in biologically susceptible individuals.

High-dose chemo-radiotherapy for relapsed or refractory Hodgkin lymphoma and the significance of pre-transplant functional imaging.

We previously reported that three risk factors (RF): initial remission duration <1 year, active B symptoms, and extranodal disease predict outcome in relapsed or refractory Hodgkin lymphoma (HL). Our goal was to improve event-free survival (EFS) for patients with multiple RF and to determine if response to salvage therapy impacted outcome. We conducted a phase II intent-to-treat study of tailored salvage treatment: patients with zero or one RF received standard-dose ifosfamide, carboplatin, and etoposide (ICE); patients with two RF received augmented ICE; patients with three RF received high-dose ICE with stem cell support. This was followed by evaluation with both computed tomography and functional imaging (FI); those with chemosensitive disease underwent high-dose chemoradiotherapy and autologous stem cell transplantation (ASCT). There was no treatment-related mortality. Compared to historical controls this therapy eliminated the difference in EFS between the three prognostic groups. Pre-ASCT FI predicted outcome; 4-year EFS rates was 33% vs. 77% for patients transplanted with positive versus negative FI respectively, P = 0.00004, hazard ratio 4.61. Risk-adapted augmentation of salvage treatment in patients with HL is feasible and improves EFS in poorer-risk patients. Our data suggest that normalisation of FI pre-ASCT predicts outcome, and should be the goal of salvage treatment.

Prognosis of a normal positron emission tomography 82Rb myocardial perfusion imaging study in women with no history of coronary disease.

OBJECTIVES: Myocardial perfusion imaging (MPI) with positron emission tomography (PET) has advantages over single-photon emission computerized tomography, particularly for women. This investigation was undertaken to define the prognosis of a normal stress PET MPI study in women. METHODS: The cohort comprised 457 women evaluated for suspected coronary artery disease (CAD) who had normal pharmacologic stress (82)Rb PET MPI. No patient had clinically evident CAD. Kaplan-Meier estimates were used to determine death and initial nonfatal cardiac event rates over 7 years. Log rank tests were used to assess the relationship between baseline cardiac risk and events during follow-up, and to contrast survival in the cohort with age- and gender-matched US census comparators. RESULTS: During follow-up, there were 11 deaths (all nonischemic), 3 nonfatal myocardial infarctions, 3 percutaneous coronary interventions and 1 coronary artery bypass operation. Average risks of death and initial nonfatal cardiac events were 0.72 and 0.47% per year, respectively. Cardiac events were associated with a history of diabetes (p < 0.0003) and a family history of CAD (p < 0.05). CONCLUSION: A normal cardiac PET study is associated with a very low rate of future cardiac events. Women with diabetes and a strong family history of CAD are more likely to sustain events and require close surveillance for the development of coronary disease.

Multiple sclerosis prevalence and possible lead exposure.

This study was conducted to estimate the current prevalence of multiple sclerosis (MS) in Jefferson County, Missouri, USA, and to address community concerns about a perceived excess of MS around an active lead smelter. The study population consisted of the residents of Jefferson County, Missouri between 1998 and 2002. An aggressive MS case finding with capture-recapture analysis was used. The spatial clustering was examined using a spatial scan statistic. The capture-recapture analysis showed the case ascertainment to be 95%. The crude five-year period prevalence of MS in Jefferson County was 105 per 100,000 population (95% confidence interval [CI], 91-121), and 107 per 100,000 (95% CI, 95-119) when age-standardized to the 2000 U.S. population. No significant spatial clusters of MS cases were identified in the study area. The estimates of MS prevalence in Mid-western community of USA appeared to be comparable to estimates from other areas of similar latitude in the United States and Western Europe. The MS cases did not appear to cluster around the lead smelter.

An epidemiologic investigation of amyotrophic lateral sclerosis in Jefferson County, Missouri, 1998-2002.

