Differentials
Common
Insomnia disorder
History
difficulty in initiating sleep, waking frequently, poor concentration, depressed mood
Exam
decreased alertness, red and puffy eyes, absence of physical signs suggesting organic illness
1st investigation
- none:
diagnosis based on history and clinical examination
Other investigations
Depression
History
depressed mood, sadness, emotional distress, anxiety, irritability, anhedonia, feeling hopeless, loss of self-esteem, sleep problems, appetite troubles, weight loss or gain, loss of energy, poor concentration, suicidal ideation, symptoms of psychosis or mania
Exam
psychomotor slowing, agitation, blunted affect
1st investigation
Other investigations
Iron-deficiency anaemia
History
asthenia, hair loss, dyspnoea, menorrhagia, dysphagia (Plummer-Vinson's syndrome)
Exam
pallor, tachycardia, systolic ejection murmur, blue sclera
1st investigation
- FBC:
decreased Hb and Hct; decreased MCV, MCH, and MCHC
More - ferritin:
decreased
Other investigations
Iron deficiency without anaemia
History
asthenia, hair loss, menorrhagia
Exam
examination may be unrevealing
1st investigation
- FBC:
normal
- ferritin:
<67 picomol/L (<30 nanograms/mL)
More
Other investigations
Chronic heart failure
History
decreased exercise tolerance, dyspnoea on exertion, orthopnoea, paroxysmal nocturnal dyspnoea, previous myocardial infarction
Exam
oedema, displaced cardiac apex, hepatojugular reflux, jugular venous distension, S3 gallop, pulmonary rales, hepatomegaly
1st investigation
- brain natriuretic peptide (BNP)/N-terminal prohormone BNP (NT-proBNP):
elevated
- chest x-ray:
cardiomegaly, pulmonary oedema, pleural effusion
- ECG:
anterior q waves or bundle branch block, atrial or ventricular arrhythmias, left axis deviation, ventricular hypertrophy
More
Other investigations
- FBC:
normal or abnormal
More - echocardiogram:
may show systolic and/or diastolic dysfunction, valve lesions, signs of pericardial injury or cardiomyopathy
Diabetes mellitus
History
polyuria, polydipsia, weakness, myalgia, weight loss, polyphagia, nausea, vomiting, altered state of consciousness, decreased vision
Exam
signs of volume depletion (dry mucous membranes, decreased skin turgor); confusion (in ketoacidosis or non-ketotic hyperglycaemia); neuropathy, retinopathy
1st investigation
Other investigations
- oral glucose tolerance test:
2-hour post-load blood sugar ≥11 mmol/L (≥199 mg/dL)
More
Hypothyroidism
History
weakness, cold intolerance, dry skin, hair and eyebrow loss, weight gain, constipation, peri-orbital swelling, depression, hoarseness, dyspnoea on exertion, menstrual disturbance (menorrhagia), cognitive dysfunction
Exam
bradycardia, hypothermia, hypotension (if severe); diastolic hypertension, slow movement and speech, delayed relaxation of tendon reflexes, peri-orbital oedema, enlargement of the tongue, goitre; myxedema coma (unusual)
1st investigation
- TSH:
elevated
More
Other investigations
- T4 (serum free thyroxine):
low or normal
More
Hyperthyroidism
History
decreased weight despite increased appetite, emotional lability, oligomenorrhoea, heat intolerance
Exam
weight loss, hyper-reflexia, tachycardia, irregularly irregular pulse (atrial fibrillation), fine tremor, goitre may be present
1st investigation
- TSH:
low
- free T4 and/or free T3:
elevated
Other investigations
- radioiodine scan:
shows increased uptake in areas of hyperfunction
EBV infection
Influenza infection
History
winter season, fever with cough, sore throat, runny nose, current influenza outbreak
Exam
decreased breath sounds, presence of rales (uncommon, occurs in secondary bacterial pneumonia)
1st investigation
- none:
diagnosis is clinical (febrile respiratory illness during a known seasonal influenza outbreak)
More
Other investigations
- rapid diagnostic tests:
positive for influenza A and/or influenza B, depending on particular test used
- viral culture:
detection of influenza virus or viral antigen
- direct immunofluorescent-antibody staining:
detection of influenza virus
- reverse transcription polymerase chain reaction:
detection of influenza virus
- enzyme immunoassay:
detection of influenza virus
- serology:
4-fold or greater rise in antibody titre from acute to convalescent sample
- chest x-ray:
normal in uncomplicated cases; may show infiltrates consistent with pneumonia in complicated cases
Long COVID
History
breathlessness, fatigue, post-exertional malaise and/or poor endurance, 'brain fog', cough, chest pain, headache, palpitations, arthralgia, myalgia, paraesthesia, abdominal pain, diarrhoea, insomnia and other sleep difficulties, lightheadedness, impaired daily function and mobility, pain, mood changes, anosmia or dysgeusia, menstrual cycle irregularities
