Internal Medicine Cram ListInternal Medicine

The Frank-Starling mechanism states that increased end diastolic volume stretches sarcomeres, optimizes actin-myosin overlap, and augments stroke volume. On a PV loop, greater preload shifts the point rightward with higher stroke work until excessive stretch reduces contractile efficiency. Neurohormonal activation (sympathetic, RAAS) further modulates inotropy and venous tone, changing the slope of ESPVR and venous return curves that govern cardiac output at a given right atrial pressure.

Atherosclerosis begins with endothelial dysfunction, LDL infiltration, and oxidation, recruiting monocytes that become foam cells and form fatty streaks. Smooth muscle migration and extracellular matrix deposition create fibrous caps of varying stability. Vulnerable plaques have large lipid cores and thin caps rich in macrophages and MMP activity, predisposing to rupture and thrombosis rather than gradual stenosis alone.

In myocardial ischemia, ATP depletion impairs the Na/K ATPase and sarcoplasmic reticulum Ca handling, causing cellular swelling and diastolic dysfunction within minutes. Subendocardium is most vulnerable due to higher wall stress and perfusion during diastole only. Prolonged ischemia causes coagulative necrosis, neutrophil infiltration, and later macrophage-mediated removal with granulation tissue and scar formation via type I collagen.

Left-sided versus right-sided murmurs vary with preload and afterload. Handgrip elevates afterload, accentuating regurgitant murmurs (MR, AR) and reducing HCM gradient; Valsalva and standing decrease preload, intensifying HCM and MVP clicks; squatting increases venous return and afterload, diminishing HCM murmur and delaying MVP click. Maneuvers alter chamber size, leaflet coaptation, and transvalvular gradients.

Action potentials differ across cardiac tissues. Fast-response myocytes (atria, ventricles, Purkinje) rely on phase 0 Na influx, with plateau phase (Ca in, K out). Nodal cells exhibit slow upstroke via L-type Ca channels and funny current (If) mediated by HCN channels during phase 4. Autonomic tone shifts slope of phase 4 in SA/AV nodes, modulating heart rate and conduction.

Types of shock show distinct hemodynamics. Hypovolemic: decreased preload, increased SVR, decreased CO; Distributive (sepsis): decreased SVR with relative or absolute hypovolemia, often high or normal CO early; Cardiogenic: increased preload, increased SVR, decreased CO; Obstructive: mechanical impediment (PE, tamponade) with similar profile to cardiogenic. Lactate reflects impaired perfusion and mitochondrial dysfunction across categories.

BNP/NT-proBNP are released by ventricular myocytes under stretch, activating cGMP pathways that promote natriuresis and vasodilation while antagonizing RAAS. Levels correlate with wall stress and filling pressures but can be influenced by age, renal function, and obesity. BNP physiologically counterbalances maladaptive neurohormonal activation in chronic heart failure.

Primary hyperlipidemias reflect genetic defects in lipoprotein metabolism: familial hypercholesterolemia (LDL receptor/apoB-100), familial combined hyperlipidemia, and Lp(a) excess. Elevated apoB-containing particles drive atherogenesis by penetrating endothelium and becoming oxidized. HDL participates in reverse cholesterol transport via ABCA1 and LCAT pathways, affecting plaque burden and stability.

Valvular lesions impose pressure or volume overload with characteristic ventricular remodeling. Aortic stenosis causes concentric hypertrophy from pressure load, preserving wall stress until diastolic dysfunction ensues. Chronic aortic regurgitation triggers eccentric hypertrophy from volume overload, increasing end diastolic volume and stroke volume but ultimately causing systolic failure.

Hypertrophic cardiomyopathy arises from sarcomeric protein mutations (beta-myosin heavy chain, myosin-binding protein C) causing myocyte disarray, dynamic LV outflow tract obstruction, and impaired relaxation. The obstruction worsens with decreased preload or afterload and improves with increased ventricular volume and afterload.

Pericardial tamponade elevates and equalizes diastolic pressures across chambers, limiting ventricular filling and stroke volume. Rapid accumulation impairs hemodynamics at lower volumes than slow effusions. Pulsus paradoxus (>10 mmHg inspiratory drop in systolic BP) reflects enhanced RV filling at the expense of LV during inspiration.

