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Weakness
Other namesAsthenia
SpecialtyNeurology

Weakness is a symptom of many different medical conditions.[1] The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, including muscular dystrophy and inflammatory myopathy. It occurs in neuromuscular junction disorders, such as myasthenia gravis.[citation needed]

Pathophysiology

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See also: Muscle contraction

Muscle cells work by detecting a flow of electrical impulses from the brain, which signals them to contract through the release of calcium by the sarcoplasmic reticulum. Fatigue (reduced ability to generate force) may occur due to the nerve, or within the muscle cells themselves. New research from scientists at Columbia University suggests that muscle fatigue is caused by calcium leaking out of the muscle cell. This makes less calcium available for the muscle cell. In addition, the Columbia researchers propose that an enzyme activated by this released calcium eats away at muscle fibers.[2]

Substrates within the muscle generally serve to power muscular contractions. They include molecules such as adenosine triphosphate (ATP), glycogen and creatine phosphate. ATP binds to the myosin head and causes the 'ratchetting' that results in contraction according to the sliding filament model. Creatine phosphate stores energy so ATP can be rapidly regenerated within the muscle cells from adenosine diphosphate (ADP) and inorganic phosphate ions, allowing for sustained powerful contractions that last between 5–7 seconds. Glycogen is the intramuscular storage form of glucose, used to generate energy quickly once intramuscular creatine stores are exhausted, producing lactic acid as a metabolic byproduct. Contrary to common belief, lactic acid accumulation doesn't actually cause the burning sensation felt when people exhaust their oxygen and oxidative metabolism, but in actuality, lactic acid in presence of oxygen recycles to produce pyruvate in the liver, which is known as the Cori cycle.[citation needed]

Substrates produce metabolic fatigue by being depleted during exercise, resulting in a lack of intracellular energy sources to fuel contractions. In essence, the muscle stops contracting because it lacks the energy to do so.[citation needed]

Differential diagnosis

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True vs. perceived weakness

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  • True weakness (or neuromuscular) describes a condition where the force exerted by the muscles is less than would be expected, for example muscular dystrophy.
  • Perceived weakness (or non-neuromuscular) describes a condition where a person feels more effort than normal is required to exert a given amount of force but actual muscle strength is normal, for example.[3]

In some conditions, such as myasthenia gravis, muscle strength is normal when resting, but true weakness occurs after the muscle has been subjected to exercise. This is also true for some cases of Myalgic encephalomyelitis/chronic fatigue syndrome, where objective post-exertion muscle weakness with delayed recovery time has been measured and is a feature of some of the published definitions.[4][5][6][7][8][9]

Asthenia vs. myasthenia

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Asthenia or asthaenia (Greek: ἀσθένεια, literally lack of strength but also disease) is a medical term referring to a condition in which the body lacks or has lost strength either as a whole or in any of its parts. It is a poorly defined condition that can include true or primary muscle weakness or perceived muscle weakness.[10] For perceived muscle weakness, asthenia has been described as the feeling of weak or tired muscles in the absence of muscle weakness, that is the muscle can generate a normal amount of force but it is perceived as requiring more effort.[11][12]

General asthenia occurs in many chronic wasting diseases (such as tuberculosis and cancer), sleep disorders or chronic disorders of the heart, lungs or kidneys, and is probably most marked in diseases of the adrenal gland. Moreover, asthenia can be a symptom of mast cell activation syndrome (MCAS).[13] Asthenia may be limited to certain organs or systems of organs, as in asthenopia, characterized by ready fatiguability. Asthenia is also a side effect of some medications and treatments, such as Ritonavir (a protease inhibitor used in HIV treatment). [14]

Differentiating psychogenic (perceived) asthenia and true asthenia from myasthenia is often difficult, and in time apparent psychogenic asthenia accompanying many chronic disorders is seen to progress into a primary weakness.[citation needed]

Myasthenia or myasthaenia (my- from Greek: μυο meaning "muscle" + -asthenia [ἀσθένεια] meaning "weakness"), or simply muscle weakness, is a lack of muscle strength. The causes are many and can be divided into conditions that have either true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, including muscular dystrophy and inflammatory myopathy. It occurs in neuromuscular diseases, such as myasthenia gravis. Perceived muscle weakness occurs in diseases such as sleep disorders, and depression.[11]

Types

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Muscle fatigue can be central, neuromuscular, or peripheral muscular. Central muscle fatigue manifests as an overall sense of energy deprivation, and peripheral muscle weakness manifests as a local, muscle-specific inability to do work.[15][16] Neuromuscular fatigue can be either central or peripheral.[citation needed]

