brand logo

SCOTT T. LARSON, MD, AND JASON WILBUR, MD

Am Fam Physician. 2020;101(2):95-108

Related letter : Differential Diagnosis of Muscle Weakness in Adults

Author disclosure: No relevant financial affiliations.

Although the prevalence of muscle weakness in the general population is uncertain, it occurs in about 5% of U.S. adults 60 years and older. Determining the cause of muscle weakness can be challenging. True muscle weakness must first be differentiated from subjective fatigue or pain-related motor impairment with normal motor strength. Muscle weakness should then be graded objectively using a formal tool such as the Medical Research Council Manual Muscle Testing scale. The differential diagnosis of true muscle weakness is extensive, including neurologic, rheumatologic, endocrine, genetic, medication- or toxin-related, and infectious etiologies. A stepwise approach to narrowing this differential diagnosis relies on the history and physical examination combined with knowledge of the potential etiologies. Frailty and sarcopenia are clinical syndromes occurring in older people that can present with generalized weakness. Asymmetric weakness is more common in neurologic conditions, whereas pain is more common in neuropathies or radiculopathies. Identifying abnormal findings, such as Chvostek sign, Babinski reflex, hoarse voice, and muscle atrophy, will narrow the possible diagnoses. Laboratory testing, including electrolyte, thyroid-stimulating hormone, and creatine kinase measurements, may also be helpful. Magnetic resonance imaging is indicated if there is concern for acute neurologic conditions, such as stroke or cauda equina syndrome, and may also guide muscle biopsy. Electromyography is indicated when certain diagnoses are being considered, such as amyotrophic lateral sclerosis, myasthenia gravis, neuropathy, and radiculopathy, and may also guide biopsy. If the etiology remains unclear, specialist consultation or muscle biopsy may be necessary to reach a diagnosis.

Given its broad differential diagnosis, muscle weakness can be challenging to evaluate in primary care practice. Although its prevalence in the general population is not well described, muscle weakness occurs in 5% of U.S. adults 60 years and older. 1 Physicians must distinguish true muscle weakness from subjective fatigue or pain-related motor impairment with normal motor strength. This requires a history and physical examination, which guide laboratory testing, imaging, electrodiagnostic testing, and muscle biopsy. 2 – 5

Usual practice and expert opinion
, , , Usual practice and expert opinion
, , , Expert opinion
, Expert opinion

Etiology and Differential Diagnosis

The differential diagnosis of muscle weakness in adults is extensive because it can occur when pathology affects any level of the neuromuscular pathway (upper or lower motor neurons, neuromuscular junction, and muscle fibers). Table 1 lists selected causes of muscle weakness and their clinical findings. 5 – 22

Amyotrophic lateral sclerosisVariable, typically starts unilaterally in one peripheral region of the body and progresses into others; may present with impairment of the ninth to 12th cranial nerves (bulbar palsy)BothGradualMuscle cramps, muscle atrophy (often in the hands); fasciculations, including in the tongue; spasticity; may exhibit pseudobulbar affectMRI of brain and spinal cord may help rule out other causes of weaknessNormal or elevatedReduced CMAP amplitude with normal sensory nerve amplitude; fibrillation potentials, positive sharp wavesNot typically performed
Cerebral lesion (stroke, hemorrhage, mass)Variable depending on lesion location, often unilateralUpperAcute (stroke), subacute or gradual (mass, subdural hematoma)May present with headache, altered cognition, or altered sensoriumMRI may reveal etiologyNot typically obtainedNot typically performedNot typically performed
Compressive neuropathy of the peripheral nerve, (e.g., carpal tunnel syndrome, lumbar radiculopathy)Variable, unilateralLowerVariablePain, paresthesia; spinal nerve root compression may cause radicular symptomsUltrasonography may reveal nerve entrapmentNot typically obtainedFibrillation potentials, positive sharp waves; reduced MUAP amplitude distal to offending lesionNot typically performed
Guillain-Barré syndromeSymmetric, bilateral; affects distal and proximal muscles; may progress to include respiratory and bulbar involvementLowerAcuteHistory of recent , Epstein-Barr virus, cytomegalovirus, or mycoplasma infection; recent vaccination; may be associated with back pain and symmetric sensory changes (e.g., paresthesias)Anti-GM1 antibody, anti-GD1a antibody; cerebrospinal fluid analysis may show increased protein and normal leukocytes after the first week of illnessNot typically obtainedMay be normal in first week of illness; later shows patchy demyelination findings of temporal dispersion of CMAPs; slowed motor conduction velocity and/or conduction blockNot typically performed
Lambert-Eaton syndromeProximal, caudocranial progression; initially improves with repetition; diminished tendon reflexesLowerVariableDysautonomia, impotence, hypotension, xerostomia; often develops as a paraneoplastic syndrome associated with small cell lung cancer but may be idiopathicAnti–voltage-gated calcium channel antibodyNormalLow CMAP amplitude with rest, improvement postexercise; fibrillation potentials Not typically performed
Motor neuropathyDistal, eventually proximalLowerGradualMay have accompanying sensory neuropathy with paresthesia or numbness; toe deformities, foot ulcers; impaired balanceVarious genetic tests depending on suspected etiology; elevated serum glucose or A1C level if caused by diabetic neuropathy; muscle atrophy on MRINot typically obtainedLow CMAP amplitude in lower extremities; demyelination signs in upper extremitiesNot typically performed
Multiple sclerosisVariable depending on location, often unilateralUpperVariableMay present with bladder dysfunction, cognitive impairment, sensory changes, monocular vision loss due to optic neuritis, cerebellar ataxiaMRI may show characteristic white matter lesions of the brain or spinal cordNot typically obtainedNot typically performedNot typically performed
Myasthenia gravisProximal, cephalocaudal progression; worsens with repetition (fatigability); oculomotorLowerVariableWorsening of symptoms throughout the dayAnti–acetylcholine receptor antibody testing; anti–striated muscle antibody and anti–muscle specific tyrosine kinase antibody testing have less utilityNormalNormal CMAP amplitude at rest, reduced CMAP amplitude with repetitive nerve stimulation; fibrillation potentials Not typically performed
Spinal cord lesion (stroke, hemorrhage, mass)Variable depending on lesion location, may be unilateral or bilateralUpperAcute (stroke), gradual (mass)Back pain, bowel or bladder incontinenceMRI may reveal etiologyNot typically obtainedNot typically performedNot typically performed
DermatomyositisProximalAcute or subacuteViolaceous rash on the knuckles and extensor surfaces of the upper extremities (Gottron papules [ ]), violaceous rash on the eyelids and periorbital edema (heliotrope rash), violaceous rash on the upper chest and neck (V-sign) or back (shawl sign); calcinosis; interstitial lung disease; disordered GI motility; dysphagiaElevated myoglobin; positive for antinuclear antibodies; may be positive for myositis autoantibodiesGreater than 10 times the normal elevationsActive and chronic myopathic unitsInflammatory infiltrate with myopathic changes and replacement by adipose and collagen
Inclusion body myositisDistal, especially forearm and hand; later stage may involve proximal weaknessGradualDysphagia (present in up to 80% of cases); extramuscular involvement not as commonElevated myoglobin; antinuclear antibodies less common; myositis autoantibodies may be presentElevatedActive and chronic myopathic unitsInflammatory infiltrate with vacuoles containing eosinophilic inclusions; ragged red or ragged blue fibers
Necrotizing myositisProximal, often profoundAcuteMay be associated with viral illness, malignancy, or statin use; dysphagiaAnti–signal recognition particle antibody; anti–3-hydroxy-3-methylglutaryl coenzyme A reductase antibodyMarkedly elevated (can be over 50 times normal limit)Active myopathic unitsScattered necrosis, deposits of complement may be noted on capillaries
PolymyositisProximalAcute or subacuteSimilar in presentation to dermatomyositis but without dermatologic signs; interstitial lung disease; disordered GI motility; dysphagiaElevated myoglobin; antinuclear antibodies less common; myositis autoantibodies may be presentGreater than 10 times normal elevationsActive and chronic myopathic unitsInflammatory infiltrate with myopathic changes and replacement by adipose and collagen
Adrenal insufficiency (Addison disease)GeneralizedVariableHypotension, hypoglycemia, bronzing of the skinHyponatremia, hyperkalemia; adrenocorticotropic hormone assay and stimulation testNormalMyotonic discharges Diminished glycogen content
Elevated thyroid hormone (hyperthyroidism)Proximal, bulbarVariableWeight loss, tachycardia, increased perspiration, tremorElevated thyroxine (T ) and triiodothyronine (T ) hormones; thyroid-stimulating hormone variable depending on causeNormal or elevatedMyopathic MUAPs with or without fibrillation potentials Usually normal
Endogenous glucocorticoid excess (Cushing syndrome)ProximalVariableBuffalo hump, purple striae, osteoporosisElevated urine-free cortisol, dexamethasone suppression, or corticotropin-releasing hormone stimulation testsNormal or lowMyopathic MUAPs Selective atrophy of type II muscle fibers, absent necrosis
Low/absent thyroid hormone (hypothyroidism)ProximalVariableMenorrhagia, bradycardia, goiter, delayed relaxation of deep tendon reflexesThyroid-stimulating hormoneElevatedWith or without myopathic MUAPs and fibrillation potentials Myopathic changes, glycogen accumulation
Parathyroid hormone (secondary hyperparathyroidism )Proximal, lower extremity more than upper extremityVariableUsually has associated comorbidities (cardiovascular disease, diabetes mellitus); positive Chvostek or Trousseau signsHypocalcemia; uremiaNormalMyopathic MUAPs Atrophy of type II muscle fibers;increased lipofuscin beneath cell membrane; calcium deposits in muscle
Becker muscular dystrophyHip, proximal leg and armGradualIntellectual disability, cardiomyopathyVarious specific molecular genetic tests are availableElevatedMyopathic MUAPs with fibrillation potentials Myopathic changes, decreased and patchy staining of dystrophin
Glycogen and lipid storage diseases, mitochondrial diseasesProximalVariableVariable; exercise intolerance and cardiomyopathy more commonSome glycogenoses associated with abnormal findings on forearm ischemic exercise testing Variable, may increase with exerciseNormal or myopathic MUAPs with or without fibrillation potentials Myopathic changes with glycogen deposits, lipid deposits, or ragged red fibers (for glycogen, lipid, or mitochondrial disease, respectively)
Limb-girdle muscular dystrophyVariable; usually proximal limb, pelvic, and shoulder girdle musclesGradualVariable, may have cardiac abnormalitiesVarious specific molecular genetic tests availableVariable, normal, or elevatedMyopathic MUAPs with or without fibrillation potentials Myopathic changes, may demonstrate absence of specific protein on immunohistochemical staining
Myotonic dystrophy type 1Distal greater than proximal, foot drop, oropharyngeal, temporal and masseter wasting, difficulty opening hand after tight gripGradualCardiac conduction abnormalities, balding, intellectual disability, gonadal atrophy, cataracts, insulin resistance, scoliosisMolecular genetic testing may demonstrate unstable CTG trinucleotide repeat in the DMPK gene of chromosome 19Normal to minimally elevatedMyopathic MUAPs, myotonic discharges Less necrosis and remodeling than in muscular dystrophy, atrophy of type I muscle fibers, ring fibers
FluoroquinolonesDistalAcute or subacuteTendon swelling or erythema, tendon rupture in severe casesUltrasonography or MRI may demonstrate tendon ruptureNot typically performedNot typically performed
GlucocorticoidsTypically affects proximal and postural musclesAcute, subacute, or gradualBuffalo hump, purple striaeNo reliable biomarkers; may have leukocytosisNormal or lowMyopathic MUAPs Selective atrophy of type II muscle fibers, absent necrosis
StatinProximal (may be distal)Acute or subacuteMyalgia often affecting bilateral large muscle groups, such as back, buttock, thigh, and shoulder girdle muscles; onset shortly after medication initiation; higher risk in females, older people, and those with lower muscle massNoneElevatedMyopathic MUAPs Myonecrosis in severe cases
Alcohol (myopathy or neuropathy)Proximal (may be distal)Alcoholic neuropathy: lower; alcoholic myopathy: —VariableChange in mental status, telangiectasia, peripheral neuropathyElevated transaminase and gamma-glutamyltransferase levels, anemia, decreased vitamin B levels Normal to elevatedNormalMyopathic changes, selected atrophy of type II muscle fibers
Sarcopenia and frailtyVariable, slow gait speed, diminished grip strengthGradual onset in patients older than 65 yearsLoss of muscle mass, cachexiaNo specific biomarkers but may have low creatinine, decreased insulinlike growth factor 1, albumin, or vitamin D levels; may have elevated interleukin-6Normal or lowNot typically performedSample may be inadequate because of lack of muscle mass; fatty infiltration

Upper motor neurons, which are located in the cerebral cortex, brainstem, and corticospinal tracts, may be injured from stroke, multiple sclerosis, and spinal cord or brain masses. Lower motor neurons, which are located in the anterior horn of the spinal cord, nerve roots, and peripheral nerves, may be damaged by infections, Guillain-Barré syndrome, hereditary sensorimotor disorders (e.g., Charcot-Marie-Tooth disease), compressive neuropathy (e.g., carpal tunnel syndrome), radiculopathy from intervertebral disk herniation, inflammation, spinal muscular atrophy type IV, or amyloid infiltration. 2 , 23 – 25

Upper and lower motor neurons are involved in amyotrophic lateral sclerosis. 24 The neuromuscular junction is the site of pathology in myasthenia gravis and Lambert-Eaton syndrome, which are rare autoimmune-mediated disorders. 7 , 8

Weakness is the predominant feature of primary muscle disorders, or myositides. Some of these disorders, such as dermatomyositis, polymyositis, and necrotizing myositis, present with acute or subacute proximal weakness and may be associated with malignancy or connective tissue disorders. Conversely, inclusion body myositis, which tends to occur in older adults, has a gradual course, affecting distal muscles early and progressing in an asymmetric pattern. 9 , 10 , 26 , 27

