The frontal lobe houses the primary motor cortex (precentral gyrus, homunculus organization), prefrontal cortex (executive function, personality, judgment), Broca area (dominant hemisphere, expressive language), and frontal eye fields. The parietal lobe contains the primary somatosensory cortex (postcentral gyrus), superior parietal lobule (visuospatial processing), and inferior parietal lobule (including supramarginal and angular gyri, important for language and arithmetic). The temporal lobe includes the primary auditory cortex (Heschl gyrus), Wernicke area (dominant hemisphere, receptive language), hippocampus (memory consolidation), amygdala (emotion), and inferotemporal cortex (object recognition). The occipital lobe is dedicated to vision, with the primary visual cortex (calcarine sulcus, V1) surrounded by association areas (V2-V5) that process motion, color, and form. The insula is involved in autonomic function, pain processing, and addictive behaviors. The limbic system (cingulate gyrus, hippocampus, amygdala, fornix, mammillary bodies, anterior thalamus) mediates emotion, memory, and motivation.

The basal ganglia consist of the caudate, putamen (together = striatum), globus pallidus interna (GPi) and externa (GPe), subthalamic nucleus (STN), and substantia nigra pars compacta (SNc) and pars reticulata (SNr). The direct pathway (cortex to striatum to GPi/SNr to thalamus to cortex) facilitates movement by disinhibiting thalamocortical projections via D1 receptors. The indirect pathway (cortex to striatum to GPe to STN to GPi/SNr to thalamus to cortex) inhibits movement via D2 receptors. The hyperdirect pathway (cortex to STN to GPi/SNr) provides rapid, global inhibition. Dopamine from SNc modulates these pathways, stimulating D1 and inhibiting D2. Loss of SNc dopamine in Parkinson disease produces bradykinesia, rigidity, and tremor. Hemiballismus results from STN lesion (contralateral flailing movements).

The cerebellum is organized into three functional zones: vestibulocerebellum (flocculonodular lobe, balance and eye movements), spinocerebellum (vermis and paravermis, proprioception and gait), and cerebrocerebellum (lateral hemispheres, coordination of fine movements and motor planning). Cerebellar cortex has three layers: molecular (stellate and basket cells), Purkinje cell layer (sole output of cortex, GABAergic), and granular (granule cells, most numerous neurons in brain). Deep cerebellar nuclei (fastigial, interposed, dentate) receive Purkinje output and project to brainstem and thalamus. Cerebellar lesions produce ipsilateral signs: dysmetria (past-pointing), dysdiadochokinesia (impaired rapid alternating movements), intention tremor, ataxic gait, nystagmus (worse looking toward lesion), scanning speech, and hypotonia. The cerebellum is also involved in cognitive functions (cerebellar cognitive affective syndrome, CCAS).

The midbrain contains CN III (oculomotor, nucleus and Edinger-Westphal parasympathetic), CN IV (trochlear, dorsal exit, decussates), the cerebral peduncles (corticospinal tracts), periaqueductal gray (pain modulation), and substantia nigra. The pons contains CN V (trigeminal), CN VI (abducens), CN VII (facial), and CN VIII (vestibulocochlear). The medulla contains CN IX (glossopharyngeal), CN X (vagus), CN XI (spinal accessory), and CN XII (hypoglossal). Key brainstem syndromes: Weber syndrome (CN III palsy + contralateral hemiparesis, midbrain), Millard-Gubler (CN VI + CN VII palsy + contralateral hemiparesis, pons), Wallenberg lateral medullary syndrome (ipsilateral Horner, facial pain, ataxia, dysphagia + contralateral pain/temperature loss, PICA occlusion).

The dorsal column/medial lemniscus pathway carries vibration, proprioception, and fine touch. First-order neurons enter the dorsal root and ascend ipsilaterally in the gracile (leg, T7 and below) and cuneate (arm, T6 and above) fasciculi to synapse in the dorsal column nuclei in the medulla. Second-order neurons decussate as internal arcuate fibers and form the medial lemniscus to the VPL of thalamus. The spinothalamic tract carries pain and temperature; first-order neurons synapse in substantia gelatinosa, second-order decussate within 1-2 segments via the anterior white commissure and ascend contralaterally. The corticospinal tract originates in primary motor cortex, descends through internal capsule (posterior limb), cerebral peduncle, and medullary pyramids, where 85-90% decussate (lateral corticospinal tract). Clinically: dorsal column lesion = ipsilateral loss of vibration/proprioception; spinothalamic lesion = contralateral pain/temperature loss 1-2 segments below; corticospinal lesion = ipsilateral UMN signs.

The circle of Willis connects the anterior (ICA) and posterior (vertebrobasilar) circulations via the anterior (ACom) and posterior (PCom) communicating arteries. ACA supplies medial frontal/parietal; MCA supplies lateral cortex, basal ganglia, internal capsule; PCA supplies occipital lobe and medial temporal. The ventricular system: lateral ventricles to foramen of Monro to third ventricle to aqueduct of Sylvius to fourth ventricle to foramen of Luschka and Magendie. CSF produced by choroid plexus at 20 mL/hr, total volume 150 mL. Normal pressure hydrocephalus: Hakim triad (gait apraxia, urinary incontinence, dementia). Herniation syndromes: subfalcine (ACA compression), uncal transtentorial (CN III palsy, contralateral hemiparesis, Duret hemorrhages), tonsillar (through foramen magnum, respiratory arrest).

Stroke is the second leading cause of death globally (~6.5M deaths/yr) and the leading cause of acquired adult disability. In the United States, ~795,000 people experience a stroke annually (87% ischemic, 10% ICH, 3% SAH). Approximately 25% of strokes occur in patients with prior stroke or TIA. Lifetime risk of stroke is ~25% for adults over age 25. Direct and indirect costs of stroke in the US exceed $56 billion annually. The global burden of stroke has increased by ~70% in incidence over the past three decades, driven by population aging and increasing prevalence of risk factors. Risk factors: hypertension (most important), atrial fibrillation, diabetes, smoking, hyperlipidemia, obesity, physical inactivity, alcohol, illicit drug use (cocaine, methamphetamine).

Ischemic stroke results from cessation of blood flow to brain tissue, leading to a central irreversibly damaged core surrounded by a potentially salvageable penumbra maintained by collateral circulation. Thrombotic stroke occurs from in-situ occlusion of a large artery due to atherosclerotic plaque rupture or small vessel lipohyalinosis (lacunar). Embolic stroke arises from a distant source: cardioembolic (atrial fibrillation, valvular vegetations, LV thrombus, PFO), artery-to-artery (carotid or aortic arch plaques), or cryptogenic. The ischemic cascade involves energy failure (ATP depletion), excitotoxicity (glutamate release, NMDA receptor activation, calcium influx), oxidative stress, inflammation, blood-brain barrier disruption, and ultimately cell death. Hemorrhagic stroke: ICH from hypertensive microangiopathy (basal ganglia, thalamus, pons, cerebellum), CAA (lobar in elderly), or anticoagulant-related. SAH from saccular aneurysm rupture at circle of Willis bifurcations.

FAST: Facial droop, Arm weakness, Speech difficulty, Time to call emergency. MCA syndrome: contralateral hemiparesis (face/arm > leg), hemisensory loss, homonymous hemianopia, gaze preference toward lesion, aphasia (dominant) or neglect (non-dominant). ACA: leg > arm weakness, abulia, incontinence. PCA: homonymous hemianopia, visual agnosia, alexia without agraphia. Brainstem: crossed signs (ipsilateral CN palsy + contralateral hemiparesis), diplopia, vertigo, ataxia, dysarthria, locked-in syndrome. Lacunar: pure motor hemiparesis, pure sensory stroke, ataxic hemiparesis, clumsy hand-dysarthria. ICH: sudden severe headache, N/V, decreased consciousness, HTN, focal deficits. SAH: thunderclap "worst headache of life," neck stiffness, photophobia, syncope at onset.

Non-contrast head CT to rule out hemorrhage (first-line). CTA from arch to vertex identifies LVO, stenosis, dissection, aneurysm. CT perfusion differentiates core from penumbra, critical for extended-window thrombectomy. MRI DWI is most sensitive for acute infarction (bright within minutes). NIHSS quantifies stroke severity (0-42, severe >=21). Etiology workup: carotid imaging, echocardiogram (TTE/TEE for PFO/valvular/aortic arch), telemetry/Holter for paroxysmal AF, extended loop recorder for cryptogenic stroke. Labs: CBC, PT/PTT/INR, glucose, troponin, lipids, HbA1c, hypercoagulability panel if indicated.

IV alteplase (tPA 0.9 mg/kg, max 90 mg, 10% bolus, 90% over 60 min) within 4.5 hours. Strict criteria: age >=18, NIHSS >=4 or disabling, BP <185/110, platelets >=100K, INR <=1.7, no major surgery 14d, no prior stroke 3mo, no ICH, glucose >50. Mechanical thrombectomy for LVO within 6h or up to 24h with favorable perfusion (DAWN/DEFUSE-3). BP: before/during tPA <185/110; after tPA <180/105 x24h. No tPA: permit HTN up to 220/120. Decompressive hemicraniectomy for malignant MCA (>50% MCA territory, midline shift, age <60, within 48h).

Antiplatelet: aspirin 50-325 mg or clopidogrel 75 mg or aspirin/dipyridamole ER. Minor stroke/TIA: DAPT (aspirin + clopidogrel) for 21-90 days. Anticoagulation for AF: DOACs preferred; timing by 1-2-3-4 rule (TIA=immediate, mild=day3, moderate=day6, severe=day12). High-intensity statin regardless of LDL. BP target <130/80. Carotid revascularization for symptomatic >=50% stenosis. Lifestyle: smoking cessation, Mediterranean diet, exercise 150 min/week. GLP-1 RA/SGLT2i for T2DM with CV benefit.

TIA: transient neurological dysfunction without acute infarction (tissue-based definition). ABCD2 score: Age >=60 (1), BP >=140/90 (1), Clinical (unilateral weakness=2, speech=1), Duration (>=60min=2, 10-59min=1), Diabetes (1). Total 0-7; 2-day stroke risk: low 1%, mod 4%, high 8%. Urgent evaluation within 24h: MRI DWI (if positive = stroke), vascular imaging, ECG, echo. Management: DWI negative + no high-risk etiology = aspirin + statin. Hospitalize for ABCD2 >=3, crescendo TIAs, or concerning etiology.

ICH accounts for 10-15% of strokes with 40-50% 30-day mortality. ICH Score (0-6): GCS, age >=80, infratentorial, volume >=30 mL, IVH. Predicts 30-day mortality (0=0%, 5=100%). Acute management: intensive BP to SBP <140 within 1h (avoid <110). Reverse anticoagulation: warfarin to 4F-PCC + IV vitamin K; dabigatran to idarucizumab; rivaroxaban/apixaban to andexanet alfa. Platelet transfusion NOT recommended. Surgical evacuation: cerebellar ICH >3 cm with brainstem compression/hydrocephalus. Seizure prophylaxis not routine. Hydrocephalus: EVD. Preventative: long-term BP control, avoid anticoagulation after warfarin-related ICH.

SAH accounts for ~3% of strokes. Etiology: saccular aneurysms (85%), perimesencephalic (10%), AVM, dissection. Hunt-Hess: I (mild HA) to V (coma). Fischer CT scale. Management: CT head -> LP for xanthochromia if negative; CTA identifies aneurysm. Secure aneurysm: coiling vs clipping. Nimodipine 60 mg PO q4h x21 days. Vasospasm management: TCD monitoring, euvolemia, intra-arterial vasodilators, balloon angioplasty. Complications: rebleeding (peak first 6h), DCI (peak day 7-10), hydrocephalus, hyponatremia, neurogenic stunned myocardium. Screen for unruptured aneurysms if >=7mm or high-risk.

