The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill.

Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca(2+) dysregulation is present through altered Ca(2+) homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models.

Mice lacking the myotonic dystrophy protein kinase develop a late onset progressive myopathy.

Myotonic dystrophy (DM) is an autosomal dominant disorder resulting from the expansion of a CTG repeat in the 3' untranslated region of a putative protein kinase (DMPK). To elucidate the role of DMPK in DM pathogenesis we have developed Dmpk deficient (Dmpk-/-) mice. Dmpk-/-mice develop a late-onset, progressive skeletal myopathy that shares some pathological features with DM. Muscles from mature mice show variation in fibre size, increased fibre degeneration and fibrosis. Adult Dmpk-/-mice show ultrastructural changes in muscle and a 50% decrease in force generation compared to young mice. Our results indicate that DMPK may be necessary for the maintenance of skeletal muscle structure and function and suggest that a decrease in DMPK levels may contribute to DM pathology.

The MuSK-BMP pathway regulates synaptic Nav1.4 localization and muscle excitability.

The neuromuscular junction (NMJ) is the linchpin of nerve-evoked muscle contraction. Broadly considered, the function of the NMJ is to transduce a nerve action potential into a muscle fiber action potential (MFAP). Efficient information transfer requires both cholinergic signaling, responsible for the generation of endplate potentials (EPPs), and excitation, the activation of postsynaptic voltage-gated sodium channels (Nav1.4) to trigger MFAPs. In contrast to the cholinergic apparatus, the signaling pathways that organize Nav1.4 and muscle fiber excitability are poorly characterized. Muscle-specific kinase (MuSK), in addition to its Ig1 domain-dependent role as an agrin-LRP4 receptor, is also a BMP co-receptor that binds BMPs via its Ig3 domain and shapes BMP-induced signaling and transcriptional output. Here we probed the function of the MuSK-BMP pathway at the NMJ using mice lacking the MuSK Ig3 domain ('ΔIg3-MuSK'). Synapses formed normally in ΔIg3-MuSK animals, but the postsynaptic apparatus was fragmented from the first weeks of life. Anatomical denervation was not observed at any age examined. Moreover, spontaneous and nerve-evoked acetylcholine release, AChR density, and endplate currents were comparable to WT. However, trains of nerve-evoked MFAPs in ΔIg3-MuSK muscle were abnormal as revealed by increased jitter and blocking in single fiber electromyography. Further, nerve-evoked compound muscle action potentials (CMAPs), as well as twitch and tetanic muscle torque force production, were also diminished. Finally, Nav1.4 levels were reduced at ΔIg3-MuSK synapses but not at the extrajunctional sarcolemma, indicating that the observed excitability defects are the result of impaired localization of this voltage-gated ion channel at the NMJ. We propose that MuSK plays two distinct roles at the NMJ: as an agrin-LRP4 receptor necessary for establishing and maintaining cholinergic signaling, and as a BMP co-receptor required for maintaining proper Nav1.4 density, nerve-evoked muscle excitability and force production. The MuSK-BMP pathway thus emerges as a target for modulating excitability and functional innervation, which are defective in conditions such as congenital myasthenic syndromes and aging.

Disruption of Trkb-mediated signaling induces disassembly of postsynaptic receptor clusters at neuromuscular junctions.

Neurotrophins and tyrosine receptor kinase (Trk) receptors are expressed in skeletal muscle, but it is unclear what functional role Trk-mediated signaling plays during postnatal life. Full-length TrkB (trkB.FL) as well as truncated TrkB (trkB.t1) were found to be localized primarily to the postsynaptic acetylcholine receptor- (AChR-) rich membrane at neuromuscular junctions. In vivo, dominant-negative manipulation of TrkB signaling using adenovirus to overexpress trkB.t1 in mouse sternomastoid muscle fibers resulted in the disassembly of postsynaptic AChR clusters at neuromuscular junctions, similar to that observed in mutant trkB+/- mice. When TrkB-mediated signaling was disrupted in cultured myotubes in the absence of motor nerve terminals and Schwann cells, agrin-induced AChR clusters were also disassembled. These results demonstrate a novel role for neurotrophin signaling through TrkB receptors on muscle fibers in the ongoing maintenance of postsynaptic AChR regions.

In vivo imaging shows loss of synaptic sites from neuromuscular junctions in a model of myasthenia gravis.

