Differentials
Uraemia
SIGNS / SYMPTOMS
Various signs associated with the primary cause for end-stage renal disease (ESRD) may be present.
May co-exist with DN.
INVESTIGATIONS
Abnormal urea, creatinine, GFR consistent with ESRD.
Cyanocobalamin deficiency
SIGNS / SYMPTOMS
Poor nutrition, alcoholism, certain drugs (e.g., trimethoprim, methotrexate, phenytoin), pernicious anaemia, atrophic gastritis, malabsorption, or infection with Helicobacter pylori more likely to be present.
Patients are more likely to be older (>65 years).
INVESTIGATIONS
FBC reveals macrocytic anaemia.
Reduced serum vitamin B12 levels.
Hypothyroidism
SIGNS / SYMPTOMS
Fatigue, cold intolerance, weight gain, constipation, myalgia, menstrual irregularities, delayed relaxation of deep tendon reflexes, bradycardia (if severe).
INVESTIGATIONS
Thyroid-stimulating hormone elevated in primary hypothyroidism.
Free serum thyroxine (T4) may be low.
Acute intermittent porphyria
SIGNS / SYMPTOMS
Abdominal pain, vomiting, muscle weakness, constipation, fever, diarrhoea, sensory loss, seizures, tachycardia, hypertension may all occur.
Abdominal pain is severe and more typical than in DN.
INVESTIGATIONS
Elevated aminolevulinic acid, porphobilinogen.
Chronic high alcohol intake
SIGNS / SYMPTOMS
Signs of malnutrition, Wernicke encephalopathy, and Korsakoff amnestic syndrome may be present.
INVESTIGATIONS
Severe cases present with associated anaemia, thiamine deficiency, and deranged LFTs.
Heavy metal poisoning
SIGNS / SYMPTOMS
May present with a peripheral neuropathy that frequently manifests with extensor weakness, or wrist/ankle drop, due to an axonal degeneration, primarily affecting motor nerves.
Abdominal pain ('lead colic'), constipation, joint pains, muscle aches, headache, anorexia, decreased libido, difficulty concentrating and deficits in short-term memory, anaemia, nephropathy, and other symptoms and signs in various combinations.
INVESTIGATIONS
Abnormally high blood levels of lead or other metals.
Drug-induced neuropathy
SIGNS / SYMPTOMS
Diabetes less likely and drug history likely to include a drug that is known to be a risk for development of neuropathy, such as (in descending order of likelihood of association) antivirals, antibacterials, antineoplastic and immunosuppressants, and cardiovascular, central nervous system, gastrointestinal, and metabolism agents.
History may include the following specific drugs suspected of causing neuropathies: stavudine, didanosine, lamivudine, thalidomide, ritonavir, zalcitabine, and amiodarone.
INVESTIGATIONS
No differentiating investigations.
Chronic inflammatory demyelinating neuropathy (CIDP)
SIGNS / SYMPTOMS
People with diabetes may develop features of CIDP.
Severe, predominantly motor neuropathy that is progressive in nature. Features progress despite optimal glycaemic control.
INVESTIGATIONS
May be difficult to differentiate.
Nerve conduction studies show a combination of slowed conduction velocities, prolonged distal latencies, prolonged F-wave latencies, and conduction block in ≥1 nerves.
Nerve biopsies demonstrate increased numbers of macrophages.
Unusually high cerebrospinal fluid protein.
Sarcoidosis
SIGNS / SYMPTOMS
Various signs, including fever, skin signs (e.g., erythema nodosum), joint and/or eye lesions.
INVESTIGATIONS
Chest x-ray may show bilateral hilar lymphadenopathy and pulmonary reticular opacities.
Biopsies of accessible lesions are diagnostic.
Leprosy
SIGNS / SYMPTOMS
Travel to or residence in endemic countries.
Nerves commonly involved include the ulnar and median (claw hand), the common peroneal (foot drop), the posterior tibial (claw toes and plantar insensitivity), facial, radial cutaneous, and great auricular.
INVESTIGATIONS
Skin smear is positive for acid-fast bacilli (AFB).
Biopsy of lesions reveal the presence of AFB plus other associated signs.
Polyarteritis nodosa (PAN)
SIGNS / SYMPTOMS
Systemic symptoms (e.g., fatigue, weakness, fever, arthralgias) and signs (e.g., hypertension, renal insufficiency, neurological dysfunction, abdominal pain) of multisystem involvement more likely.
INVESTIGATIONS
There is no diagnostic laboratory test for PAN.
Basic laboratory tests help ascertain the extent of organs affected and their degree of involvement.
Amyloidosis
SIGNS / SYMPTOMS
Muscle weakness and enlargement due to amyloid infiltration (myopathy), disorders of the joints (arthropathy), and lesions of bone (osteopathy) more likely to be present.
INVESTIGATIONS
Presence of a paraprotein in the serum (as an M protein on protein immunoelectrophoresis or immunofixation) or urine (as monoclonal light chains) in approximately 90% of cases.
Dysproteinaemias and paraproteinaemias
SIGNS / SYMPTOMS
Possibly no differentiating signs or symptoms.
INVESTIGATIONS
Presence of a monoclonal protein in the serum or urine.
Paraneoplastic syndrome
SIGNS / SYMPTOMS
Varies, based on primary aetiology.
