The Link Between Empty Sella Syndrome, Fibromyalgia, and Chronic Fatigue Syndrome: The Role of Increased Cerebrospinal Fluid Pressure.

The etiopathogenesis of fibromyalgia (FM) and chronic fatigue syndrome (CFS) is not yet elucidated. Hypothalamo-pituitary-adrenal (HPA) axis dysfunction is reflected in the hormonal disturbances found in FM and CFS. Some study groups have introduced a novel hypothesis that moderate or intermittent intracranial hypertension may be involved in the etiopathogenesis of FM and CFS. In these conditions, hormonal disturbances may be caused by the mechanical effect of increased cerebrospinal fluid pressure, which hampers blood flow in the pituitary gland. Severe intracranial pressure may compress the pituitary gland, resulting in primary empty sella (ES), potentially leading to pituitary hormone deficiencies. The aim of this narrative review was to explore whether similar hormonal changes and symptoms exist between primary ES and FM or CFS and to link them to cerebrospinal fluid pressure dysregulation. A thorough search of the PubMed and Web of Science databases and the reference lists of the included studies revealed that several clinical characteristics were more prevalent in primary ES, FM or CFS patients than in controls, including increased cerebrospinal fluid pressure, obesity, female sex, headaches and migraine, fatigue, visual disturbances (visual acuity and eye motility abnormalities), vestibulocochlear disturbances (vertigo and neurosensorial hearing loss), and bodily pain (radicular pain and small-fiber neuropathy). Furthermore, challenge tests of the pituitary gland showed similar abnormalities in all three conditions: blunted adrenocorticotropic hormone, cortisol, growth hormone, luteinizing hormone, and thyroid stimulating hormone responses and an increased prolactin response. The findings of this narrative review provide further support for the hypothesis that moderately or intermittently increased cerebrospinal fluid pressure is involved in the pathogenesis of FM and CFS and should stimulate further research into the etiopathogenesis of these conditions.

Large- and Small-Fiber Neuropathy in Patients with Tarlov Cysts.

PURPOSE: Tarlov cysts (TCs) are dilated nerve root sheaths originating from increased cerebrospinal pressure. Patients with TCs often complain of neuropathic pain and paresthesia. The aim of this study was to retrospectively review intraepidermal nerve fiber density (IENFD) and electrodiagnostic (EDX) data from TC patients. PATIENTS AND METHODS: Lower leg skin biopsy results and EDX data from the L2-S4 myotomes of patients with lumbar or sacral TCs ≥8 mm were retrieved from a database of a physical medicine clinic. Patients with compressive pathology, diabetes mellitus and chemotherapy were excluded. RESULTS: IENFD data from 17 patients and EDX data from 24 patients with TCs ≥8 mm were available. The mean age was 47 ± 10y, and 83% were women. In 82% of patients, the IENFD was below the 5th percentile by age and sex. EDX showed increased Hoffmann reflex latencies in 25%, increased anal reflex latencies in 95%, and a patchy distribution of neurogenic motor unit potentials in 100%. More than 50% of needle EMG abnormalities appeared in myotomes unrelated to the location of the TCs. CONCLUSION: Small- and/or large-fiber neuropathy was documented in a significant proportion of patients with TCs. The novel findings may add to the understanding of the mechanisms involved in symptomatic TCs. We propose that pathologically elevated cerebrospinal fluid pressure not only dilates some of the nerve root sheaths to form TCs but also potentially damages axons in nondilated nerve root sheaths and neurons in the dorsal root ganglia.

Limiting the fascia incision length in a DIEP flap: Repercussion on abdominal wall morbidity.

BACKGROUND: The evolution from free muscle-sparing transverse rectus abdominis myocutaneous flap to deep inferior epigastric perforator (DIEP) flap leads to less donor-site morbidity. However, rectus fascia is usually incised longitudinally from perforator(s) to iliac vessels, often exceeding 15 cm when including longitudinal muscle spreading. By using a limited fascia incisional (LFI-) technique, we try to diminish abdominal wall functional decrease. METHODS: Twenty-seven patients who underwent unilateral breast reconstructions using free DIEP-flap with limited fascia incision between December 2014 and October 2017 were included in the study. Each patient received a periumbilical electromyogram (EMG) preoperatively, at 6 and 14 weeks postoperatively. They were compared with 27 patients having unilateral breast reconstructions using classic free DIEP-flap, performed at the same department between November 2009 and May 2011. RESULTS: In our LFI-technique, one vertical (4 cm) incision is made where the pedicle exits the muscle. A second, oblique (3 cm) incision is made more distally where the pedicle runs into the iliac vessels. After release, the pedicle is tunneled through the incisions, leaving all fascia, and therefore muscle, intact. In the LFI-group small neurogenic changes were noticed in only 26% and 11% of the patients at, respectively, 6 and 14 weeks postoperatively. By contrast, in the control group, postoperative neurogenic deviations remained in 37% of the patients at 14 weeks postoperatively; significant different compared to the LFI-group. CONCLUSION: This study shows the importance of preserving anterior rectus fascia. Nerve supply and abdominal rectus muscle function are less endangered using small segmental fascia incisions. We believe that our technique diminishes donor-site morbidity significantly and improves the postoperative recovery.