Epilepsy affects approximately 50 million people worldwide, making it one of the most common neurological diseases globally. The lifetime incidence of at least one seizure is ~10%, while epilepsy (recurrent unprovoked seizures) affects ~1% of the population. Incidence is highest in children under 5 and adults over 60. In the US, ~3.4 million have active epilepsy with annual costs of ~$28 billion. Approximately 30% have drug-resistant epilepsy (failure of 2+ appropriate AED trials). The mortality rate is 2-3 times the general population, driven by SUDEP (1.2/1,000 patient-years, higher with frequent GTC seizures). Stigma, driving restrictions, employment challenges, and psychosocial comorbidities significantly impact quality of life.

Seizures are classified by onset: focal (networks limited to one hemisphere), generalized (bilaterally distributed networks), or unknown. Focal seizures by awareness: focal aware (consciousness preserved) or focal impaired awareness. Motor onset: automatisms, atonic, clonic, epileptic spasms, hyperkinetic, myoclonic, tonic. Non-motor: autonomic, behavior arrest, cognitive, emotional, sensory. Focal to bilateral tonic-clonic. Generalized: tonic-clonic (grand mal), absence (typical 3 Hz spike-wave), myoclonic, clonic, tonic, atonic (drop attacks). Epilepsy syndromes: juvenile myoclonic epilepsy (myoclonic on awakening, GTC, photosensitivity), childhood absence epilepsy (3Hz, often remits), Lennox-Gastaut (slow spike-wave, multiple types, intractable), West syndrome (infantile spasms, hypsarrhythmia).

Seizures result from abnormal excessive synchronous neuronal discharge due to imbalance of excitation (glutamate, NMDA/AMPA) and inhibition (GABA). Mechanisms: ion channel mutations, synaptic reorganization (mossy fiber sprouting), impaired GABAergic inhibition, network-level changes in synchronization. EEG is essential for diagnosis. Interictal: epileptiform discharges (spikes, sharp waves, spike-wave complexes, polyspikes). Focal discharges localize regionally; generalized discharges appear synchronously. Prolonged video-EEG is gold standard for presurgical evaluation and differentiating epileptic from psychogenic nonepileptic spells (PNES). Ictal EEG: rhythmic activity evolving in frequency, amplitude, and spatial distribution. Nonconvulsive status epilepticus (NCSE) requires high clinical suspicion.

Detailed history: semiology, duration, postictal state, provoking factors (sleep deprivation, alcohol withdrawal, fever, metabolic, medications, illicit drugs). Differentiate from syncope (convulsive syncope: prodromal lightheadedness, rapid recovery, no postictal confusion). Labs: glucose, electrolytes, renal/hepatic, tox screen, AED levels if indicated. LP if concern for CNS infection. MRI brain epilepsy protocol (3T: thin T2, FLAIR, SWI, volumetric). EEG routine or sleep-deprived (sensitivity ~30-50%). Diagnosis of epilepsy: >=2 unprovoked seizures >24h apart, or 1 unprovoked seizure with >=60% recurrence risk (epileptiform EEG, structural lesion, remote symptomatic cause). Recurrence risk after first seizure: 35-50% overall, higher with epileptiform EEG, prior brain insult, abnormal MRI.

Focal seizures: lamotrigine (broad, well-tolerated, slow titration to avoid rash), levetiracetam (broad, rapid, behavioral SEs), oxcarbazepine (focal, hyponatremia), lacosamide (IV form for status). Generalized: valproate (most effective for generalized, but teratogenic, weight gain, tremor, avoid in women of childbearing potential), lamotrigine (absence + GTC), levetiracetam (GTC + myoclonic). Absence: ethosuximide (first-line, 3Hz). Myoclonic: valproate or levetiracetam; avoid carbamazepine, oxcarbazepine, phenytoin, gabapentin. Pregnancy: valproate contraindicated (MCM 10-15%). Lamotrigine and levetiracetam preferred; levels drop during pregnancy, monitor monthly. Seizure-free for 9-12 months before attempting AED withdrawal; recurrence risk 25-50%.

Status epilepticus (SE): >=5 min continuous seizure or >=2 without full recovery. Mortality 15-20%. Phases: early (0-30 min), established (30-60 min), refractory (>60 min, needs anesthetics), super-refractory (>24h). Stage 1 (0-5 min): benzodiazepine (IM midazolam 10 mg or IV lorazepam 0.1 mg/kg). Stage 2 (5-30 min): fosphenytoin 20 PE/kg, valproate 20-40 mg/kg, or levetiracetam 40-60 mg/kg (ESETT trial: all equivalent). Stage 3 (refractory): continuous IV anesthetic (midazolam, propofol, or pentobarbital). Continuous EEG monitoring for 24-48h. Treat underlying cause (infection, stroke, metabolic, autoimmune, neoplastic, AED nonadherence).

Epilepsy surgery should be considered early in drug-resistant epilepsy (failure of 2+ appropriate AEDs). Presurgical evaluation: video-EEG, 3T MRI epilepsy protocol, PET, ictal SPECT, MEG, neuropsych testing, fMRI for language/memory. Invasive monitoring (SEEG) if noninvasive data discordant. Anterior temporal lobectomy achieves 70-80% seizure freedom in mesial temporal sclerosis. Neurostimulation: VNS (vagus nerve stimulator, ~40-50% reduction), RNS (responsive neurostimulation, closed-loop), DBS (anterior thalamic nucleus). Corpus callosotomy for drop attacks/atonic seizures. Ketogenic diet for refractory epilepsy, especially children. SUDEP: incidence 1.2/1,000 overall, 6-9/1,000 in refractory. Risk factors: GTC frequency, nocturnal seizures, nonadherence, alcohol. Prevention: optimize seizure control, nocturnal supervision, seizure detection devices. Driving restrictions: 3-12 months seizure-free. Pregnancy: monotherapy with lamotrigine or levetiracetam, folate 1-5 mg/day. PNES: video-EEG diagnosis, CBT and psychotherapy.

Headache disorders are among the most common neurological conditions, with global prevalence ~52% for active headache disorders. Migraine affects ~12-15% of adults worldwide (18% women, 6% men), peak prevalence ages 30-39. Tension-type headache is most common (lifetime prevalence ~78%). Cluster headache affects 0.1-0.3% (male predominance 3-5:1). Migraine is the second leading cause of years lived with disability globally, first among neurological disorders. Despite effective treatments, ~50% of migraineurs have never received a formal diagnosis. Chronic migraine (>=15 headache days/month, >=8 migraine days) affects 1-3% of the population. Trigeminal autonomic cephalalgias (TACs) are less common but highly disabling.

Migraine is a neurovascular disorder involving the trigeminovascular system, brainstem modulation, and cortical spreading depression (CSD). CSD is a wave of neuronal depolarization spreading across cortex at 2-5 mm/min, correlating with aura. CSD activates trigeminal afferents innervating meningeal vessels, releasing CGRP, substance P, and NO, causing neurogenic inflammation and peripheral sensitization. Central sensitization follows, producing cutaneous allodynia. Key brainstem regions (PAG, locus coeruleus, raphe, trigeminal nucleus caudalis) modulate pain processing and are dysfunctional interictally. Genetics: polygenic; familial hemiplegic migraine associated with CACNA1A, ATP1A2, SCN1A. CGRP is the key therapeutic target. Serotonin (5-HT1B/1D) is the target for triptans.

ICHD-3 criteria: >=5 attacks lasting 4-72h with >=2 of 4 pain features (unilateral, pulsating, moderate-severe, aggravated by/avoiding activity) AND >=1 of N/V or photo+phonophobia. Migraine with aura: fully reversible visual (scintillating scotoma, fortification), sensory, or language aura spreading over >=5 min, lasting 5-60 min, headache within 60 min. Phases: prodrome (12-48h: yawning, cravings, neck stiffness, mood changes), aura, headache (4-72h), postdrome (fatigue, cognitive dullness, soreness). Chronic migraine: >=15 headache days/month for 3mo with >=8 migraine days. Risk factors for chronification: high attack frequency, medication overuse, obesity, depression, sleep disorders. Status migrainosus: attack >72h; treatment: IV DHE, IV valproate, IV magnesium, IV ketorolac, corticosteroids.

Mild-moderate: NSAIDs (ibuprofen, naproxen, diclofenac) + antiemetic (metoclopramide, prochlorperazine). Severe: triptans (oral, ODT, nasal spray, SC). Sumatriptan 6 mg SC is fastest and most effective. Triptan contraindications: ischemic heart disease, uncontrolled HTN, cerebrovascular disease, hemiplegic/basilar migraine. Limit triptans to <=9 days/month to avoid MOH. Gepants (ubrogepant, rimegepant): CGRP antagonists, no vasoconstriction, no MOH risk. Lasmiditan (ditan, 5-HT1F agonist): no vasoconstriction, dizziness/fatigue, driving restriction 8h. DHE IV/IM for status migrainosus. Avoid opioids and butalbital. Peripheral nerve blocks (GON, supraorbital) for refractory attacks.

Initiate when >=4 migraine days/month or significant disability. First-line oral: beta-blockers (propranolol 40-160 mg, metoprolol 50-200 mg), topiramate (25-200 mg, weight loss, paresthesias, word-finding difficulty, nephrolithiasis, teratogenic), amitriptyline (10-100 mg qHS, useful in mixed tension-type, insomnia). Valproate (effective but weight gain, tremor, teratogenic - 2nd/3rd line). CGRP mAbs: erenumab (anti-receptor), galcanezumab, fremanezumab, eptinezumab (anti-ligand) - highly effective, well-tolerated, monthly/quarterly injections. OnabotulinumtoxinA (Botox) for chronic migraine (PREEMPT protocol, 31 injections q12wk). Neuromodulation: sTMS, nVNS, REN, Cefaly. Supplements: riboflavin 400 mg, magnesium 400-600 mg, CoQ10. Behavioral: CBT, biofeedback, sleep hygiene, trigger avoidance.

TTH: bilateral pressing/tightening, mild-moderate, not aggravated by activity, no N/V, one of photo/phonophobia. Episodic (<15 days/month) vs chronic (>=15). Acute: simple analgesics (limit <=14 days/month). Prevention for chronic TTH: amitriptyline first-line (10-75 mg qHS). MOH: paradoxical headache increase from frequent acute medication (>=10-15 days/month depending on class). Stop offending medication for 1-2 months. Bridge therapy: naproxen 500 mg BID, steroid taper, or DHE. Triptan MOH: stop abruptly. Opioid/barbiturate MOH: hardest to treat, taper gradually.

Cluster headache: strictly unilateral severe orbital/temporal pain lasting 15-180 min + ipsilateral autonomic features (conjunctival injection, lacrimation, rhinorrhea, miosis, ptosis) and/or agitation/restlessness. Attacks 1-8/day, often nocturnal. Episodic (cluster periods with remission) vs chronic. Acute: high-flow O2 12-15 L/min, SC sumatriptan 6 mg, nasal zolmitriptan. Transitional: prednisone 60-100 mg/day x2-5 days, GON block. Prevention: verapamil 240-960 mg (ECG monitoring), lithium, topiramate, melatonin. Paroxysmal hemicrania: indomethacin 100% response. SUNCT/SUNA: very short (1-600 sec), lamotrigine. Hemicrania continua: indomethacin-responsive.