History of a primary neoplastic condition.
INVESTIGATIONS
Varies, based on primary aetiology.
Leukaemias and lymphomas
SIGNS / SYMPTOMS
Symptoms and signs vary but may include anaemia, fever, weight loss, and lymphadenopathy.
INVESTIGATIONS
Abnormal blood cell count and bone marrow aspirate.
Specific abnormalities are diverse depending on the type of leukaemia or lymphoma present.
Hereditary neuropathies (e.g., Charcot-Marie-Tooth disease)
SIGNS / SYMPTOMS
Both motor and sensory nerve manifestations are more common, with distal leg weakness, foot deformities (pes cavus, hammer toes), and sensory deficits.
INVESTIGATIONS
Genetic testing is diagnostic.
Functional neurological and somatic symptom disorders
SIGNS / SYMPTOMS
May also present with pains and paraesthesias but without neurological deficit.
There is no sensory loss, although this is not essential as painful neuropathy arises due to small fibre neuropathy.
INVESTIGATIONS
Clinical diagnosis with judicious use of investigations to rule out other diagnoses, and assessment for associated comorbid psychiatric conditions.
Multiple system atrophy/Shy-Drager syndrome
SIGNS / SYMPTOMS
May present with symptoms and signs of autonomic neuropathy, as in DN.
May also have parkinsonism, varying degrees of dysautonomia, cerebellar involvement, and pyramidal signs.
INVESTIGATIONS
An excellent response to dopaminergic therapy is an important supportive feature for establishing the diagnosis.
Riley-Day syndrome
SIGNS / SYMPTOMS
Progressive sensorimotor neuropathy but sympathetic autonomic dysfunction is responsible for most clinical manifestations (i.e., orthostatic hypotension, swallowing dysfunction, gastrointestinal motility dysfunction, bladder dysfunction, decreased or absent tearing, pupil dilation, hypohidrosis, and episodic hyperhidrosis).
INVESTIGATIONS
Genetic evaluation is sensitive and specific for the diagnosis: a truncated form of I kappa B kinase complex associated protein (IKBKAP) mutation on chromosome 9q31.
Autonomic neuropathy: idiopathic orthostatic hypotension
SIGNS / SYMPTOMS
Severe postural dizziness and weakness.
INVESTIGATIONS
Reduction of systolic BP of at least 20 mmHg, or diastolic BP of at least 10 mmHg, within the first 3 minutes of standing.
Guillain-Barre syndrome
SIGNS / SYMPTOMS
Progressive, fairly symmetrical muscle weakness accompanied by absent or depressed deep tendon reflexes.
Weakness can vary from mild difficulty with walking to nearly complete paralysis of all extremity, facial, respiratory, and bulbar muscles.
INVESTIGATIONS
Albuminocytological dissociation in cerebrospinal fluid (i.e., elevated protein with a normal WBC count), present in 80% to 90% of patients at 1 week after onset of symptoms.
Myasthenia gravis
SIGNS / SYMPTOMS
Fluctuating degree and variable combination of weakness in ocular, bulbar, limb, and respiratory muscles.
INVESTIGATIONS
Antibodies against acetylcholine receptors or receptor associated proteins are present.
Tensilon test, ice pack test, repetitive nerve stimulation studies, and single-fibre electromyography assist in confirmation of the diagnosis.
Degenerative spinal disc disease
SIGNS / SYMPTOMS
May present with symptoms and signs of a femoral neuropathy, including asymmetrical pain, weakness, and sensory loss.
INVESTIGATIONS
MRI demonstrates specific vertebral disc pathology.
Femoral neuropathy: intrinsic spinal cord mass lesion
SIGNS / SYMPTOMS
May present with symptoms and signs of a femoral neuropathy, including asymmetrical pain, weakness, and sensory loss.
INVESTIGATIONS
MRI demonstrates the spinal cord mass.
Cauda equina lesions
SIGNS / SYMPTOMS
May present with symptoms and signs of a femoral neuropathy, including weakness and sensory loss.
INVESTIGATIONS
Diagnosis usually confirmed by MRI.
Carotid aneurysm
SIGNS / SYMPTOMS
May present with symptoms and signs of a cranial neuropathy, including diplopia and Bell's palsy.
INVESTIGATIONS
Magnetic resonance angiography and CT angiography confirm diagnosis.
Mononeuropathy multiplex: vasculitis
SIGNS / SYMPTOMS
May present with symptoms and signs including nerve damage in ≥2 named nerves in separate parts of the body.
Wrist drop, for example, is caused by infarction of the radial nerve, and foot drop by damage to either the sciatic or peroneal nerve.
INVESTIGATIONS
Vasculitis and lymphocytic infiltrates on nerve biopsies.
Acromegaly
SIGNS / SYMPTOMS
Very slow onset over decades.
Typical clinical phenotype, including acral and soft tissue overgrowth; enlargement of jaw, nose, frontal bones, hands, and feet; articular overgrowth.
INVESTIGATIONS
Abnormal IGF-1 levels.
Pituitary MRI may reveal pituitary tumour.
Coagulopathies
SIGNS / SYMPTOMS
May present with haemorrhages or thrombosis.
INVESTIGATIONS
Abnormal platelets, prothrombin time, D-dimer, fibrinogen, and fibrin degradation products.
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