Generalised weakness

Generalised weakness is a reduction in the force that muscles can generate across several body regions, usually both sides. Patients often use the word for tiredness, so true neuromuscular weakness, shown by reduced power on testing, must be separated from fatigue, sleepiness and pain limited effort. This article covers diffuse or symmetrical weakness. Weakness that follows one limb, one root or one vascular territory is a different problem.

Clinical relevance. Weakness of sudden or rapid onset with bulbar or respiratory involvement is an emergency because respiratory failure can develop within hours. Gradual weakness is more often myopathic, endocrine, nutritional or drug related. A dangerous cause may present as a mild complaint.

Anatomy of the motor unit. Movement depends on the upper motor neurone (cortex, brainstem, spinal cord), the anterior horn cell, the root and plexus, the peripheral nerve, the neuromuscular junction and the muscle. Weakness is localised by the pattern of tone, reflexes, bulk, fasciculation and sensation.

Classification by site.

• Upper motor neurone: spasticity, brisk reflexes, extensor plantars, no wasting early, often a sensory level.
• Lower motor neurone (anterior horn cell, root, nerve): flaccidity, reduced reflexes, wasting, fasciculation.
• Neuromuscular junction: fatigable weakness, ocular and bulbar involvement, normal reflexes.
• Muscle: proximal weakness, normal or reduced reflexes, preserved sensation, often a raised creatine kinase.
• Systemic or nonneuromuscular: weakness with sepsis, hypotension, anaemia, electrolyte disorder, adrenal insufficiency or frailty.

Classification by distribution. Proximal weakness (difficulty rising from a chair, climbing stairs, lifting arms) suggests myopathy or neuromuscular junction disease. Distal weakness (foot drop, dropping objects) suggests neuropathy. Mixed upper and lower motor neurone signs without sensory loss suggest motor neurone disease.

Classification by tempo. Acute is hours to days. Subacute is weeks. Chronic is months to years. Episodic weakness with complete recovery between attacks suggests periodic paralysis, electrolyte disorders or myasthenia.

History.

• Onset and tempo, distribution (proximal or distal), symmetry, fatigability (worse through the day or with repetition), cramps, myalgia, fasciculation, stiffness, and relation to meals, exercise and rest.
• Ocular and bulbar symptoms: ptosis, diplopia, dysphagia, dysarthria, nasal speech, jaw fatigue when chewing.
• Respiratory: breathlessness lying flat, weak cough, sleep disturbance, morning headache.
• Sensory symptoms, pain, autonomic symptoms (dry mouth, postural dizziness, constipation, urinary retention, impotence), sphincter disturbance.
• Preceding illness: diarrhoea (Campylobacter), upper respiratory infection, vaccination, surgery, tick bite, wound or food exposure (botulism), dark urine after exertion.
• Drugs and toxins: statins, fibrates, corticosteroids, colchicine, chloroquine, amiodarone, zidovudine, diuretics, laxatives, liquorice, amphotericin B, isoniazid, stavudine, vincristine, aminoglycosides, fluoroquinolones, macrolides, magnesium, penicillamine, checkpoint inhibitors, alcohol, organophosphates, lead, arsenic.
• Systemic: weight loss, fever, rash, arthralgia, dry eyes, thyroid or adrenal symptoms, vomiting or diarrhoea, poor diet.
• Past history: diabetes, cancer, HIV, thymoma, thyroid disease, previous episodes, family history of muscle disease or periodic paralysis, long stay in intensive care.
• Region specific: cassava dependence (konzo), HTLV-1, schistosomiasis, snake bite, polio exposure.

Examination.