High Prevalence of Perineural Cysts in Patients with Fibromyalgia and Chronic Fatigue Syndrome.

OBJECTIVE: Pain in fibromyalgia (FM) and chronic fatigue syndrome (CFS) is assumed to originate from central sensitization. Perineural cysts or Tarlov cysts (TCs) are nerve root dilations resulting from pathologically increased cerebrospinal fluid pressure. These cysts initially affect sensory neurons and axons in dorsal root ganglia and produce sensory symptoms (pain and paresthesia). Symptomatic TC (STC) patients often complain about widespread pain and fatigue. Consequently, STC patients may initially be diagnosed with FM, CFS, or both. The objective of this study was to document the prevalence of TCs in patients diagnosed with FM or CFS. DESIGN: A retrospective study. SETTING: An outpatient clinic for musculoskeletal disorders. SUBJECTS: Patients diagnosed with FM according to the 1990 American College of Rheumatology criteria or with CFS according to the 1994 Centers for Disease Control criteria were selected. METHODS: Review of lumbar and sacral magnetic resonance imaging scans including TCs ≥5 mm in size. RESULTS: In total, 197 patients with FM, CFS, or both underwent magnetic resonance imaging. Ninety-one percent were women. The mean age was 48.1 (±11.9) years. TCs were observed in 39% of patients, with a mean size of 11.8 (±5.2) mm. In males, the prevalence was 12%, vs. 42% in females. CONCLUSIONS: In patients diagnosed with FM or CFS, the prevalence of TCs was three times higher than that in the general population. This observation supports the hypothesis that STCs, FM, and CFS may share the same pathophysiological mechanism, i.e., moderately increased cerebrospinal fluid pressure, causing irritation of neurons and axons in dorsal root ganglia.

Electrodiagnostic Abnormalities Associated with Fibromyalgia.

PURPOSE: Increasing evidence suggests that fibromyalgia most likely represents a neurological dysfunction. We previously hypothesized that at least some fibromyalgia cases may be caused by irritation of nerve root fibers and sensory neurons due to moderately increased cerebrospinal pressure. Because of the rostro-caudal hydrostatic pressure gradient, neurogenic abnormalities are expected to be most pronounced in sacral nerve roots. The purpose was to review electrodiagnostic tests of patients with fibromyalgia. METHODS: A retrospective review of electrodiagnostic test results, including the lumbar and sacral nerve root myotomes of patients diagnosed with fibromyalgia according to the 1990 criteria of the American College of Rheumatology was done. RESULTS: All 17 patients were female. Sural nerve responses could not be elicited in 12% and S1-Hoffmann reflex latencies were increased in 41%. In 12% of the patients, fibular motor nerve distal latency and conduction velocity were outside normal limits. Needle-EMG revealed neurogenic motor unit potentials in 0% of L2, 6% of L3, 29% of L4, 71% of L5, 47% of S1, 94% of S2, and 76% of S3-S4 myotomes. S3-S4 nerve-supplied anal reflexes were delayed in 94%. CONCLUSION: This is the first time that electrodiagnostic data of both lumbar and sacral nerve root myotomes in fibromyalgia patients are presented. All patients showed neurogenic abnormalities that were more pronounced in the sacral than in the lumbar myotomes with a rather patchy distribution pattern. We propose that, in addition to skin punch biopsies to assess small fiber neuropathy, assessment of the anal reflex may be a useful part of the diagnostic pathway in patients with fibromyalgia.

Five-year impact of ICU-acquired neuromuscular complications: a prospective, observational study.

