What is the differential diagnosis for intermittent paresthesias?

Differential Diagnosis for Intermittent Paresthesias

Intermittent paresthesias arise from either central nervous system pathology (ischemia, structural compression, inflammation, demyelination, infection) or peripheral nervous system disorders (entrapment neuropathies, metabolic disturbances, nutritional deficiencies, toxins, inflammatory conditions), with the pattern, distribution, and associated features guiding the diagnostic approach. 1

Central Nervous System Causes

Demyelinating Disease

• Multiple sclerosis presents with paresthesias that are often multifocal, affecting different body regions at different times, with MRI showing periventricular white matter lesions that are sharply demarcated, round or flame-shaped, and may enhance with gadolinium during acute phases 2
• Lesions typically spare U-fibers initially and involve the corpus callosum, distinguishing MS from other white matter diseases 2
• Symptoms evolve over hours to days, typically stabilize, and may resolve spontaneously even without therapy 2

Vascular Causes

• Cerebral venous thrombosis involving the sagittal sinus can cause bilateral paresthesias and motor signs 3
• Spinal cord ischemia presents with acute onset paraparesis and sensory changes, particularly following thoracic aortic procedures (2-6% incidence) 3
• Brainstem stroke should be considered when paresthesias are accompanied by cranial nerve findings or crossed sensory/motor deficits 2

Inflammatory/Infectious CNS Disorders

• Brainstem or spinal cord inflammation from sarcoidosis, Sjögren syndrome, neuromyelitis optica, or transverse myelitis can cause intermittent or progressive paresthesias 2
• Lyme disease encephalomyelitis is rare but presents with multifocal white matter involvement, CSF lymphocytic pleocytosis, and positive two-tier serology with intrathecal antibody production 2

Peripheral Nervous System Causes

Neuropathies

• Guillain-Barré syndrome presents with progressive bilateral paresthesias and weakness over days to 4 weeks, with absent or decreased reflexes, elevated CSF protein, and electrodiagnostic evidence of neuropathy 2
• Miller-Fisher syndrome (5-25% of GBS cases) presents with the triad of ataxia, areflexia, and ophthalmoplegia, though incomplete forms with isolated features occur 4
• Late Lyme disease peripheral neuropathy manifests as mild, diffuse "stocking-glove" paresthesias with reduced vibratory sensation, confluent mononeuritis multiplex on electrodiagnostic studies, and positive serum IgG antibody 2

Entrapment Syndromes

• Rucksack palsy (brachial plexus compression) causes paresthesias, paralysis, and weakness of the upper limb from shoulder strap pressure 5
• Meralgia paresthetica affects the lateral femoral cutaneous nerve, causing anterolateral thigh paresthesias 6
• Notalgia paresthetica presents with localized paresthesias in the interscapular region 6
• Digitalgia paresthetica causes toe paresthesias from digital nerve compression during load carriage 5

Metabolic and Nutritional Causes

• Vitamin B12 deficiency causes paresthesias that may be central (myelopathic) or peripheral (neuropathic), with subacute combined degeneration of the spinal cord 2, 7
• Hypokalaemia, hypomagnesaemia, hypophosphataemia can trigger intermittent paresthesias through altered nerve excitability 2
• Hypocalcemia from hypoparathyroidism or pseudohypoparathyroidism causes paresthesias, particularly perioral and acral 2
• Hyperthyroidism can precipitate paroxysmal symptoms including paresthesias 2

Movement Disorders with Sensory Phenomena

Paroxysmal Dyskinesias

• Paroxysmal kinesigenic dyskinesia (PKD) presents with brief (<1 minute) attacks of dystonia, chorea, or ballism triggered by sudden movement, often preceded by aura including paresthesias 2
• Attacks occur multiple times daily, respond to low-dose carbamazepine/oxcarbazepine, and high-knee exercise test can provoke symptoms 2
• Age of onset typically before 20 years; onset after 20 years is a red flag for secondary causes 2

Physiologic Mechanisms in Normal Subjects

• Hyperventilation-induced paresthesias occur through alkaline shift selectively increasing persistent sodium conductance in cutaneous afferents 8
• Ischemia-induced paresthesias result from membrane depolarization affecting sodium channels 8
• Post-ischemic paresthesias occur when hyperpolarization by Na+/K+ pump is transiently prevented by raised extracellular potassium 8

Other Causes

Restless Legs Syndrome

• Urge to move legs with uncomfortable sensations that begin or worsen during rest, are relieved by movement, and occur predominantly in evening/night 2
• Serum ferritin <50 ng/mL supports diagnosis and indicates need for iron supplementation 2
• Differential includes peripheral neuropathy, vascular disease, neuroleptic-induced akathisia, and arthritides 2

Medication-Induced

• Tricyclic antidepressants, SSRIs, lithium, and dopamine antagonists can exacerbate or cause paresthesias 2
• Statins, colchicine, chloroquine may cause toxic myopathy with associated sensory symptoms 2

Critical Red Flags Requiring Urgent Evaluation

• Acute onset with fever suggests infection or inflammatory process requiring immediate CSF analysis 2
• Sharp sensory level indicates spinal cord injury requiring emergent imaging 2
• Bladder/bowel dysfunction at onset suggests cauda equina syndrome or spinal cord compression 2
• Altered consciousness (except in Bickerstaff brainstem encephalitis) suggests CNS pathology beyond typical peripheral neuropathy 2
• Progressive symptoms >4 weeks without respiratory involvement suggests alternative diagnosis to GBS 2

Diagnostic Approach Algorithm

Initial evaluation should document:

• Temporal pattern (acute vs. subacute vs. chronic) 3
• Distribution (focal, multifocal, symmetric, length-dependent) 1
• Triggers (movement, rest, position, hyperventilation) 2, 8
• Associated symptoms (weakness, pain, autonomic dysfunction) 2

Laboratory assessment:

• Complete blood count, comprehensive metabolic panel, thyroid function 2, 3
• Vitamin B12, serum ferritin 2, 7
• Calcium, phosphorus, magnesium, parathyroid hormone 2
• Two-tier Lyme serology if endemic area exposure 2

Neurophysiologic studies:

• Nerve conduction studies and EMG differentiate demyelinating from axonal neuropathies and identify entrapment sites 2
• EEG if seizure disorder suspected, though often normal in frontal lobe epilepsy 2

Imaging:

• Brain and/or spine MRI with gadolinium for suspected CNS pathology 2
• FLAIR sequence preferred for detecting subcortical MS lesions 2

CSF analysis when indicated:

• Lymphocytic pleocytosis with elevated protein suggests GBS or Lyme neuroborreliosis 2

• 50×10⁶/L cells casts doubt on GBS diagnosis 2