Differentials

Common

Parkinson's disease (PD)

History

unilateral or asymmetrical rest tremor, slowed movements, stiffness, micro-graphia, drooling, difficulty turning over in bed, difficulty with buttons and utensil use, shuffling gait, and decreased arm swing; history of hyposmia, history of rapid eye movement sleep behaviour disorder

Exam

masked facies (reduced facial animation), hypophonia, unilateral or asymmetrical rest tremor (may be pill rolling), slow or low-amplitude finger taps and hand grips, rigidity, difficulty standing from chair, shuffling gait, stooped posture, decreased arm swing, retropulsion on pull-back testing, stooped posture

1st investigation
  • dopaminergic agent trial:

    positive response to levodopa or other dopaminergic agent (dopamine agonist). The diagnosis of PD is made clinically, and in cases without atypical features, no additional diagnostic testing is indicated. Warranted if atypical features or unclear clinical diagnosis. In tremor-predominant disease, doses as high as 1200 mg of levodopa may need to be reached before concluding lack of efficacy.

Other investigations
  • MRI brain:

    normal image in most patients

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  • functional neuroimaging (e.g., PET or single-photon emission CT):

    decreased basal ganglia pre-synaptic dopamine uptake

Dementia with Lewy bodies

History

fluctuating cognition, cognitive impairment, and parkinsonism occurring within 1 year of each other, visual hallucinations (not related to dopaminergic therapy) and delusions, sensitivity reactions to neuroleptics

Exam

muscle rigidity, stooped posture, cogwheel rigidity, shuffling gait, impairment on cognitive testing

1st investigation
  • none:

    clinical diagnosis

Other investigations
  • CT or MRI brain:

    normal

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  • serum vitamin B12:

    normal

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  • serum TSH:

    normal

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  • metabolic panel:

    normal

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  • formal neuropsychometric testing:

    visuospatial and visuoconstructive impairment prominent

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  • thyroid function test:

    normal

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Enhanced physiological tremor

History

tremor noticed in situations of stress, anxiety, or excessive caffeine use; absence of neurological disease

Exam

anxious appearance; fine high-frequency postural and kinetic tremor that occurs in arms, legs, and voice but not the head

1st investigation
  • none:

    clinical diagnosis

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Other investigations
  • thyroid function test:

    normal

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  • metabolic panel:

    normal

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Hypoglycaemia (enhanced physiological tremor)

History

history of diabetes or glucose intolerance, history of insulin use

Exam

sympathoadrenal or neuroglycopenic symptoms; action tremor

1st investigation
  • serum glucose:

    low

Other investigations
  • thyroid function test:

    normal

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Thyrotoxicosis (enhanced physiological tremor)

History

weight loss, diaphoresis (excessive sweating), heat intolerance, palpitations, anxiety

Exam

diaphoresis, tachycardia, enlarged thyroid gland; action tremor

1st investigation
  • serum TSH, free T3, free T4:

    TSH: low; free T3: high; free T4: high

Other investigations

    Alcohol withdrawal (enhanced physiological tremor)

    History

    history of alcohol misuse

    Exam

    tremulousness, seizures, delirium, hallucinations, spider angiomata, gynaecomastia, enlarged liver, signs of autonomic hyper-activity, no alcohol for 6 hours produces intention tremor; hypertension; tachycardia

    1st investigation
    • FBC:

      elevated MCV

    • liver function tests:

      elevated gamma-GT

    Other investigations
    • thyroid function test:

      normal

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    Essential tremor or essential tremor plus

    History

    tremor mainly affects hands, shaky handwriting or utensil use; positive family history; tremors may improve with alcohol use

    Exam

    postural and/or kinetic tremors of hands, tremors may also involve head and voice; essential tremor occurs in absence of other neurological signs; if subtle neurological signs such as impaired tandem gait, subtle body posturing suggestive of dystonia, or mild memory impairment are present, then essential tremor plus is the more appropriate classification