The oxygen-hemoglobin dissociation curve shifts with pH, CO2, temperature, and 2,3-BPG (Bohr effect). Rightward shifts facilitate O2 unloading in metabolically active tissues; leftward shifts enhance loading in lungs but impede tissue delivery. Fetal hemoglobin binds 2,3-BPG poorly, explaining its left-shifted curve.

RAAS activation increases afterload and promotes sodium retention and fibrosis via ATII receptor signaling, TGF-beta, and mineralocorticoid pathways. Chronic activation remodels myocardium and vasculature, sustaining heart failure progression beyond hemodynamics.

Obstructive diseases reduce FEV1 disproportionately to FVC, lowering the FEV1/FVC ratio; air trapping elevates residual volume and functional residual capacity. Emphysema destroys alveolar walls and elastic recoil, while chronic bronchitis narrows airways with mucus and inflammation. Asthma features reversible bronchoconstriction driven by Th2 inflammation and hyperreactive smooth muscle.

Alveolar gas equation estimates alveolar oxygen: PAO2 = PIO2 X (PaCO2/R). The A-a gradient widens with V/Q mismatch, diffusion limitation, or shunt, but remains normal in pure hypoventilation. Diffusion capacity depends on surface area, membrane thickness, and hemoglobin reaction rate, altered in emphysema, fibrosis, and anemia.

Acute respiratory distress syndrome features diffuse alveolar damage with protein rich edema, hyaline membrane formation, and severe shunt physiology unresponsive to high FiO2. Inflammatory cytokines injure endothelium and epithelium, increasing permeability and reducing surfactant, which collapses alveoli and worsens compliance.

Pulmonary embolism causes dead space ventilation and acute pulmonary vascular resistance elevation. Thrombus typically arises from deep veins of the legs, especially proximal DVT. Embolic obstruction creates areas with high V/Q ratios and reflex hyperventilation leading to respiratory alkalosis initially.

Interstitial lung diseases produce restrictive physiology with reduced total lung capacity, reduced diffusion capacity, and increased elastic recoil. Repetitive injury to alveolar epithelium stimulates fibroblast proliferation and extracellular matrix deposition, thickening the blood-gas barrier.

Sleep disordered breathing alters chemoreceptor set points and ventilatory drive. Obstructive sleep apnea features recurrent upper airway collapse despite respiratory effort, causing intermittent hypoxemia, sympathetic surges, and endothelial dysfunction that promote hypertension and arrhythmias.

Carbon monoxide binds hemoglobin with high affinity, forming carboxyhemoglobin and reducing O2 content while left-shifting the dissociation curve. Pulse oximetry cannot distinguish COHb from oxyhemoglobin, leading to falsely normal readings.

Asthma pathogenesis involves dendritic cell antigen presentation, Th2 polarization, IL4/IL5/IL13 signaling, and IgE-mediated mast cell activation leading to bronchoconstriction, mucus hypersecretion, and airway hyperresponsiveness. Airway remodeling with smooth muscle hypertrophy contributes to chronicity.

Compliance is ΔV/ΔP and depends on tissue elasticity and surface tension. Emphysema increases compliance by destroying elastic fibers; fibrosis decreases compliance via stiff collagen deposition. Chest wall compliance also affects total respiratory system behavior.

Methemoglobinemia arises when Fe2+ is oxidized to Fe3+, reducing O2 binding and delivery. Causes include oxidant drugs (dapsone, nitrates) and congenital cytochrome b5 reductase deficiency. Blood appears chocolate colored; pulse oximetry plateaus around 85%.

Hypoxic pulmonary vasoconstriction diverts blood from poorly ventilated regions to better ventilated alveoli, optimizing V/Q matching. Generalized alveolar hypoxia, as in high altitude, increases pulmonary arterial pressure and can cause right heart strain over time.

Pleural effusions classify by Light's criteria, distinguishing exudates (inflammation, malignancy) from transudates (hydrostatic, oncotic). Exudates have higher protein and LDH relative to serum due to increased capillary permeability and impaired lymphatic drainage.

The glomerular filtration barrier comprises fenestrated endothelium, the GBM with type IV collagen and heparan sulfate, and podocyte slit diaphragms (nephrin, podocin). Charge and size selectivity normally restrict albumin passage; injury causes proteinuria and hematuria depending on site and mechanism.