• Vital signs, respiratory pattern, use of accessory muscles, paradoxical abdominal movement. Single breath count (counting aloud after a full breath; under 20 suggests a vital capacity under about 1.5 litres) and neck flexion strength.
• Cranial nerves: ptosis and fatigability (sustained upgaze for 60 seconds), eye movements, facial strength, palate, tongue wasting and fasciculation, voice fade on counting to 50.
• Muscle bulk, fasciculation, tone, power in each muscle group graded 0 to 5, reflexes, plantar responses, clonus.
• Sensation to pinprick, vibration and proprioception, sensory level, saddle sensation, anal tone.
• Gait: waddling, high stepping, spastic. Gowers sign. Repeated sit to stand.
• Skin and joints: heliotrope rash, Gottron papules, mechanic hands, sclerodactyly, joint swelling. Thyroid, cushingoid features, hyperpigmentation, blood pressure lying and standing.
• Hoover sign and give way weakness suggest functional weakness; positive signs of functional disorder need to be present, not just absence of disease.

Red flags.

• Rapid progression over hours to days, ascending weakness, areflexia.
• Dyspnoea, single breath count under 20, weak cough, difficulty swallowing saliva.
• Bulbar weakness, ptosis, diplopia.
• Autonomic instability, urinary retention, sensory level, saddle anaesthesia.
• Cardiac arrhythmia or ECG changes, serum potassium under 3.0 or over 6.0 mmol/L.
• Dark urine, severe muscle pain, recent exertion, seizure or crush.
• Fever with neck stiffness, tick exposure, wound, or ingestion of home preserved food.
• Known malignancy or HIV with new weakness.

Upper motor neurone and spinal cord. Bilateral hemispheric or brainstem stroke, transverse myelitis, multiple sclerosis, neuromyelitis optica spectrum disorder, cervical spondylotic myelopathy, spinal cord compression (tumour, abscess, tuberculosis, haematoma), spinal cord infarction, subacute combined degeneration (vitamin B12 deficiency), copper deficiency myelopathy, syphilis, HIV vacuolar myelopathy, HTLV-1 associated myelopathy (tropical spastic paraparesis), schistosomal myelopathy, konzo, syringomyelia.

Anterior horn cell. Motor neurone disease, poliomyelitis and postpolio syndrome, acute flaccid myelitis (enterovirus), West Nile virus, adult onset spinal muscular atrophy.

Root and polyradiculopathy. Guillain-Barre syndrome and variants (acute inflammatory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy, Miller Fisher syndrome), chronic inflammatory demyelinating polyradiculoneuropathy, cytomegalovirus polyradiculopathy, carcinomatous or lymphomatous meningitis, cauda equina syndrome, Lyme radiculopathy.

Peripheral nerve (polyneuropathy). Diabetes, alcohol, vitamin B12 deficiency, uraemia, hypothyroidism, HIV neuropathy, leprosy, drugs (isoniazid, stavudine, vincristine, cisplatin, dapsone, nitrofurantoin, linezolid), vasculitis, amyloidosis, acute intermittent porphyria, diphtheria, toxins (lead, arsenic, thallium, organophosphates), paraneoplastic and paraproteinaemic neuropathy, hereditary neuropathy, critical illness polyneuropathy.

Neuromuscular junction. Myasthenia gravis, Lambert-Eaton myasthenic syndrome, botulism, tick paralysis, organophosphate poisoning, neurotoxic snake envenomation, drug induced worsening (aminoglycosides, fluoroquinolones, macrolides, magnesium, beta blockers, checkpoint inhibitors), hypermagnesaemia.

Muscle.