Some endocrine disorders can cause weakness. These include hyperthyroidism and hypothyroidism, adrenal insufficiency (Addison disease), endogenous glucocorticoid excess (Cushing syndrome), acromegaly, and primary hyperaldosteronism (Conn syndrome). 3 Diabetic neuropathy may affect motor neurons, including the oculomotor nerve. 28

ELECTROLYTE DISTURBANCES

Numerous electrolyte imbalances are linked to muscle weakness, including disturbances in calcium, phosphate, potassium, and sodium. Hypokalemia is particularly common and can be caused by medications, such as diuretics; Gitelman syndrome (hypokalemic periodic paralysis); renal tubular acidosis; primary hyperaldosteronism; thyrotoxicosis; or infections, such as dengue fever. 3 , 4 , 29 – 31

Muscular dystrophy usually presents during childhood or adolescence, but certain subtypes (e.g., Becker muscular dystrophy, myotonic dystrophy) can present during adulthood. 11 Disorders of lipid and glycogen metabolism and disorders of mitochondria can also cause weakness, myopathy, and rhabdomyolysis; these disorders may be exacerbated by exercise or febrile illnesses and rarely present in adults. 32 , 33

MEDICATIONS

Numerous medications have been reported to cause muscle weakness ( Table 2 4 , 12 – 14 , 34 ) , including several commonly used medications. For example, statins are well known to cause myopathy and rhabdomyolysis, although the mechanism is unclear. 12 , 13 Fluoroquinolones are linked to tendinopathies, rhabdomyolysis, and tendon ruptures. 12 Glucocorticoids can cause a noninflammatory myopathy, primarily affecting postural muscles. 12 , 14 A medication review is thus essential in the evaluation of muscle weakness. 4 , 12 , 35

Amiodarone
Antimicrotubular medications (colchicine, vincristine)
Antiretroviral medications (nucleoside reverse transcriptase inhibitors, such as zidovudine [Retrovir], stavudine, and lamivudine [Epivir]; protease inhibitors, such as indinavir [Crixivan], saquinavir [Invirase], and ritonavir [Norvir])
Any medication causing hypocalcemia/hypercalcemia or hypokalemia/hyperkalemia
Fibrates
Fluoroquinolones
Gemfibrozil (Lopid)
Glucocorticoids (systemic)
HMG-CoA reductase inhibitors (statins) Hydroxychloroquine (Plaquenil)
Hydroxyurea
Interferon alfa
Local anesthetics
Omeprazole (Prilosec)
Penicillamine (Cuprimine)
Phenytoin (Dilantin)
Silicone gel (ruptured breast implant)

Exposure to heavy metals, such as arsenic, lead, thallium, and mercury, can cause motor neuropathy; therefore, a toxin review should be completed in patients with muscle weakness . 4 , 35 Organophosphate poisoning causes weakness at the level of the neuromuscular junction, with severe cholinergic effects (toxidrome). Alcohol and certain recreational drugs (e.g., “glue sniffing,” cocaine, amphetamines, opioids) can also cause muscle weakness. Alcohol is neurotoxic and myotoxic at high doses and can cause acute muscle weakness in individuals who binge drink. 15

Envenomation, including from tick bites (tick paralysis) and certain venomous snake bites, may cause weakness. Exposure to Clostridium botulinum toxin from eating contaminated or undercooked food causes acute paralysis by blocking release of acetylcholine into the neuromuscular junction. 4 , 11 , 35

Certain infections are linked to muscle weakness. These include West Nile virus infection, HIV infection, Lyme disease, diphtheria, dengue fever, neurocysticercosis, trichinosis, Chagas disease, rabies, botulism, herpes zoster, cytomegalovirus infection, hepatitis C, and herpes simplex virus 1 infection. Lyme disease, herpes zoster, and potentially herpes simplex virus 1 infection can cause facial nerve palsy (Bell palsy). Poliomyelitis was historically a significant cause of flaccid paralysis but now rarely occurs because of worldwide vaccination efforts. 3 , 23 , 24 , 29 , 30 , 36 , 37

SARCOPENIA AND FRAILTY

When evaluating generalized weakness in older adults, sarcopenia and frailty should be considered in the differential diagnosis. Sarcopenia and frailty are common multifactorial syndromes that typically do not occur in younger people. They are associated with increased morbidity, disability, institutionalization, and mortality. Sarcopenia is thought to be catabolic age-related loss of muscle mass and strength and can be evaluated by measuring grip strength, gait speed, and muscle mass. 38 , 39 Frailty, which often coexists with sarcopenia, can be defined as the presence of three or more of the following: grip weakness, slow gait speed, unintentional weight loss, subjective exhaustion, and low physical activity. 40

Physicians should inquire about onset, duration, and progression of symptoms. Acute onset of weakness (hours to days) should prompt timely evaluation, because it may indicate vascular, infectious, inflammatory, metabolic, or toxin-mediated disorders. Subacute presentation (days to weeks) may suggest electrolyte, inflammatory, or rheumatologic disorders. More gradual progressive weakness often suggests neurologic, genetic, or metabolic disorders or inclusion body myositis. 2 , 9 , 11 , 29

The history should be guided by knowledge of the potential diagnoses and proceed in a stepwise approach ( Figure 1 2 – 5 , 7 – 24 , 26 – 33 , 35 – 38 , 41 – 44 ) . Specific elements of the history may provide diagnostic clues ( Table 3 2 – 4 , 7 – 11 , 13 , 22 – 24 , 26 – 28 , 31 , 35 , 43 , 44 ) .

case study of muscle weakness

Diplopia, blurry visionMyasthenia gravis (intermittent), diabetic neuropathy (permanent)
DysphagiaInflammatory myopathy, motor neuron disease, myasthenia gravis, muscular dystrophy, botulism
Facial nerve paralysis (Bell palsy)Lyme disease, herpes zoster (Ramsay Hunt syndrome), herpes simplex virus 1 infection
Fevers, arthralgias, rashInflammatory or infectious myopathy
Monocular vision loss, bladder dysfunctionMultiple sclerosis
PainNerve compression, rhabdomyolysis, inflammatory myopathy, inflammatory neuropathy (e.g., Parsonage-Turner syndrome), muscle damage due to toxins or medications (e.g., statins, fluoroquinolones)
ParesthesiaHereditary sensorimotor disorders (e.g., Charcot-Marie-Tooth disease), nerve compression, nerve damage due to toxins, multiple sclerosis
Raynaud phenomenonInflammatory myopathy
Tendon ruptureFluoroquinolone use
Cardiac arrhythmiasInflammatory myopathy, genetic disorders, electrolyte imbalances
Cholinergic toxidromeOrganophosphate poisoning
Chvostek sign, Trousseau sign, tetanyHypocalcemia
Cushingoid appearance (buffalo hump, purple striae)Glucocorticoid excess (endogenous [Cushing syndrome] vs. exogenous [long-term glucocorticoid use])
Fatigable weakness, ptosisMyasthenia gravis
HyperreflexiaUpper motor neuron lesion, hyperthyroidism, hypercalcemia
HyporeflexiaHypothyroidism, lower motor neuron lesion
Muscle atrophyLower motor neuron pathology, frailty/sarcopenia
Skin bronzingHypoaldosteronism (Addison disease)
Third cranial nerve (oculomotor nerve) palsyDiabetic neuropathy
Violaceous rash on the knuckles and extensor surfaces of upper extremities (Gottron papules [ ]), violaceous rash on the eyelids and periorbital edema (heliotrope rash), violaceous rash on the upper chest and neck (V-sign) or back (shawl sign)Dermatomyositis

In particular, identifying the distribution of weakness helps narrow the broad differential diagnosis. Patients with proximal (limb-girdle) weakness may have difficulty rising from a chair, climbing stairs, or lifting their arms overhead to perform activities of daily living (e.g., combing hair). 2 , 26 Proximal weakness is more common in myopathies. Patients with distal weakness may have difficulty opening jars or may drop objects or have foot drop. Distal weakness is more typically caused by certain toxins (e.g., organophosphates), hereditary motor neuropathy, or early inclusion body myositis. 3 , 9 , 16 , 41 Simultaneous proximal and distal weakness may result from inclusion body myositis or Guillain-Barré syndrome.

Asymmetric weakness is typically neurologic and may be due to central nervous system lesions or peripheral nerve inflammation or compression. The physician should also inquire about the presence of oropharyngeal symptoms (e.g., dysphagia, dysarthria), vision loss, or diplopia, which can be indicative of inflammatory myopathy, multiple sclerosis, or myasthenia gravis, respectively. 2 , 9 – 11 , 27

The presence of accompanying sensory symptoms suggests a neuropathic etiology from intrinsic or extrinsic factors. For example, pain in the same distribution as the weakness suggests nerve compression, inflammatory neuropathy or myopathy, or muscle damage due to toxins or medications. History of fevers, arthralgias, rash, or Raynaud phenomenon suggests inflammatory etiologies. Fever also suggests infectious etiologies. All types of inflammatory myopathy can present with pain and muscle tenderness. 3 , 10 , 26

Patients with myasthenia gravis often present with intermittent blurry vision or diplopia and less commonly with more generalized weakness. In addition, symptoms of myasthenia gravis often fluctuate, worsen throughout the day, and may be exacerbated by elevated temperatures. 7

A family history may help identify hereditary causes of muscle weakness. 2 , 11 , 17 A medication review and screening for substance use should always be performed in patients with muscle weakness. 15 , 35

Physical Examination

Physical examination is crucial to diagnosing the cause of muscle weakness. Weakness should be formally graded and documented with a tool such as the Medical Research Council Manual Muscle Testing scale ( Table 4 45 ) .

5: Muscle movement/activation against examiner's full resistance
4: Muscle strength is reduced but movement/activation against some resistance is possible
3: Muscle movement/activation against gravity (e.g., raising leg or arm) but not against resistance
2: Muscle movement/activation only when not moving against gravity (e.g., not lifting leg or raising arm)
1: Trace muscle movement/activation (e.g., a twitch)
0: No muscle movement/activation

NEUROLOGIC EXAMINATION

A neurologic examination should be performed in patients with muscle weakness to observe signs of upper motor neuron vs. lower motor neuron pathology. Upper motor neuron findings include spasticity (e.g., spastic gait), hyperreflexia, upgoing-toe plantar reflexes (positive Babinski reflex), dysarthria, clonus, and poor coordination. Lower motor neuron findings include diminished or absent reflexes, hypotonia, muscle atrophy (e.g., hoarse voice from laryngeal muscle atrophy), and fasciculations. Visual inspection of the muscles with attention to bulk, involuntary movements, and symmetry is also important.

Hyperreflexia can occur with upper motor neuron lesions, hyperthyroidism, and hypercalcemia. Hypocalcemia is suggested with tetany, Chvostek sign (tapping the facial nerve anterior to the earlobe and inferior to the zygomatic arch elicits ipsilateral facial nerve spasm), and Trousseau sign (inflation of a brachial blood pressure cuff induces distal carpopedal spasm). Up to 94% of patients with hypocalcemia present with Trousseau sign, although Chvostek sign is neither sensitive nor specific for hypocalcemia. 43 , 44

Cranial nerve examination can reveal facial nerve weakness suggesting Lyme disease, herpes simplex virus 1 infection, or herpes zoster (Ramsay Hunt syndrome). 37 Ptosis or diplopia may suggest myasthenia gravis. Motor strength worsens with repetition in patients with myasthenia gravis, whereas strength and reflexes may transiently improve after repetitive muscle contraction in patients with Lambert-Eaton syndrome. 7 , 8

The distribution of weakness elicited in the history should be confirmed on physical examination with careful attention to proximal vs. distal strength and symmetric vs. asymmetric strength.

EXTRANEUROLOGIC FINDINGS

Extraneurologic findings may help narrow the diagnosis in patients with muscle weakness. As noted earlier, fever suggests inflammatory or infectious myopathy. Cushingoid appearance (buffalo hump, purple striae) suggests endogenous or exogenous glucocorticoid excess. A violaceous rash on the knuckles and extensor surfaces of the upper extremities (Gottron papules; Figure 2 46 ) , a heliotrope rash, the V-sign (violaceous rash on the upper chest and neck), and the shawl sign (violaceous rash on the back) occur with dermatomyositis. Cardiac arrhythmias may occur with inflammatory myopathy, genetic disorders, and electrolyte imbalances. 3 , 9 , 10 , 14 , 26

case study of muscle weakness

Numerous screening tools are available to evaluate weakness in older patients if sarcopenia or frailty is suspected. They include the Fried frailty index, FRAIL (fatigue, resistance, ambulation, illnesses, loss of weight) scale, grip strength analysis, and gait speed analysis. 47 Grip strength can be measured objectively with a dynamometer, and gait speed can be measured by timing a patient's usual walking gait to the examination room or by using the Timed Up and Go test. 48 Age-specific normative values for grip strength and gait speed are available. 38 , 39

Laboratory Evaluation

Depending on clinical findings and suspected diagnosis, focused or expansive laboratory testing may be indicated in patients with muscle weakness.

Creatine kinase elevation is nonspecific but can help narrow the differential diagnosis and confirm myopathy. 26 Creatine kinase levels should not be checked immediately after electrodiagnostic testing because they may be transiently elevated. 5 , 18 Myoglobinuria may also indicate myopathy. 3

Because metabolic abnormalities may contribute to weakness, an electrolyte panel should be considered to determine levels of calcium, potassium, sodium, phosphate, and magnesium. Thyroid function testing and cortisol measurement should also be considered.

Serum testing for infectious etiologies, including HIV infection, Lyme disease, West Nile virus infection, and dengue fever, may be indicated if a pathogen is suspected. Lumbar puncture may be indicated if central nervous system infection is suspected.