Central fatigue

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The central fatigue is generally described in terms of a reduction in the neural drive or nerve-based motor command to working muscles that results in a decline in the force output.[17][18][19] It has been suggested that the reduced neural drive during exercise may be a protective mechanism to prevent organ failure if the work was continued at the same intensity.[20][21] The exact mechanisms of central fatigue are unknown, though there has been considerable interest in the role of serotonergic pathways.[22][23][24]

Neuromuscular fatigue

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Nerves control the contraction of muscles by determining the number, sequence, and force of muscular contraction. When a nerve experiences synaptic fatigue it becomes unable to stimulate the muscle that it innervates. Most movements require a force far below what a muscle could potentially generate, and barring pathology, neuromuscular fatigue is seldom an issue.[citation needed]

For extremely powerful contractions that are close to the upper limit of a muscle's ability to generate force, neuromuscular fatigue can become a limiting factor in untrained individuals. In novice strength trainers, the muscle's ability to generate force is most strongly limited by nerve's ability to sustain a high-frequency signal. After an extended period of maximum contraction, the nerve's signal reduces in frequency and the force generated by the contraction diminishes. There is no sensation of pain or discomfort, the muscle appears to simply 'stop listening' and gradually cease to move, often lengthening. As there is insufficient stress on the muscles and tendons, there will often be no delayed onset muscle soreness following the workout. Part of the process of strength training is increasing the nerve's ability to generate sustained, high frequency signals which allow a muscle to contract with their greatest force. It is this "neural training" that causes several weeks worth of rapid gains in strength, which level off once the nerve is generating maximum contractions and the muscle reaches its physiological limit. Past this point, training effects increase muscular strength through myofibrillar or sarcoplasmic hypertrophy and metabolic fatigue becomes the factor limiting contractile force.

Peripheral muscle fatigue

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Peripheral muscle fatigue during physical work is considered[by whom?] an inability for the body to supply sufficient energy or other metabolites to the contracting muscles to meet the increased energy demand. This is the most common case of physical fatigue—affecting a national[where?] average of 72% of adults in the work force in 2002. This causes contractile dysfunction that manifests in the eventual reduction or lack of ability of a single muscle or local group of muscles to do work. The insufficiency of energy, i.e. sub-optimal aerobic metabolism, generally results in the accumulation of lactic acid and other acidic anaerobic metabolic by-products in the muscle, causing the stereotypical burning sensation of local muscle fatigue, though recent studies have indicated otherwise, actually finding that lactic acid is a source of energy.[25]

The fundamental difference between the peripheral and central theories of muscle fatigue is that the peripheral model of muscle fatigue assumes failure at one or more sites in the chain that initiates muscle contraction. Peripheral regulation therefore depends on the localized metabolic chemical conditions of the local muscle affected, whereas the central model of muscle fatigue is an integrated mechanism that works to preserve the integrity of the system by initiating muscle fatigue through muscle derecruitment, based on collective feedback from the periphery, before cellular or organ failure occurs. Therefore, the feedback that is read by this central regulator could include chemical and mechanical as well as cognitive cues. The significance of each of these factors will depend on the nature of the fatigue-inducing work that is being performed.[citation needed]

Though not universally used, "metabolic fatigue" is a common alternative term for peripheral muscle weakness, because of the reduction in contractile force due to the direct or indirect effects of the reduction of substrates or accumulation of metabolites within the myocytes. This can occur through a simple lack of energy to fuel contraction, or through interference with the ability of Ca2+ to stimulate actin and myosin to contract.

Management

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References

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Weakness

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Weakness is the quality or state of being weak, defined as a lack of strength, vigor, or power, which can apply to physical, mental, , or structural contexts, and may also denote a fault, defect, or in individuals, materials, or systems. In , weakness typically refers to a reduction in muscle strength or overall bodily vigor, often presenting as generalized or localized impairment, and serves as a common symptom of underlying conditions such as , , infections, nutritional deficiencies, or imbalances. It is distinct from , though the two may overlap, with weakness involving an objective decrease in force generation rather than subjective tiredness alone. Diagnosis requires distinguishing true from pain-related limitations or perceived debility through clinical evaluation, including history, , and targeted testing.