Systemic symptoms (fever, weight loss, cancer, HIV, immunosuppression, pregnancy). Neurologic (AMS, papilledema, focal deficits, seizures, meningismus). Onset sudden/thunderclap (<1 min: SAH, CVST, dissection, RCVS, pituitary apoplexy). Onset after 50 (GCA, mass). Prior headache change (new type, progressive). Precipitating factors (Valsalva = Chiari/colloid cyst; exertion/orgasm = SAH/dissection; positional = low/high ICP). Papilledema (IIH, mass, CVST, meningitis). Progressive/atypical (worsening over days). Pregnancy/postpartum (CVST, RCVS, pituitary apoplexy, preeclampsia). Cancer (metastases, carcinomatous meningitis). Immunocompromise (infection, lymphoma). Painkiller overuse (MOH). Workup: CT head, CTA if SAH, MRI/MRA/MRV, LP, ESR/CRP. Fundoscopic exam mandatory.

Neurodegenerative diseases represent a growing global health crisis as populations age. Alzheimer disease (AD) is the most common cause of dementia, affecting ~55 million people worldwide, projected to triple by 2050. Parkinson disease (PD) affects ~1% over age 60 (10 million globally). ALS incidence is ~1.5-2.7/100,000 person-years (lifetime risk ~1:400). Huntington disease prevalence ~5-10/100,000. Frontotemporal dementia (FTD) accounts for 5-10% of dementias, onset typically 45-64, a leading cause of early-onset dementia. Dementia with Lewy bodies (DLB) represents ~5-10% of dementia cases. The combined economic burden exceeds $1 trillion annually globally. APOE e4 is the strongest genetic risk factor for late-onset AD.

AD is defined by extracellular amyloid-beta (A-beta42) plaques and intracellular hyperphosphorylated tau neurofibrillary tangles, leading to synaptic loss and progressive neuronal death in entorhinal cortex, hippocampus, and temporoparietal association cortex. The amyloid cascade hypothesis: A-beta accumulation triggers tau pathology, inflammation, and cognitive decline. APOE e4 increases risk 3-15x per allele. Early-onset AD (<65, <5% of cases) associated with APP, PSEN1, PSEN2 mutations. Course: amnestic MCI (objective memory impairment without functional decline) to dementia (short-term to long-term memory, executive, visuospatial, language, apraxia). Neuropsychiatric symptoms (>80%): depression, apathy, agitation, psychosis. Diagnosis: MoCA <26, MRI showing hippocampal/medial temporal atrophy (coronal T1). CSF: low A-beta42, high p-tau 181/217, high total tau. Amyloid PET (florbetapir, flutemetamol) and tau PET (flortaucipir). FDG PET: temporoparietal hypometabolism. Treatment: cholinesterase inhibitors (donepezil, rivastigmine, galantamine) for mild-moderate; memantine (NMDA antagonist) for moderate-severe. Anti-amyloid mAbs: lecanemab (27% slowing at 18mo in Clarity AD, ARIA-E/H risk), donanemab (22-29% slowing in TRAILBLAZER-ALZ 2). Monitor for ARIA with serial MRI. Manage NPS non-pharmacologically first; antidepressants for depression; avoid anticholinergics.

PD is characterized by loss of dopaminergic neurons in substantia nigra pars compacta with Lewy bodies (alpha-synuclein). Motor symptoms appear when ~60-70% of SNc neurons are lost. UK Brain Bank criteria: bradykinesia + at least one of: resting tremor (4-6 Hz, pill-rolling, asymmetric), rigidity (cogwheel or lead-pipe), postural instability (late). Asymmetric onset is hallmark. Non-motor symptoms often precede motor onset: anosmia, REM sleep behavior disorder, constipation, depression, anxiety. Treatment: Levodopa/carbidopa is gold standard. Start 100/25 mg TID, titrate. Side effects: nausea, orthostatic hypotension, hallucinations, dyskinesias (peak-dose after years). Dopamine agonists (pramipexole, ropinirole, rotigotine) — risk of ICDs, hallucinations, sleep attacks. MAO-B inhibitors (selegiline, rasagiline) — mild benefit. COMT inhibitors (entacapone, opicapone) — reduce wearing-off. Amantadine for dyskinesias. DBS (STN or GPi) for motor fluctuations/dyskinesias in advanced PD with good LD response, no dementia. Non-pharmacologic: exercise (LSVT BIG, boxing, dance, tai chi, cycling). Physical, occupational, speech therapy (LSVT LOUD). Dementia in PD: ~80% after 15-20 years.

Parkinson-plus syndromes have more rapid progression, poor/absent L-DOPA response, and distinguishing features. MSA: autonomic failure (orthostatic hypotension, urinary incontinence, erectile dysfunction) + LD-unresponsive parkinsonism (MSA-P) or cerebellar ataxia (MSA-C). Other: stridor (nocturnal, CPAP/tracheostomy), RBD, antecollis, inspiratory sighs. MRI: hot cross bun sign, putaminal rim, MCP atrophy. Survival ~6-9 years. PSP: vertical supranuclear gaze palsy (downgaze first), early falls (within first year), axial rigidity, executive dysfunction, pseudobulbar affect. MRI: hummingbird sign (midbrain atrophy), Mickey Mouse sign. Survival ~5-7 years. CBD: asymmetric apraxia (profound), alien limb phenomenon, cortical sensory loss, myoclonus, dystonia. MRI: asymmetric frontoparietal atrophy. Survival ~6-8 years. DLB: fluctuating cognition, well-formed visual hallucinations, RBD, Parkinsonism. Severe neuroleptic sensitivity. Cholinesterase inhibitors for cognition/hallucinations. LD for motor symptoms (modest response). Avoid typical antipsychotics.

ALS is a progressive neurodegenerative disease involving both UMN (corticospinal tract) and LMN (brainstem/spinal cord anterior horn cells). UMN: spasticity, hyperreflexia, Hoffman, Babinski, pseudobulbar affect. LMN: progressive weakness, muscle wasting/atrophy, fasciculations, hyporeflexia. Onset types: spinal/limb (~70%, asymmetric focal limb onset, spreads contiguously), bulbar (~25%, dysarthria, dysphagia, drooling, aspiration), respiratory (~5%, initial dyspnea, orthopnea). Diagnosis: El Escorial (definite = UMN + LMN in 3 regions). EMG/NCS: widespread denervation, normal NCS (no conduction block). Genetic testing: C9orf72 (most common familial ~40-50%, sporadic ~7%), SOD1, FUS, TARDBP. Treatment: Riluzole 50 mg BID (modest survival benefit 2-3 months). Edaravone (slows functional decline in early stage). Multidisciplinary ALS clinic improves survival. Respiratory: NIPPV when FVC <80%, tracheostomy if needed. Nutrition: PEG/RIG when FVC >50%. Symptomatic: spasticity (baclofen, tizanidine), sialorrhea (glycopyrrolate, botox, radiation), pseudobulbar affect (Nuedexta), pain, depression, anxiety. Prognosis: median survival 3-5 years.

HD: autosomal dominant CAG repeat expansion in HTT gene (full penetrance >=40). Anticipation with paternal transmission. Clinical triad: chorea (involuntary jerky dance-like), cognitive decline (executive dysfunction to global dementia over 10-20 years), psychiatric symptoms (depression most common, irritability, psychosis, suicide risk). Onset 30-50 years; juvenile HD (<20, paternal transmission, Parkinsonism). MRI: caudate atrophy (boxcar ventricles). No disease-modifying therapy. Symptomatic: tetrabenazine/deutetrabenazine for chorea (VMAT2 inhibitors). FTD: focal frontal and temporal atrophy, onset 45-64. bvFTD: disinhibition, apathy, loss of empathy, compulsive behaviors, hyperorality, with executive dysfunction. svPPA: fluent aphasia, anomia, loss of word meaning. nfvPPA: effortful speech, agrammatism, apraxia of speech. Genetics: C9orf72 (most common), MAPT, GRN. Pathology: tau, TDP-43, FUS. No FDA-approved treatments. Symptomatic: SSRIs for disinhibition/compulsions. Supportive care.

Multiple sclerosis affects ~2.8 million people worldwide (~35.9/100,000). Higher prevalence in temperate climates. Female:male ratio ~3:1, mean onset age 30-35. RRMS accounts for 85-90% of initial diagnoses; ~50% of untreated converts to SPMS within 15-20 years. PPMS accounts for 10-15% (older onset 40-60, equal sex ratio). EBV infection is a necessary prerequisite (~99.5% seropositivity in MS, 32-fold increased risk after infectious mononucleosis). Other risk factors: vitamin D deficiency, smoking (increases risk and progression), obesity in adolescence, HLA-DRB1*15:01.

MS is a chronic inflammatory demyelinating disease of the CNS, initiated by autoreactive T cells that cross the BBB and recognize myelin antigens. Activated T cells recruit macrophages, B cells, and CD8+ T cells, leading to demyelination, oligodendrocyte loss, axonal transection, and astrogliosis. B cells play a critical role (antibody production, antigen presentation, cytokine secretion) explaining high efficacy of anti-CD20 therapies. Lesions: perivenular (Dawson fingers), periventricular, juxtacortical, infratentorial, spinal cord (short segment, <2 vertebral bodies). Gray matter involvement (cortical lesions, deep gray atrophy) correlates with cognitive impairment. Progressive phase involves compartmentalized inflammation behind repaired BBB, meningeal B cell follicles, microglial activation, mitochondrial dysfunction, and neurodegeneration.

Optic neuritis: acute monocular vision loss, periocular pain with EOM, color desaturation, APD, central scotoma. Most recover over weeks. Brainstem/cerebellar: INO (MLF, adduction lag + nystagmus, highly specific for MS), trigeminal neuralgia (young adults, bilateral), facial nerve palsy, vertigo, ataxia, Lhermitte sign (electric shock on neck flexion). Transverse myelitis: bilateral weakness/sensory level below well-demarcated spinal level, bladder/bowel dysfunction, back pain. Motor: pyramidal weakness (spasticity, hyperreflexia, Babinski). Fatigue: 70-90%, most disabling. Cognitive: processing speed, memory, executive function (40-65%). Pain: neuropathic (paresthesias, Lhermitte, trigeminal neuralgia, tonic spasms). Bladder: detrusor hyperreflexia (urgency, frequency) or detrusor-sphincter dyssynergia. Paroxysmal symptoms: tonic spasms, dysarthria, diplopia, Lhermitte. Depression (50%), anxiety, pseudobulbar affect.

Dissemination in space (DIS): >=1 T2 lesion in >=2 of 4 locations (periventricular, cortical/juxtacortical, infratentorial, spinal cord). Dissemination in time (DIT): simultaneous asymptomatic gadolinium-enhancing + non-enhancing lesions OR new T2/enhancing lesion on follow-up OR CSF-specific oligoclonal bands (OCBs) can substitute for DIT. PPMS: 1 year disability progression + 2 of 3 (>=1 T2 lesion in MS-typical region, >=2 T2 spinal cord lesions, positive CSF). MRI: FLAIR for periventricular/juxtacortical, axial T2/proton density, T1 pre-/post-gad. Typical lesions: ovoid, >3mm, perivenular (central venule sign on SWI). CSF: OCBs (sensitivity ~90-95%), elevated IgG index. Evoked potentials: VEP (prolonged P100). Differential: NMOSD (AQP4-IgG), MOGAD, neurosarcoidosis, CNS vasculitis, CADASIL.

MS relapse: new/worsening neurologic symptoms attributable to CNS demyelination, lasting >=24h, without fever/infection (pseudoexacerbation from Uhthoff/infection). Always rule out UTI before treating. First-line: IV methylprednisolone 1000 mg daily x3-5 days or high-dose oral methylprednisolone (equivalent efficacy). Incomplete response: plasma exchange (5-7 exchanges). ACTH gel for steroid-intolerant. Symptom-specific: PT/OT, pain management (gabapentinoids, TCAs, SNRIs), bladder management. Do not start/escalate DMT during acute relapse.

