Tremor

Tremor is an involuntary, rhythmic, oscillatory movement of a body part.

Mechanisms. Rest tremor arises from basal ganglia dysfunction. Postural and kinetic tremors arise from oscillation in the cerebello-thalamo-cortical loop. Enhanced physiological tremor reflects amplified normal oscillation from sympathetic and metabolic drive.

Classification by activation. Rest tremor (limb fully supported, not voluntarily active), postural tremor (against gravity), kinetic tremor (during voluntary movement, including intention tremor that increases on approaching a target), task specific tremor (writing), and isometric tremor.

Frequency and typical patterns.

• Enhanced physiological tremor 8 to 12 Hz.
• Essential tremor 4 to 12 Hz, bilateral, postural and kinetic, often with head or voice involvement.
• Parkinsonian rest tremor 4 to 6 Hz, usually asymmetric.
• Cerebellar intention tremor 3 to 5 Hz.
• Midbrain (Holmes) tremor under 4.5 Hz with rest, postural and intention components.
• Orthostatic tremor 13 to 18 Hz in the legs on standing.

Key distinctions. The activation condition, symmetry, speed of onset, associated bradykinesia, rigidity, dystonia or neuropathy, and the response to distraction guide diagnosis. Functional tremor is variable, distractible and entrainable.

History.

• Age at onset, speed of onset (abrupt onset suggests drug, functional or vascular cause), progression and laterality.
• Which activities are affected (eating, writing, pouring, phone use).
• Response to alcohol (improvement suggests essential tremor).
• Family history of tremor, effect of anxiety, fatigue and caffeine, head or voice involvement, falls, and handwriting change.

Associated symptoms.

• Slowness, small handwriting, reduced facial expression, reduced arm swing, soft voice, loss of smell, constipation, acting out dreams, depression (Parkinson disease).
• Weight loss, palpitations, heat intolerance, sweating, anxiety (thyrotoxicosis).
• Sweating, palpitations, headache (phaeochromocytoma, hypoglycaemia).
• Liver disease or psychiatric symptoms under age 50 (Wilson disease).
• Cognitive change, neuropathic symptoms, and vomiting or diarrhoea on lithium.

Drug and toxin history. Salbutamol and other beta agonists, theophylline, caffeine, nicotine, amphetamines, lithium, valproate, tricyclic antidepressants, selective serotonin reuptake inhibitors, antipsychotics, metoclopramide, prochlorperazine, amiodarone, excess levothyroxine, corticosteroids, tacrolimus, ciclosporin, and alcohol (current use and withdrawal). Occupational exposure to mercury, lead, manganese and organophosphates.

Examination

• Observe at rest (hands supported on lap, distraction by counting backwards), with arms outstretched, in wing beating position, during finger to nose testing, pouring water, drawing a spiral, writing and walking.
• Tone (cogwheel rigidity, with contralateral activation), finger tapping with decrement (bradykinesia), gait, arm swing, postural reflexes (pull test), eye movements (vertical gaze palsy), dystonic posture of the head or hand, cerebellar signs, neuropathy, and asterixis.
• General: pulse, blood pressure, thyroid, eyes (lid lag, proptosis, Kayser Fleischer rings), jaundice, hepatomegaly, anxiety, signs of alcohol withdrawal.
• Tremor that varies in direction and frequency, stops with distraction, entrains to a voluntary tapping rhythm, and co-activates antagonist muscles, indicates functional tremor.

Red flags

• Abrupt onset, or onset within days after a drug is started
• Unilateral tremor with rigidity or bradykinesia
• Onset under age 40 with dystonia, psychiatric or liver signs
• Cerebellar signs, ophthalmoplegia, autonomic failure, early falls or cognitive decline
• Fever, rigidity, clonus or hyperreflexia (serotonin syndrome, neuroleptic malignant syndrome)
• Weight loss with tachycardia, or paroxysmal sweating with hypertension
• Tremor with confusion, vomiting or diarrhoea in a patient taking lithium
• Alcohol withdrawal features
• Sudden onset after head injury or stroke

Special groups. Older adults: drug induced parkinsonism and tremor from polypharmacy are common. Children: hyperthyroidism, hypoglycaemia, drug effects, and functional tremor. Pregnancy: propranolol and primidone need specialist input; thyrotoxicosis needs review.