• Inflammatory: polymyositis, dermatomyositis, inclusion body myositis, immune mediated necrotising myopathy (including statin associated anti HMGCR), overlap myositis, sarcoid myopathy.
• Toxic and drug: statins, fibrates, corticosteroids, colchicine, chloroquine, amiodarone, zidovudine, alcohol, daptomycin.
• Endocrine and metabolic: hypothyroidism, hyperthyroidism, Cushing syndrome, adrenal insufficiency, hyperparathyroidism, vitamin D deficiency and osteomalacia, hypokalaemia, hypophosphataemia, hypomagnesaemia, hypercalcaemia.
• Rhabdomyolysis: exertion, seizure, trauma, drugs, infection, heat, alcohol.
• Channelopathies: hypokalaemic periodic paralysis (familial and thyrotoxic), hyperkalaemic periodic paralysis.
• Inherited: muscular dystrophies (limb girdle, facioscapulohumeral, myotonic), Pompe disease, McArdle disease, carnitine palmitoyltransferase II deficiency, mitochondrial myopathy.
• Infective: HIV myopathy, pyomyositis, trichinosis, cysticercosis, viral myositis.
• Critical illness myopathy, paraneoplastic myopathy.

Systemic and nonneuromuscular. Sepsis, hypotension and shock, severe anaemia, heart failure, hypoxia and hypercapnia, adrenal insufficiency, hypoglycaemia, malnutrition and cachexia, sarcopenia and frailty, deconditioning, depression, polymyalgia rheumatica (pain limited), fibromyalgia, functional weakness.

1. Assess stability first: airway, respiratory effort, oxygen saturation, bedside vital capacity or single breath count, ECG with potassium, glucose, blood pressure.
2. Localise the lesion by pattern (upper or lower motor neurone, neuromuscular junction, muscle, nonneuromuscular), then choose tests.
3. Initial blood tests: urea, creatinine, sodium, potassium, calcium, magnesium, phosphate, glucose, creatine kinase, full blood count, C reactive protein or ESR, liver function tests, thyroid stimulating hormone, cortisol, vitamin B12, and HIV test with consent. Arterial or venous blood gas when respiratory fatigue is suspected. Urine myoglobin and urine drug screen when relevant.
4. Interpretation.

• Potassium under 3.0 mmol/L causes weakness; periodic paralysis usually has potassium under 3.0 mmol/L during attacks with normal urinary potassium excretion and shifts into cells.
• Creatine kinase over 5 times the upper limit of normal (or over 1,000 units/L) with myalgia and dark urine indicates rhabdomyolysis. Creatine kinase may be normal in steroid, thyroid and inclusion body myopathies, and in neuropathic and neuromuscular junction disease.
• Vital capacity: intubation is considered when it falls under 20 mL/kg, or by 30% from baseline, or maximal inspiratory pressure is weaker than minus 30 cmH2O.

1. Nerve conduction studies and electromyography localise neuropathy, radiculopathy and myopathy. In the first 1 to 2 weeks of Guillain-Barre syndrome they may be normal; delayed or absent F waves are early clues. Repetitive nerve stimulation: decrement over 10% at 3 Hz in myasthenia gravis; increment over 100% after brief exercise or at 20 to 50 Hz in Lambert-Eaton syndrome.
2. Guillain-Barre syndrome: lumbar puncture shows raised protein with a normal cell count (albuminocytological dissociation) after the first week; a cell count over 50 cells/microlitre points to HIV, Lyme disease or another infection. Antiganglioside antibodies (anti GQ1b in Miller Fisher syndrome), stool for Campylobacter, and spirometry.
3. Myasthenia gravis: acetylcholine receptor antibodies (positive in about 85% of generalised disease), muscle specific kinase antibodies, CT of chest for thymoma, ice pack test for ptosis. Lambert-Eaton syndrome: voltage gated calcium channel antibodies and a search for small cell lung cancer.
4. Myopathy: myositis antibody panel (Jo-1, Mi-2, SRP, HMGCR), muscle MRI, and muscle biopsy. Genetic testing for inherited myopathy and periodic paralysis. Thyroid function in all periodic paralysis.
5. Cord disease: MRI of the whole spine, urgently within 24 hours when compression is suspected, plus brain MRI, vitamin B12, syphilis serology, HTLV-1 serology, HIV test and copper level.
6. Peripheral neuropathy: glucose, HbA1c, vitamin B12, serum protein electrophoresis, creatinine, hepatitis serology, HIV, porphobilinogen in acute abdominal pain with neuropathy, heavy metals, nerve biopsy when vasculitis or leprosy is suspected.

