Diagnostic algorithm for peripheral neuropathy

1. Confirm that it is peripheral neuropathy

• Myelopathy or spinal cord disease
• Radiculopathy
• Myopathy
• Motor neuron disease
• Neuromuscular-junction disorders
• Functional symptoms

2. History

• Onset and course: acute (<4 weeks), subacute, chronic; progressive, relapsing, or stepwise.
• Distribution: distal symmetric, asymmetric, multifocal, proximal, upper-limb predominant.
• Fiber type symptoms:
  • Large sensory fibers: loss of vibration, sensory ataxia
  • Small fibers: burning pain, temperature loss
  • Motor: weakness, cramps, foot drop
  • Autonomic: postural dizziness, sweating abnormality, bowel/bladder or erectile dysfunction
• Risk factors: diabetes, alcohol, renal failure, liver disease, hypothyroidism, nutritional deficiency.
• Drugs/toxins: chemotherapy, antitubercular drugs such as isoniazid, antiretrovirals, amiodarone, metronidazole, heavy metals.
• Family history: pes cavus, long-standing gait disorder, similar illness in relatives suggests hereditary neuropathy.
• Systemic clues: fever, weight loss, rash, joint symptoms, sicca symptoms, malignancy, HIV/hepatitis exposure.

3. Examination and clinical classification

Flowchart

Suspected peripheral neuropathy
            ↓
History + examination
            ↓
Is neuropathy clinically likely?
            ↓
No → Consider mimics: myelopathy, radiculopathy, myopathy, NMJ disorder
Yes
            ↓
Classify pattern:
symmetrical/asymmetrical, acute/chronic,
motor/sensory/autonomic, large/small fiber
            ↓
Baseline investigations + EMG/NCS
            ↓
Is a common cause identified?
            ↓
Yes → Treat underlying cause
No / atypical pattern
            ↓
Targeted tests: autoimmune, infective, CSF,
genetic tests, skin biopsy, nerve biopsy, imaging
            ↓
Neurology referral and final etiologic diagnosis

4. Initial investigations

• Complete blood count, ESR/CRP
• Blood glucose, HbA1c, and oral glucose tolerance test if required
• Renal function tests and liver function tests
• Serum vitamin B12, with methylmalonic acid if B12 is borderline
• Thyroid-stimulating hormone
• Serum protein electrophoresis with immunofixation, with or without serum free light chains
• HIV and hepatitis B/C testing where clinically indicated

5. Electrodiagnostic studies

• Confirm neuropathy
• Distinguish axonal from demyelinating neuropathy
• Define motor, sensory, or mixed involvement
• Identify symmetric versus multifocal disease
• Help exclude radiculopathy and entrapment neuropathy

• Axonal neuropathy: reduced amplitude of sensory/motor responses; conduction velocity relatively preserved.
• Demyelinating neuropathy: markedly slowed conduction velocity, prolonged distal latencies, conduction block or temporal dispersion.

6. Targeted tests for selected cases

• CSF analysis: raised protein with few cells suggests Guillain-Barré syndrome or CIDP.
• Autoimmune/vasculitic screen: ANA, ANCA, ENA, rheumatoid factor, complement, cryoglobulins if painful, asymmetric or systemic neuropathy.
• Anti-ganglioside antibodies: suspected GBS variants or multifocal motor neuropathy.
• Genetic testing: early onset, positive family history, pes cavus, slowly progressive neuropathy.
• Skin biopsy: confirms small-fiber neuropathy when NCS is normal.
• Autonomic function tests: if orthostatic hypotension, sweating or gastrointestinal/bladder symptoms.
• Nerve with or without muscle biopsy: suspected vasculitis, amyloidosis, leprosy, infiltrative neuropathy, or unexplained rapidly progressive asymmetric neuropathy.
• MRI spine/plexus: if radiculopathy, plexopathy, cord lesion, or structural compression is suspected.

7. Red flags requiring urgent referral

• Acute or rapidly progressive weakness
• Respiratory, bulbar, or autonomic involvement
• Predominantly motor neuropathy
• Marked asymmetry or mononeuritis multiplex
• Severe sensory ataxia
• Systemic features suggesting vasculitis, malignancy, infection, or amyloidosis

Cerebral venous thrombosis (CVT)

Etiopathogenesis

Predisposing causes

1. Female-specific
   • Pregnancy and puerperium
   • Oral contraceptive pills, estrogen therapy
2. Inherited thrombophilia
   • Factor V Leiden mutation
   • Prothrombin G20210A mutation
   • Protein C, protein S, or antithrombin deficiency
   • Hyperhomocysteinemia
3. Acquired prothrombotic states
   • Antiphospholipid syndrome
   • Malignancy
   • Nephrotic syndrome
   • Dehydration, severe anemia, polycythemia
   • Inflammatory bowel disease, systemic lupus erythematosus, Behçet disease
4. Infections
   • Otitis media, mastoiditis, sinusitis
   • Facial/orbital infection causing cavernous sinus thrombosis
   • Meningitis and systemic sepsis
5. Others
   • Head injury or neurosurgery
   • Drugs such as OCPs, corticosteroids, chemotherapeutic agents
   • Lumbar puncture
   • COVID-19 infection or vaccine-induced immune thrombotic thrombocytopenia in a compatible clinical setting