    1st investigation
    • thyroid function test:

      normal

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    • metabolic panel:

      normal

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    • serum ceruloplasmin:

      normal

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    Other investigations

      Drug-induced tremor

      History

      occurs following ingestion of certain drugs; rest tremors can be caused by dopamine receptor blockers such as antipsychotics and antiemetics (e.g., metoclopramide, prochlorperazine, promethazine), or dopamine depletors (e.g., tetrabenazine); action tremors are common following treatment with antidepressants (e.g., selective serotonin-reuptake inhibitors [SSRIs], tricyclic antidepressants, monoamine oxidase inhibitors [MAOIs]), mood stabilisers (e.g., lithium), anticonvulsants (e.g., valproic acid), cardiac drugs (e.g., amiodarone), immunosuppressants (e.g., ciclosporin, tacrolimus, corticosteroids), drugs for asthma (e.g., salbutamol, theophylline), and stimulants (e.g., amphetamines); tremor occurs in a reasonable time frame following drug ingestion

      Exam

      rest or action tremor

      1st investigation
      • none:

        clinical diagnosis

      Other investigations
      • thyroid function test:

        normal

        More

      Uncommon

      Multiple system atrophy

      History

      lightheadedness and syncope, erectile dysfunction, urinary dysfunction, dysarthria, gait difficulty, slow movements, rest tremor, lack of coordination, early postural instability

      Exam

      orthostatic hypotension, parkinsonism, ataxia, hyper-reflexia, shuffling or ataxic gait

      1st investigation
      • none:

        clinical diagnosis

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      Other investigations
      • MRI brain:

        cerebellar and/or brainstem atrophy, putaminal hypo-intensity with slit-like hyper-intensity of outer margin of putamen on T2-weighted imaging[20]

      • dopaminergic agent trial:

        minimal or no response to levodopa

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      Progressive supra-nuclear palsy (PSP)

      History

      frequent falls, visual problems, axial rigidity, dysarthria, dysphagia, personality and cognitive change, rest tremor

      Exam

      supra-nuclear gaze palsy, dysarthria, 'surprised' facial expression, axial rigidity, bradykinesia, frontal release signs, cognitive impairment, marked gait instability

      1st investigation
      • MRI brain:

        pronounced atrophy in the midbrain and superior cerebellar peduncles with relatively intact pons is supportive (but not definitive) of a PSP diagnosis; this feature can result in various radiographic signs, including 'hummingbird', 'Mickey Mouse', and 'morning glory' signs in the midsagittal and axial planes

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      Other investigations
      • dopaminergic agent trial:

        negative response to levodopa

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      Cortico basal syndrome

      History

      asymmetrical rest tremor; disorder of skilled, learned, purposeful movement; dystonic limb posturing; alien limb phenomenon

      Exam

      parkinsonism (rest tremor, rigidity, bradykinesia, postural instability), limb apraxia, dystonia, spontaneous and reflex focal myoclonus, rigidity

      1st investigation
      • none:

        clinical diagnosis

      Other investigations
      • MRI brain:

        usually normal

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      • serum vitamin B12:

        normal

        More
      • serum TSH:

        normal

        More
      • metabolic panel:

        normal

        More
      • formal neuropsychometric testing:

        visuospatial and visuoconstructive impairment prominent

        More
      • dopaminergic agent trial:

        negative response to levodopa

        More

      Toxin-induced tremor

      History

      history of toxic exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (heroin addicts), carbon monoxide, manganese (may be seen in welders or in patients receiving parenteral nutrition), methanol, or cyanide

      Exam

      parkinsonism (rest tremor, rigidity, bradykinesia, and postural instability)

      1st investigation
      • none:

        clinical diagnosis

      Other investigations
      • MRI brain:

        shows high signal intensity on T1-weighted images in the globus pallidus in patients actively exposed to high levels of endogenous or iatrogenic manganese, as with intravenous hyper-alimentation and cirrhosis, or with environmental-industrial exposure such as with welding, smelting, or manganese mining; may show bilateral globus pallidus lesions in carbon monoxide poisoning

      Phaeochromocytoma (enhanced physiological tremor)

      History

      headache, sweating, palpitations

      Exam

      hypertension, tachycardia, action tremor

      1st investigation
      • 24-hour urine collection for catecholamines, metanephrines, normetanephrines:

        high

      • serum free metanephrines, normetanephrines:

        high

      Other investigations
      • thyroid function test:

        normal

        More

      Cerebellar tremor (multiple sclerosis, trauma, or stroke)

