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• Headaches Cluster: - Unilateral- 15 mins-3 hours; repetitive- Excruciating periorbital pain ("suicide headache") with lacrimation and rhinorrhea. - May present with Horner syndrome.- Treatment: Acute sumatriptan, 100% O2. - Prophylaxis: verapamil. Tension: - Bilateral- >30 min (typically 4-6 hours); constant- Steady, "band-like" pain. No photophobia or phonophobia. No aura.- Treatment: Analgesics, NSAIDs, acetaminophen; amitriptyline for chronic pain. Migraine: - Unilateral- 4-72 hours- Pulsating pain with nausea, photophobia, or phonophobia. May have aura. - Due to irritation of CN V, meninges, or blood vessels (release of substance P, CGRP, vasoactive peptides).- Treatment: Acute NSAIDs, triptans, dihydroergotamine.- Prophylaxis: Lifestyle changes (eg, sleep, exercise, diet), β-blockers, amitryptyline, topiramate, valproate.
• Alzheimer disease Most common cause of dementia in elderly. Down syndrome patients have ↑ risk of developing Alzheimer disease, as APP is located on chromosome 21.- ↓ ACh Associated with the following altered proteins:- ApoE-2: ↓ risk of sporadic form- ApoE-4: ↑ risk of sporadic form- APP, presenilin-1, presenilin-2: familial forms (10%) with earlier onset - Widespread cortical atrophy, especially hippocampus. - Narrowing of gyri and widening of sulci. - Senile plaques in gray matter: extracellular β-amyloid core; may cause amyloid angiopathy → intracranial hemorrhage; Aβ (amyloid-β) synthesized by cleaving amyloid precursor protein (APP).- Neurofibrillary tangles: intracellular, hyperphosphorylated tau protein = insoluble cytoskeletal elements; number of tangles correlates with degree of dementia.
• Frontotemporal dementia (Pick disease) Early changes in personality and behavior (behavioral variant), or aphasia (primary progressive aphasia). - May have associated movement disorders (eg, parkinsonism). - Frontotemporal lobe degeneration.- Inclusions of hyperphosphorylated tau (round Pick bodies) or ubiquinated TDP-43.
• Lewy body dementia Visual hallucinations, dementia with fluctuating cognition/alertness, REM sleep behavior disorder, and parkinsonism. Called Lewy body demenia if cognitive and motor symptom onset <1 year apart, otherwise considered dementia 2° to Parkinson disease. - Intracellular Lewy bodies primarily in cortex.
• Vascular dementia Result of multiple arterial infarcts and/or chronic ischemia. - Step-wise decline in cognitive ability with late-onset memory impairment. - 2nd most common cause of dementia in elderly. - MRI or CT shows multiple cortical and/or subcortical infarcts.
• Creutzfeldt-Jakob disease Rapidly progressive (weeks to months) dementia with myoclonus ("startle myoclonus") and ataxia. - Commonly see periodic sharp waves on EEG and ↑ 14-3-3 protein in CSF. - Spongiform cortex. - Prions (PrPc → PrPsc sheet [β-pleated sheet resistant to proteases])
• Idiopathic intracranial hypertension (Pseudotumor cerebri) ↑ ICP with no apparent cause on imaging (eg, hydrocephalus, obstruction of CSF outflow). Risk factors include female gender, obesity, vitamin A excess, tetracyclines, danazol. Findings: - Headache- Tinnitus- Diplopia (usually from CN VI palsy)- No change in mental status- Impaired optic nerve axoplasmic flow → papilledema seen on fundoscopy- Visual field testing shows enlarged blind spot and peripheral constriction.- Lumbar puncture reveals ↑ opening pressure and provides temporary headache relief. Treatment: weight loss, acetazolamide, topiramate, invasive procedures for refractory cases (eg, CSF shunt placement, optic nerve sheath fenestration surgery for visual loss).