Prerenal azotemia reflects renal hypoperfusion with intact parenchyma, characterized by high BUN:Cr (>20), low FeNa (<1%), and concentrated urine. Intrinsic AKI (ATN, AIN, GN) shows impaired concentrating ability with FeNa >2% and muddy brown casts in ATN.

The countercurrent multiplier in the loop of Henle and urea recycling establish a corticomedullary osmotic gradient enabling water reabsorption in the collecting duct under ADH. Aquaporin-2 insertion is cAMP-dependent via V2 receptors.

Renal tubular acidosis subtypes reflect segmental defects. Type I (distal) fails H secretion causing alkaline urine and nephrolithiasis; Type II (proximal) fails HCO3 reabsorption with variable urine pH; Type IV reflects hypoaldosteronism or resistance with hyperkalemia and mild acidosis.

Minimal change disease features podocyte effacement on electron microscopy with preserved light microscopy and negative immunofluorescence. Cytokine-mediated injury increases glomerular permeability primarily to albumin, causing selective proteinuria and edema.

Diuretics act at specific nephron sites: acetazolamide in proximal tubule (carbonic anhydrase), loop diuretics at NKCC2 in thick ascending limb, thiazides at NCC in distal convoluted tubule, and K sparing agents at ENaC or mineralocorticoid receptor in collecting duct.

Secondary hyperparathyroidism in chronic kidney disease arises from phosphate retention, decreased calcitriol synthesis, and hypocalcemia, stimulating PTH secretion and renal osteodystrophy. High FGF23 further suppresses 1-alpha hydroxylase and promotes phosphate excretion.

ANCA associated vasculitides (GPA, MPA) cause pauci-immune crescentic glomerulonephritis via neutrophil priming and degranulation against small vessels. Immunofluorescence is typically negative despite severe inflammation.

Hyperkalemia depolarizes cell membranes, inactivating voltage-gated Na channels and slowing conduction. EKG changes progress from peaked T waves to widened QRS and sinewave patterns with risk of ventricular fibrillation.

Hyponatremia severity depends on acuity and brain adaptation via osmolyte loss. Rapid correction of chronic hyponatremia risks osmotic demyelination, especially in malnourished or liver disease patients. Hypertonic saline is reserved for severe symptomatic cases with careful correction targets.

Renovascular hypertension from renal artery stenosis activates RAAS, raising aldosterone and causing hypokalemic metabolic alkalosis. Unilateral disease shows asymmetric renal size; bilateral disease makes ACE inhibitors trigger rises in creatinine by reducing efferent arteriolar tone.

Acute interstitial nephritis features interstitial edema and inflammatory infiltrates, often eosinophils, from drug hypersensitivity (beta-lactams, PPIs, NSAIDs). Tubular dysfunction causes sterile pyuria, WBC casts, and sometimes rash and fever.

In Type 2 diabetes, insulin resistance in muscle and liver precedes beta-cell failure driven by lipotoxicity, glucotoxicity, and islet amyloid deposition from amylin. Hepatic gluconeogenesis remains inappropriately elevated, and adipokine imbalance (adiponectin, leptin resistance) worsens metabolic milieu.

Graves disease features TSH-receptor-stimulating immunoglobulins, thyroid hyperplasia, increased Na/K ATPase, and heightened adrenergic tone. Orbitopathy stems from fibroblast TSH receptors promoting glycosaminoglycan deposition and edema in extraocular muscles.

Primary hyperaldosteronism increases Na reabsorption via ENaC and stimulates K and H secretion, causing hypertension, hypokalemia, and metabolic alkalosis with suppressed renin. Adrenal adenoma and bilateral hyperplasia are common etiologies.

Cushing syndrome reflects chronic glucocorticoid excess with muscle wasting, central adiposity, insulin resistance, and immunosuppression. ACTH_dependent causes (pituitary adenoma, ectopic secretion) versus ACTH_independent adrenal tumors are distinguished by ACTH levels and dexamethasone suppression tests.

Diabetic ketoacidosis arises from absolute or relative insulin deficiency with counterregulatory hormones driving lipolysis and ketogenesis. Acidemia causes K shift extracellularly while total body K is depleted. Osmotic diuresis leads to volume depletion and electrolyte losses.

