• Heart Failure
  • Cardiovascular Clinical Consult
  • Adult Immunization
  • Hepatic Disease
  • Rare Disorders
  • Pediatric Immunization
  • Implementing The Topcon Ocular Telehealth Platform
  • Weight Management
  • Monkeypox
  • Guidelines
  • Men's Health
  • Psychiatry
  • Allergy
  • Nutrition
  • Women's Health
  • Cardiology
  • Substance Use
  • Pediatrics
  • Kidney Disease
  • Genetics
  • Complimentary & Alternative Medicine
  • Dermatology
  • Endocrinology
  • Oral Medicine
  • Otorhinolaryngologic Diseases
  • Pain
  • Gastrointestinal Disorders
  • Geriatrics
  • Infection
  • Musculoskeletal Disorders
  • Obesity
  • Rheumatology
  • Technology
  • Cancer
  • Nephrology
  • Anemia
  • Neurology
  • Pulmonology

Weakness: Guidelines for a Cost-Effective Workup


The differential diagnosis of generalized weakness is enormous; it includes disorders at all levels of the neur-axis. A variety of electrophysiological, pathological, radiographic, and other laboratory studies may be indicated depending on the specific diagnostic possibilities; costs can be controlled if such investigations are selected judiciously.

"Weakness" is a common presenting complaint. Physicians who evaluate patients with this symptom face a formidable diagnostic challenge, since the clinical possibilities are vast.

True neuromuscular weakness may result from pathological processes affecting any level of the neur- axis. Disease may involve the muscles (myopathy), neuromuscular junctions (neuromuscular transmission disorder), nerves (neuropathy), anterior horn cells (motor neuron disease), spinal cord (myelopathy), or more central processes. Weakness may portend a benign or life-threatening disorder. Effective treatments may exist and vary according to the specific disease. Accurate diagnosis is therefore essential.

Here we focus on issues related to diagnosis of the cause of true neuromuscular weakness in patients who present in an office setting. Guidelines are presented in the context of time and cost constraints.


In approaching the adult patient complaining of generalized weakness, 4 questions must be considered:

  • Is there true weakness?
  • Where does the primary pathological process reside?
  • What are the diagnostic possibilities?
  • What is the specific diagnosis?

As the 5 accompanying cases illustrate (see page 1269), the answer to the first question confirms the problem. The answer to the second question, the "anatomic localization," is determined by the findings on the neurological examination. The initial differential diagnosis is generated by the anatomic localization; this list is further refined by particular elements of the history, thereby providing an answer to the third question. Adjuvant laboratory tests can assist in establishing a final diagnosis.


The first step in evaluating patients who complain of generalized weakness is to determine whether true weakness is present. Although many patients complain of "fatigue" and "weakness," many of those with true neuromuscular weakness do not actually use the word "weakness" to characterize their symptoms. Rather, they refer to task-specific dysfunction-eg, difficulty in climbing stairs, getting out of a chair, combing hair, opening jars, or using keys or "foot slapping."

Conversely, patients who do not have true weakness typically offer less specific complaints of "generalized fatigue and weakness" and report being unable to carry out their usual routine activities, such as housework or job-related responsibilities. Some may experience myalgias or depressive symptoms. They do not demonstrate true weakness on physical examination. Psychosocial factors often underlie these patients' difficulties, and effective treatment requires attention to those issues.

However, one must exercise caution in assigning the diagnosis of psychogenic weakness. Nonspecific "generalized fatigue" (in the absence of true neuromuscular weakness) may represent a manifestation of an underlying systemic illness, such as anemia, hypoxemia/hypercapnia secondary to hypoventilation or congestive heart failure, sleep disruption associated with sleep apnea, malignancy, or a low-grade systemic infection. Usually, however, such systemic conditions produce other symptoms or general physical findings that facilitate diagnosis.

In addition, while complaints of nonspecific "generalized fatigue" may not suggest neuromuscular disease, exercise-induced, task-specific "fatigability" is the hallmark of myasthenia gravis. Patients with this disorder may not appear severely weak during a cursory routine examination, but significant weakness may become apparent with repetitive maneuvers.