• Hydrocephalus ↑ CSF volume → ventricular dilation +/- ↑ ICP Communicating:- Communicating hydrocephalus: ↓ CSF absorption by arachnoid granulations (eg, arachnoid scarring post-meningitis) → ↑ ICP, papilledema, herniation.- Normal pressure hydrocephalus: Affects the elderly; idiopathic; CSF pressure elevated only episodically; does not result in increased subarachnoid space volume. Expansion of ventricles distorts the fibers of the corona radiata → triad of urinary incontinence, gait apraxia (magnetic gait), and cognitive dysfuncion (sometimes reversible). Symptoms potentially reversible with CSF shunt placement. Noncommunicating (obstructive) hydrocephalus: Caused by structural blockage of CSF circulation within ventricular system (eg, stenosis of aqueduct of Sylvius; colloid cyst blocking foramen of Monro; tumor). Hydrocephalus mimics:- Ex vacuo ventriculomegaly: Appearance of ↑ CSF on imaging, but is actually due to ↓ brain tissue and neuronal atrophy (eg, Alzheimer disease, advanced HIV, Pick disease, Huntington disease). ICP is normal; NPH triad is not seen.
• Metachromatic leukodystrophy Autosomal recessive lysosomal storage disease, most commonly due to arylsulfatase A deficiency. Buildup of sulfatides --> impaired production and destruction of myelin sheath.  Findings: central and peripheral demyelination with ataxia, dementia.
• Krabbe disease Autosomal recessive lysosomal storage disease due to deficiency of galactocerebrosidase. Buildup of galactocerebroside and psychosine destroys myelin sheath. Findings: peripheral neuropathy, developmental delay, optic atrphy, globoid cells.
• Charcot-Marie-Tooth disease Also known as hereditary motor and sensory neuropathy (HMSN). Group of hereditary nerve disorders related to the defective production of proteins involved in the structure and function of peripheral nerves or the myelin sheath. Typically autosomal dominant inheritance pattern and associated with foot deformities (eg, pes cavus, hammer toe), lower extremity weakness (eg, foot drop), atrophy of the calf muscles ("stork leg") and sensory deficits.- Nerve conduction studies: ↓ impulse conduction velocity Most common type, CMT1A, is caused by PMP22 gene duplication (a myelin protein gene).
• Acute disseminated (postinfectious) encephalomyelitis Multifocal inflammation and demyelination after infection or vaccination. Presents with rapidly progressive multifocal neurologic symptoms, altered mental status. Symptoms often resolve spontaneously after several months.
• Adrenoleukodystrophy X-linked genetic disorder typically affecting males. Disrupts metabolism of very-long-chain fatty acids → excessive buildup in nervous system, adrenal gland, testes. Progessive disesae that can lead to long-term coma/death and adrenal gland crisis.
• Neurofibromatosis Type I (von Recklinghausen disease)- Mutation in NF1 tumor suppressor gene on chromosome 17 (17 letters in "von Recklinghausen"), which normally codes for neurofibromin, a negative regulator of RAS.- Autosomal dominant, 100% penetrance.- Café-au-lait spots, cutaneous neurofibromas, optic gliomas, pheochromocytomas, Lisch nodules (pigmented iris hamartomas). Type II:- Mutation in NF2 tumor suppressor gene on chromosome 22.- Autosomal dominant.- Bilateral acoustic schwannomas, juvenile cataracts, meningiomas, and ependymomas.NF2 affects 2 ears, 2 eyes, and 2 parts of the brain.
• von Hippel-Lindau disease Deletion of VHL gene on chromosome 3p (VHL = 3 letters).- Autosomal dominant.- pVHL ubiquinates hypoxia-inducible factor 1a. - Characterized by development of numerous tumors, both benign and malignant.- Hemangioblastomas (high vascularity with hyperchromatic nuclei) in retina, brain stem, cerebellum, spine.- Angiomatosis (eg, cavernous hemangiomas in skin, mucosa, organs).- Bilateral renal cell carcinomas- Pheochromocytomas
• Hemangioblastoma - Most often cerebellar.- Associated with von Hippel-Lindau syndrome when found with retinal angiomas. - Can produce erythropoietin → 2° polycythemia. - Patients often have seizures.- Lesions have tendency to bleed. - Blood vessel origin. - Closely arranged, thin-walled capillaries with minimal intervening parenchyma.