Treatment shift toward early high-efficacy therapy (induction approach). Moderate-efficacy: interferon beta (IM weekly, SC 3x/week, SC qod, ~30% relapse reduction), glatiramer acetate (SC daily/TIW, ~30%), teriflunomide (PO daily, ~35%), dimethyl fumarate (PO BID, ~50%, flushing/ GI side effects). High-efficacy: fingolimod (PO daily, S1P modulator, ~55%, bradycardia first-dose, macular edema, VZV risk), natalizumab (IV q4w, anti-alpha4 integrin, ~68%, PML risk with JCV+), ocrelizumab (IV q6mo, anti-CD20, ~50% RRMS, first DMT for PPMS), ofatumumab (SC monthly, anti-CD20, self-injectable). Alemtuzumab (IV, anti-CD52, very high efficacy but safety concerns: secondary autoimmunity, ITP, nephropathy). Cladribine (PO short courses, purine analog). Siponimod (PO, for active SPMS). HSCT for highly refractory RRMS. Monitoring: CBC, LFTs, infection screening (HIV, HBV, HCV, VZV, TB before start), vaccinations (influenza, COVID, pneumococcal, VZV if not immune), avoid live vaccines.

SPMS: initial RRMS followed by gradual disability progression (PIRA). Siponimod for active SPMS. PPMS: progression from onset; ocrelizumab approved (24% reduction in disability progression). Symptomatic management: fatigue (modafinil, amantadine), spasticity (baclofen, tizanidine, gabapentin, botox, ITB), neuropathic pain (pregabalin, gabapentin, TCAs, duloxetine), bladder (anticholinergics, self-cath), depression (SSRIs), walking (fampridine 10 mg BID for improved walking speed in ~40%). NMOSD: AQP4-IgG autoimmune astrocytopathy. Features: severe bilateral ON, LETM (>=3 segments), area postrema syndrome (intractable hiccoughs/N/V). Acute treatment: IV steroids + PLEX if refractory. Prevention: eculizumab (anti-C5, meningococcal vax needed), inebilizumab (anti-CD19), satralizumab (anti-IL6R). Avoid interferon, fingolimod, TNF-alpha inhibitors. MOGAD: younger, better prognosis than NMOSD, steroid-responsive.

Neuromuscular disorders encompass diseases of the motor unit: anterior horn cell, peripheral nerve, neuromuscular junction, and muscle. Myasthenia gravis incidence ~1-2/100,000/year, prevalence 20-40/100,000. LEMS is rare (~0.5/100,000). ALS lifetime risk ~1:400. GBS incidence 0.5-2/100,000/year. CIDP incidence 0.5-2/100,000/year. Respiratory failure is the most common cause of death in many neuromuscular disorders. Advances in immunomodulation (IVIG, PLEX, rituximab, eculizumab) and targeted genetic therapies have significantly improved outcomes.

MG is an autoimmune disorder of the NMJ with antibodies against postsynaptic AChR (~85% generalized, ~50% ocular), MuSK (~8%), or LRP4. Clinical: fluctuating, fatigable weakness - ptosis (worsens with sustained upgaze), diplopia, dysphagia, dysarthria, facial weakness, proximal limb weakness (neck flexors, deltoids, hip flexors, triceps). Thymoma in 10-15%. Ocular MG remains ocular. MuSK-MG: prominent oculobulbar, severe facial/tongue atrophy, poor response to pyridostigmine. Diagnosis: AChR/MuSK antibodies. RNS: decremental response at 2-5 Hz. SFEMG: increased jitter (most sensitive, 95-99%). Ice-pack test. Chest CT for thymoma. Treatment: pyridostigmine 30-60 mg q4-6h (cholinergic SEs: diarrhea, cramps, miosis). Immunosuppression: prednisone (start after symptoms controlled to avoid crisis), azathioprine (check TPMT), mycophenolate, cyclosporine, rituximab (especially MuSK). Eculizumab (anti-C5) for refractory AChR+ MG. Efgartigimod (FcRn blocker, IV weekly x4) for generalized MG. Thymectomy for thymoma or generalized AChR+ MG ages 18-60.

Myasthenic crisis: respiratory failure from MG requiring intubation or NIV. Precipitants: infection (most common), surgery, medication changes, stress, pregnancy. Signs: tachypnea, accessory muscle use, paradoxical breathing, weak cough, difficulty clearing secretions, orthopnea. Bedside: NIF (intubate if >-20 cm H2O), FVC (intubate if <10-15 mL/kg). Management: ICU, BiPAP for mild-moderate, intubation for impending failure. Avoid succinylcholine and nondepolarizing NMBDs. PLEX (5-7 exchanges) or IVIG (2 g/kg over 5 days) - both effective. Start/increase prednisone. Treat underlying infection. Medications to avoid: aminoglycosides, fluoroquinolones, macrolides, beta-blockers, calcium channel blockers, magnesium, botulinum toxin, checkpoint inhibitors. Cholinergic crisis: excessive pyridostigmine causing miosis, fasciculations, diarrhea, bradycardia. Differentiate with edrophonium test. Mortality 4-5% in modern ICU.

LEMS is a presynaptic autoimmune disorder caused by P/Q-type VGCC antibodies (~85%), reducing ACh release. ~60% have underlying malignancy (mostly SCLC). Proximal weakness (lower > upper) that improves with repeated effort (facilitation) - opposite of MG. Autonomic dysfunction: dry mouth, metallic taste, erectile dysfunction, constipation. Hyporeflexia/areflexia that augments after sustained contraction. Diagnosis: VGCC antibodies, RNS shows increment >100% at high-rate or post-exercise. Treatment: treat underlying cancer. Symptomatic: amifampridine (3,4-DAP, potassium channel blocker, improves strength), pyridostigmine (limited). Immunosuppression: IVIG, prednisone, azathioprine. Avoid calcium channel blockers.

GBS is an acute, post-infectious, immune-mediated peripheral neuropathy. Subtypes: AIDP (acute inflammatory demyelinating polyneuropathy, most common in US/Europe), AMAN/AMSAN (axonal, more common in Asia), Miller Fisher (ophthalmoplegia + ataxia + areflexia, anti-GQ1b). Antecedent infection: Campylobacter jejuni (most common, especially AMAN), CMV, EBV, Mycoplasma, Zika, COVID-19. Clinical: ascending symmetric flaccid paralysis (areflexia, hypo/absent DTRs), paresthesias, back pain. Autonomic dysfunction in ~50% (arrhythmias, BP lability, ileus, urinary retention). Miller Fisher: ophthalmoplegia, ataxia, areflexia, anti-GQ1b antibodies. Diagnosis: LP (albuminocytologic dissociation: elevated protein, normal WBC), EMG/NCS (demyelinating: prolonged distal latencies, conduction block, temporal dispersion, slow CV; axonal: reduced amplitudes). Management: IVIG (0.4 g/kg/day x5 days) or PLEX (5-7 sessions) - both equally effective, do not combine. ICU monitoring for respiratory failure: serial NIF/FVC (intubate if NIF <-20, FVC <15-20 mL/kg, or signs of respiratory failure). Monitor for autonomic instability. Prognosis: ~80% recover, 5-10% have severe residual disability, 3-5% mortality. Poor prognosis: older age, rapid onset, severe axonal involvement, need for ventilation.

CIDP is a chronic (>8 weeks) immune-mediated peripheral neuropathy with symmetric proximal and distal weakness, sensory loss, and areflexia/hypereflexia. Progressive, relapsing-remitting, or monophasic course. Diagnosis: EMG/NCS demyelinating criteria (prolonged distal latencies, conduction block, temporal dispersion, slowed CV, prolonged F-waves). LP: elevated protein, normal WBC. MRI: nerve root enhancement/hypertrophy. Nerve biopsy: demyelination with onion-bulb formation, macrophage infiltration, no vasculitis. Treatment: first-line - corticosteroids (prednisone 60-100 mg/day with slow taper), IVIG (2 g/kg load, then maintenance 1 g/kg q3-4 weeks), PLEX (5-7 sessions). Long-term immunosuppression: azathioprine, mycophenolate, cyclophosphamide, rituximab. Distinguish from GBS: CIDP: >8 weeks, chronic course, steroid-responsive, relapsing-remitting, no antecedent infection. Variants: multifocal motor neuropathy (MMN, pure motor, conduction block, anti-GM1, responsive to IVIG but NOT steroids), Lewis-Sumner syndrome (MADSAM, asymmetric, multifocal).

Peripheral neuropathy affects ~2-8% of the general population, increasing to ~20-30% in older adults and ~50% in patients with diabetes. Diabetic neuropathy is the most common cause in the developed world. Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy (~1 in 2,500). CIDP prevalence ~2-7/100,000. Mononeuritis multiplex is associated with vasculitis, diabetes, and infectious causes. The global burden is substantial, with neuropathic pain affecting ~7-10% of the general population. Nerve biopsy and skin biopsy for small fiber neuropathy are important diagnostic tools for specific clinical scenarios.

Peripheral neuropathies are classified by pattern: mononeuropathy (single nerve: carpal tunnel, ulnar, peroneal, meralgia paresthetica), polyneuropathy (length-dependent, symmetric, "stocking-glove" distribution: diabetic, toxic, hereditary), and mononeuritis multiplex (multiple individual nerves, asymmetric: vasculitis, diabetes, sarcoid, infectious). Temporal course: acute (<4 weeks), subacute (4-8 weeks), chronic (>8 weeks). Fiber type: motor (weakness, atrophy, fasciculations), sensory (positive symptoms: burning, tingling, allodynia; negative: numbness, loss of balance), autonomic (orthostatic hypotension, gastroparesis, bladder dysfunction, erectile dysfunction, anhidrosis). Pathophysiology: axonal (Wallerian degeneration, reduced amplitudes on NCS, normal/near-normal velocity) vs demyelinating (segmental demyelination, prolonged distal latencies, conduction block, temporal dispersion, slowed velocity on NCS).

Diabetic neuropathy is the most common complication of diabetes, affecting ~50% of patients with long-standing disease. Distal symmetrical sensorimotor polyneuropathy is the most frequent pattern (stocking-glove sensory loss, burning, tingling, pain, weakness in intrinsic foot muscles, loss of ankle reflexes). Autonomic neuropathy: gastroparesis, diabetic diarrhea/constipation, orthostatic hypotension, erectile dysfunction, cardiac autonomic neuropathy (silent ischemia). Mononeuritis multiplex (diabetic amyotrophy): acute onset proximal leg pain and weakness, femoral neuropathy, cranial nerve palsies (CN III, VI). Treatment: strict glycemic control is the only disease-modifying approach (DCCT, EDIC). Symptomatic neuropathic pain: pregabalin (150-300 mg/day, first-line), duloxetine (60 mg/day, first-line), gabapentin, amitriptyline/nortriptyline, venlafaxine, topical lidocaine, capsaicin. Avoid opioids. Alpha-lipoic acid (antioxidant) may provide modest benefit. Acetyl-L-carnitine has limited evidence. Foot care: daily inspection, emollients, proper footwear, podiatry referral, education about early recognition of ulcers.

CIDP is an acquired immune-mediated polyneuropathy with chronic progressive or relapsing course (>8 weeks). Clinical: symmetric proximal AND distal weakness, sensory loss, areflexia or hyporeflexia, ataxia, numbness. Subtypes: typical (sensorimotor), pure motor, pure sensory (sensory ataxic), multifocal (MADSAM, Lewis-Sumner), distal (DADS, with IgM monoclonal gammopathy), focal (brachial or lumbar plexus), CIDP with CNS demyelination. Diagnosis: EMG/NCS demyelinating criteria (prolonged distal latencies, conduction block, temporal dispersion, slowed CV, prolonged F-waves) in at least 2 nerves. LP: elevated CSF protein with normal WBC (less than 10 cells). MRI: nerve root hypertrophy/enhancement in lumbosacral or cervical region. Nerve biopsy: demyelination, onion-bulb formation, endoneurial edema, macrophage-mediated demyelination (rarely needed, reserved for atypical cases). Treatment: prednisone 60-100 mg/day with slow taper or IVIG 2 g/kg load then 1 g/kg q3-4 weeks (both equally effective first-line). PLEX for refractory. Long-term immunosuppression: azathioprine, mycophenolate, cyclophosphamide, rituximab. Poor prognosis: axonal loss, older age, comorbid medical conditions, delayed treatment. Multifocal motor neuropathy (MMN): pure motor, asymmetric, upper > lower, conduction block on NCS, anti-GM1 antibodies in ~50%, responds to IVIG but NOT steroids (steroids can worsen).