Calcium homeostasis relies on PTH, calcitriol, and calcitonin. PTH increases renal Ca reabsorption, decreases phosphate reabsorption, and stimulates 1-alpha-hydroxylase and osteoclast-mediated bone resorption via osteoblast RANKL signaling.

Addison disease (primary adrenal insufficiency) features autoimmune destruction of adrenal cortex leading to low cortisol and aldosterone with hyperpigmentation from elevated ACTH and POMC-derived MSH. Hyperkalemia and hyponatremia are common.

Thyroid hormone increases basal metabolic rate via Na-/K-ATPase, augments beta-adrenergic receptor expression, and is essential for growth and CNS development. Peripheral deiodinases convert T4 to active T3 or inactive reverse T3 in chronic illness.

Hyperosmolar hyperglycemic state features extreme hyperglycemia, dehydration, and hyperosmolarity without significant ketosis due to residual insulin activity suppressing lipolysis. Neurologic symptoms predominate from cellular dehydration.

SIADH causes euvolemic hyponatremia with inappropriately concentrated urine and elevated urine sodium due to persistent ADH signaling. Cerebral edema risk relates to acuity and correction speed.

Pheochromocytomas secrete catecholamines from chromaffin cells, often with germline mutations (RET, VHL, NF1). Paroxysmal headaches, palpitations, and diaphoresis reflect episodic surges; tumor staining is chromogranin A positive.

Osteoporosis involves reduced bone mass and microarchitectural deterioration from imbalance between osteoclast and osteoblast activity. Estrogen deficiency increases RANKL signaling and osteoclast lifespan; glucocorticoids impair osteoblast function.

Portal hypertension arises from increased resistance within the hepatic sinusoids due to fibrosis and regenerative nodules, plus splanchnic vasodilation driven by nitric oxide, which increases portal inflow. Collateral formation leads to varices and ascites via Starling forces.

Hepatitis B serology tracks antigen and antibody timelines: HBsAg appears first, followed by anti-HBc (IgM -> IgG), then HBeAg indicating high infectivity. Window period shows anti-HBc as the sole marker before anti-HBs emerges indicating immunity.

Peptic ulcer disease reflects gastric acid and pepsin injury versus mucosal defenses. H. pylori increases gastrin and reduces somatostatin in antral-predominant infection; NSAIDs inhibit prostaglandins that maintain mucosal blood flow and bicarbonate secretion.

Pancreatitis arises from premature trypsinogen activation and autodigestion, causing fat necrosis and systemic inflammation. Gallstones and alcohol are leading causes; hypertriglyceridemia and drugs are additional triggers. Hypocalcemia reflects saponification.

Inflammatory bowel disease features inappropriate immune responses to gut microbiota in genetically predisposed hosts. Crohn disease shows transmural inflammation, skip lesions, and granulomas; ulcerative colitis is mucosal, continuous, and limited to colon with crypt abscesses.

Hemochromatosis involves excessive iron absorption via low hepcidin, leading to iron deposition in liver, pancreas, heart, and joints with oxidative injury. Classic triad includes cirrhosis, diabetes, and skin hyperpigmentation.

Wilson disease features impaired copper excretion due to ATP7B mutations, causing hepatic, neurologic, and psychiatric symptoms. Copper accumulates in basal ganglia and cornea (Kayser-Fleischer rings).

Celiac disease is an autoimmune enteropathy triggered by gluten, with villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Anti-tTG IgA is a sensitive serologic marker, but IgA deficiency necessitates alternative testing.

Primary biliary cholangitis involves autoimmune destruction of intrahepatic bile ducts with antimitochondrial antibodies and granulomatous inflammation, causing cholestasis and pruritus. Fat_soluble vitamin deficiency may develop.

Nonalcoholic fatty liver disease begins with hepatic steatosis from insulin resistance, progressing to steatohepatitis with ballooning degeneration and eventual fibrosis. Lipotoxicity and oxidative stress drive stellate cell activation.

Colorectal carcinogenesis follows the adenoma-carcinoma sequence with APC inactivation, KRAS activation, and p53 loss. Microsatellite instability from mismatch repair defects represents an alternative pathway particularly in Lynch syndrome.

Lactose intolerance arises from lactase deficiency in the brush border, causing osmotic diarrhea and fermentation with hydrogen production. Secondary forms follow mucosal injury such as gastroenteritis or celiac disease.