Enhanced physiological tremor

• Caffeine, nicotine, anxiety, fatigue, fever, exercise
• Drugs: beta agonists, theophylline, lithium, valproate, tricyclic antidepressants, selective serotonin reuptake inhibitors, corticosteroids, excess levothyroxine, tacrolimus, ciclosporin, amphetamines
• Thyrotoxicosis, hypoglycaemia, phaeochromocytoma

Rest tremor

• Parkinson disease
• Atypical parkinsonism: multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies
• Drug induced parkinsonism (antipsychotics, metoclopramide, prochlorperazine)
• Wilson disease, vascular parkinsonism
• Midbrain (Holmes) tremor from stroke, multiple sclerosis or tumour

Postural and kinetic tremor

• Essential tremor and essential tremor plus
• Dystonic tremor, task specific tremor
• Neuropathic tremor (inflammatory demyelinating neuropathy, IgM paraproteinaemic neuropathy, Charcot Marie Tooth disease)
• Alcohol withdrawal, benzodiazepine withdrawal, delirium tremens
• Heavy metal toxicity (mercury, lead, manganese)
• Hepatic encephalopathy (asterixis), uraemia

Intention tremor and cerebellar

• Cerebellar stroke, multiple sclerosis, tumour
• Alcohol related cerebellar degeneration, hereditary ataxias, fragile X associated tremor ataxia syndrome
• Lithium toxicity, phenytoin toxicity

Other

• Orthostatic tremor
• Functional tremor
• Serotonin syndrome, neuroleptic malignant syndrome, malignant hyperthermia
• Myoclonus, clonus, focal motor seizures, chorea, and shivering as mimics

Reasoning. Classify by activation and distribution, review drugs, caffeine and alcohol, look for features of parkinsonism, dystonia, neuropathy and cerebellar disease, then test for reversible systemic causes. Diagnosis is clinical for typical essential tremor and Parkinson disease.

First line tests. Capillary glucose, thyroid stimulating hormone and free thyroxine, full blood count, urea, electrolytes, creatinine, calcium, magnesium, liver function, and vitamin B12. Add lithium level (12 hours after the last dose; usual therapeutic range 0.4 to 1.0 mmol/L; toxicity over 1.5 mmol/L) and levels of other relevant drugs.

Targeted tests

• Caeruloplasmin, serum copper, 24 hour urinary copper and slit lamp examination for Kayser Fleischer rings in anyone under 50 with unexplained tremor, dystonia, liver disease or psychiatric features. A low caeruloplasmin is not sufficient alone; confirm with the other tests, and genetic testing when equivocal.
• Plasma free metanephrines or 24 hour urinary metanephrines for paroxysmal tremor with sweating, palpitations and hypertension.
• Nerve conduction studies and serum protein electrophoresis for tremor with neuropathy.
• MRI brain for atypical features: abrupt or unilateral onset, cerebellar signs, tremor with focal deficit, early cognitive decline or non-response to usual treatment. MRI is not needed in typical essential tremor.
• Dopamine transporter imaging when parkinsonism is uncertain: reduced uptake supports degenerative parkinsonism and normal uptake supports essential tremor, drug induced parkinsonism or functional tremor. It does not separate Parkinson disease from atypical parkinsonism.
• Surface electromyography with accelerometry confirms orthostatic tremor (13 to 18 Hz) and helps to identify functional tremor.

Limitations. Essential tremor and early Parkinson disease are often confused, and mixed disease occurs. Levodopa response supports parkinsonism but a negative response does not exclude it. Genetic testing is limited to selected cases.

Treat reversible causes. Reduce caffeine and nicotine, review each culprit drug and reduce or substitute when safe (do not stop lithium, antiepileptics or immunosuppressants abruptly without specialist advice), treat anxiety, correct hypoglycaemia and electrolytes. Thyrotoxicosis: propranolol 40 mg orally 3 or 4 times daily for symptoms (maximum 240 mg daily) while starting antithyroid therapy through the specialist route.

Serotonin syndrome and neuroleptic malignant syndrome. Stop the offending drugs, give IV fluids, benzodiazepines for agitation and rigidity (diazepam 5 to 10 mg IV, repeated as needed), external cooling, and admit to a monitored setting. Specialist and intensive care input for temperature over 38.5 degrees Celsius, rigidity or autonomic instability.