Limits. Early electrophysiology and cerebrospinal fluid can be normal in Guillain-Barre syndrome. Antibody tests miss about 15% of generalised and about half of ocular myasthenia. Muscle MRI and biopsy can be patchy.

Immediate. Secure the airway and breathing. Check vital capacity or single breath count every 2 to 4 hours when Guillain-Barre syndrome or myasthenic crisis is possible. Intubate for vital capacity under 15 to 20 mL/kg or falling by 30%, maximal inspiratory pressure weaker than minus 30 cmH2O, bulbar failure, hypercapnia or exhaustion. Avoid suxamethonium in denervation, prolonged immobility and rhabdomyolysis (risk of fatal hyperkalaemia). Intensive care for rapid progression. Continuous ECG monitoring for arrhythmia.

Electrolytes.

• Hypokalaemia with weakness or ECG change: potassium chloride 10 mmol/hour intravenously through a peripheral line (maximum 20 mmol/hour with central access and monitoring; peripheral concentration not over 40 mmol/L), or 40 to 80 mmol orally daily in divided doses when mild. Replace magnesium (magnesium sulphate 8 mmol intravenously over 20 minutes to 1 hour, or as needed). Recheck potassium every 2 to 4 hours.
• Thyrotoxic periodic paralysis: potassium at the lower rate (not over 10 mmol/hour) because of rebound hyperkalaemia, with propranolol 3 mg/kg orally (maximum usually 240 mg) given early to reverse the paralysis, and definitive thyroid treatment.
• Hyperkalaemia with weakness or ECG change: calcium gluconate 10% 10 mL intravenously over 2 to 5 minutes, soluble insulin 10 units with glucose 25 g intravenously, salbutamol 10 to 20 mg nebulised, and treat the cause.
• Hypophosphataemia (severe when under 0.32 mmol/L): sodium glycerophosphate 20 mmol intravenously over 8 to 12 hours, repeated as directed by serum levels; oral phosphate supplements for mild disease. Monitor calcium, potassium and renal function; reduce the dose in renal impairment.

Guillain-Barre syndrome. Intravenous immunoglobulin 0.4 g/kg daily for 5 days (total 2 g/kg) or plasma exchange (200 to 250 mL/kg over 4 to 5 sessions in 1 to 2 weeks), started within 4 weeks of onset and ideally within 2 weeks. No benefit from combining the two or from corticosteroids. Caution with immunoglobulin in IgA deficiency, renal impairment (use a sucrose free product) and thrombotic risk.

Treat neuropathic pain with gabapentin 300 mg orally at night, increasing to 300 to 900 mg three times daily as needed. Monitor for autonomic instability (arrhythmia, labile blood pressure, ileus, retention). Thromboprophylaxis.

Myasthenic crisis and myasthenia gravis. Intensive care, intravenous immunoglobulin 0.4 g/kg daily for 5 days or plasma exchange (200 to 250 mL/kg over 4 to 5 sessions), and stop precipitating drugs. Pyridostigmine 30 to 60 mg orally every 4 to 6 hours while awake (maximum 360 mg daily; withhold in ventilated crisis); watch for cholinergic effects. Prednisolone started low (10 to 20 mg daily) and increased slowly because early worsening occurs.

Azathioprine 2 to 3 mg/kg daily as a steroid sparing agent after thiopurine methyltransferase testing. Thymectomy for thymoma and for acetylcholine receptor antibody positive generalised disease in patients under about 65 years. Avoid magnesium, aminoglycosides, fluoroquinolones, macrolides and beta blockers.

Inflammatory myopathy. Prednisolone 1 mg/kg orally daily (maximum 60 to 80 mg) with methotrexate 15 to 25 mg once weekly or azathioprine 2 to 3 mg/kg daily as a steroid sparing agent. Intravenous immunoglobulin for refractory dermatomyositis. Screen for malignancy. Calcium, vitamin D and bone protection, and Pneumocystis prophylaxis when combined immunosuppression is used.