      History

      complaints of incoordination, imbalance, family history of cerebellar ataxia, history of multiple sclerosis, head trauma, stroke, or cerebellar haemorrhage

      Exam

      coarse irregular kinetic tremor generated proximally, abnormal finger-to-nose testing and heel-to-shin testing, dysdiadochokinesis, wide-based ataxic gait, dysarthria (speech problems)

      1st investigation
      • MRI brain:

        may see signs of cerebellar atrophy, or may suggest demyelinating disease in multiple sclerosis, or show changes consistent with stroke, trauma, or haemorrhage

      Other investigations
      • thyroid function test:

        normal

        More

      Fragile X tremor ataxia syndrome

      History

      occurs in upper limbs, age >60 years, more common in men, gait ataxia, may be a family history of premature ovarian failure in females and/or intellectual disability (fragile X syndrome) in males

      Exam

      intention tremor, ataxic gait, often have acquired cognitive impairment especially executive dysfunction

      1st investigation
      • MRI brain:

        middle cerebellar peduncle hyperintensities

      Other investigations
      • genetic testing:

        positive fragile X premutation in FMR1 gene

      • thyroid function test:

        normal

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      Orthostatic tremor

      History

      tremor in legs that occurs on standing, accompanied unsteadiness, tremor disappears on sitting or walking

      Exam

      high-frequency tremor of legs when standing

      1st investigation
      • none:

        clinical diagnosis

      Other investigations
      • surface EMG:

        13-18 Hz pattern of alternating contractions of leg muscles

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      • thyroid function test:

        normal

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      Primary writing tremor

      History

      tremor of hand only when writing

      Exam

      hand tremor when writing only

      1st investigation
      • none:

        clinical diagnosis

      Other investigations
      • thyroid function test:

        normal

        More

      Dystonic tremor

      History

      tremor in a body region (usually head or neck, but may be limb) often with a directional pulling or jerking quality

      Exam

      often irregular head and neck tremor with a jerky, directional quality; patient may use a sensory trick (geste antagoniste) to relieve or diminish tremor; tremor may be very sensitive to task-specific or positional factors e.g., may disappear at a specific position (‘null point’)

      1st investigation
      • none:

        clinical diagnosis

      Other investigations
      • MRI brain:

        normal in most cases

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      Wilson's disease

      History

      tremor, dysarthria, incoordination, dystonia, gait abnormalities, psychiatric changes, <40 years of age, hepatitis or cirrhosis

      Exam

      Kayser-Fleischer rings, tremor, dysarthria, dystonia, ataxia

      1st investigation
      • serum ceruloplasmin:

        <200 mg/L (<20 mg/dL) suggests Wilson's disease

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      • 24-hour urine copper:

        >100 micrograms indicates disease

      • liver function tests:

        abnormal

      • slit-lamp examination:

        Kayser-Fleischer rings, greenish deposits as an arc across the outer rim of the top of the cornea

      • MRI brain:

        bilateral T2 hyperintensities in any or all of basal ganglia, thalamus, or midbrain; hypointensities can also be seen

      Other investigations
      • liver biopsy:

        liver copper >250 micrograms/g

      • thyroid function test:

        normal

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      • DNA testing for ATP7B mutations:

        causative mutations found on both copies of the gene definitively diagnose Wilson's disease

      Holmes tremor (rubral or midbrain tremor)

      History

      history of stroke or central nervous system insult such as multiple sclerosis; uncontrollable coarse tremor

      Exam

      tremor of arm with equal rest, action, and intention components

      1st investigation
      • MRI brain:

        may show damage to the red nucleus or cerebellothalamic pathways

      Other investigations
      • thyroid function test:

        normal

        More

      Functional tremor

      History

      sudden onset of tremor, history of anxiety or depression, history of sexual or child abuse

      Exam

      tremor that is distractible or can be entrained to a new frequency; may be associated with other non-organic signs such as give-way weakness; non-anatomical sensory examination; astasia-abasia (inability to either stand or walk in a normal manner)

      1st investigation
      • none:

        clinical diagnosis

      Other investigations
      • thyroid function test:

        normal

        More

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