• Pituitary adenoma Adenoma may be nonfunctioning (silent) or hyperfunctioning (hormone producing). - Most commonly from lactotrophs (prolactinoma) → hyperprolactinemia- Less commonly adenoma of somatotrophs (GH) → acromegaly/gigantism; corticotrophs (ACTH) → Cushing disease. - Rarely, adenoma of thyrotrophs (TSH) and gonadotroph (FSH, LH). - Nonfunctional tumors present with mass effect (bilateral hemianopia, hypopituitarism, headache).- Bitemporal hemianopia due to pressure on optic chiasm.- Sequelae include hyper- or hypopituitarism, which may be caused by pituitary apoplexy.
• Schwannoma Classically at the cerebellopontine angle involving both CN VII and VIII, but can be along any peripheral nerve. - Often localized to CN VIII in internal acoustic meatus → vestibular schwannoma. - Bilateral vestibular schwannomas found in NF-2. - Resection or stereotactic radiosurgery. - Schwann cell origin, S-100 ⊕. Biphasic.- Dense, hypercellular areas containing spindle cells alternating with hypocellular, myxoid areas.- Verocay bodies composed of eosinophilic cores (Antoni A pattern).
• Herniation syndromes Cingulate (subfalcine) herniation under falx cerebri → Can compress anterior cerebral artery. Transtentorial (central/downward) herniation → Caudal displacement of brain stem → rupture of paramedian basilar artery branches → Duret hemorrhages. Usually fatal. Uncal herniation: - Uncus = medial temporal lobe→ Herniation compresses unilateral CN III (blown pupil, "down-and-out" gaze) and contralateral crus cerebri against Kernohan notch (causes contralateral CN III palsy and/or ipsilateral hemiparesis; ie, a false localizing sign). Cerebellar tonsillar herniation into the foramen magnum→ Coma and death result when these herniations compress the brain stem.
• Motor neuron signs Upper motor neuron lesion:- Weakness: +- Atrophy: -- Fasciculations: -- Reflexes: ↑- Tone: ↑- Babinski: + (physiologic in infants up to 1 year)- Spastic paresis: +- Flaccid paresis: - - Clasp knife spasticity: + Lower motor neuron lesion:- Weakness: +- Atrophy: +- Fasciculations: +- Reflexes: ↓- Tone: ↓- Babinski: -- Spastic paresis: -- Flaccid paresis: +- Clasp knife spasticity: -
• Amyotrophic lateral sclerosis (Lou Gehrig disease) Combined UMN (corticobulbar/corticospinal) and LMN (medullary and spinal cord) degeneration. - No sensory or bowel/bladder deficits. - Can be caused by defect in superoxidase dismutase 1. - LMN deficits due to anterior horn cell involvement (eg, dysarthria, dysphagia, asymmetric limb weakness, fasciculations, atrophy) - UMN deficits (pseudobulbar palsy, eg, dysarthria, dysphagia, emotional lability, spastic gait, clonus).- Fatal. Treatment: Riluzole
• Complete occlusion of anterior spinal artery - Spares dorsal columns and Lissauer tract.- Mid-thoracic ASA territory is watershed area, as artery of Ademkiewicz supplies ASA below T8. - Can be caused by aortic aneurysm repair. - UMN deficit below the lesion (corticospinal tract).- LMN deficit at the level of the lesion (anterior horn).- Loss of pain and temperature sensation below the lesion (spinothalamic tract).
• Tabes dorsalis - Caused by 3° syphilis. - Results from degeneration (demyelination) of dorsal columns and roots → progressive sensory ataxia (impaired proprioception → poor coordination). - ⊕ Romberg sign and absent DTRs. - Associated with Charcot joints, lancinating pain (sharp, shooting pain that may last minutes to hours), Argyll Robertson pupils.
• Vitamin B12 deficiency Subacute combined degeneration (SCD) – demyelination of spinocerebellar tracts, lateral corticospinal tracts (vs Tabes dorsalis), and dorsal columns. Ataxic gait, paresthesia, impaired position/vibration sense.
• Cauda equina syndrome Compression of spinal roots from L2 and below, often due to intravertebral disk herniation or tumor. - Unilateral radicular pain- Absent knee and ankle reflex- Loss of bladder and anal sphincter control- Saddle anesthesia. Treatment: Emergent surgery and steroids.
