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Calcium links electrical excitation to contraction, although the source of the signal and the proteins that interpret it differ between muscle types. In skeletal muscle the dihydropyridine receptor on the T-tubule is a voltage sensor, not a channel. When the membrane depolarises, it mechanically opens the ryanodine receptor RyR1, and calcium pours from the sarcoplasmic reticulum onto troponin C. Smooth muscle reads the same signal differently: calcium binds calmodulin, which activates myosin light chain kinase, and the phosphatase relaxes. At the neuromuscular junction the receptor is nicotinic, and it is this receptor that myasthenic antibodies attack.

Visceral and somatic afferents share second-order neurons in the spinal cord, not the medulla, so the brain assigns visceral pain to the skin. Gallbladder and diaphragmatic irritation travel with the phrenic nerve, C3 to C5, and are felt in the right shoulder. Cardiac ischaemia shares T1 to T4 and radiates to the left arm and jaw. Taste travels with the seventh, ninth and tenth nerves, never the trigeminal. Only nasal retinal fibres cross at the chiasm, which is why a pituitary tumour produces bitemporal hemianopia.

Acute loss of vision in one eye is sorted by three questions: is it painful, how old is the patient, and what does the disc show? A young adult with pain on eye movement, red desaturation and a relative afferent pupillary defect has optic neuritis. In about two-thirds the lesion is retrobulbar, so a normal disc excludes nothing. Painless sudden loss in an older patient points to vascular occlusion: a cherry-red spot in arterial occlusion, a blood-and-thunder fundus in venous occlusion. Temporal headache, jaw claudication and a high ESR after fifty mean giant cell arteritis, and corticosteroids are started before the biopsy, because the other eye will not wait.

The Optic Neuritis Treatment Trial fixed two rules. Intravenous methylprednisolone hastens recovery and delays a second demyelinating event, whereas standard-dose oral prednisone alone increases the recurrence rate and is therefore forbidden. Final acuity is similar whatever is given. The MRI, not the steroid, determines the future. With no white matter lesions the fifteen-year risk of multiple sclerosis is about 25 per cent; with one or more lesions it is about 72 per cent.

Pure abduction belongs to the lateral rectus and the sixth nerve; depression in adduction belongs to the superior oblique and the fourth nerve. A hypermetropic child accommodates at every distance, over-converges and develops accommodative esotropia, for which full hypermetropic spectacles, not surgery, are the first treatment. The sixth nerve runs the longest intracranial course, hugging the clivus, so raised intracranial pressure or a posterior fossa tumour compresses it first. An older diabetic with a sixth nerve palsy may be observed for about three months, but a child needs imaging at once. Bilateral palsies suggest idiopathic intracranial hypertension, and myasthenia may present with one drooping eyelid alone, worse by evening.

The central distinctions can be recalled as follows.

All young adults with painful monocular visual loss and an afferent pupillary defect receive intravenous methylprednisolone, never standard-dose oral prednisone alone.
Is the loss painless, sudden and in an older patient? Think arterial or venous occlusion, and treat suspected giant cell arteritis with steroids before biopsy.
On the spinal cord, not the medulla, visceral and somatic afferents converge, which is why gallbladder pain surfaces in the right shoulder.
Lucid rule for the sixth nerve: an older diabetic may be observed for three months, but a child is imaged today.

The clinical effects of a spinal cord lesion become clearer when the major ascending and descending pathways are related to the levels at which they cross. The lateral corticospinal tract has already decussated in the medullary pyramids, so within the cord it serves the same side. The dorsal columns, carrying proprioception and vibration, also cross in the medulla and are ipsilateral. The spinothalamic tract carries pain and temperature and crosses within one or two segments of entry, so within the cord it is contralateral. Within the corticospinal tract the arm fibres lie medially and the leg fibres laterally. A central contusion from hyperextension in a degenerate neck therefore weakens the arms more than the legs.

Brown-Séquard hemisection removes ipsilateral power and proprioception and contralateral pain and temperature from one or two segments below. Anterior cord infarction removes power and pain but spares the posteriorly supplied dorsal columns. Syringomyelia cuts the crossing spinothalamic fibres centrally, producing a cape of dissociated sensory loss with preserved touch. Jefferson is a C1 burst from axial loading, type II odontoid fractures are the commonest and least likely to unite, and Hangman is bilateral C2 pars fracture from hyperextension.