Definition and Classification

Definition

In , weakness is defined as a loss of muscle strength, characterized by a reduced capacity of one or more skeletal muscles to generate the expected force or power output during voluntary contraction. This symptom can be localized to specific muscle groups or generalized across the body and is evaluated objectively through standardized techniques such as manual muscle testing on a 0-5 scale or dynamometry using hand-held devices to quantify maximal isometric strength, while subjective assessment relies on patient-reported difficulties in performing routine tasks. True weakness differs fundamentally from normal , which represents a reversible state of diminished following prolonged or inadequate recovery, typically resolving with rest without altering baseline muscle power. In contrast, weakness indicates a pathological impairment where maximal voluntary effort fails to produce , often persisting independently of rest and signaling disruption in neuromuscular function. Clinically, weakness serves as a frequent presenting symptom in , where it constitutes a common complaint among patients seeking evaluation for functional limitations, and in emergency settings, where it may herald acute, life-threatening conditions such as , , or imbalances. Affecting approximately 5% of adults aged 60 years and older in the United States based on criteria for weak muscle strength from the 2011-2012 and Examination Survey (NHANES), weakness substantially impairs quality of life by restricting mobility, independence in daily activities, and overall physical functioning, thereby underscoring the need for timely assessment to mitigate long-term disability.

Types of Weakness

Weakness in clinical medicine is broadly classified into several subtypes based on its objective measurability, subjective experience, and patterns of fatigability or generalization. True weakness refers to an objective loss of muscle power, verifiable through , such as the inability to generate sufficient force to overcome in affected limbs. This contrasts with perceived weakness, which involves a subjective sensation of reduced strength without demonstrable loss on testing, often arising from psychological factors or . Asthenia represents a generalized feeling of bodily weakness that is not confined to specific muscle groups, commonly observed in the context of chronic illnesses where patients report an overall debility rather than localized impairment. In distinction, myasthenia denotes a specific form of fatigable weakness, characterized by muscle power that diminishes with repeated use and recovers with rest, as exemplified by the fluctuating symptoms in affecting ocular or bulbar muscles. Fatigue-based types of weakness further delineate based on the site of predominant dysfunction. Central weakness originates from or cortical levels, leading to profound tiredness that limits sustained effort, such as in where patients experience exacerbated exhaustion with activity. Neuromuscular weakness involves failure at the , resulting in transmission-related fatigability that impairs repetitive actions. Peripheral weakness stems from muscle fiber dysfunction, manifesting as localized power deficits that worsen with exertion but are distinct from central origins.

Clinical Presentation

Symptoms

Patients commonly describe muscle weakness subjectively as a sensation of heaviness or fatigue in the affected limbs, often reporting that they tire easily during routine activities or feel unable to perform familiar tasks, such as climbing stairs or lifting objects. This subjective experience is distinguished from general tiredness by its specific impact on motor function, where patients note a progressive decline in their ability to sustain effort. Objectively, weakness manifests as measurable reductions in muscle power, such as diminished when squeezing an examiner's hand, in leading to stumbling or falls, or visible drooping of the eyelids (ptosis) in cases involving facial or ocular muscles. These signs are typically elicited during and help quantify the extent of impairment beyond patient reports. While weakness frequently co-occurs with associated symptoms like localized during muscle use, sensory numbness, or unexplained , the core descriptors remain centered on motor limitations, including rapid fatigability and reduced in repetitive movements. These accompanying features provide context but do not define the primary complaint of diminished strength. The functional impact of weakness profoundly disrupts (ADLs), such as difficulty dressing due to inability to raise arms overhead or challenges in walking that necessitate assistive devices. Clinicians often assess severity using the (MRC) scale for muscle strength, a validated 0-5 grading system where 0 indicates no visible contraction, 3 represents movement against but not resistance, and 5 denotes normal power against full resistance. This scale enables standardized evaluation of how weakness compromises independence in tasks like or mobility.