• Poliomyelitis Caused by poliovirus (fecal-oral transmission). Replicates in oropharynx and small intestine before spreading via bloodstream to CNS. Infection causes destruction of cells in anterior horn of spinal cord (LMN death). - Signs of LMN lesion: asymmetric weakness (vs Werdnig Hoffman, SMA), hypotonia, flaccid paralysis, fasciculations, hyporeflexia, muscle atrophy. Respiratory muscle involvement leads to respiratory failure.- Signs of infection: malaise, headache, fever, nausea, etc. - CSF shows ↑ WBCs (lymphocytic pleocytosis) and slight ↑ of protein (with no change in CSF glucose). Virus recovered from stool or throat.
• Brown-Séquard syndrome Hemisection of spinal cord. Findings:- Ipsilateral loss of all sensation at level of lesion- Ipsilateral LMN signs at level of lesions- Ipsilateral UMN signs below level of lesion (due to corticospinal tract damage)- Ipsilateral loss of proprioception, vibration, light touch, and tactile sense below level of lesion (due to dorsal column damage)- Contralateral pain, temperature and crude (non-discriminative) touch below level of lesion (due to spinothalamic tract damage) If lesion occurs above T1, patient may present with ipsilateral Horner syndrome due to damage of oculosympathetic pathway.
• Friedreich ataxia Autosomal recessive trinucleotide repeat disorder (GAA)n on chromosome 9 in gene that encodes frataxin (iron binding protein).- Leads to impairment in mitochondrial functioning. - Degeneration of lateral corticospinal tract (spastic paralysis), spinocerebellar tract (ataxia), dorsal columns (↓ vibratory sense, proprioception), dorsal root ganglia (loss of DTRs).- Staggering gait, frequent falling, nystagmus, dysarthria, pes cavus, hammer toes, diabetes mellitus, hypertrophic cardiomyopathy (cause of death). - Presents in childhood with kyphoscoliosis.
• Facial nerve lesions Upper motor neuron lesion: Destruction of motor cortex or connection between motor cortex and facial nucleus in pons --> contralateral paralysis of lower muscles of facial expression. Forehead is spared due to its bilateral UMN innervation. Lower motor neuron lesion: Destruction of facial nucleus or CN VII anywhere along its course --> ipsilateral paralysis of upper and lower muscles of facial expression, hyperacusis, loss of taste sensation to anterior tongue.- When idiopathic (most common), facial nerve palsy is called Bell palsy. May also be caused by Lyme disease, herpes simplex, herpes zoster (Ramsay Hunt syndrome), sarcoidosis, tumors (eg, parotid gland), diabetes mellitus. Treatment is corticosteroids, acyclovir. 
• Regional specification of developing brain Prosencephalon (forebrain)→ Telencephalon → Cerebral hemispheres, lateral ventricles→ Diencephalon → Thalamus, hypothalamus, third ventricle Mesencephalon (midbrain) → Mesencephalon → Midbrain, cerebral aqueduct Rhombencephalon (hindbrain) → Metencephalon → Pons, cerebellum, upper part of forth ventricle→ Myelencephalon → Medulla, lower part of forth ventricle
• Tongue development 1st and 2nd branchial arches form anterior 2/3 (thus sensation via CN V3, taste via CN VII).3rd and 4th branchial arches form posterior 1/3 (thus sensation and taste mainly via CN IX, extreme posterior via CN X). Motor innervation is via CN XII to hyoglossus (retracts and depresses tongue), genioglossus (protrudes tongue), and styloglossus (draws sides of tongue upward to create a trough for swallowing).Motor innervation is via CN X to palatoglossus (elevates posterior tongue during swallowing).
• Neurons Signal-transmitting cells of the nervous system. - Permanent cells – do not divide in adulthood.- Signal-relaying cells with dendrites (receive input), cell bodies, and axons (send output).- Cell bodies and dendrites can be seen on Nissl staining (stains RER).- RER is not present in the axon. Injury to axon → Wallerian degeneration – degeneration of axon distal to site of injury and axonal retraction proximally; allows for potential regeneration of axon (if in PNS). Macrophages remove debris and myelin.
• Astrocytes Most common glial cell type in CNS. Physical support, repair, extracellular K+ buffer, removal of excess neurotransmitter, component of blood-brain barrier, glycogen fuel reserve buffer. - Reactive gliosis in response to neural injury. - Derived from neuroectoderm. - Astrocyte marker: GFAP.