Acute care begins with airway, breathing, circulation and immobilisation, then CT for bone and MRI for cord oedema, haematoma and ligament. Neurogenic shock is haemodynamic: injury above T6 severs sympathetic outflow while the vagus persists, producing hypotension with bradycardia and warm skin. Vasopressors, not fluid alone, maintain a mean arterial pressure of 85 to 90 mmHg for seven days. Spinal shock is reflex: every reflex below the lesion vanishes, and the returning bulbocavernosus reflex marks its end. High-dose methylprednisolone is no longer standard care; at most it is an option within eight hours and is never given for penetrating injury.

Chronic injury above T6 breeds autonomic dysreflexia. A noxious stimulus below the lesion, most often a distended bladder, drives unopposed sympathetic discharge and a systolic rise of 20 to 40 mmHg or more. Above the lesion the vagus slows the heart and the face flushes. Treatment is to sit the patient up, loosen clothing and remove the trigger, giving nifedipine only if the systolic pressure remains at 150 mmHg or above. Voluntary anal contraction excludes ASIA grade A, and grade C becomes D when at least half the key muscles reach grade three. Urinary infection is the commonest complication, and heterotopic ossification is never excised while alkaline phosphatase remains raised. Reflex erection depends on S2 to S4 and psychogenic erection on T11 to L2.

Below the conus at L1 to L2 the roots form the cauda equina. Asymmetric saddle anaesthesia, absent ankle reflexes and urinary retention demand decompression within 24 to 48 hours. An upper trunk plexus injury at C5 to C6 produces the waiter's tip posture of Erb palsy. A lower trunk injury at C8 to T1 produces a claw hand with Horner syndrome, because T1 carries the sympathetic fibres to the eye.

The central distinctions can be recalled as follows.

All motor and proprioceptive fibres are ipsilateral within the cord, whereas pain and temperature cross within two segments and are therefore contralateral.
Is the blood pressure low with a slow pulse and warm skin? That is neurogenic shock, treated with vasopressors rather than fluid alone.
On autonomic dysreflexia, sit the patient up, remove the trigger, usually a full bladder, and lower the pressure only if it stays high.
Lumbosacral roots below the conus form the cauda equina, and saddle anaesthesia with retention demands decompression within forty-eight hours.

An acute change in attention or cognition in an older person warrants prompt assessment for delirium and its underlying cause. Delirium is acute and fluctuating, and its core deficit is inattention; consciousness drifts between drowsiness and agitation and worsens at night. It almost always has a precipitant: infection, electrolyte disturbance, hypoxia, drugs or alcohol withdrawal. Dementia, by contrast, is chronic and steadily progressive, with attention relatively spared until late. The first task is therefore to search for the cause, not to label. Once a chronic course is established, the single boundary between mild cognitive impairment and dementia is impairment of daily activities; language and executive scores cannot draw it.

Each dementia is a misfolded protein in a particular place. Alzheimer disease deposits extracellular amyloid-beta plaques and intracellular hyperphosphorylated tau tangles, so cerebrospinal fluid amyloid-beta 42 falls while phosphorylated tau rises. Dementia with Lewy bodies combines fluctuating cognition, visual hallucinations, spontaneous parkinsonism and REM sleep behaviour disorder. Its striatal dopamine receptors are fragile, so haloperidol provokes severe parkinsonism or a neuroleptic malignant-like state and is contraindicated; low-dose levodopa and cholinesterase inhibitors are used instead. Normal pressure hydrocephalus impairs gait first, then continence, then cognition, because the leg fibres beside the ventricles are compressed earliest. Removing 30 to 50 millilitres of cerebrospinal fluid predicts shunt response. Every new dementia is screened for B12 deficiency, hypothyroidism and syphilis, the treatable causes.