CMT is the most common inherited neuropathy, typically autosomal dominant. CMT1 (demyelinating, ~50%): PMP22 duplication (CMT1A, most common: ~70% of CMT1), MPZ, GJB1 (X-linked). CMT2 (axonal): MFN2 (CMT2A), MPZ, MFN2, GDAP1, NEFL. Clinical: slowly progressive, symmetric distal weakness (foot drop, hand intrinsic atrophy), distal sensory loss, pes cavus (high-arched feet), hammer toes, distal leg atrophy ("inverted champagne bottle" or "stork legs"), areflexia, ataxia, scoliosis. Onset: CMT1 typically childhood/adolescence; CMT2 variable. Mildly elevated CSF protein in CMT1. EMG/NCS: CMT1 = markedly slowed CV (15-30 m/s), CMT2 = normal/near-normal CV with reduced amplitudes. Nerve biopsy: onion-bulb formation (demyelinating/remyelination). Genetic testing: PMP22 duplication, MPZ, GJB1, MFN2, GDAP1, NEFL. No disease-modifying therapy. Management: physical/occupational therapy, orthotics (AFO for foot drop), ankle-foot orthoses, wrist splints for hand weakness, surgical correction of foot deformities, pain management (gabapentinoids, TCAs). Avoid neurotoxic drugs (vincristine, platinum, taxanes, nitrofurantoin, metronidazole, dapsone, disulfiram, isoniazid, pyridoxine). Ascorbic acid has not shown benefit. Prognosis: slowly progressive, most patients ambulatory into late adulthood.

Vasculitic neuropathy: painful mononeuritis multiplex due to ischemic infarction of peripheral nerves. Associated with PAN, microscopic polyangiitis, EGPA, rheumatoid arthritis, SLE, Sjogren, sarcoidosis, cryoglobulinemia, diabetes. Diagnosis: nerve biopsy (epineurial perivascular inflammation, fibrinoid necrosis, vessel wall destruction, hemosiderin deposition, luminal thrombosis). Treatment: high-dose steroids + cyclophosphamide or rituximab. Nutritional: B12 deficiency (subacute combined degeneration: dorsal column + corticospinal tract + peripheral neuropathy, macrocytic anemia, elevated MMA/homocysteine), thiamine deficiency (alcoholism, beriberi, painful neuropathy), vitamin E deficiency (ataxia, areflexia, proprioceptive loss), copper deficiency (myeloneuropathy mimicking B12 deficiency), pyridoxine deficiency (painful neuropathy) or toxicity (sensory neuronopathy, from high-dose B6 supplements). Toxic: alcohol (dose-related, length-dependent axonal, superimposed nutritional deficiency), chemotherapy (platinum, taxanes [paclitaxel], vinca alkaloids [vincristine], bortezomib, thalidomide, cisplatin, oxaliplatin — acute cold-aggravated dysesthesias), heavy metals (lead, arsenic, mercury, thallium, gold), medications (isoniazid [pyridoxine prophylaxis], nitrofurantoin, metronidazole, dapsone, amiodarone, disulfiram, chloroquine, statins [rare], fluoroquinolones). Small fiber neuropathy: painful burning, allodynia, autonomic symptoms (sweating, flushing), normal NCS/EMG; skin biopsy shows reduced intraepidermal nerve fiber density. Causes: diabetes, impaired glucose tolerance, sarcoid, Sjogren, HIV, celiac, Fabry, paraneoplastic (anti-FGFR3, anti-TS-HDS), idiopathic.

CNS infections are a major cause of morbidity and mortality worldwide, particularly in immunocompromised populations and resource-limited settings. Bacterial meningitis incidence ~2-5/100,000 in developed countries, higher in developing regions. The most common causative organisms in adults: Streptococcus pneumoniae (~50%), Neisseria meningitidis (~15%), Listeria monocytogenes (~10% in elderly/immunocompromised), Haemophilus influenzae (~10% in unvaccinated). Neonatal meningitis: Group B Streptococcus, E. coli. Viral meningitis (enterovirus most common) is more frequent than bacterial but generally self-limited. HSV encephalitis incidence ~1/500,000/year, the most common cause of sporadic fatal encephalitis. Tuberculous meningitis is common in endemic areas. Neurocysticercosis is the most common parasitic CNS infection worldwide and the leading cause of acquired epilepsy in endemic regions. HIV-associated CNS infections remain a significant burden despite ART (toxoplasmosis, cryptococcal meningitis, PML, CMV).

Meningitis: inflammation of the meninges presenting with fever, headache, neck stiffness, photophobia, phonophobia, and altered mental status (classic triad in <50%). Kernig sign (resistance to knee extension with hip flexed 90 degrees) and Brudzinski sign (hip flexion with neck flexion) are specific but not sensitive. Bacterial meningitis: acute onset (hours to <24h), rapid progression, high fever, petechial/purpuric rash (meningococcemia). Viral meningitis: more subacute, less severe, self-limited, often with prodromal viral symptoms. Tuberculous meningitis: subacute to chronic (weeks), basilar exudates, cranial nerve palsies, hydrocephalus, stroke. Fungal meningitis: chronic, indolent (cryptococcal in HIV, coccidioidal, histoplasmal). CSF analysis is diagnostic: bacterial (low glucose <40, high protein >150, high WBC >1000 with neutrophil predominance, positive Gram stain), viral (normal glucose, normal-mild protein, WBC 10-500 lymphocytic), fungal (low glucose, high protein, lymphocytic, India ink/cryptococcal antigen). Empiric antibiotics: ceftriaxone 2 g IV q12h + vancomycin 15-20 mg/kg IV q8-12h + ampicillin 2 g IV q4h (if >50, immunocompromised, pregnant, or Listeria risk). Dexamethasone 10 mg IV before/with first antibiotic (pneumococcal meningitis reduces mortality and hearing loss). Viral: acyclovir 10 mg/kg IV q8h if HSV suspected. Tuberculous: RIPE regimen + dexamethasone. Cryptococcal: amphotericin B liposomal + flucytosine for induction.

Encephalitis: inflammation of brain parenchyma presenting with fever, headache, altered mental status, seizures, and focal neurological deficits. HSV-1 encephalitis: most common cause of sporadic fatal encephalitis, preferentially affects temporal lobe and limbic system. Clinical: acute onset of fever, headache, behavioral changes, aphasia, memory loss, seizures (temporal lobe), rapidly progressive. MRI: T2/FLAIR hyperintensity in medial temporal lobe, insula, inferior frontal gyrus (sparing basal ganglia). EEG: periodic lateralized epileptiform discharges (PLEDs) in temporal region. CSF: lymphocytic pleocytosis, normal glucose, elevated protein, HSV PCR (high sensitivity >95% after 48h). Treatment: IV acyclovir 10 mg/kg q8h x14-21 days (adjust for renal function). Mortality: ~15-30% even with treatment; survivors often have residual memory and cognitive deficits. Other viral encephalitides: VZV (can occur without rash, PCR, acyclovir), West Nile virus (flaccid paralysis, movement disorder, IgM in CSF, supportive care), Enterovirus, CMV (HIV/transplant, ventriculitis, ganciclovir/foscarnet), EBV, HHV-6 (post-transplant), Rabies (almost uniformly fatal, Milwaukee protocol offers rare survival). Autoimmune encephalitis: anti-NMDA receptor (young women, ovarian teratoma, psychiatric prodrome, movement disorder, hypoventilation, immunotherapy + tumor removal), anti-LGI1 (factobrachial dystonic seizures, hyponatremia, responsive to steroids/IVIG/rituximab), anti-CASPR2, anti-GABA-B, anti-AMPAR, anti-GAD. Diagnosis requires CSF/serum antibody panel. Treatment: high-dose steroids, IVIG, PLEX, rituximab, cyclophosphamide.

Brain abscess: encapsulated collection of pus within brain parenchyma. Sources: contiguous (sinusitis, otitis media, mastoiditis, dental infection) or hematogenous (endocarditis, pulmonary infection, congenital heart disease). Microbiology: streptococci (viridans, anginosus/milleri group, most common), S. aureus, anaerobes (Bacteroides, Fusobacterium, Prevotella), Enterobacteriaceae. Immunocompromised: Toxoplasma, Nocardia, Aspergillus, Candida, TB. Clinical: headache (most common), fever (~50%), focal deficits, seizures, altered mental status. CT/MRI: ring-enhancing lesion with surrounding edema, restricted diffusion on DWI (helps distinguish from tumor). Treatment: empiric ceftriaxone 2 g IV q12h + metronidazole 500 mg IV q8h + vancomycin if concern for Staph. Duration: 4-8 weeks IV followed by oral if appropriate. Aspiration or surgical drainage if >2.5 cm, mass effect, or no response to medical therapy. Corticosteroids controversial, only for significant edema/mass effect. Neurosyphilis: Treponema pallidum. Stages: asymptomatic, meningeal, meningovascular (stroke), general paresis (dementia, Argyll Robertson pupils), tabes dorsalis (dorsal column degeneration, lancinating pain, areflexia, ataxia). Diagnosis: serum treponemal (FTA-ABS, TPPA) + CSF VDRL (specific but not sensitive). Treatment: IV penicillin G 18-24 million U/day x10-14 days. Neurocysticercosis: Taenia solium, most common cause of acquired epilepsy. Parenchymal (calcified or viable cysts, seizures) vs extraparenchymal (ventricular, subarachnoid, racemose, hydrocephalus, mass effect). Treatment: albendazole 15 mg/kg/day + praziquantel 50 mg/kg/day for viable cysts + corticosteroids (dexamethasone) to reduce inflammation. Seizure management. Surgical resection for large lesions or hydrocephalus. HIV-related CNS: toxoplasma encephalitis (CD4 <100, ring-enhancing lesions with edema, SPECT/ PET differentiates from lymphoma, treat with pyrimethamine + sulfadiazine + folinic acid), PML (JC virus, CD4 <200, multifocal T2 hyperintense subcortical U-fiber lesions, no enhancement, no mass effect, ART + supportive care), cryptococcal meningitis (CD4 <100, CSF India ink + CrAg, L-AmB + flucytosine induction, fluconazole maintenance, ART timing must be cautious to avoid IRIS), CMV ventriculitis/retinitis (CD4 <50, ganciclovir/foscarnet).

Primary brain tumors account for ~1-2% of all neoplasms, with an incidence of ~25/100,000/year. The most common primary brain tumors: meningioma (~37%, mostly benign), glioblastoma (~15%, most aggressive), pituitary adenoma (~15%), schwannoma (~8%), other gliomas (low-grade, anaplastic, oligodendroglioma ~12%), CNS lymphoma (~4%). Brain metastases are far more common than primary brain tumors, occurring in 20-40% of cancer patients. Common primary sources: lung (40-50%), breast (15-25%), melanoma (5-20%), renal cell (5-10%), colorectal (3-8%). Spinal tumors: intramedullary (ependymoma, astrocytoma), intradural extramedullary (meningioma, schwannoma, neurofibroma), extradural/metastatic (most common spinal tumor). The incidence of primary CNS lymphoma has increased in immunocompromised populations (HIV, transplant, immunosuppressed).