PURPOSE: To assess the independent association between ICU-acquired neuromuscular complications and 5-year mortality and morbidity. To explore the optimal threshold of the Medical Research Council (MRC) sum score, assessing weakness, for the prediction of 5-year outcomes. METHODS: Sub-analyses of a prospective, 5-year follow-up study including 883 EPaNIC patients (Early versus Late Parenteral Nutrition in Intensive Care) (Clinicaltrials.gov:NCT00512122), systematically screened in ICU for neuromuscular complications with MRC sum score ('MRC-cohort', N = 600), electrophysiology on day 8 ± 1 to quantify compound muscle action potential ('CMAP-cohort', N = 689), or both ('MRC&CMAP-cohort', N = 415). Associations between ICU-acquired neuromuscular complications and 5-year mortality, hand-grip strength (HGF, %predicted), 6-min-walk distance (6-MWD, %predicted) and physical function of the SF-36 quality-of-life questionnaire (PF-SF-36) at 5-years were assessed with Cox regression and linear regression, adjusted for confounders. The optimal threshold for MRC at ICU discharge to predict 5-year outcomes was determined by martingale residual plots (survival) and scatterplots (morbidity). RESULTS: Both lower MRC sum score at ICU discharge, indicating less strength [HR, per-point-increase: 0.946 (95% CI 0.928-0.968), p = 0.001], and abnormal CMAP, indicating nerve/muscle dysfunction [HR: 1.568 (95% CI 1.165-2.186), p = 0.004], independently associated with increased 5-year mortality. In the MRC&CMAP-cohort, MRC [HR: 0.956 (95% CI 0.934-0.980), p = 0.001] but not CMAP [HR: 1.478 (95% CI 0.875-2.838), p = 0.088] independently associated with 5-year mortality. Among 205 survivors, low MRC independently associated with low HGF [0.866 (95% CI 0.237-1.527), p = 0.004], low 6-MWD [105.1 (95% CI 12.1-212.9), p = 0.043] and low PF-SF-36 [- 0.119 (95% CI - 0.186 to - 0.057), p = 0.002], whereas abnormal CMAP did not correlate with these morbidity endpoints. Exploratory analyses suggested that MRC ≤ 55 best predicted poor long-term morbidity and mortality. Both MRC ≤ 55 and abnormal CMAP independently associated with 5-year mortality. CONCLUSIONS: ICU-acquired neuromuscular complications may impact 5-year morbidity and mortality. MRC sum score, even if slightly reduced, may affect long-term mortality, strength, functional capacity and physical function, whereas abnormal CMAP only related to long-term mortality.

Hydrocephalus associated with multiple Tarlov cysts.

Tarlov cysts (TCs) consist of dilated nerve root sheaths filled with cerebrospinal fluid (CSF) and are most frequently found in the sacrum. It is estimated that 25% of detected TCs cause chronic pain and intestinal and urogenital symptoms due to compression of the sacral nerve root fibers inside the TC. Unfortunately, symptomatic TCs are frequently overlooked. It is assumed that TCs result from pathologically increased hydrostatic pressure (HP) in the dural sac that forces CSF into the nerve root sheaths. We hypothesize that in patients with TCs, increased spinal hydrostatic pressure is always associated with increased intracranial pressure. This hypothesis of increased cerebrospinal pressure might explain why patients with sacral TCs frequently report distant symptoms, such as headaches and pain in the neck and arms. In this paper, we describe a case report that provides evidence for this hypothesis. A 30-year-old man presented for the first time in our clinic complaining of lower back, leg, thoracic, neck, and arm pain; headaches; and bladder, bowel, and sphincter symptoms. He was born prematurely and suffered cerebral intraventricular bleeding followed by progressive hydrocephalus. Progression was stabilized with acetazolamide and lumbar punctures. At 19 years of age, his head circumference had further increased and he reported back pain and headaches. Fundoscopy showed no papilledema, and lumbar puncture for CSF evacuation improved the headaches and back pain. The former medical team chose not to insert a ventriculo-external shunt. Brain magnetic resonance imaging (MRI) showed significant dilation of all the ventricles. No CSF flow obstruction between the ventricles was observed. Surprisingly, MRI of the lumbar and sacral spine showed multiple large TCs. This case report indicates that hydrocephalus with a patent aqueduct may be associated with TCs because the increased intracranial pressure is transferred to the spinal canal. While increased intracranial pressure causes dilation of the ventricles, the associated increased spinal pressure may cause dilation of multiple spinal nerve root sheaths to form TCs. Furthermore, while the increased volume of the ventricles gradually compresses the neurons and axons of the brain against the bony skull, simultaneously, the increased pressure inside the nerve sheaths may also gradually compress the neurons and axons located inside the dorsal root ganglia and spinal nerves, resulting in neuropathic pain, sensory abnormalities, and neurogenic bladder and bowel symptoms. Hydrocephalus patients reporting neuropathic pain should be screened for the presence of TCs.