Pathogenesis

Risk factor / hypercoagulable state
                ↓
Thrombosis of dural sinus or cerebral vein
                ↓
Obstruction to venous drainage
                ↓
Venous hypertension + impaired CSF absorption
                ↓
Raised intracranial pressure, cerebral edema
                ↓
Venous infarction, often hemorrhagic

Clinical features

1. Features of raised intracranial pressure

• Headache, often progressive and diffuse
• Vomiting
• Papilledema
• Diplopia due to sixth cranial nerve palsy
• Transient visual obscurations and visual loss

2. Seizures

• Focal or generalized seizures
• Frequently occur with cortical vein involvement or venous infarction

3. Focal neurological deficits

• Hemiparesis, hemisensory loss, dysphasia
• Visual field defects
• Ataxia
• May fluctuate or not conform to a single arterial territory

4. Encephalopathy

• Altered behavior, confusion, drowsiness, delirium
• Stupor or coma in extensive thrombosis, deep venous thrombosis, or large hemorrhagic infarcts

5. Site-specific features

• Cavernous sinus thrombosis: fever, chemosis, proptosis, painful ophthalmoplegia, cranial nerve III, IV, V1/V2 and VI palsies.
• Lateral/transverse sinus thrombosis: headache, papilledema, otalgia, vertigo, and abducens palsy.
• Deep venous thrombosis: bilateral thalamic lesions, reduced consciousness, memory disturbance, coma.

Diagnosis

1. Clinical suspicion

• Hemorrhagic
• Bilateral or multifocal
• Associated with marked edema
• Not confined to an arterial territory

2. Neuroimaging

• Absent flow in a venous sinus or cortical vein
• Direct visualization of thrombus
• Loss of normal flow void
• Venous infarction, edema, or hemorrhage

• Hyperdense thrombosed sinus or cortical vein
• Hemorrhagic venous infarction
• Edema
• “Empty delta sign” after contrast in superior sagittal sinus thrombosis

3. Laboratory evaluation

• Complete blood count with platelet count
• PT/INR, aPTT, renal and liver function
• D-dimer may support suspicion but a normal value does not exclude CVT, particularly in isolated headache or delayed presentation.
• Evaluate the precipitating cause: pregnancy test where relevant, infection work-up, malignancy evaluation when indicated.
• Thrombophilia testing in unprovoked/recurrent CVT or strong family history. Ideally, test protein C, protein S and antithrombin after the acute event and after anticoagulants are stopped, because acute thrombosis and therapy can alter results.

Management

1. General measures

• Admit to stroke unit or intensive care unit if severe.
• Head elevation, airway and ventilation support if needed.
• Treat dehydration, anemia, infection, seizures, and the underlying cause.
• Manage raised intracranial pressure.
• Avoid routine corticosteroids unless there is another indication, such as inflammatory disease.

2. Anticoagulation: mainstay of treatment

• Start therapeutic low-molecular-weight heparin (LMWH) as soon as CVT is confirmed, unless there is a major contraindication.
• Unfractionated heparin is preferred if rapid reversal may be needed or in severe renal failure.
• Intracerebral hemorrhage caused by venous infarction is not a contraindication to anticoagulation. Anticoagulation prevents thrombus extension and promotes recanalization.

• Vitamin K antagonist such as warfarin, or
• A direct oral anticoagulant in selected nonpregnant patients.

3. Duration of anticoagulation

• Provoked CVT: usually 3-6 months
• Unprovoked CVT: usually 6-12 months
• Recurrent venous thrombosis or severe thrombophilia: consider long-term anticoagulation after specialist assessment

4. Management of complications

• Seizures: treat with antiseizure medication. Give prophylaxis in patients with a supratentorial venous lesion, hemorrhage, or early seizure according to clinical judgment.
• Raised intracranial pressure: analgesia, antiemetics, acetazolamide for papilledema where appropriate, and therapeutic lumbar puncture only after excluding dangerous mass effect.
• Impending herniation due to large infarction/hematoma: decompressive hemicraniectomy or hematoma evacuation may be lifesaving.

5. Endovascular therapy

6. Septic CVT

• Prompt intravenous broad-spectrum antibiotics
• Drainage or treatment of the primary infection, such as sinusitis, mastoiditis, or orbital infection
• Anticoagulation is individualized in consultation with neurology, infectious-disease, and surgical teams.

One-line conclusion