Glioblastoma (GBM, WHO grade 4): most common and most aggressive primary brain tumor. IDH-wildtype constitutes the vast majority of GBMs (de novo, primary GBM, older patients, worse prognosis). IDH-mutant GBM (secondary GBM, younger, better prognosis, progresses from lower-grade glioma). Molecular markers: MGMT promoter methylation (predicts response to temozolomide, better prognosis), EGFR amplification, TERT promoter mutation, chromosome 7 gain/10 loss, p53/RB pathway alterations. Clinical: headaches (worse in morning, with Valsalva, positional), seizures, focal deficits, cognitive decline, personality change, increased ICP. Treatment: maximal safe surgical resection, followed by radiotherapy + concurrent and adjuvant temozolomide (Stupp protocol). Tumor-treating fields (TTFields, Optune) improve survival when added to maintenance temozolomide. Bevacizumab (anti-VEGF) for recurrent disease (decreases edema, improves PFS but not OS). Prognosis: median survival ~15 months (Stupp protocol ~14.6 mo, ~25% survive 2 years). MGMT-methylated: ~22 months; MGMT-unmethylated: ~12 months. Meningioma: most common primary intracranial tumor, >90% benign (WHO grade 1). Arises from arachnoid cap cells. Common locations: parasagittal, convexity, sphenoid wing, olfactory groove, planum sphenoidale. Asymptomatic: observation with serial imaging. Symptomatic or growing: complete surgical resection (Simpson grade). Radiosurgery (Gamma Knife) for residual, recurrent, or surgically inaccessible. Atypical (WHO 2) or malignant (WHO 3) require closer follow-up and possible radiation. Low-grade gliomas (WHO 2): diffuse astrocytoma (IDH-mutant, 1p/19q intact, ATRX loss, p53 mutation) and oligodendroglioma (IDH-mutant, 1p/19q codeleted, TERT promoter mutation, NOTCH1). Clinical: seizures are most common presentation (60-80%). Treatment: maximal safe resection. Adjuvant therapy: observation vs RT + PCV or temozolomide based on risk factors (age >40, tumor >6cm, crossing midline, neurological deficit, IDH-wildtype). Prognosis: oligodendroglioma (median survival 10-15 years), astrocytoma (6-10 years). CNS lymphoma: primary (PCNSL, brain-only) vs secondary (systemic lymphoma with CNS involvement). Associated with HIV (EBV-driven) and immunocompromise. Typically B-cell (DLBCL). MRI: homogeneously enhancing periventricular lesions, often multiple, restricted diffusion (DWI bright). Steroids can lyse lymphoma cells leading to false-negative biopsy (avoid steroids before biopsy if lymphoma suspected). Treatment: high-dose methotrexate-based chemotherapy + whole brain RT (WBRT, associated with neurotoxicity in elderly). Rituximab may be added. Prognosis: median survival ~3-5 years in immunocompetent.

Brain metastases are the most common intracranial tumor in adults. Up to 25% of patients with solid tumors develop brain metastases during their disease course. Common sources: lung (NSCLC > SCLC), breast, melanoma, renal, colorectal, unknown primary. Presentation: headache, seizures, focal deficits, cognitive change, N/V. Diagnosis: MRI brain with contrast (gadolinium). Multiple lesions with surrounding vasogenic edema are typical. Contrast enhancement pattern: ring-enhancing or solid enhancing. Differential: primary brain tumor, brain abscess (DWI restriction), demyelinating disease (open-ring enhancement), radiation necrosis, subacute infarct. Treatment: symptomatic — corticosteroids (dexamethasone 4-8 mg/day, titrated, taper as able; steroid-sparing with bevacizumab if prolonged). Antiseizure medications for patients with seizures (prophylactic AEDs NOT recommended). Definitive treatment depends on number, size, location, and systemic disease status. Single or limited (<3-5) metastases: surgical resection + postoperative SRS (stereotactic radiosurgery) or SRS alone (if <3 cm, deep location, eloquent). Multiple metastases (>5): whole brain RT (WBRT) vs SRS alone. WBRT: associated with cognitive decline (hippocampal avoidance technique can mitigate). SRS alone for limited number (<5-10) with close MRI surveillance. Targeted therapy: for actionable mutations - NSCLC EGFR (osimertinib penetrates CNS), ALK (alectinib, lorlatinib), BRAF V600E melanoma (BRAF/MEK inhibitors), breast HER2+ (trastuzumab deruxtecan, tucatinib, neratinib). Immunotherapy: checkpoint inhibitors (anti-PD-1/PD-L1) have activity in CNS metastases from melanoma, NSCLC, RCC. Prognosis: GPA (Graded Prognostic Assessment) score based on age, KPS, number of metastases, primary tumor type. Median survival varies from 3-15 months depending on GPA. Leptomeningeal disease: CSF dissemination of cancer cells, presents with multifocal neurologic symptoms (headache, CN deficits, radicular pain, myelopathy). Diagnosis: CSF cytology (sensitivity 50-60%, increase with repeat taps, large volume), flow cytometry. Prognosis poor (median survival 2-6 months). Treatment: intrathecal chemotherapy (methotrexate, cytarabine, thiotepa, topotecan), WBRT, systemic therapy with CNS penetration, Ommaya reservoir.

Spinal cord compression is a neurologic emergency requiring immediate diagnosis and intervention to prevent permanent paralysis. Most common cause: metastatic epidural spinal cord compression (MESCC) from solid tumors (breast, lung, prostate, renal, melanoma, multiple myeloma). Thoracic spine most frequently affected (~70%). Clinical: back pain (often first symptom, worse with lying flat, night pain, radicular), motor weakness, sensory level, gait difficulty, autonomic dysfunction (bladder/bowel: urinary retention, incontinence). Diagnosis: STAT whole-spine MRI with contrast (T1, T2, STIR). DEXAMETHASONE 10 mg IV bolus then 4-6 mg q6h. Emergent radiation therapy or surgical decompression (separation surgery + stabilization) before irreversible motor loss occurs. Prognosis: ambulatory before treatment = 80-90% maintain; non-ambulatory before treatment = 30-50% regain ambulation. Urgency: treatment within 24-48h of motor deficit onset. Paraneoplastic neurologic syndromes: immune-mediated neurologic dysfunction triggered by cancer (tumor expression of neural antigens). Classic well-characterized syndromes: Lambert-Eaton (VGCC, SCLC), limbic encephalitis (anti-Hu/ANNA1, anti-Ma2, anti-CV2/CRMP5, anti-amphiphysin — SCLC, testicular, breast, thymoma), opsoclonus-myoclonus-ataxia (anti-Ri/ANNA2, anti-Hu, breast, ovarian, SCLC, neuroblastoma in children), cerebellar degeneration (anti-Yo/PCA1, anti-Tr/DNER, anti-mGluR1 — ovarian, breast, lung, Hodgkin lymphoma), sensory neuronopathy (anti-Hu, SCLC), stiff-person syndrome (anti-amphiphysin, breast, SCLC), dermatomyositis (anti-TIF1-gamma, anti-NXP2 — ovarian, lung, GI, lymphoma). Diagnosis: serum/CSF paraneoplastic antibody panel + cancer screening (CT chest/abdomen/pelvis, PET-CT, testicular US, mammogram, pelvic US). Treatment: treat underlying cancer + immunotherapy (IV steroids, IVIG, PLEX, rituximab, cyclophosphamide). Prognosis: depends on cancer type and stage; often improves with cancer treatment.

Sleep disorders are highly prevalent and underdiagnosed. Insomnia affects ~10-30% of adults, with chronic insomnia (~10%) defined by symptoms at least 3 times/week for >3 months. OSA affects ~25% of men and ~10% of women in North America (AHI >=5), but ~80% remain undiagnosed. Narcolepsy prevalence ~0.02-0.05% (type 1 with cataplexy ~25-50/100,000). Restless legs syndrome (RLS) affects ~5-10% of adults, increasing with age. REM sleep behavior disorder (RBD) prevalence ~0.5-1%, but strongly associated with synucleinopathies (PD, DLB, MSA). The economic burden of sleep disorders exceeds $100 billion/year in the US (lost productivity, accidents, healthcare). Untreated OSA increases risk of hypertension, stroke, heart failure, AF, and all-cause mortality. Chronic insomnia is a risk factor for depression, anxiety, and suicide.

Normal sleep is organized into 4-6 cycles per night, each lasting ~90-120 minutes, progressing through NREM (N1, N2, N3) and REM sleep. N1 (2-5%): light sleep, easy arousal, theta waves on EEG. N2 (45-55%): sleep spindles (sigma rhythm 11-16 Hz, generated by thalamic reticular nucleus, important for memory consolidation) and K-complexes (high-amplitude sharp wave, response to external stimuli). N3 (15-25%): slow-wave sleep (delta, 0.5-4 Hz, >75 uV), deepest sleep, growth hormone secretion, synaptic homeostasis, most difficult to arouse. REM (20-25%): rapid eye movements, low-amplitude mixed-frequency EEG (sawtooth waves), skeletal muscle atonia (except diaphragm and extraocular muscles), dreaming (vivid, narrative, bizarre), autonomic variability (HR, BP, RR). Sleep regulation: circadian rhythm (suprachiasmatic nucleus, ~24.1h intrinsic period, entrained by light via retinohypothalamic tract, melatonin synthesis in pineal gland peaks 2-4 AM, dim light melatonin onset [DLMO] best marker) and homeostatic drive (adenosine accumulates during wakefulness, cleared during sleep). Normal sleep latency: 10-20 min. Normal total sleep time: 7-9 hours in adults. Sleep changes with age: more N1, less N3, more arousals, less total sleep time, earlier bedtime/wake time (phase advance).

Insomnia: difficulty initiating sleep, maintaining sleep, or early morning awakening with daytime consequences (fatigue, mood disturbance, cognitive impairment, reduced performance) despite adequate opportunity and circumstances for sleep. Chronic insomnia disorder: >=3 nights/week for >=3 months. Risk factors: female sex, older age, medical/psychiatric comorbidities (depression, anxiety, chronic pain, COPD, heart failure, hyperthyroidism, RLS, OSA), shift work, poor sleep hygiene, caffeine/alcohol/nicotine, stress, medications (steroids, stimulants, beta-blockers, SSRI, NDRI, theophylline, decongestants). Diagnosis: clinical history + sleep diary (2 weeks) + actigraphy if indicated. Polysomnography not indicated for uncomplicated insomnia. Treatment: first-line is CBT-I (cognitive behavioral therapy for insomnia) — stimulus control (go to bed only when sleepy, get out of bed if awake >20 min, use bed only for sleep/sex), sleep restriction therapy (limit time in bed to average total sleep time, then increase by 15 min when sleep efficiency >85%), cognitive restructuring, relaxation training, sleep hygiene education. CBT-I is more effective and durable than medications. Pharmacotherapy: short-term (<4 weeks) — benzodiazepine receptor agonists (zolpidem 5-10 mg, zaleplon 5-20 mg [especially for sleep onset], eszopiclone 1-3 mg [sleep onset and maintenance]), melatonin receptor agonist (ramelteon 8 mg, for sleep onset, no abuse potential), DORA (dual orexin receptor antagonists: suvorexant 10-20 mg, lemborexant 5-10 mg, daridorexant 25-50 mg for sleep onset and maintenance, low abuse potential, next-day sedation), sedating antidepressants (trazodone 25-100 mg, doxepin 3-6 mg, mirtazapine 7.5-30 mg). Avoid benzodiazepines (tolerance, dependence, falls, cognitive impairment), antihistamines (tolerance, anticholinergic, cognitive impairment), and melatonin OTC (limited efficacy, product inconsistency). CBT-I is preferred for maintenance treatment. Underlying cause: treat primary psychiatric, medical, or sleep disorder.