Symptomatic Tarlov cysts are often overlooked: ten reasons why-a narrative review.

PURPOSE: Tarlov cysts (TCs) are dilations of nerve roots arising from pathologically increased hydrostatic pressure (HP) in the spinal canal. There is much controversy regarding whether these cysts are a rare source of pain or often produce symptoms. The aim of this review was to identify the reasons that symptomatic TCs (STCs) are easily overlooked. METHODS: The literature was searched for data regarding pathogenesis and symptomatology. RESULTS: TCs may be overlooked for the following reasons: (1) STCs are considered clinically irrelevant findings; (2) it is assumed that it is clinically difficult to ascertain that TCs are the cause of pain; (3) MRI or electromyography studies only focus on the L1 to S1 nerves; (4) TCs are usually not reported by radiologists; (5) degenerative alterations of the lumbosacral spine are almost always identified as the cause of a patient's pain; (6) it is not generally known that small TCs can be symptomatic; (7) examinations and treatments usually focus on the cysts as an underlying mechanism; however, essentially, increased HP is the main underlying mechanism for producing symptoms. Consequently, STCs may relapse after surgery; (8) bladder, bowel and sphincter dysfunction are not inquired about during history taking. (9) Unexplained pain is often attributed to depression, whereas depression is more likely the consequence of debilitating neuropathic pain. (10) The recognition of STCs is subject to gender bias, confirmation bias and cognitive dissonance and unconscious bias in publishing. CONCLUSION: There are several reasons STCs are underdiagnosed, mostly due to persistent misconceptions and biases. These slides can be retrieved under Electronic Supplementary Material.

The link between idiopathic intracranial hypertension, fibromyalgia, and chronic fatigue syndrome: exploration of a shared pathophysiology.

PURPOSE: Idiopathic intracranial hypertension (IICH) is a condition characterized by raised intracranial pressure (ICP), and its diagnosis is established when the opening pressure measured during a lumbar puncture is elevated >20 cm H2O in nonobese patients or >25 cm H2O in obese patients. Papilledema is caused by forced filling of the optic nerve sheath with cerebrospinal fluid (CSF). Other common but underappreciated symptoms of IICH are neck pain, back pain, and radicular pain in the arms and legs resulting from associated increased spinal pressure and forced filling of the spinal nerves with CSF. Widespread pain and also several other characteristics of IICH share notable similarities with characteristics of fibromyalgia (FM) and chronic fatigue syndrome (CFS), two overlapping chronic pain conditions. The aim of this review was to compare literature data regarding the characteristics of IICH, FM, and CFS and to link the shared data to an apparent underlying physiopathology, that is, increased ICP. METHODS: Data in the literature regarding these three conditions were compared and linked to the hypothesis of the shared underlying physiopathology of increased cerebrospinal pressure. RESULTS: The shared characteristics of IICH, FM, and CFS that can be caused by increased ICP include headaches, fatigue, cognitive impairment, loss of gray matter, involvement of cranial nerves, and overload of the lymphatic olfactory pathway. Increased pressure in the spinal canal and in peripheral nerve root sheaths causes widespread pain, weakness in the arms and legs, walking difficulties (ataxia), and bladder, bowel, and sphincter symptoms. Additionally, IICH, FM, and CFS are frequently associated with sympathetic overactivity symptoms and obesity. These conditions share a strong female predominance and are frequently associated with Ehlers-Danlos syndrome. CONCLUSION: IICH, FM, and CFS share a large variety of symptoms that might all be explained by the same pathophysiology of increased cerebrospinal pressure.

Can patients with symptomatic Tarlov cysts be differentiated from patients with specific low back pain based on comprehensive history taking?

