Taylor Harrison

Early development of critical illness myopathy and neuropathy in patients with severe sepsis

Objectives: To characterize the prevalence, time of onset, and cause of neuromuscular dysfunction in patients with severe sepsis. Methods: We conducted a prospective cohort study in which participants with severe sepsis underwent weekly neurologic examinations and nerve conduction studies (NCSs) within 72 hours of developing severe sepsis until intensive care unit (ICU) discharge. Electromyography was preformed if clinical weakness developed or if there was a significant reduction in nerve conduction response amplitudes. Results: Abnormal NCS were present upon enrollment in 63% of patients (31/48). The presence of abnormal baseline NCS was predictive of hospital mortality (55% vs 0% for patients with normal baseline NCS; p < 0.001). Development of acquired neuromuscular dysfunction could be predicted by NCS done on day 7. Twenty patients remained in the ICU long enough to have serial NCSs; 50% of these patients developed acquired neuromuscular dysfunction. Most patients with acquired neuromuscular dysfunction had electrophysiologic evidence of both critical illness myopathy and critical illness neuropathy. Conclusion: Changes in nerve conduction studies occur in the majority of patients early in the course of severe sepsis and predict the development of acquired neuromuscular dysfunction and mortality in intensive care unit patients. Most patients with acquired neuromuscular dysfunction after sepsis have both critical illness myopathy and critical illness neuropathy.

A dangerous dilemma : management of infectious intracranial aneurysms complicating endocarditis

A 41-year-old right-handed man with bicuspid aortic valve and a 3-month history of chronic fever and weight loss presented with sudden onset of severe headache. Computerised tomography of the head revealed a right basal ganglia haemorrhage. Further investigation documented Streptococcus mitis bacteraemia, a fusiform right middle cerebral artery aneurysm, and an abscess at the base of the anterior leaflet of the mitral valve. The patient subsequently died when repeat aneurysmal haemorrhage resulted in cerebral herniation and brain death while on antibiotic therapy. Infectious intracranial aneurysms (IIAs) are uncommon but severe complications of bacterial endocarditis. Several case series have been published evaluating the management of IIAs, but no randomised controlled trials exist to guide treatment decisions. Improved diagnostic techniques, microvascular neurosurgical approaches, and endovascular therapies hold the promise of improved outcomes in the future. This difficult case is used to show an approach towards the management of IIAs complicating bacterial endocarditis based on a review of the published work.

HIV neuropathy in South Africans: Frequency, characteristics, and risk factors

The purpose was to estimate the frequency, characteristics, and risk factors of HIV‐associated distal sensory polyneuropathy (DSP) among South Africans who attend an urban community‐based clinic. In a cross‐sectional study, neuropathy status was determined in 598 HIV‐infected adults using validated tools (Brief Peripheral Neuropathy Screen and a modified version of the Total Neuropathy Score) to categorize subjects as DSP versus no DSP. Symptomatic DSP (SDSP) required the presence of at least two neuropathic signs together with symptoms. Clinical, anthropometric, and laboratory evaluations were prospectively performed. CD4 counts, antiretroviral therapy (ART), and questionnaires regarding previous tuberculosis (TB) and alcohol exposure were collected retrospectively. Approximately half (49%) of the study population were diagnosed with DSP, and 30% of the study population were diagnosed with SDSP. In multivariate analyses the odds ratio (OR) (95% confidence interval) of DSP were independently associated with ART use (OR 1.7, 1.0–2.9), age (per 10 year increment) (OR 1.7, 1.4–2.2), and prior TB (OR 2.0, 1.3–3.0). Pain or paresthesias were reported as moderately severe by 70% of those with SDSP. Stavudine use was significantly associated with DSP. DSP is a clinically significant problem in urban HIV‐infected Africans. Our findings raise the possibility that the incidence of DSP may be reduced with avoidance of stavudine‐containing regimens in older subjects, especially with a history of prior TB infection. Muscle Nerve, 2010

Mechanisms of Neuromuscular Dysfunction in Critical Illness

The development of neuromuscular dysfunction (NMD) during critical illness is increasingly recognized as a cause of failure to wean from mechanical ventilation and is associated with significant morbidity and mortality. At times, it is difficult to identify the presence of NMD and distinguish the etiology of the weakness in patients with critical illness, but subtle clinical findings and bedside electrophysiologic testing are helpful in establishing the diagnosis. This article describes the clinical spectrum of acquired neuromuscular weakness in the setting of critical illness, provides an approach to diagnosis, and discusses its pathogenesis. Finally, a defective sodium channel regulation as a unifying mechanism underlying NMD in critically ill patients is proposed.