Patterns of Weakness

Weakness patterns in clinical practice are characterized by the distribution and temporal evolution of muscle involvement, which help clinicians localize the underlying issue to specific neural or muscular structures. Proximal weakness predominantly affects the muscles of the and hip girdles, such as difficulty rising from a or combing hair, and is commonly observed in conditions involving the muscle fibers themselves, like inflammatory myopathies. In contrast, distal weakness involves the extremities farther from the , such as impaired fine finger movements or , and is more typical in disorders affecting peripheral nerves, where involvement starts in the hands and feet. Symmetry in weakness distribution further refines localization, with bilateral symmetric patterns often indicating widespread processes affecting both sides equally, such as in systemic inflammatory or toxic conditions that impact muscles or diffusely. Asymmetric weakness, however, suggests focal , including unilateral involvement on one side of the body, as seen in vascular events disrupting localized neural pathways. The tempo of progression distinguishes acute from chronic patterns; sudden acute weakness develops rapidly over minutes to hours, often pointing to central vascular or traumatic events, while subacute progressive weakness over days to weeks, reaching peak severity within two weeks, suggests inflammatory or immune-mediated processes affecting the , such as Guillain-Barré syndrome. Chronic patterns, by comparison, evolve gradually over months to years, with insidious worsening that may include periods of stability, characteristic of degenerative conditions involving motor neurons. Fatigability refers to weakness that worsens with repeated muscle use and improves with rest, a hallmark of disorders at the where transmission fatigues under sustained activity. Non-fatigable weakness remains relatively constant regardless of repetition, as occurs in structural disruptions like vascular lesions, where the deficit stems from fixed neural damage rather than dynamic failure.

Pathophysiology

Central Mechanisms

Central mechanisms of weakness originate in the (CNS), encompassing the and , where disruptions impair the neural drive to muscles without directly affecting peripheral neuromuscular junctions. Upper motor neurons (UMNs), particularly those in the corticospinal tracts, play a pivotal role in initiating and modulating voluntary movement. Lesions or dysfunction in these tracts lead to spastic weakness, characterized by increased , , and pathological reflexes such as the Babinski sign, due to the loss of over lower motor neurons. This spasticity arises from the disinhibition of spinal reflex arcs, resulting in velocity-dependent resistance to passive movement and a characteristic pattern of weakness that is more pronounced in muscles. Central fatigue represents another key CNS-driven process, involving diminished motivational drive and reduced neural output from higher centers, often linked to imbalances in neurotransmitters. Elevated serotonin levels relative to in the can contribute to this by altering the perception of effort and suppressing excitability, as observed in conditions involving prolonged . depletion, in particular, impairs reward processing and sustained activation of motor pathways, leading to a subjective sense of exhaustion despite intact peripheral muscle function. These imbalances disrupt the supraspinal regulation of motor commands, manifesting as a progressive decline in force generation during repeated efforts. Contributions from the and further elucidate CNS mechanisms, where coordination failures produce -like weakness. Cerebellar dysfunction interrupts the fine-tuning of motor commands, resulting in impaired timing and precision of movements that mimic weakness through ineffective force application and . lesions, affecting pathways like the rubrospinal or reticulospinal tracts, exacerbate this by altering postural stability and excitatory drive to spinal motor pools, leading to and that compound the perception of limb debility. At a quantitative level, central mechanisms often involve failures in , where the CNS inadequately activates available motor units to meet force demands. In healthy neural signaling, motor units are recruited in an orderly manner based on the size principle, starting with smaller, fatigue-resistant units and progressing to larger ones for greater force. Disruptions in corticospinal volleys reduce the efficiency of this recruitment, leading to suboptimal firing rates and incomplete activation of the motor pool, as evidenced by decreased electromyographic (EMG) activity during maximal efforts. This central inefficiency highlights the CNS's role in scaling muscle activation without peripheral fatigue.

Peripheral Mechanisms

Peripheral mechanisms of weakness involve disruptions at the level of the s, peripheral nerves, , and muscle fibers themselves, leading to impaired force generation distinct from origins. In lesions, occurs when motor neurons fail to innervate muscle fibers, resulting in flaccid weakness characterized by reduced and . This triggers rapid due to the absence of neural trophic support, with affected muscles exhibiting fibrillations and fasciculations as denervated fibers become hyperexcitable. Axonal transport failure in peripheral nerves exacerbates this process by impairing the delivery of essential proteins, organelles, and to distal axons, leading to axonal degeneration and subsequent . For instance, disruptions in anterograde or retrograde transport, as seen in toxic neuropathies or hereditary motor neuropathies, cause accumulation, axonal swelling, and distal axonopathy, culminating in progressive weakness and . At the , defects such as blockade impair synaptic transmission, producing fatigable weakness that worsens with repeated activity. In , autoantibodies target postsynaptic receptors, reducing their density through complement-mediated destruction and internalization, which diminishes the and safety factor of neuromuscular transmission. This leads to incomplete muscle activation and rapid fatigue during sustained or repetitive contractions. Muscle fiber contributes to weakness through either failures or structural . In metabolic myopathies, enzymatic defects in , fatty acid oxidation, or mitochondrial function cause ATP depletion during exercise, preventing cross-bridge cycling and leading to acute weakness and . For example, deficiencies in or carnitine palmitoyltransferase result in rapid fatigue due to insufficient substrates for contraction. Structural defects, such as the absence of in , destabilize the , making muscle fibers susceptible to mechanical stress and calcium influx, which triggers , , and progressive weakness with fiber replacement by fibrofatty tissue. Peripheral fatigue arises from local ionic imbalances during prolonged muscle activity, independent of central drive. Potassium efflux from muscle fibers during repeated contractions elevates extracellular potassium concentrations in the , depolarizing the membrane and inactivating sodium channels, which blocks propagation and reduces force output. This mechanism contributes to the decline in muscle performance, particularly in high-intensity efforts, by disrupting excitation-contraction coupling.