Sepsis pathobiology involves dysregulated host response with cytokine storm, endothelial injury, and microvascular thrombosis causing maldistribution of flow and mitochondrial dysfunction. Nitric oxide-mediated vasodilation lowers SVR, while capillary leak reduces effective circulating volume.

β-lactam antibiotics inhibit transpeptidation by binding PBPs, disrupting peptidoglycan cross-linking. Resistance mechanisms include β-lactamases, altered PBPs (MRSA), and reduced porin entry in gram-negatives. Time-dependent killing favors prolonged infusion strategies.

Vancomycin inhibits cell wall synthesis by binding D_Ala_D_Ala termini; resistance in VRE involves D_Ala_D_Lac substitution reducing affinity. Therapeutic monitoring uses AUC/MIC targets to balance efficacy and nephrotoxicity risk.

Aminoglycosides irreversibly bind 30S ribosomal subunits causing misreading and bactericidal activity with concentration-dependent killing. Oxygen-dependent uptake limits efficacy in anaerobic environments; synergy with β-lactams improves gram-negative coverage.

HIV targets CD4 T cells via gp120 binding to CD4 and CCR5/CXCR4 co-receptors. Reverse transcription and integration establish latent reservoirs that evade immune clearance and necessitate lifelong therapy.

Mycobacterium tuberculosis triggers granulomatous inflammation with Th1-mediated IFN-γ activation of macrophages. Caseating granulomas represent immunologic containment; cavitary disease reflects tissue destruction and high organism burden.

Antifungal classes exploit ergosterol pathways: azoles inhibit 14-α-demethylase; polyenes bind ergosterol forming pores; echinocandins block β-glucan synthesis; flucytosine inhibits DNA/RNA synthesis after conversion by fungal cytosine deaminase.

Vaccines elicit adaptive immunity through antigen presentation and germinal center reactions producing affinity-matured B cells and memory. Adjuvants enhance innate signals (TLRs) that support robust T_cell help.

Endocarditis pathogenesis involves bacteremia seeding damaged valves with platelet-fibrin vegetations. Viridans streptococci adhere to exposed fibrin via dextran; Staphylococcus aureus can infect normal valves and cause acute, destructive disease.

Hepatitis C establishes chronic infection through quasispecies diversity and immune evasion. Progressive fibrosis reflects stellate cell activation from inflammatory cytokines and oxidative stress.

Clostridioides difficile produces toxins A/B that disrupt the cytoskeleton via Rho-glucosylation, causing pseudomembranous colitis after microbiome disruption by antibiotics. Spores resist alcohol-based sanitizers.

Herpesviruses establish latency in neurons or lymphocytes with reactivation under stress or immunosuppression. Viral thymidine kinase and DNA polymerase are key drug targets for nucleoside analogs like acyclovir.

Rheumatoid arthritis features synovial hyperplasia (pannus) with cytokine-driven inflammation (TNF-α, IL-6) eroding cartilage and bone via RANKL pathways. Autoantibodies include rheumatoid factor and anti-CCP, the latter being more specific.

SLE involves loss of tolerance with immune complex deposition and complement activation causing multi-organ damage. Anti-dsDNA and anti-Sm are specific; low complement indicates active consumption during flares.

Gout results from monosodium urate crystal deposition in joints under supersaturation, driven by hyperuricemia from underexcretion or overproduction. Needle-shaped, negatively birefringent crystals are diagnostic.

Spondyloarthropathies are seronegative (RF-negative) diseases associated with HLA-B27, featuring enthesitis and axial involvement. Reactive arthritis follows gastrointestinal or genitourinary infections and may present with conjunctivitis and urethritis.

Polymyalgia rheumatica presents with proximal stiffness and elevated inflammatory markers, often associated with giant cell arteritis, a granulomatous vasculitis affecting branches of the carotid artery.

Systemic sclerosis features fibroblast activation and excessive collagen deposition with vascular dysfunction (Raynaud) and esophageal hypomotility. Autoantibodies include anti-centromere (limited) and anti-Scl-70 (diffuse).

ANCA-associated small-vessel vasculitis features neutrophil activation against MPO or PR3, causing necrotizing inflammation without immune complex deposition. Pulmonary-renal syndrome reflects diffuse alveolar hemorrhage plus rapidly progressive glomerulonephritis.