Seizure and syncope are separated by their prologue and epilogue. Syncope follows an autonomic warning and ends in rapid, complete recovery; a seizure bites the lateral tongue and leaves post-ictal confusion. Absence seizures show three-hertz spike-and-wave discharges without a post-ictal phase, and myoclonic jerks usually spare consciousness. Temporal lobe epilepsy arises from the hippocampus and amygdala, and bilateral hippocampal resection is forbidden because it abolishes new memory. Status epilepticus is declared at five minutes. A benzodiazepine, lorazepam 0.1 mg/kg intravenously or midazolam 10 mg intramuscularly, comes first because it increases GABA-A channel opening. Repeating it endlessly fails through respiratory depression and receptor desensitisation, so levetiracetam, valproate or fosphenytoin follows, and anaesthesia with intubation is the third step.

Images keep their own timetable. Diffusion-weighted imaging shows cytotoxic oedema within minutes of ischaemia, whereas FLAIR needs six to twelve hours. Gradient echo and susceptibility sequences detect microbleeds and haemosiderin more sensitively than CT. Raised intracranial pressure declares itself through the Cushing reflex of hypertension, bradycardia and irregular breathing. An empty delta sign after contrast marks venous sinus thrombosis in a young woman on the pill or in the puerperium.

Under the microscope, proteins name the disease: alpha-synuclein for Parkinson and Lewy body disease, TDP-43 and SOD1 rather than tau for amyotrophic lateral sclerosis, prion protein for spongiform change. Hypertensive haemorrhage arises deep, from Charcot-Bouchard microaneurysms of the perforating arteries, whereas amyloid angiopathy deposits amyloid-beta in cortical vessels and bleeds lobar. Herpes simplex encephalitis shows Cowdry type A inclusions and haemorrhagic necrosis of the medial temporal lobes, reached along the trigeminal and olfactory routes.

The central distinctions can be recalled as follows.

All sudden confusion in an older person is delirium until proven otherwise; find the infection, the drug or the electrolyte before naming dementia.
Is the dementia fluctuating, with visual hallucinations and parkinsonism? It is Lewy body disease, and haloperidol is contraindicated.
On the fifth minute a convulsive seizure becomes status epilepticus; give a benzodiazepine first, then levetiracetam, valproate or fosphenytoin.
Lumbar drainage of thirty to fifty millilitres is the tap test that predicts shunt response in normal pressure hydrocephalus.

In acute ischaemic stroke, the duration and severity of impaired perfusion help determine which tissue is irreversibly injured and which may still be salvaged. Ischaemia exhausts ATP, the sodium-potassium pump fails, water enters the cell and cytotoxic oedema precedes death. About 1.9 million neurons die in each untreated minute, and each hour ages the brain by 3.6 years. A sudden focal deficit is stroke until proven otherwise. The first test is non-contrast CT to exclude haemorrhage, because a normal early CT never excludes infarction.

Ischaemic subtypes carry their own signatures. Large artery atherosclerosis produces cortical signs such as aphasia, neglect and hemianopia. Cardioembolism from atrial fibrillation is maximal at onset and may strike several territories. Lacunar infarcts from hyaline perforators give pure motor or pure sensory syndromes and never cortical signs. The thalamus gives contralateral pure sensory loss, the ventral pons a locked-in state with only vertical gaze, and the lateral medulla the Wallenberg syndrome. There a single posterior inferior cerebellar artery silences crowded neighbours at once: crossed pain and temperature loss, Horner syndrome, dysphagia and hoarseness, vertigo and ipsilateral ataxia.

Around the dead core lies the penumbra, tissue perfused at roughly 25 to 50 per cent that is electrically silent yet structurally alive. Alteplase within 4.5 hours rescues it. Beyond that window the failing blood-brain barrier turns reperfusion into symptomatic haemorrhage in about six per cent, outweighing what remains to save. Thrombectomy for large vessel occlusion extends to 6 to 24 hours when perfusion imaging shows a small core and a large penumbra, as DAWN and DEFUSE-3 demonstrated. Before thrombolysis the blood pressure must fall below 185 over 110. Without thrombolysis, pressures up to 220 over 120 are tolerated so that the penumbra is not starved. Cardioembolic stroke is prevented thereafter with anticoagulation, the rest with antiplatelet therapy, statins and blood pressure control.