Anti–acetylcholine receptor antibodies are present in 80% to 90% of patients with generalized myasthenia gravis but in only 50% to 55% of patients with isolated ocular myasthenia gravis. 7 , 11 If clinical suspicion is high despite negative findings on serum anti–acetylcholine receptor antibody testing, the patient should be referred to a neurologist. 4 , 7 , 11

Specific serum molecular genetic testing may be performed if there is concern for genetic disorders, although this testing is typically ordered by a specialist (e.g., neurologist, rheumatologist, geneticist).

Imaging and Electrodiagnostic Testing

Timely neuroimaging is critical in the evaluation of suspected stroke and cauda equina syndrome. If other neurologic diagnoses (e.g., multiple sclerosis, spinal stenosis, stroke) are suspected, appropriate imaging should be performed. Magnetic resonance imaging and ultrasonography of muscle tissue may be used in the diagnosis of inflammatory myopathy. 5

Electromyography should be performed in patients with muscle weakness if the diagnosis is unclear after a history, physical examination, and targeted laboratory evaluation. 5 , 18 , 19 , 26 Electromyography assists in localizing the cause of weakness to the motor neuron, neuromuscular junction, or muscle. 3 Although electromyography complements the neurologic examination, the findings are not pathognomonic for specific diseases. Abnormal findings on electromyography, with or without muscle imaging, may help localize a suitable site for muscle biopsy. 5 , 18 , 19

Muscle Biopsy

Muscle biopsy is considered the definitive test for diagnosing myopathies; however, it is invasive and used sparingly. Muscle biopsy should be considered to clarify the diagnosis in patients who have objective weakness with elevated creatine kinase levels or abnormal findings on electromyography or on muscle magnetic resonance imaging. 20 , 21 Biopsy may also be necessary in cases of suspected inflammatory myopathy if the skin findings of dermatomyositis are absent. 9 , 10

Muscle biopsy is generally performed as an outpatient procedure by a surgical consultant. The ideal biopsy site is a muscle that exhibits mild-to-moderate clinical weakness. Severely weak muscles should be avoided, because biopsy of a muscle in an advanced stage of myopathy often shows signs of fibrosis or fatty infiltration, yielding nondiagnostic results. 5 , 9 Muscle biopsy in older patients with significant sarcopenia is unlikely to be diagnostic. 5 Complications of muscle biopsy are uncommon but include pain, stiffness, bleeding, and infection. 5 , 21

This article updates a previous article on this topic by Saguil . 6

Data Sources: We searched PubMed, the Cochrane database, and Essential Evidence Plus for the terms muscle weakness, muscle weakness evaluation, myopathy, motor neuropathy, muscle biopsy, neurologic weakness, electrodiagnostic testing weakness, myasthenia gravis, Lambert Eaton, inflammatory myopathy, sarcopenia, frailty, Guillain Barré, Parsonage Turner, hypocalcemia, Chvostek, Trousseau calcium, and multiple sclerosis. Search dates: January 12 to June 13, 2019, and September 22, 2019.

Looker AC, Wang CY. Prevalence of reduced muscle strength in older U.S. adults: United States, 2011–2012. January 2015. Accessed February 17, 2019. https://www.cdc.gov/nchs/products/databriefs/db179.htm

Barohn RJ, Amato AA. Pattern-recognition approach to neuropathy and neuronopathy. Neurol Clin. 2013;31(2):343-361.

Chawla J. Stepwise approach to myopathy in systemic disease. Front Neurol. 2011;2:49.

Nayak R. Practical approach to the patient with acute neuromuscular weakness. World J Clin Cases. 2017;5(7):270-279.

Rosow LK, Amato AA. The role of electrodiagnostic testing, imaging, and muscle biopsy in the investigation of muscle disease. Continuum (Minneap Minn). 2016;22(6):1787-1802.

Saguil A. Evaluation of the patient with muscle weakness. Am Fam Physician. 2005;71(7):1327-1336. Accessed August 23, 2019. https://www.aafp.org/afp/2005/0401/p1327.html

Juel VC, Massey JM. Myasthenia gravis. Orphanet J Rare Dis. 2007;2:44.

Hülsbrink R, Hashemolhosseini S. Lambert-Eaton myasthenic syndrome. Clin Neurophysiol. 2014;125(12):2328-2336.

Dalakas MC. Inflammatory muscle diseases. N Engl J Med. 2015;372(18):1734-1747.

Lundberg IE, Miller FW, Tjärnlund A, et al. Diagnosis and classification of idiopathic inflammatory myopathies. J Intern Med. 2016;280(1):39-51.

McDonald CM. Clinical approach to the diagnostic evaluation of hereditary and acquired neuromuscular diseases. Phys Med Rehabil Clin NAm. 2012;23(3):495-563.

Klopstock T. Drug-induced myopathies. Curr Opin Neurol. 2008;21(5):590-595.

Thompson PD, Panza G, Zaleski A, et al. Statin-associated side effects. J Am Coll Cardiol. 2016;67(20):2395-2410.

Minetto MA, D’Angelo V, Arvat E, et al. Diagnostic work-up in steroid myopathy. Endocrine. 2018;60(2):219-223.

Simon L, Jolley SE, Molina PE. Alcoholic myopathy: pathophysiologic mechanisms and clinical implications. Alcohol Res. 2017;38(2):207-217.

Andersen H. Motor neuropathy. Handb Clin Neurol. 2014;126:81-95.

Iyadurai SJ, Kissel JT. The Limb-Girdle muscular dystrophies and the dystrophinopathies. Continuum (Minneap Minn). 2016;22(6, Muscle and Neuromuscular Junction Disorders):1954-1977.

Lacomis D. Electrodiagnostic approach to the patient with suspected myopathy. Neurol Clin. 2012;30(2):641-660.

Valls-Solé J. The utility of electrodiagnostic tests for the assessment of medically unexplained weakness and sensory deficit. Clin Neurophysiol Pract. 2016;1:2-8.

Wilson D, Breen L, Lord JM, et al. The challenges of muscle biopsy in a community based geriatric population. BMC Res Notes. 2018;11(1)-830.

Joyce NC, Oskarsson B, Jin LW. Muscle biopsy evaluation in neuromuscular disorders. Phys Med Rehabil Clin N Am. 2012;23(3):609-631.

Reich DS, Lucchinetti CF, Calabresi PA. Multiple sclerosis. N Engl J Med. 2018;378(2):169-180.

Garg N, Park SB, Vucic S, et al. Differentiating lower motor neuron syndromes. J Neurol Neurosurg Psychiatry. 2017;88(6):474-483.

Tiryaki E, Horak HA. ALS and other motor neuron diseases. Continuum (Minneap Minn). 2014;20(5, Peripheral Nervous System Disorders):1185-1207.

Shin SC, Robinson-Papp J. Amyloid neuropathies. Mt Sinai J Med. 2012;79(6):733-748.

Schmidt J. Current classification and management of inflammatory myopathies. J Neuromuscul Dis. 2018;5(2):109-129.

Schmidt K, Schmidt J. Inclusion body myositis: advancements in diagnosis, pathomechanisms, and treatment. Curr Opin Rheumatol. 2017;29(6):632-638.

Callaghan BC, Cheng HT, Stables CL, et al. Diabetic neuropathy. Lancet Neurol. 2012;11(6):521-534.

Kumar Singh A, Kumar Maurya P, Kulshreshtha D, et al. Analysis of clinical and metabolic profile of acute neuromuscular weakness related to hypokalemia. Acta Neurol Taiwan. 2017;26(3):97-105.

Lana-Peixoto MA, Pedrosa D, Talim N, et al. Myelitis and cauda equina involvement following dengue fever. Mult Scler Relat Disord. 2018;20:48-50.

Diringer M. Neurologic manifestations of major electrolyte abnormalities. Handb Clin Neurol. 2017;141:705-713.

Pennisi EM, Garibaldi M, Antonini G. Lipid myopathies. J Clin Med. 2018;7(12):E472.

Frezza E, Terracciano C, Giacanelli M, et al. Late-onset Pompe disease with nemaline bodies. Case Rep Neurol Med. 2018:4127213.

Zhou SF, Xue CC, Yu XQ, et al. Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit. 2007;29(6):687-710.

Mammen AL. Toxic myopathies. Continuum (Minneap Minn). 2013;19(6 Muscle Disease):1634-1649.

Gabbai AA, Castelo A, Oliveira AS. HIV peripheral neuropathy. Handb Clin Neurol. 2013;115:515-529.

Hehir MK, Logigian EL. Infectious neuropathies. Continuum (Minneap Minn). 2014;20(5, Peripheral Nervous System Disorders):1274-1292.

Dodds R, Sayer AA. Sarcopenia and frailty: new challenges for clinical practice. Clin Med (Lond). 2015;15(suppl 6):s88-s91.

Liguori I, Russo G, Aran L, et al. Sarcopenia. Clin Interv Aging. 2018;13:913-927.

Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146-M156.

Dimachkie MM, Barohn RJ. Distal myopathies. Neurol Clin. 2014;32(3):817-842.

Feinberg JH, Radecki J. Parsonage-Turner syndrome. HSS J. 2010;6(2):199-205.

Cooper MS, Gittoes NJ. Diagnosis and management of hypocalcaemia [published correction appears in BMJ . 2008;336(7659):10.1136/bmj.a334]. BMJ. 2008;336(7656):1298-1302.

Hujoel IA. The association between serum calcium levels and Chvostek sign: a population-based study. Neurol Clin Pract. 2016;6(4):321-328.

Naqvi U, Sherman AI. Muscle strength grading. StatPearls. Accessed February 17, 2019. https://www.ncbi.nlm.nih.gov/books/NBK430685/

Kim HS, Kim SM, Lee JD. Erythematous papules on dorsum of both hands. Am Fam Physician. 2017;95(12):803-804. Accessed August 26, 2019. https://www.aafp.org/afp/2017/0615/p803.html

Cesari M, Calvani R, Marzetti E. Frailty in older persons. Clin Geriatr Med. 2017;33(3):293-303.

Savva GM, Donoghue OA, Horgan F, et al. Using Timed Up-and-Go to identify frail members of the older population. J Gerontol A Biol Sci Med Sci. 2013;68(4):441-446.

Continue Reading

case study of muscle weakness

More in AFP

More in pubmed.

Copyright © 2020 by the American Academy of Family Physicians.

This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP.  See permissions  for copyright questions and/or permission requests.

Copyright © 2024 American Academy of Family Physicians. All Rights Reserved.

  • Open access
  • Published: 30 October 2021

Development of the Myasthenia Gravis (MG) Symptoms PRO: a case study of a patient-centred outcome measure in rare disease

  • Sophie Cleanthous 1 ,
  • Ann-Christin Mork 2 ,
  • Antoine Regnault 3 ,
  • Stefan Cano 1 ,
  • Henry J. Kaminski 4 &
  • Thomas Morel   ORCID: orcid.org/0000-0002-0690-5359 2 , 5  

Orphanet Journal of Rare Diseases volume  16 , Article number:  457 ( 2021 ) Cite this article

6399 Accesses

11 Citations

12 Altmetric

Metrics details

Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease, characterised by fluctuating muscle weakness which makes it challenging to assess symptom severity. Mixed methods psychometrics (MMP), which combines evidence from qualitative research and modern psychometrics, is a versatile approach to the development of patient-centred outcome measures (PCOM) in the context of rare disease. Our objective was to develop the MG Symptom patient-reported outcome (PRO) to assess key aspects of MG severity from the patient perspective.

We used MMP to develop a novel PRO instrument in a multi-step process. An initial conceptual model for MG patient experience was developed and expanded based on preliminary literature review and two waves of concept elicitation interviews with people with MG (Step 1). Based on this, the novel PRO instrument, the MG Symptoms PRO, was drafted. The draft instrument was refined by combining qualitative and quantitative data collected in a Phase 2 clinical study (Step 2).

Findings from the literature review and concept elicitation interviews (n = 96) indicated that patient experience in MG includes proximal muscle weakness symptoms related to several body parts, along with muscle weakness fatigability and general fatigue. Then, a set of 42 items across five scales (ocular-, bulbar-, and respiratory muscle weakness, physical fatigue, and muscle weakness fatigability) was developed. Qualitative evidence endorsed its relevance, clarity, and ease of completion; quantitative analysis with Rasch measurement theory methods demonstrated strong measurement properties, including good targeting and high reliability. Classical test theory analyses showed adequate reliability of the instrument and mild to moderate correlations with other widely used MG-specific outcome measures.

Conclusions

The MG Symptoms PRO has potential to be used both to measure treatment benefit in clinical trials and monitor symptom severity in clinical practice. Its component scales were purposefully designed to stand alone, enhancing interpretability of scores given the heterogeneity of MG, and enabling modular use. Compared with existing MG PROs, it contains more detailed assessments of muscle weakness and muscle weakness fatigability symptoms, which are of key importance to people with MG. The MMP approach used may serve as a case study for developing PCOMs across rare disease indications.

Introduction

Patient-centred outcome measures (PCOMs) are essential for demonstrating that treatment effects translate into a clinical benefit that is meaningful to patients. PCOMs are powerful tools because they focus on issues that matter most to patients, ensuring that their experiences are accurately reflected in clinical research and practice. Unfortunately, for many rare disease indications PCOMs are either not available or not widely used [ 1 ]. Development of patient-reported outcome (PRO) instruments in the context of rare disease is challenging, because low prevalence limits the number of patients available to participate in PRO development efforts, and because heterogeneity of symptom presentation, disease severity and progression often further complicates the process [ 1 , 2 , 3 ].

In the recent IRDiRC Orphan Drug Development Guidebook, PCOMs were identified as a ‘building block’ for orphan drug developers, and their use is encouraged as efficacy endpoints in clinical trials, outcome measures in registries, or tools to monitor care delivery. The Guidebook outlines several requirements for developing a PCOM, including the generation of extensive patient evidence (preferably through mixed methods research) and psychometric data, multi-stakeholder collaboration and, for developing de novo PCOMs in particular, regular scientific advice from regulatory bodies [ 4 ].