We examined the pre- and postsynaptic elements of the neuromuscular junction during immune attack on the postsynaptic acetylcholine receptors (AChRs) in a model of myasthenia gravis (MG). We followed, in the sternomastoid muscle of living mice, the staining of nerve terminals and postsynaptic AChRs at individual neuromuscular junctions in situ for up to 16 days after exposure to a monoclonal anti-AChR antibody. Several exposures to this antibody over 6 days led to spotty loss of AChR staining 1 to 3 days later within individual neuromuscular junctions. In addition, we observed loss of motor nerve terminal staining at presynaptic sites opposed to postsynaptic regions that had lost AChRs. Sites that lost pre- and postsynaptic staining were often immediately adjacent to other junctional regions that maintained a high density of AChRs and still stained presynaptically. Ultimately, the loss of synaptic sites resulted in neuromuscular junctions that appeared to be abnormally fragmented. To determine whether junctions recovered from the immune attack, we followed some antibody-treated muscle fibers for an additional 8 days without further exposure to antibody. Signs of recovery were evident because some of the synaptic regions that had previously lost AChRs subsequently regained them. But these junctions still remained fragmented both pre- and postsynaptically. These findings suggest that the postsynaptic membrane is affected in a highly local way by the immune attack on AChRs occurring in MG. One consequence of this attack is a long-term loss of not only postsynaptic components but also the overlying nerve terminals.

Muscle is electrically inexcitable in acute quadriplegic myopathy.

We directly stimulated muscle in three patients with acute quadriplegic myopathy to determine whether paralyzed muscle in this syndrome is electrically excitable. Two of the patients had been treated with neuromuscular blocking agents and corticosteroids, and one patient had been treated with corticosteroids alone. We found that paralyzed muscle is electrically inexcitable in affected patients. Muscle regained electrical excitability over weeks to months. The recovery of muscle excitability paralleled the clinical recovery of patients, suggesting that paralysis in this syndrome is secondary to electrical inexcitability of muscle membrane.

Elevation of the medical plateau of the tibia in the treatment of Blount disease.

Seven children, between ten and thirteen years old, had elevation of the medial plateau of the tibia for correction of severe varus deformity secondary to Blount disease. The deformity was severe (grade V or VI according to the system of Langenskiöld and Riska) in all patients; the average preoperative varus deformity, determined by the angle formed by the femoral shaft and the tibial shaft, was 25 degrees. The goal of the operation was restoration of a more normal configuration of the articular surface of the proximal end of the tibia. This was accomplished by direct elevation of the depressed medial tibial plateau. All patients had an osteotomy to correct the alignment of the tibia. The osteotomy was performed concomitant with the elevation of the plateau in three patients, before the elevation in three, and after the elevation in one patient. Four patients had a concomitant osteotomy of the femur to align the knee joint parallel to the floor. The results were good in five patients and fair in two.

Use of an intramedullary rod for the treatment of congenital pseudarthrosis of the tibia.

The use of an intramedullary rod as described by Williams, combined with implantation of an autogenous bone graft, resulted in union of an established congenital pseudarthrosis of the tibia in nine of ten patients. One patient needed additional bone-grafting before union occurred. The average age at the time of the operation was five years and three months. A rod of the appropriate length was inserted at the site of the non-union, antegrade through the distal part of the tibia and the hindfoot and then retrograde through the proximal fragment. This resulted in splinting of the tibia, ankle, and subtalar joints. Solid osseous union occurred an average of six months after the procedure in all ten patients. Five patients had a refracture of the tibia after the initial consolidation. Three of the five needed one or more additional operative procedures; one was managed with a cast; and one patient, who had been followed for four years before the refracture, did not return for treatment of the refracture. As is the plan with this method of treatment, the distal part of the tibia grew off the rod and the distal tip of the rod was located proximal to the foot and ankle, or it was located more proximally than it had been at the operation, in six patients. The rod was removed from three patients. At an average of six years, all ten patients were able to walk without pain.

Painful idiopathic rigid flatfoot in children and adolescents.

Nine patients (13 feet) were identified whose primary complaints were of atraumatic-onset, chronic pain in the hindfoot exacerbated with increased activity and who had the diagnosis of idiopathic rigid flatfeet. Eight of 11 were greater than the 95th percentile in weight for their age. Exam under anesthesia showed moderate to significant improvement in hindfoot motion in 9 feet; 4 feet required fractional peroneal lengthenings. Only 5 of 11 patients have had sustained relief of pain and report unlimited activity level. Children and adolescents with painful idiopathic rigid flatfeet without known causation can have significant, persistent, disability and do not uniformly respond well to traditionally-described nonoperative Interventions.