Other patients may complain of "weakness" in moving their limbs, when the cause is not true neuromuscular weakness. Pain or other mechanical factors may limit a patient's movement or restrict mobility of a joint. Stiffness or rigidity (for example, secondary to parkinsonism) may be perceived by the patient as "weakness." A careful physical examination will identify these conditions.

Finally, one must identify the patient who is malingering or has a conversion disorder. Such patients may offer diffuse or multiple complaints. There may be inconsistencies in the history: the patient may profess that he or she is unable to carry out a certain movement yet report no difficulty in engaging in other activities that require normal function of the muscle groups in question.

Similarly, inconsistencies may be evident in the physical examination: while lying flat, the patient may be "unable" to lift a leg off the bed, but have no difficulty with flexing the hip (elevating a bent knee) in a sitting position. The patient may appear unable to carry out a selected movement when the examination focuses on a specific task, but may perform the same maneuver smoothly and without difficulty when distracted. On formal strength testing, the patient may "give way" suddenly or yield in a "tremor-like" fashion when the examiner provides resistance rather than exerting a smooth, consistent effort. The patient's gait may appear wild, uncontrolled, and unsteady but never eventuate in a fall; the patient may reproducibly lurch into the arms of the examiner.

If such features are unequivocally demonstrated on examination (and no other abnormal physical findings are identified), management should focus on elucidating the relevant psychosocial factors contributing to the patient's difficulties. Further diagnostic evaluations are unwarranted and might actually serve to reinforce the patient's errant perception of physical illness. Since factitious illness and true illness may coexist in the same patient, however, it is important to accurately identify any true pathology before assigning a definite diagnosis of a conversion disorder or malingering.


In neurological diagnosis, the history and physical examination are of paramount importance. When a patient is being evaluated, the history is taken first. However, when a differential diagnosis is being formulated for a patient with generalized weakness, the examination is considered first.

Assuming that the patient has true documented weakness, the next step is to characterize the pattern of weakness. Neurologists distinguish between paralysis or plegia (absence of movement) and paresis (partial weakness), although the terms are generally used interchangeably. Weakness of the arm and leg on one side is called hemiplegia; weakness of the legs only, paraplegia; and weakness of all 4 extremities, quadriplegia.

It is important to determine whether the weakness is generalized and symmetric, generalized but asymmetric, multifocal, proximally or distally predominant, and lower or upper extremity predominant. Establishing the location of the primary pathological process first requires defining the pattern of weakness, then assessing the patient for the presence of associated neurological findings, such as sensory loss, hypertonicity, hyporeflexia, hyperreflexia, pathological toe signs, or sphincter and cranial nerve dysfunction.

The physical findings seen in various neurological disorders are summarized in Table 1. Although exceptions exist, proximally predominant weakness suggests myopathy or a neuromuscular transmission disorder (eg, myasthenia gravis); distally predominant weakness, a neuropathy; and spinal segmental weakness, a motor neuron disease (eg, amyotrophic lateral sclerosis [ALS]). Hypertonicity indicates upper motor neuron dysfunction, which is seen in spinal cord lesions and often in motor neuron disease. Sensory loss or pain suggests neuropathy or spinal cord dysfunction. Hyporeflexia indicates neuropathy (also Lambert-Eaton myasthenic syndrome and, occasionally, lower motor neuron presentations of ALS); hyperreflexia and upgoing toes suggest myelopathies or anterior horn cell disorders. Bowel or bladder dysfunction indicates a spinal cord process.

Cranial nerve dysfunction is common in neuromuscular transmission disorders (diplopia, ptosis, dysarthria, dysphagia, bilateral facial weakness in myasthenia gravis) and motor neuron disease (dysarthria, dysphagia, tongue weakness in ALS). It is rare in neuropathies (with the exception of bilateral facial weakness in those with Guillain-Barré syndrome). It is also rare in myopathies (bilateral facial weakness occurs in myotonic dystrophy; ophthalmoplegia, in the rare oculopharyngeal dystrophies and selected mitochondrial disorders).