• Microglia Phagocytic scavenger cells of CNS (mesodermal, mononuclear origin).  - Activated in response to tissue damage. - Not readily discernible by Nissl stain. - HIV-infected microglia fuse to form multinucleated giant cells in CNS.
• Ependymal cells Glial cells with a ciliated simple columnar form that line the ventricles and central canal of spinal cord.  Apical surfaces are covered in cilia (which circulate CSF) and microvilli (which help in CSF absorption).
• Schwann cells and oligodendrocytes Schwann cells: Each Schwann cell myelinates only 1 PNS axon. Also promote axonal regeneration. Derived from neural crest. - Injured in Guillain-Barré syndrome. Oligodendrocytes: Each oligodendrocyte can myelinate many axons (~30) in CNS. Predominant type of glial cell in white matter. Derived from neurectoderm. "Fried egg" appearance histologically. - Injured in multiple sclerosis, progressive multifocal lymphencephalopathy (PML), leukodystrophies.
• Peripheral nerve Endoneurium – invests single nerve fiber layers (inflammatory infiltrate in Guillain-Barré syndrome). Perineurium (blood-nerve permeability barrier) – surrounds a fascicle of nerve fibers. Must be rejoined in microsurgery for limb reattachment. Epineurium – dense connective tissue that surrounds entire nerve (fascicles and blood vessels).
• Chromatolysis Reaction of neuronal cell body to axonal injury. Changes reflect ↑ protein synthesis in effort to repair the damaged axon. Characterized by:- Round cellular swelling- Displacement of the nucleus to the periphery- Dispersion of Nissl substance throughout cytoplasm Concurrent with Wallerian degeneration.
• Neurotransmitter changes with disease Acetylcholine:- Location of synthesis: Basal nucleus of Meynert- ↓ Alzheimer disease, Huntington disease- ↑ Parkinson disease Dopamine:- Location of synthesis: Ventral tegmentum, substantia nigra compacta- ↓ Depression, Parkinson disease- ↑ Schizophrenia, Huntington disease GABA:- Location of synthesis: Nucleus accumbens- ↓ Anxiety, Huntington disease Norepinephrine:- Location of synthesis: Locus ceruleus- ↑ Anxiety- ↓ Depression Serotonin: Raphe nucleus- ↓ Anxiety, depression, Parkinson disease
• Meninges Three membranes that surround and protect the brain and spinal cord:- Dura mater – thick outer layer closest to skull. Derived from mesoderm.- Arachnoid mater – middle layer, contains web-like connection. Derived from neural crest.- Pia mater – thin, fibrous inner layer that firmly adheres to brain and spinal cord. Derived from neural crest. CSF flows in the subarachnoid space, located between arachnoid and pia mater. Epidural space – a potential space between the dura mater and skull containing fat and blood vessels.
• Vomiting center Coordinated by nucleus tractus solitarius (NTS) in the medulla, which receives information from the chemoreceptor trigger zone (CTZ, located within area postrema in 4th ventricle), GI tract (via vagus nerve), vestibular system, and CNS. CTZ and adjacent vomiting center nuclei receive input from 5 major receptors: muscarinic (M1), dopamine (D2), histamine (H1), serotonin (5-HT3), and neurokinin (NK-1) receptors.- 5-HT3, D2, and NK-1 antagonists used to treat chemotherapy-induced vomiting.- M1 and H1 antagonists used to treat motion sickness and hyperemesis gravidarum.
• Cerebral perfusion Brain perfusion relies on tight autoregulation. Cerebral perfusion is primarily driven by PCO2 (PO2 also modulates perfusion in severe hypoxia). Cerebral perfusion relies on a pressure gradient between mean arterial pressure (MAP) and ICP. ↓ blood pressure or ↑ ICP → ↓ cerebral perfusion pressure (CPP). Therapeutic hyperventilation → ↓ PCO2 → vasoconstriction → ↓ cerebral blood flow → ↓ intracranial pressure (ICP). May be used to treat acute cerebral edema (eg, 2° to stroke) unresponsive to other interventions. CPP = MAP - ICP. If CPP = 0, there is no cerebral perfusion → brain death. Hypoxemia increases CPP only if PO2 <50 mmHg.CPP is directly proportional to PCO2 until PCO2 >90 mmHg.