Lithium toxicity. Stop lithium, give 0.9 percent sodium chloride IV (avoid thiazides, NSAIDs, ACE inhibitors), monitor levels every 6 hours, and discuss haemodialysis with nephrology for reduced consciousness, seizures, life threatening arrhythmia, or lithium over 4.0 mmol/L with impaired kidney function.

Alcohol withdrawal. Diazepam 10 mg IV over 2 minutes, repeated every 10 to 15 minutes until calm, with thiamine 500 mg IV every 8 hours for 3 days and correction of magnesium, potassium and glucose.

Essential tremor. Treat when function or quality of life is affected. Avoid alcohol as a treatment.

• Propranolol 40 mg orally twice daily (10 to 20 mg twice daily in older adults), increased every 1 to 2 weeks to a usual 80 to 160 mg daily in divided doses; maximum 240 mg daily.
• Propranolol cautions: check pulse and blood pressure. Avoid in asthma, heart block, bradycardia, severe peripheral arterial disease and decompensated heart failure. It may mask hypoglycaemia in diabetes. Do not stop abruptly.
• Primidone 12.5 to 25 mg orally at night, increased every 1 to 2 weeks to a usual 50 to 250 mg daily in 2 doses; maximum 750 mg daily. The first dose commonly causes nausea, sedation and unsteadiness. It induces enzymes (reducing the efficacy of hormonal contraception and warfarin), and is contraindicated in porphyria.
• Topiramate 25 mg orally at night, increased by 25 mg weekly to a usual 100 to 200 mg daily in 2 doses; maximum 400 mg daily. Halve the dose when creatinine clearance is under 70 mL/min. Warnings: cognitive slowing, paraesthesia, weight loss, kidney stones, metabolic acidosis, angle closure glaucoma, teratogenicity.
• Gabapentin 300 mg orally at night, increased by 300 mg every 3 to 7 days to a usual 1.2 to 1.8 g daily in 3 doses; maximum 3.6 g daily. Sedation and dizziness are common.
• Gabapentin renal dosing: creatinine clearance 30 to 59 mL/min, 400 to 1,400 mg daily in 2 doses; 15 to 29, 200 to 700 mg once daily; under 15, 100 to 300 mg once daily.
• Refractory disabling tremor: specialist referral for botulinum toxin (head, voice or hand), focused ultrasound thalamotomy, or deep brain stimulation of the ventral intermediate thalamic nucleus.

Parkinson disease. Refer to neurology before starting treatment. Levodopa with carbidopa (25 mg/100 mg tablets) half to one tablet orally three times daily, taken 30 minutes before meals, increased every 3 to 7 days; usual maximum 8 tablets (carbidopa 200 mg, levodopa 800 mg) daily, and specialists may exceed this.

Warnings: nausea, orthostatic hypotension, hallucinations, dyskinesia, impulse control disorders; avoid with non-selective monoamine oxidase inhibitors and in closed angle glaucoma. Rest tremor responds less well than bradykinesia and may need an added agent chosen by the specialist.

Wilson disease. Same day specialist hepatology and neurology referral; chelation or zinc therapy is started by specialists.

Functional tremor. Give a positive diagnosis with a clear explanation, physiotherapy and occupational therapy with specialist neurology or neuropsychiatry input. Avoid repeated investigation and unnecessary drug courses.

Orthostatic tremor. Specialist referral; clonazepam 0.25 to 0.5 mg orally at night, increased by 0.25 mg weekly to a usual 1 to 3 mg daily in divided doses, with monitoring for sedation, falls and dependence.

Monitoring. Tremor severity by function, handwriting and spiral drawing; pulse and blood pressure on beta blocker; sodium, blood count and liver function on topiramate or valproate; weight, cognition and drug adverse effects.

Referral and escalation. Neurology for suspected Parkinson disease or atypical parkinsonism, young onset, rapid progression, cerebellar or other neurological signs, and refractory essential tremor. Endocrinology for thyrotoxicosis and phaeochromocytoma. Hepatology for Wilson disease. Psychiatry or neuropsychiatry for functional tremor.

Admission criteria. Serotonin syndrome, neuroleptic malignant syndrome, lithium toxicity with neurological features, delirium tremens, thyroid storm, severe hypoglycaemia, or an acute structural cause.

Discharge and safety netting. Follow up in 4 to 6 weeks. Return for fever with rigidity, confusion, falls, swallowing difficulty, palpitations with weight loss, or any new neurological sign. Advise on driving and on tasks such as handling hot liquids.