BACKGROUND: Tarlov cysts (TCs) are expanded nerve root sheaths that occur near the dorsal root ganglion and result from increased intraspinal hydrostatic pressure. TCs most frequently affect the lumbosacral plexus and therefore may cause specific symptoms such as perineal pain and neurogenic bladder, bowel, and sphincter problems. It has been estimated that 1% of the population has symptomatic Tarlov cysts (STCs). However, STCs appear to be underdiagnosed, with the pain reported by patients commonly attributed to degenerative alterations seen on MRI. The aim of the present study is to investigate the utility of a comprehensive questionnaire for use by physicians in establishing the diagnosis of STCs. METHODS: We compared questionnaire responses regarding patient history between 33 patients diagnosed with symptomatic TCs and 42 patients with chronic low back pain and sciatica due to disc problems or degenerative or inflammatory disorders. The diagnosis of STCs was confirmed using nerve conduction studies (NCS) and electromyography (EMG) of the sacral myotomes by an expert neurophysiologist. RESULTS: The questionnaire responses revealed specific differences in perineal symptoms (perineal pain, dyspareunia, coccygodynia), bowel symptoms (constipation, diarrhea), bladder symptoms (hesitation, retention, frequency), and anal sphincter problems (anal pain, mild fecal incontinence). Additionally, sitting, walking, and straining aggravated pain more frequently in STC patients, and STC patients were more often forced to stop working and/or reduce their social activities. CONCLUSIONS: Including the above-listed items in the patient history might facilitate differentiation of low back pain and sciatica due to STCs from that due to disc problems or degenerative or inflammatory disorders.

Autonomic components of Complex Regional Pain Syndrome (CRPS) are favourably affected by Electrical Twitch-Obtaining Intramuscular Stimulation (ETOIMS): effects on blood pressure and heart rate.

INTRODUCTION: Favourable pain relief results on evoking autonomous twitches at myofascial trigger points with Electrical Twitch Obtaining Intramuscular Stimulation (ETOIMS). AIM: To document autonomic nervous system (ANS) dysfunction in Complex Regional Pain Syndrome (CRPS) from blood pressure (BP) and pulse/heart rate changes with ETOIMS. METHODS AND MATERIALS: A patient with persistent pain regularly received serial ETOIMS sessions of 60, 90, 120 or ≥150 min over 24 months. Outcome measures include BP: systolic, diastolic, pulse pressure and pulse/heart rate, pre-session/immediate-post-session summed differences (SDPPP index), and pain reduction. His results were compared with that of two other patients and one normal control. Each individual represented the following maximal elicitable twitch forces (TWF) graded 1-5: maximum TWF2: control subject; maximum TWF3: CRPS patient with suspected ANS dysfunction; and maximum TWF4 and TWF5: two patients with respective slow-fatigue and fast-fatigue twitches who during ETOIMS had autonomous twitching at local and remote myotomes simultaneously from denervation supersensitivity. ETOIMS results between TWFs were compared using one-way analysis of variance test. RESULTS: The patients showed immediate significant pain reduction, BP and pulse/heart rate changes/reduction(s) except for diastolic BP in the TWF5 patient. TWF2 control subject had diastolic BP reduction with ETOIMS but not with rest. Linear regression showed TWF grade to be the most significant variable in pain reduction, more so than the number of treatments, session duration and treatment interval. TWF grade was the most important variable in significantly reducing outcome measures, especially pulse/heart rate. Unlike others, the TWF3 patient had distinctive reductions in SDPPP index. CONCLUSIONS: Measuring BP and pulse/heart rate is clinically practical for alerting ANS dysfunction maintained CRPS. SDPPP index (≥26) and pulse/heart rate (≥8) reductions with almost every ETOIMS treatment, plus inability to evoke autonomous twitches due to pain-induced muscle hypertonicity, are pathognomonic of this problem.

Electromyographic Abnormalities Associated with Symptomatic Sacral Tarlov Cysts.

Tarlov or perineural cysts (TC) are commonly overlooked as a cause of sacral and ischial pain, and urogenital and bowel problems. TC can be seen on MRI, but are often considered asymptomatic. This is especially true for smaller cysts. Moreover, there are only few diagnostic characteristics that can be used to confirm that the cysts are the cause of the symptoms. As a consequence, a lot of controversy remains regarding the clinical importance of TC. Because of this underdiagnosed condition, patients often suffer for several years from unrecognized chronic neuropathic pain and neurological conditions. In this article, case reports of three patients with giant and smaller symptomatic sacral cysts are presented, in which electromyographic testing was performed to demonstrate nerve damage. We suggest that electromyography of the sacral nerve roots can be a reasonable tool for the diagnosis of symptomatic TC, as well as for the differentiation from other pathological entities causing sacral and ischial pain. Moreover, using electromyography it was also documented that smaller cysts of < 1 cm can cause nerve damage. Therefore incidence of symptomatic TC may be higher than initially thought.

Inflammatory Neuropathy of the Lumbosacral Plexus following Periacetabular Osteotomy.