Statin and drug myopathy. Stop the drug, check creatine kinase and renal function, and restart a different statin at a lower dose after resolution only if needed. Persistent weakness after stopping suggests immune mediated necrotising myopathy and needs antibody testing.

Rhabdomyolysis. Isotonic crystalloid 1 to 2 litres in the first hour then 200 to 300 mL/hour, aiming for a urine output of 200 to 300 mL/hour, continued until creatine kinase is under 1,000 units/L and myoglobinuria has cleared. Monitor potassium, calcium, phosphate, creatinine and creatine kinase every 6 to 12 hours. Renal replacement therapy for refractory hyperkalaemia, acidosis, volume overload or oliguria. Avoid calcium unless hyperkalaemic ECG change or symptomatic hypocalcaemia.

Cord compression. Immediate MRI. For metastatic compression give dexamethasone 16 mg orally or intravenously once daily with gastric protection, with urgent neurosurgical and oncology review. Antimicrobial or specific therapy after culture for abscess or tuberculosis.

Neuromuscular toxins. Botulism: botulinum antitoxin as soon as suspected (specialist supply), debridement of any wound, benzylpenicillin for wound botulism, respiratory support. Organophosphate poisoning: atropine 1 to 2 mg intravenously, doubled every 5 minutes until secretions dry; pralidoxime 30 mg/kg intravenously over 30 minutes then 8 mg/kg/hour. Neurotoxic snake bite: polyvalent antivenom, airway protection, and for cobra post synaptic block neostigmine 0.5 mg intravenously with atropine 0.6 mg for a response test.

Endocrine and nutritional causes. Adrenal insufficiency, hypothyroidism, hyperthyroidism, vitamin D deficiency, vitamin B12 deficiency and malnutrition are treated with specific replacement. Refeeding needs thiamine 100 mg intravenously or orally daily and electrolyte monitoring.

Functional weakness. Explain the diagnosis positively (the nervous system works but its signals are disrupted), physiotherapy with a neurological rehabilitation approach, and treatment of anxiety and depression.

Supportive care. Thromboprophylaxis with enoxaparin 40 mg subcutaneously once daily (20 mg when eGFR is under 30 mL/min), speech and swallowing assessment, nutrition, pressure area care, bowel and bladder care, rehabilitation.

Monitoring. Vital capacity, oxygen saturation, swallowing, potassium, creatine kinase and renal function, and neurological status twice daily in acute disease.

Referral and escalation. Immediate: respiratory compromise, bulbar weakness, rapidly progressive weakness, suspected cord compression, botulism or poisoning. Urgent neurology for acute or subacute weakness and for suspected myasthenia, myositis or motor neurone disease. Rheumatology for myositis, endocrinology for periodic paralysis and adrenal disease.

Admission. Acute or progressive weakness, respiratory or bulbar involvement, severe electrolyte disturbance, rhabdomyolysis, suspected Guillain-Barre syndrome, cord compression, adrenal crisis, or inability to cope at home.

Special groups. Pregnancy: hyperemesis causes hypokalaemia; magnesium sulphate for eclampsia can unmask or worsen myasthenia; Guillain-Barre syndrome and myasthenia are managed with immunoglobulin or plasma exchange. Children: acute flaccid paralysis requires stool samples for poliovirus and notification, and Guillain-Barre syndrome, botulism, myelitis and tick paralysis are the usual causes.

Older adults: frailty, sarcopenia, polypharmacy, vitamin D deficiency and electrolyte loss from diuretics; adjust drug doses for kidney function. Endemic regions: poliomyelitis, konzo (cassava cyanide), HTLV-1 myelopathy, spinal tuberculosis, schistosomal myelopathy, snake envenomation and organophosphate exposure.