Certain physical examination patterns indicate central disease. A hemiparesis suggests a lesion in the brain. Neck pain indicates a disorder of the cervical spinal cord, whereas alterations of speech, attention, or cortical sensation suggest a hemispheric localization. A quadriparesis with brisk references and hypertonicity (in the absence of cerebral symptoms) suggests a cervical cord process. A paraparesis (sparing the arms) with spasticity and brisk reflexes suggests a disorder of the thoracic spinal cord. (A paraparesis with flaccidity and hypoactive reflexes indicates a peripheral disorder, unless the symptoms were of sudden recent onset [ie, spinal shock]). Bibrachial paresis, or weakness of the arms with sparing of the legs, is seen rarely following cerebral ischemia ("man-in-the-barrel syndrome") but more typically reflects lower motor neuron disease (eg, early ALS).


Myopathies, neuromuscular transmission disorders, neuropathies, motor neuron diseases, and myelopathies each have their own differential diagnoses (Tables 2, 3, 4, 5, and 6). Some general principles can provide a framework for the initial evaluation of the patient.

Table 3 – Neuromuscular transmissiondisorders
Myasthenia gravis
Neonatal myasthenia gravis
Lambert-Eaton myasthenic syndrome
Congenital myasthenic syndromes
Drugs/toxins (more than 50 agents)

Demographic information, including age, is important. Gender may play a role (as in X-linked hereditary neuropathies); ethnic and geographic origin may also be factors (for example, in sarcoid myopathy/neuropathy in African Americans), as may occupational/toxic exposures (for example, in heavy metal neurop-athies and toxic myopathies).

A medical history is essential, since many neuropathic and myopathic disorders are associated with underlying systemic illnesses. A drug history is important to exclude drug-induced nerve and muscle disorders. Alcohol abuse can cause nerve and muscle disease. A history of infection, surgery, or vaccination may provide clues to a postinfectious or inflammatory neuropathy.

The temporal profile of the symptoms is vital: is the cause acute (hours to days), subacute (weeks), chronic (months to years), or relapsing? A family history of similarly affected persons, hand/foot deformities, early use of a wheelchair or cane, or consanguinity may reveal a hereditary disorder.

The broad differential diagnosis of myopathic disorders (Table 2) includes inflammatory, congenital, metabolic, endocrinological, dystrophic, toxic, and drug-induced disorders. A family history might suggest a congenital or dystrophic myopathy (which may first come to attention in the adult patient). Underlying collagen-vascular disease may suggest an inflammatory myopathy. The temporal profile is important: an acute or relapsing process might suggest periodic paralysis or a metabolic myopathy; a subacute disorder, polymyositis; and a chronic process, a congenital myopathy.

Neuropathic disease has an even broader differential diagnosis (Table 4), with more than 100 causes. A temporal profile is helpful in defining disorders that evolve over hours (eg, shellfish poisoning, hypophosphatemia); days (eg, Guillain-Barré syndrome, porphyria, tick paralysis, arsenic toxicity); weeks or months (eg, inflammatory, nutritional, toxic, metabolic, or paraneoplastic disorders); or years (eg, diabetes, paraproteinemias, genetic disease); or that are relapsing (eg, chronic inflammatory demyelinating polyneuropathy, vasculitis).

Medical history defines the setting. Collagen-vascular diseases, endocrinological disorders, infectious processes (eg, HIV infection, Lyme disease), granulomatous disorders, malignancies, and various drugs (such as neoplastic agents) have all been associated with neuropathies.

When the lesion is central in origin (Table 6), the temporal profile assists greatly in defining the diagnostic possibilities, as in the following examples:

  • Abrupt hemiparesis suggests a stroke or cerebral hemorrhage; if the disorder is subacute (days to weeks), suspect a mass lesion (eg, tumor or abscess).
  • Acute quadriparesis of central origin may represent a brain stem infarct (eye movement abnormalities or bulbar dysfunction is usually present); a subacute disorder may indicate a transverse myelitis, multiple sclerosis (MS), or a herniated disc (pain is characteristic of the latter).
  • A chronic cervical myelopathy may indicate cervical spondylosis or arteriovenous malformation.
  • Acute central paraparesis could suggest spinal cord infarction, whereas a subacute disorder (manifesting over a period of days) may reflect a compressive process, such as disc disease, metastatic tumor, or transverse myelitis. Pain is usually present in these cases.
  • Subacute paraparesis, particularly in a patient with cerebellar signs or a history of visual loss, suggests MS.