Causes

Neurological Causes

Neurological causes of weakness primarily involve disorders of the (CNS) or (PNS), leading to disruption of motor pathways and resulting in various patterns of muscle impairment. These etiologies often present with focal or symmetric weakness, depending on the site of involvement, and require prompt evaluation to distinguish from other causes. and transient ischemic attacks (TIAs) represent acute ischemic events in the brain that commonly cause sudden focal weakness, such as affecting one side of the body. In ischemic , occlusion of cerebral arteries leads to infarction in motor areas, resulting in contralateral weakness that may include facial droop and limb ; TIAs produce similar transient symptoms resolving within 24 hours due to temporary hypoperfusion. These conditions account for a significant portion of acute weakness presentations in emergency and settings, with occurring in approximately 80% of acute cases. Multiple sclerosis (MS) is an autoimmune of the CNS that leads to relapsing-remitting episodes of weakness due to and loss of in white matter tracts. This process disrupts nerve conduction in motor pathways, causing transient focal or generalized weakness, often accompanied by sensory changes or ; the relapsing-remitting form, the most common initial presentation, features episodes of symptom exacerbation followed by partial or full recovery. Amyotrophic lateral sclerosis (ALS) involves progressive degeneration of upper and lower motor neurons in the CNS and PNS, leading to insidious onset of that spreads from distal limbs to proximal muscles and bulbar regions. Pathophysiologically, the loss of motor neurons results in , fasciculations, and eventual respiratory compromise, with weakness typically asymmetric at onset but becoming generalized over time. Myasthenia gravis is an autoimmune disorder affecting the , leading to fatigable weakness that worsens with activity and improves with rest, often involving ocular, bulbar, and proximal limb muscles due to autoantibodies against receptors. Guillain-Barré syndrome, an acute post-infectious autoimmune , causes rapid symmetric ascending weakness starting in the lower limbs, potentially progressing to respiratory involvement, mediated by demyelination or axonal damage in peripheral nerves. Peripheral neuropathies, including diabetic and inflammatory types such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), cause symmetric distal weakness through damage to peripheral nerves. In , chronic hyperglycemia leads to axonal degeneration, manifesting as stocking-glove distribution sensory loss and weakness starting in the feet; CIDP, an immune-mediated demyelinating disorder, produces proximal and distal symmetric weakness that progresses over weeks to months, often responsive to . Neurological causes constitute a substantial proportion of weakness evaluations in outpatient clinics, often requiring electrodiagnostic studies for confirmation.

Musculoskeletal Causes

Musculoskeletal causes of weakness primarily arise from disorders affecting the muscles, tendons, bones, or joints directly, leading to impaired muscle function or structural limitations that reduce strength. These conditions often present with localized or symmetrical weakness, distinguishable from neural or systemic origins by their focus on tissue-level . Common examples include myopathies, disturbances impacting muscle excitability, from injury or inactivity, and joint-related instabilities. Myopathies, disorders of , are a leading musculoskeletal cause of , characterized by intrinsic muscle damage or dysfunction. Inflammatory myopathies, such as , involve autoimmune-mediated inflammation of muscle fibers, resulting in symmetrical proximal affecting the shoulders, hips, and thighs, often progressing over weeks to months. Genetic myopathies, exemplified by , stem from mutations in genes like DMD, leading to progressive proximal muscle that typically begins in , with initial involvement of pelvic and muscles, causing difficulties in walking, climbing , and rising from a seated position. These myopathies disrupt muscle fiber integrity and contractility, often without , and may briefly intersect with peripheral mechanisms through impaired excitation-contraction coupling. Electrolyte imbalances, particularly (serum below 3.5 mEq/L), can precipitate acute by altering membrane potentials and impairing muscle cell depolarization, sometimes manifesting as . In severe cases, triggers episodes of generalized weakness or , often reversible with repletion, and is frequently linked to dietary deficiencies, gastrointestinal losses, or medications like diuretics. Trauma and disuse contribute to weakness through , where prolonged immobilization or reduces muscle protein synthesis and promotes breakdown, leading to measurable strength loss. Post- atrophy, common after fractures or damage, can lead to significant within weeks of immobility, resulting in reversible weakness that improves with rehabilitation. Disuse from casting or similarly induces via reduced mechanical loading, exacerbating weakness in affected limbs. Osteoarticular disorders, such as , often mimic or exacerbate through joint , pain, and instability that limit effective muscle use. In , degenerative changes in joints like the or lead to surrounding , with studies showing up to 19% reduction in cross-sectional area due to disuse and , creating a cycle of instability and perceived weakness. similarly causes joint laxity and erosions, contributing to proximal weakness in the upper and lower extremities by compromising biomechanical support for muscle action.