OSA is characterized by repetitive episodes of complete (apnea) or partial (hypopnea) upper airway collapse during sleep, leading to intermittent hypoxia, hypercapnia, and arousals. Risk factors: obesity (BMI >30 is strongest risk factor, ~70% of OSA patients), male sex (2-3:1), age (40-70), craniofacial abnormalities (retrognathia, macroglossia, tonsillar hypertrophy, high Mallampati score, large neck circumference >17 inches men, >16 inches women), family history, menopause, hypothyroidism, acromegaly. Clinical: loud snoring (disruptive, often reported by bed partner), witnessed apneas (gasps/choking), excessive daytime sleepiness (Epworth Sleepiness Scale >10), unrefreshing sleep, morning headache, dry mouth, nocturia, cognitive impairment, mood changes, decreased libido, erectile dysfunction. Complications: hypertension (dose-dependent, resistant HTN), cardiovascular disease (stroke, heart failure, CAD, AF), pulmonary hypertension, metabolic syndrome, type 2 diabetes, non-alcoholic fatty liver disease, cognitive decline, motor vehicle accidents (2-3x increased risk). Diagnosis: polysomnography (PSG, in-lab or home sleep apnea test [HSAT] for moderate-high risk without comorbidities). AHI (apnea-hypopnea index): mild (5-14.9), moderate (15-29.9), severe (>=30). RDI (respiratory disturbance index) includes respiratory effort-related arousals (RERAs). Oxygen desaturation nadir, time spent with SpO2 <90%. Treatment: CPAP (continuous positive airway pressure) is first-line for moderate-severe OSA (AHI >=15) and symptomatic mild OSA (AHI 5-14.9). Pressure titration (optimal: eliminate apneas/hypopneas/flow limitation, supine REM AHI <5). Auto-CPAP for variable pressure requirements. BiPAP if hypoventilation or CPAP intolerance. Alternative therapies: oral appliance (mandibular advancement device, for mild-moderate OSA, especially if CPAP intolerant or preferred). Positional therapy (avoid supine sleep) for position-dependent OSA. Weight loss (goal 10-15% reduction, can cure mild-moderate OSA). Surgery: uvulopalatopharyngoplasty (UPPP), hypoglossal nerve stimulation (Inspire, for moderate-severe OSA with BMI <35, no concentric palatal collapse). Avoid alcohol/sedatives before sleep. Outcomes: improved daytime sleepiness, quality of life, BP (3-5 mmHg reduction), cardiovascular risk (observational data). Adherence crucial: use >=4h/night, >=70% of nights.

Narcolepsy is a chronic neurologic disorder of hypersomnolence due to loss of hypocretin (orexin)-producing neurons in the lateral hypothalamus. Type 1 (narcolepsy with cataplexy, ~90%): undetectable/low CSF hypocretin-1, associated with HLA-DQB1*0602 (>95%). Cataplexy: sudden bilateral loss of muscle tone triggered by strong emotions (laughter, surprise, anger, excitement), ranging from brief ptosis/facial sagging/head drop to complete collapse (preserved consciousness). Type 2 (narcolepsy without cataplexy): normal CSF hypocretin, less strongly HLA-associated. Clinical tetrad: excessive daytime sleepiness (EDS, irresistible sleep attacks, automatic behaviors, <2 min sleep latency), cataplexy, sleep paralysis (at sleep onset or awakening, inability to move/speak, can last seconds-minutes), hypnagogic/hypnopompic hallucinations (vivid dream-like imagery at sleep-wake transition, often frightening). Nighttime sleep disruption (frequent awakenings, fragmented sleep) is common. Diagnosis: overnight polysomnography (to rule out other causes of EDS) followed by MSLT (Multiple Sleep Latency Test). MSLT: mean sleep latency <8 min (mean of 4-5 naps at 2h intervals) AND >=2 sleep-onset REM periods (SOREMPs). CSF hypocretin-1 measurement (if available, <110 pg/mL = type 1). Treatment: EDS — modafinil 200-400 mg (first-line, less abuse potential than stimulants), armodafinil 150-250 mg, methylphenidate 10-60 mg, dextroamphetamine, solriamfetol (dopamine-norepinephrine reuptake inhibitor, 75-150 mg, effective for EDS), pitolisant (H3 receptor inverse agonist, 4.5-36 mg, also reduces cataplexy). Cataplexy — sodium oxybate (gamma-hydroxybutyrate, GHB, Xyrem/Xywav) at bedtime and 2.5-4h later: highly effective for cataplexy, EDS, and fragmented night sleep; serious side effects (respiratory depression, CNS depression, abuse potential, sodium content in Xyrem). Antidepressants: venlafaxine 37.5-150 mg (first-line for cataplexy, not FDA approved but widely used), fluoxetine, protriptyline, clomipramine. Lifestyle: scheduled naps (15-20 min) 2-3x/day, sleep hygiene, driving safety counseling (narcolepsy increases MVA risk 2-4x). Driving restrictions: medicated patients with good control may drive; discuss risks.

Restless legs syndrome (Willis-Ekbom disease): urge to move legs (arms) with unpleasant sensations (creeping, crawling, aching, pulling, tingling, electric, "cola-like"), worse at rest or inactivity (sitting, lying), temporarily relieved by movement (walking, stretching, rubbing), worse in evening/night (circadian pattern). Diagnostic criteria: all 4 essential features (URGE: Urge to move, worse at Rest, Gets better with movement, Evening/night worsening). Supportive: periodic limb movements (PLMS, repetitive dorsiflexion of great toe/foot at 20-40 sec intervals during sleep, in >80% of RLS patients), family history (40-60% autosomal dominant), response to dopaminergic therapy. Secondary causes: iron deficiency (serum ferritin <50-75 ng/mL, MCV low, TSAT <20%), pregnancy (3rd trimester, resolves after delivery), ESRD (uremia), peripheral neuropathy (diabetes, amyloid), medications (SSRIs, SNRIs, bupropion less, antihistamines, antipsychotics, lithium, caffeine, alcohol). Diagnosis: clinical (ICSD-3 criteria). Polysomnography not required unless concern for PLMD, OSA, or other sleep disorder. Labs: ferritin, iron, TIBC, TSAT, CBC, B12, folate, Mg, creatinine, glucose. Treatment: FIRST-LINE — treat iron deficiency (ferrous sulfate 325 mg BID with vitamin C, IV iron if ferritin <50-100 and oral fails). Mild-moderate (infrequent, minimally bothersome): non-pharmacologic (exercise, avoid triggers [caffeine, alcohol, nicotine, antihistamines, SSRIs], massage, stretching, pneumatic compression), intermittent use of gabapentin 300-600 mg or pregabalin 150-300 mg. Moderate-severe (frequent, bothersome): alpha-2-delta ligands (gabapentin enacarbil 600 mg [gabapentin prodrug, FDA-approved], pregabalin, gabapentin) — preferred over dopaminergics due to lower risk of augmentation. Dopamine agonists (pramipexole 0.125-0.5 mg, ropinirole 0.5-4 mg) — effective but risk of augmentation (worsening of symptoms, earlier onset, spread to arms, shorter latency to onset after lying down, during daytime) and impulse control disorders. Rotigotine patch (1-3 mg/24h) has lower augmentation risk. If augmentation occurs: stop dopamine agonist, switch to alpha-2-delta ligand (gabapentinoid) or opioid (tramadol, oxycodone for severe refractory). Avoid opioids in opioid-naive patients due to risk. REM sleep behavior disorder (RBD): loss of REM atonia leading to dream enactment behavior (vocalizations, limb movements, complex behaviors [punching, kicking, sitting up, falling out of bed] corresponding to dream content [fighting, defending, running]). Often violent. Diagnosis: video-PSG (increased chin EMG tone + excessive limb jerking during REM). RBD is strongly associated with synucleinopathies (PD, DLB, MSA) — up to 50-80% of patients with idiopathic RBD develop a synucleinopathy within 10-15 years. Treatment: safety (padding bed, remove dangerous objects, put mattress on floor, lock windows and doors, bed partner sleep separately). First-line: clonazepam 0.25-1 mg qHS (effective in ~90%, but side effects: sedation, cognitive, falls, tolerance, abuse potential; avoid in OSA, dementia, elderly). Melatonin 3-15 mg qHS (safer, better tolerated, less side effects, may also reduce REM without atonia). Pramipexole (limited evidence). Avoid antidepressants (SSRIs, SNRIs, MAOIs, mirtazapine, TCAs) that can worsen or induce RBD.

The neurological exam is a systematic assessment of the nervous system, organized into 7 domains. Mental status: level of consciousness (AVPU, Glasgow Coma Scale: Eye [1-4] + Verbal [1-5] + Motor [1-6] = 3-15), orientation (person, place, time, situation), attention (digit span, serial 7s), language (fluency, comprehension [auditory and written], repetition, naming, reading, writing), memory (immediate recall, recent [5 min], remote), visuospatial (clock draw, cube copy, line bisection, neglect testing), executive function (Trail Making B, fluency [animals, F-words], Stroop). MoCA (Montreal Cognitive Assessment) screens cognition in 10 min (<26 = abnormal). MMSE is less sensitive (especially for frontal/executive). CN exam: CN I (olfaction, not routinely tested unless frontal lobe or head trauma), CN II (visual acuity [Snellen], visual fields by confrontation, fundoscopy [optic disc: papilledema vs atrophy, retinal vessels, hemorrhages, exudates], pupillary light reflex [direct and consensual, APD]), CN III/IV/VI (EOMs in 6 cardinal directions, saccades, smooth pursuit, convergence, nystagmus assessment), CN V (facial sensation 3 divisions [V1, V2, V3], motor: masseter/temporalis strength, jaw jerk reflex), CN VII (upper and lower face strength, taste anterior 2/3 of tongue if needed), CN VIII (hearing by finger rub/tuning fork, Weber and Rinne tests, check for nystagmus, vertigo), CN IX/X (palate elevation, gag reflex, swallowing, voice quality), CN XI (sternocleidomastoid and trapezius strength), CN XII (tongue protrusion, strength, fasciculations, atrophy). Motor: inspection (bulk: atrophy/hypertrophy, fasciculations, abnormal movements: tremor, chorea, dystonia, myoclonus, tics), tone (spasticity [clasp-knife, velocity-dependent, UMN], rigidity [cogwheel, lead-pipe, extrapyramidal, parkinsonism], paratonia/gegenhalten [frontal lobe], hypotonia [cerebellar, LMN, acute spinal shock]), power (MRC scale 0-5), coordination (Finger-to-nose, heel-to-shin, rapid alternating movements, dysmetria, dysdiadochokinesia, intention tremor), gait (normal, heel/toe/tandem walk, Romberg test). Sensory: spinothalamic (pain [pinprick], temperature, crude touch), dorsal column (vibration [128 Hz tuning fork], proprioception, fine touch, 2-point discrimination, graphesthesia, stereognosis, double simultaneous stimulation [extinction]). Reflexes: DTRs (biceps [C5/6], brachioradialis [C6], triceps [C7], patellar [L3/4], Achilles [S1]), Hoffman (C8, hyperreflexia = UMN, intrinsic hand muscle contraction with flicking of middle finger), Babinski (upgoing = UMN), clonus (>3 beats = UMN), primitive reflexes (frontal release signs: glabellar, snout, palmar-mental, grasp if diffuse frontal dysfunction). Localization is the clinical skill of determining where in the neuraxis the lesion is based on pattern of deficits: cortical (cognitive, aphasia, neglect, visual field cut, seizures), subcortical (pure motor/ sensory ± homonymous hemianopia, no cortical signs), brainstem (crossed signs: ipsilateral CN + contralateral motor/sensory, multiple CN, ataxia, Horner, diplopia, vertigo, nystagmus, dysarthria), spinal cord (sensory level, bilateral UMN below and LMN at level of lesion, Brown-Sequard, bladder/bowel), nerve root (dermatomal pain/sensory loss, myotomal weakness, reflex loss), PNS (stocking-glove, length-dependent, distal > proximal, areflexia, multifocal), NMJ (fluctuating, fatigable, ocular/bulbar/proximal, decremental RNS), muscle (proximal > distal, myopathic pattern on EMG, normal sensation, elevated CK, myopathic on needle EMG).