Accuracy of repetitive nerve stimulation for diagnosis of the cramp-fasciculation syndrome.

The goal of this retrospective cohort study was to test the hypothesis that the cramp–fasciculation syndrome (CFS) represents a disorder of peripheral nerve hyperexcitability and to evaluate the accuracy of repetitive nerve stimulation (RNS) for its diagnosis. A consecutive series of 108 patients were evaluated with posterior tibial RNS at 1, 2, and 5 HZ. Abnormal peripheral nerve excitability was defined by the presence of afterdischarges, cramp potentials, or continuous motor unit activity. RNS demonstrated abnormal nerve hyperexcitability in 29 of 36 subjects (81%) with CFS, defined operationally by the presence of both muscle cramps and fasciculations. Based on receiver operating characteristic (ROC) curve analysis, tibial RNS correctly classified the presence or absence of CFS in 75% of subjects. These results suggest that CFS represents a form of peripheral nerve hyperexcitability and, furthermore, that RNS is a clinically useful test for CFS. Muscle Nerve, 2007

Experience and Challenges Presented by a Multicenter Crossover Study of Combination Analgesic Therapy for the Treatment of Painful HIV-Associated Polyneuropathies

OBJECTIVE There is limited evidence for efficacy of analgesics as monotherapy for neuropathic pain associated with HIV-associated polyneuropathies, in spite of demonstrated efficacy in other neuropathic pain conditions. We evaluated the tolerability and analgesic efficacy of duloxetine, methadone, and the combination of duloxetine-methadone compared with placebo. DESIGN This study was a phase II, randomized, double-blind, placebo-controlled, four-period crossover multicenter study of analgesic therapy for patients with at least moderate neuropathic pain due to HIV-associated polyneuropathy. Duloxetine, methadone, combination duloxetine-methadone, and placebo were administered in four different possible sequences. The primary outcome measure was mean pain intensity (MPI) measured daily in a study-supplied pain diary. RESULTS A total of 15 patients were enrolled from eight study sites and eight patients completed the entire trial. Study treatments failed to show statistically significant change in MPI compared with placebo. Adverse events were frequent and associated with high rates of drug discontinuation and study dropout. CONCLUSIONS Challenges with participant recruitment and poor retention precluded trial completion to its planned targets, limiting our evaluation of the analgesic efficacy of the study treatments. Challenges to successful completion of this study and lessons learned are discussed.

Mumps and rubella.

Abstract This chapter reviews the major neurologic manifestations associated with mumps and rubella infection. Both mumps and rubella demonstrate neurotropism and are associated with multiple central nervous system infectious as well as parainfectious syndromes. While infections are waning globally with the successful implementation of large-scale vaccination programs, these viruses remain important pathogens given inconsistent vaccination in some areas of the developing world, particularly so in politically unstable regions. The facility of international travel for unimmunized individuals continues to contribute to neurologic complications across the globe. Important elements of neuropathogenesis, disease epidemiology and natural history, and associated clinical syndromes of mumps and rubella infection are highlighted in this chapter.

Isoniazid exposure and pyridoxine levels in human immunodeficiency virus associated distal sensory neuropathy.

SETTING Distal sensory polyneuropathy (DSP) may manifest in human immunodeficiency virus (HIV) infected individuals before or after antiretroviral therapy (ART). DSP can also occur in response to isoniazid (INH); this can be prevented by pyridoxine supplementation. N-acetyltransferase 2 (NAT2) polymorphisms influence drug acetylation and possibly the risk for INH-associated DSP. OBJECTIVE To investigate the relationship between previous/current TB, pyridoxine deficiency and DSP in HIV-infected individuals enrolled in a government-sponsored HIV programme. DESIGN Neuropathy assessments were performed among 159 adults pre-ART and 12 and 24 weeks thereafter. DSP was defined as ⩾1 neuropathic symptom and sign. NAT2 genotypes predicted acetylation phenotype. Serum pyridoxine levels (PLP) were quantified at baseline and week 12. RESULTS DSP was present in 16% of individuals pre-ART and was associated with previous/current TB (P = 0.020). Over 50% were pyridoxine deficient (PLP < 25 nmol/l), despite supplementation with vitamin B complex supplements (2-4 mg/day pyridoxine). Those with a history of TB and pre-ART DSP were more likely to be pyridoxine deficient (P = 0.029), and slow/intermediate NAT2 phenotypes impacted on their PLP levels. Incident/worsening DSP after ART developed in 21% of the participants. PLP levels remained low after ART, particularly among those with prior TB, but without an association between DSP or NAT2 phenotypes. CONCLUSION Adequate pyridoxine supplementation before ART initiation should be prioritised, particularly in those with a history of TB or current TB.