A variety of laboratory and imaging studies may be pertinent, but only in specific instances. The history and physical examination will generate a limited list of diagnostic possibilities, which, in turn, will suggest a specific set of recommended laboratory studies.

Electromyography and nerve conduction studies. These tests are very useful when a disorder of the peripheral motor unit (myopathy, neuromuscular transmission disorders, neuropathy, or motor neuron disease) is suspected. Electromyography (EMG) can verify the presence of a peripheral nervous system disorder (as opposed to a central process, such as a myelopathy or factitious weakness attributable to psychogenic factors), and it can also help you differentiate among the peripheral nervous system disorders mentioned above.

In addition to helping pinpoint a specific anatomic location, EMG may provide additional information that will further limit the differential diagnosis within a specific category of disease. For example, in neuropathic disorders, EMG may reveal 6 different electrodiagnostic patterns, each of which is associated with its own differential diagnosis, thus helping to narrow the focus of subsequent laboratory studies. In certain clinical settings (including suspected Guillain-Barré syndrome, motor neuron disease, and myasthenia gravis), confirming EMG may be the only ancillary test required to establish the diagnosis.

Nerve/muscle biopsy. Nerve biopsy is not required to document the presence of a neuropathy, nor is it necessary if other noninvasive laboratory studies provide a plausible etiology. This procedure is most helpful in progressive neuropathies of undisclosed cause, and in neuropathies that present in a generalized asymmetric or multifocal pattern. These include mononeuropathy multiplex secondary to ischemic conditions (eg, vasculitis); infiltrative disorders (eg, leukemia, amyloidosis, or sarcoidosis); or infectious diseases (eg, leprosy). In such instances, nerve biopsy may provide a specific diagnosis.

Muscle biopsy can assist in confirming the presence of a myopathy. Often the diagnosis is suggested by the history, physical examination, and EMG. Muscle biopsy can further provide a specific diagnosis (eg, polymyositis, dystrophinopathy, metabolic myopathy, congenital myopathy, or sarcoid). This is important in muscle disease; it may facilitate genetic counseling in certain instances and provide a justification for treatment in others (such as in inflammatory myopathies).

Imaging studies. Spinal cord imaging is mandated when a myelopathy is suspected. If the symptoms are acute, emergent imaging is indicated. The level to be imaged (cervical or thoracic spine) depends on the anatomic localization. This, in turn, is based on an examination of the sensory systems (eg, spinal sensory level) and motor systems; for example, involvement of the arms indicates cervical spine pathology. The choice of study (MRI or CT) depends on the specific clinical setting and is best determined by a specialist. Imaging may reveal evidence of a transverse myelitis, disc disease, vascular malformation, or central demyelinating disorder (such as MS). If a process in the brain stem or cerebral hemisphere is suspected, cranial MRI is indicated.

Lumbar puncture. A spinal fluid analysis is warranted if Guillain-Barré syndrome or MS is suspected. In Guillain-Barré syndrome, cerebrospinal fluid analysis reveals elevated protein and no cells. In MS, there are often elevated levels of protein, cells, and oligoclonal bands, and an increased IgG index. Lumbar puncture is not indicated in disorders of muscle, the neuromuscular junction, or the anterior horn cells.

Tensilon test. This rapid bedside test can assist in the diagnosis of myasthenia gravis. It is helpful only if obvious, unequivocal weakness is present (eg, ptosis or extraocular muscle weakness) and, ideally, requires a blinded saline control. Typically, however, equivocal responses are distressingly frequent. EMG or antibody studies (see below) are therefore probably more reliable.