Haemorrhage names its cause by location. Deep bleeding in the putamen, thalamus, pons or cerebellum comes from hypertensive Charcot-Bouchard microaneurysms; lobar bleeding in the elderly comes from amyloid angiopathy. Systolic pressure is lowered towards 140 mmHg, corticosteroids are withheld because they harm without helping, and a cerebellar haematoma over three centimetres is evacuated. Thunderclap headache with neck stiffness is subarachnoid haemorrhage until proven otherwise. When CT is negative, lumbar puncture seeks xanthochromia, and nimodipine 60 mg four-hourly for 21 days guards against vasospasm, which peaks between days 4 and 14. Moyamoya narrows the terminal carotid and the anterior and middle cerebral origins while sparing the posterior circulation; children present with ischaemia, adults with haemorrhage, and bypass surgery is the treatment.

Survival is only the first half. Broca aphasia is non-fluent with preserved comprehension, Wernicke fluent but uncomprehending, conduction aphasia fails at repetition, and the transcortical aphasias preserve it. The Barthel index scores ten basic activities and excludes medication and finances. Shoulder-hand syndrome spares the elbow, a subluxed shoulder must never be pulled, and spasticity responds to baclofen and botulinum toxin. Venous thrombosis is prevented by early mobilisation rather than bed rest.

Four sentences hold this battlefield.

All ischaemic stroke care begins with a non-contrast CT, because only the absence of blood permits alteplase within four and a half hours.
Is the blood pressure above 185 over 110? Lower it before thrombolysis, but otherwise tolerate up to 220 over 120 to feed the penumbra.
On large vessel occlusion, perfusion mismatch imaging extends thrombectomy to twenty-four hours after the patient was last seen well.
Lumbar puncture for xanthochromia follows a negative CT in thunderclap headache, and nimodipine for twenty-one days guards against vasospasm.

Within the classical model of basal ganglia function, the direct pathway facilitates movement while the indirect pathway restrains competing motor activity. Dopamine from the substantia nigra excites D1 receptors on the direct pathway and inhibits D2 receptors on the indirect one. When these neurons degenerate, the accelerator weakens and the brake tightens, yielding bradykinesia, cogwheel rigidity and pill-rolling rest tremor, with Lewy bodies of alpha-synuclein as the pathological signature.

The receptor and the rhythm of stimulation decide the side effects of treatment. Levodopa, given with carbidopa to block peripheral decarboxylation, is the most effective drug, yet its short half-life stimulates the striatum in pulses, and over years wearing-off and dyskinesia emerge. Agonists such as pramipexole act longer and cause less dyskinesia, but they stimulate D3 receptors in the mesolimbic reward pathway, provoking impulse-control disorders, hallucinations, somnolence and oedema. Entacapone prolongs each dose by inhibiting COMT, and any D2 antagonist such as haloperidol worsens the parkinsonism.

Site and tremor type place the other movement disorders. Carbon monoxide destroys the hypoxia-sensitive globus pallidus rather than the substantia nigra, and delayed parkinsonism follows. Huntington's disease, a CAG repeat disorder with caudate atrophy, produces early chorea that recedes late as dystonia and akinesia replace it. Wilson's disease is suspected under forty when tremor or parkinsonism accompanies liver disease or psychiatric change, and a Kayser-Fleischer ring, low caeruloplasmin and high urinary copper confirm it.

Headache assessment begins by excluding a secondary cause, and every SNOOP flag has a mechanism. Systemic features suggest infection or vasculitis; deficits or papilloedema suggest a mass. A thunderclap onset means a ruptured vessel until subarachnoid haemorrhage is excluded. New headache after fifty raises giant cell arteritis, which demands corticosteroids before biopsy. Orthostatic headache with diffuse dural enhancement is intracranial hypotension, whereas an obese young woman with papilloedema and a raised opening pressure has idiopathic intracranial hypertension.

Among primary headaches, migraine arises from trigeminovascular activation with CGRP release, and its aura is cortical spreading depression; cluster headache follows the hypothalamic clock and the trigeminal autonomic reflex. Triptans, agonists at 5-HT1B and 5-HT1D receptors, constrict meningeal vessels and suppress CGRP release, but coronary disease and uncontrolled hypertension forbid them. Cluster attacks respond to high-flow oxygen and verapamil prevents them, whereas migraine prevention uses propranolol, topiramate, valproate or amitriptyline, never carbamazepine, which belongs to trigeminal neuralgia.