An official American Thoracic Society Clinical Practice guideline: the diagnosis of intensive care unit-acquired weakness in adults

RATIONALE: Profound muscle weakness during and after critical illness is termed intensive care unit-acquired weakness (ICUAW). OBJECTIVES: To develop diagnostic recommendations for ICUAW. METHODS: A multidisciplinary expert committee generated diagnostic questions. A systematic review was performed, and recommendations were developed using the Grading, Recommendations, Assessment, Development, and Evaluation (GRADE) approach. MEASUREMENT AND MAIN RESULTS: Severe sepsis, difficult ventilator liberation, and prolonged mechanical ventilation are associated with ICUAW. Physical rehabilitation improves outcomes in heterogeneous populations of ICU patients. Because it may not be feasible to provide universal physical rehabilitation, an alternative approach is to identify patients most likely to benefit. Patients with ICUAW may be such a group. Our review identified only one case series of patients with ICUAW who received physical therapy. When compared with a case series of patients with ICUAW who did not receive structured physical therapy, evidence suggested those who receive physical rehabilitation were more frequently discharged home rather than to a rehabilitative facility, although confidence intervals included no difference. Other interventions show promise, but fewer data proving patient benefit existed, thus precluding specific comment. Additionally, prior comorbidity was insufficiently defined to determine its influence on outcome, treatment response, or patient preferences for diagnostic efforts. We recommend controlled clinical trials in patients with ICUAW that compare physical rehabilitation with usual care and further research in understanding risk and patient preferences. CONCLUSIONS: Research that identifies treatments that benefit patients with ICUAW is necessary to determine whether the benefits of diagnostic testing for ICUAW outweigh its burdens.(AU)

Sodium channel inactivation in an animal model of acute quadriplegic myopathy.

We previously demonstrated that muscle fibers become unable to fire action potentials in both patients and an animal model of acute quadriplegic myopathy (AQM). In the animal model, skeletal muscle is denervated in rats treated with high-dose corticosteroids (steroid-denervated; SD), and muscle fibers become inexcitable despite resting potentials and membrane resistances similar to those of control denervated fibers that remain excitable. We show here that unexcitability of SD fibers is due to increased inactivation of sodium channels at the resting potential of affected fibers. A hyperpolarizing shift in the voltage dependence of inactivation in combination with the depolarization of the resting potential induced by denervation results in inexcitability. Our findings suggest that paralysis in the animal model of AQM is the result of an abnormality in the voltage dependence of sodium channel inactivation.

In vivo visualization of pre- and postsynaptic changes during synapse elimination in reinnervated mouse muscle.

Using a vital nerve terminal dye (4-Di-2-ASP) and fluorescently tagged alpha-bungarotoxin to stain postsynaptic acetylcholine (ACh) receptors, we viewed the same muscle fibers at multiple times in the sternomastoid muscle of living mice during the process of reinnervation following nerve crush. Soon after axons reenter the muscle, they precisely reoccupy the original endplate sites. However, in contrast to normal adult muscle, during the first several weeks of reinnervation, anatomical and physiological measures show that many of the endplate sites are innervated by more than one axon. Typically, one axon reinnervates the original endplate site by growing up the old Schwann cell tube while another originates as a sprout from a nearby endplate. Within 2 weeks after reinnervation nerve terminal staining shows that most of the sprouts have regressed and physiological evidence of multiple innervation has returned to the normal low level. By repeatedly observing the same endplates during the period of synapse elimination, we could directly view this phenomenon. At some endplates, nerve terminal boutons in one region of the endplate were eliminated at the same time a sprout entering that area regressed. These unoccupied sites seemed permanently eliminated as they are not subsequently occupied by sprouts from the axon remaining at the endplate. We were surprised to find that there is a corresponding permanent loss of ACh receptors within the muscle fiber membrane precisely underneath the eliminated nerve terminals. The decrease in receptors at sites of synapse elimination is due to both a selective loss of ACh receptors already incorporated into these sites and to a lack of insertion of new receptors at the same regions. These sites of pre- and postsynaptic loss, however, maintain cholinesterase staining in the basal lamina for long periods. Control experiments showed that endplates that were permanently denervated, incompletely reoccupied by reinnervating axons, or stained and viewed multiple times in normal muscle do not lose postsynaptic receptor regions. Interestingly, receptors appear to be eliminated before there is any obvious change in the staining of the overlying nerve terminal. Because of the lag between receptor and nerve terminal loss, we could predict which synaptic boutons would be eliminated by looking for lightly stained receptor regions. One interpretation of these data is that the removal or redistribution of relevant postsynaptic molecules by one innervating axon may instigate the elimination of competing terminals.

Multiple innervation of tonic endplates revealed by activity-dependent uptake of fluorescent probes.

During development of the vertebrate nervous system, there is a widespread reduction in the number of axons innervating target cells. This phenomenon, often called synapse elimination, has been particularly well studied at the neuromuscular junction of developing twitch muscle fibres: following a period of polyneuronal innervation, axonal branches are retracted, usually leaving each twitch fibre endplate innervated by only one axon. Here we describe a new technique for the study of synapse elimination--activity-mediated uptake of fluorescent probes. These probes selectively and supravitally label all the terminals of individual axons. The technique is used here in adult and embryonic snakes to study the innervation pattern of a thin muscle containing two fibre types: twitch fibres, which are fast-contracting and have propagated action potentials, and tonic fibres, which are slow-contracting and lack action potentials. We find that twitch muscle fibres, as expected, eliminate all polyneuronal innervation during development; in contrast, tonic fibre endplates remain polyneuronally innervated into adulthood. The persistence of multiple innervation at tonic endplates may be related to the lack of action potential activity in tonic muscle fibres.