Amyotrophic lateral sclerosis (ALS) cases diagnosed between 1998 and 2002 were identified to study ALS prevalence and spatial clustering in Jefferson County, Missouri, where an active lead smelter is located. The study used the El Escorial criteria for ALS diagnosis, the capture-recapture analysis for ALS case ascertainment, and the spatial scan statistic for cluster analysis. The estimated crude prevalence of ALS in Jefferson County was 3.9 per 100,000 population (95% CI, 1.7-7.7) at the time point on December 31, 2002. After age-adjustment to the 2002 U.S. population, the prevalence was 4.2 per 100,000 (95% CI, 1.9-6.6). This prevalence estimate was comparable to recent prevalence estimates from Western Europe. A small but significant cluster (p=0.04) was detected around the smelter area. An ALS registry utilizing outpatient, inpatient, and death certificate data is needed to provide comprehensive information for ALS case ascertainment. Etiologic studies are needed to assess whether living in proximity to a lead smelter is associated with the development of ALS.

The diagnostic workup of patients with neuropathic pain.

Neuropathic pain is initiated or caused by damage or dysfunction of the peripheral or central nervous systems in various disorders, each having pain-related symptoms and signs thought secondary to common pain mechanisms. Ancillary testing may demonstrate associated nervous system abnormalities, however its specificity is inadequate at present, as it makes inferential conclusions from indirect data. Symptom assessment and physical findings remain paramount in the diagnosis of neuropathic pain.

The diagnostic workup of patients with neuropathic pain.

Determining the causes of neuropathic pain is more than an epistemological exercise. At its essence, it is a quest to delineate mechanisms of dysfunction through which treatment strategies can be created that are effective in reducing, ameliorating, or eliminating symptomatology. To date, predictors of which patients will develop neuropathic pain or who will respond to specific therapies are lacking, and present therapies have been developed mainly through trial and error. Our current inability to make therapeutically meaningful decisions based on ancillary test data is illustrated by the following: In a study specifically designed to assess the response of patients with painful distal sensory neuropathies to the 5% lidocaine patch, no relationship between treatment response and distal leg skin biopsy, QST, or sensory nerve conduction study results could be established. From a mechanistic perspective, the hypothesis that the lidocaine patch would be most effective in patients with relatively intact epidermal innervation, whose neuropathic pain is presumed attributable to "irritable nociceptors," and least effective in patients with few surviving epidermal nociceptors, presumably with "deafferentation pain," was unproven. The possible explanations are multiple and outside the scope of this review. However, these findings, coupled with the disparity in C-fiber subtype involvement in diabetic small-fiber neuropathy, and the recently reported inability of enzyme replacement therapy in Fabry disease to influence intraepidermal innervation density, while having mixed effects on cold and warm QST thresholds, and beneficial effects on sudomotor findings, when therapeutic benefit was demonstrated, lead one to conclude that the specificity of ancillary testing in neuropathic pain is inadequate at present, and reinforce the aforementioned caveats about inferential conclusions from indirect data. The diagnosis of neuropathic pain mechanisms is in its nascent stages and ancillary testing remains "subordinate," "subsidiary," and "auxiliary" as defined in Webster's Third New International Dictionary. As a consequence of these difficulties, the recent approach by Bennett and his colleagues may have merit. They have hypothesized (and provide data in support) that chronic pain can be more or less neuropathic on a spectrum between "likely," "possible," and "unlikely," based on patient responses on validated neuropathic pain symptom scales, when compared with specialist pain physician certainty of the presence of neuropathic pain on a 100-mm visual analog scale. The symptoms most associated with neuropathic pain were dysesthesias, evoked pain, paroxysmal pain, thermal pain, autonomic complaints, and descriptions of the pain as being sharp, hot, or cold, with high sensitivity. Higher scores for these symptoms correlated with greater clinician certainty of the presence of neuropathic pain mechanisms. Considering each individual patient's chronic pain as being somewhere on a continuum between "purely nociceptive" and "purely neuropathic" may have diagnostic and therapeutic relevance by enhancing specificity, but this requires clinical confirmation. Thus, symptom assessment remains indispensable in the evaluation of neuropathic pain, ancillary testing notwithstanding

Recent clinical advances in diabetic polyneuropathy.