A tumour announces itself through raised pressure from its mass, deficits from local destruction and seizures from cortical irritation. Growth rate decides which comes first, so slow low-grade gliomas present with seizures more often than glioblastoma, which destroys and compresses. Meningioma, arising from arachnoid cap cells outside the brain with a dural tail, is the commonest primary intracranial tumour. Vestibular schwannoma grows from the vestibular nerve; bilateral tumours define neurofibromatosis type 2, and surgery most often injures the facial nerve.

All impulse control disorders and hallucinations in Parkinson's disease point to the D3 agonist, whereas dyskinesia points to pulsatile levodopa.
Is the headache thunderclap, new after fifty, positional or with deficits? Then it is secondary until proven otherwise, and suspected giant cell arteritis receives corticosteroids before biopsy.
On the pituitary stalk, compression raises prolactin mildly by removing dopaminergic inhibition, whereas a prolactinoma raises it markedly and is treated first with cabergoline.
Lung, breast and melanoma metastases at the grey-white junction are the commonest intracranial tumours overall, while meningioma with its dural tail is the commonest primary.

Weakness, seizures and altered consciousness describe clinical presentations rather than diagnoses; anatomical localisation helps narrow the mechanisms that could account for them. Synapse, muscle, peripheral or central myelin, meninges, parenchyma and the immature brain each fail in their own way, and the level decides name, treatment and prognosis.

Neuromuscular transmission has two steps: calcium enters through presynaptic P/Q-type channels to release acetylcholine, which then opens postsynaptic nicotinic receptors. Myasthenia gravis attacks the postsynaptic receptor, so each burst of acetylcholine finds too few targets and strength fatigues with use. It associates with thymoma, decrements on low-frequency stimulation and responds to pyridostigmine and thymectomy. Lambert-Eaton syndrome attacks the presynaptic calcium channel, so release is scant at rest but calcium accumulates with repetition and strength improves with use. Reflexes return after exercise, high-frequency stimulation increments, and small-cell lung cancer is the usual companion.

Muscle itself fails in Duchenne dystrophy, an X-linked loss of dystrophin with calf pseudohypertrophy and a very high creatine kinase; myotonic dystrophy is dominant, distal and facial. Guillain-Barré syndrome arises one to three weeks after Campylobacter or a respiratory infection, when antibodies raised against microbial lipo-oligosaccharide cross-react with gangliosides on peripheral myelin. Weakness ascends symmetrically and reflexes vanish. Vital capacity is measured serially, because diaphragmatic failure is the main cause of death. Immunoglobulin or plasma exchange treats it; corticosteroids alone do not.

Multiple sclerosis is central demyelination in which T and B cells cross the blood-brain barrier to attack oligodendrocytes. Optic neuritis is a common first attack, and heat worsens symptoms in Uhthoff's phenomenon. Periventricular ovoid plaques, oligoclonal bands and dissemination in time and space satisfy the McDonald criteria. A relapse takes intravenous methylprednisolone, disease-modifying therapy reduces relapses, and cognitive impairment affects around half of patients.

Cerebrospinal fluid separates the infections of the meninges and brain. Bacterial meningitis gives neutrophils, low glucose and high protein. After blood cultures, vancomycin with a third-generation cephalosporin follows at once, with ampicillin for Listeria after fifty and dexamethasone alongside. Viral meningitis gives lymphocytes with normal glucose, tuberculous meningitis lymphocytes with very low glucose and very high protein. Herpes simplex encephalitis attacks the medial temporal lobes with fever, seizures and personality change, and aciclovir starts before the PCR returns, because each hour of delay worsens outcome. A brain abscess enhances in a ring like glioblastoma, but its pus restricts diffusion, so the centre is bright rather than dark on diffusion imaging.

In children, spastic diplegic cerebral palsy follows periventricular leukomalacia of prematurity, whereas the athetoid form follows kernicterus and carries hearing loss. A simple febrile seizure between six months and five years lasts under fifteen minutes, is generalised and does not recur within a day; it needs reassurance, not antiepileptic drugs. Infantile spasms with hypsarrhythmia between four and eight months are West syndrome, which needs ACTH or vigabatrin without delay.