Systemic Causes

Systemic causes of weakness encompass a range of non-neuromuscular disorders that affect the body broadly, leading to generalized and reduced muscle performance through mechanisms such as metabolic disruption, , or nutritional deficits. These conditions often present with asthenia, a subjective sense of profound tiredness and weakness that impairs daily activities, and they are particularly prevalent in older adults where multiple factors like chronic and comorbidities contribute to multifactorial . Endocrine disorders, notably thyroid dysfunction, frequently manifest as generalized weakness. Hypothyroidism, characterized by insufficient thyroid hormone production, leads to hypothyroid myopathy, which causes proximal muscle weakness, cramps, and stiffness due to impaired energy metabolism in muscle fibers. In contrast, hyperthyroidism, often from , results in with proximal weakness, muscle wasting, and asthenia, exacerbated by increased catabolism and electrolyte imbalances. Infectious diseases can induce weakness through persistent systemic effects. Post-viral fatigue syndromes, following infections like Epstein-Barr virus or , produce prolonged muscle weakness and exhaustion that worsen with exertion, linked to immune dysregulation and mitochondrial dysfunction. Bacterial infections such as , caused by , may lead to with associated limb weakness and sensory loss, stemming from affecting nerve function. Metabolic imbalances are key contributors to weakness via reduced oxygen delivery or neural integrity. , particularly iron-deficiency or chronic disease-related types, diminishes levels, causing tissue hypoxia that manifests as profound and generalized weakness. triggers subacute combined degeneration of the , resulting in demyelination of posterior and lateral columns, which produces progressive limb weakness, , and paresthesias. Malignancies contribute to weakness through paraneoplastic syndromes or . Paraneoplastic processes, such as Lambert-Eaton myasthenic associated with small-cell , cause proximal and fatigability due to autoantibodies targeting neuromuscular junctions. Cancer , a wasting in advanced tumors, involves severe muscle loss, weakness, and fatigue from cytokine-driven inflammation and metabolic alterations, affecting up to 80% of patients with progressive disease.

Diagnosis

History and Examination

The evaluation of weakness begins with a detailed patient history to characterize the symptom and guide subsequent . Key elements include the onset, which may be acute (suggesting vascular events like or infectious processes), subacute (implicating toxic, metabolic, or inflammatory etiologies), or chronic progressive (pointing toward hereditary or degenerative conditions). Duration helps differentiate transient episodes from persistent deficits, while the anatomic distribution—such as symmetric proximal involvement (e.g., difficulty rising from a ) versus asymmetric or distal patterns—provides clues to underlying mechanisms, including potential patterns of weakness like pyramidal or disorders. Exacerbating or alleviating factors are also elicited, such as fatigability worsened by repetitive activity or later in the day, which is characteristic of . Physical examination focuses on systematic assessment of muscle power, tone, and coordination to localize the lesion. Strength is graded using the scale, a standardized 0-5 ordinal system where grade 0 indicates no contraction, 1 is flicker or trace contraction without movement, 2 is movement with gravity eliminated, 3 is movement against gravity but not resistance, 4 is movement against some resistance, and 5 is normal power against full resistance. This is applied to major muscle groups bilaterally, starting proximally and comparing sides for asymmetry. Reflex testing evaluates deep tendon reflexes (e.g., , patellar) on a 0-4 scale (0 absent, 4+ ), with suggesting involvement and indicating or peripheral issues. The sensory examination assesses light touch, pinprick, vibration, and in dermatomal distributions to identify concurrent neuropathy or contributing to perceived weakness. Additional maneuvers include observing for (arm weakness) or heel-toe walking deficits (distal lower limb involvement). Certain features in the history and examination warrant urgent attention as red flags. Sudden onset unilateral weakness, often with facial droop or arm drift, raises concern for ischemic stroke requiring immediate intervention. Progressive bulbar symptoms, such as , , or tongue weakness, signal possible (ALS), particularly if accompanied by upper and lower motor neuron signs like fasciculations. Objective functional assessments quantify the impact of weakness on daily activities. The Timed Up and Go (TUG) test measures mobility by timing the sequence of rising from a , walking 3 meters, turning, returning, and sitting; times exceeding 13.5 seconds indicate increased fall risk and mobility impairment due to lower limb weakness. The 6-minute walk test (6MWT) evaluates endurance by recording the distance covered on a flat course at self-selected pace, with rests allowed; reduced distances (e.g., <300 meters in adults) reflect submaximal capacity limited by proximal or generalized weakness in conditions like myopathy or neuropathy. These tests complement bedside findings by providing measurable outcomes tied to observed patterns of weakness.

