Algorithms for Diagnosis

This section provides interactive diagnostic algorithms designed for rapid clinical decision-making at the point of care. Each algorithm walks through history, examination, investigations, and pattern recognition β€” with expandable detail panels and clickable nodes for deeper reference.

Peripheral Neuropathy

NoteπŸ”— Related Topics

The algorithm below covers five major neuropathy subtypes evaluated in the general neurology outpatient setting: large fiber sensorimotor, small fiber, autonomic, mononeuropathy/entrapment, and hereditary neuropathy. It follows a six-step diagnostic sequence from initial presentation through subtype-specific workup.

How to use:

  • Tap β–Ά Details on any card to expand clinical guidance for that step.
  • Tap any colored subtype card (Step 5 or the Dx row) to navigate to detailed workup and management for that neuropathy type.
  • The algorithm is fully interactive and works on desktop and mobile.
Suspected peripheral neuropathy
Step 1
History & focused examination
Onset & tempo
Acute (<4 wk), subacute, chronic (>8 wk)?
  • Acute onset β†’ GBS, vasculitis, toxic/metabolic
  • Relapsing-remitting β†’ CIDP, hereditary, porphyria
  • Slowly progressive β†’ CMT, CIDP, metabolic
  • Length-dependent vs. non-length-dependent pattern?
Symptom character
Pain, paresthesias, weakness, autonomic symptoms?
  • Burning/allodynia β†’ small fiber predominant
  • Lancinating pain β†’ large fiber, radiculopathy
  • Orthostasis, gastroparesis, anhidrosis β†’ autonomic
  • Asymmetric distribution β†’ mononeuropathy multiplex
  • Distal symmetric β†’ length-dependent polyneuropathy
Risk factors & exposures
Diabetes, alcohol, B12, toxins, malignancy, medications?
  • DM, prediabetes, metabolic syndrome
  • Alcohol use (B1, B6, B12 deficiency)
  • Chemotherapy: taxanes, platinum, vinca alkaloids, thalidomide
  • HIV, hepatitis B/C, Lyme, leprosy
  • Paraneoplastic: lung, breast, thymoma
  • Amyloidosis: hereditary TTR or AL
Family & genetic history
Pes cavus, hammer toes, scoliosis in family members?
  • Pes cavus, hammertoes, scoliosis β†’ CMT
  • Autosomal dominant β†’ CMT1A (PMP22 dup), CMT2A (MFN2)
  • X-linked β†’ CMTX1 (GJB1/Cx32)
  • FAP (TTR), Fabry disease, Refsum disease
Step 2
Neurological examination
Sensory modalities
Separate large vs. small fiber findings
Large fiber:
  • Vibration (128 Hz tuning fork)
  • Proprioception / Romberg
  • Light touch (monofilament)
Small fiber:
  • Pin-prick (spinothalamic)
  • Temperature (warm/cold)
  • Allodynia to light brush
Motor & reflex
Distal weakness, wasting, areflexia pattern?
  • Distal > proximal weakness β†’ length-dependent axonal
  • Proximal + distal β†’ CIDP, GBS
  • Asymmetric foot drop β†’ peroneal neuropathy, MMN
  • Absent ankle jerks Β± preserved knee jerks β†’ classic DSPN
  • Global areflexia β†’ GBS, severe CIDP, hereditary
Autonomic signs
Postural BP drop, trophic changes, anhidrosis?
  • Orthostatic hypotension: β‰₯20/10 mmHg drop at 1–3 min
  • Trophic: dry skin, hair loss, nail changes, ulcers
  • Anhidrosis pattern (stocking-glove vs. segmental)
  • Pupillary light reflex (afferent/efferent)
Distribution pattern
Distal symmetric vs. asymmetric/focal?
  • Stocking-glove, symmetric β†’ DSPN (metabolic, toxic)
  • Asymmetric, multiple nerves β†’ mononeuropathy multiplex
  • Single nerve territory β†’ mononeuropathy / entrapment
  • Proximal leg > distal β†’ diabetic amyotrophy (DLRPN)
Step 3
Initial laboratory workup
First-line labs
CBC, CMP, HbA1c/FPG, OGTT, B12, TSH, ESR/CRP, SPEP/IFE
  • CBC: macrocytosis (B12/folate), eosinophilia (vasculitis)
  • HbA1c + 2-hr OGTT: up to 30% of "idiopathic" PN have IGT
  • B12: check MMA if borderline (200–400 pg/mL)
  • SPEP + IFE: MGUS-associated neuropathy (anti-MAG)
  • Urine porphyrins if acute presentation
Immune / infectious
ANA, ANCA, RF; HIV, HBV, HCV; Lyme if exposure
  • ANA, anti-Ro/La β†’ SjΓΆgren's (SFN, sensory ganglionopathy)
  • ANCA (MPO, PR3) β†’ vasculitic neuropathy
  • Cryoglobulins β†’ HCV-related vasculitis
  • HIV VL + CD4; HBV/HCV serology
  • Lyme ELISA + reflex Western blot (2-tier)
If malignancy suspected
Anti-Hu, Yo, CV2, amphiphysin; CT chest/abdomen/pelvis
  • Subacute sensory neuronopathy β†’ anti-Hu (SCLC)
  • Anti-CV2/CRMP5 β†’ SCLC, thymoma
  • Anti-amphiphysin β†’ breast, SCLC
  • PET-CT if antibody negative but strong clinical suspicion
  • Serum/urine free light chains β†’ amyloid (AL)
Step 4
Electrodiagnostic studies
Nerve conduction studies
Axonal vs. demyelinating, distribution, severity
Demyelinating pattern:
  • CV <38 m/s (median motor), prolonged DL, temporal dispersion, conduction block β†’ CIDP, CMT1, GBS
Axonal pattern:
  • Reduced CMAP/SNAP amplitudes, preserved CV β†’ DM, alcohol, toxic, axonal GBS (AMAN/AMSAN)
Uniform vs. non-uniform slowing:
  • Uniform β†’ hereditary (CMT1A)
  • Non-uniform β†’ acquired demyelinating (CIDP)
Needle EMG
Active denervation, reinnervation, neurogenic MUPs?
  • Fibrillations/PSWs: active axonal loss (β‰₯3 weeks after onset)
  • Large polyphasic MUPs: chronic reinnervation
  • Normal EMG with abnormal SNAP: sensory ganglionopathy
  • Normal NCS + normal EMG: consider SFN or proximal pathology
NCS normal β†’ SFN workup
Skin biopsy IENFD, QST, QSART, autonomic testing
  • Skin punch biopsy (3 mm): IENFD at thigh & distal leg
  • QST: warm/cool detection thresholds (8 body sites)
  • QSART: sudomotor function (postganglionic sympathetic)
  • TST: total anhidrosis pattern
  • Evaluate: DM/IGT, SjΓΆgren's, sarcoid, celiac, HIV, Nav1.7 mutations
Step 5
Pattern classification β†’ subtype-specific workup
Large fiber / sensorimotor
Length-dependent, reduced vibration/proprioception, absent ankle jerks, axonal or demyelinating NCS
AxonalDemyelinating
Small fiber neuropathy
Normal NCS, burning pain, allodynia, reduced pin/temp, reduced IENFD on skin biopsy
Skin biopsyQSART
Autonomic neuropathy
OH, anhidrosis, gastroparesis, urogenital dysfunction; may co-exist with SFN or large fiber PN
Tilt tableQSART
Mononeuropathy / entrapment
Single nerve territory; CTS, cubital tunnel, peroneal at fibular head, or multiplex pattern
NCS/EMGImaging
Hereditary neuropathy
Slowly progressive, pes cavus, family history, uniform slowing on NCS, onset in childhood/young adult
GeneticsCMT panel
Step 6
Second-line / specialist investigations
CSF analysis
Albumino-cytologic dissociation, cytoalbuminous pattern
  • Elevated protein (no pleocytosis) β†’ GBS (100–300), CIDP, CMT
  • Pleocytosis β†’ Lyme neuroborreliosis, CMV, sarcoid, lymphoma
  • Cytology β†’ leptomeningeal malignancy, lymphoma
  • VDRL β†’ neurosyphilis
Nerve biopsy
Sural or superficial peroneal; LM, EM, teased fiber
  • Indications: vasculitic PN, amyloid, leprosy, POEMS, undiagnosed inflammatory
  • Light microscopy: epineurial inflammation, onion-bulb formation
  • Congo red stain: amyloid deposits
  • Teased fiber prep: demyelination quantification
Neuroimaging
MRI nerve, plexus, spinal cord; nerve ultrasound
  • MRI brachial/lumbosacral plexus: DLRPN, Parsonage-Turner, malignant infiltration
  • Nerve ultrasound: CSA enlargement in CMT, CIDP, entrapment
  • Whole-body PET-CT: POEMS, occult malignancy
Autonomic battery
HUT, QSART, TST, Valsalva, 30:15 ratio, CASS score
  • CASS (composite autonomic severity score): 0–10
  • Valsalva ratio & phase II/IV BP: cardiovagal & adrenergic
  • 30:15 ratio: R-R interval at 30th vs 15th beat on standing
  • Plasma norepinephrine supine/standing: ganglionic vs. postganglionic
Genetic testing
CMT panel, WES/WGS, TTR gene if amyloid suspected
  • PMP22 duplication/deletion MLPA (CMT1A/HNPP): first-line if demyelinating + family Hx
  • MFN2 (CMT2A), GJB1 (CMTX), MPZ: axonal or X-linked
  • TTR gene sequencing: hereditary transthyretin amyloidosis
  • Nav1.7 (SCN9A), Nav1.8 (SCN10A): painful SFN
  • WES/WGS: undiagnosed hereditary PN with negative panel
Dx
Diagnosis established β†’ classify and treat
Metabolic / toxic DSPN
DM, IGT, alcohol, B12 deficiency, uremia, thyroid β€” treat underlying cause + neuropathic pain management
Small fiber neuropathy
Treat underlying etiology; pain management with lidocaine patch, low-dose naltrexone, SNRIs, alpha-lipoic acid
Autonomic neuropathy
Treat cause; OH β†’ fludrocortisone, midodrine, droxidopa; gastroparesis and urogenital: supportive
Mononeuropathy
Entrapment β†’ splinting, steroid injection, surgical decompression; vasculitic β†’ immunosuppression
Hereditary
CMT: supportive (PT/OT, AFOs); hereditary ATTR amyloid: tafamidis, patisiran, vutrisiran
Cryptogenic / CSPN
~25–30% remain unexplained; serial follow-up, lifestyle optimization, repeat evaluation in 2 years
Subtype color key
Large fiber / sensorimotor
Small fiber neuropathy
Autonomic neuropathy
Mononeuropathy
Hereditary
Cryptogenic

Tap β–Ά to expand clinical details. Colored subtype cards link to disease-based approach chapters.

White Matter Lesions β€” Brain & Spinal Cord

NoteπŸ”— Related Topics

Abnormal white matter on MRI is one of the most common β€” and most diagnostically challenging β€” incidental and symptomatic findings in neurology. This algorithm navigates the key decision points: brain vs. spinal cord, lesion pattern and location, clinical context, and investigations, arriving at a final diagnostic category across six major etiologic groups: inflammatory/demyelinating, vascular/ischemic, infectious, neoplastic, toxic/metabolic, and hereditary/genetic.

How to use:

  • Tap β–Ά Details on any card to expand pattern-recognition criteria and investigation guidance.
  • Tap any colored diagnosis card in the final tier to navigate to the full disease chapter.
  • Work through Steps 1–5 sequentially; the pattern in Step 3 is the pivotal branch point.
Abnormal white matter on MRI β€” brain or spinal cord
Step 1
Clinical context & history
Presenting symptoms
Acute vs. chronic? Focal deficits, cognitive change, seizure, pain?
  • Acute focal deficit (hours–days) β†’ ischemic stroke, demyelinating attack, ADEM
  • Relapsing-remitting episodes β†’ MS, NMOSD, MOGAD
  • Progressive cognitive decline + gait β†’ SVD, leukodystrophy, CADASIL
  • Headache + focal signs β†’ CNS vasculitis, PCNSL, metastasis
  • Fever + confusion β†’ CNS infection, ADEM, CLIPPERS
  • Asymptomatic incidental finding β†’ age-related WMH, migraine, early SVD
Tempo & course
Hyperacute, acute, subacute, or chronic/progressive?
  • Hyperacute (<24 hr) β†’ ischemic stroke (DWI restriction), demyelination with acute inflammation
  • Acute (days) β†’ ADEM, MS relapse, NMOSD attack, infectious encephalitis
  • Subacute (weeks) β†’ PCNSL, CNS vasculitis, CLIPPERS, paraneoplastic
  • Chronic progressive (months–years) β†’ SVD, leukodystrophy, CADASIL, MS-progressive
  • Monophasic β†’ ADEM, stroke; polyphasic β†’ MS, NMOSD, MOGAD
Risk factors & exposures
Age, vascular risk, immunosuppression, family history?
  • Age >50 + HTN/DM/smoking β†’ vascular WMH (SVD)
  • Young adult, female, relapsing β†’ MS
  • HIV, immunosuppression (natalizumab, transplant) β†’ PML (JC virus)
  • Recent infection/vaccination (child or adult) β†’ ADEM
  • Family history of early strokes/dementia + migraines β†’ CADASIL (NOTCH3)
  • Systemic autoimmune disease (SLE, SjΓΆgren's, sarcoid) β†’ CNS involvement
  • IV drug use, travel, HIV risk β†’ CNS infection
  • Radiation, chemotherapy (MTX, cyclosporine) β†’ toxic leukoencephalopathy
Brain vs. spinal cord
Lesion location shapes the differential significantly
Brain-predominant:
  • SVD, CADASIL, migraine-related WMH, leukodystrophy, PML
Spinal cord-predominant:
  • NMOSD (long-segment β‰₯3 vertebrae, central), MS (short <2 vertebrae, peripheral), MOGAD, B12 deficiency (posterior columns), ALD (lateral corticospinal)
Both brain + cord:
  • MS, NMOSD, MOGAD, neurosarcoidosis, CNS vasculitis, ADEM
Step 2
MRI characterization
T2/FLAIR signal
Size, shape, margins, distribution β€” periventricular, juxtacortical, subcortical, infratentorial?
MS pattern (McDonald 2017):
  • Periventricular (perpendicular to ventricles β€” Dawson fingers)
  • Juxtacortical / cortical
  • Infratentorial (brainstem, cerebellar peduncle)
  • Spinal cord (lateral/posterior, <2 vertebral segments)
Vascular/SVD pattern:
  • Deep white matter, basal ganglia, lacunar infarcts; spares corpus callosum & U-fibers early
NMOSD / MOGAD:
  • NMOSD: long-segment cord (>3 vertebrae), area postrema, periaqueductal; MOGAD: bilateral optic nerve, cortical FLAIR, lepto-cortical, LETM
ADEM:
  • Large, confluent, bilateral, asymmetric; deep gray matter involvement; juxtacortical sparing uncommon
DWI / ADC
Restricted diffusion narrows the differential substantially
  • DWI bright + ADC dark (true restriction) β†’ acute ischemic stroke, CJD (cortical ribboning), hypercellular PCNSL
  • DWI bright + ADC bright (T2 shine-through) β†’ demyelination, edema, vasogenic
  • Rim restriction (ring) β†’ abscess (pyogenic), tumefactive MS, high-grade glioma
  • Posterior column restriction β†’ B12 subacute combined degeneration
  • Entire WM restriction β†’ osmotic demyelination syndrome (CPM/EPM)
Gadolinium enhancement
Pattern and morphology of enhancement
  • Open-ring (incomplete ring, open toward cortex) β†’ MS, tumefactive demyelination
  • Closed ring β†’ abscess, metastasis, high-grade glioma
  • Homogeneous solid + restricted diffusion β†’ PCNSL
  • Punctate + perivascular β†’ CNS vasculitis, neurosarcoidosis, CLIPPERS (pepper-like pontine)
  • Leptomeningeal + parenchymal β†’ neurosarcoidosis, Lyme, TB meningitis, carcinomatous
  • No enhancement β†’ SVD, leukodystrophy, chronic MS, migraine WMH
Additional sequences
SWI, MRS, perfusion, spine β€” key discriminators
  • SWI/GRE: microbleeds β†’ CAA, CADASIL, hypertensive; black holes β†’ chronic MS axonal loss
  • MRS: choline↑ / NAA↓ β†’ high-grade glioma, PCNSL; lactate peak β†’ MELAS, abscess
  • Perfusion: hyperperfusion β†’ tumefactive MS; hypoperfusion β†’ high-grade tumor core
  • Spinal cord: sagittal T2 lesion length (short <2 = MS; long β‰₯3 = NMOSD/MOGAD); axial location (peripheral = MS, central = NMOSD)
  • T1 hypointense lesions (black holes) β†’ chronic irreversible MS plaques
Step 3
Pivotal pattern classification
Periventricular + ovoid + Dawson fingers
Β± juxtacortical, infratentorial, short cord lesions β†’ MS pattern
  • McDonald 2017 criteria: dissemination in space (DIS) + time (DIT)
  • DIS: β‰₯2 of 4 zones (periventricular, juxtacortical/cortical, infratentorial, spinal cord)
  • DIT: simultaneous Gd+ and non-Gd+ lesions, OR new T2/Gd+ on follow-up MRI
  • CIS (clinically isolated syndrome): first demyelinating event β€” check OCBs, VEP, follow MRI
  • RIS (radiologically isolated): asymptomatic McDonald DIS β€” annual MRI, 50% convert in 10 yrs
Long cord β‰₯3 segments + area postrema
Central cord, bilateral optic neuritis, hiccups/vomiting β†’ NMOSD/MOGAD pattern
  • NMOSD: anti-AQP4 seropositive in ~75%; long-segment LETM (central cord), area postrema lesion
  • MOGAD: anti-MOG Ab; bilateral ON, LETM (H-sign on axial), ADEM-like, cortical FLAIR
  • Key distinction: NMOSD β†’ spinal cord necrosis, severe attacks; MOGAD β†’ better recovery
  • CSF: neutrophilic pleocytosis during attack (both); OCBs absent or transient
Deep WM + lacunar + basal ganglia
Vascular risk factors, age >50, spares U-fibers and corpus callosum β†’ SVD pattern
  • Fazekas scale I–III: periventricular caps/bands β†’ Grade I (normal aging) to Grade III (confluent)
  • Lacunar infarcts: <15 mm, deep gray/white matter β€” HTN, DM, hyperlipidemia
  • CADASIL: young (<50), anterior temporal pole + external capsule WMH + lacunar strokes + migraine with aura β†’ NOTCH3 gene
  • CAA: older, cortical/subcortical, lobar microbleeds on SWI β€” risk of lobar hemorrhage
  • No Gd enhancement; DWI restriction only if acute lacunar infarct
Large confluent Β± mass effect Β± ring enhancement
Tumefactive lesion β€” demyelination vs. neoplasm vs. abscess
  • Open-ring Gd + + perilesional edema + young patient β†’ tumefactive MS
  • Solid Gd + + DWI restriction + periventricular + immunocompromised/elderly β†’ PCNSL
  • Closed-ring + DWI restriction (center dark ADC) β†’ pyogenic abscess
  • Multiple ring lesions β†’ metastasis, abscess (toxoplasma in HIV)
  • MRS: markedly elevated choline, decreased NAA β†’ high-grade glioma; lipid-lactate peak β†’ abscess/necrosis
  • Consider stereotactic biopsy if diagnosis uncertain after MRS, perfusion, and CSF
Symmetric posterior/anterior WM Β± U-fibers
Childhood/young adult, hereditary β€” leukodystrophy pattern
  • X-ALD (ALD): parieto-occipital WM + splenium + corticospinal tract; boys; elevated VLCFA
  • Metachromatic leukodystrophy: symmetric parietal deep WM, tigroid pattern; arylsulfatase A deficiency
  • Krabbe disease: posterior WM + pyramidal tracts; galactocerebrosidase deficiency
  • Alexander disease: frontal-predominant WM + swollen frontal lobes; GFAP mutation
  • MELAS: cortical/subcortical (not WM-only), stroke-like episodes, elevated lactate, maternal inheritance
  • Key: leukodystrophies β€” symmetric, non-enhancing, begin in specific WM tracts
Punctate/patchy + perivascular + infratentorial
Systemic disease, immune dysregulation, or infection β€” inflammatory/infectious pattern
  • CLIPPERS: punctate pepper-like Gd+ lesions centered on pons/brainstem β€” responsive to steroids
  • Neurosarcoidosis: leptomeningeal Gd+, cranial nerve enhancement, periventricular WMH
  • CNS vasculitis: multifocal WMH + infarcts in multiple vascular territories, Β± vessel wall enhancement on 7T/VWMRI
  • PML: large, non-enhancing, subcortical U-fiber-involving, JC virus in immunosuppressed
  • Lyme neuroborreliosis: punctate WMH (MS mimic), cranial neuritis, meningitis, CSF pleocytosis
  • HIV encephalitis: bilateral symmetric deep WMH, atrophy, low CD4
Step 4
Targeted investigations
CSF analysis
OCBs, IgG index, cell count, protein, cytology
  • OCBs (β‰₯2, CSF-specific) + elevated IgG index β†’ MS (sensitivity ~95%); absent in NMOSD, MOGAD
  • Lymphocytic pleocytosis β†’ ADEM, CNS infection, neurosarcoidosis, Lyme, CLIPPERS
  • Neutrophilic pleocytosis β†’ bacterial meningitis, early viral, NMOSD/MOGAD attack
  • Very high protein (>100 mg/dL) β†’ GBS, CNS vasculitis, PCNSL, tuberculosis
  • Cytology + flow cytometry β†’ PCNSL (malignant lymphocytes), carcinomatous meningitis
  • JC virus PCR β†’ PML; EBV PCR β†’ PCNSL in HIV; TB PCR/culture; Lyme Ab index
  • Lactate ↑ β†’ MELAS, mitochondrial disease, meningitis
Serum antibody panel
AQP4-IgG, MOG-IgG, ANA, ANCA, antiphospholipid, paraneoplastic
  • Anti-AQP4 IgG (cell-based assay): NMOSD β€” sensitivity 73%, specificity >99%
  • Anti-MOG IgG (cell-based assay): MOGAD β€” check both serum and CSF if seronegative
  • ANA, anti-dsDNA, complement (C3/C4) β†’ neuropsychiatric SLE
  • ANCA (MPO, PR3) β†’ CNS vasculitis, eosinophilic granulomatosis
  • Antiphospholipid Ab (aCL, anti-Ξ²2GP1, lupus anticoagulant) β†’ APS-related strokes/WMH
  • ACE level Β± chest CT β†’ neurosarcoidosis (ACE insensitive; biopsy often needed)
  • Anti-Ro/La β†’ SjΓΆgren's CNS; VLCFA β†’ X-ALD; NOTCH3 gene β†’ CADASIL
Evoked potentials & OCT
Subclinical lesion detection for dissemination in space
  • Visual evoked potentials (VEP): delayed P100 β†’ subclinical optic neuritis; supports MS DIS
  • SSEP, BAEP: additional subclinical demyelination in brainstem/cord
  • OCT (optical coherence tomography): peripapillary RNFL thinning β†’ prior optic neuritis; tracks MS/NMOSD/MOGAD retinal damage
  • Severe RNFL loss disproportionate to visual acuity β†’ NMOSD (worse than MS)
Vascular & metabolic workup
For SVD, CADASIL, APS, metabolic leukodystrophy
  • MRA brain/neck β†’ large vessel stenosis, vasculitis beading, moyamoya
  • Vessel wall MRI (VWMRI) β†’ CNS vasculitis (concentric enhancement), atherosclerotic plaque
  • Echocardiogram + cardiac monitoring β†’ cardioembolic source in young stroke/WMH
  • HbA1c, lipids, homocysteine, thrombophilia screen
  • NOTCH3 gene β†’ CADASIL; skin biopsy (EM: GOM deposits) as alternative
  • B12, methylmalonic acid, copper, vitamin E β†’ metabolic cord/WM disease
  • Arylsulfatase A, galactocerebrosidase, VLCFA β†’ leukodystrophy panel
Dx
Diagnosis established β†’ disease category & management direction
Inflammatory / demyelinating
MS, NMOSD, MOGAD, ADEM, CLIPPERS β€” disease-modifying therapy, acute attack treatment (steroids, PLEX)
MSNMOSDMOGAD
Vascular / ischemic
SVD, CADASIL, APS, CAA β€” vascular risk factor modification, antiplatelet/anticoagulation, genetic counseling
SVDCADASILCAA
Infectious
PML, Lyme, TB, HIV encephalitis, abscess β€” targeted antimicrobial/antiviral; PML: restore immune function
PMLLymeAbscess
Neoplastic
PCNSL, glioma, metastasis β€” biopsy for tissue diagnosis, oncology referral, do not give steroids before biopsy in suspected PCNSL
PCNSLGliomaMets
Hereditary / metabolic
Leukodystrophies (X-ALD, MLD, Krabbe), MELAS, Fabry β€” enzyme replacement, gene therapy, mitochondrial supplements, transplant in selected cases
X-ALDMELASFabry
Systemic autoimmune / inflammatory
CNS vasculitis, neurosarcoidosis, neuropsychiatric SLE, SjΓΆgren's β€” immunosuppression, treat underlying systemic disease
VasculitisSarcoidSLE
Pattern color key
MS / demyelinating pattern
NMOSD / MOGAD pattern
Vascular / SVD pattern
Tumefactive / neoplastic pattern
Leukodystrophy pattern
Inflammatory / infectious pattern

Tap β–Ά to expand MRI pattern criteria and investigation details. Colored diagnosis cards link to full disease chapters.

Headache Evaluation

NoteπŸ”— Related Topics

Headache is the most common neurological complaint in outpatient and emergency settings. The fundamental task is distinguishing secondary headache β€” caused by an underlying structural, vascular, or systemic disorder β€” from primary headache, where headache is the disorder itself. This algorithm follows four sequential steps: red flag screening, phenotype characterization, targeted investigation, and final diagnosis across seven headache categories.

How to use:

  • Step 1 is the most critical β€” any red flag mandates urgent investigation before proceeding to phenotyping.
  • Tap β–Ά Details on any card to expand diagnostic criteria, investigation thresholds, and clinical pearls.
  • Tap any colored diagnosis card in the final tier to navigate to the full disease chapter.
Patient presenting with headache
Step 1
⚠️ Red flag screening β€” exclude secondary headache first
SNOOP4 red flags
Any single flag warrants urgent evaluation β€” do not assume primary headache
SNOOP4 mnemonic:
  • Systemic symptoms: fever, weight loss, myalgias β†’ meningitis, GCA, malignancy
  • Neurological deficits or altered consciousness β†’ mass, stroke, encephalitis
  • Onset sudden/thunderclap β†’ SAH, RCVS, CVST, pituitary apoplexy
  • Older age (>50, new headache) β†’ GCA, mass, subdural
  • Postural component: worse lying flat β†’ IIH; worse standing β†’ CSF leak/SIH
  • Papilledema β†’ raised ICP, IIH, venous thrombosis
  • Prior headache history change: new pattern or accelerating frequency β†’ secondary cause
  • Precipitated by Valsalva (cough, strain, sex) β†’ Chiari, mass, RCVS
Thunderclap headache
Maximal intensity within 60 seconds β€” emergency until SAH excluded
Mandatory workup:
  • Non-contrast CT head within 6 hr of onset: sensitivity ~98% for SAH if <6 hr
  • LP (xanthochromia + RBC count): if CT negative but <6 hr, LP at 12 hr post-onset; if >6 hr, LP immediately
  • CT angiography / MRA: aneurysm, RCVS (beading), CVST (cord sign)
  • MRI brain + MRV: CVST, pituitary apoplexy, posterior fossa mass
Causes:
  • SAH (~25%), RCVS (~40%), CVST, pituitary apoplexy, spontaneous ICH, cervical artery dissection, hypertensive emergency, primary thunderclap (diagnosis of exclusion)
Fever + meningismus
Headache + fever Β± neck stiffness Β± photophobia β†’ infectious emergency
  • Bacterial meningitis: do NOT delay antibiotics for LP if CT indicated β€” start empiric ceftriaxone + vancomycin + dexamethasone
  • Kernig's sign (pain/resistance on knee extension with hip flexed) and Brudzinski's sign (hips flex on neck flexion) β€” low sensitivity but high specificity
  • CT head before LP if: focal deficit, papilledema, seizure, immunocompromised, GCS <15, new onset seizure
  • Viral meningitis (HSV, enterovirus): LP CSF β€” lymphocytic pleocytosis, normal glucose
  • HSV encephalitis: temporal lobe changes on MRI, EEG (PLEDs), CSF HSV PCR
  • Consider also: brain abscess, subdural empyema, cryptococcal meningitis (India ink, CrAg in HIV)
Age >50 + new headache
Giant cell arteritis, intracranial mass, subdural hematoma
Giant cell arteritis (GCA):
  • Age >50 (usually >70), temporal tenderness/thickening, jaw claudication, PMR symptoms
  • ESR >50 mm/hr + CRP elevated; ESR can be normal in 10%
  • Start prednisolone 40–60 mg immediately if vision threatened β€” do not wait for biopsy
  • Temporal artery biopsy within 2 weeks (skip lesions: bilateral biopsy increases yield)
  • Visual loss (AION) is the feared complication β€” irreversible if not treated urgently
Other age >50 red flags:
  • Progressive headache + focal signs/cognitive change β†’ CT/MRI for mass, metastasis, subdural
  • Morning headache + papilledema + nausea β†’ raised ICP until proven otherwise
No red flags β†’ proceed to phenotyping
Step 2
Headache phenotype characterization
Pain characteristics
Location, quality, severity, radiation β€” the most discriminating phenotypic features
  • Unilateral throbbing, moderate–severe β†’ migraine (bilateral in ~40%)
  • Bilateral, pressing/tightening, mild–moderate, non-pulsating β†’ tension-type
  • Periorbital/retro-orbital, severe/excruciating, unilateral β†’ cluster (TAC)
  • Electric shock/lancinating, V2/V3 distribution, triggered by touch β†’ trigeminal neuralgia
  • Occipital + neck stiffness, worse with movement β†’ cervicogenic or posterior fossa
  • Bifrontal/bioccipital, worse lying flat, pulsatile β†’ IIH (raised ICP)
  • Bifrontal/bioccipital, worse standing, relieved lying β†’ SIH/CSF leak
Duration & timing
Episode length and circadian pattern are highly diagnostic
  • Seconds (3–5 s) β†’ SUNCT/SUNA, ice-pick headache
  • 15–180 minutes, circadian clustering, nocturnal β†’ cluster headache
  • 2–30 minutes, multiple/day, autonomic β†’ paroxysmal hemicrania (indomethacin-responsive)
  • 4–72 hours, episodic β†’ migraine without aura
  • 30 min – 7 days, featureless β†’ tension-type
  • Continuous, unilateral, fluctuating β†’ hemicrania continua (indomethacin-responsive)
  • Daily from onset (>3 months) β†’ new daily persistent headache (NDPH)
  • Nocturnal, wakes from sleep β†’ cluster, hypnic headache (age >50), raised ICP
Associated features
Nausea, photophobia, phonophobia, autonomic, aura, visual symptoms
  • Nausea/vomiting + photophobia + phonophobia β†’ migraine (ICHD-3: β‰₯2 of 3)
  • Ipsilateral autonomic features (lacrimation, conjunctival injection, ptosis, nasal congestion, miosis) β†’ TACs (cluster, PH, SUNCT)
  • Visual aura: positive (scintillating scotoma, fortification spectra) β†’ migraine with aura; spreading over 20–60 min distinguishes from TIA (abrupt onset)
  • Sensory/motor/aphasic aura preceding headache β†’ migraine with aura (hemiplegic if motor)
  • Tinnitus + pulsatile sound + visual obscurations β†’ IIH
  • Horner's syndrome + neck pain β†’ carotid/vertebral dissection
  • Diplopia + headache β†’ CVST, IIH (VI nerve palsy), posterior fossa mass
Triggers, modifiers & medication use
Precipitants, postural changes, analgesic frequency
  • Triggers (sleep deprivation, stress, menstruation, certain foods/alcohol) β†’ migraine
  • Worse with activity β†’ migraine; not aggravated by activity β†’ tension-type
  • Postural: worse upright, better supine within minutes β†’ SIH; worse supine/morning β†’ IIH, mass
  • Triggered by Valsalva (cough, strain, exercise, sexual activity) β†’ Chiari, intracranial mass, RCVS
  • Triggered by touch, chewing, cold β†’ trigeminal neuralgia
  • Analgesic/triptan use β‰₯10–15 days/month β†’ medication overuse headache (MOH); suspect if escalating daily headache in migraineur
  • Seasonal clustering, alcohol-triggered attack β†’ cluster headache
Step 3
Targeted investigations (when indicated)
Neuroimaging indications
MRI brain Β± contrast, CT head, CTA/MRA β€” when and what
Image immediately (CT Β± CTA):
  • Thunderclap headache β†’ non-contrast CT then LP if negative; CTA for aneurysm/RCVS
  • Focal neurological deficit + headache
  • Fever + headache + altered consciousness (after LP safe exclusion)
  • Papilledema β†’ CT first to exclude mass before LP
Image semi-urgently (MRI Β± Gd):
  • New headache in age >50, immunocompromised, known malignancy
  • Postural headache (SIH: MRI brain with Gd β€” pachymeningeal enhancement, brain sag)
  • Progressive headache over weeks, awakens from sleep, morning nausea
  • Headache + cranial nerve palsy (III, VI) β†’ IIH, mass, CVST
Imaging NOT routinely needed:
  • Classic migraine/tension-type meeting ICHD-3 criteria, no red flags, normal exam
Lumbar puncture
Opening pressure, xanthochromia, RBC count, OCBs, culture
  • Opening pressure >250 mmHβ‚‚O (lateral decubitus) β†’ IIH; <60 mmHβ‚‚O β†’ SIH/CSF leak
  • Xanthochromia + elevated RBC (non-traumatic, non-clearing) β†’ SAH confirmed; spectrophotometry preferred over visual inspection
  • Lymphocytic pleocytosis + elevated protein + low glucose β†’ bacterial meningitis, TB, fungal
  • Lymphocytic pleocytosis + normal glucose β†’ viral meningitis, Lyme, sarcoid, RCVS
  • OCBs β†’ MS-related headache (rare primary indication); also seen in CNS infection, NMOSD
  • CSF culture + India ink + CrAg β†’ cryptococcal meningitis (HIV/immunocompromised)
  • Therapeutic LP: IIH β€” drain to closing pressure of 200 mmHβ‚‚O; temporary visual relief
Blood tests
ESR, CRP, CBC, metabolic panel, coagulation β€” targeted by context
  • ESR + CRP: GCA (ESR >50, CRP elevated); also elevated in meningitis, malignancy
  • CBC: anemia (headache trigger), thrombocytosis/thrombocytopenia (CVST risk), leukocytosis (infection)
  • Coagulation + thrombophilia screen β†’ CVST workup (antiphospholipid Ab, protein C/S, factor V Leiden)
  • BMP + TFTs: hyponatremia, uremia, thyroid dysfunction β€” secondary headache causes
  • Hypercoagulable screen, OCP/pregnancy status β†’ CVST risk
  • Serum lactate + ammonia: metabolic encephalopathy, MELAS
  • Toxicology: carbon monoxide (headache + nausea + confusion in winter, multiple household members)
Specialist investigations
For complex, refractory, or atypical presentations
  • MRV brain β†’ CVST (filling defect in dural sinuses); contrast-enhanced MRV superior to MRA
  • CT/MR myelography or digital subtraction myelography β†’ SIH with CSF leak (epidural fluid, meningeal diverticulum)
  • Temporal artery biopsy β†’ GCA (within 2 weeks of steroid start)
  • Temporal artery ultrasound (halo sign) β†’ GCA: sensitivity 75–80% for cranial GCA
  • Indomethacin trial (75–150 mg/day): complete response β†’ paroxysmal hemicrania or hemicrania continua (pathognomonic)
  • Headache diary (β‰₯4 weeks): frequency, duration, triggers, analgesic use β€” essential for MOH assessment and preventive therapy indication
  • Ophthalmology: formal visual field testing + OCT retinal nerve fiber layer β†’ IIH monitoring
Dx
Diagnosis established β†’ category & management direction
Migraine spectrum
Migraine without/with aura, chronic migraine, hemiplegic, vestibular β€” acute: triptans, NSAIDs, anti-emetics; preventive: topiramate, amitriptyline, propranolol, CGRP mAbs
EpisodicChronicWith aura
Trigeminal autonomic cephalalgias
Cluster, paroxysmal hemicrania, SUNCT/SUNA, hemicrania continua β€” cluster: Oβ‚‚ 100% + sumatriptan SC; PH/HC: indomethacin (diagnostic + therapeutic)
ClusterPH/HCSUNCT
Tension-type & MOH
Episodic/chronic tension-type, medication overuse headache β€” tension: NSAIDs, amitriptyline; MOH: analgesic withdrawal (bridging with naproxen/prednisone), preventive therapy
Episodic TTHMOH
Vascular / structural secondary
SAH, RCVS, CVST, carotid/vertebral dissection, hypertensive emergency β€” urgent neurosurgical/neurovascular referral; RCVS: nimodipine, avoid vasoconstrictors
SAHRCVSCVST
CSF pressure disorders
IIH: weight loss + acetazolamide Β± topiramate; optic nerve sheath fenestration or shunting if vision threatened. SIH: epidural blood patch, CT/MR myelography for leak localization
IIHSIH
Systemic / infectious / other secondary
GCA: steroids urgently; meningitis/encephalitis: antimicrobials; brain tumor/metastasis: oncology; cervicogenic: physio, nerve block; trigeminal neuralgia: carbamazepine, MVD
GCAMeningitisCervicogenic
Category color key
Migraine spectrum
Trigeminal autonomic cephalalgias
Tension-type & MOH
Vascular / structural secondary
CSF pressure disorders
Systemic / infectious / other secondary

Step 1 red flag cards are always evaluated first regardless of headache pattern. Tap β–Ά for diagnostic criteria and clinical pearls. Colored diagnosis cards link to full disease chapters.

Myopathy Evaluation

NoteπŸ”— Related Topics

Myopathy β€” intrinsic disease of skeletal muscle β€” presents with proximal weakness, elevated CK, and myopathic EMG, but the underlying etiology spans a wide spectrum from treatable inflammatory and immune-mediated disorders to progressive genetic dystrophies and reversible metabolic or toxic causes. This algorithm follows five sequential steps: confirm myopathic pattern, characterize the clinical phenotype, perform electrodiagnostic and laboratory workup, apply myositis-specific antibody testing, and arrive at a final diagnostic category with management direction.

How to use:

  • Step 1 distinguishes myopathy from neuromuscular junction and motor neuron disease before proceeding.
  • Steps 2–3 separate the major etiologic branches: inflammatory vs. genetic vs. metabolic/toxic.
  • Step 4 is specific to the inflammatory branch β€” myositis-specific and myositis-associated antibody profiling.
  • Tap β–Ά Details to expand criteria, investigation thresholds, and clinical pearls. Colored Dx cards link to disease chapters.
Suspected myopathy β€” proximal weakness, elevated CK, or myalgia
Step 1
Confirm myopathic pattern & exclude mimics
Myopathic clinical pattern
Symmetric proximal > distal weakness, preserved reflexes early, no sensory loss
Classic myopathy features:
  • Proximal > distal weakness: difficulty rising from chair, climbing stairs, raising arms overhead
  • Symmetric limb-girdle pattern (shoulder + hip girdle)
  • Reflexes preserved until late (unlike neuropathy β€” early loss)
  • No sensory deficits (distinguishes from neuropathy)
  • Myalgia, muscle tenderness Β± cramps (especially inflammatory)
  • Elevated serum CK (except IBM, some congenital myopathies β€” may be normal)
  • Myopathic EMG: short-duration, low-amplitude, polyphasic MUPs; early recruitment; Β± fibrillations (inflammatory)
Distal > proximal β€” consider instead:
  • IBM (distal finger flexor + quadriceps), myotonic dystrophy, distal myopathies (Welander, Nonaka, Miyoshi)
Exclude neuromuscular mimics
Motor neuron disease, NMJ disorders, neuropathy with proximal predominance
NMJ (fatiguability distinguishes from myopathy):
  • Myasthenia gravis: fluctuating, fatigable weakness; ptosis/diplopia; AChR/MuSK Ab; decremental response on 3 Hz RNS
  • LEMS: proximal leg > arm; autonomic features; incremental response on 50 Hz RNS; VGCC Ab
Motor neuron disease:
  • ALS: UMN + LMN signs, fasciculations, bulbar involvement, normal CK or mildly elevated
  • SMA: pure LMN, no sensory loss, SMN1 gene
Neuropathy with proximal predominance:
  • CIDP: reduced reflexes, sensory involvement, elevated CSF protein, demyelinating NCS
  • Diabetic amyotrophy (DLRPN): unilateral, painful, asymmetric proximal leg
Onset & tempo
Acute, subacute, or chronic/slowly progressive β€” shapes the differential immediately
  • Acute (<4 weeks) + very high CK (>10,000) β†’ rhabdomyolysis, toxic myopathy, viral myositis, IMNM
  • Subacute (weeks–months) + elevated CK + systemic features β†’ inflammatory myopathy (DM, PM, IMNM, anti-synthetase)
  • Chronic progressive (years) + family history β†’ hereditary muscular dystrophy (DMD, LGMD, FSHD)
  • Slowly progressive, onset >50, distal finger flexors + quadriceps β†’ IBM
  • Episodic weakness Β± exercise-induced β†’ metabolic myopathy, channelopathy (periodic paralysis)
  • Onset in infancy/childhood β†’ congenital myopathy, Pompe, DMD
  • Progressive proximal weakness + respiratory failure β†’ Pompe disease (acid maltase deficiency); check GAA enzyme activity
CK level & interpretation
Degree of CK elevation guides probability toward specific etiologies
  • Normal or mildly elevated (≀5Γ— ULN): IBM, congenital myopathy, endocrine myopathy, steroid myopathy, some FSHD
  • Moderately elevated (5–50Γ— ULN): DM, PM, LGMD, FSHD, Pompe, statin myopathy
  • Markedly elevated (>50Γ— ULN): IMNM (anti-SRP, anti-HMGCR), DMD/BMD, rhabdomyolysis, acute necrotizing myopathy
  • Asymmetric or fluctuating CK: metabolic myopathy (McArdle), channelopathy, exertional rhabdomyolysis
  • Very high CK (>10,000) β†’ assess for rhabdomyolysis: urine myoglobin, renal function, electrolytes, urine dipstick (blood without RBCs)
  • CK-MB fraction: cardiac involvement in DM, IMNM, overlap myositis β€” also check troponin and ECG
Step 2
Clinical phenotype & extramuscular features
Skin & extramuscular features
Skin findings are pathognomonic in dermatomyositis; systemic features narrow the inflammatory subtype
Dermatomyositis skin (pathognomonic):
  • Gottron's papules: violaceous papules over MCP/PIP joints
  • Heliotrope rash: periorbital violaceous erythema with edema
  • V-sign (anterior chest), shawl sign (posterior shoulders/neck)
  • Mechanic's hands: hyperkeratotic fissuring of lateral fingers (anti-synthetase syndrome)
  • Calcinosis cutis: calcium deposits in skin/subcutaneous tissue (juvenile DM)
Systemic features by subtype:
  • ILD (interstitial lung disease): anti-synthetase syndrome (Jo-1, PL-7, PL-12, EJ, OJ), MDA5 (rapidly progressive ILD)
  • Arthritis + Raynaud's + mechanic's hands: anti-synthetase syndrome
  • Malignancy association: DM > PM (check CT chest/abdomen/pelvis, PET, mammogram, PSA)
  • Cardiac: myocarditis, arrhythmia in DM/IMNM/overlap; check ECG + troponin + echo
  • Dysphagia: IBM (early), DM/PM (late), oculopharyngeal MD
Weakness distribution pattern
Selective muscle involvement is the key to hereditary subtype classification
  • Symmetric proximal limb-girdle: DM, PM, LGMD, Pompe, Becker MD
  • Proximal arm + scapular winging + facial weakness: FSHD (asymmetric, face-shoulder-arm)
  • Distal finger flexors (FDP) + quadriceps: IBM (characteristic pattern β€” finger curl grip weakness)
  • Axial (neck flexors, paraspinals) + proximal: anti-SRP IMNM, DM, overlap myositis
  • Ptosis + ophthalmoplegia + proximal: mitochondrial myopathy (CPEO), oculopharyngeal MD
  • Calf hypertrophy + pelvic girdle + Gowers' sign: DMD/BMD (boys)
  • Highly selective (e.g., tibialis anterior only): myotonic dystrophy type 1, Nonaka/GNE myopathy
  • Asymmetric involvement: IBM, FSHD, scapuloperoneal myopathy
Family history & genetic clues
Inheritance pattern, onset age, associated features suggesting hereditary cause
  • X-linked (males affected): DMD/BMD (dystrophin), Emery-Dreifuss (EDMD1/FHL1)
  • Autosomal dominant: FSHD (D4Z4 repeat), myotonic dystrophy 1 & 2, LGMD1 subtypes, oculopharyngeal MD (PABPN1)
  • Autosomal recessive: LGMD2 subtypes (sarcoglycan, dysferlin, calpain-3), Pompe (GAA), Bethlem (COL6)
  • Maternal inheritance Β± multisystem (CPEO, hearing loss, diabetes, CNS): mitochondrial myopathy (mtDNA mutation)
  • Myotonia (grip myotonia, percussion myotonia, paramyotonia): myotonic dystrophy, myotonia congenita (CLCN1), SCN4A channelopathy
  • Contractures early (elbow, Achilles) + cardiac conduction: Emery-Dreifuss MD
  • Rigid spine + respiratory failure disproportionate to limb weakness: SEPN1/SELENON, LMNA
Drug, toxic & systemic exposures
Statins, steroids, alcohol, ICIs, endocrine disorders β€” always screen before invasive workup
Common toxic/drug myopathies:
  • Statins: proximal myalgia Β± mild CK elevation; IMNM (anti-HMGCR) persists after statin cessation β€” CK very high
  • Steroids (chronic): type II fiber atrophy; CK normal; EMG normal or mild; diagnosis of exclusion
  • Colchicine, hydroxychloroquine: vacuolar myopathy Β± neuropathy; biopsy β€” autophagic vacuoles
  • Immune checkpoint inhibitors (anti-PD1, anti-CTLA4): immune myositis Β± myocarditis Β± MG overlap
  • Alcohol: acute (rhabdomyolysis) or chronic (proximal myopathy + cardiomyopathy)
  • Zidovudine (AZT): mitochondrial myopathy; ragged-red fibers on biopsy
Endocrine myopathies:
  • Hypothyroidism: proximal weakness, elevated CK, myoedema, slow relaxing reflexes; TSH diagnostic
  • Hyperthyroidism: proximal weakness, CK normal/low, thyroid ophthalmopathy clue
  • Cushing's / exogenous steroids: type II atrophy, CK normal, pain absent
  • Hyperparathyroidism, hypokalemia, hypophosphatemia: metabolic myopathy; correct electrolytes first
Step 3
Core investigations
Electrodiagnostics (NCS / EMG)
Confirm myopathy, assess activity, exclude NMJ and neuropathy
EMG myopathic pattern:
  • Short-duration, small-amplitude, polyphasic MUPs with early (full) recruitment
  • Fibrillation potentials + positive sharp waves: active inflammatory myopathy (DM, PM, IMNM, anti-synthetase)
  • Complex repetitive discharges (CRDs): chronic myopathy (IBM, dystrophies)
Special patterns:
  • Myotonic discharges (waxing-waning, dive-bomber sound): myotonic dystrophy, myotonia congenita, paramyotonia congenita, DM1/DM2
  • Normal EMG + proximal weakness: consider steroid myopathy, endocrine, early Pompe
  • IBM: mixed myopathic + neurogenic features (chronic reinnervation in distal muscles)
  • RNS 3 Hz decremental (>10%): MG; incremental on 50 Hz: LEMS β€” rules out primary myopathy
  • Paraspinal EMG: active if inflammatory; spared in dystrophies
NCS:
  • Normal in most myopathies; reduced CMAP amplitude in severe/acute necrotizing myopathy
  • Axonal neuropathy co-existing: overlap syndrome, anti-synthetase neuropathy
Laboratory panel
CK isoforms, aldolase, LDH, myoglobin, inflammatory markers, metabolic screen
Muscle enzymes:
  • CK (total + MM isoform): primary marker; MM fraction predominates in skeletal muscle disease
  • Aldolase: elevated in DM even when CK is near-normal
  • LDH, AST, ALT: elevated in myopathy (often misattributed to hepatic disease)
  • Troponin + CK-MB: cardiac myositis in DM/IMNM β€” ECG + echo if elevated
Inflammatory & metabolic:
  • ESR, CRP: elevated in inflammatory myopathy; may be normal in IBM
  • TSH, free T4: hypothyroid/hyperthyroid myopathy
  • Electrolytes (K, Mg, PO4, Ca): metabolic myopathy, periodic paralysis
  • Urinalysis: myoglobinuria (urine dipstick positive for blood without RBCs on microscopy)
  • Forearm ischemic exercise test (modified lactate/ammonia test): failure of lactate rise β†’ glycogenolysis/glycolysis defect (McArdle, GSD); failure of ammonia rise β†’ myoadenylate deaminase deficiency
  • Acid alpha-glucosidase (GAA) enzyme activity: Pompe disease (dried blood spot screen)
  • Serum lactate + pyruvate (fasting): mitochondrial myopathy; confirm with muscle biopsy respiratory chain
Muscle MRI
STIR edema, T1 fatty replacement β€” localizes biopsy site, defines pattern of involvement
  • STIR hyperintensity (edema/inflammation): active inflammatory myopathy (DM, PM, IMNM) β€” guides biopsy to most active area
  • T1 fatty replacement: chronic dystrophic change β€” selective pattern aids genetic classification
  • IBM pattern: selective FDP (forearm) + vasti (quadriceps) T1 fatty change
  • FSHD: periscapular + tibialis anterior + medial gastrocnemius; asymmetric; T1 fatty infiltration
  • LGMD subtypes: characteristic patterns (e.g., LGMD2B/dysferlin: posterior thigh + calf; calpain-3: posterior thigh + lumbar paraspinals)
  • Mitochondrial myopathy: patchy STIR signal; may be normal
  • Whole-body MRI: survey pattern of involvement across all muscle groups before targeted biopsy
Muscle biopsy
Light microscopy, immunohistochemistry, EM β€” the definitive diagnostic test in most myopathies
Inflammatory patterns:
  • DM: perifascicular atrophy + perivascular CD4+ T cells + B cells (complement C5b-9 on capillaries)
  • PM: endomysial CD8+ T cell invasion of non-necrotic fibers (MHC-I upregulation)
  • IBM: rimmed vacuoles + endomysial inflammation + COX-negative fibers + p62/TDP-43 inclusions
  • IMNM: necrosis + regeneration, minimal inflammation; MHC-I upregulation; anti-SRP/HMGCR IHC
Genetic/structural patterns:
  • Dystrophinopathy: absent/reduced dystrophin on IHC (DMD = absent; BMD = reduced/altered)
  • Sarcoglycanopathy (LGMD): absent sarcoglycan on IHC panel
  • Pompe: periodic acid-Schiff (PAS) positive vacuoles; acid phosphatase in lysosomes; GAA IHC
  • Mitochondrial: ragged-red fibers (Gomori trichrome), COX-negative fibers, SDH-positive vessels
  • Nemaline myopathy: nemaline rods on Gomori trichrome; EM confirms
  • Congenital myopathy: central nuclei (centronuclear), cores (central core/multiminicore) on NADH/ATPase
Biopsy site:
  • Choose moderately weak muscle with STIR signal on MRI; avoid severely atrophied muscle; avoid previously biopsied or EMG-sampled site
Step 4
Myositis antibody panel & genetic testing
Myositis-specific antibodies (MSA)
Define inflammatory subtype, predict ILD risk, guide cancer screening and prognosis
Anti-synthetase antibodies (ILD + arthritis + mechanic's hands):
  • Anti-Jo-1 (most common, ~20% IIM): DM/PM phenotype, ILD, arthritis, Raynaud's, mechanic's hands
  • Anti-PL-7, anti-PL-12, anti-EJ, anti-OJ, anti-KS: similar syndrome; ILD often dominant; weaker myositis
DM-specific antibodies:
  • Anti-MDA5: amyopathic DM + rapidly progressive ILD; skin ulceration; high mortality without early aggressive Rx
  • Anti-TIF1-Ξ³ (anti-p155/140): DM + strong malignancy association (lung, ovary, breast, GI); cancer screen mandatory
  • Anti-NXP2 (anti-p140): DM + calcinosis + malignancy (adult-onset)
  • Anti-Mi-2: classic DM rash (Gottron's, heliotrope, shawl sign); low ILD risk; good treatment response
  • Anti-SAE1: DM + dysphagia; Β± malignancy; often amyopathic onset
IMNM-specific antibodies:
  • Anti-SRP: severe necrotizing myopathy; very high CK (>10,000); cardiac involvement; resistant to therapy
  • Anti-HMGCR: statin-triggered or de novo necrotizing myopathy; CK very high; persists after statin cessation
IBM-associated:
  • Anti-cN1A (anti-Mup44): present in ~30–50% IBM; not diagnostic alone; also seen in SLE, SjΓΆgren's
Myositis-associated antibodies (MAA)
Indicate overlap with systemic autoimmune disease
  • Anti-Ro52 (TRIM21): often co-occurs with MSAs; associated with ILD in anti-synthetase syndrome; not myositis-specific
  • Anti-PM/Scl (PM-Scl75/100): PM-scleroderma overlap; ILD + sclerodactyly + Raynaud's
  • Anti-U1-RNP: MCTD (myositis + scleroderma + SLE features); high-titer ANA, speckled pattern
  • Anti-Ku: PM-scleroderma overlap; ILD; arthritis
  • ANA (homogeneous/speckled): SLE overlap myositis β€” check anti-dsDNA, complement
  • Anti-Ro/La: SjΓΆgren's overlap β€” sicca symptoms, sensory neuronopathy
Genetic testing strategy
Targeted gene panel vs. WES/WGS β€” guided by phenotype, biopsy, and inheritance pattern
First-line targeted testing:
  • Dystrophinopathy (DMD/BMD): dystrophin gene deletion/duplication MLPA; sequence if negative
  • FSHD: D4Z4 repeat contraction analysis (chr 4q35); SMCHD1 for FSHD2
  • Myotonic dystrophy: DMPK CTG repeat (DM1); CNBP CCTG repeat (DM2)
  • Pompe: GAA gene sequencing; confirm with enzyme activity (dried blood spot)
  • LGMD: NGS panel covering CAPN3, DYSF, SGCA/B/C/D, FKRP, ANO5, DNAJB6, FLNC (30+ genes)
Second-line / undiagnosed:
  • WES or WGS: undiagnosed hereditary myopathy with negative panel; captures novel variants
  • Mitochondrial genome (mtDNA) sequencing: CPEO, MELAS, MERRF, Kearns-Sayre; also check tRNA variants
  • RNA sequencing of muscle: detects cryptic splice variants missed by DNA-level analysis
Malignancy screening
DM carries highest cancer risk β€” screen at diagnosis and annually for 3 years
  • Highest risk: DM (RR ~6); especially anti-TIF1-Ξ³, anti-NXP2, anti-SAE1 positive
  • Moderate risk: PM (RR ~2); IMNM (especially anti-SRP)
  • Low risk: anti-synthetase syndrome, IBM, juvenile DM
  • Screen: CT chest/abdomen/pelvis + PET-CT; mammogram; PSA; colonoscopy; pelvic US (women)
  • Repeat screening: annually for 3 years after diagnosis (peak cancer risk in first 1–3 years)
  • Anti-MDA5 positive: low malignancy risk; focus on ILD surveillance (HRCT, PFTs) instead
Dx
Diagnosis established β†’ category & management direction
Inflammatory myopathy (IIM)
DM, PM, anti-synthetase syndrome, MDA5-DM β€” high-dose steroids + steroid-sparing (azathioprine, MMF, IVIG, rituximab); ILD: cyclophosphamide or tacrolimus for refractory
DM PM Anti-synthetase
Immune-mediated necrotizing myopathy (IMNM)
Anti-SRP or anti-HMGCR β€” high-dose steroids + IVIG + rituximab; often refractory to single agent; stop statin if HMGCR (necessary but insufficient)
Anti-SRP Anti-HMGCR
Inclusion body myositis (IBM)
No proven disease-modifying therapy; immunosuppression not effective; focus on dysphagia management, PT/OT, ankle-foot orthoses, aspiration precautions
Distal finger flexors Quadriceps
Hereditary muscular dystrophy
DMD: exon-skipping (eteplirsen), ataluren (nonsense); LGMD: gene therapy trials; cardiac surveillance; respiratory support (NIV); PT/OT; multidisciplinary care
DMD/BMD LGMD FSHD
Metabolic & mitochondrial myopathy
Pompe: enzyme replacement therapy (alglucosidase alfa / avalglucosidase alfa); McArdle: avoid intense exercise, sucrose pre-exercise; mitochondrial: CoQ10, riboflavin, carnitine (limited evidence); avoid valproate, metformin
Pompe McArdle Mitochondrial
Toxic, endocrine & other secondary
Statin myopathy: cease statin, switch class or CoQ10 if needed; steroid myopathy: reduce dose, resistance exercise; hypothyroid: levothyroxine; ICB myositis: hold ICI, steroids Β± IVIG; correct electrolytes for metabolic causes
Statin Endocrine ICI myositis
Category color key
Inflammatory myopathy (IIM)
Immune-mediated necrotizing (IMNM)
Inclusion body myositis (IBM)
Hereditary muscular dystrophy
Metabolic & mitochondrial
Toxic / endocrine / secondary

Tap β–Ά for diagnostic criteria, antibody profiles, and biopsy patterns. Colored Dx cards link to full disease chapters.

Tremor Evaluation

NoteπŸ”— Related Topics

Tremor β€” rhythmic, involuntary oscillatory movement of a body part β€” is the most common movement disorder. The critical first step is classifying by activation condition (rest, action, intention), since this single feature most powerfully narrows the differential. This algorithm follows five sequential steps: tremor classification, clinical phenotype, key discriminators, targeted investigation, and final diagnosis across six major etiologic categories.