LP is performed for CSF analysis in suspected meningitis, encephalitis, SAH (xanthochromia), demyelinating (OCBs), Guillain-Barre (albuminocytologic dissociation), or elevated opening pressure (IIH). Contraindications: increased ICP with mass lesion (risk of herniation — do CT first if focal signs, papilledema, AMS, or immunocompromised), coagulopathy (INR >1.4, platelets <50K, therapeutic anticoagulation), local skin infection at puncture site, spinal cord compression, severe spinal stenosis. Technique: lateral decubitus (preferred for accurate opening pressure) or sitting (easier in obese). L3-L4 or L4-L5 interspace (Tuffier line between iliac crests = L4 spinous process or interspace). Clean with betadine/chlorhexidine, sterile gloves/drape. Local anesthesia: lidocaine 1%, skin and deeper tissues. Insert spinal needle with bevel parallel to longitudinal fibers (sagittal plane). Opening pressure measured with manometer (normal 10-20 cm H2O, 20-25 borderline, >25 = elevated). Collect 3-4 tubes: tube 1 = cell count (WBC, RBC, differential), tube 2 = protein and glucose (serum glucose simultaneous), tube 3 = microbiology (Gram stain, culture, sensitivity), tube 4 = special studies (OCBs, IgG index, cytology, flow cytometry, PCR, VDRL, etc.). Traumatic tap: distinguish by clearing from tube 1 to 4, CSF:blood WBC ratio ~1:500-700, presence of xanthochromia indicates SAH (supernatant after centrifugation, yellow from bilirubin, takes ~12h to develop). CSF findings: bacterial = high WBC (>1000, neutrophils), high protein (>150), low glucose (<40), Gram stain positive; viral = WBC 10-500 (lymphocytes), normal/mild protein, normal glucose; fungal = WBC lymphocytic, high protein, low glucose, cryptococcal antigen; TB = WBC lymphocytic, high protein, low glucose, AFB <20% sensitive, PCR; MS = OCBs (>=2 bands not in serum), elevated IgG index, mild lymphocytic pleocytosis, mildly elevated protein. Post-LP headache: due to CSF leak, positional (worse upright, better lying down), onset 12-48h after LP, risk factors (young, female, low BMI, use of cutting vs atraumatic needle, >1 attempt). Treatment: conservative (bed rest, fluids, caffeine, analgesics) for 24-48h; if persistent, epidural blood patch (10-20 mL autologous blood). Atraumatic needle (Sprotte, Whitacre) reduces PDPH rate to <5%.

CT: fast, widely available, excellent for hemorrhage (hyperdense acute blood, 24-72h), bone (fractures, sinus disease, calcification), screening for mass effect, hydrocephalus, and large structural lesions. Non-contrast CT: acute ischemic stroke (hyperdense artery sign [MCA, basilar] within hours, loss of gray-white differentiation, sulcal effacement), ICH (hyperdense, perilesional edema, mass effect), SAH (hyperdense cisterns/sulci within 24h, sensitivity >95% in first 6h), fractures, sinusitis. CT angiography (CTA): vascular anatomy (circle of Willis, carotid/vertebral arteries), stenosis, occlusion (LVO), dissection (intimal flap, string sign, double lumen), aneurysm. CT perfusion: evaluates ischemic penumbra vs core (CBF, CBV, MTT, Tmax), extends thrombolysis/thrombectomy window. MRI: superior soft tissue contrast, better sensitivity for pathology. T1-weighted: anatomy, structural lesions, post-contrast enhancement (blood-brain barrier breakdown: tumor, infection, inflammation, demyelination). T2-weighted: edema, demyelination, chronic infarction, most pathology is T2 hyperintense. FLAIR (T2 with CSF suppression): periventricular/juxtacortical lesions (MS, small vessel disease, vasogenic edema), subarachnoid/cisternal pathology (SAH, meningitis). DWI (diffusion-weighted): acute infarction (restricted diffusion = bright within minutes, correlates with ADC dark = true restriction vs T2 shine-through), abscess (restricted), epidermoid (restricted), lymphoma (restricted). SWI/GRE: hemorrhage (microbleeds, hemosiderin, cavernous malformation, CAA, DAI), calcifications. Post-contrast T1: tumor, infection, inflammation, autoimmune (active MS plaques, infection), metastatic. MRA (time-of-flight, contrast-enhanced): vascular anatomy, stenosis, aneurysm, dissection. MRV: dural venous sinus thrombosis (T2 hyperintense, GRE susceptibility, filling defect). Indications for contrast: tumor, infection/inflammation (meningitis, encephalitis, abscess), active demyelination (enhancing = active), post-surgical evaluation. Gadolinium: risk of NSF in ESRD (avoid in dialysis, GFR <30, recent transplant, severe hepatic disease). Preference for macrocyclic GBCA (gadoterate meglumine, Dotarem) over linear agents (lower gadolinium deposition in brain/bone). Functional MRI (fMRI): maps eloquent cortex (language, motor, sensory) for presurgical planning. MR spectroscopy (MRS): metabolite peaks (NAA [neuronal integrity, decreased in tumor/dementia], choline [cell membrane turnover, increased in tumor], creatine [energy metabolism, internal reference], lactate [anaerobic metabolism, tumor, ischemia, mitochondrial], lipids [necrosis], myo-inositol [glial marker, increased in AD, low in tumor]). MR perfusion: CBV, CBF, MTT distinguishes tumor (high CBV) from radiation necrosis/abscess (low CBV). PET: FDG hypometabolism (AD temporoparietal, FTD frontotemporal), hypermetabolism (tumor). Amyloid and tau PET for AD. DaTscan (FP-CIT SPECT): dopamine transporter in striatum, distinguishes Parkinson disease (asymmetric decreased) from essential tremor (normal), DLB from AD.

EEG: records cortical electrical activity from scalp electrodes (10-20 system). Indications: seizure/epilepsy (interictal epileptiform discharges: spikes, sharp waves, polyspikes, spike-wave, PLEDs, periodic discharges), status epilepticus (continuous ictal activity), encephalopathy (diffuse slowing, triphasic waves in metabolic/toxic, burst suppression in anoxia/barbiturate coma), brain death (electrocerebral silence, no reactivity >30 min, no EKG artifact from cortex, lack of all brainstem reflexes, no confounding factors: hypothermia <36C, drugs, severe metabolic). Normal sleep/wake cycling, sleep stages (N1-N3, REM). Normal variants (wicket spikes, BETS, POSTS, lambda waves, mu rhythm). Prolonged monitoring for seizure detection in EMU, ICU cEEG for NCSE. EMG/NCS: evaluates neuromuscular junction, nerve (conduction velocity, amplitude, latency), muscle (MUAP morphology, recruitment, spontaneous activity). NCS: motor (stimulate at 2 or more points along nerve, record CMAP amplitude, distal latency, conduction velocity, F-wave), sensory (antidromic or orthodromic, SNAP amplitude, distal latency, conduction velocity). Abnormalities: demyelinating (prolonged distal latencies, slowed CV <70% normal, conduction block, temporal dispersion, prolonged F-waves), axonal (reduced CMAP/SNAP amplitudes, normal or near-normal CV). EMG needle exam: insertional activity, spontaneous activity (fibrillations, positive sharp waves, fasciculations, myotonic discharges, CRDs), MUAP morphology and recruitment. Patterns: neurogenic (large MUAPs, reduced recruitment, increased jitter, fibrillation/PSWs -> reinnervation), myopathic (small polyphasic MUAPs, full recruitment, early recruitment, no spontaneous activity except inflammatory myopathy [fibrillations/PSWs]), NMJ (MG: decrement on RNS 2-5 Hz, increased jitter on SFEMG; LEMS: increment >100% on high-rate or post-exercise), myotonia (repetitive discharges waxing/waning frequency, myotonic dystrophy, myotonia congenita, paramyotonia, channelopathies). Autonomic testing: heart rate variability to deep breathing (parasympathetic), Valsalva ratio, quantitative sudomotor axon reflex test (QSART), thermoregulatory sweat test (TST), tilt-table test for orthostatic hypotension. Skin biopsy: 3mm punch biopsy at distal leg and thigh, stained with PGP9.5, quantifies intraepidermal nerve fiber density (IENFD) for small fiber neuropathy diagnosis.

Coma: state of unarousable unresponsiveness (no eye opening to stimulation, no appropriate motor response, no meaningful response to commands, no language output). Glasgow Coma Scale (E1-4 + V1-5 + M1-6 = 3-15). Etiologies (I WATCH DEATH): Infection (meningitis, encephalitis, abscess), Withdrawal/ Wernicke encephalopathy, acute metabolic (hyponatremia, hypercalcemia, hepatic encephalopathy, uremic encephalopathy, CO2 narcosis, thyroid/ adrenal), Trauma (subdural/epidural hematoma, contusion, DAI), CNS pathology (stroke, SAH, ICH, tumor, hydrocephalus, demyelination), Hypoxia/ischemia (cardiac arrest, shock, severe hypotension), Deficiencies (thiamine, niacin, B12, pyridoxine), Endocrinopathies (diabetic: DKA, HHS, hypoglycemic), Acute vascular (malignant HTN, posterior reversible encephalopathy syndrome [PRES], reversible cerebral vasoconstriction syndrome [RCVS]), Toxins/drugs (opioids, benzodiazepines, barbiturates, alcohol, carbon monoxide, cyanide, solvents, lithium, anticonvulsants, TCAs, salicylates), Heavy metals / Hashimoto encephalopathy (SREAT/steroid-responsive encephalopathy associated with autoimmune thyroiditis). Initial management: stabilize ABCs, check fingerstick glucose (D50W if hypoglycemic or Wernicke: thiamine 100 mg IV before glucose), check oxygen saturation, BP (hypotensive, hypertensive, treated accordingly), temperature (hyperthermia, hypothermia), full bloodwork, tox screen, CT head (blood, mass, stroke), if suspicion for infection -> LP (after CT), if no cause and stroke pattern -> MRI, MRA, MRV. Brain death determination (AAN guidelines): prerequisites (known catastrophic brain injury, no confounding factors: hypothermia <36C, drugs, severe electrolyte/acid-base/endocrine, severe shock, locked-in syndrome, Guillain-Barre, botulism, organophosphate poisoning). Clinical examination: no pupillary light reflex (midposition or dilated, fixed 4-9mm), no corneal reflex, no oculocephalic (doll's eyes) and no oculovestibular (caloric) reflex, no gag reflex, no cough reflex to deep suctioning, no motor response to painful stimuli (corticothalamic, no spinal reflexes), no respiratory drive on apnea test (PaCO2 >=60 or >20 above baseline, no respiratory effort). Ancillary testing (if clinical exam cannot be completed, or apnea test cannot be performed): cerebral angiography (no intracranial flow), nuclear medicine (Tc-99m HMPAO scan: no cerebral perfusion), EEG (electrocerebral silence for 30 min), transcranial Doppler (diastolic flow reversal or small systolic peaks without diastolic flow). Two separate examinations (by attending, ideally 2) separated by at least 6 hours (12-24h in children). Documentation per hospital policy and state law. Family discussion: compassionate communication, support, options for organ donation.