Fatigue. For the patient with complaints of generalized fatigue in the absence of demonstrable weakness or true task-specific fatigability, a limited workup is recommended. Selected laboratory investigations might be performed to exclude the possibility of an occult systemic disorder. Appropriate screening tests might include a complete blood cell count, erythrocyte sedimentation rate, fluorescent antinuclear antibody assay, and chest roentgenogram, as well as levels of electrolytes, creatine kinase, thyroid-stimulating hormone, and cortisol. Obtain a comprehensive psychosocial history.

Exercise tolerance should be assessed in the office: ask the patient to perform 10 deep knee bends or climb up and down a flight of stairs and take measurements of muscle strength, heart rate, and respiratory rate before and after the exercise. If true weakness-either at rest or provoked by exercise-is demonstrated, further neuromuscular evaluation is indicated.

Myopathic disease. If the history and physical examination suggest a myopathy, this should be verified by EMG (which will also exclude other possibilities). If the EMG is positive, biopsy of a relevant muscle (identified by EMG) should be performed to try to establish a specific diagnosis. A creatine kinase analysis is usually recommended in this setting. A decision about whether to order additional laboratory studies would be guided by the EMG/biopsy results and the clinical setting (for example, symptoms suggestive of an underlying collagen-vascular or endocrine disorder).

Neuromuscular junction disease. If myasthenia gravis is suspected, confirmation by EMG (immediate results) or acetylcholine receptor antibodies (1 to 2 weeks) is recommended. The sensitivity of these studies varies depending on the clinical pre-sentation: in generalized myasthenia, thorough repetitive stimulation studies (conventional EMG) have a sensitivity of 80% to 85%; single-fiber EMG, 90% to 95%; and antibody studies, 80% to 90%. In ocular myasthenia (symptoms are restricted to the eyes), single-fiber EMG has a sensitivity of 90% to 95% and antibody studies, 50% to 60%. Thyroid studies should also be performed in this setting. In 50% to 70% of "antibody-negative" myasthenia patients, antibodies to muscle specific kinase (MuSK) can be identified, especially in those patients with prominent craniobulbar symptoms.

Neuropathy. If a neuropathy is suggested by the history and examination, obtain an EMG for confirmation. A directed laboratory investigation is performed, based on the electrophysiological pattern. If Guillain-Barré syndrome is suspected, a cerebrospinal fluid analysis is obtained. Nerve biopsy is helpful in specific situations, as discussed above.

Anterior horn cells. Confirming EMG is sufficient for establishing the diagnosis if ALS is suspected, particularly if the patient presents with a characteristic combination of upper and lower motor neuron findings. In certain instances, other imaging and diagnostic studies may be indicated, particularly when diagnostic uncertainty persists.

Spinal cord disease. In suspected myelopathy, appropriate imaging studies are indicated, as discussed above. In recent years, copper deficiency has emerged as an important reversible cause of myelopathy.

For 5 real-world examples on diagnosing weakness, read "The Differential Diagnosis of Weakness: 5 Cases"



Burns T, Schaublin G, Dyck P. Vasculitic neuropathies.

Neurol Clin.

Deymeer F, Gungor-Tuncer O, Yilmaz V. Clinical comparison of anti-MuSK- vs anti-AChR-positive and seronegative myasthenia gravis.


2007;68: 609-611.
Machuca-Tzili L, Brook D, Hilton-Jones D. Clinical and molecular aspects of the myotonic dystrophies: a review.

Muscle Nerve.

Mastaglia FL, Garlepp MJ, Phillips BA, Zilko PJ. Inflammatory myopathies: clinical, diagnostic, and therapeutic aspects.

Muscle Nerve.

Rowland L, Shneider N. Amyotrophic lateral sclerosis.

N Engl J Med.

Saperstein D, Katz J, Amato A. Clinical spectrum of chronic acquired demyelinating polyneuropathies.

Muscle Nerve.

Walsh R, Amato A. Toxic myopathies.

Neurol Clin.


Related Videos
Donna H Ryan, MD Obesity Expert Highlights 2021 Research Success and Looks to 2022 and Beyond
© 2023 MJH Life Sciences

All rights reserved.