How to use:

  • Step 1 is the pivotal branch point β€” rest vs. action vs. intention tremor drives the entire differential.
  • Tap β–Ά Details on any card to expand diagnostic criteria, examination pearls, and investigation thresholds.
  • Colored Dx cards link to full disease chapters.
Patient presenting with tremor
Step 1
Tremor classification by activation condition β€” the pivotal branch point
Rest tremor
Present at rest, suppressed or reduced by voluntary movement, re-emerges after postural hold (re-emergent)
  • Classic frequency: 3–6 Hz; typically affects distal limb (pill-rolling in PD)
  • Suppressed by target-directed movement β†’ distinguishes from cerebellar intention tremor
  • Re-emergent rest tremor: disappears on arm extension, re-appears after 10–15 s delay β†’ PD (not ET)
  • Asymmetric onset strongly favors Parkinson’s disease
  • Chin, lip, or tongue tremor: PD; head tremor at rest: atypical (consider PSP, MSA, CBS)
  • Associated: rigidity, bradykinesia, postural instability, hypomimia, micrographia β†’ PD
Action tremor β€” postural / kinetic
Present when limb is maintained against gravity (postural) or during voluntary movement (kinetic); absent at rest
Postural tremor (arm outstretched):
  • Bilateral, symmetric, high-frequency (6–12 Hz): essential tremor, enhanced physiologic tremor
  • Low-amplitude, fine: enhanced physiologic tremor (anxiety, caffeine, fatigue, medications)
  • Head tremor (yes-yes or no-no): ET, dystonic tremor, cervical dystonia
  • Voice tremor: ET (titubation), spasmodic dysphonia
Kinetic tremor (during movement, consistent amplitude):
  • Simple kinetic β†’ ET (worsens during movement, maximal at midpoint)
  • Task-specific β†’ writer’s tremor (primary writing tremor), musician’s tremor
  • Isometric (during contraction against fixed object) β†’ ET, dystonic tremor
Intention tremor
Worsens as limb approaches target; maximal at end of movement; absent at rest
  • Frequency: 2–4 Hz; amplitude increases toward target on finger-nose-finger test
  • Indicates cerebellar or cerebellar outflow pathway pathology
  • Causes: MS (dentate nucleus, cerebellar peduncle), stroke (SCA territory), SCA, alcohol, medications (lithium, amiodarone, phenytoin toxicity)
  • Titubation (head/trunk oscillation at rest or with posture): cerebellar vermis lesion
  • Holmes tremor (midbrain/rubral): mixed rest + postural + intention tremor, low frequency (2–4 Hz), large amplitude β†’ thalamic/midbrain lesion (stroke, MS, trauma)
  • Associated: dysmetria, dysdiadochokinesia, nystagmus, gait ataxia β†’ cerebellar syndrome
Special / task-specific / position-specific
Occurs only in specific conditions: standing, writing, certain postures
  • Orthostatic tremor: 13–18 Hz leg tremor exclusively on standing; inaudible visually but palpable; EMG diagnostic; worsened walking, relieved sitting/lying
  • Primary writing tremor: tremor only during writing; focal dystonia spectrum
  • Palatal tremor: rhythmic soft palate movement; essential (ear click) vs. symptomatic (inferior olivary hypertrophy after brainstem/cerebellar lesion)
  • Chin tremor (geniospasm): familial or sporadic; present at rest and with emotion
Step 2
Clinical phenotype & associated features
Body part & distribution
Localization and symmetry provide immediate diagnostic clues
  • Unilateral hand, rest, pill-rolling β†’ PD (classic); asymmetric onset typical
  • Bilateral hand, postural + kinetic, no rest β†’ ET, enhanced physiologic tremor
  • Head tremor (no-no horizontal) β†’ ET, dystonic tremor, cervical dystonia; rare in PD
  • Head tremor (yes-yes vertical) β†’ ET, less commonly dystonic
  • Voice/laryngeal tremor β†’ ET (essential voice tremor), PD (monotone, not oscillatory)
  • Bilateral leg tremor on standing only β†’ orthostatic tremor
  • Chin/lip tremor β†’ PD (vs. ET which rarely affects chin)
  • Tongue tremor β†’ PD, Wilson’s disease
  • Trunk tremor β†’ atypical parkinsonian syndromes, cerebellar (titubation)
Examination maneuvers
Key bedside tests to classify and grade tremor
  • Rest: observe hands in lap, distract with mental task (serial 7s) β†’ accentuates PD rest tremor
  • Postural: arms outstretched, then wings position (elbows flexed, hands at shoulder height) β†’ ET, physiologic
  • Kinetic: finger-nose-finger, rapid alternating movements (dysdiadochokinesia) β†’ cerebellar
  • Intention: amplitude increases approaching target on FNF β†’ cerebellar
  • Re-emergent test: hold arms outstretched; tremor in PD disappears then returns after 10–15 s; ET tremor persists immediately
  • Entrainment test: ask patient to tap contralateral hand at given rhythm; functional tremor entrains (changes frequency); organic tremor does not
  • Distractibility: functional tremor β€” amplitude decreases or stops with cognitive loading
  • Archimedes spiral: document and grade tremor severity (ET score)
  • Writing sample: macrographia (cerebellar, ET) vs. micrographia (PD)
  • Tandem gait, Romberg: cerebellar vs. sensory ataxia
Associated neurological features
Accompanying signs distinguish isolated tremor from a broader syndrome
Parkinsonism features (TRAP):
  • Tremor + Rigidity (cogwheel) + Akinesia/Bradykinesia + Postural instability β†’ PD, MSA, PSP, CBS, DLB
Cerebellar features:
  • Intention tremor + dysmetria + dysdiadochokinesia + ataxic gait + nystagmus β†’ cerebellar syndrome
Dystonic features:
  • Abnormal posture + overflow movements + sensory trick (geste antagoniste) β†’ dystonic tremor; often irregular, direction-changing
Red flags for atypical parkinsonism:
  • Early falls (PSP), vertical gaze palsy (PSP), alien limb (CBS), cerebellar signs (MSA-C), autonomic failure (MSA-P), symmetric onset, levodopa non-responsive
History & contextual factors
Onset, family history, medications, triggers, and temporal pattern
  • Age of onset: young (<40) β†’ Wilson’s, dystonic tremor, FXTAS (men >50 with FMR1 premutation), ET; older β†’ PD, ET
  • Family history (AD): ET (50% FH); FMR1 premutation (FXTAS); SCA subtypes
  • Alcohol response: improvement β†’ strongly suggests ET; worsening β†’ enhanced physiologic
  • Medications causing tremor: valproate, lithium, amiodarone, SSRIs, antipsychotics (drug-induced parkinsonism), stimulants, corticosteroids, cyclosporine, levothyroxine excess
  • Drug-induced parkinsonism (DIP): symmetric rest tremor, usually from D2 blockers (antipsychotics, metoclopramide); reversible after stopping
  • Diurnal variation: worsens with fatigue, stress, caffeine; improves with alcohol (ET)
  • Onset after CNS insult (stroke, trauma, MS) β†’ Holmes/symptomatic tremor
  • Psychiatric comorbidity + sudden onset + inconsistent β†’ functional tremor
Step 3
Key discriminating features between major tremor syndromes
PD vs. essential tremor
The most common clinical dilemma β€” separating these two is critical for management
Feature PD ET
Tremor type Rest (pill-rolling) Postural + kinetic
Frequency 3–6 Hz 6–12 Hz
Distribution Asymmetric, hand Bilateral, hands + head
Head tremor Rare Common (no-no/yes-yes)
Voice tremor Monotone, no oscillation Oscillatory voice tremor
Writing Micrographia Macrographia (large, tremulous)
Alcohol response No change Marked improvement
Other signs Rigidity, bradykinesia Usually isolated tremor
Re-emergent test Delayed return (10–15 s) Immediate on arm extension
Family history ~15% (LRRK2, SNCA) ~50% (AD)
DaTscan Reduced uptake Normal
Functional (psychogenic) tremor
Positive features are required β€” not a diagnosis of exclusion
Positive clinical signs (Fahn-Williams criteria):
  • Entrainment: tremor adopts frequency of voluntary rhythmic contralateral tapping β€” pathognomonic
  • Distractibility: tremor diminishes/disappears with mental task (serial 7s, dual task)
  • Variability: frequency or amplitude changes spontaneously or with suggestion
  • Tremor stops during ballistic voluntary movement of the affected limb
  • Inconsistency between activation conditions on repeated examination
  • Sudden onset, maximum severity at onset; remission with distraction or psychotherapy
  • Co-activation sign: co-contraction of agonist + antagonist on EMG (increases tremor stiffness)
Supporting features:
  • Psychiatric comorbidity; secondary gain; inconsistent neurological exam; somatization history
  • Worsens with attention, improves with distraction β†’ opposite of most organic tremors
Wilson’s disease β€” always exclude in young tremor (<40)
Autosomal recessive copper metabolism disorder; treatable if caught early
  • Wing-beating tremor: proximal arm tremor with elbows abducted β†’ classic but not specific
  • Mixed tremor (rest + postural + intention) in young patient β†’ strong suspicion
  • Kayser-Fleischer rings: slit-lamp exam; present in ~95% neurological Wilson’s
  • Hepatic dysfunction (cirrhosis, elevated LFTs) in young patient with neurological symptoms
  • Dysarthria, dysphagia, personality change, psychiatric symptoms
  • Screen: serum ceruloplasmin (<20 mg/dL), 24-hr urine copper (>100 ΞΌg/day), liver biopsy copper
  • MRI: β€œface of the giant panda” sign (midbrain), T2 hyperintensity in basal ganglia, thalamus
  • ATP7B gene mutation (chromosome 13q14)
Drug-induced & toxic tremor
Always review medication list β€” one of the most common and reversible causes
Postural/action tremor (enhanced physiologic):
  • Lithium (dose-dependent; also cerebellar at toxic levels)
  • Valproate (postural; can be severe; dose-related)
  • Amiodarone (postural + cerebellar; can persist after cessation)
  • SSRIs, SNRIs, TCAs; Ξ²-agonists (salbutamol), theophylline
  • Corticosteroids, ciclosporin, tacrolimus
  • Excess levothyroxine (enhanced physiologic)
Rest tremor / drug-induced parkinsonism:
  • D2 blockers: haloperidol, risperidone, metoclopramide, prochlorperazine
  • Symmetric onset, normal DaTscan β†’ DIP (reversible weeks–months after stopping)
Toxic:
  • Mercury (intention tremor, intentional β†’ cerebellar), manganese (parkinsonism, β€œcheek” tremor), alcohol (enhanced physiologic acutely; cerebellar in chronic use)
Step 4
Targeted investigations
Blood tests
Metabolic, endocrine, toxic, and genetic screen
First-line (all patients):
  • TFTs (TSH, free T4): hyperthyroidism β†’ enhanced physiologic tremor; hypothyroidism β†’ rarely tremor
  • Calcium, magnesium, glucose: metabolic tremor
  • LFTs, renal function: hepatic/renal encephalopathy
  • Drug levels: lithium, valproate, phenytoin, cyclosporine
Young tremor (<40) / atypical:
  • Serum ceruloplasmin + 24-hr urine copper: Wilson’s disease
  • FMR1 premutation (CGG repeat): FXTAS (men >50 with intention/action tremor + cerebellar ataxia + cognitive decline)
  • Heavy metal screen (mercury, manganese, arsenic): occupational/toxic exposure
Genetic testing:
  • LRRK2, SNCA, GBA, PINK1, DJ-1, Parkin: PD genetics panel if young-onset (<50) or family history
  • SCA genetic panel (SCA1, 2, 3, 6, 12, 17): cerebellar ataxia + tremor + family history
Neuroimaging
MRI brain, DaTscan β€” when and what
MRI brain (standard sequences + SWI):
  • Atypical parkinsonism: β€œhummingbird sign” (midbrain atrophy) β†’ PSP; β€œhot cross bun” (pons) β†’ MSA; putaminal atrophy/hypointensity β†’ MSA-P
  • Wilson’s: T2 hyperintensity basal ganglia + thalamus + midbrain; β€œface of the giant panda”
  • Cerebellar/brainstem atrophy: SCA, MSA-C, alcohol, prion disease
  • Focal lesion (stroke, MS plaque, tumor) at dentate, red nucleus, or thalamus β†’ Holmes tremor
  • SWI/GRE: reduced signal in substantia nigra pars compacta β†’ neuromelanin loss (PD, MSA-P)
  • DWI restriction: CJD (β€œcortical ribboning”) presenting with tremor/myoclonus
DaTscan (ΒΉΒ²Β³I-Ioflupane SPECT):
  • Reduced striatal dopamine transporter uptake β†’ PD, MSA, PSP, CBS, DLB (distinguishes from ET, DIP, functional tremor β€” all normal)
  • Indications: clinically uncertain parkinsonism; ET vs. PD; DIP vs. PD; DLB vs. AD
  • Asymmetric putaminal loss β†’ PD; symmetric loss β†’ MSA, PSP
  • Normal DaTscan does NOT exclude PD in very early disease
Tremor analysis & EMG
Frequency characterization, entrainment testing, accelerometry
  • Surface EMG: alternating agonist-antagonist bursts (ET, PD) vs. synchronous co-contraction (functional tremor)
  • Tremor frequency: <4 Hz β†’ cerebellar / Holmes; 4–6 Hz β†’ PD rest; 6–12 Hz β†’ ET / physiologic; 13–18 Hz β†’ orthostatic tremor
  • Accelerometry: quantitative amplitude + frequency; tracks progression and treatment response
  • Entrainment test on EMG: functional tremor β€” burst frequency shifts to match voluntary tapping; organic tremor maintains intrinsic frequency
  • Orthostatic tremor: EMG of leg muscles (tibialis anterior) during standing β†’ high-frequency (13–18 Hz) burst pattern; pathognomonic
  • Coherence analysis: bilateral cortical-muscular coherence on EEG-EMG β†’ cortical tremor (epilepsia partialis continua differential)
Neuropsychological & specialist assessments
Cognitive testing, autonomic evaluation, smell testing, slit-lamp
  • MoCA / MMSE: cognitive impairment in PD (PD-MCI, PDD), DLB, PSP, CBS, Wilson’s
  • UPDRS / MDS-UPDRS: standardized parkinsonism severity and tremor rating
  • Fahn-Tolosa-MarΓ­n Tremor Rating Scale: ET-specific severity scale
  • University of Pennsylvania Smell Identification Test (UPSIT): hyposmia β†’ PD (present in >90%); normal in MSA, PSP, ET
  • Autonomic testing (QSART, tilt table): orthostatic hypotension, anhidrosis β†’ MSA, PD autonomic variant
  • Slit-lamp exam: Kayser-Fleischer rings β†’ Wilson’s disease (mandatory in young-onset tremor)
  • Psychiatric assessment: functional tremor, anxiety-related enhanced physiologic tremor
Dx
Diagnosis established β†’ category & management direction
Parkinson’s disease & atypical parkinsonism
PD: levodopa/carbidopa (gold standard), dopamine agonists, MAO-B inhibitors; DBS for refractory tremor. Atypical (MSA/PSP/CBS): supportive; poor levodopa response; multidisciplinary care
PDMSAPSP/CBS
Essential tremor spectrum
First-line: propranolol or primidone; second-line: topiramate, gabapentin, benzodiazepines; refractory: focused ultrasound thalamotomy (Vim), DBS Vim, MRgFUS
ETET-plusIsolated voice
Metabolic & toxic tremor
Wilson’s: D-penicillamine or trientine (chelation), zinc; treat hyperthyroidism; withdraw offending drug (DIP reverses in weeks–months); alcohol abstinence; correct electrolytes
Wilson’sDIPToxic
Functional tremor
Psychoeducation (explain the diagnosis positively); physiotherapy (movement retraining); CBT; treat comorbid depression/anxiety; avoid unnecessary investigations; prognosis better with early diagnosis
FNDCBTPhysiotherapy
Task-specific & orthostatic tremor
Orthostatic tremor: clonazepam (first-line), gabapentin, primidone, levodopa; DBS Vim in refractory cases. Primary writing tremor: botulinum toxin, anticholinergics
OTWriting tremorPalatal
Cerebellar & symptomatic tremor
Treat underlying cause (MS: DMT; stroke: rehab; SCA: genetic counseling, supportive). Symptomatic: clonazepam, propranolol, isoniazid (MS tremor); DBS Vim or thalamotomy for severe cases
CerebellarHolmesSCA
Tremor type color key (Step 1)
Rest tremor β†’ Parkinsonian
Action tremor β†’ ET / physiologic
Intention tremor β†’ Cerebellar
Task-specific / position-specific

Step 1 tremor classification is the mandatory first branch point. Tap β–Ά to expand examination maneuvers, discriminating features, and investigation thresholds. Colored Dx cards link to full disease chapters.

