Rachel Nardin

Norepinephrine Precursor Therapy in Neurogenic Orthostatic Hypotension

Background—In patients with neurogenic orthostatic hypotension (NOH), the availability of the sympathetic neurotransmitter norepinephrine (NE) in the synaptic cleft is insufficient to maintain blood pressure while in the standing posture. Methods and Results—We determined the effect of oral administration of the synthetic amino acid L-threo-3,4-dihydroxyphenylserine (L-DOPS), which is decarboxylated to NE by the enzyme L–aromatic amino acid decarboxylase (L-AADC) in neural and nonneural tissue, on blood pressure and orthostatic tolerance in 19 patients with severe NOH (8 with pure autonomic failure and 11 with multiple-system atrophy). A single-blind dose-titration study determined the most appropriate dose for each patient. Patients were then enrolled in a double-blind, placebo-controlled, crossover trial. L-DOPS significantly raised mean blood pressure both supine (from 101±4 to 141±5 mm Hg) and standing (from 60±4 to 100±6 mm Hg) for several hours and improved orthostatic tolerance in all patients. After L-DOPS, blood pressure increases were closely associated with increases in plasma NE levels. Oral administration of carbidopa, which inhibits L-AADC outside the blood-brain barrier, blunted both the increase in plasma NE and the pressor response to L-DOPS in all patients Conclusions—Acute administration of L-DOPS increases blood pressure and improves orthostatic tolerance in patients with NOH. The pressor effect results from conversion of L-DOPS to NE outside the central nervous system.

Infective Endocarditis in the U.S., 1998–2009: A Nationwide Study

Background Previous studies based on local case series estimated the annual incidence of endocarditis in the U.S. at about 4 per 100,000 population. Small-scale studies elsewhere have reported similar incidence rates. However, no nationally-representative population-based studies have verified these estimates. Methods and Findings Using the 1998–2009 Nationwide Inpatient Sample, which provides diagnoses from about 8 million U.S. hospitalizations annually, we examined endocarditis hospitalizations, bacteriology, co-morbidities, outcomes and costs. Hospital admissions for endocarditis rose from 25,511 in 1998 to 38, 976 in 2009 (12.7 per 100,000 population in 2009). The age-adjusted endocarditis admission rate increased 2.4% annually. The proportion of patients with intra-cardiac devices rose from 13.3% to 18.9%, while the share with drug use and/or HIV fell. Mortality remained stable at about 14.5%, as did cardiac valve replacement (9.6%). Other serious complications increased; 13.3% of patients in 2009 suffered a stroke or CNS infection, and 5.5% suffered myocardial infarction. Amongst cases with identified pathogens, Staphylococcus aureus was the most common, increasing from 37.6% in 1998 to 49.3% in 2009, 53.3% of which were MRSA. Streptococci were mentioned in 24.7% of cases, gram-negatives in 5.6% and Candida species in 1.0%. We detected no inflection in hospitalization rates after changes in prophylaxis recommendations in 2007. Mean age rose from 58.6 to 60.8 years; elderly patients suffered higher rates of myocardial infarction and death, but slightly lower rates of Staphylococcus aureus infections and neurologic complications. Our study relied on clinically diagnosed cases of endocarditis that may not meet strict criteria. Moreover, since some patients are discharged and readmitted during a single episode of endocarditis, our hospitalization figures probably slightly overstate the true incidence of this illness. Conclusions Endocarditis is more common in the U.S. than previously believed, and is steadily increasing. Preventive efforts should focus on device-associated and health-care-associated infections.

Mitochondrial dysfunction and neuromuscular disease

Mitochondrial diseases are a heterogeneous group of disorders with widely varying clinical features, due to defects in mitochondrial function. Involvement of both muscle and nerve is common in mitochondrial disease. In some cases, this involvement is subclinical or a minor part of a multisystem disorder, but myopathy and neuropathy are a major, often presenting, feature of a number of mitochondrial syndromes. In addition, mitochondrial dysfunction may play a role in a number of classic neuromuscular diseases. This article reviews the role of mitochondrial dysfunction in neuromuscular disease and discusses a rational approach to diagnosis and treatment of patients presenting with a neuromuscular syndrome due to mitochondrial disease.