Myasthenia gravis (MG) is a rare, clinically heterogeneous autoimmune neuromuscular disease [ 5 ] with an estimated annual incidence of 1 in 500,000 people in the US and an estimated prevalence of between 1 in 2500 and 1 in 200,000 people [ 6 ]. In Europe, it is estimated that 2 in 10,000 people are affected by MG [ 7 ]. MG is caused by the production of pathogenic IgG autoantibodies against neuromuscular junction components (AChR, MuSK and LRP4) and manifestation can be generalised (gMG), affecting bulbar, limb and respiratory muscles [ 8 ], or limited to ocular (oMG), where weakness is confined to extraocular muscles [ 9 ]. Most people present with oMG, but 80–85% of cases progress to gMG [ 10 , 11 ].

gMG is characterised by fluctuating and variable muscle weakness, muscle fatigability (i.e., triggering or worsening of an impairment with usual or normal activities, or onset/worsening of an impairment over the course of the day) and generalised fatigue (i.e., becoming increasingly tired). Symptoms contribute differently to the degree of clinical disability [ 12 ] but collectively impact many aspects of the quality of life of people living with MG. These range from physical exertions (e.g., walking and doing housework), social activities, sleep, psychological health and professional development [ 13 , 14 , 15 ]. In cases where muscle weakness extends to the respiratory muscles, the condition may become life-threatening [ 8 ].

Due to this fluctuating and unpredictable disease course and the subjective nature of symptoms such as fatigue, PRO instruments have the potential to provide greater insight into the experience of people living with MG than traditional clinical endpoints, and regulators are encouraging their use as primary efficacy trial endpoints [ 12 ]. However, the heterogeneity of the disease can lead to a lack of correlation between some clinical measures at onset and remission or worsening episodes (e.g., the Myasthenia Gravis Foundation of America [MGFA] clinical classification) [ 16 ]. Robust PCOM and PRO instruments genuinely grounded in the patient experience would complement the currently widely-used clinician-reported measures that aim to quantify the severity of MG based on impairments to body functions, such as Quantitative Myasthenia Gravis Score (QMG) and Myasthenia Gravis Composite (MGC) [ 17 , 18 ].

Multiple PRO instruments have been developed to capture the impact of MG on an individual’s life, including the Myasthenia Gravis Activities of Daily Living (MG-ADL) [ 19 ], MG Disability Assessment (MG-DIS) [ 14 ], the MG Fatigue Scale (MGFS) [ 20 ], and the MG Quality of Life 15 (MG-QoL-15) [ 21 ]. However, these PRO instruments may not comprehensively assess the range of symptoms and functional impact proximal to the MG experience [ 12 ] and fatigability, in particular, is often overlooked [ 22 ]. Additionally, these PRO instruments largely fail to meet the latest regulatory and expert recommendations in relation to having patients involved in the development process [ 4 , 23 , 24 ].

Mixed methods psychometrics (MMP) is an approach that can be used in the development of PCOM instruments. MMP combines evidence from both qualitative and quantitative sources in an iterative process, on the premise both evidence sources are essential, but neither sufficient independently. As such, MMP is ideal for patient-centred research, as it encompasses both patient experience and feedback throughout the instrument development process to ensure that the PRO item content is important and relevant to patients [ 25 ]. The versatility of MMP is valuable in challenging contexts such as rare disease, where trial cohorts are small, as it maximises the amount of evidence that can be used in the PCOM development process [ 1 ].

The objective of this paper is to describe the development of a new PRO instrument, the MG Symptoms PRO, which was developed and validated using state-of-the-art MMP psychometric analyses, including interviews with over 90 patients and examination of measurement performance in people living with MG. Development of the MG Symptoms PRO can be used as a test-case for developing PCOMs in rare disease.

Study design and data collection

We performed a two-step MMP study (Fig.  1 ). Step 1 involved a literature review and two waves of interviews with people with MG, leading to the development of a preliminary conceptual model of the patient experience in MG and draft items for the new PRO instrument. In Step 2, the analysis of qualitative and quantitative data from the phase 2 clinical trial MG0002 [ 26 ], in which the draft items were tested, led to the refinement of the conceptual model and draft item set. The study provided qualitative evidence from participant exit interviews and qualitative evidence from the analysis of the draft items in line with RMT. Additionally, supportive evidence on measurement properties was generated in the MG0002 study cohort sample using CTT. Feedback from clinical experts with more than 20 years of experience in treating MG was sought to inform interpretation of results and decision making.

figure 1

Study design for development of the MG Symptoms PRO, a new PCOM in rare disease. MG myasthenia gravis, PCOM patient-centred outcome measure, PRO patient-reported outcome, RMT Rasch measurement theory

Step 1: Literature review and two waves of interviews

The literature review appraised qualitative studies related to the patient perspective of disease experience in MG and disease-specific PRO instruments. Analysis of the reviewed qualitative studies led to the development of a preliminary conceptual model. The content of available PRO instruments was further mapped onto the conceptual model to examine the coverage of these instruments against the concepts important to people living with MG.

Step 1 also included two waves of interviews conducted with individuals recruited from the Myaware MG patient association in the UK ( www.myaware.org ) based on self-reported MG diagnosis. In Wave 2, people with oMG or diagnosis of Lambert-Eaton myasthenic syndrome (LEMS) were excluded. Interviews were conducted over the telephone using a semi-structured interview guide. Ethical approval for the interviews in Step 1 was granted by the UK NHS Health Research Authority ( https://www.hra.nhs.uk/ ).

Wave 1 of the interviews focused on concept elicitation to explore concepts important to patients; including their symptom experience and the impact of MG on their daily life. Analysis led to the development of a preliminary conceptual model of the patient experience in MG; generation of bespoke draft PRO items related to MG symptoms; and identification of the FATIGUE-PRO Physical Fatigue subscale as a candidate PRO instrument with content relevance in MG warranting further examination with participants [ 27 ].

Wave 2 of the interviews comprised both concept elicitation and cognitive debriefing, aiming to further build on the MG experience model while reviewing the draft items resulting from Wave 1 analysis as well as the FATIGUE-PRO Physical Fatigue items. Cognitive debriefing followed a ‘think-aloud’ process [ 28 , 29 , 30 ] to elicit spontaneous and probed feedback on the items` relevance, clarity, and ease of completion.

Step 2: MG0002 study exit interviews and PRO instrument completion

Face-to-face exit interviews were conducted locally by study personnel at the final study visit of the Phase 2 MG clinical study, MG0002 (ClinicalTrials.gov Identifier: NCT03052751), conducted across the US, Canada and Europe (Belgium, Czech Republic, Denmark, Germany and Spain) [ 26 ].

The objectives and design of the exit interviews were similar to those in Wave 2 of Step 1, comprising both a concept elicitation and cognitive debriefing section. MG0002 included people with moderate-to-severe gMG who were being considered for treatment with immunological therapy and had evidence of anti-AChR or anti-MuSK autoantibodies [ 26 ]. The draft MG Symptoms PRO was completed by MG0002 participants at 13 study visits during the treatment and observation periods. Ethical approval for the interviews in Step 2 was granted as part of the MG0002 study ethical approval/consent process.

MMP analysis

We applied an MMP approach in Step 1 and Step 2, combining qualitative and quantitative analytic techniques, to generate evidence to inform item selection and refinement and to identify any anomalies in the item set [ 25 ].

Qualitative analysis

Interviews were transcribed verbatim and translated into English where applicable (22 of 36 interviews at Step 2 required translation). Thematic analysis was performed [ 31 ] with ATLAS.ti using a detailed, line-by-line, open and inductive coding approach [ 32 , 33 , 34 ]. Analytic techniques of conceptual model development were used to categorise the codes into higher order domains reflecting their underlying conceptual content [ 32 , 33 , 35 ]. Cognitive debriefing analysis involved multiple-level codes containing information on the corresponding item, response scale or instruction and the corresponding issue identified, findings of which were reviewed descriptively for each scale and item.

Item generation

Following both Step 1, Wave 1 and Step 2 analysis, new PRO items were generated based on the concept elicitation findings. Item generation followed item construction principles [ 24 , 36 , 37 , 38 , 39 ], aiming to include an adequate range of items to cover the conceptual breadth within each of the target concepts of interest. Lay language and as many of the participants’ own words as possible were used, while aiming for brevity and minimal semantic overlap.

Quantitative analysis

The measurement properties of the PRO item sets were examined using both modern psychometrics (RMT) and traditional psychometrics (CTT). RMT analysis was used to first evaluate the measurement properties and make decisions on item selection and refinement, whereas CTT analysis was used to produce supportive evidence on the final PRO item sets.

RMT analysis was used to examine the measurement properties of each of the proposed draft item sets [ 40 , 41 , 42 ]. Specifically, it examined whether item response data achieved the requirements specified by the Rasch model in relation to (1) scale-to-sample targeting, (2) item response thresholds, (3) item fit, (4) item dependency and (5) person separation index (PSI). The principles of RMT analysis have been extensively described elsewhere [ 43 ]. We applied RMT analysis in two steps of the study design. First, a macro-level RMT analysis was performed on the data collected in the Wave 2 interviews of Step 1 to gain early insight on the item set. Second, a full RMT analysis was performed on the stacked data from all thirteen time-points of MG0002 in Step 2 using RUMM2030 software (RUMM Laboratory; Perth, Australia). In Step 2, RMT analysis was conducted in two rounds: First on the draft version of the scales; and, second on the available data of the revised version of the scales following the MMP results interpretations (Fig.  4 ). Stacked data were used to maximise the sample size of these analyses, which were repeated for comparative purposes on the first time-point of MG0002.

CTT psychometric analyses were further conducted on the MG0002 study data (Step 2) to generate complementary evidence for each scale of the PRO instrument that resulted from the RMT analysis. Investigated psychometric properties included reliability, both internal consistency (Cronbach’s alpha coefficient) and test–retest reliability (intraclass correlation coefficients were calculated in various sample and at various time-points), and construct validity (association of the reviewed scales with other available clinical outcome measures: QMG, MG Composite, MG-ADL). CTT analyses were performed using SAS v9.4 (SAS Institute, Thousand Oaks, NC, USA).

Integration of qualitative and quantitative analyses

All decisions regarding item modification or selection were informed by both qualitative and quantitative results, according to a pre-defined frame of reference devised to guide the decisions according to the following criteria [ 27 ]:

Comprehensiveness: Informed by the breadth of coverage by the item set of both the qualitative conceptual model and of the quantitative measurement continuum from the Rasch model;

Targeting and item quality: Informed by the endorsement of the items by participants in the qualitative feedback and match between the distribution of items and persons and appropriate item fit in the RMT analysis;

Conceptual uniqueness: Informed by the lack of overlap between items reported by participants in the qualitative feedback, and the spread of the items on the continuum and absence of local dependency in the RMT analysis; and

Appropriateness of response scale: Informed by any issues raised with the ease of selecting a response option by participants in the qualitative feedback, and the ordering of the item respond thresholds in a successive manner in the RMT analysis.

Sample characteristics

A total of 60 participants were recruited for the interviews conducted in Step 1 (30 participants for each wave). A further 43 participants were included from the MG0002 clinical study in Step 2 (Table 1 ), 36 of whom participated in the exit interviews.

Conceptual model of the patient experience in MG

Concept elicitation analyses across both steps of the study resulted in a consolidated model of MG patient experience (Fig.  2 ). The model summarises the experience of living with MG in two overarching domains: Proximal symptoms and bodily functions affected by MG (i.e., disease-defining concepts, e.g., core signs and symptoms); and more distal impacts of MG on patients` lives (e.g., social functioning). The model was updated and refined at every step of research whilst the distinction of the proximal and distal concepts was informed by consultation with MG clinical experts.

figure 2

Conceptual model of the patient experience in MG. a Activities of Daily Living (ADL) relates to routine activities including eating, bathing, dressing, toileting, transferring, and continence; b Instrumental activities of daily living (IADL) are activities related to independent living such as preparing meals, shopping for groceries or personal items, performing light or heavy housework, doing laundry, and using a telephone

Proximal symptoms were grouped into conceptual sub-domains in line with recognised MG symptomatology muscle groups, including ocular, bulbar and respiratory, as well as limbs axial and the entire body. Within each conceptual sub-domain examples of how muscle weakness manifests itself or affects bodily functions were included. For example, the bulbar sub-domain comprises a wide range of concepts, including general bulbar movements, facial drooping, saliva, liquid control, speech, and voice problems as well as chewing and choking. Concepts may also reflect different manifestations of each symptom and/or different severity levels of the symptom experience. The fatigue sub-domain appears to be relevant and proximal to the MG experience, particularly in relation to its physical manifestation. This is distinct from fatigability, which is a prominent proximal concept that can be relevant across symptoms and muscle groups for MG participants and is therefore present in multiple sub-domains in the model.

In addition, issues with motor and cognitive functioning were suggested by participants as relevant to their experience, as well as issues related to physical pain sensations and sleep, but these were deemed as less proximal upon consultation with the clinical experts. Lastly, a wide range of impact sub-domains were further identified with participants describing the impact of MG on their daily lives, from their basic daily activities to their instrumental, social and leisure activities, professional life, interpersonal relations, and feelings (psychological impact).