• Watershed zones Between anterior cerebral/middle cerebral, posterior cerebral/middle cerebral arteries (cortical border zones); or may occur between the superficial and deep vascular territories of the middle cerebral artery (internal border zones). Damage by severe hypotension → proximal upper and lower extremity weakness (if internal border zone stroke), higher order visual dysfunction (if posterior cerebral/middle cerebral cortical border zone stroke).
• Dural venous sinuses Large venous channels that run through the periosteal and meningeal layers of the dura mater. Drain blood from cerebral veins and receive CSF from arachnoid granulations. Empty into internal jugular vein. Venous sinus thrombosis – presents with signs/symptoms of ↑ ICP (eg, headache, seizures, focal neurologic deficits). May lead to venous hemorrhage. Associated with hypercoagulable states (eg, pregnancy, OCP use, factor V Leiden).
• Cranial nerve nuclei Located in tegmentum portion of brain stem (between dorsal and ventral portions):- Midbrain – nuclei of CN III, IV- Pons – nuclei of CN V, VI, VII, VIII- Medulla – nuclei of CN IX, X, XII- Spinal cord – nucleus of CN XI Lateral nuclei = sensory (alar plate)–Sulcus limitans–Medial nuclei = motor (basal plate)
• Cranial nerve and vessel pathways Anterior cranial fossa:- Cribriform plate – CN I Middle cranial fossa (through sphenoid bone):- Optic canal – CN II, ophthalmic artery- Superior orbital fissure – CN III, IV, VI, CN V1- Foramen rotundum – CN V2- Foramen ovale – CN V3- Foramen spinosum – Middle meningeal artery Posterior cranial fossa (through temporal or occipital bone):- Internal auditory meatus: CN VII, VIII- Jugular foramen: CN IX, X, XI, jugular vein- Hypoglossal canal: CN XII- Foramen magnum: Brain stem, spinal root of CN XI, vertebral arteries
• Mastication muscles 3 muscles close jaw: masseter, temporalis, medial pterygoid1 muscle opens jaw: lateral pterygoid All are innervated by trigeminal nerve (V3).
• Ascending tracts Dorsal column:- Pressure, vibration, fine touch, proprioception- 1st-order neuron: Sensory nerve ending → bypass pseudounipolar cell body in dorsal root ganglion → enter spinal cord → ascend ipsilaterally in dorsal columns- Synapse 1: Nucleus gracilis, nucleus cuneatus (ipsilateral medulla)- 2nd order neuron: Decussates in medulla → ascends contralaterally as the medial lemniscus Spinothalamic tract:- Lateral: pain, temperature- Anterior: crude touch, pressure- 1st order neuron: Sensory nerve endings (Aδ and C fibers) → bypass pseudounipolar cell body in dorsal root ganglion → enter spinal cord- Synapse 1: Ipsilateral gray matter (spinal cord)- 2nd order neuron: Decussates in spinal cord as the anterior white commissure → ascends contralaterally → VPL (thalamus) → sensory cortex
• Descending tract Lateral corticospinal tract- Voluntary movement of contralateral limbs- 1st order neuron: UMN: cell body in 1° motor cortex → descends ipsilaterally (through posterior limb of internal capsule), most fibers decussate at caudal medulla (pyramidal decussation) → descends contralaterally- Synapse 1: Cell body of anterior horn (spinal cord)- 2nd order neuron: LMN: leaves spinal cord- NMJ → muscle fibers
• Ischemic stroke Acute blockage of vessels → disruption of blood flow and subsequent ischemia → liquefactive necrosis. 3 types:- Thrombotic – due to a clot forming directly at site of infarction (commonly the MCA), usually over an atherosclerotic plaque.- Embolic – embolus from another part of the body obstructs vessel. Can affect multiple vascular territories. Examples: atrial fibrillation, carotid artery stenosis, DVT with patent foramen ovale.- Hypoxic – due to hypoperfusion or hypoxemia. Common during cardiovascular surgeries, tends to affect watershed areas. Treatment: tPA (if within 3-4.5 hr of onset and no hemorrhage/risk of hemorrhage). Reduce risk with medical therapy (eg, aspirin, clopidogrel); optimum control of blood pressure, blood sugars, lipids; and treat conditions that ↑ risk (eg, atrial fibrillation, carotid artery stenosis). 

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