Introduction. During periacetabular osteotomy (PAO), the sciatic, femoral, and obturator nerves are at risk. Most frequently nerve lesions can be attributed to a mechanical cause; however, in the absence of a clear mechanical cause surgeons are faced with a diagnostic problem and in many cases no diagnosis will be established. We report a case of inflammatory neuropathy of the lumbosacral plexus following a PAO. Case Presentation. A 31-year-old female developed weakness of ankle and knee flexion and extension 6 months after a PAO. Electrophysiological studies revealed damage to the obturator, femoral, and sciatic nerve consistent with an inflammatory lumbosacral plexopathy. MRI of the lumbosacral plexus was normal. The patient was treated with multimodal pain therapy and prolonged physiotherapy; nevertheless, symptoms worsened over time. At 2-year follow-up, there were no signs of recovery. Discussion. Inflammatory neuropathy of the lumbosacral plexus is a potential cause of pain and weakness after ipsilateral orthopaedic procedures. It should be distinguished from more frequently encountered mechanical causes of postsurgical neuropathy based on clinical suspicion, electrophysiological studies, MRI, and nerve biopsy. It is important that the orthopaedic community is aware of this complication since there is some evidence that early recognition and initiation of immunosuppressive therapy can lead to improved clinical outcome.

Predictive value for weakness and 1-year mortality of screening electrophysiology tests in the ICU.

PURPOSE: Muscle weakness in long-stay ICU patients contributes to 1-year mortality. Whether electrophysiological screening is an alternative diagnostic tool in unconscious/uncooperative patients remains unknown. We aimed to determine the diagnostic properties of abnormal compound muscle action potential (CMAP), sensory nerve action potential (SNAP), and spontaneous electrical activity (SEA) for Medical Research Council (MRC)-defined weakness and their predictive value for 1-year mortality. METHODS: Data were prospectively collected during the EPaNIC trial (ClinicalTrials.gov: NCT00512122). First, sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of abnormal CMAP, SNAP, and SEA for weakness were determined. Subsequently, association between 1-year mortality and abnormal findings on electrophysiological screening was assessed by univariate and multivariate analyses correcting for weakness and other risk factors and the prediction model involved only a development phase. RESULTS: A total of 730 patients were electrophysiologically screened of whom 432 were tested for weakness. On day 8, normal CMAP excluded weakness with a high NPV (80.5 %). By day 15, abnormal SNAP and the presence of SEA had a high PPV (91.7 and 80.0 %, respectively). Only a reduced CMAP on day 8 was associated with higher 1-year mortality [35.6 vs 15.2 % (p < 0.001)]. This association remained significant after correction for weakness and other risk factors [OR 2.463 (95 % CI 1.113-5.452), p = 0.026]. Also among conscious/cooperative patients without weakness, reduced CMAP was independently associated with a higher likelihood of death occurring during 1 year [HR 2.818 (95 % CI 1.074-7.391), p = 0.035]. CONCLUSIONS: The diagnostic properties of electrophysiological screening vary over time. Abnormal CMAP documented early during critical illness carries information about longer-term outcome, which should be further investigated mechanistically.

Feasibility of neuromuscular electrical stimulation in critically ill patients.