Step 1: Cardinal concepts and item generation for the new MG PRO

Review of the conceptual model (Fig.  2 ) led to the identification of the cardinal concepts of the proximal MG experience related to weakness and functional issues of the limb and axial, ocular, bulbar and respiratory muscles, and muscle weakness fatigability related to them, as well as physical fatigue (Fig.  3 ). The content of existing PRO instruments, including the MG-ADL [ 19 ], MG-QoL-15 [ 21 ], MG-DIS [ 14 ] and MGFS [ 20 ] identified and reviewed in the literature review (data not shown) was compared against the cardinal concepts in a qualitative mapping exercise. This exercise revealed gaps in the coverage of the reviewed PRO instruments, which either focused on more distal concepts or did not capture the proximal symptom concepts comprehensively. On this basis, 21 muscle weakness items across four muscle groups (i.e., ocular, bulbar, limbs and axial, and respiratory), and nine muscle weakness fatigability items were generated. Review of the physical fatigue concepts indicated that FATIGUE-PRO [ 27 ], a PRO instrument originally developed for systemic lupus erythematosus, was conceptually relevant to the aspects of the physical fatigue experience described in the context of MG. The physical fatigue domain scale (16 items) of the FATIGUE-PRO was therefore selected for further examination in MG alongside the newly generated items.

figure 3

MG Symptoms PRO domains and underlying concepts with example quotes from cognitive debriefing. *Limbs and Axial concepts merged with Physical Fatigue scale in the final MG Symptoms PRO scoring structure

MMP analysis indicated that the newly generated muscle weakness and muscle weakness fatigability items were clear, relevant, and easy to complete by people with MG. Some of the items, however, appeared to measure closely-related concepts (i.e., conceptual overlap), such as ‘pronouncing words’ and ‘slurred speech’, ‘nasal’ and ‘hoarse’ voice, and ‘swallowing’ and ‘controlling liquids in mouth’. Response scale issues were also identified, where participants were unable to distinguish accurately between the six different response options, particularly between ‘very mild’ and ‘mild’ options. The macro-level RMT analysis identified further issues related to potential conceptual overlap or uniqueness, item quality and appropriateness of response scale. Considering the small-scale basis of this analysis, the six-level response scale was retained with the plan to make a final decision on this issue at Step 2 of the work. Three items related to ‘aching’ were nonetheless deleted in response to clinical expert feedback in relation to their lack of specificity with MG pathology. A further item was rephrased to improve its clarity and interpretability resulting in the draft MG Symptoms PRO comprising two domain scales comprising 27 items: ‘Muscle weakness’ across ocular, bulbar, limbs and axial, and respiratory muscle groups (6-level severity scale; 18 items) and ‘muscle weakness fatigability’ (5-level frequency scale; 9 items) (Fig.  4 ).

figure 4

Item refinement of the MG Symptoms PRO. MG myasthenia gravis, MMP mixed methods psychometrics, PRO patient-reported outcome

The FATIGUE-PRO Physical Fatigue scale items were well-received with minimal interpretation or relevance issues and the macro-level RMT analysis demonstrated excellent targeting of this scale to the MG participants; therefore all 16 items (5-level frequency scale) were included in Step 2 analyses.

Step 2: Psychometric evaluation of draft scales and PRO instrument refinement based on MMP evidence

Comprehensiveness.

Participants did not specifically suggest that any symptom concepts were missing during the debriefing section; however, a qualitative comparison of item content against the refined conceptual model (Fig.  2 ) indicated minor gaps within the ocular and respiratory muscle weakness, which could be addressed with further item generation. Quantitative analyses showed good coverage of the targeted concepts in the participant sample (Additional file 1 ). Based on these findings, and in consultation with clinical experts, four additional items were generated: two related to ocular muscle weakness and two related to respiratory muscle weakness (Fig.  4 ).

Targeting and quality of items

Qualitative findings were supportive of the relevance, clarity, and ease of completion of items. Participants endorsed the relevance of the draft MG Symptoms PRO item content: On an individual item basis, items were found to be relevant to 86–100% of the sample. A few items related to bulbar symptoms proved not to be relevant for up to 14% of participants. This is in line with measurement development principles, aiming to generate item content reflective of different severity levels of the underlying construct of measurement, as well as clinical expectation of the increased relevance of bulbar symptoms in cases of higher MG disease severity. Findings for the FATIGUE-PRO physical fatigue scale were equally supportive, with items relevant to 86–100% of participants.

Quantitative RMT results (Table 2 ) indicated that all draft scales had good targeting, demonstrating the relevance of the item content in this population. No issues were identified with either the recall period or the instructions of these scales and there were few issues of clarity and interpretation; the draft MG Symptoms PRO items were found to be conceptually clear and unambiguous to 94–100% of the participants. A few items also showed some misfit to the Rasch model (Table 2 ).

Conceptual uniqueness of items and scales

Qualitatively, some conceptual overlap was suggested, particularly in the draft MG symptoms PRO bulbar items, where 3–28% of participants indicated conceptual overlap of four different items, and within the FATIGUE-PRO physical fatigue items, where 3–17% of participants indicated overlap with six items. Some item dependency issues were also identified in the quantitative analysis, suggesting potential overlap/redundancies in the content of the items, as well as potentially more than one concept underpinning these scales. Based on these findings, it was decided that the muscle weakness scale would be revised to move away from a single total score of muscle weakness and instead use standalone domain scales reflecting each of the different muscle groups. This would better reflect the heterogeneity of MG pathology, which was indicated by item fit issues, as well as the qualitative and clinical expert information. In addition, considering the relative relevance and overlap between the FATIGUE-PRO scales and the newly generated draft MG Symptoms PRO scales, it was decided to merge the FATIGUE-PRO physical fatigue scale with the limbs and axial items of the muscle weakness scales.

Appropriateness of response scale

Minimal issues were raised with the response scale during the interviews: Only one participant raised issues with selecting a response option for five of the draft MG Symptom PRO items. No response scale issues were identified for the FATIGUE-PRO physical fatigue scale. RMT analysis also uncovered some issues with the ordering of the item response thresholds, particularly with the muscle weakness 6-level severity scale, where more than a third of the items displayed disordering, suggesting participants could not distinguish between six unique levels of severity for these items in the draft MG Symptoms PRO. Based on these findings, and in consultation with clinical experts, the muscle weakness items` severity response scale was reduced to four levels (Fig.  4 ).

Step 2: Psychometric evaluation of the refined version of the PRO instrument

The outcome of the MMP steps described above was a refined version of the MG Symptoms PRO instrument (Fig.  4 ). A final round of psychometric evaluation was performed for this refined PRO instrument (Table 2 ) demonstrating supportive overall results for all scales (Fig.  5 ; Additional file 1 ).

figure 5

Exemplar sample-to-scale targeting plot—RMT analysis results for the Physical Fatigue scale. This figure depicts the person-item threshold distributions for the MG Symptoms PRO Physical Fatigue scale score, with persons (sample) distribution on top and scale item threshold distribution plotted on the same linear measurement continuum of physical fatigue. The sample distribution a represents the total score estimates for the physical fatigue scale plotted on a continuum of physical fatigue severity ranging from left (low severity) to right (high severity). The five-category response scale leads to four thresholds for each item. Therefore, the item threshold distribution b represents each of the four thresholds estimates for each item, plotted on the lower end of the same measurement continuum of physical fatigue. A threshold reflects the location on the measurement continuum where two adjacent response categories are equally likely to be endorsed. Targeting is assessed by examining the relative range and coverage of the sample distribution by the available item thresholds. The lower part of the figure c depicts the 15 items of the physical fatigue scale in the y-axis in order of increasing difficulty from top to bottom. The x-axis represents the most probable of the five response categories in the different coloured blocks across the range of the physical fatigue continuum. RMT expects the ordering of the response categories to reflect the intended severity i.e., from none of the time to all the time

Targeting analyses demonstrated that the scales covered a good range of the participant sample locations (Additional file 1 ). Figure  5 shows the RMT analysis results for the Physical Fatigue scale, as an example. Only the bulbar muscle weakness scale had a relatively narrow coverage and larger floor effects, suggesting that items were not as relevant to participants with lower disease severity, which is in line with clinical expectations of bulbar symptoms (Additional file 1 ).

The person separation indices were high for all scales except the ocular muscle weakness scale (Table 2 ) which could be linked to the relatively small item number (n = 3) in the available data, but also to the specific composition of the sample, which excluded patients with ocular symptoms alone. The refined four-level severity scale of the muscle weakness items largely resolved the disordering of the original response scale with disordering being limited to one item. However, some item misfit and dependency issues persisted, particularly for the bulbar muscle weakness and physical fatigue scales (Fig.  5 ; Additional file 1 ).

Relative to the 18-item muscle weakness draft scale, the refined bulbar muscle weakness scale demonstrated sub-optimal targeting, and the ocular muscle weakness scale demonstrated reduced reliability. However, these findings were in line with clinical and measurement expectations. As bulbar symptoms are linked with higher levels of disease severity, the sub-optimal targeting of the scale for people with lower disease severity levels aligns with clinical expectation. The limited number of items of the ocular scale could further contribute to the reduced reliability of the scale. However, the generation of two additional ocular items could likely lead to improvement in the scale`s reliability, as shown by the conceptual clarity gained by refined muscle-group-specific scales in the context of a heterogenous condition, as opposed to the draft versions where all of these were part of a single muscle weakness score.

CTT results were also supportive of all revised scales, with good to excellent reliability demonstrated for most scales. Internal consistency (Cronbach’s alpha coefficients ranged from 0.70 to 0.95) with the scale comprising the fewer items; ocular muscle weakness showing the lowest reliability coefficient. Test–retest reliability coefficients were also supportive, particularly between study visits 13 and 15 (range 0.78 to 0.97) (Additional file 1 ). The correlations of the MG Symptoms PRO scale scores with clinician-reported measures (i.e., QMG, MGC) and the MG-ADL were at best moderate, which was expected given the difference in the targeted concept (Additional file 1 ).

We have developed a new MG-specific PCOM, the MG Symptoms PRO, using mixed methods evidence generated across 103 people living with MG, combined with sustained interactions with clinical experts and regulatory agencies. This new PRO instrument comprises 42 items across five scales: ocular-, bulbar-, and respiratory muscle weakness, physical fatigue, and muscle weakness fatigability—all rated on a recall period of 7 days (Fig.  4 ). The scales were purposefully designed as standalone to enhance score interpretation, and to allow for modular use (each scale can be used independently, depending on the specific concept of interest to be measured), given the heterogeneity of MG.

Compared with currently available PRO instruments, such as the MG-ADL [ 19 ], MG-DIS [ 14 ], MGFS [ 20 ], MG-QoL-15 [ 21 ] and MG Impairment Index (MGII) [ 44 ], the MG Symptoms PRO benefits from wider conceptual coverage and more patient-centred test design. Specifically, the MG Symptoms PRO contains more granular content and a detailed assessment of muscle weakness across different muscle groups, elaborate assessment of muscle weakness fatigability, as well as specific assessment of physical fatigue not currently included in other PRO instruments [ 22 ].

Unlike currently available PRO instruments, the development of the MG Symptoms PRO incorporated patient input at every stage, in line with regulatory and expert guidance for PCOMs [ 23 , 24 ]. The MG Symptoms PRO further benefits from the application of the MMP approach and incorporation of complementary quantitative evidence, early in the item development process. This helped inform decisions on: Item and response scale refinement; scoring structure; and further demonstrated the strengths of the instruments` measurement properties early in the development process.

In a rare disease context, MMP proved to be a nimble and powerful approach to define and then refine a clinically meaningful set of items to assess MG severity. The extensive qualitative research has helped to provide a better understanding of MG, with a clear conceptualisation of the patient experience. The extensive qualitative patient input has ensured that the MG Symptoms PRO contains items covering all concepts relevant to the patient experience of MG, and worded in an appropriate way, whilst removing items linked to less relevant concepts. Moreover, the quantitative RMT analyses demonstrated the measurement robustness of the MG Symptoms PRO.

This study has three main limitations. First, although screening/inclusion criteria were applied to participants recruited for Step 1 of the work, no diagnostic confirmation of MG status was provided for participants as Myaware UK is a small patient advocate group. We aimed to correct for this by expanding our concept elicitation research in a clinically-defined sample [ 26 ]. Second, the item ‘neck weakness’, which is scored on a severity response scale, was included in the draft 18-item ‘muscle weakness scale’ in Step 1 but was moved to the ‘physical fatigue’ scale in Step 2, where other items are assessed by a frequency response scale. Third, the development and generation of early psychometric evidence on the MG Symptom PRO was performed in a relatively older, Caucasian sample, where mean ages in Step 1 were 64.2 years (range 26–85) and 66.9 years (range 24–84) for waves 1 and 2 respectively. The MG Symptoms PRO would benefit from further evaluation in participants of a wider age range, different socioeconomic status, and from different ethnicities or cultures.

Whilst the MG Symptoms PRO has an improved conceptual coverage as well as test design compared to other PRO instruments used in MG (MG-ADL, MG-DIS, MGFA, MG-QoL-15), it still requires further validation. Our currently available results indicated some outstanding conceptual overlap between items of the bulbar muscle weakness scale and other gaps for the measurement of ocular symptoms and respiratory symptoms. Four additional items have been developed to bridge those gaps and more data are needed to document their measurement performance, as well as explore possible refinement of the scales by excluding conceptually redundant items. For this purpose, the MG Symptoms PRO is being used in clinical studies to provide more data on the instrument. The next stage of this research will involve gathering additional qualitative and quantitative evidence on items generated following Step 2 and further exploration of some of the less optimal findings, as well as exploration of clinical meaningful change thresholds for this PRO instrument.

In comparison to currently available PRO instruments used in MG, the MG Symptoms PRO contains more granular content and a detailed assessment of muscle weakness and muscle weakness fatigability symptoms, presented in a simple patient-centred way. This instrument also includes a detailed assessment of physical fatigue, an aspect of generalised fatigue not included in other PRO instruments. The MMP approach has allowed enhanced interpretation of not only item suitability, but also scale appropriateness. Most importantly, this instrument was developed with input from people with MG throughout the whole process leading to an instrument that is truly patient-centric, from the development of a conceptual model of MG through to the design of the actual instrument, including item terminology, item appropriateness and responses levels. Considering our qualitative and quantitative findings, the MG Symptoms PRO instrument shows promise as a measure of the symptoms experienced by people living with MG. It has great potential for both demonstration of treatment benefits in a clinical trial context and monitoring of symptom severity in a clinical practice setting, benefitting from a modular scale structure which enhances assessment and interpretability of outcomes in a heterogenous condition such as MG. Finally, the rigorous MMP approach followed in the development of the MG-Symptoms PRO offers a strong methodological framework for the development of future fit-for-purpose PRO instruments in the context of rare disease.