Exam
new onset postural orthostatic tachycardia syndrome (POTS), tachycardia, fever, rash (e.g., urticaria, 'covid toes'), cognitive impairment, muscle weakness, generalised focal neurological signs
1st investigation
- blood count, electrolytes, liver and renal function, CRP, vitamin D, vitamin B12:
usually normal in long covid; investigations to exclude other causes of fatigue
- SARS-CoV-2 antibodies:
positive
More - fatigue severity scale:
score ≥4 indicates fatigue
- modified Medical Research Council Dyspnoea Scale (mMRC):
0 = dyspnoea only with strenuous exercise; 1 = dyspnoea when hurrying or walking up a slight hill 2 = walks slower than people of the same age because of dyspnoea or has to stop for breath when walking at own pace; 3 = stops for breath after walking 91 m or after a few minutes; 4 = too dyspnoeic to leave house or breathless when dressing
Other investigations
- chest x-ray:
may show pulmonary sequelae of acute infection including loss of lung volume, fibrosis, ground glass opacification and reticular opacities/peripheral atelectasis
More - Montreal Cognitive Assessment (MoCA):
abnormal below 26
- high-sensitivity troponin:
elevated in infarction and myocarditis
More - D-dimer to rule out pulmonary emboli:
abnormal above 500 ng/mL
More
Medicine-induced fatigue
History
history of taking medicine associated with fatigue: most commonly antihistamines, antihypertensives, anti-arrhythmics, antidepressants, anti-emetics, antiepileptics, corticosteroids, diuretics, or neuroleptic agents
Exam
no specific findings
1st investigation
- medicine withdrawal if safely achievable:
resolution of fatigue
More
Other investigations
Alcohol dependence
History
history of alcohol misuse
Exam
malnutrition, ascites, jaundice, peripheral neuropathy, palmar erythema, splenomegaly, telangiectasias, caput medusae
1st investigation
Drug dependence
History
history of drug misuse, insomnia (particularly associated with nicotine, caffeine, marijuana, cocaine, and heroin misuse), aggressive behaviour, agitation, depressed mood; specific symptoms related to type of drug
Exam
clinical signs vary depending on the type of drug
1st investigation
HIV infection
History
often asymptomatic; fever, myalgia, diarrhoea, unexplained weight loss, rashes; history of high-risk sexual activity (multiple partners, unprotected or male-male intercourse) or intravenous drug use
Exam
persistent generalised lymphadenopathy, other signs vary depending on the stage of disease
1st investigation
- HIV antibodies:
positive; may be negative in early disease
More
Other investigations
- HIV RNA:
positive
More
Acute myocardial ischaemia
History
history of cardiovascular risk factors: hypertension, obesity, diabetes mellitus, smoking, family history of heart disease; chest pain, nausea, vomiting, sweating, dizziness, shortness of breath
Exam
variable, may appear pale or grey, hypotension
1st investigation
- ECG:
ischaemic changes: ST elevation, inverted T waves
- troponin:
elevated in infarction
- chest x-ray:
may be normal or have evidence of pulmonary oedema
Other investigations
- coronary angiography:
vessel narrowing, occluding thrombus in acute infarction
Atrial fibrillation
History
exercise intolerance, palpitations, lightheadedness, syncope, dyspnoea
Exam
tachycardia, signs of heart failure: oedema, displaced cardiac apex, hepatojugular reflux, jugular venous distension, pulmonary rales
1st investigation
- ECG:
absent P waves; presence of fibrillatory waves that vary in size, shape, and timing; irregularly irregular QRS complexes
More
Other investigations
- chest x-ray:
cardiomegaly, in particular left atrial enlargement; signs of heart failure; other precipitating pathology, such as pneumonia
- TSH:
normal or decreased
More
COPD
History
dyspnoea, chronic cough, smoking history
Exam
barrel chest, findings on auscultation: hyper-resonance, decreased breath sounds, wheezing, rhonchi, decreased oxygen saturation on pulse oximetry
1st investigation
Other investigations
- FBC:
elevated haematocrit, possible increased WBC count
More
Tuberculosis
History
fever, chills, chronic cough, weight loss, night sweats; history of travel to endemic areas, HIV infection, or immunosuppression
Exam
pulmonary signs: tachypnoea, decreased breath sounds, crackles, dullness to percussion; extrapulmonary: findings dependent on site affected, generalised lymphadenopathy common
1st investigation
- chest x-ray:
may demonstrate atelectasis from airway compression, pleural effusion, consolidation, pulmonary infiltrates, mediastinal or hilar lymphadenopathy, upper zone fibrosis
More - sputum acid-fast bacilli smear and culture:
presence of acid-fast bacilli (Ziehl-Neelsen stain) in specimen.