OBJECTIVE: Critically ill patients often develop intensive care unit-acquired weakness. Reduction in muscle mass and muscle strength occurs early after admission to the intensive care unit (ICU). Although early active muscle training could attenuate this intensive care unit-acquired weakness, in the early phase of critical illness, a large proportion of patients are unable to participate in any active mobilization. Neuromuscular electrical stimulation (NMES) could be an alternative strategy for muscle training. The aim of this study was to investigate the safety and feasibility of NMES in critically ill patients. DESIGN: This is an observational study. SETTING: The setting is in the medical and surgical ICUs of a tertiary referral university hospital. PATIENTS: Fifty patients with a prognosticated prolonged stay of at least 6 days were included on day 3 to 5 of their ICU stay. Patients with preexisting neuromuscular disorders and patients with musculoskeletal conditions limiting quadriceps contraction were excluded. INTERVENTION: Twenty-five minutes of simultaneous bilateral NMES of the quadriceps femoris muscle. This intervention was performed 5 days per week (Monday-Friday). Effective muscle stimulation was defined as a palpable and visible contraction (partial or full muscle bulk). MEASUREMENTS: The following parameters, potentially affecting contraction upon NMES, were assessed: functional status before admission to the ICU (Barthel index), type and severity of illness (Acute Physiology And Chronic Health Evaluation II score and sepsis), treatments possibly influencing the muscle contraction (corticosteroids, vasopressors, inotropes, aminoglycosides, and neuromuscular blocking agents), level of consciousness (Glasgow Coma Scale, score on 5 standardized questions evaluating awakening, and sedation agitation scale), characteristics of stimulation (intensity of the NMES, number of sessions per patient, and edema), and neuromuscular electrophysiologic characteristics. Changes in heart rate, blood pressure, oxygen saturation, respiratory rate, and skin reactions were registered to assess the safety of the technique. RESULTS: In 50% of the patients, an adequate quadriceps contraction was obtained in at least 75% of the NMES sessions. Univariate analysis showed that lower limb edema (P<.001), sepsis (P=.008), admission to the medical ICU (P=.041), and treatment with vasopressors (P=.011) were associated with impaired quadriceps contraction. A backward multivariate analysis identified presence of sepsis, lower limb edema, and use of vasopressors as independent predictors of impaired quadriceps contraction (R2=59.5%). Patients responded better to NMES in the beginning of their ICU stay in comparison with after 1 week of ICU stay. There was no change in any of the safety end points with NMES. CONCLUSIONS: Critically ill patients having sepsis, edema, or receiving vasopressors were less likely to respond to NMES with an adequate quadriceps contraction. Neuromuscular electrical stimulation is a safe intervention to be administered in the ICU.

Interventions for preventing critical illness polyneuropathy and critical illness myopathy.

BACKGROUND: Critical illness polyneuropathy or myopathy (CIP/CIM) is a frequent complication in the intensive care unit (ICU) and is associated with prolonged mechanical ventilation, longer ICU stay and increased mortality. This is an interim update of a review first published in 2009 (Hermans 2009). It has been updated to October 2011, with further potentially eligible studies from a December 2013 search characterised as awaiting assessment. OBJECTIVES: To systematically review the evidence from RCTs concerning the ability of any intervention to reduce the incidence of CIP or CIM in critically ill individuals. SEARCH METHODS: On 4 October 2011, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, and EMBASE. We checked the bibliographies of identified trials and contacted trial authors and experts in the field. We carried out an additional search of these databases on 6 December 2013 to identify recent studies. SELECTION CRITERIA: All randomised controlled trials (RCTs), examining the effect of any intervention on the incidence of CIP/CIM in people admitted to adult medical or surgical ICUs. The primary outcome was the incidence of CIP/CIM in ICU, based on electrophysiological or clinical examination. Secondary outcomes included duration of mechanical ventilation, duration of ICU stay, death at 30 and 180 days after ICU admission and serious adverse events from the treatment regimens. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data and assessed the risk of bias in included studies. MAIN RESULTS: We identified five trials that met our inclusion criteria. Two trials compared intensive insulin therapy (IIT) to conventional insulin therapy (CIT). IIT significantly reduced CIP/CIM in the screened (n = 825; risk ratio (RR) 0.65, 95% confidence interval (CI) 0.55 to 0.77) and total (n = 2748; RR 0.70, 95% CI 0.60 to 0.82) population randomised. IIT reduced duration of mechanical ventilation, ICU stay and 180-day mortality, but not 30-day mortality compared with CIT. Hypoglycaemia increased with IIT but did not cause early deaths.One trial compared corticosteroids with placebo (n = 180). The trial found no effect of treatment on CIP/CIM (RR 1.27, 95% CI 0.77 to 2.08), 180-day mortality, new infections, glycaemia at day seven, or episodes of pneumonia, but did show a reduction of new shock events.In the fourth trial, early physical therapy reduced CIP/CIM in 82/104 evaluable participants in ICU (RR 0.62. 95% CI 0.39 to 0.96). Statistical significance was lost when we performed a full intention-to-treat analysis (RR 0.81, 95% CI 0.60 to 1.08). Duration of mechanical ventilation but not ICU stay was significantly shorter in the intervention group. Hospital mortality was not affected but 30- and 180-day mortality results were not available. No adverse effects were noticed.The last trial found a reduced incidence of CIP/CIM in 52 evaluable participants out of a total of 140 who were randomised to electrical muscle stimulation (EMS) versus no stimulation (RR 0.32, 95% CI 0.10 to 1.01). These data were prone to bias due to imbalances between treatment groups in this subgroup of participants. After we imputed missing data and performed an intention-to-treat analysis, there was still no significant effect (RR 0.94, 95% CI 0.78 to 1.15). The investigators found no effect on duration of mechanical ventilation and noted no difference in ICU mortality, but did not report 30- and 180-day mortality.We updated the searches in December 2013 and identified nine potentially eligible studies that will be assessed for inclusion in the next update of the review. AUTHORS' CONCLUSIONS: There is moderate quality evidence from two large trials that intensive insulin therapy reduces CIP/CIM, and high quality evidence that it reduces duration of mechanical ventilation, ICU stay and 180-day mortality, at the expense of hypoglycaemia. Consequences and prevention of hypoglycaemia need further study. There is moderate quality evidence which suggests no effect of corticosteroids on CIP/CIM and high quality evidence that steroids do not affect secondary outcomes, except for fewer new shock episodes. Moderate quality evidence suggests a potential benefit of early rehabilitation on CIP/CIM which is accompanied by a shorter duration of mechanical ventilation but without an effect on ICU stay. Very low quality evidence suggests no effect of EMS, although data are prone to bias. Strict diagnostic criteria for CIP/CIM are urgently needed for research purposes. Large RCTs need to be conducted to further explore the role of early rehabilitation and EMS and to develop new preventive strategies.