Differential Diagnosis

The differential diagnosis of weakness begins with distinguishing true muscle weakness, characterized by objective loss of motor power, from perceived or subjective weakness, where patients report fatigue or effort without measurable deficit. True weakness is confirmed through objective assessments such as the Medical Research Council (MRC) Manual Muscle Testing scale, which grades strength from 0 (no contraction) to 5 (normal power against resistance), revealing deficits in specific muscle groups. In contrast, perceived weakness often stems from non-neuromuscular factors like depression, chronic fatigue syndrome, or deconditioning, and requires psychological evaluation to identify functional components, such as inconsistent effort or give-way weakness during exam. Electromyography (EMG) further supports differentiation by detecting abnormalities in muscle or nerve function indicative of true pathology, absent in purely subjective cases. A key distinction arises between asthenia, a general sense of fatigue or debility without fatigability, and myasthenia, as in myasthenia gravis, where weakness worsens with repetitive activity and improves with rest. Asthenia may reflect systemic issues like anemia or hypothyroidism, lacking the fluctuating pattern seen in myasthenia gravis, which typically involves ocular or bulbar muscles initially. Endurance tests, such as sustained upward gaze for 30 seconds or repetitive handgrip, help differentiate: in myasthenia, ptosis or grip strength declines progressively, while asthenia shows stable but reduced baseline effort. Repetitive nerve stimulation (RNS) at 2-3 Hz confirms myasthenia by demonstrating a ≥10% decrement in compound muscle action potential, a finding not seen in asthenia. Investigative tools are selected based on clinical suspicion to narrow the differential. Blood tests include creatine kinase (CK) levels, which elevate in myopathies (e.g., >5 times upper limit in inflammatory or toxic forms), and electrolytes like , as can mimic proximal weakness. (TSH) screens for endocrine causes, while EMG/nerve conduction studies (NCS) localize lesions: myopathic changes (small, polyphasic potentials) suggest muscle disorders, whereas neuropathic patterns indicate peripheral nerve issues. MRI of the or spine is prioritized for asymmetric or acute weakness to detect central lesions, such as or demyelination, guiding further confirmatory tests like if needed. Common pitfalls in diagnosis include overlooking functional disorders, where patients exhibit non-anatomic weakness patterns responsive to , or medication side effects, such as statin-associated muscle symptoms (SAMS) in approximately 5-20% of users, with confirmed (often with elevated CK and proximal symptoms) being less common (1-5%). Glucocorticoids can exacerbate weakness through , often with normal CK, necessitating review early in evaluation. An algorithmic approach to proceeds stepwise: (1) Elicit history for onset, distribution (proximal vs. distal, symmetric vs. asymmetric), and associated symptoms (e.g., fatigability suggesting disorder); (2) Perform targeted exam with grading and endurance testing to confirm objective weakness; (3) Order initial labs (CK, electrolytes, TSH) and, if indicated, EMG/NCS to classify as myopathic, neuropathic, or central; (4) Use MRI for focal deficits and consider specialist referral (e.g., ) or advanced testing (e.g., panels) if initial results are inconclusive; (5) Reassess for pitfalls like drugs or psychological factors before proceeding to invasive diagnostics. This structured process minimizes misdiagnosis and ensures efficient progression to confirmatory studies.