Availability of data and materials

Data sharing from non-clinical studies is outside of UCB’s data sharing policy, therefore the datasets used and/or analysed during development of the MG Symptoms PRO are available from the corresponding author on reasonable request. However, data from the MG0002 clinical trial may be requested by qualified researchers 6 months after product approval in the US and/or Europe, or global development is discontinued, and 18 months after trial completion. Investigators may request access to anonymised individual patient-level data and redacted trial documents which may include: Analysis-ready datasets, study protocol, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a prespecified time, typically 12 months, on a password protected portal.

Morel T, Cano SJ. Measuring what matters to rare disease patients—reflections on the work by the IRDiRC taskforce on patient-centered outcome measures. Orphanet J Rare Dis. 2017;12(1):171.

Article   Google Scholar  

Kempf L, Goldsmith JC, Temple R. Challenges of developing and conducting clinical trials in rare disorders. Am J Med Genet A. 2018;176(4):773–83.

Nestler-Parr S, Korchagina D, Toumi M, Pashos CL, Blanchette C, Molsen E, et al. Challenges in research and health technology assessment of rare disease technologies: report of the ISPOR rare disease special interest group. Value Health. 2018;21(5):493–500.

IRDiRC. Orphan drug development guidebook. Building block I415: development and use of patient-centered outcome measures (PCOM). 2020 Available from: https://irdirc.org/building-block-forms-development-practices/ .

Binks S, Vincent A, Palace J. Myasthenia gravis: a clinical-immunological update. J Neurol. 2016;263(4):826–34.

Article   CAS   Google Scholar  

NIH Genetic and Rare Diseases Information Center. Myasthenia gravis 2020. Updated 2016. Available from: https://rarediseases.info.nih.gov/diseases/7122/myasthenia-gravis .

European Medicines Agency. EU/3/20/2272 2020. Available from: https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3202272 .

Gilhus NE, Tzartos S, Evoli A, Palace J, Burns TM, Verschuuren J. Myasthenia gravis. Nat Rev Dis Prim. 2019;5(1):30.

Nair AG, Patil-Chhablani P, Venkatramani DV, Gandhi RA. Ocular myasthenia gravis: a review. Indian J Ophthalmol. 2014;62(10):985–91.

Wang L, Zhang Y, He M. Clinical predictors for the prognosis of myasthenia gravis. BMC Neurol. 2017;17(1):77.

Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future. J Clin Investig. 2006;116(11):2843–54.

Thomsen JLS, Andersen H. outcome measures in clinical trials of patients with myasthenia gravis. Front Neurol. 2020;11:596382.

Chen YT, Shih FJ, Hayter M, Hou CC, Yeh JH. Experiences of living with myasthenia gravis: a qualitative study with Taiwanese people. J Neurosci Nurs. 2013;45(2):E3–10.

Raggi A, Schiavolin S, Leonardi M, Antozzi C, Baggi F, Maggi L, et al. Development of the MG-DIS: an ICF-based disability assessment instrument for myasthenia gravis. Disabil Rehabil. 2014;36(7):546–55.

Richards HS, Jenkinson E, Rumsey N, Harrad RA. The psychosocial impact of ptosis as a symptom of myasthenia gravis: a qualitative study. Orbit. 2014;33(4):263–9.

Khadilkar SV, Chaudhari CR, Patil TR, Desai ND, Jagiasi KA, Bhutada AG. Once myasthenic, always myasthenic? Observations on the behavior and prognosis of myasthenia gravis in a cohort of 100 patients. Neurol India. 2014;62(5):492–7.

Barnett C, Merkies IS, Katzberg H, Bril V. Psychometric properties of the quantitative myasthenia gravis score and the myasthenia gravis composite scale. J Neuromuscul Dis. 2015;2(3):301–11.

Silvestri NJ, Wolfe G. Myasthenia gravis: classification and outcome measures. In: Tarsy D, editor. Myasthenia gravis and related disorders. 3rd ed. Cham: Springer; 2018.

Google Scholar  

Wolfe GI, Herbelin L, Nations SP, Foster B, Bryan WW, Barohn RJ. Myasthenia gravis activities of daily living profile. Neurology. 1999;52(7):1487–9.

Kittiwatanapaisan W, Gauthier DK, Williams AM, Oh SJ. Fatigue in myasthenia gravis patients. J Neurosci Nurs. 2003;35(2):87–93.

Burns TM, Conaway MR, Cutter GR, Sanders DB, Muscle Study G. Less is more, or almost as much: a 15-item quality-of-life instrument for myasthenia gravis. Muscle Nerve. 2008;38(2):957–63.

Barnett C, Bril V, Kapral M, Kulkarni A, Davis AM. A conceptual framework for evaluating impairments in myasthenia gravis. PLoS ONE. 2014;9(5):e98089.

Food and Drug Administration. Patient-focused drug development—collecting comprehensive and representative input 2020 updated June 2020. Available from: https://www.fda.gov/media/139088/download .

Food and Drug Administration. Guidance for industry: patient-reported outcome measures: use in medical product development to support laveling claims 2009 [Available from: https://www.fda.gov/media/77832/download .

Regnault A, Willgoss T, Barbic S, International Society for Quality of Life Research Mixed Methods Special Interest G. Towards the use of mixed methods inquiry as best practice in health outcomes research. J Patient Rep Outcomes. 2018;2(1):19.

Bril V, Benatar M, Andersen H, Vissing J, Brock M, Greve B, et al. Efficacy and safety of rozanolixizumab in moderate-to-severe generalised myasthenia gravis: a phase 2 RCT. Neurology. 2021;96(6):e853–65.

CAS   PubMed   PubMed Central   Google Scholar  

Cleanthous S, Regnault A, Haier B, Stach C, Cano S, Morel T. A mixed methods psychometrics program for the development of a measure of fatigue in SLE. Qual Life Res. 2019;28:S152.

Blair J, Presser S. Survey procedures for conducting cognitive interview to prestest questionnaires: a review of theory and practice. In: JSM proceedings, survey reesearch methods section [Internet]. Alexandria, VA: American Statistical Association; [370–6]; 1993. Available from: http://www.asasrms.org/Proceedings/papers/1993_059.pdf .

Streiner D, Norman GR, Cairney J. Health measurement scales: a practical guide to their development and use. New York: Oxford University Press; 2015.

Book   Google Scholar  

Kerr C, Nixon A, Wild D. Assessing and demonstrating data saturation in qualitative inquiry supporting patient-reported outcomes research. Expert Rev Pharmacoecon Outcomes Res. 2010;10(3):269–81.

Braun V, Clarke V. Using thematic analysis in psychology. Qual Res Psychol. 2006;3(2):77–101.

Bryman A, Burgess RG, Paulsen Chico N, Droes N, Evans K, Hatton D, et al. Analyzing qualitative data. New York: Routledge; 1994.

Thomas DR. A general inductive approach for analyzing qualitative evaluation data. Am J Eval. 2006;27(2):237–46.

Bowling A. Research methods in health: investigating health and health services. Maidenhead: Oxford University Press; 2014.

Klassen AF, Pusic AL, Scott A, Klok J, Cano SJ. Satisfaction and quality of life in women who undergo breast surgery: a qualitative study. BMC Womens Health. 2009;9:11.

Kline P. A handbook of test construction: introduction to psychometric design. London: Routledge; 2015.

Feinstein AR. Clinical biostatistics. XLI. Hard science, soft data, and the challenges of choosing clinical variables in research. Clin Pharmacol Ther. 1977;22(4):485–98.

Fowler FJJ. Applied social research methods series. Improving survey questions: design and evaluation, vol. 38. Thousand Oaks: Sage Publications Inc.; 1995.

DeVellis RF. Scale development: theory and applications. 4th ed. Thousand Oaks: Sage Publications Inc.; 2017.

Andrich D. Rating scales and Rasch measurement. Expert Rev Pharmacoecon Outcomes Res. 2011;11(5):571–85.

Rasch G. Probabilistic Models for some intelligence and attainment tests. Chicago: Mesa Press; 1960.

Wright BD, Stone MH. Best test design: Rasch measurement. Chicago: Mesa Press; 1979.

Hobart J, Cano S. Improving the evaluation of therapeutic interventions in multiple sclerosis: the role of new psychometric methods. Health Technol Assess. 2009;13(12):1–177.

Barnett C, Bril V, Kapral M, Kulkarni A, Davis AM. Development and validation of the myasthenia gravis impairment index. Neurology. 2016;87(9):879–86.

Download references

Acknowledgements

The authors thank the participants and the Myaware patient association in addition to the investigators and their teams who contributed to these interviews and trial; Nadine McGale for her support in the qualitative analyses and Flora Mazerolle for her support with quantitative CTT analyses. Veronica Porkess, PhD, CMPP, of UCB Pharma provided editorial review and assistance. Paolo Eusebi provided data visualisation support. Rebekka Harding-Smith of Ogilvy Health provided writing and editorial support.

Authors' information

Dr. Kaminski is a practicing neurologist who primarily sees people with MG. He also performs clinical and translational research in myasthenia gravis. He is the Principal Investigator of the Myasthenia Gravis Rare Disease Network (MGNet), which is part of the US National Institutes of Health’s Rare Diseases Clinical Research Network (RDCRN). Dr. Thomas Morel is also Research Fellow at KU Leuven (Belgium). He is also a member of the International Rare Diseases Research Consortium (IRDiRC)’s Therapies Scientific Committee.

This research and the MG0002 clinical study mentioned herein were funded by UCB Pharma, which is developing rozanolixizumab for use in MG. Medical writing support was provided by Niall Harrison and Rebekka Harding-Smith of Ogilvy Health, Oxford, UK, and funded by UCB Pharma, in accordance with Good Publications Practice (GPP3) guidelines ( http://www.ismpp.org/gpp3 ).

Author information

Authors and affiliations.

Modus Outcomes, Letchworth Garden City, UK

Sophie Cleanthous & Stefan Cano

UCB S.A., Allée de la Recherche, 60, 1070, Brussels, Belgium

Ann-Christin Mork & Thomas Morel

Modus Outcomes, Lyon, France

Antoine Regnault

George Washington University, Washington, DC, USA

Henry J. Kaminski

KU Leuven, Leuven, Belgium

Thomas Morel

You can also search for this author in PubMed   Google Scholar

Contributions

Authors have been included in this manuscript based on ICMJE recommendations. All authors read and approved the final manuscript. SCl contributed to research design, interview conduct, item generation, qualitative and quantitative data analysis, interpretation, and manuscript development. ACM contributed to research design and interpretation. AR contributed to research design, quantitative data analysis, interpretation, and manuscript development. SCa contributed to research design, item generation, qualitative and quantitative data analysis and interpretation. HK contributed to research design, interpretation, and manuscript development. TM contributed to research design, item generation, qualitative and quantitative data analysis, interpretation, and manuscript development. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Thomas Morel .

Ethics declarations

Ethics approval and consent to participate.

The MG0002 clinical study and the MG Symptoms PRO development study were performed in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonisation Guidance for Good Clinical Practice. Study protocol (appendix), amendments, and patient-informed consent were reviewed by national, regional, or independent ethics committees or institutional review boards. Written informed consent was obtained from all patients.

Consent for publication

Not applicable.

MG Symptoms PRO Copyright and Use

The copyright to the MG Symptoms PRO is owned by UCB Biopharma SRL, Belgium.

Competing interests

SCl, AR and SCa are employees of Modus Outcomes, which received payment from UCB to conduct this research. HK is principal investigator of the Rare Disease Clinical Research Network (U54 NS115054); a consultant for Alnylam Pharmaceuticals, Caballata Bio, Roche, and UCB Pharma; and is CEO and CMO of ARC Biotechnology, LLC, based on US Patent 8961981. ACM and TM are employees and shareholders of UCB Pharma.

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1..

Quantitative RMT and CTT results. Threshold distributions and CTT analysis results for original and revised scales.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

Cleanthous, S., Mork, AC., Regnault, A. et al. Development of the Myasthenia Gravis (MG) Symptoms PRO: a case study of a patient-centred outcome measure in rare disease. Orphanet J Rare Dis 16 , 457 (2021). https://doi.org/10.1186/s13023-021-02064-0

Download citation

Received : 04 June 2021

Accepted : 30 September 2021

Published : 30 October 2021

DOI : https://doi.org/10.1186/s13023-021-02064-0

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

  • Myasthenia gravis
  • Rare disease
  • Patient-centred
  • Mixed methods psychometrics

Orphanet Journal of Rare Diseases

ISSN: 1750-1172

  • Submission enquiries: Access here and click Contact Us
  • General enquiries: [email protected]

case study of muscle weakness

Search

U.S. flag

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

  • Publications
  • Account settings
  • My Bibliography
  • Collections
  • Citation manager

Save citation to file

Email citation, add to collections.

  • Create a new collection
  • Add to an existing collection

Add to My Bibliography

Your saved search, create a file for external citation management software, your rss feed.