Peroneal nerve injury as a complication of pediatric tibial osteotomies: a review of 255 osteotomies.

A retrospective study of 255 consecutive tibial osteotomies performed for correction of frontal, sagittal, and rotational deformities in children is presented. Eleven (4.3%) peroneal neurapraxias were identified; seven were motor and sensory (2.7%), and four were sensory only (1.6%). In all cases, traction on the peroneal nerve, either by intraoperative retraction, or by anatomic displacement of the osteotomy fragments, was felt to produce the neurapraxia. There were no vascular injuries or compartment syndromes. Increased patient age, estimated blood loss and tourniquet time, difficulty in exposure, and male sex were associated with an increased risk of peroneal neurapraxia. Rotational osteotomies were of little risk for peroneal nerve injury, whereas angulatory osteotomies, particularly proximal procedures, were more prone to complication. Prophylactic anterior compartment release and fibular osteotomy are recommended to avoid anterior compartment syndrome after tibial osteotomy. In cases of persistent peroneal nerve palsy due to suspected anatomic traction and displacement, exploration of the peroneal nerve is warranted.

Altered gene expression in steroid-treated denervated muscle.

In rats treated with high-dose corticosteroids, skeletal muscle that is denervated in vivo (steroid-denervated) develops electrical inexcitability similar to that seen in patients with acute quadriplegic myopathy. To determine whether changes in muscle gene transcription might underlie inexcitability of steroid-denervated muscle we performed RNase protection assays to quantitate adult (SkM1) and embryonic (SkM2) sodium channel isoforms and chloride channel (CLC-1) mRNA levels in control, denervated, steroid-innervated, and steroid-denervated skeletal muscle. While SkM1 mRNA levels were relatively unaffected by denervation or steroid treatment, SkM2 mRNA levels were increased by both. These effects were synergistic and high levels of SkM2 mRNA were expressed in denervated muscle exposed to corticosteroids. Skeletal muscle CLC-1 mRNA levels were decreased by denervation. To better understand the marked upregulation of SkM2 in steroid-denervated muscle we examined changes in myogenin and glucocorticoid receptor mRNA levels. However, changes in these mRNA levels cannot account for the upregulation of SkM2 in steroid-denervated muscle.

Roentgen rounds #94. Osteomyelitis of the left ilium--left iliacus muscle abscess.

A left iliac osteomyelitis and left iliacus muscle abscess occurred in a patient who underwent bipolar hemiarthroplasty of the left hip six months prior for avascular necrosis of the left femoral head, secondary to sickle-cell disease. This illness followed an upper respiratory tract infection, and her physical examination was suggestive of a septic process involving the left hip. An aspirate of the hip was not confirmative for septic arthritis. The plain roentgenograms demonstrated that the prosthesis was in an acceptable position, but had limited value in the remainder of the differential diagnosis. In this case, the bone scan contributed significant information distinguishing osteomyelitis from osteonecrosis. The CT scan allowed rapid localization of an occult abscess and destructive changes in the left ilium secondary to osteomyelitis and guided surgical treatment.

Lambert-Eaton antibodies inhibit Ca2+ currents but paradoxically increase exocytosis during stimulus trains in bovine adrenal chromaffin cells.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease that affects neurotransmitter release at peripheral synapses. LEMS antibodies inhibit Ca2+ currents in excitable cells, but it is not known whether there are additional effects on stimulus-secretion coupling. The effect of LEMS antibodies on Ca2+ currents and exocytosis was studied in bovine adrenal chromaffin cells using whole-cell voltage clamp in perforated-patch recordings. Purified LEMS IgGs from five patients inhibited N- and P/Q-type Ca2+ current components to different extents. The reduction in Ca2+ current resulted in smaller exocytotic responses to single depolarizing pulses, but the normal relationship between integrated Ca2+ entry and exocytosis (Enisch and Nowycky, 1996) was preserved. The hallmark of LEMS is a large potentiation of neuromuscular transmission after high-frequency stimulation. In chromaffin cells, stimulus trains can induce activity-dependent enhancement of the Ca2+-exocytosis relationship. Enhancement during trains occurs most frequently when pulses are brief and evoke very small amounts of Ca2+ entry (Engisch et al., 1997). LEMS antibody treatment increased the percentage of trains eliciting enhancement through two mechanisms: (1) by reducing Ca2+ entry and (2) through a Ca2+-independent effect on the process of enhancement. This leads to a paradoxical increase in the amount of exocytosis during stimulus trains, despite inhibition of Ca2+ currents.