Sensory polyneuropathy in human immunodeficiency virus-infected patients receiving tuberculosis treatment.

SETTING Human immunodeficiency virus (HIV) infection and treatments for HIV infection and tuberculosis (TB) are associated with the risk of developing sensory polyneuropathy (SPN). Vitamin B6 and genetically determined slow isoniazid (INH) acetylation are believed to play key roles in the development of SPN in a TB treatment setting. OBJECTIVE To investigate slow acetylation and risk factors for SPN in HIV-infected patients receiving TB treatment, and establish vitamin B6 status and its association with SPN. METHODS HIV-infected in-patients were prospectively assessed after initiating TB treatment and vitamin B6 supplementation, and monthly during hospitalisation. SPN was defined as ≥1 symptom plus ≥1 sign. NAT2 genotyping predicted acetylation status, and plasma high performance liquid chromatography estimated vitamin B6 status. A survival analysis estimated hazard ratios (HRs) for SPN during TB treatment. RESULTS Of 116 participants, 56% had SPN at study entry. Participants developed SPN at a rate of 26/100 person-months (95%CI 18-35) during TB treatment, which was independently associated with slow acetylation (HR 2.5; 95%CI 1.1-5.9), as well as black race, previous TB and extra-pulmonary/disseminated TB. Vitamin B6 status was normal, irrespective of SPN. CONCLUSIONS Risk factors for SPN suggest a multi-factorial pathogenesis related to INH and other potential nervous system insults. SPN developed despite normal vitamin B6 status, suggesting other mechanisms of injury.

Update of HIV-Associated Sensory Neuropathies

Purpose of reviewHIV-sensory neuropathy (HIV-SN) remains a common complication of HIV infection and may be associated with significant morbidity due to neuropathic pain. The overall purpose of this review is to discuss trends in the changing epidemiology in HIV-SN, new data regarding the pathophysiology of the condition, and discuss approaches to management.Recent findingsWhile HIV-SN has been historically considered the most common neurological complication of HIV infection, improved accessibility to effective combination antiretroviral therapy (cART), use of less neurotoxic antiretroviral medication regimens, and trends towards earlier introduction of treatment have impacted the condition: overall incident HIV-SN is likely decreased compared to prior rates and patients afflicted by HIV-SN may more frequently have asymptomatic or subclinical disease. Traditional predictors of HIV-SN have also changed, as traditional indices of severe immune deficiency such as low CD4 count and high viral load no longer predict HIV-SN. Emerging evidence supports the contention that both peripheral and central mechanisms underlying the generation as well as persistence of neuropathic pain in HIV-SN exist. It is important to recognize that even mild neuropathic pain in this clinical population is associated with meaningful impairment in quality of life and function, which emphasizes the clinical importance of recognizing and treating the condition. The general approach to management of neuropathic pain in HIV-SN is the introduction of symptomatic analgesic therapy. There exist, however, few evidence-based analgesic options for HIV-SN based on available clinical data. Symptomatic treatment trials are increasingly recognized to have been potentially confounded by more robust placebo response than that observed in other neuropathic pain conditions. In the authors’ experience, use of analgesic therapies with proven efficacy in other neuropathic pain conditions is appropriate, bearing in consideration potential pharmacokinetic interactions with the cART regimen. Combination analgesic regimens may also achieve meaningful analgesic responses, particularly when drugs with differing mechanisms of action are utilized. It is paramount that the patient is appropriately counseled regarding expectations and the anticipated benefit of analgesic therapy, as pain relief is often incomplete but clinically meaningful improvement in pain and function can be achieved.