How does brain activation differ in children with unilateral cerebral palsy compared to typically developing children, during active and passive movements, and tactile stimulation? An fMRI study.

The aim of the functional magnetic resonance imaging (fMRI) study was to investigate brain activation associated with active and passive movements, and tactile stimulation in 17 children with right-sided unilateral cerebral palsy (CP), compared to 19 typically developing children (TD). The active movements consisted of repetitive opening and closing of the hand. For passive movements, an MRI-compatible robot moved the finger up and down. Tactile stimulation was provided by manually stroking the dorsal surface of the hand with a sponge cotton cloth. In both groups, contralateral primary sensorimotor cortex activation (SM1) was seen for all tasks, as well as additional contralateral primary somatosensory cortex (S1) activation for passive movements. Ipsilateral cerebellar activity was observed in TD children during all tasks, but only during active movements in CP children. Of interest was additional ipsilateral SM1 recruitment in CP during active movements as well as ipsilateral S1 activation during passive movements and tactile stimulation. Another interesting new finding was the contralateral cerebellum activation in both groups during different tasks, also in cerebellar areas not primarily linked to the sensorimotor network. Active movements elicited significantly more brain activation in CP compared to TD children. In both groups, active movements displayed significantly more brain activation compared to passive movements and tactile stimulation.

Muscle atrophy and preferential loss of myosin in prolonged critically ill patients.

OBJECTIVE: Muscle weakness contributes to prolonged rehabilitation and adverse outcome of critically ill patients. Distinction between a neurogenic and/or myogenic underlying problem is difficult using routine diagnostic tools. Preferential loss of myosin has been suggested to point to a myogenic component. We evaluated markers of muscle atrophy and denervation, and the myosin/actin ratio in limb and abdominal wall skeletal muscle of prolonged critically ill patients and matched controls in relation to insulin therapy and known risk factors for intensive care unit-acquired weakness. DESIGN: Secondary analysis of two large, prospective, single-center randomized clinical studies. SETTING: University hospital surgical and medical intensive care unit. PATIENTS: Critically ill patients and matched controls. INTERVENTIONS: Intensive care unit patients had been randomized to blood glucose control to 80-110 mg/dL with insulin infusion or conventional glucose management, where insulin was only administered when glucose levels rose above 215 mg/dL. MEASUREMENTS AND MAIN RESULTS: As compared with controls, rectus abdominis and vastus lateralis muscle of critically ill patients showed smaller myofiber size, decreased mRNA levels for myofibrillar proteins, increased proteolytic enzyme activities, and a lower myosin/actin ratio, virtually irrespective of insulin therapy. Increased forkhead box O1 action may have played a role. Most alterations were more severe in patients treated with corticosteroids. Duration of corticosteroid treatment, independent of duration of intensive care unit stay or other risk factors, was a dominant risk factor for a low myosin/actin ratio. The immature acetylcholine receptor subunit γ messenger RNA expression was elevated in vastus lateralis, independent of the myosin/actin ratio. CONCLUSIONS: Both limb and abdominal wall skeletal muscles of prolonged critically ill patients showed downregulation of protein synthesis at the gene expression level as well as increased proteolysis. This affected myosin to a greater extent than actin, resulting in a decreased myosin/actin ratio. Muscle atrophy was not ameliorated by intensive insulin therapy, but possibly aggravated by corticosteroids.