  • Search in PubMed
  • Search in NLM Catalog
  • Add to Search

Understanding Clinical Characteristics of Muscle Weakness

  • PMID: 33538459
  • DOI: 10.1097/JNN.0000000000000574

BACKGROUND: Muscle weakness is a debilitating condition that can lead to frailty, falls, and functional decline. Muscle weakness is found across many diseases; therefore, understanding what constitutes this condition is paramount. The National Library of Medicine provides 2 definitions of muscle weakness, both from a disease perspective. These definitions are narrow and do not account for overlapping causes of muscle weakness. Nurses are holistic practitioners, so they need to understand the clinical characteristics of muscle weakness, regardless of underlying disease processes. METHODS: Secondary analysis of data from an earlier qualitative study. Using content analysis of transcripts of semistructured interviews with a multidisciplinary group of 12 experts in the management of muscle disorders, we identified characteristics of muscle weakness from the clinicians' perspectives. RESULTS: Muscle weakness has characteristics of debility, loss of function, and asymmetry. The characteristics of debility include lack of strength, atrophy, and fatigue. Muscle weakness does coexist with muscle tightness. CONCLUSIONS: The characteristics of muscle weakness identified in our study are markedly different from those included in National Library of Medicine definitions. As a condition, muscle weakness has both subjective and objective traits. Therefore, clinician assessment and patient input combined capture the comprehensive nature of muscle weakness. Nurses' awareness of what constitutes muscle weakness, regardless of diagnosis, is the first step in optimal management of this condition.

Copyright © 2021 American Association of Neuroscience Nurses.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Similar articles

  • Understanding Symptoms of Muscle Tightness, Weakness, and Rigidity From a Nursing Perspective. Bhimani RH, Soomar D. Bhimani RH, et al. Rehabil Nurs. 2019 Sep/Oct;44(5):271-281. doi: 10.1097/rnj.0000000000000151. Rehabil Nurs. 2019. PMID: 30624311
  • Consensus Definition of Muscle Tightness From Multidisciplinary Perspectives. Bhimani R, Gaugler JE, Felts J. Bhimani R, et al. Nurs Res. 2020 Mar/Apr;69(2):109-115. doi: 10.1097/NNR.0000000000000404. Nurs Res. 2020. PMID: 31702702
  • Understanding Symptoms of Muscle Tightness, Weakness, and Rigidity From a Nursing Perspective. [No authors listed] [No authors listed] Rehabil Nurs. 2019 Sep/Oct;44(5):E14. doi: 10.1097/RNJ.0000000000000241. Rehabil Nurs. 2019. PMID: 31469814 No abstract available.
  • [Neuromuscular Practical Knowledge: Focus On Muscle Weakness]. Schubert KM, Schreiner B. Schubert KM, et al. Praxis (Bern 1994). 2023 Jul;112(9):459-468. Praxis (Bern 1994). 2023. PMID: 37632430 Review. German.
  • Neuromuscular electrical stimulation for muscle weakness in adults with advanced disease. Jones S, Man WD, Gao W, Higginson IJ, Wilcock A, Maddocks M. Jones S, et al. Cochrane Database Syst Rev. 2016 Oct 17;10(10):CD009419. doi: 10.1002/14651858.CD009419.pub3. Cochrane Database Syst Rev. 2016. PMID: 27748503 Free PMC article. Review.
  • A comprehensive study of the academic benefits and practical recommendations to include resistance training programs in institutional education. Fraile-Martinez O, García-Montero C, Fraile-Martinez M, Pekarek L, Barrena-Blázquez S, López-González L, Álvarez-Mon MÁ, Pekarek T, Casanova C, Álvarez-Mon M, Diaz R, Saez MA, Ortega MA. Fraile-Martinez O, et al. Front Psychol. 2024 May 16;15:1387162. doi: 10.3389/fpsyg.2024.1387162. eCollection 2024. Front Psychol. 2024. PMID: 38817830 Free PMC article. Review.
  • A non-volitional skeletal muscle endurance test measures functional changes associated with impaired blood flow. Brandenberger KJ, Rawdon CL, Armstrong E, Lonowski J, Cooper L. Brandenberger KJ, et al. J Rehabil Assist Technol Eng. 2023 Apr 3;10:20556683231164339. doi: 10.1177/20556683231164339. eCollection 2023 Jan-Dec. J Rehabil Assist Technol Eng. 2023. PMID: 37035543 Free PMC article.
  • National Library of Medicine. Medical Subject Heading (MeSH) descriptor data. Paresis. Available at https://www.ncbi.nlm.nih.gov/mesh/68010291
  • National Library of Medicine. Medical Subject Heading (MeSH) descriptor data. Muscle weakness. Available at https://www.ncbi.nlm.nih.gov/mesh/68018908
  • Larson ST, Wilbur J. Muscle weakness in adults: evaluation and differential diagnosis. Am Fam Physician . 2020;101(2):95–108.
  • Oliveira MJP, Rodrigues F, Firmino-Machado J, et al. Assessment of respiratory muscle weakness in subjects with neuromuscular disease. Respir Care . 2018;63(10):1223–1230. doi:10.4187/respcare.06136 - DOI
  • Basso-Vanelli RP, Di Lorenzo VA, Labadessa IG, et al. Effects of inspiratory muscle training and calisthenics-and-breathing exercises in COPD with and without respiratory muscle weakness. Respir Care . 2016;61(1):50–60. doi:10.4187/respcare.03947 - DOI
  • Search in MeSH

Related information

Linkout - more resources, full text sources.

  • Ovid Technologies, Inc.
  • Wolters Kluwer

Other Literature Sources

  • scite Smart Citations

Research Materials

  • NCI CPTC Antibody Characterization Program

full text provider logo

  • Citation Manager

NCBI Literature Resources

MeSH PMC Bookshelf Disclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

  • Case report
  • Open access
  • Published: 01 October 2024

Functional movement disorder similar to Parkinson’s disease: a case report

  • Sarah Goudarzzadeh 1 ,
  • Shayan Shekarabi 1 &
  • Mahnaz Abdi 1  

Journal of Medical Case Reports volume  18 , Article number:  453 ( 2024 ) Cite this article

237 Accesses

Metrics details

Introduction

Functional neurological disorder challenges conventional medical understanding, presenting neurological symptoms without organic explanations. This report delves into the intricate interplay between psychological and physical manifestations, emphasizing the importance of timely diagnosis and intervention and its impact on a patient’s mental health and quality of life.

Case presentation

A 40-year-old single Iranian man was admitted for the third time owing to exacerbation of mood symptoms, including depression, irritability, aggression, suicidal ideation, and movement and sensory problems. The patient’s symptoms began with psychological stressors and family conflict, leading to muscle weakness and tremors in the left hand. Over a year, muscle weakness escalated, leading to slow movement, motor impairment in the lower limbs, and reliance on a cane for walking. The patient still exhibited symptoms, such as a mask-like face, stooped walking posture, and a relative improvement of symptoms periodically. At first, the patient was suspected of Parkinson’s disease and was placed on levodopa and amantadine. However, the medication was discontinued owing to an unsatisfactory response and the lack of strong evidence in favor of neurological problems on frequent examinations and reviews. Despite multiple hospitalizations, the patient’s symptoms remained unresolved. Finally, after years of investigations, based on specialists’ recommendations, he was admitted to the psychosomatic ward for diagnostic evaluationele, and he was diagnosed with functional neurological disorder (psychogenic parkinsonism). He underwent pharmacotherapy, electroconvulsive therapy, and psychotherapy. He was discharged with partial improvement of symptoms, but showed periods of relapse and remission during the following years.

This case study illuminates functional neurological disorder complexities, emphasizing the need for a holistic diagnostic approach. Timely interventions, including psychological support, can alleviate symptoms, reduce healthcare costs, and improve the overall prognosis. The report contributes to evolving functional neurological disorder understanding in psychiatry and neurology. The report underscores early recognition, advocating for comprehensive interventions involving psychiatric support, cognitive-behavioral therapy, and patient psychoeducation.

Peer Review reports

Functional neurological disorder (FND) is a condition in which the signs and symptoms are not effectively explained by known neurological or medical illnesses, or there is a discrepancy between the symptoms and ailments recognized as disorders [ 1 ].

FND represents a complex and often misunderstood category of conditions where patients experience neurological symptoms without an apparent organic cause. This enigmatic disorder challenges the conventional understanding of brain–body interactions, delving into the intricate interplay between psychological factors and physical manifestations. Mental health may be negatively impacted by the unpredictability of FND symptoms and their correlation with psychological variables, which may result in social isolation, stigma, and strained relationships [ 2 ]. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM5) lists a wide range of symptoms as specifiers for this illness, such as “with weakness or paralysis,” “with abnormal movement,” “with swallowing symptoms,” and so on [ 3 ].

Functional movement disorder (FMD) is a subtype of FND (also known as conversion disorder) and is characterized by abnormal body movements owing to abnormal functioning of the nervous system. The signs and symptoms of this condition do not resemble known neurologic disorders [ 2 ]. Neurologists or neuropsychiatrists should make the diagnosis based on the presence of “positive signs” of inconsistency and incongruency with neurological diseases [ 4 ]. According to the DSM-5, a current method for diagnosing FND involves identifying “positive signs” that can confirm the diagnosis of FMD rather than relying on excluding other neurological illnesses [ 4 , 5 ]. Exploring the etiology of FND reveals the role of stress, trauma, and emotional distress in triggering symptoms that mimic neurological disorders. FMD is common in clinical settings, but the diagnosis is often delayed or missed, and the prognosis for complete remission is generally poor. Despite its prevalence, FND remains underdiagnosed, with epidemiological studies shedding light on the substantial impact it has on individuals and healthcare systems. Over time, more emphasis has been placed on physical examination signs to guide the diagnosis and use of evidence-based treatments, including physiotherapy and multidisciplinary rehabilitation [ 6 ].

In this article, we present a case of functional Parkinsonism (psychogenic Parkinsonism), previously diagnosed as Parkinson’s disease and followed up at neurology clinics with antiparkinsonian treatment. As a striking example of functional Parkinsonism with an atypical presentation and a chaotic clinical course of Parkinsonism symptoms, we aimed to discuss the recognition of the disorder through specific findings and observations based on “rule-in” diagnosis during psychiatric evaluations to emphasize the importance of timely diagnosis and early intervention.

This report also endeavors to unravel the nuances of FND and a patient’s unique condition, offering insights into the intricate landscape of functional disorders within psychiatry and neurology.

A 40-year-old unmarried Iranian man with a bachelor’s degree in management was admitted to the psychiatric ward with self-consent for the third time owing to movement problems and exacerbation of mood symptoms, including depressed mood, irritability, aggression, and suicidal ideation. At the same time, he blamed his family for the above problems.

Neuropsychiatric symptoms began 4 years ago with the manifestation of physical symptoms such as weakness and numbness in the left upper limb, gradually involving the left shoulder, lower limb, and face. Despite comprehensive examinations by various specialties, such as neurologists and rheumatologists in various hospitals, to diagnose and treat physical symptoms, physicians have not reached a definitive diagnosis. It is noteworthy that the patient was farmer before his illness. He used to do other work, such as tiling and welding, but in recent years he has not been able to perform effectively owing to his illness. The patient and his family have no history of substance use, and no physical or mental illnesses were found in their medical records. There was no secondary gain in the investigations and during the follow up.

His issues, initially related to psychological stress and family and emotional stressors. The psychological stressors in patient’s life was love loss and emotional breakdown owing to the family’s opposition to their marriage, and the patient’s symptoms gradually manifested 1 or 2 months later as muscle weakness and tremors in the left hand following prolonged work in the garden. Subsequently, the muscle weakness intensified, causing motor impairment in the lower limbs, and he relied on a cane for walking. Despite multiple medical visits and thorough examinations, there was no improvement, and over the course of a year, his muscle weakness continued. The lower jaw and neck muscles also experienced weakness and occasional stiffness, making swallowing difficult and reducing appetite, leading to weight loss. Additionally, spasms in the facial region occurred, and the patient could only move his eyes during certain periods, particularly improving during sleep and recurring upon waking. During a neurological visit, there was a suspicion of Parkinson’s disease, and he was placed on a trial treatment with levodopa and amantadine. However, owing to the lack of proper treatment response, the side effects of the drug, and the patient’s intolerance, the drug was stopped after a while. Through numerous hospitalizations, consultations with neurology and internal medicine services, as well as various tests including Electromyography Test and Nerve Conduction Velocity (EMG-NCV), and radiological evaluations, such as brain and cervical magnetic resonance imaging (MRI), barium swallow endoscopy, and various laboratory tests, the only paraclinical finding was partial damage to the left ulnar nerve. Other evaluations were reported as normal.

Finally, based on specialists’ recommendations, he was admitted to the psychosomatic unit for diagnostic evaluation by a psychiatrist. In the clinical description, in addition to somatic symptoms, mood swings, irritability, sudden anger attacks, and aggression toward family members were noted. He exhibited a mask-like face and stooped walking posture during the physical examination. Although he used a cane for assistance, he could sit, stand, and walk without it during neurological examinations. He walked easily on his toes and heels and had good balance. There was stiffness in the elbow and wrist joints, which mostly favored Gegenhalten (oppositional paratonia). He performed well in the clock drawing test.

Muscle force was measured at 5/5 without fasciculations. No colonic movements in the limbs were noticed. His speech was incomprehensible owing to a low voice tone and jaw movement weakness, which fluctuated throughout the interview, but the form and content of his thoughts appeared normal. Tremors were also seen in the upper limbs, which fluctuated in intensity and frequency during the examination. The association between psychiatric manifestations and their impact on the deterioration of somatic symptoms (motor and sensory problems) was also highlighted. Consequently, with the initial diagnosis of major depressive disorder and FND (psychogenic parkinsonism), he underwent pharmacotherapy with sertraline (100 mg/day) and quetiapine (12.5 mg/day). After partially improving his emotional and movement symptoms, he was discharged. Following poor therapeutic compliance, he was urgently rehospitalized owing to the discontinuation of medications and a recurrence of symptoms, including suicidal thoughts. On the second admission, he received treatment with electroconvulsive therapy (ECT). Despite a satisfactory improvement after three sessions, he left the hospital with personal consent.