More - acid-fast bacilli smear and culture of extrapulmonary biopsy specimen:
positive
More - nucleic acid amplification tests (NAAT):
positive for M tuberculosis
More
Other investigations
- bronchoscopy and bronchoalveolar lavage:
positive for acid-fast bacilli
More - lateral flow urine lipoarabinomannan (LF-LAM) assay:
positive
More - contrast-enhanced chest computed tomography scan:
primary TB: mediastinal tuberculous lymphadenitis with central node attenuation and peripheral enhancement, delineated cavities; postprimary TB: centrilobular nodules and tree-in-bud pattern
More
Toxoplasmosis
History
mild fever, chills, sweats; rarely: headaches, myalgia, sore throat, rash; most cases are asymptomatic
Exam
bilateral cervical adenopathy, pharyngitis, maculopapular rash, hepatosplenomegaly
1st investigation
- serology:
positive IgG and IgM antibodies
More
Other investigations
Stroke
History
weakness of the face, blurred vision, diplopia, decreased vision, sudden paresis/paralysis of limbs, headache, vomiting
Exam
abnormal neurological examination, difficulty in speaking: slurred speech, confused speech; paresis/paralysis of limbs
1st investigation
- CT head:
ischaemic: hypo-attenuation (darkness) of the brain parenchyma; loss of grey matter-white matter differentiation, and sulcal effacement; haemorrhagic: enhancing lesion
Other investigations
Uncommon
Obstructive sleep apnoea/hypopnoea syndrome (OSAHS)
History
snoring, diurnal somnolence, agitation and sweating at night, headache, morning xerostomia (dry mouth) and sore throat, depressed mood, irritability, loss of libido; total score of ≥11 on Epworth sleepiness scale supports the diagnosis
Exam
elevated BP, obesity, nasal obstruction, macroglossia, tonsillar hypertrophy, obstruction by the palate, low soft palate, retrognathism, micrognathia
1st investigation
Other investigations
- fibre-optic endoscopy:
may see nasal polyps or tumours, or hypertrophic lingual tonsils
Obesity hypoventilation syndrome (OHS)
History
obesity (body mass index [BMI] ≥ 30 kg/m²), dyspnoea, nocturia, lower extremity oedema, excessive daytime sleepiness, fatigue, loud disruptive snoring, witnessed apnoeas, waking headaches
Exam
mild hypoxaemia awake (arterial oxygen saturation less than 94% on air), with significant hypoxaemia when asleep, awake daytime hypercapnia, unexplained polycythaemia
Other investigations
- polysomnography:
demonstrates hypoventilation, particularly during REM sleep
More
Restless legs syndrome
History
limb discomfort at rest, involuntary limb movement, restlessness, disturbed sleep, depressed mood
Exam
no specific findings
1st investigation
- none:
diagnosis is clinical
Other investigations
Coeliac disease
History
diarrhoea, steatorrhoea, abdominal pain, weight loss
Exam
pallor, easy bruising, aphthous stomatitis; abdominal distension
1st investigation
Other investigations
- small intestine biopsy:
presence of intra-epithelial lymphocytes, villous atrophy, and crypt hyperplasia
More
Addison's disease
History
weakness, anorexia, weight loss, nausea, vomiting, abdominal pain, fever, myalgia, arthralgia
Exam
signs of volume depletion (dry mucous membranes, decreased skin turgor), hypotension, tachycardia, hyper-pigmentation
1st investigation
- morning serum cortisol:
decreased
More - serum electrolytes:
decreased sodium; elevated potassium, creatinine, and urea
Other investigations
- short ACTH stimulation test:
cortisol <497 nanomol/L (<18 micrograms/dL)
More
Hypopituitarism
History
symptoms vary depending on underlying cause: energy loss, muscle weakness, decreased sweating, anorexia, weight loss or weight gain, abdominal pain, reduction in amount of axillary and pubic hair in women, erectile dysfunction, oligomenorrhoea/amenorrhoea, breast atrophy, loss of libido, infertility, cold intolerance, dry skin, polyuria, polydipsia, nocturia
Exam
may have increased central adiposity, dry skin, reduced muscle mass and strength, visual field defects, circulatory collapse if acute presentation
1st investigation
- LH:
low
- FSH:
low
- oestrogen:
low
More - TSH:
low
- free T4 and T3:
low
- basal serum cortisol:
low
Other investigations
- testosterone:
low
- prolactin:
low or high
More - cortisol reserve:
low (with cosyntropin stimulation)
- FBC:
anaemia
- metabolic panel:
may show hyponatraemia, hyperkalaemia, hypoglycaemia
- insulin tolerance test:
reduced growth hormone and cortisol responses
More - urine specific gravity:
low in diabetes insipidus
- water deprivation test:
urine osmolality less than serum osmolality following water deprivation
More - desmopressin test:
after desmopressin, urine osmolality increases in central diabetes insipidus
More
Myelodysplastic syndrome
History
dyspnoea, leg swelling, bleeding, history of bacterial or fungal infections
Exam
petechiae, purpura, leg oedema
1st investigation
- FBC and differential:
pancytopenia, abnormal cells, anaemia
Other investigations
- bone marrow biopsy:
hyperactive or hypoactive marrow and abnormal cells
Chronic myeloid leukaemia
History
fever, weight loss, night sweats, history of bruising
Exam
hepatosplenomegaly, petechiae, purpura
1st investigation
- FBC and peripheral blood smear:
elevated or abnormal WBC count, low platelet count; myeloid maturing cells, elevated basophils and eosinophils
Other investigations
- bone marrow biopsy:
granulocyte hyperplasia
More
Non-Hodgkin's lymphoma
History
persistently enlarged lymph nodes, possibly extranodal sites, constitutional or B symptoms (fevers, night sweats, and/or weight loss) and occasionally pruritus
Exam
generalised, local, or regional lymphadenopathy; hepatosplenomegaly
1st investigation
- lymph node excision biopsy:
histology and immunohistochemistry, cytogenetics, flow cytometric and molecular genetic analysis confirm the type and grade of lymphoma
Other investigations
- FBC:
evaluation for cytopenias
More - LDH:
elevated
More - bone marrow biopsy:
indicated for staging in newly diagnosed lymphoma
- CT scan of neck, chest, abdomen, and pelvis:
evaluation of the extent of lymphadenopathy and performance of accurate staging
More - whole-body positron emission tomography (PET scan) or integrated PET/CT:
regions affected by lymphoma will appear to be highly metabolically active on PET scan
- HIV serology:
may be positive
More - hepatitis B and C serology:
may be positive
More
Hodgkin's lymphoma
History
painless cervical and/or supraclavicular lymphadenopathy in a young adult is common; constitutional or B symptoms (fevers, night sweats, and/or weight loss), occasionally pruritus, possibly pain following alcohol ingestion at sites of lymphadenopathy
Exam
generalised, local, or regional lymphadenopathy; hepatosplenomegaly
1st investigation
- lymph node excision biopsy:
Hodgkin's cell can be a characteristic Reed-Sternberg cell, or variants such as the lacunar cell in the nodular sclerosis subtype; in nodular lymphocyte-predominant Hodgkin's lymphoma, the characteristic cell is the lymphocytic and histiocytic cell (popcorn cell)
Other investigations
- FBC:
evaluation for cytopenia
- bone marrow biopsy:
indicated for staging in newly diagnosed lymphoma
- CT scan of neck, chest, abdomen, and pelvis:
evaluation of the extent of lymphadenopathy and performance of accurate staging
More - whole-body positron emission tomography (PET scan) or integrated PET/CT:
regions affected by lymphoma will appear to be highly metabolically active on PET scan
Cytomegalovirus infection
History
usually asymptomatic unless immunocompromised; fever, malaise, night sweats, arthralgia, weakness, weight loss; symptoms specific to infection site: for example, reduced vision, pneumonia, encephalitis, diarrhoea
Exam
dependent on site of infection; includes lymphadenopathy and hepatosplenomegaly, retinal changes
1st investigation
- CMV IgM and IgG antibodies:
positive
More
Lyme disease
History
fever, lethargy, headache, myalgia, neck stiffness, inflammation of large joints
Exam
erythema migrans: bull's-eye lesion(s)
1st investigation
- immunofluorescence assay (IFA):
antibodies to Borrelia burgdorferi
- ELISA:
positive
Brucellosis
History
history of animal contact or ingestion of unpasteurised dairy products; fever, sweats, malaise, arthralgia, depression, weight loss
Exam
fever, lymphadenopathy, hepatosplenomegaly
1st investigation
- blood culture:
positive for Brucella
Other investigations
- bone marrow culture:
positive for Brucella
Chronic renal disease
History
weakness, pruritus, loss of appetite, nausea, vomiting, headache, dizziness, muscle pain, cramps, arthralgia, dyspnoea
Exam