Diplopia Evaluation

NoteπŸ”— Related Topics

Diplopia is one of neurology’s most localizing symptoms. The algorithm below follows a four-step sequence: monocular vs. binocular (the mandatory first branch point), oculomotor pattern recognition (which nerve or muscle), urgency triage (identify emergencies before imaging), and targeted investigation. It covers cranial nerve palsies (CN3/4/6), internuclear ophthalmoplegia (INO), neuromuscular junction disease, restrictive myopathy, and orbital/cavernous sinus lesions.

How to use:

  • Tap β–Ά Details on any card to expand examination technique and discriminating features.
  • The cover test (Step 1) is non-negotiable β€” monocular diplopia goes to ophthalmology, not neuro-imaging.
  • Red-flag urgency cards in Step 3 identify same-day imaging indications.
Patient reports double vision
Step 1
Cover test β€” monocular vs. binocular (mandatory first step)
Perform cover test
Cover one eye: does diplopia resolve? If yes β†’ binocular. If no β†’ monocular.
  • Cover each eye in turn β€” if diplopia resolves when either eye is covered β†’ binocular (neurological)
  • Diplopia persists with one eye covered β†’ monocular (ocular media, refractive)
  • Monocular diplopia: dry eye, corneal irregularity, lens opacity (cataract), macular pathology, refractive error β†’ refer ophthalmology
  • Functional/non-organic: may persist with cover test but inconsistent across examinations
History essentials
Onset, direction worst, constant vs. intermittent, pain, associated symptoms?
  • Horizontal diplopia β†’ CN6 (lateral gaze), CN3 (all directions), INO (adduction lag)
  • Vertical diplopia β†’ CN4 (worse down-gaze, head-tilt), CN3, skew deviation
  • Oblique (combined) β†’ CN3 (mixed vertical + horizontal), orbital
  • Painful β†’ CN3 aneurysm, cavernous sinus, GCA, orbital pseudotumor, Tolosa-Hunt
  • Painless β†’ microvascular CN palsy (DM/HTN), MG, CN4 palsy
  • Intermittent + fatigable β†’ MG, thyroid eye disease
  • Acute onset + headache β†’ PCom aneurysm, PICA/basilar stroke, RCVS β€” emergency
  • Duration: seconds (gaze-evoked nystagmus), minutes (TIA), hours–days (stroke, demyelination, MG crisis)
Directed examination
Ptosis, proptosis, pupil, EOM β€” 9-position gaze testing
  • Ptosis: CN3 (complete), Horner (partial, 1–2 mm), MG (fatigable), myopathy (bilateral)
  • Proptosis: thyroid eye disease, orbital pseudotumor, cavernous sinus fistula, orbital tumor
  • Pupil: dilated + unreactive β†’ CN3 (aneurysm), Adie's; miosis + ptosis β†’ Horner; normal pupil + CN3 palsy β†’ microvascular
  • 9-position gaze: document limitation in each position β€” map to individual muscles
  • Fatigability: sustained upgaze for 60 s β†’ ptosis worsening = MG (Cogan lid twitch)
  • Head tilt test (Parks-Bielschowsky 3-step): CN4 palsy diagnosis
  • Red glass or Maddox rod: quantify deviation and identify false image
Step 2
Oculomotor pattern recognition β€” localize the lesion
CN3 palsy pattern
Ptosis + "down and out" eye Β± mydriasis; adduction, elevation, depression all limited
  • Complete CN3 with dilated unreactive pupil β†’ PCom aneurysm until proven otherwise β€” CTA/MRA brain stat
  • Pupil-sparing complete CN3 β†’ microvascular (DM, HTN, hyperlipidemia) β€” observe; resolves in 3 months
  • Rule: pupil-sparing only reliable if complete ptosis and complete EOM limitation; partial CN3 with partial pupil sparing still needs imaging
  • Painful CN3 + any pupil involvement β†’ aneurysm, cavernous sinus thrombosis
  • CN3 + other CN palsies β†’ cavernous sinus or orbital apex lesion
  • Bilateral CN3 β†’ top-of-basilar syndrome, midbrain lesion, MG
  • Divisional palsy (superior or inferior division) β†’ orbital apex, cavernous sinus, fascicular
CN4 palsy pattern
Vertical diplopia worst on contralateral gaze and ipsilateral head tilt; compensatory contralateral head tilt
  • CN4 palsy: superior oblique weakness β†’ hypertropia ipsilateral to paretic eye
  • Parks-Bielschowsky 3-step: (1) which eye higher? (2) worse on which lateral gaze? (3) worse on which head tilt? β†’ localizes to superior oblique
  • Head tilt toward paretic side worsens diplopia; patients compensate with contralateral head tilt
  • Most common cause of vertical diplopia β€” often congenital (decompensated), or post-trauma (bilateral after head injury)
  • Bilateral CN4 palsy: alternating hypertropia on lateral gaze + V-pattern exotropia β†’ head trauma (bilateral trochlear nerve)
  • Isolated, painless, microvascular CN4 β†’ observe; resolves in 3–6 months
  • Persistent or progressive β†’ MRI posterior fossa (trochlear nerve, midbrain dorsal)
CN6 palsy pattern
Horizontal diplopia worst on ipsilateral gaze; esotropia at rest; abduction failure
  • Lateral rectus weakness β†’ esotropia, horizontal diplopia maximum on ipsilateral gaze
  • Most common isolated CN palsy; most common cause = microvascular (DM, HTN)
  • False localizing sign: CN6 palsy with raised ICP (bilateral CN6 + papilledema β†’ pseudotumor cerebri, hydrocephalus, venous sinus thrombosis)
  • CN6 + ipsilateral CN7 (facial nerve) + contralateral hemiparesis β†’ Foville syndrome (pontine lesion)
  • CN6 + horizontal gaze palsy (not just abduction) β†’ PPRF or abducens nucleus lesion
  • Young patient + painful CN6 β†’ Gradenigo syndrome (petrous apex β€” otitis media, cholesteatoma)
  • Persistent or progressive, or associated signs β†’ MRI brain with gadolinium; LP if meningitis/IIH suspected
INO / supranuclear pattern
Adduction lag ipsilateral + abducting nystagmus contralateral; vergence intact; WEBINO, skew
  • INO: MLF lesion ipsilateral to adduction failure; bilateral INO in young patient β†’ MS (pathognomonic)
  • Unilateral INO in older patient β†’ brainstem infarct (basilar perforator); also Wernicke, MG can mimic
  • WEBINO (Wall-Eyed Bilateral INO): bilateral adduction failure + exotropia β†’ bilateral MLF lesion
  • One-and-a-half syndrome: ipsilateral horizontal gaze palsy + ipsilateral INO β†’ only contralateral abduction remains; pontine lesion (MLF + PPRF/CN6 nucleus)
  • Skew deviation: vertical misalignment, otolithic pathway (utricle β†’ INC); higher eye on side of lesion in lateral medullary syndrome
  • HINTS exam (Head Impulse, Nystagmus, Test of Skew) for acute vertigo: normal head impulse + direction-changing nystagmus + skew deviation β†’ central (stroke); abnormal head impulse + unidirectional nystagmus + no skew β†’ peripheral
  • Vertical gaze palsies: upgaze palsy + convergence-retraction nystagmus + light-near dissociation β†’ Parinaud (dorsal midbrain, pineal tumor)
Step 3
Urgency triage β€” identify same-day emergencies before further workup
🚨 CN3 + pupil involvement
Dilated unreactive pupil Β± painful β†’ PCom aneurysm until proven otherwise
  • Action: CTA brain immediately (or MRA if CTA unavailable) β€” do not wait for MRI scheduling
  • PCom aneurysm compresses CN3 from outside β†’ parasympathetic fibers on surface affected first β†’ mydriasis
  • If CTA negative but strong suspicion: MRA + DSA (catheter angiography); CTA sensitivity ~97% for aneurysms β‰₯3 mm
  • Even if headache is mild or absent β€” "sentinel" headache preceding rupture
  • Other causes of CN3 + pupil: uncal herniation, cavernous sinus thrombosis, basal meningitis (TB, fungal)
🚨 Acute diplopia + headache/vertigo/ataxia
Posterior circulation stroke β€” basilar artery, PICA, AICA territory
  • Action: MRI/MRA brain + DWI immediately (CT has poor posterior fossa resolution)
  • Basilar artery occlusion: bilateral CN palsies + long tract signs + altered consciousness β€” thrombolysis/thrombectomy window
  • Lateral medullary (PICA) syndrome: ipsilateral face numbness, Horner, dysphagia, ataxia + contralateral body sensory loss + skew deviation
  • AICA syndrome: ipsilateral CN6/7/8 + Horner + cerebellar ataxia
  • Basilar tip aneurysm or top-of-basilar embolism: upgaze palsy, bilateral CN3, altered consciousness
⚠ Cavernous sinus syndrome
Multiple CN palsies (CN3/4/V1/V2/6) Β± proptosis Β± Horner β€” septic or aseptic
  • Contents of cavernous sinus: CN3, CN4, CN6, V1, V2, sympathetics, internal carotid artery
  • Septic cavernous sinus thrombosis: fever + proptosis + chemosis + multiple CN palsies β†’ IV antibiotics stat; often from facial/sinus infection (S. aureus)
  • Aseptic (tumor, dural fistula, Tolosa-Hunt): painful ophthalmoplegia, V1 sensory loss
  • Key distinction: CN6 involved early in cavernous sinus (travels freely); CN4 palsy suggests cavernous involvement over superior orbital fissure
  • MRI brain + orbit with gadolinium + MRV; CT if septic (faster)
  • Tolosa-Hunt: steroid-responsive granulomatous inflammation β€” diagnosis of exclusion after imaging
⚠ Wernicke encephalopathy
Ophthalmoplegia + ataxia + confusion in at-risk patients (alcohol, malnutrition, prolonged vomiting)
  • Thiamine (B1) deficiency β†’ bilateral CN6 palsy, nystagmus, horizontal/vertical gaze palsy most common EOM finding
  • Classic triad (ophthalmoplegia + ataxia + confusion) present in only ~16% β€” treat empirically if any feature present in at-risk patient
  • Action: IV thiamine 500 mg TID Γ— 3 days before any glucose β€” glucose without thiamine precipitates acute Wernicke
  • MRI: periaqueductal, mammillary body, dorsomedial thalamus T2/FLAIR signal β€” but imaging often normal; clinical diagnosis
  • At-risk: chronic alcohol use, bariatric surgery, hyperemesis gravidarum, malnutrition, prolonged IV feeding without B vitamins
⚠ GCA in patient β‰₯50 years