On the third admission, after a few months and a detailed evaluation of the clinical condition, the relationship between psychological conflicts and vivid clinical manifestations became more apparent. The patient was referred for psychotherapy after treatment with escitalopram (10 mg/day), sodium valproate (200 mg/day), and quetiapine (25 mg/day). At the time of discharge, after 3 weeks of hospitalization, the patient showed an acceptable improvement in physical and mental symptoms and had no specific drug side effects.

The patient has been followed up for more than 2 years. During this period, the patient’s symptoms had episodes of relapse and subsidence, which were related to mental stress and the discontinuation of medications. The patient is visited monthly by a psychiatrist, although he does not cooperate during psychotherapy. Thus far, he has not required readmission to the hospital.

In this case, the patient showed motor and sensory symptoms resulting from psychological problems, which disappeared following psychiatric treatments.

The patient’s medical and psychiatric history and its alignment with neurological findings and clinical observations, the pattern of recurrent remission and relapses in symptoms and complaints, along with the association with psychiatric symptoms, suggests the basis of functional issues in patients with movement disorders. FMD is characterized by the main presentation of tremors, dystonia, gait disturbance, or other forms of aberrant movement. Individuals diagnosed with FMD experience neurological symptoms that do not align with recognized neurological conditions yet are authentic, resulting in discomfort and psychosocial impairment [ 1 ]. Functional neurological disorders have an incidence of 4 to 12 per 100,000 population per year (4 to 5 per 100,000 population per year for FMD) and a prevalence of 50 per 100,000 population based on a community registry [ 7 ]. The frequency of psychogenic Parkinsonism among patients with psychogenic movement disorders is variable in different series, but is usually less than 10% [ 8 ].

Women are more frequently affected, although specific presentations such as functional myoclonus or Parkinsonism appear to have similar or greater frequency in men [ 7 ]. Given the diagnostic challenges, there is concern about misdiagnosis. Diagnosis by DSM-5 no longer requires identifying precipitating stressors, because these are not always found despite recent and historical stressors being more common in FNDs. Furthermore, the specificity and sensitivity of positive signs, which are essential in supporting a phenotype-based diagnosis, may be biased by several factors, including lack of gold standards against which to compare them, Inappropriate patient cooperation, coexistence of other neurological diseases, and unblinded assessments in most studies [ 7 ].

The tremor in Parkinson’s disease is referred to as a “resting tremor” since it presents primarily at rest. It goes away with movement but often returns when the limb, usually a hand or fingers, is held in one position. In contrast, tremors persist equally in resting and action states in FMDs. Functional tremor exhibits several distinct indicators, such as prominent features of distractibility (improvement with distraction), variability (changing pattern over time), effect of holding weight (tremor may be increase in amplitude or transmitted to other body segments), and entrainability, distinguishing it from Parkinson’s illness. Additionally, suggestibility, motor inconsistency and enhancement with attention favor functional disorders [ 9 ]. Entrainment can be demonstrated by asking the patient to copy a rhythmic movement with an unaffected limb, such as finger tapping. In functional tremor, tremor will either improve or change to match the frequency of the voluntary movement or the patient will have trouble copying the movement [ 8 ].

In our patient, tremor complaints were accompanied by fluctuations, diminished with distraction and exacerbated with attention, and temporarily arrested when the patient was asked to perform a ballistic contralateral movement (entrainability) and increased amplitude with a weight load, favoring functional tremor.

Other signs or symptoms that raised suspicion of Parkinson’s disease in this patient were bradykinesia and rigidity. Short-lived rigidity in the muscles of the left upper limb without cogwheeling was obtained, which is insufficient for a definitive diagnosis of true Parkinsonism but has led to persistent diagnostic uncertainties, numerous evaluations, and unsuccessful therapeutic efforts. Functional bradykinetic movements are slow and effortful but lack the typical decrement in speed or amplitude observed with successive movements in true bradykinesia (slowing without decrement). Moreover, a functional increase in muscle tone is the result of gegenhalten or paratonia rather than true rigidity (involuntary resistance to passive movement), and cogwheeling is absent. Additionally, unlike Parkinson’s disease, reinforcement maneuvers in psychogenic Parkinsonism reduce rigidity [ 4 , 8 , 10 ]. Atypical gait abnormalities and postural instability are often present in functional Parkinsonism. Postural stability testing (pull test) may reveal positive signs, such as arm-flailing and reeling backward without falling ( 10 ).

In our patient, bradykinetic movements were slow and laborious without typical reductions in speed or amplitude, simple movements appeared difficult (huffing and puffing sign), and rigidity was also without cogwheel and as involuntary resistance to passive movement (paratonia), suggesting functional impairment. Additionally, inconsistent deficit in gait and stance with normal period of walking was observed; pull test revealed arm-flailing and reeling backward without falling.

In addition to the above, abrupt onset of disease, history of precipitating event, fast progression to maximum symptom severity and disability, incongruity of symptom with a known neurological disease, waxing and waning symptoms over time, and functional disability out of proportion to examination findings in our patient was in favor of functional disorders.

In addition to the atypical and perplexing manifestations of FNDs, recent years have brought about other challenges, such as poor insight and acceptance, denial, obsessive doubts, excessive internet searches, and illness-related anxiety, affecting the patient’s psychological adjustment to these issues. This has left the patient and their family fatigued, hopeless, and trapped in a vicious circle. Ultimately, it has led to poor medication compliance and rendered treatment efforts less effective, with an increased frequency of hospitalizations marked by manifestations of mood and behavioral disturbances. Although clinical and laboratory findings, along with further follow-up over time, will evaluate this hypothesis. Here, the importance of early diagnosis of functional disorders and proper differentiation from medical conditions becomes prominent. Early intervention and psychiatric support, coupled with cognitive-behavioral therapy (CBT) in tandem with the treatment of comorbid psychiatric disorders, such as mood disorders, anxiety, and obsessive–compulsive disorders, along with education for the patient and their family, can significantly mitigate the exacerbation of symptoms in the future. A careful diagnosis is important in order to avoid unnecessary and invasive therapies such as harmful escalation of anti-parkinsonian medication, surgical ablative therapies, and deep brain stimulation. Moreover, this approach can also prevent unnecessary costs imposed on the patient and the healthcare system, improving the disease’s prognosis.

FMD is not a diagnosis of exclusion; it is a “rule-in” diagnosis that requires the presence of characteristic clinical features and the demonstration of positive signs. Investigations should be done as appropriate to rule out comorbid neurologic diseases. This case study illuminates FND complexities, emphasizing the need for a holistic diagnostic approach. Timely interventions, including psychological support, can alleviate symptoms, reduce healthcare costs, and improve the overall prognosis. The report contributes to evolving FND understanding in psychiatry and neurology. The report underscores early recognition, advocating for comprehensive interventions involving psychiatric support, cognitive-behavioral therapy, and patient psychoeducation.

Availability of data and materials

Data supporting our findings were taken from the patient’s folders.

Geddes JR, Andreasen NC. New Oxford textbook of psychiatry. Oxford: Oxford University Press; 2020.

Book   Google Scholar  

VandeVrede L. Oxford textbook of neuropsychiatry. J Neuropsychiatry Clin Neurosci. 2022;34(3):275.

Article   Google Scholar  

American Psychiatric Association D, Association AP. Diagnostic and statistical manual of mental disorders: DSM-5. Washington, DC: American psychiatric association; 2013.

Serranová T, Di Vico I, Tinazzi M. Functional movement disorder: assessment and treatment. Neurol Clin. 2023;41(4):583–603.

Article   PubMed   Google Scholar  

Aybek S, Perez DL. Diagnosis and management of functional neurological disorder. BMJ. 2022;376: o64.

Gilmour GS, Nielsen G, Teodoro T, Yogarajah M, Coebergh JA, Dilley MD, et al . Management of functional neurological disorder. J Neurol. 2020;267(7):2164–72.

Article   PubMed   PubMed Central   Google Scholar  

Espay AJ, Aybek S, Carson A, Edwards MJ, Goldstein LH, Hallett M, et al . Current concepts in diagnosis and treatment of functional neurological disorders. JAMA Neurol. 2018;75(9):1132–41.

Baizabal-Carvallo JF, Fekete R. Recognizing uncommon presentations of psychogenic (functional) movement disorders. Tremor Other Hyperkinet Mov. 2015;5:279.

Schwingenschuh P. Functional tremor. In: LaFaver K, Maurer CW, Nicholson TR, Perez DL, editors. Functional movement disorder: an interdisciplinary case-based approach. Cham: Springer International Publishing; 2022. p. 67–79.

Chapter   Google Scholar  

Kola S, LaFaver K. Updates in functional movement disorders: from pathophysiology to treatment advances. Curr Neurol Neurosci Rep. 2022;22(5):305–11.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Download references

Acknowledgements

The authors would like to express their gratitude to the Deputy of Research and Technology of Kurdistan University of Medical Sciences for the technical and editorial assistance.

No source of funding.

Author information

Authors and affiliations.

Neurosciences Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran

Sarah Goudarzzadeh, Shayan Shekarabi & Mahnaz Abdi

You can also search for this author in PubMed   Google Scholar

Contributions

Sara Goudarz Zadeh and Shayan Shekarabi drafted the manuscript and participated in collecting and interpreting the clinical data. Mahnaz Abdi revised the manuscript and collected and interpreted the clinical data. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Mahnaz Abdi .

Ethics declarations

Ethics approval and consent to participate.

This study was approved by the ethics committee of the Kurdistan University of Medical Sciences (code: IR.MUK.REC.1403.011).

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ .

Reprints and permissions

About this article

Cite this article.

Goudarzzadeh, S., Shekarabi, S. & Abdi, M. Functional movement disorder similar to Parkinson’s disease: a case report. J Med Case Reports 18 , 453 (2024). https://doi.org/10.1186/s13256-024-04767-x

Download citation

Received : 11 May 2024

Accepted : 21 August 2024

Published : 01 October 2024

DOI : https://doi.org/10.1186/s13256-024-04767-x

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

  • Psychogenic
  • Parkinsonism
  • Conversion disorder
  • Functional movement disorder

Journal of Medical Case Reports

ISSN: 1752-1947

  • Submission enquiries: Access here and click Contact Us
  • General enquiries: [email protected]

case study of muscle weakness

IMAGES

  1. AP2 WK1 Case Study Muscles

    case study of muscle weakness

  2. Muscle Actions Case Study S22.docx

    case study of muscle weakness

  3. Case Study Study Guide 15 Management of Patients With Musculoskeletal

    case study of muscle weakness

  4. Case Study Muscle Weakness.pdf

    case study of muscle weakness

  5. Muscle Weakness & Mesothelioma

    case study of muscle weakness

  6. Case Study (Weakness)

    case study of muscle weakness

VIDEO

  1. A case of ARM WEAKNESS & NUMBNESS

  2. Skeletal Muscle Fatigue & Post-Exertional Malaise in People w/Long Covid & Implications for ME/CFS

  3. To study muscle relaxants and drugs acting on CNS, using "Rota Rod" (Exam Mode & Download Option)

  4. Do Muscle Growth Studies Actually Work Or Are They Just Hype?

  5. Some training progress, 2013-10-15

  6. How to Study Muscle Action, Origin, and Insertion

COMMENTS

  1. Case 13-2024: A 27-Year-Old Man with Leg Weakness

    A 27-year-old man presented with weight loss, diarrhea, tremor, and proximal muscle weakness. The blood level of potassium was 1.8 mmol per liter. A diagnosis was made.

  2. Case 12-2023: A 44-Year-Old Woman with Muscle Weakness and ...

    A 44-year-old woman with rheumatoid arthritis was evaluated because of proximal muscle weakness and myalgia. She had difficulty raising her arms above her head. Diagnostic tests were performed.

  3. Case 14-2024: A 30-Year-Old Woman with Back Pain, Leg ...

    On examination, patients with classic stiff-person syndrome do not have weakness or sensory loss, and testing for increased muscle tone in the arms may show normal findings.

  4. Evaluation of the adult with acute weakness in the emergency ...

    The diagnosis of potentially life-threatening neurologic and neuromuscular processes requires a systematic, anatomic approach based upon a careful history, physical examination, and in some cases, imaging studies.

  5. Muscle Weakness in Adults: Evaluation and Differential ... - AAFP

    Determining the cause of muscle weakness can be challenging. True muscle weakness must first be differentiated from subjective fatigue or pain-related motor impairment with normal motor...

  6. Development of the Myasthenia Gravis (MG) Symptoms PRO: a ...

    Compared with existing MG PROs, it contains more detailed assessments of muscle weakness and muscle weakness fatigability symptoms, which are of key importance to people with MG. The MMP approach used may serve as a case study for developing PCOMs across rare disease indications.

  7. Approach to the patient with muscle weakness - UpToDate

    The approach to evaluating a person with muscle weakness is a rewarding and challenging practice, integrating various aspects of the medical history with a multisystem physical examination and the judicious use of ancillary testing.

  8. Case-Study: Weight Gain and Muscle Weakness in a 54-Yr-Old ...

    Weight Gain and Muscle Weakness in a 54-Yr-Old Man / Brought to you by Merck & Co, Inc. Rahway, NJ. USA (known as MSD outside the US and Canada) - dedicated to using leading-edge science to save and improve lives around the world.

  9. Understanding Clinical Characteristics of Muscle Weakness

    BACKGROUND: Muscle weakness is a debilitating condition that can lead to frailty, falls, and functional decline. Muscle weakness is found across many diseases; therefore, understanding what constitutes this condition is paramount. The National Library of Medicine provides 2 definitions of muscle wea …

  10. Functional movement disorder similar to Parkinson’s disease ...

    Introduction Functional neurological disorder challenges conventional medical understanding, presenting neurological symptoms without organic explanations. This report delves into the intricate interplay between psychological and physical manifestations, emphasizing the importance of timely diagnosis and intervention and its impact on a patient’s mental health and quality of life. Case ...