generalised oedema, elevated BP, purpura, mental status changes
1st investigation
- serum creatinine:
elevated
Other investigations
- estimation of GFR:
reduced GFR
More - renal ultrasound:
small kidney size; presence of obstruction/hydronephrosis; kidney stones
Multiple sclerosis
History
unilateral visual disturbance, leg cramping, strange sensory phenomena, bladder and bowel dysfunction
Exam
increased muscle tone, increased deep tendon reflexes, abnormalities on eye examination
1st investigation
- MRI brain and spinal cord:
hyper-intensities in the peri-ventricular white matter
Other investigations
Parkinson's disease
History
tremor, bradykinesia, dysphagia, blurred vision
Exam
tremor, bradykinesia, rigidity, postural instability, hypomimia (masked facial expression), speech impairment, sialorrhoea, hypometric saccades, impaired vestibulo-ocular reflex, micrographia, dystonia, myoclonus
1st investigation
- none:
diagnosis is clinical
More
Other investigations
Fibromyalgia
History
widespread musculoskeletal pain, abdominal pain, chest pain, pelvic pain, bladder symptoms suggestive of cystitis
Exam
>11 out of 18 tender points present on palpation of soft tissues
1st investigation
- none:
diagnosis is strictly clinical
Other investigations
Vitamin D deficiency (osteomalacia)
History
often asymptomatic, diffuse bone pain, myalgia, muscle weakness
Exam
fractures, diffuse bony tenderness; skeletal deformities are rare in adults
1st investigation
- serum vitamin D 25-hydroxy level:
<50 nanomol/L (20 nanograms/mL)
Other investigations
- DEXA:
reduced bone density, thinning of the cortex
More
Systemic lupus erythematosus
History
rash, fever, weight loss, hair loss, arthralgia, chest pain and dyspnoea, abdominal pain, nausea, vomiting, diarrhoea
Exam
oral ulcers, alopecia, butterfly rash, discoid rash, photosensitive rash, lymphadenopathy, hypertension, oedema, Raynaud's phenomenon
1st investigation
- ANA, dsDNA, Smith antigen:
positive
More
Other investigations
Primary biliary cirrhosis
History
personal history or family history of autoimmune disease, history of hypercholesterolaemia, pruritus, sleep disturbance, family history of primary biliary cirrhosis, dry eyes and mouth, postural dizziness/blackouts
Exam
hepatomegaly; less commonly, signs associated with advanced liver disease and portal hypertension (e.g., skin hyperpigmentation, splenomegaly, jaundice, xanthelasmata)
1st investigation
- LFTs:
elevated gamma-GT, bilirubin, and Alk phos
- anti-mitochondrial antibodies:
present
More
Other investigations
Underlying malignancy (non-lymphoma)
History
history of weight loss, possible family history of cancer, additional symptoms dependent on cancer type
Exam
variable; lymphadenopathy and/or hepatosplenomegaly may be present; more specific findings related to cancer type
1st investigation
- variable (e.g., mammography, CT scan, pathology):
depends on cancer type
Other investigations
Chronic fatigue syndrome (myalgic encephalomyelitis)/systemic exertion intolerance disease
History
severe disabling fatigue lasting >6 months; not due to ongoing exertion, not relieved with rest, reduced levels of activity, symptoms present for >50% of time; may involve memory/cognitive impairment, myalgia, arthralgia, headache, unrefreshing sleep, post-exertional malaise (lasting >24 hours), and/or orthostatic intolerance
Exam
tender lymphadenopathy, muscle pain, and other non-specific signs
1st investigation
- none:
diagnosis is based on history, and clinical signs and symptoms
More
Other investigations
Chronic idiopathic fatigue
History
fatigue lasting more than 6 months, does not meet criteria for chronic fatigue syndrome
Exam
tender lymph nodes, muscle pain, and other non-specific signs
1st investigation
- none:
diagnosis is clinical
Other investigations
Heavy metal toxicity
History
history of metal-on-metal hip implant (cobalt or chrome toxicity); dental amalgams, excess fish consumption (mercury toxicity); exposure to very old paints, glass artisans, battery production, use of Ayurvedic medicines (lead toxicity); paraesthesias, blurred vision, psychiatric changes, cognitive decline
Exam
tremor, ataxia
1st investigation
- serum level (lead, mercury, cobalt, chrome):
elevated
Other investigations
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