A pilot randomized trial of oxandrolone in inclusion body myositis

BackgroundInclusion body myositis (IBM) remains without effective therapy. As anabolic steroids have myotrophic properties, the authors studied whether a synthetic androgen, oxandrolone, would have efficacy in IBM. MethodsA double-blind, placebo-controlled, crossover design was used. Patients received oxandrolone or placebo for 12 weeks followed by a minimum 2-month washout period, followed by 12 weeks of the alternative treatment. Maximal voluntary isometric contraction testing (MVICT), manual muscle testing (MMT), and functional performance testing were obtained before and after each treatment period, with the whole-body MVICT score as the primary outcome measure. ResultsOf 19 patients enrolled, 16 (14 men, 2 women; median age 68.5 years) had complete data for at least the first treatment period, with 13 completing the entire study. Whole-body MVICT improved by a median of 15.5 kg with drug and 4.1 kg with placebo (p = 0.06), whereas MMT demonstrated a median increase of 2.0 Medical Research Council points with drug and 0.9 point with placebo (p = 0.33). Upper-extremity MVICT demonstrated a significant treatment effect, with strength increasing a median 6.3 kg with drug vs 2.5 kg with placebo (p = 0.006). Stair climbing also increased a median of 1 step on average with drug versus no change with placebo (p < 0.001). Minimal adverse effects occurred. ConclusionsOxandrolone had a borderline significant effect in improving whole-body strength and a significant effect in improving upper-extremity strength as measured by MVICT. Given these findings, further study of this drug, possibly in combination with an immunomodulating agent, is warranted.

Evaluation and treatment of low back pain: an evidence-based approach to clinical care.

Low back pain is a common reason for patient visits to a health care provider. For most patients, low back symptoms are nonspecific, meaning that the pain is localized to the back or buttocks and is due to a presumed musculoligamentous process. For patients with radicular leg symptoms, a precise etiology is more commonly identified. The history and physical examination usually provide clues to the uncommon but potentially serious causes of low back pain, as well as to those patients at risk for prolonged recovery. Diagnostic testing should not be a routine part of the initial evaluation, but used selectively based upon the history, examination, and initial treatment response. For patients without significant neurological impairment, initial treatments should include activity modification, nonnarcotic analgesics, and education. For patients whose symptoms are not improving over 2 to 4 weeks, referral for physical treatments is appropriate. A variety of therapeutic options of limited or unproven benefit are available for patients with radicular leg symptoms or chronic low back pain. Patients with radicular pain and little or no neurological findings should receive conservative treatment, but elective surgery is appropriate for those with nerve root compression who are unresponsive to conservative therapy. Muscle Nerve 27: 265–284, 2003

Sural/radial amplitude ratio in the diagnosis of mild axonal polyneuropathy.

As proximal nerves are relatively spared in length‐dependent, axonal polyneuropathy, we theorized that a sural/radial amplitude ratio (SRAR) might be a sensitive indicator of mild polyneuropathy. In this study, sural amplitudes and SRARs in patients with signs of mild axonal polyneuropathy were compared to those of normal, age‐matched control subjects. Sural and radial sensory responses were measured in a standard fashion in all subjects. Thirty polyneuropathy patients had an average SRAR of 0.29 as compared to 0.71 for the 30 normal subjects. An SRAR of less than 0.40 was a strong predictor of axonal polyneuropathy, with 90% sensitivity and 90% specificity, as compared to an absolute sural amplitude of less than 6.0 μV, which had sensitivity of only 66%. Additionally, unlike the sural amplitude, the ratio did not vary significantly with age. We conclude that the SRAR is a sensitive, specific, age‐independent electrodiagnostic test for mild axonal polyneuropathy.

