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

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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

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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

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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

πŸ”— 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.