PURPOSE OF REVIEW: Recent dramatic increases in the incidence and prevalence of diabetes make an understanding of chronic symmetric sensorimotor diabetic polyneuropathy, the most common and problematic of chronic diabetic complications, essential for a wide range of medical practitioners. RECENT FINDINGS: The demonstration of neuropathic dysfunction in patients with prediabetes or impaired glucose tolerance emphasizes the susceptibility of peripheral nerve fibers, especially small A delta fibers and C fibers, to relatively mild, short-duration hyperglycemia. New testing can reveal peripheral nerve dysfunction prior to clinical neuropathic symptoms and signs. In the absence of effective medications to halt or reverse nerve damage or promote nerve regeneration, early diagnosis of diabetic polyneuropathy, followed by tight glycemic control with diet and exercise, offers the best opportunity to prevent progressive symptoms of sensory loss, pain, autonomic dysfunction, ulcerations, and amputations. Some patients with impaired glucose tolerance have a reversal of neuropathic features with tight glycemic control. Nonpharmacologic therapies for neuropathic pain in diabetic polyneuropathy appear promising. SUMMARY: Tight glycemic control, especially early in diabetes, is the best approach to minimizing the prevalence and severity of diabetic polyneuropathy and makes research into the deleterious effects of even mild hyperglycemia imperative.

IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event.

BACKGROUND: The Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) showed that IM interferon beta-1a (IFNbeta-1a) significantly slows the rate of development of clinically definite multiple sclerosis (CDMS) over 2 years in high-risk patients who experience a first clinical demyelinating event. This report highlights the primary results of a 5-year, open-label extension of CHAMPS (the Controlled High Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance [CHAMPIONS Study]). OBJECTIVE: To determine if the benefits of IFNbeta-1a observed in CHAMPS are sustained for up to 5 years. METHODS: CHAMPS patients at participating CHAMPIONS sites were enrolled in the study. All patients were offered, but not required to take, IFNbeta-1a 30 microg IM once weekly for up to 5 years (from CHAMPS randomization). Patients who received placebo in CHAMPS were considered the delayed treatment (DT) group, and patients who received IFNbeta-1a in CHAMPS were considered the immediate treatment (IT) group. The primary outcome measure was the rate of development of CDMS. Additional outcomes included disease state classification at 5 years, annualized relapse rates, disability level at 5 years (Expanded Disability Status Scale), and MRI measures at 5 years. RESULTS: Fifty-three percent (203/383) of patients enrolled in CHAMPIONS (n = 100, IT group; n = 103, DT group) and 64% (32/50) of CHAMPS study sites participated in CHAMPIONS. The median time to initiation of IFNbeta-1a therapy in the DT group was 29 months. The cumulative probability of development of CDMS was significantly lower in the IT group compared with the DT group (5-year incidence 36 +/- 9 vs 49 +/- 10%; p = 0.03). Multivariate analysis suggested that the only factors independently associated with an increased rate of development of CDMS were randomization to the DT group and younger age at onset of neurologic symptoms. Few patients in either group developed major disability within 5 years. CONCLUSIONS: These results support the use of IM interferon beta-1a after a first clinical demyelinating event and indicate that there may be modest beneficial effects of immediate treatment compared with delayed initiation of treatment.

Peripheral neurophysiology of acute distal spinal cord infarction.

F-wave abnormalities, in the presence of normal distal motor nerve conduction, most often are the first indicators of proximal peripheral nerve dysfunction in demyelinating polyradiculoneuropathies. However, a 15-year-old female-who developed lumbosacral spinal cord infarction with paraplegia, sensory loss, and incontinence beginning 15 hours after a fall-studied electrophysiologically at 2 days postparaplegia manifested absent lower-extremity f-waves and H-reflexes and normal compound muscle action potentials and distal motor and sensory conduction velocities. Subsequent evaluations demonstrated permanent loss of compound muscle action potentials, f-waves, and H-reflexes and prominent acute denervation in paralyzed lower-extremity muscles. Thus early f-wave and H-reflex loss can also occur in spinal cord disease, thereby representing the first evidence of motoneuron destruction.

Treatment of sporadic hemiplegic migraine with calcium-channel blocker verapamil.

Gene mutations within the P/Q type neuronal calcium channel in familial hemiplegic migraine (FHM) suggest a therapeutic role for calcium-channel blockade. The authors have previously reported abortive therapy of FHM with IV verapamil. Here the authors describe four cases of sporadic hemiplegic migraine (SHM) responsive to verapamil, administered either orally or IV. The findings indicate that verapamil is effective therapy for both SHM and FHM.