Fibrillations in lumbosacral paraspinal muscles of normal subjects

Although paraspinal muscle fibrillations and positive sharp waves (PSWs) are used to help identify neuromuscular disorders, the frequency of these abnormalities in normal subjects is uncertain. We performed lumbosacral paraspinal electromyography in 65 normal subjects. Twenty‐seven (42%) had fibrillations and/or PSWs, with the prevalence of these findings increasing with age (r = 0.830, P = 0.040). These data suggest isolated fibrillations and PSWs in lumbosacral paraspinal muscles, especially of older subjects, are nonspecific findings.

Sural and radial sensory responses in healthy adults: Diagnostic implications for polyneuropathy

We prospectively performed sural and radial sensory nerve conduction studies in 92 healthy subjects, aged between 21 and 88 years, both to determine the lower limits of normal (LLN) and to assess the effects of age and body mass index (BMI) on the sural and radial sensory nerve action potential (SNAP) amplitudes and on the sural/radial amplitude ratio (SRAR). Using the nonparametric bootstrap method to calculate 95% confidence intervals, we found that the 5% LLN values for sural and radial SNAPs were 14 μV and 25.5 μV in subjects aged ≤39 years, 7 μV and 17.4 μV in subjects aged 40–59 years, and 3 μV and 12 μV in subjects aged ≥60 years. The 5% LLN for SRAR for all patients was 0.21. Sural and radial SNAP amplitudes but not SRAR were strongly and inversely correlated with age and BMI. These age‐adjusted normal values and revised SRAR will aid in the electrodiagnosis of polyneuropathy. Muscle Nerve, 2005

Diagnostic accuracy of electrodiagnostic testing in the evaluation of weakness

Electrodiagnostic testing is often used in the evaluation of patients presenting with weakness, but the diagnostic accuracy of the test in this setting is unknown. We prospectively identified 100 patients presenting to our electromyography (EMG) laboratory with the chief complaint of weakness, and compared their referring diagnosis with the electrophysiological diagnosis reached after electrodiagnostic testing. We reviewed each patients medical record 9 months after EMG to yield a final diagnosis. Electrodiagnostic testing led to a single diagnosis in 79% of the cases; in 31%, this diagnosis was unsuspected by the referring clinician. Adequate follow‐up was available for 79% of the patients. The electrodiagnostic testing resulted in a single, correct diagnosis in 73% of the patients and provided more than one possible diagnosis, one of which was correct, in an additional 18%, for an overall diagnostic accuracy of 91% in this group of patients presenting with weakness.

Impaired Distal Thermoregulation in Diabetes and Diabetic Polyneuropathy

OBJECTIVE To determine how thermoregulation of the feet is affected by diabetes and diabetic polyneuropathy in both wakefulness and sleep. RESEARCH DESIGN AND METHODS Normal subjects, diabetic subjects without neuropathy, diabetic subjects with small-fiber diabetic polyneuropathy, and those with advanced diabetic polyneuropathy were categorized based on neurological examination, nerve conduction studies, and quantitative sensory testing. Subjects underwent foot temperature monitoring using an iButton device attached to the foot and a second iButton for recording of ambient temperature. Socks and footwear were standardized, and subjects maintained an activity diary. Data were collected over a 32-h period and analyzed. RESULTS A total of 39 normal subjects, 28 patients with diabetes but without diabetic polyneuropathy, 14 patients with isolated small-fiber diabetic polyneuropathy, and 27 patients with more advanced diabetic polyneuropathy participated. No consistent differences in foot temperature regulation between the four groups were identified during wakefulness. During sleep, however, multiple metrics revealed significant abnormalities in the diabetic patients. These included reduced mean foot temperature (P < 0.001), reduced maximal temperature (P < 0.001), increased rate of cooling (P < 0.001), as well as increased frequency of variation (P = 0.005), supporting that patients with diabetic polyneuropathy and even those with only diabetes but no diabetic polyneuropathy have impaired nocturnal thermoregulation. CONCLUSIONS Nocturnal foot thermoregulation is impaired in patients with diabetes and diabetic polyneuropathy. Because neurons are highly temperature sensitive and because foot warming is part of the normal biology of sleep onset and maintenance, these findings suggest new potentially treatable mechanisms of diabetes-associated nocturnal pain and sleep disturbance.