New diplopia + jaw claudication + scalp tenderness + elevated ESR/CRP β†’ GCA
  • GCA causes diplopia via ischemia to extraocular muscles or cranial nerve branches (CN6 most common)
  • ESR β‰₯50 + CRP elevated + age β‰₯50 + cranial symptoms β†’ start high-dose prednisolone 60 mg/day immediately (do not wait for biopsy)
  • Temporal artery biopsy: within 1–2 weeks of starting steroids (histology still positive); β‰₯2 cm segment, bilateral if unilateral negative
  • Risk of irreversible bilateral visual loss if untreated β€” diplopia may precede visual loss by days
  • TAB-negative GCA: consider large vessel GCA β€” PET-CT or MRA of aorta + branches
Step 4
Etiology-specific patterns β€” neuromuscular, restrictive, and orbital
Myasthenia gravis
Fatigable ptosis, variable diplopia, no pain, no pupil β€” any EOM muscle; worse at day end
  • Ocular MG: ptosis + diplopia, confined to eyes in ~50%; generalizes in ~50% over 2 years
  • Key feature: variability β€” changes from hour to hour, worse with fatigue, better after rest or sleep
  • Ice pack test: apply ice to closed eyelid for 2 minutes β†’ improvement of ptosis β‰₯2 mm = positive (sensitivity ~80%)
  • AChR antibody: positive in ~50% ocular MG, ~85% generalized
  • Anti-MuSK: seronegative generalized MG; rarely isolated ocular
  • Edrophonium (Tensilon) test: short-acting AChE inhibitor β€” dramatic improvement in ptosis/EOM
  • EMG: repetitive nerve stimulation (3 Hz) β†’ decremental response β‰₯10%; SFEMG: most sensitive (jitter)
  • CT chest: thymoma in ~15% (must screen all MG patients)
  • MG may mimic any CN palsy pattern β€” consider in any painless, variable, pupil-sparing ophthalmoplegia
Thyroid eye disease (TED)
Restrictive myopathy; proptosis; inferior rectus most common; elevation limited; lid lag
  • Graves' ophthalmopathy: lymphocytic infiltration + glycosaminoglycan deposition β†’ muscle enlargement + fibrosis
  • Most common: inferior rectus (elevation limited) β†’ vertical diplopia; then medial rectus (abduction limited); then superior rectus
  • Forced duction test: positive (restricted) β†’ distinguishes restrictive myopathy from CN palsy (no restriction)
  • Proptosis Β± lid retraction Β± lid lag β†’ clinical diagnosis; thyroid function may be normal (euthyroid Graves')
  • MRI/CT orbits: enlarged muscle bellies (tendon-sparing β€” distinguishes from orbital myositis where tendon involved)
  • Optic neuropathy complication (dysthyroid optic neuropathy): compressive; urgent orbital decompression if visual acuity or color vision threatened
  • TSH, free T4, TSH-receptor antibodies (TRAb) β€” TRAb most specific for Graves'
Mitochondrial / CPEO
Chronic progressive external ophthalmoplegia; bilateral symmetric ptosis; symmetric EOM limitation; no diplopia initially
  • CPEO: bilateral, symmetric, slowly progressive β†’ patients often have no diplopia despite severe EOM limitation (symmetric restriction)
  • Oculopharyngeal muscular dystrophy (OPMD): PABPN1 mutation; ptosis + dysphagia; autosomal dominant; onset 40s–50s; French-Canadian, Bukharan Jewish
  • Kearns-Sayre syndrome: CPEO + pigmentary retinopathy + cardiac conduction block (must screen ECG) Β± ataxia + sensorineural deafness; mitochondrial DNA deletion
  • MELAS, MERRF: EOM involvement less prominent; check serum lactate, mitochondrial DNA panel
  • Muscle biopsy: ragged red fibers (modified Gomori trichrome); COX-negative fibers
  • Ptosis surgery + prism glasses β€” no specific treatment for CPEO
Miller Fisher / GBS variants
Ophthalmoplegia + ataxia + areflexia; post-infectious; anti-GQ1b antibody
  • Miller Fisher syndrome (MFS): triad of ophthalmoplegia + cerebellar ataxia + areflexia; anti-GQ1b Ab in ~90%
  • Post-infectious (1–3 weeks after URTI or GI illness, esp. C. jejuni)
  • External ophthalmoplegia + ptosis; can involve any EOM β€” may look like bilateral CN3 palsy
  • Bickerstaff brainstem encephalitis (BBE): MFS + impaired consciousness/hyperreflexia β†’ anti-GQ1b + MRI brainstem changes
  • Overlap with GBS: ~25% of MFS have or develop limb weakness β€” check for descending weakness
  • Investigations: anti-GQ1b IgG (serum), CSF (albumino-cytologic dissociation), NCS (absent H-reflex)
  • Treatment: IVIg; most recover fully in 1–3 months without treatment
Orbital lesions
Proptosis Β± injection Β± pain; orbital pseudotumor, lymphoma, metastasis, AV fistula
  • Orbital pseudotumor (idiopathic orbital inflammation): painful proptosis + EOM restriction + chemosis; steroid-responsive; biopsy if atypical or steroid-resistant
  • Orbital myositis: tendon-involving muscle enlargement (vs. TED which spares tendons); painful; steroid-responsive
  • Orbital lymphoma: painless proptosis + EOM limitation; CT/MRI orbits; biopsy for diagnosis
  • Carotid-cavernous fistula (CCF): pulsatile proptosis + conjunctival corkscrew vessels + bruit; trauma (direct) or spontaneous dural fistula (indirect); MRI/MRA + DSA
  • Orbital fracture (blowout): post-trauma vertical diplopia with inferior rectus entrapment in orbital floor fracture; forced duction test positive
  • MRI orbits with fat-suppression + gadolinium: modality of choice for most orbital pathology
Step 5
Targeted investigations β€” based on localization and urgency
Neuroimaging
MRI brain + orbits Β± MRA/CTA; specific sequences by clinical pattern
  • CN3 + pupil β†’ CTA brain first (aneurysm), then MRI if negative
  • Acute stroke suspected β†’ MRI DWI + MRA brain and neck
  • Cavernous sinus/orbital β†’ MRI brain + orbits with gadolinium, fat suppression
  • INO β†’ MRI brain (posterior fossa, MLF); bright DWI β†’ acute infarct; T2 lesion β†’ MS plaque
  • Isolated microvascular CN palsy (age >50 + DM/HTN + pupil-sparing) β†’ observe 3 months; image if no recovery or new features
  • Young patient + isolated CN palsy β†’ MRI brain + gadolinium (leptomeningeal enhancement, demyelination, tumour)
  • MRV β†’ suspected cavernous sinus or cortical venous thrombosis
Serology & metabolic panel
Targeted labs based on localization: vascular, immune, NMJ, thyroid
  • Microvascular CN palsy: HbA1c, fasting glucose, lipids, BP, CBC, CRP
  • MG suspected: AChR Ab (binding, blocking, modulating), anti-MuSK, anti-LRP4
  • Thyroid eye disease: TSH, free T4/T3, TSH receptor antibodies (TRAb), TPO Ab
  • GCA (β‰₯50 yrs): ESR, CRP, CBC (normocytic anemia + thrombocytosis), LFTs (ALP elevated)
  • Miller Fisher: anti-GQ1b IgG (serum); anti-GT1a (pharyngeal-cervical-brachial variant)
  • Meningeal process: Lyme serology, ACE, syphilis (VDRL/RPR + TPPA), ANA/ANCA, HIV
  • Cavernous sinus thrombosis: blood cultures, coagulation screen, D-dimer, thrombophilia panel
  • Thiamine level (unreliable) β€” treat empirically if Wernicke suspected
CSF analysis
Indications: meningeal process, demyelination, GBS/MFS, raised ICP
  • Opening pressure: raised β†’ IIH (bilateral CN6 + papilledema); low β†’ spontaneous intracranial hypotension
  • Albumino-cytologic dissociation (elevated protein, normal cells) β†’ GBS/MFS, CIDP
  • Lymphocytic pleocytosis β†’ viral/bacterial meningitis, Lyme, sarcoid, carcinomatous meningitis
  • OCBs β†’ MS (CSF-specific bands); send both serum and CSF simultaneously
  • Cytology + flow cytometry β†’ leptomeningeal lymphoma or carcinoma
  • Lyme Ab index; HSV/CMV/EBV PCR; TB PCR + culture; cryptococcal antigen (HIV)
  • IIH management: weight loss + acetazolamide; CSF diversion (LP shunt/optic nerve sheath fenestration) if severe papilledema
Neuromuscular / electrophysiology
EMG, RNS, SFEMG β€” for MG, CPEO, botulism, Lambert-Eaton
  • Repetitive nerve stimulation (3 Hz): β‰₯10% decremental response β†’ MG; β‰₯200% facilitation at 50 Hz β†’ Lambert-Eaton (VGCC Ab)
  • Single-fiber EMG (SFEMG): most sensitive for MG (~99%); increased jitter, blocking
  • Botulism: descending paralysis + fixed dilated pupils + autonomic dysfunction; toxin assay; EMG: small motor units + facilitation on high-frequency stimulation
  • Muscle biopsy (orbicularis oculi): ragged red fibers β†’ CPEO/KSS; COX-deficient fibers β†’ mitochondrial
  • VEP: delayed P100 β†’ optic neuritis (subclinical MS demyelination β€” supports diagnosis)
Dx
Diagnosis established β†’ classify and manage
Microvascular CN palsy
CN3 (pupil-sparing complete), CN4, or CN6 in patient β‰₯50 with DM/HTN β€” optimize vascular risk; resolves in 3 months; image if no recovery
CN3CN4CN6
Myasthenia gravis
AChR/MuSK Ab, SFEMG β€” pyridostigmine for ocular symptoms; immunosuppression if generalizing; thymectomy if thymoma or AChR+ generalized MG
Ocular MGGeneralized
Structural / compressive
Aneurysm (clipping/coiling), cavernous sinus (targeted by cause), tumor (biopsy/resection), IIH (acetazolamide, weight loss, shunting)
AneurysmCavernousIIH
Inflammatory / demyelinating
MS (INO β†’ DMT), MFS (IVIg, monitor for GBS overlap), Tolosa-Hunt (steroids), neurosarcoidosis (steroids Β± steroid-sparing agents)
MS/INOMFSTH
Restrictive / orbital
TED (selenium, teprotumumab, steroids, orbital decompression), CPEO (prisms, ptosis surgery), orbital pseudotumor (steroids Β± biopsy)
TEDCPEOOrbital
Vascular emergencies treated
Posterior fossa stroke β†’ secondary prevention; PCom aneurysm β†’ neurosurgical/endovascular; Wernicke β†’ thiamine; GCA β†’ long-term steroids Β± tocilizumab
StrokeGCAWernicke
Urgency & etiology color key
Same-day emergency (aneurysm, basilar stroke, septic cavernous)
Urgent same-day workup (Wernicke, GCA, cavernous sinus)
CN3 palsy
CN4 palsy
CN6 palsy
INO / supranuclear