Management

Initial Assessment

The initial assessment of a presenting with weakness prioritizes stabilization to address life-threatening complications, beginning with of the airway, breathing, and circulation (ABCs). In acute settings, such as the , clinicians must rapidly assess for respiratory compromise, particularly in conditions involving neuromuscular involvement like Guillain-Barré syndrome (GBS), where up to 25% of patients develop respiratory insufficiency requiring . , including , , and , should be monitored closely for signs of autonomic instability, such as or , which can occur in progressive weakness syndromes. Risk stratification follows ABC stabilization to identify patients needing urgent intervention, focusing on red flags such as bulbar involvement (e.g., or ), rapid progression over hours to days, or bilateral symmetric weakness suggesting peripheral causes. For instance, in GBS, characterized by ascending weakness and , immediate to intensive care is warranted if falls below 20 mL/kg or if there is a 50% daily decline, as these indicate impending . Patients with these features should be referred urgently to or critical care for further evaluation, while those with stable, non-progressive weakness may undergo outpatient follow-up. Supportive care during initial assessment aims to prevent secondary complications, including provision of intravenous hydration to maintain and avoid , which can exacerbate in neuromuscular disorders. Nutritional support, such as early enteral feeding within 24-48 hours for patients at risk of , helps preserve muscle mass and prevent , with energy targets around 30 kcal/kg body weight recommended for non-ventilated individuals. Mobility aids, like canes or wheelchairs, should be provided promptly to reduce fall risk, especially in elderly or deconditioned patients with lower extremity weakness. Ongoing monitoring in acute settings involves serial neurological examinations every 4-6 hours to track weakness progression, alongside repeated assessments of respiratory function using tools like measurements or single-breath counts. This allows for timely escalation of care, such as trials in stable patients with diaphragmatic involvement, ensuring dynamic adjustment to the patient's evolving status.

Therapeutic Approaches

Therapeutic approaches to weakness prioritize addressing the underlying to restore muscle function and improve , with treatments ranging from pharmacological agents to rehabilitative and supportive interventions. Evidence-based strategies are tailored to specific causes, such as inflammatory, neuromuscular, or systemic disorders, and often combine multiple modalities for optimal outcomes. Pharmacological treatments target disease-specific mechanisms to alleviate weakness. In inflammatory myopathies like and , first-line typically involves corticosteroids such as , often combined with immunosuppressants including or to reduce and muscle damage; these agents have demonstrated efficacy in improving strength and function in responsive patients. For , a disorder, —an —is the cornerstone , enhancing availability to counteract fatigable weakness; it is generally safe for long-term use and improves daily function in most patients. Disease-modifying therapies aim to halt or slow progression in acute or neurodegenerative conditions. For acute inflammatory neuropathies such as Guillain-Barré syndrome, intravenous immunoglobulin (IVIG) or is recommended as first-line treatment to remove pathogenic antibodies and accelerate recovery from and weakness; randomized trials show both modalities reduce disability at four weeks with comparable efficacy, though IVIG is often preferred for ease of administration. In (ALS), —a glutamate release inhibitor—extends survival by approximately three months on average when initiated early, modestly slowing degeneration and weakness progression. Additional approved therapies include , an that slows functional decline in early-stage ALS, and , an antisense oligonucleotide for patients with SOD1 mutations that reduces disease progression markers. Rehabilitative interventions focus on preserving and rebuilding muscle strength through structured exercise protocols. , particularly resistance training, effectively counters disuse by stimulating muscle protein synthesis and increasing strength; meta-analyses of randomized controlled trials confirm that progressive resistance exercises mitigate muscle loss during immobilization, with gains in and function observed in both younger and older adults. Supportive measures enhance mobility and prevent complications from weakness. , such as ankle-foot orthoses (AFOs), provide stability for lower limb weakness, improving and reducing fall risk in conditions like or post-stroke deficits; clinical studies support their use in compensating for plantar flexion weakness without substituting for active rehabilitation. Nutritional supplementation addresses deficiency-related causes, as in where therapy—typically 50,000 IU weekly initially—reverses proximal muscle weakness by promoting bone and muscle health; treatment normalizes serum levels and alleviates symptoms within months. Prognosis for weakness varies markedly by cause, influencing therapeutic expectations. imbalances, such as or , often lead to reversible weakness that resolves rapidly with correction, restoring full strength without residual deficits in most cases. In contrast, presents a progressive course where weakness advances despite and supportive care, with median survival of 2–5 years from symptom onset and limited functional recovery. Overall, multidisciplinary approaches improve outcomes in treatable etiologies, emphasizing early intervention to maximize reversibility.

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