All myasthenic weakness fatigues with use because postsynaptic receptors are scarce, whereas Lambert-Eaton weakness improves with use as presynaptic calcium accumulates.
Is the demyelination peripheral or central? Guillain-Barré needs immunoglobulin or plasma exchange, never steroids alone, whereas a multiple sclerosis relapse takes intravenous methylprednisolone.
On cerebrospinal fluid, neutrophils with low glucose mean bacteria, lymphocytes with normal glucose mean a virus, and suspected herpes encephalitis receives aciclovir before the PCR returns.
Lumbar puncture in Guillain-Barré shows raised protein with normal cells, and a simple febrile seizure under five needs reassurance rather than long-term antiepileptic drugs.

Neuronal structure reflects the demands of maintaining a specialised cell whose signalling and transport processes may extend far beyond its cell body. Nissl bodies, stacked rough endoplasmic reticulum, fill the soma and dendrites but never the axon. Kinesin carries cargo forward to the terminal and dynein returns it, the same retrograde train that carries tetanus toxin back to the cord. Oligodendrocytes myelinate many central axons each, Schwann cells one internode each, and microglia, the only glia of mesodermal origin, clear debris that oligodendrocytes cannot. Astrocytic end-feet, endothelial tight junctions and basement membrane form the blood-brain barrier, which the area postrema deliberately lacks.

The neural tube folds from a plate, and its front end swells into three vesicles, then five. The telencephalon becomes cortex and basal ganglia around the lateral ventricles, and the diencephalon becomes thalamus, retina and posterior pituitary around the third ventricle. The mesencephalon keeps the aqueduct, and the metencephalon forms pons and cerebellum. The anterior neuropore closes around day 25 and the posterior around day 27 to 28; failure gives anencephaly or, with folate deficiency, spina bifida. Dandy-Walker bulges outward from an absent vermis, whereas Chiari II drags vermis and medulla down through the foramen magnum.

Medicines act on three switches: channels, receptors and reuptake. Ethosuximide blocks thalamic T-type calcium channels in absence seizures, benzodiazepines increase the frequency and barbiturates the duration of GABA-A opening, and baclofen agonises GABA-B. Beta receptors raise cAMP through Gs, alpha-1 and M3 raise calcium through Gq, alpha-2 and M2 lower cAMP through Gi, and cGMP belongs to nitric oxide. Hence alpha-1 closes the bladder sphincter while M3 contracts the detrusor, so overactive bladders take M3 antagonists or a beta-3 agonist and prostatic obstruction takes an alpha-1 antagonist.

Localisation asks the height, the side and the system. The striatum is caudate, putamen and globus pallidus; the substantia nigra and subthalamic nucleus belong to the circuit but not to the striatum. A destroyed frontal eye field lets the eyes drift toward the lesion, whereas a destroyed pontine gaze centre drives them away. Hearing relays in the medial geniculate body, which is thalamic, not midbrain, and vision in the lateral geniculate.

The mandibular nerve leaves through the foramen ovale, the maxillary through the rotundum, the facial nerve exits at the stylomastoid foramen, and the vestibulocochlear enters the internal acoustic meatus. Genioglossus protrudes the tongue, so a hypoglossal palsy deviates it toward the lesion; the anterior two-thirds taste through the chorda tympani and the posterior third through IX. The vagus drives the pharyngeal constrictors, palate and vocal cords, so its injury causes aspiration. Deep intrinsic back muscles, the erector spinae that arch the tetanic spine, are supplied by dorsal rami, whereas the superficial extrinsic layer answers to ventral rami.

All myelin in the central nervous system comes from oligodendrocytes and is cleared by microglia, whereas Schwann cells both myelinate and repair peripheral nerves.
Is the second messenger cAMP or calcium? Beta receptors raise cAMP through Gs, alpha-1 and M3 raise calcium through Gq, and cGMP belongs to nitric oxide, never beta.
On gaze, a destroyed frontal eye field lets the eyes drift toward the lesion and a destroyed pontine centre drives them away; the corneal reflex runs V1 in, VII out.
Lumbar disc herniation in the paracentral position compresses the traversing root below, so L4-5 takes L5 and L5-S1 takes S1, and only a far-lateral herniation catches the exiting root.