The cover test (Step 1) is mandatory before neuroimaging β€” monocular diplopia is ophthalmological, not neurological. CN3 with any pupil involvement requires same-day CTA brain to exclude aneurysm. Tap β–Ά to expand examination techniques and discriminating features.

Papilledema

NoteπŸ”— Related Topics

Papilledema β€” optic disc swelling caused by raised intracranial pressure β€” is a critical neuro-ophthalmological sign that demands urgent evaluation. The algorithm follows a five-step sequence: confirm true papilledema (distinguish from pseudopapilledema and optic neuritis), grade severity, triage for emergencies (malignant hypertension, mass lesion, venous sinus thrombosis, acute meningitis), targeted neuroimaging and LP, and etiology-specific management. Bilateral disc swelling is papilledema by definition until proven otherwise; unilateral swelling has a broader differential.

How to use:

  • Tap β–Ά Details on any card to expand examination findings and clinical pearls.
  • Step 3 urgency cards identify conditions requiring same-day imaging or treatment β€” do not proceed to LP without first excluding a mass lesion.
  • Fundoscopic grading (FrisΓ©n scale) and OCT guide monitoring and treatment response.
Disc swelling on fundoscopy
Step 1
Confirm true papilledema β€” distinguish from mimics
Fundoscopic features of true papilledema
Bilateral disc swelling, blurred margins, venous engorgement, peripapillary haemorrhages, absence of spontaneous venous pulsations
  • FrisΓ©n grade 0: normal; Grade 1: C-shaped peripapillary halo, nasal margin blurred; Grade 2: circumferential halo, all margins blurred; Grade 3: disc elevation, obscuration of β‰₯1 major vessel; Grade 4: complete obscuration of vessels on disc; Grade 5: dome-shaped protrusion, no visible vessels
  • Spontaneous venous pulsations (SVP): present in ~80% of normals β†’ if absent, does not confirm raised ICP but absence is expected in papilledema
  • Key early features: loss of nasal disc margin clarity, peripapillary RNFL thickening on OCT β€” more sensitive than fundoscopy alone
  • Peripapillary flame haemorrhages, cotton-wool spots, disc hyperaemia β†’ active/severe papilledema
  • Chronic papilledema: disc pallor + "champagne cork" gliotic elevation + atrophy of RNFL β†’ irreversible visual loss if untreated
Pseudopapilledema β€” rule out
Optic disc drusen, tilted discs, hypermetropia; disc appears elevated but no true swelling
  • Optic disc drusen (ODD): most common cause of pseudopapilledema; calcified hyaline deposits buried in disc β†’ lumpy, irregular disc elevation; no peripapillary haemorrhages; SVP usually present
  • B-scan ultrasound: high reflectivity calcified drusen (sensitivity ~90%) β€” key discriminating test
  • OCT: drusen visible as hyper-reflective deposits beneath RNFL; autofluorescence: drusen are autofluorescent
  • Fluorescein angiography: true papilledema β†’ early disc leakage; drusen β†’ no leakage (late autofluorescence only)
  • Tilted disc / hypermetropic disc: appears crowded / elevated; regular borders; no haemorrhages; normal OCT RNFL thickness
  • Myelinated nerve fibres: feathery white streaks extending from disc margin β€” do not obscure vessels; do not indicate raised ICP
Unilateral vs. bilateral disc swelling
Bilateral = papilledema (raised ICP) until proven otherwise; unilateral has broader differential
  • Bilateral: raised ICP (mass, IIH, venous sinus thrombosis, meningitis, hypertensive crisis, hydrocephalus) β€” image urgently
  • Unilateral disc swelling: optic neuritis (painful, young, afferent pupillary defect), anterior ischaemic optic neuropathy (AION β€” painless, altitudinal field defect, older patient), central retinal vein occlusion (flame haemorrhages in all 4 quadrants), orbital compressive lesion
  • Foster Kennedy syndrome: unilateral optic atrophy (compression) + contralateral papilledema (raised ICP) β†’ frontal lobe/olfactory groove meningioma
  • Pseudo-Foster Kennedy: bilateral sequential AION mimicking Foster Kennedy
  • In all cases: check visual acuity, colour vision, visual fields, and afferent pupillary defect (RAPD)
Step 2
History and examination β€” identify aetiology and assess visual threat
Focused history
Headache character, onset, postural variation; visual symptoms; medications; systemic symptoms; BMI
  • Headache: early morning, positional (worse lying flat) β†’ raised ICP; thunderclap β†’ SAH or CVST; progressive + nausea/vomiting β†’ mass lesion
  • Pulsatile tinnitus (pulse-synchronous) + headache in obese young woman β†’ IIH
  • Visual obscurations: brief bilateral grey-outs lasting seconds on positional change β†’ classic for raised ICP
  • Diplopia: bilateral CN6 palsy = false localising sign of raised ICP
  • Medications: tetracyclines (doxycycline, minocycline), vitamin A / isotretinoin, lithium, steroids (withdrawal), growth hormone, nitrofurantoin β†’ drug-induced IIH
  • Systemic: fever + neck stiffness β†’ meningitis; weight gain + hoarse voice + cold intolerance β†’ hypothyroidism; pregnancy / OCP use β†’ CVST risk
  • BMI: obesity (BMI >30) + female + reproductive age β†’ IIH profile; recent significant weight gain
Directed neurological examination
Blood pressure, visual fields, CN6, fundoscopy grading, signs of meningism, focal neurology
  • Blood pressure: BP β‰₯180/120 + papilledema β†’ hypertensive emergency (grade IV retinopathy); urgent BP control
  • Visual fields (confrontation then formal perimetry): enlarged blind spot (early IIH/papilledema); nasal step β†’ glaucoma; inferior arcuate β†’ NAION; constricted fields β†’ severe/chronic papilledema
  • Visual acuity + colour vision: reduced colour discrimination β†’ optic nerve compromise; urgent if acuity affected
  • Afferent pupillary defect (RAPD): absent in bilateral symmetric papilledema; present if asymmetric or unilateral optic nerve damage
  • CN6 palsy (abduction failure, esotropia) β†’ raised ICP false localising sign; assess all 9 positions of gaze
  • Focal deficits (hemiparesis, aphasia, ataxia) β†’ mass lesion, abscess, CVST infarct
  • Neck stiffness + Kernig/Brudzinski β†’ meningitis/SAH; urgent CT before LP
  • BMI and waist circumference: document for IIH assessment
Visual function monitoring
Assess severity of visual threat β€” guides urgency of treatment
  • OCT RNFL thickness: most sensitive marker; baseline + serial monitoring in IIH; thinning despite treatment β†’ progressive optic atrophy
  • Humphrey visual fields (24-2 or 30-2): enlarged blind spot is earliest change; monitor regularly in IIH treatment
  • Visual acuity: β‰₯2 line Snellen reduction β†’ urgent escalation of treatment; acuity often preserved until late in papilledema
  • Colour vision (Ishihara/D15): colour desaturation may precede acuity loss
  • FrisΓ©n grade β‰₯3 or deteriorating vision β†’ consider urgent optic nerve sheath fenestration or CSF diversion
  • Visual fields are the key treatment endpoint in IIH β€” more sensitive than acuity for monitoring optic nerve function
Step 3
Urgency triage β€” identify life-threatening and vision-threatening emergencies
🚨 Space-occupying lesion
Progressive headache Β± focal deficits Β± altered consciousness β†’ mass lesion, abscess, haematoma
  • Action: CT head immediately (non-contrast) β€” do NOT perform LP until mass lesion excluded; LP can precipitate fatal transtentorial herniation
  • Brain tumour: subacute progressive headache + papilledema Β± focal deficits; contrast-enhancing lesion on MRI
  • Cerebral abscess: fever + raised CRP + ring-enhancing lesion; may present without fever in immunocompromised
  • Subdural/extradural haematoma: trauma history (may be trivial in elderly/anticoagulated); CT: hyperdense crescent (acute SDH) or biconvex (EDH)
  • Hydrocephalus: dilated ventricles on CT/MRI β€” obstructive (aqueduct stenosis, posterior fossa mass) vs. communicating; urgent neurosurgical referral
  • Raised ICP with herniation signs (Cushing triad: hypertension + bradycardia + irregular respirations) β†’ neurosurgical emergency
🚨 Hypertensive emergency
BP β‰₯180/120 + papilledema Β± retinal haemorrhages, exudates β†’ hypertensive emergency (grade IV retinopathy)
  • Action: Controlled IV BP reduction (target 20–25% reduction in MAP over first hour β€” not normalisation); admit to HDU/ICU
  • Grade IV retinopathy (Keith-Wagener): papilledema + haemorrhages + exudates + BP crisis β†’ hypertensive encephalopathy if + confusion/seizures
  • Agents: IV labetalol (first line), nicardipine, sodium nitroprusside; avoid rapid reduction β†’ watershed ischaemia
  • Secondary hypertension workup: renal artery stenosis, phaeochromocytoma, Conn syndrome, coarctation β€” check in all young patients or severe/refractory cases
  • PRES (Posterior Reversible Encephalopathy Syndrome): headache + seizures + visual disturbance + confusion + papilledema; MRI: bilateral parieto-occipital T2/FLAIR hyperintensity; BP control β†’ reversal
  • Eclampsia: papilledema + BP crisis + proteinuria + seizures in pregnancy β†’ urgent delivery + MgSO4
🚨 Cerebral venous sinus thrombosis (CVST)
Headache + papilledema Β± focal deficits/seizures; high-risk groups: pregnancy, OCP, thrombophilia
  • Action: CT venogram or MR venogram urgently β€” plain CT/MRI may miss CVST; do not delay anticoagulation if confirmed
  • CVST mimics IIH in young women β†’ always exclude with MRV before diagnosing IIH
  • Delta sign (on non-contrast CT): hyperdense thrombus in superior sagittal sinus; empty delta sign (on contrast CT): filling defect in SSS
  • MRV: absent flow in affected sinus; MRI: T1 hypersignal in sinus (subacute thrombus)
  • Risk factors: OCP, pregnancy/puerperium, dehydration, infection (mastoiditis β†’ lateral sinus thrombosis), thrombophilia (Factor V Leiden, antiphospholipid), malignancy
  • Treatment: IV unfractionated heparin β†’ LMWH β†’ warfarin/DOAC (3–12 months depending on provoked vs. unprovoked); anticoagulate even with haemorrhagic infarct
  • Decompressive craniectomy for malignant CVST with herniation threat
⚠ Meningitis / encephalitis
Fever + neck stiffness + papilledema β†’ bacterial meningitis; CT before LP if papilledema present
  • Action: Blood cultures + IV ceftriaxone + dexamethasone immediately β€” do not delay antibiotics for CT/LP in suspected bacterial meningitis
  • CT before LP if: papilledema present, focal neurological deficit, GCS <15, immunocompromised, new-onset seizure
  • Cryptococcal meningitis: HIV/immunosuppressed + subacute headache + papilledema Β± minimal meningism; LP: high opening pressure + India ink positive; cryptococcal antigen in CSF/serum
  • TB meningitis: subacute onset; basilar meningitis pattern; cranial nerve palsies; CSF: lymphocytic pleocytosis + high protein + low glucose; TB PCR + culture
  • Carcinomatous meningitis: known malignancy + papilledema + multiple CN palsies; CSF cytology + flow cytometry
  • Viral encephalitis: fever + papilledema + altered behaviour/seizures; HSV most common β€” IV aciclovir empirically; MRI: temporal lobe T2/FLAIR signal in HSV
⚠ Severe visual loss β€” optic nerve threatened
FrisΓ©n grade β‰₯4, declining visual acuity or fields β†’ urgent CSF diversion or optic nerve sheath fenestration
  • Rapid visual deterioration despite maximum medical therapy β†’ same-day ophthalmic + neurosurgical review
  • Optic nerve sheath fenestration (ONSF): incision in meningeal sheath decompresses optic nerve locally; effective for visual preservation; does not reliably reduce ICP or headache
  • CSF diversion: ventriculoperitoneal (VP) or lumboperitoneal (LP) shunt β€” more durable ICP control; risk of shunt failure/revision
  • Serial therapeutic LPs: temporising measure in IIH; effective short-term; not sustainable long-term
  • Venous sinus stenting: emerging option in IIH with venous stenosis; good evidence for headache and visual outcomes
  • OCT RNFL thinning + visual field loss = nerve already damaged; treatment must be escalated urgently
Step 4
Targeted investigations β€” neuroimaging first, then LP with opening pressure
Neuroimaging β€” mandatory before LP
MRI brain + MRV (preferred); CT if unavailable or emergency; exclude mass and venous thrombosis before LP
  • MRI brain with gadolinium + MR venogram: modality of choice for papilledema workup β€” excludes mass, CVST, meningeal enhancement, hydrocephalus
  • MRI features of raised ICP: flattening of posterior globe (scleral flattening), distended optic nerve sheath (>5.8 mm on axial), empty sella turcica, transverse venous sinus stenosis, tonsillar descent
  • Empty sella: CSF herniation into sella β†’ highly supportive of chronic raised ICP / IIH
  • CT head (non-contrast) first if emergency: rule out haemorrhage, mass, acute hydrocephalus before LP
  • CT venogram alternative to MRV if MRI unavailable or contraindicated (pacemaker)
  • Plain MRI may be normal in IIH β€” MRV essential to exclude CVST in all cases before IIH diagnosis
  • Posterior fossa mass / Chiari malformation β†’ specific cause of obstructive hydrocephalus
Lumbar puncture β€” opening pressure is key
LP in lateral decubitus with legs extended; opening pressure >25 cmHβ‚‚O diagnostic of raised ICP
  • Opening pressure: normal <20 cmHβ‚‚O (obese patients up to 25); >25 cmHβ‚‚O = raised; >30 cmHβ‚‚O = significantly elevated
  • Position: lateral decubitus with legs as straight as possible (extended); sitting position gives falsely high pressure
  • IIH diagnostic criteria (revised ICHD-3): papilledema + normal neurological exam (except CN6 palsy) + normal MRI brain + normal CSF composition + opening pressure >25 cmHβ‚‚O
  • CSF composition in IIH: normal (no cells, normal protein and glucose) β€” abnormal CSF β†’ seek another aetiology
  • Therapeutic LP: remove CSF to closing pressure of 15–20 cmHβ‚‚O; immediate symptomatic relief; effect temporary
  • Always measure and document: opening pressure, appearance, cell count, protein, glucose, oligoclonal bands; also send for cytology, cultures, and cryptococcal antigen if clinically indicated
  • Contraindications: mass lesion on imaging, coagulopathy, skin infection at puncture site
Blood investigations
Tailored to suspected aetiology: inflammatory, endocrine, haematological, thrombophilia screen
  • All patients: BP (mandatory), FBC, CRP/ESR, renal function, LFTs, glucose, HbA1c
  • Endocrine: TFTs (hypothyroidism β†’ raised ICP), vitamin A level (excess β†’ IIH), growth hormone level (if receiving GH therapy)
  • CVST workup: coagulation screen, thrombophilia panel (Factor V Leiden, protein C/S, antithrombin, antiphospholipid antibodies), D-dimer, blood cultures
  • Inflammatory/infectious: ANA, ANCA, ACE (sarcoidosis), Lyme serology, VDRL/RPR + TPPA, HIV, blood cultures
  • Malignancy: chest X-ray, tumour markers, CT chest/abdomen/pelvis if carcinomatous meningitis suspected
  • Iron studies: iron-deficiency anaemia associated with IIH (independent of obesity)
Step 5
Aetiology-specific management β€” treat underlying cause and protect vision
Idiopathic intracranial hypertension (IIH)
Young obese female + papilledema + raised CSF pressure + normal imaging/CSF β†’ IIH; weight loss is cornerstone treatment
  • IIH without papilledema (IIHWOP): headache + raised ICP + normal discs β€” diagnosis requires careful exclusion of all secondary causes
  • Weight loss (5–10% body weight): most effective long-term treatment β€” reduces ICP; bariatric surgery if BMI >40 and medically refractory
  • Acetazolamide: 250 mg BD increasing to 2–4 g/day as tolerated; reduces CSF production; first-line pharmacological treatment; check renal function and electrolytes; avoid in sulfa allergy and G6PD deficiency
  • Topiramate: alternative to acetazolamide; also promotes weight loss; monitor cognitive side effects
  • Furosemide: weak evidence; used as adjunct
  • Venous sinus stenting: effective in IIH with transverse sinus stenosis β€” high-pressure gradient across stenosis on venography
  • Withdraw causative medications: tetracyclines, isotretinoin, vitamin A, steroids (taper not abrupt withdrawal)
  • GLP-1 agonists (semaglutide): emerging evidence for weight loss + ICP reduction in IIH
Secondary raised ICP β€” treat underlying cause
Mass lesion, hydrocephalus, CVST, meningitis β€” each requires targeted treatment; ICP management is adjunctive
  • Brain tumour: neurosurgical resection Β± radiotherapy Β± chemotherapy; dexamethasone for vasogenic oedema (reduces papilledema acutely)
  • Hydrocephalus: VP or ETV (endoscopic third ventriculostomy) for obstructive; communicating hydrocephalus β†’ LP shunt
  • CVST: anticoagulation (heparin β†’ warfarin/DOAC); endovascular thrombolysis for deteriorating cases
  • Bacterial meningitis: targeted antibiotics based on CSF gram stain/culture; dexamethasone reduces ICP and neurological sequelae
  • Cryptococcal meningitis: IV amphotericin B + flucytosine (induction) β†’ fluconazole (consolidation + maintenance); serial LPs for ICP control (target <20 cmHβ‚‚O)
  • Hypertensive emergency: IV antihypertensives; controlled reduction over hours
  • General ICP measures: head of bed 30Β°, avoid hypercapnia, osmotherapy (mannitol 0.25–1 g/kg IV) for acute ICP spikes
Monitoring and follow-up
Serial visual fields, OCT RNFL, FrisΓ©n grading β€” frequency determined by visual threat
  • Acute phase: visual fields + OCT every 2–4 weeks until stabilised
  • Stable IIH on treatment: 3-monthly visual fields + OCT + FrisΓ©n grading; 6-monthly if well controlled
  • Treatment response: papilledema grade reduction + stable/improving visual fields + OCT RNFL stabilisation
  • Red flags for deterioration: declining visual acuity, worsening visual fields, FrisΓ©n grade increase, OCT RNFL thinning (irreversible loss) β†’ escalate treatment
  • Repeat MRI: if clinical deterioration, new focal signs, or atypical IIH features develop
  • Long-term: 10–25% of IIH patients relapse β€” reassess if weight regain or symptoms recur
  • Chronic papilledema with gliotic disc (pale, elevated): even if ICP normalised, visual field monitoring must continue β€” optic atrophy progresses independently
Dx
Diagnosis established β†’ classify and manage
Idiopathic intracranial hypertension
Weight loss + acetazolamide Β± topiramate; serial visual fields + OCT; shunt/ONSF/venous stenting if refractory or vision threatened
IIHDrug-inducedIIHWOP
Venous sinus thrombosis
Anticoagulation (heparin β†’ DOAC 3–12 months); treat precipitant; MRV at 3–6 months
CVSTThrombophilia
Mass lesion / hydrocephalus
Neurosurgical referral; resection/drainage; dexamethasone for oedema; VP/LP shunt for hydrocephalus
TumourAbscessHydrocephalus
Meningitis / encephalitis
Targeted antibiotics/antivirals/antifungals; serial LPs for cryptococcal ICP; steroids for bacterial meningitis
BacterialCryptococcalTB
Hypertensive emergency
IV antihypertensives (controlled reduction); secondary hypertension workup; PRES β†’ BP control; eclampsia β†’ delivery + MgSO4
Malignant HTNPRESEclampsia
Pseudopapilledema confirmed
Reassure; optic disc drusen monitoring (risk of RNFL loss and visual field defects); ophthalmology follow-up; no ICP treatment
DrusenTilted discHypermetropia
Urgency & aetiology color key
Same-day emergency (mass lesion, hypertensive emergency, CVST)
Urgent same-day workup (meningitis, vision-threatening papilledema)
IIH and primary raised ICP
Secondary causes (treated by underlying aetiology)
Monitoring and follow-up

Never perform LP without first excluding a mass lesion on neuroimaging β€” papilledema is a contraindication to LP until CT/MRI confirms it is safe. MRV must be performed in all cases before diagnosing IIH to exclude cerebral venous sinus thrombosis. Visual fields and OCT RNFL are the primary endpoints for monitoring treatment response. Tap β–Ά to expand examination techniques and management details.