Dermatomyositis shows perifascicular atrophy and complement-mediated capillary injury, presenting with proximal muscle weakness and characteristic rash (heliotrope, Gottron papules). Cancer association is notable in adults.

Henoch-Schönlein purpura (IgA vasculitis) results from IgA immune complex deposition in small vessels, often after upper respiratory infections, causing palpable purpura, arthralgia, abdominal pain, and renal involvement.

Antiphospholipid syndrome features autoantibodies (lupus anticoagulant, anticardiolipin, anti-β2 glycoprotein I) that paradoxically prolong PTT in vitro but cause hypercoagulability in vivo, leading to venous and arterial thromboses and pregnancy morbidity.

Iron deficiency anemia stems from insufficient iron for heme synthesis, producing microcytosis and elevated RDW. Ferritin is low, transferrin high, and saturation reduced. Pica and restless legs may accompany chronic deficiency.

Hemolytic anemias raise LDH and unconjugated bilirubin with low haptoglobin. Intrinsic defects include hereditary spherocytosis and G6PD deficiency; extrinsic causes include autoimmune hemolysis and microangiopathic processes causing schistocytes.

Heparin potentiates antithrombin to inhibit thrombin and factor Xa

Warfarin inhibits vitamin K epoxide reductase, reducing γ-carboxylation of factors II, VII, IX, X, and proteins C and S. Early protein C depletion creates a transient hypercoagulable state.

Myeloproliferative neoplasms such as polycythemia vera arise from JAK2 mutations driving cytokine-independent signaling, increasing red blood cell mass and blood viscosity. Erythromelalgia and aquagenic pruritus reflect histamine release and microvascular changes.

Hodgkin lymphoma features Reed–Sternberg cells within an inflammatory background and classically presents with contiguous lymph node spread and B symptoms. EBV association is common in certain subtypes.

Tumor lysis syndrome releases potassium, phosphate, and nucleic acids metabolized to uric acid, precipitating renal failure and arrhythmias. Risk is highest in high-grade lymphomas and leukemias after cytotoxic therapy.

Antimetabolite chemotherapies target nucleotide synthesis: methotrexate inhibits dihydrofolate reductase; 5-FU inhibits thymidylate synthase; cytarabine impairs DNA polymerase. Cell-cycle specificity influences scheduling and toxicity profiles.

Ischemic stroke pathophysiology involves excitotoxicity from glutamate release, calcium influx, and free radical–mediated injury. Core infarct tissue is irreversibly damaged within minutes; the penumbra remains salvageable with timely reperfusion.

Myasthenia gravis features autoantibodies against postsynaptic acetylcholine receptors causing fatigable weakness; thymic abnormalities are common. Miniature end-plate potentials decrease due to reduced receptor density.

Multiple sclerosis involves demyelination with relative axonal preservation mediated by autoimmune attack against CNS myelin. Plaques impair saltatory conduction, producing conduction block and fatigue-related worsening.

Parkinson disease results from loss of dopaminergic neurons in the substantia nigra pars compacta with Lewy body alpha‑synuclein aggregates. Dopamine deficiency disrupts basal ganglia circuitry, reducing thalamocortical motor activation.

Peripheral neuropathies result from axonal degeneration or demyelination. Diabetes causes length‑dependent axonopathy via microvascular ischemia and glycation end products; inflammatory demyelination produces slowed conduction velocities and conduction block.

Status epilepticus reflects persistent seizure activity causing altered GABA and NMDA receptor trafficking and metabolic stress. Prolonged seizures increase neuronal injury via excitotoxicity and systemic instability.

Guillain–Barré syndrome features autoimmune attack on peripheral myelin or axons after infections (Campylobacter), causing ascending weakness and areflexia. Albuminocytologic dissociation appears in CSF.

Migraine involves cortical spreading depression triggering trigeminovascular activation and CGRP release, leading to meningeal vasodilation and neurogenic inflammation. Aura reflects transient cortical dysfunction.

Delirium reflects acute, fluctuating deficits in attention and cognition from global cortical dysfunction, often due to infections, medications with anticholinergic properties, metabolic derangements, or withdrawal. Pathophysiology includes cholinergic deficiency and inflammatory cytokines disrupting neurotransmission. EEG shows generalized slowing except in alcohol withdrawal where fast activity may appear.